Poster abstracts

P.001

ADIPOSE-DERIVED MESENCHYMAL STROMAL CELLS IN A MOUSE MODEL OF SYSTEMIC SCLEROSIS: IMPACT ON DISEASE MANIFESTATIONS AND ON MYELOID CELL POPULATIONS

Francois Zimmermann¹, Laura Morin¹, Severine Loisel², Elise Dessauge³, Marie Lelong¹, Juliette Gauthier³, Thomas Lejeune³, Céline Delaloy³, Karin Tarte^2,3, Alain Lescoat^1,4, Valérie Lecureur¹

¹Univ Rennes, CHRU Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, Rennes, FRANCE, ²aboratoire Suivi Immunologique des Thérapeutiques Innovantes, Centre Hospitalier Universitaire de Rennes, F-35033, Rennes, FRANCE, ³Université Rennes, INSERM, EFS Bretagne, UMR U1236, Rennes, France, INSERM, Microenvironment, Cell Differentiation, Immu, Rennes, FRANCE, ⁴Médecine interne, CHRU Rennes - Hôpital Pontchaillou, Rennes, FRANCE

Introduction: Bone marrow-mesenchymal stromal cells (BM-MSC) have demonstrated immunomodulatory and anti-fibrotic properties in a phase I trial in systemic sclerosis (SSc). Adipose-derived MSCs (ASCs) are more accessible for therapeutic use than BM-MSC and could represent a relevant alternative treatment. Their mechanisms of action, i.e. direct cell-to cell effect through efferocytosis or indirect paracrine effects, are still debated. This study aimed to evaluate the impact of ASCs injections on disease manifestations and myeloid populations in the SSc mouse model induced by intradermal injections of bleomycin (BLM).

Material and Methods: ASCs were isolated from the stromal fraction of healthy donors and were pre-activated (ASCa), or not (ASCna), with IFN-gamma (20 UI/ml) and TNF-alpha (1.5 UI/ml) for 24h (ASCa). Eight aged female C57BL/6 mice were allocated in groups to receive either induction of SSc (BLM ID injection (100 µl, 0.4 mg/ml) 5 days a week for 4 weeks or NaCl 0.9% and IV injection of 0.25 million of ASCa or PBS. Blood cell populations were characterized by flow cytometry. Skin and lung fibrosis were evaluated by histological analysis (dermal thickness). The efferocytosis capacity of GFP+ ASCa by alveolar (AM) and interstitial macrophages (IM) was assessed by flow cytometry.

Results: Injection of ASCa has prevented development of skin (dermal thickness (p-value = 0,008)) and lung (lung weights (p- value = 0,002) and Ashcroft histological score (p-value 0,043)) fibrosis in comparison to the BLM without ASCs. Similar but less significant therapeutic effects were observed with ASCna as compared to BLM without ASC (no effect on dermal thickness and Ashcroft score in lungs, reduction of lung weight p-value 0,0021). The therapeutic impact of ASCa was associated with pulmonary anti-inflammatory effects (decrease of lL-6 and SPP1 mRNA expressions, p-value <0,0001 and 0,0128 respectively). Myeloid cell populations were impacted by ASCa, as they prevented: a) BLM-induced mRNA expression of CCL2 (p-value 0.0023) in the lung, a chemokine involved in monocyte recruitment and b) BLM-induced circulating non-classical monocytes number (Ly6clow) (p-value = 0,002) in the blood. Lung macrophage subpopulations from BLM-induced SSc differed in terms of efferocytosis capacities, as GFP+-ASC efferocytosis capacities were decreased in AM (SiglecFpos) (p-value < 0.001) and increased in IM (CD64pos / CD 11bpos) (p-value = 0.028) when compared to control group.

Conclusions: ASCa represent an accessible therapeutic option for SSc. Initial data suggest an effect of ASCs on circulating non-classical monocytes. ASCs are efferocytosed in the lung, with heterogeneity according to macrophage subtypes.

P.002

THE BETA SECRETASE BACE1 DRIVES FIBROBLASTS ACTIVATION IN SYSTEMIC SCLEROSIS THROUGH THE APP/B-CATENIN/NOTCH SIGNALLING AXIS

Christopher Wasson¹, Enrico De Lorenzis¹, Eva Clavane², Rebecca Ross¹, Begona Caballero-Ruiz¹, Rebecca Wells¹, Paul Meakin², Francesco Del Galdo¹

¹Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, UNITED KINGDOM, ²Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, UNITED KINGDOM

Introduction: The beta-amyloid precursor protein cleaving enzyme 1 (BACE1) is well known for its role in the development of Alzheimer’s disease via the generation of B-amyloid. Recent publications, including our own, have demonstrated a role for this enzyme in other chronic inflammatory diseases, including type 2 diabetes and cardiovascular disease. However, to date there has been no studies looking into the role of BACE1 in the autoimmune condition Systemic Sclerosis (SSc). The aim of this study was to investigate the role of BACE1 in SSc tissue fibrosis.

Material and Methods: Patient fibroblasts were obtained from full thickness forearm skin biopsies from healthy and early diffuse SSc patients. BACE1 was inhibited with 3 small molecule inhibitors and siRNA specific to BACE1. Morphogen signalling was activated with recombinant TGF-B, Wnt-3a or the smoothened agonist SAG. Xenotransplant mouse model using patient pDC was used to interrogate in vivo expression of BACE1 in fibrosis.

Results: Here we show that BACE1 protein levels are elevated in SSc patient skin biopsies, as well as dermal fibroblasts (2.3 fold increase, N=4). The increased expression of BACE1 correlated with increased expression of the BACE1 substrate AB40/42 in SSc patient sera. BACE1 protein levels were elevated in the bleomycin skin fibrosis model. Inhibition of BACE1 with small molecule inhibitors or siRNA blocked pro-fibrotic gene (alpha SMA, Collagen Type 1 and CTGF) expression in SSc fibroblasts. In addition overexpression of BACE1 in healthy fibroblasts resulted in myofibroblast activation. Disruption of BACE1 blocked morphogen mediated fibroblasts activation. The BACE1 inhibitors blocked TGF-B, Wnt-3a and Hedgehog mediated alpha SMA expression in healthy fibroblasts. Furthermore, we show that BACE1 regulation of dermal fibroblast activation is dependent on the B-catenin and Notch signalling pathway activation. BACE1 ability to regulate non-canonical Wnt receptors lead to elevated B-catenin and Notch signalling. Finally, we showed for the first time that BACE1 expression levels were regulated by the Brain Derived Neurotrophic Factor (BDNF) and BDNF levels are dysregulated in SSc patient sera.

Conclusions: The ability of BACE1 to regulate SSc fibroblast activation reveals an exciting new therapeutic target in SSc. Several BACE1 inhibitors have been shown to be safe in clinical trials for Alzheimer’s disease.

P.003

ORAL TOLERANCE WITH COLLAGEN V ALPHA 1 CHAIN REDUCES PULMONARY FIBROSIS AND VASCULOPATHY IN SSC/IMU-COLV MODEL: A PRELIMINARY STUDY

Ana Paula Velosa¹, Thays de Matos Lobo¹, Zelita Aparecida de Jesus Queiroz¹, Antonio dos Santos Filho¹, Vitor Daniel Souza¹, Jaíne Almeida¹, Sandra Fernezlian³, Lizandre Ramos da Silveira¹, Sergio Catanozi², Vera Luiza Capelozzi³

¹Division of Rheumatology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BRAZIL, ²Laboratory of Carbohydrates and radioimmunoassays-Lim18, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BRAZIL, ³Department of Pathology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BRAZIL

Introduction: Type V collagen (COLV), a nucleator of the heterotypic collagenous fibrils, is considered a hidden antigen due its immunogenic and antigenic properties and potential to became a self-antigen. Recently, we identified the prevalence of autoantibodies to the ColV alpha 1 chain [α1(V)] in patient’s serum in the early stages of systemic sclerosis (SSc). Considering these COLV characteristic, our proposal was to evaluate vascular and interstitial changes in the lung in the SSc/IMU-COLV mice model after oral tolerance with COLV and its α1(V) chain.

Material and Methods: The SSc model was induced in C57BL/6 mice (n=12) immunized with COLV emulsified in Freund's adjuvant (SSc/IMU-COLV). Two animal’s groups received oral treatment, respectively with COLV/10μg and α1(V) chain/50μg diluted in saline, 5 days before the first immunization with COLV. Posteriorly, each group of animals received two more doses of COLV or α1(V) on the second and fourth days after the first immunization. The group SSc/IMU-COLV untreated received saline orally. The animals were maintained by 60 days and after euthanasia, lung samples were collected to immunofluorescence, immunohistochemistry, and histologic and histomorphometric evaluation.

Results: The pulmonary tissue of SSc/IMU-COLV showed abundant cellular infiltration around small vessels and bronchioles, thickening of the lung parenchyma and intense collagen deposition in the peribronchovascular region, besides thickening of the vessels walls and vascular occlusion. The SSc/IMU-COLV oral treatment with COLV/10μg (p=0,0046) and α1(V)/50μg (p=0,0015) decreased cellular infiltrate and collagen deposition in the lung interstitium (p=0.0006). Histomorphometry identified decreased in the collagen I amount in the interstitium and around the vessels from SSc/IMU-COLV treated with α1(V)/50μg in relation to untreated group (p=0,0194) and the group treated with COLV/10μg (p= 0,0009). In addition, the group treated with α1(V)/50μg showed reduced amount of collagen V in relation to untreated group (p=0,0278). In contrast, oral treatment with COLV/10μg was more effective in reducing the collagen III content (p=0,0360) in relation to untreated group. Furthermore, both COLV/10μg (p<0,0001) and α1(V)/50μg (p=0,0084) oral treatments were effective in reducing vascular manifestations, visualized by Factor VIII+ immunostaining.

Conclusions: Oral tolerance induced to COLV and α1(V) was effective in reducing cellular infiltrate, fibrosis and vasculopathy in the SSc/IMU-COLV model. However, in the general, α1(V)-induced oral tolerance showed a broader benefit in reducing collagen expression and vasculopathy in the SSc model. Our preliminary study, suggest that oral tolerance with the immunogenic α1(V) chain can be a helpful approach to develop an adjunctive immunotherapy for the treatment of SSc.

P.004

SYSTEMIC S100A4 LEVELS ARE INCREASED IN SCLERODERMA-INTERSTITIAL LUNG DISEASE, DECREASE UPON CYCLOPHOSPHAMIDE/RITUXIMAB TREATMENT, AND PREDICT THE TREATMENT RESPONSE AND PROGRESSION TO EARLY DISEASE

Hana Storkanova^1,2, Lucie Andres Cerezo^1,2, Sabina Oreska^1,2, Aneta Jirankova¹, Anna Bobrova¹, Katerina Bobrova¹, Barbora Hermankova^1,3, Jörg Klingelhöfer⁴, Rizwan I Hussain⁴, Jonas Hallén⁴, Jörg HW Distler⁵, Karel Pavelka^1,2, Ladislav Senolt^1,2, Jiri Vencovsky^1,2, Radim Becvar^1,2, Michal Tomcik^1,2

¹Institute of Rheumatology, Prague, CZECH REPUBLIC, ²Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, CZECH REPUBLIC, ³Department of Physiotherapy, Faculty of Physical Education and Sport, Charles University, Prague, CZECH REPUBLIC, ⁴Arxx Therapeutics, Oslo, NORWAY, ⁵Clinic for Rheumatology, Hiller Research Center, University Hospital Düsseldorf, Medical Faculty of Heinrich-Heine Unive, Düsseldorf, GERMANY

Introduction: Our previous studies demonstrated that S100A4 is overexpressed in scleroderma (SSc) skin, fibroblasts, and preclinical models of SSc. Inactivation of S100A4 prevented dermal fibrosis induced by bleomycin and in Tsk-1 mice. Inhibition of S100A4 by murine mAbs (6B12) prevented the progression and induced regression of established dermal fibrosis induced by bleomycin. The aim of this study was to assess the potential role of systemic S100A4 levels as a biomarker of SSc-related features and a predictor of treatment response and disease progression.

Material and Methods: Systemic levels of S100A4 were measured by ELISA (CUSABIO, Houston, USA) in 104 age-/sex-matched healthy controls (HC) and four different cohorts:

• 1) cross-sectional SSc patients (n=117; 67 lcSSc/50 dcSSc; mean age 55.8, disease duration 5.0 years);

• 2) SSc patients with active interstitial lung disease (ILD) treated with 6 (n=24) or 12 (n=16) months of iv cyclophosphamide;

• 3) SSc patients with progressive skin involvement and/or arthritis and/or ILD non-responsive to methotrexate/cyclophosphamide/mycophenolate treated with 2 (n=8) or 3 (n=16) 6-month cycles of rituximab; and

• 4) VEDOSS (Very Early Diagnosis of SSc) patients with Raynaud’s phenomenon who did not progress (n=15) or progressed (n=11) to SSc. Data are presented as median (IQR).

Results:

• 1) S100A4 was significantly increased in SSc (67.2(43.1-88.7) vs. 51.1(35.9-60.8)ng/mL in HC;p<0.0001), especially in SSc with ILD (72.7(49.1-95.2) vs. 54.7(37.5-77.1)ng/mL in SSc without ILD; p=0.0124) and borderline with gastrointestinal involvement (69.3(50.3-96.7) vs. 63.1 (38.9-84.4)ng/mL without gastrointestinal involvement;p=0.0854). S100A4 was associated with lung function tests and borderline with disease duration (Table1).

• 2) Treatment of active SSc-ILD with cyclophosphamide significantly decreased S100A4 over 6 months (76.3(52.9–98.6) vs. 73.2(44.4–98.6)ng/mL;p=0.013), whereas baseline S100A4 predicted the decrease in systemic inflammation (Table1).

• 3) Treatment of progressive SSc (non-responsive to csDMARDs) with rituximab significantly decreased S100A4 over 6 months (83.7(70.4-109.6) vs. 81.5(60.2-100.4)ng/mL;p=0.0455). Baseline S100A4 predicted an improvement in hand function, fatigue, depression, and borderline in soilage, whereas a change in S100A4 was associated with function, quality of life, fatigue, and physical activity (Table1).

• 4) Over an average of 3.5 years of follow-up in VEDOSS patients, S100A4 significantly decreased (p=0.0073) in non-progressors (13/15), whereas increased in 8/11 progressors (inter-group p=0.0429). S100A4 was associated with CRP and age in non-progressors and the titer of antinuclear antibodies in progressors (Table1).

Conclusions: Systemic S100A4 levels are elevated in SSc (especially in ILD), decrease with cs/bDMARD treatment, and predict the treatment response and progression to early disease.

Acknowledgment: Supported by MHCR023728.

P.005

DO EARLY AND LATE HISTOPATHOLOGICAL AND RADIOLOGICAL FINDINGS VARY DEPENDING ON ANIMAL SPECIES AND STRAINS IN THE BLEOMYCIN-INDUCED ANIMAL MODEL?

Duygu Temiz Karadag¹, Seda Duman Ozturk², Ozgur Cakir³, Cuneyt Ozer⁴, Gurler Akpinar⁵, Murat Kasap⁵, Ayten Yazici¹, Ayse Cefle¹

¹Kocaeli University Faculty of Medicine, Department of Internal Medicine, Division of Rheumatology, Kocaeli, TURKEY, ²Kocaeli University Faculty of Medicine, Department of Pathology, Kocaeli, TURKEY, ³Kocaeli University Faculty of Medicine, Department of Radiology, Kocaeli, TURKEY, ⁴Faculty of Medicine, Experimental Medicine Research Unit, Kocaeli, TURKEY, ⁵Kocaeli University Faculty of Medicine, Medical Biology, Kocaeli, TURKEY

Introduction: Our study aimed to compare the early and late phases of bleomycin (BLM) induced animal models in 2 different animal species, including three different strains (Wistar rat, BALB/c mice, and C57BL/6 mice) histopathologically and radiologically

Material and Methods: We subjected half of the female C57BL/6 and BALBC-C (n=4 for each, 20-25 g and six weeks old) and female Wistar rats (n=4, 200-250 g and six weeks old) to subcutaneously BLM (10 mg/kg/day) and the rest to Phosphate Buffered Saline (PBS) every other day for four weeks.Half of the animals in each arm were terminated at the end of the second week to detect early changes.We performed high-frequency ultrasonography (GE Healthcare, linear probe 4-20mHz) twice from the right and left sides of the vertebra.Skin biopsies were taken from four different quadrants in the dorsal region of each animal (vertebra central).Collagen homogenization score, eosinophil count, basophil count, inflammatory response score, and histological skin thickness (between the epidermis and adipose layer) were calculated from 3 sections and ten different high-power fields (HPF) in each biopsy.Collagen homogenization score ranged between 0-3 according to the thickness and firmness of the collagen. Eosinophil and mast cell density and inflammatory response score ranged between 0-2 (1-2/HPF=0; 3-7/ HPF=1 and more than 8/ HPF=2) according to the density of cells.

Results: Collagen homogenization score, eosinophil density, mast cell density, inflammatory response score, and skin thickness in the BLM arm were higher than PBS for all models (Table 1).For the early inflammatory versus late fibrotic stage, we compared the BLM arms at weeks 2 and 4.While the collagen homogenization score was similar for all three models, inflammatory response score, eosinophil and mast cell densities were higher at week two compared to week 4.The eosinophil, mast cell and inflammatory response score at week 2 were highest in BALB/c and Wistar.Histological skin thickness was higher in Wistar than BALB/c and C57BL at week 2. Radiologic skin thickness increased for all three animals over time and decreased after the 3rd week (Figure 1).

Conclusions: We showed that skin fibrosis model can be created with BLM in 2 different species/3 strains (BALB/c, C57BL, and Wistar), and the model reflects early inflammatory and late fibrotic phases.Based on our results, the early inflammatory response was more severe in BALB/c and Wistar, but all were comparable regarding collagen density and skin thickness.

P.006

MIRNAS IN SYSTEMIC SCLEROSIS PATIENTS WITH DIGITAL ULCER: MARKERS AND EFFECTORS

Yair Levy^1,2, Campochiaro Corrado³, Tzipi Hornik-Lurie¹, Dana Shalmiav^1,2, Itzchak Amoyal^1,2, Maia Yamila Koho^1,2, Liat Drucker^1,2, Serena Guiducci⁴, Dilia Giuggioli⁵, Lorenzo Dagna³, Marco Marco Matucci Cerinic³, Shelly Tartakover Matalon^1,2

¹Meir Medical Center, Kfar-Saba, ISRAEL, ²Tel Aviv University, Tel-Aviv, ISRAEL, ³IRCCS San Raffaele Hospital, Milan, ITALY, ⁴University of Modena, Modena, ITALY, ⁵University of Florence, Florence, ITALY

Introduction: In systemic-sclerosis (SSc), vascular involvement is characterized by widespread vascular complications including pulmonary-hypertension (PAH), gastric antral vascular ectasia (GAVE), renal-crisis (RC) and digital-ulcers (DU). Endothelial cells' (ECs) function in significantly impaired, is linked to endothelial-mesenchymal transition (EndMT), which is then heavily involved in vascular remodeling. In the last decades, it has been shown that microRNAs (mirs) derived from ECs are involved in SSc pathogenesis. Aim:to identify circulating-microRNAs in SSc patients with DU, and evaluate the connection between microRNAs and ECs dysfunction

Material and Methods: microRNAs were measured in peripheral blood of Israeli SSc patients with (n=8, SSc-DU) or without DU (n=4, SSc) using high-throughput analysis (Nanostring). The plasma level of 7 microRNAs that best differentiated SSc patients with from those without DU and of mir-let-7d (a PAH marker) were measured in 96 SSc patients with(30)/without(66) DU from Israeli and Italian patients by qPCR. The patients` clinical&laboratory data were collected (echo, autoantibodies, IgG, C3-C4, CRP, creatinine, CPK, respiratory tests (FEVIL,DELCO,FVCL,6-minute walk (6MW)), and PAH development), compared between SSc-DU to SSc (ANCOVA test, adjusted for country (Israel&Italy)), and correlated with the microRNAs levels (Partial Spearman’s Rho correlation adjusted for country). Bioinformatics (Venny, Toppgene) highlighted microRNAs targets involved in ECs biology and their GO annotations. Last, ECs were treated with TNFa+TGFb (10ng/ml) to induce EndMT (validated by western-blot), and their phenotype and microRNAs tested.

Results: In SSc-DU patients, MRSS, CRP and echo values were higher (p<0.05). More patients with PAH were found in the SSc-DU group than in the SSc (p=0.06). Mir-let-7d and mir-145 levels were lower and mir-30e higher in SSc-DU compared to SSc without DU (p<0.05). Partial correlations were found between mir-let-7d to FEV1L (r(s)xy.z=0.205, p=0.07), CRP (r(s)xy.z=-0.23, p<0.05) and creatinine levels (r(s)xy.z=-0.25, p<0.05), and between mir-145 level to 6MW (r(s)xy.z=-0.4, p<0.05) and MRSS (r(s)xy.z=-0.19, p=0.09). Eight patients developed DU during the experiment and mir-let-7d/145/30e levels were similar to the levels in patients without DU, suggesting these microRNAs cannot predict DU development. GO annotations suggest mir-let-7d's involvement in cytokine signaling (especially TNFa) and cell-death, mir-145 in motility, and mir-30e in vascular remodeling. Accordingly, exposure of ECs to TNFa+TGFb induced EndMT, increased migration and reduced proliferation, viability, let-7d and mir-145 levels.

Conclusions: mir-Let-7d, mir-145 and mir-30e may act as serological markers for SSc patients with DU. Our results connect between mir-Let-7d/145 levels to ECs impairments, suggesting explanation for the correlations between those microRNAs and vascular remodeling. The work was funded with WSF & GILS Research Grant Program.

P.007

MECHANOTRANSDUCTION VIA MYOSIN II ISOFORMS CONTRIBUTES TO TGFBETA-DRIVEN FIBROBLAST ACTIVATION

Barbara Russo¹, Maria Shutova¹, Fanny Noulet², George Romanescu¹, Nicolo Brembilla¹, Wolf-Henning Boehncke²

¹University of Geneva, Pathology and Immunology, Geneva, Switzerland, Geneva, SWITZERLAND, ²Hôpitaux Universitaires de Genève (HUG), Dermatology and Venereology, Genève, Switzerland, Geneva, SWITZERLAND

Introduction: Nonmuscle myosin II isoforms (NMIIA, NMIIB, NMIIC) are motor proteins executing virtually all cellular processes that require force, such as cell migration, adhesion and mechanotransduction. NMII motor activity is regulated by phosphorylation of myosin regulatory light chain (MLC), mainly through Rho-ROCK pathway. Recent studies portray a possible role of NMII in lung fibrogenesis. In systemic sclerosis (SSc), there is evidence of the Rho-ROCK pathway activation; nevertheless, the specific role of NMII in SSc has never been investigated.

Material and Methods: The expression and the cytoskeletal distribution of NMIIA and NMIIB and their activation through MLC phosphorylation were evaluated by immunofluorescence in primary fibroblasts from eight SSc and eight healthy donors (HD), which were stimulated with rhTGFb. The NMII activation pathways were inhibited (i) with Y-27632, a small molecule inhibitor of pan-ROCK that phosphorylate MLC, (ii) with KD025, a small molecule inhibitor of ROCK2 isoform, or (iii) with blebbistatin, a small molecule that inhibit NMII motor. The production of IL-6, type-I collagen and fibronectin by fibroblasts was assessed by ELISA.

Results: SSc fibroblasts exhibited altered re-distribution of NMII isoforms within the actomyosin cytoskeleton (n = 8, NMIIB filament/cytoplasm intensity median [range] HD 1.2 [0.8-1.7] vs SSc 1.8 [1.5-2.2], p = 0.02). HD fibroblasts exhibited a similar pattern of redistribution of NMII isoforms (n = 8, NMIIB filament/cytoplasm intensity median, [range] ctrl 1.2 [0.8-1.7] vs TGFb 1.9 [1.8-2.3], p = 0.02) and increased phosphorylation of MLC at Thr18/Ser19 upon TGFb stimulation (n = 8, ppMLC fluorescence intensity/cell median, [range] ctrl 10000 [8000-1200], TGFb 15000 [12000-17000], p 0.002). Treatment of HD fibroblasts with blebbistatin or Y-27632 substantially reduced the stimulatory effect of TGFb on IL-6 (n = 10, pg/mL median, [range] TGFb 192.6 [72-572] vs TGFb+Y 15 [4,6-81] vs TGFb+blebbistatin 25 [12-200], p = 0.003, p = 0.02 respectively) and collagen I (n = 10, ng/mL median, [range] TGFb 248 [109-572] vs TGFb+Y 109 [73-206]; TGFb vs TGFb+blebbistatin 174 [77-244], p = 0.005, p = 0.04, respectively) production. Treatment of HD fibroblasts primed or not with TGFbwith KD025 did not affected IL-6 production while impaired the type-I collagen production already in resting fibroblasts (n = 10, ng/mL median, [range]ctrl 136 [51-165] vs KD025 84 [23-95], p = 0.03).

Conclusions: Our data point to an altered actomyosin cytoskeleton dynamics and force distribution in SSc fibroblasts and indicate that NMII isoforms are a downstream mediator of the stimulatory effects of TGFb in fibroblasts.

P.008

LEVERAGING NOVEL SSC DISEASE SIGNATURES TO BUILD A HUMANIZED DRUG DISCOVERY FUNNEL

Lauren Reinke-Breen¹, Sunhwa Kim², Laura Leys¹, Lauren Olson¹, Anastasia Marinopoulos¹, Jozsef Karman³, Chris Butler⁴, Jennifer Van Camp⁴, Lisa Hazelwood¹

¹AbbVie Discovery Pharmacology, North Chicago, IL, USA, ²AbbVie Precision Medicine Immunology, South San Francisco, CA, USA, ³AbbVie Genomics Research Center, North Chicago, IL, USA, ⁴AbbVie Information Research, North Chicago, IL, USA

Introduction: Systemic sclerosis (SSc) is a chronic, progressive autoimmune disorder with significant morbidity and mortality. The lack of effective therapies for SSc is, in part, due to the poor understanding of the molecular and cellular mechanisms underlying fibrosis pathogenesis. To deepen our understanding of disease progression, we interrogated published transcriptomics datasets to deconvolute molecular signatures of SSc over time. The integrated gene signatures were applied to preclinical models of SSc, enabling optimization of models based upon human disease-relevant endpoints.

Material and Methods: Transcriptomics profiling and enrichment analyses were used to integrate three published datasets (GSE130955, GSE58095, and GSE181549). We constructed novel biomarker maps that model the dysregulation seen in early SSc (mean duration 1.3yr), late SSc (mean duration 7.7yr), and common to both early and late disease. Select biomarkers from the “early” and “common” maps were measured in preclinical models. NHDFs (normal human dermal fibroblasts) and full-thickness human skin explants were injured with complex inflammatory-fibrotic cocktails, in the presence or absence of antifibrotic agents. A 28-day bleomycin-induced mouse model of SSc was evaluated, with and without antifibrotic treatment. Across models, gene expression and secreted proteins were measured.

Results: Using published skin transcriptomics datasets, we constructed novel signatures that capture aspects of the pathobiology observed in early and late SSc. We demonstrated that treatment of NHDFs and human skin explants with complex inflammatory-fibrotic cocktails causes an upregulation of multiple genes and proteins identified from these “early” and “common” signatures, including COL6A3, Tenascin C, MMP-1, and MMP-3 (Figure 1). Treatment with LPAR1 inhibitors significantly decreased these endpoints.

We also identified over 20 genes in our novel “early” and “common” SSc signatures that are significantly increased in the skin of bleomycin-treated mice and significantly decreased by treatment with an antifibrotic agent. Identifying pathways in the mouse bleomycin model that best reflect changes seen in SSc skin will help improve the translatability of this model.

Conclusions: By profiling three highly-quality SSc skin transcriptomics datasets, we identified key affected pathways and processes throughout SSc pathogenesis. We used these signatures to identify disease-relevant endpoints and guide the optimization of preclinical models to recapitulate key aspects of SSc pathobiology, with a focus on the “early” and “common” signatures. We also demonstrated that exploratory antifibrotic agents are able to modulate these signatures. These human-centric models will allow us to improve characterization of fibrosis mechanisms and assessment of compound efficacy against key disease processes.

P.009

SEQUENCING PATIENT-DERIVED CIRCULATING MICRO-RNAS FOR IDENTIFICATION OF BIOMARKERS OF SYSTEMIC SCLEROSIS

James Pritchett¹, Fiona Wilkinson¹, Leo Zeef², Ben Parker³, Sarah Dyball³, Ian Bruce³

¹Manchester Metropolitan University, Department of Life Sciences, Manchester, UNITED KINGDOM, ²University of Manchester, Faculty of Biology, Medicine and Health, Manchester, UNITED KINGDOM, ³Manchester University Hospitals, Kellgren Centre for Rheumatology, Manchester, UNITED KINGDOM

Introduction: Systemic Sclerosis (SSc) is a devastating multisystem disease associated with substantial morbidity, poor quality-of-life (QoL) and high mortality. Some patients initially manifest with only some of the symptoms of SSc, referred to as ‘very early SSc’ or ‘undifferentiated connective tissue disorder’ (UCTD), with a proportion of these patients going on to develop definite SSc.

There is a lack of molecular biomarkers to help stratify which patients are at greatest risk of progressing from UCTD to a definitive diagnosis of SSc. miRs are small, noncoding RNAs that are crucial cell regulators, making them appealing biomarkers to monitor and/or predict disease progression. This study aimed to characterise alterations in miR expression between healthy volunteers (HV), UCTD and SSc.

Material and Methods: Participants were recruited with ethical approval, informed consent, and anonymity as part of the Lupus Extended Autoimmune Phenotype Study (LEAP). Patients with SSc, UCTD and HV were recruited from the LEAP cohort. All UCTD patients were Antinuclear Antibody Positive (ANA+), with Raynaud’s phenomenon (RP) and at least one other symptom of a CTD. Age and sex matched healthy volunteers were recruited via LEAP (n=12/group).

RNA was isolated from patient sera using miRNeasy Serum/Plasma Advanced Kit (Qiagen, UK). Libraries for sequencing were prepared from RNA samples using NEBNext Multiplex Small RNA Library Prep Kit (New England Biolabs) as per the manufacturer’s instructions. Libraries were sequenced using Novaseq (Illumina).

FastQ files were processed using FastQC and Trimmomatic and mapped using Bowtie2. Dysregulated miRNAs were identified using DEseq2 (adjusted p-value <0.1)). miR targets were identified using miRDB3 (www.mirDB.org, cut off score 90) and pathway analysis was performed using KEGG Mapper (https://www.genome.jp/kegg/mapper/).

Results: We have identified 14 circulating mIRs that are significantly differentially expressed in SSc patients compared to UCTD. 6 mIRs were significantly increased and 8 were significantly decreased in SSc compared to UCTD. miRDB target prediction has identified 100 genes for further investigation. Gene ontology and pathway mapping using the candidate gene list identified processes relevant to SSc disease processes including MAP kinase signalling.

Conclusions: miRs in patient sera are differentially expressed depending on disease status. Future work will validate the miR candidates in a larger cohort of patients using qPCR and elucidate the downstream effector proteins related to SSc disease stage. Understanding the underlying mechanisms driving disease will support the development of new diagnostic, monitoring and therapeutic approaches to improve quality-of-life and wellbeing for SSc patients.

P.010

JAK/STAT PATHWAY AS A POTENTIAL TARGET OF PPAR-GAMMA ACTIVATION IN THE REGULATION OF THE PRO-FIBROTIC PHENOTYPE OF FIBROBLASTS IN SYSTEMIC SCLEROSIS

Nicolas Perrard^1,2,3,4, Thomas Machet^1,2,3,4, Matthias Danes^1,2, Manel Jendoubi^1,2, Sebastien Sanges^1,2,3,4, Sylvain Dubucquoi^1,2,5, David Launay^1,2,3,4, Silvia Speca^1,2

¹University of Lille - U1286 - INFINITE (Institute for translational research in inflammation), LILLE, FRANCE, ²INSERM, LILLE, FRANCE, ³CHU de Lille - Department of Internal Medicine and Clinical Immunology, LILLE, FRANCE, ⁴Reference Center for Rare Systemic Autoimmune Diseases (CERAINO), LILLE, FRANCE, ⁵CHU de Lille - Institute of Immunology, LILLE, FRANCE

Introduction: Systemic sclerosis (SSc) is a severe autoimmune disease characterized by a dysregulated immune response, vascular damage, and fibrosis of the skin and internal organs. Fibrosis is defined as a chronic uncontrolled production of extracellular matrix components following the fibroblast-myofibroblast transition. The prominent and canonical player of these events is the TGF-β/SMAD pathway. Recent findings suggest a crucial role of the crosstalk of TGF-β with other major signalling pathways, such as the JAK/STAT pathway, in the development and progression of fibrosis. Peroxisome Proliferator-Activated Receptor gamma (PPAR-γ) is a main regulator of the TGF-β signal transduction and may prevent the activation of the JAK/STAT pathway. The aim of our study was to assess the interaction between TGF-β, JAK/STAT and PPAR-γ pathways in SSc fibroblasts.

Material and Methods: Fifteen SSc patients and 8 healthy subjects undergoing esthetical surgery (NCT03559465) were included in the study. The paraffin-embedded portion of skin biopsies was used to evaluate tissue structure, collagen deposition and organization by Masson’s Trichrome and/or Picrosirius Red histological staining, as well as tissue localization of STATs phosphorylation by immunohistochemistry. Human primary dermal fibroblasts (HDF) were isolated and cultured. Expression levels of main markers of fibrosis (α-SMA, collagen, fibronectin), and JAK/STAT pathways phosphorylation were evaluated by q-RT-PCR and Western Blotting. Fibroblasts were also treated with 5 ng/mL TGF-β +/- PPAR-γ inverse agonist (T0070907) +/- JAK1/JAK2 inhibitor (Ruxolitinib). Gene expression levels of main markers of fibrosis were evaluated at 12h, 24h and 48h, while JAK/STAT phosphorylation was assessed after shorter treatment times (15min – 30min – 60min).

Results: SSc patients showed a greater collagen fiber disorganization and an increase of STAT3 phosphorylation rate in myofibroblasts in the superficial dermis when compared to healthy subjects. (Figure 1). Basal phosphorylation of STAT3, JAK1 and JAK2 but not of STAT5, JAK3 and TYK2 were found in SSc-HDF. Increased levels of α-SMA (2.68 [1.18; 5.64] vs 1.55 [0.86; 2.08] fold change, p = 0.019) and increased phosphorylation rates of STAT3 in response to TGF-β were observed in SSc-HDF when compared to healthy subject (Figure 2). T0070907 additively enhanced gene expression levels of pro-fibrotic markers induced by TGF-β in SSc-HDF, whereas the JAK1/JAK2 inhibitor (Ruxolitinib) was able to revert the TGF-b-induced myofibroblasts activation (Figure 3).

Conclusions: Our results suggest an interconnection between TGF-β, JAK/STAT pathways and PPAR-γ in SSc-HDF, which could represent an important step forward in understanding the pathophysiological mechanisms of fibrosis in SSc and consequently in the development of new combined therapeutic strategies.

P.011

EFFECTS OF CRYSTALLINE SILICA EXPOSURE IN THE HOCL-INDUCED SYSTEMIC SCLEROSIS MOUSE MODEL

Laura Morin¹, Francois Zimmermann¹, Marie Lelong¹, Patrice Hemon², Alain Lescoat¹, Valerie Lecureur¹

¹University of Rennes, CHU Rennes, INSERM, EHESP, IRSET - UMR_S 1085, Rennes, FRANCE, ²U1227, LBAI, University of Brest, INSERM, CHU Brest, Brest, FRANCE

Introduction: Genetic and environmental factors concur to the development and severity of systemic sclerosis (SSc). Crystalline silica (SiO2), a mineral found in rocks to which construction workers are particularly exposed, is the main environmental risk factor of SSc, increasing the risk of more severe SSc in human. However, the pathophysiological mechanisms involved in silica-related-SSc remain unclear. The aim of this study was to determine the contribution of inhaled SiO2 to the severity of SSc and to identify immune cell populations involved in this aggravation using the HOCl-induced SSc mouse model.

Material and Methods: Intradermic injections of hypochlorous acid (HOCl) were performed five days a week during 6 weeks in the lower back of 6 weeks aged female C57BL/6 mice to induce SSc. Mice were divided in four groups (n=10/group): control, SiO2, HOCl and HOCl+SiO2. Mice were exposed accordingly to 1.5 mg of SiO2 or NaCl by oropharyngeal instillations three days before starting HOCl injections and two weeks after. Blood cell populations were identified by complete blood count (CBC) and flow cytometry while pulmonary cells were studied by mass cytometry (CyTOF). Skin and lung fibrosis were evaluated by histological analyses (dermal thickness measurement, Sirius red quantification).

Results: The percentage of blood circulating classical monocytes (Ly6Chi) was increased in SiO2-exposed HOCl mice as compared to control group (p<0.05) while it was not increased in HOCl or SiO2 groups. Skin fibrosis was not aggravated by SiO2 exposure in SSc mice whereas histological analysis shown that collagen deposition tends to be higher in the group HOCl+SiO2 when compared to HOCl or SiO2 groups. The percentages of lung immune cell populations (among CD45+ cells), identified by CyTOF in HOCl group varied from those observed in SiO2-exposed mice. Resident alveolar macrophages (CD68hi, CD11b-/low) were less represented and monocyte-derived macrophages (CD68hi, CD11bhi) and dendritic cells (CD103+ or CD24+) were increased in SiO2-exposed mice, whereas in HOCl-mice, classical monocytes (Ly6hi) were increased, as compared to control mice. However, these cell population percentages did not appear to be more represented in co-exposed mice.

Conclusions: SiO2 exposure seemed to aggravate lung fibrotic parameters (higher collagen deposition) observed in HOCl-induced murine model of SSc. However, this aggravation was not linked to one specific immune cell population. These results will be completed by 1) an unsupervised analysis of CyTOF data to be presented and 2) the characterization of autoimmunity in this model, to better understand the pathophysiology of silica-related SSc.

P.012

CHARACTERIZATION BY MASS CYTOMETRY OF IMMUNE CELL POPULATIONS IN TWO MOUSE MODELS OF SSC-INTERSTITIAL LUNG DISEASE

Laura Morin¹, Francois Zimmermann¹, Marie Lelong¹, Patrice Hemon², Alain Lescoat¹, Valerie Lecureur¹

¹University of Rennes, CHU Rennes, INSERM, EHESP, IRSET - UMR_S 1085, Rennes, FRANCE, ²U1227, LBAI, University of Brest, INSERM, CHU Brest, Brest, FRANCE

Introduction: Interstitial lung disease (ILD) is the leading cause of systemic sclerosis (SSc) related-death. Immune cells play a key role in SSc pathogenesis but the precise subpopulations involved in SSc-ILD need to be better characterized to identify new therapeutic targets. As lung tissue from SSc patients are poorly accessible, several SSc-ILD mouse models have been developed to study the pathogenesis of SSc-ILD, including hypochlorous acid (HOCl)- and Bleomycin (BLM)-induced SSc models. To better assess the complexity of immune cell involvement in SSc-ILD, single-cell techniques such as mass cytometry are needed. These techniques allow the simultaneous specific phenotyping and quantification of a large number of cell populations. Our study aimed to characterize myeloid and lymphoid immune cells using mass cytometry in the HOCl- or BLM-induced SSc-ILD as compared to control healthy mice.

Material and Methods: SSc-ILD was induced in 6 weeks aged female C57BL/6 mice by daily intradermic BLM or HOCl injections during 4 or 6 weeks respectively, and control mice received intradermic injections of sodium chloride. After euthanasia, right lung was prepared to obtain a single-cell suspension. Dead cells were sorted on magnetic column and live cells were stained with 37 metal-coupled antibody panel. Stained cells were characterized using mass cytometer Helios.

Results: The supervised analysis of lung immune cell populations shown that classical monocytes (Ly6chi), neutrophils (Ly6G+) and interstitial macrophages (CD68low/-; CX3CR1+ and/or CCR2+) were increased in the lungs of HOCl-induced SSc mice when compared to healthy group (p<0.05, p<0.01 and p<0.05 respectively). Moreover, lung eosinophils and monocyte-derived alveolar macrophages tended to increase whereas non-classical monocytes tend to decrease in the lung of HOCl mice. The percentage of resident alveolar macrophages (CD68hi; CD11blow/-) remains unchanged in HOCl group while it was decreased in lung of BLM-induced SSc when compared to control.

Conclusions: This study characterised immune cell sub-populations involved in two different SSc-ILD mouse models. Further supervised analyses in the BLM model and unsupervised analyses of both models will enable us to complete these results and are expected to be presented.

P.014

PROFILING PLASMA BIOMARKERS TO IDENTIFY M2 MACROPHAGE ASSOCIATED FIBROSIS SIGNATURE IN EARLY STAGE SYSTEMIC SCLEROSIS

Laura Leeves¹, Zestranjyan Kannan¹, Yunus Ali¹, Tamir Malley¹, David Abraham¹, Andrew Leask², Bruce Riser³, Bahja Ahmed Abdi¹, Richard Stratton¹

¹UCL Centre for Rheumatology, UCL Division of Medicine, London, UNITED KINGDOM, ²University of Saskatchewan, Saskatoon, CANADA, ³University of Michigan, Michigan, USA

Introduction: Systemic sclerosis is an autoimmune connective tissue disease characterised by vasculopathy and fibrosis. The CCN family of matricellular proteins have been found to have a regulatory role in inflammation and fibrosis. CD206, an M2 macrophage surface marker, acts as an active disease marker in systemic sclerosis. This is cleaved by metalloproteases to release soluble form of CD206. We investigated the profile of CCN2 and CCN3 in the presence of soluble CD206 (sCD206) in patients with early and late stage diffuse systemic sclerosis (dSSc).

Material and Methods: Patients with a diagnosis of dSSc at the UCL Centre for Rheumatology and Connective Tissue Diseases were recruited. Informed consent was obtained from patients and healthy controls (HC). Blood samples were taken from which plasma was isolated and stored at -80°C prior to assay. Expression of CCN2, CCN3, and sCD206 was measured in these plasma samples by ELISA.

Study participants were categorised into healthy controls (n=20), early stage dSSc (n=20) and late dSSc (n=20), with early stage defined as the blood sample taken within 2 years since diagnosis, and late stage defined as over 5 years since diagnosis.

Results: As indicated in Figure 1, plasma CCN2, CCN3 and sCD206 levels were significantly higher in early dSSc patients, when compared to HC. As a biomarker, CCN2 was raised in early dSSc patients (early dSSc mean 20,221pg/ml, SD 16,503, p<0.05) with concentration in late disease matching that of HC (late dSSc 12,893pg/ml, HC 11,289pg/ml). CCN3 was significantly higher in early and late disease when compared to HC (early mean 16,526pg/ml, late 12,838pg/ml, HC 4,201pg/ml, p<0.05).

Expression of CCN2 was higher compared to that of CCN3 in early disease, with CCN2:CCN3 ratio elevated in early dSSc (mean 3.17, SD 8.26) compared to late dSSc (mean 1.26, SD 0.99) and HC.

Conclusions: This investigation demonstrates that upregulation of CCN2 and CCN3 expression has a regulatory role in fibrosis in early stage dSSc. These biomarkers of M2 macrophage associated fibrosis are to be correlated with their clinical phenotype and have potential for a role in targeted treatment of systemic sclerosis.

P.015

PLASMA CD40L (CD154) IS INCREASED IN PATIENTS WITH EARLY SYSTEMIC SCLEROSIS AND REFLECTS PLATELES ACTIVATION

Otylia Kowal-Bielecka¹, Pawel Bielecki², Natalia Szymanska¹, Krzysztof Kowal³

¹Department of Rheumatology and Internal Medicine, Medical University of Bialystok, Bialystok, POLAND, ²Department of Otolaryngology, Medical University of Bialystok, Bialystok, POLAND, ³Dept. of Experimental Allergology and Dept. of Allergology and Internal Medicine, Medical University of Bialystok, Bialystok, POLAND

Introduction: CD40 ligand (CD40L, CD154) regulates fibrosis, inflammation and B-cell activation which are key events to the pathogenesis of systemic sclerosis (SSc).

The aim of this study was to investigated the role of CD40L in the pathogenesis of SSc through evaluations of associations between plasma concentration of soluble CD40L (sCD40L) and clinical features of SSc. Moreover, we aimed to evaluate the cellular source of plasma sCD40L in patients with SSc through correlation of sCD40L with markers of platelets, endothelium and lymphocyte activation in plasma.

Material and Methods: Soluble CD40L (sCD40L), soluble interleukin-2 receptor (sIL-2R) as marker of lymphocyte activation, beta-thromboglobulin (BTG), platelet factor 4 (PF-4), and soluble P-selectin (sP-selectin) which reflect different aspects of platelet activation, as well as soluble E-selectin (sE-selectin) as marker of endothelial activation, were measured by means of ELISA in plasma from 76 SSc patients and 20 healthy subjects

Results: The mean concentration of sCD40L was significantly higher in SSc patients as compared with healthy controls (p<0.05). In SSc patients there was significant inverse correlation between plasma sCD40L levels and disease duration (judged from the first non-Raynaud’s symptom attributable to SSc) (Spearman r = -0.7, p<0.001). Accordingly, plasma sCD40L levels were significantly higher in patients with early SSc (less than 5 years duration) compared with SSc patients of longer disease duration (p<0.001). Concentration of sCD40L was higher in diffuse SSc patents as compared with limited form of the disease (p<0.05) and correlated with skin involvement (evaluated by mRSS, r = 0,4, p<0,05). In addition, SSc patients with anti-topo I antibodies had significantly higher plasma concentration of sCD40L as compared with those with anticentromere antibodies (p<0,05). Moreover, plasma concentration of sCD40L correlated with platelet count (r=0,47, p<0.05) and concentration of CRP (r=0,43, p<0,05) in SSc patients.

In multivariate regression plasma concentrations of sCD40L showed significant association with early disease only.

Moreover, in the group of SSc patients sCD40L significantly correlated with sP-selectin (R=0.64, p<0.0001, by Spearman correlation test), but not with the levels of sIL-2R, sE-selectin, BTG or PF4.

Conclusions: The results of our study indicate that concentration of sCD40L is increased in the blood of early SSc patients and reflects increased activation of blood platelets within circulation of SSc patients. Since platelet activation is closely related to vascular injury, our observation suggest a new mechanism through which activated platelets may contribute to the pathogenesis of SSc and might be a target for future therapeutic approach.

P.016

GLOBAL DNA METHYLATION AND HISTONE 4 MODIFICATIONS IN A COHORT OF BULGARIAN PATIENTS WITH SYSTEMIC SCLEROSIS – A PILOT STUDY

Tsvetelina Kostova¹, Maria Kazakova^2,3, Rositsa Karalilova^1,4, Victoria Sarafian^2,3, Anastas Batalov^1,4

¹Medical University-Plovdiv - Department of Propaedeutics of Internal Diseases, Plovdiv, BULGARIA, ²Medical University-Plovdiv - Department of Medical Biology, Plovdiv, BULGARIA, ³Medical University-Plovdiv, Research Institute, Plovdiv, BULGARIA, ⁴Clinic of Rheumatology, UMHAT Kaspela, Plovdiv, BULGARIA

Introduction: The etiology of systemic sclerosis (SSc) remains poorly understood. While genetic studies have provided evidence for gene loci associated with disease susceptibility, they cannot be fully responsible for the development of SSc. Further, there has been a burgeoning body of literature focusing on association between environmental and occupational factors and the occurrence of the disease. Currently it is hypothesized that the initiation of SSc is likely to be the result of environmental and occupational factors inducing epigenetic alterations in a genetically susceptible individual. Here we present preliminary results from a pilot study investigating two epigenetic regulatory mechanisms in patients with SSc based on their occupational history.

Material and Methods: Twenty-three adult patients with SSc completed a structured questionnaire regarding self-reported occupational exposure. Based on the occupational history patients were divided into four groups: working in manufacturing with organic solvents, metals, polyvinyl chloride; tobacco harvesters; more than one occupational exposure; and no occupational exposure to known risk factors. Global DNA methylation level analysis in peripheral blood mononuclear cells (PBMCs) was performed with colorimetric global DNA methylation assay kit in all twenty-three patients. Additionally, ten H4 modifications were evaluated in seven patients using colorimetric H4 modification multiplex assay kit.

Results: Difference in global DNA methylation levels between the separate groups was observed as well as wide variation inside some of the groups. Patients with no exposure to known risk factors predominantly exhibited DNA hypomethylation, while patients working in manufacturing (with organic solvents, metals, polyvinyl chloride) all had DNA hypermethylation in comparison to the other groups. Patients, reporting exposure to more than one risk factor had DNA methylation levels in both extremes – hypo- and hypermethylation when compared to one another. The analysis of the H4 modification marks in all patients revealed increased number of H4K20m2, H4K20m3, H4R3m2a, H4R3m2s (associated with gene repression) in comparison to H4K5ac, H3K8ac, H4K12ac (associated with increased gene expression). One patient from the group with more than one known risk factor had the highest percent of H4K20m3 and H4R3m2s.

Conclusions: We provided evidence for dynamics of epigenetic marks in SSc patients involving alteration in histone remodeling and DNA methylation. Further analyses are required to reveal how environmental or occupational factors trigger the epigenetics mechanisms.

P.017

TREPROSTINIL RESTORES NORMAL THE FUNCTIONAL PHENOTYPE OF SCLERODERMA (SSC) VASCULAR SMOOTH MUSCLE CELLS (VSMCS) BY INHIBITING YAP AND ACTIVATING PPARG SIGNALING

Bashar Kahaleh, Yongqing Wang

Department of Medicine, Division of Rheumatology, University of Toledo Health Science Campus, Toledo, OH 43614, USA

Introduction: Progressive vascular wall thickness and fibrosis are the hallmarks of SSc vasculopathy. Overexpression of TGFB1 in SSc and activation of vSMCs are important steps in the pathogenesis of SSc vascular disease. In this study, we examined the expression levels of COL1, PCNA, PFKP, IP, EP2, IP, and PTGIS in SSc skin, the effects of Treprostinil (prostacyclin analog) on cell proliferation, TGFB1-induced collagen expression in SSc-vSMCs, PPARG expression and Yap nuclear translocation.

Material and Methods: SSc and control skin biopsies were fixed and 10uM serial sections were cut for histological examination. vSMCs were isolated from involved skin and matched healthy subjects. The expression and distribution of collagen, PCNA, PFKP, IP, EP2, PTGIS, PPARG, and Yap were measured by immunohistochemical staining or immunofluorescent staining. Cell proliferation was measured by MTT assay. The mRNA expression levels were detected by qPCR.

Results: The protein expression levels of collagen, PCNA, PFKP, and EP2 were increased, while the expression levels of PTGIS and IP were decreased in vSMCs of SSc-skin, compared to the control. These results suggested that defective PGI2-IP signaling in SSc-vSMCs may contribute to vessel wall thickness and vascular fibrosis in SSc. Treprostinil inhibited vSMCs proliferation, COL1A1, and PFKP mRNA expression in SSc-vSMCs in a dose-dependent fashion. Treprostinil also inhibited TGFB1-induced COL1A1 mRNA expression in SSc-vSMCs via engagement of EP2. The PPARG expression was significantly increased in treprostinil-treated SSc-vSMCs. Treprostinil decreased the nuclear location of YAP which is induced by 10%FBS and TGFB1.

Conclusions: Defective PGI2-IP signaling in SSc-vSMCs is associated with enhanced expression of collagen, PCNA, and PFKP in SSc vessel walls. The antiproliferative and antifibrotic activity of treprostinil is mediated through the inhibition of YAP nuclear translocation and enhanced PPARG expression. YAP and PPARG might be promising therapeutic targets for the treatment of SSc-related vasculopathy.

P.018

IDENTIFYING A SIGNATURE OF ADIPOCYTE TO FIBROBLAST TRANSITION IN SYSTEMIC SCLEROSIS

Helen Jarnagin¹, Rezvan Parvizi¹, Madeline Morrisson¹, Zhiyun Gong², Patricia A. Pioli², Michael L. Whitfield²

¹Dartmouth College, Lebanon, NH, USA, ²Dartmouth Geisel School of Medicine, Lebanon, NH, USA

Introduction: Systemic Sclerosis (SSc) is a rare autoimmune disease characterized by skin fibrosis, internal organ fibrosis, and subcutaneous fat loss. We recapitulated the previously reported adipocyte-to-fibroblast transition in vitro and used multiple datasets to define a signature for adipocyte-derived fibroblasts. Using this signature, we queried single-cell RNA-seq data in SSc skin to identify fibroblasts in SSc patients that retain adipocyte-derived traits.

Material and Methods: We isolated adipocyte-derived stem cells (ADSCs), differentiated them into adipocytes, and then exposed them to TGFB. The transition was assessed using Red Oil O stain, crystal violet viability stain, and RT-qPCR. Differential expression analyses were performed on two bulk gene expression datasets of adipocyte-derived fibroblasts to identify a gene signature for these unique cells (Marangoni et al., 2015 and GSE126514). We analyzed publicly available single-cell RNA-Seq (scRNA-Seq) datasets (Tabib et al, GSE138669 and Gur et al, GSE195452) using R, with Seurat, CAMML, fGSEA, and gprofiler2. The gene signature for the adipocyte-derived fibroblasts was projected onto the single-cell data to identify candidate fibroblast populations that may derive from this transition.

Results: ADSC and adipocytes treated with TGFB transitioned to a fibroblast-like state. Mature adipocytes shifted to a fibrotic phenotype with increased aSMA and collagen genes, reduced PPARy, and APOE retention (Fig 1B). ADSC exposure to TGFB blocked adipocyte differentiation. Lipid content assessments confirmed cellular state changes (Fig 1A). Differential expression analyses in bulk gene datasets identified adipocyte-derived fibroblast gene signatures. This signature was used in analyzing two scRNA-seq datasets, revealing a conserved CCL19high/APOEhigh inflammatory fibroblast population enriched in SSc skin (Fig 1 C, D: p-values=1.08e-02 and 4.09e-02). Gene set enrichment analysis confirmed its presence across two single-cell datasets (Fig 1 E, F: p-value= 5.26e-134). This population, enriched for adipocyte-derived signature, may originate from ADSCs (Fig 1 G, H: OR=1.9, p-value=2.47e-15). Functional analysis showed innate immune system activation, indicating an inflammatory fibroblast population.

Conclusions: We recapitulated the adipocyte-to-fibroblast transition in vitro and characterized a signature for these cells. Analysis in single-cell data indicates a population of cells that exhibits an enrichment of adipocyte-derived fibroblasts gene signature increased in SSc patients and express markers of immune cell activation. These results suggest that immune-activated fibroblasts could originate from ADSCs in SSc skin fibrosis.

P.019

OVEREXPRESSION OF BAG3 (BCL2-ASSOCIATED ATHANOGENE3) IN SERUM AND SKIN OF PATIENTS WITH SYSTEMIC SCLEROSIS

Margot De Marco^1,2, Antonia Falco^1,2, Annalisa Cammarota^1,2, Francesca Repucci^1,2, Liberato Marzullo^1,2, Alessandra Rosati^1,2, Antonina Minniti^3,4, Giuseppe Armentaro^3,4, Claudia Iannone^3,4, Maria Rosa Pellico^3,4, Silvia Cavalli^3,4, Roberto Caporali^3,4, Maria Caterina Turco^3,4, Nicoletta Del Papa^3,4

¹FIBROSYS s.r.l., Baronissi, Baronissi, ITALY, ²Department of Medicine, Surgery and Dentistry Schola Medica Salernitana, University of Salerno, Baronissi, ITALY, ³ASST Gaetano Pini-CTO, Scleroderma Clinic, Rheumatology Dept, Milan, ITALY, ⁴Department of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Univer, Milan, ITALY

Introduction: Bcl2-associated athanogene 3 (BAG3) protein is a member of a family of co-chaperones that interact with the ATPase domain of the heat shock protein 70 through their BAG domain. Recent studies demonstrates pivotal role of extracellular BAG3 in protumor cell signalling in the tumor microenvironment, as well as its involvement in the development of fibrosis in tumor tissues. BAG3 is capable to induce, in tumors with large stromal component, as pancreatic ductal adenocarcinoma, the transformation of cancer-associated fibroblasts to alpha smooth muscle actin (a-SMA) positive (+) myofibroblasts. This kind of cells enhances the intratumoral deposition of collagen matrix making the neoplasia more aggressive and drug-resistant. In SSc, alpha-SMA+ myofibroblasts play an important role in progression of fibrosis in the skin and involved internal organs.

Material and Methods: We evaluated the presence of BAG3 in serum and skin of SSc patients and investigated whether circulating levels of BAG3 could have any relationship with different SSc subsets and disease features. BAG3 serum levels were measured in 106 patients with SSc [47 with lcSSc and 59 dcSSc ], and in an equal number of age and sex-matched normal controls. BAG3 levels were then compared in patients with SSc subdivided according to their clinical subset, nailfold videocapillaroscopic (NVC) patterns, the presence and degree of ILD, and correlated with modified Rodnan skin score (mRSS) and disease activity score. BAG3 expression was investigated in skin biopsy of 8 patients with dSSc

Results: BAG3 serum levels were significantly higher, with respect to normal controls, in patients with SSc, mostly in dSSc patients. BAG3 serum levels were not correlated with disease activity and mRSS, but were significantly higher in patients with late NVC pattern and ILD presence. Finally, BAG3 was strongly expressed in skin biopsy of patients with dSSc.

Conclusions: The presence of BAG3 in the serum SSc patients has never been described so far. Serum levels of BAG3 were found to be significantly higher in the dcSSc, the disease subset with more extensive fibrosis, than lcSSc. Accordingly, BAG3 values correlated with the late pattern at NVC, usually associated with the more advanced and fibrotic stages of the disease. Conversely, serum BAG3 values did not correlate with disease activity, since these scores reflect the progression of disease rather than the extent of fibrosis. This study suggests that BAG3 pathway may be active and significantly contribute to the fibrotic process that involves both skin tissue and internal organs of patients with dcSSc.

P.020

FCΓ RECEPTORS: ORCHESTRATORS OF PRO-PHAGOCYTIC MACROPHAGES AND DISRUPTED RESOLUTION IN SYSTEMIC SCLEROSIS

Amela Hukara¹, Gino Andrea Bonazza¹, Tracy Tabib², Raphael Micheroli¹, Suzana Jordan¹, Kristina Bürki¹, Sylvie Schiltz Schönbächler¹, Michal Rudnik¹, Adrian Ciurea¹, Oliver Distler¹, Robert Lafyatis², Przemyslaw Blyszczuk¹, Gabriela Kania¹

¹Center of experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, SWITZERLAND, ²Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, USA

Introduction: Fcγ receptors (FcγR) regulate opsonic phagocytosis, demanding tight control to prevent uncontrolled activation and the ensuing pro-inflammatory responses that can lead to persistent chronic inflammation in systemic rheumatic autoimmune inflammatory diseases (RAIDs). We aimed to study if macrophages from SSc and other RAIDs exhibit a pro-phagocytic signature and how they could contribute to disease pathogenesis.

Material and Methods: Publicly available single-cell RNA sequencing (scRNA-seq) datasets (GSE138669, GSE212109) on healthy control and SSc patient skin or lung macrophage populations were analyzed using Seurat v4.3.0 package. Human monocyte-derived macrophages (hMDM) were differentiated from CD14+ blood-derived monocytes from healthy controls, SSc, RA, PsA and axSpA patients. For some experiments, M(0) hMDM were pre-treated for 24 hours with 0.1 uM nintedanib, a tyrosine kinase inhibitor. Phagocytic activity of M(0) hMDM was measured using pHrodo Red E.coli bioparticles and detected by flow cytometry. Macrophage surface markers were assessed by flow cytometry. NF-κB signaling cascade was studied by Western Blot and IL6 expression was measured using RT-qPCR.

Results: Our scRNA-seq analysis unveiled the upregulation of FCGR genes and FcγR-mediated pathways in skin macrophages from 12 dcSSc patients and lung macrophages from 5 SSc patients suffering from interstitial lung disease (ILD) (p.adj.<0.05; log2FC>0.5). We pinpointed FCGR3Ahi macrophages in the skin of dcSSc and FCN1hi macrophages in the lungs of SSc-ILD patients as the predominant phagocytic subsets. Our in vitro experiments further corroborated these findings, revealing significantly heightened phagocytic activity in M(0) SSc hMDM (n=57) compared to healthy control cells (n=36, p<0.0001). Phagocytic activity positively correlated with the expression levels of FcγRI (n=14, Pearson r=0.663, p=0.006) and FcγRII (n=14, Pearson r=0.5178, p=0.0478). Moreover, the engulfment of pHrodo Red E.coli bioparticles by SSc M(0) hMDM (n=7) triggered the activation of the NF-κB pathway, subsequently resulting in an elevated expression of the pro-inflammatory IL6 cytokine compared to healthy controls (n=5, p=0.0278). Pre-treatment of M(0) SSc hMDM with Nintedanib decreased phagocytic activity compared to untreated M(0) SSc hMDM (n=7, p=0.0066). Additionally, we observed a similar pro-phagocytic phenotype not only in SSc but also in other RAIDs, including RA (n=10, p=0.0363) and PsA (n=11, p=0.0235) patients, although it was notably absent in axSpA patients (n=9, p=0.4867).

Conclusions: Collectively, enhanced FcγR expression may serve as a novel biomarker for pro-phagocytic macrophages, indicative of their potential to provoke pro-inflammatory responses and contribute to persistent, unresolved inflammation and fibrosis (Fig.1). Consequently, exploring interventions aimed at modulating pro-phagocytic macrophages may hold promise as a therapeutic strategy for SSc and other RAIDs.

P.021

DETERMINATION OF THE FUNCTIONAL STATE OF THE M1-MACROPHAGES IN THE BLOOD IN SYSTEMIC SCLEROSIS

Elena Gerasimova¹, Tatiana Kirichenko², Alexander Markin², Anastasia Bogatyreva², Olga Koneva¹, Tatiana Popkova¹

¹V.A. Nasonova Research Institute of Rheumatology, MOSCOW, RUSSIA, ²Avtsyn Research Institute of Human Morphology, MOSCOW, RUSSIA

Introduction: The activation of M1 monocytes was manifested by a significant increase in their secretion of proinflammatory cytokines TNF-alpha and IL-1 beta both in the basal and stimulated states.

Material and Methods: Twenty nine patients with untreated SSc and 22 controls without autoimmune diseases were examined. Of the clinical forms of SSc, patients with a limited form prevailed (82%), the diffuse form was less common (18%). Participants in the control group were comparable with SSc patients in terms of sex. Primary culture of CD14+ cells from blood samples was obtained from all study participants, followed by the selection of CD14+ cells by magnetic separation on columns using paramagnetic nanoparticles (Miltenyi Biotec Inc., USA). Immune response of monocytes was stimulated with lipopolysaccharide (LPS). The concentrations of TNF-alpha, IL-1 beta in culture fluid samples were determined by ELISA using commercial kits Human TNF-alpha/TNFSF1A DuoSet ELISA, Human IL-1 beta/IL-1F2 DuoSet ELISA

Results: The basal and LPS-stimulated secretion of TNF-alpha and IL-1 beta by cultured macrophage-monocytes from the blood of SSc patients was significantly higher compared with healthy (Table 1).

Conclusions: We obtained a significant increase in the activity of M1-monocytes in patients with untreated SSc in comparison with the control.

This work was supported by the Russian Science Foundation (Grant # 22-25-00358).

P.022

MITOCHONDRIAL DNA COPY NUMBER IN PATIENTS WITH UNTREATED SYSTEMIC SCLEROSIS

Elena Gerasimova¹, Tatiana Kirichenko², Anastasia Bogatyreva², Olga Koneva¹, Yuliya Markina², Tatiana Popkova¹, Alexander Markin²

¹V.A. Nasonova Research Institute of Rheumatology, MOSCOW, RUSSIA, ²Avtsyn Research Institute of Human Morphology, MOSCOW, RUSSIA

Introduction: Mitochondrial dysfunction of circulating monocytes may underlie the progression of chronic inflammation and fibrosis in SSc. Mitochondrial DNA (mtDNA) copy number is considered a surrogate marker of mitochondrial dysfunction.

The aim of the study was to evaluate the number of mtDNA copies in CD14+ monocytes and whole blood of SSc patients in comparison with healthy individuals.

Material and Methods: Twenty five patients with untreated SSc (22 women and 3 men; mean age 50,6 years) and 25 age- and sex-matched control individuals (20 women, 5 men; mean age 48,7 years) were enrolled in this study. Exclusion criteria: the presence of diabetes mellitus, cancer, decompensated renal or liver failure, chronic cardiovascular failure NYHA class III-IV. The diagnosis of SSc met the criteria of the American College of Rheumatology / European Antirheumatic League (ACR/EULAR) 2013. Most patients (80%) were diagnosed with a limited form of SSc. 20% - with diffuse form. The most common clinical manifestations were Raynaud's phenomenon (80%), puffy fingers fingertip (48%), pitting scars (48%), telangiectasia (44%), sclerodactyly of the fingers (32%); less common - Interstitial lung disease (20%), pulmonary arterial hypertension (12%). All patients with SSc were positive for SSc related autoantibodies: 32% - Anti-topoisomerase I, 48% - Anticentromere, 8% Anti-RNA polymerase III positivity. CD14+ monocytes were isolated from whole blood samples using a standard method for isolating the leukocyte fraction in a ficoll gradient, followed by the selection of CD14+ cells by magnetic separation on columns (Miltenyi Biotec Inc., USA) using paramagnetic nanoparticles (Miltenyi Biotec Inc., USA). Isolation of DNA from CD14+ monocytes and whole blood was carried out using the ExtractDNA Blood & Cells kit (Evrogen, Russia) according to the manufacturer’s protocol. The concentration and purity of the obtained DNA were determined using a BIOSPEC-NANO spectrophotometer (Shimadzu, Japan). Absolute mtDNA copy number was measured using digital PCR on a QIAcuity Eight instrument (Qiagen, Germany).

Results: It was found that the number of mtDNA copies in CD14+ monocytes was significantly higher in SSc patients compared to control subjects (108 [31-162] vs 72 [60-79], p<0.05). The number of mtDNA copies in the whole blood did not have significant differences (5 [2-8] and 6 [4-10]), p>0.05).

Conclusions: The increased mtDNA copy number in CD14+ monocytes is a possible mechanism to maintain the reduced function of defective mitochondria in monocytes from untreated SSc patients.

P.023

RNA-CONTAINING IMMUNE COMPLEXES INDUCE TYPE I AND III INTERFERONS IN SSC BLOOD LEUKOCYTES

Shamisa Adeli, Össur I. Emilsson, Erik Hellbacher, Karin Hjorton, Paul Runeson, Anastasios Christias, Per M. Hellström, Andrei Malinovschi, Maija-Leena Eloranta

Uppsala University, Dept. of Medical Sciences, Uppsala, SWEDEN

Introduction: Activated type I interferon (IFN) system and autoantibodies are central in pathogenesis of SSc. However, the cellular response to endogenous stimuli such as RNA containing immune complexes has not been fully clarified in SSc. Herein, we studied IFN-α, -β and type III IFN (IL-28) induction by three Toll-like receptor (TLR) agonists in blood cells isolated from patients with SSc. We also investigated the IFN response in relation to pulmonary function.

Material and Methods: Forty-six patients fulfilling ACR/EULAR criteria for SSc (36 females and 10 males) visiting the rheumatology and clinical physiology clinics at Uppsala University Hospital were enrolled in the study.

Peripheral blood mononuclear cells (PBMC), PBMC depleted of CD14+ monocytes, and monocytes were isolated. The cells were stimulated with immune complexes consisting of U1 snRNP/Sm antigen and IgG containing anti-RNP/Sm autoantibodies (RNA-IC) or a RNA-oligonucleotide ORN8L targeting TLR7 and TLR8, respectively, or inactivated herpes simplex virus (HSV) sensed by TLR9. Cytokines were analyzed in the 20h cell cultures by immunoassays. Medium only did not induce any detectable levels of cytokines. Diffusing capacity of the lungs for carbon monoxide was measured.

Results: In PBMC, RNA-IC and ORN8L induced low amounts of IFN-α (median: 8 and 30 U/ml, respectively, p< 0.0001) and IFN-β (2.5 and 45 pg/ml, respectively), while HSV was a stronger IFN inducer (IFN-α: 1712 U/ml, IFN-β: 2085 pg/ml). When monocytes were removed from the PBMC, IFN-α production increased more than 50 times (p<0.0001) for the RNA-IC stimulated cells while only a low increase was detected with ORN8L (55 U/ml, p=0.04). As expected, monocytes synthesized only low levels of IFN-α (< 5 U/ml) with all three inducers.

Similarly, RNA-IC-induced IFN-β and IL-28 production increased when monocytes were depleted from the PBMC (p<0.001) whereas ORN8L triggered almost equal levels (~ 40 pg/ml) in all three cell fractions. The inhibitory effect of monocytes did not correlate with the proportion of monocytes or plasmacytoid dendritic cells among PBMC.

A weak inverse relationship was found between the diffusing capacity for carbon monoxide and RNA-IC-induced IFN-α levels (R2: 0.3, p<0.001).

Conclusions: RNA-containing IC mimicking the endogenous stimuli triggered IFN-α, -β and type III IFN in PBMC from patients with SSc, especially in absence of the monocytes. The weak but significant association between RNA-IC-induced IFN-α production and decreased lung function warrants further studies of IFN effects in SSc.

P.024

DETECTION OF EARLY PULMONARY ALTERATIONS IN THE IMU-COLV MICE MODEL

Vitória Elias Contini¹, Ana Paula Pereira Velosa¹, Zelita Aparecida de Jesus Queiroz¹, Sergio Catanozi³, Antonio dos Santos Filho¹, Sandra de Morais Fernezlian⁵, Lizandre Keren Ramos da Silveira¹, Thays de Matos Lobo¹, Camila Machado Baldavira⁵, Denise Frediane Barbeiro², Aritania Souza Santos⁴, Percival Degrava Sampaio-Barros¹, Vera Luiza Capelozzi⁵, Walcy Rosolia Teodoro¹

¹Division of Rheumatology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BRAZIL, ²Emergency Medicine Department, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BRAZIL, ³Division of Endocrinology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BRAZIL, ⁴Laboratory of Carbohydrates and radioimmunoassays-Lim18, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BRAZIL, ⁵Department of Pathology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BRAZIL

Introduction: Lung involvement is among the most serious complications associated with systemic sclerosis (SSc). Preclinical models are of great help in clarifying the pathogenesis and developing new therapies for this disease. The IMU-COLV model, induced by immunization with type V collagen (COLV), reproduces pulmonary and skin fibrosis, vasculopathy and immunological manifestations in C57BL6- mice. However, it is not known in what period these changes began in this model. The purpose of the present study was to evaluate early changes in lung tissue after immunization with COLV.

Material and Methods: The SSc model was induced in C57BL/6 mice (n=18) immunized with COLV emulsified in Freund's adjuvant (IMU-COLV). The animals were divided into: IMU-COLV-15, 30 and 45 days and the respective controls groups (n=18) were immunized with Freund's adjuvant and maintained for the same periods until euthanasia and lung tissue samples were collected. Imaging techniques such as histology, immunofluorescence, immunohistochemistry and quantitative techniques such as RT-qPCR and 4 -hydroxyproline were used to evaluate inflammatory infiltrate, total collagen content, expression of type I and V collagen and COL5α1 gene.

Results: The IMU-COLV 15-day group showed an intense inflammatory infiltrate, characterized by the presence of CD3, CD4 and CD8 T lymphocytes, when compared to the IMU-COLV-30 and 45 days groups. On the other hand, morphometric analysis of lung samples indicated an increase in type I collagen in the IM-COLV-45 days group, in relation to the IM-COLV 15 days and 30-days groups. Surprisingly, the amount of COLV was significantly higher in lung samples from the IM-COLV 45-days group compared to the IM-COLV 15 and 30-days groups. Furthermore, the IM-COLV 45-days group showed an increase in total collagen deposition when compared to the IMU-COLV 15 and 30-days groups (Table 1). Additionally, the expression of the Col5a1 gene was higher in the IMU-COLV 15-day group when compared to the control groups (p=0.017), and among the COLV 30-day group (p=0.008).

Conclusions: Our results indicate that the SSc model induced with COLV (IMU-COLV) presents inflammation and vascular reactivity in the initial phases of disease induction and activation of gene synthesis for the COLV α1 chain, and that this process evolves over time, resulting in fibrosis of the lung tissue after 45 days. The IMU-COLV mice model presents early changes in lung tissue, which will be of great value for studying the pathogenesis of lung involvement in SSc and new approaches for the early treatment of this disease.

P.025

EXPLORING MACROPHAGE RESPONSES IN SYSTEMIC SCLEROSIS: EXPERIMENTAL INSIGHTS AND THERAPEUTIC POTENTIAL OF VITAMIN D3 AND ALPHA-TOCOPHEROL ACETATE

Bohdana Doskaliuk, Liubomyr Zaiats, Roman Yatsyshyn

Ivano-Frankivsk National Medical University, Ivano-Frankivsk, UKRAINE

Introduction: Systemic sclerosis (SSc), a complex autoimmune disorder, manifests with extensive fibrosis and vascular abnormalities, impacting various organ systems. Emerging evidence suggests a pivotal role of macrophages in its pathogenesis, making them a crucial focus for understanding disease mechanisms and potential therapeutic interventions. The objective of our study was to investigate the morpho-functional alterations in macrophages during the experimental modeling of SSc and its correction using vitamin D3 (VD3) and alpha-tocopherol acetate (VE).

Material and Methods: We divided our experimental animals into three distinct groups: a control group (CG) consisting of 20 animals, an experimental group #1 (EG#1) with 25 animals, and an experimental group#2 (EG#2) also comprising 25 animals. These experimental subjects were mature laboratory rats of the Wistar lineage, weighing between 180 to 220 grams. In EG#1, SSc was induced by injecting sodium hypochlorite (NaClO), following a previously established protocol. Meanwhile, laboratory animals in the CG received isotonic solution injections following the same regimen. In the case of EG#2, rats underwent intramuscular injections of a VE solution at a dosage of 10 mg per 100 grams of body weight, and a VD3 solution at a dosage of 1000 IU per 100 grams of body weight for a duration of 3 weeks, specifically during the latter half of the experiment. All three groups of animals were removed from the experiment after 8 weeks from its initiation.

Results: Upon electron microscopic analysis, the control group exhibited normal cellular morphology. However, pronounced structural damage to macrophages was evident following SSc modeling in EG#1 (Figure 1). Macrophages within alveoli (1) displayed cytoplasm with low electron-optical density, which indicates swelling of the cell, severely distorted mitochondria lacking cristae (2), markedly expanded granular endoplasmic reticulum with scarce ribosomes (3), visible lysosomes (4) and phagosomes (5). In the case of EG#2, there was a trend toward improved cellular structure, although certain pathological changes persisted (Figure 2). Alveolar (1) macrophages exhibited a visible nucleus (2) and nucleolus (3), with the nuclear membrane displaying shallow invaginations and marginal chromatin granules. Mitochondria were notably enlarged (4), and endoplasmic reticulum tubules were mildly expanded (5). There were also lysosomes (6) and phagosomes (7) observed.

Conclusions: As a result of the use of vitamin D and alpha-tocopherol acetate, it was possible to achieve moderate positive changes in the structure of macrophages in comparison with animal samples from the systemic sclerosis modeling group.

P.026

PROPORTION OF TYPE V COLLAGEN MODULATES THE EVOLUTION OF SKIN FIBROSIS IN IMU-COLV MICE MODEL

Zelita Aparecida De Jesus Queiroz¹, Ana Paula Pereira Velosa¹, Vitória Elias Contini¹, Juliana Sampaio Silva², Sergio Catanozi³, Antonio dos Santos Filho¹, Sandra de Morais Fernezlian⁵, Lizandre Keren Ramos da Silveira¹, Thays de Matos Lobo¹, Solange Carrasco¹, Aritania Souza Santos⁴, Debora Levy², Vera Luiza Capelozzi⁵, Walcy Rosolia Teodoro¹

¹Division of Rheumatology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BRAZIL, ²Lipids, Oxidation and Cell Biology Team, Laboratory of Immunology, Heart Institute (InCor), Faculdade de Medicina da USP, São Paulo, BRAZIL, ³Division of Endocrinology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BRAZIL, ⁴Laboratory of Carbohydrates and radioimmunoassays-Lim18, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BRAZIL, ⁵Department of Pathology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BRAZIL

Introduction: Cutaneous fibrosis is the hallmark of systemic sclerosis (SSc). In this process, collagen V (ColV), who regulates the diameter of the heterotypic fibrils of collagen I and III, has the potential to become an autoantigen and associated with the pathogenesis of SSc. However, it is unknown whether ColV is involved in the progression of skin involvement and in the activation of healthy fibroblasts. We evaluated skin matrix changes during SSc model evolution, as well as the effect of ColV on normal fibroblast culture.

Material and Methods: Experimental SSc was induced in C57BL/6 mice (n=40) by immunization with ColV emulsified in Freunds adjuvant (IMU-ColV). Four animal’s groups were submitted to euthanasia at 15, 30, 45 and 120-days post-immunization. Histology, immunofluorescence, immunohistochemistry and histomorphometry were employed to evaluate the skin alteration. In addition, skin fibroblasts from normal mice were stimulated “in vitro” with 25μg, 50μg and 100μg of ColV to evaluate the collagen expression.

Results: The IMU-ColV groups showed skin thickening at 45 and 120 days (p=0.0001) and a significant increase of the Col III amount, as well as α-SMA at 120 days after induction (p<0.0001). Additionally, the IMU-ColV-45 and 120-days groups showed an intense increase in Col V compared to the other groups studied (p<0.0001). As for the expression of the Col3a1 gene, we observed a temporal increase between the IMU-ColV-15, 30, 45 and 120-days groups, in relation to their controls (p=0.0144). On the other hand, in the IMU-ColV-120-days group, the Col5a1 gene had its expression increased when compared to the IMU-ColV-30-day group (p=0.0068) and the control group (p=0.0005). Surprisingly, normal skin fibroblasts stimulated with Col V showed that this stimulus is dose dependent and that higher concentrations trigger greater expression of types III and V collagen (p<0.0001), and lower doses of Col V trigger greater expression of type I collagen and α-SMA (p=0.0279).

Conclusions: The cutaneous alterations in SSc model were progressive and more evident in the later stages of the disease. Furthermore, our data indicates that ColV proportion in cutaneous tissue modulates differential collagen expression in SSc model. This study suggests that ColV play a role in cellular signaling influencing cutaneous extracellular matrix remodeling and collagen fibrillogenesis in SSc.

P.027

EXTRACORPOREAL PHOTOPHERESIS PREVENTS INFLAMMATION AND FIBROSIS IN A MOUSE MODEL OF SYSTEMIC SCLEROSIS

Aurore Collet¹, Manel Jendoubi², Thomas Guerrier², Silvia Speca², Alexis Largy², Arnaud Lionet³, Sylvain Dubucquoi¹, David Launay⁴

¹Immunology institute, CHU Lille, Lille, FRANCE, ²INFINITE, unité Inserm 1286, Lille, FRANCE, ³Nephrology, CHU Lille, Lille, FRANCE, ⁴Internal Medicine department, CHU Lille, Lille, FRANCE

Introduction: Extracorporeal photopheresis (ECP) is an immunomodulatory procedure used in various auto-immune and fibrotic diseases. Systemic sclerosis (SSc) is a rare connective tissue auto-immune disease, characterized by progressive fibrosis of skin and internal organs, with no curative treatment. A few studies have assessed ECP in SSc with conflicting results, and mechanisms of action are unclear.

Our study assessed ECP efficiency in preventing fibrosis in a mouse model of SSc induced by hypochlorous acid (HOCl), and ECP impact on inflammatory and fibrosis biomarkers.

Material and Methods: Splenocytes of healthy mice were treated with 8MOP and then irradiated with UV-A.

Six-week-old BALB/c mice were randomized to control group (receiving daily PBS injections), HOCl group (receiving daily injections of 300 µL of HOCl), PBS + ECP group (receiving 10^7 irradiated splenocytes at day 0 and then daily PBS injections) or HOCl + ECP group (receiving 10^7 irradiated splenocytes at D0, and then daily HOCl injections); and sacrificed at D42. Skin histological sections were stained with Hematoxylin-Eosin and Picrosirius Red. Dermal thickness, collagen deposition and cell density were measured. Expression of markers of inflammation and fibrosis was assessed by RT-qPCR on skin samples.

Results: When compared to PBS at D42, HOCl injections were associated with skin fibrosis (increase of dermal thickness and collagen deposition). Dermal thickness and collagen deposition were significantly lower in the HOCl+ECP group than in the HOCl group (respectively: 149.6±7.0 microm vs. 296.7±24.5 microm, p<0.0001; and 35.8±1.3% vs. 53.7±3.1%, p=0.0003). Expression of genes associated with fibrosis was increased in HOCl mice compared to PBS mice. No difference in fibrosis gene expression was observed between HOCl and HOCl + ECP groups.

HOCl injections increased the cellular density compared to PBS mice, which was prevented by ECP (6087 cell/mm2 vs. 8539 cell/mm2 in the HOCl+ECP group vs. HOCl group respectively, p=0.0033). Expression of inflammatory mediators was upregulated in HOCl-treated mice compared to PBS mice. In the HOCl+ECP group, we found a significant decrease in mRNA expression of all these markers compared to the HOCl group, except for CCL2 whose expression did not change. This decrease was particularly marked for IL1bêta (9.7±4.0-fold vs. 117.1±51.1-fold in the HOCl+ECP group vs. HOCl group, p=0.0062) and TNFalpha (2.0 ± 1.1-fold vs. 8.8 ± 3.7-fold in the HOCl + ECP group vs. HOCl group, p=0.0155).

Conclusions: In a mouse model of SSc, a unique ECP cure can prevent the installation of inflammation and fibrosis, with a marked effect on skin inflammatory biomarkers.

P.028

MYOFIBROBLASTS IN SSC ARE A HETEROGENEOUS POPULATION WITH EPIGENETICALLY STABLE PHENOTYPE IN VITRO

Begoña Caballero-Ruiz¹, Rebecca Ross^1,2, Clarissa Corinaldesi¹, Christina Philippeos³, Fiona M. Watt³, Natalia Riobo-Del Galdo^4,5, Francesco Del Galdo^1,2

¹Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UNITED KINGDOM, ²NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals, NHS Trust, Chapel Allerton Hospital, leeds, UNITED KINGDOM, ³Kings College.Centre for Stem Cells & Regenerative Medicine ., London, UNITED KINGDOM, ⁴School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UNITED KINGDOM, ⁵Leeds Institute of Medical Research, Faculty of Medicine and Health, University of Leeds., Leeds, UNITED KINGDOM

Introduction: Most of the cellular and molecular biology knowledge acquired on the pro-inflammatory and profibrotic activation of dermal fibroblasts in Systemic Sclerosis (SSc) has derived from analysis of cellular function and RNA/protein expression of dermal fibroblasts sub-cultured from skin biopsies. The heterogeneity of the findings across fibroblast lines and over passages is a well acknowledged phenomenon in the field. Recent single cell Sequencing of SSc skin biopsies has offered a potential explanation to the heterogeneity by confirming the existence of distinct dermal fibroblasts “endotypes” with variable prevalence of specific population across patients and over time. Here we established stable cultures form single cell clones of SSc fibroblasts to characterize their function and inform next generation of cellular and molecular studies on these cells.

Material and Methods: Dermal fibroblasts from skin biopsies of Healthy (N=3) or Diffuse cutaneous SSc (N=3) patients were isolated, immortalized, and serially diluted to create single cell clone cell lines. RT-PCR and RNAseq was used to study differential transcriptomes and changes in protein levels (western blotting). In vitro phenotypic assays (collagen contraction, de-epidermised dermis (DED), proliferation assay) and endothelial co-cultured tubulogenesis assays.

Results: Firstly, we observed a highly heterogenous rate of proliferation across SSc. We selected 7 SSc clones with different proliferation rates and 3 “reference” HC clones for future analysis. Transcriptome analysis by RNAseq revealed that SSc clones clustered separately from healthy controls. The SSc cluster was driven by “classical” profibrotic genes including SFRP2, ACTA2, CNN2 confirming that the cloning procedure did not alter the biological signature of SSc fibroblasts. SSc clones showed overall increased protein levels of CCN2 and SMA as well as increased gel contraction ability compared to healthy controls. Similarly, at group level there was an overall decreased ability to sustain endothelial cell tubulogenesis in organotypic co-culture models. Nevertheless, SSc clones showed important differences in their transcriptome including OX40L, IL-6, SFRP2/4, COMP, THBS1 and LRG5. Interestingly the clones expressing high LRG5 expression were also the ones with smallest proliferation rate, supporting recent evidence form single cell RNA seq.

Conclusions: Here we show that the heterogeneity of dermal fibroblasts observed in scRNAseq is conserved following clonal expansion in vitro. Our novel approach can be exploited to dissect the dynamic changes in fibroblast populations observed within the natural history of SSc skin evolution and ultimately lead to identify appropriate targets to re-establish skin homeostasis or target specific fibroblast populations ultimately limiting toxicity of antifibrotic approaches.

P.029

MUTUAL AMPLIFICATION OF HEDGEHOG AND CJUN SIGNALING PROMOTE FIBROBLAST ACTIVATION IN SSC

Christina Bergmann¹, Sara Chenguiti Fakhouri¹, Honglin Zhu², Clara Dees¹, Benita Merlevede¹, Alexandru-Emil Matei³, Thuong Trin-Minh³, Andrea-Hermina Györfi³, Xiang Zhou³, Aline Bozec¹, Meik Kunz⁴, Oliver Distler⁵, Georg Schett¹, Jörg Distler³

¹Department Internal Medicine III, University Hospital, Erlangen, GERMANY, ²Department of Rheumatology and Immunology, Xiangya, CHINA, ³Department Rheumatology, University Hospital, Düsseldorf, GERMANY, ⁴Department Medical Informatics; Friedrich-Alexander Universität, Erlangen, GERMANY, ⁵Department Rheumatology, Universitätsspital Zürich, Zürich, SWITZERLAND

Introduction: Uncontrolled and persistent fibroblast activation is a central feature of fibrotic disorders such as Systemic Sclerosis (SSc). Dysregulation of TGFβ and Hedgehog signaling pathways is majorly involved in persistent fibroblast activation, but the consequence of their concomitant upregulation is currently unknown. Moreover, the crosstalk between individual TGFβ mediators and Hedgehog signaling in fibrosis is poorly understood. The reciprocal activation and amplification between the two pathways could be central to unregulated fibroblast activation. Identifying feedback loops between both pathways could therefore represent a way to recognize novel anti-fibrotic therapies.

Material and Methods: Interaction between cJUN and GLI2 was analyzed by confocal microscopy and by co-IP. cJUN/AP1 and GLI2 signaling were inhibited using T5224 and GANT61 respectively. Hedgehog signaling was activated in mice by fibroblast-specific overexpression of constitutively active Smoothened (SmoACT mice). The molecular mechanisms underlying the mutual regulation of AP1 and Hedgehog signaling were further investigated through ChIP Seq of GLI2 upon cJUN knockdown and overexpression in cultured fibroblasts, and vice versa.

Results: Expression profiling of all AP1 family members revealed most pronounced differences for cJUN in SmoACT mice. cJUN colocalized with the hedgehog transcription factor GLI2. Overexpression and colocalization of cJUN and GLI2 were also observed in fibroblasts in the skin of SSc patients. The number of GLI2- and cJUN double-positive fibroblasts was particularly high in involved SSc skin. The central role of the crosstalk between cJUN and GLI2 for tissue fibrosis was further highlighted by the finding that hedgehog-induced fibrosis was strongly reduced by AP1 inhibition. SmoACT mice developed extensive skin fibrosis. Treatment with the AP1 inhibitor T5224 strongly ameliorated hedgehog-induced fibrosis in SmoACT mice. Moreover, combined inhibition of AP1 and Hedgehog signaling exerted additive antifibrotic effects in a mouse model of TGFβ-driven fibrosis (TBRact mice). Specific knockdown of cJUN in cultured fibroblasts revealed concomitant downregulation of GLI2, and vice versa. Simultaneously, overexpression of cJUN resulted in an upregulation of GLI2, and a similar effect was observed on cJUN upon overexpression of GLI2.

Conclusions: Our study shows a mutual activation of AP1 and Hedgehog signaling, which amplifies fibroblast activation and tissue fibrosis. These profibrotic effects are mediated by direct interaction of cJUN and GLI2 in the nucleus. These findings could have a direct translational implication in combination therapies through combined inhibition of AP1 and Hedgehog signaling for the treatment of fibrosis.

P.030

ROLE OF THE RENIN-ANGIOTENSIN SYSTEM IN THE PATHOGENESIS OF SYSTEMIC SCLEROSIS

Miziolek Bartosz¹, Kucharz Eugene J², Bergler-Czop Beata¹, Pieczyrak Robert², Kotyla Przemyslaw²

¹Department of Dermatology, School of Medicine in Katowice, Medical University of Silesia, Katowice, POLAND, ²Department of Internal Medicine, Rheumatology and Clinical Immunology, School of Medicine in Katowice, Medical Universit, Katowice, POLAND

Introduction: Inhibitors of angiotensin-converting-enzyme comprise the first choice treatment option for scleroderma renal crisis (SRC) according to EULAR recommendations, but their prophylactic was found to be a risk factor for the occurrence of SRC. These drugs together with angiotensin-receptor blockers belong to the most commonly prescribed vasoactive agents in systemic sclerosis (SSc), although they neither help to control Raynaud’s phenomenon (RP) nor prevent from complications of generalized microvasculopathy. Plasma activity of ACE was found in 1990 to be reduced in patients with SSc but produced by the enzyme Ang II was showed later to be elevated in the serum of SSc patients with diffuse cutaneous involvement. Next study found however significantly reduced plasma of Ang II in SSc subjects but together with a depletion of circulating Ang-(1-7). Both substances are known to exert opposite effects in the cardiovascular system, and the balance between them is controlled by angiotensin-converting-enzyme 2 (ACE2). There raises the question about the role of the renin-angiotensin system in the pathogenesis of SSc.

Material and Methods: There were measured plasma levels of angiotensin II (Ang II) and angiotensin-(1-7) (Ang-1-7) in SSc patients, assayed presence of autoantibodies against ACE2 (anti-ACE2), and there was performed genetic testing to assess the associations between polymorphisms (rs879922, rs2285666, rs1978124) of the gene coding ACE2 and development of selected complications of SSc.

Results: Significantly reduced plasma level of Ang-(1-7) was found in SSc patients but Ang II remained intact, which produced unfavorable proportions of both angiotensins. Anti-ACE2 were detected only in a small percentage of SSc patients, but their presence correlated with plasma level of Ang-(1-7) under detection level. Allele C of rs879922 polymorphism was shown to be associated with the greater risk for development of arterial hypertension. A strong tendency to earlier onset of RP and SSc was seen in carriers od allele A of rs2285666 polymorphism, but these subjects had lower risk for development of any cardiovascular disease. Women with genotype AG of rs1978124 polymorphism had significantly more frequent digital tip ulcers and lower serum level of ACE2.

Conclusions: Unfavorable proportions of circulating Ang-(1-7) to Ang II is findable in SSc patients. Reduced plasma level of Ang-(1-7) could be in part due to anti-ACE2 or polymorphisms of the gene coding ACE2. Polymorphisms rs879922 and rs2285666 seem to account for primarily macrovascular disease in SSc patients, whereas rs1978124 may determine development of digital tip ulcers, which are complications of microvasculopathy.

P.031

CORDYCEPIN SUPPRESSES EXTRACELLULAR MATRIX AND ACTIN CYTOSKELETON ORGANISATION IN DERMAL FIBROBLASTS ACTIVATED BY TGF-B

Matija Bajzelj^1,4,5, Nika Bostic^1,6, Mateja Zotler², Andrej Gregori^2,3, Blaz Burja¹, Snezna Sodin-Semrl^1,4, Katja Lakota^1,4

¹University Medical Centre Ljubljana, Department of Rheumatology, Ljubljana, SLOVENIA, ²Mycomedica Ltd., Podkoren, SLOVENIA, ³University of Ljubljana, Biotechnical faculty, Ljubljana, SLOVENIA, ⁴University of Primorska, Faculty of Mathematics, Natural Sciences and Information Technologies, Koper, SLOVENIA, ⁵University of Ljubljana, Faculty of Medicine, Ljubljana, SLOVENIA, ⁶University of Ljubljana, Faculty of Pharmacy, Ljubljana, SLOVENIA

Introduction: Skin fibrosis plays a central role in systemic sclerosis (SSc) with dermal fibroblasts (DF) as the main effector cells. Current therapies are not effectively targeting fibroblasts. Cordycepin is an adenosine analogue identified as a major bioactive constituent in fungus C. militaris. Our aim was to investigate the effects of cordycepin on profibrotic processes in DF.

Material and Methods: Human DF from four different normal adult donors were cultured and treated with TGF-b (5 ng/ml) ± 30 µM cordycepin. Experiments were performed in 3 technical replicates. RNA sequencing was performed to identify differentially expressed genes and dysregulated biological processes in TGF-b activated fibroblasts after cordycepin treatment. Expression of pro-fibrotic mRNAs, such as COL1A1, a-smooth muscle actin (a-SMA) and fibronectin were analysed using qPCR. Protein levels of COL1A1, a-SMA and fibronectin were detected by Western blot. RealTime-Glo™ Annexin V Apoptosis and Necrosis Assay were used to measure apoptosis in reaFl-time.

Results: TGF-b activated DF treated with cordycepin showed an enrichment of down-regulated genes (757) in biological processes cell division, cytoskeleton organization and RNA as well as amino acids metabolism. Up-regulated genes (485) were enriched for the HDACs deacetylate histones pathway. Specifically, cordycepin down-regulated 51 genes (up-regulated by TGF-b treatment alone) were enriched in fibrosis-associated processes extracellular matrix organization (p-adj = 7.68 x 10-7) and actin cytoskeleton organization (p-adj = 2.47 x 10-2).

Suppressive effects of cordycepin on fibrotic processes were confirmed by analysing the expression of major pro-fibrotic markers. Cordycepin significantly decreased a-SMA mRNA expression levels (p=5.6x10-3, mean x-fold±SD TGFb+cordycepin 1.2±0.98 vs. TGFb 6.5±4.0) and protein levels (p=0.048, normalized O.D. TGFb+cordycepin 3.2±1.6 vs. TGFb 14±11), thus abrogating TGF-b-induced skin myofibroblast differentiation. Further, cordycepin significantly reduced the TGFB-driven production of ECM protein components, such as COL1A1 mRNA (p=2.8x10-3, x-fold TGFb+cordycepin 0.92±0.39 vs. TGFb 3.3±2.5) as well as fibronectin mRNA (p=8x10-4, x-fold TGFb+cordycepin 0.88±0.29 vs. TGFb 2.25±0.57) and protein levels (p=5.2x10-3, normalized O.D. TGFb+cordycepin 1.4±0.41 vs. TGFb 3.0±0.71) in DF. The utilized doses of cordycepin did not show any cytotoxic effects in DF.

Conclusions: Cordycepin inhibits pro-fibrotic gene signature and the major pro-fibrotic markers at the protein level in human DF, providing the rationale for its further investigation in 3D models and ex-vivo in living human skin explants. Hence, cordycepin has the potential to be an effective treatment option for halting the development of skin fibrosis in SSc.

P.032

BOSENTAN ACCELERATES DELAYED WOUND HEALING IN EPITHELIAL CELL-SPECIFIC FLI1 KNOCKOUT MICE BY RESTORING IMPAIRED REEPITHELIALIZATION

Jun Omatsu¹, Takehiro Takahashi^1,2, Takuya Miyagawa¹, Ryosuke Saigusa¹, Yuki Fukui¹, Satoshi Toyama¹, Kentaro Awaji¹, Ayumi Yoshizaki¹, Shinichi Sato¹, Yoshihide Asano^1,2

¹University of Tokyo Graduate School of Medicine, Tokyo, JAPAN, ²Tohoku University Graduate School of Medicine, Sendai, JAPAN

Introduction: Systemic sclerosis (SSc) is a multisystem autoimmune disease characterized by vasculopathy and fibrosis of the skin and various internal organs. Refractory and recurrent digital ulcers seriously affect the morbidity of this disease. Wound healing is a complex biological process mediated by the orchestrated interplay among inflammation, neovascularization, extracellular matrix (ECM) remodeling, and reepithelialization. So far, inflammation, neovascularization, and ECM remodeling have been well studied in animal models of SSc, but the nature of reepithelialization in the context of SSc has remained unknown. Under this situation, we have recently established a murine model of SSc, epithelial cell-specific Fli1 knockout mice (Fli1flox/flox; K14-Cre mice, Fli1 KcKO mice), recapitulating SSc-like phenotypes in epithelial cells. Therefore, we investigate whether keratinocytes with SSc-like features affect the process of wound healing using this animal model.

Material and Methods: For wound healing experiments, four full-thickness excisional wounds per mouse (Fli1 KcKO mice and control mice) were made using a disposable sterile 8-mm biopsy punch, and mice were caged individually. Some mice were administered bosentan intraperitoneally for 7 days after being wounded. Subcutaneous vascular network was visualized by FITC-dextran injection. The expression profiles of ECM remodeling- and angiogenesis-associated genes were determined by qRT-PCR. The activity of migration and proliferation of murine keratinocytes was assessed by trans-well migration assay and BrdU assay, respectively.

Results: Wound healing was markedly delayed in Fli1 KCKO mice compared with control mice. Histologic analyses revealed decelerated reepithelialization in Fli1 KcKO mice, while neovascularization in scar tissue evaluated by FITC-dextran injection was not altered. During wound healing, the expression of reepithelialization markers, such as epidermal growth factors and keratinocyte growth factors, was decreased in Fli1 KcKO mice, while fibrosis markers, such as CCN2, were upregulated. In vitro experiments demonstrated the decrease in migration and proliferation of Fli1-deficient keratinocytes. Of note, bosentan restored the decreased migration of Fli1-deficient keratinocytes in vitro, and delayed wound healing was restored in Fli1 KcKO mice by administration of bosentan.

Conclusions: These results indicate that wound healing is delayed in Fli1 KcKO mice due to dysregulated reepithelialization and ECM remodeling, and that bosentan-dependent acceleration of Fli1-deficient keratinocyte migration contributes to the restoration of delayed wound healing in Fli1 KcKO mice. In human SSc, bosentan may act on keratinocytes and accelerate the healing of microtrauma, contributing to preventing the development of new digital ulcers.

P.033

SYNCHROTRON-RADIATION BASED TOMOGRAPHY TO STUDY PULMONARY DAMAGE IN A MOUSE MODEL OF LUNG FIBROSIS

Silvia Agarbati¹, Chiara Paolini¹, Fiorenza Orlando², Michele Furlani³, Silvia Svegliati¹, Ada Funaro⁴, Mauro Provinciali², Alessandra Giuliani³, Gianluca Moroncini^{1, 5}

¹Marche Polytechnic University, Department of Clinical and Molecular Sciences, Ancona, ITALY, ²IRCCS INRCA, Experimental Animal Models for Aging Research, Scientific Technological Area, Ancona, ITALY, ³Marche Polytechnic University, Department of Specialistic and Odontostomatological Sciences, Ancona, ITALY, ⁴University of Turin, Department of Medical Sciences, Turin, ITALY, ⁵Marche University Hospital, Department of Internal Medicine, Ancona, ITALY

Introduction: Platelet Derived Growth Factor Receptor α (PDGFRα) is one of the targets of autoimmunity in systemic sclerosis (SSc). Human anti-PDGFRα antibodies cloned from memory B cells of SSc patients (HuPDGFRα mAbs) have previously shown to increase collagen gene transcription in healthy donor skin fibroblasts, and to induce fibrosis in human skin grafts in SCID mice. In order to verify if stimulation of PDGFRα by these autoantibodies can produce tissue fibrosis in vivo, we generated human PDGFRα-transgenic mice and exposed them to systemic transfer of HuPDGFRα mAbs.

Material and Methods: Full length human PDGFRα cDNA was knocked-in into the ubiquitously expressed Rosa26 locus on mouse chromosome 6. F2 heterozygous C57BL/6-hPDGFRα transgenic mice were used to establish the colony. On day 0 mice were subcutaneously implanted, under the back skin, with ALZET mini-osmotic pumps containing stimulatory HuPDGFRα mAbs VHPAM-Vκ16F4 or VHPAM-Vλ16F4, or a mixture of both; vehicle only administration control was included. On day 28 mice were sacrificed, and lung tissues were harvested for subsequent histological and molecular analyses. High-resolution tomography was performed at Synchrotron Radiation (SR) source (ELETTRA, Trieste, Italy) to investigate the mice lung 3D morphology and the alveolar physical density distribution in the retrieved biopsies.

Results: Continuous subcutaneous administration for 28 days of stimulatory HuPDGFRα mAbs VHPAM-Vκ16F4 or VHPAM-Vλ16F4 or a mixture of both in huPDGFRα-transgenic mice resulted in histological lung fibrosis, characterized by limited peribronchiolar/ perivascular collagen fiber deposition. 2D and 3D imaging and morphometric mapping obtained by synchrotron propagation-based phase-contrast microtomography of mouse lungs revealed increased deposition of collagen fibers around lung bronchioles and vasculature. In addition, this methodology highlighted a significant interstitial lung fibrosis, not well detectable in lung tissue staining, characterized by marked alveolar thickening, reduced alveolar space and augmented alveolar volume density in mouse treated with stimulatory antibodies compared to controls.

Conclusions: SR-based tomography allowed to investigate the mice lung 3D morphology and the alveolar physical density distribution in a novel humanized mouse model of lung fibrosis.

P.034

CHARACTERISING BLISTER MACROPHAGES IN SYSTEMIC SCLEROSIS

Sandra Lopez Garces¹, Anas Al-Oweidi¹, Tamara Searle¹, Henry Lopez^1,2, George Martin², Teresa Collins³, Jennifer Cross³, Christopher Denton¹, David Abraham¹, Richard Stratton¹

¹1UCL Centre for Rheumatology, UCL Division of Medicine, ²Riptide Bioscience Inc., ³Aurinia Pharmaceuticals Inc.

Introduction: In Systemic Sclerosis (SSc), macrophages drive inflammation and fibrosis by releasing signalling molecules. To advance beyond the simplified M1 vs. M2 dichotomy often used in vitro, our study aims to characterize monocytes and macrophages in SSc. We employ state-of-the-art single-cell RNA sequencing techniques to analyse SSc lesion-derived blister fluid, enabling us to gain a precise understanding of the heterogeneity and functional states of these cells. Concurrently, we investigate the in-situ localization of these cells within affected tissues through the examination of skin biopsies. Furthermore, we employ an in vitro disease model that closely mimics SSc conditions, allowing us to replicate key disease features and evaluate therapeutic inhibitors.

Materials and Methods: Lesional tissue fluid was derived by a suction blister method from the involved anterior forearm skin of SSc patients (n=5 diffuse cutaneous ATA positive) and healthy volunteers (n=4) and then profiled by 10X RNAseq. Downstream analyses were done using gProfiler for gene ontology and monocle3 for pseudotime analysis. SSc blood monocyte-derived macrophages were stimulated with 5% autologous patient plasma to model the disease environment. The expression of the M2 macrophage marker CD206 in SSc monocyte-derived macrophages was investigated by qPCR (n=5).

Results: We identified 13 distinct immune cell populations in blister fluid, including five monocyte/macrophage populations. Among these, two monocyte populations were observed: LYZ+CD14+ classical monocytes and FCGR3Adim intermediate monocytes. Additionally, we identified three CD163+ macrophage subsets: MS4A6A+ macrophages, NME1+PPP1R14B+FABP5 macrophages and SERPINB2+THBS1+CTSL+ macrophages. Our analysis using pseudo-time analysis further supports the classification of these cell populations, demonstrating a dynamic transition from monocytes to macrophages. Differential gene expression analysis revealed unique profiles characterizing pathogenic macrophages in SSc. Specifically, MSR1 was upregulated across all three monocyte/macrophage clusters, while ME2 was specifically upregulated in SSc macrophage clusters. Conversely, CCl2, MMP9, and FCN1 were downregulated in SSc macrophage clusters compared to healthy individuals. In our in vitro model, where autologous plasma was used to stimulate macrophages, we observed an increase in CD206 expression compared to unstimulated macrophages.

Discussion: Our analysis of blister fluid unveils distinct monocyte and macrophage subsets within blister fluid derived cell populations. This technique is minimally invasive and avoids harsh treatments required to extract immune cells from tissue samples. We investigate a novel in vitro method which increases CD206 expression and shows promise for evaluation of therapeutics. These findings advance our understanding of SSc, offering insights into immune dysregulation, potential biomarkers, and targeted interventions for further investigation.

P.035

PROGRESSION OF PULMONARY INVOLVEMENT ACCORDING TO THE AUTOANTIBODY PROFILE IN PATIENTS WITH LIMITED CUTANEOUS SYSTEMIC SCLEROSIS: A LONG-TERM FOLLOW-UP STUDY

Yasemin Yalcinkaya¹, Melodi Gizem Can², Busra Demir², Bahar Artim-Esen¹, Ahmet Gul¹, Murat Inanc¹

¹Istanbul University, Istanbul Medical Faculty, Internal Medicine, Rheumatology, Istanbul, TURKEY, ²Istanbul University, Istanbul Medical Faculty, Internal Medicine, Istanbul, TURKEY

Introduction: There is limited information on how the combination of antibodies other than anti-centromere (ACA) and limited cutaneous systemic sclerosis (lcSSc) will affect the distribution of future organ involvement and mortality.

Material and Methods: The medical records of with 155 limited cutaneous SSc (lcSSc)(145 females) were included into this retrospective analysis. The prevalence and progression of the interstitial lung disease(ILD) and pulmonary hypertension(PH) in patients with lcSSc according to the presence of antibodies (ANA only vs anti-scl70 vs ACA) were evaluated.

Results: Mean age, duration of Raynaud’s and non-Raynaud’s were 54.2(±12.5), 15.7(±11.2) and 12.8(±7.5) years, in 155 lcSSc patients with a mean follow-up of 96.2(±68.8) months. ANA was detected in 49 (31.6%) (patterns of speckled in 42.9%, nucleolar in 10.2%, homogeneous in 16.3%, nucleolar + speckled or +homogenous in 18.4%, undefined in 12.3%), anti-Scl70 in 62(40%), and ACA in 44(28.4%). Twenty-five patients (16.1%) progressed to dcSSc during the follow-up in 33.4(±49.5) of months. LcSSc patients with anti-Scl70 more frequently progressed to dcSSc (22 vs 14.3 and 9.1% for ANA and ACA groups). ACA(+)’s less frequently received immune-suppressives (43.2 vs 89.8 and 85.5%, p=0.002). ACA(+) patients who progressed to dcSSc had more frequent initial and cumulative ILD when compared to those did not progressed (p= 0.036 and p=0.032).

The frequency of initial and cumulative ILD or worsening ILD was highest in anti-Scl70(+)’s followed by ANA(+)’s and then ACA(+)’s (p=0.003 and p=0.005 or p=0.02, respectively) in lcSSc patients who were not progressed to dcSSc. Although not significant the progression of ILD took longer to occur in ACA(+)’s (med 118 vs 47 and 69 months). Cumulative PH groups were as follows; PAH in 4 patients with ACA(lcSSc), group 3-PH in 2 patients with ANA only (lcSSc), 5 patients with anti-scl70 (n=3, dcSSc) and 3 with ACA (lcSSc)(table-1). ANA(+) 4 patients (at 36., 39.,48., and 120. months), anti-Scl70(+) one patient (at 235. month) and ACA(+) one patient (at 132.month) deceased during the follow-up period.

Conclusions: LcSSc patients with anti-Scl70, tended to progress to dcSSc more frequently. Progression to dcSSc was associated with higher frequency of ILD in ACA(+) patients. Anti-Scl70 or ANA positivity was associated with a higher frequency ILD and progression compared to ACA positivity. Grup 1 PH was diagnosed only in ACA(+)’s, group3-PH was seen in all autoantibody groups. In lcSSc, mostly autoantibodies determine the course of the disease; the potential for progression to dcSSc and major organ involvement should be monitored in high risk patients.

P.036

CLINICAL FEATURES OF PATIENTS WITH SYSTEMIC SCLEROSIS POSITIVE FOR ANTI-SS-A ANTIBODY: A COHORT STUDY OF 156 PATIENTS

Tomoya Watanabe¹, Yasushi Ototake¹, Asami Akita¹, Mao Suzuki¹, Miwa Kanaoka¹, Jun Tamura², Yusuke Saigusa², Yukie Yamaguchi¹

¹Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama, JAPAN, ²Department of Biostatistics, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, JAPAN

Introduction: Anti-SS-A/Ro antibody (SSA), well known as the diagnostic marker of Sjögren's syndrome (SS), is often detected in systemic sclerosis (SSc). Some patients are diagnosed as SSc/SS overlap syndromes, while there are SSA-positive SSc without SS. Since the clinical significance of SSA in SSc remains unclear, therefore we retrospectively analysed patients with SSc to define the clinical characteristics of SSc with SSA and clarify the clinical impact of this antibody.

Material and Methods: Retrospective chart reviews were performed of 156 patients with SSc at Yokohama City University Hospital from 2018 to 2021.

Results: The cohort consisted of 18 males and 138 females, and the median age was 69.0 years. Thirty-nine patients (25.0%) were classified as dcSSc and 117 patients (75.0%) as lcSSc. Anti-centromere antibody was positive for 72 patients (46.1%); anti-topoisomerase I antibody for 27 (17.3%); anti-RNA polymerases III antibody and anti-U1RNP antibody for 14 (9.0%), respectively. Forty-four patients (28.1%) were positive for SSA. Among them, 24 patients (15.4%) fulfilled the criteria for SS. SSA-positive SSc group was significantly more common in females (P = 0.024). The proportion of patients with interstitial lung disease (ILD) (P = 0.020), digital ulcer (DU) (P = 0.011), and gastroesophageal reflux disease (GERD) (P = 0.012) in SSA positive group were higher than those in SSA-negative group. Multivariable logistic regression revealed that SSA was statistically associated with interstitial lung disease (OR=2.67; 95% CI, 1.14-6.3; P = 0.024). Meanwhile, the development of digital ulcer (OR = 2.18; 95% CI, 0.99-4.82, P = 0.054) was also non-significantly increased by SSA. In multivariate analysis in the autoantibody single-positive group and SSA/SSs-specific autoantibody double-positive group, SSA single positive group was significantly increased the risk of the development of ILD (OR = 12.1; 95% CI, 2.13-140.57; P = 0.003). Furthermore, multivariate analysis of 44 patients with SSc and SSA indicated that SSA-positive SSc without SS was strongly associated with dcSSc proportion compared to that in those with SS (OR = 6.45; 95% CI, 1.23-32.60; P = 0.024).

Conclusions: SSA positivity increases the risk of organ involvement, such as ILD in patients with SSc. Additionally, the SSA-positive SSc without SS population may have more severe skin fibrosis compared to those with SS. SSA may be a potential marker of ILD and skin severity in SSc.

P.037

AUTOANTIBODIES TO EIF2B IDENTIFY A SUBSET OF SSC PATIENTS WITH HIGH MORBIDITY AND MORTALITY

Antonio Tonutti^1,2, Francesca Motta^1,2, Angela Ceribelli^1,2, Natasa Isailovic², Carlo Selmi^1,2, Maria De Santis^1,2

¹Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, ITALY, ²Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Rozzano, ITALY

Introduction: The heterogeneity of systemic sclerosis (SSc) is largely attributable to the presence of specific serum autoantibodies; reactivities against the eukaryotic initiation factor 2b (eIF2b) have been recently linked to the diffuse cutaneous phenotype (dcSSc) and interstitial lung disease (ILD).

Material and Methods: A retrospective analysis was conducted on our cohort of patients with SSc. Demographic and clinical data were extracted from electronic health records. An extensive serum autoantibody profile was established through RNA/protein immunoprecipitation, ELISA, and immunoblots, encompassing antibodies to centromere proteins (ACA), topoisomerase I (Scl-70), RNA polymerase III (RNAP3), Ro52/TRIM21, Ro60, La, U1-RNP, Ku, PM/Scl, Th/To, NOR90, U3-RNP, E2/E3 pyruvate dehydrogenase, and eIF2b. Antiphospholipid antibody (aPL) positivity was defined as the presence of LAC, anticardiolipin, and/or anti-beta2-glycoprotein I in at least two separate determinations.

Results: A total of 289 SSc patients were included in the study, including 42 (14.5%) subjects with dcSSc, 96 (33.2%) with ILD, 41 (14.2%) with myocardial involvement, 34 (11.8%) with pulmonary arterial hypertension, and 118 (40.8%) with gastrointestinal disease. The serum autoantibody profile comprised ACA in 161 (55.7%), anti-Scl-70 in 68 (23.5%), and anti-RNAP3 in 27 (9.3%), while 6 (2.1%) patients tested negative for all analyzed antibodies. Eleven (3.8%) individuals tested positive for anti-eIF2b: in two cases as the sole serum specificity, in 2 together with ACA, in 5 with anti-Scl-70, in 2 with anti-Ro52, in 1 with anti-RNAP3, in 1 with anti-E2/E3-PDH, in 1 with anti-NOR90, in 1 with anti-Th/To, and in 2 with aPL (2/11 [18.2%] vs. 10/278 [3.6%]; p=0.017).

Patients with anti-eIF2b had a significantly higher prevalence of dcSSc (4/11 [36.4%] vs. 38/278 [13.7%]; p=0.036) and ILD (10/11 [90.9%] vs. 86/278 [30.9%]; p<0.001). No differences were observed concerning other clinical features or comorbidities. Over a median observation period of 6 (IQR 3-13) years (2800 patient-years), considering death for any cause, a lower survival was observed in patients with anti-eIF2b (7/11 alive [63.6%]) compared to the other patients (254/278 alive [91.4%]; p=0.002). Multivariable analysis revealed that anti-eIF2b and anti-Scl-70 were independent predictors of ILD, while only anti-Scl-70 antibodies predicted dcSSc.

Conclusions: Serum autoantibodies targeting eIF2b identify a subset of patients with SSc with high morbidity, i.e. higher prevalence of dcSSc and ILD, and mortality. Anti-eIF2b often co-occur with anti-Scl-70 but not ACA. The elevated prevalence of aPL in patients with anti-eIF2b-positive SSc warrants further characterization.

P.038

CLINICAL AND SEROLOGICAL CHARACTERISTICS OF PATIENTS WITH SYSTEMIC SCLEROSIS AND CANCER

Antonio Tonutti^1,2, Francesca Motta^1,2, Angela Ceribelli^1,2, Natasa Isailovic², Carlo Selmi^1,2, Maria De Santis^1,2

¹Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, ITALY, ²Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Rozzano, ITALY

Introduction: There is an increased incidence of malignancy in patients with systemic sclerosis (SSc), and established risk factors include serum anti-RNA polymerase III (RNAP3) antibodies, longstanding disease, and interstitial lung disease (ILD).

Material and Methods: A retrospective analysis was performed on a cohort of 290 patients with SSc with a median follow-up of 6 years (interquartile range 3-13), 2800 patient-years. Serum autoantibody profile was established through RNA/protein immunoprecipitation, ELISA, and immunoblots, encompassing antibodies to centromere proteins (ACA), topoisomerase I (Scl-70), RNAP3, Ro52/TRIM21, Ro60, La, U1-RNP, Ku, PM/Scl, Th/To, NOR90, U3-RNP, E2/E3 pyruvate dehydrogenase, and eIF2b. Cancer-associated scleroderma was defined if the diagnosis of SSc occurred within 3 years from malignancy.

Results: Cancer was diagnosed in 59/290 (20.3%) SSc patients, with cancer-associated scleroderma representing 23/290 (7.9%) cases, spanning over 2,800 patient-years. Breast (22/59, 37.3%), lung (8/59, 13.6%), and hematologic (7/59, 11.9%; including both myeloid and lymphoid) malignancies were the most prevalent neoplasms. Older age at diagnosis correlated with both the overall cancer risk (59±14 vs. 52±16 years; p=0.007) and cancer-associated scleroderma (62±14; p=0.006). When compared to patients without cancer, the clinical presentation did not differ, considering both the overall cancer and cancer-associated scleroderma subgroups; a trend towards an association between overall cancer risk and diffuse SSc was observed.

Serum positivity for anti-Ro52 was associated with an increased risk of both overall cancer and cancer-associated scleroderma. When considering patients with isolated anti-Ro52 antibodies, they had a higher risk of cancer-associated SSc. In our cohort, anti-RNAP3 (27/290, 9.3%) antibodies were not associated with cancer risk; however, patients with anti-RNAP3 as the sole serum positivity had a significantly higher risk of cancer (6/6, 100%) compared to patients with concurrent other autoantibody positivity (11/21, 52.4%; p=0.033). Anti-U3-RNP antibodies were significantly associated with the risk of both overall cancer and cancer-associated scleroderma, though rarely detected. There was a trend towards a negative association between anti-Scl-70 antibodies and the overall risk of cancer, although it did not reach statistical significance.

Conclusions: Advanced age at the onset of SSc is associated with an overall increased risk of cancer and cancer-associated scleroderma. Anti-Ro52 antibodies serve as predictors of cancer in SSc patients, particularly when they co-occur with other autoantibodies. Our findings indicate that anti-RNAP3 antibodies are linked to cancer risk when detected as the sole specificity.

P.039

CANCER IN SYSTEMIC SCLEROSIS: ASSOCIATION BETWEEN ANTIBODIES AND MALIGNANCY AND RESULTS FROM A THIRD-LEVEL CENTER

Cristiana Sieiro Santos¹, Ruben Rego Salgueiro², Clara Moriano Morales¹, Ismael Gonzãlez Fernãndez¹, Carolina Ãlvarez Castro¹, Elvira Dãez Ãlvarez¹

¹Complejo Asistencial Universitario de León, León, SPAIN, ²ULS Guarda, Guarda, PORTUGAL

Introduction: Systemic sclerosis (SSc) is associated with increased risk of malignancy. Risk factors predisposing a SSc patient for development of malignancy are not well defined, and the pathogenic basis of the association is yet to be explained. Some autoantibodies have been associated with a close temporal relationship with cancer. The absence of malignancy screening guidelines tailored for SSc patients raise the importance of the need for more studies on the association of SSc and cancer.

Material and Methods: To study the prevalence of cancer in SSc and the association between SSc-specific and SSc-associated autoantibodies and cancer in a third-level center.

Results: We conducted a retrospective cohort study by including patients diagnosed with SSc followed from 1980 to 2020 fulfilling the 2013 ACR/EULAR SSc criteria. Demographic features, clinical and immunological characteristics were retrieved. The primary outcome was cancer-associated SSc, defined as cancer occurring within 2, 3 and 5 years of first non-Raynaud SSc manifestation. The exposure was defined by the presence of SSc-specific/associated autoantibodies, including anti-centromere (ACA), topoisomerase I (Scl70), RNA polymerase III, fibrillarin, Th/To, PM-Scl, Ku, TIF1g, Ro52. Descriptive analysis was used to compare clinical characteristics of subjects with cancer to those without cancer. Univariate logistic regression was used to compare the odds of cancer-associated SSc between the autoantibody subgroups.

Conclusions: Out of 103 SSc subjects, 27 (26%) had a history of cancer following SSc diagnosis. Mean age was 61.9 (57-69) years, 70% were female and 88% had a smoking history. Median time between cancer and disease onset was 6.33 (3-9) years. Among patients with cancer, 12 (44%), 8 (29%) and 7 (26%) were diagnosed within 2, 5 and 10 years of SSc onset. The most frequent types were breast cancer (n=9), gastrointestinal cancer (n=5), prostatic cancer (n=4), hematological (n=3) cancers, cervical/uterine cancers (n=2), non-melanoma skin (n=2), lung cancer (n=2). Patients with cancer were more likely to be Sc70+(p 0.04), anti-TIF1g (p 0.001) and RNA pol III (p 0.04), have a history of smoking (p 0.001), myositis (p 0.005) and older age at SSc onset (p 0.04). Breast cancer was more frequent in anti-TIF1g and RNA pol-III subgroups. The risk of cancer-associated SSc was significantly increased among anti-TIF1g-positive subjects at 5 years after SSc onset (OR 2.1 CI 95% (1.45-9.94), p 0.04) and among RNA-pol III-positive subjects at 2 years after SSc onset (OR 3.5 95% CI (1.2-51.4), p 0.02).

P.040

CLINICAL PHENOTYPE IN SCLERODERMA PATIENTS WITH LIMITED AND DIFFUSE CUTANEOUS DISEASE BASED ON AUTOIMMUNITY

Cristiana Sieiro Santos, Miriam Retuerto Guerrero, Clara Moriano, Ismael Gonzalez Fernandez, Carolina Ãlvarez Castro, Elvira Dãez Ãlvarez

Complejo Asistencial Universitario de León, León, SPAIN

Introduction: Patients with lcSSc and Sc70 antibodies draw particular attention, which is why characterization of clinical phenotypes can help distinguish patient subgroups and assessing the prognosis of the disease. We aimed to characterize the clinical phenotype of patients with SSc based on autoantibodies (ACA, Scl70, ANA).

Material and Methods: We included patients with SSc who fulfilled the 2013 ACR/EULAR criteria, with disease duration of less than 15 years. Six groups of patients were defined: ACA-lcSSC, Scl-70-lcSSc, ANA-lcSSc, Scl-70-dcSSc, ANA-dcSSc and ACA-dcSSc patients. We compared the different groups of patients. In the ANA subgroup, we included patients negative for SSc-specific antibodies (Scl-70 and ACA). We assessed the following: risk of interstitial lung disease (ILD), myositis, scleroderma renal crisis, cardiac involvement, gastrointestinal involvement, pulmonary hypertension, treatment, cancer and all-cause mortality.

Results: One hundred and thirteen SSc patients were included: 72 (64%) females, 82 (73%) lcSSc and 31 (27%) dcSSc. Among patients with lcSSc, 43 (52%) were ACA+, 16 (19%) Scl-70+ and 23 (28%) ANA+, and among patients with dcSSc, 13 (42%) patients were Scl-70+, 11 (35%) ANA+ and 7 (23%) ACA+. Scl-70-lcSSc patients had a significantly shorter time from RP to SSc diagnosis (P=0.04), higher CRP (P=0.04), renal scleroderma crisis (P=0.02), ILD (P=0.03) and diastolic dysfunction (P=0.04) than ANA-lcSSc patients. Scl-70-dcSSc patients had a higher rate of myositis (P=0.04), renal crisis (P=0.03), CRP elevation (P=0.002), ILD (P=0.04), pericardial effusion (P=0.03) and cancer (P=0.04) than ANA-dcSSc patients. The risk of ILD was higher in Scl-70 patients during the first ten years than in ACA+ and ANA+ patients (P=0.03 and P=0.02, respectively). The risk of major organ involvement was higher in Scl-70+ patients, followed by ANA+ and ACA+ patients, throughout 15years of follow-up. All-cause mortality was higher in dcSSc patients than in lcSSc patients, but no differences were found regarding antibody positivity

Conclusions: We have characterized the clinical phenotype of patients based on autoantibodies: Scl-70 patients show the greatest risk of major organ involvement, followed by ANA+ patients and ACA+ patients. The risk of ILD in Scl-70+ patients suggests that these patients should be monitored closely, irrespective of skin involvement. These results might provide new ways to help with the early diagnosis and management and in assessment of the prognosis of the disease.

P.041

ASSOCIATION OF ANTI-MUSCARINIC 3 ANTIBODY WITH GASTROINTESTINAL DISEASE IN SYSTEMIC SCLEROSIS

Elen Roblin¹, Claire Beesley¹, Rory Maclean¹, Fiza Ahmed¹, Charles Murray², Voon Ong¹, Christopher Denton¹

¹Centre for Rheumatology, Division of Medicine, University College London, Royal Free Campus, London, UNITED KINGDOM, ²Department for Gastroenterology, Royal Free London Hospital, London, UNITED KINGDOM

Introduction: Gastrointestinal (GI) complications of systemic sclerosis (SSc) are frequent and debilitating with symptoms ranging from reflux to faecal soilage. The pathogenesis of GI disease in SSc is poorly understood. Circulating antibodies against Muscarinic type 3 Receptors (anti-M3R) have been implicated in GI smooth muscle dysfunction and neural activation impairment. We examine whether anti-M3R antibodies associate with objective measures of gastrointestinal symptoms.

Material and Methods: Sera were collected from SSc patients fulfilling the American College of Rheumatology (ACR) classification criteria for SSc. Healthy control (HC) sera were obtained from age-matched volunteers. SSc patients completed the UCLA GIT 2.0 (UCLA GIT) questionnaire. Serum anti-M3R antibodies were measured using specific enzyme-linked immunosorbent assay (ELISA)(CellTrend GmbH, Germany). SSc sera had elevated anti-M3R antibodies if the concentration exceeded two standard deviations above the mean of HC sera. Statistical comparisons were made using Fisher’s exact test and two sample t-test.

Results: Sera from 40 SSc patients and 5 HC were assayed for anti-M3R antibodies (Figure 1). Anti-M3R antibody was higher in SSc patients in comparison to HC (1547 vs 1183, p=0.33). Anti-M3R antibody levels were significantly elevated in 9 (23%) SSc patients. Cohort characteristics were compared based on anti-M3R antibody levels for SSc patients (Table 1). Group demographics were similar in gender, age and disease duration. There was a trend for higher anti-M3R antibodies in limited compared with diffuse cutaneous SSc subset (66.7 vs 32.2, p=0.12). Although there was no significant association between Anti-M3R antibody level and GIT score (r=0.014 p=0.51), SSc patients with elevated anti-M3R antibody did report numerically more severe reflux symptoms (1.24 vs 0.8, p=0.23) and fewer lower GI domains of severe soilage (0.56 vs 0.87, p=0.37) and constipation (0.28 vs 0.52, p=0.2).

Conclusions: These results show that there is a subset of SSc patients with elevated anti-M3R antibodies which could be pathogenic by perturbing cholinergic neurotransmission in the GI tract. The trend observed of elevated anti-M3R antibodies with more severe GI symptoms warrants further exploration in a larger cohort of SSc. If confirmed, our findings provide mechanistic rationale for reported benefit from intravenous immunoglobulin on symptom severity in SSc GI disease.

P.042

POLYAUTOIMMUNITY AND MULTIPLE AUTOIMMUNE SYNDROME IN SYSTEMIC SCLEROSIS

Miriam Retuerto, Clara Moriano, Cristiana Sieiro, Elvira Diez

Complejo Asistencial Universitario de León, Rheumatology, Leon, SPAIN

Introduction: Polyautoimmunity (PA) is defined as the presence of more than one well-defined autoimmune disease (AD) in a single patient. When three or more autoimmune diseases coexist, this condition is called multiple autoimmune syndrome (MAS). Polyauto-immunity is not well characterized in systemic sclerosis (SSc). We aim to describe the prevalence of polyautoimmunity and the multiple autoimmune syndrome in a Spanish cohort of patients with systemic sclerosis.

Material and Methods: Observational, analytical and cross-sectional monocenter study. We included 92 patients with diagnosis of SSc according to modified ACR-EULAR 2013 criteria. Demo-graphic, clinical and immunological data were collected. Continuous variables were com-pared by Student’s or Mann Whitney’s T test, and categorical variables by Chi2 test or Fisher’s exact test.

Results: The study population comprised 92 patients with SSc (73% female) with a mean age at inclusion of 65±13.6 years (Table 1). Polyautoimmunity was present in 44 patients (48%) and Multiple autoimmune syndrome was present in 15 patients (16%). The most fre-quent rheumatics ADs were Sjögren syndrome (21/44) and Systemic lupus erythematosus (8/44); the most frequent non-rheumatic ADs were Primary biliary cirrhosis (4/44) and Li-chen planus (4/44) (Table 2). The factors associated with polyautoimmunity were the treat-ment with antimalarias (p=0.004) and the number of antibodies (p=0.000). The subjects with MAS have higher rates of anti-SSA than total of patients with PA (p=0.02). Polyauto-immunity does not increase the risk of cancer.

Conclusions: In our cohort SSc patients associated PA in 48% and MAS in 16%. More studies are needed to better understand the increase of polyautoimmunity in these patients.

P.043

A RARE CASE OF ACANTHOSIS NIGRICANS ASSOCIATED WITH DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS

Carolina Ochôa Matos^1,2, Eduardo Dourado^3,4, Cláudia Brazão⁵, Pedro de Vasconcelos⁶, Luís Soares de Almeida^5,6, Nikita Khmelinskii^1,2, Sofia C. Barreira^1,2

¹Centro Hospitalar Universitário Lisboa Norte, Centro Académico de Medicina de Lisboa - Department of Rheumatology, Lisboa, PORTUGAL, ²Instituto de Medicina Molecular João Lobo Antunes, Centro Académico de Medicina de Lisboa - Rheumatology Research Unit, Lisboa, PORTUGAL, ³Centro Hospitalar do Baixo Vouga - Department of Rheumatology, Aveiro, PORTUGAL, ⁴Aveiro Rheumatology Research Centre, Egas Moniz Health Alliance, Aveiro, PORTUGAL, ⁵Centro Hospitalar Universitário Lisboa Norte, Centro Académico de Medicina de Lisboa - Department of Dermatology, Lisboa, PORTUGAL, ⁶Centro Hospitalar Universitário Lisboa Norte, Centro Académico de Medicina de Lisboa - Dermatopathology Laboratory, Lisboa, PORTUGAL

Introduction: Acanthosis nigricans (AN) is a dermatosis characterised by velvety, dark-brown, hyperkeratotic plaques, most commonly in intertriginous areas. AN is often linked with endocrine disorders or can appear as a paraneoplastic sign. It is rarely found in autoimmune diseases, usually associated with anti-insulin receptor antibodies (IRAb). We report a case of AN in a patient with diffuse cutaneous systemic sclerosis (dcSSc), showing no signs of insulin resistance or cancer.

Material and Methods: A 55-year-old man of Indian descent presented to the outpatient clinic with a four-month history of abrupt-onset Raynaud’s phenomenon, darkening and thickening of the skin, inflammatory polyarthralgia with joint swelling, nausea, vomiting, abdominal distension, diarrhoea, night sweats, occasional fever spikes, and weight loss of 27 Kg. On examination, hyperpigmented velvety plaques were observed on the face (sparing the malar region), axillae (Figure 1-A), lower abdominal and inguinal area and ankles. These findings were consistent with AN. Additionally, there was mild sclerodactyly extending to the metacarpophalangeal joints, with a modified Rodnan skin score (mRSS) of 2/51.

Results: Laboratory testing results were notable for microcytic, hypochromic anaemia (Hb 12.5 g/dL), elevated erythrocyte sedimentation rate (77 mm/h) and C-reactive protein (1.21 mg/dL), and positivity for antinuclear antibodies (titre 1:160, AC-4 pattern), anti-Ro52 and anti-PL-7 (strongly positive by immunoblot) antibodies. Blood glucose and fasting serum insulin levels were normal. The body computed tomography (CT) scan showed a non-specific interstitial pneumonia pattern and axillary, mediastinal, and hilar lymphadenopathies. Upper endoscopy revealed chronic non-atrophic antral gastritis, positive for Helicobacter pylori. A biopsy of an axillary lymph node and a positron emission tomography scan had no evidence of malignancy. Lung function tests revealed a restrictive lung pattern. Oesophageal manometry showed absent oesophageal contractility. Capillaroscopy revealed a “scleroderma-like” pattern. In the first months of follow-up, the skin thickening progressed (maximum mRSS of 23/51), and dcSSc was diagnosed. Mycophenolate mofetil, hydroxychloroquine, and vasodilators were started with clinical improvement. Nine months later, dark skin pigmentation markedly faded, especially on the axillae (Figure 1-B), and skin thickening improved (mRSS of 16/51). A skin biopsy confirmed AN (Figure 1-C).

Conclusions: The association of AN and SSc has seldom been reported in the literature. Two previous reports described AN in SSc patients with metastatic gastric adenocarcinoma and diabetes mellitus with IRAb. Two additional reports described AN as the initial manifestation of SSc without evidence of malignancy or metabolic disease, as in this case. Furthermore, as seen in patients with IRAb, AN improved with immunosuppressive treatment.

P.044

CLINICAL FEATURES OF ROMANIAN SYSTEMIC SCLEROSIS (SSC) PATIENTS NEGATIVE FOR SSC – SPECIFIC AUTOANTIBODIES: A SINGLE CENTER RETROSPECTIVE STUDY

Cristina Nita¹, Laura Groseanu^1,2, Delia Nicoara¹, Denisa Predeteanu^1,2, Violeta Bojinca^1,2, Daniela Opris^1,2, Florian Berghea^1,2, Violeta Vlad¹, Mihai Abobului^1,2, Madalina Duna¹, Magadalena Negru^1,2, Andreea Borangiu^1,2, Ioana Saulescu^1,2, Sanziana Daia^1,2, Cosmin Constantinescu^1,2, Claudia Cobilinschi^1,2, Denise Mardale^1,2, Diana Mazilu^1,2, Andra Balanescu^1,2

¹Department of Internal Medicine and Rheumatology, Bucharest, ROMANIA, ²University of Medicine and Pharmacy Carol Davila, Bucharest, ROMANIA

Introduction: Whereas the clinical features of patients with systemic sclerosis (SSc) – specific antinuclear antibodies (ANAs) have been extensively examined, litlle is known about autoantibodies (autoAbs) negative subjects. The objectives of this study were first, to determine the prevalence of negative SSc – related autoAbs, and second, to describe the clinical and serologic correlations of this SSc subgroup by determining their clinical and demographic differences compared to SSc – related autoAbs positive patients.

Material and Methods: Serum samples were collected from 270 SSc patients. Our study was designed to characterise the clinical and serological profiles of SSc subjects without specific autoAbs detected by a battery of commercially available kits, namely anti-centromere, anti-topoisomerase I, anti-RNA polymerase III, as well as anti-U3RNP, anti-Th/To, anti-NOR 90, and anti PM/Scl antibodies. In consequence, not all patients in the study were screened for other scleroderma associated ANAs. Demographic and clinical features, symptoms and parameters related to a specific organ involvement according to MEDS evaluation sheets and survival were evaluated.

Results: SSc – related autoAbs were tested in 270 patients, of whom 32 (12%) were negative for specific autoAb. The group comprised 27 females and 5 males, with a mean age of 59.7 (±14.3) years, most of them with diffuse subset (25/32). SSc-related autoAbs negative patients had significantly a longer disease duration (6 [0.1-50] vs 2 [0.1-25] years, P < .001). The presence of Raynaud’s phenomenon tended to be less common (71.8% vs 99.8%, p<0.001) in the seronegative patients. Moreover, they experienced markedly fewer digital ulcerations (18.0% vs 72.6%, p=0.001). Some critical organ involvement, including gastroesophageal reflux (5.6% vs 18.5%, p=0.002), interstitial lung disease (65.2% vs 77.9%) and pulmonary arterial hypertension (11.5% vs 29.0%), occured at lower rates in seronegative patients, but we didn’t find a statistically significant difference between the two groups. No differences in mortality were found between the groups.

Conclusions: SSc – specific autoAbs negative had generally less organ involvement than positive subjects (including skin, oesophageal, lung, muscle and joint disease). Absence of SSc – specific autoAbs in the serum identify a subgroup of patients with milder course of the disease. Whether the absence of detectable autoAbs persists and is to be viewed as a favorable prognostic factor are questions to be addressed by future studies.

P.045

FREQUENCY AND CLINICAL ASSOCIATIONS OF ANTI-RO/SSA ANTIBODIES IN PATIENTS WITH SYSTEMIC SCLEROSIS

Cristina Nita¹, Laura Groseanu^1,2, Delia Nicoara¹, Denisa Predeteanu^1,2, Violeta Bojinca^1,2, Daniela Opris^1,2, Florian Berghea^1,2, Ioana Saulescu^1,2, Violeta Vlad¹, Mihai Abobului^1,2, Andreea Borangiu^1,2, Sanziana Daia^1,2, Diana Mazilu^1,2, Magdalena Negru^1,2, Cosmin Constantinescu^1,2, Madalina Duna¹, Claudia Cobilinschi^1,2, Denise Mardale^1,2, Andra Balanescu^1,2

¹Department of Internal Medicine and Rheumatology, St. Mary Clinical Hospital, Bucharest, ROMANIA, ²University of Medicine and Pharmacy Carol Davila, Bucharest, ROMANIA

Introduction: The significance of anti-Ro/SSA antibodies in systemic sclerosis (SSc) is still unclear as their presence could represent an epiphenomenon of the strong immune response in severe visceral involvement or directly participate in tissue damages in SSc patients. The aim of our study was to define the diagnostic and prognostic role of anti-Ro/SSa antibodies in a monocentric cohort of SSc patients.

Material and Methods: A retrospective, cross-sectional study of a cohort of incident patients diagnosed with SSc and followed at our rheumatology clinic during 2000-2022. Duration of disease progression, symptoms and parameters related to a specific organ involvement according to MEDS evaluation sheets, were evaluated in all patients.

Results: Of 270 patients with SSc there was a final population of 28 (10.3%) anti-Ro/SSA positive patients. These autoantibodies were found to be the most common SSc associated-autoantibodies in this cohort. The anti-SSA/Ro group included more women (26/28) with a mean age of 47.9 ± 13.7 years, most of them with diffuse subset (16/28). The presence of anti-SSA/Ro antibodies was positively correlated with presence of anti-Scl 70 antibodies (p=0.012), elevated modified Rodnan score (p=0.041) and myositis (p=0.013). Moreover, associations were strongest for elevated CRP levels (p<0.001) and calcinosis cutis (p<0.001). As expected, comparing to non-anti-SSa/Ro patients, the anti-SSa/Ro group had significantly more frequent erosive synovitis (p=0.002), myopathy (p=0.010) and gastrointestinal involvement. Interstitial lung disease (ILD) was diagnosed earlier in patients with anti-Ro/SSA antibodies [0.3(4.9-9.0) years] compared to the other group [1.8 (10.0-28.6) years; p=0.001], with similar median through FVC in both groups (65% and 71% predicted), but with lower DLCO (p=0.019). There was no difference in median time to diagnosis of PAH from the first onset of Raynaud’s phenomenon [8.7 (1.6-19.8) years] and [7.4(0.08-60.2) years; p = 0.86], respectively. There was a greater proportion of digital ulcers and calcinosis in the anti-SSa/Ro group (42% vs 17% and 58% vs 14%), but without statistical significance. Again, among those patients, a much higher proportion (64% vs 42%) was treated with immunosuppressive agents. No differences in mortality were found between the groups. The study was limited by its retrospective nature. Moreover, the correlations between certain subtypes of anti-Ro/SSA antibodies and the clinical manifestations of the disease were not analyzed separately.

Conclusions: Anti-SSA/Ro antibodies were present in 10.3% of SSc patients, making them the most common SSc-associated autoantibodies in this SSc cohort. In addition, anti-Ro/SSA positive patients appeared to have distinct clinical associations, in particular with ILD, myositis, joint involvement and calcinosis.

P.046

SEROLOGICAL SIGNATURES OF SCLERODERMA IN THE UNITED ARAB EMIRATES: A FOCUS ON SCL-70 AND ACA AUTOANTIBODIES

Rajaie Namas, Sarah Al Qassimi, Jawahir Alameri, Esat Memisoglu, Saniya Khan, Mohamed Elarabi

Cleveland Clinic Abu Dhabi, Abu Dhabi, UNITED ARAB EMIRATES

Introduction: Systemic sclerosis (SSc) is a disease that varies geographically. The goal of this study was to look at the clinical and serological profile of a predominantly Arab patient population with SSc who had autoantibody positivity (topoisomerase antibody [Scl-70] and anticentromere antibody [ACA]).

Material and Methods: The clinical and serological characteristics, comorbidities and outcome measures of 190 patients with SSc was collected from the United Arab Emirates Scleroderma Registry at Cleveland Clinic Abu Dhabi. Descriptive statistics were performed using Pearson Chi-Square test, Fisher’s exact test, Mann-Whitney U test and independent sample t test with a significant P value of <0.05.

Results: There was a significantly higher proportion of diffuse cutaneous systemic sclerosis (dcSSc), Raynaud’s phenomenon and sclerodactyly in this population among patients with Scl-70 autoantibodies compared to those with negative Scl-70 autoantibodies. Surprisingly, the proportion of G6PD was significantly lower, as were the proportions of fatigue, digital ulcer, PAH, liver disease and joint contractures. PAH (+) ILD (+), PAH (+) ILD (-), PAH (-) ILD (+) were the three subtypes of PAH/ILD patterns, with the latter having a significantly higher proportion compared to the others. In terms of serologies, homogenous IF-ANA pattern had the highest proportion compared to other patterns. Other serologies including antichromatin, Sm/RNP, RNP Ab, ACA, PM/Scl and CK were significantly within normal limits. In terms of outcome measures, Scl-70 positive patients had a significantly higher modified Rodnan skin score (mRSS) score but a lower Charlson Comorbidity Index (CCI).

There was a significantly higher proportion of patients at the age at diagnosis and at clinic presentation among patients with ACA autoantibodies compared to those with negative ACA autoantibodies. When compared to dcSSc, there was a significantly higher proportion of limited cutaneous systemic sclerosis (lcSSc) diagnoses. Clinically, they had a lower proportion of diabetes mellitus, thyroid disease, hypertension, dyslipidemia, osteoporosis, G6PD and sicca symptoms. There was no statistical significance between the three PAH/ILD subtypes. The centromere IF-ANA pattern had the highest proportion compared to other IF-ANA patterns. In terms of outcome measures, the mRSS score and CCI were significantly lower.

Conclusions: Leveraging available registries in regions with a dearth of SSc studies is imperative to understanding the pivotal role played by autoantibodies in risk stratifying this complex disease. This approach not only holds the potential to refine disease classification and prognosis but also has the capacity to enhancing clinical decision-making and ultimately improve the quality of care for SSc patients.

P.047

CORRELATION BETWEEN QUANTITATIVE LEVEL OF ANTI-TOPOISOMERASE I ANTIBODY AND CLINICAL COURSE IN SYSTEMIC SCLEROSIS

Kamonwan Mulalin¹, Ajanee Mahakkanukrauh¹, Siraphop Suwannaroj¹, Sawinee Kasa², Patnarin Pongkulkiat¹, Tippawan Onchan¹, Chingching Foocharoen¹

¹Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, THAILAND, ²Clinical Laboratory Section, Faculty of Medicine, Khon Kaen University, Khon Kaen, THAILAND

Introduction: The presence of anti-topoisomerase-I antibody (ATA) is associated with disease severity and internal organ involvement in patients with systemic sclerosis (SSc). The correlation between ATA level and the clinical course of SSc is unclear. We aimed to determine the correlation between ATA level and survival time and onset of internal organ fibrosis in SSc patients.

Material and Methods: This historical cohort study was conducted in adult SSc patients with quantitative tests of ATA from January 2019 to December 2022. Patients with overlapping diseases and no ATA titer test were excluded. The correlation between ATA level and survival time was evaluated by Spearman Rank correlation.

Results: A total of 153 patients according to sample size calculation were included into the study with female to male ratio of 1.8:1. The respective mean age on the study date and median ATA level was 59.9±11.3 years and 370 U/ml (range 195-652). Majority of cases (107 cases; 69.9%) were diffuse cutaneous SSc subset. By univariable analysis, the ATA titer had negative correlation with the onset of pulmonary fibrosis (PF), onset of cardiac involvement, and serum albumin, but positive correlation with modified Rodnan skin score (mRSS), salt and pepper skin, and muscle weakness. ATA level was not correlated with the survival time and onset of renal crisis. By multivariable analysis, ATA titer had a negative correlation with onset of PF (Rho -0.390, p=0.04), onset of cardiac involvement (Rho -0.523, p=0.004), but positive correlation with salt and pepper skin (Rho 0.390, p=0.04).

Conclusions: High ATA titer was correlated with the short onset of PF and cardiac involvement in SSc and the presence of salt and pepper skin. Quantitative tests of ATA might be a good tool to identify the patients who are at risk of a poor prognosis. Longitudinal study of the changing of ATA level and long term clinical outcomes should be further investigated.

P.048

AUTOANTIBODIES WHICH BIND TO AND ACTIVATE KERATINOCYTES IN SYSTEMIC SCLEROSIS

Carine Moezinia, Valerie Wong, James Watson, Lydia Nagib, Sandra Lopez Garces, Siyu Zhang, Bahja Ahmed Abdi, Florence Newton, Christopher Denton, David Abraham, Richard Stratton

UCL Centre for Rheumatology, Royal Free Hospital, London, UNITED KINGDOM

Introduction: Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by pathological processes involving autoimmunity, vasculopathy, and resultant extensive skin and organ fibrosis. Recent studies have demonstrated activation and aberrant wound healing responses in the epithelial layer of the skin in SSc, implicating the epithelial keratinocytes as a source of pro-fibrotic and inflammatory mediators. We investigated the role of Immunoglobulin G (IgG) autoantibodies directed against epithelial cells, as potential initiators and propagators of pathological keratocyte activation and the ensuing SSc fibrotic cascade.

Material and Methods: Patients who fulfilled the 2013 ACR/EULAR criteria of diffuse SSc and limited SSc diagnosis were recruited, as well as healthy controls (n=30 per group). A keratinocyte cell-based ELISA was used to evaluate binding of SSc IgG. SSc skin biopsies were stained by immunofluorescence for the presence of IgG in the keratinocyte layer (n=6 early diffuse biopsies). Furthermore, IgG purified from SSc sera was evaluated for the potential to activate keratinocytes in tissue culture and to induce signaling in TLR2 & 3 reporter cell lines.

Results: Anti-epithelial cell antibody (AEpCA) ELISA assay: There was enhanced and dose dependent binding of SSc IgG in both lcSSc and dcSSc patient samples (ANOVA,p<0.001 for overall effect SSc vs HC IgG, p<0.0048 for dose effect, Kruskall-Wallace test p<0.014 for lcSSc vs HC, p<0.041 for dcSSc vs HC). Furthermore, clinical and laboratory characteristics were compared between SSc patients with positive AEpCA titre (defined as upper 95% CI for binding titre =22.5%). Amongst patients with positive AEpCA, there was a trend towards higher skin scores, higher frequency of anti-topoisomerase (ATA) antibody profile, interstitial lung disease and higher use of immunosuppressive treatments (Table 1). Purified IgG from SSc patients but not controls induced IL-1α release from keratinocyte cultures and enhanced both TLR2 and TLR3 signaling.

Positive staining for the presence of IgG in the epidermis of SSc patients skin biopsies: There was presence of IgG in cytoplasmic and cell surface distributions in some, but not all, SSc epidermal sections (observed in 2 out of 6 patients), whereas no healthy control sections showed positive staining.

Conclusions: In this study, we have shown evidence of anti-epithelial cell antibodies in the plasma of SSc patients and demonstrated that SSc IgGs are capable of activating keratinocytes, triggering relevant innate immune mechanisms. This represents a potential mechanism triggering epithelial activation and contributing to downstream fibrosis in the skin, as well as a potential target for future therapy.

P.049

ANTIPHOSPHOLIPID ANTIBODIES POSITIVITY AMONG PORTUGUESE PATIENTS WITH SYSTEMIC SCLEROSIS: IS THERE ANY ASSOCIATION WITH VASCULOPATHY?

Carlos Marques Gomes, Raquel Miriam Ferreira, Mariana Diz Lopes, Inês Santos, Miguel Bernardes, Georgina Terroso, Lúcia Costa

Centro Hospitalar São João - Rheumatology Department, Porto, PORTUGAL

Introduction: Systemic Sclerosis (SSc) is a connective tissue disease that predisposes to vasculopathy and fibrosis which leads to organ injury (skin, lung, heart, gastrointestinal tract) and symptoms such as Raynaud’s phenomenon (RP), digital ulcers (DU), gangrene or pulmonary arterial hypertension (PAH). Fibroblast activation, endothelial dysregulation, abnormal coagulation and fibrinolysis and immune-mediated chronic inflammation are mechanisms involved in arterial occlusion. An increased positivity of antiphospholipid antibodies (APPa), anti-B2 glycoprotein antibodies (aB2GPIa), anticardiolipin antibodies (aCLa) and lupus inhibitor (LI) in SSC patients has been reported and some results have suggested a role of APPa in physiopathology of vasculopathy. We intend to assess the prevalence of APPa positivity in Portuguese patients with SSc and its association with vascular manifestations.

Material and Methods: Cross-sectional retrospective single-center study with all included patients (registered on Rheumatic Diseases Portuguese Register, Reuma.pt) meeting the ACR/EULAR 2013 or ACR 1980 classification criteria for SSC diagnosis. Overlap syndromes were excluded. Descriptive analysis were performed. Data were analyzed using student’s t test for continuous variables and Pearson’s x2 or Fisher’s exact test for categorical variables.

Results: One hundred and thirty-seven patients were evaluated (table 1), mostly female (89.8%), with a mean age at diagnosis of 51.5 years (±12.3). Ten patients (7.3%) had diffuse scleroderma and 127 patients (92.7%) had limited cutaneous scleroderma. Of all patients, 133 (97.1%) experienced RP, 48 (35%) developed DU and 6 (4.4%) developed gangrene. Regarding APPa, 22 patients (16.1%) tested positive for at least 1, IgM/IgG [21 (15.3%) for aB2GPIa, 10 (7.3%) for aCLa and 1 patient for LI (0.7%)]. Mean age at diagnosis was lower among positive APPa patients (47.3±6.9). None of the clinical parameters showed a statistically significant association with APPa (table 2).

Conclusions: The prevalence of APPa seems increased in patients with SSc as described in the literature, however we did not find a statistically significant association of APPa positivity with development of DU or other features (RP, PAH). Some published data fail to establish a strong correlation due to varying study methodologies. Of note, we defined positivity using the manufacturer's specified cut-off value, whereas in some other studies, lower titers were considered. Curiously, a lower average age at diagnosis was observed in APPa positive patients’ group (p<0.05). For more consistent conclusions, further studies are necessary to understand the role these antibodies might have in SSc presentation and severity.

P.050

ANTIBODIES AGAINST BORRELIA SPECIFIC ANTIGENS IN PATIENTS WITH SYSTEMIC SCLEROSIS

Eleni Patrikiou¹, Christos Liaskos¹, Emmanouela Marou¹, Theodora Simopoulou¹, Thomas Scheper², Wolfgang Meyer², Lazaros I Sakkas¹, Dimitrios P Bogdanos¹

¹Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Thessaly, Larissa, GREECE, ²Institute of Experimental Immunology, EUROIMMUN AG, Lübeck, GERMANY

Introduction: Amongst infectious triggers of systemic sclerosis (SSc), Borrelia infection has not been studied, despite cases in the literature reporting sclerosus skin associated with Borrelia.

The aim of the study was to assess antigen-specific anti-Borrelia antibodies in patients with SSc.

Material and Methods: Serum samples from 40 patients with SSc and 17 controls were tested for the presence of antibodies against various Borellia antigens by immunoblotting (Euroline, Euroimmun AG, Lubeck, Germany). This assay can detect antibodies against various antigens, some of them are species specific (Category C) namely: p17, p19, p21, p25 (OspC), p30, p31(OspA), p39(BmpA), p83 and VIsE. According to the established criteria the result for past infection is positive if 2 or more bands of Category C are present.

Results: IgG antibody positivity against Borrelia were observed in 5 out of 40 patients (12.5%) and in 1 out of 17 controls (individuals originally suspected for Borrelia infection but confirmed negative) (5.9%, p=ns). Antibodies against p31 (OspA) were found more frequently in patients with SSc compared to disease control (14/40, 35% vs 1/17, 5.9%, p=0.025). We found 1 patient positive for anti-p25 (OspC), 3 positive for anti-p30, 3 positive for anti-p83 and 1 positive for anti-VIsE in patients with SSc compared to none in controls (p=ns, for all comparisons). None of the patients with SSc or the controls were found positive for antibodies against p17, p19, 039 (BmpA).

Conclusions: Anti-OspA (p31) Borrelia antibodies are relatively frequently found in patients with SSc but their significance remains elusive.

P.051

ANTI-RO52 ANTIBODIES ARE MORE FREQUENT IN ANTI-CENTROMERE POSITIVE PATIENTS WITH SYSTEMIC SCLEROSIS RATHER THAN ANTI-SCL70 OR ANTI-RNA POLYMERASE III POSITIVE PATIENTS

Eleni Patrikiou, Christos Liaskos, Theodora Simopoulou, Lazaros I Sakkas, Dimitrios P Bogdanos

Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thess, Larissa, GREECE

Introduction: In addition to the conventional anti-centromere, anti-Scl70 and anti-RNA polymerase III (RP 155 and/or RP 11epitopes) antibodies, other disease specific or disease related autoantibodies have been reported in patients with systemic sclerosis (SSc).

The aim of the present study was to assess the extent by which these additional autoantibodies co-occur with the diagnostically relevant SSc autoantibodies, as this topic remains less clear.

Material and Methods: A total of 188 patients with SSc, including 77 patients with anti-centromere, 77 with anti-Scl70 and 34 with anti-RNA polymerase III were tested for the con-current presence of anti-fibrillarin, anti-PDGFR anti-NOR90, anti-Th/To, anti-PM-Scl100, anti-PMScl75, anti-Ku, and anti-Ro-52 using a line immunoassay (Euroimmun, Germany).

Results: While anti-Ro52 antibodies were the most prevalent antibodies overall (33/188, 17.5%), their presence was more frequent in anti-centromere positive SSc (n=21, 27.3%) compared to anti-Scl70 positive SSc (n=5, 6.4%, p=0.0013). In anti-centromere positive, anti-fibrillarin, anti-PDGFR, anti-NOR90, anti-Th/To, anti-PM-Scl100, anti-PMScl75 and anti-Ku, were present in 0%, 0%, 3.9%, 0%,1.2%, 2.6% and1.2% respectively. In anti-Scl70 positive anti-fibrillarin, anti-PDGFR, anti-NOR90, anti-Th/To, anti-PM-Scl100, anti-PMScl75 and anti-Ku, were present in 1.2%, 0%, 1.2, 2.6%, 0%, 2.6% and 2.6% respectively. In RNA polymerase III positive, anti-fibrillarin, anti-PDGFR, anti-NOR90, anti-Th/To, anti-PM-Scl100, anti-PMScl75, and anti-Ku, were present in 5.8%, 0%, 2.9%, 2.9%, 2.9%, 5.8% and 2.9% respectively. No other statistically significant difference amongst the 3 cohorts was found.

Conclusions: Anti-Ro52 antibodies are frequently found in patients with SSc and in particular those with anti-centromere antibodies but not with anti-Scl70; such co-occurrence requires further investigation

P.052

ASSOCIATION OF MYELOPEROXIDASE-ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY WITH SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE

Yuki Ichimura, Yasushi Kawaguchi, Kae Takagi, Akiko Tochimoto, Tomoaki Higuchi, Hikaru Hirose, Masayoshi Harigai

Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, JAPAN

Introduction: Previous reports published in 1990s showed about 7–13% of patients with systemic sclerosis (SSc) showed anti-neutrophil cytoplasmic antibody (ANCA) positivity, especially myeloperoxidase (MPO)-ANCA, without any manifestation of vasculitis. ANCA-positive patients with SSc sometimes suffer from normotensive renal crisis. However, the characteristics of SSc patients with ANCA positivity were unknown. The aim of this study is to assess the prevalence of ANCA positivity in patients with SSc, and clarify the clinical characteristics of these patients including development of vasculitis during follow-up.

Material and Methods: We enrolled the 333 consecutive Japanese SSc patients who visited our department from October 2014 to September 2015, all of who were tested for MPO-ANCA and proteinase 3 (PR3)-ANCA using fluorescent-enzyme immunoassay. Two patients who had AAV at enrollment were excluded from the analysis. Clinical manifestation and laboratory data were obtained from medical chart. The data were assessed by chi-square test and Welch’s t-test.

Results: Eight patients (2.4%) revealed MPO-ANCA positivity without vasculitis manifestation, and no cases were positive for PR3-ANCA. All MPO-ANCA-positive patients were female, and mean age and disease duration were 61.1 years old and 17.2 years, respectively. MPO-ANCA-positive patients had interstitial lung disease more frequently than MPO-ANCA-negative patients (87.5% vs. 36.7%, p< 0.01). During the 8-years follow-up period, one patient developed AAV and acute renal failure, and another developed large-vessel vasculitis without renal involvement. Six cases did not reveal any vasculitis manifestations.

Conclusions: The prevalence of MPO-ANCA positivity in our SSc cohort was lower than that of the previous reports. MPO-ANCA positivity may be associated with interstitial lung disease in SSc patients. MPO-ANCA positive patients may occasionally develop AAV, and careful observation are needed.

P.053

DISEASE PROGRESSION IN ANTI-CENTROMERE POSITIVE SYSTEMIC SCLEROSIS PATIENTS

Eva Hoekstra¹, Saad Ahmed¹, David Ueckert², Nina Ajmone Marsan³, Philippine Kiès³, Maarten Ninaber⁴, Marlies Heuvers⁴, Miranda Geelhoed⁴, Tom Huizinga¹, Jeska de Vries - Bouwstra¹

¹Leiden University Medical Center, department of Rheumatology, Leiden, THE NETHERLANDS, ²Leiden University Medical Center, Department of Orthopaedics, Rehabilitation and Physical Therapy, Leiden, THE NETHERLANDS, ³Leiden University Medical Center, Department of Cardiology, Leiden, THE NETHERLANDS, ⁴Leiden University Medical Center, Department of Pulmonology, Leiden, THE NETHERLANDS

Introduction: Disease progression in systemic sclerosis (SSc) is characterized by severe and early progression in anti-topoisomerase (ATA) positive diffuse cutaneous patients and typically involves lung and skin. Disease progression in anti-centromere (ACA) patients is also frequently present, but more often consists of cardiac progression and happens typically not early but any time during the course of disease. We therefore hypothesize that disease progression in ACA-positive patients is driven by different factors than disease progression in ATA-positive patients. The aim of this study is to identify baseline characteristics that predict disease progression in ACA-positive SSc patients.

Material and Methods: SSc patients fulfilling ACR/EULAR 2013 criteria were included form the Leiden CCISS cohort. Disease progression was defined as disease progression in one or more organ domains (including skin involvement, heart involvement, interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), renal involvement, myositis and gastro-intestinal involvement) or death. To identify possible baseline predictors for disease progression univariable and multivariable logistic regression with adjustment for age, sex and immunosuppressive use at baseline was performed.

Results: In total 754 patients were included, with a median follow-up of 3.4 (1.1–7.1) years. Of 318 ACA-positive patients 160 (50%) suffered from disease progression during follow-up, compared to 62% in ACA-negative patients. In ACA-positive patients, cardiac progression occurred most frequently (31%), followed by disease subset progression (16%) and skin score progression (11%), whereas in ACA-negative patients disease progression most frequently involved cardiac progression (37%), ILD progression (20%) and skin score progression (17%) (Figure 1). In univariable analysis diffusing capacity for carbon monoxide (DLCO), 6 minute walking distance, oxygen saturation at rest and presence of contractures were significantly associated with disease progression in ACA-positive patients, while for the total group skin score, diffuse cutaneous subset, hemoglobin, and presence of radiographic ILD, pitting scars and friction rubs were predictive as well. In multivariable analysis DLCO percentage (OR 0.98 [0.97-0.99]), oxygen saturation at rest (OR 1.22 [1.04-1.43]) and contractures (OR 2.82 [1.71–4.68]) were significantly associated with disease progression.

Conclusions: Our study confirms that disease progression is substantial in ACA-positive patients. The baseline characteristics most predictive for progression in ACA-positive patients include DLCO percentage, oxygen saturation at rest and contractures, which were clearly different from predictors for the complete SSc group and should be taken into account in risk stratification in clinical practice. Our results underline the hypothesis that disease progression is driven by different factors in ACA-positive patients; further in-depth studies are warranted.

P.054

ANTI-TOPOISOMERASE POSITIVITY IS NOT ASSOCIATED WITH BASELINE ORGAN SEVERITY IN JUVENILE SYSTEMIC SCLEROSIS

Ivan Foeldvari¹, Jens Klotsche², Kathryn Torok³, Ozgur Kasapcopur³, Amra Adrovic³, Brian Feldman³, Flavio Sztajnbok³, Maria Teresa Terreri³, Ana Paula Sakamoto³, Sindhu Johnson³, Jordi Anton³, Valda Stanevicha³, Raju Khubchandani³, Dieneke Schonenberg-Meinema³, Ekaterina Alexeeva³, Maria Katsicas³, Sujata Sawhney³, Vanessa Smith³, Eslam Al-Abadi³, Simone Appenzeller³, Tadey Avcin³, Mikhail Kostik³, Thomas Lehman³, Hana Malcova³, Edoardo Marrani³, Anjali Patwardhan³, W.-Alberto Sifuentes-Giraldo³, Natalia Vasquez-Canizares³, Nicola Helmus¹

¹Hamburg Center for Paediatric and Adolescent Rheumatology, Hamburg, GERMANY, ²German Rheumatism Research Center, Berlin, GERMANY, ³jSSc Collaborative Group, Hamburg, GERMANY

Introduction: Juvenile systemic sclerosis (jSSc) is an orphan disease with a prevalence of 3 in 1 000 000 children. In adult patients anti-topoisomerase (anti-Scl70) positivity is a risk factor for diffuse cutaneous subtype and increased rate of interstitial lung disease (ILD), but data in children are scarce. Juvenile systemic scleroderma inception cohort (jSScC) is a prospective cohort of jSSc patients, who developed the first non-Raynaud’s symptom before the age of 16 years and were under the age of 18 years at the time of inclusion.

Material and Methods: We reviewed the baseline clinical characteristics of the patients, who were recruited to the jSScC prior to the 30th of April 2023 and compared their clinical characteristics based on anti-Scl 70 antibody positivity.

Results: 225 patients with jSSc were included in the cohort, 33% had anti-Scl70 antibodies (n=74). 68% (n=155) of patients had diffuse cutaneous subtype. There were no significant differences regarding diffuse subtype in the group with or without Scl70 antibodies (77% vs 65%; p=0.5). The median age at onset of Raynaud phenomenon was similar between two groups 10.3 years (7.6–12.8) in the anti-Scl70 group and 10.6 years (7.2-13.1) in the anti Scl70 negative group. At the time of inclusion, median disease duration was 2.4 years and 2.5 years, respectively. The female/male ratio did not differ significantly. There were no differences between groups regarding organ involvement, including cutaneous, vascular, cardiac, renal, gastrointestinal and musculoskeletal involvement, sicca symptoms, interstitial lung disease or pulmonary hypertension (Table 1). The only differences found were in the patient reported outcomes, namely in the patient global disease damage (p=0.024) and the reported Raynaud’s activity (p=0.019), which were significantly higher in the anti-Scl 70+ patients.

Conclusions: This is an intriguing finding that reinforces our previous published results of 80 jSSc patients, where the differences were not significant between anti Scl70 positive and negative patients1. In this study, there were differences only in the patient reported global disease damage and the patient reported Raynaud’s activity.

P.055

SHAPING MONOCYTE PATHOGENICITY IN SYSTEMIC SCLEROSIS: THE CONVERGENCE OF AT1R AUTOANTIBODIES AND EXTRACELLULAR VESICLES

Alexander Hackel¹, Reza Akbarzadeh¹, Hanna Grasshoff¹, Marieke Leiber¹, Antje Mueller¹, Xinhua Yu², Frank Petersen², Gabriela Riemekasten¹

¹University Clinic Schleswig-Holstein, Department of Rheumatology and Clinical Immunology, Luebeck, GERMANY, ²Research Center Center Borstel, Pulmonary Immune Diseases, Borstel, GERMANY

Introduction: In Systemic Sclerosis (SSc), autoantibodies (abs) directed against G protein-coupled receptors (GPCR) correlate with disease manifestations. In particular, SSc abs mediate an inflammatory immune response by monocytes and inducing a pro-fibrotic phenotype in fibroblasts (1-3). In addition, increased abundance of anti-GPCR abs is associated with increased secretion of extracellular vesicles (EVs) (5). Moreover, in SSc patients increased concentration of abs against angiotensin II type 1 receptor (AT1R) have been observed in patients (6-8). The importance of EVs in the pathogenesis is also based on packing and transfer of AT1R to different tissues and immune cells (6-10). Taken together, the relevance of studying anti-GPCR abs together with GPCR-EVs in SSc pathogenesis becomes evident.

Material and Methods: Monoclonal AT1R ab have been generated by hybridoma technique, sequenced and subsequent recombinantly expressed in HEK cells. IgG was isolated from Sera of systemic sclerosis patients (SSc-IgG) and healthy donors (HD-IgG) as control. In order to isolate EVs, Sera were differentially centrifugated and subsequently precipitated with Exoquick™ after manufacture protocol. Human peripheral blood monocytes of HD or monocytic cells were treated with EVs derived from sera of SSc patients versus sera of HD, in the presence or absence of monoclonal AT1R ab, specificity of AT1R abs was tested by using a specific AT1R blocker (telvisartan, TEL). The response of the monocytes was measured via CCL18 secretion by a commercial ELISA. Migration of monocytes were assessed by trans-well assay to SSc-EVs, HD-EVs and medium control.

Results: Purified IgG fractions obtained from SSc patients significantly increased the release of CCL18 by monocytes compared to IgG fractions derived from HD. Likewise, SSc-derived extracellular vesicles (SSc-EVs) induced heightened CCL18 secretion by monocytic cells and promoted increased monocyte migration compared to extracellular vesicles from healthy donors (HD-EVs). Additionally, the monoclonal AT1R ab triggered an inflammatory and pro-fibrotic cytokine response in peripheral blood monocytes from healthy donors. This effect was abrogated by the inhibition of AT1R with TEL. Remarkably, only co-incubation of SSc-EVs, but not HD-EVs, with the monoclonal AT1R ab on monocytes augmented their pro-inflammatory immune response.

Conclusions: The enhanced secretion of the pro-fibrotic cytokine CCL18 by human monocytes in response to SSc IgG and a monoclonal AT1R antibody suggests the involvement of anti-AT1R antibodies in the pathogenesis of systemic sclerosis. Furthermore, this effect was potentiated exclusively by SSc-derived extracellular vesicles (SSc-EVs), potentially facilitating the intercellular transfer of AT1R to recipient immune cells.

P.056

CLINICAL COURSES COMPARISON BETWEEN LIMITED CUTANEOUS SYSTEMIC SCLEROSIS AND DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS WITH POSITIVE FOR ANTI-TOPOISOMERASE I ANTIBODY: A COHORT STUDY

Chingching Foocharoen, Chana Chaovanitk, Tippawan Onchan, Patnarin Pongkulkiat, Ajanee Mahakkanukrauh, Siraphop Suwannaroj

Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, THAILAND

Introduction: There is recently no information on whether the clinical courses of anti-topoisomerase I antibody (ATA) positive in patients with limited cutaneous systemic sclerosis (lcSSc) are similar to ATA positive in diffuse cutaneous systemic sclerosis (dcSSc) or not. We aimed to evaluate clinical courses comparison between lcSSc and dcSSc with positive for ATA.

Material and Methods: We conducted a cohort study including 522 Thai adult SSc patients between January 2014 and December 2022. Patients with overlap syndrome and having only 1 visit of follow-up were excluded. Clinical courses between lcSSc and dcSSc with positive for ATA were investigated using the Chi-square test, student t-test, or Wilcoxon Rank Sum as appropriate.

Results: Female was more common than male (319 vs. 203 cases). DcSSc with ATA positive (dcSSc-posATA) was the most common presentation among Thais (321 cases; 61.5%), followed by lcSSc with ATA positive (lcSSc-posATA) (19.9%), lcSSc with ATA negative (lcSSc-negATA) (11.1%), and dcSSc with ATA negative (dcSSc-negATA) (7.5%). The risk of interstitial lung disease (ILD) of lcSSc-posATA was comparable with dcSSc-posATA and dcSSc-negATA (odd ratios (OR) 0.76; 95%CI 0.48-1.20 and 1.35; 95%CI 0.64-2.82). The median onset time at ILD detection was comparable with dcSSc-posATA (1.0 vs. 1.8 years, p=0.21) but less than dcSSc-negATA (1.0 vs. 4.8 years, p=0.001). The mortality risk of lcSSc-posATA was comparable with dcSSc-negATA (hazard ratio (HR) 1.09; 95%CI 0.55-2.19) but less than dcSSc-posATA (HR 0.52; 95%CI 0.33-0.83). LcSSc-posATA still had less clinical features of dcSSc (tendon friction rub and hand deformity) than in dcSSc-posATA.

Conclusions: The patients with lcSSc-ATApos had a similar risk of ILD development as in dcSSc irrespective of the presence of ATA but earlier ILD development than dcSSc-negATA. The prognosis seemed to be better than dcSSc-posATA.

P.057

THE ANTI-NUCLEOLAR ORGANIZER REGION 90 ANTIBODIES (NOR90) IN SYSTEMIC SCLEROSIS: A EUROPEAN SCLERODERMA TRIALS AND RESEARCH (EUSTAR) STUDY

Alina Dima¹, Madelon Vonk², Alexandru Garaiman¹, Radim Bekvar³, Michal Tomcik³, Anna-Maria Hoffmann-Vold^1,4, Ivan Castellvi⁵, Jose Luis Tandaipan Jaime⁵, Marek Brzosko⁶, Marcin Milchert⁶, Dorota Krasowska⁷, Malgorzata Michalska-Jakubus⁷, Paolo Airo⁸, Marco Matucci-Cerinic⁹, Cosimo Bruni⁹, Michele Iudici¹⁰, Jorg Distler¹¹, Ana-Maria Gheorghiu¹², Hadi Poormoghim¹³, Francesca Motta¹⁴, Maris De Santis¹⁴, Magda Parvu¹⁵, Oliver Distler¹, Carina Mihai¹

¹University Hospital Zürich - Department of Rheumatology, Zurich, SWITZERLAND, ²Radboud University Nijmegen Medical Centre - Huispost - Department of the Rheumatologic diseases, Nijmegen, THE NETHERLANDS, ³Institute of Rheumatology, 1st Medical School, Charles University, Praha, CZECH REPUBLIC, ⁴Rikshospitalet University Hospital - Department of Rheumatology, Oslo, NORWAY, ⁵Hospital de la Santa Creu i Sant Pau, Barcelona, SPAIN, ⁶Pomeranian Medical University in Szczecin - Department of Rheumatology and Internal Medicine, Szczecin, POLAND, ⁷Medical University of Lublin - Department of Dermatology, Venereology and Pediatric Dermatology, Lublin, POLAND, ⁸Spedali Civili di Brescia - Servizio di Reumatologia Allergologia e Immunologia Clinica, Brescia, ITALY, ⁹Villa Monna Tessa - Department of Medicine, Section of Rheumatology, Florence, ITALY, ¹⁰Geneva University Hospitals - Rheumatology Unit, Geneva, SWITZERLAND, ¹¹Universitätsklinikum Erlangen - Department of Internal Medicine 3, Erlangen, GERMANY, ¹²Cantacuzino Clinical Hospital - Department of Internal Medicine and Rheumatology Clinic, Bucharest, ROMANIA, ¹³Firoozgar Hospital - Department of Rheumatology, Tehran, IRAN, ISLAMIC REP, ¹⁴University of Milan - Division of Rheumatology and Clinical Immunology Humanitas Clinical and Research Center, BIOMETRA, Milan, ITALY, ¹⁵Colentina Clinical Hospital - Department of Rheumatology, Bucharest, ROMANIA

Introduction: The anti-Nucleolar Organizer Region 90 antibodies (NOR90) are rare antinuclear antibodies (ANA) described in various pathologies, including systemic sclerosis (SSc), however their clinical applicability remains unclear. The aim of this study is to analyze the prevalence and clinical relevance of NOR90 in patients with SSc.

Material and Methods: We performed a cross-sectional study based on prospectively collected data of patients with SSc from EUSTAR centers willing to participate, with additional information from extended immunoassay blots which included NOR90.

Relevant clinical associations found in bivariate analysis between SSc patients with and without NOR90 were further tested using regression models.

Results: Overall, 1318 SSc patients were included (mean age 58.3±13.7 years, 81.3% female), of whom 44 (3.3%) were positive for NOR90. Of these, 22 were also positive for other SSc-specific antibodies: anti-topoisomerase I (ATA) in 9/44 (20.5%), anti-centromere (ACA) in 18/42 (42.9%), and anti-RNA polymerase III (RNAP III) in 5/40 (12.5%).

There was no difference in the presence of severe organ manifestations including interstitial lung disease, pulmonary hypertension, and renal crisis, but patients positive for NOR90 had significantly lower modified Rodnan skin score (mRSS) than NOR90-negatives, with median (Q1, Q3) of 2.0 (0.0; 7.0) vs. 5.0 (1.2; 11.0), p=0.001. In addition, gastrointestinal symptoms were less prevalent in NOR90-positive patients: 42.5% vs. 63.7%, p=0.007 for the upper and 12.5% vs. 38.4%, p=0.001 for lower gastrointestinal tract symptoms.

In multivariable linear regression adjusted for ATA, ACA, and RNAP III, NOR90 were still significantly associated with lower mRSS and less upper and lower GI symptoms, with odds ratios (95% confidence intervals): 0.376 (0.167-0.845), p=0.018, 0.389 (0.198-0.762), p=0.006 and respectively 0.173 (0.060-0.496), p=0.001.

Conclusions: To the best of our knowledge, this study represents the largest cohort of SSc patients tested for NOR90 so far. Although we observed negative associations with both skin fibrosis and gastrointestinal symptoms, which warrant further investigation, no other significant associations were found. However, we cannot assert that SSc patients with NOR90 exhibit a milder form of the disease.

P.058

ASSESSMENT OF SYSTEMIC SCLEROSIS MARKERS UTILIZING A PARTICLE-BASED MULTI-ANALYTE TECHNOLOGY IN AN ITALIAN COHORT OF SCLERODERMA PATIENTS

Marco De Pinto¹, A. Spinella¹, A. Melegari², E. De Santis², M. Orlandi^1-4, O. Secchi¹, C. Bentow³, M. Mahler³, M.T. Mascia¹, D. Giuggioli^1-4

¹Scleroderma Unit, Rheumatology Unit, University of Modena and Reggio Emilia, Modena, ITALY, ²Autoimmunity Unit, Laboratory Department Azienda USL Modena, Modena, ITALY, ³R&Headquarters & Technology Center Autoimmunity, Werfen, San Diego, USA, ⁴Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto, Modena, ITALY

Introduction: More than 95% of patients with Systemic sclerosis (SSc) present autoantibodies (Abs) against different nuclear proteins of which three have been included in the classification criteria: anti-topoisomerase I (ATA, Scl-70), anti-centromere (ACA), and anti-RNA-Pol III (ARA).

New biomarkers are needed to close the seronegative gap and to enable patient stratification. The goal of this study was to evaluate a novel particle-based multi-analyte technology (PMAT) for the detection of autoantibodies in an Italian cohort of SSc, as well as investigating the correlation of markers to the clinical manifestations of the disease.

Material and Methods: A cohort of 188 patient samples collected at University Modena (Italy) comprising of SSc patients (126 limited cutaneous lcSSc, 45 diffuse cutaneous dcSSc, 6 VEDOSS, 7 RP, 1 sine scleroderma, and 3 unconfirmed diagnosis) were tested by three PMAT panels: (1) CTD Essential, (2) CTD Comprehensive and, (3) Myopathy (research use only). SSc-associated Abs included in these panels were directed against Scl-70, centromere, Ku, RNA-Pol III, Th/To subunit Rpp25, Th/To subunit Rpp38, PM/Scl, BICD2, and Fibrillarin. Analysis of all markers in the panels was conducted and p values less than 0.05 were considered significant.

Results: As expected, ACA and ATA were the most sensitive markers (41.5% and 34.0%, respectively) where ACA occurred more frequently in lcSSc (56.3% vs. 13.3%, p<0.0001) and ATA occurred more frequently in dcSSc (71.1% vs.23.0%, p<0.0001). ARA had a sensitivity of 4.8% (11.1% in dcSSc and 3.2% in lcSSc, p=0.0549). For the non-criteria Abs, the prevalence was as follows: Fibrillarin (5.9%), PM/Scl (5.3%), Th/To Rpp25/38 (5.3%), Ku (3.7%), and BICD2 (13.3%). In addition, 45/188 (23.9%) of the overall cohort were negative for the criteria Abs and 12/45 (26.7%) were positive for at least one of the non-criteria SSc markers (Th/To, PM/Scl, Ku, BICD-2, and Fibrillarin). ATA levels and prevalence were significantly higher in patients with dcSSc, ILD (p<0.0001) and heart involvement (p=0,0427). ACA levels and prevalence were significantly higher in patients with lcSSC (p<0.0001) and without ILD (p=0,0010), however ACA in association with Ro52 was associated with the presence of ILD (P=0.0039).

Conclusions: In addition to the expected prevalence of SSc classification criteria abs, non-criteria markers reduced the serological gap significantly. Additional markers included in the diagnostic workup of patients especially for the VEDOSS population may be beneficial for early intervention and patient stratification. Additional studies assessing autoantibody levels and involving more patients are warranted to evaluate novel biomarkers.

P.059

IMMUNOGLOBULINS G PURIFIED FROM SYSTEMIC SCLEROSIS PATIENTS INFLUENCE CYTOPLASMIC AND NUCLEAR PROTEINS PROFILE IN DERMAL FIBROBLASTS

Aurélien Chepy¹, Marie Duhamel², Solange Vivier¹, Clément Chauvet¹, Lucile Guilbert¹, Eric Hachulla³, Sylvain Dubucquoi¹, David Launay¹, Michel Salzet², Vincent Sobanski¹

¹Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, Lille, FRANCE, ²Univ. Lille, Inserm, CHU Lille, U1192 - Protéomique Réponse Inflammatoire Spectrométrie de Masse - PRISM, F-59000 Lille, Lille, FRANCE, ³CHU Lille, Département de Médecine Interne et Immunologie Clinique, Centre de Référence des Maladies Auto-immunes Systém, Lille, FRANCE

Introduction: Autoantibodies (Aab) are frequent in systemic sclerosis (SSc). While recognized as potent biomarkers, their pathogenic role is unclear. Recently, we showed that immunoglobulins G (IgG) from SSc patients can modify the phenotype and secretome of fibroblasts (FB). The aim of this study was to gain a better understanding of the effect of purified IgG on FB by analyzing cytoplasmic and nuclear proteomic profiles.

Material and Methods: Normal dermal FB (ATCC® Number: PCS-201-012 ™) were cultured in the presence of IgG from patients with diffuse cutaneous SSc (dcSSc, n=20), limited cutaneous SSc (lcSSc, n=10) or healthy controls (HC, n=10). Cytoplasmic and nuclear proteins were extracted and explored separately using mass spectrometry coupled with liquid chromatography (LC-MS/MS). Data were visualized using Principal Component Analysis (PCA) and protein profile were studied by performing differential analysis and gene set enrichment analysis.

Results: Cytoplasmic and nucleic proteomics identified and quantified 3,350 and 2,253 proteins, respectively. PCA revealed five groups of subjects according to cytoplasmic protein expression: dcSSc anti-topoisomerase-I (ATA)-positive patients (dcSSc ATA+), which appeared to be the most distinct group; dcSSc ATA negative patients (dcSSc ATA-); lcSSc anti-centromere (ACA)-positive patients (lcSSc ACA+); healthy controls (HC); and non-stimulated FB (NS) (Figure 1A). PCA performed on nuclear proteomic revealed two main groups of subjects according to protein expression: the first group comprised dcSSc patients and the second group was composed of lcSSc ACA+ patients, HC, and NS (Figure 1B).

We then focused on the dcSSc groups (ATA- and ATA+) as they appear to be the most distinct. Type 1 collagen and alpha smooth muscle actin were overexpressed in cytoplasmic proteomic in both dcSSc ATA- and ATA+ conditions (Figure 2A and 2B). Interestingly, 613 and 1,063 nucleic proteins were underexpressed in dcSSc ATA- and ATA+ conditions respectively and were enriched in transcription binding factors (Figure 2C and 2D). Thirty-five proteins belonging to transcription binding factors and implying in chromatin organization were commonly underexpressed in dcSSc. Thirty-three proteins belonging to transcription binding factors and implying in chromatin remodelling were exclusively underexpressed in dcSSc ATA+ (figure 2E).

Conclusions: IgG purified from SSc patients modified both cytoplasmic and nuclear protein expression according to cutaneous subtype and Aab profile. The dcSSc ATA + group appeared to influence most of the cytoplasmic and nuclear protein profiles. Purified IgG from dcSSc patients induced a profibrosing profile and underexpression of transcription binding factors implying in chromatin organization and remodelling in FB.

P.060

DEFINITION OF DISEASE PHENOTYPE IN PATIENTS WITH SYSTEMIC SCLEROSIS WITH ANTI-TOPOISOMERASE I ANTIBODIES: A COMPARISON BETWEEN DIFFUSE AND LIMITED CUTANEOUS FORM

Ilaria Bisconti, Davide Mohammad Reza Beigi, Greta Pellegrino, Marius Cadar, Francesca Romana Di Ciommo, Elena Platania, Jacopo Landro, Simona Truglia, Fabrizio Conti, Valeria Riccieri

Rheumatology Unit, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Universi, Rome, ITALY

Introduction: Systemic sclerosis (SSc) has historically been classified based on cutaneous involvement into two forms, limited (lcSSc) and diffuse (dcSSc), respectively associated with positivity for anti-centromere antibodies (ACA) and anti-topoisomerase I antibodies (ATA). However, 11 to 23% of ATA+ patients present lcSSc. A recent study on the EUSTAR cohort, attempting to define the characteristics of this subgroup, evaluated the prevalence of severe organ involvement among ATA or ACA+ patients, divided into dcSSc and lcSSc, finding no differences between the two forms. Other clinical-instrumental aspects that can predict cutaneous evolution at the time of diagnosis have never been examined.

The aim of our study is therefore to retrospectively evaluate a population of ATA+ patients and define, if existing, the main clinical-demographic and instrumental differences at the time of diagnosis and follow-up.

Material and Methods: We enrolled 75 consecutive patients with SSc with ATA positivity. The main clinical-demographic data (puffy fingers-PF, sclerodactyly-SD, mRSS, digital ulcers-DU, telangiectasia, calcinosis, gastrointestinal, cardiac, and pulmonary involvement), instrumental findings (nailfold videocapillaroscopy-NVC and high-resolution computed tomography-HRTC of the lungs), and treatment at diagnosis (T0) and at subsequent 1, 2, and 5-year follow-ups (T1, T2, and T3) were collected.

Differences in the various follow-ups were analyzed using Fisher and Mann-Whitney tests.

Results: At the time of enrollment, 34 out of 75 patients had dcSSc (45% of cases-group1) and 41 had lcSSc (55%-group2). Their characteristics are reported in Table1. In the retrospective evaluation at the time of diagnosis (T0), group1 had more DU (p0.03) and SD (p0.008) and a higher mRSS (p<0.001). These latter two characteristics were confirmed in the subsequent follow-ups. At T1, group1 less frequently presented the sine scleroderma form (p0.001) compared to group2 and had a higher frequency of a scleroderma pattern in NVC (p0.01), a finding confirmed at T2 and T3. At T2, group1 had more telangiectasia (p0.006) and fewer PF (p0.01), a characteristic also observed at T3 (Table2). The percentage of patients with interstitial lung disease (ILD) increased from T0 to T3 in both cohorts, regardless of the manifestations observed at baseline (Graph1).

Conclusions: Our study demonstrates that the ATA+ patients with lcSSc are underestimated in the literature, and the main alterations defining their phenotype are already present within two years of diagnosis. Moreover, these aspects, along with the absence of differences in ILD development, emphasize the importance of ATA presence in risk stratification at diagnosis. To confirm these results, it is necessary to increase the sample size.

P.061

PHENOTYPE OF DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS PATIENTS WITH POSITIVE ANTICENTROMERE ANTIBODIES: DATA FROM SYSTEMATIC LITERATURE REVIEW AND CASE SERIES FROM OUR REFERRAL CENTRE

Marco Binda, Beatrice Moccaldi, Mariangela Salvato, Andrea Doria, Elisabetta Zanatta

Unit of Rheumatology, Department of Medicine-DIMED, Padova University Hospital, Padova, ITALY

Introduction: Anticentromere antibodies (ACA) are typically found in limited cutaneous systemic sclerosis (lcSSc), whereas patients with anti-topoisomerase I antibodies (ATA) usually exhibit diffuse cutaneous involvement (dcSSc). However, few studies have reported less common and as yet poorly characterised associations (e.g., ACA-dcSSc). We aimed to clarify the clinical and serological characteristics of dcSSc patients with positive ACA in our referral centre and by performing a systematic literature review (SLR).

Material and Methods: We conducted a SLR focusing on ACA-dcSSc cases published in international journals in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eligibility was assessed independently by each author to reduce biases. A case series was also carried out: clinical records of all SSc patients who attended the Rheumatology Unit of Padova University Hospital between January 2022 and January 2023 were reviewed to identify those affected by ACA-dcSSc.

Results: The SLR yielded 177 ACA-dcSSc cases from 6 selected articles which compared prevalence, clinical manifestations, and outcomes between classical SSc subsets and inverted phenotypes. Among SSc cases in Padova cohort (n = 327), 3 (0.92%) patients with ACA positivity and dcSSc were identified and selected as eligible. The mean age at SSc onset in SLR population was 47.3 ± 7.4 years with a mean disease duration of 12.5 ± 3.1 years. The mean modified Rodnan Skin Score (mRSS) was 15.9 ± 2.8. As expected, the mRSS corresponded to skin subsets, with higher scores recorded in both ACA-positive and ATA-positive dcSSc, compared to lcSSc subjects. Among musculoskeletal manifestations, inflammatory arthritis and myositis were identified in 44 (33.6%) and 11 (8.4%) out of 131 patients with available data, respectively. Oesophageal involvement was reported in 75.6% of ACA-dcSSc patients, followed by interstitial lung disease in 27.7%, pulmonary hypertension in 20.3% and primary myocardial involvement in 16.3%. Overall, the ACA-dcSSc subset had a higher frequency of cardio-pulmonary and renal complications than ACA-lcSSc, though lower than that observed in ATA-dcSSc patients. Among ACA-positive patients, survival rate was similar in both skin subsets, whereas ATA-dcSSc patients had higher mortality vs. ACA-dcSSc in most of the studies.

Conclusions: Although uncommon, rheumatologists should be aware of the existence of the ACA-dcSSc subset, which appears to have a distinct clinical phenotype with a better prognosis than ATA-dcSSc.

P.062

EVALUATION OF THE RELATIONSHIP BETWEEN GASTROINTESTINAL INVOLVEMENT CHARACTERISTICS AND ANTI MUSCARINIC RECEPTOR 3 ANTIBODIES IN PATIENTS WITH SYSTEMIC SCLEROSIS

Fatma Rukiye Uysal¹, Gizem Ayan², Yasin Kiran³, Alper Sari⁴, Levent Kilic², Taylan Kav⁵, Sedat Kiraz², Ali Akdogan²

¹Hacettepe University Faculty of Medicine, Department of Internal Medicine, ANKARA, TURKEY, ²Hacettepe University Faculty of Medicine, Department of Internal Medicine, Division of Rheumatology, ANKARA, TURKEY, ³Hacettepe University Faculty of Medicine Central Laboratory, ANKARA, TURKEY, ⁴Etlik City Hospital Department of Internal Medicine Division of Rheumatology, ANKARA, TURKEY, ⁵Hacettepe University Faculty of Medicine, Department of Internal Medicine, Division of Gastroenterology, ANKARA, TURKEY

Introduction: Gastrointestinal tract (GIS) involvement is a leading cause of morbidity in systemic sclerosis (SSc). Non-invasive biomarkers are needed for GI involvement. The role of anti-muscarinic 3 receptor (anti-M3R) antibodies in the pathogenesis of GI tract involvement has been demonstrated. The aim of this study was to investigate the relationship between GI uptake characteristics and serum anti-M3R antibodies in SSc patients.

Material and Methods: This study was conducted with 41 SSc patients and 5 healthy controls. GI complaints of all patients were questioned. MUST and ESPEN scores were calculated for malnutrition and UCLA SCTC GIT 2.0 scores were calculated for the severity of GI involvement. Sandwich-ELISA test was used to detect anti-M3R antibody (MyBioSource, Inc. San Diego, USA). Anti-M3R antibodies were tested in 39 patients because the blood samples of two patients were haemolysed. The relationship between serum anti-M3R antibody titres and patients' clinical characteristics, GI symptoms and malnutrition scores were evaluated.

Results: Thirty-one (85.4%) of the patients were female, 32 (78%) had a diagnosis of limited SSc, mean age was 53.6 ± 13.5 years, median disease duration (IQR) was 15 (6.00-20.50) years. 37 (90.2%) patients had GIS involvement. Anti-M3R antibody was positive in 18 (46.1%) patients. Anti-M3R antibodies were negative in all (n=5) patients with positive anti-centromere antibodies and positive in all (n=4) patients with myositis (Table 1). According to the total UCLA SCTC GIT 2.0 score, no correlation was found between moderate to severe GIT involvement and anti-M3R antibody titres (all parameters, p >0.05). Anti-M3R antibody titres and the number of antibody positive patients were not different between the patient groups with and without risk of malnutrition according to MUST score (all parameters, p>0.05). Anti-M3R antibody titres and the number of antibody-positive patients were not different between the patient groups with and without malnutrition determined using ESPEN criteria (p>0.05). In terms of clinical characteristics, anti-M3R antibody titres were found to be lower in patients with faecal incontinence compared to those without (p=0.05). The comparison of antibody titres according to clinical and laboratory characteristics is given in Table 2.

Conclusions: In this study, a significant rate of anti-M3R antibody positivity was detected in SSc patients. No association was found between anti-M3R antibody positivity or titres and total UCLA SCTC GIT 2.0 score or malnutrition risk.

P.063

AUTOANTIBODY PROFILE IN IMU-COLV MICE SYSTEMIC SCLEROSIS MODEL: A PILOT STUDY

Jaíne Almeida¹, Zelita Aparecida de Jesus Queiroz¹, Vitória Contini¹, Cleonice Bueno¹, Thays de Matos Lobo¹, Antonio dos Santos Filho¹, Vitor Daniel Souza¹, Sergio Catanozi², Ana Paula Velosa¹, Vera Luiza Capelozzi³, Sandra Gofinet Pasoto¹, Walcy Teodoro¹

¹Division of Rheumatology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BRAZIL, ²Laboratory of lipids, Rheumatology Discipline, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BRAZIL, ³Department of Pathology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BRAZIL

Introduction: In systemic sclerosis (SSc), specific autoantibodies can be related to risk factors for certain organic manifestations, including vascular and fibrosis. The IMU-COLV mice model reproduces skin and lung fibrosis and vascular manifestations after induction with collagen V (ColV). In this study, we investigated the presence of antinuclear autoantibodies (ANA) during the evolution of the IMU-COLV mice model.

Material and Methods: The SSc model was induced in C57BL/6 female mice (n=47) immunized with COLV emulsified in Freund's adjuvant (IMU-COLV). The animals were divided in groups maintained by 15 (n=14), 30 (n=12), 45 (n=11) and 120 (n=10) days. The respective controls groups (n=37) were immunized with Freund's adjuvant and maintained for the same periods. After euthanasia, the peripheral blood of all animals was collected and the sera separated by centrifugation. The slides with Hep-2 cells were employed to evaluate the presence and pattern of ANA in the animal’s sera by immunofluorescence microscopy.

Results: When we analyzed the sera from the IMU-COLV15-days group, the presence of ANA was not detected. On the other hand, the microscopic analysis of sera from IMU-COLV30 (p=0.0004), 45 (p=0.0001) and 120 (p<0.0001) days detected intense fluorescence when compared to the control group sera. Furthermore, the ANA present in these sera showed two immunofluorescence patterns: cytoplasmic and dotted nuclear (isolated points) (Figure 1), characteristic of autoimmune diseases of the connective tissue. Furthermore, the frequency of the ANA pattern in the sera of IMU-COLV mice increased with the progression of the disease in the animal model: 30 days (p=0.006), 45 days (p=0.0002) and 120 days (p<0. 0001).

Conclusions: This pilot study showed that the IMU-COLV mouse model triggered autoimmunity, with ANA characterized by a speckled cytoplasmic and nuclear pattern (isolated dots). Furthermore, ANA was more frequent with model progression. These data suggest that the IMU-COLV mouse model may be a useful tool to evaluate the relationship between autoimmunity and other tissue manifestations in SSc.

P.064

PREDICTORS OF PROGRESSIVE PULMONARY FIBROSIS IN PATIENTS WITH SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE

Keina Yomono, Masataka Kuwana

Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, JAPAN

Introduction: Interstitial lung disease (ILD) is the leading cause of morbidity and mortality in patients with systemic sclerosis (SSc). Disease behavior of SSc-ILD is highly variable, while progressive fibrosing phenotype is associated with restrictive ventilatory impairment and resultant respiratory insufficiency due to progression of fibrosis in the lung parenchyma. This devastating phenotype is now recognized as progressive pulmonary fibrosis (PPF), which has been proposed by joint pulmonary communities. We investigated predictors of PPF in patients with SSc-ILD using a single-center prospective registry.

Material and Methods: Patients with SSc-ILD were selected from our SSc registry based on the presence of ILD confirmed by high-resolution CT (HRCT) at entry, irrespective of receiving pharmacologic treatment or not. Baseline characteristics that predicted development of PPF were identified using univariate and multivariate analyses, and a prediction model for PPF was created by combination of identified predictors. Receiver Operating Characteristic Curve (ROC) analysis was conducted to determine and optimal cut-off.

Results: A total of 136 patients with SSc-ILD were eligible for the analysis. During median of 44 months of follow-up, 36 (26%) patients developed PPF. Anti-topoisomerase I antibody, Krebs von den Lungen-6 (KL-6) > 820 IU/mL, usual interstitial pneumonia (UIP) pattern on HRCT, percent predicted forced vital capacity (ppFVC) <70%, ILD extent on HRCT>20%, were identified as initial predictors for PPF (P <0.01 for all predictors). Multivariate analysis revealed anti-topoisomerase I antibody (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.4-7.8), KL-6 > 820 IU/mL (OR 3.3, 95%CI 1.5-8.2), and ppFVC <70% (OR 3.1, 95%CI 1.4-8.9) were independent predictors for development of PPF, while UIP pattern was a borderline predictor (OR 2.0, 95%CI 0.85-4.5). Based on this result, we created a prediction model for PPF consisting of anti-topoisomerase I antibody, KL-6, ppFVC and UIP pattern, and the number of predictors was regarded as a risk score in individual patients (Table 1). ROC analysis showed that an optimal cut-off was 1.5 with an area under the curve of 0.78 (interquartile range 0.70-0.86), sensitivity of 68%, specificity of 75%, positive predictive value of 51%, and negative predictive value of 86%.

Conclusions: We successfully created the simple PPF prediction model in patients with SSc-ILD, but this model requires validation using independent cohorts.

P.065

THE EFFICACY OF THE BREATH-HOLDING TEST: MACHINE LEARNING APPROACH TO PREDICT PULMONARY FUNCTION IN SYSTEMIC SCLEROSIS

Jina Yeo¹, Min Hyuk Lim^2,3,4,5, Ju Yeon Kim⁶, Ji In Jung⁶, Saram Lee^2,3, Eun Bong Lee^6,7,8

¹Division of Rheumatology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, SOUTH KOREA, ²Department of Transdisciplinary Medicine, Seoul National University Hospital, Seoul, SOUTH KOREA, ³Innovative Medical Technology Research Institute, Seoul National University Hospital, Seoul, SOUTH KOREA, ⁴Institute of Medical and Biological Engineering, Seoul National University, Seoul, SOUTH KOREA, ⁵Ulsan National Institute of Science and Technology, Graduate School of Health Science and Technology, Ulsan, SOUTH KOREA, ⁶Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital, Seoul, SOUTH KOREA, ⁷Department of Internal Medicine, Seoul National University College of Medicine, Seoul, SOUTH KOREA, ⁸Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul, SOUTH KOREA

Introduction: Lung involvement is major causes of mortality in systemic sclerosis (SSc). The breath-holding test (BHT), rapid bedside test, is a useful surrogate marker of pulmonary capacity in SSc. This study aimed to develop a machine learning (ML) model to predict pulmonary parameters, using real-time data of oxygen saturation (SpO2) and pulse rates obtained during the BHT in SSc patients.

Material and Methods: Two prospective SSc cohorts were recruited for the study. Cohort 1 (n = 72) was for training a ML model and collected from August 2020 to February 2021, while Cohort 2 (n = 84) was for external validation of the established model and collected from April 2022 to September 2022. Real-time values of SpO2 and pulse rates were obtained during the BHTs and 6-min walking tests (6MWT) in Cohort 1, while the same data were collected during BHT in Cohort 2. The random forest classifier was applied to predict pulmonary functions (Forced vital capacity, FVC; diffusion capacity of carbon monoxide, DLCO), using data on SpO2 and pulse rates. In addition, demographic information such as age, gender, and body mass index, modified Rodnan skin score was also concatenated to the input feature. The validity of the ML model was evaluated using the Receiver Operating Characteristic (ROC) curve and the Area Under the ROC Curve (AUROC).

Results: A total of 72 subjects were enrolled in Cohort 1 and 84 subjects in Cohort 2, respectively. There was an overlap of 36 subjects between Cohort 1 and 2. In 4-fold cross-validation evaluation from Cohort 1, the ML algorithm using data from BHT showed AUROC of 0.739 ± 0.043 for %FVC < 70%, and 0.713 ± 0.075 for %DLCO < 60%, respectively (Figure 1A). A model using only SpO2 during BHT values showed a comparable AUROC to predict FVC and DLCO (AUROC for %FVC; 0.767 ± 0.096, and %DLCO; 0.763 ± 0.041, respectively) (Figure 1B). The ML model using data from 6MWT showed similar performance compared with BHT (AUROC for %FVC; 0.780 ± 0.040 and %DLCO; 0.754 ± 0.099, respectively). Cohort 2, an external validation cohort, showed similar AUROC (For %FVC, 0.686; for %DLCO, 0.669).

Conclusions: Our ML models showed the potential to discriminate decreased pulmonary function in SSc using data from SpO2 and pulse rates during the BHT and 6MWT. BHT combined with SpO2 monitoring can be useful to detect impaired lung capacity in SSc patient in whom a pulmonary function test is difficult to perform. (NCT04484948)

P.066

NINTEDANIB TREATMENT IN PATIENTS WITH SYTEMIC SCLEROSIS ASSOCIATED INTERSTITIAL LUNG DISEASE: A REAL LIFE EXPERIENCE

Yasemin Yalcinkaya¹, Shirkhan Amikishiyev¹, Burak Gultekin¹, Ezgi Sahin¹, Yildiz Akbal Engin¹, Bahar Artim-Esen¹, Ahmet Gul¹, Zuleyha Bingol², Gulfer Okumus², Murat Inanc¹

¹Istanbul University, Department of Internal Medicine, Division of Rheumatology, Istanbul, TURKEY, ²Istanbul University, Department of Pulmonology, Istanbul, TURKEY

Introduction: Nintedanib (NIN), a tyrosine kinases inhibitor that exhibits antifibrotic and antiinflammatory effects, has been approved for systemic sclerosis associated interstitial lung disease (SSc-ILD). We aimed to evaluate the characteristics of progressive SSc-ILD patients requiring anti-fibrotic therapy despite immunosuppressives (ISs), progression of respiratory functions and adverse events during the treatment period.

Material and Methods: Thirty-one patients (n=25, 83.9%) who fulfilled ACR/EULAR (2013) criteria for SSc and received NIN for progressive ILD in addition to ISs included into this retrospective analysis.

Results: Demographics and characteristics of SSc patients were summarised in table 1. NIN was initiated median 6(2-23) years after the onset of ILD and used median 6(2-30) months, concomitant with mycophenolate mofetil (MMF)(71%) or rituksimab+MMF(29%).

The baseline FVC (median) was 1690(930-2800) ml and 61(30-94)%, and DLCO was 41(16-75)% before the initiation of NIN. The decline in FVC (ml), FVC (%) and DLCO (%) from baseline to 1.year and 1.year to 2.year were similar to decline 1 year before the initiation of NIN (mean values, -104 and -80 vs -106 ml; -2.1 and -1.6 vs -3.0%; -3.1 and -3.2 vs -2.8%)(table-2). SSc-ILD patients with baseline FVC>1700 ml displayed numerically higher declines in FVC(ml) -124 (±224) vs -66 (130), p=0.08) within the first year of the NIN.

Adverse events (diarrhoea (22.6%), nausea/vomiting (9.7%), abdominal pain (16.1%), weight loss (9.7%), liver test abnormalities (12.9%), malignancy (3.2%)) leading to dose reduction/re-escalation was required in 9(29%) and dose interruption in 3(9.7%) patients. Seven patients (22.6%) were deceased due to small cell lung cancer (n=1), pulmonary hypertension (n=2), acute cardiac arrest (n=1), fungal pneumonia (n=2), and pulmonary embolism (n=1). Respiratory functions of the deceased patients, before the initiation NIN and 1st year, were not significantly different from those of surviving patients (table-2). In patients who deceased, DLCO(%) was numerically lower and decreased further, although not significant (figure-1).

Conclusions: NIN was used in progressive SSc-ILD patients who had predominantly diffuse cutaneous involvement, anti-SCL70 positivity and exposed to multiple ISs and/or rituximab. The annual change in FVC and DLCO were shown to be similar during the treatment period. SSc-ILD patients with higher baseline respiratory capacity displayed numerically higher declines in FVC. Although non-significant levels, DLCO(%) was lower and decline was remarkable in deceased patients. Gastrointestinal adverse events should be considered and managed. Continuous decline in respiratory functions was observed in some patients despite addition of NIN treatment to ISs and early identification of high-risk patients is mandatory to avoid progression.

P.067

C-REACTIVE PROTEIN IN SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE: RE-ENVISIONING CLINICAL TRIAL ENRICHMENT STRATEGIES BASED ON EVIDENCE

Elizabeth Volkmann¹, Alana Haussmann¹, Holly Wilhalme¹, Grace Kim², Andrea Oh², Jonathan Goldin², Michael Roth¹, Donald Tashkin¹, Shervin Assassi³

¹University of California, Los Angeles, Department of Medicine, Los Angeles, USA, ²University of California, Los Angeles, Department of Radiological Sciences, Los Angeles, USA, ³UT Health Science Science Center at Houston, Department of Medicine, Houston, USA

Introduction: Elevated C-reactive protein (CRP) is an inclusion criterion for most current trials for systemic sclerosis-associated interstitial lung disease (SSc-ILD). These trials also permit background mycophenolate mofetil (MMF) for >=6 months. While observational studies have demonstrated that elevated CRP is positively associated with progression of SSc-ILD, its role as a predictive biomarker in patients on MMF is unknown. This study investigated the role of CRP in predicting progression of SSc-ILD in MMF-treated patients.

Material and Methods: In Scleroderma Lung Study (SLS) II, serum CRP levels were measured at baseline and after 12 months of therapy with MMF or cyclophosphamide (CYC). The forced vital capacity (FVC)%-predicted was measured every 3 months over 24 months. A computer-aided design scoring system was used to calculate the change in quantitative radiological ILD from baseline to 24 months. The transitional dyspnea index evaluated changes in dyspnea. Spearman’s correlations evaluated the relationship between baseline CRP and patient features. Paired t-tests compared the change in CRP measurements from baseline to 12 months. A logistic regression model examined the relationship between baseline CRP, as well as the change in CRP (baseline to 12 months), and progressive pulmonary fibrosis (PPF) at 24 months. Analyses were performed for the entire cohort and separately by treatment arm.

Results: Among SLS II participants, 101 had CRP measurements at baseline and 12 months. Baseline CRP levels correlated with shorter disease duration (r=-0.3, P=0.005) and were higher in patients with diffuse SSc (P=0.007). CRP levels decreased from baseline to 12 months in the whole group (P=0.01), but the decrease was slightly greater in patients randomized to MMF versus CYC (-0.47 vs. -0.33 ug/mL). Patients who did not develop PPF (N=79) had a larger decline in CRP compared with patients who developed PPF (N=20) (Mean difference: -0.31 [1.6] ug/mL; Effect size 0.19). In patients randomized to MMF, the mean difference in CRP between patients who did not/did develop PPF was even larger (Mean difference -1.3 [1.9] ug/m; Effect size 0.68; P=0.048) (Figure 1). No association was observed between baseline CRP and PPF (P=0.96).

Conclusions: In patients treated with MMF in a clinical trial, the change in CRP from baseline to 12 months was associated with future PPF; whereas, the baseline CRP level was not. These findings have important implications for SSc-ILD trial design. Relying solely on baseline CRP to predict PPF in SSc-ILD patients on MMF may not effectively enrich the cohort for SSc-ILD progressors.

P.068

EFFECTS OF EARLY IMMUNOSUPPRESSIVE TREATMENT ON THE COURSE OF PULMONARY FUNCTION IN SYSTEMIC SCLEROSIS

Arthiha Velauthapillai¹, Merle F.R. Bootsma¹, Cosimo Bruni^2,3, Christina Bergmann^4,5, Marco Mattuci-Cerinic^6,7, David Launay⁸, Gabriela Riemekastan⁹, Liudmila Garzanova¹⁰, Paolo Airò¹¹, Elena Rezus^12,13, José A.P. da Silva^14,15, Francesco Del Galdo¹⁶, Nicolas Hunzelmann¹⁷, Lorinda S. Chung¹⁸, Dorota Krasowska¹⁹, Oliver Distler², Cornelia H.M. van den Ende¹, Madelon C. Vonk¹; on behalf of EUSTAR collaborators

¹Department of Rheumatology, Radboud University Medical Center, Nijmegen, THE NETHERLANDS, ²Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, SWITZERLAND, ³Department of experimental and clinical medicine, Division of Rheumatology, University of Florence Careggi University, Florence, ITALY, ⁴Department of Internal Medicine 3, Rheumatology and Clinical Immunology, Friedrich-Alexander-University (FAU) Erlangen, Erlangen, GERMANY, ⁵Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum, Erlangen, GERMANY, ⁶Department of Experimental and Clinical Medicine, University of Florence, Florence, ITALY, ⁷Unit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Hospital, Milan, ITALY, ⁸Département de Médecine Interne et d Immunologie Clinique, Univ. Lille, Lille, FRANCE, ⁹Department of Rheumatology and Clinical Immunology, University of Medical Center Schleswig-Holstein, Lübeck, GERMANY, ¹⁰VA Nasonova Research Institute of Rheumatology, Moscow, RUSSIA, ¹¹UOC Reumatologia e Immunologia Clinica, ASST Spedali Civili di Brescia, Brescia, ITALY, ¹²Department of Rheumatology, Grigore T. Popa University of Medicine and Pharmacy, Lasi, ROMANIA, ¹³Clinical Rehabilitation Hospital, Lasi, ROMANIA, ¹⁴Faculty of Medicine, University of Coimbra, Coimbra, PORTUGAL, ¹⁵Department of Rheumatology, Centro Hospitalar e Universitário de Coimbra, Coimbra, PORTUGAL, ¹⁶NIHR Biomedical Research Centre Leeds Institute Of Rheumatic And Musculoskeletal Medicine, University of Leeds, Leeds, UNITED KINGDOM, ¹⁷Department of Dermatology, University of Cologne, Köln, GERMANY, ¹⁸Department of Medicine & Dermatology, Division of Immunology & Rheumatology, Stanford University School of Medicine, Stanford, USA, ¹⁹Department of Dermatology, Venereology and Pediatric Dermatology, Medical University of Lublin, Lublin, POLAND

Introduction: While recent studies reported a favorable effect of starting immunosuppression in mild interstitial lung disease (ILD), there is no data on the effect of timing of treatment and disease course. Therefore, we aimed to analyze the association between timing of immunosuppression and the course of forced vital capacity % predicted (ppFVC), irrespective of ILD-status.

Material and Methods: A combined cohort from the EUSTAR database and Nijmegen Systemic Sclerosis cohort was created, including adult patients treated with immunosuppression (i.e. mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab and tocilizumab) after diagnosis, negative for ILD on high-resolution CT(HRCT) at or within 2 months after start treatment, and no prior treatment with biological or antifibrotic. Data between start of first immunosuppression and five years follow-up were analysed. Disease duration (time between first non-Raynaud phenomenon and start immunosuppression) was dichotomized into early and late treatment using a cut-off point of 3 years. The trajectory of ppFVC was assessed using linear regression adjusted for confounders. Where data were available, the change in ppFVC was categorized annually as followed: “significant decline“ (absolute FVC decline > 10%), “moderate decline” (absolute FVC decline 5-10%), “stable” (absolute FVC change < 5%) and “improvement” (absolute FVC improvement of >/5%).

Results: We identified 789 patients fulfilling the criteria. The early treatment group (n= 422, 60%) showed a higher prevalence of male sex, diffuse cutaneous SSc, anti-topoisomerase-I antibody positivity, anti-RNA-polymerase-III antibody positivity and elevated C-reactive protein as well as higher modified Rodnan skin score. The incidence of ILD and baseline ppFVC were comparable between the groups (see table 1). PpFVC trajectories adjusted for gender, diffuse subtype, Caucasian ethnicity, anti-topoisomerase I antibodies, anti-RNA polymerase III antibodies, age at baseline, FVC at baseline and DLCO at baseline were not different between groups (DFVC (95% CI): 1.36% (-0.52 - 3.25), p=0.16) (fig. 1). Classifying change in ppFVC annually showed that the prevalence of significant decline in ppFVC varied between 25-38% for the early group and 19-30% for the late group.

Conclusions: Concluding, starting early with immunosuppression did not influence the course of ppFVC regardless of ILD-status compared to starting late. Furthermore, the need for monitoring pulmonary function regardless ILD-status is emphasized, given the prevalence of progressive ILD in this combined cohort is comparable to SSc-ILD cohorts.

P.069

NINTEDANIP USAGE MAY PREVENT SCLERODERMA ILD PROGRESSION

Ender Terzioglu¹, Yagmur Kahraman², Funda Erbasan¹, Deniz Ozel³, Veli Yazisiz¹, Bengisu Aslan¹

¹Akdeniz University Dpt of Rheumatology, antalya, TURKEY, ²Akdeniz University Dpt of Internal Medicine, Antalya, TURKEY, ³Akdeniz University Dpt of Statistics, antalya, TURKEY

Introduction: Systemic Sclerosis related interstitial lung disease is a disease that can progress despite anti inflammatory treatments, and antifibrotic treatment may be useful in preventing progression in the long term.

Material and Methods: 16 patients with scleroderma were evaluated in this study and the patients were followed for more than 1 year. All patients were patients with interstitial lung disease receiving anti-inflammatory therapy. 4 of these patients used nintedanip from the beginning during this period. All patients received anti-inflammatory treatments. Patients who did not use nintedanip were named as the control group and those who used it were called the patient group. The patients were evaluated in terms of FVC and DLCO parameters at the end of 1 year. Student T test, Mann Whitey U test and Cohen analysis were used as statistics.

Results: Patients who used and did not use nintedanip received similar anti-inflammatory treatments. The group using nintedanip maintained its FVC and DLCO values better at the end of 1 year, and respiratory findings progressed more in the group not taking it.

Conclusions: Antifibrotic therapy can be used as a drug added to anti-inflammatory treatments in patients with systemic sclerosis lung involvement and can reduce fibrosis progression.

P.070

THE RELATIONSHIP BETWEEN DIGITAL ULCER AND CAPILLAROSCOPY FINDINGS AND LUNG PARENCHYMA AND VASCULAR INVOLVEMENT IN PATIENTS WITH SCLERODERMA

Nehir Sisman², Funda Erbasan¹, Tahir Saygin¹, Veli Yazisiz¹, Deniz Ozel³, Ender Terzioglu¹

¹Akdeniz University Dpt of Rheumatology, Antalya, TURKEY, ²Akdeniz University Dpt of Internal Medicine, antalya, TURKEY, ³Akdeniz University Dpt of statistics, Antalya, TURKEY

Introduction: Scleroderma cause inflammatory, vascular and fibrotic changes in the skin and various organs. Demonstration of capillary changes is thought to be guiding about the course of the disease. The aim of our study is to evaluate capillary involvement by physical examination and capillaroscopy and to retrospectively evaluate the relationship between it and lung involvement.

Material and Methods: 78 patients diagnosed with systemic sclerosis according to 2013 (ACR) and (EULAR) classification criteria who were being followed in the Akdeniz University were retrospectively evaluated. Patients' demographic characteristics, accompanying diseases, clinical and examination findings, capillaroscopic evaluations, laboratory and radiology results, respiratory function tests, transthoracic echocardiography reports and the treatments they received were obtained from the patient files and hospital information management system. Skin involvement and capillaroscopic evaluations were examined to determine whether there were radiological and functional differences in lung involvement (HRCT, Lung function tests).

Results: Of the 78 scleroderma patients, 74 (94.9%) were female and 4 (5.1%) were male.

According to the results of capillaroscopy; 44.9% (35 patients) of the patients had early scleroderma pattern, 29.5% (23 patients) had active scleroderma pattern, 25.6% (20 patients) had late scleroderma pattern. There was sclerodactyly in 72 of the patients (92.3%). Raynaud's phenomenon was present in 68 patients (87.2%). Digital ulcer was observed in 25 patients (52.5%).

In 55 patients (70.5%), lung findings were seen on HRCT. Those with lung involvement in HRCT had high ANA centromeric staining (76.9%). (p<0.001). The FVC value (Mean: 69.2) in patients with HRCT was lower than those without (Mean: 80.13) (p0.009). A significant relationship was found between digital ulcer and capillaroscopy variables (p<0.001). In those with digital ulcers, the rate of capillaropy 3 (64%) was higher than those without digital ulcers (7.7%). The FVC value (Median: 62) and DLCO value (Mean: 51) in those with digital ulcers were lower than the FVC (Median: 83) and DLCO values (Mean: 65) in those without digital ulcers (p<0.05).

Conclusions: In this study, a significant deterioration in capillaroscopy and respiratory tests such as FVC and DLCO was observed in patients with scleroderma lung involvement by HRCT. (figure-1) lung involvement was high in advanced disease age, and capillaroscopy findings were found to be advanced in these people. The presence of a digital ulcer was also seen to be associated with advanced capillaroscopy findings, and lung function tests were found to be low in the presence of a digital ulcer. (Figure-2)

P.071

INTERSTITIAL LUNG DISEASE IN SCLERODERMA PATIENTS: ASSOCIATION BETWEEN THE DISEASE PHENOTYPE AND FLOW CYTOMETRY DATA - PRELIMINARY RESULTS

Adela Skoumalova¹, Pavel Horak^1,2, Zuzana Mikulkova², Eva Kriegova², Ondrej Janca³

¹Olomouc University Hospital, Olomouc, CZECH REPUBLIC, ²Palacký University Olomouc, Olomouc, CZECH REPUBLIC, ³Technical University of Ostrava, Ostrava, CZECH REPUBLIC

Introduction: Lung involvement contributes significantly to the increased morbidity and mortality of patients with SSc. The pathogenesis of SSc is complex and is not completely understood. The probable mechanism is a result of pathologic interactions between cells, cytokines, and the matrix which all lead to immune activation, vascular damage, and excessive synthesis and deposition of collagen. Determining the risk of developing interstitial lung disease in individual patients is not currently possible. The aim of our study is to determine whether activation of specific immune cell populations and expression of selected chemokine receptors and regulatory molecules may correspond to the disease phenotype.

Material and Methods: In the cohort of 37 patients with SSc, the representation of immune cell populations and their subpopulations (T-lymphocytes, B-lymphocytes, monocytes, neutrophils, dendritic cells), including their activation features and the expression of selected chemokine receptors and regulatory molecules, was analysed by flow cytometry. There were 16 patients with diffuse form of SSc and 21 with limited form of SSc. 26 patients had pulmonary interstitial involvement, of them 15 with diffuse form of SSc and 11 with limited form of SSc. A total of 80 parameters were mesured. Statistical analysis by unpaired t-test/Mann-Whitney U-test was performed.

Results: When comparing the patients according to disease phenotype, the diffuse form of SSc showed a higher proportion of CCR4+ lymphocytes associated with Th2 response and pro-inflammatory Th17 lymphocytes. There was reduced number of NK cells; however, compared to the limited form, activated forms of NK cells with HLA-DR expression were more frequent. In patients with pulmonary involvement, there was an overall lower representation of lymphocytes but an increased representation of CCR4+ lymphocytes and Th17 lymphocytes. Furthermore, similar to patients with diffuse SSc, a decreased number of NK cells was found, but activated forms with HLA-DR expression were also more frequent. On the other hand HLA-DR expresion on monocytes was lower in pulmonary involment.

Conclusions: Due to the relative rarity of systemic scleroderma, it is very difficult to establish a biomarker in the true sense of the word. Our ongoing work aims to include a larger number of patients and determine whether activation of certain immune cells contributes to the phenotypic manifestations of the disease.

Supported by MH CZ – DRO (FNOl, 00098892) and by IGA_LF_2023_002

P.072

NINTEDANIB IN SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE – A MULTICENTRE NATIONWIDE COHORT STUDY

Augusto José Ser Silva¹, Ana Martins², Beatriz Samões³, Cláudia Oliveira⁴, João Aguiar¹, Laura Gago⁵, Ana Catarina Duarte⁶, Maria João Salvador⁷, Natália Melo⁸, João Eurico Fonseca¹, Maria João Gonçalves⁵, Patrícia Pinto³, Rita Prata⁴, Vasco C. Romão¹, Miguel Bernardes², Sofia Barreira¹, Catarina Resende¹

¹Rheumatology and Metabolic Bone Diseases Department, Centro Hospitalar e Universitário Lisboa Norte, Lisboa, PORTUGAL, ²Rheumatology Department, Centro Hospitalar Universitário de São João, Porto, PORTUGAL, ³Serviço de Reumatologia, Centro Hospitalar Vila Nova de Gaia/ Espinho, Vila Nova de Gaia, PORTUGAL, ⁴Rheumatology Department, Hospital Infante D. Pedro- Centro Hospitalar do Baixo Vouga, Aveiro, PORTUGAL, ⁵Rheumatology Department, Centro Hospitalar Lisboa Ocidental, Hospital Egas Moniz, Lisboa, PORTUGAL, ⁶Rheumatology Department, Hospital Garcia de Orta, Almada, PORTUGAL, ⁷Rheumatology Department, Centro Hospitalar Universitário de Coimbra, Coimbra, PORTUGAL, ⁸Pneumology Department, Centro Hospitalar Universitário de São João, Porto, PORTUGAL

Introduction: Interstitial lung disease (ILD) is a severe manifestation of Systemic Sclerosis (SSc). Conventional treatments have shown modest and short-lived success in the control of ILD. Nintedanib was recently approved for SSc-associated ILD.

This study aims to describe the clinical features and outcomes of SSc-ILD patients treated with Nintedanib, across nine Portuguese rheumatology departments.

Material and Methods: Retrospective cohort study, with chart review of the medical records for inclusion of patients with SSc-ILD treated with Nintedanib. The clinical characteristics of patients are described as frequencies for categorical variables and mean±standard deviation for continuous variables. Differences between groups were evaluated through chi-square or dependent samples t-test. A linear regression analysis was performed to verify independent association of relevant covariables.

Results: 38 patients (81.6% women) were included with a mean age at SSc and ILD diagnosis of 54.5±11.7 and 56.6±11.5 years, respectively (table 1). The mean time from ILD diagnosis to Nintedanib initiation was 4.8±3.1 years. Nonspecific interstitial pneumonia was identified in 22 (57.9%) cases, usual interstitial pneumonia in 15 (39.5%), and organizing pneumonia in one (2.6%). All patients had previously received immunosuppressive therapy, most commonly mycophenolate mofetil (30, 78.9%) and glucocorticoids (22, 57.9%). Mean Nintedanib treatment duration was 29.4±18.5 months, with 17 patients receiving treatment for more than 24 months.

Single-breath diffusing capacity of the lungs for CO (DLCO) and forced vital capacity (FVC) had no significant variation during follow-up, showing a stabilizing trend. In the subset of patients with less than one year of ILD duration (n=5), FVC variation had a significant improvement at 12 months (5.7±1.5 vs -0.6±11.7, p=0.043) which was not observed in any other time points, neither in the patients who started Nintedanib after one year of ILD duration. with less than two or three years of ILD duration. Over the period of follow-up, Nintedanib was generally well tolerated.

Conclusions: SSc-ILD patients treated with Nintedanib showed a trend for DLCO and FVC stabilization. The subset of patients who started Nintedanib within one year of ILD onset showed a benefit at 12 months, suggesting a greater benefit when Nintedanib is started earlier. Further replication in larger and prospective cohorts is warranted.

P.073

KL6 AND IL-18 LEVELS ARE NEGATIVELY CORRELATED WITH RESPIRATORY FUNCTION TESTS AND ILD EXTENT ASSESSED ON HRCT IN PATIENTS WITH SYSTEMIC SCLEROSIS-RELATED INTERSTITIAL LUNG DISEASE (SSC-ILD)

Cristiana Sieiro Santos, Sara Calleja Antolin, Javier De La Calle Lorenzo, Carmen Lãpez Garay, Clara Moriano Morales, Elena Bollo De Miguel, Elvira Dãez ÃLvarez

Complejo Asistencial Universitario de León, León, SPAIN

Introduction: Serum biomarkers have been suggested as indicators for pulmonary damage with clinical value in the diagnosis and prognosis of SSc-ILD. We aim to investigate the role of serum biomarkers (Krebs von den Lungen-6 KL-6, IL-18 and IL-18BP) as potential biomarkers reflecting the severity of SSc-ILD as assessed through high-resolution computed tomography (HRCT) and pulmonary function tests (PFT), including forced vital capacity (%FVC) and diffusing capacity of the lung for carbon monoxide (%DLCO).

Material and Methods: A cross-sectional study including patients with SSc fulfilling the 2013 ACR/EULAR criteria was performed. Patients were classified according to disease duration and presence of ILD. All SSc patients underwent chest HRCT scans and PFT at baseline. Serum concentration of KL-6, IL8 and IL18BP were determined using the quantitative ELISA technique, sandwich type (solid phase sandwich Enzyme Linked-Immuno-Sorbent Assay), with kits from MyBiosource for KL-6 and from Invitrogen for IL18 and IL18BP. A semiquantitative grade of ILD extent was evaluated through HRCT scan (grade 1, 0–20%; grade 2, >20%). Extensive disease was defined as more than 20% lung involvement on HRCT, and FVC less than 70% predicted and limited lung involvement as equal or less than 20% ILD involvement on HRCT, and an FVC equal or more than 70% predicted.

Results: 74 patients were included, 27% were male. The mean age at diagnosis was 57.5±15 years and the mean time since diagnosis was 7.67±8 years. 28 patients had ILD (38%). 64 % of patients had <20% ILD extent classified through HRCT scan. SSc-ILD patients had elevated serum KL-6 and IL-18 levels compared to patients without ILD (p=0.003 and p=0.04), and those findings were preserved after adjusting for age and sex (table 1). Negative correlation between KL-6 levels and %FVC (β=-0.25, p 0.037) and %DLCO (β=-0.28, p 0.02) and between IL-18 levels and %FVC (β=-0.20, p 0.03) and %DLCO (β=-0.14, p 0.04) were found. Serum KL-6 and IL-18 levels successfully differentiated grades 1 and 2 of the semiquantitative grades of ILD extent (p = 0.028 and p=0.021). Semiquantitative grades of ILD on the HRCT scan were significantly proportional to the KL-6 (p 0.01) and IL-18 (P=0.03)

Conclusions: Serum KL-6 levels and IL-18 were increased in patients with SSc-ILD and showed a positive correlation with ILD severity as measured using a semiquantitative CT grading scale, whereas serum KL-6 levels had a negative correlation with PFT parameters. Serum KL-6 and IL-18 could be a clinically useful biomarker in screening/evaluating SSc-ILD.

P.074

PREDICTORS OF INTERSTICIAL LUNG INVOLVEMENT IN SYSTEMIC SCLEROSIS

Cristiana Sieiro Santos, Miriam Retuerto Guerrero, Clara Moriano Morales, Carolina Ãlvarez Castro, Alejandra López Robles, Elvira Dãez Ãlvarez

Complejo Asistencial Universitario de León, León, SPAIN

Introduction: Interstitial lung disease (SSc-ILD) and pulmonary hypertension are the leading causes of death in patients with systemic sclerosis (SSc). Identifying SSc-ILD development and initiating treatment is essential to optimize therapeutic benefit.

Objectives: We aimed to identify predictors of SSc-ILD and compared early (<5 years from diagnosis) versus late (>5 years from diagnosis) onset.

Material and Methods: We conducted a retrospective cohort study by including patients diagnosed with SSc from 1980 to 2020 followed in our unit and compared the clinical profile of patients with SSc-ILD to control SSc-non-ILD patients. Demographic features, clinical and immunological characteristics, baseline pulmonary function and capillaroscopy data were retrieved. Logistic regression modelling was run to identify factors associated with SSc-ILD development. Factors associated with ILD were then determined as factors associated with early or late onset using multivariate analysis. Bonferroni correction was used to limit Type I errors.

Results: We have included 103 patients from our patient registry from 1980 to 2021 (42% with SSc-ILD). Logistic regression identified risk factors associated with increased or decreased odds ratio for developing ILD is summarized in table 1. Smoking history, male sex, the presence of myositis, anti-Scl70 and anti-Ro52 positivity, baseline pulmonary function including FVC and DLCO, mMRC (Modified Medical Research Council) dyspnea scale>2, mMSS (Modified Rodnan Skin Score), and late pattern in capillaroscopy were identified as SSc-ILD predictors. Older age at SSc diagnosis, the presence of telangiectasias and smoking status were correlated with of SSc-ILD onset before 5 years, while male gender, the presence of myositis and antiphospholid antibodies were correlated with late-onset SSc-ILD.

Conclusions: Conclusions: We identified 10 factors significantly associated with risk of developing SSc-ILD: smoking, male sex, diffuse cutaneous involvement, the presence of myositis, shorter Raynaud duration to SSc diagnosis, anti-Scl70 and anti-Ro52 positivity and baseline pulmonary function (lower baseline DLCO and FVC increasing risk) and late capillaroscopy pattern and identified predictors for early and late-onset SSc-ILD.

P.075

IDENTIFICATION AND CHARACTERIZATION OF CLINICAL AND RADIOLOGIC MARKERS OF DISEASE PRESENTATION AND PROGRESSION IN PATIENTS WITH SCLERODERMA RELATED INTERSTITIAL LUNG DISEASE (SSC-ILD) IN ONTARIO

Jessica Scott¹, Rachel Gerber², Margaret Larché¹

¹McMaster University, Hamilton, CANADA, ²University of Toronto, Toronto, CANADA

Introduction: Systemic sclerosis (SSc) is a connective tissue disease characterized by immune dysfunction causing vasculopathy, inflammation and fibrosis of multiple organs including the skin, lungs, heart, and GI tract. Lung involvement, characterized by interstitial lung disease (SSc-ILD) and pulmonary hypertension, affects around 50-70% percent of patients and together are presently the leading cause of death for patients with systemic sclerosis. Previous studies have identified a number of risk factors for development of SSc-ILD, including older age, African American descent, CK elevations, the presence of specific autoantibodies, and the diffuse subtype of scleroderma. In this study, we examined the clinical risk factors that predict incident ILD in patients with scleroderma, as well as the risk factors that predict early versus late development of incident ILD in patients with scleroderma in a Canadian context. We also examined whether patients with evidence of fibrosis on chest x-ray predictably undergo high-resolution computed tomography (HRCT).

Material and Methods: Approximately 200 patients in Hamilton, Ontario with SSc are registered in the Canadian Scleroderma Research Group, a national longitudinal registry of adult SSc patients. We performed chart reviews of all Hamilton patients enrolled in the CSRG registry and extracted data related to our study question. We used descriptive statistics to compare clinical risk factors between patients who do versus do not develop ILD, and those who develop early versus late ILD during the follow-up of the CSRG. We also used descriptive statistics to determine the proportion of patients with abnormal chest x-rays who did and did not receive HRCT.

Results: Preliminary data analysis reveals that, among a Hamilton cohort of patients, the most important risk factors for the development of SSc-ILD include diffuse subtype of scleroderma, the presence of anti-topoisomerase I antibodies, and an early abnormal forced vital capacity on spirometry. Our preliminary data also show that only 47% of Hamilton patients with abnormal chest X-ray findings proceed with HRCT.

Conclusions: Our data reveals an important gap in the care of scleroderma patients within a Canadian context and argues for more routine monitoring and testing of scleroderma patients with evidence of abnormalities on routine testing.

P.076

COMPLIANCE OF PATIENTS WITH SYSTEMIC SCLEROSIS TO PULMONARY FUNCTION TESTS

Gül Sandal Uzun¹, Oguz Karcioglu², Alper Sari³, Elifnaz Sancar², Erdinc Unaldi¹, Busra Firlatan¹, Levent Kilic¹, Ali Akdogan¹

¹Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, TURKEY, ²Hacettepe University, School of Medicine, Department of Pulmonary Diseases, Ankara, TURKEY, ³Etlik City Hospital, Ankara, TURKEY

Introduction: Interstitial lung disease (ILD) is a significant cause of death in patients with systemic sclerosis (SSc). FVC measurement of force vital capacity, an important parameter in respiratory function testing, is evaluated in the diagnosis and follow-up of ILD. FVC is used in all randomized controlled trials to assess ILD and treatment response and progression. Various diseases such as reduction of the interincisal distance, fibrosis of the skin over the chest, malnutrition, presence of muscle weakness and joint contracture can affect the measurement of lung function in patients with systemic sclerosis (SSc). In this study, we aimed to evaluate the quality of forced vital capacity (FVC) examination in patients with SSc according to the American Thoracic Society (ATS) guidelines.

Material and Methods: 77 patients with SSc and 100 age-sex-matched patients who applied to the outpatient chest clinic (control group) were included in the study. Demographic and clinical data were recorded. Decreased interincisal distance and restriction of chest expansion were defined as <40 mm and <2.5 cm, respectively. Malnutrition risk status was evaluated using MUST score. FVC test quality of patients was assessed according to the ATS guideline. SSc patients and control group were further divided into two groups according to the grading system of the ATS guidelines (high quality FVC test = grade A/B/C and low quality FVC test= grade D/E/F/U).

Results: The median age ofSSc patients (93.5% female) was 56.8 (21.4-76) years. 26 (33.8%) patients had diffuse skin involvement and 33 (42.9%) had interstitial lung disease (ILD). The frequency of patients with high quality FVC test was lower among SSc patients than control group (55.8% vs 80%; p=0.001). SSc patients with low quality FVC test were older, had higher mRSS and more frequently had hand contractures and decreased chest expansion. Diffuse disease subset and ILD were also slightly more common in patients with low quality FVC test. The presence of more than one risk factor that affected FVC was statistically significantly higher in patients with low quality FVC test.

Conclusions: The rate of high FVC test in patients with SSc is lower than control group. The severity of skin involvement, restriction of chest expansion and the presence of joint contracture may influence the appropriateness of these measurements. These parameters should be considered when evaluating FVC measurement in SSc patients.

P.077

BRONCHIECTASIS IN SYSTEMIC SCLEROSIS: A SINGLE-CENTER ANALYSIS

Miriam Retuerto, Clara Moriano, Cristiana Sieiro, Elvira Diez

Complejo Asistencial Universitario de León, LEON, SPAIN

Introduction: Bronchiectasis (BC) has been observed in association with Systemic Sclerosis (SSc). Oesophageal dysmotility, immunosuppressive drugs and the direct effect of collagen deposition in the airway are postulated as causes of bronchiectasis in patients with SSc. We aim toObservational, analytical and cross-sectional monocenter study. We included 92 patients with diagnosis of SSc according to modified ACR-EULAR 2013 criteria, who had under-gone high-resolution computed tomography (HRCT) of the chest within the last two years. Patients with traction bronchiectasis associated to pulmonary fibrosis were ex-cluded. Continuous variables were compared by Student’s or Mann Whitney’s T test, and categorical variables by Chi2 test or Fisher’s exact test. evaluated the bronchiectasis prevalence in an SSc population and its possible association with clinical and immunological features.

Material and Methods: Observational, analytical and cross-sectional monocenter study. We included 92 patients with diagnosis of SSc according to modified ACR-EULAR 2013 criteria, who had under-gone high-resolution computed tomography (HRCT) of the chest within the last two years. Patients with traction bronchiectasis associated to pulmonary fibrosis were ex-cluded. Demographic, clinical and immunological data were collected. Continuous variables were compared by Student’s or Mann Whitney’s T test, and categorical variables by Chi2 test or Fisher’s exact test.

Results: In 21 (23%) of the patients, bronchiectasis were present (within fibrosis or honeycomb). Median age was 61 (52-67.5), 67% were female and 48% had a smoking history. No pa-tient has a previous personal history of Mycobacterium tuberculosis infection. Two pa-tients suffer from chronic cough but neither presented with pulmonary infectious compli-cations. No significant association between bronchiectasis and oesophageal dysmotility or dilatation (observed in 33% and 46% respectively), any demographic variable, SSc duration or cutaneous subclass (Table 1). Patients with bronchiectasis were more likely to be Anti-CENP positivity and had a higher rate of secondary Sjogren's syndrome (p=0.044 and p=0.006 respectively). Interstitial lung disease and immunosuppressants had a negative association with bronchiectasis (p=0.032 and p=0.01).

Conclusions: Bronchiectasis should be included in the list of pulmonary manifestations of SSc, a nega-tive association between bronchiectasis and ILD reflects that bronchiectasis is an inde-pendent entity. Given that bronchiectasis was more frequent in patients with secondary Sjogren's syndrome, but not in SSA-positive participants, we hypothesize that its devel-opment is related to sicca symptoms in the tracheocronchial tree. Since neither esopha-geal nor immunosuppressive involvement was found as a cause of bronchiectasis, the infectious origin of bronchiectasis could not be concluded.

P.078

CRTAC1 AS A POTENTIAL BIOMARKER OF PULMONARY INVOLVEMENT IN SYSTEMIC SCLEROSIS

Aneta Pekacova, Sabina Oreska, Hana Storkanova, Jiri Baloun, Radim Becvar, Ladislav Senolt, Michal Tomcik

¹Institute of Rheumatology and Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, CZECH REPUBLIC

Introduction: The current primary cause of mortality in Systemic Sclerosis (SSc) patients is interstitial lung disease (ILD). In this context, Cartilage acidic protein-1 (CRTAC1), secreted by alveolar type-2 epithelial (AT2) cells, is linked to ILD and considered a potential biomarker for assessing AT2 cell health in lavage fluid and plasma. However, there is currently no data available on CRTAC1 in SSc. Therefore, we explore the role of CRTAC1 in SSc patients and their lung involvement.

Material and Methods: We collected plasma samples from 76 SSc patients (65 females, mean age 43.6, mean disease duration 6.7 years, lcSSc:45, dcSSc:31, ILD:43, all fulfilled the 2013 ACR/EULAR criteria) and 89 healthy individuals (HC, 37 females, mean age 41.1). Patients were examined by experienced rheumatologists and assessed for the European Scleroderma Study Group activity score (ESSG), modified Rodnan skin score (mRSS), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), diffusing capacity for carbon monoxide (DLCO) and Medsger Disease Severity Scale (DSS). CRTAC1 levels were measured using the CRTAC1 ELISA (Bio-Rad).

Results: CRTAC1 levels in plasma were significantly lower in SSc patients compared to HCs (p<0.001). CRTAC1 was decreased in SSc patients with ILD compared to SSc patients without ILD (p= 0.048). Regression analysis adjusted for body mass index, C-reactive protein and age showed a negative association with DSS pulmonary involvement (p=0.016, B =-2.46) and ESSG (p=0.1, B=-1.66) and a positive association with DLCO (p=0.081, B =1.77), FEV1 (p=0.099, B =1.68) and FVC (p=0.098, B =1.68). CRTAC1 levels were also decreased in SSc patients with gastrointestinal tract (p=0.014) and joint (p=0.005) involvement and pulmonary arterial hypertension (p=0.018). No other significant associations between the systemic levels of CRTAC1 and the examined clinical or laboratory parameters of interest were detected. Gender was not found to be a confounding factor.

Figure 1. Systemic levels of CRTAC1 in (A) patients with systemic sclerosis (SSc) vs. healthy controls (HC), and (B) the presence of interstitial lung disease (ILD) or (C) stratified according to the degree of severity of pulmonary involvement (Medsger Disease Severity Scale (DSS)). The error bars represent 95% confidence intervals with the estimated mean. * p<0.05; ** p<0.01; *** p<0.001

Conclusions: Systemic levels of CRTAC1 are reduced in SSc patients, especially those with ILD, reduced lung function, and increased disease activity.

Supported by MHCR023728 and GAUK266523.

P.079

COMBINATION TREATMENT OF TOCILIZUMAB AND NINTEDANIB, WITH OR WITHOUT MYCOPHENOLATE, IN SYSTEMIC SCLEROSIS: ONE-YEAR, SINGLE CENTER EXPERIENCE IN 20 PATIENTS

Stylianos Panopoulos¹, Vasileios Tzilas^2,3, Vasiliki-Kalliop Bournia¹, Maria Tektonidou¹, Petros Sfikakis¹

¹1st Department of Propaedeutic and Internal Medicine, Joint Rheumatology Program, Medical School, University of Athens, Athens, GREECE, ²5th Respiratory Department, Chest Diseases Hospital “Sotiria”, Athens, GREECE, ³Department of Pulmonary Medicine, Mayo Clinic, Rochester, Minnesota, USA

Introduction: Data on combination treatment regimens with immunosuppressives and Nintedanib in refractory Systemic Sclerosis (SSc) is scarce. Our objective was to report real-life experience on the clinical efficacy and safety of the co-administration of Tocilizumab and Nintedanib, with or without mycophenolate mofetil (MMF), in our SSc patients with interstitial lung disease.

Material and Methods: Twenty patients [(15 women, 16 with diffuse SSc, mean age: 52±15 years, mean disease duration: 6.3±4.2 years, 10 with early (<5 years) SSc)] with active disease were included. All patients, but 3 with early severe disease, were refractory to various regimens, including cyclophosphamide (n=5), MMF (n=6), methotrexate (n=2) or their combinations (n=4). All 20 patients received Tocilizumab (162 mg subcutaneously weekly) and Nintedanib (150 mg twice daily p.os) for at least one year; 7/20 patients received also MMF (2 gr daily p.os). Changes in modified activity index (MAI), lung function tests (LFTs) and modified Rodnan skin score (mRSS), were analyzed and compared, by pair samples t-test, between baseline and 6 and 12 months.

Results: After 6 and 12 months of combined treatment, 11 (of whom 5 in triple combination) and 14 (of whom 6 in triple combination) patients, respectively, had achieved low disease activity (mean+SD MAI at baseline of 3.7±1.9 and changes of -1.9±1.4, p<0.001, at 6 months and -2.2±1.6, p<0.001, at 12 months). Improvement in skin thickening was evident in 11/20 patients at 6 months and in 14/20 at 12 months (mRSS at baseline of 14.8±7.8 and changes of -1.8±2.1, p=0.004, at 6 months and -3.4±3.8, p=0.002, at 12 months). Stabilization of LFTs [(<10% change in Forced Vital Capacity (FVC) and <15% in Diffusing Lung Capacity for carbon monoxide (DLCO)] was observed in 19/20 patients (baseline FVC of 77%±21% of predicted and changes of +0.3%±6.5, and +4.8%±9.0, at 6 and 12 months, respectively) (baseline DLCO of 44%±17% of predicted and changes of +2.2%±3.5 and +3.9%±6.0, at 6 and 12 months, respectively). These results were comparable when 10 patients with early SSc and the remaining 10 patients were analyzed separately. Combination treatment was well tolerated by all patients; 5/20 patients developed diarrhea and 2/5 had to reduce the dosage of Nintedanib.

Conclusions: Co-administration of Tocilizumab and Nintedanib, with or without MMF, seems to safely stabilize lung fibrosis and improve skin thickening in refractory SSc. Additional larger studies and longer follow-up periods are clearly needed.

P.080

THE SCLERODERMA CLINICAL TRIALS CONSORTIUM DAMAGE INDEX (SCTC-DI) IN PATIENTS WITH SYSTEMIC SCLEROSIS-INTERSTITIAL LUNG DISEASE

Olga Ovsyannikova, Lidiya Ananyeva, Olga Koneva, Ludmila Garzanova, Oxana Desinova, Maya Starovoitova, Rushana Shayahmetova, Anna Helkovaskaya-Sergeeva

V.A. Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: Systemic sclerosis (SSc) is a multiorgan disease wherein the pathogenic processes of inflammation, vasculopathy and fibrosis lead to multiple disease manifestations. The course of SSc is often one of progressive damage to multiple organs including the skin, joints, heart, lungs, gastrointestinal tract and kidneys. The scleroderma clinical trials consortium damage index (SCTC-DI): a new instrument to quantify organ damage in systemic sclerosis.

Objective: To assess the scleroderma clinical trials consortium damage index (SCTC-DI) in patients with systemic sclerosis in Russian cohort patients.

Material and Methods: Data from 104 patients with systemic sclerosis (mean age was 51,7±12,5;64% have limited subset of the disease; 88% were female) all fulfilling the ACR criteria for SSc. Functional lung tests, high-resolution CT (HRCT), echocardiography, SSc activity (by the European Scleroderma Study Group (EScSG) activity index), HAQ, SHAQ, the six minute walk test (6MWT), scleroderma clinical trials consortium damage index (SCTC-DI) were evaluated. Other data collected including biological results (high-sensitivity C-reactive protein (hsCRP) and erythrocyte sedimentation rate (ESR). Statistical analysis: descriptive data are presented as means (±SD) or medians (with interquartile range [IQR]) for continuous variables, while categorical variables are expressed as counts and percentages. Univariate comparisons were made with 2-sample t tests. we used the Spearman's rank-order (Spearman's p) correlations coefficients.

Results: A significant positive correlations were found between the SCTC-DI values and HAQ (r=0.31, p=0.003), SHAQ (r=0.28, p=0.0087), and values of EScSG activity index (r=0.31, p=0.0066) accordingly. The SCTC-DI values inversely correlated to values of 6MWT (r=-0.246, p=0.003). Moreover, the SCTC-DI values correlated inversely with forced vital capacity (r=-0.543, p<0.00000), forced expiratory volume in 1s (r=-0.487, p<0.00000) and diffusion capacity for carbon monoxide (r=-0.484, p<0.000001). A significant positive correlations the SCTC-DI values were found with pulmonary arterial pressure (PAP) (r=0.232, p=0.022), but didn’t find any correlation with left ventriculi injection fraction (r=-0.104, p>0.05). Also we didn’t find any correlations the SCTC-DI values with ESR levels and hsCRP levels (r=0.18, p>0.05 and r=0.15, p>0.05).

Conclusions: The SCTC-DI values correlate with dates of HAQ, SHAQ, EScSG activity index, values of 6MWT pulmonary function tests, supporting their use as measures of SSc severity.

P.081

SENSITIVITY AND SPECIFICITY OF ULTRASOUND FOR DIAGNOSIS OF INTERSTITIAL LUNG DISEASE IN PATIENTS WITH RHEUMATIC DISEASES

Olga Ovsyannikova, Olga Koneva, Lidiya Ananyeva, Ludmila Garzanova, Maya Starovoytova, Oxana Desinova, Rushana Shayahmetova, Anna Helkovskaya-Sergeeva*

V.A. Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: Pulmonary disease is one of the most relevant with interstitial lung disease (ILD) being one of the most frequents forms of involvement with resultant worsening of morbidity and mortality in disorders such as systemic sclerosis (SSc), rheumatoid arthritis (RA), or inflammatory myopathies. High-resolution computed tomography (HRCT), which is the current gold standard for diagnosis and evolutionary control, is problematic owing to ionizing radiation, cost, and accessibility. In this context, lung ultrasound (LUS) is an attractive tool in a growing research and validation process.

Objectives: to assess specificity and sensitivity of LUS in rheumatic diseases of patients.

Material and Methods: 110 pts with ILD of rheumatic disease such as: systemic sclerosis(n=60) (mean age 49.8±13.3,fem 57); vasculitis n=11(mean age 40.7± 9.1,fem 5); dermatomyositis(DM), anti-synthetase syndrome(ASS), polymyositis(PM) n=20, (mean age48.7± 11.9, fem13); rheumatoid arthritis(RA) n=9(mean age 56.5± 6.3, fem 7); Sjogren’s syndrome (SSj)n=9 (mean age 59.6± 12.3, fem 8). Chest HRCT were evaluated. Control group (n=30) without rheumatic diseases and ILD (mean age 51.4±15.4, fem24); (chest X-ray(CXR) were evaluated). LUS examination protocol was used. In each patient (ULC)-score was obtained by summing the number of comets.

Results: The analysis included all the 110 patients enrolled in the study. ROC cure analysis the ULC score of anterior chest area was (AUC =0.876; 95% CI 0.82-0.96; p<0.0001); ROC cure analysis the ULC score of posterior chest area was (AUC =0.908; 95% CI 0.858-0.958; p<0.0001); ROC cure analysis for the total ULC score was (AUC =0.932; 95% CI 0.892-0.972; p<0.0001).

Pic 1.Accuracy of echographic signs (B-line) in the different chest areas in the detection of interstitial lung disease: Total B-line Score (TBLS) more than 5 by anterior chest area

Using the TBLS to identify a positive LUS examination, sensitivity and specificity were different depending on the area investigation. The best results were in the posterior area and all chest areas.

Conclusions: Our research documented the high diagnostic accuracy of LUS in the detection of ILD. Our findings support the use of LUS a sensitive tool for ILD detection, especially considering that it’s an inexpensive and nonionizing technique.

P.082

RITUXIMAB AND TOCILIZUMAB AND THEIR EFFECT ON LUNG DISEASE PROGRESSION IN SCLERODERMA: A RETROSPECTIVE COHORT STUDY AT A SINGLE CENTRE

Voon Ong¹, Nina Goldman¹, Claire Beesley¹, Aoife Tynan², Rizgar Mageed³, Christopher Denton¹

¹Centre for Rheumatology, University College London Royal Free Campus, London, UNITED KINGDOM, ²Department of Pharmacy, Royal Free Hospital, London, UNITED KINGDOM, ³Centre for Translational Medicine & Therapeutics, Queen Mary University of London, London, UNITED KINGDOM

Introduction: Interstitial lung disease (ILD) is the leading cause of death in systemic sclerosis (SSc). Prognostic factors for SSc-ILD progression and mortality include diffuse subset, anti-topoisomerase I antibody (ATA) positivity and elevated acute-phase reactants. Recent studies report beneficial effects of rituximab and tocilizumab on lung function, however, it is unclear if these results from highly selective clinical trial populations can be generalised to real-world SSc-ILD patients receiving concomitant immunosuppressive therapies.

Material and Methods: We performed a retrospective analysis of all SSc patients attending a single centre who had received tocilizumab and/or rituximab. Clinical data was collected with serial lung function. HRCT was scored as limited (<20%) or extensive disease (>20%). Data was analysed for lung function treatment response based on ATA status and other clinical characteristics. Linear mixed-effect models were used to identify factors associated with changes in lung function.

Results: 129 patients (80.3% females,59.1% diffuse SSc) were included, of which 87 received rituximab and 32 tocilizumab. Pre-treatment lung function decline was similar for both biologics with predicted change %FVC/year for rituximab 3.22% and tocilizumab 3.15%. Both treatments had an impact on lung function with improvement in predicted change %FVC/year for rituximab 1.23% and tocilizumab 1.03%. Concurrent mycophenolate (MMF) treatment on biologic initiation conferred a greater response in %FVC change with tocilizumab (5.21%, p=0.038) but not with rituximab (1.66%, p=0.528). Male patients had a lower baseline %FVC (p = 0.024) with a greater response to rituximab (4.28%, p = 0.031) but not tocilizumab(2.13%, p = 0.737). ATA patients had lower baseline %FVC (p = 0.001) with greater response to tocilizumab patients than non-ATA (p = 0.049) although response was noted in both groups (Figure 1). In contrast, ATA status did not affect treatment response to rituximab (p=0.107). Disease subset, disease duration, elevated CRP and disease extent on CT had no effect on either treatment response.

Conclusions: Our study provides real-life data supporting the use of both rituximab and tocilizumab to stabilise SSc-ILD among those refractory to standard immunosuppressive therapies. Differential response based on autoantibody specificity may optimise patient selection for biological therapy.

P.083

THE IMPACT OF SCREENING PROGRAMS WITH HRCT FOR THE IDENTIFICATION OF ILD IN SSC

Cristina Nita¹, Laura Groseanu¹, Daniela Opris-Belinski¹, Mihaela Mirea-Popescu¹, Athir Eddan², Emily Langball³, Phuong Phuong Diep⁴, Håvard Fretheim^5,6, Torhild Garen³, Michael T Durheim⁴, Øyvind Midtvedt³, Trond Mogens Aaløkken⁷, Øyvind Molberg^3,4, Andra Balanescu¹, Anna-Maria Hoffmann-Vold^3,8

¹Department of Internal Medicine and Rheumatology, St. Mary Clinical Hospital, Bucharest, ROMANIA, ²Department of Radiology, Marius Nasta Pneumophthisiology Institute, Bucharest, ROMANIA, ³Department of Rheumatology, Oslo University Hospital, Oslo, NORWAY, ⁴Department of Respiratory Diseases, Oslo University Hospital, Oslo, NORWAY, ⁵Institute of Clinical Medicine, University of Oslo, Oslo, NORWAY, ⁶Department of Rheumatology, Lillehammer Rheumatology Hospital, Oslo, NORWAY, ⁷Department of Radiology, Oslo University Hospital, Oslo, NORWAY, ⁸Department of Rheumatology, University Hospital Zurich, Zurich, SWITZERLAND

Introduction: Universal high-resolution computed tomography (HRCT) screening for systemic sclerosis–interstitial lung disease (SSc-ILD) remains unavailable, potentially resulting in delayed or missed diagnoses. This study investigates the impact of HRCT screening frequency on lung function decline and mortality in two countries with distinct screening approaches.

Material and Methods: A multicenter study involved 310 SSc patients from Saint Mary Clinical Hospital in Bucharest (with non-universal ILD screening) and 907 SSc patients from Oslo University Hospital (routine screening since 2000). We assessed the number of SSc patients diagnosed with ILD through HRCT imaging over three time periods: 2000-2010, 2010-2020, and 2020-2023. Pulmonary function decline and mortality in patients with and without HRCT were assessed by Cox regression with hazard ratios (HR) and 95% confidence intervals (CI).

Results: The cohorts exhibited significant demographic and characteristic differences (Table 1). Across the time periods, HRCT usage increased significantly in the Romanian cohort, while it remained stable in the Norwegian cohort (Table 2). Patients without HRCT were younger, more frequently female, with less impaired lung function and more frequent limited cutaneous SSc and anti-centromere antibodies (Table 2). The identification of ILD in HRCT underwent significant temporal shifts in both cohorts, declining in Romania but rising in the Norwegian cohort (Figure 1). Among Romanian SSc patients assessed for baseline lung function (54% of the cohort), FVC decline occurred in 31% (40/128) without HRCT and 48% (89/182) with HRCT. In the Norwegian cohort, FVC decline was absent in those without HRCT, but 23% (144/614) with HRCT experienced a decline. In the Romanian cohort, patients with HRCT died by 42%, 21%, and 12% compared to patients without HRCT by 17%, 9%, and 0% with corresponding HRs: 1.24 (95% CI 0.51-2.9), 1.02 (95% CI 0.50-2.09), and 0.46 (95% CI 0.01-3.48)]. In the Norwegian cohort, patients with HRCT had mortality rates of 51%, 19%, and 3%, and without HRCT only 2 patients died [HRs: 5.4 (95% CI 1.32-22.3), 1.21 (95% CI 0.17-9.23), and 1.8 (95% CI 1.07-3.09)].

Conclusions: In countries where screening programs are hampered by health care systems, the likelihood of missing an ILD diagnosis is high, leading to underdiagnosis of ILD progressors, with lost opportunities for adequate management and increased mortality. This supports the implementation of screening programs for SSc-ILD in all countries.

P.084

THE DIFFERENT TREND OF TUMOR ANTIGENS IN SYSTEMIC SCLEROSIS COMPARED TO OTHERS CONNECTIVE TISSUE DISEASES

Caterina Naclerio¹, Giovanna Cuomo²

¹Unit of Rheumatology Scarlato Hospital, Scafati, ITALY, ²Department of Precision Medicine University of Campania, Naples, ITALY

Introduction: Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. During the disease certainly the lung involvement is represented by interstitial lung disease (ILD). Altough ILD has an important course; there are no prognostic factors useful to predict prognosis of ILD. Therefore, it is necessary to develop other markers to evaluate disease severity which is essential to identify different subsets of lung involvement in order to prepare a targeted therapy. Many Authors have demonstrated that in patients affects by Connective Tissue Diseases and Interstitial Lung Disease related, serum Carcinoembryonic Antigen (CEA) and serum Carbohydrate Antigen 19-9 (CA19-9) are elevated and can be indicators of disease severity.

Material and Methods: We have conducted the study in the affected population by SSc and ILD associated and we also enrolled 45 CTD-ILD patients including 12 with Connective Indifferentiate, 15 with Rheumatoid Arthrits, 8 with Sjogren Syndrome 5 with Systemic Lupus Erythematosus and 5 with polimyositis.

SSc and CTD–ILD patients performed a blood examination to assess the levels of tumor markers including CEA, CA125, CA19-9, carcinoembryonic antigen and alpha fetoprotein. In order to detect the interstitial lung involvement SSc and CTD-ILD associated patients underwent an high resoluted computed tomography (HRCT).

Results: In the cohort of patients with Connective tissue diseases there is a tendency to increase in tumor antigens especially CA 19-9 in correlation with ILD associated when pathologies are considered as a whole.

Conclusions: When SSC is separated from other connective tissue pathologies, it is noted that there is no significant correlation between the increase in tumor antigens especially CA19-9 and the extension of pulmonary fibrosis.

P.085

IMPACT OF INTERSTITIAL LUNG DISEASE WITH AND WITHOUT PULMONARY HYPERTENSION ON SURVIVAL - LARGE COHORT STUDY OF THE GERMAN NETWORK FOR SYSTEMIC SCLEROSIS

Pia Moinzadeh¹, Francesco Bonella², Max Oberste³, Jithmi Weliwitage³, Norbert Blank⁴, Gabriela Riemekasten⁵, Ulf Mueller-Ladner⁶, Joerg Henes⁷, Elise Siegert⁸, Claudia Guenther⁹, Ina Koetter¹⁰, Christiane Pfeiffer¹¹, Marc Schmalzing¹², Gabriele Zeidler¹³, Peter Korsten¹⁴, Laura Susok¹⁵, Aaron Juche¹⁶, Margitta Worm²¹, Ilona Jandova¹⁷, Jan Ehrchen¹⁸, Gernot Keyßer¹⁹, Cord Sunderkoetter²⁰, Andreas Ramming²², Tim Schmeiser²³, Alexander Kreuter²⁵, Hanns-Martin Lorenz⁴, Nicolas Hunzelmann¹, Michael Kreuter²⁴

¹University Hospital Cologne, Department of Dermatology and Venereology, Cologne, GERMANY, ²Center for Interstitial and Rare Lung Diseases, Ruhrlandklinik, Department of Pneumonology, University of Duisburg-Essen, Essen, GERMANY, ³Institute of Medical Statistics and Computational Biology, Faculty of Medicine, University Hospital Cologne, Cologne, GERMANY, ⁴University Hospital Heidelberg, Division of Rheumatology, Internal Medicine V, Heidelberg, GERMANY, ⁵University Hospital Schleswig-Holstein, Clinic for Rheumatology and Clinical Immunology, Luebeck, GERMANY, ⁶Kerckhoff Clinic, Department of Rheumatology, Bad Nauheim, GERMANY, ⁷University Hospital Tuebingen, Centre for Interdisciplinary Rheumatology, Auto-inflammatory Diseases and Internal Medici, Tuebingen, GERMANY, ⁸Charite, Department of Rheumatology and Clinical Immunology, Berlin, GERMANY, ⁹University Hospital Carl Gustav Carus, TU Dresden, Department of Dermatology, Dresden, GERMANY, ¹⁰University Hospital Hamburg, Division of Rheumatology and Systemic Inflammatory Diseases, Rheumatology Clinic BBramstedt, Bad Bramstedt, GERMANY, ¹¹University Medical Center Ulm, Department of Dermatology and Allergology, Ulm, GERMANY, ¹²University Hospital Würzburg, Rheumatology/Clinical Immunology, Department of Internal Medicine II, Wuerzburg, GERMANY, ¹³Johanniter-Hospital Treuenbrietzen, Department of Rheumatologie, Treuenbrietzen, GERMANY, ¹⁴University Medical Center Göttingen, Department of Nephrology and Rheumatology, Goettingen, GERMANY, ¹⁵St. Josef Hospital Bochum, Department of Dermatology, Venereology and Allergology, Bochum, GERMANY, ¹⁶Immanuel Hospital Berlin-Buch, Department of Rheumatology, Berlin, GERMANY, ¹⁷University Medical Center Freiburg, Rheumatology and Clinical Immunology, Freiburg, GERMANY, ¹⁸University Hospital Muenster, Department of Dermatology, Muenster, GERMANY, ¹⁹University Hospital Halle (Saale), Department Internal Medicine 3, Rheumatology and Immunology, Halle, GERMANY, ²⁰University Hospital Halle (Saale), Department of Dermatology, Halle, GERMANY, ²¹Charite, Department of Dermatology, Venerology and Allergology, Berlin, Germany, ²²University Hospital Erlangen, Department of Internal Medicine 3, Rheumatology and Immunology, Erlangen, Germany, ²³Hospital St. Josef Wuppertal, Internal Medicine – Rheumatology and Osteology, Wuppertal, Germany, ²⁴Mainz Center for Pulmonary Medicine, Departments of Pneumology, Mainz University Medical Cneter of Pumonary Critical Care&Sleep Medicine, Mainz, Germany, ²⁵Helios St. Elisabeth Oberhausen, University Witten/Herdecke, Department of Dermatology, Oberhausen, Germany

Introduction: Pulmonary involvement is the leading cause of death in systemic sclerosis (SSc) and may manifest as interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), or in combination of both (ILD-pulmonary hypertension (PH)). Aim of this analysis was to determine prevalence, clinical characteristics, and survival of these different forms within the registry of the German Network for Systemic Sclerosis (DNSS).

Does SSc-associated ILD with or without PH affect survival and which risk factors have an additional impact?

Material and Methods: Clinical data of 5,831 SSc patients were collected in the DNSS registry, Kaplan-Meier estimates were used to compare overall survival (OS) in patients with SSc-ILD with PH (ILD-PH) and without PH (ILD-w/o-PH) to patients without pulmonary involvement and those with PAH. The Cox proportional hazard model was used to analyze the influence of pulmonary involvement and other potential predictors on patient survival.

Results: Clinical data of 3,257 patients with a mean follow-up time of 5.64±4.51 years have been included in our analysis. At baseline, ILD was present in 34.5%, while PH (w/o-ILD) had a lower prevalence with 4.5%. At the end of follow-up, 47.6% of SSc patients had ILD, 15.2% ILD-PH, and 6.5% PAH. ILD was more frequent in the diffuse cutaneous form (57.3%), while PAH did not differ significantly between SSc subtypes. Significant differences in baseline characteristics between PAH vs. ILD-PH vs. ILD-w/o-PH were found for age at diagnosis, gender, SSc-subsets, antibody-status, FVC, DLCO and therapy. OS at 5 years was 96.4% for patients without pulmonary involvement and differed significantly between patients with ILD-w/o-PH, PAH, being worst in patients with ILD-PH. Female gender, a higher BMI and higher DLCO values were associated with a lower mortality risk.

Conclusions: ILD is the most prevalent pulmonary involvement in SSc, while the combination of ILD and PH is associated with the most detrimental survival.

P.086

DETECTION OF SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE USING ELECTRONIC NOSE TECHNOLOGY

Emiel Marges¹, Iris G. van der Sar², Jeska K. de Vries-Bouwstra³, Tom W.J. Huizinga³, Paul L.A. van Daele⁴, Marlies S. Wijsenbeek², Catharina C. Moor², J.J. Miranda Geelhoed¹

¹Leiden University Medical Center, department of Respiratory Medicine, Leiden, THE NETHERLANDS, ²Erasmus University Medical Center, department of Respiratory Medicine, Rotterdam, THE NETHERLANDS, ³Leiden University Medical Center, department of Rheumatology, Leiden, THE NETHERLANDS, ⁴Erasmus University Medical Center, department of Internal Medicine, Rotterdam, THE NETHERLANDS

Introduction: Interstitial lung disease (ILD) is the leading cause of death in patients with systemic sclerosis (SSc). Timely detection of SSc-ILD remains a major challenge. The analysis of volatile organic compounds in exhaled breath using a sensor-based electronic nose (eNose) device is increasingly studied, also for the detection of ILD. We therefore investigated the accuracy of using eNose technology to detect SSc-ILD.

Material and Methods: We conducted a cross-sectional multicenter cohort study in patients with a confirmed diagnosis of SSc according to the current diagnostic criteria. Breath analysis using an eNose (SpiroNose®) was performed. ILD was confirmed or excluded by a recent HRCT scan. eNose data of patients with SSc-ILD and with SSc without ILD were compared. Patients with SSc-ILD were also compared to patients with other forms of ILD not due to SSc. Cohorts were split in a training and test set (2:1). eNose data were analysed using partial least square discriminant analysis and ROC analysis.

Results: 223 patients with SSc were included of whom 110 had ILD. Mean age of patients was 60.0 years (51.0-69.0), most were female (74.7%). eNose distinguished patients with SSc-ILD from those without ILD with an AUC of 0.79 (95% CI 0.72-0.87) in the training set and an AUC of 0.84 (0.75-0.94) in the test set. Comparison of SSc-ILD with other forms of ILD (n=300) resulted in an AUC of 0.87 (0.81-0.95) in the training set and an AUC of 0.74 (0.60-0.88) in the test set. SSc-ILD was separated from other types of CTD-ILD with an AC of 0.88 (0.80-0.95). Results were not influenced by age gender, type of SSc, auto-antibodies, smoking status or use of immunosuppressive drugs.

Conclusions: eNose technology is able to detect ILD in patients with SSc. Thus, eNose technology might have potential as a screening tool for ILD in patients with SSc.

P.087

CORRELATION BETWEEN NAILFOLD VIDEOCAPILLAROSCOPY AND PULMONARY FUNCTION TESTS IN SYSTEMIC SCLEROSIS: A MONOCENTRIC STUDY

Marco Manca, Alberto Floris, Valentina Ibba, Alessandra Vacca, Alberto Cauli

Rheumatology Unit, Department of Medical Sciences, University and AOU of Cagliari, Cagliari, ITALY

Introduction: In the last decade we have seen a growing interest in potential role of Nailfold Videocapillaroscopy (NVC) and its relationship with interstitial lung disease (ILD). Studies usually focus on determine an association between changes on NVC and abnormal pulmonary function test (PFTs), mostly with cross-sectional studies. The aim of this study is to determine if any change can be observed in nailfold capillaries and PFTs during multiple assessments.

Material and Methods: In our cohort of 191 systemic sclerosis (SSc) patients, 121 of them (100 females and 20 males) had at least one NVC and one PFTs (n= 200) during a period of six months. Videocapillaroscopy was performed by V.I., A.F. and M.M. with DsMedica Videocap® 3.0 D1 collecting five different data (pattern, density, number of microhemorragies, number of giant capillaries and presence of avascular areas. PFTs (FEV1%, FVC%, TLC%, DLCO%, DL/VA%) were conducted by an external subject. Furthermore, we analysed the data of 55 patients (47 females and 8 males) who underwent two or more different assessments of both NVC and PFTs (n=80).

Results: In the first part of our study, based on single assessments, we have found a more severe NVC pattern related with lower DLCO% (p = 0.046, n = 189) and, in patients with ILD, the presence of avascular areas related with decreasing DLCO% (p = 0.019, n = 101) and DL/VA% (p = 0.013, n = 101). In the second part of the study, where multiple assessments were performed, we have noticed a significant correlation in patients with ILD, where a higher number of giant capillaries is associated with lower DL/VA% (p = 0.003, n =38), especially in females. Moreover, the occurrence of a more severe NVC pattern is linked with reduced FEV1% in females (p = 0.038, n = 66) and in the limited cutaneous subset (p = 0.016, n = 72).

Conclusions: The value of single assessments corroborates the findings available in literature, and we have detected new associations between videocapillaroscopy and PFTs repeated in time. Therefore, we think that examination of capillaries could be a powerful tool for follow-up in SSc patients, especially in those who present a with pulmonary involvement.

P.089

DLCO IMPAIRMENT IN EARLY-SSC IS ASSOCIATED TO DISEASE PROGRESSION

Samuel Leal¹, de la Rubia Marta², Alcántara Iago², Chalmeta Verdejo Inmaculada², Charia Hikmat¹, González Puig Luis², Grau García Elena¹, Huaylla Quispe Anderson Víctor², Ivorra Cortés José², Martínez Isabel², Mas Sánchez Laura², Muñoz Martínez Pablo Francisco², Negueroles Rosa², Oller Rodríguez José Eloy², Daniel Ramos Castro², Riesco Bárcena Carmen², Torrat Novés Alba², Tovar Sugrañes Ernesto², Vicens Bernabeu Elvira², Villanueva Mañes Belén²

¹Instituto de Investigación Sanitaria La Fe - Rheumatology Division, Valencia, SPAIN, ²Hospital Universitari i Politècnic La Fe - Rheumatology Department, Valencia, SPAIN

Introduction: Lung involvement is common in systemic sclerosis (SSc), either in form of interstitial lung disease (ILD) or pulmonary hypertension (PH). Pulmonary Function Test (PFT) is a major tool for the detection of lung involvement at early stages of disease. Early-SSc is now a well-defined preliminary stage of SSc according to LeRoy classification criteria, i.e., Raynaud’s phenomenon plus selective SSc antibodies and/or SSc nailfold capillary pattern.

We aim to analyze the diffusing capacity of the lung for carbon monoxide (DLCO) in patients with Early-SSc to identify disease progression.

Material and Methods: We carried out a retrospective observational study with data collected from patients with Early-SSc diagnosis. Through the search of medical electronic records, we identified all SSc patients fulfilling LeRoy criteria at the first visit but not meeting ACR/EULAR 2013 classification criteria for SSc. Patients were followed until they fulfilled SSc classification criteria or last visit up to August 2023, whatever event happened first. All PFTs were obtained at the first visit in our center. Statistical analysis was carried out using R software and Welch t-test was used for mean differences.

Results: A total of 129 patients treated in our hospital under any diagnosis of SSc were screened and 52 fulfilling Early-SSc LeRoy criteria were included. Baseline characteristics and PFT results are shown in Table 1. PFT data were missing for 7 patients who did not progress to SSc. No restrictive patterns were identified. Expectedly, Early-SSc patients presented higher median DLCO at the first visit in comparison with other SSc subgroups (Figure 1), being the only above the normal limit (80%).

Nineteen Early-SSc patients progressed to SSc (36.5%), mostly towards limited cutaneous SSc (90%) and sine scleroderma subtypes (10%). DLCO was 15.8 (5.4) in the Early-SSc subgroup who eventually progressed versus 19.6 (4.2) ml/(min*mmHg) in those who did not fulfill SSc classification criteria (95% CI: [0.8 – 6.9]; p < 0.05) (Figure 2). No statistically significant differences were found for the rest of spirometric values.

Conclusions: In our study, impaired DLCO was useful for the identification of lung involvement in Early-SSc patients, pointing to an eventual disease classification as SSc. Early-SSc tends to progress to milder forms with no or little skin involvement.

P.090

ANALYSIS OF CIRCULATING ANGIOGENIC T-CELLS IN PATIENTS WITH SYSTEMIC SCLEROSIS: A POTENTIAL BIOMARKER FOR SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE

Jergus Krc¹, Yehya Al-Adwi², Berber Doornbos-van der Meer¹, Alja Stel², Wayel Abdulahad¹, Harry van Goor³, Johanna Westra¹, Douwe Johannes Mulder²

¹Department of Rheumatology and Clinical Immunology, University Medical Centre Groningen, University of Groningen, Groningen, THE NETHERLANDS, ²Department of Internal Medicine, Division of Vascular Medicine, University Medical Centre Groningen, University of Groni, Groningen, THE NETHERLANDS, ³Department of Pathology and Medical Biology, University Medical Centre Groningen, University of Groningen, Groningen, THE NETHERLANDS

Introduction: Systemic sclerosis (SSc) is a rare autoimmune disease with high morbidity and mortality. Its underlying causes remain unclear. This study explores the association between a recently identified T-cell subgroup, known as angiogenic T-cells (Tang), and SSc-related interstitial lung disease (ILD) – the leading cause of mortality in SSc. Tang cells have been linked to vasculogenesis and endothelial repair, and their levels have been associated with microvascular damage in SSc. Tang proportions have been shown to decrease in autoimmune-disease-related ILD when compared to healthy controls. However, their specific role in SSc is unclear. Consequently, we hypothesize that a potential decrease in circulating Tang levels in SSc-ILD+ patients could be due to their migration to the site of lung-endothelial injury.

Material and Methods: Thus far, this study included 38 SSc patients and 22 healthy controls (HC). Eleven SSc-ILD patients were included, diagnosed with HRCT. Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples and stored in liquid nitrogen. PBMCs were thawed and resuscitated and stained with fluorescently labeled antibodies. Flow cytometry analysis was performed to identify angiogenic T-cells (considered as CD3+CD31+CXCR4+), and their proportions were compared across patients with and without ILD, and control groups, using the nonparametric Mann-Whitney U test. Additionally, Tang levels have been tested for correlation with relevant patient characteristics and lung function test values. Tang levels were corrected for patient medication using regression analysis.

Results: Tang proportions were significantly lower in SSc-ILD+ patients compared to SSc-ILD- patients when expressed as a proportion of all T-cells (p = 0.003), CD8+ T-cells (p = < 0.001), and CD4+ T-cells (p = <0.001). Similarly, Tang proportions were lower in SSc-ILD+ when compared to HC when expressed as a proportion of all T-cells (p = 0.011), CD8+ T-cells (p = <0.001), and CD4+ T-cells (p = 0.002) (Figure 1). No significant differences were found in the proportions of Tang cells between SSc patients and HC when expressed as a percentage of total T-cells, CD8+ T-cells, or CD4+ T-cells.

Conclusions: Our preliminary findings suggest that Tang cells are associated with, and potentially play a role in the development of ILD in SSc patients. We propose that the role of these cells in this process be elucidated and their potential as biomarkers or therapeutic targets in SSc-ILD be explored in future studies.

P.091

ANTIFIBROSIS THERAPY IN PATIENTS WITH SYSTEMIC SCLEROSIS WITH INTERSTITIAL LUNG DISEASE: IMPACT ON CLINICAL MANIFESTATION AND QUALITY OF LIFE

Olga Koneva, Liudmila Garzanova, Lidia Ananyeva, Oxana Desinova, Olga Ovsyannikova, Mayya Starovoytova, Rushana Shayakhmetova

V.A. Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis (SSc), affecting more than 60% of patients. Despite current immunosuppressants, SSc-ILD may progress, so there is a need for new therapies targeting both inflammation and fibrosis, able to modify this poor prognosis. One of these drugs is Nintedanib. However, there are currently a limited number of studies of this drug in patients with SSc-ILD.

The purpose of the study: To study the effect of Nintedanib on the main clinical manifestations (pulmonary function, cutaneous fibrosis, signs of cardiopathy), disease activity and quality of life in patients with SSc-ILD.

Material and Methods: 20 patients (the average age 52.7±11.9 years, females 90%, SSc duration 10±6.3 years, diffused:limited forms 1:3.5) with the confirmed SSc diagnosis and signs of progressive ILD were enrolled into the study. All patients received low- and moderate-dose of prednisolone regimens. Nintedanib was added to immunosuppressants (Mycophenolate mofetil, Azathioprine, Cyclophosphamide) due to inadequate efficacy of the previous therapy. 13 patients received Nintedanib (300 mg per day) over the follow-up period 9,7±6,2 months. The time courses FVC(%), DLCO (%), 6-MWT (meters), dyspnea index (NYHA), modified skin count (mRss, points), activity index (EScSG, points), left ventricle ejection fraction (LVEF,%), pulmonary arterial systolic pressure (EchoCG), and cardiac rhythm and conductivity disorders (ECG), diastolic dysfunction, HAQ, S-HAQ, ESR, CRP were evaluated.

Results: The therapy was associated with significant decrease in EScSG (from 3.96±1.6 to 1.7±1.1, p=0.0015), increase in tolerance for exercise (for a 6-MWT) and stabilization of FVC and DLCO indicators.

A decrease in the dyspnea index (from III to II according to NYHA) was observed in 8 (62%) pts, a downward trend in PASP - in 5 (38%) patients, 5% and more FVC increase -in the third of the pts (4/30%).

During the follow-up period no change of mRss, LVEF,%, cardiac rhythm disorders (ECG), in the quality of life and indicators of laboratory inflammatory activity was observed.

Against the background of therapy, there was a tendency to increase the number of patients with cardiac conduction disorders and the left ventricle diastolic dysfunction.

Conclusions: Nintedanib therapy was associated with stabilization of pulmonary function indicators, accompanied by a decrease in the dyspnea severity, increased tolerance for exercise, and decreased SSc activity.

There was no significant effect of the drug on other clinical manifestations of SSc.

Nintedanib can be used as a second-line therapy for the treatment of SSc-ILD with the ineffectiveness of immunosuppressive therapy.

P.092

REAL-LIFE MULTICENTRIC NATIONAL OBSERVATIONAL STUDY OF THE USE OF NINTEDANIB IN SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE

Vincent Koether¹, David Launay¹, Martine Reynaud Gaubert², Gregoire Prevot³, Luc Mouthon⁴, Raphael Borie⁵, Kinan El Husseini⁵, Paul Decker⁶, Stephanie Dirou⁷, Elodie Blanchart⁸, Amelie Leurs⁹, Sabine Berthier¹⁰, Xavier Delbrel¹¹, Marie Durel¹², Christian Agard⁷, Ana Nievez-Martinez², Eric Hachulla¹, Denise Aydindag¹³, Vincent Cottin¹³, Yurdagul Uzunhan¹⁴

¹Département de Médecine Interne et Immunologie Clinique, CERAINO, Lille, FRANCE, ²Service de pneumologie centre hospitalier universitaire nord, Marseille, FRANCE, ³Service de pneumologie du centre hospitalier universitaire de Toulouse, Toulouse, FRANCE, ⁴Service de médecine interne de l'hopital Cochin, Paris, FRANCE, ⁵Service de Pneumologie A, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, FRANCE, ⁶Département de médecine interne et d immunologie clinique, CHU Nancy, Nancy, FRANCE, ⁷Service de pneumologie, l'institut du thorax, hôpital G.-et-R.-Laënnec, CHU de Nantes, Nantes, FRANCE, ⁸CHU de Bordeaux, Service des Maladies Respiratoires, Service d'Exploration Fonctionnelle Respiratoire, Bordeaux, FRANCE, ⁹Département de médecine interne, CH Dunkerque, Dunkerque, FRANCE, ¹⁰Médecine interne et immunologie clinique, CHU DIJON, DIJON, FRANCE, ¹¹Service de médecine interne et rhumatologie, CH de Pau, Pau, FRANCE, ¹²Service de médecine interne de l'hopital Robert Schuman, Vantoux, FRANCE, ¹³Service de pneumologie du centre hospitalier universitaire louis pradel, Lyon, FRANCE, ¹⁴Département de pneumologie de l'hopital Bobigny, Paris, FRANCE

Introduction: Systemic Sclerosis-associated interstitial lung disease (SSc-ILD) is the first cause of mortality in this disease. Forced vital capacity (FVC) is a key part of the follow-up of patient and its significative decline is one of the major prognostic factor in SSc-ILD. Nintedanib, a tyrosine kinase inhibitor and antifibrotic drug, has been shown to be effective in SSc-ILD. To date, few real-life data of antifibrotic drugs use are available in SSc-ILD.

Objectives: Evaluation of efficacy and tolerance profile of nintedanib in SSc-ILD patients in real life in France

Material and Methods: We collected epidemiological, clinical and paraclinical parameters (CT scan and functional findings) in SSc-ILD patients treated by nintedanib. Patients were identified in an ambispective and multicentric design through a call for observations within French research groups, reference centers and academic society.

Results: 116 patients were included in 11 centers. 89 (77%) were female and mean age of patients was 59±11 years. 57 (49%) had diffuse cutaneous SSc, 61 (53%) had anti-topoisomerase 1. Median time from 1st non-Raynaud's manifestation to introduction of nintedanib was 6 years (1; 41). SSc-ILD was extensive (>20% of the lung) in 60% of cases, and CT pattern was NSIP in 88 % of cases. Mean FVC at nintedanib introduction was 1.96±0.47L (64±15%). Mean DLCO was 36 ±11%. Data were available at 6 months after introduction of nintedanib in 75 patients. Two patients had severe infections. 26 (35 %) patients experienced adverse events and 7 patients had lost weight >5 kg. Nine patients (12%) had discontinued treatment because of digestive intolerance (diarrhea in 5 cases, 2 significant weight loss, 2 unknown) and 1 patient had died (congestive heart failure). The mean loss of FVC was 25 ± 93 mL at 6 months versus 165 ± 225 mL in the year before the introduction of nintedanib.

Conclusions: SSc-ILD population in this real-life study had similar epidemiological characteristics to those included in SENSCIS trial (3). However, respiratory functional impairment was worse at nintedanib introduction in our study than in the pivotal trial. At 6 months after the start of nintedanib, we observed a smaller decline in FVC compared to the decline in the year before starting the treatment. The current results at 6 months show a tolerance profile similar to that observed in idiopathic pulmonary fibrosis and reinforce the need for better management of digestive-tract side effects. This ongoing study will provide additional data at 6, 12 and 24 months of follow-up.

P.093

OUTCOMES IN PATIENTS WITH SYSTEMIC SCLEROSIS FOLLOWING LUNG TRANSPLANTATION: AN ITALIAN MULTICENTRE EXPERIENCE

Claudia Iannone^1,2, Maria Rosa Pellico^1,2, Letizia Corinna Morlacchi^3,4, Valeria Rossetti^3,4, Marco Vicenzi⁵, Paolo Airò⁶, Lorenzo Beretta⁷, Adriana Severino⁷, Eleonora Zaccara⁸, Fabio Cacciapaglia⁹, Stefano Stano⁹, Antonina Minniti^1,2, Silvia Cavalli^1,2, Giorgia Trignani^1,2, Marta Saracco¹⁰, Anna Maria Iagnocco¹⁰, Francesco Blasi^3,4, Roberto Caporali^1,2, Nicoletta Del Papa^1,2

¹ASST Gaetano Pini-CTO, UOC Clinica Reumatologica, Scleroderma Clinic, Milan, ITALY, ²Department of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Uni, Milan, ITALY, ³Respiratory Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, ITALY, ⁴Thoracic Surgery and Lung Transplantation Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, ITALY, ⁵Unità di Cardiologia, Dipartimento di Medicina Interna, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Mi, Milan, ITALY, ⁶Ospedali Civili di Brescia, Scleroderma UNIT, UOC Reumatologia ed Immunologia Clinica, Piazzale Spedali Civili 1, 251, Brescia, ITALY, ⁷Referral Center for Systemic Autoimmue Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, ITALY, ⁸Asst Ovest Milanese-Internal Medicine Unit, Legnano Hospital, Milan, Italy, Legnano, ITALY, ⁹Unità di Reumatologia, Dipartimento di Emergenza e Trapianto di Organi (DETO), Università di Bari, 70124 Bari, Pugli, Bari, ITALY, ¹⁰Unità di Reumatologia, Ospedale Mauriziano-Umberto I, Torino, Italia., Torino, ITALY

Introduction: Lung transplantation (LT) is gaining ground in managing advanced ILD in SSc patients. However, concerns remain among surgeons due to SSc complexity, multiorgan involvement (including oesophagus), and heightened risk of post-transplant complications. To date, studies focused on survival rates, lacking a comprehensive evaluation regarding the effects of LT and related immunosuppressive therapy affect SSc disease activity and progression.

The aim of this study was to evaluate in a cohort of SSc patients, survival, complications, and post-LT outcomes regarding extra-pulmonary involvement, disease activity according to the EUSTAR activity index, and lung function.

Material and Methods: A retrospective analysis on SSc patients. Outcome variables (mRSS, FVC, ulcers, EUSTAR activity) were evaluated at baseline, 6 months, 1 and 2 years after LT.

Results: We evaluated 11 patients, 9 with dcSSc and 2 lcSSc. M/F=8/3. Median disease duration: 10.33 yrs (IQR 9,42). Main reason for LT was ILD-related end-stage lung disease (11/11); 6/11 patients had concomitant PAH. NSIP pattern at HRTC scan was the most common one (9/11). Bilateral LT was performed in all patients but 1, who underwent unilateral procedure. Maintenance therapy with tacrolimus was the standard of care after LT and the mean dosage decreased from 4.31 mg at 6 months to 1.22 at 2 years. Perioperative complications included 4 acute rejects, with only 1 exitus. The survival at 1 and 2 years was of 100%, and 81,8% respectively. Mean value of FVC significantly increased from 42±10% at baseline, to 63.6±18% at 6 months, 69.8±22% at 1 year, and 76.6±6% at 2 years (p<0.001 for all). Mean mRSS at baseline was 6.8 decreasing at 6 months (4.6), 1yr (4.2) and 2yr (1.5) (p<0.0001). 7 patients with active ulcers experienced their resolutions after 6 months, and only one patient relapsing after 1 year. NVC features improved from late to active pattern. The EUSTAR activity index decreased progressively over time from 3.23 ±1.5 at baseline to 0,7 ±0.6 after 2 years (p<0.0001).

Conclusions: Our data show that LT in SSc patients is effective, with 82% of survival rate and no unexpected complications, confirming that LT represents a valuable therapeutic option in SSc patients with end-stage lung. In addition, after LT we observed a significant improvement of vascular clinical features and the decrease of disease activity, Altogether, these data suggest that amelioration in tissue perfusion and prolonged immunosuppressive therapy might be responsible for fostering vascular remodelling and modulating global disease behaviour.

P.094

PREDICTION OF PROGRESSIVE FIBROSING INTERSTITIAL LUNG DISEASE IN SYSTEMIC SCLEROSIS PATIENTS: INSIGHT FROM THE CRDC COHORT STUDY

Min Hui¹, Xinwang Duan², Jiaxin Zhou¹, Mengtao Li¹, Qian Wang¹, Jiuliang Zhao¹, Yong Hou¹, Dong Xu¹, Xiaofeng Zeng¹

¹Peking Union Medical College Hospital, Beijing, CHINA, ²The Second Affiliated Hospital of Nanchang University, Nanchang, CHINA

Introduction: Systemic sclerosis (SSc) patients can develop progressive fibrosing interstitial lung disease (PF-ILD), linked to a poor outcome. This study aims to establish a reliable prediction model of PF-ILD in SSc-ILD patients, to achieve early risk stratification, and to help better preventing disease progression.

Material and Methods: Three hundred and four SSc-ILD patients registered on Chinese Rheumatism Data Center (CRDC) database since January 2008, with no less than three pulmonary function tests within 6-24 months, were included. The major outcome was development of PF-ILD, which was defined as an absolute annualized forced vital capacity (FVC) decline no less than 5% predicted. We collected data at baseline and compared differences between SSc patients with PF-ILD (SSc PF-ILD) group and SSc patients without PF-ILD (SSc non-PF-ILD) group. Lasso regularization regression was performed for further screening. Multivariable Cox regression were used to construct the prediction model, which were presented as nomogram and forest plot.

Results: SSc-ILD patients were divided into SSc PF-ILD group (n=154) and SSc non-PF-ILD group (n=150). Compared with SSc non-PF-ILD group patients at baseline, SSc PF-ILD patients were at older age (48.5±11.9 years vs 44.9±11.3 years, p<0.001), had more male patients (9.7% vs 6.0%, p=0.012), more diffused SSc (dcSSc) subtype (58.4% vs 32.7%, p<0.001), and a significant higher incidence of hyperlipidemia (31.2% vs 8.7%, p<0.001), smoking history (18.2% vs 5.3%, p<0.001), arthritis (38.3% vs 24.7%, p<0.001), shortness of breath (84.4% vs 80.0%, p<0.001) and anti Scl-70 antibody positivity (53.2% vs 40.0%, p<0.001), as well as more serum IgA deficiency (11.0% vs 5.3%, p<0.001). The use of cyclophosphamide (CYC) and/or mycophenolate mofetil (MMF) were less common in SSc PF-ILD group compared with SSc non-PF-ILD group (58.4% vs 68.7%, p<0.001). Based on the results of univariable Cox analysis and Lasso regularization regression, a 9-variable prediction model was constructed, including age no less than 50 years, hyperlipidemia, smoking history, dcSSc subtype, arthritis, shortness of breath, serum IgA deficiency, positive anti-Scl70 antibody and usage of CYC/MMF. C-index for the model was 0.874, while the Brier scores were 0.144 after bootstrap resampling internal validation.

Conclusions: This study developed the first prediction model for PF-ILD in SSc-ILD patients based on data from CRDC database, and internal validation showed favorable accuracy and stability of the model.

P.095

CHARACTERISATION OF INCIDENT INTERSTITIAL LUNG DISEASE IN LATE SYSTEMIC SCLEROSIS

Sabrina Hoa¹, Maggie Larche^2,3, Nouha Lahmek¹, Joshua Levy¹, Marie Hudson⁴

¹Université de Montréal, Department of Medicine, Montreal, CANADA, ²McMaster University, Department of Medicine, Montreal, CANADA, ³University of Calgary, Department of Medicine, Calgary, CANADA, ⁴McGill University, Department of Medicine, Montreal, CANADA

Introduction: Interstitial lung disease (ILD) is a common and potentially severe complication of systemic sclerosis (SSc). Screening by HRCT is recommended in all SSc patients, particularly in the presence of risk factors, including early disease. Little is known on the incidence, characteristics and prognosis of ILD presenting in late SSc. The objective of this study was therefore to characterize late-onset ILD in comparison to earlier-onset ILD.

Material and Methods: Subjects enrolled in the Canadian Scleroderma Research Group (CSRG) cohort from 2004 to 2021 without prevalent ILD were included. Demographic, clinical and serological characteristics were compared between patients with incident vs no incident ILD on HRCT across disease duration strata. Chi-square and Mann-Whitney-U tests were done as appropriate. Survival analyses with Kaplan-Meier and Cox proportional hazard models adjusted for age, sex and anti-topoisomerase I were used to assess association between disease duration and time to ILD progression (CTD-ILD OMERACT criteria).

Results: Out of 1117 CSRG patients without prevalent ILD at baseline, 199 (18%) developed incident ILD over a median [IQR] duration of 2.4 [1.2, 4.3] years. Of these, ILD was diagnosed at least 7 years after first non-Raynaud manifestation in 131 (66%) patients. When disease duration was stratified as <3, 3-6, 6-9, 9-12 and 12-15 years, cumulative incidence of ILD within each stratum ranged from 8 to 10%. Compared to patients without ILD, those with incident ILD had higher frequencies of diffuse subtype, anti-topoisomerase I positivity, anti-centromere negativity and elevated C-reactive protein levels, irrespective of disease duration. Out of 107 patients with follow-up data, ILD progression was seen in 47 (44%) patients, mostly within the first 4 years of ILD diagnosis. The risk of ILD progression was not associated with disease duration in unadjusted (Figure 1, log rank p = 1) and adjusted analyses (HR 1.00, 95% CI 0.51-1.97).

Conclusions: In patients with long SSc duration, ILD occurred more frequently in those with diffuse subtype, anti-topoisomerase I autoantibodies and high C-reactive protein levels, similarly to those with early SSc and consistent with known risk factors for ILD. ILD progression mostly occurred within the first 4 years of diagnosis and its occurrence did not vary according to SSc duration at time of ILD diagnosis. Surveillance for incident ILD should continue even in patients without early SSc but presenting with high-risk features, as patients are equally at risk of having progressive disease, but how and how often screening should be done remain to be defined.

P.096

DIFFUSE JUVENILE SYSTEMIC SCLEROSIS PATIENTS SHOW DISTINCT ORGAN INVOLVEMENT, ANTIBODY PATTERN AND HAVE MORE SEVERE DISEASE IN THE LARGEST JSSC COHORT OF THE WORLD

Ivan Foeldvari¹, Jens Klotsche², TorokKathryn Torok³, Ozgur Kasapcopur³, Amra Adrovic³, Brian Feldman³, Flavio Sztajnbok³, Maria Teresa Terreri³, Ana Paula Sakamoto³, Sindhu Johnson³, Jordi Anton³, Valda Stanevicha³, Raju Khubchandani³, Dieneke Schonenberg-Meinema³, Eslam Al-Abadi³, Ekaterina Alexeeva³, Maria Katsicas³, Sujata Sawhney³, Vanessa Smith³, Simone Appenzeller³, Tadey Avcin³, Mikhail Kostik³, Thomas Lehman³, Hana Malcova³, Edoardo Marrani³, Clare Pain³, Anjali Patwardhan³, W.-Alberto Sifuentes-Giraldo³, Natalia Vasquez-Canizares³, Nicola Helmus¹

¹Hamburg Center for Paediatric and Adolescent Rheumatology, Hamburg, GERMANY, ²German Rheumatism Research Center, Berlin, GERMANY, ³jSSc Collaborative Group, Hamburg, GERMANY

Introduction: Juvenile systemic sclerosis(jSSc) is an orphan disease with a prevalence of 3 in 1,000,000 children. In adult patients there are significant differences between clinical presentation of cutaneous diffuse(djSSc) and cutaneous limited phenotypes(ljSSc).

Material and Methods: We reviewed the baseline clinical characteristics of the patients, who were recruited to the jSScC prior to April 2023. jSScC is a prospective cohort of jSSc patients, who developed the first non-Raynaud’s symptom before the age of 16 years and were under the age of 18 years at the time of inclusion

Results: The jSScC included 238 patients, 69% had cutaneous diffuse subtype. The median age at onset of Raynaud’s phenomenon was 10.4 years and the median age at the first non-Raynaud’s symptom was 10.9 years. The female/male ratio was not significantly lower in the djSSc subtype. Antibody profile was similar, with the exception of a significantly higher number of anticentromere positive patients in the ljSSc (10% vs 2%, p=0.019). Patients with djSSc had significantly higher modified Rodnan Skin Score (17 vs 4, p=0.011), more frequently sclerodactyly (85% vs 56%, p<0.001), Gottron papules (31% vs 15%, p=0.008), a history of digital ulceration (61% vs 29%, p<0.001), active ulceration (20% vs 8%, p=0.024), telangiectasia(45% vs 22%, p=0.001), a decreased Body Mass Index (BMI) z score < -2 (19% vs 6%, p=0.010) and decreased joint range of motion (64% vs 47%, p=0.017). Patients with ljSSc had significantly higher rate of cardiac involvement (11% vs 2%, p=0.006).

Regarding patient related outcomes assessed by visual analogue scales (VAS 0 to 100), djSSc patients had more severe disease related to patient reported global disease activity (40 vs 30, p=0.041), patient reported global disease damage (40 vs 25, p=0.001), and patient reported Raynaud activity by (30 vs 18, p=0.025). Additionally, physician related outcomes assessed by VAS, the physician reported global disease activity (35 vs 20, p=0.034), and physician reported global disease damage (30 vs 20, p=0.011), were significantly higher in djSSc patients.

Conclusions: In the largest jSSc cohort in the world, djSSc patients have significantly more severe disease according to patient and physician related outcomes than ljSSc patients. Patients with djSSc also had more cutaneous, vascular, and musculoskeletal involvements and patients with ljSSc had more cardiac involvement. Interestingly, we found no significant differences regarding interstitial lung disease, pulmonary hypertension or gastrointestinal involvement, although the number of patients with decreased BMI <-2 z score was significantly higher in the djSSc patients.

P.097

ANTIBODIES AGAINST RO52 ARE ENRICHED IN THE LUNGS AND ARE ASSOCIATED WITH PROGRESSIVE INTERSTITIAL LUNG DISEASE IN PATIENTS WITH SYSTEMIC SCLEROSIS

Viggo Hamberg¹, Azita Sohrabian², Elizabeth R Volkmann^3,4, Marie Wildt¹, Anna Löfdahl⁵, Dirk M Wuttge¹, Roger Hesselstrand¹, Göran Dellgren⁶, Gunilla Westergren-Thorsson⁵, Johan Rönnelid², Kristofer Andréasson¹

¹Section of Rheumatology, Department of Clinical Sciences, Lund University, Lund, SWEDEN, ²Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SWEDEN, ³Department of Medicine, Division of Rheumatology, University of California, Los Angeles, USA, ⁴David Geffen School of Medicine, Los Angeles, USA, ⁵Lung Biology, Department of Experimental Medical Science, Lund University, Lund, SWEDEN, ⁶Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SWEDEN

Introduction: Interstitial lung disease (ILD) is the most common cause of death in patients with systemic sclerosis (SSc). Autoantibodies against Ro52 has been specifically associated with the presence of ILD in SSc patients. Presence and enrichment of anti-Ro52 in bronchoalveolar lavage (BAL) fluid and in serum was investigated. Additionally, anti-Ro52 was investigated as a predictive marker of progressive SSc-ILD. Finally, we investigate the presence of Ro52 antigen in lung tissue from healthy controls and subjects with SSc.

Material and Methods: In a first cohort, autoantibody levels were analyzed from BAL fluid and the serum from fifteen patients with new onset SSc-ILD. In a second longitudinal cohort of 43 patients with early SSc-ILD, autoantibodies in serum were measured at baseline and pulmonary function tests were performed at least 2 times over the course of at least 2 or more years to investigate the relationship between specific autoantibodies and progression of SSc-ILD. Finally, lung tissue from healthy controls and from subjects with SSc was analyzed for the presence of the Ro52 antigen using immunohistochemistry.

Results: Among SSc-ILD patients who were positive for anti-Ro52 (N = 5), 3 (60%) had enrichment of anti-Ro52 in BAL fluid at a ratio exceeding 50x. In the longitudinal cohort, 10/43 patients (23%) were anti-Ro52 positive and 16/43 (37%) were anti-Scl-70 positive. Presence of anti-Scl-70 was associated with a lower vital capacity (VC) at baseline (-12.6% predicted VC [%pVC]; 95%CI: -25.0, -0.29; p = 0.045), but was not significantly associated with loss of lung function over time (-1.07%pVC/year; 95%CI: -2.86, 0.71; p = 0.230). The presence of anti-Ro52 was significantly associated with the loss of lung function over time (-2.41%pVC/year; 95% CI: -4.28, -0.54; p = 0.013). Rate of loss of lung function increased linearly with increasing anti-Ro52 antibody levels (-0.03%pVC per arbitrary units/mL and year; 95%CI: -0.05, -0.02; p < 0.001). Immunohistochemical staining localized the Ro52 antigen to alveolar M2 macrophages in peripheral lung tissue both in subjects with and without SSc.

Conclusions: This study suggests that antibodies targeting Ro52 are enriched in the lungs of patients with new-onset SSc-ILD, linking Ro52 autoimmunity to the pulmonary pathology of SSc. Clinical data corroborates these findings and suggest that anti-Ro52 may serve as a potential biomarker of progressive SSc-ILD. Immunohistochemical analysis show that the Ro52 antigen is naturally present in the lungs and may indicate an origin of Ro52 autoimmunization.

P.098

CHANGES OF PULMONARY FUNCTION TESTS IN PATIENTS WITH SYSTEMIC SCLEROSIS AND DIFFERENT SEVERITY OF INTERSTITIAL LUNG DISEASE

Lidia Ananyeva, Liudmila Garzanova, Olga Koneva, Oxana Desinova, Mayya Starovoytova, Olga Ovsyannikova, Rushana Shayakhmetova, Alena Kolomeychuk

V.A. Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: The optimal treatment strategy of interstitial lung disease (ILD) associated with systemic sclerosis (SSc) is still a dilemma. The therapeutic decision largely depends on the degree of lung involvement, including the severity of ILD-SSC. The aim of our study was to compare changes of lung function between patients with mild and severe ILD-SSc treated during long-term follow-up.

Material and Methods: This study included 82 pts with ILD-SSc. over the mean follow-up period of 36.8±2 month. Patients were categorized as having mild ILD if baseline forced vital capacity (FVC % predicted) was more than 80% (Group I, 48 pts) and as having severe ILD if FVC was less than 80% pred (Group 2, 34 pts). The mean disease duration was 8.3±7.2years for group 1 and 5.8±4.6years for group 2. Based on key SSc-ILD characteristics group 1 pts received therapy with prednisolone (Ps) and/or immunosuppressants (IS). Group 2 patients had added rituximab (RTX) to the previous therapy due to either insufficient efficacy or inability to carry out standard therapy with Ps and IS. The cumulative dose of RTX was 3±1g. FVC and diffusion capacity for carbon monoxide % predicted (DLCO) at three years (36.8±2 month) was compared.

Results: Pts in both groups were comparable at gender and age, all of them received prednisolone. A limited form the disease (75%), low activity and slightly reduced DLCO prevailed in group 1. During the study 67% of pts received IS. A diffuse form of the disease (59%) and significantly reduced FVC and DLCO prevailed in group 2. There was no significant change in FVC levels in group 1 (100.7±11 at baseline and 98.4±14.3% at the end of study, delta FVC=2.3%), but DLCO significantly decreased from 64.7±16.3 to 61.1±14.5%, p=0.001 (delta DLCO=-3.6%). In group 2, despite the initially more pronounced decrease of pulmonary function parameters, there were the positive changes. FVC increased from 66±11 to 76±17%, p=0.01 (delta FVC=10%). DLCO remained stable (changes from 39±12.4 to 40.6±11.4%, delta DLCO=1.6%). The dose of Ps was reduced from 11.2±3.7 to 9.4±2.5mg/day (p=0.01).

Conclusions: In pts with mild ILD-SSc a stable level of FVC was stored for a long time. This suggest the sufficient effectiveness of “standard” therapy in mild form of the ILD-SSc. In patients with severe form of the ILD-SSc, the progression of ILD ceased after escalation of therapy with the addition of RTX and leads to clinically significant improvement.

P.099

ELEVATED SERUM CCL18 IS A POTENTIAL BIOMARKER OF INTERSTITIAL LUNG DISEASE IN SYSTEMIC SCLEROSIS

Kristóf Filipánits¹, Gabriella Nagy¹, Gábor Kumánovics¹, Cecília Varjú¹, Diána Simon², Szabina Erdo-Bonyar², Tímea Berki², László Czirják¹, Tünde Minier¹

¹University of Pécs Medical School - Department of Rheumatology and Immunology, Pécs, HUNGARY, ²University of Pécs Medical School - Department of Immunology and Biotechnology, Pécs, HUNGARY

Introduction: The C-C Motif Chemokine Ligand-18 (sCCL18) is a chemokine which role was confirmed in the pathogenesis of systemic sclerosis (SSc)-associated interstitial lung disease (SSc-ILD). The aim of the study was to investigate the association between sCCL18 levels and different organ involvement in SSc.

Material and Methods: Single-center study, where 121 SSc patients without overlap syndromes and 53 age- and sex-matched healthy controls(HCs) were recruited. sCCL18 concentrations were measured by ELISA. Internal organ involvements were systematically investigated. SSc-ILD was diagnosed based on HRCT findings. Elevated sCCL18 titres were considered those higher than the mean+2 times the standard deviation(SD) of HCs, namely values >130700.4 pg/ml.

Results: 68 patients had diffuse cutaneous SSc (dcSSc) and 88% were female. Median (IQR) disease duration was 8 (4;15) years, and 28 patients had early-stage disease (duration <=3 years). sCCL18 concentrations were higher in the whole SSc cohort, dcSSc and limited cutaneous SSc (lcSSc) subtypes compared to HCs (Figure 1,p<0.05). Higher sCCL18 levels in early dcSSc but not early lcSSc were detected compared to HCs (102208.6±48011.5pg/ml vs. 75538.4±27581.5pg/ml,p<0.05). Patients with early-stage disease had higher sCCL18 levels if SSc-ILD was diagnosed (n=15) compared to patients without ILD (n=6) (112930.1±46546.9pg/ml vs. 67765.9±28333pg/ml,p<0.05). SSc-ILD was more frequently associated with elevated sCCL18 level based on cut-off (84% vs. 56%, X² test,p<0.05). Gastrointestinal involvement was more common at normal sCCL18 levels, mainly due to GERD and subjective sicca symptoms (GERD:82% vs. 60%; sicca:67% vs. 44%, both p<0.05). In the total cohort the sCCL18 level showed weak positive correlation with the left ventricular mass index, weak negative correlation with E/A (rho: .206 and -.247; p<0.05, respectively) and patients with diastolic dysfunction had higher sCCL18 levels (75410.9±38689.7pg/ml vs. 102732.88±40522.5pg/ml,p<0.05). The latter two findings could be also detected in the dcSSc subgroup (rho:-.294,p<0.05 for E/A and p<0.05 for diastolic dysfunction). DcSSc patients with mRSS>14 had higher sCCL18 values(p<0.05). Small joint contractures were more common in patients with elevated sCCL18 levels (68% vs. 42%,p<0.05).

Conclusions: Higher sCCL18 levels were detectable already in early dcSSc and absent in early lcSSc patients. Elevated sCCL18 concentration may be helpful to identify patients with higher risk of developing SSc-ILD in both SSc subsets. Normal sCCL18 levels were associated with more frequent GERD and sicca symptoms. Screening patients with elevated sCCL18 levels for other SSc-related manifestations (cardiac, joint) is proposed.

Project no. TKP-2021-EGA-10 has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the TKP-2021-EGA funding scheme.

P.100

TRAJECTORIES OF FORCED VITAL CAPACITY (FVC) IN PATIENTS WITH SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE (SSC-ILD)

Oliver Distler¹, Madelon C Vonk², Arata Azuma³, Maureen D Mayes⁴, Dinesh Khanna⁵, Kristin B Highland⁶, Gerrit Toenges⁷, Margarida Alves⁸, Yannick Allanore⁹

¹Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, SWITZERLAND, ²Department of Rheumatology, Radboud University Medical Center, Nijmegen, THE NETHERLANDS, ³Director of Respiratory Medicine and Clinical Research Center, Meisei Hospital, Saitama, JAPAN, ⁴Division of Rheumatology, University of Texas McGovern Medical School, Houston, Texas, USA, ⁵University of Michigan Scleroderma Program, Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA, ⁶Cleveland Clinic, Cleveland, Ohio, USA, ⁷Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, GERMANY, ⁸Boehringer Ingelheim International GmbH, Ingelheim, GERMANY, ⁹Department of Rheumatology A, Descartes University, APHP, Cochin Hospital, Paris, FRANCE

Introduction: The SENSCIS trial enrolled patients with SSc-ILD without a requirement for them to have evidence of recent progression. During the trial, nintedanib reduced the rate of decline in FVC (mL/year) versus placebo. The open-label extension of the SENSCIS trial, SENSCIS-ON, assessed changes in FVC in patients treated with nintedanib over the longer term. We assessed the trajectory of FVC decline in patients who received placebo in the SENSCIS trial and then nintedanib in SENSCIS-ON.

Material and Methods: In the SENSCIS trial, patients with SSc-ILD were randomized to receive nintedanib or placebo double-blind until the last patient reached week 52 but for <=100 weeks. Patients who completed the SENSCIS trial on treatment (nintedanib or placebo) and attended a follow-up visit were eligible to enter SENSCIS-ON. The protocol allowed an off-treatment period between SENSCIS and SENSCIS-ON of <=12 weeks. We calculated the trajectory of FVC in patients who received placebo in SENSCIS and initiated nintedanib in SENSCIS-ON. The baseline measurement in SENSCIS-ON was considered the anchor measurement (time point 0) (Figure 1). FVC was measured at time points before the anchor measurement (when patients were receiving placebo in SENSCIS or were off treatment between SENSCIS and SENSCIS-ON) and at time points after the anchor measurement (when patients were receiving open-label nintedanib in SENSCIS-ON). Analyses were descriptive and based on observed FVC values.

Results: In total, 231 patients received placebo in SENSCIS and then nintedanib in SENSCIS-ON. In these patients, mean (SD) FVC was 2593 (833) mL at baseline of SENSCIS and 2441 (833) mL at baseline of SENSCIS-ON. The mean decline in FVC in the 52 weeks prior to baseline of SENSCIS-ON (when patients were receiving placebo in SENSCIS or were off treatment) was -98.5 mL (Figure 2). The mean decline in FVC from baseline of SENSCIS-ON to week 52 of SENSCIS-ON (when patients were receiving nintedanib) was -42.8 mL (Figure 2).

Conclusions: In patients who received placebo in the SENSCIS trial, the decline in FVC over 52 weeks was reduced by approximately 57% following initiation of open-label nintedanib in SENSCIS-ON. These analyses illustrate the progressive nature of SSc-ILD in the population enrolled in SENSCIS and the effectiveness of nintedanib on slowing the progression of SSc-ILD.

P.101

FACTORS PROGNOSTIC OF RAPID PROGRESSION OF SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE (SSC-ILD)

Oliver Distler¹, Jérôme Avouac², Anna-Maria Hoffmann-Vold³, Vanessa Smith⁴, Gerrit Toenges⁵, Margarida Alves⁶, Masataka Kuwana⁷

¹Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, SWITZERLAND, ²Department of Rheumatology - Hôpital Cochin, Assistance Publique - Hôpitaux de Paris, Paris Descartes University, Paris, FRANCE, ³Department of Rheumatology, Oslo University Hospital, Oslo, NORWAY, ⁴Ghent University Hospital and Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center (IRC), Ghent, BELGIUM, ⁵Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, GERMANY, ⁶Boehringer Ingelheim International GmbH, Ingelheim, GERMANY, ⁷Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, JAPAN

Introduction: The course of SSc-ILD is difficult to predict. We aimed to identify factors associated with progression of SSc-ILD over 52 weeks in the SENSCIS trial.

Material and Methods: Using logistic regression models, we analysed associations between baseline characteristics and absolute decline in FVC % predicted >5% or death over 52 weeks in all patients with SSc-ILD in the placebo group of the SENSCIS trial and in the subgroup who had risk factors for rapid FVC decline at baseline (<18 months since first non-Raynaud symptom, elevated inflammatory markers [C-reactive protein >/=6 mg/L and/or platelets >/=330 x 10 to the power 9/L], or modified Rodnan skin score [mRSS] >18). In multivariate models, variables were selected via stepwise selection based on p-values. Mycophenolate use was a fixed variable. Model performance was assessed using the area under the receiver operating characteristic curve (AUC).

Results: In the placebo group overall (n=288), 86 (29.9%) had an absolute decline in FVC % predicted >5% or died over 52 weeks. The performance of the final model for predicting this outcome was weak (AUC of 0.635). In the subgroup with risk factors for rapid FVC decline at baseline (n=155), the final model for predicting this outcome had an AUC of 0.749 and included anti-topoisomerase I antibody (ATA) status (positive vs negative odds ratio 1.63 [95% CI 0.71, 3.75]), mycophenolate use (yes vs no 0.71 [0.33, 1.55]), DLco % predicted (0.95 [0.92, 0.98]), mRSS (1.06 [1.02, 1.10]), time since first non-Raynaud symptom (0.74 [0.58, 0.93]). A nomogram was constructed using the final multivariate model in patients with risk factors for rapid FVC decline at baseline (Figure).

Conclusions: SSc-ILD is a heterogeneous disease and prediction of progression may require different approaches in different subgroups.

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FREQUENCY AND FACTORS ASSOCIATED WITH LUNG INVOLVEMENT IN SYSTEMIC SCLEROSIS IN A COLOMBIAN POPULATION

Jennifer Delgadillo¹, Kevin Maldonado^1,2, Gerardo Quintana^1,2,3

¹Department of Internal Medicine, School of Medicine, Universidad Nacional de Colombia, Bogotá, COLOMBIA, ²Reumavance Group, Bogotá, COLOMBIA, ³2.Department of Internal Medicine. School of Medicine, Universidad de Los Andes, Bogotá, COLOMBIA

Introduction: Systemic sclerosis (SS) is a heterogeneous autoimmune disease characterized by vasculopathy and dysregulation of fibroblasts that frequently compromises either the parenchyma or the pulmonary vasculature; both Diffuse Interstitial Lung Disease and Pulmonary Arterial Hypertension associated with SS are the leading causes of death in these patients; In Colombia, the disease has a prevalence rate of 23.7 cases per 100,000 individuals, with a higher prevalence among women (77% of cases) and those aged between 65-69 years. Unfortunately, there is currently no available data regarding the specifics of lung involvement in this population.

Material and Methods: Objectives This study aims to identify the clinical characteristics of the population and associations or risk factors in patients with SS and pulmonary involvement.

Methodology: We conducted a retrospective study of patients with SS and pulmonary involvement in two care centers in Bogotá (Fundación Santa Fe de Bogotá University Hospital and National University Hospital). Patients with a diagnosis of systemic sclerosis established by the 2013 classification criteria or those with an early variety who had lung involvement documented by imaging or biopsy for diffuse interstitial lung disease or right heart catheterization for pulmonary arterial hypertension were included. Participants were identified using the ICD-10 codes, and their clinical records were manually reviewed to register the corresponding variables on a REDCap-based database.

Results: We examined data from 169 patients, of whom 79 (38.5%) experienced pulmonary complications. Among these, 57 ILD, 29 PAH, and 7 individuals had both ILD and PAH. Most of our study participants were female (91.7%), with limited SSc being the most prevalent subtype of the disease (50.9%), followed by diffuse (28.4%) and early SS (14.2%). We observed that in patients with pulmonary complications, anticentromere antibodies were linked to the development of PAH but not ILD. Additionally, telangiectasias were associated with overall lung involvement. For a more comprehensive breakdown of our analysis, please refer to Table 1.

Conclusions: Our study found that females and older patients were more likely to experience pulmonary complications in a group of patients with SS. Telangiectasias were also associated with the development of pulmonary complications in the form of ILD and PAH. We also observed that ACA positivity is related to PAH, and ILD is less likely to develop. Our results suggest that Colombian SS patients experience similar factors associated with the disease as other populations.

P.103

LUNG FUNCTION CHANGES IN PATIENTS WITH SSC AND IPF TREATED WITH NINTEDANIB: A REAL LIFE OBSERVATIONAL STUDY

Fiammetta Danzo¹, Linda Pelosi¹, Peter Dilov¹, Dejan Radovanovic¹, Pierachille Santus¹, Giovanna Cuomo²

¹Division of Respiratory Diseases, Ospedale L. Sacco, ASST Fatebenefratelli-Sacco, Department of Biomedical and Clinical, Milan, ITALY, ²Dipartimento medicina di precisione-università degli studi della Campania L Vanvitelli, Naples, ITALY

Introduction: Pulmonary involvement in systemic sclerosis (SSc) is the main cause of death, and the only validated treatment is Nintedanib. Idiopathic pulmonary fibrosis (IPF) represents the prototype of chronic progressive fibrosing pneumonia and the use of Nintedanib was validated since 2014. In literature, few studies have explored the potential clinical differences between SSc and IPF.

Our objective is to describe the spirometric changes in pulmonary function test (PFTs) at baseline and after 12 months of Nintedanib in SSc and IPF patients.

Material and Methods: We retrospectively enrolled consecutive patients with SSc attending the Rheumatology Department at L. Vanvitelli in Naples and patients with IPF attending the Interstitial Lung Disease Clinic at Sacco Hospital in Milan.

For all patients PFTs (including spirometry and diffusion lung capacity of CO, DLCO) at baseline and after 12 months of treatment and clinical data (anthropometric variables, disease duration, treatment start) were collected.

Results: IPF recruited patients were 24 (16 males, mean age of 77, SD 5.77). Patients with SSc were 26 (6 males, mean age of 56, SD 11.51). At baseline, the mean forced vital capacity (FVC) was 67% of predictive value for SSc patients and 87% for IPF patients (p<0,0001). After 12 months of treatment, the mean FVC% was 69 (SD 15,6 p=0,588) and the DLCO was 52% (SD 14,9, p=0,3752) in SSc patients, while, in IPF patients the median FVC% was 79 (IQR 69-89, p=0,176) and the mean DLCO of 50% (SD 12,24, p=0,838). The mean age at the start of the treatment was 56 (SD 5,69) years for SSc patients and of 76 (SD 11,63) for IPF (p<0,0001), while the time gap between the diagnosis and the start of the treatment and were of 7 and 1 year for SSc and IPF patients, respectively (p<0,0003).

Conclusions: Our results showed that IPF patients treated with Nintedanib, despite having a significantly higher FVC% at baseline and despite starting the antifibrotic treatment earlier, tend to have a more rapid decline in lung function compared to SSc patients. However, longer-term follow-up data and larger study populations could offer a more comprehensive understanding of antifbrotic treatments’ effects in both diseases.

P.104

EXTRACELLULAR VESICLES IN SYSTEMIC SCLEROSIS. DO WE HAVE A NEW BIOMARKER OF PROGRESSIVE INTERSTITIAL LUNG DISEASE PHENOTYPE?

Jelena Colic¹, Iva Pruner², Nemanja Damjanov³, Jovan Antovic², Mirjana Sefik-Bukilica³, Aleksandra Antovic⁴

¹Institute of Rheumatology, Belgrade, SERBIA, ²Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, SWEDEN, ³Department of Rheumatology Unit, Faculty of Medicine, University of Belgrade, Institute of rheumatology, Belgrade, SERBIA, ⁴Department of Medicine, Rheumatology Unit, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, SWEDEN

Introduction: Interstitial lung disease (ILD) is the leading cause of mortality in patients with systemic sclerosis (SSc). So far, only one study has demonstrated increased extracellular vesicle (EVs) levels in patients with SSc-ILD; however, the association between EVs and progressive ILD (pILD) phenotype has not been investigated

Material and Methods: A prospective cohort study included 59 SSc patients without any comorbidity (31 (52.5%) with ILD and 28 (47.5%) without). ILD was defined either as X-ray or on HRCT positive findings. EVs were analyzed with flow cytometry after staining of platelet-poor plasma with fluorescent cell-specific monoclonal antibodies. Following PS+EVs were analyzed at baseline: endothelial EVs (EEVs; CD144+), platelet EVs (PEVs; CD42b+), leucocyte EVs (LEVs; CD45+), EVs expressing ICAM1 (CD54+), TF (CD142+) and HMGB1. The serum concentration of ICAM1, VEGF, and IL6 was measured by ELISA. PFTs were done every 6-12 months over a 3-year follow-up (FU) period. pILD was defined by the decline of forced vital capacity FVC from baseline visit of >10%, or an FVC decline of 5-9% along with a DLCO decline of >15%.

Results: At baseline, an inverse relation was noticed in SSc patients between all investigated EVs and FVC (r=0.3, p<0.05). Increased VEGF, ICAM1, IL6, PEVs, and EVs expressing ICAM1, TF or HMGB1 were found in SSc ILD patients (p<0.05, respectively). There was a positive association between all explored EVs and VEGF in the ILD group (p<0.05). Multivariable (Ml) logistic regression adjusted for VEGF revealed that PEVs (OR 1.004, 95%CI 1.001-1.01) and EVs ICAM1 (OR 1.3, 95%CI 1.1-1.5) were independently associated with ILD. Over FU period, 12/31 ILD patients developed a pILD pattern, of which 58% had early diffuse subtype with <1 year disease duration and were ATA+. Only 4/12 pILD patients have ever been treated with imunossupresive therapy. pILD occurred within 1st FU year in 50% of patients. All analyzed EVs and VEGF were elevated in the pILD cohort (p<0.05, respectively). The levels of PEVs, EVs expressing ICAM1 (AUC 0.9, p<0.001, respectively), TF, HMGB1, EEVs and LEVs (AUC 0.7, p<0.05, respectively) showed good validity in identifying pILD. There was only a positive relation between VEGF and both EVs ICAM1 (r=0.8, p<0.01) and EVs HMGB1 (r=0.7, p<0.01) within pILD group. Applying Ml Cox regression controlling for VEGF, EVs ICAM1 left independently significantly associated with pILD (OR 1.1, 95% CI 1.02-1.1)

Conclusions: EVs-ICAM1 could be a novel pILD biomarker, identifying at-risk patients who would benefit from early aggressive treatment.

P.105

ASSOCIATION BETWEEN PFT BASELINE CHARACTERISTICS AND ATS/ERS 2022 PROGRESSIVE PULMONARY FIBROSIS CRITERIA IN SSC BEFORE AND AFTER ILD DIAGNOSIS

Ivan Castellvi Barranco¹, Helena Codes Mendez¹, Jose Luis Tandaipan Jaime¹, Berta Magallares Lopez¹, Patricia Moya Alvarado¹, Cesar Diaz Torne¹, Hye Sang Park¹, Ana Laiz Alonso¹, Hector Corominas Macias¹, Diego Castillo Villegas²

¹Department of Rheumatology, Hospital Universitari de la Santa Creu i Sant Pau, Barcelona, SPAIN, ²Respiratory Diseases Department, Hospital Universitari de la Santa Creu i Sant Pau, Barcelona, SPAIN

Introduction: Systemic sclerosis (SSc) is a complex disease and interstitial lung disease (ILD) is the leading mortality cause. Limited data exist regarding the comparative features of ILD progression in established SSc-ILD.

Our objectives were to describe lung function’s decline in SSc-ILD patients’ meeting the staging system proposed by Goh et al (2008) (%FVC<70) and ATS/ERS PPF criteria; and to compare evolving features between patients meeting Goh’s staging system and ATS/ERS criteria.

Material and Methods: Retrospective study conducted on a cohort of 415 SSc patients at a national reference center, including those with confirmed ILD by HRCT and who underwent PFT’s pre-SSc/ILD diagnosis and yearly until follow-up’s end (lost to follow-up or deceased). We collected epidemiological, clinical and analytical data, and categorized patients based on Goh’s (%FVC<70) and ATS/ERS PPF criteria (>/=5% absolute FVC decline and/or >/=10% DLCO). Statistical significance was assumed with p-values<0.05.

Results: Among 64 individuals meeting SSc-ILD inclusion criteria, most were female (93.8%), 59.4% had limited SSc, and anti-topoisomerase was the predominant autoantibody (28.1%). Mean SSc duration was 18.77 years, ILD duration 11.94 years. Patients meeting ATS/ERS PPF criteria based on PFTs are summarized in Table 1.

Patients with %FVC<70 or %FVC<80 at SSc and ILD onset showed more pronounced FVC decline (p<0.02) during follow-up, while DLCO showed high variability.

Table 2 outlines patients’ characteristics meeting ATS/ERS PPF criteria based on %FVC at the study end. These individuals showed worse pulmonary function at ILD diagnosis but not at SSc diagnosis. Individuals meeting PPF criteria based on %DLCO did not exhibit poorer pulmonary function at either SSc or ILD onset.

In the comparison between Goh and ATS/ERS criteria, patients meeting PPF criteria based on %FVC at follow-up’s end showed a higher proportion of %FVC<70 and %FVC<80 at ILD onset but no significant differences at SSc onset. Increased mortality was observed in patients meeting %FVC PPF criteria and receiving more ILD therapy. No significant differences were observed in other clinical characteristics. Conversely, %DLCO PPF criteria showed no significant differences in baseline characteristics.

Conclusions: We found that Goh criteria (%FVC<70) was useful to predict PPF in our cohort, while %FVC<80 was also associated with PPF. However, these criteria were only useful to predict PPF after ILD onset, not before. ATS/ERS PPF criteria based on %FVC also showed reliability only after ILD diagnosis. %DLCO-based criteria exhibited greater variability, being less dependable as prognostic indicators. Multicentric, prospective studies are needed to validate progression criteria in SSc-ILD.

P.106

CLINICAL INSIGHTS INTO ESTABLISHED SYSTEMIC SCLEROSIS INTERSTITIAL LUNG DISEASE: A COMPREHENSIVE STUDY

Helena Codes Méndez¹, Jose Luis Tandaipan Jaime¹, Diego Castillo Villegas², Berta Magallares Lopez¹, Patricia Moya Alvarado¹, Cesar Diaz Torne¹, Hye Sang Park¹, Luis Sainz Comas¹, Ana Laiz Alonso¹, Hector Corominas Macias¹, Ivan Castellvi Barranco¹

¹Department of Rheumatology, Hospital Universitari de la Santa Creu i Sant Pau, Barcelona, SPAIN, ²Respiratory Diseases Departament, Hospital Universitari de la Santa Creu i Sant Pau, Barcelona, SPAIN

Introduction: At present, Interstitial lung disease (ILD) is the leading cause of mortality in patients with Systemic Sclerosis (SSc). While several risk factors have been identified for the development of ILD in SSc, their contribution to the progression of established SSc-ILD has received limited research attention.

Our objectives were to assess clinical characteristics in SSc patients with ILD and to compare these features between SSc-ILD patients with progressive lung function decline and those without progression.

Material and Methods: From a SSc cohort, we retrospectively enrolled patients with ILD confirmed by HRCT. We collected demographic, clinical, analytical and PFT’s parameters before and after ILD onset. Statistical significance was assumed with p-values<0.05.

Results: A total of 64 out of 415 patients presented SSc-ILD. The majority (93.8%) were females with a mean age at diagnosis of 60.5 years. Among them, 59.4% had limited SSc, and anti-topoisomerase was the predominant specific autoantibody (28.1%). Table 1 summarizes the patient’s characteristics.

During follow-up, we observed in all patients a significant FVC decline since SSc onset (2.80±0.7 vs 2.16±0.76, p=0.000) and after ILD detection (2.37±0.69 vs 2.16±0.76, p=0.000).

Male sex was associated with worse %FVC at SSc-ILD onset, persisting throughout follow-up. However, no differences were found in FVC decline based on clinical SSc subset (limited vs. diffuse) or SSc autoantibodies (ATA vs. ACA) after ILD onset.

Smoking history, digital ulcers, and pulmonary hypertension were associated with worse pulmonary function at follow-up’s end. No significant differences were observed in other clinical features.

Rheumatoid factor (RF) positivity was associated with poorer pulmonary function after ILD diagnosis (p=0.034).

The presence of a UIP pattern did not indicate worse lung function at ILD onset or follow-up’s end compared to non-UIP patterns.

Among the twenty-four patients who received ILD treatment, %FVC and ml-FVC outcomes worsened, with no significant differences in DLCO.

Conclusions: In our cohort, male sex, smoking history, digital ulcers, pulmonary hypertension, and RF positivity were associated with poor lung function outcomes after SSc-ILD onset. Unlike patients at risk of developing SSc-ILD, no significant differences were found concerning SSc subset or SSc autoantibodies in established ILD.

All patients showed significant early volume decline during follow-up, even preceding ILD onset. Given the inclusion of patients with unfavorable prognosis factors and the retrospective nature of the analysis, treatment did not appear to prevent pulmonary function decline.

Further prospective, multicentric studies are crucial to evaluate risk factors for poor prognosis and the ILD progression SSc patients.

P.107

HIGH BRONCHOALVEOLAR FLUID NEUTROPHILS INDEPENDENTLY PREDICT 15-YEAR MORTALITY IN SCLERODERMA PATIENTS WITH INTERSTITIAL LUNG DISEASE NAIVE TO IMMUNOSUPPRESSANT

Gabriella Alonzi, Enrico De Lorenzis, Gerlando Natalello, Lucrezia Verardi, Pier Giacomo Cerasuolo, Silvia Fiore, Andrea Zoli, Stefano Di Murro, Valentina Boni, Maria Antonietta D'agostino, Silvia Laura Bosello

Division of Rheumatology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, ITALY

Introduction: Scleroderma interstitial lung disease (SSc-ILD) has a variable and poorly predictable course. Data on independent role of bronchoalveolar lavage fluid (BALF) analysis in prognostic stratification of SSc-ILD patients (pts) are conflicting. We retrospectively evaluated the role of BALF analysis to predict severe course of disease in our cohort of SSc-ILD.

Material and Methods: Forty SSc-ILD pts naive to immunosuppressants underwent comprehensive clinical evaluation, bronchoalveolar fluid analysis with total and differential leukocyte count, pulmonary function tests (PFTs), high-resolution computed tomography (HRCT). All the pts had fibrosing lung disease affecting more than 10% of lung volume on HRCT. Baseline alveolar (AS) and interstitial score (IS) on HRCT were computed. The 15-year crude mortality rate was retrospectively assessed.

Results: The enrolled pts (male 20 %, aged 53.9±13years) had a disease duration of 4.3±3.4 years. Diffuse LeRoy variant was reported in 47.5% of patients and anti-Scl70 and anti-centromere antibodies were detected in 57.5% and 12.5% of pts, respectively. The average AS and IS were 6.5±4.8 and 6.2±2.7, respectively, while 25% had FVC<=80% and 35. % had DLco<=50%. During follow-up 18 pts received immunosuppressants. BALF neutrophilia (>=3.0%), eosinophilia (>=1.0%) and lymphocytosis (>=15.0%) were reported in 40%, 16% and 5% of patients, respectively. Twenty-five pts (62.5%) died within 15 years after bronchoscopy with a mean survival of 12.7 years (95% IC 11.5-13.9) overall. Fifteen-year mortality was predicted by BALF alveolitis (HR 2.87, 95% IC 1.26-6.56), and neutrophilia (HR 3.74, 95% IC 1.64-8.55), log-transformed absolute count of total cells (HR 2.52, 95% IC 1.12-5.58), neutrophils (HR 1.80, 95% IC 1.28-2.54), and eosinophils (HR 1.31, 95% IC 1.05-1.62), and percentages of neutrophils (HR 1.8, 95% IC 1.26-2.73) and eosinophils (HR 1.32, 95% IC 1.01-1.73) (Figure). Only absolute and relative neutrophil counts were independently associated with mortality also in all models adjusted for demographics (age, gender), main disease traits (diffuse LeRoy variant, anti-Scl70 positivity), baseline pulmonary function tests (FVC, DLco), baseline HRCT involvement (AS, IS) and presence of vascular involvement (pulmonary hypertension, digital ulcers).

Conclusions: High BALF neutrophils were associated with high 15-year mortality independently from other established clinical risk factors. Given the negative prognosis of SSc-ILD, its poorly predictable clinical course, and the availability of new promising biomarkers, BALF analysis may be considered in assessing these pts to improve prognosis prediction.

Figure.

Survival curves according to the presence of alveolitis (A), neutrophilia (B), and eosinophilia (C) in BALF.

P.108

CONCORDANCE AND PROGNOSTIC RELEVANCE OF DIFFERENT DEFINITIONS OF SYSTEMIC SCLEROSIS INTERSTITIAL LUNG DISEASE PROGRESSION

Enrico De Lorenzis¹, Francesco Del Galdo², Gerlando Natalello¹, Stefano Di Donato², Lucrezia Verardi¹, Vishal Kakkar², Pier Giacomo Cerasuolo¹, Francesco Varone³, Luca Richeldi³, Maria Antonietta D'agostino¹, Silvia Laura Bosello¹

¹Division of Rheumatology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli, Rome, ITALY, ²University of Leeds - Leeds Institute of Rheumatic and Muskuloskeletal Medicine, Leed, UNITED KINGDOM, ³Division of Pulmonology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli, Rome, ITALY

Introduction: Interstitial Lung Disease (ILD) in systemic sclerosis (SSc) is a common manifestation that has varied progression rate and prognosis. Different progression definitions include minimal clinically important worsening of forced vital capacity (FVC MCIW), EUropean Scleroderma Trials and Research group (EUSTAR) progression, Outcome Measures in Rheumatology Clinical Trials (OMERACT) progression, and INBUILD/ Erice ILD working group progression. The aim of the study was to assess the concordance and prognostic value of these different definitions in SSc-ILD patients overall and in specific clinical subsets.

Material and Methods: Progression status in consecutive SSc-ILD patients was assessed over 24 months, comparing SSc-ILD-related mortality between progressors and non-progressors according to different definitions over the following 60 months. The prediction performances of different progression definitions were investigated with Cox Regression analysis and compared using Akaike information criterion (AIC) with a difference greater than 2 considered as evidence in favour of the model with the smaller AIC.

Results: The 245 SSc-ILD patients enrolled had a mean age of 54.6± 3.2 years and a median disease duration of 4 (IQR 2-8) years from the first non-Raynaud symptoms. Among these patients, 18.8% were males, and 54.7% had the diffuse LeRoy cutaneous variant, 59.2% had anti-Scl70 positivity, and 14.3% anti-centromere antibody positivity.

Twenty-six deaths were reported, and mortality was linked to progression per FVC MCIW (HR 2.27, 95% CI 1.03 – 4.97, p=0.041), OMERACT (HR 2.90, 95% CI 1.28 – 6.57, p=0.011), and INBUILD/Erice trial definitions (HR 11.02, 95% CI 2.38 – 51.08, p=0.002) (Figure 1). Prognostic prediction using these four definitions was challenging in patients with longer disease duration, mild pulmonary function impairment, and pulmonary artery systolic pressure (PASP)>=40 mmHg (Figure 2) Erice criteria were superior in patients with disease duration >3 years, limited cutaneous variant, and PASP< 40 mmHg (δAIC >2). OMERACT criteria performed better in diffuse cutaneous variant patients with severe baseline functional impairment (δAIC >2).

Conclusions: The proposed SSc-ILD progression definitions are not interchangeable, risking potential misdiagnosis in up to a third of progressors. Regardless of criteria, progressors frequently showed diffuse skin disease variant, shorter disease duration, and worse functional impairment.

P.109

ESOPHAGEAL EROSIONS CAN PREDICT THE DETERIORATION OF LUNG FUNCTION OVER A FOUR-YEAR FOLLOW-UP PERIOD AND LONG-TERM MORTALITY IN PATIENTS WITH INTERSTITIAL LUNG DISEASE ASSOCIATED WITH SCLERO

Pier Giacomo Cerasuolo¹, Enrico De Lorenzis¹, Gerlando Natalello¹, Ludovica Berardini², Lucrezia Verardi¹, Alfredo Papa³, Luca Richeldi², Gabriella Alonzi¹, Maria Antonietta D'agostino¹, Silvia Laura Bosello¹

¹Division of Rheumatology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, ITALY, ²Division of Pulmonology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, ITALY, ³Division of Gastroenterology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, ITALY

Introduction: Interstitial lung disease (ILD) is a major cause of morbidity and disease-related death in systemic sclerosis (SSc). Esophageal disease is common in SSc, and micro-aspiration of gastroesophageal reflux may contribute to the pathogenesis of ILD. The aim of this study is to explore the association of erosive esophagitis (EE) determined by esophagogastroduodenoscopy (EGD) with lung function deterioration and survival in patients with SSc.

Material and Methods: Consecutive patients presenting with symptoms of gastro-esophageal involvement who underwent EGD from 2005 to 2015 were characterized based on the occurrence of EE, following the Los Angeles criteria1, and longitudinally evaluated. Patients with SSc-ILD were assessed over a 48-month period for pulmonary function test deterioration according to OMERACT criteria2. Both raw and SSc-associated mortality were documented over a ten-year period for the entire cohort. SSc patients, with or without EE, were compared though survival analysis. A competing risk survival analysis was specifically performed to investigate the association of EE with SSc-related mortality with death due to alternative causes as competing event.

Results: Of the 214 SSc patients studied, 9.8% were male, the mean age was 58.8±13.5 years, the median disease duration was 5.0 years (IQR 1.0-9.0), and the diffuse variant was present in 36.9%. Out of these patients, 33.6% had EE and 59.8% had ILD and no association was found between these two disease characteristics. Forty-nine SSc-ILD patients experienced OMERACT deterioration. EE was associated with a reduced OMERACT progression-free survival (Log-Rank p=0.015) (Fig.A) and an independently doubled risk of progression (HR 1.97, 95% CI 1.09-3.55 adjusted for age, gender, digital ulcers, disease duration, p=0.025). In the overall cohort, fifty-one deaths were reported, 37 of which were SSc-related. In the ILD group, there were a total of 27 deaths due to any cause, with 23 specifically due to SSc. EE was associated with the risk of SSc-related death in the ILD group (HR 2.08, 95% CI 1.05-5.28, Fine-Gray p=0.038) (Fig.B), but not in SSc patients without ILD.

Conclusions: In our cohort, EE represents a risk factor for functional deterioration and SSc-related long-term mortality specifically in SSc patients with ILD, supporting a detrimental role of gastro-esophageal micro-aspiration in exacerbating lung fibrosis.

P.110

PREDICTORS OF RESPONSE AND LONG-TERM EFFICACY AND SAFETY OF NINTEDANIB IN SYSTEMIC SCLEROSIS-INTERSTITIAL LUNG DISEASE: DATA FROM AN ITALIAN MULTICENTRE STUDY

Corrado Campochiaro¹, Giacomo De Luca¹, Maria Grazia Lazzaroni², Giuseppe Armentaro³, Anna Stanziola⁴, Barbara Ruaro⁵, Devis Benfaremo⁶, Enrico De Lorenzis⁷, Beatrice Moccaldi⁸, Francesco Bonomi⁹, Lorenzo Bianchessi¹⁰, Fabio Cacciapaglia¹¹, Marco Confalonieri⁵, Serena Guiducci⁹, Gianluca Moroncini⁶, Elisabetta Zanatta⁸, Veronica Codullo¹⁰, Eisabetta Bosello⁷, Florenzo Iannone¹¹, Paolo Airò², Giovanna Cuomo⁴, Nicoletta Del Papa³, Lorenzo Dagna¹, Marco Matucci-Cerinic^1,9

¹IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, ITALY, ²Unit of Rheumatology and Clinical Immunology, Spedali Civili di Brescia, Brescia, ITALY, ³Scleroderma Clinic, Dip. Reumatologia, ASST G. Pini-CTO, Milan, ITALY, ⁴Department of Precision Medicine - University of Campania L. Vanvitell, Naples, ITALY, ⁵Unit of Respiratory Medicine, University Hospital of Cattinara, Trieste, ITALY, ⁶Unit of Internal Medicine, Marche Polytechnic University, Ancona, ITALY, ⁷Unit of Rheumatology, Catholic University of the Sacred Heart, Rome, ITALY, ⁸Unit of Rheumatology, Padova University, Padova, ITALY, ⁹University of Florence, Florence, ITALY, ¹⁰Unit of Rheumatology, San Matteo Hospital, Pavia, ITALY, ¹¹Unit of Rheumatology, Università degli Studi di Bari Facoltà di Medicina e Chirurgia, Bari, ITALY

Introduction: Nintedanib (NTD) has been shown to reduce the rate of decline in Interstitial Lung Disease (ILD) in Systemic Sclerosis (SSc) following the positive results of the SENSCIS trial and sustained effects have been shown in the SENSCIS-ON study. Here we analyse the predictors of response and NTD-related side effects at 1-year and efficacy and safety of NTD at 2-year in SSc-ILD in a real-life setting

Material and Methods: The clinical data of SSc-ILD patients treated with NTD from 10 Italian SSc centres were retrospectively evaluated at 12 prior to NTD introduction; at baseline, and at 12 and 24 months after NTD introduction. The following parameters were recorded: SSc clinical features, concomitant therapies, NTD tolerability, pulmonary function tests (PFTs) and modified Rodnan skin score (mRSS). Progression was defined according to ATS definition (drop in predicted% FVC>=5% or DLCO>=10% or high-resolution chest tomography (HRCT) evolution and worsening of respiratory symptoms). Logistic regression analyses were performed to assess predictors of response at 1-year and predictors of NTD reduction/suspension

Results: 124 SSc-ILD patients treated with NTD were identified, disease features are summarized in Table 1. A progressive phenotype prior to NTD introduction was observed in 88(71%) of patients. In those who achieved 1-year follow-up (80(64%) patients), the percentage of 1-year progressors was significantly lower compared to the previous 12 months(69%versus35%,p<0.001). No significant change was observed for the mRSS at 12 months in dcSSc patients(7.5±6.4versus6.1±4.9,p=0.20). After a median time of 4(1.5–9.0) months, NTD dose was reduced to 200 mg daily and maintained in 42(34%) patients. In 17(14%) patients, NTD was stopped after a median time of 3(1-9) months. At logistic regression analysis only the presence of a diffuse cutaneous subset (OR 0.375(0.141–0.998)) was associated with 12-month progression-free response whereas the use of high-dose proton pump inhibitors (PPI) (OR 3.600(1.077–12.0.37)) was associated with NTD reduction/suspension. At 2 years, the percentage of progressors did not change compared to the first year(38%,p=0.865). The prevalence of NTD-related side-effects and causes of reduction and suspension are summarized in Figure 1. During the follow-up, 6 patients died after a median time of 10(10–24) months.

Conclusions: In a real-life clinical scenario, NTD, in combination with immunosuppressants, reduced the rate of progressors and this effect in maintained at 2 years. A diffuse cutaneous subset seems a predictor of poorer response whereas the baseline use of high-dose PPI is a risk factor for poor drug tolerance.

P.111

Real-World Evaluation Of Lung Function Tests In Patients With Connective Tissue Disease And Pulmonary Fibrosis, After Nintedanib Treatment

Maria Boutel¹, Afroditi Boutou², Georgia Pitsiou³, Alexandros Garyfallos¹, Theodoros Dimitroulas¹

¹Aristotle University of Thessaloniki-Hippokration General Hospital- 4th Department of Internal Medicine, Thessaloniki, GREECE, ²Aristotle University of Thessaloniki- G. Papanikolaou Hospital -Department of Respiratory Medicine, Thessaloniki, GREECE, ³Aristotle University of Thessaloniki- G. Papanikolaou Hospital - Department of Respiratory Failure, Thessaloniki, GREECE

Introduction: Connective Tissue Disease-Interstitial Lung Disease (CTD-ILD) is a severe and fatal manifestation of systemic autoimmune disorders. Therapies rely on immunomodulators but their efficacy in ILD progression remains uncertain. Nintedanib, an antifibrotic agent that slows pulmonary function decline, has been approved for CTD-ILD treatment. The aim of this study was to assess the effectiveness and safety of nintedanib in CTD-ILD patients in a real-world data setting.

Material and Methods: A single-center, retrospective, and descriptive analysis of CTD-ILD patients treated with nintedanib from June 2019 to November 2022 was performed. The assessment of nintedanib treatment's efficacy was judged solely on the evolution of pulmonary function tests (PFTs), which were evaluated before and after treatment.

Results: Twenty-one patients [67% females, median age 64 years (IQR = 9)] with CTD-ILD (systemic sclerosis n= 9, rheumatoid arthritis n= 5, dermatomyositis n= 4, juvenile rheumatoid arthritis n= 1, undifferentiated CTD n= 1, interstitial pneumonia with autoimmune features n= 1), 18 of whom were on concomitant immunosuppressives, had a median follow-up period of 10 months (IQR = 5). PFTs before and after treatment did not significantly differ. The mean FVC% difference was +0.9 (sd = 7.6) and the mean DLco% difference was +3.4 (sd = 12.6), suggesting numerical improvement of PFTs. The average percentage change was -0.3% and +7.6% for FVC% and DLco%, respectively, indicating stabilization of lung function. A significant increase in the mean duration of CTD-ILD of 2.5 years was observed in patients with extrapulmonary involvement, highlighting the cumulative effect of inflammation on various organs in patients with CTD. Additionally, a significant improvement in DLco% measurements was noticed in the group that received MMF (p-value = 0.03), enhancing the importance of the coadministration of nintedanib with immunosuppressive drugs. Concerning the adverse effects, two patients (10%) experienced intolerable, severe and persistent nausea and one patient (5%) mild diarrhea, manageable with dietary changes and antidiarrheal treatment.

Conclusions: Our real-world data across a broad spectrum of CTD-ILD suggest that nintedanib could be beneficial in combination with immunosuppressives in slowing the rate of lung function decline.

P.112

REAL LIFE DATA ON EFFICACY AND TOLERABILITY OF NINTEDANIB IN A SMALL ITALIAN COHORT OF CTD PATIENTS WITH PROGRESSIVE LUNG FIBROSIS

Lorenzo Mattia Bianchessi¹, Sara Lettieri², Valentina Vertui², Paola Putignano², Sara Bozzini², Eleonora Bozza², Cecilia Bagnera², Giovanni Zanframundo¹, Meloni Federica², Cavagna Lorenzo¹, Codullo Veronica¹

¹Rheumatology Unit IRCCS San Matteo Hospital Foundation, Pavia, ITALY, ²Respiratory Disease Unit IRCCS San Matteo Hospital Foundation, Pavia, ITALY

Introduction: Interstitial lung involvement (ILD) in connective tissue diseases (CTD) reduces life expectancy as it is the leading cause of death. The recent INBUILD trial uncovered the efficacy of Nintedanib to reduce the FVC decline rate in non-IPF progressive lung fibrosis.

Material and Methods: 22 CTD patients with progressive ILD, despite immunosuppression, followed at the multidisciplinary Pneumo-Rheumatologic Clinic of Policlinico San Matteo were prescribed Nintedanib on top of usual treatment (table 1). PFTs were assessed at 0-6 months. We compared our results with those of the placebo autoimmune (PA) cohort of the INBUILD trial by t-test

Results: Demographic features of patients are shown in table 1. In 16/22 patients nintedanib was associated to an immunosuppressant drug. The average delta FVC at 6 months from our cohort was +40 ml (SEM 55.8 ml) vs. -92,8 ml (SEM 21.9 ml) in the PA cohort. There was no significant difference in deltaFVC between different diagnosis (SSc vs ASSD vs MPA vs RA) but the small sample size might have affected this result. The most frequent side effect was diarrhea (11 pts, 50%); the second was transient hyper-transaminasemia (2 pts, 9%). No dropout or death was registered during follow-up.

Conclusions: Our real life data confirm and reinforce results from the INBUILD study on the effectiveness and tolerability of Nintedanib in CTD patients with progressive ILD.

P.113

PROGNOSTIC VALUE OF SELECT CIRCULATING BIOMARKERS IN PATIENTS WITH SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE (SSC-ILD)

Shervin Assassi¹, Sudha Visvanathan², Masataka Kuwana³, Carina Ittrich⁴, Margarida Alves⁵, Oliver Distler⁶

¹Division of Rheumatology, University of Texas Health Science Center at Houston, Houston, USA, ²Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, USA, ³Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, JAPAN, ⁴Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, GERMANY, ⁵Boehringer Ingelheim International GmbH, Ingelheim am Rhein, GERMANY, ⁶Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, SWITZERLAND

Introduction: To evaluate the prognostic potential (for FVC decline or change in modified Rodnan skin score [mRSS] at week 52) of candidate biomarkers, we evaluated circulating biomarkers of epithelial injury (KL-6) and inflammation (CRP, CCL2) with prognostic potential in the placebo group of the SENSCIS trial.

Material and Methods: Subjects had SSc with first non-Raynaud symptom in the prior less than 7 years and an extent of fibrotic ILD on high-resolution computed tomography (HRCT) more than 10%. Associations between baseline biomarker levels and i) rate of decline in FVC (mL/year) over 52 weeks, ii) absolute change from baseline in mRSS at week 52 were assessed in subjects who received placebo. Immunoassays were utilized to assess KL-6 and CCL2 levels; CRP was assessed on the Roche Cobas platform. Baseline biomarker levels were included in the models as a continuous covariate or dichotomized by quantile-based cut-offs.

Results: In total, 288 subjects received placebo. Higher baseline levels of selected biomarkers were associated (p<0.05) with a greater rate of decline in FVC over 52 weeks (KL-6) and a worsening in mRSS at week 52 (CRP, CCL2). Further, select biomarkers were not significantly correlated with one another, suggesting the ability of these biomarkers to identify unique patient subsets associated with changes in FVC or mRSS. There were minimal differences in the levels of these biomarkers at baseline in the presence or absence of mycophenolate (MMF) treatment. Using a dichotomized analysis of these baseline biomarkers, we identified different cut-off levels for KL-6 (more vs. less than 960.0 U/mL: -131.7 vs. -53.7 mL/yr; p<0.0072) as significantly associated with FVC decline at week 52 and CRP (more vs less than 2.5 ng/L: -0.7 vs. -2.8; p=0.0002) and CCL2 (more vs. less than 198.0 pg/mL: -0.8 vs. -2.8; p=0.0002) as significantly associated with change in mRSS at week 52.

Conclusions: Biomarkers prognostic of disease progression based on FVC decline and mRSS worsening have been identified in the placebo group of the SENSCIS trial and have the potential to be utilized as part of patient selection in future trials in SSc/SSc-ILD.

P.114

PREDICTIVE SIGNIFICANCE OF SERUM PROTEINS FOR THE COURSE OF SYSTEMIC SCLEROSIS RELATED INTERSTITIAL LUNG DISEASE IN THE MULTICENTER CONQUER COHORT

Shervin Assassi¹, Masataka Kuwana², Meng Zhang¹, Flavia Castelino³, Lorinda Chung⁴, Luke Evnin⁵, Tracy Frech⁶, Jessica Gordon⁷, Faye Hant⁸, Laura Hummers⁹, Kimberly Lakin⁷, Dorota Lebiedz-Odrobina¹⁰, Yiming Luo¹¹, Dinesh Khanna¹², Ashima Makol¹³, Jerry Molitor¹⁴, Duncan Moore¹⁵, Carrie Richardson¹⁵, Nora Sandorfi¹⁶, Ankoor Shah¹⁷, Victoria Shanmugam¹⁸, Brian Skaug¹, Virginia Steen¹⁹, Elizabeth Volkmann²⁰, Jessica Alvey¹⁰, John VanBuren¹⁰, Elana Bernstein¹¹

¹The University of Texas Health Science Center at Houston, Houston, USA, ²Nippon University, Tokyo, JAPAN, ³Harvard University, Boston, USA, ⁴Stanford University, Stanford, USA, ⁵Scleroderma Research Foundation, San Francisco, USA, ⁶Vanderbilt University, Nashville, USA, ⁷Hospital for Special Surgery, New York City, USA, ⁸Medical University of South Carolina, Charleston, USA, ⁹Johns Hopkins University, Baltimore, USA, ¹⁰University of Utah, Salt Lake City, USA, ¹¹Columbia University, New York City, USA, ¹²University of Michigan, Ann Arbor, USA, ¹³Mayo Clinic, Rochester, USA, ¹⁴University of Minnesota, Minneapolis, USA, ¹⁵Northwestern University, Evanston, USA, ¹⁶University of Pennsylvania, Philadelphia, USA, ¹⁷Duke University, Durham, USA, ¹⁸George Washington University, Washington, D.C., USA, ¹⁹Georgetown University, Washington, D.C., USA, ²⁰University of California - Los Angeles, Los Angeles, USA

Introduction: Higher baseline levels of two serum pneumoproteins, KL-6 and CCL18 predicted worse interstitial lung disease (ILD) course in Scleroderma Lung Study II (Volkmann et al. Arthritis Rheumatol. 2019). Moreover, higher levels of two interferon inducible cytokines (IFN gamma-inducible 10-kd protein [IP-10] and monokine induced by IFN gamma [MIG]) were associated with better response to mycophenolate in this trial (Assassi et al. ARD 2021). Patients enrolled in clinical trials tend to have more homogeneous clinical characteristics than those in observational cohorts in terms of disease characteristics, co-morbidities, and treatment regimens, contributing to the fact that the discovered prognostic/predictive biomarkers in clinical trial settings often do not replicate in observational cohorts. We sought to determine the predictive significance of the aforementioned serum proteins for the course of ILD in the Collaborative National Quality and Efficacy Registry (CONQUER), which is a multicenter, observational, US-based registry of patients with early systemic sclerosis (SSc).

Material and Methods: All patients in CONQUER fulfilled the 2013 ACR/EULAR Classification Criteria and had a disease duration < 5 years at enrollment based on the 1st non-Raynaud’s phenomenon symptom. Patients who had signs of ILD on high resolution Chest CT and were treated with mycophenolate between the baseline and 12-month visits were included in this study (n=122). Patients concurrently treated with nintedanib or tocilizumab were excluded. In addition to baseline serum protein level and time, baseline forced vital capacity % predicted (FVC%) and mycophenolate treatment status at enrollment were included as independent variables in mixed effect linear regression models. All available longitudinal FVC%s after the baseline visit were used as the outcome variable.

Results: At enrollment, the mean disease duration (standard deviation) was 2.7 (1.4) years and 77 (63.1%) of patients had diffuse cutaneous disease type. Higher baseline serum KL-6 predicted worse ILD course (i.e., lower longitudinally obtained FVC%s) while higher baseline serum IP-10 and MIG levels were predictive of better ILD course (i.e., higher longitudinally obtained FVC%s). Serum CCL18 levels did not show predictive significance for the ILD course in our cohort (Table).

Conclusions: In agreement with SLS II findings, the predictive significance of the pneumoprotein, KL-6, for worse ILD course, as well as two interferon inducible cytokines, IP-10 and MIG, for better ILD course in SSc-ILD patients on mycophenolate treatment was validated in the CONQUER cohort, underscoring their utility as prognostic/predictive biomarkers in a nationally-representative, “real-life” clinical setting.

P.115

LUNG QUANTIFICATION PREDICTS MORTALITY IN INTERSTITIAL LUNG DISEASE IN SYSTEMIC SCLEROSIS

Fernanda Amorim, Cristiane Kayser

Universidade Federal de São Paulo - UNIFESP, São Paulo, BRAZIL

Introduction: Interstitial lung disease (ILD) is the leading cause of death in systemic sclerosis (SSc). High-Resolution Computed Tomography (HRCT) and pulmonary function tests (PFTs) are useful but presents limitations such as low reproducibility and low sensitivity. Quantitative CT (qCT) methods, including Computed Aided Lung Informatics for Pathology Evaluation and Rating (CALIPER), are new tools that objectively measures parenchymal abnormalities and vascular features on CT images in a fully automated analysis. We aimed to investigate CALIPER and evaluate its capacity to predict 5-year mortality in patients with SSc.

Material and Methods: Patients diagnosed with SSc were retrospectively selected from 2011 to 2022. Patients should have had volumetric HRCTs and PFTs performed at baseline and at 24 months of follow-up. The following parameters were evaluated in HRCTs using CAPILER: ground glass opacities, reticular pattern, honeycombing, and pulmonary vascular volume (PVV). The extent of ILD (ILD-extent: ground glass+ reticular pattern + honeycombing) and the fibrosis score (reticular pattern + honeycombing) were also evaluated. Factors associated with death were evaluated by Kaplan-Meier survival curves and multivariate analysis models with Generalized Linear Models (GLM).

Results: Seventy-one patients were included with a mean age of 54.2 ± 11.6 years (mean disease duration of 10 years). Eleven patients (15.49%) died during follow-up and all had ILD. FVC was of 73.6 ± 19.1% at baseline and of 69.6 ± 18.9 at follow-up (p=0.001). There was no significant variation in CALIPER variables at baseline and at 24 months of follow-up. The Kaplan Meier curves show mortality between the different CALIPER parameters at baseline and follow-up (Figure 1). The independent predictors of mortality using multivariate analysis were age (Exp 0.906, CI95% 0.826-0.995), FVC decline greater than or equal to 5% at follow-up (Exp 15.01, CI95%1.90-118.5), and reticular pattern (Exp 2.70, CI95% 1.26-5.82).

Conclusions: CAPILER is a useful tool for assessing lung damage and predict mortality in patients with SSc.

P.116

INTERFERON SCORES ARE HIGHER IN SSC-ILD PATIENTS AND CORRELATE WITH DECLINED LUNG FUNCTION

Yehya Al-Adwi¹, Jergus Krc², Salome Mooij², Britt Martijn², Berber Doornbos-van der Meer², Alja Stel², Wayel Abdulahad², Harry van Goor³, Johanna Westra², Douwe J Mulder¹

¹University of Groningen, University Medical Centre Groningen, Department of Internal Medicine, Groningen, THE NETHERLANDS, ²University of Groningen, University Medical Centre Groningen, Department of Rheumatology and Clinical Immunology, Groningen, THE NETHERLANDS, ³University of Groningen, University Medical Centre Groningen, Department of Pathology and Medical Biology, Groningen, THE NETHERLANDS

Introduction: ILD is the primary cause of mortality in systemic sclerosis (SSc). Inflammation through interferon (IFN)-mediated pathways is known to play a significant role in SSc disease progression and IFNs are emerging potential therapeutic targets. However, little is known about the extent of IFN-activation in SSc-ILD patients. Since fibrosis is an irreversible process, targeting inflammatory axes may attenuate the disease before overt fibrosis. We propose IFN-scores using representative IFN genes to understand the extent of IFN activation in SSc-ILD patients compared to those without ILD. We hypothesize that IFN signalling is hyperactivated in SSc-ILD patients and that monocytes overexpressing IFN-induced protein lead to aggravated lung damage.

Material and Methods: Eighty-five SSc patients consisting of 32 with ILD (based on lung function and HRCT), 53 without ILD, and 23 age and sex-matched healthy control were included. PAXgene, serum, and whole blood tubes for peripheral blood mononuclear cells (PBMCs) isolation were collected. IFN-11 scores were calculated based on 11 IFN-associated genes by RT-qPCR. Scores are the sum of (relative expression of patient per gene - mean of relative expression of HCs)/(standard deviation of HC relative expression) for each patient and HC.

Serum CXCL10, an IFN-induced chemokine, was measured using ELISA. Monocytes in PBMCs were characterized according to CD14 and CD16 expression (CD14+/CD16- classical, CD14-/CD16+ non-classical, CD14+/CD16+ intermediate). Expression of Siglec-1 (CD169), a type I interferon-induced protein, on monocytes was detected using anti-CD169 antibody by measuring mean fluorescence intensity (MFI).

Results: In SSc-ILD patients, IFN-11 score is substantially higher compared to patient without ILD [median (IQR): 24.33 (2.03–63.20) vs 6.55 (0.11–22.50), P=0.046] Figure.1. Serum CXCL10 levels are significantly higher in the SSc-ILD group compared to non-ILD [102.6 (58.68–162.3) vs 56.4 (44.0–77.35), P=0.0006]. In monocyte, CD169 expression was significantly higher on the intermediate monocyte in SSc-ILD (N=20) patients compared to SSc-without ILD (N=46) [8577 (7379–12849) vs 7321 (5140–9671), P=0.039]. SSc-ILD patients with high IFN-11 scores (>median) showed worse lung function and their scores correlated strongly with CD169 MFI (rs=0.73, P=0.014) and negatively with %(predicted) forced vital capacity (rs=-0.65, P=0.014) but not with %(predicted) diffusion capacity for carbon monoxide (rs=-0.007, P=0.985) Figure.2.

Conclusions: IFN activation is higher in SSc-ILD patients than in patients without ILD on humoral and cellular levels even in patients with longstanding disease. Future studies should locally investigate IFN-activation in the lungs as it may potentially lead to worsening of lung function. This activation may also serve as target for IFN inhibitory therapies.

P.117

PROGRESSIVE INTERSTITIAL LUNG DISEASE IN SYSTEMIC SCLEROSIS

Catarina Abreu, Ana Cordeiro, Maria José Santos

Hospital Garcia de Orta, Almada, PORTUGAL

Introduction: Interstitial lung disease (ILD) is a significant contributor of morbidity and mortality in systemic sclerosis (SSc). Progressive ILD is defined according to pulmonary function tests (PFTs) as a decline in forced vital capacity (FVC) of >10% or a decline in FVC of 5–9% in association with a decline in diffusing capacity of the lung for carbon monoxide (DLco) of >15% over one year period.

Our aim is to determine the prevalence of progressive ILD in SSc and to describe demographic and clinical characteristics of ILD progressors based on PFTs.

Material and Methods: Adult patients with SSc and ILD who had baseline FVC measurements and one and/or five-years follow-up data available were included. SSc-ILD progression was categorized according to FVC decline at one-year follow-up as moderate (5%-9%) or significant (>10%); and at five-years follow-up as moderate (5-9%), significant (10-19%) or major (>20%)

Results: Out of 189 SSc patients, 42 had SSc-ILD of whom 15 fulfilled the inclusion criteria. Eleven (73.3%) were female, and 13 (86.7%) were Caucasian. The mean age at SSc diagnosis was 52.6±15.9 years. Eleven patients (73.3%) had limited (lcSSC) and 4 (26.7%) had diffuse cutaneous involvement (dcSSC). The predominant SSc-associated autoantibody was anti-Scl70 (55.5%) followed by anti-centromere (13.3%). The mean baseline FVC was 76.5±19.9% and DLco was 53.1±18.0%.

At one-year follow-up we identified 4 progressors, all female with lcSSc and a mean age at SSc diagnosis of 64±7.5 years. Three of them experienced moderate FVC decline (one with DLco decline >15% and one with <15%), while one had a significant decline. Non-progressors had a significantly lower baseline DLco compared to progressors (45.0±15.3 vs 71.5±5.3; p<0.001).

At five-year follow-up, 4 patients were classified as progressors. Three were female with a mean age at diagnosis of 60.5±10.7 years: 1 had a moderate decline in FVC, 2 had significant declines and one had a major decline. Only one patient progressed at both one and five-year follow-up, showing a significant decline at one-year follow-up and a major decline at five-year follow-up.

Conclusions: The prevalence of progressors at one-year follow-up was 28.4%, increasing to 44.4% at five-year follow-up. To explain lower baseline DLco values in non-progressors at 1-year follow-up, prevalence of pulmonary hypertension and the timing of diagnosis of SSc and ILD should be considered. Timely diagnosis of SSc, routine ILD screening and monitoring of progression of PFTs values is important, regardless of FVC absolute values and immunological profiles.

P.118

COMBINED PULMONARY FIBROSIS AND EMPHYSEMA IN SYSTEMIC SCLEROSIS: CLINICAL, FUNCTIONAL AND IMAGING FEATURES

Houssem Abida¹, Zeineb Meddeb¹, Mariem Affès², Cherifa Abdelkefi¹, Amira El Ouni¹, Sana Toujani¹, Saoussen Hantous², Lamia Ben Hassine³, Kamel Bouslama¹, Thara Larbi¹, Saloua B'chir Hamzaoui¹

¹Internal medicine department, Mongi Slim University Hospital, La Marsa, Tunis, TUNISIA, ²Radiology department, Abderrahmen Mami University Hospital, Ariana, TUNISIA, ³Internal medicine department B,Charles Nicolle University, Tunis, TUNISIA

Introduction: Combined Pulmonary Fibrosis and Emphysema (CPFE) is an entity that consists of the association of both centrolobular and/or paraseptal emphysema and interstitial lung disease (ILD). Initially, it was described as an idiopathic entity. Recently, It has been reported in the context of Connective Tissue Diseases.

The aim of our study was to describe the clinical, functional and imaging features of Systemic Sclerosis (SS) patients presenting with CPFE.

Material and Methods: A retrospective and descriptive study carried out in 2 internal medicine departments and an imaging department in Tunisia. It included data of SS patients presenting with ILD. Lung involvement was assessed to all patients with Chest CT Scans.

Results: Thirty-one patients with ILD were included. Seven among them presented emphysema in the CT scans (23%). Mean age of patients with CPFE was 54,28 years [30;81] with a sex ratio (M/F) of 0,4. Three patients were smokers with a mean of 39 Pack-year [10;58]. None of the non-smoking patients had a history of passive smoking or exposure to wood smoke. Three patients reported dry cough and five subjects reported dyspnea. Three of the patients had crackles on auscultation. None of the patients had an oxygen pulse below 94% on room air.

Mean of Forced Vital Capacity (FVC) was 69,5% [47%; 82%]. Mean of Forced Expiratory Volume in 1 second (FEV1) was 69,75% [50;79%].

Echocardiography was performed in 5 patients. The estimated mean of systolic artery pulmonary pressure was 46,6 mmHg [22;100]. It was higher than 35 mmHg in 2 patients.

Antinuclear antibodies (ANA) were present in all seven patients.

The predominant elemental lesions on chest CT were: septal thickening (n=7); traction bronchiectasis or bronchiolectasis (n=7); ground-glass opacities (n=6) and reticulations (n=6). Anatomic distribution of the ILD lesions were as follows: subpleural predominance (n=6); central (n=1). ILD patterns were the following: non-specific interstitial pneumonia (n=4) and usual interstitial pneumonia (n=3). Emphysema was paraseptal in 4 patients and centrilobular in 3 patients. It was present in the upper lobes in all patients.

Pulmonary artery diameter was greater than 29 mm in three patients.

Conclusions: Clinical and imaging features of patients with SS-CPFE in our study seemed to be similar to those with idiopathic CPFE. Yet, the small number of patients in our study cannot be conclusive. Further studies are needed to assess the impact of the presence of emphysema lesions on the respiratory prognosis for SS-ILD patients.

P.119

FREQUENCY AND IMPACT OF SECONDARY SJÖGREN'S SYNDROME IN CONNECTIVE TISSUE DISEASE-RELATED INTERSTITIAL LUNG DISEASE

Alida Aliyeva¹, Derya Kocakaya², Ozlem Demircioglu³, Nuri Cagatay Cimsit³, Semra Akkaya Turhan⁴, Gonca Mumcu⁵, Nevsun Inanc¹

¹Department of Internal Medicine, Division of Rheumatology, School of Medicine, Marmara University, Istanbul, Turkey, ²Department of Pulmonology, School of Medicine, Marmara University, Istanbul, Turkey, ³Department of Radiology, School of Medicine, Marmara University, Istanbul, Turkey, ⁴Department of Ophthalmology, School of Medicine, Marmara University, Istanbul, Turkey, ⁵Department of Health Management, Faculty of Health Sciences, Marmara University, Istanbul, Turkey

Introduction: Interstitial lung diseases (ILD) have a broad etiological spectrum besides becoming idiopatic, characterized by inflammation, fibrosis and structural deterioration that diffusely affects the lung parenchyma. Sjögren's syndrome (SjS) can be seen as primary SjS(pSS), it can also be seen as secondary Sjögren's syndrome (sSS) accompanying other autoimmune diseases such as rheumatoid arthritis(RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc). The presence of the sSS can have a significant impact on the phenotype of the associated autoimmune disease and on the quality of life. In this study, we determined the frequency of sSS in connective tissue diseases (CTD) with ILD and investigated the radiographic course based on high-resolution computed tomography (HRCT) findings in association with secondary Sjögren's disease. It was aimed to demonstrate its relationship with lung inflammation and fibrosis pattern.

Method: Eighty patients with CTD whom were followed up for ILD at Marmara University, Rheumatology Clinic were recruited to this study. Demographic characteristics of the patients were determined. The results of ANA and ENA profile performed during the patients' follow-up were recorded. HRCT and pulmonary function tests performed in the last year were recorded. At the outpatient clinic visit, ultrasonography (US) of the parotid and submandibular glands was performed for glandular involvement, and US images were scored with the OMERACT scoring method. On the same day, unstimulated saliva samples of the patients were collected and patients referred to the Department of Ophthalmology for the evaluation of dry eye. sSS patients were selected in accordance with the 2016 ACR/EULAR Sjögren's syndrome classification criteria.

Material and Methods: Of the 80 patients included in the study, 14 were diagnosed with sSS. In the group with sSS, 35.7% (n=5) of the patients had RA, 50%(n=7) had SSc and 14.3% (n=2) had inflammatory myopathy. Four of the sSS patients had salivary gland US was scored as grade 2-3 with OMERACT scoring method. The comparison of demographic data such as age, gender, smoking and PFT/DLCO and HRCT findings of the CTD-ILD patients with and without sSS is shown in the ?mage 1. SSc accounts for 50% of sSS patients with ILD and their data is shown image.

Conclusion: Although there was no significant difference in HRCT findings between the CTD-ILD patients with and without sSS, the presence of sSS resulted in more ground glass areas and more deterioration in respiratory function tests. Scleroderma constitutes the majority of sSS patients with ILD.

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COMPATIBILITY OF FORCED INSPIRATORY VITAL CAPACITY MEASURED BY INCENTIVE SPIROMETRY WITH PULMONARY FUNCTION TESTS IN PATIENTS WITH SYSTEMIC SCLEROSIS

Erdinc Unaldi¹, Alper Sari², Oguz Karcioglu³, Gizem Ayan¹, Gul Sandal Uzun¹, Alptug Hekimcan Kaynar⁴, Aytekin Idikut³, Levent Kilic¹, Ali Akdogan¹, Ata Murat Kaynar⁵

¹Hacettepe University Faculty of Medicine, Department of Internal Medicine, Division of Rheumatology, Ankara, Turkey, ²Ankara Etlik City Hospital, Internal Medicine, Rheumatology Clinic, Ankara, Turkey, ³Hacettepe University Faculty of Medicine, Department of Pulmonary Medicine, Ankara, Turkey, ⁴Columbia University, New York, USA, ⁵Pittsburg University, Department of Anesthesia and Intensive Care Medicine, Pittsburg, USA

Introduction: INTRODUCTION: Interstitial lung disease (ILD) is a leading cause of mortality in systemic sclerosis (SSc). Pulmonary function tests (PFTs) are used to determine the severity of ILD and for follow-up care. In addition to being used in postoperative pulmonary rehabilitation, the incentive spirometry device also provides a measurement function with its 4,000 ml reservoir. In our study, we aimed to evaluate the compatibility of forced inspiratory vital capacity (FIVC) measured with the incentive spirometry device with the classical PFTs forced vital capacity (FVC) and FIVC measurements.

Methods: Seventeen SSc patients admitted to Hacettepe University Rheumatology outpatient clinic were included. FVC and FIVC measurements were performed as part of classical PFTs. Acceptability of PFTs was assessed in accordance with ATS guidelines. Only patients with acceptable PFTs in the A/B/C group according to the guidelines were included in the study. FIVC measurements were performed with incentive spirometry. The use of the device was explained practically to the patients by the investigator (EU) and a training video was shown afterwards, and then the measurement (instructed FIVC) was performed. The same measurement was repeated alone to determine the accuracy of the patient's measurement technique, and this measurement was observed and evaluated by a different researcher without instructions (Supervised FIVC). The agreement between the measurements was assessed by Spearman's Rho correlation coefficient.

Results: All 17 SSc patients enrolled in the study were women with a median age of 49 years (28-65). Five patients (29.4%) had diffuse SSc and seven patients (41.1%) had ILD. Demographic and clinical characteristics of the patients are summarized in Table. There was a high level of positive correlation between FVC obtained by classical PFTs and instructed FIVC (rho:0.84, p<0.001) and supervised FIVC (rho:0.78, p<0.001) measured by incentive spirometry (Figures 1 and 2). There was also a high positive correlation between classical PFTs FIVC measurements and insentive spirometry instructed FIVC (rho:0.80, p<0.001) and supervised FIVC measurements (rho:0.71, p<0.001). There was a very high correlation between instructed and supervised incentive spirometry FIVC measurements (rho:0.94, p<0.001).

Discussion-Conclusion: The measurement of FIVC by incentive spirometry is highly correlated with FVC and FIVC measurements in conventional PFTs. The simplicity of the method allows the patient to repeat this measurement on their own. With this method, which can also be realized with telemedicine, FIVC measurement with incentive spirometry can be used to measure the pulmonary function of SSc patients at frequent intervals and without the need for hospitalization.

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THE ROLE OF IVIG TREATMENT ON GASTROINTESTINAL INVOLVEMENT

Jose Tandaipan¹, Alfredo Guillén-Del-Castillo², Carmen Pilar Simeón-Aznar², Patricia Carreira³, Carlos De la Puente⁴, Javier Narváez⁵, Judit Lluch⁵, Manuel Rubio-Rivas⁶, Juan Jose Alegre-Sancho⁷, Gema Bonilla⁸, Clara Moriano⁹, Ivette Casafont-Sole¹⁰, Rosario García-Vicuña¹¹, Vera Ortiz-Santamaría¹², Elena Riera¹³, Belén Atienza-Mateo¹⁴, Ricardo Blanco¹⁴, Carlos Galisteo¹⁵, Jorge Juan Gonzalez-Martin¹⁶, Jose Maria Pego-Reigosa¹⁷, Ana Pros¹⁸, Sergi Heredia¹⁹, Ivan Castellví¹

¹Department of Rheumatology and Systemic Autoinmune Diseases, Hospital Universitari de la Santa Creu i Sant Pau, BARCELONA, SPAIN, ²Unit of Systemic Autoimmune Diseases, Department of Internal Medicine, Hospital Universitari Vall d'Hebrón., BARCELONA, SPAIN, ³Department of Rheumatology, Hospital Universitario 12 de Octubre., MADRID, SPAIN, ⁴Department of Rheumatology, Hospital Universitario Ramon y Cajal., MADRID, SPAIN, ⁵Department of Rheumatology, Hospital Universitari de Bellvitge, Hospitalet de Llobregat., Hospitalet de Llobregat, SPAIN, ⁶Department of Internal Medicine, Hospital Universitari de Bellvitge., Hospitalet de Llobregat, SPAIN, ⁷Department of Rheumatology, Hospital Universitario Doctor Peset., VALENCIA, SPAIN, ⁸Department of Rheumatology, Hospital Universitario La Paz., MADRID, SPAIN, ⁹Department of Rheumatology, Complejo Asistencial Universitario de León., LEON, SPAIN, ¹⁰Department of Rheumatology, Hospital Germans Trias i Pujol, Badalona., BADALONA, SPAIN, ¹¹Department of Rheumatology, Hospital Universitario de La Princesa., MADRID, SPAIN, ¹²Department of Rheumatology, Hospital General de Granollers., GRANOLLERS, SPAIN, ¹³Department of Rheumatology, Hospital Universitari Mútua de Terrassa., TERRASSA, SPAIN, ¹⁴Department of Rheumatology, Hospital Universitario Marques de Valdecilla, Immunopathology Group, IDIVAL, SANTANDER, SPAIN, ¹⁵Department of Rheumatology, Hospital Universitari Parc Taulí., SABADELL, SPAIN, ¹⁶Department of Rheumatology, Hospital Universitario HM San Chinarro., MADRID, SPAIN, ¹⁷Department of Rheumatology, Complejo Hospitalario Universitario de Vigo, IRIDIS, VIGO, SPAIN, ¹⁸Department of Rheumatology, Hospital del Mar, BARCELONA, SPAIN, ¹⁹Department of Rheumatology, Hospital Sant Joan Despí Moisès Broggi, Sant Joan Despí, SPAIN

Introduction: Gastrointestinal involvement (GI) is the most frequently affected internal organ system in systemic sclerosis (SSc). According to the EULAR recommendations for SSc, symptomatic treatments are recommended for GI, despite its high prevalence in SSc, and considering the associated morbidity and mortality, awaiting new treatment options for the management of this type of involvement. Intravenous Immunoglobulins (IVIG) showed beneficial effects in some case series and observational studies in SSc patients. The response of gastrointestinal involvement to IVIG therapy would be due to an antibody inhibition mechanism, as in vitro studies have observed that IVIG can inhibit smooth muscle cell contraction, through antibodies directed against muscarinic M3 receptors.

Objective: To analyse the effectiveness and safety of IVIG given in routine care to patients with GI in SSc patients

Material and Methods: A retrospective multicenter observational study was conducted in SSc patients treated with IVIG. We collected data on epidemiological parameters and clinical outcomes. Firstly, we assessed changes in organ manifestations during IVIG treatment. Secondly, we analysed the frequency of adverse effects. The following parameters were collected from baseline to the last follow-up: the patient's weight, haemoglobin and protein levels) and The University of California Los Angeles Scleroderma Clinical Trials Consortium gastrointestinal tract 2.0 (UCLA GIT 2.0) questionnaire.

Results: Data were collected on 24 patients(83% females; 50% with diffuse SSc). Anticentromere was the most frequent antibody (38%). The time since Raynaud's phenomenon and SSc onset were 8.8±18 and 6.2±6.7 years respectively. The median number of cycles given were 4. 13, 9 and 3 patients have been treated previously with glucocorticoids, synthetic disease-modifying antirheumatic drugs and biologic therapies respectively. After IVIG use we found significant improvement in total score of UCLA GIT 2.0 (p=0.05). A total of 6 adverse events were reported, 3 of them were withdrawn, only one due to serious adverse effect.

Conclusions: this study suggest that IVIG may improve gastrointestinal involvement in SSc patients treated in routine care and seems to have a good safety profile.

P.122

ESOPHAGEAL DYSMOTILITY IN SYSTEMIC SCLEROSIS: DEMOGRAPHIC AND CLINICAL FINDINGS

Inês Santos¹, Raquel Miriam Ferreira^2,3, Carlos Gomes^2,3, Mariana Diz Lopes^2,3, Georgina Terroso², Lúcia Costa²

¹Rheumatology Unit, Centro Hospitalar Tondela-Viseu, Viseu, PORTUGAL, ²Rheumatology Department, Centro Hospitalar e Universitário de São João, Porto, PORTUGAL, ³Department of Medicine, Faculty of Medicine, University of Porto, Porto, PORTUGAL

Introduction: The relationship between manometric changes and esophageal dilation on high-resolution computed tomography (HRCT) is well established in Systemic Sclerosis (SSc), but its association with extra-esophageal manifestations is inconsistent. This study aims to characterize manometric findings in SSc patients and to determine predictive factors of manometric esophageal body involvement.

Material and Methods: This is a retrospective single-center study including adult patients with SSc registered in Reuma.pt fulfilling ACR/EULAR 2013 classification criteria who had undergone conventional or high-resolution esophageal manometry (HRM). Patients with prior upper gastrointestinal (UGI) surgery or myositis overlap were excluded. Demographic and clinical data were collected. The associations between esophageal motility and disease duration, immunologic profile, cutaneous and pulmonary involvement, as well as endoscopic or tomographic esophageal alterations were evaluated.

Results: A total of 76 patients were included. Manometric characterization was performed (table 1). Sixty patients (78.9%) underwent a conventional manometry. The most common finding was aperistalsis in 23 (38.3%), followed by normal peristalsis in 21 (35.0%), hypoperistalsis in 13 (21.7%) and nutcracker esophagus in 3 (5.0%). A normotonic lower esophageal sphincter (LES) was present in 45 (75.0%), hypotonic in 14 (23.3%) and hypertonic in 1 (1.7%). HRM was performed in 16 patients (21.1%). Normal motility was seen in 9 (56.3%), ineffective esophageal motility and absent contractility in 3 each (18.8%) and esophagogastric junction outflow obstruction in 1 (6.3%). A normotonic LES was present in 9 (56.3%) and a hypotonic LES in 7 (43.8%). Altogether, manometric studies revealed a total of 46 patients (60.5%) with esophageal body dysmotility and 54 (71.1%) with normotonic LES.

Baseline characteristics were analyzed globally and by motility group (table 2). Sixty-four patients (84.2%) had limited cutaneous disease. The median disease duration was 5 years (IQR 11) with mean age of 54.1±12.4 years. Seventy-one patients (93.4%) were females.

Potential predictive factors of manometric involvement were compared between patients with normal motility and dysmotility (table 3). Esophageal dilation on HRCT was more frequent in patients with dysmotility (p=0.005). There were no statistically significant differences regarding disease duration, immunologic profile (antinuclear, anti-Scl70 or anticentromere antibodies), modified Rodnan skin score, esophagitis, Barrett's esophagus, interstitial lung disease, forced vital capacity or single-breath carbon monoxide diffusing capacity.

Conclusions: Esophageal involvement was frequent in our sample, although LES was more commonly spared.

An association between esophageal dysmotility and its dilation on HRCT was found, highlighting the utility of HRCT for identification of UGI involvement in SSc.

No association was found between manometric changes and extra-esophageal manifestations.

P.123

CHARACTERISTICS OF PATIENTS WITH SYSTEMIC SCLEROSIS (SSC) WITH DYSPHAGIA

Tatsuaki Naganawa¹, Ayako Kuwabara², Yumi Ito¹, Ai Umeda¹, Konomi Akamatsu¹, Megumi Kurumizawa¹, Takako Hashimoto¹, Jo Nishino¹, Syusaku Fukaya¹, Youko Inamoto², Seiko Shibata³, Otaka Yohei³, Hidekata Yasuoka¹

¹Fujita Health University School of Medicine - Department of Internal Medicine, Section of Rheumatology, Toyoake, JAPAN, ²Fujita Health University School of Health Science - Faculty of Rehabilitation, Toyoake, JAPAN, ³Fujita Health University School of Medicine - Department of Rehabilitation, Toyoake, JAPAN

Introduction: SSc is characterized by fibrosis of various organs including the gastrointestinal (GI) tract. SSc patients can suffer from dysphagia, which can increase the risk of aspiration. However, only few studies associated with SSc patients with dysphagia were reported. Our aim is to determine the prevalence of dysphagia in SSc. Also, the association among dysphagia, clinical features of SSc, and components of GI involvement were examined.

Material and Methods: Patients with SSc who were examined by videofluoroscopic swallowing study (VFSS) between September 2022 and March 2023 were consecutively involved. By VFSS, esophageal involvement (E) was defined by the residue after swallowing a liquid bolus, pharyngeal involvement (P) by the presence of vallecular residue, and gut involvement (G) by the presence of diarrhea. Dysphagia was identified by the existence of residue and aspiration and/or laryngeal penetration evaluated by the Penetration Aspiration Scale (PAS) using VFSS. Both univariate and multivariate analysis were examined to extract the risk factors associated with dysphagia. The logistic regression models were used for the multivariate analysis.

Results: Fifty SSc were enrolled. Seventy-eight percent was female. The age at VFSS was 63.4±13.2 years. Based on the PAS, 27(54%) had no penetration, 21(42%) had penetration, and 2(4%) had aspiration. As for the association with clinical characteristic, aspiration and/or laryngeal penetration was associated with esophageal residue (p=0.008), diarrhea (p=0.004), GIT-2.0 total score(p=0.006), and HAQ-DI(p=0.017), and had a tendency with pharyngeal residue, reflux and prefrail/frail by the univariate analysis. By the multivariate analysis, pharyngeal residue(p=0.012), esophageal residue(p=0.01), diarrhea(p=0.006), and GIT-2.0(p=0.048) were extracted. As for the association with components of GI involvements in 50 patients, E was found in 48(96%), P in 41(82%), and G in 25(50%) by VFSS. Most of E had P(40/48, 83%), and almost half P had G(22/40, 55%). All with G had E(100%), and most of G were with P(22/25, 88%). Interestingly, the E+P+G+ group was younger onset (p=0.024), more frequent with aspiration and/or laryngeal penetration(p=0.006) and had a higher GIT-2.0(p=0.002) compared with patients with E+P+G-.

Conclusions: Almost half of the patients were affected by dysphagia. The presence of the entry of material into the airway was associated with other components of GI involvement. Development of GI involvement seem to start from esophageal or esophageal plus pharyngeal involvement, and then reach to gut involvement. However, since the development of gut involvement was associated with younger onset, patients with extended GI involvement might be a unique SSc subset.

P.124

ALTERNATION OF GASTROINTESTINAL TRACT MICROBIAL COMPOSITION IN PATIENTS WITH SYSTEMIC SCLEROSIS AND PREDICTING THEIR FUNCTIONAL CAPABILITIES

Su-Jin Moon¹, Bong-Woo Lee², Hae-Rim Kim³, Seung-Ki Kwok²

¹Yeuuido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, SOUTH KOREA, ²Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, SOUTH KOREA, ³Division of Rheumatology, Department of Internal Medicine, Research Institute of Medical Science, Konkuk University Scho, Seoul, SOUTH KOREA

Introduction: Systemic sclerosis (SSc) is a rare autoimmune-mediated chronic inflammatory disease characterized by vascular abnormalities and progressive fibrosis in affected organs such as skin, lung and gastrointestinal tract (GIT). While the exact causes of SSc remains unclear, recent several studies have shown that the GIT dysbiosis may be a pathological feature of SSc.

Tax4Fun is a software package that predicts the functional capabilities of microbial communities based on 16S rRNA datasets. This study was conducted to compare faecal microbial composition in SSc patients with controls and to get insight regarding the SSc pathophysiology through Tax4Fun software.

Material and Methods: Forty-one patients with SSc and 28 healthy controls (HCs) participated in this study. All participants provided stool specimens for 16S rRNA sequencing, and clinical features such as autoantibody, and presence of interstitial lung disease (ILD) were collected simultaneously.

Taxonomic differences at specific levels were examined using linear discriminant analysis effect size (LEfSe). We used Tax4Fun analysis through Kyoto Encyclopedia of Genes and Genomes to predict possible pathways of fecal microbiome involved in the SSc pathophysiology.

Results: The majority of SSc participants were female (85 %) with a median age of 58.0 (interquartile range: 45.5 to 65.0). The mean age of onset for SSc was 48.1 (± 15.0), and the mean duration of SSc disease was 4.73 (± 6.4) years. Principal component analysis (PCA) found the different microbial taxa between feces of SSc individuals and HCs. Based on PCA results, there was no significant difference in the distribution of GIT microbiome with respect to ILD status, type of autoantibodies, disease duration, or SSc type (limited vs. diffuse).

Microbiome analysis showed that the Firmicutes to Bacteroidetes ratio was significantly higher in the fecal samples of SSc patients compared to those of HCs. Additionally, the abundance of Christensenellaceae, Ruminococcaceae, and Faecalibacterium was significantly lower in the fecal samples of SSc patients compared to HCs, while Enterobacteriaceae family and Proteobacteria were significantly higher in SSc patients. Among lactate-producing bacteria, the Lactobacillus genus was found to be significantly higher in SSc patients, whereas the proportion of Bifidobacterium did not dffer between SSc and HCs. Predictive analysis of functional capacity suggested the possible involvement of several pathway such as lysosome, sugar and purine metabolism in SSc pathophysiology.

Conclusions: The present analysis revealed specific alterations in the gut microbiota of SSc patients compared to controls. The functional pathway inferred from the gut microbiome data can be further elucidated through additional research.

P.125

DOES THERAPY WITH IMMUNOSUPPRESSIVE DRUGS IMPROVE GASTROINTESTINAL SYMPTOMS IN PATIENTS WITH SYSTEMIC SCLEROSIS?

Lea Stamm¹, Alexandru Garaiman¹, Mike Oliver Becker¹, Cosimo Bruni^1,2, Rucsandra Dobrota¹, Muriel Elhai¹, Sherif Ismail³, Suzana Jordan¹, Norina Zampatti¹, Aurora Tatu⁴, Oliver Distler¹, Carina Mihai¹

¹University Hospital Zurich, University of Zurich, Rheumatology, Zurich, SWITZERLAND, ²University of Florence, Dept. Experimental Medicine, Division of Rheumatology, Azienda Ospedaliero Universitaria Careggi, Florence, ITALY, ³National Research Center, Dept. of Internal medicine, Cairo, EGYPT, ⁴University Hospital Zurich, University of Zurich, Gastroenterology, Zurich, SWITZERLAND

Introduction: The gastro-intestinal (GI) tract is frequently affected in systemic sclerosis (SSc), leading to considerable morbidity and even mortality. While important progress has been made regarding the treatment of SSc, there is no evidence-based disease-modifying treatment available for SSc-related GI manifestations.

In this observational cohort study of real-life patients with SSc, we aimed to identify an association between immunosuppressive therapy and the severity of GI symptoms, measured by the University of California at Los Angeles / Scleroderma Clinical Trial Consortium Gastro-Intestinal Tract instrument 2.0 (GIT).

Material and Methods: We selected patients with SSc from our EUSTAR center who fulfilled the 2013 ACR/EULAR criteria for SSc and had at least two visits (further referred to as “baseline” and “follow-up”) with completed GITs, within an interval of 12±3 months. The study outcome was the GIT score at follow-up. We used multivariable linear regression with the following covariates: immunosuppressive therapy during the observation period, immunosuppressive therapy before baseline, baseline GIT, and several baseline parameters selected by clinical judgment as potentially influencing GI symptoms.

Results: We included 209 patients. Baseline characteristics were: 82.3% female, median (IQR) age 59.0 (48.6, 68.2) years, median disease duration 6.0 (2.7, 12.5) years, 40 (19.1%) diffuse cutaneous SSc, median baseline GIT score 0.19 (0.06, 0.43). At baseline, 39 patients (19%) were already on immunosuppressive therapy and 114 (55%) were taking proton pump inhibitors. During the observation period, 71 patients were exposed to immunosuppressive therapy : 27/71 methotrexate, 1/71 cyclophosphamide, 17/71 mycophenolate mofetil, 3/71 leflunomide, 3/71 azathioprine, 6/71 glucocorticoids >10mg/d, 16/34 rituximab, 18/34 tocilizumab. Patients on immunosuppressive therapy during the observation period had, compared to patients without such treatment, overall more severe SSc, higher prevalence of treatment with proton pump inhibitors, similar GIT scores at baseline and at follow up and tendentially less severe GI symptoms at baseline and follow-up by medical history.

In multivariable linear regression, with and without imputation for missing data, we found a relevant and statistically significant negative relationship between immunosuppressive therapy during the observation period and the total GIT at follow-up. Similar results were obtained in several sensitivity analyses, including one with a study-effect design and patient matching.

Conclusions: Our study showed, for the first time in a large cohort of unselected patients with SSc, a robust association between exposure to immunosuppressive treatment and lower GIT scores. This finding suggests potential effects of immunosuppressants on GI manifestations in patients with SSc and needs to be confirmed in prospective studies.

P.126

THE ROLE OF SURGERY IN THE MANAGEMENT OF OESOPHAGEAL INVOLVEMENT IN SYSTEMIC SCLEROSIS: A SYSTEMATIC LITERATURE REVIEW

Pietro Matucci Cerinic¹, Akpabio Akpabio², Michael Hughes^3,4, Zsuzsanna H McMahan⁵, Giovanni Terrosu¹, Antonio Martino⁶, Massimo Vecchiato⁶, Roberto Petri⁶, Marco Matucci Cerinic^7,8, Alessia Alunno⁹

¹University Hospital, ASUFC Santa Maria della Misericordia, Division of Surgery and Transplantation, Udine, ITALY, ²Rheumatology Department, Royal National Hopital for RHeumatic Disease, Bath, UNITED KINGDOM, ³Northern Care Alliance NHS Foundation Trust, Salford Care Organisation, Salford, UNITED KINGDOM, ⁴Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Manchester, UNITED KINGDOM, ⁵Johns Hopkins University, Department of Medicine, Division of Rheumatology, Baltimora, USA, ⁶Division of Surgery, Department of Surgery, ASUFC Santa Maria della Misericordia, Udine, ITALY, ⁷Unit of Immunology, Rheumatology, Allergy and Rare diseases (UnIRAR), IRCCS San Raffaele Hospital, Milan, ITALY, ⁸Dept. Experimental and Clinical Medicine, University of Florence, and Division of Rheumatology AOUC, Florence, ITALY, ⁹Internal Medicine and Nephrology Unit, MeSVA Department, University of L Aquila, L'Aquila, ITALY

Introduction: Gastroesophageal reflux disease (GERD) is one of the earliest clinical manifestations of systemic sclerosis (SSc). Proton pump inhibitors are ineffective in controlling symptoms in up to 40% of cases, while the chronic PPI use at high doses is a concern for long-term side effects (e.g., cardiovascular disease and infections). In SSc, surgery has been proposed as an option for refractory GERD but consensus on optimal surgical procedure is lacking. The aim of our analysis is to evaluate and compare the safety, efficacy, indications, timing and feasibility of fundoplication (FP) with different surgical approaches to treat refractory GERD in SSc.

Material and Methods: Four research questions based on the PICO framework were developed to guide the systematic literature review (SLR) conducted up to 10 April 2023. The search was performed across different databases including PubMed, MEDLINE (OVID), EMBASE, Cochrane Library, Web of Science, Google Scholar, Emcare and Academic Search Premier. References were independently screened by two reviewers (PMC and AA) who also independently assessed the full text of eligible articles and extracted data. Due to the heterogeneity of retrieved studies, narrative summaries are used to present the data.

Results: Out of 955 papers retrieved papers, only 23 were eligible for inclusion: in these studies, 184 SSc patients underwent an anti-reflux surgical procedure and were included in the analysis. Most of the studies were conducted in surgical settings but relevant rheumatological data were largely missing. Refractory GERD symptoms were the most common indication for surgery, with post-operative dysphagia being the most frequent complication. In 15 studies, fundoplication (FP) was effective, while 4 studies show a favourable outcome of Roux-en-Y Gastric by-pass. All the data extracted demonstrated a low mortality and morbidity rate related to surgery.

Conclusions: The SLR data demonstrate that a broad application of surgery for the management of refractory GERD in SSc remains a challenge. In fact, only limited evidence, largely of poor quality, is available. In the majority of SSc patients, the fact that FP was safe and beneficial may suggest that it might help a group of patients. In SSc, the definition of minimal requirements to perform surgical studies on refractory GERD, the identification of patient cohorts who would most likely benefit from surgical referral, and a determination of the appropriate timing for surgery are warranted.

P.128

MALIGNANCIES AND THEIR EFFECTS ON DISEASE COURSE IN PATIENTS WITH SYSTEMIC SCLEROSIS WITH 10 YEARS FOLLOW-UP

Ibrahim Gunduz¹, Mehmet Ali Balci², Lufti Akyol², Remzi Cevik³, Suleyman Serdar Koca¹

¹FIRAT University, Faculty of Medicne, Department Of Rheumatology, Elazig, TURKEY, ²Gazi Yasargil Hospital, Department of Rheumatology, Diyarbakir, TURKEY, ³DICLE University, Faculty of Medicine, Department of Rheumatology, Diyarbakir, TURKEY

Introduction: Systemic sclerosis (SSc) is an inflammatory disease. It is well known that systemic inflammatory diseases have increased malignancy risk. Malignancy prevalence has been reported previously as 3.6-10.7% in SSc. Standardized incidence ratio (SIR) are calculated for lung cancer (4.9), skin cancer (4.2), hepatocellular carcinoma (3.3), hematological malignancies (2.3), esophageal cancer (15.9) and oropharyngeal carcinoma (9.6). Thus, the aim of study was documenting the prevalence of malignancies and their potential effect on disease course in patients with SSc with 10 years follow-up.

Material and Methods: SSc patients from two territory hospitals diagnosed between 2010 and 2020 were include in the study. Demographical, clinical and laboratory features were recorded. Cancer types and their effect on the features of SS were analyzed with suitable statistical methods.

Results: 5 (3.4%) of 149 SSc patients (137 females and 12 males) had cancer diagnosis and their mean age was 54±6.4 years. All of 5 were females and the mean age of cancer diagnosis was 50±6.6 years. Two of them had breast cancer, one had ovary cancer, one had soft tissue sarcoma and the last one had basal cell carcinoma. Time to cancer diagnosis form SSc diagnosis was 6.6±5.5 (min-max: 2-14) years. One of them was died at follow-up period. 3 of SSc with concomitant cancer were diffuse cutaneous SSc and 2 ones were limited cutaneous SSc subtype. Only one of the had received cyclophosphamide treatment. Dysphagia and gastroesophageal reflux disease (GERD) were prevalent in patients with cancer (Table 1 ).

Conclusions: This study shows that 3.4% of SSc patients have cancer risk. Dysphagia and other GERD symptoms are more prevalent in patients with concomitant cancer than in without ones. Dysphagia and other GERD symptoms may be candidate surrogate marker for malignancy in patients with SSc.

P.129

APPROACHES TO TREATING GASTRIC ANTRAL VASCULAR ECTASIA IN SYSTEMIC SCLEROSIS: CLINICAL CASES UTILIZING APC, TOCILIZUMAB, AND IVIG THERAPIES

Hyun-Sook Kim¹, HeeWon KIM¹, Hye-Ji JEON¹, Kyung-Ann LEE¹, TaeHee LEE²

¹Division of Rheumatology, Soonchunhyang University Seoul Hospital, Soonchunhyang University School of Medicine, Seoul, SOUTH KOREA, ²Institute for Digestive Research, Digestive Disease Center, S Soonchunhyang University Seoul Hospital, Seoul, SOUTH KOREA

Introduction: Gastric antral vascular ectasia (GAVE) is a rare condition that can occur in patients with systemic sclerosis (SSc), and it is characterized by dilated blood vessels in the stomach that can cause chronic blood loss.

Material and Methods: We report a case of a 62-year-old female patient diagnosed with diffuse systemic sclerosis accompanied by interstitial lung disease (ILD), who presented with severe anemia and GAVE. At the time of diagnosis, the patient had a hemoglobin level of 4.9 g/dL and a modified Rodnan skin score (mRSS) of 24. Initial endoscopic examination showed prominent erythematous stripes from the pylorus to the antrum, typically known as “watermelon stomach” (Figure 1A). The patient's blood test had positive ANA (1:160, nuclear speckled), anti-polymerase lll (+), and anti-Ro/SSA (+). Three months after the diagnosis, the patient rapidly developed progressing skin thickening in the proximal area and exhibited tendon friction rubs in the fingers, wrists, and elbows (Figure 2).

Results: Argon plasma coagulation (APC) was applied to coagulate the bleedings three times per week, 15 times in total. Concurrently, Tocilizumab was initiated for SSc and concomitant ILD. Due to neutropenia and thrombocytopenia, tocilizumab was discontinued. Subsequently, we administered an intravenous immunoglobulin (IVIG) of 1g/kg every month for four months and then switched to mycophenolate mofetil 2000 mg/day (Figure 3).

As reported in various cases, adding immune-modulating agents such as tocilizumab or IVIG into the GAVE treatment has demonstrated effectiveness and the potential to stabilize hemoglobin levels, particularly in cases where patients continue to experience persistent bleeding even after successive endoscopic coagulation procedures.

Over the five months, the patient improved her anemia and GAVE, with a hemoglobin level of 9.9 g/dL and complete resolution of GAVE lesions on follow-up endoscopy (Figure 1-B-D).

Conclusions: It highlights the successful management of GAVE using repeated APC procedures and concomitant immune-modulating agents in a patient with early progressive SSc.

P.131

HOW OFTEN DO WE USE GASTROINTESTINAL ENDOSCOPY IN PATIENTS WITH SYSTEMIC SCLEROSIS? - SINGLE-CENTER EXPERIENCE

Busra Firlatan, Gozde Sevgi Kart Bayram, Erdinc Unaldi, Gul Sandal Uzun, Mustafa Ekici, Levent Kilic, Ali Akdogan

Hacettepe University School of Medicine, Department of Internal Medicine, Division of Rheumatology, Ankara, TURKEY

Introduction: In patients with systemic sclerosis (SSc), involvement may occur in every part of the gastrointestinal tract (GIT). Severe GI involvement is usually noticed when complications develop, which is often irreversible and difficult to manage. This study evaluated the rate of upper and lower GIT endoscopic procedures, GIT involvement characteristics, and malnutrition in patients with SSc.

Material and Methods: The eighty SSc patients consecutively presented to the tertiary center between April 2023 and July 2023 were included in the study. Demographic and clinical characteristics of the patients and GI symptoms were recorded. If available, the results of upper (E/S) and lower (C/S) GI endoscopy were documented. The malnutrition risk of the patients was assessed with 'Malnutrition Universal Screening Tool' (MUST) and the criteria of 'The European Society for Clinical Nutrition and Metabolism' (ESPEN). The severity of GIT involvement was determined by 'The University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract 2.0' (UCLA SCTC GIT 2.0).

Results: Of 80 patients (76 females), the mean age at the last visit was 54 ± 13, and the age at diagnosis was 39.8 ± 13. The most common GI symptoms were reflux (55%), retrosternal burning (53.8%), and bloating (53.8%). Among nine patients at high risk of malnutrition according to the MUST, seven met the ESPEN criteria. After the diagnosis of SSc, 54 (67.5%) patients underwent E/S, and 35 (43.8%) underwent C/S. A total of 102 E/S procedures were performed (once in 28 patients, twice in 12 patients, thrice in 9 patients, four times in 2 patients, and five times in 3 patients) along with 43 C/S procedures (once in 27 patients and twice in 8 patients). Reports were available for 60 E/S and 32 C/S. No patients were diagnosed with GI malignancy. Patients categorized by UCLA SCTC GIT 2.0 total score [<0.50 none-mild (58 patients) vs. equal or >0.50 moderate-severe (22 patients)] were evaluated for the number of endoscopic procedures performed within the last two years. The rates of E/S were 20.7% and 36.3%, while the rates of C/S were 17.2% and 36.2%, respectively (p>0.05). The number of procedures performed in patients with malnutrition did not differ from those without (p>0.05).

Conclusions: In this study, it was determined that SSc patients are frequently evaluated through endoscopic procedures. However, it was found that the frequency of procedures performed did not change in relation to the severity of GI involvement assessed by UCLA scores or the presence of malnutrition.

P.132

BOTH UCLA-GIT 2.0 AND EUSTAR-AI ARE LINKED TO MALNUTRITION IN PATIENTS WITH SYSTEMIC SCLEROSIS

Alexandra Maria Burlui¹, Ioana Bratoiu (Harton)¹, Patricia Richter¹, Ioana Ruxandra Mihai¹, Anca Cardoneanu^1,2, Luana Andreea Macovei^1,2, Elena Rezus^1,2

¹Department of Rheumatology, 'Grigore T. Popa' University of Medicine and Pharmacy, IASI, ROMANIA, ²Department of Rheumatology I, Clinical Rehabilitation Hospital, IASI, ROMANIA

Introduction: Patients with systemic sclerosis (SS) exhibit multiple risk factors for an altered nutritional status. Digestive involvement is frequent in SS, yet the connection between symptom severity and weight loss or malnutrition remains a matter of debate. Furthermore, there is little evidence linking disease activity with weight loss and malnutrition. We aimed to investigate the connection between malnutrition and gastrointestinal symptoms, as well as disease activity in SS.

Material and Methods: We performed a prospective observational study including adult patients diagnosed with SSc with disease duration over 1 year who presented in the Rheumatology Department of the Clinical Rehabilitation Hospital of Iasi for routine visits. The patients’ gastrointestinal involvement was analyzed using the University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument 2.0 questionnaire (UCLA-GIT 2.0). We evaluated the patients’ nutritional status using the Mini Nutritional Assessment (MNA), the Malnutrition Universal Screening Tool (MUST), and the Global Leadership Initiative on Malnutrition (GLIM) criteria. We estimated the extent of skin involvement using the mRSS (modified Rodnan Skin Score). We assessed disease activity using EUSTAR-AI (European Scleroderma Trials and Research Group Activity Index).

Results: The study group consisted of 73 SSc patients with a mean disease duration of 9.78 years (Table 1). The UCLA-GIT scores showed notable correlations with MNA (Malnutrition Indicator Score: p=0.001, Screening: p<0.001, Assessment: p=0.004). The MNA Malnutrition Indicator Score was significantly associated with higher values recorded in the Reflux and Distension sections of the UCLA-GIT (p=0.022, p=0.002, p=0.003, and p<0.001). The patients with severe malnutrition (Stage 2) according to the GLIM criteria and those with a high risk of malnutrition according to MUST had the highest UCLA-GIT scores (p=0.017 and p=0.025). UCLA-GIT was associated with significantly higher mRSS (p=0.043), not EUSTAR-AI (p=0.068). EUSTAR-AI was correlated with the total MNA score (p<0.001), as well as the Screening and Assessment scores (p<0.001 and p=0.012). We found a similar relationship between the mRSS and the MNA scores (Malnutrition Indicator Score: p<0.001, Screening: p<0.001, Assessment: p=0.033). The patients with severe malnutrition (Stage 2) according to the GLIM criteria exhibited the highest EUSTAR-AI values (p=0.006). Both EUSTAR-AI and mRSS were significantly higher in the group with a high risk of malnutrition according to MUST (p=0.005 and p=0.030). Age and disease duration were not correlated with the patients’ nutritional status.

Conclusions: In our study group, digestive symptoms, the extent of cutaneous involvement and disease activity were connected to malnutrition according to MNA, MUST and the GLIM criteria.

P.133

DIFFERENT GUT MICROBIOME PROFILES AMONG PATIENTS WITH SYSTEMIC SCLEROSIS COMPARED TO RHEUMATOID ARTHRITIS

Yolanda Braun-Moscovici¹, Nofar Asulin², Katya Dolnikov¹, Sami Giryes¹, Vika Shataylo¹, Doron Markovits¹, Rita Erlich¹, Yonit Tavor¹, Kochava Toledano¹, Sondra Turjeman², Alexandra Balbir-Gurman¹, Omry Koren²

¹Rheumatology Institute, Rambam Health Care Campus, Rappaport Faculty of Medicine, Technion, Haifa, ISRAEL, ²Azriely Faculty of Medicine, Bar-Ilan University, Safed, ISRAEL

Introduction: A growing body of evidence suggests that the gut microbiota plays a significant role in the development of autoimmune diseases. An altered microbiota composition has been associated with gastrointestinal and extraintestinal features in systemic sclerosis (SSc) patients.

We aimed to characterize differences in the gut microbiota between SSc patients and rheumatoid arthritis (RA) patients and to look for associations between microbial profiles and SSc subtypes, disease manifestations and treatment.

Material and Methods: SSc and RA patients seen at our center were recruited in a prospective study. The exclusion criteria included antibiotic or probiotic treatment during the month prior to recruitment, recent hospitalizations, BMI>30, diabetes mellitus or concomitant inflammatory bowel disease. Fecal samples were collected and processed and 16S rRNA gene sequences were analyzed using the QIIME2 package. Microbiome composition was determined, beta diversity and alpha diversity were calculated and ANCOM analyses was performed.

Results: During 7/2018-4/2022, 49 SSc patients (mean age [SD] 53.5[13.8] and disease duration 9.4 [8.0] years) and 21 RA patients (mean age [SD] 57.1[10.4] and disease duration 15.1[10.0] years) fulfilled the criteria and were willing to participate in the study. Significant differences in beta diversity (Unweighted q=0.019, and Weighted UniFrac q=0.005) were found between RA and SSc patients’ stool microbiota, but not in alpha diversity. Composition analysis revealed higher abundance of Actinomyces among SSc patients compared to RA.

Significant variations in beta diversity (unweighted and weighted) were associated with the subtype of SSc (diffuse - 27 vs limited - 22 patients, p [weighted] = 0.01), occurrence of interstitial lung disease (22 patients, p=0.011), renal crisis (3 patients, p=0.016), immunomodulatory treatment (33 patients, p=0.018) and biological treatment (11 patients, p=0.017). Composition analysis revealed higher relative abundance of Firmicutes in patients with GAVE (12). Patients on biologicals (11) had higher abundance of Synergistaceae and lower of Firmicutes. The changes were consistent in recurrent fecal samples.

Conclusions: Significant differences on beta diversity were found between RA and SSc patients’ stool microbiota, but not on alpha diversity. Diffuse SSc, interstitial lung disease, renal crisis and immunomodulatory treatment were associated with shifts in the microbiome of SSc patients. The impact of these changes on SSc disease progression needs further elucidation.

P.134

COLOR DOPPLER ULTRASOUND, A POWERFUL TOOL TO DISCLOSE AND ASSESS BOWEL VASCULOPATHY IN SYSTEMIC SCLEROSIS

Giulia Bandini¹, Khadija El Aoufy², Elisa Martinelli¹, Francesco Bonomi³, Esterita Accogli⁴, Michael Hughes^5,6, Zsuzsanna H. McMahan⁷, Corrado Campochiaro⁸, Serena Guiducci³, Gemma Lepri³, Laura Cometi³, Gabriele Ciuti¹, Gianluca Moroncini⁹, Silvia Bellando Randone³, Lorenzo Dagna⁸, Marco Matucci Cerinic^3,8, Alberto Moggi Pignone¹

¹University of Florence, Department of Experimental and Clinical Medicine, Division of Internal Medicine, Florence, ITALY, ²University of Florence, Department of Experimental and Clinical Medicine, Florence, ITALY, ³University of Florence, Department of Experimental and Clinical Medicine, Division of Rheumatology, Florence, ITALY, ⁴Department of Internal Medicine, Centre of Research and Learning in Ultrasound, Maggiore Hospital, Bologna, ITALY, ⁵Northern Care Alliance NHS Foundation Trust, Salford Care Organisation, Salford, UNITED KINGDOM, ⁶Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Manchester Academic Health Sc, Manchester, UNITED KINGDOM, ⁷University of Texas Health Science Center at Houston, Department of Medicine, Division of Rheumatology, Houston, USA, ⁸IRCCS San Raffaele Hospital, Unit of Immunology, Rheumatology, Allergy and Rare diseases (UnIRAR), Milan, ITALY, ⁹Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, ITALY

Introduction: Gastrointestinal (GI) tract is affected in the majority of patients with Systemic Sclerosis (SSc) (>90%), and it’s associated with significant morbidity and mortality. Moreover, bowel vasculopathy seems to significantly contribute to the progressive deterioration of the GI system. In fact, color Doppler Ultrasound (CDU) has recently shown that the splanchnic vessels may be involved in SSc patients. The aim of our work was to confirm, in a larger cohort of SSc patients, splanchnic vessels involvement assessed with CDU.

Material and Methods: In 50 SSc patients (92% females; mean age 52.30 ± 12.02), fulfilling the ACR/EULAR 2013 classification criteria, and in 32 healthy controls (HC) (66% females; mean age 36.78 ± 13.45) CDU was performed after a fasting time of 8 hours. Patients with a history of peripheral/coronary arterial disease were excluded. For Superior Mesenteric Artery (SMA) and Inferior Mesenteric Artery (IMA), caliber (mm), Peak Systolic Velocity (PSV; cm/sec), Reverse Velocity (RV; cm/sec), End-Diastolic Velocity (EDV; cm/sec), Mean Velocity (mV; cm/sec), Blood-flow (cm/sec), Resistive Index (RI) and Pulsatility Index (PI) were measured.

Results: In all patients, SMA were evaluable; 45 IMA in SSc patients and 28 in HC were detectable. The SMA caliber was significantly smaller in SSc than HC (6.5 ± 0.69 vs 5.9 ± 0.71; p<0,0001), while IMA caliber was not significantly different. In fasting state, the shape of the Doppler wave differed in SSc as the early negative diastolic component was reduced (or absent) in the majority of SSc patients. Moreover, the SMA evaluation identified a significant reduction of RV (11.82 ± 12.54 vs 18.33 ± 6.06, p<0.001), RI (0.88 ± 0.4 vs 0.90 ± 0.3, p = 0.002) and PI (3.37 ± 0.73 vs 4.37 ± 1.06, p<0.001) in SSc vs HC. The IMA, RI and PI were significantly lower in SSc than in HC (RI: 0.88 ± 0.40 vs 0.91 ± 0.30, p=0.002; PI: 3.59 ± 0.90 vs 5.95 ± 1.45, p<0.001)(Figures 1-2).

Conclusions: Our data confirm that in SSc the splanchnic vessel involvement may be assessed with CDU. In this large cohort of patients, CDU parameters were significantly modified with an altered resistance either in SMA and IMA. This clearly shows that in the GI tract of SSc patients, the vasculature is significantly affected. Moreover, it should be highlighted that CDU is a non-invasive, repeatable examination that should be taken into consideration when assessing the GI tract involvement in SSc patients.

P.135

A MULTINATIONAL SURVEY INVESTIGATING THE UNMET NEEDS AND PATIENT PERSPECTIVES CONCERNING PROTON PUMP INHIBITORS IN SYSTEMIC SCLEROSIS

Giulia Bandini¹, Alessia Alunno², Filipe Oliveira Pinheiro³, Corrado Campochiaro⁴, Ilaria Galetti⁵, Pietro Matucci Cerinic⁶, Barbara Ruaro⁷, Khadija El Aoufy⁸, Maria Ramona Melis⁸, Alberto Moggi Pignone¹, Lorenzo Dagna⁴, Marco Matucci Cerinic^4,8, Zsuzsanna McMahan⁹, Michael Hughes^10,11

¹University of Florence, Department of Experimental and Clinical Medicine, Division of Internal Medicine, Florence, ITALY, ²University of L Aquila, Department of Clinical Medicine, Life, Health, and Environmental Sciences, Internal Medicine, L Aquila, ITALY, ³Centro Hospitalar Universitário de São João, Department of Rheumatology, Porto, PORTUGAL, ⁴IRCCS San Raffaele Hospital, Unit of Immunology, Rheumatology, Allergy and Rare diseases (UnIRAR), Milan, ITALY, ⁵FESCA (Federation of European Scleroderma Associations) Belgium, GILS (Gruppo Italiano Lotta alla Sclerodermia), Milan, ITALY, ⁶University of Udine, Division of Surgery and Transplantation, Department of Surgery, Udine, ITALY, ⁷Pulmonology Unit, Department of Medical Surgical and Health Sciences, University Hospital of Cattinara, University of, Trieste, ITALY, ⁸University of Florence, Department of Experimental and Clinical Medicine, Florence, ITALY, ⁹Johns Hopkins University, Department of Medicine, Division of Rheumatology, Baltimore, USA, ¹⁰Northern Care Alliance NHS Foundation Trust, Salford Care Organisation, Salford, UNITED KINGDOM, ¹¹Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Manchester Academic Health Sc, Manchester, UNITED KINGDOM

Introduction: The gastrointestinal (GI) tract is largely (>95%) affected in systemic sclerosis (SSc) and its involvement is associated with significant morbidity, mortality and huge impact on the quality of life. Upper GI tract dysfunction, often presenting with gastroesophageal reflux disease (GERD) is one of the principal complaints. Proton pump inhibitors (PPIs) are widely used to treat GERD in SSc. However, not all patients respond to this therapy, and many remain on long-term treatment. Moreover, significant concerns about PPI long-term safety have been raised. Our aim was to identify perspectives and unmet needs of SSc patients on PPIs.

Material and Methods: An online English survey, targeting SSc patients on PPIs was developed and distributed through social media and international patient associations. The survey was launched on 4th November 2022 and kept open for 4 weeks. (please specify also here as in the clinicians survey that language is a limitation).

Results: 301 respondents from 14 countries completed the survey (UK 19.3% and US 70.4%). Most respondents were between 30-70 years of age and the majority were female (95%). The most frequently reported symptoms (Figure 1) were acid reflux (97%), dysphagia (60%), and trouble swallowing or food got stuck in the chest (32%) (Figure 1). Multiple PPIs use (two: 30% and three: 21%; in series) was common and the majority (89%) reported improvement in GI symptoms with PPIs. Even though only 19% experienced side effects on PPIs, most respondents (79%) were potentially concerned. 47% experienced a flare of symptoms after initial improvement with PPIs and 58% received lifestyle information, while most (85%) searched online for information about PPIs. A minority (12%) of cases, reported that a surgical approach was discussed, and 46% indicated that they would be willing to undergo surgery to resolve their GERD symptoms, despite they had significant concerns.

Conclusions: Our survey highlights the importance of upper GI symptoms in SSc patients and the frequent use of PPIs. There is significant heterogeneity in use, and treatment is often not fully effective. Moreover, patients have concerns about side effects related to long-term PPI use. There is a clear unmet need regarding patients’ education about PPIs, as they frequently relied on online sources for information. Finally, a surgical approach is rarely discussed, although patients would potentially consider this approach, as GERD can deeply affect their quality of life. Further research is needed to optimize the therapeutic strategy concerning PPI use in SSc.

P.136

A MULTI-NATIONAL SURVEY TO IDENTIFY THE CLINICIANS’ PERSPECTIVES CONCERNING PROTON PUMP INHIBITORS IN PATIENTS WITH SYSTEMIC SCLEROSIS

Giulia Bandini¹, Alessia Alunno², Filipe Oliveira Pinheiro³, Corrado Campochiaro⁴, Ilaria Galetti⁵, Pietro Matucci Cerinic⁶, Barbara Ruaro⁷, Alberto Moggi Pignone¹, Lorenzo Dagna⁴, Marco Matucci Cerinic^4,8, Zsuzsanna McMahan⁹, Michales Hughes^10,11

¹University of Florence, Department of Experimental and Clinical Medicine, Division of Internal Medicine, Florence, ITALY, ²University of L Aquila, Department of Clinical Medicine, Life, Health, and Environmental Sciences, Internal Medicine, L Aquila, ITALY, ³Centro Hospitalar Universitário de São João, Department of Rheumatology, Porto, PORTUGAL, ⁴IRCCS San Raffaele Hospital, Unit of Immunology, Rheumatology, Allergy and Rare diseases (UnIRAR), Milan, ITALY, ⁵FESCA (Federation of European Scleroderma Associations) Belgium, GILS (Gruppo Italiano Lotta alla Sclerodermia), Milan, ITALY, ⁶University of Udine, Division of Surgery and Transplantation, Department of Surgery, Udine, ITALY, ⁷Pulmonology Unit, Department of Medical Surgical and Health Sciences, University Hospital of Cattinara, University of, Trieste, ITALY, ⁸University of Florence, Department of Experimental and Clinical Medicine, Florence, ITALY, ⁹University of Texas Health Science Center at Houston, Department of Medicine, Division of Rheumatology, Houston, USA, ¹⁰Northern Care Alliance NHS Foundation Trust, Salford Care Organisation, Salford, UNITED KINGDOM, ¹¹Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Manchester Academic Health Sc, Manchester, UNITED KINGDOM

Introduction: Proton Pump Inhibitors (PPIs) are widely used in Systemic Sclerosis (SSc) for the treatment of gastroesophageal reflux disease (GERD). However, there is scarse evidence to support their use while long-term safety has been questioned. The aim of our study was to identify healthcare providers’ (HCP) perspectives and experience regarding PPIs therapy in SSc patients

Material and Methods: An online survey in English language targeting clinicians involved in the care of SSc patients, was developed and distributed through social media and international physician networks. The survey was launched on 27th November 2022 and kept open for 3 weeks.

Results: Responses from 227 clinicians from 36 countries were recorded: most of them (86%) were aged between 30-70 years and gender was equally represented (F: 52%; M: 48%). The majority ‘agreed’ (41%) or ‘strongly agreed’ (45%) that GERD is a major cause of morbidity in SSc.

Lifestyle modifications and non-pharmacological approaches alone were seldom (16%) considered effective. Only half of the respondents ‘agreed’ (43%) or ‘strongly agreed’ (11%) there is solid evidence supporting PPIs efficacy in SSc. A range of PPIs was prescribed by clinicians, most frequently pantoprazole (74%), esomeprazole (72%), omeprazole (72%), and lansoprazole (68%). The most common reasons for PPIs prescription (Table 1) were symptomatic GERD unresponsive to lifestyle modification (95%), objective evidence of GERD (82%), and hoarseness or respiratory symptoms (71%). Multiple concerns were raised about PPI long-term safety in SSc (Figure 1). The three highest (mean, 10 being very concerned) reasons were: small intestinal bacterial overgrowth (5.5), osteoporosis (5.4), and drug interactions (5.2).

There were significant differences in attitudes towards surgery for refractory GERD: ‘strongly disagreed’ (14%), ‘disagreed’ (26%) ‘neutral’ (52%), ‘agreed’ (13%), ‘strongly agreed’ (3%). Furthermore, half of respondents had concerns about potential complications (i.e., worsening of dysphagia): ‘disagreed’ (26%) or ‘strongly disagreed’ (6%), ‘neutral (52%), ‘agreed’ (13%), ‘strongly agreed’ (3%).

Conclusions: Our survey confirms that PPIs are frequently prescribed for GERD in SSc patients, despite the absence of randomized clinical trials demonstrating their efficacy and safety. However, clinicians are concerned about side effects, especially regarding long-term use. There is significant heterogeneity in attitudes towards surgery for refractory GERD. Future research and practical treatment recommendation are urgently needed.

P.137

ORAL MANIFESTATIONS IN SYSTEMIC SCLEROSIS: CLINICAL EVALUATION OF A PERSONAL CASE SERIES OF 13 SCLERODERMA PATIENTS

Amelia Spinella¹, Giacomo Setti², Marco De Pinto¹, Samuele Veronesi², Gabriele Amati¹, Federica Lumetti¹, Ottavio Secchi¹, Martina Orlandi^1,3, Gilda Sandri^1,3, Dilia Giuggioli^1,3

¹Scleroderma Unit, Rheumatology Unit, University Hospital of Modena, University of Modena and Reggio Emilia, Modena, ITALY, ²Dentistry and Oral and Maxillofacial Surgery, University of Modena and Reggio Emilia, Modena, ITALY, ³Department of Medical and Surgical Sciences of Children and Adults, University of Modena and Reggio Emilia, Modena, ITALY

Introduction: Systemic Sclerosis (SSc) is a rare chronic connective tissue disorder of unknown origin characterized by diffuse fibrosis and vascular abnormalities of the skin and internal organs, with reduced life expectancy. Hand and face skin thickening is pathognomonic. In particular, the oral cavity may be the place of pathological manifestations within hard and soft tissues. These alterations lead to pain, functional impairment, aesthetic damage, and psychological distress, resulting in complicated dental procedures. Our project is aimed at analyzing main orofacial manifestations of a cohort of SSc patients admitted to the Scleroderma Unit and the Dental Clinic of the University Hospital of Modena.

Material and Methods: We collected data from 13 SSc patients referred to the Scleroderma Unit and the Dental Clinic of the Policlinico of Modena between January 2022 and April 2023 (M/F 1/12, age 56.5±23.6 SD yrs, lc/dcSSc 7/6). Clinical-biohumoral data (including autoantibody screening and HAQ scores) together with patient demographics were collected; we also gathered odontostomatological data, especially regarding the Decayed Missing and Filled Teeth index (DMFT), periodontal parameters such as probing depth (PD) and clinical attachment level (CAL), plaque index (PI), overall mouth range opening and salivary function assessed by means of salivary flow rate (SFR).

Results: Among the main results collected, we observed an interesting correlation between the bleeding of probing index (BoP) and positive anti-centromere antibodies; a reduced range of mouth opening had a significant correlation with interstitial lung disease detected by means of CT scan; the limited cutaneous subset was associated to lower SFR values; and finally the PI index was correlated to the majority of items in the HAQ questionnaire and in particular with the overall disability index.

Conclusions: Despite having a limited impact compared to the systemic involvement of SSc, oral conditions severely compromise the quality of life of our patients. Notwithstanding the small size of the sample we analyzed, the data emerging from our study offers compelling correlations and insights regarding odontostomatological conditions affecting Scleroderma patients, which are worthy of future studies on larger series of patients.

P.138

EVALUATING THE ASSOCIATIONS BETWEEN DYSAUTONOMIA, GASTROINTESTINAL TRANSIT AND CLINICAL PHENOTYPE IN PATIENTS WITH SYSTEMIC SCLEROSIS

María Paula Álvarez¹, Brittany Adler², Jamie Perin³, Michael Hughes^4,5, Zsuzsanna H. McMahan⁶

¹Hospital Clínico San Carlos, Department of Rheumatology, Madrid, SPAIN, ²Johns Hopkins University, Department of Medicine, Division of Rheumatology, Baltimore, USA, ³Johns Hopkins Bloomberg School of Public Health, Department of International Health, Baltimore, USA, ⁴Northern Care Alliance NHS Foundation Trust, Salford Care Organisation, Salford, UNITED KINGDOM, ⁵Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Manchester, UNITED KINGDOM, ⁶The University of Texas Health Science Center at Houston,McGovern Medical School, Houston, USA

Introduction: It is common for patients with Systemic Sclerosis (SSc) to experience gastrointestinal (GI) symptoms at some point during the disease, with up to 90% of patients affected. The clinical expression of GI involvement can vary widely, and pathogenesis is not entirely understood. It is known that the autonomic nervous system plays a crucial role in controlling GI motility, and the dysfunction of the sympathetic and parasympathetic pathways could contribute to the clinical heterogeneity in SSc disease. That is why we aim to identify SSc patients with a high burden of dysautonomia and determine if they have a distinct clinical phenotype and specific GI transit issues.

Material and Methods: In a prospective cohort study, we obtained clinical data from SSc patients with GI disease during routine clinical visits. We used the Composite Autonomic Symptom Score (COMPASS)-31 questionnaire to identify autonomic symptoms and whole-gut (WGT) scintigraphy to measure GI transit. We compared clinical, demographic, and GI transit characteristics between patients with global autonomic dysfunction (GAD; >5 positive COMPASS-31 subdomains) and patients with limited autonomic dysfunction (LAD; <5 positive subdomains).

Results: We included 99 SSc patients with GI involvement in our study. The mean age was 58 (IQR 49-67), 90% were female, and 74% had limited cutaneous disease. Most of the patients (83%) had significant GI disease (Medsger score >2), and 88% had Sicca syndrome. The mean COMPASS-31 score was 36.7 ± 14.2 (SD). Thirty-one percent had GAD, and 69% had LAD. Patients with GAD were more likely to be women (100% vs 85%; p=0.052), had Sicca symptoms (100% vs 83%; p=0.027), had upper GI involvement (modified Medsger GI score of 1 or 2) as shown in Figure 1 (96% vs 78%; p=0.03), and had more gastric emptying of solids at 4 hours (97% vs 94% p=0.023).

Conclusions: Our study highlights the significance of the autonomic nervous system in SSc patients with GI involvement. We have identified the characteristics of a specific group of patients affected by significant symptoms of dysautonomia and examined the relationship between autonomic symptom burden and GI motility. Our findings may pave the way for developing novel treatments that target the ANS and improve the quality of life of these patients.

P.139

SEVERE GASTROINTESTINAL DYSMOTILITY IS THE MAIN PREDICTOR OF PPI-REFRACTORY GASTROESOPHAGEAL REFLUX DISEASE IN PATIENTS WITH SYSTEMIC SCLEROSIS

Luis Gerardo Alcala-Gonzalez¹, Alfredo Guillen Del Castillo², Ariadna Aguilar Cayuelas¹, Antonio Marin¹, Claudia Barber Caselles¹, Alberto Palacios¹, Carolina Malagelada¹, Carmen Pilar Simeon Aznar²

¹Unidad de Enfermedades Digestivas, Hospital Universitario Vall d’Hebron, Barcelona, BARCELONA, SPAIN, ²Unidad de Enfermedades Sistémicas Autoinmunes, Hospital Universitario Vall d’Hebron, Barcelona, BARCELONA, SPAIN

Introduction: Patients with systemic sclerosis (SSc) frequently complain of gastroesophageal reflux disease (GERD) symptoms. Esophageal exposure to gastric reflux is the primary determinant of disease severity in GERD. More severe GERD cause complications in patients with SSc, such as erosive esophagitis, Barrett esophagus, and an increased risk of esophageal adenocarcinoma.

Patients with SSc and esophageal dysmotility (i.e., aperistalsis) are known to have more severe GERD and also, more PPI-refractory GERD. Nevertheless, the severity of esophageal dysmotility is not consistently associated with the presence and severity of symptoms nor the total acid exposure time in patients with SSc. With this background, the main objective of the present study was to identify the factors associated with PPI-refractory GERD in patients with SSc

Material and Methods: Nested case-control study from a cohort of patients with SSc (n=166) evaluated for gastrointestinal symptoms using standard questionnaires (GI symptom and UCLA GIT 2.0). From these, 69 patients had an upper endoscopy performed under PPI treatment and were included. Demographic, clinical, inmunological data and gastrointestinal examination results (esophageal manometry, gastric emptying scintigraphy, and CT scans) were collected from the clinical records. Patients with PPI-refractory GERD (i.e erosive esophagitis) were compared to those with endoscopically normal esophageal mucosa.

Results: Among patients who underwent upper endoscopy under PPI treatment, 23 patients (33%) had PPI-refractory GERD (erosive esophagitis; Grade A, n=11; Grade B, n=7; Grade C, n=2; Grade D, n=3) and 46 (67%) did not. Patients with PPI-refractory GERD had a higher prevalence of the diffuse subtype of SSc (43% vs. 18%; p=0.008) and clinically reported more regurgitation (65% vs. 37%; p= 0.008) than patients with normal mucosa. Evaluating the clinical factors associated with PPI-refractory GERD, Severe gastrointestinal dysmotility (gastroparesis and/or intestinal pseudo-obstruction; OR=5.9, 95% 1.1 – 31.0, p=0.037) and calcium channel blocker use (OR=10.3, IC 95% 2.6 – 40.5, p=0.001) were independently associated with PPI-refractory GERD. Evaluating the results of gastrointestinal motility examinations, the main predictor of PPI-refractory GERD was the presence of severe gastrointestinal dysmotility (OR=9.2, IC 95% 2.2-38.9 p=0.002). In contrast, neither aperistalsis of the esophageal body (OR=1.9, 95% 0.6-6.4 p=0.351) nor a hypotonic lower esophageal sphincter (OR=0.984, IC 95% 0.3-2.8 p=1.000) were independent predictors of PPI-refractory GERD.

Conclusions: These findings suggest that gastric and/or small intestinal dysmotility may be an important determinant of PPI-refractory GERD in patients with systemic sclerosis.

P.140

SMALL INTESTINAL DYSMOTILITY IN PATIENTS WITH SYSTEMIC SCLEROSIS: OBJECTIVE EVALUATION USING INTESTINAL HIGH-RESOLUTION MANOMETRY

Luis Gerardo Alcala-Gonzalez¹, Alfredo Guillen Del Castillo², Antonio Marin¹, Ariadna Aguilar Cayuelas¹, Claudia Barber Caselles¹, Alberto Palacios¹, Carolina Malagelada¹, Carmen Pilar Simeon Aznar¹

¹Unidad de Enfermedades Digestivas, Hospital Universitario Vall d’Hebron, Barcelona, BARCELONA, SPAIN, ²Unidad de Enfermedades Sistémicas Autoinmunes, Hospital Universitario Vall d’Hebron, BARCELONA, SPAIN

Introduction: Gastrointestinal involvement is nearly universal in patients with systemic sclerosis (SSc). Among all digestive organs, small intestine involvement has the highest associated mortality and manifests as malnutrition, bacterial overgrowth, and in severe cases, chronic intestinal pseudo-obstruction. In SSc, clinical manifestations of intestinal involvement are secondary to intestinal dysmotility, which can be objectively evaluated using manometry studies.

At the Vall d'Hebron University Hospital, we have developed intestinal high-resolution manometry (iHRM) with multiple sensors closely placed together, allowing for a more precise evaluation of the motor function of the small intestine, evaluating contraction propagation patterns that went unnoticed with conventional systems. The objectives of this study were to evaluate the diagnostic capacity of iHRM in patients with SSc and its correlation with other digestive motility tests.

Material and Methods: Prospective study of consecutive patients with SSc and digestive symptoms referred for evaluation of gastrointestinal motor involvement. Demographic, clinical, and immunological data were obtained from the medical history. Digestive motility evaluation tests were performed, including esophageal manometry, gastric emptying by scintigraphy, and iHRM. Small intestinal manometry tracings (total 5 hours, 3 hours fasting + 2 hours during continuous nutrient perfusion at 2 kcal/min) were analyzed first in search for previously established criteria of intestinal dysmotility, (neuropathic and/or myopathic patterns) and second, searching for new parameters discriminating patients from healthy subjects. Cohen's Kappa was used to evaluate the agreement between tests to diagnose intestinal dysmotility.

Results: Fourteen patients were included (34–67 years, 100% women, 4 diffuse-SSc, 10 limited-SSc), and 14 healthy subjects (22–38 years, 78% women) served as controls. iHRM detected established criteria of intestinal dysmotility in 8 (57%) patients (myopathic pattern in 5, neuropathic pattern in 3) and in none of the healthy subjects. Searching for new discriminating criteria, iHRM detected alterations in the pattern of propagation of motor events (impaired propagation) in 11 patients compared to healthy subjects; three patients with this abnormality did not present classic criteria for intestinal dysmotility (diagnostic gain of 21%).

Esophageal manometry revealed esophageal aperistalsis in 8 (57%), and gastric emptying was compatible with gastroparesis in 7 (50%). When contrasting these findings with high-resolution intestinal manometry, neither esophageal dysmotility (kappa coefficient of 0.089) nor gastric emptying alteration (kappa coefficient of 0.143) were significant predictors of intestinal dysmotility in patients with SSc.

Conclusions: In patients with systemic sclerosis, intestinal dysmotility, as objectively assessed by high-resolution intestinal manometry, is frequent and not necessarily associated with the presence of esophageal or gastric dysmotility.

P.141

EVALUATION OF ESOPHAGEAL INVOLVEMENT IN SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE

Houssem Abida¹, Zeineb Meddeb¹, Mariem Affès², Cherifa Abdelkefi¹, Amira El Ouni¹, Sana Toujani¹, Saoussen Hantous², Lamia Ben Hassine³, Kamel Bouslama¹, Thara Larbi¹, Saloua B'chir Hamzaoui¹

¹Internal medicine department, Mongi Slim University Hospital, La Marsa, Tunis, TUNISIA, ²Radiology department, Abderrahmen Mami University Hospital, Ariana, TUNISIA, ³Internal medicine department B, Charles Nicolle University Hospital, Tunis, TUNISIA

Introduction: Even though it is not part of the classification criterias of Systemic Sclerosis (SSc), esophageal involvement represents one of its most frequent manifestations. Apart from the degeneration risk, studies suggest a role in the pathogenesis of SSc-related Interstitial lung disease (SSc-ILD).

The aim of our study was to look for a correlation between digestive data and the respiratory involvement in ScS.

Material and Methods: It was a retrospective and descriptive study carried out at the Internal Medicine Departments of Mongi Slim Hospital and Charles Nicolle hospitals. It included data of patients with systemic sclerosis. All patients had a chest CT at the time of diagnosis.

Results: 49 patients were included. The mean age of our patients was 43 years. 31 patients had ILD. Dysphagia was the most common digestive symptom reported among 27 patients (55%). 20 patients reported pyrosis (41%). Upper digestive endoscopy was performed in 45 patients (92%). Peptic oesophagitis was present in 24 cases (49%). Gastroduodenal telangiectasia was present in 4 cases (8%). Esophageal manometry was conducted in 13 patients (27%). It revealed esophageal hypomotility in 12 cases (25%). Esophageal dilatation was present in 22 chest CTs (45%). The mean esophagus diameter was 28,41 mm [12,5-49 mm]. The statistical analysis showed associations between clinical and CT abnormalities with pulmonary involvement. Among clinical features, only pyrosis was statistically associated with the presence of ILD (0,044). A statistically significant relationship was established between esophageal dilatation of CT and the presence of ILD (p=0.015). Increased esophagus diameter on CT was statistically associated with pulmonary involvement (p=0.009). No significant link was found between endoscopic or manometric abnormalities and ILD.

Conclusions: Chest CT represents a helpful tool to assess esophageal involvement in systemic sclerosis. We have concluded that esophageal abnormalities correlate with the presence of ILD.

P.142

GASTROESOPHAGEAL INTUSSUSCEPTION TREATED THROUGH CTIF IN A PATIENT WITH SYSTEMIC SCLEROSIS

Areeka Memon¹, Monique Hinchcliff², Nicholas Dugan³, Amir Masoud⁴

¹Department of Internal Medicine, University of Connecticut, Farmington, CT, ²2Section of Rheumatology, Allergy & Immunology, Yale School of Medicine, New Haven, CT, ³3Department of General Surgery, Hartford Healthcare, Hartford, CT, ⁴4Neurogastroenterology and Motility Center, Hartford Healthcare, Hartford, CT, Connecticut GI PC

Introduction: Introduction Systemic sclerosis (SSc) is a rheumatic disease with the highest case-fatality rate whose pathogenesis involves autoimmunity and fibrosis. 50 to 90% of SSc patients experience GI symptoms, and GI involvement is the underlying cause of death in up to 12% of patients. Gastroesophageal (GE) intussusception is the invagination of the stomach into the esophagus and is mostly reported in felines and canines. Here, we present the first reported case of an SSc patient with hiatal hernia and GE intussusception who was successfully treated with concomitant hiatal hernia repair and transoral incisionless fundoplication (cTIF).

Case: A 49-year-old woman with a history of psoriasis, Raynaud phenomenon, polymyositis, interstitial lung disease, and diffuse cutaneous SSc was referred to gastroenterology for persistent pill dysphagia and progressive GE reflux despite pharmacologic treatment. The physical exam was noteworthy for microstomia, facial telangiectasia, sclerodactyly complicated by digital contractures of multiple interphalangeal (PIP) joints, classic for SSc. Laboratory studies revealed 1:320 anti-nuclear antibodies with a speckled pattern and CBC and CMP were within normal limits.

She underwent an esophagogastroduodenoscopy (EGD) which revealed an obstructing mass-like structure at the GE junction concerning for gastric intussusception, overlaying gastric polyp, and hiatal hernia (Image A). The gastric polyp was initially thought to be a lead point, and the patient underwent endoscopic mucosal resection and stenting (Image B). Unfortunately, she was unable to tolerate the stent due to intractable pain, and it was subsequently removed. Due to persistent reflux and dysphagia the patient underwent cTIF (Image C). Post-intervention dysphagia resolved, and reflux improved. She reported a mild decrease in ability to belch and some bloating after a follow-up period of six weeks.

Discussion: GE intussusception is an exceptionally rare phenomenon that occurred in the setting of SSc-related esophageal dilation and hiatal hernia. Symptoms can be refractory despite maximal medical therapy. SSc is a relative contraindication for laparoscopic fundoplication and a roux-en-y procedure has become the suggested standard of care for refractory GI symptoms in SSc patients. However, we demonstrate successful cTIF with near-complete resolution of GI symptoms.

Figure A. Photo during EGD revealing gastric mucosa intussuscepting through the distal portion of the esophagus.

Figure B. Repeat EGD following polyp removal and stent placement revealing return of GE intussusception.

Figure C. EGD following TIF and hiatal hernia repair revealing resolution of GE intussusception.

P.143

ARRHYTHMIAS AND CONDUCTION DISTURBANCES IN PATIENTS WITH SYSTEMIC SCLEROSIS- A SYSTEMATIC LITERATURE REVIEW

Cristina Andreea Vrancianu¹, Dragos Emanuel Popa², Jeffrey Shi Kai Chan³, Danish Itlaf Satti³, Yan Hiu Athena Lee³, Jeremy Man Ho Hui³, Gary Tse^3,4,5, Ioan Ancuta¹, Ana Ciobanu², Mihai Bojinca¹, Ana Maria Gheorghiu¹

¹Carol Davila University of Medicine and Pharmacy; Internal Medicine and Rheumatology Department, Cantacuzino Hospital, BUCHAREST, ROMANIA, ²Carol Davila University of Medicine and Pharmacy; Cardiology Department, Theodor Burghele Hospital, BUCHAREST, ROMANIA, ³Epidemiology Research Unit, Cardiovascular Analytics Group, China-UK Collaboration, HONG KONG, CHINA, ⁴Kent and Medway Medical School, Canterbury CT2 7FS, Kent, CANTERBURY, UNITED KINGDOM, ⁵Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, TIANJIN, CHINA

Introduction: Heart involvement is a potentially severe manifestation of systemic sclerosis (SSc), accounting for up to 26% of deaths according to European Scleroderma Trials and Research group (EUSTAR) reports, especially due to heart failure and arrhythmias. The latter mainly occur secondary to myocardial fibrosis, which causes electrical inhomogeneity. The aim of this study was to identify the features and risk factors associated with the occurrence of arrhythmias and conduction disturbances in SSc patients, which could facilitate diagnosis and treatment earlier in the course of the disease.

Material and Methods: A systematic literature review was performed using PubMed, Embase, Web of Science and Scopus, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A total of 2796 articles in English with arrhythmias as the main topic published until 21 April 2022 were identified, of which 1115 duplicates were removed. Following title and abstract screening, 231 articles were selected for full-text screening, of which 60 articles were finally included. The quality of the included studies was overall good. Most studies (54 papers) were prospective cohort studies. There were no randomized control trials among the included studies.

Results: The most frequent arrhythmias identified were premature supraventricular and ventricular contractions, with a prevalence in the studied populations varying from 2.6% to 90%, respectively from 3.7% to 100% in a SSc cohort with prolonged QT. Among the conduction disturbances, right bundle branch blocks (RBBB) had the highest prevalence, up to 6.6% for complete and 13.3% for incomplete RBBB in a study published in 2018. Higher concentrations of N-terminal prohormones of brain natriuretic peptides (NT-pro BNP) were associated with several types of atrial and ventricular dysrhythmias, as well as with the occurrence of RBBB. Moreover, a lower value of the turbulence slope (TS) on electrocardiogram (ECG) Holter was an independent predictor for ventricular arrhythmias.

Conclusions: In conclusion, arrhythmias and conduction disturbances are frequent in SSc cohorts. Laboratory and paraclinical parameters are useful tools that could lead to early diagnosis, ideally in the subclinical stage.

P.144

GETTING TO THE HEART OF THE MATTER - ELECTROCARDIOGRAM AND ECHOCARDIOGRAPHY IN THE ASSESSMENT OF CARDIAC INVOLVEMENT IN PATIENTS WITH SYSTEMIC SCLEROSIS

María José Villar Cofre¹, Francisca Bozan^1,3, Joanne Manning¹, Ariane Herrick¹, Graham Dinsdale¹, Muditha Samaranayaka¹, Michael Hughes^1,4

¹Department of Rheumatology, Salford Care Organisation, Northern Care Alliance NHS Foundation Trust, Stott Lane, Salford, UNITED KINGDOM, ²Padre Hurtado Hospital and Clínica Alemana, Santiago, CHILE, ³Hospital Clínico Universidad de Chile, Santiago, CHILE, ⁴Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Manchester, UNITED KINGDOM

Introduction: Systemic sclerosis (SSc) is an autoimmune rheumatological disease characterized by vasculopathy including endothelial dysfunction and progressive vascular damage, immune system activation, and fibrosis of the skin and internal organs. Cardiac involvement in SSc is frequently subclinical and associated with a poor prognosis. Therefore, early detection is important to facilitate early treatment intervention and improve survival of SSc patients. Non-invasive electrocardiogram (ECG) and transthoracic echocardiogram (TTE) are very helpful in this owing to their lack of ionizing radiation, reproducibility sensitivity, and availability. Furthermore, these investigations are commonly repeated routinely (e.g., annually) in clinical practice for SSc-pulmonary hypertension (PH) screening. The aim of our study was to describe the frequency of cardiac involvement as assessed by ECG and TTE in a well-defined cohort of patients with SSc.

Material and Methods: A retrospective study of patients with a clinical diagnosis of SSc seen in a national tertiary referral service between December 2015 and May 2023. We collected patient and disease-related demographic data including comorbidities, treatment, and mortality. Cardiac abnormalities as detected by ECG and TTE were extracted, using the most recent investigation where repeated testing was performed. Data are presented as descriptive statistics.

Results: We studied 301 SSc patients with a median [IQR] age at diagnosis of 52 [42-63] years. Most (n=249, 82,7%) were female and had limited cutaneous SSc (n=235, 78.1%). Patient and disease-related characteristics are presented in Table 1. Known history of cardiovascular was uncommon: arrythmias (9.3%), coronary artery disease (8.3%), and vascular accident (3.6%). Important cardiovascular risk factors were present: hypertension (18.2%), dyslipidemia (17.2%), and smoking (13.2%), and with a lower prevalence of diabetes mellitus type 2 (4.98%).

ECG and TTE abnormalities are presented in Table 2.

Over half of patients with an ECG (n=185) had a detected abnormality (n=107, 57,8%). Common abnormalities were left atrial enlargement (n=23, 21.4%), left ventricular hypertrophy (n=14, 13.08%), left bundle branch block (n=9, 8,4%), and atrial fibrillation (n=8, 7.4%).

Over one-third (n=101, 33,5%) had TTE abnormalities, the most common abnormalities were valvular insufficiency (n=74, 73.2%), diastolic dysfunction (n=27, 26.7%), and PH (n=26, 25,7%).

In cohort, 40 (13.2%) patients died during the follow-up period, and the median age at death was 68.5 years.

Conclusions: Cardiac involvement is common in patients with SSc, with wide-ranging abnormalities detected on ECG and TTE. Future research is required to understand the clinical relevance of cardiac involvement in SSc, including subclinical disease, and to define the role for proactive screening to optimize the therapeutic strategy.

P.146

CARDIOVASCULAR RISK IN PATIENTS WITH SYSTEMIC SCLEROSIS COMPARED TO THE GENERAL POPULATION

Sabina Oreská¹, Aneta Pekacova¹, Hana Storkanova¹, Jaroslav Kudlicka³, Vladimir Tuka³, Ondrej Mikes³, Zdislava Krupickova³, Martin Satny³, Eva Chytilova³, Jan Kvasnicka³, Maja Spiritovic², Barbora Hermankova², Petr Cesak⁴, Marian Rybar⁵, Karel Pavelka¹, Ladislav Senolt¹, Radim Becvar¹, Jiri Vencovsky¹, Michal Vrablik³, Michal Tomcik¹

¹Institute of Rheumatology, Department of Rheumatology and 1st Faculty of Medicine, Charles University, Prague, Czech Rep, Prague, CZECH REPUBLIC, ²Institute of Rheumatology, Department of Physiotherapy and Faculty of Physical Education and Sport, Charles University, Prague, CZECH REPUBLIC, ³3rd Department of Internal Medicine, General University Hospital and 1st Faculty of Medicine, Charles University, Prague, Prague, CZECH REPUBLIC, ⁴Department of Human Movement Laboratory, Faculty of Physical Education and Sport, Charles University, Prague, Czech Repu, Prague, CZECH REPUBLIC, ⁵Department of Biomedical Technology, Faculty of Biomedical Engineering, Czech Technical University in Prague, Kladno, Cz, Prague, CZECH REPUBLIC

Introduction: Patients with systemic sclerosis (SSc) may be burdened by increased cardiovascular (CV) risk due to accelerated atherosclerosis (ATS) due to systemic inflammation, and vascular impairment. This study aimed to evaluate CV risk in SSc patients SSc compared to healthy controls (HC) and to assess its association with disease-specific features.

Material and Methods: 92 patients with SSc (81 females; mean age 52; mean disease duration 6.8 years; dcSSc: n=28, lcSSc: n=64) and 197 HC (147 females, mean age 56.7) with no history of CV disease (angina pectoris, myocardial infarction, cerebrovascular, and peripheral arterial vascular events) were included. Disease activity and organ involvement were evaluated in SSc. In all participants comorbidities and current treatment were recorded, examinations of carotid intima-media thickness (CIMT), pulse wave velocity (PWV), ankle-brachial index (ABI), and body composition (by densitometry and bioelectrical impedance analysis) were performed. The risk of fatal CV events was evaluated by the Systematic COronary Risk Evaluation (SCORE) and its modifications: SCORE multiplied by the coefficient 1.5 (mSCORE), and SCORE2.

Results: SSc patients had a trend to higher prevalence of dyslipidemia (p=0.063) and significantly more often prediabetes (p<0.001), but a comparable prevalence of arterial hypertension, diabetes mellitus, and current smoking to HC. Nevertheless, SSc used significantly more frequently antihypertensives than HC (p<0.001), including calcium channel blockers (indicated for Raynaud’s phenomenon). SSc had significantly increased prevalence of carotid artery disease, more unfavorable CIMT and ABI (p<0.05 for all), and a trend to lower SCORE and overall CV risk based on SCORE but no significant difference in SCORE2 compared to HC.

On the contrary, the overall CV risk based on US examination was significantly higher in SSc. A comparison of calculated CV risk with US examination showed inaccuracy of the CV risk scoring systems in SSc (Figure 1). Nevertheless, SCORE2 underestimated the real CV risk significantly less than SCORE (p=0.043), while SCORE2 vs. mSCORE and SCORE vs. mSCORE were comparable. In SSc, the CV risk and markers of subclinical ATS were associated especially with age, HbA1c, disease duration, and mean arterial pressure (p<0.05 for all).

Conclusions: This cross-sectional case-control study demonstrated a significantly increased risk of subclinical ATS in SSc compared to HC, although there was an opposite trend in CV risk estimated by calculated SCORE. The CV risk in SSc was associated especially with age, disease duration, and HbA1c levels. Scoring systems underestimated the CV risk, while SCORE2 was significantly more accurate than SCORE.

Supported by MHCR (023728; NV18-01-00161A; NU21-01-00146).

P.147

RELATION OF NON-SPECIFIC CAPPILAROSCOPIC FINDINGS, PATIENT’S CLINICAL DATA AND OUTCOME IN A MONOCENTRIC COHORT OF SYSTEMIC SCLEROSIS PATIENTS

Cristina Nita¹, Laura Groseanu^1,2, Delia Nicoara¹, Violeta Bojinca^1,2, Denisa Predeteanu^1,2, Daniela Opris^1,2, Florian Berghea^1,2, Violeta Vlad¹, Ioana Saulescu^1,2, Mihai Abobului^1,2, Magdalena Negru^1,2, Andreea Borangiu^1,2, Sanziana Daia^1,2, Diana Mazilu^1,2, Cosmin Constantinescu^1,2, Claudia Cobilinschi^1,2, Madalina Duna¹, Denise Mardale^1,2, Andra Balanescu^1,2

¹Department of Internal Medicine and Rheumatology, St. Mary Clinical Hospital, Bucharest, ROMANIA, ²University of Medicine and Pharmacy Carol Davila, Bucharest, ROMANIA

Introduction: The „scleroderma” – type capillaroscopic pattern is met in the majority of patients with systemic sclerosis (SSc) (>90%). However, several gaps in knowledge remain regarding the evaluation of normal and/or nonspecific findings, especially with regard to prediction of disease progression. This study aims to investigate the clinical and immunologic characteristics of SSc patients with normal and/or non-specific nailfold videocapillaroscopy (NVC) abnormalities and to compare them to those with a scleroderma pattern.

Material and Methods: This was a single-center retrospective study which enrolled 270 SSc patients referred for NVC since January 2000, in our rheumatology department. Demographic and clinical features, symptoms and parameters related to a specific organ involvement according to MEDS evaluation sheets and survival were evaluated.

Results: Among the cases, 8 (2.96%) had normal NVC and 11 (4.07%) had nonspecific NVC changes, characterized by isolated ramified capillaries in 42%, curved capillary limbs in 33%, giant capillaries in 16% and focal microhemorrhages in 9 % of patients. The group comprised 14 females and 5 males, with a mean age of 52.7 (±17.4) years, most of them with diffuse subset (12/19). Presence of elongated capillaries and prominent subpapillary plexus was positively associated with synovitis (p=0.010) and myositis (p<0.001). Higher percentage of cases had a longer mean durations of RP (18.4 ± 14.4) and first non-RP manifestation (12.5 ± 13.1 years), compared to the other group (10.2 ± 1.5), respectively (8.3 ± 7 years), but no significant between-group difference could be established (p=0.107). Although fewer cases had PAH and/or DLCO < 80% than controls, the differences did not reach statistical significance. Furthermore, the cases had lower overall frequency of digital ulcers (28% vs 51%, p=0.04). No differences in mortality were found between the groups.

Conclusions: Musculoskeletal involvement was the only factor independently associated with normal/nonspecific NVC. It is possible that SSc with normal NVC may be at lower risk of progression to severe visceral and skin involvements. However, the follow-up period was different for each enrolled patient, both in overall time and in timepoints of observation. Some important clinical data, could have been lost, possibly altering results interpretation. Focus on the association between normal and/or nonspecific NVC pattern and organ involvement should be sought in order to define distinctive features of the disease.

P.148

PREVALENCE AND SEVERITY OF CORONARY ARTERY CALCIFICATION ASSESSED BY HIGH-RESOLUTION CT SCANS OF THE LUNGS IN PATIENTS WITH SYSTEMIC SCLEROSIS

Esben Naeser¹, Frederik Enevoldsen¹, Simon Winther², Morten Bøttcher², Klaus Søndergaard¹, Ellen Hauge¹

¹Department of Rheumatology, Aarhus, DENMARK, ²Department of Cardiology, Gødstrup, DENMARK

Introduction: Coronary artery calcification (CAC) is an established predictor of cardiovascular events.

We aimed to (I) validate the use of routinely performed HRCT-scans in the detection of coronary artery calcification, and (II) to evaluate the prevalence and severity of CAC in a clinical SSc cohort using HRCT, and to identify potential risk factors among these patients.

Material and Methods: A cross-sectional study including 390 patients with SSc aged between 50 years to 75 years, who had a HRCT scan performed between 2012 – 2022. Validation of CACS using HRCT were performed among 43 patients, who had an ECG-gated CT within 18 months of the HRCT. CAC was assessed using a simple visual scoring method ranging from no calcium over minimal and moderate to heavy calcium burden.

Results: Visual score of CAC on HRCT showed good agreement with Agatston CAC on ECG-gated CT (kappa = 0.72-0.79). Moderate to heavy calcium burden (CACS> 100) was present in 40.8% of patients with SSc. In multivariate analysis, age (OR: 1.09, P<0.001), male gender (OR: 1.95, p=0.001), smoking (OR: 2.28, p=0.001), diabetes mellitus (OR: 6.44, p<0.001), and digital ischemic ulcers (OR: 2.6, p=0.001) were associated with moderate to heavy calcium burden.

Conclusions: CAC is frequent present in patients with SSc. Visually assessment of CAC by HRCT show good agreement with Agatston CAC on ECG-gated CT.

P.149

PREVALENCE OF PULMONARY HYPERTENSION IN SYSTEMIC SCLEROSIS COMPLICATED BY INTERSTITIAL LUNG DISESASE (ILD). ANALYSIS IN A COHORT OF SOUTHERN ITALY

Caterina Naclerio¹, Fabio Crescibene², Giovanna Cuomo³

¹Scarlato Hospital-Rheumatology Unit, Scafati, ITALY, ²Scarlato Hospital-Cardiology Unit, Scafati, ITALY, ³Università di Campania-Vanvitelli, Naples, ITALY

Introduction: PAH occurs in up to 27% of patients with SSc. Pulmonary hypertension that occurs in the context of ILD, confers a fivefold increased risk of death compared with PAH alone. PAH occurs from 5% to 12% of patients with SSc complicated by ILD.

The aim of this study is to measure the prevalence of different types of pulmonary hypertension (PH) and to identify patients with systemic sclerosis (SSc) at highest risk in a chort of Southern Italy.

Material and Methods: 48 Patients with systemic sclerosis, according to the American College Rheumatology (ACR)/ European League Against Rheumatism (EULAR) 2013 criteria treated at our Rheumatology departments from July 2014 to January 2022, were invited to participate in a systematic screening procedure for and early SS-PH diagnosis. Patients had clinical and epidemiological characteristics as described in the attached table 1.

Results: Patients performed, as scheduled, blood tests including the autoantibody profile. In addition, patients underwent echocardiographic examination with estimation of transvalvular flows, computed tomography examination with high resolution of the lung and spirometric examination with estimate DLCO-DLCO/VA. Of the 48 patients who performed laboratory and instrumental tests; 25/40 (52%) of patients had a PAPs > 20 mmhg and < to 40 mmhg; 8/48 (16%) patients had PAPs values > 40 mmhg and less than 60 mmhg and finally in 4% of patients we observed PAPs values > 60 mmhg.

Of the 20 patients with paps values between 40 and 80 mmhg; 9/20patients (45%) had moderate lung involvement and 3/20 patients (15%) had severe lung involvement.

Conclusions: The study shows a slight increase in the prevalence of PH in patients with complicated ILD ssc in our case studies.

Further studies are needed.

P.150

CLINICAL CHARACTERISTICS, RISK FACTORS, AND PROGNOSIS OF LEFT VENTRICULAR DIASTOLIC DYSFUNCTION IN SYSTEMIC SCLEROSIS ; A SINGLE-CENTER EXPERIENCE

Su-Jin Moon¹, Bong-Woo Lee², Hae-Rim Kim³, Hae Ok Jung², Seung-Ki Kwok²

¹Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, SOUTH KOREA, ²Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, SOUTH KOREA, ³Konkuk University Medical Center, Seoul, SOUTH KOREA

Introduction: Cardiac involvement is one of major causes of death in systemic sclerosis (SSc). Left ventricular diastolic dysfunction (LVDD) has been regarded to be a precursor of heart failure with preserved ejection fraction. Until now, there has been limited data on LVDD in SSc patients. The present study aimed to determine the frequency and independent risk factors and prognosis of LVDD in SSc patients.

Material and Methods: SSc patients enrolled in the Seoul St. Mary’s Hospital Scleroderma Cohort between 2011 to 2020 with at least one analyzable 2D echocardiogram were included. LVDD was assessed by echocardiography according to the 2016 American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines.

Results: The majority of participants were female (87 %) with a median age of 57.0 (IQR 48.0, 64.3). Among 320 enrolled patients, 112 (35 %) met the LVDD criteria on their echocardiography. The majority of SSc patients with LVDD showed grade I (n = 97), and the remaining patients showed grade II.

The female sex, the presence of interstitial lung disease, the type of SSc, and medications), the distribution of autoantibodies did not differ between LVDD and non-LVDD group.

The SSc disease duration in patients with LVDD were significantly longer than those of non-LVDD group. The onset age and age at echocardiogram were older in LVDD group than non-LVDD group. The BMI is higher in SSc patients in LVDD than non-LVDD group (23.5 vs. 21.8, p value < 0.001). The proportion of statin use, the presence of diabetes or hypertension were higher in patients with LVDD, compared with those without LVDD. LVDD group showed significantly higher systolic blood pressure, pulse pressure, and pulse pressure index (PPI), compared with non-LVDD patients. Multivariate logistic regression showed that age at echo, SSc disease duration, and high BMI are independent risk factor for LVDD in SSc patients.

After a median follow-up of 4.0 years, echocardiograms showed that the proportion of LVDD increased from 35 % to 44 %. Among SSc patients with the presence of LVDD at baseline, the majority (60.3 %) showed stable DD grade, whereas only 11 % showed LVDD progression. Among the patient without LVDD at baseline, 26 % showed newly developed LVDD at follow-up echocardiographic exam.

Conclusions: LVDD is a common cardiac manifestation in SSc. It is important to pay special attention to monitoring the development of LVDD, especially in SSc patients with a prolonged disease duration, obesity, and the elderly.

P.151

PERIARTERIAL SYMPATHECTOMY IN SCLERODERMA ISCHEMIC DIGITAL ULCERS

Antonella Marcoccia¹, Mariagrazia Modesti¹, Cecilia Cianfrocca¹, Rosalia Privitera¹, Vito Marchese², Francesco Fabi²

¹Scleroderma Center -Sandro Pertini Hospital, Roma, ITALY, ²Hand Surgery Unit - San Pietro fatebenefratelli Hospital, Roma, ITALY

Introduction: Systemic Sclerosis is associated with a vasculopathy of the arterial-capillary district. Raynaud Phenomenon resulting from excessive vasospasm carried by the sympathetic nervous fibers which travel on the adventitia of the artery. As a result the technique of microsurgical adventatictomy has been proposed since the early 80’s to stop this hyperactive dysfunction. The peripheral sympathectomy of the radial and ulnar arteries and digital arteries allows the interruption of the selectively periaterious sympathetic pathway through the circumferential removal of perivascular fibrous tissue allowing an increase in the caliber of the arteries and an increase in microcirculation flow with minimal invasiveness, no significant complications.

Material and Methods: We present the clinical case of a female Scleroderma patient with digital gangrene, with severe raynaud syndrome Raynaud condition score RCS 0-10 > 5 and intense unresponsive painful symptoms to increased antalgic therapy with opioids and neuroleptics (VAS 0-10 > 8). The patient was subjected with an intraoperative microscope to micro-surgical adventatictomy of the radial and ulnar arteries and the handheld arterial arch

Results: Treatment resulted in a reduction in the painful symptoms VAS < 3 and the intensity and frequency of the RCS <2 since the immediate postoperative, good compliance of the patient to the procedure without any complications in surgical sutures.

Conclusions: Digital sympathectomy, represents a technique with a valid rational and with excellent prospects of employment in scleroderma patients still little known in rheumatology and vascular field because the results however good emerge from cases that are still too limited. Therapy is only rarely offered to sclerodermal patients and is carried out only by very few specialized centers. Surely a greater knowledge of the technique, the post-operative course and the final outcome through the experience of the cases treated as well as the creation of interdisciplinary networks between rheumatology, vascular medicine and hand microsurgery will be promote this technique as well as an early timing to a better conservative outcome for the patient.

P.152

ACUTE EFFECTS OF INTRAVENOUS ILOPROST ON FINGER POWER DOPPLER ULTRASOUND IN SCLERODERMA PATIENTS

Luca Magnani¹, Sofia Testoni², Pierluigi Macchioni¹, Gianluigi Bajocchi¹, Carlo Salvarani¹

¹IRCCS-ASMN, Reggio Emilia, ITALY, ²Universita' di Modena e Reggio Emilia, Modena, ITALY

Introduction: So far few studies explored ultrasound (US) as a tool to assess vascular subcutaneous involvement in pts affected by SSc. We aim to evaluate the acute vascular effects of intravenous iloprost (ILO) infusion by power Doppler US (PDUS) examination at periungual (PU) and finger pulp (FP) subcutaneous areas in a consecutive series of SSc patients.

Material and Methods: Seventy-seven consecutive observations were done in 38 SSc pts (ACR/EULAR criteria). FP and PU vascularization of the 1st, 2nd and 3rd finger of the dominant hand were evaluated before and after ILO infusion (dosage 0.5-2.0 ng/kg/min for 4-6 hours) using an Esaote MylabClassC, (Genoa, Italy) machine equipped with a 22-8 Mhz multifrequency linear probe. The image with the highest presence of PD signal at PU and FP for each finger was scored according to a semiquantitative 0-5 scale (0 = no signal, 5 = signal of healthy controls) and summed up to obtain a total patient PD score (TotS). Values before and after ILO treatment were compared by T-test for paired samples. No improvement in TotS was defined as a difference between T1 and T0 observation < 0; improvement if difference between T1 and T0 was > 1.

Clinical demographic and US data entered in a multivariate logistic regression analysis to evaluate factors predictive of TotS improvement. Single finger PU PD scores were summed to obtain total PU PD score (TotPU). Single finger FP PD scores were summed to obtain total FP PD score (TotFP).

Results: Clinical and laboratory features of the enrolled pts are reported in Table 1. The effects of ILO infusion on TotS are reported in table 2. TotS improved in 60 observations, while in 17 there was no variation or worsening. At multivariate logistic regression analysis concomitant therapy with calcium channel blockers (CCB) was predictive of PD total score improvement > 0 (OR 4.53; 95% CI 1.14-18.1 p=0.032) and concomitant pulmonary hypertension (HAP) was associated to lack of response (OR 0.27; 95% CI 0.08-0.94 p=0.04).

Conclusions: PDUS examination of the PU and FP area can demonstrate an ILO acute effect in SSc patients with long- lasting disease. Therapy with CCB and presence of HAP impact on PD score improvement.

P.153

ROLE OF NEUTROPHIL-LYMPHOCYTE RATIO AND PLATELET-LYMPHOCYTE RATIO IN ATHEROSCLEROSIS IN SSC PATIENTS

Laura Perea-Galera¹, Joaquin Lacasa-Molina¹, Alida Taberner-Cortés¹, Àngels Martínez-Ferrer¹, Elia Valls-Pascual¹, Ignacio Gómez-Vázquez¹, Desamparados Ybáñez-García¹, Carlos Valera-Ribera¹, Pablo Andújar-Brazal¹, Adrián Mayo-Juanatey¹, Juan José Alegre-Sancho¹

¹Servicio de Reumatología, Hospital Universitario Dr Peset, Valencia, SPAIN

Introduction: Systemic autoimmune diseases, including systemic sclerosis (SSc), are associated with early atherosclerosis. Neutrophil-Lymphocyte Ratios (NLR) and Platelet-Lymphocyte Ratios (PLR) are related to systemic inflammation and atherosclerosis. In SSc, NLR could predict disease progression and mortality.

The objective is to evaluate the potential value of baseline NLR and PLR determination as predictors of atherosclerosis and disease severity in SSc patients.

Material and Methods: All patients from a longitudinal SSc cohort followed at a hospital in eastern Spain between 1984 and 2023 were included. The NLR and PLR ratios were calculated using their initial diagnostic blood test. Epidemiological, clinical, laboratory and radiological findings were obtained by examining the patient database. The presence of atheromatous plaques (subclinical atherosclerosis) was evaluated using extracranial carotid artery ultrasound (ESAOTE MyLab XV70) or radiological studies (pulmonary HRCT). In case of death, the cause (attributable or not to the disease) was recorded.

Results: The cohort consists of 175 patients, 93% women and 7% men, 80% lcSSc and 20% dcSSc, with an average age at diagnosis of 53 years (SD ± 16.07). 35% had dyslipidemia, 33% had arterial hypertension, and 7% had diabetes mellitus. Of the total patients included, 49% exhibited subclinical atherosclerosis. After a mean follow-up of 10 years (SD ± 7.84) and an average disease duration from the first non-Raynaud symptom of 22 years (SD ± 10.50), 19% of the patients experienced one or more vascular events (50% cardiac, 32% limb, and 29% cerebral) and 22% of the patients passed away. Only 29% of the deaths were related to Ssc; from the remaining, 37% resulted from vascular events. The mean values of NLR and PLR were 2.44 (SD ± 1.53) and 139.83 (SD ± 90.63), respectively. Higher NLR values were significantly associated with the development of subclinical atherosclerosis (p = 0.001), a higher number of vascular events (p = 0.02), and overall mortality (p = 0.000), both vascular (p value = 0.026) and attributable to SSc (p = 0.034). Values above 2.09 were associated with increased mortality in our patients (AUC = 0.713; p = 0.0001). We found no relationship between PLR and the studied variables.

Conclusions: Baseline NLR determination can be useful in predicting atherosclerosis, vascular events and mortality in SSc patients.

P.154

THERAPEUTIC CHALLENGES IN AGGRESIVE SYSTEMIC SCLEROSIS WITH MULTISYSTEMIC INVOLVEMENT

Elena Icatoiu, Laura Groseanu, Andra-Rodica Balanescu, Violeta-Claudia Bojinca

Saint Mary Clinical Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, ROMANIA

Introduction: Three main mechanisms converge on systemic sclerosis (SSc): fibrosis, vascular wall damage and autoimmunity. They generate multiple clinical features of the disease, thus requiring a holistic multidisciplinary approach.

Material and Methods: This report introduces the case of a 47-year-old female patient diagnosed with SSc at the age of 41 when she was already experiencing multisystemic involvement.

Results: The patient presented in the Emergency Department complaining of a severe dyspeptic syndrome with asthenia, abdominal pain, dyspnea and dry cough. She was undergoing treatment with azathioprine, low-dose corticosteroids, beta-blocker and loop diuretic. Her medical records mentioned an episode of acute renal failure and subsequent cyclophosphamide pulses, gastric stasis and grade B esophagitis.. Cardiac MRI documented myocardial fibrosis of the left ventricle.

Clinical examination revealed byzantine facies, sclerodactyly, evolving digital ischemia, Raynaud’s, lethargia. Soon after hospitalization, she associated precordial pain and palpitations. Cardiac auscultation was positive for mitral systolic murmur, while the pulmonary auscultation was normal. ECG showed sinus rhythm with multiple supraventricular extrasystoles, trifascicular block and left ventricular hypertrophy. Echocardiography confirmed mitral, tricuspid regurgitation and extremely low left ventricular ejection fraction (LVEF 15%). Angiotensin II receptor blocker/neprilysin inhibitor and amiodarone were added. Laboratory tests identified iron deficiency anemia, hepatocytolisis, impaired renal function and inflammatory syndrome. Abdominal and pelvic CT described alithiasis cholecystitis that did not require surgical intervention. Probable severe toxicity to azathioprine was considered, so the drug was stopped and complex therapeutic approach was expanded to nasal oxigen therapy, diuretics, beta-blocker, inotropic support, anticoagulant drugs and antibiotics in order to compensate for the SSc-multiorgan dysfunction. Within two weeks, her medical condition improved so intravenous prostaglandin E1 was initiated and mycophenolate mophetil was recommened upon discharge. Her periodic cardiac evaluation reported the severe yet stabilized myocardial impairment, LVEF 25-30%. Peripheral vascular disorder responded favourably to specific therapy. One year later, she was clinically assessed after significant weight loss, isomnia, palpitation, abnormal sweating. Endocrinological examination concluded amiodarone induced thyrotoxicosis, so the medication was withdrawn and thyrozol was administered, with normal hormonal levels at further examinations.

Conclusions: Heart involvement in SSc is responsible for 40% of SS related mortality. Progressive fibrosis along myocardial inflammation leads to systolic and diastolic dysfunction of the left ventricle. Nevertheless, impaired LV contractility with abnormal LVEF is rarely encountered. Cardiac complications point to a poorer prognosis and might be associated to a rapidly progressive skin fibrosis.

P.155

NOVEL TISSUE TURNOVER BIOMARKERS ARE ASSOCIATED WITH PROLONGED QTC AND PULMONARY ARTERIAL HYPERTENSION IN PATIENTS WITH SYSTEMIC SCLEROSIS

Christoffer Tandrup Holst Nielsen^1,6, Signe Holm Nielsen², Sine Søndergaard Korsholm³, Axel Diderichsen⁴, John Bonde Knudsen⁵, Morten Karsdal², Anne-Christine Bay-Jensen², Louise Diderichsen^1,6

¹Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen, DENMARK, ²Immunoscience, Nordic Bioscience, Herlev, DENMARK, ³Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen, DENMARK, ⁴Dept of Cardiology, OUH, Odense, DENMARK, ⁵Dept of Rheumatology, OUH, Odense, DENMARK, ⁶Copenhagen University Hospital, Rigshospitalet, Copenhagen, DENMARK

Introduction: Systemic sclerosis (SSc) is characterized by vasculopathy and fibrosis of the skin and internal organs. Cardiovascular involvement is a frequent and significant contributor to morbidity and mortality in SSc. They can develop clinically silent and be difficult to detect. Novel tissue turnover biomarkers hold the potential to detect the manifestations before clinical overt disease, identify risk patients and monitor the disease course as well as improve our understanding of the pathophysiology in SSc. The objective of this study is to measure a panel of collagen biomarkers in SSc and explore associations to cardiac involvement detected by ECG and to pulmonary arterial hypertension (PAH).

Material and Methods: One-hundred and two patients fulfilling the 2013 ACR/EULAR criteria for SSc were included in the study (mean age 59, 77% female, disease duration 0.5-30 years). At study visit, participants completed a questionnaire concerning co-morbidities (confirmed by medical records review), current medication, family history of CV events, heart symptoms, and smoking habits. Systolic and diastolic blood pressures and standard 12-lead electrocardiogram (ECG) were measured. Biomarkers of type III and VI collagen formation (PRO-C3 and PRO-C6) and degradation (C3M and C6M) were measured in serum by competitive ELISAs. Differences between biomarker levels in SSc patients with myocardial involvement presented as the prolongation of the corrected QT (QTc) interval (QTC<450ms or QTC>450ms), and with or without PAH, were calculated by Mann-Whitney U test.

Results: A total of 8 patients were diagnosed with PAH, and they presented higher levels of PRO-C3 and PRO-C6 (p=0.041 and p=0.019, Fig. 1), compared to SSc patients without PAH. Similarly, PRO-C3 and PRO-C6 were significantly increased in patients with prolonged QTc (>450ms) (p=0.0424 and p=0.0264, Fig. 2). No differences were found for C3M and C6M in relation to PAH or prolonged QTc.

Conclusions: Patients with SSc and prolonged ECG presented an altered tissue turnover, by an increased level of PRO-C3 and PRO-C6. In addition, SSc patients with presence of PAH had increased levels of PRO-C3 and PRO-C6 as well. presented an altered tissue turnover in presence of PAH, and with a QTc>450 ms. Our study indicates that they could serve as biomarkers of these manifestations and warrant further studies in cardiac disease in SSc.

P.156

RIGHT VENTRICULAR DYSFUNCTION BY CARDIAC MAGNETIC RESONANCE, ASSOCIATED RISK FACTORS AND PROGNOSTIC VALUE IN PATIENTS WITH SYSTEMIC SCLEROSIS

Alfredo Guillen-Del-Castillo¹, Jorge Rodrigo Fernandez², Federica Illuminato², Claudia Codina-Clavaguera¹, Filipa Valente², Lucia Rodriguez-Eyras², Jose Fernando Rodriguez-Palomares², Carmen Pilar Simeon-Aznar¹

¹Hospital Universitari Vall d'Hebron, Unit of Systemic Autoimmune Diseases, Internal Medicine Department, Barcelona, SPAIN, ²Hospital Universitari Vall d'Hebron, Cardiology Department, Barcelona, SPAIN

Introduction: Several studies demonstrated that right ventricular involvement is a predictor of mortality in patients with systemic sclerosis (SSc). The aims of our study were to evaluate the prevalence of right ventricular dysfunction (RVD), to assess the predictors associated with RVD and to analyze its prognostic impact in terms of cardiovascular events (death and/or hospitalization due to heart failure (HF) and/or ventricular arrhythmia).

Material and Methods: Retrospectively, 91 patients with SSc were included. All patients underwent cardiac magnetic resonance (CMR) with gadolinium contrast. RVD was defined as right ventricular ejection fraction <53% in men and <52% in women. Clinical associations were analyzed using Chi-square test, multivariate logistic regression and survival study with Log-Rank test and Cox-Regression analysis.

Results: Mean age at CMR was 60 ±12 years, 83% female, and 26% had pulmonary hypertension at baseline. Most patients had limited cutaneous SSc (67%). The prevalence of RVD was 35%, of which 72% presented mild dysfunction, 22% moderate dysfunction, and 6% severe dysfunction. In patients with RVD, RV longitudinal strain values were lower than in those without RVD (-15.4% vs -25%; p< 0.001). Late gadolinium enhancement (LGE) was more frequent in RVD (40.6% vs 13.8%; p=0.004).

The univariate analysis showed that male sex, history of myositis, the absence of ischemic heart disease, the presence of left bundle branch block (LBBB), pericardial effusion, LV ejection fraction (LVEF), the presence of LGE of both ventricles, pulmonary trunk dilation (PTD), baseline BNP, DLCO and FVC levels were significantly associated with RVD.

In the multivariate analysis, the absence of ischemic heart disease (OR 0.60; p=0.035), a lower LVEF (OR 0.56; p=0.023), PTD (OR 1.48; p=0.029) and decreased DLCO values (OR 1.08; p=0.038) were found to be the only independent risks factors associated with RVD.

During the follow-up, patients with RVD had higher all-cause mortality (53% vs 22%; p < 0.003) and more commonly presented hospitalization for HF (41% vs 16%; p=0.001). No ventricular arrhythmias were observed. The mortality for all causes and the combined outcome of death and/or hospitalization for HF were also significantly more frequent in patients with RVD (HR 3.35 and HR 3.44; both p<0.001).

Conclusions: RVD is prevalent in patients with SSc. The presence of LV dysfunction and PTD are independent risk factors of RVD evaluable by CMR. Male sex and lower DLCO levels are clinical factors independently associated with higher risk of RVD. RVD is associated with higher mortality and prevalence of adverse clinical events.

P.157

HEART INVOLVEMENT OF SYSTEMIC SCLEROSIS ON LONG-TERM RITUXIMAB THERAPY

Liudmila Garzanova, Lidia Ananyeva, Olga Koneva, Olga Ovsyannikova, Mayya Starovoytova, Oxana Desinova, Rushana Shayakhmetova, Anna Khelkovskaya-Sergeeva

V.A. Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: One of the serious manifestations of systemic sclerosis (SSc) is heart involvement. Rituximab (RTX) could be promising therapy option for cardiac involvement in SSc, according to some studies. The aim of our study was to assess prevalence of cardiac complications in SSc patients (pts) and effect of RTX therapy in long-term follow-up.

Material and Methods: Our prospective study included 113 patients with SSc. Mean age was 48.1±13 years, female - 96 patients (85%). The mean disease duration was 6.1±5.4 years. The diffuse cutaneous subset of the disease had 62 patients, limited – 40, overlap – 11. All pts had interstitial lung disease (ILD). All patients received prednisolone at mean dose of 11.6±4.8 mg/day and 53 of them - immunosuppressants at inclusion (cyclophosphamide, mycophenolate mofetil in most cases). Patients received RTX due to the ineffectiveness of previous therapy for ILD. Arterial hypertension was found in 26 pts, dyspnea at inclusion had 83% pts (NYHA 2-3). There was no pts with initial pulmonary artery hypertension. Parameters were evaluated over the periods: at baseline (point 0), 13±2.3 month (point 1), 42±14 month (point 2) and 79±6.5 month (point 3) after initiation of RTX therapy.

Results: Changes of evaluated heart parameters during RTX treatment are presented in the Table 1. There was no worsening of cardiac function during long-term RTX therapy. There was insignificant decrease in the number of pts with cardiac arrhythmias and conduction blocks. Diastolic dysfunction of left ventricular was found did not change on RTX therapy. Left ventricular ejection fraction (LVEF) was stable at point 1 and increased at point 2 and 3. PASP also remains stable in general for the group. There was 33 pts with elevated PASP (less than 35mmHg by echocardiography). In this pts PASP decreased from 47±13.7 to 44.3±11.5 mmHg in point 1 (p=0.04). At further observation (point 2-3), there was a significant decrease in PASP in this group of patients (p=0.001).

Conclusions: Heart manifestations were detected almost in half of the pts in with SSc in our cohort. There was not observed any worsening of cardiac function during long-term RTX therapy. There was significant improvement of PASP in pts with an initial disturbance of these parameter. RTX could be an effective and safe treatment option for SSc with cardiac involvement, but further studies are required.

P.158

CHARACTERIZATION OF THE PERICARDIAL INVOLVEMENT IN SYSTEMIC SCLEROSIS AND RELATED CARDIAC COMPLICATIONS

Carlos Fernandes¹, Ana Cordeiro de Sousa Cabral², Maria José Parreira dos Santos³

¹Faculty of Medicine of the University of Lisbon - Rheumatology University Clinic, Lisbon, PORTUGAL, ²Hospital Garcia de Orta - Rheumatology Department, Lisbon, PORTUGAL, ³Hospital Garcia de Orta - Rheumatology Department, Lisbon, PORTUGAL

Introduction: Systemic sclerosis (SSc) is a rare systemic rheumatic disease with heterogeneous manifestations that can affect multiple organ systems, characterized by a high case-specific mortality rate and non-lethal complications. Cardiac involvement is a common and early clinical manifestation, often underestimated in the early stages of disease. This study aimed to investigate pericardial effusion and its possible associations with pulmonary hypertension (PH) and disease prognosis.

Material and Methods: We included patients prospectively followed in the National Registry of Rheumatic Patients (Reuma.pt) at Hospital Garcia de Orta who had a clinical diagnosis of SSc and available echocardiogram records. Descriptive data analysis was performed using SPSS software, and logistic regression models were used to explore the associations between pericardial effusion, PH and vital status.

Results: Among the 148 patients enrolled, 32 (21,6%) had pericardial effusion documented by echocardiography. The presence of effusion was associated with the SSc subtype, gastrointestinal and pulmonary involvement, heart failure (HF), a restrictive pattern on pulmonary function tests (PFTs), PH and pulmonary artery systolic pressure (PASP) estimated by echocardiography. Patients with pericardial effusion were more likely to have PH both in unadjusted analysis and in analysis adjusted for age, SSc subtype, presence of HF and arterial hypertension (ORadjusted 8.47; IC95% 2.07 a 34.64) and more likely to die in the model adjusted for age and SSc subtype (ORadjusted 3.51; IC95% 1.12 a 11.05).

Conclusions: Pericardial effusion occurs in about one-fifth of patients with SSc. Demographic, clinical, and immunological differences were observed between patients with and without effusion. This study confirms that pericardial effusion occurs concomitantly with PH and that the statistically significant association persists after accounting for confounding factors. These results show that the presence of pericardial effusion is an indicator of poorer vital prognosis in these patients. A prospective study to characterize pericardial effusion in SSc patients is suggested for future studies, to clarify the temporal relationship between the detection of effusion and the outcomes analyzed.

P.159

SAFETY AND EFFICACY OF INTRAVENOUS ILOPROST IN THE TREATMENT AND PREVENTION OF SCLERODERMA-RELATED DIGITAL ULCERS

Gabriele Amati¹, Amelia Spinella¹, Gilda Sandri¹, Marco De Pinto¹, Benedetta Bongiovanni¹, Giorgia Patrono¹, Ottavio Secchi¹, Federica Lumetti¹, Dilia Giuggioli¹

¹Rheumatology Unit, University Hospital of Modena, University of Modena and Reggio Emilia, Modena, ITALY

Introduction: Digital ulcers (DUs) are one of the most frequent manifestations of systemic sclerosis (SSc), present in up to 50% of SSc patients, and are responsible for limitations in daily personal and occupational activities leading to an important reduction in the patients’ quality of life. Intravenous (i.v.) Iloprost represents one of the most effective therapeutic agents in the treatment and prevention of digital ulcers in SSc. The objective of this study was to assess the safety and efficacy of Iloprost in the treatment of digital ulcers in scleroderma and highlight the correlations which influence the outcome of the treatment and/or the onset of side effects.

Material and Methods: Between January 2019 and April 2022, 100 consecutive SSc patients admitted to the Scleroderma Unit of the University Hospital of Modena were enrolled and treated with i.v. Iloprost over a 12-month follow-up. Demographic data, the presence of cardiovascular (CV) risk factors, clinical and/or in-strumental characteristics of the underlying condition, and the autoantibody pattern were analyzed.

Results: When analyzing the occurrence of DUs pre- and post-treatment, a significant improvement was ob-served (42% vs 15%, McNeman test p<0.001). For the evaluation of factors influencing outcome, the onset of ulcers at T12 or a lack of improvement were considered as a worsening of the clinical picture, while a lack of new ulcers at T12 or the healing of pre-existing ulcers were considered as an improvement of the clinical picture.

We observed a worsening of ulcers when correlated to diabetes (100% vs 11%, p<0.001), arterial hy-pertension (23% vs 1%, p=0.033), atherosclerosis (75% vs 13%, p=0.010), presence of thyroid disease (32% vs 11%, p=0.027), increased CRP levels (43% vs 10%, p=0.006), hyperuricemia (33% vs 11%, p=0.027) and diuretic therapy (32% vs 10%, p=0.0020).

Overall, 21 patients reported side effects during infusion (12% headache, 7% nausea, 2% flushing and/or palpitations), which were managed by decreasing the speed of infusion or symptomatic treat-ment. The onset of side effects was correlated with increased ESR (p=0.015) and a BMI falling between 20 and 24.99 (p=0.058).

Conclusions: Our data shows that i.v. IIoprost has proved to be safe and effective for treating and preventing ulcers in scleroderma. The correlation between CV risk factors and the worsening of DUs underlines the importance of managing these conditions, not just in terms of prevention, but also as an integral part of the course of treatment for vasculopathy in scleroderma.

P.160

TWO CASE REPORTS OF HEART CONDUCTION SYSTEM DEFECTS IN SYSTEMIC SCLEROSIS

Catarina Abreu, Vanessa Fraga, Alice Castro, Ana Cordeiro, Maria Jose Santos

Hospital Garcia de Orta, Almada, PORTUGAL

Introduction: Cardiac manifestations in systemic sclerosis (SSc) can be primary or secondary. The prevalence of primary cardiac involvement is difficult to determine and is underestimated due to subclinical disease. Cardiac manifestations are more frequent in patients with anti-topoisomerase I antibodies (Scl70) and, together with pulmonary manifestations, are the main cause of death in patients with SSc.

Material and Methods: We report two cases of heart conduction system defects in SSc.

Results: Case 1: A 63-year-old Caucasian female diagnosed with SSc since 2014 with anti-Ro60 positivity. Clinically she presented with cutaneous (sclerodactyly), vascular (Raynaud phenomenon and digital ulcers), pulmonary (usual interstitial pneumonia), upper and lower gastrointestinal (gastroesophageal reflux (GER) and fecal incontinence), and musculoskeletal (arthritis and myositis) involvement. A 24-hour Holter monitoring (24hHm) performed at the time of diagnosis revealed bigeminy. In 2016, she presented with progressive exertional fatigue and increased N-terminal prohormone of brain natriuretic peptide (NT-proBNP). The echocardiogram revealed reduced ejection fraction due to hypokinesis. She placed drug eluting stents due to sub-occlusive lesions of 3 coronary arteries. In 2017, despite being asymptomatic, she presented with a complete right bundle branch block and frequent ventricular extrasystole with bigeminy and trigeminy (less than 10,000/24 hours) on 24hHm. In 2021, she implanted a definitive pacemaker due to new onset second degree atrioventricular block.

Case 2: A 20-year-old Caucasian male presented in 2020 with significant weight loss, distal skin thickness, Raynaud phenomenon, digital pitting and ulcers and GER complaints. He was diagnosed with limited cutaneous SSc with Scl70 positivity. At diagnosis he was asymptomatic with a normal echocardiogram but elevated NT-proBNP. Six months later, he was admitted to another hospital due to exertional dyspnea and thoracic pain. He performed a cardiac magnetic resonance (CMR) suggestive of myocardial fibrosis confirmed by myocardial biopsy, without signs of inflammation. A 24hHm demonstrated right bundle branch block with bigeminy and a 7-day register monitoring failed to correlate symptoms with the register findings. Due to maintenance of symptoms with elevated troponin T (TnT) a loop recorder was implanted for continuous monitoring of events. Refractoriness to immunosuppressive therapy and deterioration of heart function led to stem cell and cardiac transplant.

Conclusions: Heart conduction system defects can present early in the course of SSc and may not be identified in initial clinical evaluation. It is important to regularly perform appropriate screening exams, including soluble biomarkers (TnT, NT-proBNP), echocardiogram and electrocardiogram. If alterations are documented, a 24hHm, exercise testing or CMR may be necessary.

P.161

CHARACTERISTICS OF PATIENTS WITH CONCOMITANT AXIAL SPONDYLOARTHRITIS AND SYSTEMIC SCLEROSIS

Jose Tandaipan, Helena Codes, Ivan Castellvi

Hospital Universitari de la Santa Creu i Sant Pau., Barcelona., SPAIN

Introduction: Objective: to describe the prevalence and clinical features in patients with concomitant axial spondyloarthritis (SpA) and systemic sclerosis (SSc).

Material and Methods: observational retrospective study made in a cohort of SSc patients followed in a SSc reference center. Patients with a diagnosis of SpA and fulfilling ASAS criteria.

Results: From 415 systemic sclerosis, we found 3 patients with AS, 2 with non-radiographic axial spondyloarthritis (nr-axSpA) and one ankylosing spondylitis(AS). All of them were female and HLA-B27 positive.

Case 1, a 58-year-old patient with diffuse SSc who developed nr-axSpA. The patient had a 3 years history of SSc with articular, cutaneous and gastrointestinal involvement, during the last years she was started with inflammatory back pain, without answer to conventional treatment, finally was diagnosticated of nr-axSpA by MRI. She received two anti-IL-17 agents, were ineffective both of them, subsequently she received JAK inhibitor, achieving remission. Also, we found significant improvement in the Modified Rodnan skin score (mRss) (16 to 9).

Case 2, a 59-year-old women, who was diagnosed 3 years ago of diffuse SSc, during the second year was diagnosed of nr-axSpA. In this patient the ILD interstitial lung disease were the main involvement, in addition of articular and cutaneous involvement. We started with anti-IL-6 agent, but it was removed due to repeated infections, now she is being treated with mycophenolate mofetil, waiting for clinical response. Regarding of back pain, she had a low disease activity (ASDAS 1.8) in treatment with NSAIDs.

Case 3, a 50-year-old women, at the age of 31, she was diagnosed of AS after a large history of backpain. Her limited SSc started when she was 41-year-old. Both diseases are stabilized with symptomatic treatment.

Conclusions: Axial spondyloarthritis findings are not common in SSc patients. A global assessment must be in the management of both diseases, because some of the treatments could be ineffective in one of them. In one case we found promising results with JAK inhibitors therapying skin involvement

P.162

MUSCLE FUNCTION IMPAIRMENT IN SYSTEMIC SCLEROSIS –SARC-F QUESTIONNAIRE AND PHYSICAL TESTS FOR DIAGNOSIS OF SARCOPENIA

Marina Simões, Carlos Teixeira, Marilia Santos, Juliana Gaino, Luciana Palhares, Zoraida Sachetto, Ana Paula Del Rio

University of Campinas, Campinas, BRAZIL

Introduction: Sarcopenia is the skeletal muscle insufficiency and is associated with systemic sclerosis (SSc) in more aggressive disease, greater prevalence in the diffuse form, longer duration of disease activity, greater skin involvement with higher modified Rodnan skin score (mRss). The mainly causes of sarcopenia in SSc are malnutrition, chronic inflammation, advanced age and physical inactivity due to the progression of the disease itself. The objective of this study is to evaluate the frequency of positive screening for sarcopenia in patients with SSc followed up at a tertiary hospital, through the application of the SARC-F questionnaire, followed by physical tests, and to evaluate the association of positive screening and clinical features.

Material and Methods: Patients over 18 years of age, diagnosed with SSc were selected. Patients with chronic use of corticosteroids and overlap syndromes were excluded. SARC-F questionnaire was applied. Then, physical tests such as handgrip strength, chair stand test, calf circumference and 4-meter-walk gait speed test were performed.

Results: We collected data from 56 patients: 32% were diffuse form, 19% limited form and 5% sine scleroderma form. SARC-F positivity was 46%. According to the obtained data, there was no statistically significant difference between SARC-F positivity and the clinical subtype (p=0.550), lung involvement (p=0.108), use of supplemental oxygen (p=0.234), extension of the mRss (p=0.130) and body mass index (p=0.588). There was statistical relevance when comparing the positivity of the screening and the handgrip strength test (p=0.003), chair stand test (p<0.001) and the 4-meter walk gait speed test (p=0.003). There was no statistical relevance between positive SARC-F and calf circumference (p=0.839).

Conclusions: A high frequency of positive screening results was observed, suggesting this would be good method for assessing sarcopenia in those patients, despite the low to moderate sensitivity of the test in general population. There was a statistical difference between positive screening and handgrip strength test, chair stand test and the 4-meter walk gait speed test, suggesting that they are good objective tests to be performed on an outpatient basis. Our study emphasizes the relevance of evaluating sarcopenia in the clinical practice in SSc.

P.163

CORRELATION BETWEEN THE PEAK OF SKIN THICKNESS PROGRESSION RATE AND ONSET OF CARDIOPULMONARY INVOLVEMENT IN THAI SYSTEMIC SCLEROSIS PATIENTS

Piyanart Rujirawinitchai, Chingching Foocharoen, Ajanee Mahakkanukrauh, Siraphop Suwannaroj, Patnarin Pongkulkiat, Tippawan Onchan

Department of medicine, Faculty of medicine, Khon Kaen University, Khon Kaen, 40002, Thailand, Khon Kaen, THAILAND

Introduction: Assessing skin thickness using the modified Rodnan skin score (mRSS) is the standard method for evaluating disease severity in systemic sclerosis (SSc) patients. Rapid skin thickness progression is associated with poor outcomes in SSc; however, the correlation between patterns of skin thickness and the onset of internal organ involvement remained unclear. Our objective was to determine the correlation between the peak rate of the skin thickness progression (pSTPR) and the onset of internal organ involvement, particularly interstitial lung disease (ILD) and pulmonary hypertension (PHT), among Thai SSc patients.

Material and Methods: A historical cohort study was conducted on adult SSc patients who experienced the onset of their first non-Raynaud’s phenomenon symptoms between January 2013 and December 2020 and had at least a 2-year follow-up. Patients with overlap syndrome were excluded. The pSTPR was calculated by dividing the peak of mRSS by the duration of disease at the peak of mRSS. The correlation between pSTPR and the onset of ILD and PHT was investigated using Spearman rank correlation.

Results: A total of 509 patients were included in the study. The majority of cases were female (351; 69.0%) and had diffuse cutaneous SSc subset (353 cases; 69.4%). The respective mean age and median of pSTPR was 48.2±11.6 years and 1.63 points/month (IQR 3.94). ILD and PHT was revealed in 282 cases (55.4%) and 82 cases (16.2%), respectively. The respective mean duration of disease at the onset of ILD and PHT was 6.8±5.9 years and 8.0±4.9 years. According to multivariable analysis, pSTPR had a negative correlation with the duration of disease at the onset of ILD (Rho -0.71, p<0.001) and the duration of disease at the onset of PHT (Rho -0.55, p<0.001), but had a positive correlation with the age at onset (Rho 0.17, p<0.001).

Conclusions: SSc patients with a high skin thickness progression rate reaching the maximum point of mRSS were at risk of developing early ILD and/or PHT. The pSTPR may be used to assess individuals at risk of experiencing an early onset of cardiopulmonary involvement in SSc.

P.164

IN SYSTEMIC SCLEROSIS (SSC) PATIENTS, PERIPHERAL BLOOD CD21LOW B CELLS INFLUENCE JOINTS INVOLVEMENT

Chiara Pellicano¹, Amalia Colalillo¹, Lorenzo Vantaggio¹, Umberto Basile², Edoardo Rosato¹

¹Department of Translational and Precision Medicine, Sapienza University of Rome, ROME, ITALY, ²UOC of Clinical Pathology DEA II level, Hospital Santa Maria Goretti-ASL Latina, ROME, ITALY

Introduction: Joint involvement in Systemic sclerosis (SSc) patients as an early manifestation of disease ranges from 12% to 65% of SSc patients. Erythrocyte sedimentation rate for disease activity score of 28 joints (DAS28-ESR) showed the best performance regarding reliability and construct validity for assessing arthritis in SSc patients. SSc is a complex autoimmune disease, which shares with rheumatoid arthritis (RA) several clinical and immunological features such as an increased frequency of CD21low B cells in peripheral blood. It has been demonstrated that in RA patients CD21low B cells correlated with joint erosions and destruction. To the best of our knowledge, no study has specifically investigated the role of CD21low B cells in SSc articular involvement. Aim of this study was to investigate the possible influence of peripheral blood CD21low B cells on joint involvement in a cohort of SSc patients.

Material and Methods: Fifty-two consecutive SSc patients, fulfilling the 2013 ACR/EULAR classification criteria for SSc were enrolled. Inflammatory articular involvement was assessed by DAS28-ESR and a value of less than 3.2 was defined as the threshold for a low disease activity state. Immunophenotyping of peripheral blood samples was performed with combinations of fluorochrome-labeled monoclonal antibodies to CD19-PC5.5, CD21-PE, CD27-APC, IgD-FITC.

Results: SSc patients had a median age of 57.5 years (IQR 48.75-63) with a median disease duration of 11.5 years (IQR 6-16). SSc patients were predominantly female (92.3% vs 7.7%). 29 (55.8%) SSc patients had limited cutaneous (lc) SSc and 23 (44.2%) had diffuse cutaneous (dc) SSc, with a median mRSS of 11 (IQR 7.75-15.25). Median visual analog scale (VAS) for arthritis reported was 2.5 (IQR 2-5.25). Median DAS28-ESR was 2.32 (IQR 1.5-3.57) and 16 (30.77%) patients had DAS28-ESR>3.2. Median peripheral blood CD21low B cells was 6.3% of total B cells (IQR 3.97-13). SSc patients with DAS28-ESR>3.2 had statistically significant higher peripheral blood CD21low B cells [12.65 % of total B cells (IQR 7.11-13.79) vs 5.08 % of total B cells (IQR 3.76-7.45), p<0.01] compared to SSc patients with DAS28-ESR less than 3.2. We found a significant positive linear correlation between peripheral blood CD21low B cells and VAS for arthritis (r=0.361, p<0.01) and DAS28-ESR (r=0.452, p<0.001). At multivariable analysis, peripheral blood CD21low B cells were independently associated with DAS28-ESR>3.2. [OR 1.301 (95% CI 1.099;1.540), p<0.01].

Conclusions: Elevated peripheral blood CD21low B cells were associated with higher articular disease activity in SSc patients suggesting a possible role in the pathogenesis of SSc joint involvement.

P.165

CALCINOSIS IN SYSTEMIC SCLEROSIS, STILL AN UNMET NEED - A RETROSPECTIVE SINGLE-CENTER STUDY

Cristina Nita¹, Laura Groseanu^1,2, Delia Nicoara¹, Daniela Opris^1,2, Violeta Bojinca^1,2, Denisa Predeteanu^1,2, Florian Berghea^1,2, Violeta Vlad¹, Ioana Saulescu^1,2, Sanziana Daia^1,2, Diana Mazilu^1,2, Magdalena Negru^1,2, Cosmin Constantinescu^1,2, Claudia Cobilinschi^1,2, Madalina Duna¹, Denise Mardale^1,2, Mihai Abobului^1,2, Andra Balanescu^1,2

¹Department of Internal Medicine and Rheumatology, St. Mary Clinical Hospital, Bucharest, ROMANIA, ²University of Medicine and Pharmacy Carol Davila, Bucharest, ROMANIA

Introduction: Calcinosis is a common complication of systemic sclerosis (SSc) and has a substantial impact on quality of life. While its pathogenesis is still poorly defined, pharmacologic treatment is not standardized nor efficient to date and it remains a therapeutic challenge. The objectives of this study were to describe the prevalence and characteristics of calcifications, and to investigate the relationships between calcinosis and clinical features in a population of patients with SSc. The primary endpoint was the evaluation of impact of calcinosis on survival in patients with SSc.

Material and Methods: Demographic and clinical features, including duration of disease progression, symptoms and parameters related to a specific organ involvement according to MEDS evaluation sheets, were evaluated in all SSc patients since January 2000.

Results: 154 SSc patients were selected in the database, from which we identified a final group of 63 (40.9%) patients with SSc - related calcinosis. The calcinosis cohort comprised 54 females and 9 males, with a mean age of 52.6 (±14.3) years, most of them with diffuse subset (38/63). Mean disease duration was 5.6 years (±3.1). Mean modified Rodnan skin score (mRSS) was 9.46 (±3.4) and mean adjusted EScSG activity index in the subgroup with calcinosis was 3.6 (±1.9). 49.2% (31/63) patients from the calcinosis subgroup developed interstitial lung disease (ILD) vs 43.9%; pulmonary hypertension was seen in 53.9% (34/63) cases vs 14.2% (13/91). As expected, calcifications were closely associated with vascular (p=0.004) and but also with gastrointestinal (p=0.001) involvement and pulmonary hypertension (p=0.049). Associations were stronger for severe gastrointestinal involvement defined as chronic intestinal pseudo-obstruction (p=0.001). Females (p=0.024), patients with digital ulcers (p=0.004), those with disease duration longer than 10 years (p=0.001), those with pulmonary hypertension (p=0.049) and patients with gastrointestinal involvement (p=0.044) presented significantly more calcinosis. Although no significant correlation was observed between calcification appearance and clinical aspects, lesions of less than 1cm in diameter were associated with ILD (p=0.011), with joint involvement (p=0.023), and with digital ulcerations (p=0.029), while those larger than 4cm, with malignancy (p=0.011), with severe peripheral artery disease (p=0.007), but also with systemic arterial hypertension (p<0.001). Furthermore, in the logistic regression equation we identified calcinosis as a risk factor for all-cause mortality in SSc patients [OR:2.607 (CI:1.062,6,397), p=0.037].

Conclusions: Patients with SSc – related calcinosis experiences a higher comorbidity burden. The fact that this study was retrospective may limit the interpretation of these results. Larger cohorts of patients should be evaluated to confirm and validate our data.

P.167

LOW BONE MINERAL DENSITY AND INCREASED FREQUENCY OF OSTEOPOROSIS IN PATIENTS WITH SYSTEMIC SCLEROSIS

Kerstin Lillpers¹, Kristofer Andreasson¹, Fiona McGuigan², Kristina E Åkesson², Roger Hesselstrand¹

¹Lund University, Department of Clinical Sciences. Department of Rheumatology, Skåne University Hospital, Lund, SWEDEN, ²Lund University, Department of Clinical Sciences, Clinical and Molecular Osteoporosis Research Unit, Malmö, SWEDEN

Introduction: Osteoporosis, as a comorbidity among patients with systemic sclerosis (SSc) is poorly described. The aim of this cross sectional case-control study was to investigate bone mineral density (BMD) and prevalence of osteoporosis in patients with SSc.

Material and Methods: We included 211 patients, 182 females and 29 males, with SSc and 506 controls, matched for age and sex, from the same catchment area in the very south of Sweden (female patients mean age (SD) 61.3 (12.9) and controls 62.1 (12.6), male patients mean age 62.2 (16.7) and controls 63.5 (15.5)). All participants underwent dual-energy X-ray absorptiometry (DXA). BMD (mg/cm²) and T-score were measured in lumbar spine L1-L4 and total hip. For patients, disease characteristics were obtained. Students T-test, one-way ANOVA or Chi-square test were used to compare groups and multiple regression for risk factors. Osteoporosis (T-score < -2.5) and osteopenia (T-score -1.0- -2.5) were defined using WHOs definitions.

Results: Female patients had significantly lower BMD than their controls; total hip 0.858 (SD 0.143) vs 0.927 (SD 0.144) (p<0.001) and spine 1.066 (SD 0.162) vs 1.108 (SD 0.192) (p=0.011). Total hip T-score mean difference between groups was -0.555 (95 % CI -0.756- -0.353). In younger women <45 years of age (SSc n=18, co n=38) the difference was even greater -0.928 (0.315) (p=0.005). The same tendency with lower BMD for patients was seen among males but did not reach significance, total hip (p=0.06) and femoral neck (p=0.065). Among females more than half had osteopenia (51.6%) and a further 16% had osteoporosis compared to 42.2% and 11% of the controls; (p=0.001). Just over half of male patients had low BMD (T-score <1.0) although only one had osteoporosis. In patients, we evaluated vascular and fibrotic features. Female patients with vascular features (finger ulcers or pitting scars and teleangectasias and NT-ProBNP >125) showed a significant lower BMD compared to those without (T-score mean -1.657 (0.987) vs. -1.058 (1.145)). Higher NT-pro-BNP alone showed positive association with lower BMD (adjusted for BMI and menopause). Features of fibrosis were not associated with BMD, ie there were no difference in BMD between patients with diffuse (17.6 % females and 31.0 % males) or limited disease or antibody status.

Conclusions: Female patients with systemic sclerosis have lower BMD and osteoporosis is more frequent than among controls. It seems to be pronounced even in young woman. Vasculopathy may be a risk factor for low BMD.

P.168

COMPARISON OF RADIOGRAPHIC AND ULTRASOUND EVALUATIONS OF THE HAND TO DECIPHER JOINT INVOLVEMENT IN SSC PATIENTS : A CROSS SECTIONAL STUDY

Marine Tas¹, Romain Lecigne¹, Nicolas Belhomme², François Robin³, Claire Cazalets², Guillaume Coiffier⁴, Alain Lescoat²

¹Department of Radiology, CHU Rennes, Rennes, FRANCE, ²Department of Internal Medicine and Clinical Immunology, CHU Rennes, Rennes, FRANCE, ³Department of Rheumatology, CHU Rennes, Rennes, FRANCE, ⁴Department of Rheumatology, CH Dinan, Dinan, FRANCE

Introduction: Attesting the existence of a specific Systemic sclerosis (SSc)-related synovial or tenosynovial involvement is challenged by concomitant joint involvement due to other causes such as osteoarthritis or overlap with rheumatoid arthritis. The primary objective of this study was to evaluate the prevalence and severity of radiographic abnormalities in the hands of patients with SSc, whether specific to SSc or not, and compare them with ultrasound findings (presence of synovitis/tenosynovitis) to discuss the existence of a specific SSc-related rheumatism. Secondary objectives included identifying potential independent risk factors for SSc-related tenosynovial and/or synovial involvement.

Material and Methods: This retrospective cross-sectional study included patients fulfilling the 2013 ACR/EULAR classification criteria for SSc who underwent both hand radiography and ultrasound (US) of the hand. Hand X-rays were evaluated by two radiologists, blinded from the results of clinical findings and US evaluation. US of the hand were performed by the same rheumatologists, to avoid inter-rater variability, who was blinded from the results of X-rays and clinical findings. US evaluation specifically recorded the presence of doppler positive (active) synovitis or tenosynovitis, and the presence of fibrotic tenosynovitis.

Results: 173 patients were included. Mean disease at the time of X-rays and US was 7.6 ± 7.9 years, 29.5% had diffuse SSc, 53% had osteoarthritis, 39.3% had acro-osteolysis, and 54.3% had calcinosis. Other joint manifestations (chondrocalcinosis or Hydroxyapatite) were only recorded in 12 patients. After exclusion of patients with poly-osteoarthritis and rheumatoid arthritis (RA), 15 patients had active synovitis or tenosynovitis, and 27 patients had active or fibrotic synovitis or tenosynovitis, confirming the existence of a specific SSc-related joint involvement. In multivariate analysis, after exclusion of patients with poly-osteoarthritis or rheumatoid arthritis, independent risk factors for synovitis or tenosynovitis (active or fibrotic) were the history of scleroderma renal crisis (OR=NA, p=0.043), male gender (OR=2.90 (1.08-7.76), p=0.034). In the same multivariable model, positivity for anti-centromere antibody was protective from SSc-related joint involvement (OR=0.189 (0.058-0.61), p=0.005).

Conclusions: The prevalence of osteoarticular lesions on hand X-rays directly or indirectly related to SSc is similar to those reported in the literature. This study contributes to demonstrating the existence of a distinct scleroderma-related rheumatism, independently from overlap with RA or from osteoarthritis. Independent risk factors for SSc-related joint involvement included male gender, history of renal crisis, and the absence of anti-centromere antibodies.

P.169

VARIABLES ASSOCIATED WITH THE HAND FUNCTIONING IN PATIENTS WITH SYSTEMIC SCLEROSIS

Patrycja Kaczmarek¹, Eugene J. Kucharz¹, Bartosz Miziolek², Magdalena Kopec-Medrek¹, Robert Pieczyrak¹, Przemyslaw Kotyla¹

¹Department of Internal Medicine, Rheumatology and Clinical Immunology, Medical University of Silesia, Katowice, POLAND, ²Department of Dermatology, Medical University of Silesia, Katowice, POLAND

Introduction: The hand involvement is a common manifestation of systemic sclerosis (SSc). Impaired hand functioning has a significant influence upon life qquality, and is resulted from a complex of pathological changes, including the skin and subcutaneous tissue fibrosis and calcinosis, fibrosis of tendons and other ligamental structures, vascular abnormalities associated with ischemic ulceration, amputations as well as joint contractures, arthritis and phalangeal bone resorption.

The study was designed to evaluate hand functional impairment in patients with SSc in relation to a number of factors.

Material and Methods: Forty-four patients with SSc (female 31, male 13) fulfilling ACR/EULAR 2013 classification criteria were investigated. Patients with previous injures of the hands, suffering from disease that may affect the hand functioning were excluded from the study.

Finger goniometry was used to mmeasure range of motion in the finger joints. Total active motion (TAM) was described as the sum of active MCP, PIP and DIP arc of motion in degrees of an individual digit. The handgrip strength test was applied to measure the maximum isometric strength of the hand and forearm muscles. Hand Mobility in Scleroderma (HAMIS) was performed. The test consists of 9 items designed to measure all movements assessed in an ordinary range of motion measurements. Measurement of fingertip to palm (FTP) was performed.

Results: Hand functioning was defective in the majority of SSc patients. Seventy-one per cent of the right hand and 67 per cent of fingers of the left hand had impaired range of motion. More than half of the patients was unable to perform pronation and supination of the forearm, abduction of the fingers. About 70 per cent presented impaired pincer grip, palmar flexion of the wrist and thumb abduction.

Defective hand functioning in various tests correlated with skin involvement measured with modified Rodnan skin scale. In male patients, the handgrip strength test correlated positively with the pulmonary functional test, total lung capacity, and forced vital capacity. Skin involvement in female patients only correlated negatively with the hand grip strength test. Some relationship between capillaroscopic pattern and range of movements of the third finger of the dominating hand was revealed.

Conclusions: Detailed evaluation of the hand functioning in patients with SSc may be considered as a sensitive test of the disease advancement, and is related mostly to cutaneous involvement and duration of the disease. Further studies on mutual relationship of the hand and lung manifestations are needed.

P.170

OSTEOLYSIS OF THE PARIETAL BONE IN A PATIENT WITH SYSTEMIC SCLEROSIS MIMICKING GORHAM-STOUT DISEASE

Jae-Bum Jun, Bon San Koo, Seunghun Lee

Hanyang University Hospital for Rheumatic Diseases, Seoul, SOUTH KOREA

Introduction: Systemic sclerosis is a rare connective tissue disease that is characterized by soft tissue fibrosis and vasculopathy. Osteolysis is also a feature of systemic sclerosis, and bone resorption can occur in the distal phalanx, causing acro-osteolysis, which leads to shortening or clubbing of fingers or toes, the mandible, and long bones. Gorham-Stout disease is a rare disease of unknown etiology in which massive osteolysis occurs due to proliferation of vascular or lymphatic vessels. It can affect both axial and appendicular skeleton.

Material and Methods: We present a patient diagnosed with diffuse cutaneous systemic sclerosis who developed osteolysis in the parietal bone of the skull, mimicking Gorham-Stout disease. The patient, a 67-year-old woman, initially presented 23 years ago with color changes and pain in the tips of the fingers. She was diagnosed with systemic sclerosis based on the presence of Raynaud phenomenon, positive anticentromere antibody, proximal scleroderma, and mild pulmonary hypertension. She also suffered from extensive calcinosis cutis. She has been treated with calcium channel blocker, aspirin, and D-penicilamine.

Results: On a recent visit, the patient complained that the skull bones were sinking. She had no previous history of trauma. On physical examination, the parietal bone area of the skull was dented when lightly pressed with the hand. There were no neurological abnormalities. Brain computed tomography showed focal skull thinning at both parietal bones and chronic subdural hematoma along right cerebral convexity and left parietal convexity (Figure 1).

Although osteolysis has been reported in various bone regions in patients with systemic sclerosis, there has been no report of osteolysis in the parietal bone of the skull. However, it has been reported that massive osteolysis occurs in the skull bone in Gorham-Stout disease. Considering that bone resorption may occur in systemic sclerosis, we diagnosed osteolysis related to systemic sclerosis rather than Gorham-Stout disease.

Conclusions: The patient was treated with supplementation of vitamin D and denosumab and instructed to avoid pressure or trauma to the head. There were no neurological symptoms other than parietal area pain. The patient will be monitored with computed tomography for the progression of bone resorption. Although it is very rare for patients with systemic sclerosis to complain of skull bone abnormalities, osteolysis of the skull bone should also be considered, as in this case.

P.171

INFLAMMATORY MYOPATHIES WITH CANCER

Anna Khelkovskaya-Sergeeva, Liudmila Garzanova, Rushana Shayakhmetova, Alena Kolomeychuk, Olga Koneva, Lidia Ananyeva, Anastasia Koltakova, Olga Ovsyannikova, Oxana Desinova, Mayya Shayakhmetova

V.A. Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: To describe the main characteristics of patients with inflammatory myopathies(IM) with cancer.

Material and Methods: The study included 33 (17.2%) patients with IM and cancer In a group of 191 patients. with IM, 33 patients (17.2%). Neoplasm was identified 3 years before, during the development of myositis, or within 3 years after. The mean age was 57 ± 12.7 years, there were 25 women (75.7%). The median disease duration was 3 [4;12] months. Median follow-up duration 9 months [3;18].

Results: Among patients with IM and cancer, dermatomyositis (DM) were in 21(64%) patients, polymyositis (PM) 7(21%), amyopathic DM-1(3%), systemic sclerosis overlap-myositis (SS-OM)-2(6%), antisynthetase syndrome (ASS)-1(3%), necrotizing myopathy-1(3%). Proximal muscle weakness had–32(97%). The median creatine kinase level was 1300 U/L [320-5000] (normal range 24-195 U), and CPK levels were normal in 3 patients (9%). Moderate dysphagia occurred in 18(54.5%)patients, and in 8(24%)-dysphagia was life-threatening. The main extramuscular manifestations were skin typical DM rash-23(79%), cutaneous vasculitis-21(24%)patients. Interstitial lung disease was detected in 4 patients (2 patients with SS-OM, 1 patient with ASS, 1-with DM). Arthritis was in 1 (3%) patient with ACC. 2 (6%) patients with SS-OM had Raynaud's syndrome. In 30 (90%) patients had high titer of ANA-HEp-2. Positive a-Ro antibodies had 3 (9%)patients, a-Jo-1 -1 ASS, a-RNP-1 and a-PM/Scl+++-1 in a patients SS-OM, a-SRP++-1. No myositis-specific antibodies were detected in other patients. A-TIF1 gamma and a-NXP antibodies were not evaluated. Localization of neoplasms: ovaries-7(21%), breast-8(24%), lungs-5(15%), colon-4(12%), bladder-2(6%), oropharynx-2(6%), stomach-2(6%), cervix-1(3%). The diagnosis of cancer preceded the development of symptoms of myositis in 7(21.1%) cases; during examination in patients with a newly diagnosed IM-19(57.5%), after a year or more it was detected in 7(21%). 11(33%) patients died. Of the 11 patients who died, 3 died from complications of dysphagia, 7 from tumor progression.

Conclusions: The main form of paraneoplastic IM was DM, less commonly - PM. ASS and SS-OM are rarely combined with cancer. Paraneoplastic IM(DM and PM) are characterized by a high incidence of dysphagia, including severe dysphagia, which, along with the presence of cancer, worsens the prognosis of the disease and requires immunosuppressive therapy. Also, patients with paraneoplastic DM are characterized by the development of severe cutaneous vasculitis. Paraneoplastic forms of IM are characterized by high mortality, both due to cancer and severity of IM.

P.172

ARTHROPATHY IN SYSTEMIC SCLEROSIS ON RITUXIMAB THERAPY DURING LONG-TERM FOLLOW UP

Liudmila Garzanova, Lidia Ananyeva, Olga Koneva, Olga Ovsyannikova, Oxana Desinova, Mayya Starovoytova, Rushana Shayakhmetova, Anna Khelkovskaya-Sergeeva

V.A. Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: Articular and tendon involvement in systemic sclerosis (SSc) could be one of the common manifestations of the disease and could significantly reduce the quality of life of patients. There is very few data on changes of the arthropathy manifestations (arthritis, arthralgia, contractures, etc.) in SSc on rituximab (RTX) therapy. The aim of our study was to assess the severity of joint involvement in SSc patients(pts) and its changes during RTX therapy in long-term follow-up.

Material and Methods: This study included 113 patients with SSc. Mean age was 48.1±13 years, female - 96 patients (85%). The mean disease duration was 6.1±5.4 years. The diffuse cutaneous subset of the disease had 62 patients, limited – 40, overlap – 11. All pts had interstitial lung disease (ILD). All patients received prednisolone at mean dose of 11.6±4.8 mg/day and 53 of them - immunosuppressants at inclusion. Patients received RTX due to the ineffectiveness of previous therapy for ILD. Parameters were evaluated over the periods: at baseline (point 0), 13±2.3 month (point 1), 42±14 month (point 2) and 79±6.5 month (point 3) after initiation of RTX therapy.

Results: There was an improvement of almost all outcome parameters on RTX therapy. Changes of evaluated parameters during RTX treatment are presented in the Table 1. There was a significant decrease in the number of pts with arthritis, arthralgias and tendon friction rubs (p=0.001). Number of pts with contractures didn't change. There was a significant decrease of morning stiffness (p=0,002). Acute phase parameters - ESR and C-reactive protein also improved - there was a significant decrease of both parameters in all points of follow-up (p=0.001). The dose of prednisolone was significantly reduced already at the first observation point and then continued to decrease towards the end of observation (p=0.001).

Conclusions: In our study, there was an improvement of joint involvement associated with SSc during long-term follow-up. The improvement of arthropathy was accompanied by a decrease in acute phase parameters (ESR and C-reactive protein). There was a significant reduce of the dose of glucocorticosteroids. RTX is effective option for treatment of arthropathy associated with SSc.

P.173

THE IMPACT OF LOW 25(OH) VITAMIN D LEVELS IN A PORTUGUESE POPULATION WITH SYSTEMIC SCLEROSIS

Mariana Diz Lopes¹, Raquel Miriam Ferreira¹, Carlos Marques Gomes¹, Inês Santos², Georgina Terroso¹, Teresa Martins Rocha¹, Lúcia Costa¹

¹Rheumatology Department, Centro Hospitalar Universitário de São João, PORTO, PORTUGAL, ²Rheumatology Department, Centro Hospitalar Tondela-Viseu, VISEU, PORTUGAL

Introduction: Suboptimal 25(OH) vitamin D (VD) levels have been associated with Systemic Sclerosis (SSc). This has been hypothesized to be related with cutaneous thickening, insufficient solar exposition, or gastrointestinal malabsorption. Portugal is one of the European Union countries with higher prevalence of hypovitaminosis D. Genetic polymorphisms have been identified as possible contributors. This study aimed to evaluate the VD levels in a portuguese population with SSc and its association with clinical and immunological features of the disease.

Material and Methods: Cross-sectional single-centre study with data extracted from Reuma.pt/SSc (the Portuguese national registry of SSc patients). Data included demographic information, clinical and immunological characteristics. All patients fulfilled the ACR/EULAR 2013 or ACR 1980 criteria for SSc.

Results: A total of 70 patients were included. The mean VD levels at diagnosis was (20,4±10,7). 17,1% patients had deficient VD levels (<10 ng/mL) and 70% insufficient (10-30 ng/mL). Almost all patients (80%) were under VD supplementation. Telangiectasias (52,9%), Raynaud phenomenon (97,1%) and esophageal dysmotility (50%) were the most common clinical features. The median modified Rodnan Skin Score (mRSS) was 5 (IQR 9,3).

Mean VD levels were lower in diffuse SSc type (11,8±5,9), but were insufficient in all disease subsets and the differences were not statistically significant (p=0,244). The median (IQR) mRSS was 5,5 (10) in the group with VD deficiency, 4 (9) in the group with insufficient VD levels and 7 (14) in the group with normal VD levels. No linear correlation was found between VD levels and mRSS values (r=-0,04, p=0,971).

Patients with suboptimal VD levels developed more frequently arthritis (p=0,023). Patients with articular involvement had lower mean VD levels (17,8±5,8 vs 21,9±12,5, p=0,295).

The patients with suboptimal VD levels had a higher incidence of telangiectasias, gastric and intestinal involvement, but these differences did not reach statistical significance. There was no correlation between vitamin D levels and other clinical features or autoantibody specificity (Table 1).

Conclusions: Suboptimal VD levels in SSc are highly prevalent (87,1%). In our study, the expression of VD deficiency was independent of the disease subtype. No correlation was found between VD and mRSS values. This suggests that cutaneous thickening may not be the main cause for VD insufficiency in SSc. VD insufficiency in SSc patients is associated with the development of arthritis and this can be related with the anti-inflammatory and immunomodulatory properties of VD. Further studies are needed to understand the impact of VD supplementation in articular involvement in SSc.

P.174

ASSESSMENT OF SARCOPENIA IN PATIENTS WITH SYSTEMIC SCLEROSIS: A MULTIDISCIPLINARY APPROACH

Alessandra Della Rossa, Marco Di Battista, Alessandra Rossi, Gaia Pisano, Mattia Da Rio, Elisabetta Bertolucci, Marta Mosca

Rheumatology Unit - University of Pisa, Pisa, ITALY

Introduction: Systemic sclerosis (SSc) is a complex connective tissue disease with a chronic course that heavily affects the functionality and quality of life of patients. Sarcopenia is an insidious complication of SSc, often poorly recognized and underdiagnosed, but difficult to manage and with important prognostic repercussions. We aimed to evaluate the prevalence of sarcopenia in a large cohort of SSc patients through a multiparametric characterization according to the diagnostic algorithm proposed by the EWGSOP2 consensus in 2019.

Material and Methods: Consecutive adult SSc patients were evaluated by a multidisciplinary team of rheumatologists, nutritionists and physiotherapists to identify the presence of sarcopenia. After completing the SARC-F questionnaire, generally used for the case finding, the patients' muscle strength was measured with the hand grip test and the 5-times sit to stand test (5STS) to identify patients with probable sarcopenia. Muscle quantity was then evaluated by the appendicular skeletal muscle mass (ASSM)/height ratio, a parameter from bioimpedance vector analysis (BIVA) which is a method also used to identify subjects with a state of malnutrition, thus eventually confirming the presence of sarcopenia. Finally, the severity of sarcopenia was assessed using the following physical performance tests: short performance physical battery (SPPB - composite score of balance tests, 4m linear walk and 5STS), time up and go (TUG - static and dynamic balance) and gait speed.

Results: 147 SSc patients (84% female, mean age 60.1 ± 15 years) were evaluated. Pathological SARC-F scores raised the suspicion in 23.3% of the cohort, whereas low muscle strength was observed in 46.9% and 42% of the hand grip and 5STS tests, respectively. All combined, 79 patients (53.7%) were identified as probably having sarcopenia. The ASSM/height ratio was found pathologically reduced in 26 of those patients, thus confirming sarcopenia in 17.7% of the cohort. Among them, physical performance tests highlighted the presence of severe sarcopenia in 15 cases (57.7%). In addition, BIVA found malnutrition in 35.8% of SSc patients, and this happened in combination with a sarcopenic state in 65.3% of cases. Malnourished subjects had significantly lower hand grip strength values (p<0.001), worse SPPB scores (p<0.001), and longer TUG times (p=0.01) (Figure 1).

Conclusions: Sarcopenia emerges as a relatively frequent and severe complication in SSc, with important repercussions on the physical-dynamic sphere and a deep interrelationship with nutritional status. A multidisciplinary approach is essential for an accurate diagnosis of sarcopenia in potentially high-risk individuals such as those with SSc.

P.175

SYSTEMIC SCLEROSIS-POLYMYOSITIS/DERMATOMYOSITIS-OVERLAP SYNDROME IN CLINICAL PRACTICE

Oxana Desinova, Mayya Starovoytova, Lidia P. Ananyeva, Olga Koneva, Liudmila Garzanova, Olga Ovsyannikova, Rushana Shayakhmetova

VA Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: Systemic Sclerosis (SSc) overlap syndromes not very well studied clinical variants of SSc that are characterized by certain clinical and immunological features. Systemic Sclerosis-polymyositis/dermatomyositis overlap syndrome (SSc-PM/DM) occurs in 10 to 37% of cases and has great differential diagnostic difficulties.

Material and Methods: Identify clinical and immunological features of the SSc-PM/DM overlap syndrome. 80 pts with SSc-PM/DM pts undergoing standard clinical examination and laboratory immunological evaluation.

Results: ANA Hep2 was positive in 98% of SSc-PM/DM pts; a-Scl-70 was in 34%, a - PM-Scl and RF were in 20%. ACA (6%), a-RNP (9%), and a - Jo-1 (5%) were significantly less common. Correlation analysis showed significant prevalence of conduction abnormalities in pts with a-Scl-70- (p<0.03); PM-Scl was rarely associated with cardiac arrhythmia (p<0.02) and pericarditis (p<0.03), but there was an association between ACA and presence of digital ischemia (p<0.04). Three pts with limited skin had Scl-70 and PM-Scl antibodies, two of them manifested clinical features of DM. A-Jo-1 was found in 3 pts with a longstanding disease (14,10 and 7 years), and one of these pts was also positive for a-Scl-70. All pts had limited skin and two had interstitial lung disease with FVC less 80% (79% and 74.8%).

Conclusions: Laboratory findings display specific pathogenetic features of SSc-overlap syndromes; laboratory abnormalities can be used to measure the activity and specify characteristics of the pathological process.

P.176

CHEST WALL MUSCLE AREA AND EXERCISE CAPACITY IN SYSTEMIC SCLEROSIS

Amalia Colalillo¹, Nicola Galea², Chiara Pellicano¹, Emanuele Possente¹, Gregorino Paone³, Antonella Romaniello⁴, Maurizio Muscaritoli¹, Edoardo Rosato¹, Antonietta Gigante¹

¹Department of Translational and Precision Medicine, Sapienza University of Rome, ROME, ITALY, ²Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, ROME, ITALY, ³Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic, Geriatric Sciences, Sapienza University of Rome, ROME, ITALY, ⁴Division of Cardiology, Sant'Andrea Hospital, Sapienza University of Rome, ROME, ITALY

Introduction: Cardio-pulmonary exercise testing (CPET) has been used in systemic sclerosis (SSc) to establish the etiology of breathlessness. CPET defines maximum exercise capacity through measurement of maximum rate of oxygen consumption in one minute (VO2 max) and its evaluation during a maximal symptom limited CPET is the most proven method to assess functional capacity. VO2 max is an important predictor of prognosis in patients with heart failure and is influenced by other factors not related to cardiac involvement such as gender, age and muscle mass. In SSc patients without pulmonary involvement has been demonstrated that reduced exercise capacity was probably due to abnormal reduced skeletal muscle blood flow. Respiratory muscles and joints may also be primarily affected by SSc, and the resulting hypotrophy of the chest wall muscles may have a role on the exercise tolerance. The aim of the study was to investigate the potential contribution of chest wall muscle area (CWMA) to the exercise capacity assessed by CPET in a cohort of SSc patients without interstitial lung disease (ILD).

Material and Methods: This single-center, retrospective study enrolled consecutive SSc patients without ILD [forced vital capacity (FVC)>80%, diffusing capacity for carbon monoxide (DLco)>60% and no radiological signs of ILD]. CPET was used to assess VO2 max (ml/min) in all SSc patients. The CWMA (cm2) was evaluated at the level of the ninth thoracic vertebra on CT images. The Pearson or Spearman correlation test was used for bivariate correlations. Multiple regression analysis was performed to evaluate correlations between dependent variables (VO2 max) and independent variables [age, body mass index (BMI), DLco, aystolic pulmonary artery pressure (sPAP) and CWMA].

Results: Forty-four consecutive SSc patients [median age 53.5 years (IQR 43.5-58), 37 (84.1%) female, 22 (50%) diffuse cutaneous SSc, median disease duration 9.5 years (IQR 5.5-15)] were enrolled in this study. Median CWMA was 43.9 cm2 (IQR 36.8-56.5) and median VO2 max was 1211 ml/min (IQR 1028.5-1451). A statistically significant positive correlation was found between CWMA and VO2 max (r=0.380, p<0.01). In multiple regression analysis, VO2 max was significantly associated with CWMA [Beta coefficient=0.527 (95% CI: 2.824, 7.628); p<0.001], DLco [Beta coefficient=0.305 (95% CI: 1.460, 12.039); p<0.05] and BMI [Beta coefficient=0.326 (95% CI: 8.802, 74.161); p<0.05].

Conclusions: In SSc patients without ILD, CWMA is an important variable in exercise capacity and can be evaluated by the mediastinal window available in the HRCT images required for lung disease staging.

P.177

OSTEOPOROSIS IN SYSTEMIC SCLEROSIS: A SINGLE CENTER STUDY OF RISK FACTORS. A POSSIBLE ROLE FOR BONE-VASCULAR AXIS?

Marius Cadar¹, Davide Mohammad Reza Beigi¹, Greta Pellegrino², Ilaria Bisconti¹, Franecesca Roman Di Ciommo¹, Jacopo Landro¹, Elena Platania¹, Simona Truglia¹, Fabrizio Conti¹, Valeria Riccieri¹

¹Sapienza University of Rome - Clinical Internal, Anesthesiological and Cardiovascular Sciences, Rome, ITALY, ²IRCCS Ospedale Galeazzi - Sant'Ambrogio, Milan, ITALY

Introduction: Systemic sclerosis (SSc) is a rare and progressive autoimmune disease, that has been associated with an increased risk of osteoporosis (OP), but well defined risk factors are still debated. The aim of our study was to investigate possible risk factors for osteoporosis in SSc and to evaluate if any feature of the disease could increase the risk of osteoporosis.

Material and Methods: In this cross-sectional study we included 104 consecutive patients, fulfilling the 2013 ACR/EULAR classification criteria of SSc, attending our Rheumatology Unit from July 2022 to July 2023. All the patients performed a Dual-energy X-ray absorptiometry (DXA) between 2020 and 2023. Osteoporosis was defined as a T score less than -2.5 SD and osteopenia as a T-score between -1.0 and -2.5 SD. We divided patients in two groups according to the diagnosis of osteoporosis (OP+) and non-osteoporosis (OP-), including osteopenia. We collected the main clinical-demographic, instrumental and laboratory features of the patients and we looked for any association with OP.

Results: Of 104 patients, 103 were women with a mean age (mean±SD) of 69.0±10.1 years, 66 had a diagnosis of osteoporosis (OP+ group) and 38 patients were included in the OP- group, in which 19 patients had osteopenia. The two groups were comparable for BMI, disease duration, menopause presence and smoking habit. We found statistically significant differences between the two groups for age (p=0.03), modified Rodnan Skin Score (mRSS) (p=0.004), and presence of NVC scleroderma pattern (NVC SP) (p=0.02), pulmonary hypertension (p=0.02), calcinosis (p=0.04) and telangiectasia (p=0.02). We found a positive correlation among OP and mRSS (r= 0.29, p= 0.003), calcinosis (r= 0.20, p= 0.04), telangiectasia (r= 0.21, p= 0.03) and presence of NVC SP (r= 0.23, p= 0.02). There was no difference between the two groups as regards autoantibodies, digital ulcers and ILD.

Conclusions: This retrospective study confirms the traditional association of OP with an older age. We also found an increased mRSS and the presence of calcinosis, of pulmonary hypertension, telangiectasias and NVC scleroderma pattern associated to OP in our patients. These SSc features underline the importance of an early evaluation of bone health and an early referral to DXA in our patients, independently from the traditional risk factors of OP. Of interest in our opinion is the rather high prevalence of calcinosis and vascular involvement (identified by telangiectasias, NVC SP and PH) in the OP+ group, suggesting a possible role of bone-vascular axis in the development of OP in our patients.

P.178

SPINAL CALCINOSIS IN SCLERODERMA PATIENTS, SEVERE MORBIDITY AND DANGEROUS ALARM

Alexandra Balbir-Gurman¹, Daniela Militianu², Natali Puchkov², Vika Vika Shataylo³, Yolanda Braun-Moscovivi¹

¹Rheumatology Institute, Rambam Health Care Campus, The Rappaport Faculty oif Medicine, Technion, Haifa, ISRAEL, ²Musculo Skeletal Unit, Division of Imaging, Rambam Health Care Campus, The Rappaport Faculty of Medicine-Technion, Haifa, ISRAEL, ³Rheumatology Institute, Rambam Health Care Campus, Haifa, ISRAEL

Introduction: About 23-25% of Systemic sclerosis (SSc) patients develop subcutaneous or soft tissue calcinosis, in some patients calcified mass are seen occasionally on imaging performed for various indications; in other, tumoral calcinosis occur in sensitive areas such as spinal cord (paraspinal and intraspinal calcinosis) and may cause pain and neurologic complications of various severity. We aimed to analyze clinical features of spinal calcinosis (SpC).

Material and Methods: We conducted a retrospective analysis of SSc patients' files with information on cervical, thoracic and lumbar spine (CT or PET FDG or MRI) imaging kept in the Rambam electronic archive. All images were assessed by senior rheumatologist (ABG, YBM) and imaging musculo-skeletal imaging specialist (DM, NP). Presence of paraspinal and/or intraspinal calcinosis was correlated with clinical parameters and outcome. Statistics included Student's T-test and Pearson's chi-squared test ( p<0.05, significant).

Results: Among 261 SSc patients (male 18.8%, age 60.4 [SD11.6] and disease duration 12.3 [SD7.8] years), 29 (11.1%) patients had at least one paraspinal and 18 (6.9%) - intraspinal calcinosis. Distribution of calcinosis was: cervical 10/60 (16.7%) - paraspinal and 9/60 (15%) - intraspinal (C2,3,4,5), thoracic - 20/243 (8.2%) paraspinal and 7/243 (2.9%) - intraspinal (D6,7,11,12), lumbar - 10/39 (25.6%) paraspinal and 8/39 (20.5%) intraspinal (L1-4); 39 patients had imaging of the whole spine. There was not statistical difference in age, sex, disease duration, incidence of lung cancer, aortic stenosis and myositis between patients with and without SpC; 17/29 (58.6%) of SpC patients died compared to 88/232 (37.9%) without (p<0.0306). Patients with SpC cared more ATA (19/29 [65.5%] versus 81/212 [38.2] and less ACA (3/19 [10.3] versus 66/212 [31.1]) antibodies. Hands calcinosis and acroosteolysis and soft tissue (except hands) calcinosis were more often in patients with spinal calcinosis: 12/19 (63.2%) versus 42/137 (30.7%) p<0.009, 17/19 (89.5%) versus 56/138 (40.6%), p<0.001, and 22/28 (78.6%) versus 38/196 (19.4%) p<0.001, accordingly; 5 patients with spinal calcinosis had severe acroosteolysis of large bones (2 -mandibula and one clavicula, humerus and hip head each). Eight (27.6%) patients with intraspinal calcinosis had severe pain and myelopathy, four underwent surgery (1 - cervical and 3 lumbar; one patient dead shortly after surgery from urosepsis).

Conclusions: In SSc patients, SpC is associated with severe bone and soft tissue damage (extraspinal calcinosis and acroosteolysis), severe neurologic morbidity and consequences such as neurosurgery and high mortality. SpC lesions could be observed on routine imaging, awareness on SpC is important particularly in patients with neuro-symptoms.

P.179

THE EVALUATION OF CLINICAL CALCINOSIS CUTIS IN SYSTEMIC SCLEROSIS: CLINICAL CHARACTERISTICS AND RISK FACTORS FROM THE EUROPEAN SCLERODERMA TRIAL AND RESEARCH GROUP (EUSTAR) DATABASE

Aslihan Avanoglu Guler¹, Michael Hughes², Giacomo De Luca³, Silvia Bellando Randone⁴, David Launay⁵, Anna Wojteczek⁶, Simona Rednic⁷, Emmanuel Chatelus⁸, Alexandra Balbir-Gurman⁹, Paolo Airò¹⁰, Ulf Muller-Ladner¹¹, Petros P Sfikaki¹², Luca Idolazzi¹³, Nicoletta Del Papa¹⁴, Oliver Distler¹⁵, Marie Elise Truchetet¹⁶, Madelon C Vonk¹⁷, Francesco Del Galdo¹⁸, Marco Matucci-Cerinic⁴, Corrado Campochiaro³

¹Department of Internal Medicine, Division of Rheumatology, Gazi University Hospital, Ankara, TURKEY, ²Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Manchester, UNITED KINGDOM, ³Unit of Immunology, Rheumatology Allergy and Rare diseases, IRCSS San Raffaele Hospital, Milan, ITALY, ⁴Division of Rheumatology, Department of Experimental and Clinical Medicine, University of Florence, Florence, ITALY, ⁵Department of Internal Medicine and Clinical Immunology, CHU Lille, Lille, FRANCE, ⁶Department of Internal Diseases, Connective Tissue Diseases and Geriatrics, Medical University of Gdansk, Gdansk, POLAND, ⁷Department of Rheumatology, Emergency County Teaching Hospital, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, ROMANIA, ⁸Rheumatology, Hôpitaux universitaires de Strasbourg, Strasbourg, FRANCE, ⁹Rheumatology Institute, Rambam Health Care Campus, The Rappaport Faculty of Medicine, Technion, Haifa, ISRAEL, ¹⁰Rheumatology and Clinical Immunology, Spedali Civili of Brescia, Brescia, ITALY, ¹¹Justus Liebig University Giessen, Department of Rheumatology and Clinical Immunology, Campus Kerckhoff, Bad Nauheim, GERMANY, ¹²Joint Academic Rheumatology Program, National and Kapodistrian University of Athens Medical School, Athens, GREECE, ¹³Section of Rheumatology, Department of Medicine, University of Verona, Verona, ITALY, ¹⁴Clinical Rheumatology Unit, ASST Pini-CTO, Department of Clinical Science and Community Health, Milan, ITALY, ¹⁵Department of Rheumatology, University Hospital Zurich, Zurich, SWITZERLAND, ¹⁶Rheumatology Department, Bordeaux University Hospital, Bordeaux, FRANCE, ¹⁷Department of Rheumatology, Radboud University Medical Center, Nijmegen, THE NETHERLANDS, ¹⁸Faculty of Medicine and Health, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UNITED KINGDOM

Introduction: Calcinosis Cutis (CaC) represents one of the most frequent manifestations in systemic sclerosis (SSc). We aimed to determine the association between CaC and SSc-related clinical features and risk factors associated with the development of CaC in SSc patients.

Material and Methods: SSc patients registered in the EUSTAR database and with available information about their CaC status were included. First, we compared the characteristics of patients with and without CaC at baseline, then we analyzed the predictors of CaC development at 5 years in those without CaC at baseline. Logistic regression analyses were used and data were reported as odds ratio and 95% confidence interval.

Results: 7114 SSc patients with available CaC status were included. The mean age of patients was 57.2 ±13.5 years and the majority (83.8%) were female. 11.9% of SSc patients had CaC at baseline evaluation. Compared to those without CaC, patients with CaC were more frequently female, had a longer disease duration, a higher modified Rodnan Skin Score (mRSS), telangiectasia, digital ischemic findings (digital ulcers, gangrene, and amputation), a late capillaroscopy pattern, joint contractures, tendon friction rubs, and gastrointestinal involvement (all p<0.001), pulmonary arterial hypertension (PAH) (p=0.02), joint synovitis, and renal crisis (both p=0.04). Moreover, the sine scleroderma subset was less frequently associated with CaC (p<0.001). Anticentromere and anti PM/Scl antibody positivity were more frequent in patients with calcinosis (p<0.001; p=0.03 respectively) while anti-Scl-70 positivity was significantly higher in patients without Cac (p<0.001) (Table 1). The evaluation of patients without CaC (n=1008), who had recorded data for the first five years of follow-up after baseline visit, demonstrated that 403 patients (40%) developed calcinosis. Multivariate regression analyses showed that independent predictors for the development of CaC were longer disease duration (OR:1.04 [%95 CI:1.025-1.061]), increased mRSS (OR:1.03 [%95 CI:1.01-1.05]), presence of heart involvement (OR: 1.95 [%95 CI:1.26-3.02]), interstitial lung disease (ILD) (OR:1.48 [%95 CI:1.08-2.03]), PAH (OR:2.32 [%95 CI:1.23-4.36]), and telangiectasia (OR:1.94 [%95 CI:1.40-2.66]). The presence of digital ulcers or digital ulcer history (OR:3.24 [%95 CI: 2.39-4.37]) and late capillaroscopic pattern (OR:2.66 [%95 CI:1.64-4.31]) were the strongest risk factors for CaC development in the first five years after baseline visit (Table 2).

Conclusions: The incidence of clinical CaC was 11.9% in SSc patients at baseline. CaC was associated with significant organ involvements such as ILD, PAH, and cardiac involvement. The most remarkable risk factors for the development of CaC were the presence of digital ulcers and late capillaroscopic pattern.

P.180

DEVELOPING A COMPOSITE PHARMACODYNAMIC SERUM MARKER OF SKIN SEVERITY IN SYSTEMIC SCLEROSIS

Elen Roblin, Kristina Clark, Claire Beesley, Voon Ong, Christopher Denton

Centre for Rheumatology and Connective Tissue Diseases, Division of Medicine, UCL, London, UNITED KINGDOM

Introduction: Previously, through multilevel and high dimensional analysis, we derived a composite biomarker for modified Rodnan Skin Score (mRSS) in systemic sclerosis (SSc) patients using a derivation cohort (BIOPSY). This identified 4 blood proteins (COMP, COL4A1, TNC and SPON1) that independently correlated with mRSS and also with skin gene and dermal blister expression at a separate 12-month timepoint. These proteins likely reflect overlapping aspects of SSc skin pathobiology that are not overly influenced by other disease compartments. In the present study, we undertake technical and biological validation of this novel composite marker in well characterised SSc patients.

Material and Methods: COMP (DCMP0, R&D Systems), COL4A1 (CSB-EL005741HU, Cusabio), TNC (ab213831, Abcam) and SPON1 (CSB-EL022599HU, Cusabio) were examined in serum samples from diffuse cutaneous SSc (dcSSc) cases in two independent cohorts of patients, BIOPSY (n=33) and MODERNISE (n=37). The BIOPSY cohort was previously used to derive the composite marker and MODERNISE was a novel validation cohort. Later, early dcSSc patients from both cohorts were combined into a third analysis group (n=36). Six samples exceeded measurable serum concentration of COL4A1 and were allocated maximum readable concentration (200ng/ml). Multiple regression analysis derived a formula for a composite biomarker score which predicted mRSS based on serum ELISA protein concentration.

Results: In general, serum concentration of COMP, COL4A1 and TNC positively correlated with mRSS, particularly in early diffuse cutaneous systemic sclerosis patients (r=0.10, p=0.05; r=0.08, p=0.09; r=0.13, p=0.03 respectively). Interpretable data could not be obtained for SPON1 due to technical limitations of the ELISA. Multiple regression analysis derived a formula for the prediction of mRSS using the three remaining serum proteins(r=0.19, p=0.001):

mRSS = 8.311 + 0.01731(COMP) + 0.02382(COL4A1) – 0.04121(TNC).

Patients receiving mycophenolate mofetil showed numerically lower serum concentrations of COMP (p=0.16), COL4A1 (p=0.13), TNC (p=0.15) and a lower composite biomarker score (p=0.28) with increasing treatment duration in early dcSSc cases (Figure 1).

Conclusions: Our results highlight promising trends for a three-protein composite serum assay assessing skin severity in SSc. Whilst further validation with additional samples is necessary, this blood-based approach may have potential for evaluating treatment response to standard immunosuppression. Further work will establish utility of this composite measure as a predictive or prognostic biomarker.

P.181

SERUM LIPOPOLYSACCHARIDE-BINDING PROTEIN (LBP) IS ASSOCIATED WITH DIGITAL ULCERS (DUS) IN SYSTEMIC SCLEROSIS (SSC) PATIENTS

Chiara Pellicano¹, Alessandra Oliva², Amalia Colalillo¹, Elisa D'alesio², Claudio Maria Mastroianni², Edoardo Rosato¹

¹Department of Translational and Precision Medicine, Sapienza University of Rome, ROME, ITALY, ²Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy, ROME, ITALY

Introduction: Digital ulcers (DUs) represent a severe complication in Systemic sclerosis (SSc) and are significantly associated with reduced quality of life and disability. The key pathophysiological factors driving DUs encompass ischaemia-reperfusion injury, endothelial dysfunction and platelet activation with fibrin deposition. Low-grade endotoxemia may be implicated in the thrombotic complications of SSc, which is characterized by a chronic low-grade inflammation state, possibly due to dysbiosis and microbial translocation. Circulating levels of lipopolysaccharide (LPS) induces production of lipopolysaccharide-binding protein (LBP), a well-known marker of microbial translocation. The aim of this study was to evaluate LBP levels in SSc patients and in healthy controls (HC) and to correlate LBP levels with the development of DUs.

Material and Methods: Sixty consecutive SSc patients, fulfilling the 2013 ACR/EULAR classification criteria for SSc, and 20 HC were enrolled and tested for serum levels of LBP using an ELISA kit. Nailfold videocapillaroscopy (NVC) pattern, disease activity index (DAI), disease severity scale (DSS), modified Rodnan skin score (mRSS) and the presence of DUs were assessed. Patients with severe cardiac/hepatic/renal failure, diabetes, peripheral vascular disease, coagulopathy or concomitant infectious diseases were excluded. We also excluded smokers, pregnant or breastfeeding women and patients treated in the last 6 months with immunosuppressive agents and corticosteroids at an equivalent dose of prednisone more than 10 mg/day.

Results: SSc patients had a median age of 56 years (IQR 49-63) with a median disease duration of 13 years (IQR 7-19) and were predominantly female (81.7% vs 18.3%). 27 (45%) SSc patients had limited cutaneous (lc) SSc and 33 (55%) had diffuse cutaneous (dc) SSc, with a median mRSS of 12 (IQR 7-20). Early NVC pattern was early for 9 (15%) patients, active for 16 (26.7%) patients and late for 35 (58.3%) patients. Median DAI and DSS were 2.3 (IQR 1.2-3.8) and 6 (IQR 4-9), respectively. DUs were present in 25 (41.7%) SSc patients. LBP was significantly higher in SSc patients than in HC [10745 ng/ml (IQR 9138-13620) vs 7839 ng/ml (IQR 6194-9256); p<0.001]. SSc patients with active DUs showed higher LBP than patients without DUs [13710 ng/ml (IQR 11090-15630) vs 10160 ng/ml (IQR 8030-10980), p<0.001]. We found a positive linear correlation between serum LBP and DAI (r=0.447; p<0.001). Finally, LBP was independently associated with DUs at multivariable analysis [OR 1 (95% CI 1-1.001), p<0.01].

Conclusions: SSc patients had increased level of marker of microbial translocation compared to HC and LBP was independently associated with DUs.

P.182

PREVALENCE OF CYP2C19 AND CYP3A5 POLYMORPHISMS IN THAI SYSTEMIC SCLEROSIS WITH GASTROESOPHAGEAL REFLUX DISEASE

Tippawan Onchan¹, Patnarin Pongkulkiat¹, Chingching Foocharoen¹, Ajanee Mahakkanukrauh¹, Siraphop Suwannaroj¹, Suda Vannaprasaht^2,3

¹Division of Rheumatology, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, THAILAND, ²Division of Toxicology, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, THAILAND, ³Division of Pharmacology, Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, THAILAND

Introduction: Proton pump inhibitors (PPIs) are a standard therapy for gastroesophageal reflux disease (GERD) in systemic sclerosis (SSc), with varying clinical responses to the treatment. Omeprazole is a PPI primarily metabolized by cytochrome P450 2C19 (CYP2C19) and CYP3A family. Since there has been no genetic background study of Thai SSc conducted, genetic polymorphism studies in the SSc population may contribute to the advancement of precision medicine for therapeutic management. This study aims to investigate the prevalence of CYP2C19 and CYP3A5 genetic polymorphisms in Thai SSc with GERD.

Material and Methods: A descriptive study was conducted on adult SSc patients with GERD who received omeprazole at the Scleroderma clinic, Khon Kaen University, Thailand. Blood samples were collected from patients who provided consent for genetic analysis. The genotypes of CYP2C19 was categorized into CYP2C19*1, *2, *3, and *17 allele frequencies, while CYP3A5 included CYP3A5*1, and *3. The phenotypes of CYP2C19 were divided into normal metabolizer (NM), intermediate metabolizer (IM), poor metabolizer (PM), and ultra-rapid metabolizer (URM), while CYP3A5 had NM, IM and PM phenotypes. The allele frequencies were analyzed for Hardy-Weinberg equilibrium, and differences in allele prevalence were compared using Pearson’s Chi-square test or Fisher’s exact test, along with p-value.

Results: A total of 197 SSc patients were included, with a total of 394 individual alleles (N=394). The allele frequencies for CYP2C19 were 279 (70.8%), 96 (24.4%), 16 (4.0%), and 3 (0.8%) for CYP2C19*1, *2, *3, and *17, respectively. There were no significant differences in CYP2C19 allele frequencies among the Thai population (p = 0.572). The CYP3A5*3 mutant allele frequency in Thai SSc patients was approximately 62%. The CYP2C19 phenotypes were NM (48.7%), IM (36.6%), PM (5.1%), and URM (1.5%), while CYP3A5 phenotypes were NM (18.4%), IM (39.3%), and PM (42.4%).

Conclusions: The predominant CYP2C19 phenotype was NM, while CYP3A5 was primarily PM. Genetic polymorphisms of CYP2C19 and CYP3A5 were observed among Thai SSc patients. This genetic study can provide valuable background information for further investigations into clinical correlations and precision medicine among SSc patients.

P.183

PREDICTORS OF PERSISTENT DISEASE ACTIVITY AND DAMAGE IN SYSTEMIC SCLEROSIS: DATA FROM A MONOCENTRIC COHORT

Beatrice Moccaldi¹, Marco Binda¹, Salvatore Prete¹, Andrea Martini², Maria Favaro¹, Andrea Doria¹, Elisabetta Zanatta¹

¹Rheumatology Unit, Department of Medicine (DIMED), Padova University Hospital, Padova, ITALY, ²Division of Internal Medicine and Hepatology, Department of Medicine (DIMED), Padova University Hospital, Padova, ITALY

Introduction: The concepts of “disease activity” and “damage” have recently been defined in systemic sclerosis (SSc), with the creation of composite indices. Our primary aim was to identify predictors of persistent disease activity and moderate-severe damage in our monocentric SSc cohort; our second aim was to evaluate the mortality rate in our cohort and the impact of persistent disease activity and moderate-severe damage on mortality.

Material and Methods: This is a retrospective observational cohort study carried out on prospectively collected data. Adult SSc patients (ACR/EULAR 2013 criteria) with a disease duration < 10 years from our monocentric cohort were enrolled in the study. Clinical and serological findings, organ involvement and clinimetric indices were evaluated at baseline and at each follow-up visit. Disease activity was evaluated by European Scleroderma Trials and Research group Activity Index (EUSTAR-AI), severity by Medsger severity scale (MSS) and damage by Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI). Active disease was defined as EUSTAR-AI >/= 2,5, persistent disease activity as EUSTAR-AI >/= 2,5 in more than 50% of follow-up visits and moderate-severe damage as SCTC-DI >/= 6.

Results: 101 SSc patients were enrolled and followed up for a median time of 3 years. 19 (18.8%) showed persistent disease activity over time; diffuse cutaneous subset (dcSSc), interstitial lung disease (ILD) with lower lung volumes, erythrocyte sedimentation rate (ESR), MSS and SCTC-DI values at baseline were associated with persistent disease activity; anticentromere antibodies (ACA)-positive patients were more frequently persistently inactive. ESR values (OR 1.08, 95% CI 1.03 – 1.15), MSS (OR 1.52, 95% CI 1.04 – 2.21) and SCTC-DI values (OR 1.36, 95% CI 1.03 – 1.78) at baseline were independent predictors of persistent disease activity. Patients with moderate-severe damage at the end of follow-up (13.8%) showed a higher prevalence of dcSSc, ILD with lower lung volumes and pulmonary arterial hypertension (PAH) with higher systolic pulmonary arterial pressure (sPAP) on echocardiography at baseline; they also had higher MSS values at baseline. Total lung capacity (TLC) values (OR 0.93, 95% CI 0.87 – 0.98) and sPAP values (OR 1.13, 95% CI 1.02 – 1.25) were independent predictors of moderate-severe damage at the end of follow-up. A correlation was observed between both persistent disease activity (p=0.0138) and moderate-severe damage at the end of follow-up (p<0.001) and mortality.

Conclusions: Identifying predictors of disease activity persistence and damage accrual at baseline may help identify at-risk patients who require prompter treatment and give additional prognostic information.

P.185

COHORT TO ASSESS PATHOPHYSIOLOGY OF FATIGUE, POST-EXERTIONAL MALAISE AND FURTHER SYMPTOMS OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME IN SYSTEMIC SCLEROSIS

Hanna Grasshoff, Moritz Jaegemann, Konstantinos Fourlakis, Sophie Biedermann, Tanja Lange, Gabriela Riemekasten

Department of Rheumatology and Clinical Immunology, UKSH Lübeck/University of Lübeck, Lübeck, GERMANY

Introduction: Fatigue is a frequent symptom in systemic sclerosis (SSc) occurring early in disease development. Fatigue is characterized by physical or mental exhaustion interfering with an individual's ability to perform at normal capacity. Compared to fatigue, there are only few studies assessing the frequency of Post-Exertional Malaise (PEM) in patients with SSc. PEM is the key symptom in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Currently, the frequency of further symptoms of ME/CFS has not been investigated in patients with SSc. Moreover, the underlying pathophysiology of PEM and ME/CFS has not been elucidated. As fatigue, PEM and further symptoms of ME/CFS cause severe socio-economic consequences and limit individual’s capacity to perform everyday tasks, we assume an urgent unmet medical need to investigate the underlying pathophysiology of these symptoms and subsequently develop targeted therapies. With this study we aim to assess the frequency of fatigue, PEM and further symptoms of ME/CFS in patients with SSc. Based on the described cohort, we plan further analyses to enable stratification of patients according to their underlying pathophysiology.

Material and Methods: In this study, we included 168 patients with SSc fulfilling ACR criteria 2013. The frequency of fatigue was assessed using either Chalder Fatigue Scale (n=96) or FACIT-F questionnaire (n=44). The occurrence of PEM and further symptoms of ME/CFS was investigated by assessing the DePaul Symptom Questionnaire (n=124) and Canadian Consensus Criteria (n=67), respectively. Patients were characterized regarding demographic and clinical parameters according to parameters assessed by EUSTAR database.

Results: Assessed by Chalder Fatigue Scale 56.3% of patients reported fatigue. PEM criteria according to DePaul Symptom Questionnaire were fulfilled by 37.1% of patients. None of the patients met the diagnostic criteria for ME/CFS. Nevertheless, the patients reported a frequent presence of further symptoms of ME/CFS. The most common symptoms reported were temperature intolerance (64.2%), thirsty sleep disturbances (58.2%) and joint pain (47.8%). Moreover, 55.2% of patients reported stress intolerance with subsequent exacerbation of fatigue.

Conclusions: The underlying pathophysiology of fatigue, PEM and further symptoms of ME/CFS might be heterogenous. The basis for targeted treatment development for these disease symptom is to stratify patients according to their underlying pathophysiology. As evidence supports the involvement of autoantibodies directed to G-protein coupled receptors in several disease manifestations in SSc, we plan to measure the levels of these autoantibodies in the described cohort and perform functional analyses. In addition, further analyses including alterations in mitochondrial signature or tryptophane metabolism are planned.

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THE ROLE OF SERUM FERRITIN LEVEL IN PREDICRION OF MAJOR SSC COMPLICATIONS AND MORTALITY

Alexandra Balbir-Gurman¹, Shirley Markovich Sholomon², Yolanda Braun Moscovici¹

¹Rheumatology Institute, Rambam, Health Care Campus, Rappaport Faculty of Medicine-Technion, Haifa, ISRAEL, ²Rappaport Faculty of Medicine-Technion, Haifa, ISRAEL

Introduction: Systemic sclerosis (SSc) has various clinical features such as skin thickening, microangiopathy and ischemic changes in tissues, and fibrosis of internal organs (lungs, heart, kidneys, and gastro-intestinal tract) and skin. In patients with early diffuse SSc inflammatory component may be prominent in skin (induration), joints, muscles, and peri/myocardium. Acute phase reactants (APR) such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) replicate the degree inflammation in many inflammatory conditions (RA, SLE, dermatomyositis, vasculitis, thyroiditis, infections, etc.). Ferritin is a protein bound to iron; its reduced levels correlate with iron deficiency and/or anemia. From other site, high ferritin levels reflect inflammatory activity in various inflammatory diseases such as Still's disease, SLE, dermatomyositis, pulmonary fibrosis, severe COVID-19, vasculitis, but also and non-inflammatory tissue damage, thromboembolic complications, and metastatic cancer. The possible role of ferritin in SSc as APR is unclear.

Material and Methods: To analyze if ferritin levels can reflect the severity of SSc and predict the disease outcome. We conducted a retrospective analysis of SSc patients' files with information on serum ferritin level (ferritin >300 mg/dL defined as elevated) treated at the Rambam Rheumatology Institute in the years 2004-2022. Patients' demographic, clinical, laboratory, imaging, and respiratory function data were collected from electronic hospital files. Statistics included Student's T-test, Pearson's chi-squared test, and Kaplan-Meier curve; statistical significance was determined as p<0.05.

Results: Among 241 files, 36 patients (FerH-SSc) had elevated ferritin; the rest (n=205) had normal ferritin levels and comprised the control group (FerN-SSc). We revealed significant differences in gender (male 44.4% - 15.6%), disease duration (4.6 - 7.7 years), modified Rodnan skin score (12.3 - 6.9), incidence of ILD (65.7% - 38.7%), cardiomyopathy (51.4% - 21.1%), and kidney (28.6% - 5.9%) involvement, levels of anticentromere (11.8% - 30.3%) and mean numbers of clinical manifestations (3.3 - 2.1). Elevated ferritin correlated with abnormal ESR, CRP, creatinine, creatine kinase, troponin, and reduced hemoglobin, reduced pulmonary function and left ventricular ejection fraction but not with antibodies. Elevated ferritin significantly correlated with mortality rates (52.8% and 35.1%) and non-significant reduction in survival.

Conclusions: We demonstrated that ferritin is a sensitive marker for SSc severity in term of skin thickening, vital organ complications, and mortality. The ferritin test is simple and inexpensive, it can add to the complex SSc assessment and contribute to treatment decision-making in complicated SSc.

P.187

DECONVOLUTION REVEALS DIFFERENCES IN CELL TYPE COMPOSITION AMONG SYSTEMIC SCLEROSIS INTRINSIC SUBTYPES DEFINED BY UNSUPERVISED LEARNING IN MULTIPLE COHORTS

Zhiyun Gong^1,3, Rezvan Parvizi^1,2, Helen Jarnagin^1.2, Haobin Chen^1,3,4, Madeline Morrisson^1,2, Michael L. Whitfield^1,2

¹Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA, ²Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA, ³Program in Quantitative Biomedical Sciences, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA, ⁴The Dartmouth Institute for Health Policy and Clinical Practice, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA

Introduction: Genome-wide transcriptomic profiling has allowed for the discovery and validation of four intrinsic subtypes of systemic sclerosis (SSc) patients, named fibroproliferative, inflammatory, limited, and normal-like, using unsupervised learning methods across multiple independent SSc cohorts. In this study, we re-analyzed these data in a consistent manner and performed unsupervised analyses on the largest integrated discovery dataset to date to revisit SSc patient subtyping and to interrogate specific cell types that may drive the heterogeneity.

Material and Methods: SSc skin gene expression data from three cohorts (GSE9285, GSE32413, and GSE59787) representing 304 forearm and back skin samples from 183 patients at baseline were processed using a consistent pipeline to generate single channel data and merged using COCONUT. Probes with the highest ‘intrinsic’ within-between scores were calculated using a modified F-statistic and filtered by skewness. Principal Component Analysis (PCA) was performed, and 3 principal components highly associated with clinical diagnosis and original subtype labels were selected. Samples were clustered using K-means, and the optimal number of clusters with the highest Silhouette score was chosen. A public scRNA-Seq dataset of human SSc skin (GSE138669) was reannotated and used as a reference for bulk cell-type deconvolution using Scaden.

Results: We compared and mapped the 6 clusters (Fig. 1A) to the original subtype labels in the three publications and assigned subtype names (Fig. 1B). 82% of inflammatory and 90% of fibroproliferative samples stayed in the same subtype or were reassigned to an intermediate inflammatory-fibroproliferative type, demonstrating concordance with prior analyses of individual datasets. Clusters 2 and 3 both consisted of healthy controls, normal-like SSc and limited SSc. No significant differentially expressed genes (DEGs) were found between these two groups. Differences in cell type composition across subtypes were observed after deconvolution using Scaden (Fig. 3C). The inflammatory subtype had a higher proportion of CXCR4 - CD52 T cells, while CXCL8 - HLA-DRA macrophages and SFRP2 – COMP fibroblasts were enriched in the inflammatory-fibroproliferative group. These cells had low predicted numbers in fibroproliferative and normal-like skin.

Conclusions: These results confirm and extend our previously published subtyping results and support the existence of major gene expression subtypes, including an Inflammatory-Fibroproliferative overlap group, which was previously observed in a single study. By leveraging cell-type deconvolution, compositional differences across SSc subtypes are predicted, shedding light on changes in cellular composition as one factor leading to differential bulk gene expression signatures and highlighting the importance of taking this heterogeneity into account in SSc studies.

P.188

UNUSUAL CASE OF SCLERODERMA MIMICKER

Julia Zhu^1,2, Jayden Wong³, Karen Koch¹, Kamal Solanki^2,4

¹Dermatology Department, Waikato Hospital, Te Whatu Ora, Hamilton, NEW ZEALAND, ²Rheumatology Department, Waikato Hospital, Te Whatu Ora, Hamilton, NEW ZEALAND, ³Oncology Department, Waikato Hospital, Te Whatu Ora, Hamilton, NEW ZEALAND, ⁴Waikato School of Medicine, University of Auckland, Waikato Hospital, Te Whatu Ora, Hamilton, NEW ZEALAND

Introduction: Immune checkpoint inhibitors are increasingly utilised with broadening indications in the setting of cancer treatment. It is well recognised that this group of drugs is associated with immune-related adverse events given its mechanism of action. There are existing reports of immune checkpoint inhibitors associated with scleroderma, as well as scleroderma mimickers such as morphoea and eosinophilic fasciitis.

Material and Methods: We report a case of a 70-year-old, non-diabetic woman who developed scleredema, a rare imitator of scleroderma, following initiation of pembrolizumab treatment for advanced lung cancer. The patient presented with diffuse thickening of her skin affecting her face and limbs after 5 cycles of pembrolizumab. (Figure 1)

Results: She was first investigated for possible scleroderma and her serological panel was negative for ANA and scleroderma blot. (Table 1) Incisional skin biopsies revealed diffuse interstitial dermal mucin deposition with minimal inflammation. (Figure 2) This correlated with a clinical diagnosis of scleredema. Systemic involvement was excluded with whole body MRI and dedicated cardiac MRI. The patient was managed with phototherapy and supportive care.

Conclusions: Scleredema is a sclerotic skin condition where mucin deposition leads to diffuse skin induration. There are no existing treatment protocols for this condition given its rarity. This unusual presentation adds to the myriad of immune-related adverse effects related to immune checkpoint inhibitors.

Clinicians need to be vigilant in the assessment of patients who are receiving immune checkpoint inhibitors.

Acknowledgment: photos and histology slides permitted by the patient. Thanks to Dr Duncan Lamont (Pathologist) for the slides.

P.189

RECOMMENDATIONS OF NON-PHARMACOLOGICAL MANAGEMENT OF SSC AND SLE: ASSESSING ALIGNMENT WITH CLINICAL CARE

Rita Schriemer¹, Els van den Ende², Agnes Kocher³, Valentin Ritschl⁴, Birgit Barten⁵, Francesca Marchiori⁵, Ilaria Galetti⁶, Rene van Westhovens⁷, Oliver Distler⁸, Carina Bostrom⁹, Ioannis Parodis⁹

¹NVLE, Dutch Patient organisation for people with CTD's, also working at (2), Utrecht, THE NETHERLANDS, ²Sint Maartenskliniek, dept of Research and Innivations, Nijmegen, THE NETHERLANDS, ³Department Public Health, Institute of Nursing Science, Basel, SWITZERLAND, ⁴Institute of Outcomes Research, Center for Medical Data Science, Medical University of Vienna, Vienna, AUSTRIA, ⁵EULAR- PARE, Kilchberg, SWITZERLAND, ⁶FESCA, Saint Maur, BELGIUM, ⁷Universiteit Leuven, Leuven, BELGIUM, ⁸Department of Rheumatology, University Hospital Zurich, Zurich, SWITZERLAND, ⁹Neurobiology, care sciences and society, Karolisnka Intitutet, Stockholm, SWEDEN, ¹⁰Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Stockholm, SWEDEN

Introduction: Systemic sclerosis (SSc) and Systemic Lupus Erythemathosis have a high disease burden which cannot be sufficiently alleviated with pharmacological treatment alone. This summer, the EULAR recommendations for non-pharmacological management of SSc and SLE were published. http://dx.doi.org/10.1136/ard-2023-224416

Dissemination and implementation of the recommendations into daily clinical practice is crucial for the desired changes and quality improvement.

Material and Methods: To make the recommendations part of clinical practice, raising awareness about them is an important preparatory step. We have formed national teams consisting of patient representatives, HPRs, and physicians engaging in the care of people with SSc and SLE.

Each team will first disseminate the recommendations among their peers (translated when needed) in publications, mailings, presentations, etc ( step 1).

We will next send out an online survey (step 2) to HPRs and physicians engaging in the care of people with SSc and SLE, as well as to people living with these conditions. The survey gauges both the professional and experiential opinion of stakeholders’ perceived alignment of each recommendation with current clinical practice in their respective country. This will be evaluated quantitatively with a numeric scale for each recommendation and with qualitative (open-ended text) responses on self-reported drivers and barriers. The survey will be first translated and checked by native speakers, pilot-tested in a smaller group of patients and among the members of the EULAR study group on non-pharmacological treatment of CTD's. Qualitative data will be translated, checked by native speakers, and analysed using qualitative methodology such as thematic analysis. National and global project reports will be published (step 3).

Results: We have formed 12 national teams consisting of patient representatives, HPRs, and physicians engaging in the care of people with SSc and SLE. It is open for more teams. At the congress meeting we will discuss the recommendations, some first results from the responses to efforts of the national teams in disseminating the recommendations and invite stakeholders from other countries to participate in the project.

Conclusions: Following the recent publication of EULAR recommendations for the non-pharmacological management of SSc and SLE, we developed a project that provides a foundation for their dissemination and implementation. We identify this as a unique project in which all stakeholder groups can use their network to disseminate the recommendations and amplify the reach of the recommendations in a multi-tiered approach. This is a type of action research, where all stakeholders work together and the the role of patient representatives is imperative.

P.190

MALIGNANCY IN SYSTEMIC SCLEROSIS. A CLINICAL SERIES FROM UNIVERSITY OF DEBRECEN CLINICAL CENTRE

Gyöngyike Emese Majai¹, Dóra Nemes-Tömöri¹, Dóra Tari², Tünde Tarr¹, Antónia Szántó¹, Zoltán Griger¹, Éva Zöld¹, Ildikó Fanny Horváth¹, Melinda Nagy-Vincze¹, Szilvia Szamosi², Edit Végh², Nóra Bodnár², Zsófia Petho², Levente Bodoki², Ágnes Horváth², Zoltán Szekanecz², Gabriella Szucs², Gyöngyike Emese Majai¹

¹Division of Clinical Immunology, Institute of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, HUNGARY, ²Division of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, HUNGARY

Introduction: Systemic sclerosis is an autoimmune disease affecting several organs. In the pathogenesis fibrosis, vascularis abnormalities, autoimmunity, oxidative stress plays an important role. Several studies have been published showing that malignant tumors are more common in systemic sclerosis.

Material and Methods: A retrospective study was conducted on systemic sclerosis patients from Division of Clinical Immunology and Division of Rheumatology, University of Debrecen from 2018 to 2023. In our research we investigated the occurrence of individual tumors, their correlation with the type of systemic sclerosis, autoantibodies, immunosuppressive and immunomodulatory treatments.

Results: We analyzed a group of 396 patients, of which 14.6% (n=58) developed one or more tumors. Men made up 13,8 % (n=8) and women 86,2 % (n=50) of this group. In total 67 tumors were detected, of which the most frequent malignant tumors included skin tumors (n=21), breast cancers (n=10), pulmonary (n=7) and haematological (n=7) malignancies but among these, the prevalence of skin cancers were prominently significant, along with breast cancers. The tumors were diagnosed at an average age of 61. In the group of cancerous patients, the most common type of systemic sclerosis was the limited cutaneous type, however comparing this group with the non-cancerous patients, the diffuse cutaneous type was significantly prevalent in cancerous patients. Among the patients with tumors, the immunoserological positivity for ANA, anti-Scl70, anti-centromere, anti-RNSPIII, anti-PM/Scl75 and anti-PM/Scl100 were examined. Our study showed that in the group of anti-centromere positive patients, the date of diagnosis of malignancies and systemic sclerosis was the nearest. During the 5-year course, 14 of the tumor positive patients died, 3 patients due to the malignancy and its complications, and 11 because of other reasons. Comparing the mortality between sexes and systemic sclerosis types, women suffering from limited cutaneous systemic sclerosis had significantly higher mortality. Immunosuppressive or immunomodulant treatments were administered in 31 patients out of the 58 cancerous patients. Before the diagnosis of malignancies due to systemic sclerosis or other autoimmune diseases, two-thirds of tumor positive patients were treated with methotrexate and one-third with cyclophosphamide.

Conclusions: The results of our research support the fact that malignancies are more frequent in patients diagnosed with systemic sclerosis and bring attention to the importance of screening tests, especially for skin tumors and breast cancers.

P.191

SYSTEMATIC LITERATURE REVIEW FOR THE 2023 UPDATE OF EULAR RECOMMENDATIONS FOR THE TREATMENT OF SYSTEMIC SCLEROSIS

Alain Lescoat¹, Eugenia Bertoldo^2,3, Jelena Colic^2,4, Tânia Santiago^2,5, Yossra Suliman^2,6, Jenny Emmel⁷, Philip G Conaghan^8,7, Yannick Allanore^8,9, Francesco Del Galdo^8,7

¹Internal Medicine and Clinical immunology, CHU Rennes, Rennes, FRANCE, ²Equal contribution, ., ITALY, ³Rheumatology Unit, Department of Medicine, University of Verona, Verona, ITALY, ⁴Department of Rheumatology, Institute of Rheumatology, Belgrade, SERBIA, ⁵Rheumatology, Centro Hospitalar e Universitario de Coimbra, Coimbra, PORTUGAL, ⁶Department of Rheumatology and Rehabilitation, Assiut University Hospital, Assiut, EGYPT, ⁷Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UNITED KINGDOM, ⁸Equal supervision, ., UNITED KINGDOM, ⁹Departement of Rheumatology, Cochin Institute, Paris, FRANCE

Introduction: EULAR recommendations for the treatment of Systemic Sclerosis (SSc) were updated in 2017, informed by a systematic literature review (SLR) completed in 2014. A new SLR providing the most up-to-date literature to underpin contemporary recommendations for the management of SSc was required to informed up-coming recommendations.

Material and Methods: 67 clinical questions addressing 30 interventions were explored. Three question types were defined: Type I : Questions that were unchanged as compared to the previous set of recommendations; Type II : exploring the efficacy/effectiveness of an intervention already mentioned in the previous recommendations but with new outcome(s); Type III : including interventions not mentioned in the previous recommendations. Questions were divided among 5 reviewers and three databases were screened (Embase, pubmed and Cochrane Library).

Results: For the first round of SLR, search periods were defined as follows in all three databases: new abstracts released from 1/10/2014 to 31/03/2022 for type I & type II questions and from database inception to 31/03/2022 for type III. 14490 abstracts were retrieved and 18 abstracts were selected manually from 31/03/2022 to 11/10/2014 (date of the nominal group technique (NGT) exercise). 483 new full-texts were evaluated and 172 new articles were included. 187 articles from the SLR for the 2017 recommendations were included as well. For each question, reviewers provided a summary, specifying the level of evidence (1 to 5) and the level of recommendations (A to D). Each summary was reviewed by task force leaders and presented during the NGT meeting to inform discussion and voting on the new recommendations. The majority of the questions covered by this SLR explored new interventions that had not been explored in previous recommendations (40% of type III questions) or with new outcomes (26% of type II questions). New interventions included targeted therapies such as abatacept, JAK inhibitors or nintedanib, and updated questions incorporated the results from key game-changing RCTs including trials on tocilizumab, mycophenolate or rituximab in SSc-interstitial lung disease (ILD). A second round of SLR covered the time period April 2022 to December 2022, and 9 new articles were included, with one phase II RCT on cyclophosphamide versus rituximab for SSc-ILD.

Conclusions: This SLR provides the highest level of evidence to address questions prioritized in the 2023 update of EULAR recommendations for the treatment of SSc, providing an unprecedented comprehensive overview of recent knowledge on SSc treatments.

P.192

CALCINOSIS CUTIS: EXCELLENT OUTCOME FOLLOWING EXCISION AND SPLIT SKIN GRAFTING IN SYSTEMIC SCLEROSIS

Buket Beresford-Wylie, Graham Dinsdale, Susie Zhi-Jie Yao, Muditha Samaranayaka, Nuala O'Donoghue

Northern Care Alliance NHS Foundation Trust, Manchester, UNITED KINGDOM

Introduction: The management of calcinosis cutis in the context of systemic sclerosis can be very challenging. This dystrophic calcification is due to the deposition of hydroxyapatite and amorphous calcium phosphate crystals in the extracellular matrix of the damaged or abnormal dermis and subcutaneous tissues. Calcinotic lesions are often extremely painful, particularly when they occur over the joints, and frequently become infected. Various medical and surgical therapies exist but outcomes are extremely variable and often interventions fail. We report a patient, with several risk features for poor wound healing, who achieved an excellent outcome from surgery.

Material and Methods: Here, we present a case of a 61-year-old female patient with diffuse cutaneous systemic sclerosis. It had been 17 years since her first non-Raynaud’s phenomenon symptom, she had a positive anti-centromere autoantibody, and a previous history of digital ulceration and calcinosis confirmed via radiograph. She smoked and had peripheral vascular disease. She developed right knee infected calcinosis following trauma. The wound (Figure 1A, 6 months prior to surgery) eventually became infected. The decision was made to manage it with surgical excision. The wound was excised down to fascia and split skin grafting was carried out directly. There were no intraoperative complications. Post-surgically, vacuum-assisted closure of the wound was carried out to promote healing.

Results: This patient had excellent post-surgical outcome of her wound and had no complications. Complete re-epithelialisation was achieved (Figure 1B, 6 months post-surgery) resulting in full functional restoration and resolution of pain.

Conclusions: Patient factors that are known to promote poor wound healing include smoking and the presence of peripheral vascular disease – both of which our patient had. In addition, sites on the lower extremities are known to be higher risk. Despite these factors, we were able to achieve an excellent outcome of complete re-epithelialisation without post-surgical complications.

P.194

EFFECT OF PHOSPHODIESTERASE-5 INHIBITOR AND ENDOTHELIN RECEPTOR ANTAGONIST USE ON MICROVASCULAR COMPLICATIONS, RESPIRATORY PARAMETERS AND PULMONARY ARTERY PRESSURE IN SYSTEMIC SCLEROSIS PATIENTS

Ender Terzioglu¹, yagmur kahraman², Funda Erbasan¹, Deniz Ozel³, Veli Yazisiz¹, Bengisu Unlu¹

¹Akdeniz University Dpt of Rheumatology, Antalya, TURKEY, ²Akdeniz University Dpt of Internal Medicine, Antalya, TURKEY, ³Akdeniz University Dpt of Statistics, Antalya, TURKEY

Introduction: Systemic sclerosis (SSc) is a rare multisystemic connective tissue disease, characterized by vascular dysfunction and progressive fibrosis of the skin and internal organs.

Material and Methods: The aim of this study was to retrospectively evaluate the effects of bosentan, sildenafil and combination therapy of these drugs on Raynaud's phenomenon (RF), number of digital ulcer attacks, respiratory parameters (FVC and DLCO), and pulmonary artery pressure (PAP) in patients with systemic sclerosis (SSc).

103 patients with a diagnosis of SSc were evaluated retrospectively treatment they received, there were four groups: those who used only bosentan (group 1), those who used only sildenafil (group 2), those who received both treatments (group 3), and those who did not receive both treatments (group 4). Raynaud's Condition Score (RCS) was evaluated before treatment, 6 and 12 months after treatment. The number of digital ulcer attacks was evaluated before and after treatment. Respiratory parameters and PAP were evaluated before treatment and in the 1st year after treatment in patients who received treatment.

Results: There was a statistically significant decrease in RCS between baseline, 6th and 12th months in group 1, group 2 and group 3 (p=0.00, p=0.03, p=0.004, respectively). There was a decrease in the number of digital ulcer attacks in Group 3 and it was found to be statistically significant (p=0.027). The mean FVC value of the patients in Group 1 increased after treatment, but it was not statistically significant (p=0.125). FVC values of the patients in group 2, group 3 and group 4 were decreased but not statistically significant (p=0.892, p=0.160, p=0.465, respectively). The mean DLCO values of the patients in group 1, group 2 and group 3 decreased after treatment, but it was not statistically significant (p=0.173, p=0.588, p=0.051, respectively). The DLCO values of the patients in Group 4 decreased and it was found to be statistically significant (p=0.00). The mean PAP values of the patients in group 1, group 2 and group 3 decreased after treatment, (p=0.254, p=0.234, p=0.172, respectively). The mean PAP values of the patients in group 4 increased and it was found to be statistically significant (p=0.017).

Conclusions: In the treatment of RF secondary to SSc, sildenafil and/or bosentan treatment improved RCS. In the treatment of digital ulcer associated with SSc, especially sildenafil and bosentan combined therapy can be considered.. In conclusion, it was observed that sildenafil and/or bosentan treatment improved some complications and reduced disease progression in SSc patients.

P.195

INCIDENCE OF PULMONARY ARTERIAL HYPERTENSION AMONG A HUNGARIAN SYSTEMIC SCLEROSIS PATIENT COHORT

Dóra Tari, Szilvia Szamosi, Edit Végh, Zsófia Pethö, Ágnes Horváth, Levente Bodoki, Nóra Bodnár, Zoltán Szekanecz, Gabriella Szücs

Department of Rheumatology, Clinical Center, University of Debrecen, Hungary, Debrecen, HUNGARY

Introduction: Systemic sclerosis (SSc) is a complex connective tissue disease characterised by fibrosis and thickening of the skin and variable organ involvement, including the lungs, heart, kidney, gastrointestinal tract and the musculoskeletal system as well. Pulmonary arterial hypertension (PAH) can be one of the severe complications of the disease and despite of the advances in the treatment of PAH, the survival is still poor among these patients.

Material and Methods: Our aim was to assess the incidence of PAH, the therapy and the effect of PAH on survival among our Hungarian SSc patient cohort cared at the Department of Rheumatology, Clinical Center, University of Debrecen between 2013-2023.

Results: We analyzed the data of 282 SSc patients of which 27 patients were diagnosed with SSc-PAH. Out of the 27 SSc-PAH patients 22 were women and 5 were men, 15 patients had limited and 12 had diffuse cutan form of SSc. The most frequent autoantibodies were as follows ANF positivity (41%), anti-Scl70 (26%), anti-centromere (22%) and anti-RNA polymerase III (11%). The average age at the diagnosis of PAH was 60.7 years and the average time between the diagnosis of SSc and PAH was 7.4 years. Regarding to the therapy the most frequent PAH targeted therapy groups were as follows PDE-5 inhibitors, endothelin receptor antagonists, prostacyclin receptor agonists and prostacyclin analogs. 4 patients required no PAH specific therapy, 11 patients recieved targeted monotherapy, 8 patients recieved dual and 4 patients triple combination. Out of the 27 SSc-PAH patients 11 patients died (we have no data on 3 patients), only one of them died directly as a consequence of PAH. The average age at death was 63.2 years and the average time between the diagnosis of PAH and the patient’s death was 3.3 years. In our SSc cohort the survival was worse in the SSc-PAH group than in the non-SSc-PAH group. Among the SSc-PAH patients the survival was poorer when the pulmonary vascular resistance (PVR>2WU, PVR>5WU) and the mean pulmonary artery pressure (mPAP) was higher.

Conclusions: Reviewing the literature data our results correspond to international outcomes.

P.196

PREDICTORS OF 5-YEARS SURVIVAL IN SYSTEMIC SCLEROSIS PATIENTS AFFECTED BY PULMONARY ARTERIAL HYPERTENSION: DATA FROM REAL LIFE EXPERIENCE

Stefano Stano¹, Claudia Iannone², Andrea Cito¹, Marco Capodiferro¹, Nicoletta Del Papa², Roberto Caporali², Fabio Cacciapaglia¹

¹Rheumatology Unit, University of Bari, Bari, ITALY, ²Division of Clinical Rheumatology, ASST Gaetano Pini-CTO Institute, Milano, ITALY

Introduction: Pulmonary arterial hypertension (PAH) may complicate systemic sclerosis (SSc) and represents a significant cause of death in these patients. According to recent epidemiological evidence about 10% of SSc patients may be affected by PAH, with a 50% mortality rate after 3 years from SSc-PAH diagnosis. Therefore, our study aimed to identify 5-years survival predictors of SSc-PAH patients in a real-life setting.

Material and Methods: SSc patients, fulfilling the 2013 EULAR/ACR classification criteria and affected by PAH, confirmed at right heart catheterization (RHC) according to the updated ESC/ERS guidelines for pulmonary hypertension, were included in our cohort. Demographic, clinical, laboratory and instrumental data of SSc-PAH patients, visited until September 2023, were recorded and analyzed using SPSS with appropriate statistical tests. Survival rate of SSc-PAH patients was assessed using the Kaplan-Meier method, while predictors of mortality were expressed as Odds Ratios (OR) and 95% Confidence Intervals (CI).

Results: Forty-three SSc patients with PAH diagnosis after RHC were included in our study cohort. After a median follow-up time of 4.0 years since PAH diagnosis, the 5-years survival rate in our cohort of SSc-PAH patients was 69.5% (Figure). Those patients with a worse WHO functional class (NYHA III-IV) and with a 4-strata class of risk intermediate-high/high at PAH diagnosis had a lower survival probability. Furthermore, SSc-PAH patients with poorer prognoses had a significantly lower % of predicted FVC and DLCO. Notably, predicted FVC <70% (OR 8.0 95%CI 1.5-32 - p<0.01), and predicted DLCO<40% (OR 16.0, 95%CI 2.1-100 - p<0.01) were statistically significant poor survival predictors. On the contrary, age and gender, disease duration, cutaneous or gastrointestinal involvement, autoantibody profile, echocardiographic parameters and starting therapeutic strategy in monotherapy or combination, did not statistically impact survival. Noteworthy, all PAH treatments were upgraded during follow-up, and after 3 years all SSc patients were at least in combination therapy.

Conclusions: Effective screening and early diagnosis of PAH, with tight clinical monitoring and timely effective therapeutic adjustments, positively impact on SSc patients’ survival. Low predicted %FVC and %DLCO, NYHA class III-IV and COMPERA 2.0 four-strata risk chart intermediate-high/high-risk profile at PAH diagnosis represent the main poor prognostic factors for SSc patients survival.

P.197

PULMONARY ARTERIAL HYPERTENSION SCREENING AND MANAGEMENT IN SYSTEMIC SCLEROSIS: APPLICATION OF THE DETECT ALGORITHM AND THE ESC/ERS GUIDELINES IN REAL-LIFE SETTING

Stefano Stano¹, Andrea Cito¹, Marco Capodiferro¹, Elisabetta De Tommasi², Lucrezia De Michele², Carlo DAgostino², Florenzo Iannone¹, Fabio Cacciapaglia¹

¹UOC Reumatologia, University of Bari, Bari, ITALY, ²Division of Hospital Cardiology, Policlinico University Hospital of Bari, Bari, ITALY

Introduction: Pulmonary arterial hypertension (PAH) represents one of the leading causes of poor survival in systemic sclerosis (SSc) patients. Early PAH detection and effective treatment strategies may improve SSc patients’ prognosis. The aim of this study was to assess the effectiveness of the DETECT algorithm and the 2015 ESC/ERS guidelines, updated in 2022, for PAH screening and management in SSc patients.

Material and Methods: SSc patients, fulfilling the 2013 ACR/EULAR classification criteria, with available data for PAH screening by the DETECT algorithm and the 2015 ESC/ERS guidelines were consecutively enrolled from January to June 2017, then followed-up for 5 years with screening and management strategies according to updated ESC/ERS guidelines for PAH. All patients with at least one positive screening tool, aged <80 years, without signs of left ventricular compromise, and consenting to right heart catheterization (RHC), underwent this procedure for the diagnosis of PAH. Data were recorded in all subjects at baseline. Appropriate statistical analysis was carried out using SPSS software

Results: Ninety-two SSc patients were included (Table 1). Thirty-seven patients (40.2%) received indication to RHC with DETECT algorithm, while 19 (20.7%) were at high risk for ESC/ERS guidelines. In 19 (50%) high risk SSc patients a RHC was performed, with 14 (73.7%) diagnosis of PAH confirmed. Patients at high risk of PAH with indication to but not performing the RHC for any reason, had a grimer prognosis. As screening tool, the DETECT algorithm had higher sensitivity and negative predictive value but lower specificity for PAH diagnosis compared to the 2015 ESC/ERS guidelines (Figure 1). In our cohort, the 5-years mortality rate was 16.3% (15/92) overall, 12.7% (10/79) in SSc patients without PAH, and 35.7% (5/14) in SSc-PAH patients (RR 3.1; 95%CI 1.18-7.30; p=0.02). The positivity to DETECT algorithm or ESC/ERS guidelines was linked to higher mortality risk for any reason with a RR of 9.66 (95%CI 2.64-36.95; p<0.0001) and 4.39 (95%CI 1.82-10.21; p=0.0006), respectively. According to the 2022 ESC/ERS four-strata risk classification model, the 9 SSc-PAH patients still alive, after appropriate treatment adjustments, had an acceptably low 1-year mortality risk.

Conclusions: In daily clinical practice, the use of the DETECT algorithm for early diagnosis and appropriate management of SSc-PAH patients is easily applicable. Noteworthy, SSc patients with negative DETECT are unlikely to develop PAH, with promising 5-years survival rates. The 2022 ESC/ERS four-strata risk chart may help in decision of treatment adjustments, improving SSc patients’ prognosis.

P.198

MORTALITY AND ASSOCIATED FACTORS IN 44 PATIENTS WITH SYSTEMIC SCLEROSIS ASSOCIATED PULMONARY ARTERIAL HYPERTENSION WITH AND WITHOUT INTERSTITIAL LUNG DISEASE

Amikishiyev Shirkhan¹, Yasemin Yalçinkaya¹, Konul Mammadova², Numune Aliyeva¹, Gorkem Durak³, Bahar Artim-Esen¹, Ahmet Gül¹, Ahmet Kaya Bilge⁴, Gulfer Okumus², Murat Inanc¹

¹Istanbul Faculty of Medicine, Istanbul University, Division of Rheumatology, Istanbul, TURKEY, ²Istanbul Faculty of Medicine, Istanbul University, Department of Chest Diseases, Istanbul, TURKEY, ³Istanbul Faculty of Medicine, Istanbul University, Department of Radiology, Istanbul, TURKEY, ⁴Istanbul Faculty of Medicine, Istanbul University, Department of Cardiology, Istanbul, TURKEY

Introduction: We aimed to analyze the prevalence, mortality, and prognostic factors in systemic sclerosis (SSc) patients with pulmonary arterial hypertension (PAH) with or without interstitial lung disease (ILD), followed by a dedicated multidisciplinary team from Turkey.

Material and Methods: In this retrospective study, the associations between mortality and demographics, transthoracic echocardiography, right heart catheterization (RHC), pulmonary functional parameters at baseline, and treatment modalities in patients with SSc-PAH were evaluated. We evaluated these patients in two groups; PAH-only and PAH with limited ILD in the first group (PAH) and PH with extensive ILD (PH +ILD) in the second group. Lung involvement severity was based on the algorithm recommended by Goh et al.¹

Results: The mean age of the patients was 56.6±13.5 (range: 34-82, 44 women/ 2 men), and 23 (52.3%) were deceased during a median follow-up of 45 months. The survival rates of PAH-SSc patients were 91% for the first year, 75% for 2 years, 68% for 3 years, and 43.1% for 5 years. The majority of deceased patients were in the PH + ILD group (36.4% versus 15.9%, p=0.007; Table 1). The PH + ILD group had more anti-Scl-70 positivity, high C-reactive protein, low FVC, and lower DLCO values (p < 0.001; Table 1 and 2). The deceased patients had higher ePASP, low CO, and FVC values compared to surviving patients (Table 3). Median survival time was significantly better in patients on combined therapy and in the PAH group (Figure 1). The mortality-related factors were a low value of initial FVC, high ePASP on echocardiography, low cardiac output on RCH, high functional class, and monotherapy.

Conclusions: This is the first reported SSc-PAH cohort that was evaluated by RHC and long-time follow-up from Turkey by a multidisciplinary team after the implementation of PAH-specific drugs. SSc-PAH is a severe complication of SSc with high mortality especially in patients with accompanying severe ILD.

Reference

1.  Goh NS, Desai SR, Veeraraghavan S, et al. Interstitial lung disease in systemic sclerosis: a simple staging system. American journal of respiratory and critical care medicine 2008; 177: 1248-1254.

P.199

OCCURENCE OF MAJOR CARDIO-VASCULAR EVENTS IN A SMALL COHORT OF SSC PATIENTS WITH LOW-RISK RANGE OF PAH: COEXISTING OF SUBCLINICAL CORONARY ATHEROSCLEROSIS, A WORSE NEW “NOT PURE” PATTERN OF PAH?

Cinzia Rotondo, Stefania Sciacca, Valeria Rella, Francesco Paolo Cantatore, Addolorata Corrado

Clinic of University Rheumatology - Policlinico Riuniti - Foggia University, Foggia, ITALY

Introduction: In systemic sclerosis patients (SSc-pts) cardio-pulmonary complications such as interstitial lung fibrosis, and pulmonary arterial hypertension (PAH) are the leading causes of death. Few data are available on cardiovascular risk and subclinical atherosclerosis in SSc-pts. The aim of this study is to evaluate the occurrence of major cardiovascular events (MCVE) in 6 years of follow-up in a group of SSc-pts with a low-risk range of PAH, well controlled by treatments.

Material and Methods: We enrolled 12 consecutive SSc patients with PAH (diagnosed and treated according to current ESC/ESR guidelines), at low-risk range according to ESC guidelines for PAH stratification risk at the time of the diagnosis. Clinical and laboratoristics evaluations were assessed in all patients at baseline and at follow-up visits. Cardiovascular (CV) impairment and risk assessment were evaluated by coronary artery calcium score (CAC-score) (to define the presence of subclinical coronary atherosclerosis (SCA), the presence of carotid plaque (CP), and/or peripheral artery disease (PAD), and several international cardiovascular risk scores. All patients with systemic arterial hypertension, diabetes, dyslipidemia, PAD, CP, and SCA were treated according to the guidelines of the main scientific societies in the specific field, respecting good clinical practice.

Results: In six-years of follow-up MCVE occurred in 6 (50%) SSc-pts (3 deaths for cardiovascular events, 1 myocardial infarction, 1 hospitalized for heart failure, 1 coronary revascularization). No significant differences were found in SSc-pts in which occured MCVE (MCVE-pts) vs those without MCVE (no-MCVE-pts) in age, BMI, lipid profiles, rate of smokers, presence of systemic arterial hypertension, metabolic syndrome, diabetes, PAD and CP. Higher values of Framingham risk score (17.1±3.2 vs 12.8±3.4, p=0.049) and QRISK-3 (32.8±11.8 vs 13.3±12.3, p=0.019) were found in MCVE-pts vs no-MCVE-pts.

Of note, CAC-score >50 was capable of discriminating patients with higher MCVE risk with AUC 0.889 (p=0.025) evidencing higher sensitivity (83%) and specificity (84%).

MCVE-pts presented a higher value of CAC-score (87.5 (IQR: 348) vs 15 (IQR:50), p=0,026) with a higher rate of CAC-score>50 (100% vs 17%, p=0.003) and CAC-score>100 (50% vs 17%, p=n.s.) than no-MCVE-pts. Of note, all 3 dead SSx-pts had CAC-score>50.

Conclusions: The presence of SCA, defined by CAC-score>50, could identify a new “not pure form” of PAH with a worse prognosis. Careful evaluation of the presence of subclinical coronary atherosclerosis in SSc-pts, especially those with PAH, should merit wide attention in clinical and therapeutic management to improve MCVE-free survival.

P.200

EXPERT PANEL TO IDENTIFY OPTIMAL STANDARDS OF CARE AND PROVIDE CONSENSUS ON MANAGEMENT BEST PRACTICES FOR PATIENTS WITH CTD-PAH

Francesco Del Galdo¹, Gerry Coghlan², Sean Gaine³, Catalina Rojas Acosta⁴, Richard Perry⁵, Daisy Bridge⁵, Ekkehard Gruenig⁶

¹University of Leeds and Leeds Teaching Hospital NHS Trust, West Yorkshire, UNITED KINGDOM, ²Royal Free Hospital, London, UNITED KINGDOM, ³Mater Misericordiae University Hospital, Dublin, IRELAND, ⁴Janssen Pharmaceuticals, High Wycombe, UNITED KINGDOM, ⁵Adelphi Values PROVE, Manchester, UNITED KINGDOM, ⁶Heidelberg University Hospital and the German Center for Lung Research (DZL), Heidelberg, GERMANY

Introduction: Diagnosis of pulmonary arterial hypertension (PAH) has a major impact on the prognosis of patients with connective tissue diseases (CTDs), with high morbidity, quality of life burden and poor overall survival.

The recent 2022 ESC/ERS guidelines highlight the importance of timely and accurate screening, referral, diagnosis, treatment, and follow-up of patients with PAH. Given the multi-system nature of CTD-PAH, disease management is complex and requires a multi-disciplinary approach. Current modern management strategies for CTD-PAH are suboptimal; there remains an unmet need to understand the current standards of care for CTD-PAH and strategies required to improve disease management. Notably, disconnects between treating PAH experts and rheumatologists may limit the effectiveness of existing management approaches.

Objective: To collate, clarify, and develop a consensus of expert clinical opinion of cardiologists, pulmonologists, and rheumatologists on current standards of care for CTD-PAH, identify potential areas of improvement when considering existing management, and provide expert guidance on best practices of care in CTD-PAH, with a specific focus on systemic sclerosis. To inform clinical management pathways that rely on strong collaboration between rheumatology and PAH centres beyond diagnosis and improve the efficiency of clinical management for patients and specialists.

Material and Methods: A modified Delphi has been planned including two rounds of survey and a final consensus meeting. * Panellists have been identified through local CTD-PAH clinical management networks and include healthcare professionals (physicians [n=20] and nurse practitioners [n=12]) from Belgium, France, Germany, Italy, Spain, Sweden, and the United Kingdom. Panellists will remain double-blinded throughout the study. The questionnaires will explore the perceptions on the current standards of care for patients with CTD-PAH and identify areas of improvement in the patient management pathway and barrier in optimal implementation of ESC/ERS 2022 guidelines. Consolidated responses from panellists will be discussed in a final consensus meeting, where conclusions and recommendations can be made on management best practices for CTD-PAH.

Results: To our knowledge this is the first multidisciplinary, multinational exercise that aims at improving reception and implementation of 2022 ESC/ERS guidelines.

Conclusions: The key topics explored within this Delphi panel span from screening, referral, diagnosis, to treatment decision making, and follow-up strategies for CTD-PAH. Central focus is devoted to optimisation of patient management across specialities, improving patient experience and outcome.

*This study is funded by Janssen Pharmaceutical, NV.

P.201

QUANTIFICATION OF T CELL SUBSETS IN PATIENTS WITH SYSTEMIC SCLEROSIS-ASSOCIATED PULMONARY ARTERIAL HYPERTENSION REVEALS A DISTINCT T HELPER CELL PROFILE

Theodoros-Ioanni Papadimitriou¹, Jacqueline Lemmers¹, Arjan van Caam¹, Jacqueline Vos³, Marije Koenders¹, Hans Koenen², Ruben Smeets^2,4, Robin Nijveldt³, Madelon Vonk¹, Rogier Thurlings¹

¹Department of Rheumatology, Radboudumc, Nijmegen, THE NETHERLANDS, ²Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, THE NETHERLANDS, ³Department of Cardiology, Radboudumc, Nijmegen, THE NETHERLANDS, ⁴Radboudumc Laboratory for Diagnostics, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, THE NETHERLANDS

Introduction: Pulmonary arterial hypertension (PAH) is a severe, progressive vascular complication in systemic sclerosis (SSc), and is one of the main causes of death. Recent studies demonstrate that T lymphocyte abnormalities can drive vascular dysfunction, however, their potential involvement in SSc associated PAH is not clear. The aim of this study was to determine if and which peripheral T cell subsets associate with PAH in SSc patients.

Material and Methods: Peripheral blood and clinical data were collected from 30 SSc patients with and without PAH, 5 IPAH patients and 15 healthy donors (HD), age and sex-matched. T lymphocyte subsets were quantified by multi-color flow cytometry of peripheral blood mononuclear cells. Production of granzyme B (GZMB) and the cytokines interleukin(IL)-4, IL-13, and IL-21 was measured by intracellular flow cytometry after T cell activation.

Results: SSc patients exhibited lower frequency of T helper (Th)1 cells versus HD and elevated percentages of CD4+CD8+ T cells. The CD28- population was increased in both CD4+ and CD8+ T cells in SSc and was further characterized by an increased cytotoxic and pro-inflammatory signature early in disease progress. Percentages of pro-fibrotic IL-4+/IL-13+ cells were elevated in both the T helper and cytotoxic T cells from SSc patients compared to HD. Furthermore, CD4+GZMB+ cytotoxic T cells were expanded in SSc blood, while barely detectable in HD. Patients with early diagnosed disease exhibited elevated numbers of effector cytotoxic CD8+ T cells responses, while patients with late and active disease showed increased levels of CD4+ T helper cells. Interestingly, the presence of PAH in SSc was accompanied by a distinct T helper profile, characterized by raised percentages of Th17 and peripheral helper T cells (Tph).

Conclusions: Our results suggest that cytotoxic T cell responses may be especially important in early SSc disease processes, while aberrant T helper responses may be related with active disease progression in later stages of SSc. Strikingly, patients with PAH exhibited a distinct expansion of the pro-inflammatory Th17 and auto-antibody related Tph subsets, suggesting for a potential role of auto-immune inflammation in SSc vascular complications.

P.202

PULMONARY ARTERY HYPERTENSION IN PATIENTS WITH SYSTEMIC SCLEROSIS IN THE UKRAINIAN POPULATION

Tetiana Karasevska¹, Kateryna Mulyk¹, Oleksiy Ivashkivskyi², Hanna Novytska², Ruslana Potomka², Marta Dzhus^1,2

¹Bogomolets National Medical University, Kyiv, UKRAINE, ²Oleksandrivska Clinical Hospital, Kyiv, UKRAINE

Introduction: Pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality in patients with systemic sclerosis (SSc).

Material and Methods: The study aimed to determine the factors that may influence PAH in SSc. This study included 38 patients with determined SSc by 2013 ACR/EULAR classification criteria. We evaluated the influence of age, sex, disease duration, duration of Raynaud’s phenomena (RH) onset, positivity by the SSc-specific auto-antibodies (anti-Scl-70 antibodies and anti-centromere antibodies), and the presence of interstitial lung disease (ILD) on developing PAH. PAH was obtained by echocardiography (more 30 mmHg), and ILD was detected by HRCT. The exclusion criteria were other conditions that may lead to PAH (pulmonary embolism, COPD, etc.).

Results: The study involved 27 female and 11 male patients. The average age of the patients was 52,5±16,1 years; the average disease duration was 8,7±5,1 years. Anti-Scl-70 antibodies and anti-centromere antibodies were detected in 19 and 12 patients, respectively.

Our study did not recognize any correlation between PAH, age, or disease duration. We did not detect gender differences in the level of PAH (female 42,5±15,0 and male 44,1±12,3 mm Hg). Patients who suffered from RP for over 20 years have significantly higher PAH than those with RP in less than 10 years (48,6±10,3 vs 35,3±6,4 mmHg; t=3,4; p=0,003). There were no significant differences in the level of PAH in patients of anti-Scl-70 and anticentromere antibodies positively (44,4±12,1 vs 41,4±9,7 mm Hg respectively). In patients with ILD, we estimated PAH – 46,3±11,8 mmHg, and without ILD – 38,6 ±5,1 mmHg without significant statistical difference.

Conclusions: RP is a crucial clinical sign in early diagnosis and systemic vessel involvement and can be a predictor of disease progression. According to our findings, patients who suffered from RP for more than 20 years have significantly higher PAH than those with RP in less than 10 years. PAH was not directly connected with auto-antibodies positivity (neither anti-topoisomerase I nor anti-centromere antibodies). The level of PAH did not depend on the presence of ILD. That may indicate the primary role of systemic vessel involvement in PAH. To provide effective management, further research is needed to identify the risk factors for developing PAH in SSc patients.

P.203

PULMONARY ARTERIAL HYPERTENSION IN SCLERODERMA SPECTRUM DISEASES: EPIDEMIOLOGICAL CHARACTERISTICS AND EVOLUTION OF A COHORT ASSISTED IN A PUBLIC HOSPITAL IN AUTONOMOUS CITY OF BUENOS AIRES, ARGENTINA

Paula Judith Kaplan¹, Nicolás Matías D'amelio², Sandra Fabiana Montoya³, Pablo Szwarstein⁴, Eduardo Mario Kerzberg⁵, Martín Luis Sívori⁶, Justo Carbajales⁷

¹Hospital General de Agudos Dr J. M. Ramos Mejía-Pulmonology Unit-Pulmonary Hypertension Program, Autonomous City of Buenos Aires, ARGENTINA, ²Hospital General de Agudos Dr J. M. Ramos Mejía- Emergency Medicine Division- Pulmonary Hypertension Program, Autonomous City of Buenos Aires, ARGENTINA, ³Hospital General De Agudos Dr J. M. Ramos Mejía- Reumathology Division- Scleroderma Section, Autonomous City of Buenos Aires, ARGENTINA, ⁴Hospital General De Agudos Dr J. M. Ramos Mejía- Pulmonology Unit, Autonomous City of Buenos Aires, ARGENTINA, ⁵Hospital General De Agudos Dr J. M. Ramos Mejía- Reumathology Division, Autonomous City of Buenos Aires, ARGENTINA, ⁶Hospital General De Agudos Dr J. M. Ramos Mejía- Pulmonology Unit, Autonomous City of Buenos Aires, ARGENTINA, ⁷Hospital General De Agudos Dr J. M. Ramos Mejía- Cardiology Division, Autonomous City of Buenos Aires, ARGENTINA

Introduction: Pulmonary arterial hypertension is a condition that complicates the evolution of patients with systemic sclerosis, with a prevalence of 5 to 19%,and increases mortality. It is associated more frequently but not exclusively with the limited clinical form (LSCL). We report the epidemiological, clinical and hemodynamic features, the diagnostic, therapeutic approach and the outcome of a cohort of patients assisted in a Pulmonary Hypertension Program (PHP) in a public hospital in the Autonomous City of Buenos Aires, Argentina.

Material and Methods: Patients consecutively admitted to the PHP between 2013 and 2023 were retrospectively analyzed, including only those with diagnostic right heart catheterization confirming the pattern of precapillary pulmonary hypertension according to the current Practice Guidelines (GPHP). The procedures suggested by the current GPHP on the management of PAH were implemented throughout the follow-up. Clinical complications, hospitalizations, and death or loss to follow-up were documented.

Results: Thirteen female patients were identified, mean age 56.3± 12 years. 61.5% were LSCL, 23% were diffuse scleroderma (DSCL) and two were diagnosed with overlap syndrome with SLE and rheumatoid arthritis. Two patients with LSCL and one with DSCL had stable moderate pulmonary fibrotic involvement at the time of PAH diagnosis. The average time between the onset of symptoms and diagnosis was 2.1 years. In the initial hemodynamics, the mean pulmonary artery pressure was 32 ± 8 mmHg, right atrial pressure 7 ± 4 mmHg, cardiac index 3 ± 0.47 L/min/m2, pulmonary vascular resistance 4.65 ± 1.77 WU and pulmonary artery saturation 70± 4%. Baseline NTproBNP was 655±749. 54% of the cohort initially had functional class 3. Seven patients had to be hospitalized at least once, 84% received initial pulmonary vasodilator monotherapy, which was modified to 46% at the end of follow-up with 4 patients on triple therapy. Overall survival was 91% at 1 year, 80% at 2 years and 80% at 5 years.

Conclusions: This information is representative of patients with scleroderma and PAH in a public hospital in a city where privately managed, high-resource expert centers coexist with others like the one presented, which has limited resources. The overall survival of our cohort allows us to infer that the management implemented was adequate and close to the standards proposed by GPHP, although the number of patients is small.

P.204

SCREENING FOR PULMONARY ARTERIAL HYPERTENSION IN PATIENTS WITH SYSTEMIC SCLEROSIS IN THE ERA OF NEW PULMONARY ARTERIAL HYPERTENSION DEFINITIONS

Mustafa Erdogan¹, Burcak Kilickiran Avcu², Cansu Ebren², Yagmur Ersoy³, Zeki Ongen², Gul Ongen⁴, Vedat Hamuryudan¹, Gulen Hatemi¹

¹Istanbul University-Cerrahpasa, Department of Internal Medicine, Division of Rheumatology, Istanbul, TURKEY, ²Istanbul University-Cerrahpasa, Department of Cardiology, Istanbul, TURKEY, ³Istanbul University-Cerrahpasa, Department of Internal Medicine, Istanbul, TURKEY, ⁴Istanbul University-Cerrahpasa, Department of Chest Disease, Istanbul, TURKEY

Introduction: This study compares the performance of three composite pulmonary arterial hypertension (PAH) screening tools in a real-life SSc cohort, using both previous and recent hemodynamic criteria.

Material and Methods: Consecutive SSc patients without a previous diagnosis of pulmonary hypertension (PH) were screened for PAH using the European Society of Cardiology / European Respiratory Society (ESC/ERS), DETECT, and Australian Scleroderma Interest Group (ASIG) algorithms. Right heart catheterization (RHC) referral performances for PAH were compared according to the 2022 ESC/ERS PAH criteria.

Results: Thirty-five of the 81 patients required RHC; 15 (18.5%) according to ESC/ERS, 27 (33.3%) according to DETECT, and 25 (31%) according to ASIG. The final diagnoses were no-PH in 17 patients, WHO group 1 PH (PAH) in 8 patients, WHO group 2 PH in 8 patients, and WHO group 3 PH in 2 patients. When the hemodynamic criteria of the previous ESC/ERS guideline were applied, only one patient was diagnosed with PAH. The sensitivity of the algorithms for the diagnosis of PAH was 62.5% for ESC/ERS, 75% for DETECT, 87.5% for ASIG according to the 2022 ESC/ERS guideline definition, and 100% for all according to the previous ESC/ERS guideline.

Conclusions: With the recent criteria, PAH diagnosis in patients with SSc increased by 1.8-fold. Current algorithms for screening PAH are less sensitive with these revised criteria. Although the ASIG algorithm seems more sensitive, it can still miss the diagnosis. The multimodal/algorithmic approach seems to be the best option for predicting PAH.

P.205

TREATMENT OF PULMONARY ARTERIAL HYPERTENSION IN PATIENTS WITH CONNECTIVE TISSUE DISEASES: A SYSTEMATIC REVIEW AND META-ANALYSIS

Mustafa Erdogan¹, Sinem Nihal Esatoglu², Burcak Kilickiran Avci³, Gulen Hatemi²

¹Marmara University, Department of Rheumatology, Istanbul, TURKEY, ²Istanbul University-Cerrahpasa, Department of Rheumatology, Istanbul, TURKEY, ³Istanbul University-Cerrahpasa, Department of Cardiology, Istanbul, TURKEY, ⁴Istanbul University-Cerrahpasa, Department of Rheumatology, Istanbul, TURKEY

Introduction: Treatment options for pulmonary arterial hypertension (PAH) have expanded in the last two decades. However, evidence for the treatment of connective tissue disease-associated PAH (CTD-PAH) mostly depends on subgroup analysis of randomized controlled trials (RCTs). Thus, we performed a meta-analysis of the RCTs reporting outcomes for CTD-PAH.

Material and Methods: The search strategy is summarized in Figure 1. The outcomes selected for meta-analysis were functional class (FC) change, survival rates, six-minute walk distance (6-MWD), clinical worsening (CW), N-terminal prohormone BNP (NT-proBNP), pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (mPAP), right atrial pressure (RAP), and cardiac index (CI). The systematic review and meta-analysis protocol was registered in PROSPERO (CRD42020153560).

Results: PubMed and Embase searches revealed 1216 and 468 articles, respectively. After excluding the irrelevant articles and studies without available data for meta-analysis, 12 RCTs, including 1837 patients, were selected (Figure 1). The diagnoses were SSc in 59%, SLE in 20%, and other CTDs in 21%. The follow-up duration of selected trials ranged between 12 weeks to 192 weeks. The pharmacological interventions were prostacyclin analogs in 3 studies (epoprostenol in 1 study and treprostinil in 2 studies), PDE-5 inhibitors in 2 studies (sildenafil and tadalafil in one study each), ERA in 4 studies (bosentan in 2 studies, macitentan and, ambrisentan in 1 study each), riociguat in 1 study, selexipag in 1 study and, ambrisentan and tadalafil combination in 1 study. There was a significant difference between the groups in FC, 6MWD, CW, PVR, RAP, and CI, favoring the intervention arms (Figure 2.) Our analysis showed a 30% reduction in the risk of CW with PAH treatment. The reduction was higher (46%) with combination therapies. However, the groups had similar short-term (24-26 weeks) survival and mean serum NT-proBNP level changes. The RoB of the studies were summarized in Figure 3.

Conclusions: Although treatment for CTD-PAH had favorable effects on many of the clinical and hemodynamic outcomes, the effect on survival and NT-proBNP levels were not significant. This is the first meta-analysis on CTD-PAH that reported the pooled analysis of change in functional class, hemodynamic measurements (RAP, PVR, CI), and NT-proBNP, some of which have important prognostic value for PAH. Improvement in exercise capacity and reduction in risk of CW in CTD-PAH patients were less pronounced compared to idiopathic PAH (IPAH). However, changes in hemodynamic parameters in patients with CTD-PAH in our meta-analysis were similar to those in patients with IPAH in the published RCTs.

P.206

THE PROMISING ROLE OF TAPSE/PAPS RATIO FOR PULMONARY ARTERIAL HYPERTENSION SCREENING IN SYSTEMIC SCLEROSIS. IS IT POSSIBLE TO IMPROVE THE SPECIFICITY?

Marco De Pinto¹, Francesca Coppi^2-3, Francesca Tampieri², Matteo Boschini², Giulio Leo², Vernizia Morgante², Rosario Rossi^2-4, Amelia Spinella², Giuseppe Boriani^2-4, Anna Vittoria Mattioli³, Dilia Giuggioli^1-3

¹Scleroderma Unit, Rheumatology Unit, Azienda Ospedaliero-Universitaria Policlinico di Modena, University of Modena an, Modena, ITALY, ²Cardiology Unit, Policlinico di Modena Hospital., Modena, ITALY, ³Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, ITALY, ⁴Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, ITALY

Introduction: Despite therapeutic advances, pulmonary arterial hypertension (PAH) still represents a leading cause of Systemic sclerosis (SSc)-related death, especially due to a delay in diagnosis. Screening algorithms, namely DETECT and ASIG, has been proposed in SSc patients, however both presents several limitations, with a low specificity and high referral rate to right heart catheterization (RHC).

TAPSE/PAPs ratio has recently emerged as a new predictive risk factor for PH and of cardiovascular events and mortality, however its role in SSc has been poorly investigated.

The aim of our study was to correlate the TAPSE/sPAP ratios with the hemodynamic parameters (mPAP, PVR) at the right heart catheterization (RHC) and clinical parameter associated with PAH.

Material and Methods: Single-center study in which we retrospectively analysed all the patients affected by SSc, according to ACR/EULAR classification criteria, who underwent RHC at the Cardiology Unit of Policlinic of Modena, from January 2018 to August 2023.

All SSc patients underwent recurrent clinical examination, routine blood chemistry analysis, functional and instrumental evaluation. All echocardiogram measurements were performed by senior researcher, maximum 12 months before RHC. P-values of <0.05 were considered significant.

Results: 50 patients (F/M 44/6) were enrolled in the study, 45 patients had a confirmed PH at RHC. A significant correlation between TAPSE/PAPs <0.6 ratio mm/mmHg and mean PAP at RHC and PVR was observed. Notably, a strong correlation with known risk factors for PH, namely uric acid elevation, right axis deviation, low 6-minute walking test distance, DLCO and tricuspid regurgitation velocity (TRV), was also seen.

Conclusions: TAPSE/sPAP ratio <0.6 mm/mmHg demonstrated to be a reliable predictive risk factor for PAH and also showed a strong correlation with clinical parameter associated with PAH. A prospective study is ongoing to confirm the promising role of TAPSE/PAPs ratio in SSc-associated PAH screening, in order to improve screening algorithm specificity and reduce the number of referrals for RHC.

P.207

APPLICATION OF REVEAL 2.0 SCORE AT DIAGNOSIS OF ALL-CAUSE PULMONARY HYPERTENSION IN A COHORT OF SYSTEMIC SCLEROSIS PATIENTS, TO DETERMINE ITS USEFULNESS AS A PROGNOSIS TOOL. A MULTICENTRIC STUDY

Ivette Casafont Solé¹, Laura Calvo², Anne Riveros¹, Judit Font¹, Pau Alcubilla³, Carlos De La Puente², Ivan Castellví⁴

¹Hospital Universitari Germans Trias i Pujol, Badalona, SPAIN, ²Hospital Universitario Ramón y Cajal, Madrid, SPAIN, ³Hospital Clínic de Barcelona, Barcelona, SPAIN, ⁴Hospital de la Santa Creu i Sant Pau, Barcelona, SPAIN

Introduction: Pulmonary arterial hypertension (PAH) is a leading cause of death in Systemic Sclerosis (SSc). REVEAL 2.0 score was developed to stratify their prognosis and 1-year survival. It demonstrated greater risk discrimination compared to European Society of Cardiology/European Respiratory Society strategy (ESC/ERS). REVEAL 2.0 had been validated in SSc-PAH. However, SSc can develop other etiology of pulmonary hypertension (PH).

There are no studies that apply REVEAL 2.0 to PH different than SSc-PAH.

Our objective is to apply REVEAL 2.0 in SSc cohort with all-cause PH and analyze its usefulness to predict one-year mortality in SSc patients.

Material and Methods: Retrospective multicenter study made in SSc-PH cohort of 3 expert centers in SSc. All SSc-PAH were diagnosed by right heart catheterization. Clinical, laboratory, haemodynamic and ecographic data were recorded. REVEAL 2.0 was applied at the disease diagnosis. We determined the comparison between REVEAL 2.0 and ESC/ERS scores, as well as the relationship between REVEAL 2.0 and 1-year mortality and death during follow-up.

Results: Data from 49 patients with SSc-PH was analyzed. Table 1 and 2 summarize the features of the sample.

During the follow-up REVEAL 2.0 showed that patients at intermediate risk had a HR of 6.76 (CI95% 0.7 - 62.3, p=0.09) of mortality in comparison with low risk patients. Patients at high risk presented higher mortality than low risk patients (p=0.039). The global model was statistically significant (p=0.025). Regarding the first year of follow-up, REVEAL 2.0 showed that patients at intermediate and high risk at diagnosis presented more mortality than low risk (p=0.039; p=0.021) (Table 3)

Regarding to ESC/ERS score during whole follow-up, patients at intermediate risk did not show differences compared to low-risk patients (p=0.096), while patients at high risk had a HR of 9.4 (CI95% 1.01 – 86.9, p= 0.048). At 1-year follow up, we did not observe differences comparing intermediate to low-risk (p = 0.077), but higher mortality was observed with high risk patients, HR 9.33 (CI95% 1.7 – 50.9, p = 0.01) (Table 4)

When comparing REVEAL 2.0 and ESC/ERS, we observed a correlation for low and high risk cathegories, but not for intermediate risk.

Conclusions: REVEAL 2.0 score could be a good tool to categorize the death risk for all-cause SSc-PH at first year of PH diagnosis. It correlates with ESC/ERS for low and high risk, but not for intermediate risk. REVEAL 2.0 seems to have more capacity for predicting mortality at 1 year and during the follow-up compared to ESC/ERS.

P.208

IMMUNOSUPPRESSION WITH TARGETED THERAPIES REDUCES MORBIDITY AND MORTALITY IN PRE-CAPILLARY PULMONARY HYPERTENSION ASSOCIATED WITH SYSTEMIC SCLEROSIS: A EUSTAR SENSITIVITY ANALYSIS BASED ON THE HEMODYN

Cosimo Bruni^1,2, Lorenzo Tofani³, Havard Fretheim⁴, Yannick Weber¹, Eric Hachulla⁵, Patricia Carreira⁶, Dilia Giuggioli⁷, Paolo Airò⁸, Elise Siegert⁹, Ulf Muller-Ladner¹⁰, Marco Matucci-Cerinic^2,11, Gabriela Riemekasten¹², Carmen-Pilar Simeon-Aznar¹³, Jeska De Vries-Bouwstra¹⁴, Lesley-AnnA Saketkoo¹⁵, Jorg Distler¹⁶, Alexandra Balbir-Gurman¹⁷, Ivan Castellví¹⁸, Elisabetta Zanatta¹⁹, Vanessa Smith²⁰, Cristopher Denton²¹, Britta Maurer²², Alessandro Giollo^19,23, Florenzo Iannone²⁴, Lorenzo Dagna¹¹, Marie-Elise Truchetet²⁵, Masataka Kuwana²⁶, Yannick Allanore²⁷, Yoshiya Tanaka²⁸, Mickael Martin²⁹, Edoardo Rosato³⁰, Ana-Maria Georghiu³¹, Francesco Del Galdo³², Kamal Solanki³³, Alessandra Vacca³⁴, Ines Cordeiro³⁵, Susana Oliveira³⁶, Laszlo Czirják³⁷, Marco Baresic³⁸, Francesco Paolo Cantatore³⁹, Valeria Riccieri⁴⁰, Krisstof Andréasson⁴¹, Lorinda Chung⁴², Carolina De Souza Müller⁴³, Daniela Opris-Belinski⁴⁴, Simona Rednic⁴⁵, Petros Sfikakis⁴⁶, Yair Levy⁴⁷, Vivien Hsu⁴⁸, Stefan Heitmann⁴⁹, Jorg Henes⁵⁰, Gabriele Moroncini⁵¹, Michele Iudici⁵², Ellen De Langhe⁵³, Ariane Herrick⁵⁴, CarloMaurizio Montecucco⁵⁵, Anna-Maria Hoffmann-Vold^1,4, Oliver Distler¹, on behalf of the EUSTAR collaborators.

¹Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland, ²Department of experimental and clinical medicine, Division of Rheumatology, Azienda Ospedaliero Universitaria Careggi, University of Florence, Florence, Italy, ³Department of Statistics, Computer Science, Applications, University of Florence, Florence, Italy, ⁴Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Oslo, Norway, ⁵Department of Internal Medicine and Clinical immunology, Huriez Hospital, University of Lille, F-59037 Lille, France, ⁶Servicio de Reumatología, Hospital 12 de Octubre, Avda. De Córdoba, S/N, 28041 Madrid, Spain, ⁷Scleroderma Unit, Rheumatology Unit, University Hospital of Modena and Reggio Emilia, Modena, Italy, ⁸Spedali Civili di Brescia, Scleroderma UNIT, UOC Reumatologia ed Immunologia Clinica, Piazzale Spedali Civili 1, 25123 Brescia, Italy, ⁹Department of Rheumatology, Charité University Hospital, Charité Platz 1D-10117 Berlin, Germany, ¹⁰Lehrstuhl für Innere Medizin mit Schwerpunkt Rheumatologie der Justus-Liebig-Universität Giessen, Abteilung für Rheumatologie und Klinische Immunologie, Kerckhoff-Klinik Bad Nauheim, Benekestr. 2-8, D-61231 Bad Nauheim, Germany, ¹¹Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UniRAR), IRCSS San Raffaele Hospital, Milan, Italy, ¹²Department of Rheumatology and Clinical Immunology, University Clinic Schleswig-Holstein, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany, ¹³Department of Internal Medicine, Systemic Autoimmune Diseases Unit, Hospital Universitario Vall d’Hebronh, Address of the Center:Passeig Vall d’Hebron 119-129,08035, Barcelona, Spain, ¹⁴Leiden University Medical Center, Department of Rheumatology, Leiden, the Netherlands, ¹⁵Tulane University and Louisiana State University Schools of Medicine / University Medical Center Scleroderma and Sarcoidosis Patient Care and Research Center, New Orleans, LA 70112, United States of America, ¹⁶Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany, ¹⁷B. Shine Rheumatology Institute, Rambam Health Care Campus, Rappaport Faculty of Medicine, Technion, Haifa, Israel, ¹⁸Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret 167 Barcelona, Spain, ¹⁹Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Padova, Via Giustiniani, 2, I-35128 Padova, Italy, ²⁰Ghent University Hospital, Department of Rheumatology, Ghent, Belgium; Ghent University Hospital, Department of Internal Medicine, Ghent, Belgium; Vlaams Instituut voor Biotechnologie (VIB), Inflammation Research Center (IRC), Unit for Molecular Immunology and Inflammation, Ghent, Belgium, ²¹Centre for Rheumatology, Royal Free and University College London Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, United Kingdom, ²²Department of Rheumatology and Immunology, Inselspital, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland, ²³Rheumatology Unit, Department of Medicine, University of Verona, Verona, Italy, ²⁴Rheumatology Unit - DiMePReJ - University of Bari, Italy, Piazza Giulio Cesare 11, 70124 Bari, Italy, ²⁵Department of Rheumatology, UMR5164 ImmunoConcept, Bordeaux University, Bordeaux University Hospital, CNRS, Raba Leon, Place Amelie, 33076, Bordeaux Cedex, France, ²⁶Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan, ²⁷Rheumatology A dpt, Paris 5 University, Cochin Hospital, 27 rue Faubourg Saint-Jacques, 75014 Paris, France, ²⁸University of Occupational and Environmental Health, Address of the Center:1-1 Iseigaoka Yahata-nishi, Kitakyushu 807-8555 Japan, ²⁹Department of Internal Medicine, INSERM U1313, Poitiers University, Poitiers University Hospital, 2 rue de la Milétrie, 86021 Poitiers cédex, France, ³⁰Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy, ³¹Department of Internal Medicine and Rheumatology, Ion Cantacuzino Clinical Hospital, 5-7 Ion Movila Street, 020475 Bucharest, Romania, ³²Raynaud’s and Scleroderma Programme, Institute of Rheumatic and Musculoskeletal Medicine, and Biomedical Research Centre, University of Leeds, 2nd Floor, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, United Kingdom, ³³Waikato Hospital, Rheumatology Unit, Private Bag 3200, Hamilton City, New Zealand, ³⁴Rheumatology Unit, University Hospital of Cagliari, Monserrato (CA), Italy, ³⁵Serviço de Reumatologia e Doenças Ósseas Metabólicas, Hospital de Santa Maria, CHLN, Avenida Professor Egas Moniz, 1649-035 Lisboa, Portugal, ³⁶Systemic Immunomediated Diseases Unit,Department of Medicine IV, Fernando Fonseca Hospital, Address of the center: 19 Venteira, 2720-276 Amadora, Portugal, ³⁷Department of Immunology and Rheumatology, Medical School, University of Pécs, H-7632 Pécs, Akác u.l., Hungary, ³⁸Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, University of Zagreb, School of Medicine, University Hospital Center Zagreb, Kišpatićeva 12, 10 000 Zagreb, Croatia, ³⁹Rheumatology Clinic – Department of Medical and Surgical Sciences, University of Foggia – Italy, ⁴⁰Department of Clinical, Internal and Cardiovascular Specialities, Sapienza University of Rome, Rome, Italy, ⁴¹Section of Rheumatology, Department of Clinical Sciences, Lund University, Lund, Sweden, ⁴²Division of Immunology and Rheumatology, Stanford University School of Medicine, 300 Pasteur Road, Palo Alto, CA 94403, USA, ⁴³Hospital de Clinicas da Universidade Federal do Parana, Rua General Carneiro, 181, Curitiba – Parana – Brazil, 80060-900, ⁴⁴Department of Internal Medicine and Rheumatology -Sf. Maria Hospital, University of Medicine and Pharmacy “Carol Davila” Bucharest, Romania, ⁴⁵Clinica Reumatologie, University of Medicine & Pharmacy “Iuliu Hatieganu” Cluj, Str. Clinicilor nr. 2-4, 400006 Cluj-Napoca, Romania, ⁴⁶Rheumatology Unit, First Propaedeutic and Internal Medicine, Athens University Medical School. Agiou Thoma 17, Goudi, Athens 11527, ⁴⁷Meir medical center, Address: 59 th tchernechovski st, Kfar-saba, Israel, ⁴⁸Rutgers- Robert Wood Johnson Medical School, Department of Medicine, Division of Rheumatology – 125 Paterson Street, MEB 458, French Street, New Brunswick NJ 08903, ⁴⁹Department of Rheumatology, Marienhospital Stuttgart, Böheimstrasse 37, D-70199 Stuttgart, Germany: Dr.Medele, ⁵⁰University Hospital Tuebingen, center for interdisciplinary rheumatology, immunology and autoinmmune diseases (INDIRA) Otfried Mueller-Strasse 10, 72076 Tuebingen, Germany, ⁵¹Clinica Medica, Azienda Ospedaliero-Universitaria delle Marche, Marche Polytechnic University, Ancona, Italy, ⁵²Division of Rheumatology, Internal Medicine Specialties, Geneva University Hospitals and University of Geneva, Switzerland, ⁵³Division of Rheumatology, University Hospitals Leuven, Leuven, Belgium, ⁵⁴The University of Manchester, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9PT, UK, ⁵⁵Unita’ Operativa e Cattedra di Reumatologia, IRCCS Policlinico S Matteo, 27100 Pavia, Italy

Introduction: Our previous EUSTAR analysis showed that targeted immunosuppressive therapies reduce the risk of mortality and precapillary pulmonary hypertension (precapPH) worsening in SSc-precapPH patients. As the efficacy of pulmonary arterial hypertension (PAH) drugs has been demonstrated in patients fulfilling the 2015 ESC/ERS precapPH definition (mPAP>=25 mmHg, PWP=<15 mmHg, PVR>=3 WU), we aimed to confirm the independent effectiveness of targeted therapies on morbidity and mortality when separating patients according to the new 2022 ESC/ERS precapPH definition (mPAP>=21 mmHg, PWP=<15 mmHg, PVR>=2 WU).

Material and Methods: SSc-precapPH patients from the EUSTAR cohort, fulfilling the 2022 ESC/ERS precapPH definition with at least 3 months follow-up, were eligible. Targeted therapies included abatacept, rituximab, tocilizumab, TNFi and JAKi. PrecapPH patients were categorized into group 1 (no ILD), mild ILD group 3 (ILD and FVC >=70%) and severe ILD group 3 (ILD and FVC<70%). The morbidity-mortality outcome was defined by the occurrence of either death or precapPH worsening (one of 6MWD decrease >=15%, worsening of NYHA class, onset of right heart failure, additional PAH medication, starting iv/sc prostanoids, lung transplantation, atrial septostomy). Death and precapPH worsening were also separate secondary outcomes.

We evaluated the association between therapies and time to first event with a multiple Cox regression model. Baseline covariates included the WHO precapPH class, the 2022 ESC/ERS precapPH definition, SSc-related risk factors for mortality, possible reasons for use of immunosuppresants and parameters of risk stratification for PAH.

Results: Among the 755 SSc-precapPH patients included, 68 (9%) received targeted therapies and 179/755 (23.7%) fulfilled only the 2022 ESC/ERS definition (Table 1).

With a median follow-up of 2.9 years, 70% patients developed a morbidity-mortality event. When adjusting for the 2022 ESC/ERS definition, targeted therapies were still associated with reduced risk of morbidity-mortality [HR 0.57, 95% CI 0.34-0.94] and both secondary outcomes [death, HR 0.42, 95% CI 0.20-0.87; precapPH worsening, HR 0.40, 95% CI 0.21-0.77] – Figure 1.

Similarly, the hemodynamic precapPH criteria did not affect the risk reduction of tocilizumab for morbidity-mortality (HR 0.35, 95% CI 0.16-0.79) and precapPH worsening (HR 0.18, 95% CI 0.04-0.77, respectively), and of rituximab for death (HR 0.28, 95% CI 0.08-0.93) – Figure 2.

Conclusions: Targeted immunosuppressive therapies are associated with reduced risk of mortality and precapPH worsening, independent from WHO group and the precapPH hemodynamic definition, supporting the use of the 2022 ESC/ERS precapPH definition as inclusion criteria in RCTs testing the impact of targeted therapies on long-term outcomes in SSc-precapPH.

P.209

CURRENT THERAPEUTIC APPROACH IN SYSTEMIC SCLEROSIS. THE PROBLEM OF PULMONARY FIBROSIS AND ITS MANAGEMENT

Panagiotis Athanassiou, Spyridon Mitsoulis, Nikolaos Koukosias, Lambros Athanassiou, Niki Sarianidou, Pavlos Tsakiridis

Department of Rheumatology, St. Paul's Hospital, Thessaloniki, GREECE

Introduction: Systemic sclerosis is an autoimmune fibrosing systemic disease which may be successfully managed, however it may also lead to progressive incurable disease affecting pulmonary function and may lead to death. Its pathogenesis is currently unknown and actively investigated. As its prognosis in cases of pulmonary involvement may be dismal, new therapeutic developments are underway to inhibit fibrosis. In particular, nintedanib is applied in order to inhibit pulmonary fibrosis.

The aim was to present cases of severe systemic sclerosis, followed up over a period of one year, which needed hospitalization and were therapeutically managed with immune modulating and antifibrotic agents.

Material and Methods: A cohort of 14 cases (13 female and 1 male) of severe systemic sclerosis patients, aged 49-71 years (mean 60.6 years), disease duration 6-29 years (mean 14.6 years) is presented. All patients needed hospitalization for the management of the disease.

Results: All patients had to be hospitalized for the management of the disease. Within this cohort 11 patients had pulmonary involvement and digital ulcers, while 2 had pulmonary involvement without digital ulcers and 1 had digital ulcers without pulmonary involvement. All patients needed management for the systemic manifestations of the disease. In 7 patients prednisolone was administered, in 5 patients azathioprine was given, methotrexate was given to 2 patients, 2 patient received rituximab and 1 patient received sildenafil. In 5 patients the dual endothelin receptor antagonist bosentan was administered for the management of digital ulcers, while 3 patients received the antifibrotic agent nintedanib. In 2 patients in this cohort, one male and one female, the disease had a fatal outcome.

Conclusions: Systemic sclerosis is a severe autoimmune systemic fibrosing disorder which needs active continuous management for all its manifestations. Pulmonary involvement may lead to a fatal outcome. However, nowadays the administration of nintedanib may improve quality of life and the disease outcome.

P.210

ATTITUDES AND BARRIERS TO PULMONARY ARTERIAL HYPERTENSION SCREENING IN SYSTEMIC SCLEROSIS PATIENTS: A SURVEY OF UK-BASED RHEUMATOLOGISTS

María Paula Álvarez¹, Yannick Allanore², Ivo Andrare³, Maya H. Buch^4,5, Gerry Coghlan⁶, Francesco Del Galdo^7,8, Chistopher P. Denton^9,10, Dinesh Khanna¹¹, David G. Kiely^12,13, John D. Pauling¹⁴, Sheila Ramjug¹⁵, Michael Hughes^16,17

¹Rheumatology department, Hospital Clínico San Carlos, Madrid, SPAIN, ²Rheumatology department, Cochin Hospital, APHP, Université Paris Cité, Paris, FRANCE, ³Echocardiography Department, Manchester University NHS Foundation Trust, Manchester, UNITED KINGDOM, ⁴Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Manchester Academic Health Sci, Manchester, UNITED KINGDOM, ⁵NIHR Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester, UNITED KINGDOM, ⁶National Pulmonary Hypertension Service, Royal Free Hospital, London, UNITED KINGDOM, ⁷Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UNITED KINGDOM, ⁸Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UNITED KINGDOM, ⁹Centre for Rheumatology and Connective Tissue Diseases, Royal Free Hospital, London, UNITED KINGDOM, ¹⁰UCL Division of Medicine, University College London, London, UNITED KINGDOM, ¹¹Scleroderma Program, University of Michigan, Ann Arbor, Michigan, USA, ¹²National Pulmonary Hypertension Service, Royal Hallamshire Hospital, Sheffield, UNITED KINGDOM, ¹³NIHR Biomedical Research Centre, Sheffield, Sheffield, UNITED KINGDOM, ¹⁴Department of Rheumatology, North Bristol NHS Trust, Southmead Hospital, Bristol, UNITED KINGDOM, ¹⁵Department of Respiratory Medicine, Northern Care Alliance NHS Foundation Trust, Salford Care Organisation, Salford, UNITED KINGDOM, ¹⁶Department of Rheumatology, Northern Care Alliance NHS Foundation Trust, Salford Care Organisation, Salford, Salford, UNITED KINGDOM, ¹⁷Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Manchester, UNITED KINGDOM

Introduction: Pulmonary arterial hypertension (PAH) affects approximately 10% of patients with SSc, and is a major cause of morbidity and mortality. PAH is often asymptomatic, and therefore proactive screening is crucial for early detection and improved survival, including through early treatment intervention. Although there are various proposed international guidelines for screening, there is currently no dedicated UK-based guidance. Our aim to explore current UK screening practices for SSc-PAH patients, including to identify barriers and potential solutions.

Material and Methods: A survey of 31 questions was developed with expert input from a multidisciplinary Steering Committee. The survey was widely disseminated among rheumatologists working in the UK.

Results: Fourty-four UK rheumatologists participated in the study, and the majority completed all the questions. Around half worked in university or general hospital (54.5% and 45.4%, respectively), and 37% in a specialised SSc unit.

The majority (91%) recognised that SSc-PAH is a significant cause of morbidity and mortality. Similarly, the vast majority indicated that they considered that PAH screening in SSc patients would help to achieve earlier diagnosis (97.7%), earlier treatment intervention (97.8%), and reduce morbidity rate (95.5.%). Most (88.7%) also considered that screening would reduce morality rate.

Most (85%) respondents screen patients with SSc for PAH every 12 months, and half 50% if the clinical situation changes (i.e., the development of new signs or symptoms). Fewer screen more often (every 6 months: (7.5 %)) or less frequently (every 2 years: 12.5 %)). Over half (60%) reported using the DETECT algorithm to screen for SSc-PAH, although other algorithms are also used by some respondents, including the ECS/ERS guidelines (10%) and ASIG algorithm (2.5%). All respondents utilised transthoracic echocardiogram, and the vast majority (95%) performed pulmonary function tests for screening purposes. Less commonly requested tests were NT-pro-BNP (62.5%), serum urate/uric acid (42.5%), and electrocardiogram (42.5%).

Various challenges and barriers were identified relating to SSc-PAH screening (Figure 1A), with the difficulty in interpreting results from other hospitals and extended wait times for diagnostic tests being the most reported (76% and 74%, respectively). Most respondents agreed that access to key investigations (87%), ongoing clinician education (82%), multidisciplinary meetings (79.5%), and better understanding of screening algorithms (79.5%) could be potential solutions (Figure 1B).

Conclusions: Rheumatologists recognise that SSc-PAH screening is crucial to improve outcomes including survival; however, variable practices exist. There are various barriers to SSc-PAH screening and we have identified a number of practical potential solutions.

P.211

MATERNAL AND FETAL OUTCOMES OF PROSPECTIVELY FOLLOWED PREGNANCIES IN SYSTEMIC SCLEROSIS: THE EXPERIENCE OF A MULTIDISCIPLINARY PREGNANCY CLINIC IN 2008-2023

Liala Moschetti¹, Laura Andreoli¹, Paolo Semeraro¹, Eleonora Pedretti¹, Andrea Lojacono², Cecilia Nalli¹, Francesca Crisafulli¹, Francesca Ramazzotto³, Daniele Lini¹, Matteo Filippini¹, Cristina Zanardini³, Micaela Fredi¹, Marco Taglietti¹, Chiara Loardi³, Franco Franceschini¹, Angela Tincani¹, Sonia Zatti³, Paolo Airo'¹, Maria Grazia Lazzaroni¹

¹Rheumatology and Clinical Immunology, ASST Spedali Civili and University of Brescia, Brescia, ITALY, ²Obstetrics and Gynecology, ASST Garda, Desenzano Del Garda, ITALY, ³Obstetrics and Gynecology, ASST Spedali Civili and University of Brescia, Brescia, ITALY

Introduction: Pregnancy in Systemic Sclerosis women is relatively infrequent and is characterized by possible increased risk of maternal and foetal complications. Considering the heterogenous nature of SSc in terms of type of organ involved and severity, counselling and management of pregnancy is particularly challenging and evolving over time.

The purpose of the study is to evaluate pregnancy outcome in a cohort of SSc patients followed in a dedicated multidisciplinary clinic with a team of Rheumatologists, Gynaecologists-Obstetrics and Neonatologists.

Material and Methods: Retrospective analysis of pregnancies in patients with SSc (2013 ACR/EULAR criteria) or undifferentiated connective tissue disease “at risk of SSc” (UCTD-SSc risk, according to Valentini 2020) prospectively followed in our Pregnancy Clinic (2008-2023).

Results: We included 44 pregnancies (4 ongoing) in 33 women: 23 SSc and 10 UCTD-SSc risk (Table 1). Median age at conception was 34 years and median disease duration was 62 months for SSc women (in 2 patients <2 years). In 35/44 cases (79%) a pre-conception counselling was provided, while in 9/44 pregnancies patients presented at 1st trimester.

None of the patients experienced worsening of disease manifestations during pregnancy, except for esophageal reflux easily manageable with anti-acids. After delivery, one patient with severe ILD who did not receive a pre-conception counselling had respiratory insufficiency and congestive heart failure; another patient with SSc onset <2 years with lcSSc anti-TopoI+ rapidly developed dcSSc and ILD. A patient with previous SRC had pre-eclampsia in her first pregnancy and gestational hypertension during the second one, both hesitated in live births >37w.

Regarding pregnancy outcomes (Table 2): excluding 4 ongoing pregnancies, the remaining 40 ended in 4 miscarriages <10w, one intrauterine death >10w and 35 live births (36 babies, one twin pregnancy; one perinatal death was recorded after pPROM at 24w). Preterm delivery (<37w) was recorded in 8 (23%), including 5 severe preterm <34w (14%), and pre-eclampsia in 3 (9%).

Conclusions: The retrospective analysis of an historical cohort of SSc pregnancies highlighted an increased frequency of preterm deliveries and hypertensive disorders as compared to general obstetric population, despite prophylaxis with LDA in 90% of patients.

A multidisciplinary dedicated setting is crucial to provide a preconception counselling and tailored management during pregnancy to reduce the rate of adverse outcomes. Patients with severe organ involvement and early diagnosis should deserve special attention.

Authors would like to thank GILS (Gruppo Italiano Lotta Sclerodermia) for substantially supporting this project.

P.212

DIFFERENCES IN THE PERCEPTION OF SYSTEMIC SCLEROSIS DISEASE MANAGEMENT BY SEX: REAL-WORLD FINDINGS FROM A MULTI-NATIONAL SURVEY

Isabel Truman, Nicola Massey, Daniel Twigg, Chloe Middleton-Dalby

Adelphi Real World, Bollington, UNITED KINGDOM

Introduction: Evidence demonstrates the clinical presentation of systemic sclerosis (SSc) differs by biological sex, with males experiencing more severe disease. Whether this difference influences patient-perceived disease management, remains unexplored. We investigated how female and male patients perceive their SSc through burden, management, and healthcare support.

Material and Methods: Data were drawn from the Adelphi SSc Disease Specific Programme™, a cross-sectional survey of rheumatologists and patients with SSc in France, Germany, Italy, Japan, Spain, United Kingdom, and United States of America between April-August 2022. Rheumatologists provided patient demographics and clinical characteristics. Patients reported symptoms, disease perception, and attitudinal data using a scale of 1 (completely disagree) to 10 (completely agree). Fisher’s Exact and t-tests were used to compare clinical characteristics between female and male patients. Linear regressions were performed on attitudinal statements, confounding for age, time diagnosed and SSc subtype (limited vs diffuse cutaneous SSc).

Results: Data for 560 patients (79.6% female) were reported. Female and male patients, respectively, had a similar mean [SD] age (52.2 [13.12] vs. 53.1 [10.93] years; p>0.05), mean [SD] time diagnosed (66.7 [68.56] vs. 57.3 [52.30] months; p>0.05), and proportion diagnosed with limited cutaneous SSc (54.7% vs. 62.3%; p>0.05). Rheumatologist-reported body areas most affected were fingers (82.1% vs. 71.1%; p=0.013), hands (73.1% vs. 65.8%; p>0.05), joints (33.4% vs. 36.0%; p>0.05), feet/toes (33.0% vs. 34.2%; p>0.05) and face (28.7% vs. 21.1%; p>0.05). The most frequent patient-reported symptoms were Raynaud’s phenomenon (70.2% vs 57.9%; p=0.014), restricted/painful movement of hands/fingers (49.8% vs. 50.0%; p>0.05), joint pain/stiffness/swelling (48.3% vs. 53.5%; p>0.05) and tiredness/fatigue (49.6% vs 39.5%; p>0.05), for females and males respectively.

Male patients provided significantly higher scores for statements “I know my SSc condition well and have learnt to manage it over a long period of time” (coefficient: 0.53; p<0.05), “I am always keen to try the next new treatment for SSc and will ask my doctor about anything new” (coefficient: 0.68; p<0.05), “I would change my doctor if I felt he/she was not willing to try new treatments” (coefficient: 1.33; p<0.001), and “It is very difficult to find an experienced doctor” (mean coefficient: 0.65; p<0.05).

Conclusions: Our data shows similarities in disease presentation between females and males but suggests perceptions of disease burden and management differ. This could be due to differences in self-management/coping strategies, or as a consequence of differing quality of care, highlighting the need to support patients based on more than their clinical profile.

P.213

SEX RELATED DIFFERENCES IN SYSTEMIC SCLEROSIS

Nikolaos Koletsos, Eleftherios Pelechas, Zoi Tziortzioti, Alexandros A. Drosos, Paraskevi V. Voulgari, Evripidis Kaltsonoudis

Rheumatology Clinic, University Hospital of Ioannina, Ioannina, GREECE

Introduction: Systemic Sclerosis (SSc) is a rare autoimmune disease with a female predominance. It is characterised by vasculopathy, inflammation and fibrosis of the skin and internal organs, leading to increased morbidity and mortality. Comorbidities are common and affect survival and the quality of life. The aim of our study was to examine the effect of sex in clinical manifestations, immunological characteristics and comorbidities in a cohort of Greek SSc patients.

Material and Methods: The study had a cross-sectional design and was conducted between January and September 2023. Consecutive patients with a diagnosis of systemic sclerosis according to the 2013 ACR/EULAR classification criteria were included. Patients were assessed in the outpatient clinic of a tertiary university hospital in Greece. During the study visit, all information about demographic characteristics, clinical and immunological features, as well as comorbidities was recorded.

Results: In total 149 adult SSc patients were included, of whom 64.2% had limited SSc. The female-to-male ratio was 4.7/1. Mean age at diagnosis was 48.7 ± 15.1 years and median follow up time was 5.4 (1.5 – 11.3) years. Median time to diagnosis after the onset of Raynaud’s was longer for female patients (24 vs 12 months respectively). Musculoskeletal involvement (arthralgias, arthritis and calcinosis) was more common in females, while heart rate abnormalities were more common in males. Moreover, forced expiratory flow at 25-75% of the forced vital capacity was significantly lower in female patients compared to males (72.8 ± 30.4 % vs 91.1 ± 41.7 %, respectively). A significantly higher percentage of antinuclear (ANA) and anti-centromere antibodies (ACA) were found in females (98.5% vs 88.5% and 30.8% vs 7.7%, for ANA and ACA respectively). A higher rate of smokers was found among men. Regarding comorbidities, osteoporosis, urinary tract infection, thyroid abnormalities and depression were more common in female patients.

Conclusions: In this cohort of SSc patients, heart involvement was more common in males, while small airway dysfunction and musculoskeletal involvement were more common in females. Females are, also, more likely to suffer from certain comorbidities. This study further supports the presence of sex-related differences in SSc, with important implications in disease management.

P.214

SYSTEMIC SCLEROSIS AND PREGNANCY OUTCOMES

Regina Goloeva, Olga Koneva, Lidia Ananyeva, Ludmila Garzanova

Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: To clarify pregnancy outcomes in patients with SSc and interstitial lung disease patients (ILD) using retrospective analysis.

Material and Methods: The study group included 74 women with SSc aged 20-40 years, and the control group 32 age-matching healthy women. Pts’ mean age was 32,5 ±5,7 yrs, disease duration 4,0 [3,0;9,0] yrs. 45 woman with SSc had ILD.

Results: Retrospective analysis of thematic maps of 74 patients with SSc revealed: 47 patients had 115 pregnancies, 70 of which ended with the birth of children; The frequency of unfavorable pregnancy outcome was similar in patients with SSc and in the control group. Patients with SSc are more likely to terminate pregnancy on their own volition 30,4% compared to control group 5,5%, p=0,02.

45 patients with ILD had 70 pregnancies, 36 of which ended with the birth of children; 3 women had 4 premature births at 28-35 weeks, one of which ended with perinatal death of the baby; 34 incomplete pregnancies in 18 patients: 30 medical abortions up to 12 weeks of gestation at the woman's request; 4 pregnancy complications had 4 patients, spontaneous abortion - 2, undeveloped pregnancy - 2. The frequency of unfavorable pregnancy outcome was similar in patients with ILD and without ILD group. Patients with ILD had more to terminate pregnancy on their own volition compared to patients without and compared to the control group.

15 children of 10 women were born during the course of the disease, all other children (55) were born before development of SSc.

Conclusions: Patients with ILD of SSc are more likely to terminate pregnancy on their own volition compared to control group.

P.215

TESTOSTERONE LEVELS IN PATIENTS WITH SYSTEMIC SCLEROSIS

Regina Goloeva, Lidia Ananyeva, Maris Cherkasova, Olga Koneva

Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: Introduction. In the literature there is evidence of a decrease in the concentration of levels total testosterone in interstitial lung disease.

Objective: To evaluate the testosterone levels in women with systemic sclerosis (SSc) and to analyze the relationship of the concentration of testosterone with the interstitial lung disease (ILD) and other organ lesions in SSc.

Material and Methods: The study included 74 SSc patients aged 18 to 40 years, the control group consisted of 32 healthy women, matched by age. Pts’ mean age was 32,5 ±5,7 yrs, disease duration 4,0 [3,0;9,0] yrs. 45 patients with SSc-ILD verified by multispiral computed tomography. Diffuse cutaneous subset of the disease had 33,7%, limited 56,8% and overlap 9,5%. The concentration of testosterone was determined by enzyme immunoassay (ELISA). The testosterone level of 0.2-3 ng/ml was taken as normative values. Values <0.2 were regarded as a decrease testosterone.

Results: In patients with SSc, the levels of testosterone were significantly lower 0.45 [0.2;0.96] versus 1.6 [0.97;2.5] (p=0.0001) in the controls. The concentration of testosterone in patients with ILD ware similar 0,48 [0,15;0,96] resus 0,45 [0,30;0,90] in patients without ILD. The frequency of testosterone reduction did not differ in patients with and without ILD (37% versus 20%, p=0.09). Pulmonary arterial hypertension was observed in 8 out of 74 patients in our study, 6 of them had low testosterone levels.

The testosterone levels (< 0.2 ng/ml) were significantly more often observed in the group of patients 27% versus 6.2% in the controls p=0,03. Correlation analysis showed association showed an association of low testosterone levels with heart r – 2,67, p=0,02 and esophageal lesions (r=-2,49, p=0,03). The correlation of testosterone with other manifestations of SSc and therapy was not revealed.

Conclusions: A decrease testosterone was significantly more often detected in women with SSs. We have not obtained an association of low testosterone levels with lung damage. Low testosterone levels correlated with damage to the heart and esophagus.

P.216

PREMATURE OVARIAN INSUFFICIENCY IN PATIENTS WITH SYSTEMIC SCLEROSIS

Regina Goloeva, Lidia Ananyeva, Maria Cherkasova, Olga Koneva

Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: The low prevalence of pregnancy in women with systemic sclerosis (SSc) is due to multi-factorial causes, including premature ovarian insufficiency (POI).

Objective: To determine the prevalence of POI and to analyze the relationship POI of the concentration of the level of anti–muller hormone (AMH) and with the organ lesions in SSc.

Material and Methods: The study included 74 SSc patients aged 18 to 40 years, the control group consisted of 32 healthy women, matched by age. Completed by all women, questionnaire covered details of obstetric history (characteristics of menstrual and reproductive function, presence of genital and extragenital pathology, previous pregnancies outcomes; previous intrauterine interventions, a history of coagulopathy). AMH quantitatively using standard chemiluminescent analysis on paramagnetic particles in blood serum. The AMG level of 1.0-10.6 ng/ml was taken as normative values. Values <1.0 were regarded as a decrease in ovarian reserve.

Results: Menstrual cycle disorders were noted by 31% of patients with SSc versus 6.2% in the control (p=0.004). POI was detected in 6.8% of patients with SSc and none in the control group (p=0.02). All 5 patients with POI had interstitial lung disease (ILD). Patients with SSc and POI did not differ in age, duration of illness, clinical manifestations and therapy of them patients without POI. The AMH levels were significantly lower in patients with SSc 1.4 [0.5;2.3] versus 2.4 [1.8;3.3] (p=0.002) in the control. A decrease in the ovarian reserve by the level of AMH was significantly more often detected in patients with SSc in 43% versus 9.4% in the control (p=0.002). Diffuse form (46.9%) and subacute course of the disease (53.1%) were more often detected in patients with SSc and with low ovarian reserve compared to those with normal ovarian reserve (23.8% (p=0.033); 23.4% (p=0.004)). The frequency of ILD and other organ lesions of SSc, immunological disorders, inflammatory markers, and the lipid spectrum in the groups did not differ depending on the level of AMH.

Conclusions: POI associated with decrease in ovarian reserve and ILD-SSc. A decrease in ovarian reserve was significantly more often detected in women with SSs. Low ovarian reserve was more often detected in patients with diffuse form and subacute course of the disease.

P.217

OVARIAN FUNCTION IN PATIENTS WITH SYSTEMIC SCLEROSIS

Regina Goloeva, Lidia Ananyeva, Ludmila Garzanova, Olga Koneva, Maria Cherkasova, Svetlana Glukhova, Tatiana Reshetnyak

Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: To evaluate the ovarian reserve in women with systemic sclerosis (SSc) and to analyze the relationship of the concentration of anti–muller hormone (AMH) with the main manifestations of the disease and therapy.

Material and Methods: The study included 74 SSc patients aged 18 to 40 years, the control group consisted of 32 healthy women, matched by age. The concentration of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, estradiol (E2) and testosterone was determined by enzyme immunoassay (ELISA), AMH quantitatively using standard chemiluminescent analysis on paramagnetic particles in blood serum. The AMG level of 1.0-10.6 ng/ml was taken as normative values. Values <1.0 were regarded as a decrease in ovarian reserve.

Results: In patients with SSD, the levels of AMH and testosterone were significantly lower than 1.4 [0.5;2.3] and 0.45 [0.2;0.96], respectively, versus 2.4 [1.8;3.3] (p=0.002) and 1.6 [0.97;2.5] (p=0.0001) in the control. The concentration of prolactin and E2 was recorded higher with SSDs - 22.23 [14.08;31.18] and 140.2 [102.43;179.74], respectively, against 10.2 [7.11;16.68], (p=0.000002) and [64.50;130.0] (p=0.002) in the control. A decrease in the ovarian reserve by the level of AMH was significantly more often detected in patients with SSD in 43% versus 9.4% in the control (p=0.002). The risk of AMH reduction in patients with SSD was 7 times higher compared to the control (OR=7,030, 95% CI: 1,97-25,11). The levels of the hormones studied were comparable in patients with low and normal ovarian reserve. Diffuse form (46.9%) and subacute course of the disease (53.1%) were more often detected in patients with SSD and with low ovarian reserve compared to those with normal ovarian reserve (23.8% (p=0.033); 23.4% (p=0.004)). The frequency of organ lesions of SSDs, immunological disorders, inflammatory markers, and the lipid spectrum in the groups did not differ depending on the level of AMH. There were also no differences in the regimens and doses of treatment with basic anti-inflammatory drugs and glucocorticoids.

Conclusions: The concentration of AMH and testosterone was significantly lower in patients with. A decrease in ovarian reserve was significantly more often detected in women with SSs. Low ovarian reserve was more often detected in patients with diffuse form and subacute course of the disease.

P.218

SYSTEMIC SCLEROSIS AND PARITY AS A RISK FACTOR - A FETAL MICROCHIMERISM THEORY

Mislav Radic¹, Hana Dogas¹, Andrea Gelemanovic², Dijana Perkovic¹, Josipa Radic¹

¹University Hospital of Split, Split, CROATIA, ²Mediterranean Institute for Life Sciences, Split, CROATIA

Introduction: Among well known theories regarding the development of systemic sclerosis (SSc) is a fetal microchimerism induced one. It has been suggested that in a pre-SSc period the number of completed pregnancies affects the development of SSc in otherwise healthy adults. Therefore, the aim of this systematic review and meta-analysis is to evaluate to what extent it affects and is parity a risk factor for developing SSc.

Material and Methods: Databases Scopus, PubMed, and Web of Science were searched on 1 September 2023 for studies that investigated the number of pregnancies and gynecological history in SSc patients prior to disease development. Included studies were observational studies assessing the number of pregnancies with a control group consisting of healthy patients. To assess methodological quality, the Nottingham-Ottawa Quality Scale was used. Random effects meta-analysis model was applied with inverse variance weighting and odds ratio with 95% CI was calculated.

Results: Of 599 studies evaluated in database search, 6 studies were included in meta-analysis consisting of 2639 SSc patients and 10683 healthy controls (HC). When observing parity (nulliparous/uniparous/multiparous), no statistically significant difference was found in SSc compared to HC (for nulliparous: z = 0.89, p = 0.37) with high heterogeneity present between studies (I2 = 75%, p < 0.01). However, there was a trend that nulliparous women had slightly higher risk of developing SSc when compared to parous women (OR 1.26, 95%-CI 0.76-2.09). Results depicted in Figure 1.

Conclusions: Contrary to some studies done in recent years, this meta-analysis shows that higher parity is not a risk factor in developing SSc. However, as there is high heterogeneity present between studies this suggests that there is a need for more structured and homogenous studies to be done in the future. Furthermore, observing parity along with possible fertility issues and pregnancy complications would further contribute in comprehending the actual risk factors and possible origins of SSc development.

P.219

CIGARETTE SMOKING INCREASES THE RISK OF ALL-CAUSE MORTALITY IN MALE PATIENTS WITH SYSTEMIC SCLEROSIS: AN ANALYSIS OF THE EUSTAR COHORT

Jacopo Ciaffi¹, Sophie Liem², Saad Ahmed², Eva Hoekstra², Piotr Wiland³, Tatsuya Atsumi⁴, Gabriella Szucs⁵, Alexandra Balbir-Gurman⁶, Laszlo Czirjak⁷, Elisabetta Zanatta⁸, Ina Koetter⁹, Jorg Henes¹⁰, Marco Matucci-Cerinic¹¹, Paolo Airo'¹², Francesco Ursini¹, Thomas Huizinga², Jeska De Vries-Bouwstra²

¹Medicine and Rheumatology Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, ITALY, ²Department of Rheumatology, Leiden University Medical Center, Leiden, THE NETHERLANDS, ³Wroclaw University of Medicine, Department of Rheumatology and Internal Diseases, Wroclaw, POLAND, ⁴Hokkaido University Hospital, Department of Rheumatology, Endocrinology and Nephrology, Sapporo, JAPAN, ⁵University Of Debrecen, Faculty Of Medicine, Department Of Rheumatology, Debrecen, HUNGARY, ⁶Rheumatology Institute, Rambam Health Care Campus, Haifa, ISRAEL, ⁷University of Pecs, Department Of Rheumatology And Immunology, Pecs, HUNGARY, ⁸Padova University Hospital, Rheumatology Unit, Padova, ITALY, ⁹Asklepios Clinic Altona, Medical Department 4, Rheumatology, Immunology, Nephrology, Hamburg, GERMANY, ¹⁰University Hospital and Faculty of Medicine, University of Tübingen, Internal Medicine II - Oncology, haematology, clini, Tubingen, GERMANY, ¹¹University of Florence, Dipartimento di Medicina Sperimentale e Clinica, Florence, ITALY, ¹²Asst Spedali Civili Of Brescia, Rheumatology And Clinical Immunology Unit, Brescia, ITALY

Introduction: Cigarette smoking is a risk factor for mortality in the general population but, in systemic sclerosis (SSc), evidence about the role of smoking in the evolution of the disease is lacking. In this study, we aim to determine whether smoking is a risk factor for reduced survival in SSc and whether smoking can contribute to the excess mortality observed in male patients.

Material and Methods: The EUSTAR database was analysed. Individuals with missing or inconsistent information about smoking status were excluded. The included patients were categorised as “never-smokers” or “ever-smokers” at the baseline visit. After stratification for sex, Kaplan–Meier estimates of time until death in ever-smokers and never-smokers were compared using a log-rank test. Follow-up time was censored at 15 years. Cox proportional hazards models adjusted for age were used to assess the risk of mortality in men and women, expressed as hazard ratios (HR) and 95% confidence intervals (95% CI). Incidence rates of mortality and 95% CI were calculated in men and women according to their smoking habit, considering never-smoking women as the reference category to determine the relative risk (RR) of death.

Results: Of the 12314 included patients, 10393 were females (84%) and 1921 were males (16%). In male patients, survival was significantly lower in ever-smokers compared to never-smokers (50% vs 60%, p <0.001), but no difference was found in ever-smoking and never-smoking female patients (75% vs 71%, p= 0.207) (Figure). In Cox regression analysis adjusted for age, smoking was associated with increased risk of mortality (HR 1.63, 95% CI 1.23 – 2.16, p= 0.001) in male patients, while no association emerged in women (HR 1.13, 95% CI 0.96 – 1.32, p= 0.148). Incidence rate for mortality was 1.77/100 patient-years in never-smoking women (reference category), 1.56/100 patient-years in ever-smoking women (RR= 0.88), 2.53/100 person-years in never-smoking men (RR= 1.43), 4.10/100 person-years in ever-smoking men (RR= 2.32). Thus, smoking increases the risk for mortality in male patients, but not in females.

Conclusions: We demonstrated for the first time that smoking exerts different effects on the risk of mortality in male and female patients. While the relative risk of death is comparable in women independently of smoking status, we found a significant association between cigarette smoking and reduced survival in men. In the effort to accurately risk stratify each individual, our results highlight that smoking might partially explain the excess mortality observed in male SSc patients.

P.220

INITIAL CHARACTERIZATION OF A SKIN SYMPTOM QUESTIONNAIRE FOR PATIENTS WITH SYSTEMIC SCLEROSIS

Jeong Min Yu¹, John VanBuren², Angela Child², Jessica Alvey², Lisa Mandl^1,3, Laura Pinheiro³, Shervin Assassi⁴, Elana Bernstein⁵, Flavia Castelino⁶, Lorinda Chung⁷, Luke Evnin⁸, Tracy Frech⁹, Faye Hant¹⁰, Laura Hummers¹¹, Dinesh Khanna¹², Kimberly Lakin¹, Dorota Lebiedz-Odrobina², Yiming Luo⁵, Ashima Makol¹³, Jerry Molitor¹⁴, Duncan Moore¹⁵, Carrie Richardson¹⁵, Nora Sandorfi¹⁶, Ami Shah¹¹, Ankoor Shah¹⁷, Victoria Shanmugam¹⁸, Brian Skaug⁴, Virginia Steen¹⁹, Elizabeth Volkmann²⁰, Jessica Gordon¹

¹Hospital for Special Surgery, New York City, USA, ²University of Utah, Salt Lake City, USA, ³Weill Cornell Medicine, New York City, USA, ⁴University of Texas Health Science Center at Houston, Houston, USA, ⁵Columbia University Irving Medical Center, New York City, USA, ⁶Massachusetts General Hospital, Boston, USA, ⁷Stanford University and Palo Alto VA Health Care System, Palo Alto, USA, ⁸Scleroderma Research Foundation, USA, ⁹Vanderbilt University Medical Center, Nashville, USA, ¹⁰Medical University of South Carolina, Charleston, USA, ¹¹Johns Hopkins University, Baltimore, USA, ¹²University of Michigan, Ann Arbor, USA, ¹³Mayo Clinic, Rochester, USA, ¹⁴University of Minnesota, Minneapolis, USA, ¹⁵Northwestern University, Chicago, USA, ¹⁶University of Pennsylvania, Philadelphia, USA, ¹⁷Duke University, Durham, USA, ¹⁸George Washington University, Washington D.C, USA, ¹⁹Georgetown University Medical Center, Washington DC, USA, ²⁰University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, USA

Introduction: The modified Rodnan Skin Score (mRSS) measures extent/severity of skin thickness in systemic sclerosis (SSc) but has several limitations, including its lack of patient input. The Scleroderma Skin Questionnaire (SSQ) is a novel patient-reported outcome (PRO) designed to capture patients’ skin symptoms. It has been collected at baseline and at 6-month intervals in CONQUER (Collaborative National Quality and Efficacy Registry), a multi-center, US-based registry of adults with early limited cutaneous (lc) and diffuse cutaneous (dc) SSc. This study sought to assess the psychometric properties of SSQ to generate evidence for its further use.

Material and Methods: The first section of the SSQ grades five skin symptoms (tight, painful, red, hard, itchy, rigid/stiff on 5-point Likert scales, from “not at all” to ‘severely”. Scores are graded from 0-4; higher=worse. Total SSQ is the average of all 5 scores). A second metric, the SSQ 6-Month, asks participants to compare current symptoms to those 6-months prior. Internal consistency was assessed with Cronbach’s alpha, and baseline response frequencies were used to investigate floor/ceiling effects. The associations between SSQ and the mRSS and legacy PROs [Scleroderma Health Assessment Questionnaire (SHAQ), Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29), Patient Global (PtGA), and Physician Global (PGA)] were explored using Pearson’s correlation. SSQ 6-Month was correlated with change in mRSS and in legacy PROs over 6-months mixed modeling with a bias-corrected confidence interval determined using cluster bootstrapping.

Results: Of 536 participants, SSQ was higher in patients with dcSSc compared with lcSSc (1.5 vs 0.9; p<0.001) (Table 1). It demonstrated internal consistency (alpha=0.90) and probable floor effect (Figure 1), which was more pronounced for lcSSc compared to dcSSc (p<0.001). SSQ was moderately correlated with mRSS (r=0.56), with stronger correlation in dcSSc (r=0.56) than lcSSc (r=0.22; all p<0.05). SSQ was strongly correlated with PROMIS-29’s physical and pain interference (r=-0.52 and 0.61), and with SHAQ’s HAQ and severity score (r=0.63 and 0.61). Similar trends were seen when stratifying by SSc subtype, baseline mRSS, and disease duration (all p<0.05; Table 2). SSQ 6-Month showed a poor correlation with 6-month change in mRSS (r=0.21; p<0.05).

Conclusions: In CONQUER, SSQ demonstrated internal consistency and moderate correlation with mRSS. SSQ showed moderate/strong correlations with a subset of legacy PROs. However, SSQ 6-Month showed weak correlation with change in the mRSS, suggesting either a poor recall for a 6-month time span or a disconnect between the patient perception and the mRSS. This study provides initial characterization of SSQ for future validation.

P.221

ATTITUDES AND FACTORS AFFECTING THE DECISION-MAKING REGARDING COVID-19 VACCINATION AMONG AUTOIMMUNE RHEUMATIC DISEASE PATIENT

Orathai Wantha¹, Ajanee Mahakkanukrauh², Kwankaew Tuydaung¹, Walailuk Donsrichan¹, Kanikar Yingyaun¹, Sumalee Kaewmeun¹, Siraphop Suwannaroj², Chingching Foocharoen²

¹Division of Nursing, Faculty of Medicine, Khon Kaen University, Khon Kaen, THAILAND, ²Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, THAILAND

Introduction: Coronavirus disease-2019 (COVID-19) vaccine hesitancy is a significant threat to the success of COVID-19 vaccination programs. We aimed to assess attitudes and factors affecting the decision-making vis-à-vis COVID-19 vaccination among patients with autoimmune rheumatic diseases (ARDs)

Material and Methods: A cross-sectional survey of adults with ARDs was conducted between January 2022 and April 2022. All enrolled ARDs patients were asked to answer a questionnaire about their attitudes regarding COVID-19 vaccination

Results: Three hundred patients were included with a female-to-male ratio of 2.5:1. The mean age of the patients was 49.2±15.6 years. Around 37% of patients who hesitated to get the COVID-19 vaccination were apprehensive regarding potential adverse events from the vaccine. About 25% (76 cases) were hesitant about vaccination, of which 15% were uncertain about the vaccine’s efficacy, and 15% thought the vaccine was unnecessary because they lived in rural areas where they practiced social distancing. “Family role as a non-working member” was the only factor strongly associated with hesitancy for vaccination (OR of 2.42 (95% CI 1.06-5.57)). The attitudes to vaccination showed that the patients were concerned about disease flaring and believed all medicine should be stopped before vaccination

Conclusions: Around one-quarter of ARDs sufferers hesitated to get COVID-19 vaccination. In addition, some patients were disinclined to get vaccinated because they were worried about its efficacy and/or associated adverse events. The findings help healthcare providers plan to counter negative attitudes toward vaccination in ARDs patients to protect them during the COVID-19 era.

P.222

COMPARISON OF PATIENT-REPORTED OUTCOME MEASURES WITH RADIOLOGICAL AND FUNCTIONAL PARAMETERS IN SYSTEMIC SCLEROSIS-RELATED INTERSTITIAL LUNG DISEASE

Duygu Temiz Karadag¹, Enes Basaran¹, Ozgur Cakir², Neslihan Gokcen¹, Ayten Yazici¹, Ayse Cefle¹

¹Kocaeli University Faculty of Medicine, Department of Internal Medicine, Division of Rheumatology, Kocaeli, TURKEY, ²Kocaeli University Faculty of Medicine, Department of Radiology, Kocaeli, TURKEY

Introduction: The diagnosis, severity, and progression of systemic sclerosis-associated interstitial lung disease (SSc-ILD) mainly depended on the results of pulmonary function tests, lung computed tomography (CT), and patient-reported outcomes. However, controversial and scarce data about the association between patient-reported outcomes and other parameters have been reported in different studies. Patient-reported outcome measures remain secondary to the others. Our study aimed to investigate the relationship between patient-reported outcomes, functional tests, and radiological parameters in patients with SSc-ILD in daily clinical practice.

Material and Methods: 48 patients with SSc-ILD who met the 2013 ACR/EULAR SSc classification criteria were included in the study. St. George Respiratory Questionnaire (sGRQ), Health Assessment Questionnaire (HAQ), and respiratory-related visual analog scale (respiratory-VAS) were administered to the patients. Patients were subjected to pulmonary function test and 6-minute walk test for functional capacity. The radiological parameters were derived from calculating the extent of fibrosis on chest CT semi-quantitatively.

Results: Demographic, clinical, and laboratory results of the patients included in the study are shown in Table 1. We found a negative correlation between the total sGRQ and FVC (r=-0.397, p=0.016); a positive between the symptom score and fibrosis extent on chest CT (r=0.347, p=0.041); and a negative between activity score and FVC (r=-0.502, p=0.002). We also found a correlation between respiratory-VAS and FVC (r=-0.369, p=0.045) and, between respiratory-VAS and oxygen saturation at the end of the 6-minute walking test (r=-0.418, p=0.033). There was a negative association between FVC and fibrosis extent on chest CT (r=-0.381, p=0.029).

Conclusions: Our study is one of the few studies investigating the link between patient-reported outcome measures, functional tests, and radiological parameters used in SSc-ILD. Our results showed that FVC, the primary outcome in ILD studies, was the parameter most correlated with the others. Since the parameters in our study provide complementary results, they should be used together to evaluate SSc-ILD patients.

P.223

UNDERSTANDING FRAILTY IN SYSTEMIC SCLEROSIS: CONTRIBUTING FACTORS AND PATIENT IMPACT

Pedro Miguel Teixeira, Susana P. Silva, Carolina Vilafanha, Carolina Mazeda, Gisela Eugenio, Anabela Barcelos

Rheumatology Department, Centro Hospitalar do Baixo Vouga, AVEIRO, PORTUGAL

Introduction: Frailty is characterized by an increased susceptibility to adverse health consequences resulting from a reduced physiological reserve. Systemic sclerosis (SSc) patients face a higher risk of developing frailty due to multisystemic involvement and damage accrual. This study explores the relationship between SSc and frailty using FRAIL-S scale to assess the vulnerability of SSc patients, associated risk factors and overall health impact.

Material and Methods: Unicentric, cross-sectional study of patients with SSc who fulfilled the 2013 ACR- EULAR classification criteria. Data on demographic, clinical, comorbidities, function (Scleroderma HAQ (SHAQ)), quality of life (EQ-5D) and laboratory variables were collected. Frailty was assessed using validated Portuguese versions of FRAIL-S, which ranges from 0 to 5, and patients were classified as robust (0), pre-frail (1-2) or frail (>2). Associated risk factors were evaluated using parametric and non-parametric tests accordingly.

Results: A total of 40 SSc patients were included: 34 (85%) were women and the mean age was 61,9±11,5 years. Most patients had limited disease (75%), while 8 (20%) had diffuse SSc and 2 (5%) had SSc sine scleroderma. Thirteen patients (32.5%) were identified as frail, 12 (30.0%) as pre-frail and 15 (37.5%) as robust. Frailty was associated with disease duration (p=0.016), interstitial lung disease (ILD) (p<0.001), gastrointestinal involvement (p=0.018), pulmonary arterial hypertension (PAH) (p=0.031), EQ5D (p<0.001), FACIT-F (p<0.001) and SHAQ VAS for overall (p<0.001), respiratory (p<0.001) and intestinal disease (p=0.006). There were no statistically significant differences regarding age, body mass index (BMI), Rodnan score, presence of Raynaud phenomenon, digital ulcers, calcinosis or inflammatory arthritis, acute phase reactants and specific auto-antibodies.

Conclusions: Physical frailty is prevalent in our cohort of SSc patients, particularly among those with longer disease duration and pulmonary or gastrointestinal involvement. This condition has also shown a significant influence on quality of life, fatigue and functional limitations. To confirm these findings and explore interventions that can enhance the overall health and well-being of these patients, further studies with larger cohorts are necessary.

P.224

CAUSES AND RISK FACTORS FOR DEATH IN JAPANESE SYSTEMIC SCLEROSIS

Kae Takagi¹, Hikari Hirose², Akiko Tochimoto², Yuki Ichimura², Tomoaki Higuchi², Yasushi Kawaguchi²

¹Adachi Medical Center, Tokyo Women's Medical University, Tokyo, JAPAN, ²Tokyo Women's Medical University, Tokyo, JAPAN

Introduction: SSc is characterized by tissue fibrosis, vascular damage, and immune abnormalities. Complications of interstitial lung disease (ILD)and pulmonary hypertension (PH) have been reported as poor prognostic factors. The purpose of this study was to investigate the causes and risk factors of death in SSc.

Material and Methods: This is a retrospective cohort study using the SSc database in our hospital between 2013 and 2021.We examined the cause of death, age at death, gender, comorbidities, autoantibodies, and treatment. SSc-related and unrelated death was defined based on EUSTAR (EULAR Scleroderma Trials And Research).

Results: Out of 458 SSc patients in our SSc database, 42 deaths (9 males, 33 females) were identified. The mean age at death was 63.9 ± 14.4 years. Cause of death was unclear in 7 cases. Of the 35 patients 21 (63.6%) were SSc-related. Of which, 12 (57.1%) were cardiovascular diseases mostly involving PH, respiratory diseases with ILD were 4 (19%), and gastrointestinal disorders were 4 (19%). Of the 14 non-SSc-related deaths, 7 (50%) were infections and 3 (20.1%) were malignancies. In the comparison between the death group and the survival group, PH, ILD, skin ulcer, diffuse type, male, and steroid treatment were significantly higher in the death group (P<0.001). In multivariate analysis, mRSS was most associated, and thus the diffuse type had higher mortality than the limited type.

Conclusions: The cause of death from SSc in Japan was mostly SSc-related. Complications at risk were pulmonary hypertension, interstitial lung disease, and skin ulcers. Despite advances in treatment, disease-related death, particularly pulmonary hypertension-related heart disease, remained the most common cause of death in SSc. Therefore, early diagnosis and therapeutic intervention to these complications, especially pulmonary hypertension, are important to improve the outcome. In addition, mRSS an indicator of severity is considered to be useful in predicting the outcome.

P.225

PREDICTORS OF ENERGY LEVELS IN SYSTEMIC SCLEROSIS PATIENTS

Yossra Suliman¹, Maitha Alfazari², Ali Alghaithi³, Daniel Furst⁴

¹Rheumatology and Rehabilitation department, Assiut University Hospital, Assiut, Egypt, Assiut, EGYPT, ²Tawam Hospital, Al Ain, United Arab Emirates, Al Ain, UNITED ARAB EMIRATES, ³Royal College of Surgeons, Dublin, Ireland, Dublin, IRELAND, ⁴Rheumatology division, David geffen school of medicine, University of California Los Angeles, USA, Los Angeles, USA

Introduction: Scleroderma (SSc) is a debilitating multi-system chronic disease, causing high morbidity and mortality rates. It is a fibrosing disorder of the skin and viscera that directly affects patient-related quality of life and mortality. We thus worked to identify and evaluate how the patient interprets their inability to work and maintain enough energy levels during daily activities. We hypothesized that there are abnormal constitutional symptoms in SSc patients (i.e. energy levels, and time to fatigue etc.) which may directly affect patient productivity, Our aim: to assess the proportion of SSc patients with abnormal energy levels, and to detect predictors that affect the energy level.

Material and Methods: Convenience sample of 175 SSc patients meeting the ACR/EULAR 2013 SSc criteria were recruited from Pacific Arthritis Scleroderma Clinic. Laboratory and clinical data were obtained from charts for statistical correlations. Data were cross-sectional and were from the first clinical record available, usually the first clinical visit.

Energy levels were assessed by the question “how is your energy?” and Fatigue was ascertained as “How long after you get up, do you start to get tired or fatigued?”. Answers were in hours, including 0 for fatigued immediately upon awakening to 12+(maximum); responses were in 0.5-hour increments.

Energy levels were dichotomized into two groups (low energy group who answered low-fair, and high energy group who responded, good or excellent.

Results: The 175 SSc patients’ characteristics were: mean age 53 (SD:14), female n=76 (89%), ILD n=41 ( 25%), mean MRSS 6 (5.6) Energy levels were reported low-fair in 101 (61%), Table 1.

Analysis of predictors of energy levels based on this dichotomized result, showed that Depression, and steroid use were strong predictors of low energy levels (p-value 0.0048,0.0171 respectively).

MD Global VAS, PT Global VAS, Pain VAS, HAQ-DI and Time to Fatigue, were identified as predictors of low energy levels (p =0.0001, 0.0001, 0.003,0.0026 and 0.0001 respectively)

Conclusions: Energy levels among other constitutional symptoms (fatigue, and pain) are significantly altered in SSc patients, more care is to be given to address possible causes, assessment tools and management plans.

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SELF-ASSESSMENT OF SCLERODERMA SKIN: VALIDATION OF THE PASTUL QUESTIONNAIRE

Julia Spierings¹, Voon H Ong¹, Paco W.J. Welsing², Michael Hughes³, John D. Pauling⁴, Francesco Del Galdo⁵, Ariane L Herrick³, Christopher P Denton¹

¹Div of Medicine, Dep of Inflammation, Centre for Rheumatology and Connective Tissue Diseases, Royal Free Hospital-UCL, London, UNITED KINGDOM, ²Dep of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, Utrecht, THE NETHERLANDS, ³Dep of Rheumatology, Northern Care Alliance NHS Foundation Trust, Salford Care Organisation, Salford, Manchester, UNITED KINGDOM, ⁴Dep of Rheumatology, North Bristol NHS Trust, Bristol, UNITED KINGDOM, ⁵Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, NIHR Leeds Biomedical Research Centre, Leeds, UNITED KINGDOM

Introduction: The PASTUL (Patient self-Assessment of Skin Thickness in Upper Limb) questionnaire was developed during covid to allow self-assessment of skin remotely in systemic sclerosis (SSc). The aim of this study was to validate PASTUL, evaluate responsiveness and assess impact of skin on quality of life.

Material and Methods: SSc patients were included in four UK centres. The PASTUL questionnaire specifies a grading of skin (normal, mild, moderate, severe thickness (0-3)) at eight sites corresponding to the modified Rodnan Skin Score (mRSS) with maximum score assigned to each site (Figure 1). Validity was assessed by comparing PASTUL scores with mRSS assessed by trained rheumatologists. Health Related Quality of Life (EQ5D5L and SSc HRQoL) and Scleroderma Skin Patient reported Outcome (SSPRO) were collected for construct validity, using Pearson’s correlation coefficient (0-0.19 = negligible, 0.2-0.39 = weak, 0.4-0.59 = moderate, 0.6-0.79 = strong, 0.8-1.0 = very strong). Test-retest reliability was estimated using intraclass correlation coefficient (ICC). Patients were followed for 6 months.

Results: 149 patients were included, mean age 56.6 years (SD 13.2), 79.7% female, 78 (56.1%) had limited cutaneous SSc (lcSSc) and 61 (43.9%) diffuse cutaneous SSc (dcSSc). Mean disease duration was 12.8 years (SD 9.2), mean mRSS was 9.2 (SD 6.2).

At baseline and 6 months follow-up, PASTUL and mRSS were strongly correlated (r=0.63 and r=0.78, p<0.001, respectively) (Table 1).

Test-retest reliability, assessed in 75 patients, was very good (ICC of 0.83, 95% CI 0.74-0.89, p<0.001). Mean PASTUL scores were 9.3 (SD 6.2) at baseline and 8.5 (SD 6.6) at 6 months follow-up. In patients with >2 points increase in mRSS, change in PASTUL was significant (p=0.042). The standardized response mean (SRM) of mRSS and PASTUL in patients with clinically significant change in HRQoL (>0.082) was 0.29 and 0.24, respectively.

Correlation between PASTUL and mRSS was moderate in lcSSc and strong in dcSSc (r=0.54 p<0.001, and 0.63 p<0.001, respectively). In patients with disease duration < 4 years, PASTUL was very strongly correlated with mRSS (r=0.84, p<0.001), and strongly correlated with HRQoL (EuroQoL, r= -0.67, p=0.004). SSPRO scores were not correlated with mRSS or PASTUL, but were moderatedly associated with SSc HRQoL scores (r=0.425, p<0.001).

Conclusions: Our preliminary results show that PASTUL is a valid and feasible outcome tool that adds a self-reported measure of skin severity to impact assessments like SSPRO. HRQoL was associated with skin thickening in patients with early disease. SRM was low and needs further assessment in a larger group.

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PRODUCTIVITY LOSS IN PORTUGUESE PATIENTS WITH SYSTEMIC SCLEROSIS – A PILOT STUDY

Susana P. Silva^1,2, Pedro Miguel Teixeira^1,2, Carolina Mazeda^1,2, Carolina Vilafanha^1,2, Gisela Eugénio^1,2, Anabela Barcelos^1,2

¹Centro Hospitalar Baixo Vouga - Department of Rheumatology, Aveiro, PORTUGAL, ²Egas Moniz Health Alliance Academic Clinical Center, Aveiro, PORTUGAL

Introduction: Systemic Sclerosis (SSc) is a chronic autoimmune disease that can affect patients of working age and significantly impact work productivity and quality of life. In Portugal, no study evaluating productivity in SSc with a portuguese translated and validated questionnaire has yet been performed.

Material and Methods: We conducted a cross-sectional study on patients, aged 18 or more, who fulfilled the ACR/EULAR 2013 classification criteria for SSc. Socio-demographic and clinical data were collected. To assess work productivity, we applied the questionnaire Work Productivity and Activity Impairment General Health (WPAI), with the calculation of 4 productivity parameters: absenteeism (A), presenteeism (P), overall work impairment (OWI), and daily activity impairment (DAI). Patients also completed the Scleroderma Health Assessment Questionnaire (SHAQ), Patient Global Assessment through visual analog scale (VAS PGA), the FACIT fatigue scale, and the health-related quality of life questionnaire EQ-5D. Spearman’s correlation (r) was used to assess the association between WPAI with other health-related outcomes.

Results: A total of 40 patients (85% female with a median age of 62 years old (ranging from 29 to 83)) agreed to participate in this study. Most of the patients had limited systemic sclerosis. Table 1 outlines the clinical and demographic features according to their work status. Less than half of the patients (n=16; 40%) were employed, and they were younger (p<0.001) and had a shorter duration of the disease (p=0.035). Retired patients exhibited more (but non-significant) organ involvement. We observed moderate to strong significant correlations between all WPAI parameters and gastrointestinal symptoms (r=0.345-0.833), respiratory symptoms (r= 0.640-0.894), and SSc global impact (A: r=0.663-0.796), reflecting the impact of these organs and SSc related incapacity/damage in work productivity. Regarding the other SHAQ parameters, Raynaud’s phenomenon only correlated with A (r=0.552) and DAI (r=0.421). Fatigue (FACIT) and EQ5D correlated negatively with all 4 parameters. In addition, HAQ (r=0-559-0.966) and PGA VAS (r=0.532-0.741) also showed an association with WPAI.

Conclusions: This study is the first to describe SSc-related work impairment in Portugal, using a validated tool. Though the study had limited data due to the small number of employed patients, moderate to strong correlations were found between WPAI parameters and various health outcome measures. However, further research with larger patient groups is necessary to verify these findings.

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PROs IN PATIENTS WITH SYSTEMIC SCLEROSIS IN REAL-WORLD PRACTICE

José Eloy Oller Rodríguez, Carmen Riesco Bárcena, Samuel Leal Rodríguez, Ernesto Tovar Sugrañes, Anderson Huaylla Quispe, Pablo Francisco Muñoz Martínez, Laura Mas Sánchez, Alba Torrat Noves, Daniel Ramos Castro, Belén Villanueva Mañes, Iago Alcántara Álvarez, Isabel Martínez Cordellat, Marta De La Rubia Navarro, Elvira Vicens Bernabeu, Rosa Negueroles Albuixech, Carmen Nájera Herranz, Inés Cánovas Olmos, Elena Grau García, Hikmat Charia, Luis González Puig, José Rafael Ivorra Cortés, José Andrés Román Ivorra

Hospital UIP LA FE - Rheumatology Department, Valencia, SPAIN

Introduction: Although the utility of PROs (Patient-Reported Outcomes) has been demonstrated in various systemic autoimmune diseases, including Systemic Sclerosis, there appears to be a lack of data on some PROs in clinical practice for this disease.

Material and Methods: A single-center descriptive cross-sectional study was conducted, including 42 patients diagnosed with Systemic Sclerosis according to the ACR-EULAR 2013 criteria, who were treated in our Rheumatology Department. These patients systematically completed the Spanish version of the SF36 quality of life questionnaire, as well as the HAQ (Health Assessment Questionnaire) and CHFS (Cochin Hand Function Scale) questionnaires, which assess functional disability. In addition, the EUSTAR activity index and the Medsger severity scale were calculated.

Results: Regarding the SF36 quality of life questionnaire, which can yield scores between 0 and 100 (with 100 representing optimal health), our sample obtained an average score of 51 (with a standard deviation of 29.5).

On the other hand, regarding the HAQ questionnaire, we obtained an average score of 0.78 points, with 64% of patients scoring below 1.

The average CHFS score in our sample was 14.29 out of a maximum of 90 points. 71% of our patients scored below 18.

Regarding the evaluation of disease activity, we used the EUSTAR activity index, which scores between 0 and 10 points. In our sample, the average score was 4.93 (1.45) points, strongly influenced by ESR values and subjective cutaneous worsening (despite an average mRSS of 4.81).

Finally, in order to assess disease severity, we used the revised Medsger scale, which reflects the involvement of a total of 9 organs, applying a score of 0 to 4 for each of them. In our sample, we found an average score of 4.05, with 72% of patients scoring below 4.

Conclusions: Our patients had an average of 51 points on the SF36 questionnaire, as well as a score of 0.78 on the HAQ and 14.29 on the CHFS. On the other hand, the average score on the EUSTAR activity scale was 4.93, while the average score on the revised Medsger scale was 4.05. The role of PROs in the disease can help us in the management of our patients.

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RELATIONSHIP BETWEEN CXCL4, CXCL8, GDF15 AND TGF-B LEVELS AND PROs IN SYSTEMIC SCLEROSIS

José Eloy Oller Rodríguez, Carmen Riesco Bárcena, Samuel Leal Rodríguez, Ernesto Tovar Sugrañes, Anderson Huaylla Quispe, Pablo Francisco Muñoz Martínez, Laura Mas Sánchez, Alba Torrat Noves, Daniel Ramos Castro, Belén Villanueva Mañes, Iago Alcántara Álvarez, Isabel Martínez Cordellat, Marta De La Rubia Navarro, Elvira Vicens Bernabeu, Rosa Negueroles Albuixech, Elena Grau García, Hikmat Charia, Carmen Nájera Herranz, Inés Cánovas Olmos, Luis González Puig, José Rafael Ivorra Cortés, José Andrés Román Ivorra

Hospital UIP LA FE - Rheumatology Department, Valencia, SPAIN

Introduction: Despite the usefulness of Patient-Reported Outcomes (PROs) in daily clinical practice, there seems to be a scarcity of data regarding the relationship between certain PROs and biomarkers of Systemic Sclerosis.

Material and Methods: A descriptive cross-sectional single-center study was conducted, including patients diagnosed with Systemic Sclerosis according to the 2013 ACR-EULAR criteria, treated at our Rheumatology Department. These patients systematically completed the Spanish version of the SF36 quality of life questionnaire, as well as the HAQ (Health Assessment Questionnaire) and CHFS (Cochin Hand Function Scale) questionnaires, which assess functional disability. In addition, the EUSTAR Activity Index and the Medsger Severity Scale were calculated. Furthermore, serum levels of CXCL4, CXCL8, GDF15, and TGF-β were obtained and we assessed to correlate them with findings derived from the PROs.

Results: A total of 42 patients were included. In Table 1, we can observe the average scores of the different PROs in our sample, as well as the score range for each PRO.

Afterwards, we explored a hypothetical correlation between CXCL4, CXCL8, GDF15, and TGF- β serum levels and PRO scores, but only found a significant correlation between GDF15 levels and the EUSTAR Activity Index (p=0.001), as depicted in Figure 1.

Conclusions: We found an association between serum levels of GDF15 and higher scores on the EUSTAR Activity Index in our SSc patients.

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THE ASSOCIATION OF RESILIENCE AND POSITIVE MENTAL HEALTH IN SYSTEMIC SCLEROSIS: A SCLERODERMA PATIENT-CENTERED INTERVENTION NETWORK (SPIN) COHORT CROSS-SECTIONAL STUDY

Marieke Neyer¹, Richard Henry^{1, 2}, Marie-Eve Carrier¹, Linda Kwakkenbos³, Gabrielle Virgili-Gervais¹, Robyn Wojeck⁴, Amanda Wurz⁵, Amy Gietzen⁶, Karen Gottesman⁷, Geneviève Guillot⁸, Amanda Lawrie-Jones⁹, Maureen Mayes¹⁰, Luc Mouthon¹¹, Warren Nielson¹², Michelle Richard¹³, Maureen Sauvé¹⁴, Daphna Harel¹⁵, Vanessa Malcarne¹⁶, Susan Bartlett¹⁷, Andrea Benedetti¹⁸, Brett Thombs^1,2,18

¹Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, CANADA, ²Department of Psychiatry, McGill University, Montreal, CANADA, ³Department of Clinical Psychology, Behavioural Science Institute, Radboud University, Nijmegen, THE NETHERLANDS, ⁴University of Rhode Island, Kingston, USA, ⁵School of Kinesiology, University of the Fraser Valley, Chilliwack, CANADA, ⁶National Scleroderma Foundation, Tri-State Chapter, Binghamton, USA, ⁷National Scleroderma Foundation, Los Angeles, USA, ⁸Sclérodermie Québec, Longueuil, CANADA, ⁹Scleroderma Australia, Melbourne, AUSTRALIA, ¹⁰University of Texas McGovern School of Medicine, Houston, USA, ¹¹Service de Médecine Interne, Centre de Référence Maladies Autoimmunes Systémiques Rares d'Ile de France, Hôpital Cochin, Paris, FRANCE, ¹²Department of Psychology, Western University, and Lawson Research Institute, London, CANADA, ¹³Scleroderma Atlantic, Halifax, CANADA, ¹⁴Scleroderma Society of Ontario, Hamilton, CANADA, ¹⁵New York University, New York, USA, ¹⁶Department of Psychology, San Diego State University, San Diego, USA, ¹⁷Research Institute of the McGill University Health Centre, Montreal, CANADA, ¹⁸Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, CANADA

Introduction: People with systemic sclerosis (SSc) face numerous challenges, including fatigue, pain, difficulty sleeping, and psychological concerns, including symptoms of anxiety and depression. Resilience is defined as the ability to maintain mental health amidst adversity. The potential role of resilience in protecting mental health in individuals with SSc has not been evaluated. A previous study using baseline data from the Scleroderma Patient-centered Intervention Network (SPIN) Cohort identified five classes of people with SSc (“low,” “normal,” “high,” “very high,” and “high/low”) based on patient-reported outcomes (fatigue, pain, sleep, anxiety, depression). Across four classes (“low,” “normal,” “high,” and “very high”), progressively greater disease severity was linked with higher mental health symptoms and poorer patient-reported outcomes. The “high/low” class, however, displayed positive mental health despite high levels of disease severity and poorer patient-reported outcomes. Our objective was to investigate whether resilience is associated with these classes.

Material and Methods: SPIN participants completed the 10-item Connor-Davidson-Resilience Scale (CD-RISC-10) (score range = 0-40) and PROMIS v2.0 domains (Fatigue 4a, Pain 4a, Sleep Disturbance 4a, Anxiety 4a, Depression 4a) during follow-up assessments from August 2022 to January 2023. We employed latent profile modelling to re-identify five classes similar to those in the previous study and conducted multiple linear regression to compare resilience levels across classes, controlling for sociodemographic and disease variables obtained both through self-report by participants and physicians.

Results: The mean CD-RISC-10 score was 27.7 (N = 1054, standard deviation [SD] = 7.3). Resilience decreased progressively across “low” to “very high” classes (mean difference 4.7 points per step). The “high/low” class deviated from this pattern. Multiple linear regression showed the “high/low” class exhibited significantly higher resilience scores than the “high” class (6.0 points, 95% confidence interval [CI] 4.9 to 7.1 points; standardized mean difference [SMD]= 0.83, 95% CI 0.67 to 0.98), despite experiencing similar disease severity, fatigue, pain interference, and sleep disturbance outcomes as the ”high class”.

Conclusions: Overall, we found that individuals with greater disease severity and worse patient-reported outcomes generally reported lower resilience. However, a unique class of patients displayed high resilience and positive mental health despite substantial disease severity, fatigue, pain, and sleep disturbance. These findings suggest that resilience may influence the association of SSc symptom severity and mental well-being and the potential for resilience-focused interventions. Future research should explore resilience factors, including coping strategies employed by highly resilient individuals with SSc.

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CONCURRENT CRITERION VALIDITY OF THE ASSESSMENT OF SYSTEMIC SCLEROSIS – ASSOCIATED RAYNAUD PHENOMENON QUESTIONNAIRE AND NAILFOLD CAPILLAROSCOPY IN SYSTEMIC SCLEROSIS ASSOCIATED RAYNAUD PHENOMENON

Krishnasai Abhis Madathanapalli¹, Kyra Ann Shelton², Amrita Makhijani², Areeka Memon³, William Odell¹, Stephanie Perez¹, Baran Ilayda Gunes¹, Sophia Esme Kujawski¹, F. Perry Wilson², Lan Yu⁴, John Pauling⁵, Monique Hinchcliff¹

¹Yale School of Medicine, Department of Rheumatology, Allergy, and Immunology, New Haven, USA, ²Yale School of Medicine, Department of Medicine, Clinical and Translational Research Accelerator, New Haven, USA, ³University of Connecticut School of Medicine, Department of Internal Medicine, Farmington, USA, ⁴University of Pittsburgh Medical Center, Division of Rheumatology and Clinical Immunology, Pittsburgh, USA, ⁵University of Bath, Department of Pharmacy and Pharmacology, Bath, UNITED KINGDOM

Introduction: There is a growing need to establish accurate methods to quantify the severity and symptom burden of systemic sclerosis-associated Raynaud phenomenon (SSc-RP). For patients with SSc-RP, we performed nailfold capillaroscopy (NFC) and administered the newly developed Assessment of Systemic Sclerosis – Associated Raynaud Phenomenon (ASRAP) questionnaire to investigate the concurrent criterion validity of these modalities.

Material and Methods: Healthy controls (HC) (n=15) and patients who fulfilled ACR/EULAR 2013 SSc Classification Criteria with RP symptoms (n=74) were prospectively recruited from December 2021 to July 2023. Following a clinic visit, patients completed the ASRAP questionnaire (range 20-80, with higher scores indicating worse symptoms) and underwent NFC of the bilateral fingers, excluding the thumb performed using the Dinolite™ (AF4515-N2UT) microscope. A blinded assessor classified NFC as having or lacking the “scleroderma pattern” as previously described. Prevalence of specific NFC morphological abnormalities (Fig. 3) was recorded. Software was used to assess the distal NFC row, and a semi-quantitative score (0 = no changes, 1 = <33%, 2 = 34–66%, 3 = > 67%) was generated to report the proportion of changes consistent with the scleroderma pattern. Descriptive statistics, univariable linear regression, and Spearman's Rho were used to investigate associations between NFC semi-quantitative score, ASRAP score, and clinical characteristics (Stata, v.17.0, College Station, TX).

Results: Patients with SSc-RP vs. HC were predominantly white (n=56, 79% vs. n=11, 73%) women (n=61, 86% vs. n=14, 93%) with a median (IQR) age of [60 (51-67) vs. 53 (46-58)], respectively. The scleroderma NFC pattern was more prevalent in SSc patients vs. HC (82% vs. 7%, p<0.001) and specific abnormalities tended to be higher in SSc (Table 1). In SSc, the mean (SD) ASRAP score was 44.39 ±10.5 and correlated significantly with the mean (SD) semi-quantitative score (1.45 ± 1.19) (rho 0.24, p=0.03). In patients studied in winter, this correlation was stronger (rho 0.35, p=0.03) (Figures 1 &2). On comparing patient characteristics and ASRAP scores, women had significantly higher ASRAP scores compared to men (Beta=[-11.75], p=0.001) and patients with a history of digital ulcers had a significantly higher ASRAP score compared to those without (Beta=[-7.34], p=0.03) (Figures 4 &5).

Conclusions: Dinolite NFC is a convenient and sensitive tool to quantify the severity of microvascular changes in SSc-RP. Patients with more NFC abnormalities (higher semi-quantitative score) had worse symptoms (higher ASRAP scores) with stronger correlation in winter months. Sex and history of digital ulcers appeared to influence ASRAP scores.

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GIANT CELL ARTERITIS OVERLAP IN SYSTEMIC SCLEROSIS AND MIXED CONNECTIVE TISSUE DISEASE TREATED WITH TOCILIZUMAB: CASE REPORTS AND LITERATURE REVIEW

Marie-Laurence Laliberté¹, Justine Lafleur-Careau¹, Charles Leduc², Jean-Paul Makhzoum³, Frédéric Lefebvre⁴, Josiane Bourré-Tessier⁴, Sabrina Hoa⁴

¹Faculty of Medicine, Université de Montréal, Quebec, CANADA, ²Department of Pathology, Centre hospitalier Université de Montréal, Quebec, CANADA, ³Division of Internal Medicine, Department of Medicine, Hôpital Sacré-Coeur de Montréal, Quebec, CANADA, ⁴Division of Rheumatology, Department of Medicine, Centre hospitalier Université de Montréal, Quebec, CANADA

Introduction: The co-existence of systemic sclerosis (SSc) and a primary vasculitis is rare, with most reported cases consisting of ANCA-associated vasculitis. Overlap of SSc or mixed connective tissue disease (MCTD) and giant cell arteritis (GCA) have rarely been reported. We wish to report the first cases of SSc/MCTD-GCA overlap to be treated with tocilizumab.

Material and Methods: Retrospective chart review of presentation and evolution on tocilizumab of two patients with SSc/MCTD-GCA overlap, and literature review.

Results: The first patient is a 75-year-old woman with a 3-year history of limited anti-centromere-positive SSc presenting with 6 weeks of bitemporal headaches and jaw claudication, left anterior ischemic optic neuropathy, and elevated inflammatory markers. The second patient is an 80-year-old woman with a 40-year history of MCTD with anti-U1-RNP autoantibodies and sclerodactyly, presenting with 3 months of bilateral morning headaches, three episodes of amaurosis fugax in her left eye, and normal inflammatory markers. Anti-neutrophil cytoplasmic antibodies were negative, and Doppler ultrasonography was positive for halo and compression signs in both patients. Biopsy of the left temporal artery showed an active lymphohistiocytic arteritis in the first patient, whereas cerebral MRI demonstrated right temporal enhancement compatible with temporal arteritis in the second patient.

Given the potential risk for scleroderma renal crisis, intermediate doses of intravenous methylprednisolone and oral prednisone were given to the first patient, and tocilizumab was added as a steroid-sparing agent for a total period of two years. Six months after tocilizumab cessation, her giant cell arteritis relapsed with large vessel vasculitis on PET scan and Doppler ultrasonography, requiring resumption of prednisone and tocilizumab. The second patient was treated with tocilizumab, intravenous methylprednisolone and a 6-month prednisone taper following the GiACTA protocol, with resolution of symptoms and no residual ophthalmologic deficit. Neither patient developed renal crisis.

Only seven other cases of GCA and SSc overlap have been reported since 1978: all were women aged 64 to 82, five had limited SSc, and all were treated with glucocorticoids alone. No case of MCTD and GCA overlap has yet been reported.

Conclusions: We report the first two cases of SSc/MCTD with GCA overlap treated with tocilizumab. Given the potential risk of glucocorticoids exposure in SSc and the role of IL-6 in both SSc and GCA, tocilizumab may be considered as a steroid-sparing agent in the context of overlapping GCA. Despite its rarity, GCA should be added to the differential diagnosis of headaches in SSc, given its potentially life-threatening consequences.

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LONGITUDINAL CHANGES IN THE SCLERODERMA HEALTH ASSESSMENT QUESTIONNAIRE VISUAL ANALOGUE SCALES IN PATIENTS WITH SYSTEMIC SCLEROSIS: A RETROSPECTIVE COHORT STUDY

Michael Hughes¹, Yvonne Sylvestre², Joanne Manning¹, Melissa Mandzuk¹, Muditha Samaranayaka¹, Graham Dinsdale¹, Ariane Herrick^1,3,4

¹Northern Care Alliance NHS Foundation Trust, Salford Care Organisation, Salford, UNITED KINGDOM, ²Centre for Biostatistics, The University of Manchester, Manchester, UNITED KINGDOM, ³Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Manchester, UNITED KINGDOM, ⁴NIHR Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester, UNITED KINGDOM

Introduction: The aim of our study was to examine the course, impact of baseline predictors, and relationship with functional ability, of the six Scleroderma Health Assessment Questionnaire (SHAQ) visual analogue scales (VAS) over time in patients with SSc.

Material and Methods: A retrospective analysis of data from patients attending annual review visits at a single tertiary SSc center between 2005 and February 2020. Linear Mixed-effect models were used to assess longitudinal trajectories and the effect of potential prognostic factors on the six different SHAQ VAS, apart from finger ulcers where the VAS scale was dichotomised (presence/absence) and analysed using a random intercept logistic regression model. To assess whether longitudinal changes in SHAQ VAS correlated with the HAQ-DI and 11-point scleroderma functional index, we obtained the gradients of individual linear regression models, overall and by disease type.

Results: 537 patients with at >2 available time-points were included. Patients were followed for a mean of 6.8 (SD=±4.2) years, and a mean of 6.4 (SD=±3.7) review visits. Seventy-five per cent of patients had the limited cutaneous subset. The mean (SD) disease duration (defined as the first non-RP symptom) were 7.6 (11.9) and 8.0 (8.2) years, respectively.

Time-in-study (Table 1) was associated with increase in VAS intestinal (p=0.004), overall disease (p=0.001) and presence of ulcers (p=0.013). There was a trend (Table 1) which did not reach statistical significance observed concerning RP VAS (p=0.068) and VAS breathing (p=0.074), but no difference with VAS pain (p=0.183).

Time since RP onset showed a significant negative association with VAS pain (b=-0.01 [95%CI = -0.01 to -0.00], p=0.032). Age had a significant negative effect on intestinal VAS (b=-0.01 [95%CI = -0.01 to -0.00], p=0.040). Presence of ulcers increased with disease duration (OR=0.97 [95%Cl = 0.94 to 1.00], p=0.026), and in those with diffuse disease (OR=0.54 [95%CI = 0.31 to 0.95], p=0.033). For patients who were anti-RNP positive (compared to negative), the overall disease score VAS was higher (b=0.23, 95%Cl = 0.00 to 0.45, p=0.048) higher.

All correlations between SHAQ VAS scales and function (HAQ-DI and 11-point scleroderma functional index) were positive (Table 2), although the strengths of these associations were variable, and almost exclusively stronger in patients with diffuse disease.

Conclusions: Longitudinal assessment of the SHAQ VAS scales provides important insights into disease trajectory. We have identified baseline factors associated with VAS outcomes, and associations with function over time.

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IMPROVEMENT ACROSS ORGAN SYSTEM, PHYSICIAN AND PATIENT REPORTED OUTCOME MEASURES OVER A 36-TIME PERIOD IN THE JUVENILE SYSTEMIC SCLERODERMA INCEPTION COHORT

Ivan Foeldvari¹, Jens Klotsche², Ozgur Kasapcopur³, Amra Adrovic³, Kathryn Torok³, Brian Feldman³, Maria Teresa Terreri³, Ana Paula Sakamoto³, Jordi Anton³, Simone Appenzeller³, Edoardo Marrani³, Tadey Avcin³, Maria Katsicas³, Dana Nemcova³, Maria Jose Santos³, Flavio Sztajnbok³, Lillemor Berntson³, Jürgen Brunner³, Gerd Horneff³, Sindhu Johnson³, Tilmann Kallinich³, Mikhail Kostik³, Kirsten Minden³, Farzana Nuruzzaman³, Anjali Patwardhan³, Nicola Helmus¹

¹Hamburg Center for Paediatric and Adolescent Rheumatology, Hamburg, GERMANY, ²German Rheumatism Research Center, Berlin, GERMANY, ³jSSc Collaborative Group, Hamburg, GERMANY

Introduction: Juvenile systemic sclerosis (jSSc) is an orphan disease with a prevalence of 3 in 1, 000, 000 children. The Juvenile Systemic Scleroderma Inception cohort (jSScC) is the largest cohort of jSSc patients in the world. The jSScC collects longitudinal data prospectively in jSSc, allowing the evaluation of the development of organ involvement and patients and physician reported outcomes in jSSc over time.

Material and Methods: The jSScC enrolls jSSc patients who developed the first non-Raynaud’s symptom before the age of 16 years and are under the age of 18 years at the time of inclusion. We reviewed jSScC patient clinical data and patient and physician reported outcomes of those with 36 months follow up from the time of inclusion until 1st of April 2023.

Results: We could extract data of 74 patients, 74% with diffuse cutaneous subtype. The female/male ratio was 3.6:1. 89% of the patients were Caucasian. Median age of onset of Raynaud symptom was 9.3 years and the median age of onset of non-Raynaud symptom was 10.3 years. Median disease duration was 2.3 years at the time of inclusion in the cohort(T0). Ninety percent of the patients were treated with disease modifying anti-rheumatic drugs at T0 and 90% after 36months (T36). Four clinical parameters improved significantly over time: the median modified Rodnan skin score decreased from 10 to 7 (p=0.041), the number of patients with swollen joints decreased from 16% to 4% (p=0.014), the number of patients with elevated CK value decreased from 25% to 9%(p=0.042) and the number of patients with muscle weakness decreased from 16% to 3% (p=0.009). All other organ involvement did not show any statistically significant change from T0 to T36.

Three of the four patient reported outcomes improved significantly from T0 to T36: patient reported disease activity(VAS 0 – 100) from 40 to 20 (p=0.014), patient reported disease damage(VAS 0 – 100) from 40 to 20 (p=0.005), patient reported Raynaud activity(VAS 0 – 100) from 20 to 10 (p=0.034). One of the three physician reported outcomes improved significantly: the physician global disease activity (VAS 0 – 100) from 30 to 15 (p=0.001).

Conclusions: Skin and musculoskeletal clinical features improved significantly over 36 months. It is reassuring that major internal organ manifestations, such as cardiac, pulmonary and gastrointestinal were stable. No renal crisis occurred over the 36-month time period. The patient and physician-reported outcomes had the most positive impact over the 36 months period in this large international cohort.

P.235

COMORBIDITY BURDEN IN SYSTEMIC SCLEROSIS : THE SYSTEMIC SCLEROSIS COMORBIDOME

Thomas Fauthoux, Damien Brisou, Estibaliz Lazaro, Julien Seneschal, Joel Constans, Sophie Skopinski, Pierre Duffau, Elodie Blanchard, Cecile Bordes, Marie-Elise Truchetet

Chu De Bordeaux, Bordeaux, FRANCE

Introduction: Systemic sclerosis (SSc) stands as a rare and severe connective tissue disease with a substantial portion of its mortality attributed not to SSc itself, but rather to comorbidities. The primary aim of our study was to delineate the prevalence of these comorbidities and their correlation with mortality, effectively establishing a comprehensive 'comorbidome.'

Material and Methods: We conducted a retrospective, single-centre observational study. Each patient's demographic information, including age and gender, as well as their vital status (deceased or alive), SSc-related organ involvements, and the presence or absence of 14 predefined comorbidities were meticulously recorded. The date of their initial encounter and the date of their most recent visit were also documented. Utilizing the Kaplan-Meier method, we constructed survival curves. Subsequently, we employed a Cox regression model for multivariate analysis to assess the association between each comorbidity and mortality, leading to the delineation of the comorbidome.

Results: Our study encompassed 400 subjects, with 74 among them having succumbed. Notably, three of the predefined comorbidities exhibited significant associations with mortality: neoplasia, cardiovascular diseases, and polypharmacy. Comprehensive evaluation, both from a statistical and clinical perspective, underscored the robustness of our findings. Our research successfully culminated in the establishment of the SSc comorbidome

Conclusions: Comorbidities manifest as a pivotal concern in patients afflicted with SSc, with cardiovascular diseases and neoplasms bearing particular significance. Intriguingly, our study shed light on the previously overlooked impact of polypharmacy in this context. The resultant comorbidome provides a synthetic and analytical overview of this intricate issue, emphasizing the interdependence of each data point. Acknowledging the limitation of our study due to its relatively small sample size, validation of our findings on a larger scale holds promise for elucidating certain nuances and potentially affording utility as a mortality scoring tool in future research endeavours.

P.236

CLINICALLY RELEVANT DIFFERENCES BETWEEN PRIMARY AND SECONDARY RAYNAUD’S PHENOMENON SECONDARY TO CONNECTIVE TISSUE DISEASES: RESULTS FROM A LARGE INTERNATIONAL SURVEY

Stefano Di Donato¹, Suiyuan Huang^2,3, John Pauling⁴, Maya Sabbagh^3,5, Francesco Del Galdo^1,6, Dinesh Khanna³, Michael Hughes^7,8

¹Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, UNITED KINGDOM, ²Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, USA, ³Department of Internal Medicine, Division of Rheumatology, Scleroderma Program, University of Michigan, Ann Arbor, USA, ⁴Department of Rheumatology, North Bristol NHS Trust Southmead Hospital, Bristol, UNITED KINGDOM, ⁵Peer Mentors Program, University of Michigan Scleroderma Program, Ann Arbor, USA, ⁶NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UNITED KINGDOM, ⁷Division of Musculoskeletal and Dermatological Sciences, Manchester Academic Health Science, University of Manchester, Manchester, UNITED KINGDOM, ⁸Department of Rheumatology, Salford Care Organisation, Northern Care Alliance NHS Foundation Trust, Salford, UNITED KINGDOM

Introduction: Raynaud’s phenomenon (RP) is a symptom complex associated with digital vascular compromise classically characterized by colour change, and neurosensory symptoms. In the majority of individuals, RP is primary (PRP), or `idiopathic`, but can occur secondary (SRP) to a broad range of underlying conditions, including connective tissue disease (CTD). RP significantly impacts on quality of life and, in more severe cases, terminate in irreversible digital ischaemia. Our aim was to examine for clinically relevant differences between PRP and SRP (CTD-associated) concerning the patient experience including physical characteristics, ischaemic sequelae, and treatment.

Material and Methods: We report cross-sectional results from the Patient Survey of experiences of Raynaud’s Phenomenon (PASRAP), which aimed to explore the broad-ranging impact of RP. The survey was widely distributed online including via social medial. Participation was voluntary and responses were anonymous.

Results: 1229 respondents completed PASRAP with self-reported RP: PRP 218 (17.7%) and SRP 1011 (82.3%) secondary to CTD. The majority (n= 747) of respondents had SSc: 260 dcSSc (34.8%) and 402 (53.8%) lcSSc, along with 85 (11.4%) SSc-overlap. Only SRP patients had experienced previous digital ulcers (36.9%) or gangrene (20.1%). The mean (SD) age was significantly lower in respondents with PRP (41.7 [11.8] vs 54.2 [12.4], p<0.0001). Only half of respondents felt that their symptoms were adequately controlled by their current medication(s), more commonly in SRP (45.2% vs 55.2%, p=0.0084).

During attacks, more subjects with SRP reported cyanotic colour changes (92.2% vs 86.5%, p=0.0089). However, patients with PRP experienced more pain (72.1% vs 55.9%, p<0.0001), numbness (80.3% vs 69.4%, p=0.0016), stinging/throbbing (93.4% vs 80.8%, p<0.0001), and tingling (84.0% vs 77.5%, p=0.0345). A higher proportion of subjects with SRP presented with blue/purple colour changes of the fingers in response to cold (82.5% vs 64.8%, p<0.0001) and stress (67.2% vs 46.9%, p<0.0001).

A higher proportion of patients with PRP reported RP attacks without the fingers changing colour (45.0% vs 25.6%, p<0.0001) and complete resolution of symptoms/ a restored sensation between RP attacks (69.9% vs 53.6%, p=0.0003). Most respondents (PRP and SRP) could identify a visible boundary between normal/ abnormal coloured skin with RP attacks (88.0% vs 83.2%, p=0.0849).

Conclusions: Patients with CTD-SRP are older compared to PRP and present with more profound ischaemic colour change with cyanosis during RP attacks in response to cold and stress, reflecting the severe vasculopathy of SRP, and less complete resolution of symptoms between attacks. Patients with PRP have more neurosensory features.

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FACTORS ASSOCIATED WITH SATISFACTION WITH SOCIAL ROLES AND ACTIVITIES AMONG PEOPLE WITH SYSTEMIC SCLEROSIS: A SCLERODERMA PATIENT-CENTERED INTERVENTION NETWORK (SPIN) COHORT CROSS-SECTIONAL STUDY

Tiffany Dal Santo¹, Danielle B. Rice², Marie-Eve Carrier¹, Gabrielle Virgili-Gervais¹, Brooke Levis¹, Linda Kwakkenbos³, Susan J. Barttlet⁴, Amy Gietzen⁵, Karen Gottesman⁶, Geneviève Guillot⁷, Marie Hudson¹, Laura K. Hummers⁸, Vanessa L. Malcarne⁹, Maureen D. Mayes¹⁰, Luc Mouthon¹¹, Michelle Richard¹², Maureen Sauvé¹², Robyn K. Wojeck¹³, Marie-Claude Geoffroy¹⁴, Andrea Benedetti⁴, Brett D. Thombs¹

¹Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, CANADA, ²Department of Psychology, St-Joseph's Healthcare Hamilton, Hamilton, CANADA, ³Department of Clinical Psychology, Behavioural Science Institute, Radboud University, Nijmegen, THE NETHERLANDS, ⁴Department of Medicine, McGill University, Montreal, CANADA, ⁵National Scleroderma Foundation, Tri-State Chapter, Buffalo, USA, ⁶National Scleroderma Foundation, Los Angeles, USA, ⁷Sclérodermie Québec, Longueil, CANADA, ⁸John Hopkins University School of Medicine, Division of Rheumatology, Baltimore, USA, ⁹Department of Psychology, San Diego State University, San Diego, USA, ¹⁰University of Texas McGovern School of Medicine, Houston, USA, ¹¹Service de Médecine Interne, Centre de Référence Maladies Autoimmunes Systémiques Rares d'Ile de France, Hôpital Cochin, Paris, FRANCE, ¹²Scleroderma Canada, Hamilton, CANADA, ¹³University of Rhode Island, Kingston, CANADA, ¹⁴Department of Psychiatry, McGill University, Montreal, CANADA

Introduction: Individuals with systemic sclerosis (SSc) face multiple challenges that can negatively affect their ability to fulfill social roles and participate in social activities. The degree to which individuals with SSc are satisfied with their ability to successfully undertake social roles and activities and associated factors are unknown. Our objectives were to (1) compare satisfaction with social roles and activities in a large multinational SSc cohort to general population normative data, and (2) identify factors associated with satisfaction with social roles and activities.

Material and Methods: Participants in the Scleroderma Patient-centered Intervention Network Cohort completed the Patient-Reported Outcomes Measurement Information System Version 2 Social Roles and Activities domain questionnaire as part of their baseline cohort assessment. Simple linear regressions were used to assess bivariate associations of sociodemographic, lifestyle, and physician-reported disease-related variables with satisfaction with social roles and activities and multivariable linear regression to assess independent associations.

Results: Among 2,385 participants with a mean age of 54.9 (standard deviation [SD] 12.6) years, 87% were female, and 83% were White. The mean Satisfaction with Social Roles and Activities T-score (48.1, SD = 9.9) was approximately 1/5 of a SD below the US general population (mean = 50, SD = 10). Multivariate analyses factors independently associated with satisfaction with social roles and activities were years of education (0.54 points per SD in years, 95% CI 0.14 to 0.93); self-reported race or ethnicity other than White (-1.13 points, 95% CI -2.18 to -0.08); living in Canada (-1.33 points, 95% CI -2.40 to -0.26 [reference = United States]) or the United Kingdom (-2.49 points, 95% CI -3.92 to -1.06); body mass index (BMI; -1.08 points per SD in BMI, 95% CI -1.47 to -0.69); gastrointestinal involvement (-3.16 points, 95% CI -4.27 to -2.05); digital ulcers (-1.90 points, 95% CI -3.05 to -0.76); moderate (-1.62 points, 95% CI -2.78 to -0.45) or severe (-2.26 points, 95% CI -3.99 to -0.52) small joint contractures; interstitial lung disease (-1.11 points, 95% CI -1.97 to -0.25); pulmonary arterial hypertension (-2.69 points, 95% CI -4.08 to -1.30); rheumatoid arthritis (-2.51 points, 95% CI -4.28 to -0.73); and Sjogren’s syndrome (-2.42 points, 95% CI -3.96 to -0.88).

Conclusions: Satisfaction with social roles and activities is only minimally lower on average in individuals with SSc compared to the general population. Many people with SSc may make adaptations to cope with challenges inherent in living with a chronic and burdensome disease.

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FACTORS ASSOCIATED WITH PHYSICAL FUNCTION AMONG PEOPLE WITH SYSTEMIC SCLEROSIS: A SCLERODERMA PATIENT-CENTERED INTERVENTION NETWORK (SPIN) COHORT CROSS-SECTIONAL STUDY

Tiffany Dal Santo¹, Danielle B. Rice², Marie-Eve Carrier¹, Gabrielle Virgili-Gervais¹, Brooke Levis¹, Linda Kwakkenbos³, Susan J. Bartlett⁴, Amy Gietzen⁵, Karen Gottesman⁶, Geneviève Guillot⁷, Marie Hudson¹, Laura K. Hummers⁸, Vanessa L. Malcarne⁹, Maureen D. Mayes¹⁰, Luc Mouthon¹¹, Michelle Richard¹², Maureen Sauvé¹², Robyn K. Wojeck¹³, Marie-Claude Geoffroy¹⁴, Andrea Benedetti⁴, Brett D. Thombs¹

¹Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, CANADA, ²Department of Psychology, St. Josephs Healthcare Hamilton, Hamilton, CANADA, ³Department of Clinical Psychology, Behavioural Science Institute, Radboud University, Nijmegen, THE NETHERLANDS, ⁴Department of Medicine, McGill University, Montreal, CANADA, ⁵National Scleroderma Foundation, Tri-State Chapter, Buffalo, USA, ⁶National Scleroderma Foundation, Los Angeles, USA, ⁷Sclérodermie Québec, Longueil, CANADA, ⁸Johns Hopkins University School of Medicine, Division of Rheumatology, Baltimore, USA, ⁹Department of Psychology, San Diego State University, San Diego, USA, ¹⁰University of Texas McGovern School of Medicine, Houston, USA, ¹¹Service de Médecine Interne, Centre de Référence Maladies Autoimmunes Systémiques Rares d'Ile de France, Hôpital Cochin, Paris, FRANCE, ¹²Scleroderma Canada, Hamilton, CANADA, ¹³University of Rhode Island, Kingston, USA, ¹⁴Department of Psychiatry, McGill University, Montreal, CANADA

Introduction: Individuals with systemic sclerosis (SSc, scleroderma) face many challenges that can impact their physical function, which appears to be impaired. There is limited evidence on the degree to which individuals with SSc have impaired physical function compared to the general population and factors associated with physical function. Our objectives were to (1) compare physical function levels in a large multinational SSc cohort to general population normative data and (2) identify factors associated with physical function.

Material and Methods: Participants in the Scleroderma Patient-centered Intervention Network Cohort completed the Patient-Reported Outcomes Measurement Information System Version 2 Physical Function domain questionnaire as part of their baseline cohort assessment. Simple linear regressions were used to assess bivariate associations of sociodemographic, lifestyle, and physician-reported disease-related variables with physical function and multivariable linear regression to assess independent associations. Multiple imputation was used to account for missing covariate data.

Results: Among 2,385 participants with a mean age of 54.9 (standard deviation [SD] 12.6) years, 87% were female, and 83% were White. The mean physical function T-score (43.7, SD = 8.9) was approximately 2/3 of a standard deviation (SD) below the US general population (mean = 50, SD = 10). Multivariable analysis factors independently associated with physical function were older age (-0.74 points per SD years, 95% CI -0.78 to -1.08), female sex (-1.35 points, -2.37 to -0.34), fewer years of education (-0.41 points per SD in years, -0.75 to -0.07), being single, divorced, or widowed (-0.76 points, -1.48 to -0.03), smoking (-3.14 points, -4.42 to -1.85), alcohol consumption (0.79 points per SD drinks per week, 0.45 to 1.14), BMI (-1.41 points per SD, -1.75 to -1.07), diffuse subtype (-1.43 points, -2.23 to -0.62), gastrointestinal involvement (-2.58 points, -3.53 to -1.62), digital ulcers (-1.96 points, -2.94 to -0.98), moderate (-1.94 points, -2.94 to -0.93) and severe (-1.76 points, -3.24 to -0.28) small joint contractures, moderate (-2.10 points, -3.44 to -0.76) and severe (-2.54 points, -4.64 to -0.44) large joint contractures, interstitial lung disease (-1.52 points, -2.27 to -0.77), pulmonary arterial hypertension (-3.72 points, -4.91 to -2.52), rheumatoid arthritis (-2.10 points, -3.64 to -0.56) and idiopathic inflammatory myositis (-2.10 points, -3.63 to -0.56).

Conclusions: Physical function is impaired for many individuals with SSc and associated with multiple disease factors. Research is needed to better understand the role each of these factors plays in physical function and to develop strategies that target specific factors to improve function.

P.239

SYSTEMIC SCLEROSIS IN MOTHER AND SON: COINCIDENTAL OR INDUCED ASSOCIATION

Abelkader Bouattou, Nadia Chougrani, Nadia Bouziani, Amal Kella, Amel Belabas, Tewfik Bounzira, Djanette Hakem

Internal Medicine Dep,Dr. Boumediene Bensmain Hospital, Mostaganem University Hospital Center. University Ibn Badis, Mostaganem, Algeria

Introduction: Familial forms of the Systemic Sclerosis (SSc) disease are rarely described in the literature. In this regard, we propose a case report.

Case Report A 73-year-old woman with family story relates that his son, aged 40 y/o, who was been working in the hydrocarbon industry for over 20 years, has been diagnosed with limited SSc 6 years ago treated with Colchicine and calcium channel blockers.

She presented with thickening of the skin, polyarthralgia. We noted that the family resides 200 meters away from a tobacco factory. Skin examination revealed Raynaud's phenomenon, sclerodactyly, pinched nose, microstomia, telangiectasias, and xerostomia. Pulmonary auscultation revealed crackles at the base of the lung fields. There were no gastrointestinal symptoms, notably no heartburn or dysphagia.

Antinuclear antibodies and anti-Scl70 antibodies were positive. Blood count, renal and liver functions, lipid profile were normal.

Thoracic CT scan revealed ground-glass opacities at the lung bases and moderate esophageal dilatation. Cardiac echocardiography indicated a low probability of pulmonary hypertension (PAH).

SSc diagnosis was established (ACR-EULAR scleroderma classification criteria). Therapy was summarized in vasodilators drugs, proton pump inhibitors, synthetic antimalarials drugs and immunosuppressants were initiated due to the rapid progression of cutaneous sclerosis and the presence of pulmonary lesions. The outcomes were favorable.

Discussion/ Conclusion: Familial cases of SSc, remain rare, highlighting the potential roles of genetics (less than 1% of patients) and environmental factors as triggering agents. Apart from the association between silica exposure and SSc (Erasmus) these cases remain of obscure etiology. The presence of a nearby tobacco factory was noted, although to our knowledge, tobacco has not been conclusively linked to SSc.

P.240

CEREBRAL LYMPHOMA AND SYSTEMIC SCLERODERMA: FORTUITOUS ASSOCIATION?

Amal Kella¹, Khadidja Bouadj¹, Nadia Bouziani¹, Amel Belabbas¹, Nadia Chougrani¹, Abdelkader Bouattou¹, Tewfik Bounzira¹, Jugurtha Rami², Karima Abacci², Abelkrim Berrah², Nazim Laraba², Abdelhalim Morsli³, Djenette Hakem¹

¹Internal Medicine, Dr Boumediéne Bensmain University Hospital, Mostaganem, Algeria, ²Internal Medicine, Dr Mohammad-Lamine Debaghine Hospital, Bab-El-Oued University Hospital, Algiers, Algeria, ³Neurosurgery, Dr Mohammad-Lamine Debaghine Hospital, CHU Bab-El-Oued, Algiers, Algeria

Introduction: The frequency of cancers in systemic sclerosis (SSc) is higher than that observed in the general population. Cancers appearing concomitantly produce synchronous cancers. Some cases of hemopathy are also reported in the literature.

Observation: Patient, 50 years old, SSc since 2019 with diffuse interstitial lung disease (ILD) treated by infusion of Cyclophosphamide, relayed by mycophenale mofetil (MMF), was explored for convulsive seizures whose brain CT showed an expansive intracranial tumor process. The patient had an ataxic gait and a deficit in motor functions. The immunological profile showed the presence of anti-topoisomerase and anti-RNA polymerase III Ab. Brain MRI revealed multiple parenchymal lesions with a right frontal necrotic component. The neurosurgical biopsy concluded that there was diffuse large B cell lymphoma (CD20+). After an extension assessment, the patient was referred to oncohematology for chemotherapy.

Conclusion: The mechanisms responsible for the development of cancer during SSc are poorly understood. It is suggested that cancer cells are induced by a mutation in the self-antigen RNA polymerase III.

P.241

ECONOMIC, HUMANISTIC, AND HEALTH-RELATED QUALITY OF LIFE (HRQOL) BURDEN IN PATIENTS WITH SYSTEMIC SCLEROSIS (SSC) INTERSTITIAL LUNG DISEASE (ILD): A SYSTEMATIC LITERATURE REVIEW (SLR)

Emily Glowienka¹, Sarah Nickolls², Kevin Coady¹, Eesha Kodi³, Ian Steinfield¹, Florence Wilson³, Svetlana Nihtyanova⁴, Roger A. Levy⁵, Daniel Moldaver⁶

¹PRECISIONheor, Boston, MA, USA, ²Research & Development, GSK, Stevenage, UK, ³PRECISIONheor, Vancouver, BC, Canada, ⁴Clinical Sciences, Research & Development, GSK, London, UK, ⁵Global Medical Affairs, GSK, Collegeville, PA, USA, ⁶Value Evidence and Outcomes, GSK, Mississauga, ON, Canada

Introduction: ILD is marked by inflammation and tissue fibrosis in the lungs. ILD affects approximately half of patients with SSc and is the leading cause of SSc-related morbidity and mortality. We sought to quantify the economic, humanistic and HRQoL burden of SSc-ILD.

Material and Methods: Two SLRs were performed, one to quantify the economic burden and another to quantify the humanistic/HRQoL burden. The target population included patients with SSc with or without ILD, irrespective of disease severity and subtype. No age restriction was applied during screening. Study design eligibility criteria are presented in the Table. Relevant studies were identified through the following databases via Ovid: EMBASE; MEDLINE; Cochrane Central Register of Controlled Trials; American Economic Association Econlit; and National Health Service Economic Evaluation Database. Searches of conference proceedings from ISPOR, EULAR, the Systemic Sclerosis World Congress and the US National Institutes of Health Clinical Trial Registry were performed. Supplemental manual searches of recent peer-reviewed SLRs/meta-analyses' bibliographies were also conducted. Included studies reported on the broad SSc population, which included patient populations aligned with the design of the BLISSc-ILD Phase 3 study, investigating the efficacy and safety of belimumab in SSc-ILD patients. The Newcastle-Ottawa Scale was used to assess the quality of economic studies. The quality of humanistic/HRQoL studies was assessed using the Cochrane Collaboration's Risk of Bias 2 tool for RCTs and the ROBINS-I for non-RCTs. A narrative synthesis of study findings was planned.

Results and Conclusion: For the economic SLR, of 3042 records identified, 243 duplicates were discarded. Of the remaining 2799 records, 61 full-text articles were screened; 13 were excluded due to study design (n=3), population (n=1), and outcomes (n=9). Grey literature searches revealed 6 additional records, totalling 54 included studies.

For the humanistic/HRQoL SLR, of 5021 records identified, 753 duplicates were discarded. Screening of the remaining 4268 records and grey literature searches is ongoing.

Results from these SLRs will be presented, including total healthcare costs, total direct costs (medical/hospitalisation/medication/assistive device/outpatient costs) and indirect costs (societal costs and patient lost paid labour/productivity costs). Humanistic/HRQoL burden will be summarised by the impact on patient-reported outcome (PRO) measures (36-Item Short Form Survey), disease-specific PROs (e.g., Health Assessment Questionnaire Disability Index and Functional Assessment of Chronic Illness Therapy-Fatigue), Physician and Patient Global Assessments and patient utilities (EQ-5D index scores). These SLRs will describe the burden of SSc-ILD on patients and health systems worldwide.

Funding: GSK.

P.242

FACTORS ASSOCIATED WITH EMPLOYMENT IN A COHORT OF PATIENTS WITH SYSTEMIC SCLEROSIS

Cristina Andreea Vrancianu¹, Cristiana Draganescu², Raida Oneata¹, Ioan Ancuta¹, Mihai Bojinca¹, Ana Maria Gheorghiu¹

¹Carol Davila University of Medicine and Pharmacy; Cantacuzino Clinical Hospital, Internal Medicine and Rheumatology Dept, BUCHAREST, ROMANIA, ²Sf. Ioan Hospital, Internal Medicine Department, BUCHAREST, ROMANIA

Introduction: Systemic sclerosis (SSc) can affect the skin, joints and major internal organs and may lead to disability and possibly early retirement. The purpose of the study is to analyze the associations between employment status (ES) and SSc features in an EUSTAR single-center cohort of patients.

Material and Methods: Consecutive patients with SSc examined in our center between 11.2001 and 06.2023, who were under the age of retirement in our country (62 years for women, 65 for men at the time) were included. In addition to performing a full SSc assessment, patients also filled in two health-related questionnaires and a work assessment questionnaire. The associations between ES and potential predictors, such as education, socio-economic status, SSc characteristics and health-related questionnaires were tested using logistic regression adjusted for age and gender.

Results: Ninety-one patients (mean±SD age 53.7±11.8 years, 22 with diffuse skin involvement, 56 with a history of digital of digital ulcers (DUs)) were included. Twenty-two patients were still employed, whereas 69 were retired, a large number because of SSc (38 patients). Of those in employment, 23 did manual labor, 23 spent many hours standing and 14 had to work in a a cold environment. Higher education (high school or above) (odds ratio (95% confidence interval) (OR (95% CI)) 11.08 (1.9, 61,6)) was highly associated with employment, whereas labor conditions such as weight lifting 5.0 (1.0, 24.5) were associated with early retirement. Other labor conditions (manual labor, stress) had no significant influence on employment status. Lack of DUs (ever) was also associated with employment (OR (95%CI) 4.5 (1.3, 15.5). We found no associations of ES with health-related questionnaires.

Conclusions: SSc is associated with significant work disability and early retirement. Completion of higher education (high school or university) and not having had DUs were highly associated with staying employed, while weight lifting was associated with early retirement.

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CORRELATION BETWEEN BASELINE MODIFIED RODNAN SKIN SCORE AND ULCER DEVELOPMENT IN SYSTEMIC SCLEROSIS: A SINGLE- CENTER RETROSPECTIVE STUDY

Carolina Vilafanha^1,2, Susana P. Silva¹, Pedro Miguel Teixeira^1,2, Carolina Mazeda^1,2, Cláudia Pinto Oliveira^1,2, Ana Rita Prata^1,2, Anabela Barcelos^1,2

¹Rheumatology Department, Centro Hospitalar do Baixo Vouga, Aveiro, PORTUGAL, ²Centro Académico Clínico Egas Moniz Health Alliance, PORTUGAL

Introduction: Skin ulcers in systemic sclerosis (SSc) are frequent and can lead to decreased quality of life. The modified Rodnan skin score (mRss) is a measure of skin thickness commonly used as an indicator of disease activity and severity. The aim of this study was to evaluate and characterize the types of skin ulcers and assess the relation between baseline mRss and ulcer development in a Portuguese SSc cohort.

Material and Methods: Retrospective cohort study including consecutive patients fulfilling the ACR/EULAR 2013 classification criteria for SSc, followed in a single Rheumatology Department with an initial diagnosis between January 1st, 2012, and January 1st, 2022. Skin ulcers occurring after diagnosis were retrospectively identified based on patients’ registries. Pearson correlation coefficient test was performed to assess the association between baseline mRss and the number of ulcers developed in SSc patients.

Results: We included 30 SSc patients (86.7% females, mean age at diagnosis 52.8 ±11.4 years, median follow-up time of 5.5 ± 5.5 years). Twenty-three patients (76.7%) had Limited Systemic Scleroderma. During follow-up, 30.0% of the patients developed skin ulcers. Ischemic ulcers were the most frequent (83.8% of all ulcers) followed by calcinosis-related (11.8%) and mechanical ulcers (4.4%). Regarding location, the hand/digits were the most frequent site of ischemic ulcers (84.2% of all ischemic), and digital lesions were more common on the third and fourth digits (35.1% and 19.3%, respectively). The most frequent sites of calcinosis-related ulcers were the first and second digits (37.5% each). All mechanical ulcers were in the skin overlying the fifth proximal interphalangeal. During follow-up, 8 patients (88.9%) received at least one course of intravenous Alprostadil and were treated with nifedipine (100%), phosphodiesterase 5 inhibitors (44.4%), topical nitrates (44.4%), and colchicine (22.2%). Baseline mRss showed a positive correlation with the number of ulcers developed during the follow-up (r = 0.898; p = 0.015).

Conclusions: In this single-center based-cohort study, skin ulcers were frequent and the most commonly reported were digital ischemic ulcers of the hands. Baseline mRss showed a positive correlation with the number of ulcers developed during follow-up, highlighting the prognostic role of this score in SSc patients. Larger sample size studies using uniform skin ulcer definitions are needed to better study SSc-associated skin ulcer factors to develop prevention strategies and improve patients’ quality of life.

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PREGNANCY IN CONNECTIVE TISSUE DISEASES: A 30 YEAR FOLLOW-UP STUDY OF 465 PREGNANCIES FROM A SPANISH MONOCENTRIC REGISTRY

Cristiana Sieiro Santos, Miriam Retuero Guerrero, Paula Pérez García, Jose Ordas Martínez, Clara Moriano Morales, Carolina Álvarez Castro, Elvira Díez Álvarez

Complejo Asistencial Universitario de León, LÉÓN, SPAIN

Introduction: Pregnancy in patients with connective tissue diseases are known to be at high risk for the occurrence of adverse pregnancy outcomes. We aim to evaluate the pregnancy outcomes in patients with systemic autoimmune diseases, including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), primary Sjögren’s syndrome (pSS) and undifferentiated connective tissue disease (UCTD).

Material and Methods: A retrospective and descriptive study was conducted from 1990 to 2020. All data were collected from the medical records of childbearing age women with SLE, SSc, SS and UTCD enrolled in our clinic at the time of their pregnancy and childbirth. The obstetric, maternal and fetal outcomes were collected and compared regarding diagnosis and adverse outcomes.

Results: The study group included 295 patients, 125 patients (42%) with SLE, 50 patients (17%) with SSc, 80 patients (27%) with Sjogren’s, 40 patients (14%) with UCTD. A total of 465 pregnancies were registered. The maternal and fetal outcomes are detailed in table 1 and figure 1. The mean age at delivery was 31.5±8.5 years and the mean duration of disease was 7.2±5.6 years. Pregnancy loss occurred in 21% of patients, live births in 66% of pregnancies, preterm delivery in 8%, postpartum haemorrhage in 6%, preeclampsia in 5%, placental abnormalities in 4%, ectopic pregnancy in 3%, premature rupture of membranes in 2%. Treatment with HCQ was received in 115 pregnancies in SLE (59%), 21 pregnancies in SSc (24%) 62 pregnancies in pSS (52%) and 32 pregnancies in UCTD (49%). Exposure to corticosteroids and biologics during pregnancy was 23 (18.4%), 6 (12%), 15 (19%) and 3 (7.5%), respectively. Patients with SLE had a higher risk of fetal morbidity, including abortion (p=0.03), mean abortion rate (p=0.03), preeclampsia (p=0.04), ectopic pregnancy (p=0.03), preterm delivery (p=0.02) and postpartum haemorrhage (p=0.01) than patients without SLE. The multivariate model adjusted for age, nulliparity, active disease activity during pregnancy, smoking and exposure to biologics, HCQ and corticosteroids found an association between unfavourable pregnancy outcomes and disease activity (OR 2.4 95% CI (1.3-7.2), p 0.003), whilst HCQ during pregnancy (OR 0.23 95% CI (0.03-0.82) had a protective effect.

Conclusions: 66% of pregnancies in patients with autoimmune diseases resulted in live births. Patients with SLE had higher rates of fetal and maternal morbidity than SSc, pSS and UCTD. Disease activity was associated with unfavourable pregnancy outcomes. Exposure to HCQ had a protective effect during pregnancy.

P.245

PREVALENCE AND CLINICAL ASSOCIATIONS WITH IMPAIRED SEXUAL FUNCTION IN SYSTEMIC SCLERODERMA WOMAN: PILOT STUDY

Lingling Salang¹, Pranorm Bupphasiri¹, Arporn Jutiviboonsuk², Chingching Foochareon²

¹Khon Kaen University, Khon Kaen, THAILAND, ²Khon Kaen University, Khon Kaen, THAILAND, ³Khon Kaen University, Khon Kaen, THAILAND, ⁴Khon Kaen University, Khon Kaen, THAILAND

Introduction: Impaired sexual function in women with systemic sclerosis (SSc) may be induce by physical and psychologic change. There is currently no data on impaired sexual function among Thai women with SSc who were commonly diffuse cutaneous SSc (dcSSc) subset.

Objectives: To determine the prevalence of impaired sexual function and associated factors of impaired sexual function in Thai female SSc patients

Material and Methods: An analytical cross-sectional study was conducted at Srinagarind hospital, Khon Kaen University between May 2019 and March 2020, among female SSc patients aged 18 – 45 years who were used to sexual intercourse. Patients with surgical amenorrhea, previous radiation, history of hormonal contraception less than 12 weeks and pregnancy were excluded. Sexual function was evaluated using the Female Sexual Function Index Scoring.

Results: A total of 27 patients were included, of which the majority (66.7%) were dcSSc subset. The respective mean age and mean disease duration was 39.4 ± 5.2 years and 9.9 ± 7.9 years. Fourteen of patients were defined as impaired sexual function with the prevalence of 51.9% (95%CI 31.9-71.3). Severe skin thickness, the presence of anti-Scl70, and vasculopathy particularly Raynaud’s phenomenon and telangiectasia tended to be associated with impaired sexual function but there was no statistical significant. The patients with impaired sexual function tended to have more severe skin thickness, more frequent of anti-Scl70, vasculopathy (Raynaud’s phenomenon, telangiectasia), and using higher dose of cyclophosphamide (CYC) with longer duration compared to those with normal sexual function, but there were no statistical significant.

Conclusions: Impaired sexual impairment was a common problem among Thai female SSc during their reproductive age. Disease severity, vasculopathy, and long-term CYC using might be a risk of impaired sexual function in SSc. Further research in a larger sample is needed to support the findings.

P.246

QUALITY OF LIFE IN SYSTEMIC SCLEROSIS: CASE REPORT

Blerta Rexhepi Kelmendi¹, Mjellma Rexhepi²

¹University Clinical Centre of Kosova, Prishtinë, KOSOVO, ²University Clinical Centre of Kosova, Prishtinë, KOSOVO

Introduction: Systemic sclerosis is a chronic autoimmune disease with significant impact on patients’ quality of life. This case presents a comprehensive evaluation of the quality of life in a 36 year old female patient diagnosed with systemic sclerosis. The patient’s path involved a various of clinical assessments, treatment and psychosocial support to address the challenges posed by the disease.

Material and Methods: Physical, emotional, and social factors were all included in the evaluation of quality of life. Modified Rodnan Skin Score for skin involvement, pulmonary function tests, and laboratory findings for disease activity were included. Additionally, the Health Assessment Questionnaire (HAQ) and the Short Form Health Survey (SF-36) for physical functioning, pain, and mental well-being were measured.

Results: Over a 24-month follow-up period, the patient’s quality of life improved significantly. Improvement was attributed to a combination of treatments, including immunosuppressive therapy and physical rehabilitation, as well as psychological support. The patient reported reduced pain, better physical function, and a greater sense of emotional health.

Conclusions: This case report shows the importance of a overall approach to systemic sclerosis management that considers not only medical treatment but also the psychosocial aspects affecting quality of life. It demonstrates how a multidisciplinary and patient-centered approach to care has the potential to significantly improve patients' well-being.

P.247

THE LONG-TERM NEURODEVELOPMENTAL OUTCOME OF CHILDREN BORN TO WOMEN WITH SYSTEMIC SCLEROSIS: ASSESSMENT THROUGH A SELF-REPORTED QUESTIONNAIRE BY THE MOTHERS AND NEUROPSYCHIATRIC EVALUATIONS OF THE CHIL

Eleonora Pedretti^1,2, Laura Andreoli², Liala Moschetti^1,2, Marzia Bendoni^2,3, Lucrezia Visconti^2,3, Anna Molinaro^2,3, Cecilia Nalli¹, Franco Franceschini^1,2, Paolo Airò¹, Jessica Galli^2,3, Elisa Fazzi^2,3, Angela Tincani^1,2, Maria-Grazia Lazzaroni^1,2

¹Rheumatology and Clinical Immunology Unit, ASST Spedali Civili, Brescia, Brescia, ITALY, ²Department of Clinical and Experimental Sciences, University of Brescia, Brescia, ITALY, ³Unit of Child and Adolescent Neuropsychiatry, ASST Spedali Civili, Brescia, Brescia, ITALY

Introduction: The long-term neurodevelopment (ND) of children born to mothers affected by autoimmune diseases (AIDs) represents a controversial topic. We focused on ND of children born to Systemic Sclerosis (SSc) mothers, starting in 2021 with the creation of an ad-hoc questionnaire administered to consecutive SSc mothers.

Here we further investigated the long-term NP outcome of SSc offspring by offering a comprehensive pediatric NP evaluation.

Material and Methods: SSc mothers (ACR/EULAR 2013 criteria) who previously completed the above-mentioned questionnaire were proposed to receive a clinical NP evaluation for their children aged <= 18 years, including:

• cognitive/adaptive functioning (Griffiths Mental Development Scales; Wechsler Scales; Vineland Adaptive Behavior Scales)

• behavioral/social problems (Child Behavior CheckList -CBCL-, fulfilled by the mothers; Youth Self Report -YSR-, for children >= 11 years)

• anxiety/depression/somatic disorders (Self-administered psychiatric scales for children/adolescents >= 8 years)

• sleep disorders

Cohen’s kappa coefficient (k) was used to evaluate the agreement between questionnaire answers and NP test results.

Results: 23 SSc mothers had 39 children aged <= 18 years, 37/39 were proposed for NP evaluation and 20 accepted (F/M 1:1; median age 8 [6-11] years). Patients reported at least one alteration in the questionnaire for 7 children (Table 1); one already had a diagnosis of autism spectrum disorder (ASD). NP evaluations recorded:

• normal scores for cognitive/adaptive functioning in all children, except the one with ASD

• an increased risk of developing behavioral/social problems especially in extra-academic/social activities in 3/20 at CBCL and in 3/6 at YSR

• an increased risk of developing depression in 4/11

• sleep disorders in 9/20

Clinical features of mothers and their offspring are shown in Table 1. The agreement between questionnaires and NP evaluation was moderate for cognitive/adaptive functioning and sleep disorders (k 0.5 and 0.6 respectively) and weak for behavioural/social problems (k 0.2).

Conclusions: At NP evaluation, children born to SSc mothers showed normal cognitive skills but a tendency toward an impairment in the behavioral/social area. Mothers seldom recognized such a difficulty, according to the self-reported questionnaire.

Clinicians caring for SSc mothers should discuss about possible NP symptoms in their children and suggest seeking for a specialist evaluation in case of doubts.

The Authors would like to thank the Italian association of SSc patients ‘GILS’ (Gruppo Italiano Lotta Sclerodermia) for kindly supporting the project.

P.248

DOES CHRONIC FATIGUE SYNDROME REFLECT A MORE SEVERE CHRONIC HYPOXIC STATE IN PATIENTS WITH LIMITED CUTANEOUS SYSTEMIC SCLEROSIS (LCSSC)? A CROSS-SECTIONAL STUDY

Charmaine van Eeden¹, Muhammad Elezzabi¹, Desiree Redmond¹, Lamia Khan¹, Douwe Mulder², Maggie Larché³, Anthony Russell¹, Robert Gniadecki¹, Andrew Mason¹, Jan Willem Cohen Tervaert¹, Mohammed Osman¹

¹Department of Medicine, University of Alberta, Edmonton, CANADA, ²University of Groningen Medical Centre, Groningen, THE NETHERLANDS, ³Department of Medicine, McMaster University, Hamilton, CANADA

Introduction: Symptoms resembling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) frequently plague rheumatic disease patients. We have recently shown that patients with SSc commonly exhibit symptoms compatible with ME/CFS early in their disease. Recently, a chronic hypoxic state has been proposed to underlie some of the symptoms in patients with certain forms of ME/CFS, although this has not been previously explored in SSc.

Material and Methods: We determined the frequency and severity of ME/CFS, pain (via the fibromyalgia symptom severity score and the wide spread pain index) and disability (via the HAQ-DI and SF-36) in patients with lcSSc early in disease duration (median, 2 years). We also determined if indicators of hypoxia: namely elevated red cell distribution width (RDW) levels and diffusion lung capacity (DLCO SB), and if other disease associated parameters associated with vascular remodeling and/or visceral complications (e.g. nailfold video capillaroscopy changes) were more prevalent in lcSSc patients with ME/CFS compared to those without ME/CFS.

Results: We show that patients with lcSSc who also have SSc-CFS (N = 22 patients) have significantly increased pain and disability compared to those without ME/CFS (N = 20 patients). We show for the first time that SSc-CFS patients have elevated markers of hypoxia – namely: elevated RDW (14.15 vs 13.25; p=0.02), and a statistical trend towards reduced diffusing lung capacity (15.2 vs 19.28; p=0.06), and reduced oximetry measurements (97 vs 98, p=0.06), compared to lcSSc patients without fatigue. Intriguingly, SSc-CFS patients also had a higher frequency of telangiectasia, and a statistical trend was evident for reduced capillary density in the SSc-CFS group (6.3 vs 7.75; respectively, p=0.07). No differences were noted in capillary microhemorrhages, enlarged/giant capillaries or iron indices. Finally, elevated RDW levels also inversely correlated with diffusion lung capacity (-0.49) (p=0.001).

Conclusions: lcSSc patients with ME/CFS have elevated RDW, associated with markers of hypoxia. We propose that ME/CFS in patients with SSc may reflect a more severe hypoxic state that may be associated with early visceral complications. Future mechanistic studies and prospective multicentered studies assessing the severity of fatigue and post-exertional malaise may provide added insights into this.

P.249

RESULTS FROM A LIVING SYSTEMATIC REVIEW OF THE PREVALENCE OF MOOD AND ANXIETY DISORDERS AND FACTORS ASSOCIATED WITH SYMPTOMS IN PEOPLE WITH SYSTEMIC SCLEROSIS

Elsa-Lynn Nassar¹, Sophie Hu^1,3, Brett Thombs^1-8

¹Lady Davis Institute of Medical Research, Jewish General Hospital, Montreal, CANADA, ²Department of Psychology, McGill University, Montreal, CANADA, ³Department of Epidemiology, Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, CANADA, ⁴Department of Psychiatry, McGill University, Montreal, CANADA, ⁵Department of Medicine, McGill University, Montreal, CANADA, ⁶Biomedical Ethics Unit, McGill, Montreal, CANADA, ⁷Department of Medicine, McGill University, Montreal, CANADA, ⁸Department of Educational and Counselling Psychology, McGill University, Montreal, CANADA

Introduction: Systemic sclerosis (SSc; scleroderma) is a rare chronic, autoimmune rheumatic disease characterized by abnormal fibrotic processes and excessive collagen production. Disease presentation is heterogeneous, and course is unpredictable. People with SSc experience substantially lower health-related quality of life compared to the general population and people with other rheumatic diseases. People with SSc may be at risk for depression and anxiety due to the unpredictable and progressive disease course and high levels of chronic pain, fatigue, body-image distress, and disability. We are conducting a regularly updated “living” systematic review to assess (1) prevalence of mood and anxiety disorders and (2) factors associated with symptoms in people with SSc. The objective was to build on our previous report, which presented findings up to March 1, 2023, and to present results up to September 1, 2023.

Material and Methods: Eligible studies are primary studies in any language that assessed prevalence of mood or anxiety disorders in people with SSc or examined factors associated with disorders or symptoms. We searched MEDLINE, CINAHL, and PsycINFO databases for eligible studies, using a strategy designed by an experienced health sciences librarian.

Results: We identified 6 eligible studies through September 1, 2023. Current or 30-day major depressive disorder prevalence was 4% (95% confidence interval [CI], 2% to 6%) for Canadian outpatients (N=345), 18% (95% CI, 12% to 27%) for Indian outpatients (N=93), 10% (95% CI, 4% to 21%) for French patient conference attendees (N=51), and 29% (95% CI, 18% to 42%) for French inpatients (N=49). Current or 30-day prevalence of any anxiety disorder was 49% (95% CI, 36% to 62%) for French conference attendees and 51% (95% CI, 38% to 64%) for French inpatients (see Table 1). In 3 studies (N=114 to 376) that examined factors, higher education and being married or living as married were associated with lower depressive symptoms and pulmonary involvement, breathing problems, and tender joint counts with higher symptoms; age and disease severity markers were not associated. Only 1 study (N=114) assessed factors associated with anxiety symptoms and found no statistically significant associations. Limitations included heterogeneous populations and assessment methods, small samples, and substantial risk of bias concerns.

Conclusions: Mood and anxiety disorder prevalence appears high in SSc, but estimates vary, and existing studies have important limitations. Future research should assess mood and anxiety prevalence and factors associated with symptoms using large representative samples and validated classification and assessment methods.

P.250

CLINICAL FINDINGS ASSOCIATED WITH POOR QUALITY OF LIFE IN SYSTEMIC SCLEROSIS - RESTORATION OF CLINICAL FINDINGS, INCLUDING MUSCLE WEAKNESS

Naoki Mugii¹, Takashi Matsushita², Yasuhito Hamaguchi², Shinichi Noto³, Pleiades Tiharu Inaoka⁴, Kazuhiko Takehara²

¹Department of Rehabilitation, Kanazawa University Hospital, Kanazawa, JAPAN, ²Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa Unive, Kanazawa, JAPAN, ³Niigata University of Health and Welfare, Niigata, JAPAN, ⁴Faculty of Health Sciences, Kanazawa University, Kanazawa, JAPAN

Introduction: In systemic sclerosis (SSc), various clinical findings lead to dysfunction and impaired QOL. Some patients experience muscle weakness during the course of the disease, leading to decreased ADL. The purpose of this study was to evaluate the muscle strength of the SSc, re-investigate the relationship with clinical findings, and clarify the symptoms and clinical findings that affect the QOL of SSc.

Material and Methods: Eighty-four Japanese patients with SSc (51 patients with diffuse cutaneous SSc and 33 patients with limited cutaneous SSc) were evaluated with HAQ-DI and EQ-5D-5L as QOL evaluation. Muscle strength was measured using a hand-held dynamometer. At the same time, skeletal muscle mass was also measured using a body composition analyzer. QOL and the clinical findings analyzed were maximal muscle strength, skeletal muscle mass, disease duration, disease classification, MRSS, ILD, pulmonary hypertension, skin ulcer, finger contracture, renal crisis, upper GI, lower GI, %VC and %DLco.

Results: The average QOL score of the subjects was 0.71 for HAQ-DI, and 0.774 for EQ-5D-5L. The average maximum muscle strength (maximum-minimum values) was 104.4% (181.9-49.7) for the right leg and 103.6% (170.9-47.9) for the left leg compared to the normal standardized value according to age and sex. According to the analysis of the relationship between each QOL and clinical findings, only %DLco was significantly correlated with the EQ-5D-5L index score. Significant correlations were observed for HAQ-DI among disease duration, presence or absence of skin ulcers, albumin level, %DLco, maximal muscle strength, and skeletal muscle mass. Multiple regression analysis indicated that muscle strength, %DLco, and loss of skeletal muscle mass contributed to the decreased QOL observed with HAQ-DI. Regarding muscle strength, a relationship was observed between skeletal muscle mass and %VC.

Conclusions: QOL in SSc was related to muscle strength and respiratory function. Although the average maximum muscle strength of SSc patients was 100% of the average in healthy subjects, in some cases was decreased to less than 50%.

P.251

PSYCHOPATHOLOGICAL SYMPTOMS AND THEIR ASSOCIATION WITH THE QUALITY OF LIFE AND THE SEXUAL FUNCTIONING IN WOMEN AFFECTED BY SYSTEMIC SCLEROSIS: A PRELIMINARY INVESTIGATION

Antonella Marcoccia¹, Antonella Guarino², Teresa Cocchiaro², Mariagrazia Modesti¹, Cecilia Cianfrocca¹, Rosalia Privitera¹, Sofia Isabelli¹, Marta Anna Stell Vizzini³, Rocco Rago², Alessia Renzi³, Michela Di Trani³

¹Scleroderma Center - Sandro pertini Hospital, Roma, ITALY, ²Reproduction Unit- Sandro pertini Hospital, Roma, ITALY, ³Department of Psychology- Sapienza University, Roma, ITALY

Introduction: Systemic sclerosis is a rare multisystem connective tissue disease that affects the skin and internal organs.

Patients with Systemic Sclerosis experience high levels of psychological distress caused by changes in physical appearance, pain, fatigue and difficulty carrying out daily activities.

Facial image dissatisfaction appears to be highly correlated with high levels of alexithymia and thus higher levels of psychological distress.

The aim of this study was to investigate the presence of psychopathological symptoms and the relations of these dimensions with the quality of life and the sexual function in a group of women affected by systemic scleroderma.

Material and Methods: The investigation was approved by the local Ethical Committee. Informed consent was obtained from all participants in accordance with local and international legislation (Declaration of Helsinki). Seventy-one women with systemic scleroderma were invited to participate in the study: 65 agreed to participate, while 6 declined. Four questionnaires were administered to the patients: a specific socio-demographic questionnaire, the Symptom Checklist-90-Revised (SCL-90-R), the Female Sexual Function Index (FSFI), and the Quality-of-Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO-41).

Results: Of all the participants in this study, 48% of patients showed a clinical score on SCL-90-R Somatization, 45% on Depression, and 37% on Obsessive-Compulsive. As hypothesized, psychopathological symptoms were related to lower quality of life, since Somatization and Depression predicted the total score of health-related quality of life, and lower sexual functions, showing a specific effect of Depression on sexuality.

Conclusions: Our findings highlighted the presence of an association between psychopathological symptoms and reduced sexual functioning and the associations between somatization and the health-related quality of life dimensions in scleroderma patients. Furthermore, our results sustain the importance of also considering the mental health of patients with systemic sclerosis, within an integrated biopsychosocial care model.

P.252

EXPLORING THE ROLE OF PALLIATIVE CARE IN THE MANAGEMENT OF SYSTEMIC SCLEROSIS: AN INTERNATIONAL SURVEY

Johnson Lily¹, Muditha Samaranayaka², Michael Hughes³, Zoe Rose⁴, Yusef Emre Akdeniz⁵, Elizabeth Wragg⁶, Timothy Jackson⁷

¹University of Manchester, Manchester, UNITED KINGDOM, ²Salford Royal Hospital, Manchester, UNITED KINGDOM, ³Salford Royal Hospital, Manchester, UNITED KINGDOM, ⁴Salford Royal Hospital, Manchester, UNITED KINGDOM, ⁵Istanbul Okan University, Istanbul, TURKEY, ⁶Salford Royal Hospital, Manchester, UNITED KINGDOM, ⁷Salford Royal Hospital, Manchester, UNITED KINGDOM

Introduction: The role of palliative care is well-established in the management of chronic progressive diseases, including neurodegenerative disorders such as Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Parkinson’s Disease and its related disorders. The aims of palliative care interventions are to improve the quality of life (QOL) of patients and their families by focusing on symptom control, supporting psychosocial and spiritual issues and discussing individual end-of-life preferences. Studies have shown this personalised and specialised care, when compared with care provided by general practice, significantly improved control of key symptoms such as pain, dyspnoea, poor quality sleep, gastrointestinal symptoms and enhanced individual QOL, and also reduced caregiver burden.

In the management of Systemic Sclerosis (SSc), there is a paucity of research in the extant literature around palliative care. However, the burden of the disease in severe and progressive organ involvement is well recognised e.g., in interstitial lung disease and pulmonary arterial hypertension, and scleroderma renal crisis. These SSc patients and their families undoubtedly face many physical and mental difficulties. The aim of our study is to investigate how we can improve the lives of SSc patients with palliative care approaches through identifying unmet needs and understanding best practice.

Material and Methods: An international survey of clinicians (rheumatology and palliative care) to understand current practice and the challenges with regards to end of life care. Descriptive statistics and appropriate testing shall be used to analyse and present the data, including international differences. Our proposed plan of investigation is presented in Figure 1.

Results: Assembly of steering committee, narrative/scoping review of the literature and design of survey questions have been completed. Once agreed with international stakeholders, the survey will be launched online. Results will be analysed in order to examine two key themes: 1) assessing unmet needs, and 2) understanding best practice.

These findings will be broadly disseminated among relevant stakeholders.

Conclusions: Palliative care for patients with SSc is an under-explored area in the literature and clinical practice currently. However, SSc is associated with a significant morbidity burden for many patients which makes palliative care a relevant treatment option. Understanding best practice will allow for the development of much needed clinical and referral guidelines providing better access to these treatment options for SSc patients.

P.253

FACTORS ASSOCIATED WITH SLEEP DISTURBANCES IN PATIENTS WITH SYSTEMIC SCLEROSIS

Eleonora Machura-Porebska, Eugene J. Kucharz, Robert Pieczyrak, Przemyslaw Kotyla

Department of Internal Medicine, Rheumatology and Clinical Immunology, Medical University of Silesia, Katowice, POLAND

Introduction: Sleep disturbances were reported in patients with systemic sclerosis (SSc). There is a number of factors that directly or indirectly are associated with impaired sleep quality. The study was designed to evaluate association of variables with disturbed features of sleep.

Material and Methods: SSc patients (45 female and 12 male) and 65 age- and sex-matched healthy controls were investigated. All the patients fulfilled the classification criteria. Patients with concomitant disorders or receiving medication known to affect sleep quality were excluded. Sleep quality was evaluated with the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Berlin Questionnaire. Additionally, quality of live, fatigue, depression as well as demographic, clinical and laboratory data were collected

Results: The significant disturbances in sleep were shown in SSc patients. It was found that only one-third of the SSc patients had good general sleep quality compared to two-thirds in the control group. Diminished sleep efficacy in SSc 0.79 ± 0.15% versus 0.91 ± 0.13% was found. SSc was associated with prolonged sleep latency. The total sleep period of the patients was similar to that of the controls. Male patients had shorter sleeping times than female patients (5.92 ± 1.42 versus 7.02 ± 1.47 hr.). Female and male patients also differed in sleep efficiency (81.78 ± 13.74 % versus 70.25 ± 17.28 %, respectively). The occurrence of various gastrointestinal symptoms was shown to be associated with sleep disturbances. Nausea or vomiting was also associated with an increased hypersomnolence index. Articular pain enhances sleep disturbances.

The correlation was shown between the disease and sleep latency (r = 0.388). A complement component C3 level positively correlated with sleep duration (r = 0.286). Hypersomnolence correlated with C-reactive protein levels (r = 0.337), and a negative correlation between hypersomnolence and potassium levels (r = -0.333), as well as serum iron levels (r = -0.594) was found. A negative correlation was shown between sleep efficiency and potassium levels (r = -0.287).

A three-year-long follow up did not reveal any relationship between sleep disturbances and mortality in SSc.

Conclusions: Sleep is profoundly disturbed in SSc. Impaired quality of sleep is resulted from a number of factors and should be always considered as cumulative effect of various manifestations of the disease. Defective sleep is significantly related to low quality of life. More attention should be paid to disturbed sleep in SSc patients.

P.254

THE ASSESSMENT OF ORGAN DAMAGE WITH SCLERODERMA CLINICAL TRIALS CONSORTIUM DAMAGE INDEX IN PATIENTS WITH SYSTEMIC SCLEROSIS IN RUSSIAN COHORT PATIENTS

Anastasia Koktakova, Valeriya Babak, Lidia Ananyeva, Olga Ovsyannikova, Olga Koneva, Liudmila Garzanova, Oxana Desinova, Mayya Starovoytova, Rushana Shayakhmetova, Anna Khelkovskaya-Sergeeva

V.A. Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: The Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI) is a new instrument to quantify organ damage in systemic sclerosis (SSc). The aim of the study was to assess the organ damage with SCTC-DI in patients with SSc in Russian cohort.

Material and Methods: A cross-sectional study was conducted on 120 patients with definite SSc according to 2013 ACR/EULAR Criteria. 85% (n=102) of patients were female, Median (Me) age was 49.5 [37; 60] years. Me of disease duration was 93 [45; 189] months. The type of the disease was limited in 76 (63.3%) cases, diffuse in 43 (35.8%), sine scleroderma in 1 (0.8%). SSc therapy was represented by oral systemic glucocorticoids with a Me dose of 10 [5; 10] mg/day of equivalent prednisone in 110 (91.7%) patients, immunosuppressants in 109 (90.8%), rituximab in 56 (46.7%). SCTC-DI were evaluated in all patients. Me with 1st and 3rd quartiles, Spearman's rank correlation coefficient (ρ) and Mann–Whitney U test for data analysis were performed.

Results: The musculoskeletal system and skin damage were found in 80 (66.7%) patients with Me score 3 [0; 4], vascular system – in 50 (41.7%) with Me score 0 [0; 2], gastrointestinal – in 98 (81.7%) with Me score 1 [1; 2], respiratory – in 46 (38.3%) with Me score 0 [0; 2], cardiovascular – in 36 (30%) with Me score 0 [0; 2], renal – in 6 (6%). The Me of summary SCTC-DI score was 6 [3; 10]. The summary SCTC-DI score did not depend on age (ρ=0.145; p=0.113) and disease duration (ρ=-0.037; p=0.686) and type of SSc (ρ=0,138).

The value of SCTC-DI score were higher in patients on glucocorticoid therapy (ρ=0.228, p=0.012) and weakly correlated with the dose of the drug (ρ=0.208; p=0.023). In addition, SCTC-DI score was significantly higher in patients treated with rituximab compared to those who did not (ρ=0.308; p<0.001). At the same time immunosuppressants treatment of SSc was not associated with SCTC-DI score (p = 0.671).

Conclusions: The musculoskeletal, skin and gastrointestinal damage were the most frequent items in the SCTC-DI score in the Russian cohort of patients with SSc. The highest SCTC-DI score was associated with SSc treatment with glucocorticoids or rituximab. This may be associated with the prescription of these drugs to patients with the most severe course of the disease.

P.255

PREDICTIVE FACTORS OF SOCIAL INTEGRATION IN WOMEN WITH SYSTEMIC SCLEROSIS

Poormoghim Hadi, Liela Azizi, Fatemeh Babaee, Maryam Salimie Benyni, Ali Kabir

Iran University of Medical Sciences, Tehran, IRAN, ISLAMIC REP

Introduction: Systemic sclerosis is a chronic autoimmune disease. Vascular presentation and fibrosis which involves skin of face and hands results to disfiguring of face, contractures and deformity on hands and disability. In addition, symptoms related to visceral involvement cause limitation in their social life. The purpose of this study is to elucidate the disease related factors on social relationship in scleroderma patients.

Material and Methods: seventy patients with systemic sclerosis who visited in Firoozgar hospital between march 2020 and 2022. All patients fulfilled 2018 ACR/EULAR criteria and gave informed consent enrolled in the study.

Demographic and baseline, clinical and laboratory data extracted from data bank in our clinic. Depression and social network integration were evaluated by using the Beck Depression Inventory (BDI), and social network integration index (SNI) in all patients. Pain was evaluated by pain scale (no pain, mild pain, discomforting, distressing, horrible, excruciating).

BDI score qualified into 4 class; no to minimal (score 0-9) mild (score 10-18), moderate (score 19-29), and severe depression (score 30 through 63).

SNI is a psychometric tool to assess 12 types of social relationships. SNI assesses the structure of social integration such as number and proximity of ties, and function of integration, like frequency and mutualism of contact.

Statistical analysis: Descriptive analysis was used for prevalence of demographic and baseline data. We used univariate analysis for the evaluation of the association between each factor (demographic and baseline variables, other data) and SNI. T test for comparison mean of two groups and one-way ANOVA was used for three or more groups of data. To find out the correlation we used Pearson’s or spearman’s coefficient. Multiple linear regression with backward method was used for determining the most independent variables associated with SNI using variable that was meaningful in univariate analysis.

Results: Demographic, baseline, clinical and paraclinical data in 70 SSc women and results of univariate analysis and statistical methods shows in table 1, 2. Findings of study show patients with prolongation of disease duration, higher mouth opening, had higher social SNI score (positive correlation B=0.186, B=0.306 respectively). Patient with lower educational levels and BDI, higher dyspnea and pulmonary arterial pressure (PAP), showed negative correlation (B= -0.362, B= -0.280, and -0.235, respectively). Table 3

Conclusions: Patients with longer disease duration and higher educational levels had better cope with the disease. Patients with higher depression, dyspnea and PAP had less social integration. Lesser mouth opening has negative effect on social integration.

P.256

HEALTH-RELATED QUALITY OF LIFE IN SYSTEMIC SCLEROSIS - A CASE-CONTROL STUDY

Ines Genrinho¹, Susana P. Silva1, Carolina Mazeda^1,2, Anabela Barcelos^1,2

¹Rheumatology Department, Centro Hospitalar Baixo Vouga, Aveiro, PORTUGAL, ²Egas Moniz Health Alliance, Aveiro, PORTUGAL, ³Rheumatology Department, Centro Hospitalar Tondela Viseu, Viseu, PORTUGAL

Introduction: There is a great heterogeneity in clinical presentation among systemic sclerosis (SSc) patients resulting in different impairments of health-related quality of life (HRQoL). The European Quality of Life-5 Dimensions (EQ-5D) is a widely used questionnaire that evaluates the generic quality of life developed in Europe. The aim of this study was to evaluate HRQoL in patients with SSc using the EQ-5D and to correlate EQ-5D scores with social and clinical data.

Material and Methods: A single-centre, case-control study was conducted enrolling SSc patients who fulfilled the 2013 ACR/EULAR criteria for the classification of diffuse SSc (dSSc) or limited SSc (lSSc) form and a healthy control group matched by sex. All patients were requested to answer EQ-5D questionnaire to assess HRQoL. Social–demographic and clinical data were collected. General descriptive analysis and independent parametric or non-parametric tests were performed using SPSS Statistics v26.

Results: A total of 25 SSc patients (8 with dSSc and 17 with lSSc form) and 25 healthy controls were included, being 21 females (84%) in both groups, with a mean age of 58.12±11.9 and 45.68±12.74 years old, respectively. SSc patients presented significantly lower EQ-5D visual analogic scale (VAS) (mean 69.0±14.65 patients vs 84.0±12.04 control) and total scores (mean 0.86±0.10 patients vs 0.94±0.10 control) when compared to the control group (p=0.001). No differences in HRQoL were found between both SSc subtypes. In patients group, older age showed a negative correlation with EQ-5D VAS score (r-0.47, p=0.02). Regarding to clinical data, the presence of skin thickening of the fingers of both hands, telangiectasias, and pulmonary disease were associated with lower EQ-5D VAS and total scores (p<0.05).

Conclusions: SSc patients presented significantly impaired HRQoL, with lower EQ-5D VAS and total scores. Older age, skin thickening of the fingers, telangiectasias, and pulmonary disease contribute to significantly decreased EQ-5D scores. Further investigations with bigger samples are needed to clarify the degree of impairment in HRQoL with other relevant clinical data since these results were limited by the small cohort included.

P.257

QUALITY OF LIFE IN INTERSTITIAL LUNG DISEASE ASSOCIATED WITH SYSTEMIC SCLEROSIS DURING RITUXIMAB TREATMENT

Liudmila Garzanova, Lidia Ananyeva, Olga Koneva, Olga Ovsyannikova, Oxana Desinova, Mayya Starovoytova, Rushana Shayakhmetova, Anna Khelkovskaya-Sergeeva

V.A. Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: Interstitial lung disease (ILD) associated with systemic sclerosis (SSc) could affect the quality of life of patients. Rituximab (RTX) therapy improves lung function in many studies and clinical observations in SSc. The aim of our study was to assess the quality of life in patients with ILD associated with SSc on RTX therapy during long-term follow-up period.

Material and Methods: Our prospective study included 81 patients with SSc. Mean age was 48.2±13 years, female - 67 patients (83%). The mean disease duration was 5.3±4.3 years. The diffuse cutaneous subset of the disease had 49 patients, limited – 27, overlap – 5. All pts had interstitial lung disease (ILD). All patients received prednisolone at mean dose of 11.8±4.1 mg/day and 40% of them - immunosuppressants at inclusion (cyclophosphamide, mycophenolate mofetil in most cases). Patients received RTX due to the ineffectiveness of previous therapy for ILD. Parameters were evaluated over the period 42±14 month after initiation of RTX therapy. Cumulative mean dose of RTX was 3.6±1.4 g. The quality of life was assessed by HAQ (Health Assessment Questionnaire). The results are presented in the form of mean values.

Results: During RTX therapy, there was a significant increase in forced vital capacity (FVC) from 79.5±20.6 to 88.3±22.4% of predicted (p=0.001), increase of diffusion capacity for carbon monoxide % predicted (DLCO) from 47.2±18.9 to 50.9±18.5% of predicted (p=0.001). There was an improvement of quality of life by a decrease of HAQ parameter from 1.3±0.8 to 0.9±0.7 (p=0.001). We found a moderate statistically significant correlation between the HAQ and the DLCO (r=-0.298; p=0.01).

Conclusions: In our study parameters of the lung function and quality of life significantly improved on RTX therapy in long-term follow-up period. There was a correlation between quality of life and increase of DLCO. RTX therapy could improve quality of life in patients with interstitial lung disease associated with systemic sclerosis.

P.258

CLINICAL OUTCOMES AND ASSOCIATED FACTORS WITH MORTALITY IN SYSTEMIC SCLEROSIS PATIENTS WITH SARCOPENIA

Chingching Foocharoen, Sirada Hongkanjanapong, Patnarin Pongkulkiat, Ajanee Mahakkanukrauh, Siraphop Suwannaroj

Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, THAILAND

Introduction: Despite the high incidence of sarcopenia in systemic sclerosis (SSc) patients, there is currently limited evidence on their outcomes. Our study aimed to determine the outcomes of the SSc patients with sarcopenia and identify factors associated with mortality in this group.

Material and Methods: A historical cohort study was conducted in adult SSc patients diagnosed with sarcopenia according to the criteria of Asian Working Group for Sarcopenia 2019, who were attending the Scleroderma Clinic at Khon Kaen University between July 2019 and November 2021. The mortality rate was assessed with its 95% confidence interval (95%CI), and Cox regression analysis was used to evaluate factors associated with mortality.

Results: A total of 41 sarcopenic SSc patients were included in the analysis, with a female-to-male ratio of 1.1:1. The respective mean age and mean duration of follow-up after being diagnosed with sarcopenia was 62.8±9.7 years and 2.4±0.5 years. Over a total of 99.04 person-years, 5 patients did not survive during the follow-up period, resulting in an incidence rate of 5.05 per 100-person-years (95%CI 2.10-12.13). All non-survivors were dcSSc subset, and 4 of them had interstitial lung disease (ILD). The survival rate after being diagnosed with sarcopenia at 6-, 12-, 18-, and 24-months was 97.6%, 95.1%, 92.7%, and 87.8%, respectively. Hospitalization was the only factor associated with the mortality risk, with a hazard ratio of 14.21 (95%CI 2.36-85.60). Neither the SSc subset nor internal organ involvement was a significant mortality risk among patients with sarcopenia.

Conclusions: The mortality rate of SSc patients with sarcopenia increased after a 2-year follow-up, particularly in dcSSc. Once these patients required hospitalization, the mortality risk increased by over 10 times. Further long-term follow-up in a large cohort is suggested.

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DEVELOPMENT OF A TOOL TO DOCUMENT SYSTEMIC SCLEROSIS PAIN SOURCES, PATTERNS, AND MANAGEMENT BARRIERS: A SCLERODERMA PATIENT-CENTERED INTERVENTION NETWORK (SPIN) PATIENT-RESEARCHER PARTNERSHIP

Tiffany Dal Santo¹, Elsa-Lynn Nassar¹, Marie-Eve Carrier¹, Sophie Hu¹, Susan Bartlett², Rina S. Fox³, Linda Kwakkenbos⁴, Yvonne Lee⁵, John Varga⁶, Jo-Ann Lapointe McKenzie⁷, Amanda Lawrie-Jones⁸, Tracy Mieszczak⁹, Silvia Petrozza¹⁰, Sandra Rideout¹¹, Maureen Sauve¹², Gayle Wixson⁹, Brett D. Thombs1

¹Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, CANADA, ²Department of Medicine, McGill University, Montreal, CANADA, ³College of Nursing, University of Arizona, USA, ⁴Department of IQ Healthcare, Radboud University Medical Center, THE NETHERLANDS, ⁵Department of Medicine (Rheumatology) and Preventive Medicine, Northwestern University, USA, ⁶Department of Internal Medicine (Division of Rheumatology), University of Michigan, USA, ⁷Scleroderma Manitoba, CANADA, ⁸Scleroderma Australia, AUSTRALIA, ⁹Scleroderma Patient-centered Intervention Network, CANADA, ¹⁰Scleroderma Society of Ontario, CANADA, ¹¹Scleroderma Atlantic, CANADA, ¹²Scleroderma Canada, CANADA

Introduction: Systemic sclerosis (SSc) is a complex disease involving multiple factors that may contribute to pain. People with SSc emphasize the impact pain has on their quality of life; however, no studies have examined the relative importance and commonality of different SSc pain sources, evaluated patterns of pain from different sources, or assessed how to improve pain management. In collaboration with researchers, healthcare providers, and patient partners, we are developing a tool to assess sources of pain in SSc, determine patterns of pain from different sources, and understand barriers to pain management.

Material and Methods: We will start by identifying validated pain assessment tools developed for other populations and, in collaboration with members of a patient advisory team, adapt them to be specific to SSc. The tool will include questions on pain sources, patterns and intensity, as well as pain management techniques and barriers to pain management in SSc. Then, we will conduct nominal group technique (NGT) sessions with people with SSc not involved in tool development to further refine the tool. NGT sessions will consist of discussing items and questions in the preliminary assessment tool that participants believe should be added, removed, or modified. We aim to conduct 4-6 NGT sessions (60-90 minutes) with 4-8 people with SSc per session, and 1-2 sessions with health care providers who care for people with SSc. The final number of sessions will be determined based on the redundancy and consistency of data obtained. People with SSc will be recruited from the Scleroderma Patient-centered Intervention Network (SPIN) Cohort, which recruits people with physician-confirmed SSc aged 18 years older from 53 sites in 7 countries. Health care providers will be volunteers from the SPIN network.

Results: Data collection is underway. After each session, we will revise the pain tool based on session results. The revised tool will be used as a template during the next NGT session.

Conclusions: The findings of this study will inform the development of the first tool specifically designed to better understand the multi-faceted nature of pain in SSc. Once completed, this tool will allow our team and other researchers to more accurately assess pain in patients with SSc and effectively describe key components of pain and its management. This knowledge will enable future studies of the pathophysiology of pain in SSc and of interventions to improve pain management.

P.260

CHANGES OF DAMAGE INDEX IN PATIENTS WITH LIMITED AND DIFFUSION FORMS OF SYSTEMIC SCLEROSIS

Valeriya Babak, Anastasia Koltakova, Lidia Ananyeva, Olga Koneva, Olga Ovsyannikova, Liudmila Garzanova, Oxana Desinova, Mayya Starovoytova, Rushana Shayakhmetova, Anna Khelkovskaya-Sergeev

V.A. Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: To reveal differences in damage of organs and systems in patients with limited and diffusion forms of systemic sclerosis (SSc) using the index of damage - Scleroderma Clinical Trials Consortium Damage Index(SCTC-DI)

Material and Methods: The cross-sectional study included 119 patients, corresponding to classification criteria of SSc (ACR/EULAR,2013). The disease form in 76 (63.3%) cases was limited, in 43 (35.8%) – diffusion. Patients with various forms of a disease didn't differ from each other on a median (Me) of age (p=0.129) and disease duration (p=0.090). Among patients with the limited form women were present more often (p=0.003) 70 (92.1%), against 31 (72.1%) with a diffusion form. In both groups immunosuppressants was presented in comparable volumes (p =0.324): 88.2% with limited form and 95.3% – diffusion. Patients with a diffuse form were statistically significantly more likely to receive rituximab therapy and high dose of glucocorticoids (p=0.001). The SCTC-DI was estimated in all patients. Me with 1st and 3rd quartile, chi-square of Pearson, exact criterion of Fischer, V-Kramer and odds ratio with the indication of 95% of the Confidential interval (95% CI), coefficient of correlation of Spirmen (ρ) and Mann-Whitney's U-criterion for data analysis were performed.

Results: Vascular change, the damage of a skeletal and muscular system and skin were comparable (p>0.5). In patients with a diffusion form identification of a contracture of large joints was 4.76 times higher (95% of D: 1.37-16.6%;p=0,008;V=0,241). Digital ulcers were more frequent in patients with limited form (p=0.040;V=0.188) and were presented 2.21 times higher (95% CI: 1.03-4.75%). The injury of lungs occured more often in patients with the diffusion form of SSc (p=0.035;V=0.193): in 23 (51.2%) with diffusion and 24 (31.6%) with limited form of the disease. After calculation of points of SP SCTC-DI at patients with the SSc various forms differences in Me of indicators of defeat of vessels (p=0.034) and lungs were noted (p=0.043): existence of a diffusion form of a disease was associated with higher account of injury of lungs (p=0.193;p=0.035) and also (are close to the level of statistical significance) – vessels (ρ=0.175;p=0.057)

Conclusions: We didn't reveal in study group significant differences in the maximum account of the index of damage of SCTC-DI. It can be connected with mild course of the disease in patients with limited form and more intensive anti-rheumatic therapy in patients with the diffusion form (having heavier forecast), in particular with more frequent use of rituximab and higher doses of glucocorticoids

P.261

HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH SYSTEMIC SCLEROSIS; COMPARISON TO THE LEADING CAUSES OF DISEASE BURDEN

Begonya Alcacer-Pitarch¹, Ruben Duarte-Fernandes¹, Anthony C. Redmond¹, Elizabeth Hensor¹, Francesco Del Galdo¹, Maya H. Buch², Anne-Maree Keenan³

¹Leeds Institute of Rheumatic and Musculoskeletal Medicine, School of Medicine, University of Leeds, Leeds, UNITED KINGDOM, ²Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, faculty of Biology, Med, Manchester, UNITED KINGDOM, ³School of Healthcare, University of Leeds, Leeds, UNITED KINGDOM

Introduction: Systemic sclerosis (SSc) can have profound physical and psychological effects resulting in psychosocial impact. This impact is commonly referred to as patients’ health-related quality of life (HRQoL), a multi-dimensional concept affected by the individual’s physical, mental, emotional, and social functioning, and levels of independence. HRQoL focuses on the impact health status has on QoL; beyond the direct measures of population health, life expectancy, and causes of death.

The MOS Short Form (SF-36) is a generic health questionnaire designed to assess a person’s perceived general health status. It consists of eight health domains, which score three aspects of health, functional status, well-being, and overall evaluation of health. Scores obtained from the questionnaire range from 0, representing the worst health state measurable, to 100 indicating the best health state.

The study's aim was to explore the impact of SSc on HRQoL as assessed by the SF-36 and to compare the scores to nine published chronic diseases, including the six global leading causes of disease burden in high-income countries and three common musculoskeletal diseases.

Material and Methods: HRQoL data were captured from SSc patients using the Short Form-36 (SF-36) and compared to previously published data for chronic diseases including unipolar major depression, ischaemic heart disease (IHD), stroke, chronic obstructive pulmonary disease (COPD), diabetes, lung cancer, osteoarthritis (OA), rheumatoid arthritis(RA) and lower back pain(LBP). These articles were selected from a database search of 2436 articles, of which 108 were eligible with only the nine selected meeting the criteria. Mean norm-based transformed scores (NBS) were compared for all eight health domains of the SF-36.

Results: Data were collected from 121 SSc patients (106 female; median age 59, median disease duration 9 years). SSc patients reported the worst general health (NBS mean 32.82) among the nine diseases, and reported high impairment in the following four health domains: a) role limitation due to physical problems (NBS mean 34.77), which was as high as that reported for stroke, RA and lung cancer patients; b) bodily pain (NBS mean 36) which was comparable to OA, RA and lower back pain; and c) vitality (NBS mean 39.69) similar to RA. SSc patients reported scores (NBS mean 41.78) in role limitations associated with emotional problems, being second to those with depression; they had similar scores to those reported for stroke and RA(fig1).

Conclusions: SSc has a significant impact on HRQOL, demonstrating substantial physical and psychological impairment, comparable to those experienced by patients with RA and stroke.

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UNDERREPRESENTED GROUPS IN RANDOMIZED CONTROLLED TRIALS OF SCLERODERMA OVER THE LAST 5 YEARS (2018-2022)

Shabnum Teja¹, Matthew Turk², Janet Pope¹

¹Western University, London, CANADA, ²University of Ottawa, Ottawa, CANADA

Introduction: Systemic scleroderma (SSc) is a progressive connective tissue disorder characterized by vasculopathy, autoantibodies, skin fibrosis with multiple organs that are affected to varying degrees. Among SSc patients, a significant proportion experiences interstitial lung disease (ILD), which is associated with increased disease burden and reduced life expectancy. The primary approach to ILD treatment in SSc centers around the use of immunosuppressants and if progressive fibrosis then antifibrotics, with ongoing investigations into novel agents. Research indicates that an individual’s ethnicity and cultural background significantly impacts susceptibility, severity, and clinical manifestations in SSc. Historically, randomized controlled trials (RCTs) have not equitably represented Black and Indigenous populations. Consequently, it is critical to enhance the inclusivity of diverse demographic groups, especially those who are disproportionately affected by SSc. Therefore, it is crucial that RCT participants reflect the broader demographics of those afflicted with SSc. Many trials were undertaken in the USA; where there is a higher burden of minorities with SSc. For example, in the USA 2% identify as Indigenous and 13.6% Black. Indigenous people get SSc in the USA 2.34 times more than Caucasians, and Blacks comprise 37.9% of SSc patients (approximately 3 times higher than the background population). The aim of this meta-analysis was to compare the representation of Black and Indigenous peoples in SSc RCTs from 2018-2022.

Material and Methods: We searched the PUBMED database, MEDLINE and clinical trial registries using the keywords “scleroderma“ or “systemic sclerosis” or “systemic scleroderma” on March 21, 2023 yielding 3,764 results. We limited the study to English language RCTs and clinical trials between 2018 and 2022 and found 42 trials. We examined demographic data to determine the proportions of participants categorized as “Black” and “Indigenous”.

Results: Only 20/42 mentioned race/ethnicity as a variable in their data collection. For each trial (when provided), trials were not adequately reflecting ethnicity of the SSc population. All trials included white/Caucasians. When ethnicity was provided, 18% of trials only included White/Caucasians; 82% of trials included participants who self-identified as Black, and only 42% who self-identified as Indigenous. None of the studies reflected the diversity of the SSc population.

Conclusions: Nearly half the trials did not provide a breakdown of race/ethnicity. There needs to be both standardized reporting of race/ethnicity in SSc RCTs and studies should reflect and be generalizable to the SSc population. The ethics of excluding minority populations who have a high burden of disease are problematic.

P.263

UNDERREPRESENTED GROUPS IN SCLERODERMA RANDOMIZED CONTROLLED TRIALS OVER THE LAST 5 YEARS (2018-2022)

Shabnum Teja¹, Matthw Turk², Janet Pope¹

¹Western University, Schulich School of Medicine & Dentistry, London, CANADA, ²University of Ottawa, Ottawa, CANADA

Introduction: Systemic scleroderma (SSc) is a progressive connective tissue disorder characterized by vasculopathy, autoantibodies, skin fibrosis with multiple organs that are affected to varying degrees. Among SSc patients, a significant proportion experiences interstitial lung disease (ILD), which is associated with increased disease burden and reduced life expectancy. The primary approach to ILD treatment in SSc centers around the use of immunosuppressants and if progressive fibrosis then antifibrotics, with ongoing investigations into novel agents. Research indicates that an individual’s ethnicity and cultural background significantly impacts susceptibility, severity, and clinical manifestations in SSc. Historically, randomized controlled trials (RCTs) have not equitably represented Black and Indigenous populations. Consequently, it is critical to enhance the inclusivity of diverse demographic groups, especially those who are disproportionately affected by SSc. Therefore, it is crucial that RCT participants reflect the broader demographics of those afflicted with SSc. Many trials were undertaken in the USA; where there is a higher burden of minorities with SSc. For example, in the USA 2% identify as Indigenous and 13.6% Black. Indigenous people get SSc in the USA 2.34 times more than Caucasians, and Blacks comprise 37.9% of SSc patients (approximately 3 times higher than the background population). The aim of this meta-analysis was to compare the representation of Black and Indigenous peoples in SSc RCTs from 2018-2022.

Material and Methods: We searched the PUBMED database, MEDLINE and clinical trial registries using the keywords “scleroderma“ or “systemic sclerosis” or “systemic scleroderma” on March 21, 2023 yielding 3,764 results. We limited the study to English language RCTs and clinical trials between 2018 and 2022 and found 42 trials. We examined demographic data to determine the proportions of participants categorized as “Black” and “Indigenous”.

Results: Only 20/42 mentioned race/ethnicity as a variable in their data collection. For each trial (when provided), trials were not adequately reflecting ethnicity of the SSc population. All trials included white/Caucasians. When ethnicity was provided, 18% of trials only included White/Caucasians; 82% of trials included participants who self-identified as Black, and only 42% who self-identified as Indigenous. None of the studies reflected the diversity of the SSc population.

Conclusions: Nearly half the trials did not provide a breakdown of race/ethnicity. There needs to be both standardized reporting of race/ethnicity in SSc RCTs and studies should reflect and be generalizable to the SSc population. The ethics of excluding minority populations who have a high burden of disease are problematic.

P.264

CO-DESIGNING DIGITAL ULCER SELF-CARE TOOLS IN SYSTEMIC SCLEROSIS

Tani Ngcozana, Christopher Denton

Royal Free NHS Foundation Trust, London, UNITED KINGDOM

Introduction: Digital Ulcers (DU) are a frequent challenge in patients with Systemic Sclerosis (SSc), as they approximately affect more than half of these patients. Management of DU is provided in secondary care and shared care between rheumatologists and primary care depending on the severity of the DU, defined by the number of the DU and their recurrence patterns. Patients with chronic or multiple DU have tended to have more access to specialist SSc clinics while those with episodic DU, access to DU care is suboptimal and may have several unmet needs. No research has been done to investigate patients' support needs in DU and co-design interventions with them. The aim of this study is to develop a practical set of evidence-based tools for self-care of DU.

Material and Methods: This is a qualitative study focusing on co-designing self-care tools to improve DU care incorporating Experienced-Based Co-design (EBCD) method. EBCD focuses on patients’ experiences and needs to assist collaborative input of patients and healthcare professionals in the establishment of concepts and interventions to improve negative experiences. It incorporates healthcare professionals and patients’ observations and interviews, patients recorded on film, to gain understanding on how patients are cared for, how they care for their DU, their unmet needs and to capture their narrative key points. The same participants will also be invited to participate in workshops involving discussion, designing, refinement and finalisation of the tools.

Results: Of 88 papers assessed at full text for eligibility, 62 papers were included in a systematic review undertaken preceding this study evaluating non-pharmacological interventions in DU and other ulcerative conditions. The review indicates a gap in studies investigating patient experience and care needs in DU. Some interventions in the included ulcerative conditions pointed towards being applicable in DU for example certain wound dressings, showed fastest symptom resolution or met patients specific needs. In order to address some of the systematic review results a finalised research protocol has been approved and ethical approval gained to conduct the EBCD study.

Conclusions: The outputs from the EBCD study will be collaboratively co-designed tools by patients and healthcare professionals to enhance DU care, and lessen DU burden. The tools developed will be fully evaluated in a definitive clinical trial before being disseminated. The tools will not only benefit local patients but other patients widely.

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PATIENT EXPERIENCES WITH TELEHEALTH DURING THE COVID-19 PANDEMIC AND PREFERENCES GOING FORWARD: A SCLERODERMA PATIENT-CENTERED INTERVENTION NETWORK (SPIN) COVID-19 COHORT CROSS-SECTIONAL STUDY

Elsa-Lynn Nassar¹, Marie-Eve Carrier¹, Linda Kwakkenbos², Richard Henry¹, Nora Østbø¹, Gabrielle Virgili-Gervais¹, Sophie Hu¹, Sabrina Provencher¹, Susan Bartlett³, Amy Gietzen⁴, Karen Gottesman⁵, Geneviève Guillot⁶, Marie Hudson³, Laura Hummers⁷, Amanda Lawrie-Jones⁸, Vanessa Malcarne⁹, Maureen Mayes¹⁰, Luc Mouthon¹¹, Michelle Richard¹², Maureen Sauvé¹³, Robyn Wojeck¹⁴, Andrea Benedetti¹⁵, Brett Thombs¹

¹Lady Davis Institute of Medical Research, Jewish General Hospital, Montreal, CANADA, ²Department of Clinical Psychology, Behavioural Science Institute, Radboud University, Nijmegen, THE NETHERLANDS, ³Department of Medicine, McGill University, Montreal, CANADA, ⁴Steffens Scleroderma Foundation, Albany, USA, ⁵National Scleroderma Foundation, Danvers, USA, ⁶Sclérodermie Québec, Montreal, CANADA, ⁷Johns Hopkins University School of Medicine, Baltimore, USA, ⁸Scleroderma Australia, Melbourne, AUSTRALIA, ⁹Department of Psychology, San Diego State University, San Diego, USA, ¹⁰University of Texas McGovern School of Medicine, Houston, USA, ¹¹APHP-CUP, Hôpital Cochin, Université de Paris, Paris, FRANCE, ¹²Scleroderma Atlantic, Halifax, CANADA, ¹³Scleroderma Society of Ontario, Hamilton, CANADA, ¹⁴School of Nursing, Duke University, Durham, USA, ¹⁵Department of Epidemiology, Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, CANADA

Introduction: People with systemic sclerosis (SSc) may face multiple barriers to accessing clinical services, including limited availability of specialists, geographical challenges, and travel difficulties. Telehealth is a promising approach for providing care, and the COVID-19 pandemic has accelerated its adoption. No studies, however, have reported data on SSc patients’ experiences with telehealth. We assessed: (1) how SSc patients accessed outpatient SSc care (telehealth, in-person, mix) during the first two years of the COVID-19 pandemic (March 2020 to March 2022) and subsequently in August 2022; (2) associations between sociodemographic and SSc variables and care received; (3) association of telehealth with perceived amount of care received, ease of access to care, and satisfaction with care; and (4) future outpatient care preferences.

Material and Methods: We analyzed cross-sectional data from participants who completed the final assessment of the multi-wave Scleroderma Patient-centered Intervention Network (SPIN) COVID-19 Cohort in August 2022. Participants provided information on current care and, retrospectively, care received between March 2020 and March 2022. Bivariate logistic regression was used to assess factors associated with receiving exclusively in-person care.

Results: Participants (N = 314; response rate = 39% of baseline cohort enrollment from April 2020) were predominantly female (88%) and White (86%). Mean age was 58 years and mean time since SSc diagnosis was 13 years. During the first two years of COVID-19, 11% used only telehealth, 20% only in-person, and 69% a mix. In August 2022, these shifted to 3%, 49%, and 48%, respectively. 34% of participants reported that having to use telehealth decreased the amount of care received, whereas the majority reported no change in the amount of care received (55%) or the ease of access to care (53%) due to telehealth. Most participants (56%) expressed a preference for a mix of telehealth and in-person care in the future, but 43% reported a preference for in-person care only. Age, education, sex, race or ethnicity, location, and SSc disease subtype were not significantly associated with receiving all in-person care, but there were differences by country (France = 40 of 62, 65%; US = 12 of 103, 12%; UK = 3 of 35, 9%; Canada = 4 of 90, 4%). See Table 1.

Conclusions: Telehealth may be a viable care option for some SSc patients, and many patients favour a hybrid approach. Given varied patient experiences, healthcare providers may consider both telehealth and in-person options and tailor care to individual patient needs.

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THE PATIENT AS THE PRIMARY EDUCATOR FOR A SCLERODERMA-FOCUSED INTERPROFESSIONAL EDUCATION EVENT: ENCOURAGING PATIENT EMPOWERMENT

Corey Fellon², Hannah Bowen¹, Lee Shapiro^1,2, Linda Meenan¹, Amy Gietzen^1,3, Steve Rosenblum¹, Peter Meenan¹

¹Steffens Scleroderma Foundation, Albany, USA, ²Albany Medical College, Albany, USA, ³National Scleroderma Foundation, Danvers, USA

Introduction: Scleroderma is a complex disease and treatment often requires input from several medical disciplines. Lack of familiarity with the disease can lead to treatment delays. Raising awareness of scleroderma should result in earlier diagnosis and treatment interventions. Individuals with scleroderma have stories regarding their disease and their care that can make them impactful educators. When developing an Interprofessional Education (IPE) Event about scleroderma, the Steffens Scleroderma Foundation placed the patient in the leading role of educator of health professional students.

Material and Methods: Over five years, the IPE event has educated over 1200 rising healthcare professional students in nine disciplines, with assistance from roughly 30 patient advocates at each event. Prior to the event, patients participate in an Art of Advocacy program to give them a better understanding of their role as educators and to instill or reinforce their confidence in sharing their health journeys. During the event, the patients participate in a round table (if in person) or breakout room (if virtual) discussion with two groups of 8-10 students in different disciplines. The patients' share their stories of the path to diagnosis, the impact of the disease, their experiences with health care, and the benefits of multidisciplinary care teams. After two distinct patient-student interactions, participants are asked to complete an anonymous post-event survey.

Results: This past spring, over 90% of students and patients agreed that the patient as an educator was important/very important. Through discussion of their condition, 90% of patients believed the IPE event was effective/very effective at increasing scleroderma awareness in students. After the event, 100% of patients felt confident/very confident as a patient educator sharing their lived experience with scleroderma and 80% felt empowered by educating students. Also, 80% of patients explained their journey with scleroderma the way they wanted to. Finally, 95% of patients who attended the Art of Advocacy program responded positively to an open-ended question regarding preparation for their role as an educator.

Conclusions: The results of the post-event surveys indicate how the IPE event empowers patients to advocate through their lived experience with scleroderma and raise awareness by educating rising healthcare professionals who may one day diagnose or treat a scleroderma patient. This IPE model can be replicated to further increase awareness of scleroderma among health care professionals.

P.267

THE RISING CHALLENGE OF HEALTH LITERACY IN SYSTEMIC SCLEROSIS: DATA FROM AN ITALIAN COHORT PROVIDE EVIDENCE FOR AN IMPORTANT UNMET NEED IN CLINICAL PRACTICE

Khadija El Aoufy¹, Maria Ramona Melis², Paolo Iovino¹, Stefano Bambi¹, Chiara Lorini³, Guglielmo Bonaccorsi³, Ilaria Galetti^4-5, Carla Garbagnati⁴, Silvia Tonolo⁶, Marco Mitola⁷, Serena Guiducci⁸, Marco Matucci Cerinic⁹, Laura Rasero¹, Silvia Bellando Randone⁸

¹Department of Health Science, University of Florence, Florence, ITALY, ²Department of Experimental and Clinical Medicine, University of Florence, Florence, ITALY, ³Department of Health Science, Health Literacy Laboratory, University of Florence, Florence, ITALY, ⁴GILS (Gruppo Italiano, Lotta alla Sclerodermia), Milan, ITALY, ⁵FESCA (Federation of European Scleroderma Associations), Belgium, BELGIUM, ⁶ANMAR Onlus (Associazione Nazionale Malati Reumatici), Rome, ITALY, ⁷ASSMAF (Associazione per lo Studio della Sclerosi Sistemica e delle Malattie Fibrosanti), Florence, ITALY, ⁸Department of Experimental and Clinical Medicine, Careggi Hospital, Rheumatology Unit, Florence, ITALY, ⁹IRCCS San Raffaele Hospital, Unit of Immunology, Rheumatology, Allergy and Rare diseases (UnIRAR), Milan, ITALY

Introduction: Patients with Systemic Sclerosis (SSc) must stick to therapies and other suggestions, make substantial lifestyle and behavioural adjustments, and learn to cope with psychological and social implications, in order to effectively manage their chronic condition. The comprehension of the disease and the ability to make clinical decisions well understood is fundamental for disease self-management by SSc patients. Thus, the aim of the present study was to assess Health Literacy (HL) levels in an Italian cohort of SSc patients, and to describe what aspects are perceived as more difficult.

Material and Methods: Patients diasgnosed as SSc according to the 2013 ACR/EULAR criteria were enrolled from September, 2022 to March, 2023 with the support of Italian patients’ associations (ASSMAF/GILS/ANMAR). SSc patients were evaluated for socio-demographic variables and HL levels with the administration of the HLS-EU-Q16 (Italian validated version).

Results: 57 SSc patients were included in the study, and the majority were females (98.2%- 56/57) with a mean age (M±SD) of 59 (13.2) years; 73.7% (42/57) of them was partnered, 67.9% (38/57) was unemployed or retired, and 75.4% (43/57) had children. In almost half of the patients, SSc was diagnosed for more than 10 years, while the Raynaud phenomenon manifested for the first time at a mean age of 19 years (before the formal diagnosis). The 29.8% of the SSc patients showed an inadequate HL level (0-8 score), 33.3% showed a problematic HL level (9-12 score), and 36.8% revealed an adequate HL level (13-16 score). The mean (M±SD) score reported by our SSc patients is 10.61±3.75.

Conclusions: SSc patients show some concerns related to the understanding of their disease, highlighting that assessing their HL levels is pivotal to identify those who need to improve self-management and self-care strategies, and ultimately enhancing their quality of life.

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LESSONS AND FEEDBACK FROM A PATIENT EVENT: SALFORD SCLERODERMA OPEN DAY 2023

Monisha Corotana¹, Muditha Samaranayaka², Graham Dinsdale^2,3, Michael Hughes^2,3, Lily Johnson¹, Elizabeth Wragg²

¹University of Manchester - Faculty of Biology, Medicine and Health, Manchester, UNITED KINGDOM, ²Salford Royal NHS Foundation Trust - Rheumatology Outpatient Department, Salford, UNITED KINGDOM, ³University of Manchester - Division of Musculoskeletal & Dermatological Sciences, Manchester, UNITED KINGDOM

Introduction: The 2023 Scleroderma Open Day at Salford Royal Hospital coincided with World Scleroderma Day on June 29, 2023 and was organised by the hospital's dedicated Scleroderma team. This serendipitous alignment heightened the event's significance. The Open Day featured a rich program, including informative expert talks, a first-hand account from a scleroderma patient, and a diverse array of stalls offering invaluable tips, trickers, information, and important contacts. Attendees, comprising patients and their supportive friends and family, actively engaged in the event and provided feedback through forms distributed during the event, generating valuable insights. A post-Open Day newsletter further disseminated key highlights and sign-posted sources for further information.

Material and Methods: The feedback forms employed in this study encompassed a wide spectrum of vital information, including demographic details of attendees, their holistic evaluations of the event, preferences for event duration, assessments of lecture quality, convenience, and reflections on the efficacy of face-to-face event delivery. Moreover, attendees were encouraged to share their perspectives on potential themes for future Open Days and express their willingness to participate in forthcoming research initiatives.

Results: The assessment of different facets of the Open Day on a scale from 1 (poor) to 5 (very good) revealed remarkable attendee satisfaction. Lectures received an admirable mean rating of 4.3 (SD = 0.57). The venue itself was highly appreciated, with an impressive mean rating of 4.7 (SD = 0.57), indicating the success of the hospital as a welcoming host. The choice of face-to-face delivery over online alternatives was favourably endorsed, earning a mean rating of 4.4 (SD = 0.55). It is noteworthy that more than half (60%) of attendees rated the Open Day as ‘good’ (4/5), while a remarkable 40% rated the Open Day as ‘exceptional’ (5/5).

Conclusions: The Scleroderma Open Day at Salford Royal Hospital proved highly successful in providing valuable information on scleroderma, its management, and access to additional resources for patients and their loved ones, including caregivers. Notably, a significant proportion of attendees expressed interest in participating in future research endeavours, promising a brighter outlook for scleroderma research and care. Potential topics for upcoming events, including the effects of scleroderma on organs, oral and dental health, and medication side effects, were also identified, offering a roadmap for addressing the evolving needs of the scleroderma community.

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APPLICATION OF WELL-BEING THERAPY IN SYSTEMIC SCLEROSIS: A RANDOMIZED CONTROLLED TRIAL

Francesco Bonomi¹, Sara Romanazzo², Elisa Fiorentini¹, Silvia Peretti¹, Carlo Cannistra'¹, Arianna Damiani¹, Gemma Lepri¹, Silvia Bellando Randone¹, Fiammetta Cosci^2,3, Serena Guiducci¹

¹Department of Experimental and Clinical Medicine, University of Florence, Florence, ITALY, ²Department of Health Sciences, University of Florence, Florence, ITALY, ³Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, THE NETHERLANDS

Introduction: Systemic sclerosis (SSc) has a relevant impact on daily life from a functional, emotional, and social point of view. SSc patients often experience psychological distress and present poor well-being, which need to be treated. Unfortunately, no studies tested the effects of interventions addressed at empowering or building up psychological well-being of SSc patients. The aim of the present randomized controlled trial is to verify the benefits of Well-Being Therapy (WBT) in SSc patients being a manualized, short-term psychotherapeutic strategy aimed at promoting psychological well-being, emphasizing self-observation through a structured diary.

Material and Methods: Among outpatients at the Scleroderma Unit of Rheumatology of the University Hospital Careggi (Florence, Italy), 32 SSc outpatients were enrolled and randomized (1:1) by an independent researcher using http://www.random.org and block randomization of size two to WBT (n=16) or clinical management (CM) (n=16) conditions. The two groups were matched a posteriori for sex, age, and severity of systemic sclerosis. Well-being represents the primary outcome, assessed via the 5-item World Health Organization Well-Being Index (WHO-5) and the Psychological Well-Being (PWB) scales. The secondary outcomes included: functional ability, assessed via the Health Assessment Questionnaire-Disability Index; psychological distress, assessed via the Symptom Checklist-90-Revised (SCL-90-R); mental pain, assessed via the Mental Pain Questionnaire (MPQ); suffering, assessed via the Pictorial Representation of Illness and Self Measure (PRISM). The WBT group was evaluated after two months (the end of WBT session 4: T1), after four months (the end of WBT session 8: T2), after seven months (the 3-month follow-up: T3), after 10 months (the 6-month follow-up: T4). Similarly, the CM group was assessed two (T1), four (T2), seven (T3), ten (T4) months after baseline assessment. To test changes overtime in both primary and secondary outcomes, generalized estimating equation models were used.

Results: Regarding primary outcomes, a significant improvement in subjective well-being (WHO-5; p=0.001), personal growth (PWB; p=0.006), and self-acceptance (PWB; p=0.003) was found in WBT group, compared to CM condition, with improvements maintained at T3 as what concerns subjective well-being (WHO-5; p=0.012). Regarding secondary outcome, WBT produced a greater decrease in psychological distress (SCL-90-R; p=0.010), mental pain (MPQ; p=0.010), and suffering (PRISM; p=0.001) compared to CM, with improvements maintained at T4 as what concerns suffering (PRISM; p=0.001). (Table 1).

Conclusions: The present study provides preliminary support for the efficacy and acceptability of WBT in SSc patients. WBT showed to be a therapeutic strategy that improves well-being levels and decreases psychological distress, mental pain, and suffering in SSc.

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UNMET NEEDS AND TREATMENT PREFERENCES CONCERNING DIGITAL ULCERS IN PATIENTS WITH Systemic Sclerosis

Giulia Bandini¹, Alessia Alunno², Barbara Ruaro³, Ilaria Galetti⁴, Begonya Alcacer-Pitarch⁵, Filipe Oliveira Pinheiro⁶, Giulia Campanaro¹, Judith Jade⁷, Stefano Di Donato⁸, Lindsay Muir⁹, Alberto Moggi Pignone¹, Khadija El Aoufy¹⁰, Francesco Del Galdo⁸, Zsuzsanna McMahan¹¹, Marco Matucci Cerinic¹², Michael Hughes^13,14

¹University of Florence, Department of Experimental and Clinical Medicine, Division of Internal Medicine, Florence, ITALY, ²University of L Aquila, Department of Clinical Medicine, Life, Health, and Environmental Sciences, Internal Medicine, L Aquila, ITALY, ³Pulmonology Unit, Department of Medical Surgical and Health Sciences, University Hospital of Cattinara, University of, Trieste, ITALY, ⁴FESCA (Federation of European Scleroderma Associations) Belgium, GILS (Gruppo Italiano Lotta alla Sclerodermia), Milan, ITALY, ⁵Leeds Institute of Rheumatic and Musculoskeletal Medicine, School of Medicine, University of Leeds, Leeds, UNITED KINGDOM, ⁶Centro Hospitalar Universitário de São João, Department of Rheumatology, Porto, PORTUGAL, ⁷Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UNITED KINGDOM, ⁸Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UNITED KINGDOM, ⁹Department of Hand Surgery, Salford Royal, Salford, UNITED KINGDOM, ¹⁰University of Florence, Department of Experimental and Clinical Medicine, Florence, ITALY, ¹¹University of Texas Health Science Center at Houston, Department of Medicine, Division of Rheumatology, Houston, USA, ¹²IRCCS San Raffaele Hospital, Unit of Immunology, Rheumatology, Allergy and Rare diseases (UnIRAR), Milan, ITALY, ¹³Northern Care Alliance NHS Foundation Trust, Salford Care Organisation, Salford, UNITED KINGDOM, ¹⁴Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Manchester Academic Health Sc, Manchester, UNITED KINGDOM

Introduction: Digital Ulcers (DU) affect around 50% of systemic sclerosis (SSc) patients and are associated with significant pain, morbidity and difficulties in daily life. Despite available treatment options, DUs are recalcitrant and recurrent, thus posing treatment challenges. Our aim was to examine the patients’ perspectives concerning the unmet needs and treatment of SSc-DUs.

Material and Methods: SSc patients who experienced at least one DU were invited through international patient associations and social media to participate in an online English-language survey. The survey was launched on 31st January 2023 and kept open for 4 weeks.

Results: A total of 358 evaluable responses were collected from 11 countries, mainly from USA (65.6%), UK (11.5%) and Canada (4.5%). 81,6% of respondents were aged 30-70 years and 93% were female. Almost all (96.1%) had more than one DU during the course of their disease (46% >10 DUs), mainly localised on the fingertips (84.9%).

DUs have broad-ranging impacts: activities of daily living (79% ‘agreed’ or ‘strongly agreed’), work activities (73% ‘agreed’ or ‘strongly agreed’), future planning (64% ‘agreed’ or ‘strongly agreed’), and interpersonal relationships and/or social activities (59% ‘agreed’ or ‘strongly agreed’). Only one quarter (26.2%) of respondents were satisfied with currently available treatments, or treatment efficacy on main ulcer symptoms such as pain (24%).

About half (51.7%) of respondents received wound/ulcer care, with only a third (31.4%) via a dedicated rheumatological/wound care clinic. The most frequent DU interventions were: wound cleaning (58.9%), ulcer dressing (63.2%) and debridement (27%), while botulinum (8.1%), fat injection (1.6%), sympathectomy (10.3%), and surgery (16.8%) were less frequent. Among respondents, the majority (71.3%) were ‘likely’ or ‘very likely’ to consider local DU treatment, 68.4% oral therapy, 43.8% intravenous treatments and 30.4% surgical approach.

Participants reported a range of perceived factors may delay DU healing (Figure 1a), and some of them are potentially modifiable. The reasons to seek healthcare professional advice are broad-ranging (Figure 1b), and when asked if patients would consider changing their DU treatment various reasons were reported (Figure 1c). Furthermore, education about the risk of complications (34.1%), how to recognise them (30.8%), and actions to be taken (25%) is limited.

Conclusions: DUs have significant broad-ranging impacts on patient experience and several unmet needs have emerged. Local wound care is not standardized across specialist centers and patient education is often neglected. Dedicated treatment recommendations are urgently needed to optimise the therapeutic strategy, including non-pharmacological interventions.

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PATIENT ENGAGEMENT IN SCLERODERMA RESEARCH: ENHANCING KNOWLEDGE AND PRACTICE

Claire Adams¹, Elsa-Lynn Nassar^1,2,7, Maureen Sauve⁹, Danielle Rice^3,4, Vanessa Cook², Brett Thombs^1,2,5-8

¹McGill University, Department of Psychiatry, Montreal, CANADA, ²Lady Davis Institute of the Jewish General Hospital, Montreal, CANADA, ³St. Joseph's Healthcare Hamilton, Department of Psychology, Hamilton, CANADA, ⁴McMaster University, Department of Psychiatry & Behavioural Neurosciences, Hamilton, CANADA, ⁵McGill University, Department of Epidemiology, Biostatistics, and Occupational Health, Montreal, CANADA, ⁶McGill University, Department of Medicine, Montreal, CANADA, ⁷McGill University, Department of Psychology, Montreal, CANADA, ⁸McGill University, Biomedical Ethics Unit, Montreal, CANADA, ⁹Scleroderma Canada and Scleroderma Ontario, Hamilton, CANADA

Introduction: Working with patients to plan, conduct, interpret and disseminate research is mandated by international funding agencies and recommended by ethical guidelines to improve the quality of health research. Engaging patients in research can increase the relevance and usefulness of research and empower them to make more informed decisions about their health and health care. The Scleroderma Patient-centered Intervention Network (SPIN) is an international collaboration of researchers, clinicians, patients, and patient organizations, who work together to improve coping and quality of life in people with scleroderma. SPIN has a cohort of >1,250 patients across 5 countries and engages patients in all levels of the network, from research planning to dissemination. SPIN’s work in patient engagement is limited by a lack of evidence on the best ways to engage patients in research and share research results with patients. Thus, SPIN launched a patient engagement project, which aims to develop more effective, evidence-based practices for patient engagement in scleroderma research.

Material and Methods: There are three components to this project: (1) A scoping review to synthesize evidence on strategies for engaging patients and the advantages and disadvantages of different strategies. We will search health and medical databases using a systematic search strategy and follow Arskey & O’Malley’s six-stage framework for conducting and reporting reviews. (2) A series of 8 randomized controlled trials, launched every 6 months, to determine which tools (e.g., infographics, comics, videos) are most effective for disseminating results to patients and facilitating understanding. Each trial will compare 2 or more tools to a plain-language summary comparator. Outcomes will include information completeness, understandability, and ease of use. (3) Project development and evaluation to develop an evidence-based framework for patient engagement in scleroderma research, through partnerships with researchers, clinicians, and patients.

Results: To our knowledge, this project is the first to work in partnership with patients to develop a strong model for patient engagement in health research. This project will provide evidence on how to best engage patients in scleroderma research and disseminate results with patients, which can be used to advise researchers on how to effectively engage with scleroderma patients and patients with other rare diseases.

Conclusions: This project will provide practical, evidence-based guidance on strategies to effectively engage patients in scleroderma research and dissemination. This will help to maximize the quality of research in scleroderma and improve knowledge translation to clinicians, organizations, and patients, to improve knowledge and health outcomes.

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IMPACT OF ONLINE PATIENT SUPPORT GROUPS IN SYSTEMIC SCLEROSIS: A STUDY OF THE ARAB COUNTRIES ONLINE GROUP

Houssem Abida, Mariem Jebri, Wiem Belhai, Mohamed Salah Hamdi, Ines Kechaou, Imen Boukhris, Eya Cherif, Samira Azzabi, Lamia Ben Hassine

Internal medicine department B, Charles Nicolle University Hospital, Tunis, TUNISIA

Introduction: Patient support groups (PSG) contribute to the management of chronic rare diseases, hence the recommendation to include them in therapeutic education programs (PTE). In Arab speaking countries, groups dedicated to patients treated for Systemic Sclerosis (SS) have been created for several years.

The objective of our work was to evaluate the interest in PSG for SS patients in Arab speaking countries.

Material and Methods: A qualitative cross-sectional study carried out in September 2023, based on a Google Forms questionnaire distributed by the moderators of the Facebook group “Scleroderma friends”. The form included questions with open answers about the expectations of the group participants, their needs and the impact of the group on them. Participation was voluntary and anonymously.

Results: Forty-two members participated, 95.2% of them were women. Countries of residence were: Irak (n=10); Egypt (n=6); Jordan (n=6); Algeria (n=5); Morocco (n=4); Tunisia (n=4); Oman (n=2); Belgium (n=1); France (n=1); Israël (n=1); Spain (n=1); Syria (n=1). The average age at the time of participation was 40,66 years [20;72]. The average membership duration in the group was 2.97 years [0.5;10].

Answers to the question “Why did you join the group?” were: To know more information about SS (n=16); seeking moral support (n=7); To look for similar cases/experience (n=7); to get updates (n=4); to help others (n=3), hoping to find a treatment (n=3).

Most reported answers for the question “how did the group help you?” were: not feeling alone (n=7); emotional support (n=7); Improved my knowledge of the disease (n=5); encouragement and positive vibes (n=5); no help (n=5); acceptance of the disease (n=2); awareness about treatment adherence (n=2).

Concerning the reliability of the information communicated in the group, 28 participants double checked them.

Thirty-two participants consider some limitations of the group: negative messages published (n=9); false information disseminated (n=8); the poor participation of doctors in the group discussions (n=6); Knowing about the death of one of the group’s members (n=5); meeting patients with diseases severe forms (n=2); the lack of commitment of some participants (n=2).

Regarding the question “what’s missing as a service in the group?”, answers were: Presence of doctors to answer questions (n=21); organizing local meetings for members from the same region (n=4); more of the members personal experiences (n=2).

Conclusions: The support group for Arab speaking patients seems to partially meet its objectives. An active presence of health professionals could strengthen its role in PTE.

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IDENTIFYING CLINICAL ASSOCIATIONS WITH SCLERODERMA RENAL CRISIS IN THE US NATIONWIDE INPATIENT SAMPLE DATASET

Amar D. Desai¹, David Fiorentino², Lorinda Chung³

¹Rutgers New Jersey Medical School, Newark, NJ, USA, ²Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA, ³Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA

Introduction: Scleroderma renal crisis (SRC) is a life-threatening yet treatable manifestation of systemic sclerosis (SSc) marked by acute kidney injury (AKI) typically in the setting of severe hypertension often requiring hospitalization. RNA polymerase III antibody and corticosteroid use have been associated with SRC in patients with diffuse cutaneous SSc. We aimed to identify demographic and clinical associations with SRC in SSc hospitalizations on a national scale compared with those without renal injury or with unspecified AKI.

Material and Methods: The 2016-2020 Nationwide Inpatient Sample was queried for SSc hospitalizations using International Classification of Diseases, Tenth Revision (ICD-10) code “M34”. SSc hospitalizations with the code for SRC (ICD-10: M34.89) were compared with those with a code for AKI (ICD-10: N17) but no SRC (unspecified AKI), and those without SRC or AKI (no AKI). Univariate and multivariable analyses were conducted to determine predictors of SRC (versus either unspecified AKI or no AKI) amongst SSc hospitalizations.

Results: Of 187,545 SSc hospitalizations, 7,660 (4.1%) had SRC and 36,025 (19.2%) had unspecified AKI; 143,860 (76.1%) lacked renal impairment (Table 1). Younger age, male sex, and Black race were associated with SRC (p<0.0001). Hospital charges and length of stay were greatest for unspecified AKI ($116,077, 8.9 days, respectively), with lower totals for patients with SRC ($91,474, 6.1 days) and without renal injury ($65,912, 5.4 days)(p<0.0001)(Table 1). The primary discharge diagnoses associated with unspecified AKI were sepsis (12.7%), heart failure (8.2%), or AKI (8.1%); hospitalizations coded with SRC were most likely to have a primary diagnosis of SSc (16.7%), with lower rates of sepsis (3.9%) and heart failure (3.6%)(p<0.0001) (Table 2). On univariate analysis, Black race, younger age, male sex, and CKD were associated with SRC (p<0.05)(Table 3). While anemia was associated with SRC, sepsis (OR: 1.31), abscess (OR: 2.27), or ARDS (OR: 1.29) during hospitalization were not associated with SRC (p<0.05). On multivariate analysis, race was not a significant predictor of SRC, but male sex, CKD, and anemia remained associated with SRC. While on univariate analysis sepsis or ARDS was not associated with SRC, on multivariate analysis, these variables were significantly associated with SRC.

Conclusions: SSc hospitalizations for SRC are associated with higher hospital charges and length of stay than those with no renal impairment. Sepsis and heart failure occur in SSc hospitalizations with unspecified AKI more frequently than with SRC. Male sex, CKD and anemia are associated with SRC.

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ILOPROST INFUSION REDUCES NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN (NGAL) SERUM LEVELS IN A COHORT OF SYSTEMIC SCLEROSIS PATIENTS

Amalia Colalillo¹, Chiara Pellicano¹, Umberto Basile², Antonietta Gigante¹, Rosario Cianci¹, Edoardo Rosato¹

¹Department of Translational and Precision Medicine, Sapienza University of Rome, ROME, ITALY, ²UOC of Clinical Pathology DEA II level, Hospital Santa Maria Goretti-ASL Latina, ROME, ITALY

Introduction: Endothelial dysfunction and microvascular damage are typical features of systemic sclerosis (SSc) with serious clinical implications. Subclinical renal involvement is frequent in SSc patients and it is characterized by vascular damage in small and medium size vessels, probably due to episodic vasospasm, named “renal Raynaud’s phenomenon”, with consequent hypoxia and vasoconstriction. In hypoxic renal tissue, macrophagic infiltrates and damaged tubular cells release several inflammatory and profibrotic cytokines and chemokines. Neutrophil gelatinase-associated lipocalin (NGAL) is an acute-phase protein released by neutrophils and renal tubular cells in conditions of acute injury associated with inflammation and oxidative stress. Iloprost is a stable analogue of natural prostacyclin and its beneficial effects, such as vasodilation, anti-platelet aggregation, cytoprotection, antioxidant effect and immunomodulation, are largely due to the modulation of small vessel vasculopathy in SSc patients. The primary aim of the study was to evaluate NGAL serum levels in SSc patients and healthy controls (HC). The secondary aim was to evaluate the influence of Iloprost infusion on NGAL serum levels in SSc patients.

Material and Methods: SSc patients and HC, matched for sex and age, were enrolled in this study. All patients had a 2-months wash-out of Iloprost infusion before of clinical, laboratory and instrumental assessment. Peripheral venous blood was collected at three different time points for SSc patients: t0 immediately before the first Iloprost infusion (after 2-months wash-out period), t1 immediately after the first Iloprost infusion and t2 the day of the next Iloprost infusion (about 14 days from the last infusion). A whithin-subjects one-way repeated-measures analysis of variance (ANOVA) was performed to compare the effect of Iloprost infusion on serum NGAL.

Results: Twenty-one SSc patients [median age 56 years (IQR 49-60), male (14.3%), diffuse cutaneous (dc) SSc (28.6%), median disease duration of 7 years (IQR 5-14)] and 20 HC were enrolled in this study. All SSc patients enrolled had eGFR>45 ml/min/1.73 m2 (CKD-EPI IIIa class) with a median eGFR of 84 ml/min (IQR 76-95). SSc patients had higher serum level of NGAL [20.9 pg/mL (±2.6) vs 14.5 pg/mL (±1.7), p<0.001] compared to HC. The one-way repeated-measures ANOVA showed that mean NGAL [F (2, 40) = 48.024, p < 0.001] differed significantly between time points.

Conclusions: SSc patients had higher NGAL serum levels than HC and Iloprost infusion reduces significantly NGAL serum levels.

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CLINICAL AND ULTRASONOGRAPHIC PHENOTYPE OF SSC PATIENTS WITH SICCA SYMPTOMS : COMPARISON WITH SJOGREN’S DISEASE AND SICCA MANIFESTATIONS FROM OTHER CAUSES

Francois Zimmermann¹, Francois Robin^3,4, Elisabeth Diot⁵, Aurore Bleuzen⁶, Sandrine Jousse-Joulin⁷, Claire de Moreuil⁸, NIcolas Belhomme^1,2, Claire Cazalet¹, Ronan Garlantezec⁹, Agnes Gazzola¹⁰, Francisco Llamas-Gutierrez¹¹, Romain Muraz¹⁰, Antoinette Perlat¹, Guillaume Coiffier^1,12, Alain Lescoat^1,2

¹Department of Internal Medicine, CHU Rennes, University of Rennes 1, Rennes, FRANCE, ²Université de Rennes, CHU Rennes, Inserm, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) - UMR_, Rennes, FRANCE, ³Department of Rheumatology, CHU Rennes, University of Rennes 1, Rennes, FRANCE, ⁴INSERM, Rennes University Hospital, UMR 1241, Institut NuMeCan (Nutrition Metabolisms and Cancer), University Rennes, Rennes, FRANCE, ⁵Department of Internal Medicine CHRU Tours, tours, FRANCE, ⁶Medical Imaging, CHRU Tours, Tours, FRANCE, ⁷Rheumatology Department, CHU de Brest, Univ Brest, Inserm, LBAI, UMR1227, Brest, FRANCE, ⁸Department of Internal Medicine CHRU Brest, Brest, FRANCE, ⁹University of Rennes, CHU Rennes, Inserm, EHESP, IRSET (Institut de recherche en santé, environnement et travail) - UMR_, Rennes, FRANCE, ¹⁰Direction de la recherche et de l'innovation, Rennes, FRANCE, ¹¹Department of Pathology, CHU Rennes, University of Rennes 1, Rennes, FRANCE, ¹²Department of Rheumatology, CH Dinan, Dinan, FRANCE

Introduction: Sicca symptoms (i.e. xerophthalmia, xerostomia) are reported in up to 80% of patients with systemic sclerosis (SSc). Ultrasound of major salivary glands (SGUS) have shown promising results for the diagnosis of Sjogren syndrome in patients with subjective sicca symptoms but data are still needed in SSc. The primary objective of this multicentric study was to characterize the whole phenotype of SSc patients with sicca symptoms, based on SGUS parameters, minor salivary glands biopsies (mSGB) and clinical findings, and to compare these characteristics with those from patients with primary Sjogren Syndrome (pSS), and patients with sicca manifestations from other causes.

Material and Methods: 60 SSc patients fulfilling the 2013 ACR/EULAR classification criteria for SSc and with subjective self-declared sicca symptoms were consecutively recruited in 3 centers and had SGUS and mSGB. Fifteen SSc patients without subjective sicca symptoms, 37 patients with isolated pSS and 23 patients with sicca manifestations from other causes were consecutively included for comparison.

Results: Our study identified a high prevalence of objective clinical (up to 83%), histological (44% of Focus score>=1/ mm2) and US abnormalities (63% of OMERACT US score >=2) in SSc patients with subjective sicca symptoms. Compared to the 15 SSc patients without subjective sicca symptoms, the 60 patients with complaints had more objective ocular or oral manifestations (83% and 53%, p = 0.03). Quality of life was lower in SSc patients with sicca symptoms (mean HAQ 1.1 versus 0.5, p = 0.012 and mean ESSPRI 4.9 versus 1.8, p < 0.001). SGUS showed no statistically significant difference between SSc patients with and without subjective complaints, suggesting the existence of a subclinical involvement of major salivary glands.

Among the 60 SSc patients with subjective complaints, 37 patients had an overlap syndrome with Sjögren (Sjogren-SSc), and 23 had sicca symptoms only related to SSc itself (sicca-SSc). Sjogren-SSc patients had more severe glandular involvement than the 37 patients with isolated pSS and the 23 patients with isolated Sicca-SSc (70 %, 48,6% and 38 % of patients with OMERACT >=2 respectively). This result suggested additive impact of both SSc and pSSc on salivary gland physiology and structure.

Conclusions: SGUS can help distinguish Sjögren-SSc patients from Sicca-SSc patients although specific SSc US patterns of salivary gland involvement are still to be defined. This study suggests that SSc and pSSc have distinct and additive impact on salivary gland involvement, potentially due to distinct pathophysiological mechanisms.

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A GLIMPSE OF MRI DEEP WHITE MATER HYPERINTENSITIES IN SYSTEMIC SCLEROSIS PATIENTS

Shihan Xu¹, Xinyu Tong², Huilin He¹, Jiaxin Zhou¹, Qian Wang¹, Dong Xu¹, Xihai Zhao², Mengtao Li¹, Xiaofeng Zeng¹

¹Department of Rheumatology and Immunology, Peking Union Medical College Hospital, Beijing, CHINA, ²Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, CHINA

Introduction: As a systemic autoimmune disease, Systemic Sclerosis (SSc) can involve multiple organs including the brain. White matter hyperintensities (WMHs), including periventricular hyperintensity (PVH) and Deep white-matter hyperintensity (DWMH), are abnormal findings on brain magnetic resonance imaging (MRI). Recently DWMHs are considered to be affected by ischemia-hypoperfusion, which may reflect vascular changes. This study attempts to evaluate the volumes of DWMHs in SSc patients and health controls.

Material and Methods: Forty-nine patients without central nervous system symptoms or histories and twenty-four health controls with matched age and sex were included in this study. Brain MR imaging was performed on a 3T scanner (Ingenia CX, Philips Healthcare, The Netherlands). T1-weighted imaging was obtained to calculate the whole white matter (WWM) volumes by using MRICloud automated segmentation pipelines. WMHs were evaluated on fluid-attenuated inversion recovery (FLAIR) images using Fazekas scores (Periventricular hyperintensity 0-3, Deep white matter hyperintensity 0-3). The volumes of DWMHs and WMHs were calculated by manually drawing regions of interest (Figure 3) in 3D Slicer open-source software (version 5.4.0, available at www.slicer.org). Volume ratios (including VR1= volume DWMHs/ volume WWM, VR2= volume WMHs/ volume WWM, VR3= volume DWMHs/ volume WMHs) of each individual were compared between groups. The statistical analyses were conducted using SPSS 27.0 (SPSS Inc. Chicago, IL, USA). Wilcoxon Mann-Whitney test was applied to compare the differences between groups and Spearman correlation coefficients (rs) for measuring the associations among quantitative variables.

Results: VR1 and VR3 were significantly larger in SSc patients than in health controls (P<0.05) (Figure 1 and Figure 2). Significant positive correlations were found between total Fazekas scores (PVH+DWMH) and VR1(rs =0.83, P<0.01), age and VR1 (rs =0.599, P< 0.01) (Table 3). The FLAIR-MRI showed DWMHs in 38 patients (77.5%) and 17 health controls (70.83%). While Fazekas scores and VR2 showed no significant differences between SSc patients and health controls (Table 1 and Table 2).

Conclusions: Compared to healthy people, the VR1 and VR3 in Systemic Sclerosis patients without central systemic symptoms or histories are larger. This suggested that in the central nervous system, vascular lesions may appear in the early stage before symptoms appear, and SSc patients are more likely to have WMH in the deep white matter rather than around the periventricular. VR1 may be a potential sensitive marker or criterion of the early SSc central nerve system involvement evaluation.

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PERIPHERAL VASCULAR COMPLICATIONS IN PATIENTS WITH SYSTEMIC SCLEROSIS ARE NOT ALWAYS CAUSED BY THE DISEASE ITSELF: A CASE REPORT

Saskia Van De Zande¹, Anne van Gessel¹, Arie van Roon¹, Bart Slijkhuis¹, Alja Stel², Julia Spierings³, Amel Abdulle¹, Anniek van Roon², Douwe Mulder¹

¹University Medical Center Groningen, Internal medicine, Groningen, THE NETHERLANDS, ²University Medical Center Groningen, Rheumatology, Groningen, THE NETHERLANDS, ³University Medical Center Utrechts, Rheumatology, Utrecht, THE NETHERLANDS

Introduction: Peripheral vascular complications in Systemic Sclerosis (SSc) is a major challenge. In the current case description we present how a thorough examination is of essential importance in patients presenting with digital ischemia, even in the presence of a classifiable disease such as SSc.

Material and Methods: First, we will describe a case history, introducing our extensive vascular protocol. Second, we performed a retrospective analysis for presence of antiphospholipid syndrome (APS) antibodies at our centre since December 2017. The vascular protocol entails ultrasound measurements performed with the Visual Sonics Vevo MD and an ultra-high frequency ultrasound transducer (70 MHz). Nailfold capillaroscopy (NCM) was performed with a handheld DinoLite CapillaryScope. Finger and toe pressures were measured with photoelectric plethysmography and pressure cuffs on 5 fingers simultaneously.

Results: A 45-year-old female presented with Raynaud’s phenomenon, she was anti-Scl70 positive, had inconclusive NCM, and no additional signs or symptoms of SSc. Our vascular protocol revealed no signs of obliterative vasculopathy (Figure 1a and 2a). Unfortunately, the following months she developed progressive diffuse SSc with skin and lung involvement for which an autologous stem cell transplantation was performed. Remarkably, before the transplantation, our vascular protocol demonstrated sequential development of vasculopathy, showing a late SSc NCM pattern and digital artery wall thickening and a decrease in lumen diameter (Figure 1b and 2b) with striking decrease in finger blood pressure (111 mmHg to 47 mmHg).

Several weeks later, she presented with blue toes and pain. Although the underlying SSc-related vasculopathy had already been clearly documented, we decided to perform additional vascular measurements because of the unusual presentation. This clearly showed a thrombus in the distal left dorsal pedal artery (see Figure 3). Laboratory testing showed positive Lupus Anticoagulans and anti-cardiolipin antibodies. Anticoagulant treatment was started and prostaglandin agonist infusion was initiated and continued until resolution of ischemic pain. The blue top of left hallux transcended into demarcated necrosis (Figure 4).

Retrospective analysis of cases at our centre revealed that APS was tested in 36/341 (11%) patients with SSc, of which 8 (22%) were positive, of which 50% had severe digital ischemia as indication for testing.

Conclusions: Digital ischemia in patients with SSc is a challenge. We advocate a thorough vascular workup in unusual clinical presentations. This may reveal conditions that necessitate to initiate additional therapies. Although antiphospholipid antibodies are frequently observed in patients with SSc, their clinical relevance can only be demonstrated when a clear vascular substrate is confirmed.

P.279

FEASIBILITY STUDY OF POLARISATION SENSITIVE OPTICAL COHERENCE TOMOGRAPHY (PS-OCT) IMAGING OF DIGITAL LESIONS: TOWARDS NON-INVASIVE LONGITUDINAL ULCER TRACKING

Lewis Smith¹, Graham Dinsdale², Joanne Manning², Sarah Wilkinson³, Ariane Herrick³, Mark Dickinson¹, Andrea Murray³

¹Dept. of Physics and Astronomy, Photon Science Institute, University of Manchester, Manchester, UNITED KINGDOM, ²Department of Rheumatology, Salford Care Organisation, Northern Care Alliance NHS Foundation Trust, Salford, UNITED KINGDOM, ³Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Manchester, UNITED KINGDOM

Introduction: Polarisation sensitive optical coherence tomography (PS-OCT) is a non-invasive optical imaging technique capable of micron scale resolution and, uniquely, high speed 3D and surface scanning of skin. The polarisation aspect of the imaging provides information on the collagen structure within the skin. Systemic sclerosis (SSc)-related digital (finger and toe) lesions including pitting and ulceration lead to significant pain, decreased hand function and reduced quality of life. Assessment is difficult, and there is a lack of objective measures for application in the clinical trials. PS-OCT offers the opportunity to image the surface area of the lesion and also to see within the skin to understand subsurface changes. This small feasibility study aimed to determine whether PS-OCT could be used to image digital lesions; including both digital pitting and ulcers in patients with SSc in order to further understand pathophysiology.

Material and Methods: Patients with SSc-related digital pitting or ulcers underwent 3D PS-OCT finger imaging (image ‘cubes’ of 4 x 4 mm² surface area, to a scan depth of 2.61 mm). Images were cross-sectioned through structural features (2D images into the depth of the skin), for all but one image. Post-processing of images was carried out, including thresholding to remove background/noise and identify the surface of the skin and polarisation properties relating to structure of collagen in proprietary software.

Results: Four participants were imaged (Figure 1). One had digital pitting, one had both pitting and a digital ulcer, and two had ulcers only. Eight 3D scans were collected in total for all patients; images captured digital ulcers and pitting, and, separately, tissue adjacent to pitting. Structural surface and subsurface features were clearly visible in scans (Figure 1).

Conclusions: This study indicates that PS-OCT is a suitable method for both 3D and surface scanning of larger and smaller lesions. Larger lesions may require multiple scans if they exceed the scan area size. The images have the potential for making measurements to track change with time; useful in understanding pathophysiology, including the relationship between what is observed at the surface of, and the structure below, the skin in terms of healing and pain. In addition, once further validated this may be of use for clinical trials; size (surface area, depth and volume could all be measured in images).

P.280

MACROVASCULAR INVOLVEMENT OF THE FOREARM IS COMMON IN SYSTEMIC SCLEROSIS

Berend Slijkhuis¹, Anne van Gessel¹, Amel Eman Abdulle¹, Tobias Stel¹, Anniek van Roon^1,2, Saskia van de Zande¹, Elisabeth Brouwer², Douwe Mulder¹

¹University Medical Center Groningen, University of Groningen, Department of Internal Medicine, Groningen, THE NETHERLANDS, ²University Medical Center Groningen, University of Groningen, Department of Rheumatology and Clinical Immunology, Groningen, THE NETHERLANDS

Introduction: The full extent of vasculopathy in systemic sclerosis (SSc) is still relatively unknown. Research concerning the influence of SSc on the macrovasculature of the forearm is limited. Further studies on this topic may give us better insight in the progression of SSc.

Material and Methods: In this study we evaluated the vessel wall of the brachial, ulnar, and radial arteries in SSc patients. Thirty-four patients (19 limited(lcSSc), 15 diffuse (dcSSc)) and twelve age matched healthy controls were studied with a median age of 65 (IQR 54;72) and 58 (IQR (54;62) respectively. Vessel walls were assessed qualitatively and quantitatively using ultra-high frequency ultrasound (Vevo MD, 48 MHz linear probe, Fujifilm, Tokyo, Japan). Intima-media thickness (IMT) and lumen diameter were measured. A severity score index was created to include vessel walls in the analysis from patients who had severely affected arteries. Categories included: (near) occlusion and severe involvement (defined as >2 standard deviations (SD) above the mean IMT measured in healthy controls).

Results: Examples of different degrees of macrovascular involvement are shown in figure 1. (Near) occlusion and severe involvement were observed in at least one ulnar artery in 29% and 21% of patients respectively. On the contrary, (near) occlusion was never observed in the radial and brachial arteries, while severe involvement was present in 12% and 15% respectively. Compared to healthy controls, patients with SSc had a smaller lumen diameter for the ulnar arteries (left 1.16mm ±0.42SD, p<0.001; right 1.23mm ±0.35SD, p<0.001), as well as the left radial artery (1.75mm ±0.38SD, p=0.002). IMT was measurable at 192 out of 204 sites (94.1%) in SSc patients. No significant differences were observed for the IMT in SSc patients when compared to the healthy controls, nor were there significant differences in IMT between dcSSc and lcSSc patients. IMT was moderately positively correlated with age in the right (r(32)=0.38, p=0.03) and left (r(32)=0.39, p=0.03) brachial artery, but not in radial and ulnar arteries.

Conclusions: This study confirms the frequent involvement of the ulnar arteries, supporting the notion that vasculopathy in SSc extends to the macrovasculature. While IMT of the brachial arteries is associated with age in patients with SSc, this association is possibly blunted in the ulnar and to a lesser extent in the radial arteries, as a result of disease related factors, as the arterial lumen in these arteries is significantly narrowed. More research is however needed to study the progression of macrovascular disease in SSc.

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NAILFOLD CAPILLAROSCOPY FOR PREDICTION OF NOVEL SEVERE ORGAN INVOLVEMENT AND MORTALITY IN SYSTEMIC SCLEROSIS

Cristiana Sieiro Santos, Paula Perez Garcia A, Jose Ordas Martínez, Miriam Retuerto Guerrero, Clara Moriano Morales, Carolina Ãlvarez Castro, Elvira Dãez Ãlvarez

Complejo Asistencial Universitario de León, León, SPAIN

Introduction: Several studies report the association between capillary loss and disease severity however, the association of NFC abnormalities with novel severe organ involvement/progression and mortality in SSc has not been evaluated. We aim to evaluate the association of nailfold capillaroscopy (NFC) abnormalities with novel major organ involvement/progression and mortality in SSc.

Material and Methods: Follow-up data from patients with SSc registered between 2000 and 2022 were analyzed. Patients underwent NFC at baseline. Baseline demographic data, antibody status, baseline pulmonary function, novel severe organ involvement/progression and mortality were registered. Novel organ involvement/progression was defined as new or progressive involvement of peripheral vasculature, lungs, heart, skin, gastrointestinal, kidney, musculoskeletal at 12 and 24 months of follow-up. The following NFC parameters were evaluated: capillary density, hemorrhages, enlarged and giant capillaries, avascular areas, organization of capillary architecture and scleroderma pattern (early/active/late). Logistic regression modelling was run to assess associations between NFC and clinical parameters, the occurrence of novel severe organ involvement and/or progression and mortality.

Results: 113 patients were included: 28 (25%) were male, 86 (76%) lcSSc and 27 (23%) dcSSc. 70 patients (61%) developed novel overall severe organ involvement/progression and 40 patients died (36%) during follow-up. Loss of capillary density was associated with overall severe organ involvement (p=0.002), peripheral vascular involvement (p=0.03), new ILD (p=0.04) and skin progression (p=0.01); avascular areas were associated with overall severe organ involvement (p=0.03), new ILD (p=0.03) and progression of ILD (p=0.02) and scleroderma pattern was associated with overall severe organ involvement (p= 0.03), peripheral vascular involvement (OR p=0.04), new ILD (p=0.004), progression of ILD (p=0.03) and skin progression (p=0.04). Mortality was associated with ILD (OR 2.56 CI 95% 1.5-7.2, p 0.04), DLCO <70% (2.34 CI 93% 1.42-6.23, p 0.03), a late pattern in NFC (3.42 95% CI 1.42-7.25, p 0.002), presence of hemorrhages (OR 1.77 95% CI 1.24-8.23, p 0.034) and avascular zones (OR 6.22 95% CI 2.54-10.3, p 0.021). Survival rates from diagnosis at 10 years were lower in patients with NFC with active a late pattern (40% and 20%) compared with those with normal, unspecific and early pattern (100%, 90% and 70%) (p=0.008 by log rank test)

Conclusions: NFC may be a potential biomarker in SSc for predicting novel severe organ involvement and/or progression and mortality. Abnormal capillary density, avascular areas and scleroderma pattern are predictors of overall severe organ involvement, peripheral vascular involvement, novel and progression of ILD and skin progression.

P.282

USING UNSUPERVISED MACHINE LEARNING CLASSIFICATION ALGORITHMS FOR THE EARLY DIAGNOSIS OF RAYNAUD'S PHENOMENON IN CHILDREN

Mario Sestan¹, Daniel Turudic¹, Nikola Skreb², Martina Held¹, Marko Baresic³, Nastasia Kifer¹, Marijan Frkovic¹, Jagoda Stipic⁴, Danko Milosevic², Marija Jelusic¹

¹University of Zagreb School of Medicine, Department of Paediatrics, University Hospital Centre Zagreb, Zagreb, CROATIA, ²University of Zagreb School of Medicine, Zagreb, CROATIA, ³University of Zagreb School of Medicine, Department of Internal Medicine, University Hospital Centre Zagreb, Zagreb, CROATIA, ⁴University of Zagreb School of Medicine, Department of Neurology, University Hospital Centre Zagreb, Zagreb, CROATIA

Introduction: Currently, the only proposed imaging method for Raynaud's phenomenon (RP) is nailfold capillaroscopy (NC). However, other additional imaging methods, such as computerized color telethermography (CCTT) may improve the correct classification of the patients with RP. Our goal was to establish the diagnostic accuracy of both imaging methods in the early detection of RP.

Material and Methods: We performed a cross-sectional retrospective study using unsupervised machine learning classification algorithms for the early diagnosis of RP.

Results: total number of 232 children with symptoms of RP in the period from 2010 to 2021 were included in this study. Using the data from medical history, clinical examination, laboratory parameters, NC, CCTT, 42.2% of the children were diagnosed with primary RP (PRP), 21.6% with secondary RP (SRP), while in 36.2% we have no observed characteristic pattern of RP (symptomatic RP, SyRP). We used three JCHAIDStar algorithms, which generate decision trees, to classify with CCTT/NC values into PRP, SRP, and SyRP subgroups. The first algorithm uses CCTT in the first node. If CCTT was consistent with PRP, the patient is diagnosed as PRP. If CCTT was consistent with SRP, beta-2 glycoprotein antibodies (beta2-GPI) (2nd node) and antinuclear antibodies (ANA) (3rd node) are used to distinguish PRP from SRP children. Precision of JCHAIDStar algorithm by using LOOCV cross-validation after recall is high for all groups (PRP : SRP: SyRP = 95.7% : 89.4% : 89.1%) with ROC areas for all groups > 0.86. The second algorithm begins with NC. If NC findings were normal, the algorithm uses beta2-GPI (2nd node) to distinguish PRP, SRP and SyRP. If NC was not normal, ANA (2nd node) and ENA (3rd node) are used to distinguish SRP from PRP. Precision of this algorithm was PRP : SRP: SyRP = 81.7% : 95.8% : 85.0% by using LOOCV cross-validation with ROC areas for all groups > 0.82. Finally, we have constructed the third algorithm that combines CCTT and NC. The CCTT findings have the highest priority in this algorithm. ENA (1st node), NC (2nd node) and IgG values (3rd node) are used to distinguish PRP from SRP, while NC was used to to distinguish SRP from SyRP. Precision was PRP : SRP: SyRP = 90.8% : 85.5% : 94.6%, with ROC areas > 0.9.

Conclusions: We recommend using both NC and CCTT in RP diagnosis and have constructed a simple and cost-effective RP classification algorithms that are applicable in routine clinical practice.

P.283

DESCRIPTIVE ANALYSIS OF CHANGES IN THE PATTERN OF CAPILLAROSCOPY IN A COHORT OF PATIENTS DIAGNOSED WITH SYSTEMIC SCLEROSIS

Carmen Riesco Bárcena, Jose Eloy Oller Rodriguez, Jose Ivorra Cortés, Elena Grau García, Pablo Martinez Muñoz, Samuel Leal Rodriguez, Luis González Puig, Anderson Victor Huaylla Quispe, Alva María Torrat Noves, Daniel Ramos Castro, Laura Mas Sánchez, Inés Cánovas Olmos, Hikmat Charia, Isabel Martinez Cordellat, Carmen Najera Herranz, Rosa Negueroles Albuixech, Marta De La Rubia Navarro, Ernesto Tovar Sugrañes, Elvira Vicens Bernabeu, Iago Alcántara Álvarez, Belén Villanueva Mañes, Jose Andrés Román Ivorra

Rheumatology Derpartment- Hospital La Fe, Valencia, SPAIN

Introduction: Systemic sclerosis (SS) is an autoimmune, systemic and chronic disease that is characterized by vascular dysfunction and microvascular alterations,

Nail bed capillaroscopy is a non-invasive technique that allows us to study the distal periungual capillaries. It is a useful tool for the early diagnosis of SS, as well as for monitoring its evolution.

The sclerodermiform pattern has been described in more than 95% of patients diagnosed with the disease. This combines the presence of hemorrhages, megacapillaries, loss of capillary density, avascular areas and neoformation phenomena.

In 2000, Cutolo et al. defined three patterns of involvement based on the presence of different manifestations: Early, active and late pattern. The finding of any of the three patterns described correlates with the risk of visceral involvement.

Patients may present changes over time, being more frequent in diffuse involvement.

In this context, the objective of our study is to analyze the changes in the capillaroscopy pattern in a cohort of patients diagnosed with SS.

Material and Methods: Cross-sectional, single-center study, with retrospective acquisition of variables. Demographic and clinical data were collected in patients with SS. We recorded the findings in the baseline capillaroscopy (considered the one performed at diagnosis) and the first capillaroscopy performed as a control.

Results: 42 patients (95.23% women) with a mean age of 5.92 years from the time of diagnosis were included in the study.

47.61% had diffuse systemic sclerosis (dcSSc), 47.61% had limited systemic sclerosis (lcSSc) and the remaining 4.76% had sclerosis sine scleroderma (ssSSc).

35 of the 42 patients (83.4%) had a control capillaroscopy performed. The average time until its completion was 2,655 years.

9 patients presented progression on control capillaroscopy to a more advanced Cutolo pattern. 66.7% were patients with a diagnosis of dcSSc.

16.7% of the total presented a non-specific pattern at the time of diagnosis (4 dcSSc, 2 lcSSc and 1 ssSSc). In the control capillaroscopy, 1 patient presented a normal pattern, 3 patients maintained the same pattern and 2 patients progressed to a sclerodermiform pattern (resulting in both dcSSc).

35 patients (83.3%) had a sclerodermiform pattern at diagnosis of the disease; 45.7% were dcSSc, 51.42% lcSSc and the remaining 2.85% were ssSSc.

Table 1 shows the evolution over time in terms of the pattern of involvement.

Conclusions: In our sample, 25.71% of patients presented progression in the capillaroscopy pattern. This progression is more frequent in patients with Diffuse Systemic Sclerosis.

P.284

NAILFOLD VIDEO CAPILLAROSCOPY PATTERNS AND ASSOCIATED CLINICAL FEATURES IN SYSTEMIC SCLEROSIS IN QATAR

Aishwariya Padmakumari, Neethu Maria Kunjumon, Fiaz Alam, Samar Al Emadi, Karima Becetti

Hamad Medical Corporation, Doha, QATAR

Introduction: The role of nailfold video capillaroscopy (NVC) in Raynaud's phenomenon (RP) is well established. Recent studies in systemic sclerosis (SSc) suggest a prognostic value to NVC. The aim of this study was to evaluate the NVC patterns in SSc in Qatar and their association with disease-specific features.

Material and Methods: Consecutive SSc patients were recruited. Demographic, laboratory and clinical information, NVC examination, and Modified Rodnan Skin Scores (MRSS) were collected. NVC images were evaluated quantitatively for capillary density (in 1 mm) and qualitatively for overall pattern (normal, non-specific changes, early/active/late scleroderma patterns). After determining the frequency of patterns, clinical variables were compared between those with “non-severe” (normal, non-specific or early) pattern vs “severe” (active or late) pattern using chi-square and student t tests. Capillary density was correlated with clinical variables.

Results: The study included 20 SSc patients with 70% women and a mean age of 41.8 + 2.4 years. Mean disease duration was 4.8 + 0.6 years and dominant disease subset was diffuse cutaneous (60%). Anti-Scl70 was present in 55% of patients while 10% had anti-centromere. RP was reported in 65% of patients, with digital ulcers (DUs) in 35% and ILD in 75% and PAH in 1 patient. Mean MRSS was 13.6 + 1.9. On NVC, 71% had severe pattern (44% active and 27% late pattern) and the remaining had early pattern in 17% and normal in 6%. The diffuse and limited cutaneous subsets had higher frequency of severe pattern (60% and 100%, respectively, p = 0.049). Severe pattern was more frequent in patients with RP (92% vs 8%, p < 0.01) and DUs (100% vs 0, p = 0.04). Mean density was significantly reduced in those who reported RP (4.1+ 0.6 vs 6.6 + 0.5, p = 0.02). No associations were observed between NVC pattern or density with disease duration, autoantibodies, ILD, PAH or MRSS.

Conclusions: In this SSc cohort, more severe NVC patterns were associated with the presence of RP and its severity (DUs). A larger sample size and follow up data will allow for a better evaluation of its association with other clinical features as well as the development of new organ disease.

P.285

THERMAL IMAGING IN CLINICAL TRIALS: EXPLORING POST-COLD CHALLENGE REWARMING TO BETTER UTILISE THERMOGRAPHY AS AN OUTCOME MEASURE

Abigail Aika Ndosi¹, Graham Dinsdale², Joanne Manning², Melissa Mandzuk², Sarah Wilkinson¹, Ariane Herrick¹, Andrea Murray¹

¹Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Manchester Academic Health Scienc, Manchester, UNITED KINGDOM, ²Department of Rheumatology, Salford Care Organisation, Northern Care Alliance NHS Foundation Trust, Salford, UNITED KINGDOM

Introduction: Thermography monitored cold-challenge offers an objective outcome measure for clinical trials of systemic sclerosis (SSc)-related Raynaud’s phenomenon (RP). Standard cold challenge monitors rewarming for 15 minutes but patients may take longer to fully rewarm. Understanding time to rewarming and which factors influence may enable more than one cold challenge to be considered in a day as part of a trial protocol (e.g. before and after treatment). The aim of this study was to test the hypotheses that patients rewarm within a 2-hour period and that 15-minute rewarming measurements are predictive of a 2-hour rewarming period.

Material and Methods: After baseline thermography imaging of the hands, a cold challenge was performed; nitrile gloved hands submerged for 1 minute into 15oC water. Post-cold challenge, thermography images were taken every 15s for 15 minutes, then every 5 minutes until 30 minutes, every 10 minutes until 60 minutes and every 15 minutes until 120 minutes. Baseline finger temperature (8 fingers, Tbase) and distal dorsal difference (DDD: temperature difference between the dorsum of the hand and the distal finger) were calculated from baseline images. Mean finger temperature difference (post-cold challenge-baseline, Tdiff), time to 25 (t25%), 50 (t50%), 100% (t100%) rewarming, maximum temperature achieved (Tmax), time to Tmax (tmax), area under the rewarming curve (AUC), and final temperature (Tf) were calculated. Cox regression assessed associations between Tbase, Tmax, Tf, DDD and AUC.

Results: Twenty patients with SSc with median (interquartile range [IQR]) age 62 (53 to 69) years, duration of RP 16 (7 to 26) years were recruited. Imaging data are shown in Table 1.

Fourteen patients (70%) rewarmed to baseline within 2 hours. Cox regression showed a negative relationship between Tbase and t50% and t100%, and a positive relationship between AUC and t25%, t50% and t100% rewarming.

13/14 patients that rewarmed achieved t25% within the first 15 minutes and 11/14 achieved t50% within 15 minutes. In contrast, in the non-rewarming subset, 3/6 and 1/6 achieved t25%, t50% in 15 minutes respectively. This suggests that 15-minute rewarming may be predictive of the likelihood of longer-term rewarming.

Conclusions: For most patients, a 2-hour window is long enough to reach Tbase. Including a second (post-dosing) or even a third cold challenge into Phase 2 study protocols can be considered. The study showed that if a patient reached t50% within 15 minutes they were highly likely to rewarm fully over 2 hours; thus 15-minute rewarming could be used to identify patients who will fully rewarm.

P.286

COMPARISON OF LUNG ULTRASOUND SCORES WITH AUTOMATED QUANTITATIVE CT: IS IT POSSIBLE TO OVERCOME THE LIMITATIONS OF THE ULTRASOUND METHOD?

Davide Mohammad Reza Beigi¹, Greta Pellegrino^1,4, Nicholas Landini², Monica Mattone², Chiara De Nardo², Gregorino Paone³, Ilaria Bisconti¹, Francesca Romana Di Ciommo¹, Marius Cadar¹, Simona Truglia¹, Valeria Panebianco², Fabrizio Conti¹, Valeria Riccieri¹

¹Dipartimento di Scienze Cliniche, Internistiche, Anestesiologiche e Cardiovascolari, Sapienza University of Rome, Rome, ITALY, ²Dipartimento di Scienze Radiologiche, Oncologiche e Anatomo Patologiche, Sapienza University of Rome, Rome, ITALY, ³Dipartimento di Scienze Cardiovascolari e Respiratorie, Sapienza University of Rome, Rome, ITALY, ⁴IRCCS Ospedale Galeazzi - Sant Ambrogio, Milan, ITALY

Introduction: Lung ultrasound (LUS) is a promising tool for the diagnosis of systemic sclerosis-associated interstitial lung disease (SSc-ILD), characterised by the findings of B-lines (BLs) and pleural line changes (PLA). Few studies have compared LUS scores with the extent of ILD by automated quantitative computed tomography (qCT). Furthermore, one of the limitations of LUS is the inability to explore deeper areas of the lung parenchyma.

The aim of the study is to compare quantitative LUS scores with 3-levels qTC analysis (apices, midfields and lung bases) and to evaluate their possible association with the extent of surface and core lung ILD.

Material and Methods: During the period 2021-2023, consecutive SSc patients underwent on the same day LUS, performed by two blinded certified operators using the 14 intercostal space assessment technique, and CT. The total number of BLs was collected, and the quantitative PLA score we previously developed was applied, dividing each lung into 3 levels. CT images were assessed by two thoracic radiologists for ILD definition and were subsequently analysed using automated texture analysis software, quantifying the volumes of total ILD, ground-glass (GG) and reticulations, also differentiating ILD of the lung surface and core.

Results: Sixty-seven patients were enrolled, with 50 (75%) presenting ILD on CT (Table 1). Detailed LUS and qCT assessment are given in Table 2. Both BLs number and PLA score of lung bases correlated positively with the extent of basal lung ILD, GG and reticulations on qCT (p<0.05). The PLA score of lung midfields correlated with the extent of ILD, GG and reticulations of the same site on qCT, whereas the number of BLs correlated only with reticulations (p<0.05). At the apices, the PLA score correlated with the extent of GG and reticulations and BLs number only with reticulations (p<0.005). The extent of ILD, ground-glass and reticulations of the lung surface on qCT was significantly higher than the equivalent of the lung core (p<0.05). The basal BLs number was found to correlate with superficial and deep ILD extent. The PLA score of the apices, mid-fields and bases correlated with surface lung ILD, GG and reticulations, and the mid-basal PLA score also correlated with deep lung alterations on qCT. The detailed analysis is shown in Table 3.

Conclusions: Our results show that the PLA score seems to more accurately reflect the structural changes detected on qCT, suggesting the possibility of overcoming LUS traditional limitation of exclusive lung surface investigation.

P.287

CAN MICROVASCULAR DAMAGE SEVERITY BE ASSOCIATED WITH GLOBAL DISEASE SEVERITY IN PATIENTS WITH SYSTEMIC SCLEROSIS?

Ana Martins, Daniela Oliveira, Raquel Ferreira, Georgina Terroso, Miguel Bernardes, Sofia Pimenta, Lúcia Costa

Centro Hospitalar Universitário de São João - Department of Rheumatology, Porto, PORTUGAL

Introduction: Systemic sclerosis (SSc) is a heterogeneous disease with variable manifestations and clinical outcomes. Nailfold videocapillaroscopy (NVC) is a simple and non-invasive method that allows direct observation of the microcirculation. Some studies support that the degree of microcirculation damage of nailfold capillaries may be associated with the severity of visceral involvement in SSc patients.

Material and Methods: A monocentric retrospective cohort study of patients with SSc diagnosis that have a NVC performed within the first 6 months after diagnosis was conducted. Demographic data, visceral involvement in the first 3 years of the disease and NVC findings were collected. NVC was evaluated according to the EULAR Study Group on Microcirculation in Rheumatic Diseases standardized capillaroscopy evaluation chart (Smith et al. 2020). The severity of microvascular damage was classified into 4 categories, according to the worsening of the NVC patterns (0=non-scleroderma, 1=early, 2=active and 3=late). The severity of organ involvement was accessed by the disease severity scale (DSS) of Medsger for each organ. As a global measure of disease severity, the sum of the Medsger DSS was used.

Results: A total of 86 patients (71 females, 82.6%, mean age of onset of 52.6±15.9 years) with SSc were included, 74 (86.1%) had a limited cutaneous disease, 5 (5.8%) diffuse cutaneous disease and 7 (8.1%) SSc sine scleroderma.

A moderate correlation was found between the severity of microvascular damage and the global measure of disease severity (r=0.55, p<0.001) and between the severity of microvascular damage and the severity of peripheral vascular involvement (r=0.43, p<0.001) and skin involvement (r=0.339, p=0.001).

Avascular areas in NVC seem to predict the presence of digital ulcers (OR 6.75, 95% CI 1.72-26.45, p=0.006), esophageal involvement (OR 3.43, 95%CI 1.10-11.57, p=0.039), muscular involvement (OR 11.67, 95%CI 1.06-138.94, p=0.04) and calcinosis (OR 22.67, 95%CI 4.76- 107.90, p<0.001). Abnormal capillary shapes seem to predict the presence of digital ulcers (OR 3.48 95%CI 1.12-10.82, p=0.025), muscular involvement (OR 29.82, 95%CI 9.14-97.32 p<0.001), severe skin involvement (OR 5.33, 95%CI 1.17-24.31, p=0.031) and calcinosis (OR 18.85, 95%CI 3.68-77.17, p<0.001).

Conclusions: In our study, the disease severity in SSc, the severity of peripheral vascular involvement and extension of skin involvement are associated with the worsening of NVC pattern. Avascular areas and abnormal shapes in NVC seem to predict the presence of digital ulcers, muscular involvement and calcinosis.

This study highlights the importance of NVC as a prognostic tool, as patients with late scleroderma pattern seem to have a higher risk of severe disease.

P.288

OPTIMIZING METHODICAL ASSESSMENT OF NORMAL PATTERN IN HEALTHY NAILFOLD USING HIGH-FREQUENCY ULTRASOUND WITH SUPERB MICROVASCULAR IMAGING

Gabija Jasionyte¹, Goda Seskute¹, Rita Rugiene^1,2, Irena Butrimiene¹

¹Clinic of Rheumatology, Orthopaedics Traumatology, and Reconstructive Surgery, Faculty of Medicine, Vilnius university, Vilnius, LITHUANIA, ²Department of Experimental, Preventive and Clinical Medicine, State Research Institute Centre for Innovative Medicine, Vilnius, LITHUANIA

Introduction: Nailfold videocapillaroscopy is a conventional method to assess microvascular damage caused by systemic sclerosis. Recently, a few reports on evaluating nailfold vascularization by ultrasound (US) have appeared yet it still remains a challenge. A novel US tool - superb microvascular imaging (SMI) - has the advantages of high frame rates, high sensitivity in visualizing vessels with low velocities, high spatial resolution, and low motion artifacts. SMI might be superior to conventional Doppler techniques in demonstrating vascularization of the dermis. We aimed to analyze the methodical technique of high-quality visualization in healthy nailfold and fingertip zones.

Material and Methods: Sixteen healthy subjects (15 women and 1 man) were recruited. Nailfold videocapillaroscopy was used to confirm the normal pattern. An experienced US operator obtained B mode and SMI images in transverse and longitudinal planes from IV fingers of non-dominant hands. All images were acquired at a fixed depth of 1 cm, and they were not magnified during the observation. The frequency used for SMI was 19 MHz. The gain was set to the maximum value of the discrepancy in which the noise disappeared (40-50). True blood flow signal was distinguished from noise as a pulsatile flow during the careful observation. When the region with the most prominent blood flow signaling was detected, findings were captured in videos and still images.

Results: There are three groups of factors affecting the quality of the US image in assessing nailfold vessels (Figure 1). 1) Characteristics of the nail plate: thickness, length, damage, foreign bodies under the plate, and gel manicure; 2) US operator dependent: amount of gel, transducer positioning, pressure on the transducer, artifacts; 3) US parameters: optimal gain. Clearly prepared images are the basis for the assessment of fingertip, subungual deeper vascularity, and nailfold zone evaluation in the longitudinal plane and the presence of two vascularity zones in the transverse plane.

Conclusions: Optimized evaluation of nailfold area in healthy subjects is the basis for the research with SSc patients. US and its modalities might be promising methods to determine microvascular injuries in the early phase of SSc. More studies with large groups of healthy patients and later with SSc patients are needed.

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STONE STUDY PROGRESS: ULTRASOUND BASED OUTCOME MEASURE OF CALCINOSIS IN SCLERODERMA

Lorraine Green¹, Robert Fairchild², Antonia Maria Valenzuela Vergara⁴, Diane Mar², Mariani Diaz Deluna², Srijana Davulari², Maria Antonietta D'Agostino³, Richard Wakefield¹, Lorinda Cheung², Francesco Del Galdo¹

¹Leeds University, Leeds, UNITED KINGDOM, ²Stanford University, Stanford, USA, ³Universita Cattolica Sacro Cuore, Rome, ITALY, ⁴Pontificia Universidad Catolica de Chile, Chile, USA

Introduction: Calcinosis is a debilitating condition in Systemic Sclerosis (SSc) causing pain and functional limitation, sometimes leading to ulceration, infection, and amputation. No effective therapeutics are available and clinical trials are hampered by the lack of validated outcome measures. Ultrasound (US) is a cost effective and safe imaging modality, providing assessment of fine anatomical details including lesion microstructure, surrounding soft tissue changes, and local vascularity. Despite this, there is no validated US definition or severity scoring system for calcinosis.

Material and Methods: An OMERACT expert group (n=32) was convened to complete a two-round consensus survey to define a US based working definition of calcinosis and associated features. Fifty-three subjects with SSc-related calcinosis involving the hands, and 10 subjects with SSc without calcinosis were recruited at two centres (Leeds and Stanford). Data included patient-reported outcome measures (PROMs), clinical and lesion outcomes, B mode US images with Power Doppler, and x-ray for comparison with a validated severity scoring system. US images from 61 subjects were randomised after grouping by patient-reported severity. Expert raters (n-15) blinded to all other data completed an electronic survey to confirm the presence of calcinosis using the agreed upon definition and to describe the associated features.

Results: The consensus survey showed excellent agreement for defining the presence (88.9%) and the operational description (81.5%) of calcinosis, using the proposed definition.

Minor refinement of the initial definition was agreed upon including reporting of Inflammation (92.6%), Skin features (74.1%), Tendinopathy (66.7%), Bone/joint pathology (66.7%) and Blood flow features (33.3%).

Validation Survey: Agreement on confirming the presence of calcinosis using the proposed definition was 71.5% which is considered a strong agreement for endorsement.

Data on PROMs and clinical characteristics cannot yet be presented due to blinding required for completion of expert rater severity scores.

Conclusions: There is currently excellent agreement for a proposed definition of SSc-related calcinosis using ultrasound imaging to be used as a promising outcome measure in both clinical practice and interventional studies.

Initial validation of the definition shows good agreement, and analysis of the associated US features will further validate and refine the components of the proposed definition.

Correlation of US features and rater severity scoring with clinical features and patient reported outcomes is due to be completed by the end of 2023 and will inform important clinical context. STONE is an important first step in the definition of an imaging outcome measure of Calcinosis.

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A CASE OF SELF-RECORDED NAILFOLD CAPILLARY CHANGES ON A MOBILE PHONE: A NEW OPPORTUNITY FOR REMOTE MONITORING OF MICROVASCULAR PROGRESSION IN SECONDARY RAYNAUD’S?

Graham Dinsdale¹, Joanne Manning¹, Melissa Mandzuk¹, Emily Collier², Emre Yusuf Akdeniz¹, Michael Hughes³, Muditha Samaranayaka¹

¹Department of Rheumatology, Salford Care Organisation, Northern Care Alliance NHS Foundation Trust, Salford, UNITED KINGDOM, ²-, Manchester, UNITED KINGDOM, ³Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, MAHSC, Manchester, UNITED KINGDOM

Introduction: Nailfold capillary microscopy (NCM) is an imaging technique well-established in assessing Raynaud’s phenomenon (RP). In the patient reporting symptoms of RP with few other risk factors for connective tissue disease, repeat assessment of the microvascular structure via NCM over long follow-up periods (months to years) can monitor for changes that may suggest further investigation, or to reassure both patient and clinician the RP is highly likely primary RP, i.e., idiopathic. The frequency of follow-up imaging is not well-defined but typically may be at 6- or 12-month intervals and has relevance to the very early diagnosis of SSc (VEDOSS). We present a case where a patient has imaged their own nailfold capillaries using their smartphone camera between routine clinic visits to record an apparent transient nailfold capillary abnormality.

Material and Methods: An 18-year-old female patient (EC) attended the rheumatology outpatient clinic (t=0). She had a long-standing history of cold sensitivity and colour change in her hands and feet, occurring even in the warmer months. She was negative for all relevant autoantibodies. She had NCM imaging as part of routine monitoring. At a second appointment (t=8months), NCM imaging was repeated. On both occasions the NCM images were reported similarly as being generally normal with one or two slightly widened loops, some mild tortuosity, and no microhaemorrhages.

At the second appointment the patient shared some photographs taken on her smartphone detailing nailfold capillary changes that she saw in the period between the two clinic appointments. The images show the left middle finger (t=1month), right thumb (t=3months), and the left middle finger again (t=5months). The images were taken with a Samsung Galaxy S22 smartphone.

Results: Figure 1 A and B show clinical nailfold capillaroscopy images captured at clinic visits. The patient captured images are shown in Figure 1 C, D and E, with inset enlargement of the relevant areas. The capillary loops are clearly inflamed and likely enlarged at all three time points. These phenomena had abated by the time of the second clinic visit at t=8months.

Conclusions: This is the first case we have encountered where a patient has recorded their own nailfold capillaries using a standard smartphone camera. The ability to capture an apparently transient abnormality shows the power of patients recording images of their conditions, fostering shared decision making and patient-centred care. In the future it is possible that patients may monitor their own capillaries for dynamic changes over long periods of time.

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DIGITAL ARTERY VOLUME INDEX (DAVIX), FIRST QUANTITATIVE CONTRAST FREE MRI-BASED SURROGATE OUTCOME MEASURE OF DIGITAL ULCER DISEASE ACTIVITY IN SYSTEMIC SCLEROSIS

Stefano Di Donato¹, Michael Hughes^2,3, Klodian Gjeloshi⁴, Giuseppina Abignano⁶, Enrico De Lorensiz⁷, Fiammetta Danzo⁵, Giovanni Lettieri⁶, Dominic Bertham⁸, Philip O'connor⁸, Olga Kubassova⁹, Jamshid Demeshkin¹⁰, Francesco Del Galdo^1,8

¹Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UNITED KINGDOM, ²Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UNITED KINGDOM, ³Department of Rheumatology, Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton under- Lyne, UNITED KINGDOM, ⁴Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, ITALY, ⁵Division of Respiratory Diseases, Ospedale L Sacco, ASST Fatebenefratelli- Sacco, Milan, ITALY, ⁶Istituto Reumatologico Lucano, Azienda Ospedaliera Regionale San Carlo, Potenza, ITALY, ⁷Division of Rheumatology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, ITALY, ⁸NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UNITED KINGDOM, ⁹Image Analysis Group, London, UNITED KINGDOM, ¹⁰Department of Computer Science, Kingston University, London, UNITED KINGDOM

Introduction: Vascular involvement in Systemic Sclerosis (SSc) is known to start even before clinical diagnosis, to drive Digital Ulcer (DU) disease and, later in the disease natural history, to cause Pulmonary Artery Hypertension (PAH), among other manifestations. Reliable outcome measures of vascular disease activity are a deep unmet need in SSc.

Material and Methods: 227 patients attending our Scleroderma Program were consecutively enrolled. Clinical features including presence or history of DUs, presence of PAH, FVC, DLCO, and mRSS were recorded. Digital Artery Vascular Index (DAVIX) of the dominant hand’s fingers was calculated using time of flight magnetic resonance images analysed through IAG proprietary algorithm, as previously described. Patients were followed up longitudinally for 12 months and assessed for the presence of new DUs as primary outcome. Medians were compared by Mann-Whitney-Wilcoxon test, correlation with clinical parameters was performed using Spearman’s or Pearson test, as appropriate (R).

Results: 145/227 patients (63.9%) fulfilled the 2013 ACR/EULAR classification criteria for SSc (47/227 diffuse cutaneous [20.7%] and 99/227 limited cutaneous [43.6%]) whereas 82/227 (36.1%) were classified as Very Early Diagnosis of Systemic Sclerosis (Criteria score between 6 and 8). 53/227 (23.3%) patients had DU disease (History of DUs in the previous 48 weeks or presence of DUs at baseline assessment), this group showed a significantly lower DAVIX compared to patients without DU disease (0.47 vs 0.84, p<0.0001). 28/227 (12.3%) patients developed new DUs during the 12-month follow up, this group had a significantly lower DAVIX compared to patients who did not develop new DUs (0.39% vs 0.80%, p<0.0001). Receiver Operating Curve for DAVIX plotted against new DU showed an AUC 0.83 (95% CI: 0.75-0.91) with highest Youden index threshold associated with 11.10 Odds Ratio (OR) of developing new DUs (95% CI 4.03-35.65, p<0.0001). DU disease at baseline conferred an OR of 4.4 (2.2-12.2, p=0.0032) of developing new DUs at 12-months. Beyond DUdisease, DAVIX correlated with DLCO (rho=0.349, p<0.0001) and inversely with FVC/DLCO ratio (rho=-0.299, p=0.0006), as well as capillaroscopy pattern (p<0.0001). DAVIX negatively correlated with mRSS (rho=-0.259, p=0.0003).

Conclusions: DAVIX is a contrast-free MRI method that shows strong clinical value as surrogate outcome measure of DU disease in SSc and excellent predictive ability for new DUs at 12-month. Prospective testing in the context of randomised controlled trials to assess reliability and sensitivity to change are ongoing to determine the value of DAVIX as surrogate endpoint for vascular disease assessment in SSc clinical trials.

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LIVER INVOLVEMENT IN PATIENTS WITH SYSTEMIC SCLEROSIS: ROLE OF TRANSIENT ELASTOGRAPHY IN THE ASSESSMENT OF HEPATIC FIBROSIS AND STEATOSIS

Giovanna Cuomo¹, Carlo Iandoli¹, Raffaele Galiero², Alfredo Caturano², Claudio Di Vico¹, Danilo Perretta¹, Piervincenzo Adamo¹, Roberta Ferrara², Luca Rinaldi², Ciro Romano², Ferdinando Carlo Sasso²

¹Precision Medicine University of Campania L. Vanvitelli, Naples, ITALY, ²epartment of Advanced Medical and Surgical Sciences, University of Campania L. Vanvitelli;, Naples, ITALY

Introduction: Background Systemic sclerosis (SSc) is a rare, multisystemic disorder of connective tissue, characterized by widespread inflammation, vascular abnormalities, and both skin and visceral organ fibrosis. Tissue fibrosis is the final phase of a complex biological process of immune activation and vascular damage.

Objectives: The aim of study was to assess hepatic fibrosis and steatosis in SSc patients by transient elastography (TE).

Material and Methods: Material and methods Fifty-nine SSc patients, satisfying the 2013 ACR/EULAR classification criteria, were recruited. Clinical and laboratory findings, modified Rodnan skin score (mRSS), activity index, video-capillaroscopy, echocardiography, and lung function data were analyzed. Liver stiffness (LS) was measured by transient elastography (TE), with 7 kPa used as the cut-off value for significant liver fibrosis and steatosis. Specifically, values >=238 CAP <= 259 dB/m were considered consistent with mild steatosis (S1), 260 >= CAP >= 290 dB/m with moderate steatosis (S2) and >=291 dB/m with severe steatosis (S3)

Results: Results The median age of patients was 51 years, with a median disease duration of 6 years. Median LS was 4.5 (2.9–8.3) kPa; 41 patients (69.5%) had no evidence of fibrosis (F=0), 16 (27.1%) displayed LS values between 5.2 and 7 kPa; only 2 patients (3.4%) had LS values >7 kPa (F3). The median CAP value for liver steatosis was 223 dB/m (IQR: 164–343). Overall, 39 patients (66.1%) did not show evidence of steatosis (CAP values <238 dB/m); 9 patients (15.2%) showed values consistent with mild (S1) steatosis (CAP value >=238 <=259 dB/m); 8 patients (13.5%) had moderate (S2) steatosis (CAP value >=260 <=290 dB/m); 3 patients (5.1%) were deemed to have severe steatosis (S3) due to CAP values >=291 dB/m.

Conclusions: Conclusions Only 3.4% of our patient population showed evidence of marked liver fibrosis, which is the same prevalence as that expected in the general population. Likewise, the prevalence of significant steatosis was low (5.1%) and depending on the same variables associated with fatty liver in the general population. TE was shown to be an easy and valuable method for detection and screening of liver fibrosis in SSc patients with no additional risk factors for liver disease.

Keywords: fibroscan 1; liver fibrosis 2, liver steatosis 3, systemic sclerosis 4

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INITIAL EXPERIENCE WITH ULTRASOUND IMAGING AS A DIAGNOSTIC TOOL FOR CONTIGUOUS OSTEOMYELITIS IN SYSTEMIC SCLEROSIS PATIENTS WITH INFECTED DIGITAL ULCERS

Natalia Puchkov¹, Zohar Keidar², Doron Markovits³, Daniela Militeanu¹, Alexandra Balbir-Gurman³, Yolanda Braun-Moscovici³

¹Department of Diagnostic Imaging, Rambam Health Care Campus, Rappaport Faculty of Medicine, Technion, Haifa, ISRAEL, ²Department of Nuclear Medicine, Rambam Health Care Campus, Rappaport Faculty of Medicine, Technion, Haifa, ISRAEL, ³Rheumatology Institute, Rambam Health Care Campus, Rappaport Faculty of Medicine, Technion, Haifa, ISRAEL

Introduction: Digital ulcers (DUs) are common in systemic sclerosis (SSc) patients and cause significant morbidity. They are often complicated by local infection which can lead to contiguous osteomyelitis (OM). The clinical and imaging diagnosis of OM is challenging. The interpretation of MRI images, the gold standard for OM diagnosis, is problematic due to digital flexion contractures and acro-osteolysis. In our center (tertiary referral center for SSc), we use 99m-Technetium-Tc-labeled white blood cells (WBC) scintigraphy, for diagnosing OM in complicated DU. Despite the high sensitivity and specificity, it may be inconclusive in certain cases and it is a costly modality.

Musculoskeletal ultrasound (US) imaging was found to be an accurate tool for OM diagnosis. We aimed to assess the accuracy of US imaging in diagnosing contiguous OM in SSc patients with DU, compared to WBC scintigraphy.

Material and Methods: SSc patients with complicated DU, clinically suspected for OM, who were referred to WBC scan, were concurrently referred to US of the suspected DU. The US was performed by a highly skilled musculoskeletal imaging specialist, blinded to WBC scan results. Examinations were performed using the GE ML6-15-D Matrix Linear Probe LOGIQE9:R4.3.0 Ultrasound Machine. The sonographic findings indicating OM were periosteal thickening, cortical erosions, increased flow within or around periosteum on power Doppler sonography and deep soft tissue swelling. All patients had baseline hands x-ray to rule out calcinosis or acro-osteolysis. Clinical reassessment of DU healing was performed within 1-3 months.

Results: Seven patients (6 females, 8 US examinations) were included in the pilot study. The mean(SD) age was 64.6(12.8), disease duration 14.6(7.4) years, 5 patients had diffuse SSc. One patient had 2 US examinations for separate events of suspected OM, in different sites.

The results of both imaging tests concurred ruling in 2 cases and ruling out OM in 3 others. In the remaining 3 cases, the WBC scan was inconclusive, but the US ruled out OM. Patients that tested negative for OM on WBC scans and/or US were treated accordingly, with significantly shorter courses of antibiotics. Healing of the complicated DUs was achieved in all of them.

Conclusions: In our pilot study, US imaging was found to be reliable in confirming and ruling out OM in SSc patients with complicated infected DUs, even in patients with inconclusive WBC scans. Musculoskeletal US may serve as a feasible and less expensive imaging technique for diagnosing contiguous OM in SSc-related DUs. Larger studies are required to confirm these preliminary results.

P.294

UTILITY OF INFRARED THERMOGRAPHY FOR THE INVESTIGATION OF MICROVASCULOPATHY IN SYSTEMIC SCLEROSIS

Miziolek Bartosz¹, Pieczyrak Robert², Bultrowicz Monika², Kucharz Eugene J², Bergler-Czop Beata¹

¹Department of Dermatology, School of Medicine in Katowice, Medical University of Silesia, Katowice, POLAND, ²Department of Internal Medicine, Rheumatology and Clinical Immunology, Medical University of Silesia, Katowice, POLAND

Introduction: Generalized microvasculopathy is a cardinal feature of systemic sclerosis (SSc). Its first manifestation is Raynaud’s phenomenon (RP), which initially occurs episodic. Structural abnormalities of microvessels contribute to reduced blood supply to fingers, causing their cooling and blueish color between the subsequent attacks of RP. The worsening of blood supply affects heat emission from the surface in acral areas of the body, which can be recorded and evaluated by infrared thermography (IRT). A flat and sufficiently big surface make hands the most frequent region of interest for IRT in SSc. There raises a question how IRT may help for the investigation of microvasculopathy in SSc.

Material and Methods: There were enrolled nineteen patients with limited cutaneous SSc (lcSSc) in the first study, then 29 lcSSc patients and 10 subjects with diffuse cutaneous disease (dcSSc) were included to the second study. All subjects underwent IRT imaging and nailfold videocapillaroscopy (NVC) after adaptation to temperature fixed at 21 °C. IRT was performed using FLIR T420 camera and handheld camera FLIR One Pro for iOS. An average temperature (Tavg) at the nailfold and a gradient of temperatures (δTavg) between the central metacarpus of the hand and the nailfold was determined for all fingers. NVC pictures were classified to capillaroscopic patterns according to Cutolo et al. system and analyzed quantitatively: density of capillaries and calculation of capillaroscopic skin ulcers risk index (CSURI) previously proposed by Sebastiani et al. Measurements of IRT were referred to disease subtype and immune profile.

Results: There was found only a moderate correlation between IRT measurements and the density of capillaries in fingers II-V. Early pattern was associated with significantly greater Tavg of nailfolds and essentially milder δTavg in fingers II-V when compared to all other capillaroscopic patterns. Fingers II–V with CSURI indicating a greater risk for development of digital ulcers (DU) had significantly lower Tavg and markedly more pronounced δTavg. Both thumbs and fingers II–V remained cooler in patients with dcSSc than in lcSSc ones regardless of the positivity to anticentromeric (ACA) or anti-Scl70 antibodies. The presence of ACA in lcSSc was associated with lower Tavg and more pronounced δTavg in fingers II–V than the positivity to anti-Scl70.

Conclusions: Conclusions: IRT seems to be promising tool to evaluate severity of microvasculopathy and to predict development of DU in SSc. It may help to investigate differences in thermal control between lcSSc and dcSSc, or dependance on immune profile.

P.296

COMPARAISON OF THE GOH SCORE AND THE MODIFIED GOH SCORE IN THE ASSESSMENT OF SYSTEMIC SCLEROSIS’S ASSOCIATED INTERSTITIAL LUNG DISEASE

Houssem Abida¹, Zeineb Meddeb¹, Affès Mariem², Abdelkefi Cherifa¹, El Ouni Amira¹, Toujani Sana¹, Ben Hassine Lamia³, Hantous Saoussen², Bouslama Kamel¹, Larbi Thara¹, B'chir Hamzaoui Saloua¹

¹Internal Medicine Department, Mongi Slim University Hospital, La Marsa, Tunis, TUNISIA, ²Radiology Department, Abderrahmen Mami University Hospital, Ariana, TUNISIA, ³Internal Medicine Department B, Charles Nicolle University Hospital, Tunis, TUNISIA

Introduction: Interstitial lung disease (ILD) is one of the most challenging complications of Systemic Sclerosis (SS) to monitor and treat. Accessible tools with high sensitivity are needed for adequate assessment.

The aim of our study was to compare two scores, Goh Score (GS) and Modified Goh Score (MGS), as tools to evaluate the severity of Systemic Sclerosis associated ILD.

Material and Methods: A retrospective and descriptive study carried out in 2 tunisian internal medicine departments and an imaging department. It included data of patients with SS. GS and MGS were calculated for all patients to assess the presence and the severity of ILD on CT.

Results: Forty-nine patients were included. The mean age of our patients at diagnosis was 47 years [18;86] with a sex-ratio of 0,36. 26 patients (53%) presented ILD on their CT scan. The predominant type of ILD patterns were: non-specific interstitial pneumonia (NSIP) (n=16), (65%), usual interstitial pneumonia (UIP) (n=6) (23%). The mean average of the different components of the GS and MGS were as following: ILD global extension (GS=33,10;MGS=34,04); The global extension of reticulations (GS=33,22;MGS=28,12), the ground-glass opacities global extension (GS=43,07; MGS= 39,92), the global severity score mean (GS=5,76;MGS=7,08), and the limited/extend lesions ratio (GS21/28; MGS=21/28). The statistical analysis showed some associations between clinical, respiratory functional data and both scores' components. On a clinical level, decreased oxygen saturation was statistically associated with the global ILD extension rate in both scores (GS: 0,049; MGS: 0,043). Crackles were associated with the degree of the reticulation extent according to the GH (p=0.002) and the MGS (0,001). They were also associated with global ILD extension in both scores GH (p=0.002) and the MGS (0,001). No significant correlation was found between dyspnea, dry cough and any of both scores components. On a functional level, a statistically significant relationship was also established between Global ILD extension in both scores and decreased total lung capacity (GS: p=0.005; MGS: p=0,043).

Conclusions: ILD in SS requires quantitative tools that can reflect impact on respiratory function. In our study both GS and MGS correlated with clinical and functional abnormalities. This suggests that GS can be sufficient for assessment, as MGS is more time consuming. Larger studies are needed for a better comparison of these two scores. The 6 different levels of the Goh and Modified Goh scores: from A to E for Goh Score and from A to F to Modified Goh Score

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COGNITIVE IMPAIRMENT AND QUALITY OF LIFE IN PATIENTS WITH SYSTEMIC SCLEROSIS AND INTERSTITIAL LUNG DISEASES

Chutchaiwat Savetamornkul, Pintip Ngamjanyaporn, Pirada Witoonpanich

Department of Internal Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, THAILAND

Introduction: In patients with Systemic Sclerosis, interstitial lung diseases (ILD) contributed to chronic hypoxia and resulted in an impaired quality of life and cognitive dysfunction. However, data comparing between patients with ILD and without ILD were unclear. Our study aims to evaluate and compare the cognitive impairment and quality of life in patients with Systemic sclerosis between the groups with ILD involvement and without ILD involvement, and assess risk factors contributed to cognitive dysfunction.

Material and Methods: Patients with age greater than or equal to 18 years who were diagnosed with Systemic Sclerosis and had undergone High Resolution Computerized Tomography of Chest (HRCT) and/or Pulmonary function test (PFT) within the last 5 years prior to the data collection date were recruited for cognitive function evaluation using Montreal Cognitive Assessment (MoCA) and quality of life assessment using 36-item Short Form Health Survey (SF-36). Baseline demographic data, level of education, comorbidities, and other disease-related factors were collected. Patients who had any prior history of cognitive impairment, head injury, neurological disease affecting cognitive function, brain surgery, chronic hypoxemia from other causes, and overlapping syndrome were excluded.

Results: Forty-five patients were eligible and recruited for assessment, 33 (73.33%) patients had ILD involvement. The mean and standard deviation of MoCA score was 24.58 ± 3.118 in the Systemic Sclerosis without ILD group and 22.03 ± 3.549 in the Systemic Sclerosis with ILD group (p-value 0.033). Cognitive impairment was found in 5 (41.67%) patients in Systemic Sclerosis without ILD group and 23 (69.70%) patients in Systemic Sclerosis with ILD group (p-value 0.163). Executive/visuospatial was the only domain that had significant difference between both groups, with the average score of 3.33 ± 0.888 and 2.27 ± 1.281 in the Systemic Sclerosis without ILD group and with ILD group, respectively (p-value 0.012). Quality of life of patients assessed with SF-36 revealed non-significance differences in all 8 domains for both patient groups.

Conclusions: In patients with Systemic Sclerosis and ILD involvement, the cognitive function assessed by MoCA resulted in lower score when compared to the Systemic Sclerosis patients without ILD, specifically in the executive and visuospatial domain. The quality of life in patients with Systemic Sclerosis was not statistically different between both groups.

P.300

RISK OF NEW-ONSET DEPRESSION IN PATIENTS WITH SYSTEMIC SCLEROSIS : A NATIONWIDE POPULATION-BASED STUDY

Su-Jin Moon¹, Bong_Woo Lee², Hae-Rim Kim³, Seung-Ki Kwok²

¹Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, SOUTH KOREA, ²Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, SOUTH KOREA, ³Konkuk University Medical Center, Seoul, SOUTH KOREA

Introduction: Previous studies have reported that depression is common in systemic sclerosis (SSc) patients, ranging from 36% to 65%. However, no study has unveiled the risk of new-onset depression in SSc patients. The present study was conducted to determine whether SSc is an indeed risk factor for the development of new-onset depression. To determine whether the incidence rate (IR) of new-onset depression in SSc patients is higher than in normal subjects, we used data from a nationwide health care database

Material and Methods: We selected subjects from National Health Insurance System database who were diagnosed with SSc between 2010 and 2016. Subjects who did not get a general health checkup in the previous 2 years, who were diagnosed with depression before their SSc diagnosis, who were less than 20 years old, or who had missing data were excluded. To minimize the possibility of reverse causality, an analysis with a 1-year lag was performed.

Kaplan-Meier analysis was conducted to assess the incidence of new-onset depression, and Cox proportional hazards regression was used to calculate adjusted and unadjusted hazard ratio (HR) and 95% CIs. HR for new-onset depression was adjusted for age, sex, smoking, drinking, physical activity, body mass index (BMI), income, diabetes, hypertension, and dyslipidemia.

Results: During follow-up periods after 1 year of lag time, the cumulative incidence of new-onset depression was significantly higher in patients with SSc vs controls (38.7 vs. 27.7 IR per 1000 person-years). After adjusting for covariates, the presence of SSc was associated with 38.1 % increased risk of new-onset depression (HR 1.381; 95% CI, 1.128-1.691), compared with controls.

SSc disease itself was determined as an independent risk factor for new-onset depression in subjects with younger age (age < 65 years; HR 1.41; 95% CI 1.122-1.773), female gender (HR 1.415; 95% CI 1.139-1.759), and absence of regular exercise (HR 1.433; 95% CI 1.143-1.795), after adjusting for covariates. Interestingly, the risk of new-onset depression after SSc diagnosis was found to be relatively higher in the low-income group (HR 1.667; 95% CI 1.121-2.479 vs HR 1.303; 95% CI 1.028-1.650).

Conclusions: The present study suggests that the SSc diagnosis is associated with a significantly increased cumulative incidence and risk of new-onset depression. This association is more pronounced in female gender, younger age group, and those who do not exercise regularly. Regular assessment of the occurrence of depressive symptoms should be more emphasized in the patients with SSc after diagnosis.

P.301

FOOT PERIPHERAL NEUROPATHY: A FREQUENT AND DISABLING MANIFESTATION IN SYSTEMIC SCLEROSIS

Begonya Alcacer-Pitarch¹, Marco Di Battista², Anthony C. Redmond¹, Anne-Maree Keenan³, Stefano Di Donato¹, Maya H. Buch⁴, Francesco Del Galdo¹

¹Leeds Institute of Rheumatic and Musculoskeletal Medicine, School of Medicine, University of Leeds, Leeds, UNITED KINGDOM, ²Rheumatology Unit, University of Pisa, Pisa, ITALY, ³School of Healthcare, University of Leeds, Leeds, UNITED KINGDOM, ⁴Division of Musculoskeletal and Dermatological Sciences, faculty of Biology, Medicine & Health, University of Manchester, Manchester, UNITED KINGDOM

Introduction: Peripheral neuropathy is an under-recognized feature in systemic sclerosis (SSc). Moreover, SSc foot involvement is frequent but poorly investigated. We aimed to provide a detailed characterization of foot peripheral neuropathy in a large cohort of SSc patients, looking for associations with disease-specific characteristics, foot disability, and health-related quality of life (HRQoL).

Material and Methods: SSc patients and healthy controls (HC) comparable for mean age and gender percentage were enrolled in a cross-sectional observational case-control study. All subjects underwent a detailed quantitative sensory testing (QST) of feet evaluating touch, vibratory, thermal, and pain sensitivity. To identify those patients with clinical symptoms of neuropathy questions on the presence of paraesthesia, numbness, burning, and stabbing pain were asked(present or absent). Symptoms severity was captured in a 10-point numeric scale(0 no symptoms; 10 very severe symptoms). The Manchester Foot Pain and Disability Index (MFPDI) and the Systemic Sclerosis Quality of Life Questionnaire (SScQoL) were used to capture the impact of the clinical symptoms on foot disability and QoL.

Results: One hundred and nine SSc patients (88.1% female, median age 59.0 years, lcSSc 78%) and 51 HC were enrolled. Out of the 109 SSc patients, 77 (71%) had peripheral sensory neuropathy on the feet. A statistically significant difference between SSc and HC was found for each sensory parameter assessed (p=<0.01 for all). SSc cases presented a significant median reduction in the number of areas with touch sensitivity and a delayed vibration perception threshold (p=0.01). Patients also showed a significant thermoreceptor impairment which resulted in a lower cold threshold and higher warm threshold (p<0.01 for both). In addition to a significantly higher heat-induced pain threshold (p<0.001)(Table 1).

The QST results were associated with age (p<0.01 for each neurosensory parameter), followed by smoking history and history of foot ulcerations. From the QST only cold sensitivity threshold showed a correlation with SScQoL (p=0.008; P= -0.249). While neuropathic symptoms presented with a small, but significant association with foot pain and disability (paraesthesia (p=0.01; P=0.240), numbness (p=0.02; P=0.220), and stabbing pain (p=0.02; P=0.220), and with quality of life (paraesthesia (p=0.004; P=0.270), numbness (p=0.02; P=0.220) and stabbing pain (p=0.005; P=0.260) showing the potential contribution of neuropathic symptoms to the disease burden.

Conclusions: Foot peripheral neuropathy is a relatively common clinical entity in SSc and represents a potential burden on foot disability and quality of life, therefore it should be taken into account during the routine SSc management.

P.302

IMPACT OF AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION ON TH1/TH2 BALANCE IN PATIENTS WITH SYSTEMIC SCLEROSIS

Ann-Christin Pecher¹, Johannes Olschner², Jörg Henes¹, Reinhild Klein³

¹Centre for Interdisciplinary Clinical Immunology, Rheumatology and Autoinflammatory diseases, University Hospital Tuebin, Tübingen, GERMANY, ²University Hospital Tuebingen, Tübingen, GERMANY, ³Internal Medicine Department II, University Hospital Tuebingen, Tübingen, GERMANY

Introduction: Patients with systemic sclerosis (SSc) and rapid progression despite standard therapy regimens may be offered therapy escalation in the form of autologous hematopoietic stem cell transplantation (HSCT). The efficacy of this therapy has been demonstrated multiple times; however, the exact mechanism of action remains unknown. It is postulated that HSCT results in a reset of the immune system with the establishment of new, non-autoreactive precursor cells. It has been described that SSc patients may exhibit altered immune responses, such as Th2 overexpression, before HSCT. The aim of this study was to investigate the effects of HSCT on the Th1/Th2 balance in patients with SSc in more detail.

Material and Methods: Previous research (Barth et al., 2003)has shown that the Th2 pathway is primarily stimulated by tetanus and represented by cytokines IL5 and IL13, while the Th1 pathway is stimulated by PPD and represented by IFN-y and TNF-b. Based on this knowledge, we conducted lymphocyte transformation tests in the form of proliferation and cytokine ELISA analyses on 32 subjects immediately before and at 7 defined time points up to 3 years after HSCT.

Lymphocytes, obtained from heparinized blood of the subjects, were incubated with normal serum and stimulated with various antigens (PWM; BCG; TET; PPD; SCL70) at different concentrations. While radioactive-labeled 3H-thymidine was added in the proliferation assay to measure the incorporation rate into the DNA of stimulated lymphocytes, serving as a measure of the proliferative activity of the aforementioned immune pathway, various cytokines (IL1a; IL5; IL6; IL13; IL10; IL17; IFN-y; TNF-a; TNF-b), secreted by stimulated lymphocytes, were measured in the cytokine ELISA assay.

Results: In the proliferation assay, there was a significant decrease (p<0.05) in tetanus-stimulated proliferation of the lymphocytes after 3, 6, and 12 months, and additionally after 30 months compared to the pre-transplantation time point. In the cytokine ELISA assay, there was also a decrease (p<0.01) in tetanus-stimulated IL5 production after 3, 6, and 12 months compared to the pre-transplantation time point.

Conclusions: Assuming that tetanus and IL5 represent the activity of the Th2 pathway, both assays showed a decrease in Th2 activity during the 3-12 months period following HSCT. HSCT thus appears to induce an immunological change in the Th1/Th2 balance during the first year. The clinical and therapeutic implications of this change for patients require further investigations.

P.303

AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION (AHSCT) IN AUTOIMMUNE DISEASES. SINGLE-CENTER EXPERIENCE

Gema María Lledó¹, Montserrat Rovira², Priscila Giavedoni³, Flor Vera-Morandini³, Sergio Prieto-González¹, Gerard Espinosa¹

¹Department of Autoimmune Diseases. Hospital Clínic de Barcelona, Barcelona, SPAIN, ²Department of Haematology. Hospital Clínic de Barcelona, Barcelona, SPAIN, ³Department of Dermatology. Hospital Clínic de Barcelona, Barcelona, SPAIN

Introduction: AHSCT has emerged as a therapeutic option for potential refractoriness to immunosuppressive treatments (IS) in organ-specific autoimmune diseases (OSAD) and systemic autoimmune diseases (SAD). Despite the associated risks, it offers potential benefits in cases where clinical remission cannot be achieved

Material and Methods: We conducted a retrospective descriptive study of patients undergoing AHSCT at the Hospital Clínic de Barcelona between 2014 and 2023. All patients had documented refractoriness to multiple lines of IS treatment and exhibited persistent immunological clinical activity with a life-threatening or severe chronicity risk. All patients were discussed by a multidisciplinary team, and ethical committee approval was obtained. Demographic data, type of SAD, prior IS treatments, indications for AHSCT, procedure-related complications, and post-transplant complications were collected. Clinical remission rates, post-transplant treatment adjustments, and long-term survival were described. Statistical analysis included prevalence estimation for qualitative variables and medians ± IQR for quantitative variables.

Results: Eight patients with persistent immunological clinical activity were candidates for AHSCT, with 87.5% being female and a median age of 55 years. Indications for AHSCT included rapidly progressive cutaneous involvement in four cases with systemic sclerosis and two cases with eosinophilic fasciitis, persistent microangiopathic activity in one patient with Susac syndrome, and refractory multiple mononeuritis in one patient with Sjögren's syndrome. The most commonly used prior IS treatments included corticosteroids [CS] (100%), especially as pulses (75%), mycophenolate [MMF] (87.5%), methotrexate [MTX] (50%), Rituximab [RTX] (87.5%), tocilizumab [TCZ] (87.5%), and intravenous immunoglobulins [IVIG] (50%). Four patients experienced mild to moderate complications during the conditioning phase, and one patient suffered a severe side effect that impeded transplantation. Post-transplant, all patients experienced complications, including isolated fever or mild infection (N 3), moderate infection (N 1), and ultimately fatal infection such as progressive multifocal leukoencephalopathy (N 1), serum sickness (N 1), and an episode of rash and hepatic cytolysis (N 1). Four patients achieved complete clinical remission, while two required rescue and maintenance treatment with IVIG (SS) and TCZ (ES) due to suboptimal response

Conclusions: HSCT was considered a therapeutic alternative in patients with refractory SAD. Clinical remission was achieved in most cases, although there were complications that must be considered as they can be severe. Currently, there are no predictive factors for response, so a thorough and individualised pre-transplant evaluation and rigorous post-transplant follow-up are necessary to detect and address early complications associated with HSCT

P.304

DIGITAL GANGRENE AND SURVIVAL FOLLOWING LUNG OR HEART-LUNG TRANSPLANTATION IN PATIENTS WITH SYSTEMIC SCLEROSIS

Brian S. Lee, Shufeng Li, Lorinda Chung

Stanford University School of Medicine, Stanford, USA

Introduction: Digital gangrene is a severe complication of systemic sclerosis (SSc) related to underlying vasculopathy. The incidence and clinical associations of digital gangrene in SSc patients after lung or heart-lung transplantation have not previously been described.

Material and Methods: A retrospective study of SSc patients (SSc group) who underwent lung or heart-lung transplant surgery from 2001 to 2021 was performed. SSc group was then compared to a cohort of all patients with other autoimmune diseases (autoimmune group) and patients without autoimmune diseases (control group) who underwent lung or lung-heart transplant. The control group was matched to the total cohort of patients with autoimmune diseases up to 2:1 based on age, gender, year of transplant, the presence or absence of pre-operative pulmonary hypertension, type of transplant, and lung allocation score or heart transplant priority status. Conditional Cox proportional hazard regression was applied to estimate the risk of death within two years.

Results: There was a total of 16, 55, and 141 patients in SSc, autoimmune, and control groups, respectively. Four patients (25%) in SSc group and none from the other groups developed digital gangrene a median of 44.5 (range 8-90) days post-operatively. Although not statistically significant, all SSc patients with digital gangrene had diabetes whereas only 4 SSc patients (33.3%) without digital gangrene had diabetes; SSc patients with digital gangrene also had a longer median duration of post-operative vasoconstrictor therapy (15.5 days) compared to those without digital gangrene (3.0 days) (Table 1). Overall survival in the first two years after transplantation was lowest in the SSc group and highest in the control group (p=0.03) (Figure 1). Within the first two years after transplantation, post-operative digital gangrene did not increase the risk of death (HR: 0.51 (0.02-18.06), p=0.71). The risk of death was higher in SSc patients compared to the control group (HR: 6.57 (1.36-31.75), p=0.02), however, statistical significance did not persist in multivariate analysis (HR: 7.42 (0.58-94.25), p=0.12) (Table 2).

Conclusions: SSc patients are uniquely at risk for post-operative digital gangrene following lung and heart-lung transplant with an incidence rate of 25% in our study. The presence of diabetes and longer duration of post-operative vasoconstrictor therapy may play a role in developing digital gangrene. Within the first two years after transplant surgery, SSc group had the highest mortality rate compared to other groups but the development of digital gangrene did not increase the risk of death.

P.305

AUTOLOGOUS FAT GRAFTING IS A PROMISING TREATMENT METHOD OF JUVENILE LOCALIZED SCLERODERMA (LOS) PATIENTS WITH FACIAL INVOLVEMENT

Louise Sander^1,2, Ivan Foeldvari², Daniel Glaser³, Rebecca Stier⁴, J. Camilo Roldán⁴

¹Asklepios Medical School, Hamburg, GERMANY, ²Hamburg Center for Paediatric and Adolescent Rheumatology, Hamburg, GERMANY, ³Yale School of Medicine, New Haven, UNITED STATES MINOR OUTLYING ISLANDS, ⁴Catholic Children’s Hospital Wilhelmstift, Hamburg, GERMANY

Introduction: Facial involvement in juvenile localized scleroderma (jlSc) leads to depletion of fat tissue compartments of the face and arrest of growth of the facial skeleton compromising thus the facial appearance and producing a consequent phycological distress. Autologous fat cell grafting (AFG) seems to be a potentially effective instrument to improve facial cosmetic changes in jlSc patients. Studies about the effectiveness of autologous fat grafting in patients with facial involvement in jlSc are rare.

Material and Methods: We retrospectively studied patients with jlSc who were followed at the Hamburg Center for Pediatric and Adolescent Rheumatology at least up to 6 months postoperatively and received at least one autologous fat transplantation for a facial lesion. AFG was conducted independent of disease modifying treatment and /or disease activity. The effectiveness of the intervention was evaluated, assessing the injected volume, in comparison to the fat retention 6 months post the intervention and till the last follow up. The volume enhancement of the existing 3D photo images were evaluated with Mirror Medical Imaging Software, Canfield Scientific (NJ, USA).

Results: Data of 22 juvenile patients was assessed from March 2006 to September 2021. In 6 patients the photos could not be evaluated for the study. The mean age of the remaining 16 patients at the beginning of the first fat graft was 12 years (range 8 to 22 years). They all have undergone in the mean 2.93 intervention (range 1 to 6). The evaluation showed that the volume enhancement around every six months post AFG is about 50%. mLoSSI value did not correlate to the gained volume after 6 months. In 4 of 16 patients a decrease of the LoSDI occurred. The mean tragus nose distance difference decreased in 7 patients ( mean decrease 1,09 cm). We did not observe any side effects.

Conclusions: In this first bigger pediatric case series the mean facial volume increased around 50% after a mean of 2.93 interventions. AFG is a promising method to improve the cosmetic appearance of these patients. We need longer follow up to find out how long the effect lasts.

P.306

DESCRIPTION OF 646 PATIENTS WITH SYSTEMIC SCLEROSIS AND FACTORS ASSOCIATED WITH MORBIDITY AND MORTALITY

Erika Diete¹, Ann-Christin Pecher², Joerg Henes²

¹University Hospital Tuebingen, Tuebingen, GERMANY, ²Centre for Interdisciplinary Clinical Immunology, Rheumatology and Autoinflammatory diseases, University Hospital Tueb., Tuebingen, GERMANY

Introduction: Systemic sclerosis (SSc) is an autoimmune disease characterized by diffuse skin fibrosis of unknown pathogenesis. In some patients also fibrosis of internal organs is present. Clinical course is variable, but mainly determined by extent of vascular and fibrosing complications. Pulmonary and cardiac involvement as well as gender and autoantibody status are known risk factors which influence morbidity and mortality. The aim of the study is to further evaluate disease and patients’ parameters in a large cohort, maybe to further understand risk factors and potentially develop a risk score, which may be used to offer intensive treatment options like stem cell transplantation at an earlier timepoint.

Material and Methods: This is a single centre retrospective analysis of 646 SSc patients at the University Hospital Tuebingen, Germany, from January 2000- March 2023. We included possible risk factors as age, inflammatory markers, organ manifestations, smoking, and clinical outcome parameters as overall survival and stem cell transplantation.

Results: About one third of the patients in this cohort (n=212; 32.8%) had a diffuse cutaneous (dcSSc) SSc. The median age at first disease manifestation (first non-Raynaud) was 46 years, with 211 patients <40 years (32.7%). In 299 (46.3%) patients we detected anti-Scl-70 and in 506 (78.3%) antinuclear antibodies (ANA). Elevated inflammatory markers (CRP and/or ESR) were present in 275 (42.6%), and 249 (38.5%) showed early lung manifestation (defined by diffusing capacity <60% and/or forced vital capacity <70% <12 months after first manifestation). Furthermore, 121 patients (18.7%) had diagnosed myositis, and 102 (15.8%) heart manifestation <12 months after first manifestation. Patients lived on average 675 months (56 years). 68 (10.5%) patients still smoked and 172 (26.6%) were ex-smokers. In average the patients had 6.4 pack years. In 79 (12.2%) of the patients stem cell transplantation after high-dose chemotherapy has been used, of which 56 patients had dcSSc. Out of 106 (16.4%) measured blood group-analysis we mostly had patients with A Rhesus positive (out of them 30.2%). 287 showed at time of first diagnosis esophagus involvement (dysmotility/reflux disease/dysphagia).

Conclusions: In this cohort one third of the patients had first disease symptoms at an age <40 years. Also, other known risk factors for an adverse outcome were frequently present. The median life expectancy was 56 years, which is below the life expectancy of the general population in Germany. Therefore, this data highlights the importance to evaluate intensive treatment options as stem cell transplantation at an early timepoint to further optimize patient morbidity and mortality.

P.307

AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN SYSTEMIC SCLEROSIS: FOUR CASES

Marta De La Rubia Navarro, Samuel Leal Rodríguez, Elena Grau García, Hikmat Chiara, Luis González Puig, Rosa Negueroles Albuixech, Elvira Vicens Bernabeu, Isabel Martínez Cordellat, Ernesto Tovar Sugrañés, José Ivorra Cortés, José Eloy Oller Rodríguez, Inmaculada Chalmeta Verdejo, Carmen Riesco Bárcena, Anderson Victor Huaylla Quispe, Iago Alcántara Alvarez, Pablo Muñoz Martínez, Laura Mas Sanchez, Belén Villanueva Mañés, Alba Torrat Novés, Daniel Ramos Castro, José Andrés Román Ivorra

Hospital Universitario Y Politécnico La Fe, Valencia, SPAIN

Introduction: Systemic sclerosis (SSc) is a heterogeneous, autoimmune disease characterized by small vessel vasculopathy, autoantibodies production, and fibroblast activation, leading to skin and internal organs fibrosis. Autologous hematopoietic stem cells transplantation (AHSCT) is generally indicated for aggressive SSc portending poor prognosis. Careful selection of patients who have a poor prognosis but lack advanced organ involvement is crucial, because of the toxicity of the procedure.

The objective is to describe clinical and serological features, previous and current treatments, adverse events, and clinical course of SSc patients undergoing AHSCT.

Material and Methods: Descriptive, cross-sectional study including data from patients with diagnosis of SSc according ACR/EULAR 2013 criteria. Previous and current treatments, clinical course post-AHSCT, adverse events and clinical and serological data were collected since 2014 to 2023.

Results: Four patients (100% women) were included, with a median age of 49 (6.78) years old and a median of 32.5 (7) months since diagnosis to AHSCT. All patients had diffuse skin thickening (mean m-Rodnan score (mRSS): 33.75) and, regarding toxic habits, all patients were ex-smoker at the time of assessment. Results obtained were included in the table:

*SSc: systemic sclerosis; **NA: non-available.

Previous treatments were shown in graphic:

Regarding current therapies, only one patient received corticosteroid (prednisone 7.5 mg/day) and one patient restarted tocilizumab after AHSCT.

Finally, only one patient presented a pneumonia post-AHSCT (two weeks after AHSCT) requiring intensive care unit admission, with improvement and complete resolution of the condition. Rest of patients have not presented any adverse event at the time of assessment.

Conclusions: AHSCT comprise a good therapeutic option in early diffuse cutaneous systemic sclerosis and interstitial lung disease, with a reasonable safety profile in our cohort.

P.308

MUSCULOESKELETAL MANIFESTATIONS IN CHRONIC GRAFT-VERSUS-HOST DISEASE

Marta De La Rubia Navarro, Samuel Leal Rodríguez, Elena Grau García, Hikmat Chiara, José Ivorra Cortés, Luis González Puig, Rosa Negueroles Albuixech, Elvira Vicens Bernabeu, Isabel Martínez Cordellat, Inmaculalda Chalmeta Verdejo, José Eloy Oller Rodríguez, Ernesto Tovar Sugrañés, Carmen Riesco Bárcena, Anderson Victor Huaylla Quispe, Pablo Muñoz Martínez, Laura Sánchez Mas, Daniel Ramos Castro, Alba Torrat Novés, Iago Alcántara Álvarez, Belén Villanueva Mañés, José Andrés Román Ivorra

Hospital Universitario y Politécnico La Fe, Valencia, SPAIN

Introduction: Graft-versus-host disease (GVHD) represents the main complication of allogenic hematopoietic stem cell transplant (AHSCT). Generally, it’s classified in acute or chronic according to a time criterion. Chronic GVHD presents dermatological, ophthalmological, and musculoskeletal manifestations and mimic those of an autoimmune disease, as systemic sclerosis o Sjögren syndrome and it’s the leading cause of morbidity and mortality in these patients.

The objective is to describe musculoskeletal manifestations (MSKM) in chronic GVHD patients.

Material and Methods: Descriptive, cross-sectional study including data from patients with diagnosis of chronic GVHD from February 2022 to September 2023 was performed. Clinical manifestations, serological and imaging data (ultrasonography or bone densitometry -DEXA-) were collected. Patients were evaluated in a multidisciplinary consultation with hematologists, ophthalmologists, and dermatologists and rheumatologists.

Results: One hundred and eighty-three undergone AHSCT in 2022. Seventeen patients with chronic GVHD were evaluated (58.8% men), with a median age of 52,7 (12,6) years old and with a mean period of 2,4 (4,1) years between oncologic diagnosis and transplantation. The time since transplantation and the onset of MSKM ranged from 6 months to 156 years, with a median period of 8 (10.8) months.

The results obtained were included in the table:

Graphic shows mucocutaneous, ophthalmic, liver and lung manifestations:

Conclusions: Most common MSK manifestations were inflammatory arthralgia and osteoporosis and ultrasonography data were synovitis and biceps longus tenosynovitis. These findings, while unknown, imply a significant deterioration in quality of life of these patients.

P.309

SUCCESSFUL AUTOLOGOUS STEM CELL TRANSPLANTATION OF THE DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS PATIENT

Marko Baresic, Ljiljana Smiljanic Tomicevic, Boris Karanovic, Miroslav Mayer, Branimir Anic

Division of Clinical Immunology and Rheumatology, Department of Medicine, University Hospital Center Zagreb, Zagreb, CROATIA

Introduction: Autologous stem cell transplantation is one of the therapeutic options reserved for the progressive forms of diffuse cutaneous systemic sclerosis. The method should be performed in a center with a transplantation experience because many complications can occur early on.

Material and Methods: A 48-year-old female presented with Raynaud's phenomenon and progressive skin thickening. The patient was hospitalized in Rheumatology department and diagnosed with progressive form of diffuse cutaneous systemic sclerosis. She was positive for RNA-polymerase III. Methotrexate and symptomatic treatment gave little result so the patient was put on pulses of cyclophosphamide. Progression of the skin thickening prompted strategy shifting.

Results: The patient underwent autologous stem cell transplantation with an excellent result. Skin thickening stopped and for the last two years the patient is not taking any immunosuppressives.

Conclusions: Autologous stem cell transplantation should be reserved for the progressive forms of diffuse cutaneous systemic sclerosis refractory to the standard immunosuppressives. Unfortunately we still miss the knowledge of perfect timing for this method.

P.310

DISEASE PROGRESSION AFTER ONE YEAR IN PATIENTS WITH VERY EARLY SYSTEMIC SCLEROSIS, RESULTS FROM THE HIT HARD AND EARLY TRIAL

Madelon Clementi Vonk¹, Brigit Kersten¹, Jacqueline Lemmers¹, Amber Vanhaecke², Arthiha Velauthapillai¹, Wieneke van den Hombergh¹, Frank van den Hoogen¹, Els van den Ende¹, Vanessa Smith²

¹Radboud University Nijmegen Medical Center, Nijmegen, THE NETHERLANDS, ²University Hospital Gent, Gent, BELGIUM

Introduction: The Hit Hard and Early study was a double-blind, randomized, placebo controlled, multicenter trial in very early SSc patients, designed to analyze the efficacy and safety of high dose glucocorticoids therapy on nailfold capillary density. We found no clinically relevant treatment effect of methylprednisolone compared with placebo. However, it provides new information on disease progression in very early SSc.

Material and Methods: We adapted the VEDOSS criteria to assure that only patients with early disease could be included in the study. The following inclusion criteria were applied: age 18 years or older; presence of Raynaud’s phenomenon; positive test for associated auto-antibodies; early or active SSc pattern at nailfold capillaroscopy; and puffy fingers for less than 3 years. Main exclusion criteria were: any skin or internal organ involvement, previous treatment for SSc and anti-RNA polymerase III auto-antibodies. Patients were evaluated at baseline, 4, 8, 12, 26, 36 and 52 weeks.

Disease progression was defined as the occurrence of any skin or internal organ involvement, such as significant interstitial lung disease, pulmonary arterial hypertension, (peri)myocarditis, renal crisis, gastric antral vascular ectasia, myositis, digital ulcers or pitting scars or tendon friction rubs. Relevant pulmonary function decline after 1 year was defined as a >=10% decrease in FVC or a decrease in FVC >=5% - < 10% and a DCLO decline of >=15%.

Results: Thirty patients (21 female) were included, with a median disease duration of 11.4 months. The median duration of puffy hands was 12.2 months (Table 1). In total, 16 patients (53%) showed either disease progression or a relevant decrease in pulmonary function at week 52. Median (IQR) time to disease progression in these patients was 26 (12 – 39) weeks (Figure 1)

Conclusions: We have shown that by adapting the VEDOSS criteria we were able to identify patients at risk of disease progression in one year. Previous research has shown that applying the VEDOSS classification criteria results in a heterogeneous mixture of patients with early disease and patients with longstanding, very mild disease. This is also shown by the fact that in follow-up of the VEDOSS study only 52,4% progressed to SSc after 5 years. However by adapting the VEDOSS criteria, we found disease progression in 53% after 1 year. Future research should focus on corroboration of this result and application of other immunomodulated treatments aiming to prevent progressive SSc.

P.311

TOWARDS A COMPREHENSIVE APPROACH TO THE MANAGEMENT AND PROGNOSIS OF SYSTEMIC SCLEROSIS’S PATIENTS: THE ROLE OF COMORBIDITIES

Martina Orlandi¹, Silvia Bellando Randone², Rossella De Angelis³, Fabio Cacciapaglia⁴, Carlo Scire'⁵, Veronica Codullo⁶, Dilia Giuggioli¹, Francesca Ingegnoli⁷, Valeria Riccieri⁸, Serena Guiducci², Clodoveo Ferri¹, Marco Matucci Cerinic^2,9, Cosimo Bruni^2,10

¹University Hospital of Modena and Reggio Emilia School of Medicine, Department of Medical and Surgical Sciences, Modena, ITALY, ²Department of Experimental and Clinical Medicine, University of Florence, Florence, ITALY, ³Rheumatology Unit, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, ITALY, ⁴Rheumatology Unit, Department of Precision and Regenerative Medicine-Ionian Area, Bari, ITALY, ⁵School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy., Milan, ITALY, ⁶Department of Rheumatology, Policlinico San Matteo, Pavia, ITALY, ⁷Division of Clinical Rheumatology, ASST Pini, Dept. of Clinical Sciences & Community Health, Milan, ITALY, ⁸Department of Rheumatology, Sapienza University, Rome, ITALY, ⁹Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Scientific Institute, Milan, ITALY, ¹⁰Department of Rheumatology, University Hospital of Zürich, University of Zurich, Zurich, SWITZERLAND

Introduction: Managing systemic sclerosis (SSc) remains a challenge for the clinician, not only due to the clinical heterogeneity of the disease, but also to comorbidities that can complicate the clinical picture. Despite comorbidities impact on patient’s outcomes and survival, no data are currently available about the role of the overall comorbidity burden in SSc activity and prognosis.

Therefore, the aim of this study was to evaluate the prevalence of comorbidities and their impact on disease activity and prognosis in the Systemic sclerosis PRogression INvestiGation (SPRING) registry.

Material and Methods: SSc patients from the SPRING registry, fulfilling the ACR/EULAR 2013 classification criteria, with complete data on baseline comorbidities were enrolled. The Charlson comorbidity index (CCI) was used to quantify the overall comorbidity burden. The disease activity was calculated using the revised EUSTAR activity index (AI). The impact of SSc features on CCI, the effect of CCI on SSc disease activity and mortality were tested with multivariable regression models.

Results: Among 1910 SSc patients enrolled, 67.3% had at least one comorbidity at baseline. The most frequent comorbidities were systemic arterial hypertension (23.7%), osteoporosis (12.9%) and dyslipidemia (11%). The mean value of CCI score was 2.9±2.3. When patients were grouped according to increasing levels of CCI, a clear separation in the distribution of SSc-related clinical features could be observed. Among over 900 patients with available follow-up, no association between baseline CCI and changes in disease activity was observed. Conversely, the risk of death over time was independently predicted by both CCI and AI.

Conclusions: Comorbidities and disease activity independently impact on the prognosis of SSc patients. This suggests that the management of comorbidities, together with the reduction of disease activity, is fundamental to improve patient survival.

P.312

ARTHRITIS AND RISK STRATIFICATION IN PATIENTS WITH VERY EARLY SYSTEMIC SCLEROSIS

Sinziana Muraru¹, Carmen-Marina Mihai¹, Muriel Elhai¹, Mike Becker¹, Suzana Jordan¹, Alexandru Garaiman¹, Cosimo Bruni^1,2, Liubov Petelytska¹, Anna-Maria Hoffmann-Vold^1,3, Oliver Distler¹, Rucsandra Dobrota¹

¹Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, SWITZERLAND, ²Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence - University Hospital, Florence, ITALY, ³Department of Rheumatology, Oslo University Hospital, Oslo, NORWAY

Introduction: Whereas arthritis is associated with a worse prognosis in established disease, knowledge about its relevance in very early systemic sclerosis (veSSc) is scarce. Our objective was to assess the prevalence of arthritis in patients with veSSc, its association with other disease features and its impact on progression to established SSc.

Material and Methods: We included patients with veSSc, defined as presence of Raynaud’s phenomenon and/or at least one of the following: puffy fingers, presence of antinuclear antibodies (ANA), abnormal capillaroscopy, but not fulfilling the ACR/EULAR 2013 classification criteria for SSc at baseline.

We defined arthritis based on the clinical diagnosis of synovitis by the treating physician. After selecting the patients with arthritis, we integrated comprehensive data from their electronic records on the pattern of joint involvement, laboratory parameters and imaging, excluding arthritis unrelated to SSc. An experienced rheumatologist assessed the conventional radiographs for presence of inflammatory bone erosions.

We investigated associations between arthritis and relevant disease features using Fisher’s test, Mann–Whitney U test and linear regression. A longitudinal analysis using Kaplan-Meier plots was performed to investigate arthritis as a potential predictor of progression towards established SSc, defined as fulfilment of ACR/EULAR criteria at any follow-up visit.

Results: SSc-related arthritis occurred in 26/159 (16.3%) veSSc cases, among which 22/26 (84.6%) at baseline; further characteristics are shown in Table 1. The pattern of joint involvement was in most cases symmetrical, oligo- or polyarticular, affecting mostly hand and finger joints. In 16/26 patients a treatment with either conventional or biological DMARDs was prescribed, with arthritis being the main indication. Patients with anti-centromere antibodies had arthritis less often (p=0.038). Other disease features, such as the other specific antibodies, presence of puffy fingers, elevated inflammatory markers or disease duration were not associated with arthritis.

Overall, 43/108 (39.8%) patients progressed to established SSc during a median follow-up of 2 years. Among these, 6/43 patients had arthritis at baseline. There was no statistically significant difference in fulfilling the classification criteria at follow-up between patients with- and without arthritis at baseline (Figure 1).

Conclusions: In this first comprehensive characterization, arthritis has a similar point-prevalence in veSSc as previously reported in established SSc. Despite the apparently mild profile, with rare erosions or increased inflammatory markers, more than 50% of patients needed treatment with DMARDs, suggesting a relevant disease burden. Patients with anti-centromere antibodies present with arthritis significantly less often. Arthritis was not a prognostic factor for progression towards established SSc in our cohort.

P.313

FEATURES OF THE VERY EARLY SYSTEMIC SCLEROSIS

Oxana Desinova, Mayya Starovoytova, Lidia P. Ananyeva, Olga Koneva, Liudmila Garzanova, Olga Ovsyannikova, Rushana Shayakhmetova

VA Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: There is now an increasing focus on early diagnosis of systemic sclerosis (SSc). The early diagnosis of SSc can be very difficult, when most of the typical symptoms are absent.

To identify the features of the early form of SSc.

Material and Methods: Within one year, out of 1400 pts with SSc 1.4% (19 pts) were diagnosed with very early SSc, male/female 5/14 pts, mean age 41±17,5 (19;76) years. Very early SSc (VESSc) characterized by Raynaud's phenomenon (RP), puffy fingers (PF), positive ANA, disease-specific autoantibodies, and microvascular alterations at capillaroscopy and the duration of the disease from the moment of the first non- Raynaud's phenomenon not more than 18 months. All pts with SSc had standard clinical examination.

Results: All pts with VESSc had RP, which was the first symptom of the disease. The duration of RP 40 + -12.5 months. Digital ulcer with necrosis had 10.5% pts. 84% of pts experienced PF with the duration 6,9±5 months, 5.2% of pts developed diffuse hyperpigmentation. Arthralgia of the hands was observed in 42% of pts. 52% of pts had esophageal hypotension. Despite the short duration of the disease, interstitial lung disease less 20% was detected in 25% of pts according to high-resolution computed tomography, FVC was more 95%. 8.3% of pts had a marked decrease DLCO to 35% and pericarditis with a relatively short disease duration of only 15 months. The presence of visceral pathology reflected the rapid progression of the disease. All pts had a positive ANA Hep-2, anti-centromere antibodies -21% of pts, topoisomerase-1 antibodies - 16% of pts, anti-RNP antibodies - 16% of pts. Early inactive scleroderma-type capillaroscopic changes were observed in all pts, and 25% of pts of them had a combination with myopathic changes. All pts were treated with calcium channel blockers, 75% with hydroxychloroquine 200 mg/day, 25% with glucocorticoids 4 mg/day, and 16% with immunosuppressants (methotrexate, mycophenolate mofetil).

Conclusions: It is important not only to diagnose, but to determine the nature of the course and possible prognosis of SSc, in order to choose early adequate, pathogenetically justified therapy. Currently, the only possible clinical strategy in the very early stages of SSc remains a close surveillance program to detect the onset of internal organ involvement.

P.314

CALCIUM-DEPENDENT MECHANISMS OF A NOVEL ANTI-FIBROTIC AGENT, M10, IN SCLERODERMA AND NORMAL LUNG FIBROBLASTS

Richard Silver, Tanjina Akter, Ilia Atanelishvili, Clementine Perry, Ahmed Ismail, Galina Bogatkevich

Medical University Of South Carolina, Charleston, USA

Introduction: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is an irreversible and progressive process and major cause of death among SSc patients.The molecular mechanisms underlying SSc-ILD are not well understood and a great need exists for more effective treatments. Dysregulated matrix remodeling in SSc-ILD is associated with disruptions of Ca2+ homeostasis. We recently identified a unique 10 amino acid peptide, M10, with low toxicity and high efficacy in mouse models of SSc-ILD. The current study was undertaken to define calcium-dependent anti-fibrotic mechanisms of M10 in normal and SSc-ILD lung fibroblasts (LF).

Material and Methods: Experiments were performed using LF from five patients with SSc-ILD and five control subjects. Proteins of interest were studied by RT-PCR at the mRNA level and by immunoblotting at the protein level. Cytosolic Ca2+ was measured by FLIPR Tetra cellular screening system. Concentration of endogenous TGF-beta1 in SSc-ILD LF was measured by ELISA. Expression and activity of matrix metalloproteinases (MMPs) were determined by antibody arrays, ELISA and fluorometric assays. Statistical analysis was performed using GraphPad Prism 7 software.

Results: In normal and SSc-ILD LF an acute increase of intracellular Ca2+ occurred within 15 sec following TGF-beta1 administration with a second peak of delayed Ca2+ efflux mobilized from intracellular stores at 60 sec. A high level of TGF-beta1-induced Ca2+ was Smad-independent and maintained throughout 10 min of cellular screening. In the presence of M10 peptide TGF-beta1-mediated Ca2+ efflux was reduced by 32.6+9.1% (p < 0.001) in normal LF and by 26.8+7.7% (p < 0.001) in SSc-ILD LF (Figure 1). M10 peptide suppressed TGF-beta1-induced mRNA and protein expression of mechano-sensitive Ca2+-permeable channel TRPV4 as well as collagen I, fibronectin and tenascin. TGF-beta1 induced MMP-3 expression and suppressed tissue inhibitor of metalloproteinase TIMP-2, whereas M10 peptide blocked TGF-beta1-mediated TIMP-2 inhibition restoring it to normal levels. M10 downregulated expression of MMP-3 in SSc-ILD LF and reduced endogenous levels of TGF-beta1 by preventing MMP-3-dependent cleavage and activation in a Ca2+-dependent manner of latent TGF-beta.

Conclusions: M10 peptide reduces ECM proteins, inhibits TGF-beta-mediated Ca2+, regulates MMPs and TIMPs and reduces endogenous TGF-beta1. These data suggest that repression of Smad-independent calcium-mediated TGF-beta signaling represents one of the antifibrotic mechanisms of M10.

P.315

THE USE OF LOCAL PLATELET-RICH FIBRIN THERAPY IN PATIENT WITH SYSTEMIC SCLEROSIS AND DIGITAL ULCER

Rushana Shayakhmetova, Lidia Ananyeva, Olga Koneva, Liudmila Garzanova, Oxana Desinova, Mayya Staravoytova, Olga Ovsyannikova, Anna Khelkovskaya-Sergeeva

V.A. Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: One of the main characteristic symptom of SSc is ischemic digital ulcers. Ulcerative defects can be sharply painful, characterized by a recurrent course and torpidity to treatment. The difficulties of therapy of such patients lie in the frequent addition of an infection associated with immunodeficiency while taking cytostatic therapy, and also often due to the lack of local sanitation of wounds, which leads to chronicity and a long-term recurrent course.

Material and Methods: A clinical case of a patient with SSc with long-term recurrent digital ulcers without response to standard therapy. In this case we used PRF-therapy (autologous platelet-rich fibrin treatment), which is a lot easier to prepare compared to other platelet concentrates such as platelet-rich plasma. The procedure involves drawing of blood that is collected into test tubes without anticoagulant followed by centrifuging instantaneously at 2700 rpm for 12 minutes. The PRF obtained is then applied over the cleaned ulcer and covered by an occlusive dressing and left for 7 days, then changed at weekly intervals. Each time 10 ml of venous blood was collected. After 2 weeks significant improvement was noted in ulcer healing and pain severity.

Results: A 45-year-old woman, suffering from diffuse cutaneous SSc for 18 years, presented with non-healing painful skin ulcer over the right index finger. She was treated with methylprednisolone 4 mg, hydroxychloroquine 400 mg, sildenofil 75 mg, rivaroxaban 10 mg. Considering the ineffectiveness of standard therapy, the PRF-therapy method was used. After local treatment of ulcerative defects using antibacterial agents (syntomycin and heparin ointments), PRF therapy was initiated. Before the therapy there was an ulcer with necrotic tissue (pic.a), after 6 days we see integration of the clot into damaged tissue (pic.b). After 2 weeks re-epithelialization of tissue over the right index finger and pain relief were noted (pic.c).

Conclusions: Therapy of vascular disorders in immunoinflammatory rheumatological diseases, in particular SSc, presents certain difficulties due to many factors, such as frequent infection, the need to take cytostatic drugs, chronic pain, etc. Application of new technologies such as PRF therapy can be an excellent approach in the treatment of refractory skin ulcer in SSc. In the case we described, we see successful healing of the digital ulcer after 2 weeks from the initiation of PRF therapy. However clinical trial is needed to have more evidence to demonstrate the role of PRF in healing of skin ulcers in patients with SSc.

P.316

EFFICACY AND SAFETY OF MACITENTAN IN REFRACTORY DIGITAL ULCERS

Miriam Retuerto¹, Clara Moriano¹, Ivan Castellví², Belén Atienza³, Elvira Díez¹

¹Rheumatology Service, University Hospital León, Leon, SPAIN, ²Unit for Rheumatology and Systemic Autoimmune Diseases, Santa Creu i Sant Pau University Hospital, Barcelona, SPAIN, ³Rheumatology Service, University Hospital Marqués de Valdecilla, Santander, SPAIN

Introduction: Raynaud's phenomenon (Rp) is used to describe a symptom complex caused by digital vascular involvement. Among the conditions that may be associated with Rp are Systemic Autoimmune Rheumatic Diseases (SARDs), especially Systemic Sclerosis (SSc). DU are a major cause of morbidity and have a high recurrence rate in most patients and may be refractory to multiple treatments.

Macitentan is a dual endothelin receptor antagonist authorized to treat pulmonary hypertension. Its efficacy in the treatment of DU associated to SSc has been assessed in two clinical trials (DULA-1 and DULA-2; Khanna D et al, 2016), without any visible effects on their prevention or reduction. However, these trials have been criticized on the methodology and profile of the patients included. We aim to assess efficacy and safety of Macitentan in patients suffering from SARDs and refractory DU.

Material and Methods: Spanish observational multicentric study. Data were retrospectively obtained from medical records of 11 patients suffering from SARDs and refractory DU secondary to severe Rp treated with Macitentan 10mg/daily. Total response was defined as the complete healing of DU and partial improvement as the reduction of the number or size of ulcers. Patients with ischemic ulcers caused by other factors were excluded.

Results: We identified 11 patients who has received treatment with Macitentan for DU, median age 59 years (IQR 52-65). Eight patients were diagnosed with limited SSc; anti-nuclear abs, anti-centromere abs and anti-phospholipidic abs were positive in 90%, 63% and 18% of the patients. Most patients (90.9%) had received previously treatment with Bosentan, and the reason for withdrawal was inefficacy in 4 cases (40%) and adverse effects (liver toxicity) in 6 (60%). 9 patients had received Intravenous prostanoids with no response. In the beginning of Macitentan the number of DU was 6 (IQR 2.5-6) and digital gangrene was reported in one case. Two patients were treated with Macitentan in monotherapy, 7 in combination with calcium ant and 2 received triple therapy (Macitentan + Calcium antag + PDE5 inh). Just one patient stopped the treatment for adverse effects (lower limb edema). Median follow-up of patients who didn’t discontinue the treatment was 4 (IQR 3.2-5.8) years. 70% had a complete response and 30% (3/10) had a partial response.

Conclusions: Our data show that Macitentan is an effective agent for ischemic digital refractory ulcers in patients suffering from SARDs with a favorable safety profile in clinical practice.

P.317

COMBINED BLOCKADE OF IL-1, IL-33 AND IL-36 SIGNALING BY TARGETING IL1RAP AMELIORATES SKIN AND LUNG FIBROSIS IN PRECLINICAL MODELS OF SYSTEMIC SCLEROSIS

Sara Rattik¹, Caitriona Grönberg¹, Petter Skoog¹, David Liberg¹, Thuong Trinh-Minh^2,3, Jörg Distler^2,3

¹Cantargia AB, Lund, SWEDEN, ²Department of Rheumatology, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, GERMANY, ³Hiller Research Center, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, GERMANY

Introduction: The IL-1 receptor accessory protein (IL1RAP) is a co-receptor required for signaling through the IL-1, IL-33, and IL-36 receptors. IL1RAP-mediated signaling results in activation of fibroblasts, endothelial cells and immune cells with production of pro-fibrotic mediators, upregulation of adhesion molecules and recruitment of inflammatory cells, all of which are events relevant for the pathogenesis of systemic sclerosis (SSc). CAN10 is a humanized IgG1-LALA antibody that binds IL1RAP and disrupts IL-1α/β, IL-33 and IL-36α/β/γ signaling and CAN10 is currently in phase 1 clinical development. Here, we investigate the anti-fibrotic potential of IL1RAP blockade by CAN10 or its murine surrogate antibody, mCAN10, in translational and preclinical models of SSc to strengthen the scientific rationale for clinical development in SSc.

Material and Methods: We analyzed RNAseq data from SSc skin samples from four different SSc cohorts to study if the IL1RAP pathway was upregulated in SSc patients and utilized imaging mass cytometry to characterize IL1RAP-expressing cell types. For efficacy studies, we used three complimentary mouse models of SSc: chronic sclerodermatous graft-versus-host disease (cGvHD), bleomycin- and topoisomerase I-induced fibrosis. In all studies, mice received therapeutic treatment with mCAN10, nintedanib or controls, initiated after establishment of fibrosis. Fibrosis was analyzed by histology, hydroxyproline content and by myofibroblast quantification. Skin biopsies from cGvHD mice were also analyzed by RNAseq.

Results: Skin samples from SSc patients showed upregulation of IL1RAP-dependent signaling compared to healthy controls and the main cell populations expressing IL1RAP were fibroblasts, macrophages and endothelial cells. IL1RAP-dependent interleukins activated human dermal fibroblasts and endothelial cells in vitro, which could be blocked by CAN10. In mice, therapeutic IL1RAP blockade reduced dermal and pulmonary fibrosis in the cGvHD-, bleomycin- and topoisomerase I-induced fibrosis models. RNAseq analysis of skin from cGvHD mice, in combination with RNAseq data on genes differentially regulated in skin from SSc patients compared to healthy individuals, indicates that mCAN10 affects a majority of the genes deregulated in both SSc patients and the cGvHD mouse model. Comparing the mCAN10 gene signature to that of nintedanib revealed that the majority of the differentially expressed genes were distinct and suggests that mCAN10 and nintedanib ameliorate fibrosis partly through different molecular mechanisms.

Conclusions: This study suggests that IL1RAP blockade by CAN10 may be a promising approach to treat several of the pathophysiological changes in inflammatory and fibrotic diseases such as SSc.

P.318

INFLUENCE OF NINTEDANIB THERAPY ON VASCULOPATHY IN PATIENTS WITH INTERSTITIAL LUNG DISEASE ASSOCIATED WITH SYSTEMIC SCLEROSIS – A PRELIMINARY STUDY

Aleksandra Nadel, Agnieszka Cieplucha, Olga Brzezinska, Filip Styrzynski, Joanna Makowska, Anna Lewandowska - Polak

Medical University in Lodz - Department of Rheumatology, Immunology and Internal Medicine, Lodz, POLAND

Introduction: Nintedanib is a novel antifibrotic drug used in the treatment of idiopathic pulmonary fibrosis and recently interstitial lung disease associated with systemic sclerosis (SSc-ILD).

However, there is no data regarding the ability of nintedanib to delay or even reverse vasculopathy. In this study, we plan to evaluate the effect of nintedanib on vascular pathology assessed by capillaroscopy in patients with SSc-ILD.

Material and Methods: Patients with SSc-ILD qualified for the progressive fibrosis treatment program have been included in the study. All patients underwent capillaroscopy before treatment and were scheduled for a control study after 12 months of treatment.

Results: Five patients were included in the study. All patients presented scleroderma-type capillaroscopic pattern on the initial capillaroscopy.

Conclusions: Results obtained during the control study (scheduled for the fourth quarter of 2023) will provide data on the impact of nintedanib therapy on vasculopathy and a possible usefulness of the drug in a broader clinical spectrum of patients with systemic sclerosis.

P.319

MYELOID-DERIVED SUPPRESSOR CELLS (MDSCS) IMPROVES SKIN AND LUNG FIBROSIS VIA EXPANSION OF IL-10-PRODUCING REGULATORY B CELLS IN BLEOMYCIN-INDUCED MOUSE MODEL OF SYSTEMIC SCLEROSIS

Bong-Woo Lee¹, Min-Jung Park², Hae-Rim Kim³, Seung-Ki Kwok¹

¹Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, SOUTH KOREA, ²The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, SOUTH KOREA, ³Division of Rheumatology, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, SOUTH KOREA

Introduction: Systemic sclerosis (SSc) is an autoimmune disease characterized by abnormalities in microcirculation, extracellular matrix accumulation, and immune activation. Despite decades of research, there is no effective treatment that combats the disease across organ systems. Myeloid-derived suppressor cells (MDSCs) are identified as a highly heterogeneous group of immature cells derived from the bone marrow and play critical immunosuppressive functions in animal models of autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. MDSCs could also play an important role in SSc, however, the specific mechanism is still largely unclear. The present study aimed to investigate whether MDSCs could inhibit fibrosis in bleomycin (BLM)-induced mouse model by regulating the adaptive immune system.

Material and Methods: The effects of MDSCs were evaluated in a murine model of BLM-induced skin and pulmonary fibrosis. C57BL/6 mice were divided into three groups: (1) Normal, (2) Control (receiving bleomycin), or (3) MDSCs (receiving bleomycin plus MDSCs). In mouse skin and lung specimens, H&E and Masson‘s Trichrome staining were performed to evaluate skin thickness and lung fibrosis. And to quantify the amount of collagen, the hydroxyproline content was measured. Furthermore, skin and lung expression of cytokines was determined by immunohistochemistry. Immune cell populations of the spleen were analyzed by flow cytometry to investigate the immunomodulatory role of MDSCs in the BLM-induced mouse model. Human and mouse skin fibroblasts were co-cultured with MDSCs in the IL-1β-induced inflammatory environment and expression of fibrosis-related genes was assessed by q-PCR.

Results: We found that MDSCs resulted in favorable therapeutic outcomes by alleviating the inflammatory infiltration and collagen deposition in both lung and skin tissues (Figure 1). Immunohistochemical results showed that MDSCs downregulated the proinflammatory and profibrotic cytokines (IL-1β, IL-6, IL-17, TNF-α, TGF-β and α-SMA) (Figure 2). Moreover, the infusion of MDSCs significantly expanded the population of IL-10-producing regulatory B-cells and inhibited selectively plasma B-cells in the spleens of the BLM-induced mouse model (Figure 3). According to the co-culture experiment of MDSCs and fibroblasts, the anti-fibrotic effect was caused by decreased gene expression of COL1A1, CTGF, and MMP13 in mouse skin fibroblasts, while COL1A1, CTGF, MMP2, TGF-β, and TIMP in human skin fibroblasts. In addition, an exogenous supply of anti-IL-10 promoted recovery from the downregulation of fibrosis-related genes (Figure 4).

Conclusions: Our results indicate the infusion of MDSCs ameliorates the fibrosis and autoimmunity in BLM-induced mouse model via IL-10-producing regulatory B cells. These findings indicate that MDSCs may be a promising therapeutic strategy for intractable SSc.

P.320

SODIUM THIOSULFATE TREATMENT OF CALCINOSIS CUTIS IN PATIENTS WITH SYSTEMIC SCLEROSIS ASSESSED BY NOVEL BIOMARKERS AND ADVANCED DIAGNOSTIC IMAGING – A STUDY PROTOCOL

Luna Toppenberg Lazar¹, Mette Mogensen², Douwe J. Mulder³, Anne Braae Olesen¹

¹Department of Dermatology and Venerology, Aarhus University Hospital, Aarhus, DENMARK, ²Department of Dermatology and Venerology, Bispebjerg University Hospital, Copenhagen University Hospitals, Copenhagen, DENMARK, ³Department of Internal Medicine, Division of Vascular Medicine, University Medical Centre Groningen, Groningen, THE NETHERLANDS

Introduction: Approximately 50% of patients with systemic sclerosis (SSc) experience calcinosis cutis (CC), a condition with painful calcium and phosphate deposits in skin and subcutaneous tissue, significantly impacting quality of life and daily activities. No effect treatment is currently available, but sodium thiosulfate (STS) has shown promising results both as injectional and topical treatment. STS is an inexpensive treatment that dissolves calcinotic lesions by acting as a calcium chelating agent. Advanced imaging methods such as dual-energy computed tomography, (DECT), cone-beam computed tomography (CBCT) and reflectance confocal microscopy (RCM) have the ability to provide unprecedented anatomic and cellular details potentially revealing subtypes of CC. Aiming to improve knowledge and treatment of CC, we explore the behavior of CC and investigate STS treatment avenues using novel blood and skin biomarkers and advanced imaging technologies.

Material and Methods: We analyse 68 SSc patients with limited type anti-centromere antibody positivity and CC randomised to receive intralesional 150 mg/ml or topical 10% STS treatment on selected knee, arm or hand lesions. Blood samples and skin biopsies focusing on collagen remodelling are collected and compared with 68 age- and sex-matched SSc patients without CC and with healthy controls. Samples are collected over a 28-week trial period and correlated with disease severity, activity and duration. Additionally, progression of CC and treatment advances are monitored using DECT, CBCT and RCM.

Results: We hypothesise that imaging and biomarker analyses reveal a variety of CC subtypes. Furthermore, we hypothesise that treatment response depends on clinical factors and CC subtypes. We compare the following outcomes: change in calcinosis severity patient- and physician global score (PtGA and PhGA), lesion improvements by imaging studies (size, density, complete/partial remission), clinical lesion assessment (remission, size, ulceration, inflammatory surroundings), paraclinical evaluation (blood and skin analyses) and photos.

Conclusions: We explore an unsolved medical conundrum as our joint research project aims to synergistically improve patient treatment and expand our understanding of the underlying biological and chemical mechanisms of CC. By closely examining STS treatment effects, this study sheds new light on the rarely acknowledged issue of CC in SSc patients. The results could provide new guidance on monitoring treatments of CC and benefit a patient group severely affected in daily life.

P.321

CD19 TARGETING CAR T CELL THERAPY IN A PATIENT WITH SEVERE SYSTEMIC SCLEROSIS

Joerg Henes, Ann-Christin Pecher, Luca Hensen, Reinhild Klein, Wolfgang Bethge, Claudia Lengerke

Department of Internal Medicine II, Hematology, Oncology, Clinical Immunology, and Rheumatology, University Hospital Tüb, Tuebingen, GERMANY

Introduction: Systemic sclerosis (SSc) is still a very challenging autoimmune disease with a high disease related morbidity and mortality and no approved immunosuppressive treatment. Recent positive results with chimeric antigen receptor (CAR) T cells targeting CD19 in different AIDs raises the hope for a new therapeutic option also for our SSc patients.

Material and Methods: A 51-year-old women was diagnosed with SSc in February 2021. Her initial manifestation included severe lung and heart impairment next to renal insufficiency. In addition, the patient lost over 20 kg bodyweight due to gastrointestinal manifestations with severe reflux and vomiting. After several months of poor response to treatment with cyclophosphamide, mycophenolate mofetil and respectively nintedanib, the patient presented at our center in 12/2022 for evaluation of autologous stem cell transplantation (HSCT). Unfortunately, she did not qualify for HSCT due to severe impairment of pulmonary function. Therefore, we offered an individual treatment with CD19 targeting CAR T cell therapy and she accepted. In July 2023 we collected T cells and transduced them with a CD19-targeting second-generation CAR lentiviral vector containing a costimulatory CD3-zeta signaling domain (Miltenyi Biotec; good manufacturing practice laboratory at the University Hospital Tübingen). Prior to reinfusion of the CD19-targeting CAR T cells, the patient received conditioning therapy with fludarabine (25 mg/m2 [5 days before until 3 days before]) and cyclophosphamide (1000 mg/m2 [3 days before]).

Results: The treatment was well tolerated and the patient hospitalized over 19 days. A mild grade 1 cytokine release syndrome was observed in the first week after CAR T cell infusion and treated successfully with tocilizumab. No immune effector cell-associated neurotoxicity syndrome (ICAN) or infectious complications appeared. Already 1 month post-therapy the patient reported marked improvement of her wellbeing and a 4kg bodyweight gain. Skin thickening was only mild in this patient but also improved early from modified Rodnan skin score (mRSS) 7 to 2. In the lung function test FVC and DLCO SB improved from 66% to 69% and 26% to 32%, respectively. Moreover, we detected normalization of sensitive troponin levels, which had been enhanced ever since diagnosis

Conclusions: This is the first report of a successful monotherapy with CD19 targeting CAR T cells in a SSc patient with severe gastrointestinal manifestation. Although it is only a short follow-up we can report an improvement with weight gain, which is essential in our SSc patients

P.322

BRENTUXIMAB VEDOTIN FOR SKIN INVOLVEMENT IN REFRACTORY DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS, AN OPEN-LABEL TRIAL WITH HISTORICAL CONTROLS

Andreu Fernandez-Codina¹, Tatiana Nevskaya¹, Murray Baron², C Thomas Appleton¹, Matthew J Cecchini³, Iago Pinal-Fernandez⁴, Janet Pope¹

¹Division of Rheumatology, Western University, London, CANADA, ²Division of Rheumatology, Jewish General Hospital, McGill University, Montreal, CANADA, ³Division of Pathology, Western University, London, CANADA, ⁴National Institute of Arthritis and Musculoskeletal and Skin Diseases, Muscle Unit, Bethesda, USA

Introduction: Systemic sclerosis (SSc) is a rheumatologic disorder in need of effective treatment for skin involvement. Brentuximab vedotin is an anti-CD30 chimeric drug conjugate approved for the treatment of lymphoma. The presence of CD30+ lymphocytes in patients with SSc makes them a potential novel target.

Material and Methods: This is a phase II proof-of-concept open-label trial exploring the use of brentuximab vedotin at a dose of 0.6 mg/Kg q3 weeks for 48 weeks in patients with severe active diffuse cutaneous SSc. Patients had a modified Rodnan skin score (mRSS) greater or equal than 15, less than5 years of disease duration (first non-Raynaud’s symptom) and/or skin worsening despite treatment. The primary endpoint was a reduction equal or greater than 8 points in mRSS at 48 weeks. The secondary endpoint was a reduction equal or greater than 8 points in mRSS at 24 weeks. Change in % forced vital capacity (%FVC) and the composite response index in diffuse cutaneous systemic sclerosis (CRISS) were also assessed. Results were compared to matched historic controls from the Canadian Scleroderma Research Group registry. Data analysis was performed using the intention to treat method for the main endpoint, and the per protocol method for the comparisons with controls.

Results: Eleven patients were treated brentuximab vedotin, with a mRSS decrease of 11.3 (95% CI 6.9, 15.8; p=0.001) after 48 weeks of treatment, and 4.3 (95% CI 0, 8.5, p=0.050) after 24 weeks. Seven patients had a mRSS reduction of equal or greater than 8 points. Twenty-six age, disease duration, mRSS-matched SSc patients were used as controls. The treatment group had similar baseline features to the ones observed for controls. Compared to controls, change in mRSS significantly improved in patients receiving brentuximab vedotin after 48 weeks (-11.3 vs -0.7; p<0.01), Table 1. Change in %FVC also favored brentuximab vedotin (7.8 vs -4; p=0.033). The CRISS score was equal or greater than 0.6 in 86% of patients treated with brentuximab vedotin, supporting the beneficial effect of the treatment. No severe adverse effects were attributed to brentuximab vedotin. There were two dropouts unrelated to treatment.

Conclusions: Treatment with brentuximab vedotin improved skin involvement along with lung function in SSc patients. No new safety concerns were raised. Future controlled trials will have to redemonstrate these promising results.

P.323

SELEXIPAG FOR THE TREATMENT OF SEVERE DIGITAL VASCULOPATHY IN SYSTEMIC SCLEROSIS: LONG-TERM CLINICAL AND PERFUSION RESULTS

Marco Di Battista, Alessandra Della Rossa, Marta Mosca

Rheumatology Unit - University of Pisa, Pisa, ITALY

Introduction: Systemic sclerosis (SSc) is characterized by a severe vasculopathy which typically determines burdensome manifestations as Raynaud’s phenomenon (RP) and digital ulcers (DUs). Sometimes, some patients are resistant to standard vasoactive therapies or cannot take them due to contraindications or intolerance. Selexipag is an oral selective IP prostacyclin receptor agonist approved for the treatment of SSc-related pulmonary arterial hypertension. Given its action on the prostacyclin pathway and some encouraging preliminary results, we aimed to evaluate the long-term clinical and instrumental efficacy of selexipag in SSc digital vasculopathy.

Material and Methods: Selexipag was administered to SSc patients who presented severe digital vasculopathy with RP and/or DUs impairing daily activities and when all the other vasoactive therapies were ineffective or contraindicated. The drug was titrated up to the maximum tolerated dose, without modifications to other ongoing vasoactive therapies. Each patient was evaluated at baseline and after three, six and twelve months. Clinical outcomes regarding RP and DUs, and digital perfusion evaluated by laser speckle contrast analysis (LASCA) were assessed.

Results: Selexipag was administered to 8 SSc patients (62.5% female, mean age 50.1 ±16.3 years, mean disease duration 13.1 ±10 years). No new safety issues emerged; however, one patient had an increase in transaminases which resolved after discontinuation of concomitant endothelin-receptor antagonist therapy. Taking into account seasonal variability, after one year of selexipag administration we observed a significant reduction in RP daily episodes (p<0.001) and RP mean duration (p=0.01). All DUs (n.10) completely healed at six months (p=0.03). As showed in Figure 1, during the treatment with selexipag it was observed a mean LASCA finger perfusion gradual increase, thus obtaining a significant improvement from 37.3 ±16.9 PU of the baseline to 76 ±21.9 PU after one year (p= 0.004). Male patients presented worse perfusion benefit, which instead was inversely correlated with age (r=-0.78, p=0.03). Clinical and perfusion outcomes were significantly better in patients with anti-centromere positivity, active capillaroscopy pattern and with DUs at baseline.

Conclusions: Following our previous preliminary results, we report long-term data on the use of selexipag for SSc digital vasculopathy. Selexipag showed a good safety profile and a significant improvement in clinical manifestations and digital perfusion without the influence of seasonal variability. These encouraging results have to be confirmed by new trials designed for the evaluation of selexipag efficacy in SSc digital vasculopathy.

P.324

ARSENIC TRIOXIDE DEMONSTRATES EFFICACY IN A MOUSE MODEL OF PRECLINICAL SYSTEMIC SCLEROSIS

Anne Cauvet¹, Arthur Decellas¹, Christophe Guignabert^3,4, Dominique Rongvaux-Gaïda⁵, Raphaël Thuillet^3,4, Mina Ottaviani^3,4, Ly Tu^3,4, François Rieger⁵, Jérôme Avouac^1,2, Yannick Allanore^1,2

¹Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, FRANCE, ²Université de Paris, Rheumatology Department, Cochin Hospital, Paris, FRANCE, ³INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, Le Plessis Robinson, FRANCE, ⁴Université Paris-Saclay, Faculté de Médecine, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Le Kremlin Bicêtre, FRANCE, ⁵MEDSENIC SAS, Strasbourg, FRANCE

Introduction: Uncontrolled T-cell activation plays a key role in systemic sclerosis (SSc). Arsenic trioxide (ATO) has immunological effects and has demonstrated potential in preclinical SSc models. In this study, we assessed the efficacy of ATO in Fra2 transgenic (Fra2TG) mice, which develop severe vascular remodeling of pulmonary arterioles and nonspecific interstitial pneumonia-like lung disease, closely resembling human SSc-associated pulmonary hypertension, therefore partially resembling to the SSc human disease.

Material and Methods: The efficacy of ATO in Fra2TG mice was evaluated through histological scoring and determination of cell infiltration. Fibrotic changes in the lungs were assessed by measuring collagen content biochemically, using second harmonic generation to measure fibrillar collagen, and imaging via computed tomography. Cardiovascular effects were determined by measuring right ventricular systolic pressure and vessel remodeling. The mechanism of action of ATO was then investigated by analyzing lung cell infiltrates using flow cytometry and bulk RNA with sequencing techniques.

Results: After ATO treatment, the Ashcroft histological score was substantially decreased by 33% in ATO-treated mice compared to control mice. Other investigations of fibrotic markers showed a trend of reduction in various measurements of fibrosis, but the differences did not reach significance. Further cardiovascular investigations revealed convergent findings supporting a beneficial effect of ATO, with reduced right ventricular systolic pressure and medial wall thickness, and a significant decrease in the number of muscularized distal pulmonary arteries in ATO-treated Fra2TG mice compared to untreated Fra2TG mice. Additionally, Inflammatory cell infiltration was also markedly reduced in lesioned lungs. A reduction in the frequency of CD4+ and T effector memory cells, and an increase in the percentage of CD4+ T naive cells in the lungs of ATO-treated Fra-2TG mice, was observed when compared to PBS group- Fra-2Tg mice. RNA-seq analysis of ATO-treated mouse lungs revealed a downregulation of biological pathways associated with immune activity and inflammation, such as T-cell activation, regulation of leucocyte activation, leucocyte cell-cell adhesion and regulation of lymphocyte activation.

Conclusions: Our results suggest the clinical relevance of ATO treatment in SSc. Using the Fra2TG mouse model, we observed significant lung histological changes, a trend towards a decrease in various fibrotic makers, and a strong reduction in vascular remodeling. The mechanism of action of ATO appears to involve a marked counteraction of the immune activation characteristic of SSc, particularly T-cell involvement. These findings pave the way for further studies in SSc.

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INTRAVENOUS IMMUNOGLOBULIN’S ROLE IN THE MANAGEMENT OF CHRONIC DIARRHEA IN SYSTEMIC SCLEROSIS: A CASE SERIES REPORT

Maria João Cadório, João Oliveira, Marcelo Neto, Fernando Albuquerque, Maria João Salvador, Tânia Santiago

Centro Hospitalar Universitário de Coimbra, Coimbra, PORTUGAL

Introduction: Gastrointestinal (GI) symptoms of systemic sclerosis (SSc), including chronic diarrhea, are prevalent, underestimated, and difficult to treat, leading to significant morbimortality. Typical management of these symptoms focuses on symptomatic control. However, recently, several case reports have indicated that intravenous immunoglobulin (IVIG) treatment yields favorable outcomes.

Material and Methods: We present two SSc patients attending our Rheumatology department, with severe incapacitating GI symptoms resistant to general immunosuppressive and symptomatic treatment. The recently validated Portuguese version of the University of California at Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract 2.0 (UCLA-SCTC-GIT 2.0) score was used to evaluate GI symptoms pre- and post-treatment with IVIG

Results: Case 1 - A 28-year-old female with a 3-year duration diffuse cutaneous SSc (dcSSc) characterized by Raynaud's phenomenon and digital ulcers, presented with severe persistent acid reflux, regurgitation, daily nausea and vomiting, and 4-5 daily bowel movements with severe cramping, in the past year. She had little relief with standard symptomatic treatment. Digestive endoscopic studies identified nodular lymphoid hyperplasia of the ileum and chronic gastritis. She consented to treatment with IVIG 2g/kg for 3 days, noticing symptomatic improvement the following 6 weeks. After two months, she underwent an identical round of IVIG, both without any reported complications. At 6-month follow-up consultation, the patient sustained improvement in GI symptoms, including 2 weeks symptom-free period following treatment. The UCLA-SCTC-GIT 2.0 score showed no benefits from pre- to post-treatment.

Case 2 - A 39-year-old man with dcSSc involving cutaneous, cardiac, and vascular system, has been complaining of anorexia, diarrhea (5 times daily), and unintentional weight loss, resistant to immunosuppressive and symptomatic therapy for the past 6 months. Upper GI endoscopy and colonoscopy revealed only non-specific colitis. The breath test for small intestinal bacterial overgrowth, fecal calprotectin and elastase were negative. He agreed to a course of IVIG (2g/kg/cycle over 5 days), with no complications. After the first cycle, there was immediate symptomatic improvement and the patient remained with 2 bowel movements daily at 1-month follow-up. The UCLA-SCTC-GIT 2.0 score remained unaltered.

Conclusions: Both patients reported fewer bowel movements, which allowed for better quality of life, despite no significant improvement in the UCLA-SCTC-GIT 2.0 score.

The IVIG treatment has shown promising results in the management of GI symptoms in this population, hopefully bringing relief to SSc patients. However, multicenter randomized placebo-controlled trials are needed.

NOTE: 1st and 2nd authors are equally contribuiting authors,

P.326

TARGETING IL-6 TO TREAT SKIN FIBROSIS: TWO CASES OF GROOVE SIGN RESOLUTION IN EOSINOPHILIC FASCIITIS

Virginia Berlengiero¹, Roberto D'Alessandro¹, Estrella Garcia Gonzalez¹, Francesca Bellisai¹, Giacomo Maria Guidelli², Bruno Frediani¹, Enrico Selvi¹

¹Rheumatology Unit - University Hospital of Siena, Siena, ITALY, ²Rheumatology and Clinical Immunology - IRCCS Humanitas Rozzano, Milano, ITALY

Introduction: Skin fibrosis is the clinical hallmark of several scleroderma-spectrum disorders including systemic sclerosis and eosinophilic fasciitis (EF).

EF is a rare syndrome which primarily affects the muscular fascia, the skeletal muscle, and the skin of arms and legs. The groove sign, represented by a linear depression along the superficial vein course of the extremities, is a characteristic feature of EF.

Although the etiology of EF and other fibrosing diseases remains unclear, some fibrogenic and inflammatory cytokines including tumour growth factor β, interleukin 1, and interleukin 6 (IL-6) seem to be involved in the pathological process.

Material and Methods: We describe two typical EF cases whose clinical improvement induced by the anti-IL-6 receptor antagonist tocilizumab (TCZ) has been accompanied by a complete resolution of the groove sign.

Results: Two middle aged men in overall good clinical conditions presented to our outpatient clinic complaining skin induration, joint stiffness, myalgia, and malaise. Clinical examination revealed fibrotic skin and vascular grooves on the extremities, while blood chemistry showed hypereosinophilia, polyclonal hypergammaglobulinemia, and increased inflammatory markers and muscle enzymes. In both cases, after excluding other inflammatory-fibrosing diseases, a full thickness lesional biopsy was performed and the histopathological findings confirmed the clinical suspicion of EF. Since the first line treatment with prednisone and methotrexate did not lead to a clinical improvement, both patients started subcutaneous TCZ at a dosage of 162 mg weekly. TCZ led to clinical and biohumoral remission within 4 months, allowing prednisone tapering to 5 mg/day in the following 8 months.

After 12 months of treatment, a complete groove sign resolution and no evolution of the disease were observed, with just a residual asymptomatic skin induration of the arms and the legs remaining.

Conclusions: In both patients, the clinical improvement obtained with TCZ was accompanied by a complete groove sign remission.

These results are in line with the growing number of data showing IL-6 blockade efficacy in the treatment of fibrosing connective tissue diseases, and strengthen the evidence that TCZ should be considered for the management of such disorders.

Additionally, we suggest that the groove sign evolution could represent a useful tool to monitor EF disease activity and treatment response.

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A PHASE I/II DOSE ESCALATION STUDY TO ASSESS THE EFFECT OF RESOLVIX ON SAFETY, TOLERABILITY AND EARLY CLINICAL EFFICACY IN ADULT PATIENTS WITH DIFFUSE SYSTEMIC SCLEROSIS

Susanne Behlke¹, Melanie Couturier¹, Sylvain Perruche^1,2, Marie-Elise Truchetet^3,4

¹Med Inn Pharma, Besancon, FRANCE, ²Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire, Besancon, FRANCE, ³Univ. Bordeaux, CNRS, ImmunoConcEpT, UMR 5164, Bordeaux, FRANCE, ⁴CHU de Bordeaux, FHU ACRONIM, Centre national de référence des maladies auto-immunes et systémiques rares Est/Sud-Ouest, Bordeaux, FRANCE

Introduction: Systemic sclerosis is a chronic and progressive disease with the highest morbidity and mortality among all autoimmune diseases without any approved drug, indicating a high unmet medical need for the development of novel disease-modifying therapies.

Currently, the most promising and potentially disease modifying therapeutic approach, able to target the complex disease driving the pathophysiology of systemic sclerosis, is stem cell transplantation. While stem cell and cell therapies not only underly complex regulatory requirements, they might only be offered to selected patients. Secretomes, the molecules released by specialized cells, might provide a simpler and yet potentially safer approach for transmitting the promising therapeutic effects of cell therapies.

We have developed a stable and potentially disease modifying drug candidate, by harnessing the secretome of resolution-type macrophages, a specialized cell type with a prominent role in reestablishing immune and tissue homeostasis, regeneration and wound repair. The latter being dysregulated in many complex autoimmune diseases, like systemic sclerosis.

Harnessing this specialized secretome into a drug candidate has been shown to provide durable and systemic effects in various pre-clinical models, demonstrated via the reprogramming of macrophages reestablishing efferocytosis (elimination of dead and dying cells) in disease-affected tissues, accompanied by de novo generated antigen-specific Tregs and most importantly pro-fibrolyic activities.

The no-observed-adverse-effect level (NOEL) of our drug candidate RESOLVIX has been established in large animal models to guide a dose escalation study in patients. A GMP production process for this complex biologic secretome drug candidate has been approved by French authorities in association with a clinical development plan in patients with diffuse cutaneous Sclerosis.

Material and Methods: This will be a first-in human Ph1/2 open-label, dose escalation study in adult patients with diffuse systemic sclerosis. Dose escalation will be guided by a standard 3 + 3 dose-escalation design up to a maximum dose of 20 ml/kg to establish the Maximum Tolerated Dose (MTD). The drug will be applied i.v.. The primary endpoint will be safety measured by dose limiting toxicities (DLT). Secondary objectives will assess exploratory efficacy using CRISS, mRSS, FVC, QoL and selected biomarkers, up to 12 month. The study will include patients with diffuse cutaneous involvement and is expected to start enrolling 21 patients in France by Q4 2024.

Results: Results of this study are highly anticipated.

Conclusions: Results will allow progressing the clinical development of an innovative and potentially diseases modifying and safe biologic drug product for patients with diffuse cutaneous Sclerosis.

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A NOVEL THERAPEUTIC OPPORTUNITY IN SYSTEMIC SCLEROSIS: THE FIBROLYTIC ACTIVITIES OF A SPECIALIZED MACROPHAGE SECRETOME

Susanne Behlke¹, Francis Bonnefoy^1,2, Sylvain Perruche^1,2

¹MED INN PHARMA, Besancon, FRANCE, ²niv. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire, Besancon, FRANCE

Introduction: Systemic sclerosis (SSc) a complex and rare immune-mediated connective tissue disorder characterized by microvascular damage, inflammatory cell infiltration, and excessive deposition of extracellular matrix proteins (ECMs) resulting in fibrosis of the skin and internal organs.

Like for many chronic inflammatory diseases the failure of achieving the resolution of inflammation programs is linked to dysfunctional macrophage activity and with that a main disease driver of disease progression in affected organs.

The objective of our preclinical study was to evaluate in experimental models of SSc the therapeutic activities and its main mechanisms by which a resolution-type macrophage secretome, Resolvix, is able to reinstate and normalize macrophage function and to drive resolution of inflammation.

Material and Methods: Two established preclinical models of SSc (bleomycin [BLM] and HOCl) were used to monitor the impact of the injection of resolution-type macrophage secretome (Resolvix) on skin (thickness and collagen deposition), lung (leucocyte infiltration and macrophage efferocytosis properties) and lymphoid organs (Tregs) as well as selected proteins and metalloproteases (MMPs). A single treatment at predetermined therapeutic activity or respective controls were administrated intravenously at week 3 post disease induction and mice were monitored daily and sacrificed for analysis 3 weeks after treatment.

Results: In both models we could show a significant reduction of skin thickening and collagen deposition in skin samples after only a single administration of when compared to controls. Leucocyte infiltrates particularly evident in the HOCl model were significantly reduced by the Resolvix treatment in skin and lung tissues. Furthermore, Resolvix treatment restored the efferocytosis activity in alveolar macrophages collected from broncho-alveolar lavage (BAL) fluids that were significant reduced in these models as sign of uncontrolled ongoing chronic inflammation, and recently reported in SSc patients. Efferocytosis capacities were restored to comparable levels as detected in healthy mice. Adoptive transfer of in vivo targeted macrophages confirmed their durable reprogramming conveying the therapeutic activity. In fibrotic skin lesion we detected an increased metalloprotease activity notably MMP9 that was restricted to fibroblasts.

Conclusions: Collectively our preclinical data demonstrate that targeting dysfunctional macrophages with a secretome harnessed from specialized resolution-type macrophages to durably revert disease activity measured as skin fibrosing, inflammatory cell infiltration and defective macrophage efferocytosis and function is possible and might represent a novel and innovative therapeutic approach in SSc.

Our resulting drug candidate Resolvix may be considered as a next generation cell-free and disease modifying biological drug candidate for further development for the treatment of SSc.

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EFFECTS OF B CELL DEPLETION BY CD19-TARGETED CAR-T CELLS IN A MURINE MODEL OF SYSTEMIC SCLEROSIS

Jérôme Avouac¹, Anne Cauvet², Cindy Orvain², Morgane Boulch³, Philippe Bousso³, Yannick Allanore¹

¹Rheumatology department and INSERMU1016, Cochin Hospital, Paris, FRANCE, ²INSERM U1016, Paris, FRANCE, ³Dynamics of Immune Responses Unit, Institut Pasteur, INSERM U1223, Paris, FRANCE

Introduction: We aimed at assessing the efficacy and tolerance of two B cell depletion strategies, including one with CD19-targeted CAR-T cells, in a preclinical model mimicking the severe lung damages observed in SSc.

Material and Methods: B-cell depletion strategies were evaluated in the Fra-2 transgenic (Tg) mouse model. We considered a first group of 16 untreated mice, a second group of 15 mice receiving a single intravenous (IV) dose (50ug) of anti-CD20 monoclonal antibody (mAb) at day 1 and a third group of 8 mice receiving 50ug anti-CD20 mAb IV at day 1 followed by the IV injection of 20*106 CD19-targeted CAR-T cells at day 3. After 6 weeks of clinical evaluation, different validated markers of inflammation, lung fibrosis and pulmonary vascular remodeling were assessed.

Results: Following treatment with anti-CD20 mAb, CD19 expression was significantly decreased in peripheral blood and lesional lungs of Fra-2 Tg mice. B cell depletion was even more pronounced in mice treated with CD19-targeted CAR-T cells (92% and 85% reduction in peripheral blood and lungs respectively, p<0.001). CAR-T cell infusion worsened clinical score and increased mortality in Fra-2 Tg mice. In line with the above findings, mice receiving CD19-targeted CAR-T cells displayed a significant increase in lung density (mean difference of 5528 Hounsfield Units, p=0.038) and a marked reduction of functional residual capacity (mean difference of 25±9%, p=0.041) as compared to control Fra-2 when assessed by chest micro-CT imaging. CAR-T cell infusion significantly increased lung collagen content (mean difference of 11.93±4.44 ug/mL, p=0.020), histological fibrosis score (mean difference 1.74±0.48, p=0.002) and right ventricular systolic pressure mean difference 8.52±2.70 mmHg, p=0.013). CAR-T cells accumulated in lesional lungs and promoted T infiltration and activation: a significant increase of CD4+ effector memory T cells was observed in CD19-targeted CAR-T cell-treated Fra-2 Tg mice compared to Fc control Fra-2 Tg mice. Moreover, the fraction of CD69 and PD1-expressing cells was significantly increased within the CD4+ and CD8+ subsets in the lung of CD19-targeted CAR-T cell-treated Fra-2 Tg mice. In addition, the levels of inflammatory cytokines IL6, TNFa and IFNg were markedly elevated in the lesional lungs of mice treated with CAR-T cells. Monotherapy with anti-CD20 mAb had no impact on lung inflammation-driven fibrosis and pulmonary hypertension.

Conclusions: B-cell therapies failed to show efficacy in the Fra2 transgenic mice. The exacerbated Fra-2 lung inflammatory burden stimulated accumulation and expansion of activated CD19-targeted CAR-T cells, secondarily inducing T-cell activation and systemic inflammation, finally leading to disease worsening.

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A NEW APPROACH FOR PROCEDURAL SEDOANALGESIA WITH TARGET CONTROLLED INFUSION OF KETAMINE AND PROPOFOL IN PATIENTS WITH SYSTEMIC SCLEROSIS UNDERGOING AUTOLOGOUS FAT TRANSPLANTATION

Amelia Spinella¹, Alessandro Carratta², Raimondo Feminò², Valentina Pinto^3,4, Marco de Pinto¹, Melba Lattanzi³, Ottavio Secchi¹, Gabriele Amati¹, Martina Orlandi^1,4, Luca Magnani⁵, Giulia Bernante³, Giorgio De Santis³, Gilda Sandri^1,4, Dilia Giuggioli^1,4

¹Scleroderma Unit, Rheumatology Unit, University Hospital of Modena, University of Modena and Reggio Emilia, Modena, ITALY, ²Anesthesiology-Rescuscitation and Intensive Care Unit, University Hospital of Modena, University of Modena and Reggio Em, Modena, ITALY, ³Plastic and Reconstrucitve Surgery Unit, University Hospital of Modena, University of Modena and Reggio Emilia, Modena, ITALY, ⁴Department of Medical and Surgical Sciences of Children and Adults, University of Modena and Reggio Emilia, Modena, ITALY, ⁵IRCSS Arcispedale Santa Maria Nuova Reggio Emilia, Reggio Emilia, ITALY

Introduction: The methods of oral/digital autologous fat transplantation (lipofilling) could enhance functional/aesthetic outcomes in Systemic Sclerosis (SSc), but undergoing this surgical procedure is painful and requires adequate sedation. Target Controlled Infusion (TCI) with propofol and remifentanil is a well-established anaesthetic technique, while procedural sedation and analgesia (PSA) with ketamine and propofol is less studied. We propose a new protocol for procedural analgesia, inducing a moderate to deep sedation for complete analgesia, amnesia and allowing a safe discharge for outpatients with SSc who undergo lipofilling procedures. The research leading to these results has received funding from MUR under PNRR M4C2I1.3 Heal Italia project PE00000019 CUP E93C22001860006 University of Modena and Reggio Emilia to Prof. Dilia Giuggioli.

Material and Methods: 23 SSc patients underwent oral/digital lipofilling between July 2022 and May 2023. After obtaining informed consent, patients were monitored with ECG/SpO2/NIBP and BIS. A peripheral venous access device was applied and TCI with 2-4mcg/ml target propofol at effect-site (Schnider) and ketamine with 400-600 ng/ml target at effect-site (Kamp) were administered. Patients had spontaneous breathing with supplemental oxygen delivered with nasopharyngeal cannula (4L/min). While the synergy between propofol and remifentanil, and the risk of excessive sedation leading to respiratory depression and hypotension are well known, such risks are less frequent when combining ketamine and propofol. The Bispectral Index, which is usually employed for monitoring the level of propofol-remifentanil sedation, was registered so as to assess the suitable range for ketamine-propofol PSA. Vital parameters were monitored every 5 minutes for potential complications (hypotension=<65 mmHg in average BP, hypoxia=SpO2<92%). 15 mg of 1 g/ketorolac Paracetamol was administered for post-surgery analgesia. 22 SSc patients who underwent lipofilling with propofol/remifentanil sedation were enrolled as control group.

Results: All patients underwent successful surgery and postoperative hospitalisation was not necessary. We compared the group of patients sedated with ketamine and propofol against the one where propofol and refentanil were administered. Preliminary data indicate that patients sedated with ketamine and propofol displayed fewer episodes of hypotension and desaturation, but awakening times were longer. No differences were found regarding usage and amount of propofol, postoperative pain, time of discharge from recovery room or postoperative patient satisfaction.

Conclusions: TCI with ketamine and propofol could be a promising anaesthetic approach for guaranteeing procedural sedation and analgesia during surgery in SSc patients and fewer cardiac and respiratory complications compared to propofol and remifentanil. Further data are necessary for evaluating the incidence of severe complications and the level of patient satisfaction.

P.331

TREATMENT WITH AUTOLOGOUS BONE MARROW TRANSPLANTATION IN PROGRESSIVE SYSTEMIC SCLEROSIS CASE

Esra Firat Senturk¹, Tugrul Elverdi², Serdal Ugurlu¹

¹Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Department of Internal Medicine, Division of Rheumatology, Istanbul, Turkey, ²Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Department of Internal Medicine, Division of Hematology, Istanbul, Turkey

Introduction: Autologous bone marrow transplantation can be a treatment option for patients with progressive systemic sclerosis, characterized by severe cutaneous fibrosis with multiorgan manifestation. In this case, we will present the clinically satisfactory outcome of an autologous bone marrow transplantation treatment due to progressive skin, cardiac, and pulmonary involvement.

Case: A twenty-one-year-old female patient presented in 2019 with Raynaud's phenomenon, sclerodactyly, and widespread digital ulcers. She was diagnosed with systemic sclerosis with negative ANA antibody titers and an extractable nuclear antigen (ENA) panel. Subsequently, she was started on nifedipine, pentoxifylline, acetylsalicylic acid, and methotrexate treatment. Initial assessment revealed gastroesophageal reflux, distal esophageal hypoperistalsis, and interstitial lung disease characterized by subpleural bilateral reticular densities. In June 2020, the patient developed shortness of breath and widespread muscle weakness with elevated Troponin (200 x reference value) and creatine kinase levels (CK=3865 IU/l). Transthoracic echocardiography revealed reduced ejection fraction (EF: 40%) and global myocardial hypokinesia. Electromyography (EMG) showed myopathic abnormalities characterized by marked widespread spontaneous activity in proximal muscles. As a concern for potential pulmonary hypertension, right heart catheterization was performed. An average pulmonary artery pressure was 16 mm-Hg, and pulmonary artery wedge pressure was eight mm-Hg. Accounting for the findings suggesting myositis, myopericarditis, and interstitial lung disease, the patient received pulse steroids, intravenous immunoglobulin, and Rituximab courses. Due to the progressive nature of the disease and treatment resistance, autologous bone marrow transplantation was decided by the consensus of the Rheumatology and Hematology Council. Mobilization regimen was carried out with 2 g/m2 cyclophosphamide (i.v.), dexamethasone (i.v.), and subcutaneous granulocyte-colony stimulating factor (G-CSF) according to the bone marrow transplant protocol, followed by 200 mg/kg cyclophosphamide (i.v.) and anti-thymocyte globulin (i.v.) treatment for lymphoablation.

Conclusion: The patient's heart failure and widespread myositis-associated symptoms ultimately resolved after autologous bone marrow transplantation. The ejection fraction was restored to the normal range (EF: 60%). Findings of severe cutaneous and subcutaneous fibrosis manifested by bilateral hand contractures were satisfactorily improved. In the first year following autologous bone marrow transplantation, no additional treatment was required due to prolonged lymphopenia. At this stage, she is undergoing mycophenolate mofetil (p.o) treatment with good tolerance.

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NAILFOLD VIDEOCAPILLAROSCOPY IN PATIENTS WITH SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE (SSC-ILD)

Vanessa Smith¹, Christopher P Denton², Ariane L Herrick³, Carina Ittrich⁴, Margarida Alves⁵, Maurizio Cutolo⁶

¹Ghent University Hospital and Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center (IRC), Ghent, BELGIUM, ²University College London Division of Medicine, Centre for Rheumatology and Connective Tissue Diseases, London, UNITED KINGDOM, ³Centre for Musculoskeletal Research, The University of Manchester, Northern Care Alliance NHS Foundation Trust, Manchester, UNITED KINGDOM, ⁴Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, GERMANY, ⁵Boehringer Ingelheim International GmbH, Ingelheim am Rhein, GERMANY, ⁶Laboratory of Experimental Rheumatology, University of Genova, IRCCS San Martino Polyclinic, Genova, ITALY

Introduction: Microvascular damage is part of the pathogenesis of systemic sclerosis (SSc). A reduction in the number of capillaries has been associated with progression of organ damage in patients with SSc. In a sub-study of the SENSCIS trial of nintedanib versus placebo in patients with SSc-ILD, we assessed changes in capillary density in patients who had risk factors for ILD progression at baseline or who experienced ILD progression over 52 weeks of the trial.

Material and Methods: The SENSCIS trial enrolled patients with SSc with first non-Raynaud symptom in the prior </=7 years and an extent of fibrotic ILD on high-resolution computed tomography >/=10%. Patients were randomised to receive nintedanib or placebo. In a sub-study, nailfold videocapillaroscopy (NVC) was performed at baseline and weeks 12, 24, 36 and 52. Images from all 8 fingers were assessed by a central reader. We assessed mean capillary density (number of capillaries/mm) in patients with risk factors for rapid FVC decline (<18 months since first non-Raynaud symptom, elevated inflammatory markers [C-reactive protein >/=6 mg/L and/or platelets >/=330 x 10*9/L], or mRSS >18) at baseline and in patients who had ILD progression (absolute decline in FVC % predicted >5% or death) from baseline to week 52. Data are presented descriptively as mean (SD) per patient.

Results: Of 120 patients in the NVC sub-study, 68 had risk factors for rapid FVC decline at baseline and 24 had ILD progression over 52 weeks. Among 35 patients with risk factors for rapid FVC decline who had NVC data at baseline, mean (SD) capillary density at baseline was 5.2 (1.9) capillaries/mm. A numerical reduction in mean capillary density over 52 weeks was observed in patients with risk factors for rapid FVC decline at baseline who received placebo, but not in those who received nintedanib (Figure). Among 13 patients with ILD progression over 52 weeks who provided NVC data at baseline, mean (SD) capillary density at baseline was 5.4 (1.9) capillaries/mm. In this subgroup, a numerical stabilization in mean capillary density was seen in the placebo group and a numerical augmentation in the nintedanib group (Figure).

Conclusions: In a sub-study of the SENSCIS trial,there was a suggestion of a beneficial effect of nintedanib on NVC. These analyses were limited by the small number of patients providing NVC data at baseline and week 52 and by the short observation period.

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VITALISSCE™: A PHASE II STUDY OF BI 685509, A NOVEL SOLUBLE GUANYLATE CYCLASE ACTIVATOR, IN PATIENTS WITH SYSTEMIC SCLEROSIS

Dinesh Khanna¹, Jeska de Vries-Bouwstra², Anna-Maria Hoffmann-Vold³, Masataka Kuwana⁴, Andrea LH Low^5,6, Susanna Proudman⁷, Mary Flack⁸, Tobias Litzenburger⁹, Nora Fagan¹⁰, Oliver Distler¹¹

¹University of Michigan Scleroderma Clinic - Department of Internal Medicine, Ann Arbor, USA, ²Leiden University Medical Center - Department of Rheumatology, Leiden, THE NETHERLANDS, ³Oslo University Hospital - Department of Rheumatology, Oslo, NORWAY, ⁴Nippon Medical School Graduate School of Medicine - Department of Allergy and Rheumatology, Tokyo, JAPAN, ⁵Singapore General Hospital - Department of Rheumatology and Immunology, SINGAPORE, ⁶Duke-National University of Singapore Medical School, SINGAPORE, ⁷University of Adelaide - Discipline of Medicine and Royal Adelaide Hospital - Rheumatology Unit, Adelaide, AUSTRALIA, ⁸Boehringer Ingelheim Pharmaceuticals, Inc. - TA Inflammation Medicine, Ridgefield, USA, ⁹Boehringer Ingelheim Pharma GmbH & Co. KG - TMCP Therapeutic Areas, Biberach, GERMANY, ¹⁰Boehringer Ingelheim Pharmaceuticals, Inc. - Global Biostatistics & Data Sciences, Ridgefield, USA, ¹¹University Hospital Zurich, University of Zurich - Department of Rheumatology, Zurich, SWITZERLAND

Introduction: Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease characterised by skin and organ fibrosis, and fibroproliferative microvascular changes. The soluble guanylate cyclase (sGC) pathway has been implicated in the pathogenesis of SSc. The sGC pathway improves vascular endothelial function and reduces fibroblast activation beyond smooth muscle relaxation in preclinical models. While several trials have examined the immunological aspects of SSc, few have targeted the fibro-vascular axis that underlies SSc manifestations. The Phase II VITALISScE™ study (NCT05559580) is assessing the efficacy, safety and tolerability of BI 685509, an sGC activator, in patients with early progressive SSc and vasculopathy.

Material and Methods: We reviewed published literature to identify clinical outcomes and biomarkers predictive of rapid fibrosis progression, focusing on vasculopathy features associated with skin and lung fibrosis. We established a hierarchy of endpoints to investigate whether amelioration of vascular symptoms could improve lung function and skin fibrosis.

Results: The VITALISScE™ study (Figure 1) is an ongoing, 48-week, multicentre (165 sites; 38 countries), placebo-controlled, double-blind, parallel-group Phase II clinical trial. To date, 94 patients have enrolled and 32 (of 200 planned) have been randomised who fulfil 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology SSc classification criteria. Patients must have SSc disease onset (first non-Raynaud’s phenomenon symptom) within 5 years of Visit 1, active progressive disease (new onset of SSc up to 2 years prior to Visit 1 or recent worsening of skin involvement or tendon friction rub), elevated biomarkers (C-reactive protein, erythrocyte sedimentation rate or KL-6), and evidence of significant vasculopathy. The primary objective is to demonstrate superiority of BI 685509 over placebo, based on the mean difference in annual rate of decline in forced vital capacity over 48 weeks. Secondary objectives are to assess absolute change from baseline at Week 48 in modified Rodnan skin score, Health Assessment Questionnaire–Disability Index score, and the proportion of responders based on the revised Composite Response Index in Systemic Sclerosis. Additional endpoints relate to vasculopathy, functioning and quality of life, safety, pharmacokinetics and exploratory biomarkers. Endpoints were chosen based on the literature review, suggesting them to be relevant and able to demonstrate treatment effects on fibrosis progression or vasculopathy.

Conclusions: The VITALISScE™ study is assessing the efficacy, safety and tolerability of BI 685509 in patients with early progressive SSc and vasculopathy. Results from this trial will inform further development of BI 685509 and future trial designs. The VITALISScE™ study (NCT05559580) is due to complete November 2025.

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EFFECTIVENESS OF NON-PHARMACOLOGICAL AND NON-SURGICAL INTERVENTIONS TO IMPROVE HEALTH OUTCOMES IN SYSTEMIC SCLEROSIS: A LIVING SYSTEMATIC REVIEW

Elsa-Lynn Nassar¹, Sophie Hu¹, Linda Kwakkenbos², Susan Bartlett³, Richard Henry¹, Marie-Eve Carrier¹, Jill Boruff⁴, Carina Boström⁵, Nicole Culos-Reed⁶, Marie Hudson³, David Leader⁷, Malin Mattsson⁵, Luc Mouthon⁸, Janet Pope⁹, Robyn Wojeck¹⁰, Elizabeth Yakes Jimenez¹¹, Amanda Wurz¹², Vanessa Malcarne¹³, Catherine Fortune¹⁴, Amy Gietzen¹⁵, Karen Gottesman¹⁵, Geneviève Guillot¹⁶, Amanda Lawrie-Jones¹⁷, Michelle Richard¹⁸, Maureen Sauvé¹⁹, Andrea Benedetti²⁰, Brett Thombs¹

¹Lady Davis Institute of Medical Research, Jewish General Hospital, Montreal, CANADA, ²Department of Clinical Psychology, Behavioural Science Institute, Radboud University, Nijmegen, THE NETHERLANDS, ³Department of Medicine, McGill University, Montreal, CANADA, ⁴Schulich Library of Physical Sciences, Life Sciences, and Engineering, McGill University, Montreal, CANADA, ⁵Department of Neurobiology, Care Sciences and Society, Division of Physiotherapy, Karolinska Institutet, Stockholm, SWEDEN, ⁶Faculty of Kinesiology, University of Calgary, Calgary, CANADA, ⁷Tufts University School of Dental Medicine, Boston, USA, ⁸Service de Médecine Interne, Centre de Référence Maladies Auto-immunes et Systémiques Rares d'Ile de France, Hôpital Coc, Paris, FRANCE, ⁹Bone & Joint Institute, University of Western Ontario, London, CANADA, ¹⁰School of Nursing, Duke University, Durham, USA, ¹¹University of New Mexico Health Sciences Center, Albuquerque, USA, ¹²School of Kinesiology, University of the Fraser Valley, Chilliwack, CANADA, ¹³Department of Psychology, San Diego State University, San Diego, USA, ¹⁴Ottawa Scleroderma Support Group, Ottawa, CANADA, ¹⁵National Scleroderma Foundation, Danvers, USA, ¹⁶Sclérodermie Québec, Montreal, CANADA, ¹⁷Scleroderma Australia, Melbourne, AUSTRALIA, ¹⁸Scleroderma Atlantic, Halifax, CANADA, ¹⁹Scleroderma Society of Ontario, Hamilton, CANADA, ²⁰Department of Epidemiology, Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, CANADA

Introduction: No known cure exists for systemic sclerosis (SSc; scleroderma). Therefore, a primary care goal is to reduce disability and maximize health-related quality of life. Non-pharmacological and non-surgical interventions (e.g., psychological, educational, rehabilitation, physiotherapy, diet) could be provided to potentially improve quality of life, but their effectiveness is not well understood. SSc patients often seek advice from healthcare providers about non-pharmacological interventions. However, SSc healthcare providers are not able to easily synthesize what is known or present it in a patient-friendly, easily comprehensible format. This poses a barrier to shared decision-making between patients and providers. In addition, individual trials, by themselves, do not typically provide the evidence needed for decision-making. We are conducting a “living” (i.e., continually updated) systematic review of evidence on the effects of non-pharmacological and non-surgical interventions on physical and mental health outcomes in SSc.

Material and Methods: Eligible studies are RCTs that examine non-pharmacological and non-surgical interventions in SSc. All RCTs included in a previous systematic review, that searched for trials through March 2014, were evaluated for inclusion. Additional trials are sought from that date onwards using a similar search strategy via MEDLINE, Embase, CINAHL, PsycINFO, Cochrane Library, and Web of Science. Two independent reviewers determine eligibility and extract data using a pre-specified standardized form. Meta-analyses will be done for interventions where there are at least 2 eligible RCTs that report similar health outcomes. For interventions where this is not possible, we will use qualitative synthesis.

Results: The database search yielded 1,617 unique titles and abstracts as of September 1, 2023. Of these, 1,539 were excluded after title and abstract review and 36 after full-text review, leaving 40 eligible primary studies, which were reported in 42 publications. These studies assessed exercise, physical or occupational therapy, or rehabilitation interventions (27 studies); oral health interventions (5 studies); body-focused interventions (2 studies); mental health interventions (3 studies); self-management interventions (2 studies); and support group leaders training interventions (1 study). Complete and updated results will be available at the time of presentation.

Conclusions: This project was prioritized by our Scleroderma Patient-centered Intervention Network (SPIN) patient partners, who have been involved in all the project stages. Preliminary findings show that most interventions were in the areas of exercise, physical or occupational therapy, and rehabilitation. We have not identified any pain interventions, which have been identified as a top intervention research priority by patients. Ongoing dissemination of results will be facilitated via posting to our project website (https://www.spinsclero.com/en/living-systematic-reviews).

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BASELINE DEMOGRAPHICS AND DISEASE CHARACTERISTICS IN A PHASE 2 STUDY TO EVALUATE EFFICACY, SAFETY, AND TOLERABILITY OF MT-7117 IN SUBJECTS WITH DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS

Dinesh Khanna¹, Patricia E Carreira², Lorinda S Chung³, Christopher P Denton⁴, Marco Matucci-Cerinic⁵, Gabriela Riemekasten⁶, Sakiko Mukai⁷, Yoshiari Yanai⁷, Shawn Liu⁷, Songjie Cai⁷, Tanya Bogoslovsk⁷

¹University of Michigan, Ann Arbor, USA, ²Hospital Universitario 12 de Octubre, Madrid, SPAIN, ³Stanford University School of Medicine, Stanford, California, USA, ⁴University College London and Royal Free Hospital, London, UNITED KINGDOM, ⁵University of Florence, Milan, ITALY, ⁶Charite University Hospital, Berlin, GERMANY, ⁷Mitsubishi Tanabe Pharma America, Inc., Jersey city, USA

Introduction: Dersimelagon (MT-7117), a novel synthetic, oral, selective melanocortin-1 receptor agonist, MT-7117 demonstrated disease-modifying effects in preclinical models of systemic sclerosis (SSc) by reducing inflammation, vascular dysfunction, and fibrosis. MT-7117 is as a potential therapeutic agent for the treatment of SSc. MT-7117-G02 (NCT04440592) is a Phase 2, multi-center, randomized, double-blind, placebo-controlled, 52-week parallel-group study to evaluate the efficacy, and safety of MT-7117 in subjects with diffuse cutaneous SSc (dcSSc). The objectives were to evaluate the demographics, baseline disease characteristics and the standard of care of the subjects randomized in MT-7117-G02 study to examine variability of these parameters by the geographic regions (North America [NA], Europe [excluding Poland], and Poland). Population in Poland was analyzed separately due to delayed inclusion in the study and the highest enrollment rate among the countries.

Material and Methods: 76 subjects were enrolled over 22 months at 33 sites in 8 countries. Eligible subjects were randomized 1:1 to either MT-7117 QD or matching placebo and stratified by the autoantibody status of anti-RNA Polymerase III at screening (positive or negative). The primary endpoint is the American College of Rheumatology Combined Response Index in diffuse cutaneous Systemic Sclerosis (ACR CRISS) composite score at Week 52. The study included subjects with dcSSc, age >= 18 years and a disease duration <= 5 years who were on a stable standard of care treatment and receiving one stable concomitant immunosuppressant (Mycophenolate/Mycophenolic acid [MMF], Methotrexate [MTX], Hydroxychloroquine [HCQ], or Azathioprine [AZA]). The subjects were also required to have a baseline Modified Rodnan skin score (mRSS) of 15-45 units and forced vital capacity (FVC%) predicted > 50%.

Results: The study population predominantly included middle-aged White females and approximately half were receiving one immunosuppressant (Table 1). MMF was the most frequently used immunosuppressant followed by MTX. Approximately ¾ of the subjects had normal CRP with comparable distribution across the regions. There were neither regional differences in the baseline mRSS nor in the predicted FVC%. The overall average frequency of anti-RNA Polymerase III antibody -positivity was 20.5%, with the lowest proportion in Poland (15.4%). The average frequency of anti-Scl-70 positivity was 50.7% with the lowest proportion in NA (23.5%). Subjects in NA were more likely to be on MMF.

Conclusions: There were no major imbalances in the baseline demographics or in the percentage on immunosuppressants among the three regions, although some variation in SSc autoantibody specificity were observed.

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A RANDOMIZED, PARALLEL-GROUP, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 3 STUDY OF THE TYPE I INTERFERON RECEPTOR ANTIBODY, ANIFROLUMAB, IN SYSTEMIC SCLEROSIS: DESIGN AND RATIONALE OF THE DAISY TRIAL

Dinesh Khanna¹, Christopher Denton², Shervin Assassi³, Masataka Kuwana⁴, Yannick Allanore⁵, Robyn Domsic⁶, Christi Kleoudis⁷, John Xu⁷, Eszter Csomor⁸, Caroline Seo⁹, Marius Albulescu⁸, Raj Tummala⁷, Hussein Al-Mossawi⁸, Rubana Kalyani⁷, Francesco Del Galdo¹⁰

¹University of Michigan Scleroderma Program, Ann Arbor, MI, USA, ²Centre for Rheumatology, Division of Medicine, University College London, London, UNITED KINGDOM, ³McGovern Medical School, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA, ⁴Nippon Medical School, Tokyo, JAPAN, ⁵Rheumatology Department, Cochin Hospital, Université Paris Cité, Paris, FRANCE, ⁶University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, ⁷BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA, ⁸BioPharmaceuticals R&D, AstraZeneca, Cambridge, UNITED KINGDOM, ⁹BioPharmaceuticals Medical Evidence, AstraZeneca, Gaithersburg, MD, USA, ¹⁰Scleroderma Programme, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UNITED KINGDOM

Introduction: Type I interferon (IFN-I) pathway activity is associated with the presence of systemic sclerosis (SSc) autoantibodies, and recombinant IFN-α treatment can cause/exacerbate SSc. Thus, IFN-I signaling is a potential therapeutic target for SSc. Anifrolumab, an approved treatment for adults with moderate to severe systemic lupus erythematosus (SLE), is an IgG1κ monoclonal antibody that blocks IFN-I receptor α subunit 1 signaling. In a phase 1 trial, anifrolumab decreased IFN-I gene expression and disease-associated circulating markers in patients with SSc. We discuss the design of a phase 3 trial to Determine the effectiveness of Anifrolumab In SYstemic sclerosis (DAISY).

Material and Methods: The multinational, randomized, DAISY trial (NCT05925803) includes a 52-week double-blind placebo-controlled period followed by a 52-week open-label active-treatment period and a 12-week safety follow-up. Eligible patients are aged 18–70 years and have limited or diffuse cutaneous (classified by Leroy and Medsger 2001) active SSc (ACR/EULAR 2013 criteria) (Figure). Standard immunosuppressants, including mycophenolate, at a stable dose are permitted. Anifrolumab or placebo will be administered subcutaneously once weekly. The primary endpoint is Revised-Composite Response Index in SSc (CRISS)-25 response at Week 52 (no significant worsening of internal organ involvement during Step 1; improvement in >=2 and worsening in <=1 components in Step 2). Key secondary endpoints include change from baseline to Week 52 in forced vital capacity in patients with SSc-associated interstitial lung disease and change in modified Rodnan Skin Score. Safety endpoints include serious adverse events (AEs) and AEs of special interest, informed by studies in SLE. Downstream treatment effects will be explored by analyzing disease- and IFN-I-specific protein/gene expression in blood and skin. The primary endpoint will be compared between treatment groups at a 2-sided α=0.05 using a Cochran-Mantel-Haenszel test; key secondary endpoints will be analyzed using a hierarchical sequential testing strategy.

Results: DAISY participation is planned for 306 eligible patients from ~175 centers and ~22 countries.

Conclusions: The DAISY trial will evaluate the efficacy of anifrolumab as a first-in-class treatment option, targeting IFN-I pathway activation, for patients with limited or diffuse cutaneous SSc. Selecting revised-CRISS-25 as the primary endpoint captures the heterogeneity of SSc by enabling measurement of improvement and worsening of a broad set of disease activity domains beyond lung function and skin, including clinician- and patient-reported outcomes. An additional strength includes an open-label period for long-term exposure, providing up to two years of on-drug data.

Acknowledgements: Sponsor: AstraZeneca. Writing assistance: Sofia Fernandes, Fishawack Health.

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EFFECTS OF LOCALLY APPLIED WATER-FILTERED INFRARED A RADIATION IN PATIENTS WITH SYSTEMIC SCLEROSIS AND SEVERE RAYNAUD'S PHENOMENON RECEIVING PROSTAGLANDIN TREATMENT – A RANDOMIZED CONTROLLED TRIAL

Priyanka Boettger¹, Joachim Baer¹, Ioannis Sagonas², Nils Schulz¹, Til Ole Kracht¹, Ulf Mueller-Ladner¹, Uwe Lange¹, Philipp Klemm¹

¹Department of Rheumatology, Clinical Immunology, Osteology & Physical Med., Campus Kerckhoff, Justus-Liebig-University, Bad Nauheim, GERMANY, ²Rheumatology Center Rhein-Ruhr, Ruhr University, Herne, GERMANY

Introduction: Most patients with systemic sclerosis (SSc) suffer from Raynaud’s phenomenon (RP) with subsequent digital ulcerations (DU). In severe RP +/- DU, intravenous application of Iloprost is often required. It was shown that these patients benefit from additional non-pharmacological hyperthermic treatment. However, it remains unclear which intensity or mode of hyperthermic treatment is optimal. We conducted a randomized controlled trial using sl-wIRA in addition to CO2 hand baths in comparison to low-intensity hyperthermic treatment routine (CO2 hand baths only) in SSc patients.

Material and Methods: Eligible patients had SSc according to the 2013 ACR/EULAR classification criteria and RP with DU requiring Iloprost treatment in an in-patient setting. The trial was conducted at Campus Kerckhoff of Justus-Liebig University Giessen. Patients were equally randomized to the control group (CG) receiving Iloprost and 15 min CO2 hand baths daily or the intervention group (IG) receiving additional sl-wIRA treatment (2 x 30 min/day for 8 days). Primary outcome was the difference in RP associated pain measured on a visual analogue scale (VAS) after intervention. Key secondary outcomes included a change in RP duration (min), frequency and intensity (VAS, 0-100mm), Health Assessment Questionnaire (HAQ), and in Interleukin (IL)-6 and Vascular Endothelial Growth Factor (VEGF) serum levels.

Results: 38 patients (IG:19, CG: 19) completed the trial and were analyzed. There was no significant difference in RP associated pain (p= 0.214,) and thus the primary outcome was not met. RP duration, frequency, and intensity were reduced in the IG, with no significant difference in intergroup comparison. HAQ, IL-6 and VEGF levels did not show significant changes either.

Conclusions: Additional high-intensity hyperthermic treatment does neither improve outcomes regarding pain levels, RP duration, frequency, intensity or HAQ, nor does it affect IL-6 and VEGF serum levels in comparison to Iloprost and low-intensity hyperthermic treatment.

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ACUTE HOSPITALISATIONS BETWEEN SUBTYPES OF SYSTEMIC SCLEROSIS IN WAIKATO, AOTEAROA NEW ZEALAND

Philippa Van Dantzig¹, Sri Depeekia Padala^1,2, Douglas White^1,2, Kamal Solanki^1,2

¹Rheumatology Department, Waikato Hospital, Hamilton, NEW ZEALAND, ²Waikato Clinical School, Auckland University, Hamilton, NEW ZEALAND

Introduction: Systemic Sclerosis (SSc) is an autoimmune disease characterised by inflammation and vasculopathy leading to fibrosis of the skin and internal organs with significant morbidity and mortality. The degree of skin involvement is divided into subtypes (as per LeRoy classification) of limited (lcSSc), diffuse (dcSSc), sine (ssSSc) and overlap (SOS). Common reasons for SSc patients to be hospitalised include cardiovascular disease (CVD), interstitial lung disease (ILD), peripheral vascular disease (PVD), pulmonary arterial hypertension (PAH) and infection. Whilst there is literature surrounding causes of hospitalisation and inpatient mortality, the question around differing risk between subtypes remains less clear. Our study is the first to primarily address this question.

Material and Methods: A search of the database at Waikato Hospital, which collects data prospectively, was used to identify patients with SSc in the Waikato, Aotearoa New Zealand (AoNZ). Patients had to meet the 2013 ACR/EULAR classification criteria for SSc and be diagnosed between January 2005 and December 2022. Data was then collected retrospectively from electronic health records on demographics, clinical features and number of hospitalisations. Hospitalisations were divided into elective, infusion-related and acute hospitalisations. The primary endpoint looked for any difference in hospitalisations (divided into total, elective, infusion-related and acute) between the four different SSc subtypes. Secondary endpoints included analysis of differences in reasons for admissions, surgical procedures, inpatient mortality and any predictors of hospitalisation or inpatient mortality.

Results: A total of 140 patients were included in the analysis with 84 patients (60.0%) with lcSSc, 40 (28.6%) with diffuse, 3 (2.1%) with ssSSc and 13 (9.3%) with SOS. Baseline characteristics are detailed in Table 1. There was a total of 867 admissions for all four groups with lcSSc having 499 (57.5%), dcSSc 264 (30.4%), ssSSc 22 (2.5%) and SOS 82 (9.5%). Detailed analysis showed no statistically significant difference between subtypes of SSc for total, elective admissions, infusions and acute admissions. Analysis of secondary outcomes is detailed in Table 2.

Conclusions: Whilst there are known differences in morbidity and mortality between systemic sclerosis subtypes, there do not appear to be differences in the number of hospitalisations between the four subtypes in our institution. There are, however, significant differences between lcSSc and dcSSc subtypes in regards to reasons for admission, surgical procedures and mortality.

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EFFICACY OF RITUXIMAB IN SCLERODERMA PATIENTS WITH PROGRESSIVE DISEASE NON-RESPONSIVE TO CSDMARDS – PRELIMINARY RESULTS OF A PROSPECTIVE, OBSERVATIONAL, MONOCENTRIC STUDY

Sabina Oreska^1,2, Aneta Jirankova¹, Anna Bobrova¹, Katerina Bobrova¹, Barbora Hermankova^1,3, Hana Storkanova^1,2, Hana Ciferska^1,2, Karel Pavelka^1,2, Ladislav Senolt^1,2, Jiri Vencovsky^1,2, Radim Becvar^1,2, Michal Tomcik^1,2

¹Institute of Rheumatology, Prague, CZECH REPUBLIC, ²Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, CZECH REPUBLIC, ³Department of Physiotherapy, Faculty of Physical Education and Sport, Charles University, Prague, CZECH REPUBLIC

Introduction: Currently, there are only a few bDMARDs with limited evidence of efficacy for the treatment of patients with systemic sclerosis (SSc) with progressive disease non-responsive to csDMARDs. The aim of this study was to assess the efficacy of rituximab in SSc patients with progressive skin involvement and/or polyarthritis and/or interstitial lung disease (ILD) non-responsive to methotrexate and/or cyclophosphamide and/or mycophenolate in a monocentric, prospective, observational study.

Material and Methods: In total, 24 SSc patients, who fulfilled the 2013 ACR/EULAR classification criteria (3 males/ 21 females, 5 lcSSc/19 dcSSc, mean±SD age 48±14 years, disease duration 5.7±3.4 years, modified Rodnan skin score (mRSS) 17±11, disease activity (ESSG, European Scleroderma Study Group) 4.1±2.0) with progressive skin thickening and/or arthritis and/or ILD non-responsive to methotrexate/myocphenolate/cyclophosphamide were treated with 2 (n=8) or 3 (n=16) series of rituximab (1g i.v. at day 0 and 14, every 6 months). Before each series of rituximab, patients were assessed by a rheumatologist experienced in the evaluation of mRSS, finger-to-palm (FTP) distance, inter-labial/incisal distance, and disease activity (Visual Analog Scale (VASph); ESSG), and filled out patient-reported outcomes assessing global function (Scleroderma Health Assessment Questionnaire, SHAQ), quality of life (Medical outcomes study Short Form 36, SF-36), fatigue (Fatigue Impact Scale, FIS), depression (Beck’s Depression Inventory-II, BDI-II), physical activity (Human Activity Profile, HAP), gastrointestinal (UCLA_SCTC_GIT_2.0) and pulmonary (St. George’s Respiratory Questionnaire, SGRQ) symptoms. Furthermore, peripheral blood was analyzed for routine laboratory parameters (e.g., CRP, ESR, C3 and C4 complement levels), and stored for biobanking.

Results: We observed a statistically significant improvement in mRSS and disease activity (VASph, ESSG) at months (M) 6 and 12, accompanied by a significant increase in C3 (M6, M12) and C4 (M6) levels and a borderline decrease in ESR (M12). Furthermore, we detected a trend toward an increase in Forced Vital Capacity (FVC) at M12 along with a significant improvement in activities impacted by breathlessness (SGRQ-Activity Scale). In addition, we demonstrated a significant improvement in the function of the left hand (deltaFTP-left-hand, M6), a borderline improvement in deltaFTP-right-hand (M6), a borderline improvement in the overall function (HAQ, M12), significant reduction of depression (BDI-II, M6), and a trend toward an improvement in mental aspects of the quality of life (SF-36-Mental Component Summary, M6) (Table1).

Conclusions: Treatment with rituximab in SSc patients with progressive skin-/articular-/ILD- involvement non-responsive to csDMARDs significantly improved the skin score, disease activity, hand function, breathlessness, depression, and increased complement levels.

Acknowledgment: Supported by MHCR023728.

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MANAGEMENT PITFALLS AND PREVALENCE OF LOST TO FOLLOW-UP DUE TO UNPREDICTED DEATH IN SYSTEMIC SCLEROSIS

Patnarin Pongkulkiat¹, Orathai Wantha², Ajanee Mahakkanukrauh¹, Siraphop Suwannaroj¹, Chingching Foocharoen¹

¹Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, THAILAND, ²Division of Nursing, Faculty of Medicine, Khon Kaen University, Khon Kaen, THAILAND

Introduction: In systemic sclerosis (SSc), some of patients was reported to be lost to follow-up. Unpredicted death occurring before scheduled visits might be attributed to pitfalls in patients care management. Our objective was to determine the prevalence of lost to follow-up due to unpredicted death in SSc and management pitfalls.

Material and Methods: A retrospective study was performed using scheduled visits to the Scleroderma Clinic, Khon Kaen University, between January 2019 and April 2020. In case of patient was identified to lost to follow-up, a direct telephone call was performed. If there was no response, the medical records were reviewed, and their current health status was sought from the Civil Registration Bureau.

Results: A total of 497 adult SSc patients with 2,040 follow-ups from 53 visits were reviewed, of whom 37 were lost to follow up due to unpredicted death, resulting in a prevalence of 7.4% (95%CI 5.3-10.1). The respective median time from death to the next scheduled visit and median duration of disease was 19.7 days (IQR 2.9-34) and 3.8 years (IQR 1.7-7.5). Six cases were defined as an improper interval of follow-up and monitoring that led to death before the scheduled visit. All had cardiopulmonary involvement. One case was defined as improper management given for cardiac involvement. Pneumonia and sepsis were the causes of death in 4 of 14 cases that received the immunosuppressant.

Conclusions: Death prior to the scheduled follow-up visit occurred among SSc patients, particularly in case with cardiopulmonary involvement and inadequate monitoring or management. It emphasizes the important of close monitoring as a standard of care for SSc patients with cardiopulmonary involvement to prevent unpredicted death.

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APPROVAL STATUS OF ESSENTIAL THERAPEUTIC DRUGS FOR SYSTEMIC SCLEROSIS VERSUS THAT OF DRUGS FOR RHEUMATOID ARTHRITIS

Ki Won Moon¹, Soo-Hee Hwang², Jin Young Lee^3,4, Jieun Yun⁵, Eun Bong Lee^6,7

¹Division of Rheumatology, Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, SOUTH KOREA, ²HIRA Research Institute, Health Insurance Review & Assessment Service, Wonju, SOUTH KOREA, ³Department of Health Policy and Management, Seoul National University College of Medicine, Seoul, SOUTH KOREA, ⁴Department of Public Health and Community Medicine, Seoul Metropolitan Government Seoul National University Boramae Med, Seoul, SOUTH KOREA, ⁵Department of Pharmaceutical Engineering, Cheongju University, Cheongju, SOUTH KOREA, ⁶Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, SOUTH KOREA, ⁷Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul, SOUTH KOREA

Introduction: Systemic sclerosis (SSc), a rare disease characterized by chronic multisystem fibrosis, requires lifelong management, necessitating enough insurance coverage for the patient. Official drug approval is the first step to ensuring that the drug is covered by insurance. In this study, we investigated the approval status of essential therapeutic drugs for SSc across eight countries, and compared it with that of drugs for rheumatoid arthritis (RA).

Material and Methods: The essential therapeutic drug lists for SSc and RA were taken from the guidelines of the American College of Rheumatology and the European Alliance of Associations for Rheumatology. Official drug approval status for the selected drugs was confirmed by searching representative internet databases from eight countries: the United States of America, the United Kingdom, Germany, France, Italy, Switzerland, Japan, and the Republic of Korea.

Results: A total of 21 and 16 drugs were selected for SSc and RA, respectively. The drug approval rates of the 21 drugs for SSc varied among countries. Most drugs used to treat pulmonary arterial hypertension, which were developed recently and are expensive, are approved by most countries; however, most older drugs, which are still essential for management of Raynaud phenomenon, digital ulcers, interstitial lung disease, and skin fibrosis, are not approved by most countries (Table 1). By contrast, almost all of the 16 drugs used to treat RA, whether old or new, are approved by most countries.

Conclusions: Approval rates for drugs used to treat SSc, a rare disease, are much lower than those for drugs used to treat RA. Thus, approval rates of essential therapeutic drugs for SS need to improve, which will benefit patients by increasing the number of drugs covered by insurance.

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THE NINTEDANIB SAFETY PROFILE IN PATIENTS WITH SYSTEMIC SCLEROSIS (SSC) ASSOCIATED WITH INTERSTITIAL LUNG DISEASE (ILD)

Olga Koneva, Liudmila Garzanova, Lidia Ananyeva, Olga Ovsyannikova, Oxana Desinova, Mayya Starovoytova, Rushana Shayakhmetova

V.A. Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: In the placebo-controlled trials in patients with a progressive phenotype SSc-ILD, Nintedanib reduced the rate of decline in forced vital capacity.The adverse events(AE) profile of Nintedanib in patients with ILD is characterized mainly by gastrointestinal AE.Gastrointestinal tract is also a common manifestation associated with SSc and with standard therapy used for SSc.The purpose of our study was to evaluate the safety and tolerability of Nintedanib in Russian patients with progressive SSc-ILD phenotype.

Material and Methods: 20 patients(the average age 52.7±11.9 years,females 90%,SSc duration 10±6.3 years,diffused:limited form ratio-1:3.5) with the confirmed SSc diagnosis and signs of progressive ILD were enrolled into the study.All patients received low- and moderate-dose of prednisolone regimens. Nintedanib was added to immunosuppressants (Mycophenolate mofetil, Azathioprine,Cyclophosphamide) due to inadequate efficacy of the previous therapy. 13 patients received Nintedanib (300 mg per day) over the follow-up period.13 patients who had received therapy with Nantedanib for at least 6 months (9,7±6,2) were included in the follow-up analysis.

Results: The percentages of patients with any AE was 92.3.More than 1 AE was observed in 8(61.5%) patients.5(38.5%) patients developed diarrhea,which required temporary withdrawal of the drug or dose reduction to 150 mg/day.In one case(7.7%) severe diarrhea led to the discontinuation of the drug.5(38.5%) patients had moderate nausea(3 pts) and vomiting(2 pts).

Laboratory disorders were detected in 4(30.1%) patients:increased levels of AST–3 pts,ALT – 4 pts,GAMMA-GTP-3 pts,alkaline phosphatase-1 pt.No patient had an overshoot of liver enzymes more than three times from the upper limit of the normal.

In one case (7.7%), there were no AE during Nintedanib therapy. The percentage of patients who had a mild and short-term adverse event was 30.8(diarrhea at the beginning of admission–2 pts,diarrhea and nausea at the beginning of admission-1 pt, nausea when increasing the dose to 300 mg/day-1 pt).

The formation of digital necrosis was noted in 3 patients.

During therapy with Nintedanib,AE from the gastrointestinal tract were the most frequent in patients with SSc-ILD,were observed in 92% of patients,but only in 1 case caused the withdrawal of the drug.

Mild laboratory disorders,namely an increase in liver enzymes,were detected in a third of patients.

The formation of digital necrosis on the background of therapy was observed in 3 cases,but all patients had progression of vascular disorders already at the time of inclusion in the study.

Conclusions: The AE profile of Nintedanib in patients with ILD is characterized mainly by gastrointestinal AE.Laboratory disorders were rare and mild.

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SAFETY OF RITUXIMAB WITH OR WITHOUT MYCOPHENOLATE MOFETIL IN SYSTEMIC SCLEROSIS: A SINGLE-CENTER STUDY IN JAPAN

Futoshi Iwata¹, Sho Fukui^1.2.3, Takehiro Nakai¹, Asano Takahiro¹, Hiroki Ozawa¹, Satoshi Kawaai¹, Haruyuki Yanaoka¹, Yukihiko Ikeda¹, Hiromichi Tamaki¹, Kenichi Yamaguchi¹, Masato Okada¹

¹St.Luke's International Hospital, Immuno-Rheumatology Center, Tokyo, JAPAN, ²Brigham and Women's Hospital and Harvard Medical School, Department of Medicine, Boston, USA, ³Kyorin University School of Medicine, Department of Emergency and General Medicine, Tokyo, JAPAN

Introduction: Limited evidence exists on the efficacy and safety of concomitant use of Rituximab (RTX) with Mycophenolate mofetil (MMF) in patients with systemic sclerosis (SSc). This study aimed to investigate the safety profile and retention of RTX with or without MMF in SSc patients.

Material and Methods: In this single-center retrospective study, we assessed SSc patients who initiated RTX at St. Luke’s International Hospital in Japan from April 1, 2018, to August 31, 2023. Patients were stratified into two groups by the use of MMF at RTX initiation: MMF group and without MMF group. We compared the cumulative incidence of serious adverse events (SAEs) that necessitated hospitalization, other adverse events (AEs), and RTX retention between the two groups.

Results: Baseline characteristics for the MMF and without MMF groups were: median age (59.9 vs 61.9 years old), Diffuse SSc (50% vs 36.4%), Anti-Scl-70 antibody (62.5% vs 36.4%), Interstitial lung disease (87.5% vs 63.6%), FVC-% of predicted value (78.5% vs 72.6%), and Median dose of Prednisolone (1.25 mg vs 0mg). In the MMF group, the median MMF dosage was 1750 mg. None of the patients had previously received Cyclophosphamide (Table 1). There were no statistically significant differences in the baseline characteristics between the two groups. The cumulative incidence of SAEs did not differ between the groups. All SAEs were infection, including the COVID-19 pneumonia and catheter-related bloodstream infection. The crude HR of MMF group for developing the first SAE was 0.55, (95%CI: 0.05 - 6.17, p=0.63) (Figure 1). Regarding the overall safety profile, 37.5% in the MMF group and 63.6% of the group without MMF experienced AEs more than twice. While patients in the MMF group had numerically more gastrointestinal symptoms (3 vs 1), <=Grade 3 lymphopenia (3 vs 0), and herpes zoster (1 vs 0), other AEs were less frequent in the MMF group (Table 2). The RTX retention between the groups was not statistically different with crude HR of 0.38 (95% CI: 0.04 - 3.66, p=0.40). 26% of overall patients in both groups discontinued RTX due to inadequate response. No patients discontinued RTX due to AEs.

Conclusions: In this study, adding RTX to MMF in patients with SSc showed no distinct differences in the safety profile and RTX retention compared to RTX alone. RTX may be safely used and well-tolerated with concomitant MMF in SSc patients.

P.344

THE PATTERN OF MEDICATION USE SIGNIFICANTLY CHANGED OVER 36 MONTHS OBSERVATION PERIOD

Ivan Foeldvari¹, Jens Klotsche², Ozgu Kasapcopur³, Amra Adrovic³, Kathryn Torok³, Brian Feldman³, Maria Teresa Terreri³, Ana Paula Sakamoto³, Jordi Anton³, Simone Appenzeller³, Edoardo Marrani³, Tadey Avcin³, Dana Nemcova³, Maria Jose Santos³, Flavio Sztajnbok³, Lillemor Berntson³, Jürgen Brunner³, Gerd Horneff³, Sindhu Johnson³, Tilmann Kallinich³, Mikhail Kostik³, Farzana Nuruzzaman³, Anjali Patwardhan³, Nicola Helmus¹

¹Hamburg Center for Paediatric and Adolescent Rheumatology, Hamburg, GERMANY, ²GermanRheumatismResearchCenter, Berlin, GERMANY, ³jSScCollaborativeGroup, Hamburg, GERMANY

Introduction: Juvenile systemic sclerosis(jSSc) is an orphan disease with a prevalence of 3 in 1,000,000 children. Currently no medications are licensed for the treatment of jSSc. Due to its rarity, only recently the first management and treatment guidelines have been published, the jSSc SHARE(Single Hub and Access point for paediatric Rheumatology in Europe) recommendations, reflecting consensus opinion upon pediatric rheumatologists. We reviewed the medication in the treatment of the patients in the juvenile systemic scleroderma inception cohort(jSScC) up to April 2023.

Material and Methods: We reviewed the change of the applied medication over 36 months in the jSScC. The frequency of medications was calculated across the cohort at timepoint 0 and 36 months. jSScC is a prospective cohort of jSSc patients, who developed the first non-Raynauds symptom before the age of 16 years and are under the age of 18 years at the time of inclusion.

Results: We extracted data from 71 patients who were followed for 36 months. 75% of the patients had diffuse subtype. We captured the recorded medications by the physicians at T0 and T36. 90% received any kind of Disease modifying drug(DMARD).

Glucocorticoid use decreased from month 0 to 36 months from 56% to 31%(p=0.004). Methotrexate use decreased from 53% to 25%(p=0.001), in opposite the mycophenolate use increased from 22% to 67%(p<0.001).Cyclophosphamide use decreased from 14% to 0%(p=0.002). Tocilizumab use increased from 0% to 17%(p=0.001). All other medication use showed no significant changes. Endothelin receptor antagonist was used in 17% patients at time point 0 and 22% at 36 months. PDE-5 blocker use increased from 3% to 9%.

Conclusions: At baseline half of the patients were on glucocorticoids. This is more frequent than typical adult SSc practice but coincides with jSSc SHARE treatment recommendations(#1). After 36 months observation over 90% of patients received a DMARD therapy. Methotrexate and mycophenolate mofetil were the most commonly prescribed DMARDs, which also reflects the SHARE treatment recommendations(#2,#3). At 36 months the use of glucocorticoids, methotrexate and cyclophosphamide decreased, and the use of mycophenolate and tocilizumab increased. In general, biological DMARDs are typically considered in severe or refractory disease(#7), reflecting the lower percentage compared to csDMARDs. Endothelial receptor antagonists, such as bosentan, were used over time in approximately 20% of the patients, reflecting SHARE recommendation #6 for pulmonary hypertension and/or digital tip ulcers. This is the first evaluation looking at clinical medication practice pattern in jSSc over 36 months, and its comparison to recently published consensus guidelines.

P.345

BOTULINUM TOXIN FOR THE TREATMENT OF PATIENTS WITH PRIMARY AND SECONDARY RAYNAUD’S PHENOMENON

Ingrid Gerhardson¹, Elisabet Dyrsmeds¹, Karina Gheorghe¹, Henrik Pettersson^2,3, Karin Gunnarsson^1,4, Nancy Vivar Pomiano¹, Marie Holmqvist^1,4

¹Karolinska University Hospital, MU Gastro, Skin and Rheumatology, Stockholm, SWEDEN, ²Karolinska Insitute, Division of Rheumatology, K2 Medicine, Solna, Stockholm, SWEDEN, ³Karolinska University Hospital, MU Occupational therapy and Physiotherapy, Stockholm, SWEDEN, ⁴Karolinska Institute, Division of Clinical Epidemiology, K2 Medicine, Solna, Stockholm, SWEDEN

Introduction: Raynaud’s Phenomenon (RP) is caused by recurring episodes of vasospasm, sometimes resulting in chronic pain and impaired finger function. In some patients, standard treatment for RP is not an option, and for those patients Botulinum toxin could be an alternative. We need to learn more about the effect botulinum toxin has on RP symptoms, hand function and how it effects patient’s daily activities.

Material and Methods: We included patients who were treated with Botulinum toxin in the rheumatology outpatient clinic from November 2021 until December 2022. The Cold Intolerance Symptom Severity Score form (CISS) was used to evaluate the effect RP had. Included in the form are questions on RP frequency, time until symptom relieve on return to warm environment, and how much symptoms effect daily life. Patients filled out the form before treatment and three weeks after. Botulinum toxin was injected with a palmar approach, depicted in picture 1. We retrieved information on physicians’ opinion on effect.

Results: Thirteen of the in total 15 patients, were women. Eight patients were diagnosed with SSc, four had primary RP and three had unspecified systemic autoimmune disease. All patients had RP several times a day and all patients reported continuous RP >30 minutes until it resolved on return to warm environment before their first Botulinum toxin treatment. Ten patients filled the SICC form before and after their first-time treatment. These 10 patients were included in the evaluation population.

After Botulinum toxin treatment, five (50%) of the patients had good results, per physicians’ opinion and results from CISS form, three (30%) had no difference compared to before and two (20%) had uncertain treatment effect. Five (50%) of the 10 patients reported RP less than 30 minutes, five (50%) that PR had a lower impact on their daily life after treatment compared to before. Four (40%) of the patients reported less problem with housework, hobbies and leisure and tying shoelaces after treatment compared to before. There was no difference in the impact on work before and after treatment.

Conclusions: Although the study population was small, we saw that RP duration and the negative effect RP had on daily life was attenuated after Botulinum toxin treatment in some patients. This observation gives us confidence to continue to study the effects of Botulinum toxin injections.

P.346

LONG-TERM RETENTION RATE, ADVERSE EVENT TEMPORAL PATTERNS AND RESCUE TREATMENT STRATEGIES OF MYCHOPHENOLATE MOFETILE IN SYSTEMIC SCLEROSIS: INSIGHTS FROM A LARGE REAL-LIFE MULTICENTRIC COHORT

Gerlando Natalello¹, Enrico De Lorenzis^1,2, Greta Pellegrino³, Lucrezia Verardi¹, Veronica Batani⁴, Gemma Lepri⁶, Giuseppe Armentano⁷, Marco De Pinto⁸, Francesca Motta⁹, Stefano Di Donato², Vishal Kakkar², Ilaria Bisconti³, Corrado Campochiaro⁴, Stefano Stano⁵, Laura Cometi⁶, Maria De Santis⁹, Dilia Giuggioli⁸, Nicoletta Del Papa⁷, Serena Guiducci⁶, Fiorenzo Iannone⁵, Fabio Cacciapaglia⁵, Giacomo De Luca⁴, Valeria Riccieri³, Marco Matucci Cerinic⁴, Maria Antonietta D'agostino¹, Francesco Del Galdo², Silvia Laura Bosello¹

¹Divion of Rheumatology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, ITALY, ²Scleroderma Program, Leeds Institute of Rheumatic and Musculoskeletal Diseases, University of Leeds, Leeds, UNITED KINGDOM, ³Rheumatology Unit, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University, Rome, ITALY, ⁴Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Hospital, Milan, ITALY, ⁵Rheumatology Unit, Department of Emergency and Organs Transplantation, Università degli Studi di Bari Aldo Moro, Bari, ITALY, ⁶Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Florence, Florence, ITALY, ⁷Rheumatic Disease Unit, Istituto G. Pini, Milan, ITALY, ⁸Department of Rheumatology, University of Modena and Reggio Emilia, Modena, ITALY, ⁹Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center, Milan, ITALY

Introduction: Mycophenolate mofetil (MMF) is a mainstay for the treatment of systemic sclerosis (SSc). Occurrence and implications of MMF-related adverse events on drug retention rates in real-life remain poorly defined. We aimed to determine the MMF retention rate, causes and patterns of discontinuation up to 5 years within a multicentric SSc cohort. Additionally, we reported AEs of interest occurring during MMF therapy and treatment options used after its discontinuation.

Material and Methods: SSc patients who started MMF treatment between 2012 and 2021 at nine tertiary care centers underwent a retrospective longitudinal assessment for up to five years using medical chart reviews. We documented the incidence, clinical correlations, and impacts on MMF treatment of severe gastrointestinal intolerance, infections, laboratory abnormalities, and cancer. Rescue strategies implemented after MMF discontinuation were also recorded.

Results: A total of 545 SSc patients were analyzed (Clinical features summarized in Table 1). The 5-year MMF retention rate stood at 70.7% (65.7-76.1%) and the 19.6% of patients stopped MMF due to adverse events (AEs). One out of every four patients experienced a dose reduction or discontinuation of MMF due to AEs, with gastrointestinal intolerance being the predominant associated factor. The 5-year cumulative incidence rates for gastrointestinal intolerance leading to MMF discontinuation, severe infections, laboratory toxicity, and cancer were 6.4%, 26.2%, 8.8%, and 5.6%, respectively. The lower respiratory tract was by far most affected, with bacteria being the predominant causative agent. Intestinal and pulmonary circulation involvement in SSc were tied to elevated AE rates (including severe infections) and MMF discontinuation (Figure 1). The most common approaches post-MMF cessation were 'watch and wait' (46.5%) and rituximab (19.7%) treatment.

Conclusions: MMF treatment in SSc appears to be limited, both in terms of persistence on therapy and dosing of the drug, by the occurrence of AEs. Our data may be useful in informing forthcoming pre-clinical and clinical studies to optimize MMF-based treatment strategies in SSc. In this real life analysia, post-MMF discontinuation, many don't receive a subsequent rescue treatment.

P.347

CD32 (FC<GAMA>RIIB) EXPRESSION IS LOW ON CD21LOW B CELLS FROM SYSTEMIC SCLEROSIS PATIENTS WITH DIGITAL ULCERS, INTERSTITIAL LUNG DISEASE, AND ANTI-TOPOISOMERASE I AUTOANTIBODIES

Enangeli Kourkouni, Sotirios G. Tsiogkas, Athanasios Mavropoulos, Theodora Simopoulou, Christina G Katsiari, Dimitrios P Bogdanos, Lazaros Sakkas

University of Thessaly Faculty of Medicine, Larissa, GREECE

Introduction: Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by microvasculopathy, excessive collagen deposition and autoantibodies (autoAbs). CD21low B cells were reported to contain autoreactive cells in systemic lupus erythematosus, and recent studies reported increased frequency of CD21low B cells in SSc patients with digital ulcers (DUs). To further characterize CD21low B cells, we studied the expression of inhibitory Fc<gama>RIIB receptor on CD21low B cells in SSc patients. B cells mainly express the inhibitory Fc<gama>RIIB isoform.

Material and Methods: Twenty-seven patients (21 women, median age 55,6 years, 7 men, median age 59,5 years) with SSc, fulfilling the ACR / EULAR 2013 criteria, and 15 age-and sex-matched healthy controls (HCs) were included in the study. Mononuclear cells were isolated from peripheral blood and B cell surface markers were detected using multicolor flow cytometry with the monoclonal antibodies anti-CD19, anti-CD27, anti-CD32 (which recognizes both isoforms Fc<gama>RIIA and Fc<gama>RIIB) and anti-CD21.

Results: CD21low B cells were significantly increased in patients with DUs (51.3%) compared to the patients without DUs (29.34%, p=0.042) and to HCs (p=0.014). They were also significantly increased in patients with ILD (53.1%) compared to HCs (p=0.014). CD21lowCD32low B cells were significantly increased in patients with DUs (23.8%) compared to patients without DUs (4.39%, p=0.015) and HCs (p=0.009), in patients with ILD (28.4%) compared to those without ILD (6.25%, p=0.007) and to HCs (p=0.001), and in anti-topoisomerase I (+) patients (21.5%) compared to anti-topoisomerase I (-) patients (2.45%, p=0.022) and to HCs (p=0.012) (Figure). There was no difference in CD21lowCD32low B cells between males and females in our patient group.

Conclusions: The increased amount of CD21lowCD32low B cells in patients with main manifestations of SSc (microangiopathy, fibrosis, anti-Topo I autoAbs) supports the notion that CD21lowCD32low B cells are likely to be autoreactive and pathogenic in SSc.

P.348

CD7 ACTIVATION REGULATES CYTOTOXICITY-DRIVEN PATHOLOGY IN SYSTEMIC SCLEROSIS, YIELDING A TARGET FOR SELECTIVE CELL DEPLETION

Theodoros-Ioanni Papadimitriou¹, Prashant Singh³, Arjan van Caam¹, Birgitte Walgreen¹, Mark Gorris^3,5, Elly Vitters¹, Iris van Ingen¹, Marije Koenders¹, Ruben Smeets^2,6, Madelon Vonk¹, Jolanda de Vries³, Peter van der Kraan¹, Ypke van Oosterhout⁴, Matijn Huijnen³, Hans Koenen², Rogier Thurlings¹

¹Department of Rheumatology, Radboudumc, Nijmegen, THE NETHERLANDS, ²Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, THE NETHERLANDS, ³Department of Medical BioSciences, Radboudumc, Nijmegen, THE NETHERLANDS, ⁴Xenikos B.V., Nijmegen, THE NETHERLANDS, ⁵Division of Immunotherapy, Oncode Institute, Radboudumc, Nijmegen, THE NETHERLANDS, ⁶Radboudumc Laboratory for Diagnostics, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, THE NETHERLANDS

Introduction: Cytotoxic T and NK cells are central effector cells in cancer and infections. Their effector response is regulated by activating and inhibitory receptors. The regulation of these cells in systemic autoimmune diseases such as systemic sclerosis (SSc) is less defined.

Material and Methods: We conducted ex vivo analysis of affected skin and blood samples from 4 SSc patient cohorts (a total of 165 SSc vs. 80 healthy individuals) using single-cell transcriptomics, flow cytometry and multiplex immunofluorescence staining. We further analyzed the effects of co-stimulatory modulation in functional assays, and in a severely affected SSc patient who was treated on compassionate use with a novel anti-CD3/CD7 bispecific immunotoxin treatment.

Results: Here, we show that SSc affected skin contains proliferating, cytotoxic T and NK cells. These cells selectively express the co-stimulatory molecule CD7 in association with cytotoxic, pro-inflammatory and pro-fibrotic genes, especially in recent-onset and severe disease. We demonstrate that CD7 regulates the cytolytic activity of T and NK cells and that selective depletion of CD7+ cells prevents cytotoxic cell-induced fibroblast contraction. Finally, anti-CD3/CD7 directed depletive treatment eliminated CD7+ skin cells and stabilized disease manifestations in a severely affected SSc patient.

Conclusions: Together the findings imply co-stimulatory molecules as key regulators of cytotoxicity-driven pathology in systemic autoimmune disease, yielding CD7 as a novel target for selective depletion of pathogenic cells.

P.349

ELEVATED SERUM IL-40 IN SYSTEMIC SCLEROSIS IS ASSOCIATED WITH DISEASE ACTIVITY, GASTROINTESTINAL INVOLVEMENT AND SERUM TGF-BETA LEVELS, AND MAY BE INVOLVED IN THE IMMUNE RESPONSE

Adéla Navrátilová¹, Katerina Bobrová², Viktor Becvar², Ondrej Kodet^3,4,5, Radim Becvar¹, Hana Ciferská¹, Aneta Pekacova¹, Karel Pavelka¹, Jiri Vencovský¹, Ladislav Senolt¹, Lucie Andrés Cerezo¹, Michal Tomcik¹

¹Institute of Rheumatology and Department of Rheumatology, First Faculty of Medicine, Charles University, Prague, CZECH REPUBLIC, ²Institute of Rheumatology, Prague, CZECH REPUBLIC, ³Institute of Anatomy, First Faculty of Medicine, Charles University, Prague, CZECH REPUBLIC, ⁴Department of Dermatovenerology, University General Hospital in Prague and First Faculty of Medicine, Charles University, Prague, CZECH REPUBLIC, ⁵BIOCEV, Biotechnology and Biomedicine Center of The Academy of Sciences and Charles University in Vestec, Vestec, CZECH REPUBLIC

Introduction: Interleukin 40 (IL-40) is a novel cytokine associated with malignancies and autoimmune rheumatic disorders. Recently, a relation between IL-40 and mediators of fibrosis was demonstrated. As inflammation and fibrosis are the hallmarks of systemic sclerosis (SSc), we aimed to analyze the expression of IL-40 in SSc and its association with SSc-related features.

Material and Methods: IL-40 expression was detected in the skin from SSc patients and healthy controls (HC) using immunohistochemistry (n=4). In the cross-sectional analysis, serum IL-40 was analyzed in 86 SSc patients and 90 HC. Serum IL-40 was evaluated in 37 individuals at risk of SSc (VEDOSS, very early diagnosis of SSc). 24 patients from the VEDOSS cohort were divided into “progressors”* (n=11) and “non-progressors”** (n=13) (mean follow-up 3.6 years) (Table 1A). Serum IL-40 was analyzed in 24 SSc patients with progressive skin thickening and/or arthritis and/or interstitial lung disease non-responsive to methotrexate, mycophenolate or cyclophosphamide who were treated with 2 (n=24) or 3 (n=16) series of rituximab (RTX†) (baseline, 6 and 12 months). Disease activity was determined using European Scleroderma Study Group (ESSG) index. Patients’ characteristics are shown in Table 1A. In vitro, peripheral blood mononuclear cells (PBMCs) from SSc patients (n=3) and HC (n=4) were treated by the recombinant IL-40. The expression of selected cytokines was analyzed by ELISA and qPCR.

Results: IL-40 was detected in the skin of SSc patients, in the fraction of dermal fibroblasts and round-shaped perivascular immune infiltrates. Serum IL-40 was increased in patients with SSc compared to HC (mean 3.93 vs. 1.49 ng/ml; p<0.0001), and associated with disease activity (ESSG; p=0.0006, r=0.365), gastrointestinal involvement (GI; p<0.05) and serum TGF-beta1 (p<0.05, r=0.301). In the RTX cohort, no significant changes in serum IL-40 were observed upon treatment; nevertheless, both baseline and change in IL-40 levels upon RTX therapy were significantly associated with a change in several clinical parameters (Table 1B). Serum IL-40 was elevated in VEDOSS compared to HC (2.49 vs. 1.53 ng/ml; p=0.0009). No significant changes were observed in progressors vs non-progressors; nevertheless, IL-40 was associated with capillaroscopy findings (p<0.05). In vitro, IL-40 induced the expression of IL-6 (p<0.001) and CCL-2 (p<0.05) in PBMCs from SSc patients and HC.

Conclusions: IL-40 was up-regulated in SSc patients and its levels associated with disease activity, GI involvement and fibrosis. In addition, our results suggest the involvement of IL-40 in the immune response in SSc.

P.350

CIRCULATING FIBROBLASTS FROM PATIENTS WITH SYSTEMIC SCLEROSIS BEHAVED DIFFERENTLY THAN FROM NORMAL CONTROLS

Mie Jin Lim¹, Won Park¹, Hyoun-Ah Kim²

¹Inha University Hospital, Incheon, SOUTH KOREA, ²Ajou University Hospital, Suwon, SOUTH KOREA

Introduction: Systemic Sclerosis (SSc) is an autoimmune disease characterized by microvascular damage, inflammatory response and diffuse fibrosis of multiple organs including skin. Circulating fibrocytes were known to play an important role in fibrotic process of SSc. In this study, we tried to compare systemic fibrotic activity including circulating fibroblasts from SSc patients to normal control group.

Material and Methods: Twenty-two SSc patients and age-sex matched 13 normal controls were recruited. Following informed consent and enrollment, 10 ml of heparinized peripheral blood was drawn from study subjects, anonymized, and transported to the laboratory. The peripheral blood mononuclear cells (PBMCs) were isolated for fibroblast culture. Area of cultured fibroblasts were measured using image program. Total RNA was extracted from the cultured fibroblast and quantitative real time PCR was performed for analysis of α-smooth muscle actin (α-SMA), collagen 1, collagen3 and TGF β1. Supernatants from culture were collected for ELISA of procollagen 1 and TGF β2. ELISA for procollagen 1 and TGF β2 were performed on serum and plasma.

Results: A total of 22 patients (3 male and 19 female patients) with systemic sclerosis and 13 normal controls (2 males and 11 females) were recruited. Serum procollagen 1 was found to be solely higher in patients with SSc than normal controls (p=0.037). However, area of cultured fibroblasts as well as gene expression of α-SMA, collagen 1, 3 and TGF β1 from cultured fibroblast failed to show difference from controls. Although age was balanced between two groups, a linear analysis showed age correlated with gene expression of α–SMA (r=0.449, p=0.007), TGF β1 from cultured fibroblast (r=0.417, p=0.013) and serum TGF β2 (r=0.375, p=0.027). The correlation analysis revealed α–SMA (r=0.708, p=0.007) and TGF β1 (r=0.737, p=0.004) increased proportional to age in the normal control group while α-SMA and TGF β1 failed to show any relationship with age in SSc group.

Conclusions: In this study, gene expression of α-SMA and TGF β1 from fibroblast cultured from PBMC of SSc patients remained stable regardless of age although normal control group showed positive correlation with age. α-SMA is a marker of myofibroblast and TGF β1 is known to play a pivotal role in tissue fibrosis. Thus, this study shows fibrotic activity of circulating fibroblasts which is normally influenced by age acts differently in SSc group.

P.351

DEFICIENCY AND ALTERED PHENOTYPE OF MUCOSAL-ASSOCIATED INVARIANT T CELLS IN SYSTEMIC SCLEROSIS

Manon Lesturgie-Talarek¹, Virginie Gonzalez¹, Lucie Beaudoin¹, Camélia Frantz², Noémie Senot¹, Zouriatou Gouda¹, Camille Rousseau¹, Jérôme Avouac², Agnès Lehuen¹, Yannick Allanore¹

¹Cochin Institute, INSERM U1016, Paris, FRANCE, ²Rheumatology Department, Cochin Hospital, Paris, FRANCE

Introduction: Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs including the lung. Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes able to produce various cytokines and cytotoxic mediators such as granzyme B. Decreased level and altered phenotype of MAIT cell have been shown in various autoimmune disease. Moreover, some data support a potential role in fibrotic disorders as highlighted in liver fibrosis.

Therefore, we herein addressed the question as whether MAIT cells may have an altered profile in systemic sclerosis.

Material and Methods: MAIT cell frequency was analyzed by flow cytometry, using fresh peripheral blood from 74 consecutive SSc patients compared to 44 healthy donors (HD). In addition, in depth MAIT cell phenotype and function were analyzed in 29 women with SSc compared to 23 healthy women donors. A

Results: Most of the healthy donors were female (93%) and the mean age was 45.6 years. Among the 74 SSc patients (85% were female, mean age: 58 years), the mean disease duration was 9 years, 43% had the diffuse cutaneous SSc and 34% had an interstitial lung disease (ILD).

Proportion of circulating MAIT cells was significantly reduced by 68% in SSc compared to HD (0.78 % in SSc vs. 2.5%, p<0.0001) (Figure 1A). Within SSc subsets, MAIT cell frequency was significantly reduced in patients with interstitial lung disease (SSc-ILD) (0.56% vs. 0.94% in patients without ILD, p=0.04) (Figure 1B) even lower in the patients with severe ILD and reduced forced vital capacity (FVC) (0.28% in patients with FVC <75% vs. 0.96% in patients with FVC >75%, p=0.0075). Deficiency of MAIT cells did not correlate with disease activity score, type of SSc (diffuse or limited), systemic inflammation, and current immunosuppressive therapy.

In SSc patients, MAIT cells displayed a strongly activated phenotype indicated by markedly increased CD69+ MAIT cell frequency compared to healthy donors (p=0.0014, Figure 1C).

Interestingly, MAIT cells from SSc-ILD patients had a more pronounced altered phenotype compared to SSc without ILD, with a correlation between MAIT cells expressing CCR6+ and MAIT cell frequency.

Conclusions: Circulating MAIT cells were reduced and exhibited an activated phenotype in SSc patients. This peripheral MAIT cell deficiency may be related to enhanced apoptosis and/or homing in inflamed tissue, in particular the lung in SSc-ILD patients.

P.352

ANGIOTENSIN 1-7, ALAMANDIN, MrgD LEVELS IN SYSTEMIC SCLEROSIS AND PRIMARY RAYNAUD’S PHENOMENON

Alper Demirkol¹, Ahmet Karatas¹, Necip Ilhan², Ramazan Fazil Akkoc³, Tuba Kaya Karatas², Mesude Seda Aydogdu¹, Süleyman Serdar Koca¹

¹Firat University, Faculty of Medicne, Department Of Rheumatology, Elazig, TURKEY, ²Firat University, Faculty of Medicne, Department of Biochemistry, Elazig, TURKEY, ³Firat University, Faculty of Medicne, Department of Anotomy, Elazig, TURKEY

Introduction: The aim of this study was to measure serum angiotensin 1-7, alamandin and MrgD levels in patients with systemic sclerosis (SSc) and primary Raynaud’s phenomenon (RP) and compare their levels to healthy controls.

Material and Methods: 30 patients with SSc fulfilling ACR/EULAR 2013 classification criteria of SSc, 30 patients with primary RP according to International Consensus criteria of RP and 30 healthy subjects, as control group, were included in the study. Disease activity and activity of RP were evaluated with Raynaud Condition Score (RCS). Serum angiotensin 1-7, alamandin and MrgD levels were measured by ELISA method.

Results: There was no statistically significant difference in terms of serum angiotensin 1-7 levels among the groups (p=0.129) (Table 1). However, serum alamandin levels were relatively lower than in healthy controls (p=0.075). But, the difference of serum MrgD levels was statistically significant among the study groups (p=0.002). Serum MrgD level was lower in SSc group compared to the RP and healthy control groups (p=0.002). The mean RCS value was higher in the RP group than in healthy ones (p<0.001). and, it was higher in the SSc group than in both RP and healthy control groups (p<0.001). Serum angiotensin 1-7, alamandin and MrgD levels were not related neither RCS values nor gender in all study groups.

Conclusions: These results can suggest that the vasoconstrictor-acting angiotensin 1-7, alamandin and MrgD levels may be parameters that can guide the diagnosis of the disease and explain the pathogenesis in SSc and related conditions. However, in order to confirm this conclusion, more comprehensive studies are required in a geographically wider area with a large number of participants.

P.353

EFFECT OF PHOSPHODIESTERASE-4 INHIBITION BY APREMILAST ON THE TGFBETA1-INDUCED EPITHELIAL-TO-MESENCHYMAL TRANSITION IN CULTURED HUMAN LUNG EPITHELIAL CELLS

Emanuele Gotelli¹, Stefano Soldano¹, Paola Montagna¹, Elvis Hysa^1-2, Rosanna Campitiello^1-2, Alberto Sulli^1-2, Vanessa Smith^3-4-5, Maurizio Cutolo^1-2

¹University of Genova-Research laboratory of Experimental Rheumatology-Department of Internal Medicine and Specialtie, Genova, ITALY, ²IRCCS Ospedale Policlinico San Martino, Genova, ITALY, ³University of Ghent - Department of Rheumatology, Ghent, BELGIUM, ⁴University of Ghent - Department of Internal Medicine, Ghent, BELGIUM, ⁵Unit for Molecular Immunology and Inflammation, Flemish Institute for Biotechnology, Inflammation Research Center, Ghent, BELGIUM

Introduction: Epithelial-to-mesenchymal transition (EMT) is a multifactorial process in which epithelial cells (ECs) change their phenotype, acquiring a spindle-shaped myofibroblast morphology, with overexpression of α-smooth muscle actin (αSMA), and exert profibrotic activity through the overproduction of extracellular matrix components, including type I collagen (COL1) and fibronectin (FN). Transforming growth factor-β1 (TGFβ1) plays an important role in inducing EMT in the lung ECs, activating phosphodiesterase (PDE)4/cyclic adenosine monophosphate (cAMP) signalling pathway.

EMT contributes to the increased amount of myofibroblasts at the level of tissues undergoing repairs, but it is also involved in fibrotic diseases, including systemic sclerosis and interstitial lung diseases.

This in vitro study investigates the effect of PDE4 inhibition by apremilast in cultured human lung ECs and how the drug might interfere with the intracellular signalling of EMT mediated by TGFβ1.

Material and Methods: Cultures of lung ECs (A549 cells) were stimulated with TGFβ1 (10ng/mL), treated with apremilast at the concentrations of 1μM or 10μM under TGFβ1 stimulation, and maintained in normal growth medium (untreated cells), for 3 and 24 hours, 2, 3 and 5 days.

ECs proliferation was investigated by methyl-tetrazolium salt test. Gene and protein expression of αSMA, COL1, FN, and EC markers (E-cadherin and cytokeratin-18) were investigated by quantitative real time polymerase chain reaction and Western blotting. TGFβ1-induced intracellular signalling pathways were investigated by western blot. Statistical analysis was carried out by Wilcoxon test.

Results: TGFβ1 significantly increased ECs proliferation after 24 hours of stimulation and upregulated both gene and protein expression of αSMA, COL1 and FN, inducing a spindle-shaped myofibroblast morphology primarily after 3 and 5 days of stimulation compared to untreated cells. At the same time, TGFβ1 downregulated E-cadherin and cytokeratin-18 gene and protein expression. These TGFβ1-induced effects involved the activation of both small mother against decapentaplegic (SMAD)-dependent signalling pathway mediated by SMAD2, and SMAD-independent signalling pathway mediated by extracellular signal-regulated kinase1 and 2 (Erk1/2) and Jun N-terminal kinase (JNK).

Of note, apremilast significantly blocked ECs proliferation, the increased gene and protein expression of αSMA, COL1, FN and the acquisition of a myofibroblast morphology induced by TGFβ1 through the inhibition of SMAD2, Erk1/2 and JNK signalling pathways.

Conclusions: Apremilast seems to block the EMT of cultured human lung ECs mediated by TGFβ1, suggesting that inhibition of PDE4 could be a novel therapeutic approach to attenuate the EMT associated to interstitial lung diseases.

P.354

ANALYSING THE METABOLIC PROFILE OF PLASMACYTOID DENDRITIC CELLS IN SYSTEMIC SCLEROSIS

Beatriz H. Ferreira^1,2, Carolina Mazeda^3,4, Daniela Barros⁵, Anabela Barcelos^3,4, Adrienne W. Paton⁶, James C. Paton⁶, Rafael J. Argüello⁵, Iola F. Duarte², Philippe Pierre^1,5, Catarina R. Almeida¹

¹Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, Aveiro, PORTUGAL, ²CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Aveiro, PORTUGAL, ³Rheumatology Department. Centro Hospitalar do Baixo Vouga, Aveiro, PORTUGAL, ⁴Centro Académico Clínico Egas Moniz. Health Alliance, Aveiro, PORTUGAL, ⁵Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), Marseille, FRANCE, ⁶Department of Molecular and Biomedical Science, Research Centre for Infectious Diseases, University of Adelaide, Adelaide, AUSTRALIA

Introduction: Plasmacytoid dendritic cells (pDC) are innate immune cells specialized in rapidly producing large amounts of type I interferon (IFN) in response to viral infections. Due to their high secretory capacity, pDC have a large endoplasmic reticulum (ER) and basal levels of ER stress, resulting from the accumulation of misfolded proteins. Moreover, differentiation and activation of immune cells, namely of pDC, is known to depend on metabolic reprogramming. In addition to their role in antiviral immunity, pDC have also been associated with autoimmune diseases, such as systemic sclerosis (SSc). Importantly, pDC have been defined as key to the onset and development of fibrosis, and pDC isolated from SSc patients were shown to have a dysregulation of ER stress signalling pathways and metabolic alterations. Nevertheless, the impact of metabolism on pDC-mediated fibrosis remains unclear. The aim of our study was to investigate the role of pDC metabolism in SSc.

Material and Methods: We directly cocultured pDC and lung fibroblasts under ER stress conditions, induced by the subtilase cytotoxin SubAB. Extracellular matrix (ECM) protein production and fibroblast activation were evaluated by immunoblotting and RT-qPCR. Supernatants were used for exometabolome analysis by nuclear magnetic resonance (NMR). In addition, the metabolic profile of pDC isolated from the blood of healthy individuals and SSc patients was analysed at the single cell level using the SCENITH method.

Results: We observed that under ER stress the direct coculture of lung fibroblasts with pDC promotes ECM protein production and triggers fibroblast activation. In these conditions, NMR analysis revealed a lower consumption of glucose and secretion of lactate, pointing to decreased glycolysis. Interestingly, we also observed that pDC isolated from patients positive for anti-centromere antibody (ACA) are more dependent on mitochondrial metabolism, than cells from patients anti-topoisomerase I antibody (ATA) positive.

Conclusions: Altogether, our results suggest that both pDC and ER stress induction contribute to fibroblast activation. Furthermore, our data pave the way for a possible contribution of pDC metabolism to SSc clinical course, which needs to be further elucidated. With this work, we aim to identify new players in fibrosis and contribute to the development of new therapeutic strategies against tissue fibrosis in SSc.

Funding: Work developed within the scope of iBiMED-Institute of Biomedicine (UIDB/04501/2020 and UIDP/04501/2020) and CICECO-Aveiro Institute of Materials (UIDB/50011/2020, UIDP/50011/2020 & LA/P/0006/2020). Funded by the project 2022.03217.PTDC, financially supported by national funds (OE), through FCT/MCTES, and by World Scleroderma Foundation. B.H.F. is supported by FCT through an individual grant (SFRH/BD/144706/2019).

P.355

SINGLE-CELL RNA SEQUENCING REVEALS DISTINCT FIBROBLAST SUBSETS IN SYSTEMIC SCLEROSIS AND THE MODULATORY EFFECTS OF MYCOPHENOLATE MOFETIL

Deborah Webb¹, Reeba Paul², Frank Li², Lei Chen¹, Dennis Delic³, Christian Wohnhaas³, Julia Soellner³, Shawn Anderson¹, Andrew Mikosz¹, LeeAnne Daley¹, Chao-Ting Wang¹, Shervin Assassi⁴, Sudha Visvanathan³, Jochen Schmitz¹, David Lenin Ebenezer¹

¹Immunology and Respiratory Research, Boehringer-Ingelheim Pharmaceuticals, Ridgefield, USA, ²Global Computational Biology & Data Sciences, Boehringer-Ingelheim Pharmaceuticals, Ridgefield, USA, ³Translational Medicine and Clinical Pharmacology, Boehringer-Ingelheim Pharmaceuticals, Biberach an der Riss, GERMANY, ⁴Division of Rheumatology, University of Texas Health Science Center in Houston, Houston, USA

Introduction: Systemic Sclerosis (SSc) represents a multifaceted autoimmune disorder characterized by fibrotic manifestations in the skin and internal organs. Fibroblasts, as the primary effector cells in fibrosis, hold a pivotal role in the pathogenesis of SSc. We utilized single-cell RNA (scRNA) sequencing to examine fibroblast subsets derived from SSc donors and assess the effect of Mycophenolate mofetil (MMF) in disease relevant cellular assays.

Material and Methods: Primary fibroblasts isolated from normal donor (n=5) and SSc (n=6) skin biopsies were cultured in DMEM supplemented with 10% FBS, 1% penicillin-streptomycin, and 1% L-glutamine. The cells were maintained at 37°C in a humidified atmosphere with 5% CO2.Single-cell suspensions were prepared from fibroblasts using a combination of mechanical and enzymatic dissociation. Approximately 10,000 cells were subjected to the 10x Genomics Chromium X Controller machine for GEM generation. Post RT-PCR, cDNA was recovered, purified, and amplified for library preparation. Sequencing was performed on an Illumina NovaSeq 6000. Data processing was done using Cell Ranger v6.0.2. For disease modeling, the cells were stimulated with TGF-β 2 ng/mL) to induce fibrosis in a Scar-in-a-Jar assay, and a cocktail of IL1β (30 pg/ml) and FGF (20 ng/ml) for proliferation assays and treated with 2.5µM mycophenolic acid (MPA).

Results: We discovered distinct SSc fibroblast subsets that maintain disease memory and exhibit differential gene expression, including interferon (IFN) genes, which contribute to disease progression. Unique biological pathways were activated in SSc fibroblasts compared to those from healthy donors, implicating these subsets in the development of fibrosis. By superimposing scRNA-Seq data onto the SSc skin bulk RNA dataset, we corroborated the involvement of these subsets in SSc-affected skin. Based on these observations, we established in vitro primary cell assays for improved disease modeling and capturing patient heterogeneity. We then assessed the effects of MMF and observed significant MPA reduction of selective fibrotic and disease-related markers, including Fibronectin (25.3±8.2%, n=4 SSc donors, p value: 0.0261), CTGF (19.8±7.2%, n=4 SSc donors, p value: 0.0522), sICAM (34.7±14.0%, n=3 SSc donors, p value: 0.0997), and IGFBP3 (82.7±6.2%, n=4 SSc donors, p value: <0.0001), but not Procollagen and α-Smooth Muscle Actin (α-SMA)

Conclusions: The findings demonstrated SSc fibroblasts preserved an aberrant response memory to the disease environment and maintained SSc-related characteristics even after extended in vitro culture.

P.356

ENDOTHELIAL CELLS-INDUCED MACROPHAGES EFFEROCYTIC ALTERATION IN SSC : A ROLE FOR SUSTAINED FIBROBLAST INFLAMMATION ?

Agathe Depaire¹, Damien Brisou¹, Matthieu Cochard¹, Sylvain Perruche², Marie-Elise Truchetet^1,3, Cécile Contin-Bordes^1,4

¹CNRS-UMR 5164 ImmunoConcEpT, Bordeaux University, Bordeaux, FRANCE, ²INSERM, EFS BFC, UMR1098 RIGHT/MEDINNPHARMA, Besançon, Besançon, FRANCE, ³Rheumatology Department, Bordeaux University Hospital, Bordeaux, FRANCE, ⁴Immunology and Immunogenetic Department, Bordeaux University Hospital, Bordeaux, FRANCE

Introduction: The concept of unresolved tissue repair leading to sustained fibrosis has emerged based on a persistent sterile inflammation that converts a self-limited repair response to a non-resolving pathological fibrosis. Resolution depends notably on the efficient elimination of apoptotic cells mainly by macrophage (Mφ)’s efferocytosis. We previously demonstrated a vicious circle implicating IL-1β, microvascular endothelial cells (MECs) activation and generation of macrophages that trigger proinflammatory fibroblasts, contributing to the sustained inflammation and fibrosis in scleroderma. We now study whether SSc-MEC-induced Mφ have altered efferocytic function and the impact on fibroblasts activation.

Material and Methods: MECs where purified from skin of 2 healthy donors, 3 early limited [SSc1 to 3] and 1 severe diffuse [SSc4] cutaneous forms. Mφ were generated with unstimulated or IL-1β-stimulated MECs conditioned medium for 6 days. After washing, Mφ efferocytosis was assessed with pH-Rhodo-stained camptothecin-induced apoptotic Jurkat cells for 24h using live cell imaging (Incucyte apparatus). Mφ’s supernatants were centrifuged, and cultured with healthy fibroblasts for 48h. Fibroblasts activation was assessed by measuring expression of COL1A1, MMP1/MMP2, and CCL2 expression by RTqPCR.

Results: Apoptotic cells phagocytosis by SSc-MECs-induced Mφ was globally comparable to HD-MECs condition, although we observed a slight decrease of phagocytosis for SSc3-MEC (Fig.1). HD-MECs-induced Mφ have little or no effect on MMP-1 and CCL2 expression by fibroblasts, as for SSc1-MEC. In sharp contrast, SSc2 to SSc4-MECs generate Mφ that induce significant more MMP-1. Interestingly, SSc4-MEC-induced Mφ were unable to limit fibroblasts MMP-1 expression post-efferocytosis. In HD settings, IL-1β-stimulated MEC-induced Mφ reproducibly up-regulate fibroblast’s MMP-1 and CCL2, while efferocytosis efficiently and reproducibly downregulated both markers (Fig.2). In SSc conditions, results were much more heterogeneous. SSc MECs-efferocytic Mφ’s supernatant of SSc 2 patient lost ability to downregulate MMP-1 and CCL2, while a slight alteration of fibroblasts CCL2 downregulation was observed for all SSc-MECs Mφ’s supernatants tested (Fig.2).

Conclusions: These data are based on a limited number of patients and need to be consolidated, notably using MEC from diffuse form of SSc. They suggests however that pre- and post-efferocytic SSc-MEC-induced φ have distinct and heterogeneous ability to modulate fibroblasts activation. Whether this observation is related to distinct clinical phenotype needs to be defined. We are now assessing whether SSc-MEC φ modulate endothelial to mesenchymal transition.

P.357

THE USEFULNESS OF NAILFOLD CAPILLAROSCOPY IN SCLERODERMA-SPECTRUM DISORDERS - A SINGLE-CENTRE OBSERVATIONAL STUDY

Ewa Wielosz, Katarzyna Wiak-Walerowicz, Magdalena Dryglewska, Maria Majdan

Department of Rheumatology, Medical University, Lublin, POLAND

Introduction: Nailfold capillaroscopy is particularly useful for diagnosis of systemic sclerosis (SSc). Moreover, this examination is helpful for diagnosis and monitoring of scleroderma-spectrum disorders, such as dermatomyositis (DM), polymyositis (PM), mixed connective tissue disease (MCTD) or undifferentiated connective tissue disease (UCTD).

Material and Methods: The aim of the study was to analyse the capillaroscopic patterns in the group of patients affected by scleroderma-spectrum disorders. Furthermore, a possible correlation of capillaroscopic abnormalities with the clinical and serological profile was assessed. The study included 15 patients with scleroderma-spectrum disorders ( 7 with DM and 8 with MCTD) hospitalized in the Department of Rheumatology and Systemic Connective Tissue Diseases of the Medical University of Lublin in 2021. All patients underwent nailfold capillaroscopy using a Dino-Lite USB-microscope with 200x magnification. The nailfold microcirculation was assessed qualitatively according to Cutolo et al., dividing the images into normal, non-specific lesions, and scleroderma-like microangiopathy.

Results: Scleroderma-like microangiopathy was found in 7/15 (47%) patients with scleroderma-spectrum disorders, including 3/7 (43%) with DM and 4/8 (50%) with MCTD. The patterns of vascular abnormalities found in the group with scleroderma-like microangiopathy were as follows: early in 3 (42%) patients with MCTD (42%), active in 2 (29%) patients (1 with DM and 1 with MCTD) and late in 2 (29%) patients. The early pattern was observed only in the group with MCTD and the late pattern only in patients with DM. Analysis of correlations with selected clinical symptoms in the group of patients with scleroderma-spectrum disorders demonstrated that a reduced number of vessels was statistically significantly more common in patients with interstitial lung disease.

Conclusions: Scleroderma-like microangiopathy is quite common in scleroderma-spectrum disorders. A significant association of capillary reduction with interstitial lung disease, has been demonstrated in dermatomyositis and mixed connective tissue disease.

P.358

STEROID HORMONES IN SYSTEMIC SCLEROSIS: ASSOCIATIONS WITH DISEASE CHARACTERISTICS AND MODIFICATIONS DURING SCLERODERMA RENAL CRISIS

Aurore Collet¹, Sebastien Sanges², Amjad Ghulam³, Michael Genin⁴, Benoît Soudan³, Vincent Sobanski², Eric Hachulla², Sylvain Dubucquoi¹, Bodale Djobo³, Stephanie Espiard⁵, Claire Douillard⁵, David Launay²

¹CHU Lille, Institut d'Immunologie, Pole de Biologie Pathologie Genetique, LILLE, FRANCE, ²CHU Lille, Departement de Medecine Interne et Immunologie Clinique, LILLE, FRANCE, ³CHU Lille, Department of Endocrinology, Diabetology, Metabolism and Nutrition, LILLE, FRANCE, ⁴Univ. Lille, CHU Lille, ULR 2694 - METRICS : evaluation des technologies de sante et des pratiques medicales, LILLE, FRANCE, ⁵CHU Lille, Department of Endocrinology, Diabetology, Metabolism and Nutrition, LILLE, FRANCE

Introduction: The renin-angiotensin-aldosterone system (RAAS) and glucocorticoids (GCs) are involved in vascular remodeling and fibrosis, but have not been extensively studied in systemic sclerosis (SSc). Our aim was to investigate the RAAS and GC hormones in SSc patients.

Material and Methods: Serum levels of renin (dosage and activity), aldosterone and its precursors (DOC, B, 18-OH-DOC, 18-OH-B), and GCs (cortisol, cortisone, 11-deoxycortisol, 18-OH-F) were assessed in 122 SSc patients and 52 healthy controls, with stringent inclusion criteria aimed at ensuring accurate hormone assessments (exclusion of interfering drugs, strict sampling conditions). Hormone levels were compared between patients and controls; and associations with disease characteristics were assessed in SSc patients.

Results: Regarding RAAS hormones, SSc patients displayed significantly lower aldosterone levels (although within normal range), similar renin levels, and higher B levels than controls. Abnormal RAAS hormone levels were associated with a more severe SSc phenotype (lung and skin fibrosis, heart and pulmonary vascular involvements, inflammation). Regarding GC hormones, SSc patients had higher levels of cortisol, 11-desoxycortisol (precursor) and 18-OH-F (metabolite) but lower levels of cortisone (inactive counterpart) than controls.

RAAS hormone levels were also assessed in 5 SSc patients before and during scleroderma renal crisis (SRC): concentrations varied considerably between patients, but consistently included normal/increased aldosterone levels and elevated renin levels.

Conclusions: RAAS and GC hormones are abnormally produced in SSc patients, especially in patients with severe SSc and during SRC. Even if our study does not make it possible to decide on the physiopathological explanation of these abnormalities, we can hypothesize that (i) antibodies targeting components of the RAAS, (ii) a drop in secretion of the angiotensin-converting enzyme linked endothelial dysfunction, and/or (iii) increased ACTH production due to chronic stress related to the disease. These results therefore suggest a participation of the RAAS and GCs in the vascular and fibrotic events associated with SS. Future larger-scale prospective work and mechanistic studies will be needed to complete knowledge on this subject.

P.359

SYSTEMIC SCLEROSIS’ OFFSPRING SHARE NAILFOLD CAPILLAROSCOPIC FEATURES WITH THEIR PARENTS. IS THERE A VASCULAR MEMORY?

Marta Amaral¹, Filipe Paula^1,2, Frederico Batista^1,2, Joana Caetano^1,2, Susana Oliveira^1,2, Paul Ames^1,3, Jose Delgado Alves^1,2

¹Immune response and vascular disease, iNOVA4Health, NOVA Medical School, Universidade Nova de Lisboa, Lisbon, PORTUGAL, ²Unidade de Doenças Imuno-Mediadas Sistémicas, Departamento de Medicina IV, Hospital Prof. Doutor Fernando Fonseca, Amadora, PORTUGAL, ³Department of Haematology, Dumfries & Galloway Royal Infirmary, Cargenbridge, Scotland, UNITED KINGDOM

Introduction: Systemic Sclerosis (SSc) is an autoimmune connective tissue disease characterized by small vessel vasculopathy, autoantibody production and collagen deposition. Raynaud's phenomenon (RP) can precede SSc by 10 to 30 years, but its presence alone is not sufficient for the development of SSc. It has been particularly difficult to understand what comes first in the “pre-clinical phase” of SSc, where an early intervention could bring a better prognosis. Hypothesising that vasculopathy is the original stimulus, we aim to identify the mechanisms underlying early functional changes in SSc.

Material and Methods: Subjects were enrolled into: group 1- patients with SSc; group 2 - offspring of these patients (with no symptoms or auto-antibodies); group 3 - Raynaud's Disease (RD) (patients with primary RP); group 4 – offspring of these patients; group 5 – controls (subjects without RP or family history of SSc). Demographic and clinical data were registered. All subjects underwent Nailfold Video-Capillaroscopy (NVC) to evaluate: number of capillaries per field, enlarged and giant capillaries, morphological abnormalities, microhaemorrhages, neoangiogenesis, avascular isolated areas, interstitial oedema, and semi-quantitative changes in blood flow. Laboratory routines and specific endothelial markers of inflammation as VCAM-1 and ICAM-1 were measured in serum.

Results: A hundred and thirty-five patients with SSc, mean age 56,3±16,1 years, mean age at diagnosis 52,0±16,0 years, 5,3±6,0 years of disease; 57 SSc’s offspring, mean age 35,2±13,4 years; 180 subjects with RD, mean age 41,1±17,2 years, mean age at diagnosis 32,4±14,2 years, 10,4±13,7 years of disease, 10 RD’s offspring, mean age 30,0±10,7; 63 controls, mean age 38,8±17,7. NVC parameters from SSc patients differed significantly from controls, (p<0,001, Chi-square test). SSc’s offspring differed from controls in almost every parameter (p<0,05, Chi-square test), except for giant capillaries, minor morphological abnormalities and microhaemorrages. SSc and their offspring shared some features as changes in morphology, flux and chronic ischaemia. RD’s patients differed significantly from controls in enlarged capillaries, blood flow and neoangiogenesis. Capillary rarefaction and “sludge” were significantly more pronounced in SSc’s offspring compared to RD’s patients. RD’s offspring had normal NVC. Concerning VCAM-1, only SSc had significant higher levels than all the other groups. In the ICAM-1 assay, controls had significant higher levels than all other groups.

Conclusions: Primary RP, or Raynaud’s disease, might be completely different in its mechanism from RP secondary to SSc. Microvasculature appears to change before the immune system and inflammation markers get activated. We may postulate the existence of a vascular anatomical memory in Systemic sclerosis.

P.360

ASSESSMENT OF THE LEVEL OF B-CELL ACTIVATION FACTOR IN PATIENTS WITH SYSTEMIC SCLEROSIS BEFORE AND AFTER RITUXIMAB THERAPY

Mayya Starovoytova, Oxana Desinova, Lidiya Ananieva, Olga Koneva, Lyudmila Garzanova, Rushana Shayakhmetova, Olga Ovsyannikova

VA Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: Systemic sclerosis (SSc) is a rare systemic connective tissue disease characterized by excessive fibrosis of the skin and various internal organs, micro-vascular inflammatory changes and immune dysregulation. A variety of immunologic abnormalities of T and B lymphocytes have been detected in SSc. B cell–activating factor (BAFF) is best known for its role in the survival and maturation of B cells

Material and Methods: Serum BAFF levels in 40 patients with SSc-ILD before and after rituximab (RTM) therapy and 16 healthy matching controls were examined by enzyme immunoassay (ELISA)

Results: Serum BAFF levels were elevated in SSc patients compared with healthy controls The study included 40 patients (21 female and 9 male), with a mean age of 49.5 ± 14.25 years, with mean disease duration of 8.8 ± 6. 7 years. 13 pts had diffuse cutaneous SSc (dcSSc), 24 pts had limited cutaneous SSc (lcSSc), 2 - visceral SSc, and 1 – overlap SSc. Serum BAFF in patients before RTM therapy ranged 0.3-11.9 ng/mL with mean BAFF 1.25 ± 2.13 ng/mL. Serum BAFF in patients after RTM therapy ranged 0.24-12.98 ng/mL with mean BAFF 1.26 ± 2.33 ng/mL. In controls serum BAFF levels ranged 0.62-5.02 ng/mL with mean BAFF 1.24 ± 1.09 ng/mL. Serum BAFF levels did not show significant correlation with RTM therapy use in the patients studied

Conclusions: These results indicate a large spread of indicators in the compared groups.There were no pronounced dynamic changes in the BAFF level during therapy, which indicates the absence of an increase in the BAFF level after depletion and, accordingly, the absence of possible undesirable stimulation of the remaining B lymphocytes.

P.361

SOLUBLE IMMUNE CHECKPOINT MOLECULES IN PATIENTS WITH SYSTEMIC SCLEROSIS

Judith Potjewijd Potjewijd¹, Rachid Tobal¹, Jan GMC Damoiseaux², Peter Heeringa³, Pieter van Paassen¹

¹Department of Internal Medicine, division Clinical and Experimental Immunology, Maastricht University Medical Center, Maastricht, THE NETHERLANDS, ²Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, THE NETHERLANDS, ³3Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, THE NETHERLANDS

Introduction: Systemic sclerosis (SSc) is a complex autoimmune disorder characterized by immune dysregulation, autoimmunity, and tissue fibrosis. Immune checkpoints play pivotal roles in regulating immune responses and self-tolerance. Dysregulation of these checkpoints can contribute to autoimmune diseases. This study investigates the role of soluble immune checkpoints (sICPs) in SSc pathogenesis, focusing on their association with disease severity and treatment response.

Material and Methods: We included SSc patients from our prospective observational cohort of treatment-naïve SSc patients. Plasma samples were collected and clinical characteristics, including disease duration, skin involvement, and pulmonary complications, were recorded. The concentrations of 14 sICPs were quantified using a multiplex immunoassay, which measures soluble concentrations of B-and T-lymphocyte attenuator, glucocorticoid-induced TNFR-related protein, herpesvirus entry mediator, indoleamine 2,3-dioxygenase, lymphocyte activation gene 3, programmed cell death protein 1 (PD1), PD1-ligand 1 (PDL1), PDL2, T-cell immunoglobulin and mucin domain 3, cluster of differentiation (CD)27, CD28, CD80, CD137 and CD152 (CTLA4/cytotoxic T-lymphocyte-associated antigen 4). Additionally, sICP concentrations were monitored longitudinally at baseline, 6 months, and 12 months in a subgroup of SSc patients with early, progressive skin and/or interstitial lung disease (ILD) receiving intensified immunosuppressive treatment with plasma exchange.

Results: The study cohort comprised 35 SSc patients with a mean age of 58 years (±SD14.6); 26 patients (74%) were female. ILD was present in 13 patients (37%). Baseline sICP concentrations showed significant correlations with disease duration, higher age, C- reactive protein levels, sIL2R, pulmonary function and ILD. Notably, SSc patients eligible for intensified immunosuppressive therapy (n=14) had higher baseline sICP concentrations, reflecting a more severe disease profile. Longitudinal analysis of sICP concentrations in these SSc patients revealed significant reductions in most sICPs at 6 and 12 months compared to baseline. This suggests that intensified treatment may influence sICP levels and potentially mitigate autoimmune responses in SSc patients.

Conclusions: This study highlights the potential role of sICPs as biomarkers of disease severity and treatment response in SSc. Dysregulation of sICPs is associated with various clinical features of SSc, and intensified immunosuppressive therapy with plasma exchange can modulate sICP levels. Further research is needed to explore the mechanistic implications of these findings and their potential for guiding therapeutic interventions in SSc patients.

P.362

DIFFERENTIAL RECOGNITION OF TOPOISOMERASE 1-DNA COMPLEXES MODULATES ACTIVATION OF TOPOISOMERASE 1-REACTIVE B CELLS IN SYSTEMIC SCLEROSIS

Sam Neppelenbroek¹, Corrie M. Wortel¹, Danique M.H. van Rijswijck², Sophie I.E. Liem¹, Marjolein J.A.L. Wetzels¹, Albert J.R. Heck², Cynthia M. Fehres¹, Jeska K. de Vries-Bouwstra¹, Rene E.M. Toes¹, Hans U. Scherer¹

¹Department of Rheumatology, Leiden University Medical Center, Leiden, THE NETHERLANDS, ²Biomolecular Mass Spectrometry and Proteomics, University of Utrecht, Utrecht, THE NETHERLANDS

Introduction: Human autoimmune diseases are frequently hallmarked by autoreactive B cell responses against nuclear antigens. In a subset of patients with systemic sclerosis (SSc), B cells target the nuclear enzyme topoisomerase 1 (TOP1). Anti-TOP1 autoantibodies (ATAs) associate with severe disease marked by progressive lung and skin fibrosis. Patients with lung fibrosis harbor TOP1-reactive B cells with an activated phenotype. Hence, mechanisms underlying the activation of TOP1-reactive B cells could determine the development of disease and disease manifestations. As DNA binding to TOP1 generates TOP1-DNA cleavage complexes (TOP1cc) that might modulate the antigenicity of TOP1, we studied the effect of DNA binding by TOP1 on the recognition by ATAs and the activation of TOP1-reactive B cells.

Material and Methods: Reactivity of monoclonal ATAs (ATA-mAbs, n=25) generated from patient-derived TOP1-reactive B cells towards TOP1 and TOP1cc was analyzed by ELISA, western blotting and mass photometry. Recognition of TOP1 and TOP1cc by polyclonal ATA-IgG/A/M and ATA-IgG subclasses was studied using plasma from ATA+ SSc patients (n=30), ATA- SSc patients (n=6) and healthy donors (n=6). ATA-expressing RAMOS B cell lines were generated to study B cell activation (Syk phosphorylation) upon stimulation with TOP1 and TOP1cc.

Results: ATA-mAbs differentially recognized TOP1 and TOP1cc. Most ATA-mAbs (20/25) displayed enhanced recognition of TOP1cc compared to TOP1 in ELISA, a finding which could be replicated by western blotting and mass photometry. Antibodies with enhanced TOP1cc recognition (termed anti-TOP1cc autoantibodies) could be observed in plasma of all ATA+ SSc patients tested. Anti-TOP1cc autoantibodies were predominantly ATA-IgG1 and ATA-IgM, but rarely ATA-IgA. Anti-TOP1cc-IgG levels correlated with levels of ATA-IgG (rs=0.81, p<0.001) and lung (rs=0.67, p<0.001) and skin fibrosis (rs=0.56, p=0.008). B cell activation upon stimulation with TOP1 variants was stronger for anti-TOP1cc-expressing RAMOS B cells, an effect which depended on the binding of TOP1 to DNA.

Conclusions: The autoreactive B cell response targeting TOP1 demonstrates remarkable heterogeneity. Our data indicates that DNA binding enhances the immunogenicity of TOP1 by changing the conformation of TOP1. The differential recognition of TOP1 and TOP1cc may be clinically relevant as it determines the degree of ATA-expressing B cell activation, a feature linked to SSc disease manifestations.

P.363

INVESTIGATING THE INTERACTION BETWEEN B CELLS AND SKIN IN SYSTEMIC SCLEROSIS

Mathilde Le Maitre¹, Thomas Guerrier¹, Aurore Collet^1,2, Mehdi Derhourhi^3,4, Benedicte Toussaint^3,4, Amelie Bonnefond^3,4,5, Jean-Pascal Meneboo⁶, Celine Villenet⁶, Sheherazade Sebda⁶, Martin Figeac⁶, Antonino Bongiovanni⁶, Meryem Tardivel⁶, Myriam Simon⁷, Manel Jendoubi¹, Blanche Daunou¹, Alexis Largy¹, Sylvain Dubucquoi^1,2, David Launay^1,7

¹Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, FRANCE, ²CHU Lille, Immunology Institute, Pôle de Biologie Pathologie Génétique, Lille, FRANCE, ³Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, FRANCE, ⁴Université de Lille, Lille, FRANCE, ⁵Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UNITED KINGDOM, ⁶CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UMS 2014 - PLBS, Lille, FRANCE, ⁷Service de Médecine Interne et d'Immunologie Clinique, CHU Lille, Lille, FRANCE

Introduction: Systemic sclerosis (SSc) is associated with alterations of the homeostasis and function of immune cells, among which B cells play a central role. Beyond the production of autoantibodies, B cells infiltrate the skin of patients with SSc as well as of experimental models, display altered phenotypes and functions, and have been shown to directly or indirectly interact with fibroblasts, the main actor of tissue fibrosis in this disease. This interaction has mostly been studied in 2-dimentional settings, suggesting that B cells and fibroblasts could have a reciprocal effect, although data are scarce and sometimes conflicting.

Material and Methods: To further explore the interaction between B cells and fibroblasts in SSc, we developed a coculture model between B cells from SSc patients or heathy donors and 3D healthy reconstructed skin including fibroblasts, keratinocytes, and an extracellular matrix. B cells infiltration was characterized by confocal microscopy and cytometry. We then explored the effect of 2D and 3D coculture conditions by a global bulk transcriptional approach. A specific focus was made on 3D cocultures involving stimulated B cells from SSc patients using single-cell RNA-sequencing. Finally, specific cytokines (IL-6, TNFa, TNFb and Galectin-3) were blocked to decipher the mechanisms of the interactions.

Results: Development of the 3D coculture model, which allows a more physiological model for B cells/skin interactions, showed a consistent infiltration of B cells from SSc patients and healthy controls in healthy skin. Differences in the intensity and nature of the B cell infiltrate were observed depending on the healthy vs SSc patient origin of the lymphocytes and their state of activation. Transcriptomic approaches on cocultures showed differential effects of B cells on fibroblasts in 2D and 3D coculture settings. As an example, activated B cells from patients upregulate genes associated with inflammation and immune response (NFKB2, NFKBIA, TNFAIP3, RELB, ICAM1, TNFAIP2. . .) in sclerodermic fibroblasts in a 2D setting.

Conclusions: The interaction of B cells and skin exists and is dependent on the origin of B cells, their state of activation, and the design of co-culture (2D and 3D).

P.364

BIOMARKERS IDENTIFIED BY DIFFERENTIALLY EXPRESSED RNA IN SYSTEMIC SCLEROSIS

Kevin John Keen¹, Alykhan Rajan², Christopher Ryerson³, Pearce Wilcox³, Basak Sahin², Beth Ann Whalen², James Vincent Dunne³

¹University of Northern British Columbia - Department of Mathematics and Statistics, Prince George, CANADA, ²Providence Health Care Research Institute - Centre for Heart Lung Innovation, Vancouver, CANADA, ³University of British Columbia - Department of Medicine, Vancouver, CANADA

Introduction: Messenger RNA (mRNA) translates genetic information from DNA into proteins. Long non-coding RNAs (lncRNAs) are non-protein coding RNAs (of more than 200 nucleotides) associated with tissue-specific cellular processes. This novel hypothesis-generating study considers the differential expression of both mRNAs and lncRNAs simultaneously in peripheral blood from patients with either the limited cutaneous (lc) or diffuse cutaneous (dc) forms of systemic sclerosis (SSc), with or without interstitial lung disease (ILD), compared to healthy controls and patients with idiopathic pulmonary fibrosis (IPF) but no autoimmune features.

Material and Methods: PAXgene RNA tubes were drawn from 12 patients with dcSSc (including 10 with ILD), 20 patients with lcSSc (including 9 with ILD), 12 patients with IPF, and 12 healthy controls (Table 1). All participants were volunteers and sequentially recruited in accordance with the Declaration of Helsinki and the authors’ Research Ethics Boards. All samples were verified to have sufficient total RNA before plating on an Arraystar Human LncRNA Array 5.0, which profiles 39,317 lncRNAs and 21,174 protein-coding mRNAs. Positive and negative probes were used for quality control. Normalization and data processing were done with GeneSpring GX v12.1 software.

Only differentially expressed lncRNAs and mRNAs with fold changes > 2.0 and P-values < 0.05 were curated for validation by qPCR expression using Arraystar’s PCR Master Mix and log-fold changes relative to GAPDH were assessed with R statistical software.

Results: The sole lncRNA (LINC01730) selected was confirmed as differentially expressed by qPCR; from five mRNAs, the four genes ANKS1A, KLRC2, PANTR1, and PARP15 were confirmed as differentially expressed in SSc by qPCR (Table 2), whereas NCBP1 was not.

Compared to controls: (1) LINC01730 expression in patients with dcSSc but not ILD was upregulated; (2) ANKS1A expression in patients with lcSSc but not ILD was downregulated; (3) PANTR1 in patients with dcSSc but not ILD was downregulated; (4) KLRC2 expression was approximately doubled in qPCR for all patient groups except for dcSSc without ILD and IPF; (5) PARP15 expression was upregulated about 2.5 times for all patient groups except for lcSSc without ILD.

Conclusions: This study found that qPCR expression relative to GAPDH of either KLRC2 or PARP15 could serve as a biomarker for SSc. In process is genome-wide DNA sequencing of these samples to assess allelic variation of the genes found in this study. A confirmatory study with 150 more samples from our Scleroderma Biobank would address the issue of small sample for this study.

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AN EXPLORATIVE ANALYSIS OF EXTRACELLULAR VESICLES AND EVS EMBEDDED MIRNAS AT DIFFERENT SYSTEMIC SCLEROSIS DISEASE STAGES

Chiara Bellocchi^1,2, Alessandro Albini³, Alessandro Santaniello¹, Lorenzo Beretta¹, Martina Iacubino², Federica Rota⁴, Laura Cantone⁴, Giulia Solazzo⁴, Laura Dioni⁴, Luca Ferrari^4,5, Valerina Bollati^4,5, Marco Vicenzi^2,6

¹Scleroderma Unit, Referral Center for Systemic Autoimmune Diseases, Fndz IRCCS Ca Granda Ospedale Maggiore Policlinico, Milan, ITALY, ²Dyspnea Lab, Department of Clinical Sciences and Community Health, University of Milan, Milan, ITALY, ³Cardio-Thoracic and Vascular Department, San Gerardo Hospital, ASST-Monza, Monza, ITALY, ⁴EPIGET Lab, Department of Clinical Sciences and Community Health, University of Milan, Milan, ITALY, ⁵Occupational Health Unit, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Milan, ITALY, ⁶Department of Cardio-Thoracic-Vascular Diseases, Foundation IRCCS Ca Granda Ospedale Maggiore Policlinico, Milan, ITALY

Introduction: the biomolecular mechanisms behind systemic sclerosis (SSc) and pulmonary arterial hypertension SSc-related (SSc-PAH) are not yet well elucidated. Some studies investigated circulating micro-RNA (miRNAs) but none study analyzed miRNAs embedded to extracellular vesicles (EV-miRNAs) in these patients. This pilot study aimed to investigate EVs and EV-miRNAs, in 3 preclinical SSc (PreSSc),3 SSc at high risk of PAH but without clinical diagnosis of PAH (SSc-PAH-), and 3 SSc with PAH diagnosis (SSc-PAH+) vs. 3 healthy controls (HCs) age and gender matched.

Material and Methods: PreSSc were characterized by solely Raynaud phenomenon, specific positive antibodies and positive capillaroscopy without any skin or internal organ fibrosis. SSc-PAH+ had a positive right heart chateterization while SSc-PAH- had not, despite a DETECT algorithm positivity (Table1). A total of 12 subjects underwent a blood sample collection at one time point and the experiment was conducted in three batches (4 patients a group, one for each condition). The isolated EVs were characterized by flow cytometry and their concentrations and dimensions were measured by Nanoparticle Tracking Analysis (NTA). The miRNAs isolated form EVs and differentially expressed among the four groups were selected for a gene-target analysis. Moreover, an in vitro study was performed by exposing a culture of murine smooth muscle cells (SMC) to EVs from SSc patients and HCs for 24h.

Results: in PreSSc vs. HCs, we observed 6 downregulated (miR-107, miR-382, miR-323-3p, miR-645, miR-379, miR-224-3p) and 1 upregulated (miR-326) EV-miRNAs. Three EV-miRNAs (miR-324-3p, miR-379, miR-363) were downregulated in SSc-PAH+ compared to HCs, and the two EV-miRNAs miR127 and miR720 were downregulated in SSc-PAH- vs HCs. EV-miRNAs miR-324-3p and miR-210-3p were downregulated in SSc-PAH+ vs. SSc-PAH-, while the miR-144-5p was upregulated (Figure1). The in vitro study showed that SSc-PAH- and PreSSc EVs vs. HCs induced a greater SMC growth (Figure2). After gene-target analysis, 29 genes were found where 2 genes, VDR and BMPR2, were targeted by more than one miRNA.

Conclusions: we observed significant differences of EV-miRNAs in SSc vs. HCs. Plasma-derived EVs from SSc can influence the in vitro growth of murine SMC with a higher effect of SSc-PAH- and PreSSc derived-EV-miRNAs. EV-miRNAs of interest emerged to be differentially expressed among the 4 groups and one gene known to be associated with a greater risk to develop PAH, BMPR2, was targeted by more than one EV-miRNA. The relationship between EV-miRNAs and pulmonary vascular disease in SSc as well as in PreSSc is worthy to be extensively further explored.

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SERUM BASED BIOMARKER ALGORITHM TO PREDICT RAPID PROGRESSION OF FVC IN SSC ACROSS DISEASE SUBSETS

Kakkar Vishal¹, Sunhwa Kim², Marco Di Battista¹, Rebecca Ross³, Yingtao Bi⁴, Thierry Sornasse¹, Francesco Del Galdo¹

¹Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UNITED KINGDOM, ²AbbVie Precision Medicine Immunology, South San Francisco, USA, ³Wellcome Trust Brenner Building, St James University Teaching Hospital, Leeds, UNITED KINGDOM, ⁴AbbVie Discovery and Exploratory Statistics, Worcester, USA

Introduction: Systemic sclerosis (SSc) is a multisystemic connective tissue disease, characterised by widespread organ fibrosis, vasculopathy and immune dysregulation, occurring at different stages of the condition. ILD remains the leading cause of mortality in SSc. In this study, we implemented a retrospective longitudinal serum proteomic analysis to identify prognostic biomarkers (pBMs) providing the likelihood of FVC decline in SSc.

Material and Methods: We identified baseline sera with matched FVC measurements (+-3 months from the date the sera were obtained) from 100 patients (33 Very Early Diagnosis of SSc [VEDOSS], 21 Limited Cutaneous SSc [LcSSc] and 46 Diffuse Cutaneous SSc [DcSSc]) from a large multicentre observational study. FVC rapid progressors (rP) were defined as patients with a monthly rate of FVC% predicted deterioration of over 0.5%. Olink proteomics was employed to determine the relative levels of 1536 pBMs (95.8% passed quality control) in the patients’ sera. Machine Learning (Random Forest) analysis was employed to identify and rank pBMs that best separated the two groups (rP vs non rP). Logistic regression and standard ROC analysis were built to determine the predictive value of pBMs. Backward elimination was then performed on the regression analysis to select the pBMs with the highest statistical significance.

Results: 20 patients (20%) met the rP criteria in the cohort (3 VEDOSS, 2 LcSSc and 15 DcSSc). Random Forest analysis prioritised 18 pBMs as the best predictors of rapid progression event independent of disease subset or duration. The discovery statistical model including all 18 pBMs, showed an 80% positive predictive value (PPV) and an 87% negative predictive value (NPV) in identifying rP patients. ROC curve analysis showed an AUC of 0.8725 (Figure 1). Backward elimination identifying a model using 4 specific pBMs had the greatest statistical significance. The PPV was 92.3% and NPV of 90.8%. ROC curve analysis showed an AUC of 0.848 (Figure 1).

Conclusions: In this study we have performed initial exploratory analysis to identify a group of pBMs potentially associated with the rapid decline in FVC across SSc subsets. Although our results are encouraging, validation through standard proteomic quantification and further studies in a large independent cohort would be necessary to confirm the reliability and robustness of this predictive model. This would also inform on the clinical value of a combined biomarker blood test in aiding the stratification for risk of ILD progression in SSc.

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HIGH THROUGHPUT MULTIPLEX ASSAY IDENTIFIES CLINICALLY MEANINGFUL CLUSTERS IN SYSTEMIC SCLEROSIS PATIENTS WITH LOW CARDIOVASCULAR RISK AND NO HISTORY OF HEART DISEASE

Rudresh Shukla^1.2, Raluca Dumitru³, Bara Erhayiem⁴, Graham Fent⁴, Francesco Del Galdo^3.5, Sven Plein⁴, Darren Plant^1,2, Maya H. Buch^1,2,3

¹University of Manchester - Centre for Musculoskeletal Research, Manchester, UNITED KINGDOM, ²Manchester University NHS Foundation Trust - NIHR Manchester Biomedical Research Centre, Manchester, UNITED KINGDOM, ³University of Leeds - Leeds Institute of Rheumatic & Musculoskeletal Medicine, Leeds, UNITED KINGDOM, ⁴University of Leeds - Multidisciplinary Cardiovascular Research Centre (MCRC) and Leeds Institute of Cardiovascular and, Leeds, UNITED KINGDOM, ⁵Leeds Teaching Hospitals NHS Trust - NIHR Leeds Biomedical Research Centre, Leeds, UNITED KINGDOM

Introduction: People with systemic sclerosis (SSc) often show subclinical evidence of primary heart involvement (pHI), which when clinically evident, is a prognostic factor of poor outcome. We aimed to profile serum proteins in patients with SSc and no history of pHI and identify clinically meaningful clusters to aid early identification and stratification for pHI.

Material and Methods: Serum from 78 patients from CONVAS (‘CONnective Tissue Disease and VASculitis Cohort’) and ELCASA (‘ELectrophysiology and CArdiac imaging in SclerodermA’) cohorts with no history of pHI, pulmonary hypertension, diabetes or more than 2 traditional cardiovascular (CV) risk factors was used to measure levels of 355 proteins across inflammation, cardiometabolic and cardiovascular II/III Olink panels. Unsupervised hierarchical clustering using scaled normalised protein expression (NPX) was used to define clusters. Demographic and clinical characteristics were compared between clusters and significant differences reported using Kruskal Wallis rank sum test for continuous or Pearson’s chi-squared test for categorical variables, at the 5% significance threshold.

Results: Clinical characteristics of the patient cohorts have been previously published and are summarised in fig 1A (column 2). Unsupervised hierarchical clustering revealed 3 patient clusters – C1 [27/78 (35%)], C2 [33/78 (42%)] and C3 [18/78 (23%)] with intermediate, low and high protein expression respectively (fig 1B). C2 patients were younger (median age 51 years) compared to C1 (61 years) and C3 (58 years) (p <0.001). High expression cluster C3 had a significantly higher proportion of males [7/18 (39%)](p = 0.009), shorter disease duration [median 1.15 years, IQR (0.66 to 7.23)], higher modified Rodnan skin scores (MRSS) [median 5.50, IQR (3.25 to 11)] (p = 0.002) and current disease modifying anti-rheumatic drugs (DMARD) use [16/18 (89%)](p = 0.005). NTproBNP and CRP were elevated in C1 and C3, and high-sensitivity troponin I (hsTnI) was highest in C3[median 6.15 IQR (5.08 to 89.58)](p = 0.002); n=3 within C1 (black box fig 1A) showed especially high NTproBNP (median 227.50pg/ml) and CRP (median 13mg/dl). No differences in antibody profiles were noted across the three clusters (fig 1A).

Conclusions: Differences in serum protein expression identifies clinically meaningful clusters of SSc patients with elevated acute phase and serum cardiac markers despite low CV risk profile. Future work should assess their utility as prognostic biomarkers of SSc-pHI.

P.368

HIGH-THROUGHPUT PROTEOMICS TO IDENTIFY NOVEL BIOMARKERS ASSOCIATED WITH LUNG FIBROSIS IN SYSTEMIC SCLEROSIS

Marija Geroldinger Simic^1,2, Federica Ress^3,4, Sofia Bergström³, Emmie Pohjanen³, Norbert Sepp¹, Mathias Uhlen³, Peter Nilsson³, Elisa Pin³

¹Department of Dermatology and Venereology, Ordensklinikum Linz Elisabethinen, Linz, AUSTRIA, ²Faculty of Medicine, Johannes Kepler University Linz, Linz, AUSTRIA, ³Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Stockholm, SWEDEN, ⁴Department of Cellular, Computational and Integrative Biology CIBIO, University of Trento, Trento, ITALY

Introduction: Systemic sclerosis (SSc) is a rare chronic disease leading to decreased quality of life and survival due to skin and/ or vital organ pathology caused by fibrosis, inflammation, and vascular damage. Early diagnosis is crucial for clinical benefit in SSc patients. Our study aimed to identify novel autoantibodies and proteins in plasma of SSc patients that could serve as early biomarkers of fibrosis.

Material and Methods: In-house developed antigen arrays were generated using 42,000 protein fragments representing 18,000 unique human proteins, as well as 2,000 full-length versions of secreted proteins from the Human Protein Atlas collection (www.proteinatlas.org). Through a well optimised workflow and data analysis pipeline, we performed proteome-wide screenings and verification of autoantibodies in plasma collected from a deeply characterised sample cohorts including 193 longitudinally collected samples from 83 SSc patients and 52 plasma samples from matched controls. Patients and controls were enrolled at the EUSTAR center in Linz (Austria). Moreover, the Olink Explore HT technology was applied on a selection of 100 SSc plasma samples to profile 5,300 proteins.

Results: The screening allowed to identify several fibrosis-associated autoantibodies and proteins that, as single or in panels, showed their potential to serve as new candidate biomarkers to improve the diagnosis, subclassification and molecular characterization of SSc patients.

Conclusions: The combination of clinical expertise and high-throughput cutting-edge proteomics allowed us to generate high quality data and combine autoantibody and protein profiling. Further studies in larger cohorts are needed to validate these results.

P.369

MULTI-OMIC ANALYSIS OF BRONCHOALVEOLAR LAVAGE FLUID FROM PATIENTS WITH SYSTEMIC SCLEROSIS

William Odell¹, Cassandra Van Horn¹, Zeljka Popovic², Giulio Fulgoni³, Vasilis Vasiliou², Richard Pierce³, Monique Hinchcliff¹

¹Yale School of Medicine, Department of Internal Medicine, Section of Rheumatology, Allergy & Immunology, New Haven, USA, ²Yale School of Public Health, Department of Environmental Health Sciences, New Haven, USA, ³Yale School of Medicine, Department of Pediatrics, New Haven, USA

Introduction: Radiographically evident interstitial lung disease (ILD) occurs in ~90% of patients with systemic sclerosis (SSc) and is the leading cause of early mortality. Bronchoalveolar lavage (BAL) affords investigators a method for obtaining tissue from patients at the site of injury. In BALF from SSc patients with and without ILD, we characterize the inflammatory proteomic and metabolomic signatures, as well as the effect of BALF on human pulmonary endothelial cell permeability.

Material and Methods: SSc patient and healthy control (HC) participants underwent BAL and chest high-resolution computed tomography. Clinical data were obtained from the electronic health record. Bronchoalveolar lavage fluid (BALF) was subjected to MesoScale Discovery Pro-Inflammatory proteomic immunoassay (Rockville, Maryland), and results (protein level reported in pg/mL) were analyzed using Discovery Workbench and Prism with unpaired t-tests. Untargeted metabolomics using liquid chromatography/mass spectrometry (LC-MS) was also performed following a biphasic extraction to capture both polar and non-polar metabolites. Metabolite identification and pathway enrichment analysis were conducted using MetaboAnalyst. Lastly, healthy human pulmonary microvascular endothelial cells (HPMEC) were plated on an electric cell impedance sensing plate (ECIS) and treated with BALF, TNF-α (positive control) or PBS (negative control) for 15 h. Trans-endothelial electrical resistance (TEER) was measured at 3-minute intervals and relative resistance (as an indirect measure of intact cell-cell barrier function) was calculated using Prism.

Results: We recruited 38 participants (n=32 SSc and 6 HC). 17 (53%) SSc patients had radiographic ILD. Compared to SSc patients without ILD, Interleukin 8 (IL-8, p = 0.32), IL-13 (p = 0.08) and TNF-α (p = 0.16) were numerically higher, and IL-10 (p = 0.02), significantly higher, in patients with ILD. Metabolites associated with aminoacyl-tRNA biosynthesis, purine metabolism, and glycine, serine, and threonine metabolism were most significantly enriched in BALF samples (p < 0.01). HPMEC treated with SSc patient BALF elicited a greater decrease in TEER compared to HC (area under the curve/AUC 13.80 vs 14.41 arbitrary units), but a smaller difference compared to TNF-α treatment (AUC 13.80 vs 14.01 arbitrary units). There were no significant differences in TEER between BALF from SSc subgroups (lcSSc vs dcSSc and SSc vs SSc-ILD).

Conclusions: Patients with SSc-ILD may have more pro-inflammatory cytokines in BALF compared to patients without ILD and HC. Metabolomic analysis revealed amino acid and nucleic acid metabolism as pathways of interest; targeted metabolomics is underway to compare quantitative differences between subgroups. Lastly, treatment of HPMEC with SSc compared to HC BALF decreased paracellular resistance, implying increased endothelial permeability.

P.370

PERTURBED PERIPHERAL IMMUNE CELL SUBSETS WITH DISTINCT EXPRESSION OF CHEMOKINE RECEPTORS AND IMMUNE CHECKPOINTS IN PATIENTS WITH ACTIVE DISEASE IN THE SYSTEMIC SCLEROSIS COHORT SINGAPORE

Maria Noviani¹, Andrea Hsiu Ling Low^1,2, Vasuki Ranjani Chellamuthu³, Ahmad Lajam³, Alfred Yu Ting Chia^2,3, Katherine Nay Yaung^2,3, Martin Wasser³, Joo Guan Yeo^3,4, Salvatore Albani^2,3,4

¹Singapore General Hospital, Department of Rheumatology and Immunology, Singapore, SINGAPORE, ²SingHealth Duke-National University of Singapore Academic Medical Centre, Translational Immunology Institute, Singapore, SINGAPORE, ³Duke-National University of Singapore Medical School, Singapore, SINGAPORE, ⁴KK Women's and Children's Hospital, Singapore, SINGAPORE

Introduction: Systemic sclerosis (SSc) is a heterogenous disease characterised by autoimmunity, vasculopathy, and fibrosis. This study aimed to identify characteristic peripheral blood-derived immune signatures that are associated with disease activity. Our findings could shed light into disease pathogenesis and potentially be integrated into clinical evaluation of active disease to guide treatment strategies.

Material and Methods: Peripheral blood mononuclear cells (PBMC) were collected from SSc patients (n=12 active, n=20 inactive, n=3 inactive with progressive interstitial lung diseases (ILD), and age-and-sex matched healthy controls (HC, n=8). Active disease was defined by composite EUSTAR-activity index score >2.5. Progressive ILD was defined by a combination of imaging, pulmonary function tests and respiratory symptoms. PBMC samples were analysed by using mass cytometry (CyTOF) with a panel of 43 unique markers. The CyTOF data was analysed using the Extended Polydimensional Immunome Characterization (EPIC) platform, which is an unsupervised machine learning algorithm to identify immune cell subset perturbations. Using cell frequencies of the identified cell subsets, multiple logistic regression model was built to classify active and inactive disease.

Results: Patient characteristics were summarised in Table 1.Dysregulations in various immune cell lineages were observed in the peripheral immunome of active SSc, as compared to inactive SSc and HC. CD45RA+ B cells expressing CCR6 (mucosal tissue targeting chemokine receptor) and CXCR5 (lymphoid organs targeting receptor) were significantly increased in active SSc, as compared to inactive SSc (Figure 2A). In the T cell compartment, CCR7+ naïve CD4+ T cell subset expressing CD152 (CTLA4), which is an immune checkpoint, was significantly reduced in active SSc, as compared to inactive SSc and HC (Figure 2B). We also observed a significant decrease in CD31+ CD8+ T cell subset in active SSc, as compared to inactive SSc and HC (Figure 2B). By using cell frequencies of the identified immune cell subsets, we built a multiple logistic regression model and the Receiver Operating Characteristic (ROC) curve analysis showed an area under the curve (AUC) of 0.9545 (95%CI=0.8862-1.000, p<0.0001), with negative predictive power of 91.30% and positive predictive power of 90.91% (Figure 2C).

Conclusions: We identified dysregulated immune cell subsets with distinct expression of chemokine receptors and immune checkpoints, suggesting perturbed immune cell trafficking and regulatory mechanism. Further studies are needed to investigate the functional significance of these immune cell subsets and their roles in the disease pathogenesis. The identified immune signatures may potentially be used as diagnostic tools to evaluate disease activity in SSc and further validation studies are needed.

P.371

REANALYSIS OF SINGLE-CELL RNA-SEQUENCING DATA REVEALS ALTERATIONS IN IMMUNE CELL PROPORTIONS AND TYPE I INTERFERON SIGNALING IN SYSTEMIC SCLEROSIS MYELOID CELLS

Daniel Nilov^1,2, William Odell², Micha Sam B. Raredon³, Sylvain Dubucquoi¹, Vincent Sobanski^1,4,5, Monique Hinchcliff^2,5

¹University of Lille, Inserm, CHU Lille, U1286-INFINITE, Institute for Translational Research in Inflammation, Lille, FRANCE, ²Department of Internal Medicine, Section of Rheumatology Allergy & Immunology, Yale School of Medicine, New Haven, CT, USA, ³Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale School of Medicine, New Haven, CT, USA, ⁴Département de Médecine Interne et Immunologie Clinique, Centre de Référence des Maladies Auto-immunes Systémiques Rares, Lille, FRANCE, ⁵co-last authors

Introduction: In a recent paper (Gur et al. Cell 2022), the authors analyzed single-cell transcriptomic data from controls’ and SSc patients’ skin and blood cells and described quantitative and functional differences in LGR5-expressing fibroblasts. Because autoimmunity is a key tenet of SSc pathogenesis, we posited that these data could be re-analyzed for a more in-depth exploration of potential immune anomalies.

Material and Methods: Unique Molecular Identifier (UMI) counts and patient metadata were obtained from GSE195452 and imported into RStudio. ATAC samples were excluded. The Seurat package (v4.1.3) was used to analyze scRNA-seq data using standard pre-processing parameters. Unsupervised clustering was used at the global and myeloid cell levels. Cell proportions, differential expression (DE), gene ontology (GO) term enrichment and gene set enrichment (GSEA) analyses were conducted on 57 controls and 94 SSc patients (41 lcSSc and 53 dcSSc). Resulting DE genes were filtered to exclude uninformative transcripts.

Results: The dataset containing information from both skin and blood samples was partitioned into 28 clusters through unsupervised clustering (Fig. 1). Cell type proportions analysis revealed decreased naïve T lymphocytes as well as increased skin plasma cells, blood monocytes and skin macrophages in SSc individuals compared to controls. GO term analysis conducted on all skin and blood immune cells showed increased activation of innate immune pathways in SSc PBMCs, prompting subsequent exploration of myeloid cells. DE testing between SSc and controls revealed 33 genes in CD14+ monocytes, 31 genes in dendritic cells, 27 genes in macrophages, and 3 genes in CD16+ monocytes (> 1.41 fold-change, Bonferroni adjusted p < 0.05). Upregulated genes in CD14+ monocytes, dendritic cells, and macrophages in the SSc group included IFI6, IFI27, IFI44L, ISG15, IFITM1/2/3, etc. indicative of a Type I Interferon (IFN) signature (Fig. 2A). GSEA performed on the aforementioned cells corroborated the Type I IFN signature as well as inflammatory pathway enrichment present in a subset of SSc patients’ monocytes, macrophages, and dendritic cells (Fig. 2B).

Conclusions: These results strengthen the growing body of evidence that supports the role of innate immunity dysregulation in SSc pathogenesis and provide interesting insights into the contribution of individual cell types due to single-cell resolution. Notably, Type I IFN myeloid cells may be implicated in specific disease pathogenesis in SSc patients. Further analyses are underway to explore upstream and downstream cell signaling.

P.373

A PROTEOMICS-BASED APPROACH FOR THE CLASSIFICATION OF PATIENTS WITH SYSTEMIC SCLEROSIS

Suzan Al-Gburi¹, Pia Moinzadeh¹, Nicolas Hunzelmann¹, Beate Eckes², Stefan Mueller³, Thomas Krieg^1;2

¹University Hospital Cologne, Cologne, GERMANY, ²Translational Matrix Biology, Cologne, GERMANY, ³CECAD / CMMC Proteomics Facility, Cologne, GERMANY

Introduction: Systemic sclerosis (SSc) is a very heterogeneous systemic disease, characterized by the development of fibrosis in multiple organs. The disease undergoes various phases depending on the activity of the inflammatory and/or fibrotic reaction. Therapeutic decisions have to be based on disease progression in individual patients. Therefore, identification of biomarkers reflecting disease activity and the specific subset are required. Whereas analysis of biopsies requires an invasive procedure, serum samples are obtained more easily. There has been a rapid development in applying state of the art proteomics to the analysis of many different diseases to obtain an unbiased approach.

Material and Methods: We here used serum samples from well characterized patients with limited (lcSSc; 12 patients) and diffuse SSc (dcSSc; 8 patients) as well as controls. Mass-spectrometry based proteomics were used with and without previous depletion of the most abundant serum proteins.

Results: The data demonstrate clear differences between controls and SSc samples. The undepleted samples showed high amounts of immunoglobulins present mainly in dcSSc patients. In a further analysis, high proteasome subunit, 14-3-3 protein and polyubiquitin-B concentrations were detected in SSc patients. Also Rho GTPases revealed induced levels in the SSc group compared to controls. Elevated levels of plasminogen activator inhibitor 1 and transforming growth factor beta-1 were detected in SSc patients, mainly in the diffuse subset. We also found induced signatures for Wnt signaling, cell cycle control and B-cell signaling in the SSc patients. Whereas significant differences in the signatures between SSc patients and controls were clearly detected, it was more difficult to identify markers differentiating between dcSSc and lcSSc patients. A heatmap analysis in both groups showed a difference in the enrichment analysis in the clusters “plasma lipid transport“ and “extracellular matrix”. Altogether, 123 proteins were found to be induced in dcSSc patients compared to controls. lcSSc patients revealed a less pronounced increase of the proteins. 36 proteins were found to be downregulated in dcSSc patients compared to controls.

Conclusions: In conclusion, we here present data from a preliminary study using a limited number of scleroderma patient serum samples, which allow a clear distinction between SSc patients and controls. The data also indicate more heterogeneity of patients in the group of the limited subset, which cannot be distinguished based on the clinical classification. Further studies are required to analyze whether state of the art proteomic studies might be helpful to reconsider the current classification of SSc.

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MULTIOMIC PROFILING OF PATIENTS WITH SYSTEMIC SCLEROSIS IN SEARCH OF MOLECULAR SIGNATURES ASSOCIATED WITH PROGRESSIVE INTERSTITIAL LUNG DISEASE

Selena Bouffette^1,2, Alice R. Cole³, Pierre Barbier Saint Hilaire⁴, G. Leclerc¹, Audrey Aussy¹, Angela Tam³, Korsa Khan³, Voon Ong³, Marc Pallardy¹, Jeanne Allinne¹, Philippe Moingeon¹, David J Abraham³, Christopher P Denton³

¹Servier, Neurology and Immuno-inflammation Therapeutic Area, Servier R&D Institute, Gif-sur-Yvette, France, ²Université Paris-Saclay, Inserm, Inflammation Microbiome and Immunosurveillance, Orsay, France, ³University College London, Institute of Immunity and Transplantation, London, United Kingdom, ⁴Technologie Servier, Servier R&D Institute, Gif-sur-Yvette,France

Introduction: Introduction Systemic Sclerosis (SSc) is a rare autoimmune connective tissue disease, whose primary cause of mortality is Interstitial Lung Disease (ILD). The underlying mechanisms of ILD and its rapid progression are still unclear and result in an unmet need for effective therapies that can preserve lung function and patients' quality of life.

The current study aims at identifying markers of ILD progression in SSc through a longitudinal multi-omics comparative analysis of SSc plasma soluble mediators, skin and blood gene expression and peripheral blood mononuclear cell (PBMC) phenotype in concurrently collected patient samples.

Material and Methods: Patients with SSc were recruited into two longitudinal cohorts. The first cohort included 30 patients selected retrospectively from the UCL database. For each patient, samples were collected at 3 separate timepoints between 2000 and 2020 to follow ILD progression or absence thereof. The second cohort included five healthy subjects and 12 patients recruited prospectively between January and December 2021, with samples collected at two separate timepoints with a six-month gap.

Plasma samples from both cohorts were available for quantification of ~400 soluble mediators by metabolomics (Biocrates analysis kit), proteomics (measurement by mass spectrometry) and cytokine analysis by multiplex (Meso Scale Discovery). Gene expression profiling of SSc blood and skin, alongside flow cytometry analysis of PBMC, was performed exclusively on samples from the second cohort only. Results were subjected to supervised statistical analysis.

Results: Patients with SSc were categorised into 2 groups based on ILD progression: "SSc-no ILD," characterized by less than 5% lung involvement on high-resolution computed tomography (HRCT) at all collection time points, and "SSc-ILD," exhibiting visible ILD progression, characterised by 20% lung involvement or more and confirmed by forced vital capacity (FVC) levels falling below 70%.

Analysis of plasma cytokine profiles in the first cohort showed notable differences in CX3CL1, CCL2, PDGF-A and IL-8 levels between the two groups. In the second cohort, preliminary results of the metabolomic and proteomic analyses of SSc plasma showed significant differences when compared to healthy controls, and the "SSc-ILD" blood and skin transcriptomes highlighted a prominent IFN- and IFN- signature.

Conclusion: This innovative study design allowed a comprehensive comparison of well-defined SSc patient subgroups over an extensive timespan. Ongoing analyses will integrate all results, offering a deeper mechanistical insight into ILD progression, which could facilitate earlier targeted treatments to improve long-term outcomes in a precision medicine approach.