02. Pulmonary including Interstitial Lung Disease and Pulmonary Arterial Hypertension

P.067

Mycophenolate Mofetil as First Line Treatment Improves Early Lung Disease in Patients with Diffuse Systemic Sclerosis

N. Zotos¹, M. Gianniki², M. Gerasimou¹, E. Tatsina¹, D. Bougias², P. Christodoulou¹, C. Mitsis¹, A. Zotou¹, A. Pournou¹, N. Tsifetaki²

¹ Immunology Department, Ioannina, GREECE, ² Rheumatology Department, Ioannina, GREECE

Introduction: The aim of this study was to find an alternative immunosuppressive treatment instead of cyclophosphamide which would be effective but also safe for the treatment of patients with diffuse systemic sclerosis and clinical evident alveolitis.

Material and Methods: We studied 4 patients with diffuse systemic sclerosis (3 with recent alveolitis and 1 with chronic alveolar fibrosis) who received mycophenolate mofetil(MMF) and low dose (<=10 mg/d) corticosteroids. At the beginning of their treatment and at predetermined points during the study, patients except from clinical evaluation, were submitted to pulmonary function tests (Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) and Forced Vital Capacity (FVC) and High-Resolution Computed Tomography (HRCT)

We have recorded all cases of major infections, leucopenia and abdominal pain.

Results: After 6 months of MMF treatment, DLCO values improved significantly compared with baseline (average DLCO:74,8% versus 63,1%).

Pulmonary lesions were minimized in 2 out of 3 patients with recent alveolitis and decreased in a patient after 6 months of MMF treatment. Dyspnoea and cough have been minimized within 3 months. There were no significant adverse events during our study.

Conclusions: Our results suggest that the use of MMF as a first-line treatment with low dose corticosteroids from patients with diffuse systemic sclerosis and early clinical evident alveolitis is likely to be an effective, well tolerated and safe alternative treatment .

P.068

Interstitial Lung Disease in SCL70-Positive Scleroderma Patients with Limited Cutaneous Form

E. Zanatta¹, P. Polito¹, E. Balestro², M. Favaro¹, E. Pigatto¹, F. Ometto¹, A. Martini³, L. Punzi¹, F. Cozzi¹

¹ Rheumatology Unit - Department of Medicine DIMED, University of Padua, Padova, ITALY, ² Respiratory Diseases Clinic, University of Padua, Padova, ITALY, ³ Unit of Internal Medicine - Department of Medicine DIMED, University of Padua, Padova, ITALY

Introduction: Anti-topoisomerase-I (SCl70) antibody positivity classically associates with diffuse cutaneuos SSc (dSSc), while anti-centromere antibody (ACA) with limited cutaneous SSc (lSSc); however, a population of patients with antiScl70 positivity and lSSc has been described.

Interstitial lung disease (ILD) is nowadays the first cause of mortality in patients with SSc; its progression can range from a self-limiting form to a rapidly progressive lung involvement despite immunosuppressive treatment.

The aim of our study was to investigate the pulmonary involvement in patients with SCl70 positivity and limited cutaneous form (SCl70-lSSc) in comparison to those affected by diffuse cutaneous form (SCl70-dSSc). Our second endpoint was to identify predictors of ILD worsening.

Material and Methods: Consecutive 110 scleroderma patients affected by ILD on HRCT (score higher than 2) attending the SSc clinic of University of Padova were included and retrospectively evaluated. 92 patients were female and 18 male, the mean age and disease duration were respectively 57.9 ±13.9 and 14.84 ± 10.55 yrs . For all patients we considered spirometry indexes (FVC e DLCO) and HRCT at ILD onset and at last follow up. Time between SSc onset and ILD first evidence was defined as “scleroderma free ILD”. ILD grading was determined according to a validated score by a trained radiologist. ILD progression was defined as either an HRCT score worsening of at least 2 points, or as a significant progression of spirometry indexes, namely 10% and 15% for FVC and DLCO respectively.

Results: SCl70-dSSc patients were more frequently affected by ILD than SCl70-lSSc (p<0.0001), which showed a longer “scleroderma free-ILD”. At ILD onset pulmonary function was worse in the SCl70-dSSc group than SCl70-lSSc group (p=0.02 e p=0.009 for FVC e DLCO respectively), even in the absence of a significant difference between HRCT scores (10.25±4.93 vs 12.73±5.25, p=0.284). The mean ILD duration was 8±4 years, similar in both group (p=0.978). Total ILD progression was significantly higher in SCl70-dSSc (p<0.0001). Multivariable regression analysis showed that diffuse cutaneous form was an independent predictors of ILD progression (OR 10.18, 95% CI 2.85-36.38, p<0.001).

Conclusions: The results of our study demonstrated that ILD is more frequent and progressive in patients SCl70-dSSc than in SCl70-lSSc. Cutaneous diffuse form resulted to be a significant predictor of ILD worsening. Since the correct classification of SSc patients is extremely important in view of a prompt treatment, our data confirm that it could be worth to identify patients with SCl70 and limited cutaneous form as a different and specific subset.

P.069

A Phase II Randomized Controlled Trial of Abituzumab in Systemic Sclerosis-Associated Interstitial Lung Disease

D. Khanna¹, D. Tashkin², A. Wells³, J. Goldin², M.W. Lubell⁴, S. Wax⁴, D. Damian⁴, C. Denton⁵

¹ University of Michigan, Ann Arbor, USA, ² University of California Los Angeles (UCLA), Los Angeles, USA, ³ Royal Brompton Hospital, London, UNITED KINGDOM, ⁴ EMD Serono, Billerica, USA, ⁵ University College London (UCL), London, UNITED KINGDOM

Introduction: Systemic Sclerosis (SSc) has features of autoimmunity and progressive fibrosis. Interstitial lung disease (ILD) develops in up to 75% of patients (pts) and mycophenolate is associated with clinical benefit.

Aim: Assess if abituzumab, a humanized monoclonal antibody against αv integrins (which activate TGFβ, which is pro-fibrotic) has benefit as add-on therapy to mycophenolate in SSc-ILD.

Material and Methods: Randomized, double-blind, placebo-controlled, multicenter, phase II study (NCT02745145). Eligible pts: 18–75 years with ACR/EULAR-defined SSc (<7 years duration) receiving mycophenolate for >=6 months (stable dose >=3 months), forced vital capacity (FVC) 40–85% predicted, diffusing capacity of the lung for carbon monoxide >=30% predicted and >=5% quantitative lung fibrosis on high-resolution computed tomography (HRCT). Pts randomized (2:1:2) to intravenous placebo, abituzumab 500mg or 1500mg every 4 weeks (wks) for 104wks.

Results: Primary endpoint: annual rate of absolute FVC change at 52 wks. Sample size (n=175) enables detection of a mean difference in annual rate of 150mL between treatment and placebo arms with 80% power, assuming the SD in both arms is 300mL. Interim futility analysis planned when 50% of pts have completed 52wks or discontinued prematurely. Key secondary endpoints: change at wk 52 in 1) dyspnea (Mahler transition dyspnea index); 2) quality of life (St George Respiratory Questionnaire); 3) modified Rodnan skin score in pts with diffuse cutaneous skin involvement; 4) quantitative lung fibrosis on HRCT; 5) overall survival. Safety is also assessed.

Conclusions: This study will evaluate the potential benefit added by abituzumab to mycophenolate in SSc-ILD.

P.070

Characteristics of Anti-U1RNP-Antibody-Positive Patients with Pulmonary Arterial Hypertension Are Influenced by the Presence or Absence of Systemic Sclerosis Features

H. Yasuoka¹, H. Takei¹, Y. Shirai², K. Yamaoka¹, M. Kuwana^1,2, T. Takeuchi¹

¹ Keio University School of Medicine, Tokyo, JAPAN, ² Nippon Medical School Graduate School of Medicine, Tokyo, JAPAN

Introduction: Pulmonary arterial hypertension (PAH) is the one of leading causes of death and predicts mortality in patients with systemic sclerosis (SSc). In SSc, it is suggested that anti-U1RNP antibody (U1) is associated with development of PAH in SSc. The aim of this study is to clarify whether the presence of SSc features can determine the characteristic of PAH in patients with anti-U1RNP antibody-positive patients with PAH.

Material and Methods: Thirty-one patients with U1(+)PAH complicated with connective tissue diseases in our cohort were involved. Patients with SSc, systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (pSS), polymyositis/dermatomyositis were fulfilled 2013 ACR/EULAR classification criteria, 2012 SLICC classification criteria, 2012 ACR classification criteria, and Bohan and Peter’s criteria, respectively. Of 31 patients, 18 patients with SSc (16 overlapped features of SSc and SLE (OL), 2 with SSc alone), 11 with SLE were extracted. Baseline clinical characteristics retrospectively collected from records were compared. Response to immunosuppressive treatment (IS) at 3 months evaluated by the improvement of world health organization (WHO)-functional class and the changes of parameters of right heart catheterization (RHC) within 12 months from baseline were evaluated using cases treated with IS.

Results: In clinical features, the age at diagnosis of PAH was tended to be higher in OL (45 ± 14 years) compared to SLE (38 ± 14 years). In concomitant organ involvements, frequency of ILD was higher in OL compared to SLE (72 % versus 18 %, P = 0.008). Hemodynamic parameters were comparable between two groups. As for IS treatment, 8 (50%) in OL and 9 (78%) in SLE were treated with IS, and short-term response was observed in 2 (25 %) and 7 (78 %), respectively (P = 0.05). The change of RHC parameters such as mean pulmonary arterial pressure (-3.1 ± 11.0 versus -11.8 ± 9.0 mmHg, P = 0.04), pulmonary vascular resistance (1.9 ± 10.8 versus -5.3 ± 1.9 wood units, P = 0.04), or cardiac output (0.7 ± 1.7 versus 0.9 ± 2.0 L/min) were worse in patients with OL compared to those with SLE.

Conclusions: Majority of U1(+) SSc-PAH patients had overlapped features of SLE. Baseline characteristics of OL patients, who were with features of SSc and SLE, were different compared with those with SLE, even hemodynamic parameters were comparable. These results suggest that anti-U1RNP-antibody-positive patients with pulmonary arterial hypertension are influenced by the presence of systemic sclerosis features.

P.071

Impact of Left Heart Disease-Associated Pulmonary Hypertension in Patients with Systemic Sclerosis in Comparison with Those with Non-Systemic Sclerosis

Y. Yamasaki¹, Y. Asari¹, S. Ooka¹, H. Hanaoka¹, K. Tonooka¹, Y. Takakuwa¹, T. Kiyokawa¹, H. Matsushita¹, S. Shinagawa¹, M. Uchida¹, T. Andoh¹, H. Iida¹, T. Okazaki¹, K. Suzuki¹, Y. Akashi¹, H. Yamada², K. Kawahata¹

¹ St. Marianna University School of Medicine, Kawasaki, JAPAN, ² Seirei-Yokohama Hospital, Yokohama, JAPAN

Introduction: Previous reports indicated that pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc) (SSc-PAH) has a significant impact on the survival. Meanwhile, favorable responses to immunosuppressants (IS) have been reported in PAH in non-SSc such as SLE or MCTD. But differences in impact of left heart disease (LHD)-associated PH (LHD-PH) on survival between patients with SSc and non-SSc was not determined.

Material and Methods: We retrospectively reviewed 39 patients diagnosed as PH by right heart catheterization (RHC) from 2006 through 2017. Of 39 patients, 11 (5 with non-SSc / 6 with SSc)(28%) were classified as group 2 PH (LHD-PH) by Nice classification. Clinical characteristics, complete remission (CR) rate, domiciliary oxygen therapy rate, and survival in patients with SSc-PH and non-SSc-PH were compared. We defined CR when patients achieved WHO-FC I and mean pulmonary arterial pressure (mPAP) <25mmHg by RHC [otherwise tricuspid regurgitation pressure gradient (TRPG) <35 mmHg by cardiac echocardiography] after treatment for LHD-PH.

Results: The mean age (SD) of patients with SSc having LHD-PH was 64 (13), which tended to be higher than those with non-SSc [45 (16), P= 0.0823]. Mean follow-up period (SD) after RHC was 32 (34) months. About 40% and 33% of the patients with non-SSc and SSc had WHO-FC III or IV, respectively. In comparison between patients with non-SSc, patients with SSc had comparable hemodynamic parameters by RHC such as mPAP [33 (6) mmHg in non-SSc / 35 (16) mmHg in SSc], pulmonary artery wedge pressure [17 (4) /20 (5) mmHg], or diastolic pulmonary gradient [5 (7) / 3 (7) mmHg]. The values of TRPG were 33 (19) mmHg in non-SSc and 51 (30) mmHg in SSc (NS). E/e’ (SD), which reflects left diastolic dysfunction, tended to be higher in patients with SSc than those with non-SSc [14 (6) vs. 9 (3), P = 0.0823]. IS was introduced in 80% and 17% of the patients with non-SSc and SSc (NS), respectively, along with conventional treatment for LHD. 40% of the patients with non-SSc achieved CR while none with SSc did it. No patients died or needed domiciliary oxygen therapy among patients with non-SSc while 50% of the patients needed domiciliary oxygen therapy and another 50% died within 29 months.

Conclusions: LHD-PH is one of the critical cardiopulmonary complications in SSc. In contrast, LHD-PH in patients with non-SSc could achieve remission with an appropriate use of IS. Establishment of therapeutic strategy for LHD is needed in patients with SSc.

P.072

Prediction of Progression of Interstitial Lung Disease in Patients with Systemic Sclerosis

W. Wu^1,2, S. Jordan¹, M.O. Becker¹, R. Dobrota¹, S. Ye², B. Maurer¹, Y. Allanore³, O. Distler¹

¹ Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, Zurich, SWITZERLAND, ² Department of Rheumatology, South Campus, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, CHINA, ³ Department of Rheumatology, Cochin Hospital, Paris Descartes University, Paris, FRANCE

Introduction: No data are available to distinguish between progressive and stable patients when mild lung fibrosis is diagnosed in systemic sclerosis (SSc) patients. This study aimed to identify clinical and laboratory parameters that can predict the progression of interstitial lung disease (ILD) within 1 year in patients with mild SSc-ILD.

Material and Methods: Data prospectively collected in our local SSc cohort were analysed in this observational study. Inclusion criteria were: diagnosis of SSc fulfilling ACR/EULAR 2013 criteria, diagnosis of ILD by HRCT, < 20% lung involvement extent on HRCT at baseline visit, available pulmonary function tests at baseline and annual follow-up visits (12+/-3 months), no concomitant pulmonary hypertension.

The primary endpoint, progression of ILD was defined if either of the following parameters was fulfilled : decrease in FVC >=15% within 1 year, or decrease in FVC >= 10% and DLCO >= 15% within 1 year.

Candidate predictors for logistic regression were selected by expert opinion based on clinical consideration. Receiver Operating Characteristic (ROC) curve analysis was performed to determine the optimal cut-off value for each significant continuous parameter.

Results: From the 98 patients included, 25 (25.5%) had progression of ILD. In univariate analysis, modified Rodnan skin score (mRSS) and incidence of arthritis ever were significantly higher while six-minute walk distance (6MWD) and worst SpO2 during 6MWT were significantly lower in progressors.

Three candidate predictors reflecting the overall disease severity including worst SpO2, arthritis ever and mRSS were selected for multivariate logistic regression by expert opinion. Worst SpO2 (p=0.004, OR: 0.77, 95% CI 0.64 to 0.92) and arthritis ever (p=0.001, OR: 6.50, 95% CI 2.16 to 19.61) were identified as independent predictors. The ROC curve analysis determined the best cut-off value for worst SpO2 as 94% (AUC: 0.76, sensitivity 0.847, specificity 0.680).

By combining worst SpO2 <=94% and arthritis ever, 11 of 12 (91.7%) patients fulfilling this prediction model were ILD progressors compared to 25.5% in the whole cohort.

Conclusions: Our study identified exercise-induced SpO2 decline and arthritis ever as independent predictor of progression of mild SSc-ILD within 1 year. The derived evidence-based prediction model might be helpful for risk stratification in clinical practice and cohort enrichment for future clinical trial design.

P.073

Bardoxolone Methyl Inhibits Markers of Endothelial-To-Mesenchymal Transition and Fibrosis in Human Pulmonary Artery Endothelial Cells

C. Wigley, G. Miller, D. Ferguson

Reata Pharmaceuticals, Irving, USA

Introduction: Bardoxolone methyl (BARD) is currently in clinical trials for the treatment of pulmonary hypertension associated with connective tissue disease (PAH-CTD) and interstitial lung disease (PH-ILD). Interim analyses of the Phase 2 LARIAT trial found that BARD significantly improved 6MWD relative to placebo. BARD potently activates Nrf2, a transcription factor that reduces oxidative stress, improves mitochondrial function, and inhibits the production of pro-inflammatory mediators. Oxidative stress and inflammation promote endothelial-to-mesenchymal transition (EndMT) and fibrosis, which contribute to the progression of PAH-CTD and PH-ILD. Nrf2 activation has been shown to inhibit epithelial-to-mesenchymal transition—a process similar to EndMT; however, the effect of Nrf2 activation on EndMT has not been characterized. In this study, we asked whether BARD activates Nrf2 and inhibits markers of EndMT in humany pulmonary artery endothelial cells (PAECs).

Material and Methods: To induce EndMT, human PAECs were treated with a mixture of TGFβ, TNFα, and IL-1β for 5 days. BARD or vehicle was added concurrently with the cytokine mixture. Markers of Nrf2 activation (NQO1, GCLM), EndMT (CD31/PECAM-1, VE-Cadherin, N-Cadherin, alpha smooth muscle actin, SM22 alpha), and fibrosis (fibronectin 1, collagen type I alpha 2 chain) were measured by reverse transcription and quantitative PCR.

Results: Following 5 days of treatment, the TGFβ/TNFα/IL-1β combination promoted EndMT in human PAECs as evidenced by changes in cell morphology and marker gene expression. The cytokine mixture reduced endothelial markers (CD31/PECAM-1 and VE-Cadherin), and increased mesenchymal markers (alpha smooth muscle actin, SM22 alpha). Markers of cell motility (N-Cadherin) and fibrosis (fibronectin 1, collagen type I alpha 2 chain) were also increased. Treatment with BARD increased mRNA levels of Nrf2 target genes (NQO1 and GCLM) in a concentration-dependent manner, demonstrating that BARD engages its primary target in PAECs. At concentrations that increased Nrf2 activity, BARD inhibited cytokine-induced expression of alpha smooth muscle actin, SM22 alpha, N-Cadherin, fibronectin 1, and collagen type I alpha 2 chain.

Conclusions: In this study, BARD increased Nrf2 activity and decreased markers of TGFβ/TNFα/IL-1β-induced EndMT and fibrosis in human PAECs.These results suggest that Nrf2 plays an important role in EndMT and that Nrf2 activation by BARD may have the potential to improve molecular parameters associated with PAH-CTD and PH-ILD.

P.074

Salvianolic Acid B Attenuates Experimental Pulmonary Inflammation by Protecting Endothelial Cells Against Oxidative Stress Injury Via the Mapk and NF-KB Signaling Pathways

Q. Liu^1,2, X. Shi¹, L. Tang², X. Xu³, S. Jiang¹, W. Ding¹, F. Qian¹, H. Chu¹, Y. Ma¹, Y. Li¹, J. Lu², W. Pu¹, X. Zhou⁴, L. Jin¹, W. Wu^2,5, J. Wang^1,5

¹ School of Life Science, Fudan University, Shanghai, CHINA, ² Huashan Hospital, Fudan University, Shanghai, CHINA, ³ The Clinical Laboratory of Shanghai Tongren Hospital, Shanghai, CHINA, ⁴ University of Texas Health Science Center at Houston, Houston, USA, ⁵ Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, CHINA

Introduction: Systemic sclerosis (SSc) is a complex autoimmune disease that typically results in fibrosis of the skin and internal organs. Pulmonary fibrosis is the leading cause for death of SSc. Endothelial cell injury and subsequent inflammation play pivotal roles in the pathogenesis of pulmonary fibrosis. We found previously that salvianolic acid B (SAB), the major ingredient of salviae miltiorrhiza, could attenuate experimental pulmonary fibrosis. Pulmonary fibrosis is driven by inflammation, but the anti-inflammatory role and mechanism of SAB on the treatment of pulmonary fibrosis is still unknown.

Material and Methods: For in vivo studies, BLM-induced pulmonary inflammation mouse model was used. HE, Masson’s trichrome and immunohistochemical stains were performed to test SAB’s ability to ameliorate pulmonary inflammation and injury. For the in vitro studies, we used H2O2-injured EA.hy926 endothelial cells to assess the protective effect of SAB against oxidative stress injury. Cell viability was measured with the xCELLigence systems. DCFH-DA was used to measure the intracellular ROS. Cell apoptosis was analyzed by flow cytometry. Real-time quantitative RT-PCR was used to examine the transcript levels of permeability and inflammation related molecules, and protein level was assayed by Western blot.

Results: The in vivo studies showed that SAB had a strong anti-inflammatory effect on bleomycin-instilled mice by inhibiting inflammatory cell infiltration and inflammatory cytokine production. Moreover, SAB protected endothelial cells against oxidative stress injury and inhibited endothelial cell apoptosis in bleomycin-treated mice. The in vitro studies also showed that SAB decreased the H2O2-induced overproduction of reactive oxygen species to protect EA.hy926 endothelial cells from oxidative damage, and further inhibited H2O2-induced permeability and overexpression of pro-inflammatory molecules. The next studies revealed that SAB inhibited the H2O2-induced cell apoptosis and attenuated the decrease of tight junction-related gene expression, resulting in a decrease of the endothelial permeability in injured endothelial cells. Furthermore, Western blot analysis suggested that SAB decreased endothelial cell permeability and expression of pro-inflammatory cytokines by inhibiting MAPK and NF-KB signaling pathways.

Conclusions: Taken together, these data indicate that SAB exerted anti-inflammatory roles in pulmonary fibrosis by protection of the endothelial cells against oxidative stress injury, mediated by inhibition of endothelial permeability and expression of pro-inflammatory cytokine via the MAPK and NF-KB signaling pathways.

P.075

Factors, Associated with Pulmonary Arterial Hypertension in Russian Systemic Sclerosis Patients: Results from Pulmonary Hypertension Registry

A. Volkov¹, E. Nikolaeva¹, T. Martynyuk²

¹ V. A. Nasonova Research Institute of Rheumatology, Moscow, RUSSIA, ² Scientific Medical Research Center of Cardiology, Moscow, RUSSIA

Introduction: Pulmonary arterial hypertension (PAH) is rare but devastating complication in patients with systemic sclerosis (SSc). We sought to determine the clinical, laboratory and immunology factors, associated with PAH in a large Russian PAH-SSc cohort.

Material and Methods: Sixty five patients with PAH-SSc and 65 SSc patients without PAH were included. PAH was diagnosed on right heart catheterization (RHC) (mPAP >25 and PAWP <15 mmHg at rest). Patients with PH secondary to interstitial lung disease, defined as abnormal HRCT scan (also with mild fibrosis) and FVC<80 % were excluded. The SSc patients without PAH was a representative cohort, there were no distinctions with Russian SSc cohort data (Ananieva L., et al., 2013). We include in analysis factors, associated with SSc only. Echo, RHC and biomarkers, as part of PAH verification, were excluded. Summary statistics, univariate and multivariable logistic regression were used to determine the factors, associated with PAH.

Results: We founded no differences in age (PAH-SSc 51,2±13,2 versus SSc without PAH 51,7±12,0), sex (6 versus 5 male respectively), duration from first non- Raynaud symptom (116±86 mnth versus 126±85 mnth respectively), digital ischemic symptoms (digital ulcers for all time of a disease 50% versus 49% respectively) between both groups. Univariate logistic regression detected 32 factors, concerning disease duration (isolated Raynaud phenomenon), late skin involvement, low skin score, tendon contracture absent, lower DLCO and higher FVC/DLCO ratio, laboratory and specific autoantibody findings.

In multivariable regression analysis, disease duration from the Raynaud more than 12 year (OR 4.9, 95 % CI 1.3-19.9, p=0.02), telangiectasia (OR 20.8, 95 % CI 4.4-97.4, p=0.0001), presence of anti-centromere antibody (ACA) (OR 6.1, 95 % CI 1.5-25.3, p=0.01), uric acid level more than 340 (OR 13.4, 95 % CI 3.4-53.0, p=0.0002), absence of topoisomerase-1 antibody (OR 0.03, 95 % CI 0.004-0.22, p=0.0006) were factors, associated with PAH presenting. This model had a 83% sensitivity and 89% specificity.

Conclusions: The revealed signs are very similar to algorithm DETECT. But our research has shown also need of assessment of disease duration from Raynaud’s syndrome and lack of topoisomerase-1 antibodies. The identified factors should be assessed to select patients eligible for screening program to make an earlier diagnosis of PAH.

P.076

Treatment with Cyclophosphamide for Systemic Sclerosis-Interstitial Lung Disease Does Not Lead to a Sustained Improvement in Lung Function in Two Independent Cohorts

E. Volkmann¹, D. Tashkin¹, M. Sim¹, N. Li¹, D. Khanna², M. Roth¹, P. Clements¹, A. Hoffmann-Vold³, D. Furst¹, G. Kim¹, J. Goldin¹, R. Elashoff¹

¹ University of California, Los Angeles, Los Angeles, USA, ² University of Michigan, Ann Arbor, USA, ³ Oslo University Hospital, Oslo, NORWAY

Introduction: Compared with placebo, treatment with cyclophosphamide (CYC) improved lung function in patients with systemic sclerosis-related interstitial lung disease (SSc-ILD) after 1 year in Scleroderma Lung Study (SLS) I (1). However, the effects of CYC waned after monitoring patients for an additional year off therapy (2). In SLS II (comparing CYC and mycophenolate [MMF]), treatment with 1-year of CYC appeared to have a more sustained effect on lung function over 2-years, although SLS II used a different analysis approach than SLS I (3). To further understand the effects of CYC on SSc-ILD outcomes, the present analysis directly compared efficacy outcomes between the CYC arms of SLS I and II.

Material and Methods: Participants enrolled in the CYC arms of SLS I (N=79) and II (N=73) were included. SLS I and II randomized participants to oral CYC for 1 year and followed patients for an additional year off therapy (In SLS II, patients received placebo in the second year). Eligibility criteria for SLS I and II were nearly identical. Outcomes included the FVC%-predicted and DLCO%-predicted (measured every 3 months) and quantitative radiographic extent of ILD (QILD) (measured at 1 and 2 years for SLS I and SLS II, respectively). Joint models were created to evaluate the treatment effect on the course of the FVC/DLCO over 2-years while controlling for baseline disease severity.

Results: SLS I and SLS II-CYC participants had similar baseline characteristics except that SLS II-CYC patients were slightly older (mean [SD] years: 52.2 [9.6] vs. 48.4 [12.2]; P=0.037) and had a higher DLCO%-predicted (mean [SD]: 54.5 [14.6] vs. 47.2 [13.9]; P=0.0002) than SLS I-CYC participants. After adjusting for baseline disease severity, there was no difference in the course of the FVC%-predicted (P=0.535), nor the DLCO%-predicted (P=0.172) between the SLS I and II-CYC arms. In both groups, treatment with CYC led to a significant improvement in the FVC%-predicted from 3-12 months, but no significant improvement beyond this point. Treatment with CYC had no effect on the DLCO for either group.

Conclusions: Treatment with 1 year of oral CYC led to similar improvements in lung function in both SLS I and II, although the effects were not sustained following cessation of CYC. These results suggest that increasing the duration of ILD therapy may improve outcomes for SSc-ILD patients.

References:

1. Tashkin DP, et al.NEJM 2006;354:2655-66.

2. Tashkin DP, et al.Am J Respir Crit Care Med 2007;176:1026-34.

3. Tashkin DP, et al.Lancet Resp Med 2016;4:708-19.

P.077

The Course of the Forced Vital Capacityduring Treatment for Systemic Sclerosis-Related Interstitial Lung Disease Predicts Long-Term Survival in 2 Independent Cohorts

E. Volkmann¹, D. Tashkin¹, M. Sim¹, D. Khanna², M. Roth¹, P. Clements¹, D. Furst¹, L. Keyes-Elstein³, A. Pinckney³, E. Goldmuntz⁴, R. Elashoff¹, K. Sullivan⁵

¹ University of California, Los Angeles, USA, ² University of Michigan, Ann Arbor, USA, ³ Rho Federal Systems, Inc., Durham, USA, ⁴ NIAID, NIH, Bethesda, USA, ⁵ Duke University, Durham, USA

Introduction: While prior observational studies have identified predictors of mortality in systemic sclerosis-interstitial lung disease (SSc-ILD), no studies have evaluated predictors of long-term mortality in a clinical trial, in which all patients receive standard care and uniform follow-up. The objective of this study was to identify predictors of mortality in patients who participated in the Scleroderma Lung Study (SLS) I (1) and II (2).

Material and Methods: SLS I randomized 158 SSc-ILD patients to 1 year of oral cyclophosphamide (CYC) versus placebo. SLS II randomized 142 patients to 1 year of oral CYC followed by 1 year of placebo versus 2 years of mycophenolate (MMF). The FVC%-predicted and DLCO%-predicted were measured every 3 months for 2 years in both trials. Counting process cox proportional hazard modeling identified variables associated with long-term mortality in SLS I and II. Internal validation was performed using joint modeling.

Results: After a median follow-up of 8 years, 48% of SLS I patients died (CYC: 35; Placebo 27). After a median follow-up for 4 years, 21% of SLS II patients died (CYC: 16; MMF: 12). For both studies, the cause of death was most often attributable to SSc, and the most common type of organ failure was respiratory failure defined as the need for supplemental oxygen therapy and/or lung transplantation. There was no significant difference in the time to death between patients randomized to CYC versus placebo in SLS I. There was a trend for a survival advantage for patients randomized to MMF compared with CYC in SLS II. Higher baseline skin score, older age, and a decline in the forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLCO) over 2 years were independently associated with an increased risk of mortality in SLS I. The course of the FVC/DLCO were better mortality predictors than the baseline FVC/DLCO. Although the follow-up period for SLS II was shorter than SLS I, the Cox model identified the same mortality predictor variables using SLS II data.

Conclusions: In addition to identifying traditional mortality risk factors in SSc (skin score, age), this study demonstrated that a decline in the FVC and the DLCO over 2 years was a better predictor of mortality than the baseline FVC and DLCO. These findings suggest that early changes in surrogate measures of SSc-ILD progression may have important effects on long-term outcomes.

References:

(1) Tashkin et al. NEJM 2006.

(2) Tashkin et al. Lancet Resp Med 2016.

P.078

Lung Ultrasonography: Possible Role as Predictor of Pulmonary Involvement in Patients Affected by Systemic Sclerosis Complicated by Either Interstitial Lung Disease or Pulmonary Arterial Hypertension

E. Tinazzi, F. Confente, G. Tacchella, G. Patuzzo, C. Lunardi

University of Verona, Verona, ITALY

Introduction: Systemic sclerosis (SSc) is an autoimmune disease characterized by a complex pathogenesis which combine aspects of endothelial dysfunction, immune abnormalities, both at humoral and cellular levels, and diffuse fibrosis.

Pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) is the major cause of death of SSc patients.

With the aim to analyze the possible role of lung ultrasonography (LUS) as predictor of ILD or PAH progression in a cohort of SSc patients and to study any possible interference or relation between ILD/PAH and other clinical features or laboratoristic parameters, we enrolled 50 SSc patients for a prospective longitudinal study. We collected SSc patients data from September 2016 and September 2017.

Material and Methods: The study included 46 females and 4 males, classified as affected either of limited or diffuse SSc (respectively lSSc 65,7% of patients or dSSc 34,3% of patients) according to LeRoy and Medsger’s criteria.

We collected different data of each patient involved in this study, such as age, sex, cutaneous fibrosis (estimated by mRSS), ANA titre, anti-centromere antibody and anti-topoisomerase II antibody, presence of digital ulcers (DUs), ILD and/or PAH and capillaroscopic pattern.

We focalized our attention on the group of patients affected by ILD and/or PAH and analysed the results of all instrumental examinations such as lung ultrasonography at the enrollment and in the follow-up, transthoracic rest echocardiographic test, right heart catheterization, high resolution chest CT (Warrick score for the assessment of the fibrotic involvement), pulmonary function tests, 6 minute walking test, capillaroscopy.

Results: Our data showed a significant correlation between LUS and ILD; in particular the presence as well as the number of B lines is related both to the extension of interstitial lung involvement as defined by Warrick score and by functional tests. Pleural thickness seems to be related better to ILD progression than to ILD diagnosis itself. No significant relation was demonstrated between B lines or pleural thickness and effusion and PAH which is indeed related to high levels or rapid increase of ANA title, as well as to the “active” and “late” capillaroscopic pattern and the presence of hystory or active DUs.

Conclusions: Our data suggest a role of LUS as predictor of ILD and as a markers of lung involvement progression indicating a potential useful application for the clinical evaluation.

P.079

Gene Expression of Aryl Hydrocarbon Receptor in Immune Cells Is Associated with Lung Involvement in Patients with Systemic Sclerosis

H. Takei, H. Yasuoka, K. Yoshimoto, K. Yamaoka, T. Takeuchi

Division of Rheumatology, Department of Internal Medicine, Keio University, Tokyo, JAPAN

Introduction: Systemic sclerosis (SSc) is characterized by autoantibody production, microvascular injury and systemic excessive fibrosis. Genetic and environmental factors are thought to be important for the trigger of development of the disease, however, direct connection between these factors is not yet elucidated. Recent reports showed that environmental toxic pollutants, such as dioxins, play a significant role in the disturbance of immune system and the trigger of autoimmunity through binding aryl hydrocarbon receptor (AhR). Thus, we hypothesized that AhR signaling is involved in the pathogenesis of SSc. The aim of this study is to investigate the association between gene expression of AhR in immune cells and the clinical characteristics of SSc.

Material and Methods: Twenty-one patients with SSc and 10 healthy controls (HC) were involved. All SSc patients fulfilled 2013 ACR/EULAR classification criteria. Peripheral blood mononuclear cells (PBMCs) were isolated from heparinized whole blood using gradient centrifugation and total RNA was extracted. Ahr mRNA expression level was examined by quantitative polymerase chain reaction (qPCR) and standardized by mRNA level of 18S ribosomal RNA in each sample. Clinical information was retrospectively collected from records of the patients, and Ahr mRNA level was compared between SSc and HC, cutaneous subsets and with and without each organ involvement or SSc-related autoantibody respectively.

Results: In patients with SSc, mean age was 61 ± 13 years, female was 95% and diffuse cutaneous subset (dcSSc) was 33%. Mean disease duration was 9 ± 9 years. Ahr mRNA expression level was tended to be higher in SSc compared to HC (1.7 ± 1.1 versus 1.2 ± 0.6, p = 0.1). Also, its expression level was significantly higher in SSc patients with ILD (n = 14) compared to those without (n = 7) (2.0 ± 1.1 versus 1.0 ± 0.4, p = 0.03), while no difference was observed between subsets of skin involvement, with or without other organ involvements or autoantibodies. When clinical features were compared between SSc patients with ILD and those without, only ratio of dcSSc was higher in SSc patients with ILD (50 % vs 0 %, p < 0.05), and other characteristic including age, sex, disease duration and autoantibody profiles were comparable between both groups.

Conclusions: Expression level of Ahr mRNA was higher in patients with SSc, especially those with ILD. These results suggest that intracellular signaling via AhR may play an important role in the disease process of ILD in SSc.

P.080

SIRT1 (SIRTUIN1) Gene Polymorphism Is Associated with Pulmonary Arterial Hypertension (PAH) and Digital Ulcers in Japanese Systemic Sclerosis (SSc)

K. Takagi¹, Y. Kawaguchi², Y. Ichimura²

¹ Department of Medicine, Tokyo Women’s Medical University medical Center East, Tokyo, JAPAN, ² Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, JAPAN

Introduction: SIRT1 encodes a Sirtuin family of protein, and known to associate with aging. SIRT1 is NAD-dependent deacetylase and regulate its down stream intracellular target proteins (p53, NFκB, PGC-1α, FOXOs, Histones H3 and H4, etc.). Notably, the SIRT1 deacetylase and the Hypoxia Inducible Factor (HIF)-1 α transcription factor, which act as redox and oxygen sensors, respectively.HIF1 αis guided in a hypoxic condition, and regulates various vascularization promoting factors. SIRT1 binds to HIF-1α and deacetylates it at Lys674. And Deacetylated HIF1a attenuates p300 recruitment and consequently HIF1 target genes expression is repressed. Hypoxia at peripheral tissue induces autoimmunity. SSc is the autoimmune disease characterized by a hypoxic state of the peripheral organization. We have previously reported that HIF1-alpha gene polymorphism rs12434438 was associated with PAH development in a Japanese SSc patient. Therefore, we have paid attention to SIRT1, upstream gene of HIF1a.

Material and Methods: One hundred ninety-five Japanese SSc patients and 544 healthy controls were recruited in this study. Hematological parameters including disease specific antibodies, Modern Rodnan Skin Score, and Word health Organization (WHO) function was evaluated. PAH was defined as mean pulmonary arterial pressure (mPAP) >25mmHg, and pulmonary arterial wedge pressure <15mmHg measured by right heart catheterization. Interstitial lung disease (ILD) was diagnosed by cardiac tomography. Five SNPs, rs7895833,rs12778366,rs3758391, rs7069102 and rs2273773 on the SIRT1 gene were genotyped using Taqman assay. Association between these SNPs and clinical manifestations, complications, and disease specific antibody was evaluated by Pearson’s chi-squared test or Fisher’s exact test.

Results: Among the SSc patients, 13% of patients developed PAH, 53% of patients developed ILD and 14% of patients developed digital ulcer (DU) . SIRT1 gene rs2273773 (C allele) was associated with protection against SSc development in Japanese. (OR 0.77 (95% CI 0, 59-0, 98) P=0.04). SIRT1 gene haplotype defined as a combination of rs7895833,rs12778366 and rs3758391 was associated with increased risk of DU and pulmonary hypertension. ILD development and presence of disease specific antibodies was not associated with any SNPs or haplotypes.

Conclusions: SIRT1 gene rs2273773 reduces increased risk of SSc development in Japanese SSc cohort. In addition, SIRT1 gene rs7895833, rs12778366 and rs375839 are associated with DU and PAH in Japanese SSc. It is known that SIRT1 functions upstream of HIF1-α and HIF-1α are overexpressed in SSc patients. Therefore, our results suggest functional modification of SIRT1 by SNPs, and affect HIF-1α functions. Inappropriate SIRT1-HIF1 axis may contribute etiology of SSc or phenotype of SSc caused by vascular damage.

P.081

Prevalence and Predictive Value of Systemic Sclerosis-Associated Antibodies: an Eastern-European Single-Center Experience

I. Szabo¹, R. Nichitean¹, A. Petcu^1,2, S. Rednic^1,2

¹ Emergency Clinical County Hospital, Department of Rheumatology, Cluj-Napoca, ROMANIA, ² Iuliu Hatieganu University of Medicine and Pharmacy, Department of Rheumatology, Cluj-Napoca, ROMANIA

Introduction: Systemic sclerosis (SSc) is a heterogeneous autoimmune disorder with high morbidity and mortality rates. SSc-associated autoantibodies are important diagnostic and predictive biomarkers of distinct clinical subtypes and internal organ manifestations. Despite variable antibody prevalence between different geographic regions, their clinical associations remain consistent. The aim of this study was to assess the clinical and immunological features of an Eastern-European single-center SSc cohort.

Material and Methods: A retrospective cohort study of 130 SSc patients was conducted. Clinical and laboratory data was collected from the EUSTAR Center 16 database and analyzed by means of descriptive and inferential statistics (Chi-square test for Independence, Relative Risk/RR). In this observational study, the prevalence of antinuclear (ANA), anti-topoisomerase I (anti-TOPO-I/anti-Scl-70) and anti-centromere (ACA) antibodies was evaluated, as well as their association with specific clinical phenotypes and organ system involvement.

Results: 2013 ACR/EULAR classification criteria were fulfilled in all cases. The mean follow-up was 48.6 months. Female to male ratio was 6:1, with an almost equal distribution among limited (48%) and diffuse (52%) SSc subtypes. ANA were present in 95% of the patients. The most frequently encountered autoantibody was anti-TOPO-I, identified in the serum of 74 (57%) patients, followed by ACA in 16 (12%) patients. A significant relationship between anti-TOPO-I and diffuse cutaneous SSc (dcSSc) was identified (p-value <.00001). Patients with anti-TOPO-I had almost a three-fold risk of developing a diffuse pattern during disease course (RR=2.91; [95%CI, 1.56-5.42]). ACA proved to be a statistically significant (p-value <.000011) risk factor for limited cutaneous SSc (lcSSc), with a RR of 2.69, [95%CI, 1.98-3.66]. Anti-TOPO-I was significantly associated with the development of lung fibrosis (p-value <.011, RR=1.47; [95%CI, 1.03-2.1]). No association was found between these autoantibodies and other clinical manifestations such as pulmonary arterial hypertension (PAH) and cardiac involvement. 11 deaths were registered, all occurring in patients with anti-TOPO-I and cardiopulmonary complications.

Conclusions: This study acknowledges the strong association between anti-TOPO-I and dcSSc, as well as the relationship between ACA and lcSSc. The prevalence of anti-TOPO-I was consistent with other literature reports, but the frequency of ACA was lower than expected, probably due to the small sample group of ACA positive patients. Anti-TOPO-I is a known risk factor for the development of lung fibrosis and therefore these patients should be actively screened for interstitial pulmonary involvement. Mortality among anti-TOPO-I patients is increased because of severe interstitial lung disease and cardiac dysfunction.

P.082

NKX2.5 Is Associated to Endomt in Pulmonary Arterial Hypertension

J. Santos Cade, I. Papaioannou, C. Denton, D. Abraham, M. Ponticos

University College London - Royal Free Campus, Division of Medicine, Department of Inflammation, London, UNITED KINGDOM

Introduction: The onset of inflammation, hypoxia or shear stress within blood vessels can result in endothelial cells undergoing endothelial-to-mesenchymal transition (EndoMT), a disease-associated process where endothelial cells lose endothelial functions and take on mesenchymal cell features. EndoMT is observed in pulmonary arterial hypertension (PAH), a condition characterized by remodeling of small vessels of the lungs and increased pulmonary pressures. Patients with scleroderma-associated pulmonary hypertension (SSc-PAH) have the highest mortality amongst all the scleroderma patient subgroups. The homeobox transcriptional factor NKX2.5 is fundamental for cardiovascular development. However, NKX2.5 expression has not yet been reported in endothelial cells of adult vessels. Here, we investigate NKX2.5 expression in activated endothelial cells undergoing EndoMT and in SSc-PAH.

Material and Methods: We used an established EndoMT in vitro experimental model. Human pulmonary artery endothelial cells (HPAECs) were treated with a cocktail of TGF-β, TNF-α, and IL-1β. Western blotting and qPCR were performed to evaluate, respectively, protein and mRNA levels of NKX2.5 and of endothelial and mesenchymal markers. Immunohistochemistry and immunofluorescence were also used to detect NKX2.5 within endothelial cells undergoing EndoMT. ALK5, ERK5, and PI3K inhibition was performed to determine the pathways that lead to NKX2.5 upregulation during EndoMT. Tissue specific deletion of NKX2.5 in a chronic hypoxia mouse model of PAH was used to assess pulmonary vascular remodelling.

Results: Immunohistochemistry of SSc-PAH human lungs stablished a strong expression of NKX2.5 by endothelial cells. Western blot analysis demonstrated a 2-fold downregulation of CD31 (p<0.05) and increased production of NKX2.5 (5.6-fold change, p<0.0001) and Procollagen I (12-fold change, p=0.0009) after 5 days of inflammatory cocktail stimulation on HPAECs. Relative mRNA expression has shown a 3-fold gene downregulation of CD31 (p=0.0002) and a 2.3-fold reduction of VE-Cadherin (p=0.0008) in EndoMT, whereas gene expression of COL1α2 (8.5-fold change, p<0.0001), and NKX2.5 (1.5-fold change, p=0.003) were upregulated. Immunofluorescence has also revealed a decreased VE-Cadherin expression concomitant with upregulation of NKX2.5 in HPAECs undergoing EndoMT. Inhibition of PI3K, ERK5 and ALK5 decreased NKX2.5 protein expression. Deletion of NKX2.5 in the mouse model of PAH reduced neo-intima formation and vascular remodeling.

Conclusions: Activated HPAECs undergoing EndoMT express NKX2.5 in vitro and in vivo, via mediation of TGF-β, ERK5 and PI3K signaling, and upregulate mesenchymal genes and extracellular matrix proteins, whereas endothelial markers are downregulated, suggesting that NKX2.5 has a major role in this process. This study highlights a new pathway associated with EndoMT and potentially a novel therapeutic target for vascular remodeling and SSc-PAH.

P.083

Factors Associated with the 6-Minute Walk Distance in Patients with Systemic Sclerosis

S. Sanges¹, J. Giovannelli¹, V. Sobanski¹, S. Morell Dubois¹, H. Maillard¹, M. Lambert¹, C. Podevin¹, N. Lamblin², P. De Groote², J.F. Bervar³, T. Perez⁴, R. Matran⁴, M. Remy Jardin⁵, P.Y. Hatron¹, E. Hachulla¹, D. Launay¹

¹ CHU Lille, Département de Médecine Interne et Immunologie Clinique, Lille, FRANCE, ² CHU Lille, Service de Cardiologie, Lille, FRANCE, ³ CHU Lille, Service de Pneumologie, Lille, FRANCE, ⁴ CHU Lille, Service d’Explorations Fonctionnelles Respiratoires, Lille, FRANCE, ⁵ CHU Lille, Département d’Imagerie Thoracique, Lille, FRANCE

Introduction: The objectives of our work are to assess the associations between the 6-minute walk distance (6MWD) and various disease parameters in patients with systemic sclerosis (SSc).

Material and Methods: Consecutive patients followed in our SSc National Reference Centre were included in this cross-sectional study if they fulfilled the 2013 ACR/EULAR criteria for SSc. Data were prospectively collected during a comprehensive evaluation that included a 6-minute walk test, clinical assessment, biological results, pulmonary function tests, transthoracic echocardiography, composite scores (EScSG-AI, Medsger, HAQ-DI) and treatments. Associations of the 6MWD with various disease parameters were assessed by linear regression in univariate analyses and in a multivariate model.

Results: The study population comprised 298 patients (females: 81%; mean age: 58.2 ± 13.3 years old; limited cutaneous SSc: 82%; interstitial lung disease (ILD): 42%; pulmonary arterial hypertension (PAH): 6%). The 6MWD was significantly and independently associated with gender, age, body-mass index, baseline heart rate (HR), HR variation during the test, PAH, history of arterial thrombosis and CRP levels; as well as with the HAQ-DI score in a sensitivity analysis. Muscle involvement, joint involvement and ILD were not independently associated with the 6MWD.

Conclusions: During SSc, the 6MWD is independently associated with HR variation (possibly implying a role for chronotropic incompetence in exercise intolerance), with PAH but not ILD (suggesting that pulmonary vasculopathy may have a greater impact than parenchymal involvement on functional limitation), and with global markers of disease activity and patient disability. These results give further insight to clinicians on how to interpret the 6MWD in the context of SSc.

P.084

Lung Ultrasound in One-Year Follow-Up of a Ssc Patient Cohort: it Could Be the Onset of Abnormal Ultrasound Signs an Important Imaging Tool to Reduce the Frequency of Chest Tomographic Assessment?

C. Rotondo, M. Nivuori, L. Urso, S. Lopriore, G. Lapadula, F. Iannone

Rheumatology Unit University A. Moro, Bari, ITALY

Introduction: Interstitial lung disease (ILD) is a typical clinical manifestation in systemic sclerosis (SSc). Even though the chest high resolution computed tomography (HRTC) is the diagnostic gold standard for ILD; in several studies, the lung ultrasound (LUS) has been proposed as non-invasive diagnostic technique to evaluate ILD. We aimed at evaluating the possible role of onset of specific LUS-signs (B-lines, higher pleural line thickness (HPLT), irregular pleural margins (IPM), subpleural cysts (SpC)) in the SSc-pts follow-up.

Material and Methods: A total of 96 SSc-pts (91 female, mean age 57,1±13,1 ys and disease duration of 9,6±6,5 ys), who fulfilled ACR/EULAR 2013 SSc classification criteria, were recruited. Just 26 patients completed the 12th-month follow-up. The patients underwent HRCT (at baseline and 12th-month) and LUS examination (at baseline, 6th-month and 12th-month). The LUS examination was performed with 7,5 Mhz. The presence of typical LUS-signs as B-lines (>3 B-lines in at least two adjacent sites), HPLT(>2mm), IPM, SpC and pleural effusion was detected.

Results: At baseline, 60 (62%) SSc-pts had ILD (18 ground-glass pattern (GG), 21 honeycombing pattern (HC), and 21 mixed patterns (GG+HC)). As regard the GG pattern the LUS sign with the highest specificity (93%), sensibility (68%) and accuracy (78%) was the B-lines; regarding the HC pattern the LUS-sign with the highest specificity (75%), sensibility (75%) and accuracy (75%) was the HPLT; regarding the mixed pattern the LUS-sign with the highest specificity (94%), sensibility (67%) and accuracy (81%) was B-lines. At the 12th-month 20 SSc-pts had ILD; in particular, 11 SSc-pts had a worsening (increasing of ILD areas) of HRTC pattern and 7 SSc-pts had the ILD-onset. As regard the LUS, in the SSc-pts with the ILD onset: the B-lines were found in 3 (42%) SSc-pts at 6th-month and in 7 (100%) SSc-pts at 12th-month; the IPM were found in 3 (42%) SSc-pts at 6th-month and in 4 (57%) SSc-pts at 12th-month. A normal LUS patter were observed in this group of SSc-pts at baseline.

Conclusions: The LUS is a good and accurately diagnostic technique for detecting ILD; in particular, the B-lines are the LUS-signs associated to the SSc-ILD active phases. The LUS could play an important role in the follow-up of SSc-pts, guiding the clinician’s decision on the timing of HRTC, without exposing the patients to high radiation doses over time. Indeed, the onset of B-lines and/or the irregularity of pleural margins might be evocative sigs of ILD and could suggest a prompt HRTC evaluation.

P.085

Prognostic Factors for Severe Pulmonary Involvement in Systemic Sclerosis

A. Radu^1,2, A.M. Gheorghiu^1,2, R. Oneata^1,2, A. Soare^1,2, R. Dobrota^1,2, S. Magda^2,3, T. Constantinescu^2,4, R. Jurcut^2,5, R. Sfrent-Cornateanu^2,6, M. Bojinca^1,2, V. Stoica^1,2, C. Mihai^1,2

¹ Internal Medicine and Rheumatology, Cantacuzino Hospital, Bucharest, Romania, Bucharest, ROMANIA, ² Carol Davila University of Medicine and Pharmacy, Bucharest, Romania, Bucharest, ROMANIA, ³ Emergency University Hospital, Bucharest, Romania, Bucharest, ROMANIA, ⁴ Marius Nasta Institute for Cardiovascular Diseases, Bucharest, Romania, Bucharest, ROMANIA, ⁵ C. C. Iliescu Institute for Cardiovascular Diseases, Bucharest, Romania, Bucharest, ROMANIA, ⁶ Physiopathology and Immunology Department, Bucharest, Romania, Bucharest, ROMANIA

Introduction: Lung involvement is the main disease- related death cause in patients with systemic sclerosis (SSc). The most frequent lung manifestations in SSc are interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH).

Material and Methods: All patients with SSc of the EUSTAR100 center, having at least two visits between 2004-2016, were included. Survival status, cause of death, dyspnea, ILD on thorax radiography or high resonance thorax computer tomography (HRCT) and lung function tests were recorded during the entire follow-up. Severe lung involvement was defined as severe or end-stage lung involvement on the Medsger severity scale at any time during follow-up, or death. Cox proportional hazards regression was used in univariate and multivariate analysis to identify prognostic factors.

Results: 89 patients were included (12.4% males, mean age±SD 49.2±12.2 years, disease duration 4.1±7.5 years), with a follow-up duration up to 13 years. 14 deaths were reported, half due to lung involvement (4 deaths due to ILD, 3 deaths due to PAH). Pulmonary involvement was identified in a large proportion: at first visit 28/55 present ILD on thorax radiography, 7/12 on HRCT scans; at the most recent visit 41/71 present ILD on X-ray, 18/24 on HRCT scans. At least 10% decrease of pulmonary diffusion capacity for carbon monoxyde (DLCO) and of forced vital capacity (FVC) was observed in 18/32 and 8/35 respectively; 24/48 developed severe or end-stage pulmonary involvement on the Medsger scale or have died. Risk factors for severe lung involvement were age>60 years, disease duration<3 years and diffuse cutaneous subset.

Conclusions: ScS often presents unfavourable disease course, mostly due to pulmonary involvement. While half of the deaths reported were due to lung involvement, only about half of the patients presenting ILD-typical findings on Rx develop end-stage lung involvement or death. It is of great importance to screen at baseline for ILD and PAH, following up annually, even while patients are asymptomatic.

P.086

Transthoracic Echocardiography to Quantify Pulmonary Vascular Resistances in Patients with Systemic Sclerosis

G. Pugnet¹, S. Billet², T. Chollet², G. Charbonnier², P. Fournier³, G. Prevot³, L. Tetu², M. Cournot⁴, H. Derumeaux², D. Carrié², M. Galinier², O. Lairez²

¹ Department of Internal Medicine, University Hospital of Purpan, Toulouse, FRANCE, ² Department of Cardiology, Rangueil University Hospital, Toulouse, FRANCE, ³ Department of Pulmonology, Larrey University Hospital, Toulouse, FRANCE, ⁴ Département d’Information Médicale, Centre Hospitalier Universitaire de Toulouse, Toulouse, FRANCE

Introduction: One of the major causes of systemic sclerosis (SSc)-related death is pulmonary hypertension (PH), which develops in 8–12% of patients with SSc and accounts for 30-40% of deaths. Cardiac involvement is common in SSc and has been reported to range from 23 to 32 %. Both pulmonary and cardiac involvement can lead to PH. Consequently, monitoring of pulmonary vascular resistances (PVR) is essential in patients with SSc. Tricuspid regurgitation velocity (TRV) to right ventricular outflow tract time-velocity integral (VTIRVOT) ratio by Doppler has been reported as a good tool to quantify PVR. The aim of the study was to explore the accuracy of TRV/ VTIRVOT ratio by Doppler to quantify PVR in patients with SSc.

Material and Methods: All consecutive patients with SSc, diagnosed according to the 2013 ACR/EULAR criteria, or the LeRoy and Medsger criteria for diffuse or limited subsets classification, had within 24H a Doppler echocardiographic examination and right-heart catheterization were performed. The ratio of peak tricuspid regurgitant velocity (TRV, ms) to the right ventricular outflow tract time-velocity integral (TVIRVOT, cm) obtained by Doppler echocardiography (TRV/TVIRVOT) was then correlated with invasive PVR measurements using regression analysis. An equation was modeled to calculate PVR in Wood units (WU) using echocardiography, and the results were compared with invasive PVR measurements.

Results: Thirty-three consecutive patients were included, 20 (57%) were female and the mean age was 64.6 ±12.1 years. Most were classified as limited cutaneous SSc (lcSSc; n=29, 87.9%). All patients tested positive for antinuclear antibodies, 18 (21.2%) for anti-scleroderma-70, 7 (54.5%) for anticentromere antibodies and 2 (6.1%) for anti-RNA polymerase III antibodies. Mean and systolic pulmonary arterial pressures were 31±8 and 53±15 mmHg. There was a good correlation between TRV/ VTIRVOT ratio assessed by Doppler and PVR measured by RHC (R=0.743, P<0.001). The equation generated by this analysis was: PVR by Doppler = 11.3 × (TRV/TVIRVOT) + 1.7. A cutoff value of 0.21 for TRV/TVIRVOT ratio provided the best sensitivity (86%) and specificity (86%) to determine PVR > 3 Wood units.

Conclusions: Transthoracic echocardiography with the TRV/TVIRVOT ratio is an interesting screening test to estimate PVR in SSc patients with suspected PH. This non-invasive tool requires further invasive workup to confirm its accuracy on larger cohort and its relevance to monitor response to treatment.

P.087

Reproducibility and Utility of the 6-Minute Walk Test in Systemic Sclerosis Patients

G. Pugnet¹, Z. Marjanovic², C. Deligny³, K. Boussardon⁴, I. Benzidia⁴, M. Puyade⁵, P. Lansiaux⁴, E. Vandecasteel⁶, V. Smith⁷, D. Farge⁴

¹ Service de Médecine Interne, CHU Purpan, Toulouse, FRANCE, ² Hématologie clinique et thérapie cellulaire, Assistance Publique Hôpitaux de Paris AP-HP, hôpital Saint-Antoine, Paris, FRANCE, ³ Service de médecine interne, CHU Martinique, Fort de Franc, FRANCE, ⁴ Unité de Médecine Interne, Maladies Auto-immunes et Pathologie Vasculaire, UF 04, Assistance Publique Hôpitaux de Paris, Paris, FRANCE,⁵ Service de Médecine Interne et Maladies Infectieuses, CHU de Poitiers, Poitiers, FRANCE, ⁶ Department of Cardiology, Ghent University Hospital, Ghent, BELGIUM, ⁷ Department of Rheumatology, Ghent University Hospital, Ghent, BELGIUM

Introduction: The six-minute walk test (6MWT) is a simple, submaximal aerobic exercise test, currently used in idiopathic pulmonary fibrosis, idiopathic Pulmonary Artery Hypertension or in Chronic Heart failure to assess disease severity and patients prognosis. Few studies have yet analyzed the correlations between the 6MWT results and systemic sclerosis (SSc) patient’s clinical characteristics and its reproducibility has only been assessed once in SSc patients with interstitial lung disease.

We therefore designed the present prospective study to investigate the reproducibility and the utility of the 6MWT in an unselected population of SSc patients, when performed during routine patient follow-up evaluation in a tertiary referral center for SSc.

Material and Methods: All SSc patients, who underwent at least two 6MWT within a minimum of 3 months interval plus simultaneous routine clinical, biological and functional evaluation, were consecutively enrolled in this observational study over 6 years. Following American Thoracic Society guidelines, each 6MWT was repeated twice to assess the 6-minute walk distance (6MWD) reproducibility, the highest value being reported for subsequent analysis.

Results: Among 56 (38 female) included patients, aged 45.6+12.7 years, with 17.1+10.3 mRSS and 1.02+0.77 SHAQ at first referral, 277 6MWT evaluations (5.0 ±3.9 6MWT per-patient) were performed over 23.3 + 22.5 months follow-up, meanwhile 8 deaths (87.5% SSc-related) occurred. The mean 6MWD absolute value was 457+116.5 meters with a 4+2.2 mean Borg scale at the end of walking. The 6MWD intra-class correlation coefficient was 0.996 (95CI 0.995 to 0.999, p< 0.0001). In multivariate linear regression analysis, gender (R2= 0.47, p<0.0001), mRSS (R2= 0.47, p=0.008), tendon friction rub (R2= 0.47, p=0.003), SHAQ (R2= 0.47, p=0.02), Muscle Disability Score (R2= 0.47, p=0.03), DLCO% (R2= 0.47, p=0.0008) and LVEF% (R2= 0.47, p=0.006) were 6MWD- independent predictors. The 6MWD absolute value at first referral was an independent predictor for the overall mortality (HR 0.99, 95CI 0.988 to 0.999; p=0.024) and the SSc-related mortality (HR 0.99, 95CI 0.988 to 0.999; p=0.039).

Conclusions: This unselected SSc prospective cohort study first shows strong reproducibility for the 6MWD. It confirms the 6MWT utility for SSc clinical evaluation and the overall prognosis of SSc patients with organ involvement. The 6MWT test is a valid tool to assess functional capacity or determine changes during follow-up in SSc patients. In SSc as in other clinical settings, a 6MWT is an independent predictor of survival and a sensitive test to indirectly evaluated SSc-myocardial and pulmonary involvement and overall survival.

P.088

Monotherapy Versus Combination Therapy in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (PAH). Retrospective Cohort Study from the Nationwide Spanish Scleroderma Registry (RESCLE)

M. Pestaña Fernandez¹, M. Rubio-Rivas¹, N. Villalba-Jiménez¹, C. Tolosa-Vilella², A. Guillen-Del-Castillo³, M. Freire⁴, J.A. Vargas-Hitos⁵, J.A. Todolí-Parra⁶, M. Rodríguez-Carballeira⁷, G. Espinosa-Garriga⁸, D. Colunga-Argüelles⁹, N. Ortego-Centeno¹⁰, L. Trapiella-Martínez¹¹, A. Marín-Ballvé¹², X. Pla-Salas¹³, I. Perales-Fraile¹⁴, I. Pons-Martín-Del-Campo¹⁵, A.J. Chamorro¹⁶, R.A. Fernández-De-La-Puebla-Gi¹⁷, A.B. Madroñero-Vuelta¹⁸, V. Fonollosa-Pla³, C.P. Simeón-Aznar³, On Behalf Of Rescle Investigators

¹ Hospital Universitario de Bellvitge, L’Hospitalet de Llobregat, SPAIN, ² Corporación Sanitaria Universitaria Parc Taulí, Sabadell, SPAIN, ³ Hospital Universitario Vall d’Hebron, Barcelona, SPAIN, ⁴ Complejo Hospitalario Universitario de Vigo, Vigo, SPAIN, ⁵ Hospital Universitario Virgen de las Nieves, Granada, SPAIN, ⁶ Hospital Universitario y Politécnico La Fe, Valencia, SPAIN, ⁷ Hospital Universitario Mútua de Terrassa, Terrassa, SPAIN, ⁸ Instituto Clínico de Medicina y Dermatología. Hospital Universitario Clínic, Barcelona, SPAIN, ⁹ Hospital Universitario Central de Asturias, Oviedo, SPAIN, ¹⁰ Hospital Campus de la Salud, Complejo Universitario de Granada, Granada, SPAIN, ¹¹ Hospital de Cabueñes, Gijón, SPAIN, ¹² Hospital Clínico Universitario Lozano Blesa, Zaragoza, SPAIN, ¹³ Consorci Sanitari Hospitalari de Vic, Vic, SPAIN, ¹⁴ Hospital Universitario Rey Juan Carlos, Móstoles, SPAIN, ¹⁵ Hospital de Igualada, Igualada, SPAIN, ¹⁶ Complejo Asistencial Universitario de Salamanca, Salamanca, SPAIN, ¹⁷ Hospital Universitario Reina Sofía, Córdoba, SPAIN, ¹⁸ Hospital General San Jorge, Huesca, SPAIN

Introduction: Until recent years, monotherapy was the first choice for PAH treatment, and it is still recommended in the most recent guidelines as first line therapy for PAH patients with World Health Organization (WHO) functional class II-III, with grade of evidence and recommendation IA-IB for most of the endothelin receptor antagonists (ERA), phosphodiesterase-5 (PDE5) inhibitors and epoprostenol. Combination therapy, either sequential or upfront, has been historically considered an interesting option for the treatment of PAH. Until the beginning of the 21st century, supporting evidence was based on personal expert opinions and randomized controlled trials data were missing. In the latest years, sequential combination therapy has been suggested to be beneficial in a few studies.

Our objective is to demonstrate the superiority of combined therapy against monotherapy for the treatment of pulmonary arterial hypertension (PAH) associated to systemic sclerosis (SSc).

Material and Methods: This is a retrospective cohort study including patients from the Spanish Scleroderma Registry (RESCLE) diagnosed with SSc-associated PAH by right heart catheterization.

Patients were split up in three groups: monotherapy vs. sequential combination therapy (more than 12 weeks between initiation of both treatments) vs. combination upfront therapy (less than 12 weeks between initiation of first and second treatment). The primary end point was death from any cause.

Results: Seventy-six patients with PAH of 1817 participants in the registry were included. Thirty-four (45%) were receiving monotherapy [with ERA (22 patients, 29%) or PDE5 inhibitors (12 patients, 16%)], 25 patients (33%) sequential combination therapy and 17 patients (22%) upfront combination therapy.

A worse FVC/DLCO in the sequential combination group was reported (2.9±1.1 vs. 1.8±0.4 vs. 2.3±0.8, p=0.085) and also a worse mPAP in both sequential and upfront combination groups (37.2±8.7 mmHg vs. 40.8±8.8 vs. 46±15.9, p=0.026). The treatment prescribed (p=0.017) and functional class at baseline (p=0.007) were found predictors of mortality. Sequential combination therapy was found a protective factor [HR 0.11 (95%CI 0.03-0.51), p=0.004] and the upfront combination therapy showed a tendency of protection [HR 0.68 (95%CI 0.23 to 1.97), p=0.476]. Survival rates from diagnosis of PAH among groups were: 78% vs. 95.8% vs. 94.1% at 1 year, 40.7% vs. 81.5% vs. 51.8% at 3 years and 31.6% vs. 56.5% vs. 34.5% at 5 years (p=0.007). Side effects were not significantly different among groups.

Conclusions: Combined sequential therapy improves survival in SSc-PAH patients.

It is possible that upfront therapy also improves survival, but due to our study limitations it did not reach statistical significance.

P.089

Association of Digital Ulcers with Severity of Lung Function Test in Systemic Sclerosis – Associated Interstitial Lung Disease in Follow up Study

O. Ovsyannikova, O. Koneva, L. Ananieva, L. Garzanova, O. Desinova, M. Starovoytova

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

Introduction: Systemic sclerosis-related interstitial lung disease (SSc-ILD) is the leading cause of death in SSc. Predictors of the outcomes of ILD in SSc are under investigation.

The aim to assess association of the digital ulcers with dynamics of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLco) in patients with SSc-ILD.

Material and Methods: It was a longitudinal study involving 83 pts with SSc-ILD (mean age was 46,2±13,4; 69% have limited subset of the disease; 95% were female). The mean duration of follow up was 58,9±12,0 months. At the end of the study a number of pts with digital ulcers (DUs) was 29 (35%). Additionally 77 pts. with SSc-ILD were investigated with HRCT and were divided into 3 groups; The 1st group (16 pts) with improvement; 2nd group (39 pts) without any changes and 3rd group (22 pts) with worsening of fibrosis.

Results: After 5 years of follow up FVC increased significantly in all pts without DUs (n=54) from 88,5% ± 19 to 96% ± 23 (p<0,05); in group 1 - from 92% ± 20.5 to 106% ± 19 (p<0,05); in group 2 from 87% ± 18 to 94% ± 23.5 (p<0,05) and only in group 3 FVC was stable (88±22 and 87±24.5) (p>0,05). The mean value of FVC in all pts with DUs didn’t change (88% ± 14 and 86% ± 16, p>0,05) with tendency to decreasing in group 3 (from 83% ± 12,5 to 74% ± 13 (p>0,05).

After 5 years of follow up DLco declined significantly in all pts with or without DUs, however in the 1st group decline of DLco wasn’t significant. The decreasing of DLCO was more prominent in group 3 than in group 2. Therefore, in group 2 in patient without DU (n=24) - from 65% ± 16 to 60% ± 11 (p<0,05) and in patients with DU (n=14) DLCO changed from 61% ± 15 to 57% ± 14 (p<0,05). In 3rd group in patients without DU (n=13) DLCO decreased from 55%±15 to 48%±15 (p<0,05) and in patients with DU (n=9)- from 50%±20 to 44,5%±15 (p<0,05).

Conclusions: In patients without DUs significant increasing of FVC during 5 years long follow up was observed. The worsening of fibrosis on HRCT in pts with DUs was associated with the lowest value of FVC and DLco at the entry and at the end of the study.

P.090

Follow-Up of Pulmonary Function in Patients Diagnosed of Early Systemic Sclerosis

F. Ortiz Sanjuán, C. Alcañiz Escandell, A. Arévalo Ruales, I. Chalmeta Verdejo, M. De La Rubia Navarro, C. Feced Olmos, J. Fragio Gil, R. González Mazarío, E. Grau García, E. Labrador Sánchez, I. Martínez Cordellat, R. Negueroles Albuixech, J. Oller Rodríguez, E. Vicens Bernabeu, L. González Puig, J. Ivorra Cortés, J.A. Román Ivorra

Hospital Universitario y Politécnico La Fe. Department of Rheumatology, Valencia, SPAIN

Introduction: Interstitial lung disease (ILD) is a frequent complication of systemic sclerosis (SSc) and is often progressive and has a poor prognosis. A restrictive ventilatory defect could suggest ILD either alone or in combination with pulmonary arterial hypertension.

Nowadays, Early-SSc is well defined as preliminary stage of SSc. Patients who meet criteria for Early-SSc could benefit from an early diagnosis of pulmonary involvement.

Our aim was to assess the pulmonary function in patients diagnosed of Early SSc.

Material and Methods: Retrospective observational study of a wide and unselected series of patients diagnosed as Early-SSc from a single university hospital from June 2012 to August 2017. Patients were classified as Early-SSc following Le Roy criteria. In spite of this, patients already did not meet 2013 ACR/EULAR classification criteria for SSc. We reviewed pulmonary function through conventional spirometry and diffusing capacity of lung for carbon monoxide (DLCO).

Results: We included a total of 43 patients with a mean age of 55.3±14.2 years (97.7% women; 2.3% men).

At the diagnosis of Early-SSc, no one of our patients evidenced a restrictive ventilatory pattern. DLCO was bellow normal limits in 11 patients (25.6%). Small airway obstruction expressed according decreased maximal (mid-) expiratory flow (MMEF) 25-75 was present in 13 patients (30.2%).

After a mean follow-up period of 36.4±27.2 months, 21 (48.8%) patients fulfilled 2013 ACR/EULAR criteria. The remaining 22 patients continued classified as Early-SSc following Le Roy criteria.

An analysis of the subgroup of patients who progressed to SSc showed that DLCO was decreased in 7 of those 21 patients (33%) and also 8 of 21 patients (38.1%) presented decreased MMEF 25-75. Comparing with the subgroup of patients who not progressed to SSc no were significant differences (Decreased DLCO: 33% vs 27.3%; p=0.8 and decreased MMEF 25-75: 38.1% vs 31.8%; p=0.9).

The analysis of pulmonary function of the subgroup of patients continued classified as Early-SSc after follow-up period did not show significative changes after follow-up.

Conclusions: In our study, about a quarter of the patients classified as Early-SSc presented at diagnosis abnormal values of DLCO and/or signs of small airway obstruction without the presence of a restrictive ventilatory pattern. Moreover, the expression of this pulmonary dysfunction tends to be more frequent in patients who progressed to definitive SSc, although this was not statistically significant. Patients who remains classified as Early-SSC did not experience significative changes in pulmonary function.

P.091

Quantitative CT Lung Texture Analysis in Interstitial Lung Involvement in Systemic Sclerosis: a Follow-Up Study

E. De Lorenzis¹, G. B. Canestrari¹, G. Natalello¹, L. Gigante¹, M. Occhipinti², A. R. Larici², L. G. Sisti³, C. De Waure³, G. Ferraccioli¹, E. Gremese¹, S. L. Bosello¹

¹ Institute of Rheumatology - Università Cattolica del Sacro Cuore, Rome, ITALY, ² Institute of Radiology - Università Cattolica del Sacro Cuore, Rome,³ Institute of Hygiene and Public Health - Università Cattolica del Sacro Cuore, Rome

Introduction: The prognosis of patients with scleroderma and interstitial lung involvement (SSc-ILD) can be evaluated by combining data of pulmonary function tests(PFTs) and high-resolution computed tomography(HRCT), but both methods have intrinsic limitations. We aimed to evaluate the performance of such an automated system (CALIPER, Imbio LLC, MN) in patients with SSc-ILD together with PFTs parameters and visual scoring of HRCT scans according to Goh’s visual reader based score. We evaluated the prognostic value of CALIPER with respect to PFTs changes.

Material and Methods: Thirty-five scleroderma patients with ILD-SSc were consecutively enrolled. PFTs as well as lung HRCT were performed at baseline and at follow-up. Quantitative analysis of parenchymal involvement on HRCT was performed by using CALIPER, which provided data on the relative volume of 5 different parenchymal patterns: normal, ground-glass, reticular, hyperlucent and honeycombing. Semi-quantitative analysis of the CT scans was performed according to the Goh’s score.

Results: Quantitative evaluation by CALIPER was successful in 31/35 patients (88.57%), requiring 20 to 30 m’ per patient for the sofware. The two most common patterns were ground-glass (16.64%) and reticular (4.48%), with a mean disease extent of 18.8% and a prevalent distribution at middle and lower zones and in peripheral areas. The correlations between PFTs and the relative volume of ground-glass were good (FVC:r=-0.72, p<0.001; TLC:r=-0.74, p<0.001;DLCO:r=-0.40,p=0.001), whereas PFTs and the relative volume of reticular pattern showed weaker correlations (FVC:r=-0.38,p=0.003;TLC:r=-0.42, p=0.02; DLCO:r=-0.31, p=0.02). The relative volume of normal lung had good correlations with FVC(r=0.63,p<0.001) and TLC(r=0.42,p=0.02). The concordance between analysis performed by CALIPER and the Gho’s visual score was weak either in the ground-glass pattern or in the reticular pattern. Patients were followed-up for 26.0±15.6 months. Variations in patterns between baseline and follow-up were not accurate in predicting disease progression as assessed by pulmonary function tests. However, variation in lung volume calculated by CALIPER accurately predicted the development of restrictive lung disease at follow-up or a combined decline in FVC% and DLco%. A reduction in lung volume greater than 7.18L predicted a progression of disease as of a combined decline in FVC% and DLco% with a sensitivity of 81% and a specificity of 70%.

Conclusions: Quantitative analysis performed by CALIPER arose as a useful tool to determine the extent and disease pattern in patients with SSc-ILD, correlating with PFT. The discriminatory performance of such an automated program to identify patients who presented a worsening of lung function suggests that quantitative analysis can help in evaluating response to therapy in SSc.

P.092

Progression of the Loss of Diffusing Capacity in Ssc Overlap Syndromes Is More Pronounced Than in Limited Ssc - Data from the German Network for Systemic Scleroderma

P. Moinzadeh¹, K. Kuhr², N. Blank³, E. Siegert⁴, J. Henes⁵, M. Worm⁶, C. Sunderkoetter⁷, M. Schmalzing⁸, A. Kreuter⁹, C. Gunther¹⁰, L. Susok¹¹, G. Zeidler¹², I. Koetter¹³, U. Mueller-Ladner¹⁴, T. Kirge¹, A. Juche¹⁵, T. Schmeiser¹⁶, G. Riemekasten¹⁷, E. Aberer¹⁸, N. Gaebelein-Wissing¹⁹, J. H. W. Distler²⁰, M. Sárdy ²¹, C. Pfeiffer ²², N. Hunzelmann ¹, F. Bonella²³, M. Kreuter ²⁴

¹ Department of Dermatology and Venerology, University of Cologne, Cologne, GERMANY, ² IMSIE, University of Cologne, Cologne, GERMANY, ³ Department of Rheumatology, University of Heidelberg, Heidelberg, GERMANY, ⁴ Department of Rheumatology, Charité University of Berlin, Berlin, GERMANY, ⁵ Department of Rheumatology, University of Tuebingen, Tuebingen, GERMANY, ⁶ Department of Dermatology, Charité University of Berlin, Berlin, GERMANY, ⁷ Department of Dermatology and Venerology, University of Muenster and Halle, Muenster, Halle, GERMANY, ⁸ Department of Rheumatology, University Hospital Wuerzburg, Wuerzburg, GERMANY, ⁹ Department of Dermatology, HELIOS St. Elisabeth Clinic Oberhausen, Oberhausen, GERMANY, ¹⁰ Department of Dermatology, University Hospital Carl Gustav Carus, Dresden, Dresden, GERMANY, ¹¹ Department of Dermatology, St. Josef Hospital Bochum, Bochum, GERMANY, ¹² Department of Rheumatology, Johanniter-Hospital Fläming Treuenbrietzen, Treuenbrietzen, GERMANY, ¹³ Department of Rheumatology, Asklepios Clinic Altona, Hambur, Hamburg, GERMANY, ¹⁴ Department of Rheumatology, Justus Liebig University Giessen, Kerckhoff Clinic, Bad Nauheim, Bad Nauheim, GERMANY, ¹⁵ Department of Rheumatology, Immanuel Hospital Berlin-Buch, Berlin, Berlin, GERMANY, ¹⁶ Department of Rheumatology, Hospital St. Josef, Wuppertal, Wuppertal, GERMANY, ¹⁷ Department of Rheumatology, University Medical Center-UKSH, Luebeck, Luebeck, GERMANY, ¹⁸ Department of Dermatology, Medical University of Graz, Graz, AUSTRIA, ¹⁹ Department of Dermatology, HELIOS University of Wuppertal, Wuppertal, GERMANY, ²⁰ Department of Rheumatology, University of Erlangen, Erlangen, GERMANY, ²¹ Dermatology, Ludwig Maximilians University Hospital, Munich, GERMANY, ²² Dermatology, University Medical Center Ulm, Ulm, GERMANY, ²³ Unit for interstitial lung diseases, Ruhrlandklinik Essen, Essen, GERMANY, ²⁴ Center for interstitial and rare lung diseases, University of Heidelberg, Heifelberg, GERMANY

Introduction: Lung involvement, i.e. interstitial lung disease (ILD) and pulmonary hypertension (PH), is a common clinical feature in patients with systemic sclerosis (SSc), which significantly influence the quality of life and limits the survival of affected patients.

Based on regular follow-up data from the German Network for Systemic Scleroderma (DNSS) this study investigate the relationship of DLCO and clinical characteristics in patients with different SSc subsets.

Material and Methods: Data of 2393 patients with 7315 visits were available for analysis, including DLCO levels at the initial visit and during follow-up visits. These DLCO levels were correlated with clinical characteristics of the three main SSc subsets (limited cutaneous SSc (lcSSc), diffuse cutaneous SSc (dcSSc) and SSc overlap syndromes).

Results: At initial presentation, 60% of the patients had DLCO levels of less than 75% predicted. Impaired DLCO levels were observed in 72% of dcSSc patients, in 61% of SSc-Overlap patients and 54% of lcSSc patients (p<0.000). Furthermore, patients with PH (79%), ILD (80%), dyspnea (78%), and those with presence of anti-topoisomerase I antibodies (70%) exhibited significantly more often DLCO levels < 75% (p<0.001) at first visit.

Interestingly, different SSc subsets revealed different mean DLCO levels; dcSSc patients showed the lowest DLCO levels (mean value, 62%), followed by patients with SSc-Overlap syndromes (mean value, 67%) and lcSSc patients (mean value, 70%). This was further supported by long-term follow-up evaluations (mean follow up, 6.0 years), which revealed that in comparison to lcSSc patients with dcSSc patients (OR 2.1; p<0.000; 95% CI 1.7-2.5) and SSc-overlap patients (OR, 1.55; p<0.000; 95% CI 1.2-2.0) had a significantly increased risk to a decrease in DLCO levels < 75% (adjusted for age, gender, disease onset).

A continuously low DLCO value below 75% (compared to a group of patients with DLCO levels constantly above 75%) was furthermore significantly associated with the presence of lung fibrosis (OR 2.5; p<0.000; 95% CI 1.7-3.8) and an increased mRSS of more than 15 (OR 2.7; p<0.000; 95% CI 1.8-4.3).

Conclusions: Deterioration of pulmonary function as determined by diffusing capacity DLCO is more pronounced in patients with dcSSc and SSc-Overlap Syndrome compared to those with lcSSc and may be a useful diagnosing and monitoring tool for pulmonary involvement. These data confirm the idea that SSc-Overlap patients carry a higher disease burden and a worse progression, although having the limited skin involvement. These data support the idea that SSc-Overlap syndromes should be regarded as a separate entity.

P.093

Survival of Connective Tissue Disease Associated to Pulmonary Hypertension

A.P. Luppino-Assad¹, F.A.G Oleas², J.L Alves³, C.V.P Jardim⁴, P.D. Sampaio-Barros⁵, R. Souza⁶

¹Sao Paulo, BRAZIL, ² Instituto do Coração, Sao Paulo, BRAZIL

Introduction: Pulmonary Hypertension is a severe complication of connective tissue diseases (CTD), being associated with poor prognosis. Studies from USA, Europe and China have investigated the clinical features and outcomes of CTD associated PAH (CTD-PAH), with discrepant results regarding the prevalence of the different diseases within this group. Data coming from the Southern hemisphere remain scarce; nevertheless, CTD-PAH has been described as the second most prevalent subgroup of PAH, accounting for 25.8% of all PAH cases in our registry, surpassed only by the idiopathic (IPAH) form, with a significantly worse prognosis. The objective of this study was describe the clinical and hemodynamic characteristics, as the survival, of different forms of connective tissue diseases associated pulmonary arterial hypertension (CTD-PAH) in a single Brazilian cohort.

Material and Methods: All newly diagnosed patients with CTD-PAH followed at the outpatient clinics of the Rheumatology and Pulmonary divisions of the University of Sao Paulo Medical School in the last Five years, were enrolled in this study. The diagnosis of PAH was established by right heart catheterization. Baseline clinical, functional, and hemodynamic data were analyzed for all patients. Survival was estimated using the Kaplan-Meier method with the log-rank test used for curve comparison.

Results: A total of 31 patients with CTD-PAH were included, 15 were located in considered as SSc group and 16 in theas non-SSc group (eleven with systemic lupus erythematosus-SLE and five with mixed connective tissue disease-MTCD). The mean age at PAH diagnosis in the SSc group was 59.9 ± 14.4 years against 39.8 ± 10.5 years inthe non-SSc group (p<0.001). The groups were similar regarding hemodynamic parameters and functional capacity. Patients with SSc were older than the non-SSc group (mean age 59.9 ± 14.4 years against vs. 39.8 ± 10.5 years;p<0.001). Overall survival rates at 1, 3 and 5 years were 86.7%, 58.7%, and40.2%, respectively, for SSc patients and 100%, 87.5%, and 76.6%, respectively, for non-SSc patients (p=0.028). Older age at PAH diagnosis was independently associated with better prognosis (p=0.008).

Conclusions: we identified that younger patients with CTD-PAH are at a particularly high risk of death, especially in SSc patients who have higher mortality rates compared with inflammatory forms of CTD-PAH connective tissue diseases associated with pulmonary vasculopathies, as SLE and MCTD

P.094

Clinical Phenotypes and Survival of Pre-Capillary Pulmonary Hypertension in Systemic Sclerosis

D. Launay¹, D. Montani², P. Hassoun³, V. Cottin⁴, J. Le Pavec⁵, P. Clerson⁶, O. Sitbon², X. Jais², L. Savale², J. Weatherald⁷, V. Sobanski¹, S. Mathai³, M. Shafiq⁸, J.F. Cordier⁴, E. Hachulla¹, G. Simonneau², M. Humbert²

¹ Univ. Lille; CHU Lille, Département de médecine interne et immunologie clinique, Lille, FRANCE, ² Université Paris-Sud; Service de Pneumologie, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, FRANCE, ³ Division of Pulmonary and Critical Care, Department of Medicine, Johns Hopkins University, Baltimore, Baltimore, USA, ⁴ Centre national de référence des maladies pulmonaires rares, hôpital Louis Pradel, Hospices Civils de Lyon, Université C, Lyon, FRANCE, ⁵ Service de Chirurgie Thoracique, Vasculaire et Transplantation Cardio-pulmonaire, Hôpital Marie Lannelongue, Le Plessis Robinson, FRANCE, ⁶ Soladis Clinical Study, Roubaix, FRANCE, ⁷ Division of Respirology, Department of Medicine, University of Calgary, Calgary, CANADA, ⁸ Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, USA

Introduction: Pulmonary hypertension (PH) is a common and severe complication of systemic sclerosis (SSc) affecting more than 10% of patients during their lifespan with a dismal prognosis. In SSc, PH is highly heterogeneous both in terms of pathogenic mechanisms, including the presence and extension of interstitial lung disease, and of heterogeneity of the underlying disease. The aim of our study was to identify and characterize homogeneous phenotypes by a cluster analysis in SSc patients with pre-capillary PH.

Material and Methods: Patients were identified from two prospective cohorts from the US and France. Clinical, pulmonary function, high-resolution chest tomography, hemodynamic and survival data were extracted. We performed cluster analysis using the k-means method and compared survival between clusters using Cox regression analysis.

Results: Cluster analysis of 200 patients identified four homogenous phenotypes that differed in clinical characteristics, extent of interstitial lung disease, hemodynamic severity, and survival. Cluster C1 included patients with mild to moderate risk pulmonary arterial hypertension with limited or no interstitial lung disease and low diffusion capacity for carbon monoxide (DLCO) with a 3-year survival of 81.5% (95% CI: 71.4-88.2) (Figure 1). C2 had pre-capillary pulmonary hypertension due to extensive interstitial lung disease and worse 3-year survival compared to C1 (adjusted hazard ratio [HR] 3.14; 95% CI 1.66-5.94; p=0.0004). C3 had severe pulmonary arterial hypertension and a trend towards worse survival (HR 2.53; 95% CI 0.99-6.49; p=0.052). Cluster C4 and C1 were similar with no difference in survival (HR 0.65; 95% CI 0.19-2.27, p=0.507) but with a higher DLCO in C4.

Conclusions: Pre-capillary pulmonary hypertension in systemic sclerosis can be characterized into distinct, homogenous phenotype clusters that differ in prognosis.

P.095

Correlation Between Skin Score and Pulmonary Involvement in Patients of Scleroderma- Prospective Study

J. Kulkarni, S. Singh, R. Mathur

Kokilaben Dhirubhai Ambani Hospital, Mumbai, India

Introduction: Scleroderma (Scl) is a complex heterogenous disease, characterised by small vessel vasculopathy, autoantibody production and excessive collagen deposit in skin and internal organs. Pulmonary complication is the most common cause of morbidity and mortality in scleroderma. Early detection and medical intervention are important to delay disease progression and improve survival.

The primary objective is to understand the spectrum of cutaneous manifestations in patients of scleroderma and to determine pattern of pulmonary involvement in limited and diffuse disease. Secondary objective is to determine the correlation between skin score and pulmonary manifestations.

Material and Methods: This is an observational study in patients aged 18 to 60 years, fulfilling the American College of Rheumatology (ACR) criteria for scleroderma, attending the Rheumatology OPD with a sample size of 54 patients over the period February 2014 to December 2016. Assessment of the cutaneous manifestation was done by the clinical signs of cutaneous involvement and calculation of the Modified Rodnan Skin Score . Assessment of pulmonary involvement included chest X-ray, HRCT chest, 2 D Echo, pulmonary function test and arterial blood gas analysis.

Results: 54 patients completed the study (50 females and 4 males). Patients with diffuse Scl were 70.3% and limited cutaneous 29.6%. The Modified Rodnan skin score varied from 7 to 51, mean score was 25.81±10.04. Raynaud’s phenomenon was noted in 90.7% patients. Cutaneous involvement was 100% in which 92.5% had skin tightening, 77.7% had sclerodactyly, 57.4% had digital pits and ulcers. 33.3% had diffuse cutaneous edema, 16.6% telangiectasia, 12.9% calcinosis and 11.1% had salt and pepper skin.

Pulmonary involvement was noted in 70.3% patients, in whom 59.2% had Interstitial Lung disease and 16.6% pulmonary hypertension. 5 out of 16 cases of lcSSc had Interstitial lung disease while 3 had pulmonary hypertension. 27 out of 38 cases of dcSSc had ILD while 6 had Pulmonary hypertension.

Conclusions: Cutaneous involvement was universal, however its extent and severity was not significantly correlated with pulmonary manifestations. No significant correlation was observed between skin score, HRCT and PASP for all patients.

P.096

Study Mofetil Mycophenolate Efficacy in the Patients with Systemic Scleroderma Receiving Long-Term Therapy (For at Least One Year)

O. Koneva, O. Ovsyannikova, L. Ananieva, O. Desinova, L. Garzanova, M. Stsrovoytova

Introduction: To evaluate mofetil mycophenolate (MMF) effects on clinical manifestations and activity of systemic scleroderma (SSc) in open prospective study. To compare MMF efficacy against interstitial lung disease (ILD) when used as induction regimen and as maintenance therapy after cyclophosphamide (CYC) induction.

Material and Methods: 45 patients with definitely diagnosed SSc (average age 49±13 years, male/female 1/10, disease duration since the first non-Raynaud syndrome 7.6±6.3 years, diffuse/limited disease 1/1.3), with ILD signs evidenced by multispiral computed tomography were enrolled into the study. The patients were treated with MMF 2 gram/day in combination with prednisolone 9±5 mg/day including 22 patients (Group A) who received MMF as induction regimen and 23 patients who receive MMF maintenance therapy (Group B) after CYC induction (total dose 20.9±18.2 g). Modified Rodnan skin score (MRSS), activity index (EScSG), gastrointestinal complaints, left ventricle ejection fraction, the presence of ventricle diastolic dysfunction, mPAP (EchoCG), the presence of heart rhythm and conduction disorders, the number of digital ulcers and necroses, dyspnea class (NYHA), FVC %, DLCO %, SSc-specific antibody level (a-Scl-70, ACA) and ANA-2 were evaluated at the baseline and 12 (13±2) months later.

Results: During MMF therapy significant decrease in MRSS (from 7.5±6.9 to 4,8±3,9, p=0.0006), EScSG (from 1.9±1.5 to 1.22±0.9, p=0,005), the number of patients with heart conduction disorder (from 13/29% to 5/11%, p=0.03), and a-Scl-70 level (from 144±67 to 118.5±76.9, p=0.02) was observed.

FVC increase and decrease by >10% was found in 6 (13%) and 4 (9%) patients, respectively. Average FVC did not change significantly both in general study population (90.3 ±20.8 vs 92.2±21, p=0.09) and in Group A (92.2±18.3 vs 94.3±19, p=0.2) and Group B (87.9±22.5 vs 90.2±21.9).

DLCO increase and decrease by >10% was found in 3 (7%) and 2 (4%) patients, respectively. Average DLCO did not change significantly both in general study population (52.2 ±17.4 vs 51.9±17. p=0.86) and in Group A (60.3±19 vs 62.6±18.8, p=0.5) and Group B (49.6±17.9 vs 48.9±17.5, p=0.5). Decrease in dyspnea class was observed in 10 (22%) patients of general study population.

No change of the other evaluated characteristics was observed during the observation period.

Conclusions: MMF treatment for one year contributed to decrease in skin density, cardiopathy manifestations, severity of immunological disorders, and EScSG. The findings obtained from ventilatory function assessment support the use of MMF in the patients with SSc associated with ILD both as induction therapy and as maintenance therapy after CYC treatment.

P.097

Rituximab Efficacy in the Patients with Systemic Scleroderma Differing in Extent of Interstitial Lung Disease

O. Koneva, L. Ananieva, O. Desinova

Nasonova Research Institute of Rheumatology, Moscow, RUSSIA

Introduction: To evaluate rituximab (RTX) therapy efficacy in the patients with systemic scleroderma (SSc) differing in extent of interstitial lung disease (ILD) based on miltispiral computed tomography (MSCT) findings.

Material and Methods: 42 patients (average age 48±2 years; male/female 1/6, diffuse/limited disease 1.5/1 (25 and 17), disease duration since the first non-Raynaud syndrome – 6.6±5.9 years) with definitely diagnosed SSc and ILD signs evidenced by MSCT were enrolled into the study. During the observation period 29±15.3 months the patients received rituximab (RTX) total dose of 2.5±1.3 grams in combination with glucocorticoids at average dose of 11.7±3.9 mg. 10 (24%) patients concurrently took immunosuppresants. The therapy efficacy was evaluated both in the general study population and in the patient subgroups with interstitial lesion extent up to 20% (Group A, n=13) and greater than 20% (Group B, n=29) of total pulmonary tissue area [Goh 2008].

Results: In the general patient population significant FVC increase from 73.2±18.8% to 82±21.8% (p=0.000031) and stabilization of DLCO (42.6±15.7% vs 44.7±14.6%, p=0.02) were observed. Median FVC increment was 6% (25th%-3,3%; 75th%-16%). FVC-based parameters increased by > 10% in 16 (38%) patients and decreased in 3 (7%) patients.

Average FVC values in Group A were significantly higher compared with Group B both at the baseline (88.8±18.6% vs 65.4±14.5%, p=0.0002) and after the treatment (103.3±15.9% vs 74.1±18.5%, p=0.0009) with statistically significant FVC increase in both groups during the treatment period (p=0.016 and p=0.0014, respectively). Median FVC increment in Group A and Group B was 10.2% (25th%-4.7%; 75th%-21.9%) and 5.9% (25th%-2.75%; 75th%-14.7%), p > 0.05, respectively. FVC-based parameters increased by >10% in 6(46%) patients in Group A, and in 10 (34%) patients in Group B, and decreased in 1 (8%) and 2(7%) patients, respectively. Average DLCO values were also significantly higher in Group A compared to Group B both before and after treatment (58.4±16.4% vs 36.3±10.1%, p=0.025; 59.3±15.2% vs 38.9±9.7%, p=0.005); DLCO values did not change over time during RTX therapy.

Conclusions: RTX therapy resulted in significant FVC increase. FVC increment in the patient group with ILD extent up to 20% achieved clinical significance level in contrast to the patients with ILD extent greater than 20%, where FVC increment was 5.9%. Obtained data suggest that initial lung lesion area is a potential predictor of response to a-B-cell therapy in the patients with SSc.

P.098

Pulmonary Manifestations of Scleroderma

M. Kechida¹, N. Lorenzo Villalba², T. Merzouki², R. Klii¹, S. Hammami¹, I. Khochtali¹

¹ Fattouma Bourguiba University Hospital, Internal Medicine and Endocrinology Department, Monastir, TUNISIA, ² Internal Medicine and Cancer Department, Saint-cyr, Villeneuve sur lot, FRANCE

Introduction: Systemic sclerosis (Ssc) is a severe connective tissue disease of unknown origin characterized by marked vascular, immunological and fibrotic abnormalities. Lungs are commonly involved in scleroderma.

Objective: our aim was to study pulmonary involvement of Ssc

Material and Methods: we conducted a retrospective bi-centric descriptive study including 48 patients having Ssc hospitalized in the internal medicine department of Fattouma Bourguiba hospital of Monastir, Tunisia and Internal medicine and cancer department of Saint Cyr, France from 2004 to 2017. All patients were diagnosed according to the ACR classification of 1980 as well as Leroy and Medsger criteria.

Results: the mean age of our population was 48 years, sex ratio M/F= 0.18.

The mean duration of the disease at diagnosis was 4 years. Scleroderma was associated with other auto immune diseases in 34.6% as following: systemic lupus erythematosus in 7.6%, rheumatoid arthritis in 7.6% and Sjogren’s syndrome in 19.2%. Pulmonary involvement was diagnosed in 53.8%. Clinical manifestations were dyspnea on exertion in 46 %. Chest x- ray revealed interstitial syndrome in all cases. Thoracic computed tomography confirmed interstitial lung disease (ILD) in all patients and revealed pulmonary fibrosis in 43%. Pulmonary arterial hypertension (PAH) was seen in 38% of cases with a mean PAP of 45 mmHg.

PAH was associated with positive anti scl70 antibodies in only 3 cases (30%).

Treatment was based on immunosuppressive drugs for progressive lung disease as well as anticoagulants and vasodilators for PAH. Clinical outcome was favorable in all patients.

Conclusions: Pulmonary complications are common in SSc leading to a loss of quality of life and a poor expectation of survival. Careful evaluation by the clinician at diagnosis and follow up is warranted.

P.099

Racial Differences in SSc Disease Presentation: a European Scleroderma Trials and Research Group Study

V. Jaeger¹, E. Siegert², E. Hachulla³, P. Airò⁴, G. Valentini⁵, M. Matucci Cerinic⁶, R. Scorza⁷, O. Distler⁸, F. Cozzi⁹, P.E. Carreira¹⁰, Y. Allanore¹¹, U. Müller-Ladner¹², L. Ananieva¹³, A. Balbir-Gurman¹⁴, J.H.W. Distler¹⁵, L. Czirják¹⁶, M. Li¹⁷, J. Henes¹⁸, S. Jimenez¹⁹, V. Smith²⁰, N. Damjanov²¹, C. Denton²², F. Del Galdo²³, M. Tikly²⁴, L.A. Saketkoo ²⁵, U.A. Walker¹

¹ Department of Rheumatology, University Hospital Basel, Basel, SWITZERLAND, ² Department of Rheumatology and Immunology, University Hospital Charité, Berlin, GERMANY, ³ Service de Médecine Interne, Hôpital Huriez, Université de Lille, Lille, FRANCE, ⁴ UO Reumatologia ed Immunologia Clinica, Spedali Civili, Brescia, ITALY, ⁵ Rheumatology Department, Second University of Naples, Naples, ITALY, ⁶ Department of Rheumatology, University of Florence, Florence, ITALY, ⁷ U.O. Immunologia Clinica - Centro di Riferimento per le Malattie, Milano, ITALY, ⁸ Department of Rheumatology, University Hospital Zurich, Zurich, SWITZERLAND, ⁹ Rheumatology Unit, Department of Medicine, University of Padova, Padova, ITALY, ¹⁰ Servicio de Reumatologia, Hospital Universitario 12 de Octubre, Madrid, SPAIN, ¹¹ Department of Rheumatology A, Paris Descartes University, Cochin Hospital, Paris, FRANCE, ¹² Justus-Liebig-University of Giessen, Kerckhoff-Klinik, Bad Nauheim, GERMANY, ¹³ VA Nasonova Institute of Rheumatology, Moscow, RUSSIA, ¹⁴ B. Shine Rheumatology Unit, Rambam Health Care Campus, Rappaport Faculty of Medicine, Haifa, ISRAEL, ¹⁵ Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, GERMANY, ¹⁶ Department of Rheumatology and Immunology, University of Pécs, Pécs, HUNGARY, ¹⁷ Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, CHINA, ¹⁸ Department of Internal Medicine II, Eberhard-Karls-University Tübingen, Tübingen, GERMANY, ¹⁹ Scleroderma Center, Thomas Jefferson University, Philadelphia, USA, ²⁰ Faculty of Internal Medicine, Ghent University, Ghent, BELGIUM, ²¹ Institute of Rheumatology, University of Belgrade Medical School, Belgrade, SERBIA, ²² Department of Rheumatology, University College London, Royal Free Hospital, London, UNITED KINGDOM, ²³ Leeds Musculoskeletal Biomedical Research Unit (LMBRU), University of Leeds, Leeds, UNITED KINGDOM, ²⁴ Division of Rheumatology, Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand, Johannesburg, SOUTH AFRICA, ²⁵ Tulane University Lung Center. University Medical Center Scleroderma and Sarcoidosis Patient Care and Research Center, New Orleans, USA

Introduction: Genetic and environmental factors play a significant role in SSc. African Americans are known for a higher SSc incidence, an earlier age of onset, and a greater frequency of ILD and PH compared to Caucasians. Data on blacks mostly stem from African Americans and may be influenced by environmental, socioeconomic factors and healthcare access. Studies on SSc in Asians are mostly from outside Asia and lack direct comparison with other racial groups.

We aimed to further evaluate differences of SSc presentations between races cross-sectionally.

Material and Methods: Caucasians, Asians or black African patients fulfilling the 1980 ACR or the 2013 ACR/EULAR criteria from the EUSTAR cohort were analysed. Demographic and disease characteristics were compared across groups; multiple logistic regression analysis was used to adjust for age, sex, disease duration and antibody status.

Results: The racial group was known in 8748 EUSTAR patients (8244 Caucasians, 344 Asians, 170 black Africans). Asians and black Africans were on average 10 years younger and had a 5 year shorter disease duration than Caucasians (both p<0.001). Caucasians were more often ACA positive (38%) than Asians (15%) or black Africans (9%; p<0.001); Asians were more often Scl-70 positive (47%) than Caucasians (35%) or black Africans (32%; p<0.001).

Diffuse skin involvement was more common in black Africans (61%) compared to Caucasians (29%) and Asians (29%; OR[black Africans]3.0, p<0.001, OR[Asians]0.6, p=0.001, vs Caucasians).

The prevalence of PH (defined as PAPsys>40mmHg estimated by echocardiography) was similar in Asians (18%), black Africans (15%) and Caucasians (14%; p=0.15); however after accounting for confounders, Asians were more likely to have PH (OR[Asians]2.0, p<0.001, OR[black Africans]1.5, p=0.12, vs Caucasians). Asians had a higher prevalence of an impaired DLCO (<80% of predicted; 84%) than black Africans (71%) or Caucasians (69%, p<0.001); these differences were significant after adjusting for confounders (OR[Asians]2.9, p<0.001; OR[black Africans]1.2, p=0.41, vs Caucasians). Both, Asians (43%) and black Africans (62%), had a higher prevalence of a reduced FVC (<80% of predicted) compared to Caucasians (23%, p<0.001) also by multivariable analysis (OR[Asians]2.4, p<0.001; OR[black Africans]4.8, p<0.001 vs Caucasians).

No significant racial difference was observed in the prevalence of renal crisis.

Conclusions: Several clinical and serological differences were evident between the three racial groups, notably a higher prevalence of diffuse skin involvement in black Africans, more ACA in Caucasians and a higher prevalence of Scl-70 and a reduced FVC in Asians.

P.100

Smoking Behaviour and the Progression of Organ Manifestations in Systemic Sclerosis: a Longitudinal European Scleroderma Trials and Research Group Study

V. Jaeger¹, G. Valentini², E. Hachulla³, F. Cozzi⁴, O. Distler⁵, P. Airó⁶, L. Czirják⁷, Y. Allanore⁸, E. Siegert⁹, E. Rosato¹⁰, M. Matucci-Cerinic¹¹, L.M. Bambara¹², J. Henes¹³, P.E. Carreira¹⁴, V. Smith¹⁵, F. del Galdo¹⁶, C. Denton¹⁷, S. Ullman¹⁸, E. de Langhe¹⁹, V. Riccieri²⁰, J.J. Alegre-Sancho²¹, S. Rednic²², U. Müller-Ladner ²³, U.A. Walker¹

¹ Department of Rheumatology, University Hospital Basel, Basel, SWITZERLAND, ² Rheumatology Department, Second University of Naples, Naples, ITALY, ³ Department of Internal Medicine, Université de Lille, Lille, FRANCE, ⁴ Rheumatology Unit, Department of Medicine, University of Padova, Padova, ITALY, ⁵ Department of Rheumatology, University Hospital Zurich, Zurich, SWITZERLAND, ⁶ UO Reumatologia ed Immunologia Clinica, Spedali Civili, Brescia, ITALY, ⁷ Department of Rheumatology and Immunology, Medical Center, University of Pécs, Pécs, HUNGARY, ⁸ Department of Rheumatology A, Paris Descartes University, Paris, FRANCE, ⁹ Department of Rheumatology and Immunology, University Hospital Charité, Berlin, GERMANY, ¹⁰ Sapienza University of Rome, Rome, ITALY, ¹¹ Department of Rheumatology, University of Florence, Florence, ITALY, ¹² University of Verona, Verona, ITALY, ¹³ Department of Internal Medicine II, University of Tuebingen, Tuebingen, GERMANY, ¹⁴ Servicio de Reumatologia, Hospital Universitario 12 de Octubre, Madrid, SPAIN, ¹⁵ Faculty of Internal Medicine, Ghent University, Ghent, BELGIUM, ¹⁶ NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UNITED KINGDOM, ¹⁷ Department of Rheumatology, University College London, Royal Free Hospital, London, UNITED KINGDOM, ¹⁸ Department of Dermatology, Copenhagen University Hospital, Copenhagen, DENMARK, ¹⁹ Department of Rheumatology, University Hospital Leuven, Leuven, BELGIUM, ²⁰ Divisione di Reumatologia, Università di Roma La Sapienza, Rome, ITALY, ²¹ Sección de Reumatología Hospital Universitario Dr Peset Valencia, SPAIN, ²² Clinica Reumatologie, University of Medicine & Pharmacy, Cluj-Napoca, ROMANIA, ²³ Department of Rheumatology and Clinical Immunology, Justus-Liebig University Giessen, Kerckhoff Clinic Bad Nauheim, Bad Nauheim, GERMANY

Introduction: SSc is a rare, multisystem autoimmune disorder. The pathogenesis is characterised by a microangiopathy to which hypoxia and oxidative stress may contribute. Tobacco inhalation induces free radicals and vasoconstriction, and promotes vascular damage. So far, data available with regards to a role of tobacco exposure with SSc severity and progression are scarce.

We aimed to assess the associations of smoking with the speed of worsening of lung involvement, skin involvement, and DU in the EUSTAR database.

Material and Methods: Adult SSc patients with a follow-up visit 12-24 months after baseline and available data on their smoking habits were included.

The associations of smoking behavior (never smokers vs ex-smokers vs current smokers) with the change in disease manifestations between baseline and follow up were assessed using multivariable regression analyses adjusting for age, sex, autoantibody status, disease duration, SSc subset.

Results: Of the 3,319 patients included (mean age 57 years, SD 14; 85% female; 29% diffuse SSc), 66% of patients stated that they never smoked; 23% were ex-smokers and 11% were current smokers. The average ex-smoker had smoked 18 pack-years (SD 21) during a time of 19 years (SD 12) and quit smoking 15 years (SD 13) ago. The average current smoker smoked 27 pack-years (SD 30) during a time of 30 years (SD 13).

On average, the FEV1/FVC ratio changed from 96.5 (SD 14) at baseline to 96.0 (SD 13) at follow up. In current smokers, the ratio decreased significantly faster during the observation period than in never smokers after adjustment (β=-4%, p<0.001). This was not observed in ex-smokers (p=0.7).

The mRSS changed between baseline and follow-up from an average of 7.7 (SD 8) to 7.3 (SD 7); the change in mRSS was not clinically meaningfully associated with smoking behaviour.

Smoking behaviour was not associated with the presence of DU at baseline. The occurrence of new DU during the observation period in patients without any DU prior to or at baseline was negatively associated with current smoking (OR 0.5, p=0.03) but not with previous smoking (OR 1.1, p=0.7).

Conclusions: The adverse effect of smoking on bronchial airways that is known in the general population is replicated in the SSc population. The lack of a measurable adverse effect of smoking on the speed of worsening of cutaneous and pulmonary SSc manifestations argues against a major role of tobacco associated free radicals and vasoconstriction in the pathogenesis of SSc vasculopathy and fibrosis.

P.101

Plasma CXCL4 Level May Not Reflect the Effects of Intravenous Cyclophosphamide Therapy for Systemic Sclerosis Associated Interstitial Lung Disease

Y. Ichimura, Y. Kawaguchi, K. Takagi, A. Tochimoto, T. Higuchi, H. Yamanaka

Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, JAPAN

Introduction: Increased level of CXCL4 has been reported to systemic sclerosis (SSc) and its complication such as interstitial lung disease (ILD) in an observational study. Recently, change in plasma CXCL4 level in 12 months after treatment with immunosuppressants is reported to be related to improvement of lung function in a study. We aimed to evaluate whether the decreases of CXCL4 levels predict the effectiveness of immunosuppressants to SSc-associated ILD (SSc-ILD).

Material and Methods: Consecutive 14 patients with SSc-ILD were enrolled to this retrospective, observational study. They received IVCY 3 to 6 times as first therapy in our hospital from April 2010 to March 2015. The protocol of IVCY was the dose of 500 mg/body surface area (m²)/4 weeks and performed 3 to 6 times. Serum and plasma CXCL4 were measured before treating with IVCY and after 2-3 months after starting treatment with IVCY. We assessed the follow-up for 1 years after IVCY therapy. All data were collected from medical record retrospectively.

Results: No cases were observed the deterioration of SSc-ILD by an IVCY therapy. The reverse correlation was observed between CXCL4 level and % vital capacity in pulmonary function test before IVCY (r2= 0.30, p= 0.04). Mean plasma CXCL4 level before and after treatment with IVCY were 2.81 x104 ng/mL and 2.59 ng/mL, respectively. We divided two groups: Group 1 was consisted of 7 patients whose CXCL4 levels were decreased after IVCY; Group 2 was 7 patients whose its levels were increased after IVCY. There’s no significant difference in clinical characteristics and the levels of KL-6 after IVCY between the 2 groups.

Conclusions: The levels of CXCL4 did not predict the efficacy of IVCY in patients with SSc-ILD.

P.102

Tacrolimus Following Intravenous Cyclophosphamide Pulse Therapy as an Alternative Treatment for Systemic Sclerosis-Associated Interstitial Lung Disease

Y. Ichimura, Y. Kawaguchi, K. Takagi, A. Tochimoto, T. Higuchi, H. Yamanaka

Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, JAPAN

Introduction: Interstitial lung disease (ILD) is a big complication for systemic sclerosis (SSc), which shows fibrosis in various organ. However, the treatment for ILD has been limited. Though intravenous cyclophosphamide pulse therapy (IVCY) is effective and widely used, the effect of the therapy does not last for a long time. In this reason, IVCY therapy followed by somewhat immunosuppressants may be needed, but it is uncertain which immunosuppressant is better for ILD in SSc. In Japan, Tacrolimus is frequently used for the treatment of ILD in polymyositis/dermatomyositis and idiopathic interstitial pneumonia. We examined the effect of sequential IVCY therapy followed by tacrolimus and low-dose corticosteroids in SSc-associated ILD (SSc-ILD).

Material and Methods: This retrospective, observational study was performed in a single center in Japan. Twenty consecutive patients with SSc-ILD who received IVCY 3 to 6 times as first therapy in our hospital from April 2010 to March 2014 were enrolled. The protocol of IVCY is the dose of 500 mg/body surface area (m²)/4 weeks and performed 3 to 6 times. In this study, we divided them two groups: treated with tacrolimus and low-dose corticosteroids following IVCY (TAC group); only low-dose corticosteroids after IVCY (IVCY group). We assessed the follow-up for 3 years after IVCY therapy in each group. Disease deterioration of ILD was defined as fulfilling more than 2 following criteria: deterioration of symptoms; expanding lung fibrosis in CT scan; DLCO decreasing more than 5% from baseline in lung function test. All data were collected from medical record retrospectively.

Results: Ten patients were in TAC group, and other 10 patients IVCY group. Age (50 ± 5 year-old in TAC group vs. 57 ± 5 year-old in IVCY group; mean ± S.E.) and Duration of illness (2.6 ± 0.9 years vs. 2.4 ± 0.9 years) were same in each group. No difference was observed in pulmonary function test at baseline in each group. After 3-year follow up, only 2 patients in IVCY group revealed disease progression. In TAC group, a case stopped taking tacrolimus due to adverse event, thrombocytopenia. Any cases in TAC group did not show neither renal crisis nor elevation of creatinine.

Conclusions: Tacrolimus following IVCY may be one of therapeutic choice for SSc-ILD, with good tolerance.

P.103

Assessing the Natural History of Interstitial Lung Disease in Systemic Sclerosis; Results from a Complete, Nationwide Cohort

A. Hoffmann-Vold¹, H. Fretheim¹, A.K. Halse², M. Seip³, H. Bitter⁴, M. Wallenius⁵, T. Garen¹, Ø. Midtvedt¹, Ø. Molberg¹

¹ Oslo University Hospital, Oslo, NORWAY, ² Haukeland University Hospital, Bergen, NORWAY, ³ University Hospital of North Norway, Tromso, NORWAY, ⁴ Hospital of southern Norway, Kristiansand, NORWAY, ⁵ St. Olav’s University Hospital, Trondheim, NORWAY

Introduction: We aimed to determine the natural history of interstitial lung disease (ILD) in systemic sclerosis (SSc) in the complete, nationwide Norwegian SSc cohort to complement existing multi-center registry data with novel, unbiased, high resolution results.

Material and Methods: The Norwegian, nationwide SSc (Nor-SSc) study cohort included all adult patients in Norway (denominator population of 5.0 million inhabitants) who were: (A) resident in Norway until 2013, (B) registered with an ICD-10 code M34 (SSc) in a public hospital database, (C) had a clinical SSc diagnosis verified by a rheumatologist and (D) met the classification criteria for SSc. Detailed electronic patient journal review was performed in all patients to assess ILD features from SSc onset to the end of the observation period (January 2013). Descriptive statistics and regression analysis were applied.

Results: The Nor-SSc cohort included 896 patients. Mean age at onset was 49 years, 84.2% were female and 77.5% had limited cutaneous SSc. Positive anti-centromere (ACA), anti-topoisomerase I (ATA) and anti-RNA polymerase III (ARA) antibodies were present in 61%, 13% and 5%. Pulmonary function analyses showed that baseline FVC was 93.5% of expected reference value in the complete cohort and declined by 0.1%, while baseline DLCO% was 68.9% and declined by 9.3%. Throughout the observation period, 66 SSc patients (34.4%) developed DLCO<60%, while 25 (9.4%) developed FVC <70%. Baseline lung HRCT images were available in 598 patients (66.7%), whereof 297 (49.7%) had findings compatible with ILD. Extent of fibrosis at baseline was 11.7%. In 198/297 SSc patients a follow-up HRCT was available whereof 105/198 patients had lung fibrosis progression (mean 2.6%), with 42.4% showing>2% and 16.5% showing>10% progression. In univariable logistic regression, factors associated with ILD at baseline were high modified Rodnan skin score (mRSS), positive ATA or ARA, male gender, diffuse cutaneous SSc, low baseline FVC and DLCO values, high extent of lung fibrosis, presence of digital ulcers and oesophagus dysmotility. In the multivariable cox regression model, male gender (HR 2.0, 95%CI 1.07-3.75, p=0.029), mRSS (HR 1.04, 95%CI 1.01-1.07, p=0.011), baseline fibrosis (HR 1.03, 95%CI 1.01-1.04, p<0.001), and ACA (HR 0.37, 95%CI 0.15-0.90, p=0.027) were associated with fibrosis progression (c-index 0.8).

Conclusions: In this population based, nationwide study, we found that a large proportion of SSc patients had ILD and showed ILD progression throughout the observation period. We identified factors associated with ILD at baseline and risk factors for ILD progression comparable to previous studies from selected cohorts.

P.104

Correlating Plasma Cytokine Levels with Right Heart Catheterization Parameters in Systemic Sclerosis Related Pulmonary Arterial Hypertension

C.H. Ho¹, S.I. Nihtyanova², B. Ahmed Abdi², J.G. Coghlan³, C.P. Denton², B.E. Schreiber⁴, V.H. Ong²

¹ Department of Medicine, Queen Elizabeth Hospital, Kowloon, HONG KONG, ² Centre for Rheumatology and Connective Tissue Diseases, University College London Medical School, Royal Free Hospital, London, UNITED KINGDOM, ³ Department of Cardiology, Royal Free Hospital, London, UNITED KINGDOM, ⁴ Department of Rheumatology, Royal Free Hospital, London, UNITED KINGDOM

Introduction: Right heart catheterization (RHC) is an important yet invasive test for diagnosis and classification of pulmonary hypertension (PH), a serious manifestation of systemic sclerosis (SSc). This exploratory study assesses the associations between plasma cytokine levels and haemodynamic parameters recorded during RHC in SSc patients.

Material and Methods: SSc patients referred for RHC (for diagnosis or monitoring treatment response) were recruited. Their blood samples, demographic and clinical data were obtained. RHC haemodynamic parameters included mean right atrial pressure (mRAP), mean pulmonary arterial pressure (mPAP), pulmonary capillary wedge pressure (PCWP), pulmonary vascular resistance (PVR), cardiac output (CO) and cardiac index (CI). Plasma samples were analysed for potential biomarkers of PH, namely IL1b, IL4, IL6, IL10, IL17A, IL17F, IL21, IL22, IL23, IL25, IL31, IL33, IFN-γ, sCD40L and TNF-α (pg/ml, Bio-Rad Pro Assays). Plasma from healthy controls (HC) were also analysed for comparison. Analytes found to be below the lower limit of detection of the assays were assumed to be equal to the lower limit of the detection as per assay’s protocol.

Non-parametric tests, including Wilcoxon-Mann-Whitney test, Kruskal-Wallis test and Spearman’s rank correlation coefficient, were used to assess associations between demographic and clinical characteristics and analyte levels as appropriate.

Results: We recruited 58 SSc patients and 10 HCs. Most SSc patients were female (n=54, 93.1%) and had limited cutaneous SSc (n=52, 89.7%). Mean age was 61.2 years. Among the 54 antibody-positive patients, the majority were anti-centromere (n=34, 63%), followed by anti-U3RNP (n=4, 7.4%) and anti-Scl70 (n=3, 5.6%). Eleven (19%) patients had pulmonary fibrosis (PF) but none of them had >20% involvement on HRCT thorax. Pulmonary arterial hypertension (PAH), defined as mPAP >25mmHg & PCWP <15mmHg, was diagnosed in 45 patients (77.6%).

There was no difference in any of the analyte levels between HCs and SSc patients. Presence of PF was associated with lower levels of IL6 (PF 4.9pg/ml, no PF 9.4pg/ml, p=0.014), IFN-γ (PF 16.9pg/ml, no PF 50.9pg/ml, p=0.016) and TNF-α (PF 1.1pg/ml, no PF 2.8pg/ml, p=0.022).

CO significantly correlated with sCD40L level (Spearman’s rho=0.35, p=0.009). RAP correlated positively with IL6 (Spearman’s rho=0.30, p=0.024) and IL25 (Spearman’s rho=0.28, p=0.037). We found no evidence for association between any of the analytes and PAP, PVR, CI or PCWP.

Conclusions: Our data provides evidence that selected analytes correlate with key RHC haemodynamic parameters, and may be implicated in pathogenic pathways of PAH. Potential role of biomarkers as a non-invasive and cost-saving alternative to RHC should be further explored.

P.105

Factors Associated with Deterioration of Interstitial Lung Disease in Systemic Sclerosis Patients with Anti-Topoisomerase I Antibody

Y. Yoshimura, T. Matsushita, Y. Hamaguchi, T. Takehara

¹ Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, JAPAN

Introduction: Systemic sclerosis (SSc) is a systemic autoimmune disease that is characterized by excessive fibrosis and microvascular damage. Interstitial lung disease (ILD) is a group of lung disorders affecting the tissue and space around the air sacs. ILD is recognized a prognostic factor and leading cause of death in patients with SSc. There are several SSc-specific autoantibodies, and anti-topoisomerase I antibody is strongly associated with ILD. In the present study, we aimed to clarify factors at an initial visit that are associated with the deterioration of ILD in SSc patients with anti-topoisomerase I antibody.

Material and Methods: This was a single center, retrospective, observational study. Fifty-three consecutive SSc patients with anti-topoisomerase I antibody were included in this study. The onset age and disease duration of the 53 patients were 47 ± 18 years old and 3.0 ± 2.9 years, respectively. The average follow-up period was 76 ± 38 months. Of the 53 patients, 43 had ILD at their first visit, whereas 10 did not. We examined clinical and immunological factors at the initial visit that were associated with the deterioration of ILD. The deterioration of ILD was defined as the administration of intravenously administrated cyclophosphamide (IVCY) therapy.

Results: In this cohort, 45 (85%) patients had ILD at the time of the final observation and only two who did not have ILD at their first visit developed ILD during the follow-up period. Until the time of the final observation, 26 (49%) patients received IVCY therapy for the progression of ILD. The age at onset, disease duration, SSc subtype, and skin score were similar between patients with and those without IVCY therapy. Approximately 60% (26 out of 43 patients) of patients with ILD at their first visit received IVCY therapy. On the other hand, none of the 10 patients without ILD at the first visit received IVCY therapy. Our multivariate analyses using Cox’s proportional hazards regression model revealed that the presence of ILD at the initial visit was an independent factor associated with the deterioration of ILD (OR = 3.9e+7, 95% CI 3.991 - uncalculated, P = 0.0017).

Conclusions: Although anti-topoisomerase I antibody is strongly associated with ILD, it was unlikely for SSc patients with anti-topoisomerase I antibody to receive IVCY therapy when they did not have ILD at the first visit.

P.106

Description and Prognosis Factors of Systemic Sclerosis-Associated Interstitial Lung Disease Outcome On Serial Hrct

A. Forestier¹, N. Le Gouellec ^1,2,3, A. Duhamel⁴, G. Kramer⁶, T. Perez⁵, V. Sobanski^1,2,3, S. Morell Dubois ^1,2,3, M. Lambert ^1,2,3, P-Y. Hatron ^1,2,3, E. Hachulla ^1,2,3, H. Behal⁴, R. Matran⁵, D. Launay ^1,2,3, M. Remy Jardin⁶

¹ CHU Lille, Département de Médecine Interne et Immunologie Clinique, Lille, FRANCE, ² Univ

Lille, U995, Lille Inflammation Research International Center (LIRIC), Lille, FRANCE, ³ Centre National de Référence Maladies Systémiques et Auto-Immunes Rares (Sclérodermie Systémique), Lille, FRANCE, ⁴ UDSL, EA 2694, UFR Médecine, LillE, FRANCE, ⁵ CHRU Lille, Service d’Explorations Fonctionnelles Respiratoires, Lille, FRANCE, ⁶ CHRU Lille, Département d’Imagerie Thoracique, Lille, FRANCE

Introduction: Interstitial lung disease (ILD) is a leading cause of morbidity and mortality in systemic sclerosis (SSc). While factors associated with the presence of ILD in SSc (SSc-ILD) are identified, those associated with ILD outcome are still debated and studies assessing the evolution of SSc-ILD on HRCT are scarce. Yet, it is important to identify patients at risk of SSc-ILD worsening because those patients are thought to benefit the most from immunosuppressants. Thus, the aims of our study were: to describe the evolution of HRCT extension and patterns of SSc-ILD, to identify baseline prognosis factors of ILD outcome on serial HRCT and to investigate whether the evolution of pulmonary function tests (PFTs) parameters correlated with the evolution on HRCT.

Material and Methods: We included 58 SSc patients with HRCT proven ILD, with at least two available HRCT, and collected clinical, biological data and PFT at baseline. We collected all HRCT and PFTs available during follow-up. We modelized PFTs and HRCT evolution using linear mixed model with random coefficients.

Results: Mean ILD extension at baseline was 32.3 ± 28.7%. During a mean follow-up of 5.3 ± 4.9 years, we found a significant mean progression of ILD extension of 0.92 ± 0.36% per year (p=0.018). Male sex, anti-topoisomerase 1 antibodies, diffuse cutaneous SSc were associated with faster progression of ILD extension. Limited ILD according to Goh et al. staging system, and a coarseness score at zero (meaning 100% of ground glass opacification) were associated with a faster progression of ILD extension. We also found a significant decline of DLCO, FVC and TLC during follow-up. There was a significant correlation between the progression of ILD extension on HRCT and the decline of DLCO, but not with the evolution of FVC.

Conclusions: Male patients, patients with diffuse SSc /antitopoisomerase 1 antibodies, patients with less severe and less extensive ILD at baseline were more likely to experiment a faster progression of ILD extension on serial HRCT. To our knowledge, this is the first study that clearly highlighted the diffuse form of SSc/presence of antitopoisomerase 1 as a worsening factor of SSc-ILD on HRCT. FVC might not be the best mirror of ILD progression while DLCO significantly correlated with change in ILD extension. Our study helps to define the profile of patients who are going to experience a progression of ILD on HRCT during follow up.

P.107

Serum Levels of Vascular Endothelial Growth Factor C Is Associated with Pulmonary Arterial Hypertension in Systemic Sclerosis

H. Didriksen¹, A.M. Hoffmann-Vold ^1,2, H. Fretheim ^1,2, A.K. Andreassen³, C. Brunborg⁴, V. Palchevskiy⁵, Ø. Midtvedt¹, T. Garen¹, J.A. Belperio⁵, Ø. Molberg ^1,2

¹ Oslo University Hospital - Department of Rheumatology, Oslo, NORWAY, ² University of Oslo - Institute of Clinical Medicine, Oslo, NORWAY, ³ Oslo University Hospital - Department of Cardiology, Oslo, NORWAY, ⁴ Oslo University Hospital - Oslo Centre for Biostatistics and Epidemiology, Oslo, NORWAY, ⁵ University of California Los Angeles - Department of Pulmonary Diseases, Los Angeles, California, USA

Introduction: Pulmonary arterial hypertension (PAH) is a common complication in Systemic Sclerosis (SSc). It is known that patients with SSc have a decrease in lymphatic vessels; and that vascular endothelial growth factor C (VEGF-C) is a major growth factor in lymphatics. The VEGF-C/VEGF-receptor 3 axis is shown to be decreased in PAH. On the other hand, the chemokine CCL21 has a key role in inflammation leading to PAH and is expressed in lymphatic endothelial cells. Based on these observations we aimed to assess characteristics of VEGF-C and correlation between VEGF-C and chemokine CCL21 in SSc associated PAH.

Material and Methods: SSc patients were characterized by right heart catheterization (RHC) where those with mean pulmonary arterial pressure (mPAP) > 25 mmHg were diagnosed with pulmonary hypertension (PH). VEGF-C and CCL21 levels in sera from the Oslo University Hospital SSc cohort (n=371) and healthy controls (n=100) were analyzed using Luminex kit form Millipore. Information collected from patients was used for statistical analysis. Descriptive data and box- and scatter plots were produced to compare and correlate the serum levels of VEGF-C and CCL21 in SSc patients vs. controls, and patients with PAH vs. without PH. The cut off in which levels of VEGF-C were considered high or low was determined by ROC-curve. Statistical analysis was performed by IBM SPSS Statistics 24.

Results: The mean age of the SSc patients was 51±15.3, where the majority was women (84.1%) and had the limited cutaneous form (74.9%). The number of SSc patients which underwent RHC was 159/371. 26 patients were diagnosed with PH-ILD, 43 with PAH, 14 with post capillary PH, 41 with borderline PH and 35 had no PH. VEGF-C levels were lower in SSc sera compared to the healthy controls (2.1±0.5 ng/ml vs. 2.5±0.4 ng/ml) as well as in sera from patients with PAH compared with those without PH (1.8±0.4 ng/ml vs. 2.4±0.5 ng/ml). VEGF-C levels were also lower in PAH compared to PH-ILD (2.1±0,5 ng/ml), post capillary PH (2.1±0.6 ng/ml) and borderline PH (2.0±0.6 ng/ml). In patients with low VEGF-C levels (<2.3 ng/ml) PAH was over 3-fold more frequent than in patients with high levels (15.1 % vs. 4.1 %). VEGF-C and CCL21 is negatively correlated in SSc patients and SSc patients with PAH, while positively correlated in healthy controls and patients with no PH.

Conclusions: VEGF-C is associated with PAH in SSc. The association makes VEGF-C a possible marker for the disease and will be further investigated.

P.108

To Evaluate Pulmonary Involvement in Patients with Systemic Sclerosis in the Daily Practice

M.A. Cusa¹, J.I. Enghelmayer², M.E. Fonrouge¹, S. Scarafia¹, M.A. Lázaro¹

¹ Instituto de Asistencia Reumatologica Integral (Iari), Buenos Aires, Argentina, ² Hospital de Clinicas Jose de San Martin, Buenos Aires, Argentina

Introduction: Systemic Sclerosis (SS) is a multi-systemic autoimmune disease. Pulmonary involvement has high morbility and mortality (up to 85%). The high resolution computed tomography scan (HRCT) (gold standard), pulmonary function test and the 6-minute walk test (6MWT), are used for diagnosis, prognostic evaluation and treatment. Our objetive was to estimate the proportion of patients with SS who can complete pulmonary tests and describe their clinical features.

Material and Methods: We evaluated patients with SS according to ACR/EULAR 2013 criteria with HRCT in the last 12 month. They were referred to a joint interview: rheumatologist/pulmonologist. Demographic and clinical data were collected. 6MWT and spirometry were performed. Patients with COPD history and uncontrolled PAH were excluded.

Results: Twenty-four patients were included, mean age 56.9 years (IQR 72.5-44.5), time evolution of disease 86.7 month (IQR 37.9-129), 41,6% were Diffuse cutaneous SS, 95.8% ANA positive, 58% antibody anti centromere positive, 4% antibody anti SCl70 positive, 20% had digital ulcers, 100% had Raynaud’s Phenomenon (RF), median modified Rodnan Skin Score 7.5 (IQR 5.5-13), 33% presented capillaroscopy with SD pattern. 74% had normal HRCT, 13% NSIP with less 20% commitment and 9% with greater 20%, 4% UIP was found. 75% were able to perform DLCO, half were normal, 28% had mild and 22 % moderate decrease. 96% performed spirometry and was normal in 86%, microstomia was the limiting factor in these tests. Sixty-six percentof the patients underwent the 6MWT, median 420 meters (IQR 475-393), baseline oxygen saturation 97.5% (DS 4.4) and final 88% (DS10.3) p 0.027. In 33% of the patients the pulse oximetry could not be performed due the RF. Initial Borg dypsnoea score median 0 (IQR 0-3). The main limitation was musculoskeletal involvement, then RF and microstomia.

Conclusions: 46% patients completed all the studies used for lung involvement assessment. Musculoskeletal involvement, RF and microstomia may be a limitation in patients with SS for the evaluation with these tools.

P.109

Serum Proteomic Profile Identifies New Biomarkers Associated with Systemic Sclerosis

A. Ceribelli¹, M. De Santis¹, E. Generali¹, N. Isailovic¹, M. Caprioli¹, G.M. Guidelli¹, C.F. Selmi^1,2

¹ Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, MI, ITALY, ² BIOMETRA Department, University of Milan, Milan, ITALY

Introduction: Systemic sclerosis (SSc) is an autoimmune disease associated with serum anti-nuclear antibodies (ANA), such as anti-centromere (ACA), anti-topoisomerase I (ant-Scl70), and anti-RNA polymerase III antibodies, identifying patient subgroups. However, no reliable biomarkers can predict SSc susceptibility and internal organ involvement. Therefore, we aimed to identify serum biomarkers associated with SSc and interstitial lung disease (ILD).

Material and Methods: We analyzed serum samples of 3 patients with SSc and ILD, 3 patients with SSc and no ILD, and 4 age- and sex-matched healthy controls (HC). Proteomic analysis was performed using the SOMAscan platform (SomaLogic, Inc., Boulder, CO, USA). SOMAscan Assay through SOMAmer reagents can identify greater than 1300 proteins in 150 µl of serum, quantifying proteins that span over 8 logs in abundance(from femtomolar to micromolar). Statistical analysis included Student’s t test and were performed using the SomaSuite software (SomaLogic, Boulder, CO, USA).

Results: Proteomic analysis identified 33 proteins with a significantly different concentration between SSc and HC; 18 were hyper-expressed and 15 hypo-expressed.

Interestingly, 21 of these proteins showed a range of concentration in SSc patients without overlapping values with HC and so specifically associated to SSc disease.

Compared to HC, SSc cases showed an altered expression of proteins involved in extracellular matrix formation and cell-cell adhesion, angiogenesis, and lymphocyte recruitment, activation, and signaling, including interferon and IL-1 signatures, while an overall inhibition of markers of neutrophil function was noted.

Nine proteins had a significantly different concentration between SSc patients with ILD and SSc patients without ILD; 7 were hyper-expressed and 2 hypo-expressedwithout overlapping values with SSc patients without ILDand so specifically associated to lung involvement. Patients with SSc and ILD showed increased protein levels related to intracellular signaling and cell cycle, along with an increase of monocyte chemoattractants, of ligands for the leukocyte adhesion, and IL-10 family signaling compared to SSc without ILD. Validation is ongoing in an independent cohort of patients with different clinical phenotypes using commercially available ELISA.

Conclusions: Serum proteomic profile can differentiate SSc from healthy controls and SSc patients with ILD from those without ILD; moreover, our results identify biomarkers with a putative pathogenic significance.

P.110

Interstitial Lung Disease Is Independently Associated with Increased Fecal Calprotectin Levels in Systemic Sclerosis

C. Caimmi¹, E. Bertoldo¹, A. Venturini¹, P. Caramaschi¹, L. Frulloni², R. Ciccocioppo², S. Brunelli², L. Idolazzi¹, D. Gatti¹, O. Viapiana¹, M. Rossini¹

¹ Rheumatology Unit, University of Verona, Verona, ITALY, ² Gastroenterology Unit, University of Verona, Verona, ITALY

Introduction: Interstitial lung disease (ILD) is one of the leading cause of death in systemic sclerosis (SSc). The aim of this paper was to evaluate the relationship between fecal calprotectin (FC) and ILD.

Material and Methods: One-hundred twenty-nine outpatients with SSc were enrolled. Data about disease characteristics, in particular lung involvement, were collected and FC was measured.

Results: Eighty-seven patients (67.4%) had a limited subset with a mean disease duration of 13.3 (7.1) years. Anti-Scl70 antibodies were found in 35 (27.1%) patients. GI tract involvement was severe/end stage in 3 cases (2.4%). ILD affected 35 patients (27.1%). Median levels of FC were 80 ug/g (157 ug/g). FC was found to be higher in patients with a moderate/severe/end stage score for gastrointestinal tract (p=0.046) and on steroids (p=0.015). In addition, it positively correlated with age (p<0.001).

Other than well-known risk factors such as higher mRSS or diffuse subset, patients with ILD had higher values of FC (p<0.001). In multivariate analysis correcting for factors affecting ILD or FC levels (i.e. disease duration, mRSS, Valentini activity score, total Medsger severity score, proton pump inhibitor, anti-Scl-70 antibody, diverticulosis, limited cutaneous subset, fecal calprotectin levels, steroid treatment), diffuse disease subset (p=0.001), higher mRSS (p=0.04), longer disease duration (p=0.046), higher severity scores (p=0.026), higher FC levels (p=0.003) and steroid treatment (p=0.014) were associated with increased risk of ILD, while diverticulosis was protective. In addition, we ran a second multivariate analysis considering the 110 cases with FC level<275 µg/g, in order to correct for a possible small intestine bacterial overgrowth. Increased FC levels (p=0.019), steroid treatment (p=0.03), higher severity scores (p=0.016) and diffuse disease subset (p=0.002) were confirmed to be associated with ILD.

Conclusions: In this paper we have found a possible link between gut inflammation and ILD. Many hypothesis may be done but it is intriguing that these data further support what previously found by other authors (Andreasson et al. 2016), that is a correlation between gut inflammation and dysbiosis and non-gastrointestinal disease manifestation. Our study may support the hypothesis of a role of gut dysbiosis in triggering a pathologic immune response leading to ILD. It may also be that increased FC simply reflects a more severe disease but this still doesn’t explain why only ILD was found to be linked with FC. Is it because lung is a filter of molecule (i.e. antigens, cytokines, metabolites, etc.) produced in the gut? Further studies with longitudinal evaluation are warranted.

P.111

The Screening of Pulmonary Arterial Hypertension in Scleroderma Patients Using the Detect Algorithm in Clinical Practice: Results from a Single Italian Centre

L. Urso¹, F. Cacciapaglia¹, E. Praino¹, S. Lopriore¹, C. Rotondo¹, E. De Tommaso², C. D’Agostino², F. Iannone¹

¹ Rheumatology Unit, Department of Emergency and Organs Transplantation - AOUC Policlinico di Bari, Bari, ITALY, ² Cardiology Unit, Department of Cardiology - AOUC Policlinico di Bari, Bari, ITALY

Introduction: The presence of pulmonary hypertension (PH) is a common complication occurring in up to 10% of patients with systemic sclerosis (SSc), carries a very severe prognosis and is one of the leading causes of mortality for these patients (1). The DETECT study described a new algorithm for early detection of PH in patients with SSc (2), but data of the performance of this algorithm in Italian Rheumatologic Centres are lacking. The aim of this prospective, single-centre, cross-sectional study was to apply the DETECT calculator in patients with SSc for the screening of pulmonary arterial hypertension (PAH) to refer patients for right heart catheterization (RHC).

Material and Methods: Seventy-seven patients (F/M = 66/9; aged 21-82 years; mean disease duration 8±7 years) with diagnosis of SSc according to 2013 ACR/EULAR criteria (3), were evaluated from 1st January to 31st August 2017, using the modified DETECT algorithm for the diagnosis of PAH. Right heart catheterization (RHC) was performed according to physician’s judgment as per the 2015 ESC/ERS guidelines (4).

Results: Using the modified DETECT calculator 26/77 (33.8%) patients were recommended for RHC, and 16 (20.8%) patients were eligible for RHC according to the ESC/ERS echocardiographic signs. Of these patients only one was modified DETECT score-negative. RHC confirmed the presence of pulmonary arterial hypertension in 12 (15.6% SSc) patients, with a good accuracy of DETECT algorithm for PAH screening (Sens. 92%; Spec. 77%; NPV 98%).

Conclusions: The modified DETECT algorithm is reliable in daily clinical practice and able to screen SSc patients to be sent to RHC for early PAH diagnosis. Specifically, in SSc patients with low DETECT score PAH is unlike.

References

1. Avouac J, Airò P, Meune C, et al. J Rheumatol. 2010 Nov; 37(11):2290-8.

2. Coghlan JG, Denton CP, Grünig E, et al. DETECT study group. Ann Rheum Dis. 2014 Jul; 73(7):1340-9.

3. van den Hoogen F, Khanna D, Fransen J, et al. Arthritis Rheum. 2013 Nov; 65(11):2737-47.

4. Galiè N, Humbert M, Vachiery JL, et al. Eur Heart J. 2016 Jan 1;37(1):67-119.

P.112

Safety and Efficacy of Intravenous Versus Oral Cyclophosphamide (CYC) in the Treatment of Systemic Sclerosis (Ssc) Related Ild and Skin Involvement

C. Bruni¹, D.P. Tashkin², V. Steen³, Y. Allanore⁴, O. Distler⁵, M. Matucci-Cerinic¹, D.E. Furst^1,6

¹ Dept of Experimental and Clinical Medicine, Division of Rheumatology, University of Flirenze, Firenze, ITALY, ² Division of Pulmonary Medicine and Critical Care, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, USA, ³ Rheumatology Division, Department of Medicine, Georgetown University, Washington, USA, ⁴ Université Paris Descartes, Sorbonne Paris Cité, Service de Rhumatologie A, Hôpital Cochin, Paris, FRANCE, ⁵ Rheumaklinik, University Hospital Zurich, Zurich, SWITZERLAND, ⁶ Department of Medicine, Division of Rheumatology, University of California Los Angeles, Los Angeles, USA

Introduction: in the last decade, po CYC has shown modest effect on SSc-ILD. However, several centres are giving priority to IV monthly CYC mainly because of expected milder toxicity. Our aim was to compare efficacy and safety of po vs iv CYC for SSc.

Material and Methods: data were obtained from the EUSTAR database and the Scleroderma Lung Studies I and II. SSc patients, receiving po or iv CYC for at least 6 months, were followed for one year from the last administration. Data on safety [serious(SAEs) and non-serious adverse events(AEs)] and efficacy (FVC, DLCO, mRSS) at end of treatment and after one-year follow-up were analyzed [mean±SD or median(IQR) as appropriate].

Results: Three-hundred-thirteen patients were eligible: 148 patients received po CYC with median daily dose 160(42) mg, treatment duration 365(1) days, while 165 patients who received iv CYC median monthly dose 1000(400) mg, treatment duration 335(321) days. The two groups were different for age (48±11 vs 52±12 years,p=0.011), ethnicity (Caucasian 69.6% vs 94.5% and Afro-American 15.5% vs 0%,both p<0.001), previous DMARD exposure (23.6% vs 40.6%,p=0.001), current/previous smoking (14.2% vs 6.7%,p=0.022), PAH (0 vs 10.3%,p=0.013) and DUs (26.4% vs 41.2%,p=0.005), respectively. Despite significantly different baseline FVC [69(15) vs 82(28)%, p<0.001] and DLCO [51(24) vs 56(29)%, p=0.016], unadjusted % changes in FVC [0.0(10) vs 0.0(14) and 0.0(13) vs -2.0(14),p=NS], DLCO [-4.0(12) vs -3.0(13) and -3.0(13) vs -4.0(18),p=NS] and mRSS [-2.0(5) vs-1.0(6) and -2.0(7) vs -2.0(6),p=NS] were respectively similar between groups both at end of treatment and follow-up visits. During po CYC, there was more leukopenia (21.6% vs 1.2%, p<0.001), thrombocytopenia (3.4% vs 0%, p=0.023), haemorrhagic cystitis (5.4% vs 0%, p=0.006) and general AEs (50%vs15.8%, p<0.001). In the iv group, there were more SAEs (8.2% vs 17.0%, p=0.029), need for oxygen (4.7% vs 14.5%, p=0.005) and SSc-related cardiomyopathy (2.0% vs 8.5%, p=0.001) during follow-up. There was also a statistically significant higher dosage of concomitant steroids and higher prevalence of DMARDs use in the iv CYC group, as a post-treatment maintenance.

Conclusions: Despite being somewhat disparate groups, in particular for the different nature of the source databases, preliminary analyses indicates that one year of po and iv CYC had similar results, although dosage of concomitant steroid was lower and subsequent immunosuppressors were less common in the po group. In contrast, AE time courses and types of AEs were different comparing po and iv CYC.

P.113

Early Diagnosis of Pulmonary Arterial Hypertension in Systemic Sclerosis: a Single Centre Experience with Detect Algorithm

F. Bonomi, G. Di Gennaro, S. Freri, L.O. Parma, C. Valena, M. Riva, S. Del Giudice, M.R. Pozzi

Internal Medicine - Rheumatology Department- Milano Bicocca University - San Gerardo Hospital, Monza, ITALY

Introduction: Pulmonary arterial hypertension (PAH) is a severe complication of Systemic Sclerosis ( Ssc) with a mortality of 50% within three years of diagnosis. The evidence that early treatment improves long-term outcome has led to the development of screening strategies aimed to identify a high risk population for PAH through right heart catheterization (RHC).

Material and Methods: The DETECT algorithm is based on a two steps score: the first step includes non-echocardiographic variables (FVC/DLCO, telangiectasias, ACA antibodies, NTproBNP, urate, ECG right axis deviation) and allow to exclude a low risk PAH patients (score < 300: sensibility 97%). The second step is based on echocardiographic variables (right atrium area and TR velocity): RHC is indicated when the score is > 35 (specifity 35%). We applied DETECT algorithm in SSc pts referring to our rheumatology ambulatory, using the inclusion and exclusion criteria proposed by the original study.

Results: We screened 100 patients (F:M 91:9), mean age 65.2 years, mean duration 10.9 years: 42.7% ACA+, DLCO % 66.09 ±25.5 SD, FVC % 98.9 ±22.6 SD. Forty patients met the eligibility criteria. Ten patients were excluded afterwards. 29/30 pts. obtained a score > 300 (mean 333.5) at step I. 17 pts underwent step II; 12 of them scored > 35 (mean 42.5): 6/12 underwent RHC, which revealed PAH in 5/6 pts WHO class I-II; mean mPAP 26.8 mmHg, RVP 3.38 Woods U, POP 11.6 mmHg, CI 2.85 l/min/m2). The mean follow-up of the 5 pts was 22 ± 12.1 SD months. Pt 1 was diagnosed as affected by combined pulmonary fibrosis and emphysema (CPFE) with PH and not treated with PAH drugs. Three pts were treated with PDE5-I and 1 with ERA: all showed a quick subjective improvement, but pt 2 underwent a significant clinical and echocardiographic worsening, requiring a combination therapy: 5 yrs before the RHC she was also treated for a concomitant ILD and for breast cancer. Pt 3 also experienced a clinical worsening: the V/Q scan showed a mismatched perfusion defects and anticoagulation was started. In our real life experience the systematic DETECT algorithm application allowed us to evaluate individually the risk for PAH and an early referral for RHC of high risk patients.

Conclusions: The severe clinical course of some PAH pts, despite the mild hemodynamic parameters and the early treatment, highlights the need of an in depth evaluation of other visceral involvement/comorbidities for a tailored therapy.

P.114

Antifibrotic Effects of Nintedanib in Lung Fibroblasts Isolated from Patients with Scleroderma Associated Interstitial Lung Disease

G. Bogatkevich¹, I. Atanelishvili¹, T. Akter¹, A. Noguchi², L. Wollin³, R. Silver¹

¹ Medical University of South Carolina, Charleston, USA, ² Hokkaido University Graduate School of Medicine, Sapporo, JAPAN, ³ Boehringer Ingelheim GmbH & Co. KG, Biberach, GERMANY

Introduction: Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis (IPF) and was demonstrated to slow disease progression in patients with IPF by reducing decline in forced vital capacity by 50%. Recently, nintedanib has been reported to exert anti-fibrotic activity on scleroderma (SSc) skin fibroblasts and to diminish skin and lung fibrosis in several mouse models. The goal of the present study was to determine the effects of nintedanib in SSc lung fibroblasts.

Material and Methods: Lung fibroblasts were derived from lung tissue collected postmortem from five patients with SSc associated interstitial lung disease (SSc-ILD) and from three control subjects. Expression of platelet derived growth factor receptor (PDGFR)α and PDGFRβ in lung fibroblasts was determined by quantitative RT-PCR. The functionality of PDGFRα and PDGFRβ and their responses to PDGF with and without nintedanib was determined by measuring of intracellular Ca2+ using Fluorescent Imaging Plate Reader (FLIPR)TM cellular screening system. Lung fibroblast proliferation was examined by cell counting and by Quick Cell Proliferation Assay; cell migration was investigated by the wound-healing “scratch” assay. Expression of collagen, connective tissue growth factor (CTGF, CCN2), and smooth muscle α-actin (α-SMA) was studied by immunoblotting and RT-PCR.

Results: The amount of PDGFRαmRNA was 7.3±0.4-fold higher then PDGFRβmRNA in SSc lung fibroblasts. Nintedanib had no effects on PDGF receptor expression and on acute increase of intracellular calcium. However, nintedanib significantly reduced PDGF-induced delayed calcium efflux in both, SSc and control lung fibroblasts. Nintedanib inhibited PDGF-induced lung fibroblast proliferation and cell migration in a concentration-dependent manner. PDGF upregulated collagen mRNA in SSc lung fibroblasts and had no effect on either CCN2 or α-SMA mRNA. Nintedanib reduced PDGF- and TGFβ-induced collagen in a concentration-dependent manner. Moreover, nintedanib down regulated high basal levels of collagen in SSc lung fibroblasts. Nintedanib did not affect basal level or TGFβ-induced CCN2 and α-SMA in both, control and SSc lung fibroblasts.

Conclusions: PDGFRα is the major PDGF receptor in SSc lung fibroblasts. Nintedanib modulates PDGF-induced calcium activity and inhibits lung fibroblast proliferation, migration and collagen production demonstrating significant antifibrotic effects in SSc lung fibroblasts.

P.115

The Histone Demethylase Jumonji Domain-Containing Protein 3 (JMJD3) as Central Mediator of Fibroblast Activation in Systemic Sclerosis (SSc)

C. Bergmann¹, A. Brandt¹, B. Merlevede¹, L. Hallenberger¹, C. Dees¹, Y. Zhang¹, C. Chen¹, T. Wohlfahrt¹, R. Liang¹, R. Kagwiria¹, A. Bozec¹, D. Abraham², R. Rieker³, A. Ramming¹, O. Distler⁴, G. Schett¹, J.H.W. Distler¹

¹ Department of Internal Medicine 3, Erlangen, GERMANY, ² UCL School of Life and Medical Sciences, London, UNITED KINGDOM, ³ Department of Pathology, Erlangen, GERMANY, ⁴ University Hospital Zurich, Zurich, SWITZERLAND

Introduction: Trimethylation of H3 at lysine residue K27 (H3K27me3) is a repressive modification, which is mediated by Polycomb-repressive-complexes and is reversible by the H3K27me3-demethylase JMJD3. We previously demonstrated that inhibition of H3K27me3 regulates fibroblast activation. However, the role of JMJD3 in SSc has not yet been defined. In this study, we characterize the role of JMJD3 as potential target for the treatment of fibrosis in SSc.

Material and Methods: JMJD3 was targeted using siRNA and GSKJ4. Fibroblast activation was analyzed by quantifying collagen synthesis and release and myofibroblast differentiation. In vivo studies were performed using the model of Topoisomerase-I induced skin and lung fibrosis and in bleomycin-induced skin fibrosis. H3K27me3 levels at the promoters of target genes was analyzed by ChIP.

Results: The expression of JMJD3 is increased in SSc skin compared to healthy controls. The overexpression was particularly pronounced in fibroblasts. Overexpression of JMJD3 was also observed in murine models of SSc. TGFβ upregulated JMJD3 in vitro and in vivo. Inhibition of JMJD3 increased the levels of H3K27me3 in cultured fibroblasts and in murine SSc models. Targeting JMJD3 in vitro ameliorated fibroblast activation with reduced collagen release and impaired myofibroblast differentiation. Inhibition of JMJD3 reduced fibroblast migration in scratch assays. We identified FRA2 as central downstream mediator of JMJD3 mediated fibroblast activation. TGFβ reduced H3K27me3 at the FRA2 promoter, which resulted in increased expression of FRA2. GSKJ4 prevented the TGFβ-induced downregulation of H3K27me3 at the FRA2 promoter. The functional importance of FRA2 for JMJD3 regulated fibroblast activation was further supported by knockdown studies: Upon knockdown of FRA2, GSKJ4 lost its inhibitory function on collagen secretion. In vivo, inhibition of JMJD3 ameliorated bleomycin induced skin fibrosis and TopoI- induced skin and lung fibrosis. GSKJ4 treatment did not affect B-cell counts in both mouse models and did not alter the levels of anti-TopoI antibodies. However, GSKJ4 treatment resulted in a slight reduction of T-cell counts.

Conclusions: We present first evidence for a dysregulation of JMJD3 in SSc. JMJD3 regulates fibroblast activation by modulating the levels of H3K27me3 at the FRA2 promoter. Targeted inhibition of JMJD3 reduces the aberrant activation of SSc fibroblasts and exerts potent antifibrotic effects in murine models of SSc.

P.116

Systemic Sclerosis in Tunisia: a Monocenter Study of 118 Patients

M. Tougorti, T. Ben Salem, M. Lamloum, I. Ben Ghorbel, M.H. Houman

Department of internal medicine, la Rabta University Hospital, Tunis, TUNISIA

Introduction: The aim of our study was to describe clinical, biological and immunological characteristics of systemic sclerosis (SS) in a group of Tunisian patients.

Material and Methods: A retrospective study was conducted in an internal medicine department over 15 years (from 2000 to 2015). Patients with SS, fulfilling ACR/EULAR classification criteria for SS, were included.

Results: One hundred eighteen patients with SS were enrolled; 107 women and 11 men. Mean age at disease onset was 44.8 ±13.8 years. Mean age at diagnosis was 48.97 ± 13 years. Raynaud’s phenomenon was noted in 96.6% of patients and presented with complications in 55% of patients. Nailfold capillaroscopy was performed in 90 patients and showed giant capillaries (n=58) and decreased capillary density (n=34). Cutaneous manifestations were seen in 95.8% of patients and revealed disease in 42.3% of cases. Among patients, 67.9% had limited cutaneous SS and 32.1% had diffuse cutaneous SS. Pulmonary manifestations were found in 75.7%. Dyspnea was the most frequent sign in patients with interstitial lung disease (n=70) and 23 patients complained of dry cough. Restrictive disorder was diagnosed in 50 patients. Gastro-intestinal involvements were seen in 100 patients (84.7%), 60 complained of dysphagia and 53 had symptoms of gastro-esophageal reflux disease. Esophageal manometry was performed in 58 patients and showed typical abnormalities of SS in 50 patients. Esophageal dilatation was noted in 22 patients.

Other systemic manifestations were: joint manifestations (74.7%), muscular (35.7%), pericarditis (23.4%), peripheral neuropathy (18.6%). Pulmonary hypertension was found in 48 patients among 108 screened with echocardiography but confirmed in only 6/10 who had right heart catheterization. Scleroderma renal crisis was noted in only one patient.

Anemia was noted in 30 patients (iron deficiency was the cause in 15). Hypoalbuminemia was found in 21 patients and 51 patients had hypergammaglobulinemia. C-reactive protein was high in 32% of patients.

Antinuclear antibodies were positive in 93.5% of cases. Anti-ENA antibodies were screened in 80 cases; anti-isotopomerase 1 (Scl-70) and anti-centromere were positive in 45 and 20 patients respectively.

Forty three patients had almost one associated auto-immune disease; Sjögren Syndrome (n=26) systemic lupus erythematosus (n=14), Hashimoto thyroiditis (n=4) and primary biliary cholangitis (n=3). SS was associated with cancers in nine patients.

Conclusions: Skin involvements are the most frequent signs of systemic sclerosis and their prevalence is similar to other ethnic groups. In our series, prevalence of pulmonary manifestations is higher than other groups whereas scleroderma renal crisis was very rare in our population

P.117

Interstitial Lung Involvement and Microvaculature Changes in Systemic Sclerosis: a Follow-Up Study

R. Becvar¹, M. Tomcik¹, S. Skacelova¹, J. Stork², A. Slovakova³

¹ Institute of Rheumatology, Prague, CZECH REPUBLIC, ² Clinic of Dermatovenerology, Prague, CZECH REPUBLIC, ³ Clinic of Pulmonology, Prague, CZECH REPUBLIC

Introduction: Lung involvement is the major cause of mortality in patients with systemic sclerosis (SSc). Gas transfer (DLCO) and FVC levels have traditionally been used as measures of disease severity and reductions of both parameters have been associated with increased mortality. In SSc repeated attacks of Raynaud‘s phenomenon lead to the reduced capillary density leads with reduced blood flow and tissue ischemia. Raynaud’s phenomenon can occur also in the lungs. Tissue hypoxia usually initiates the formation of new blood vessels from the pre-existing microvasculature. Nailfold capillaroscopy (NVC) is a safe, noninvasive routine way for the investigation of microvasculature.

The aim of this study was to assess the correlation between capillaroscopic abnormalities and parameters of interstitial lung involvement at baseline and after one year follow-up in patients with SSc.

Material and Methods: All patients underwent routine clinical examination (dyspnea, cough, crepitus), pulmonary function tests, DLCO (alveolitis grade and fibrosis), blood gases and HRCT scan of chest (1). Microvasculature changes were assessed using NVC which was performed by two independent examiners. The obtained images were analysed anonymously by two investigators blinded for the clinical and serum status of SSc patients and classified as early, active and late pattern, non specific or normal picture (2). For statistical evaluation Poisson’s correlation coefficient and T-test were used. All examinations were performed at baseline and after one year follow-up.

Results: Total 42 patients (38 females) were investigated: 30 individuals with limited form, 7 with diffuse form, 3 patients with scleroderma sine scleroderma, 1 with overlap syndrome and 1 with undifferentiated connective tissue disease. The mean age ± standard deviation (SD) of the whole cohort was 51±22 years and the mean disease duration ± SD was 10±7 years. 3 patients (7.5%) had early NVC pattern, 12 patients (30%) had active, 10 (58%) late pattern, and 17 (37.5%) had nonspecific changes or normal picture. The patients with late NVC pattern exhibited more often mild to moderate alveolitis, decreased FEV1 and FVC and DLCO. When correlating NVC patterns with clinical findings, pulmonary function test and HRCT scans we found only an association of low significance with dyspnea and alveolitis grade (both p < 0.1). After one year follow-up similar results were obtained (p < 0.001 and p < 0.01, respectively).

Conclusions: In our study NVC patterns did not seem to correlate with severity of interstitial lung disease in SSc patients even after one year follow-up

P.118

Can Implementation of the Detect Algorithm in a Systemic Sclerosis Population Already Followed with Yearly Echocardiography Identify Additional Patients with Pulmonary Arterial Hypertension?

J. Baumgartner-Nielsen, S. Mellemkjær, A. Braae Olesen

University Hospital of Aarhus, Aarhus, DENMARK

Introduction: Pulmonary arterial hypertension (PAH) is a leading cause of death in patients with systemic sclerosis (SSc). The evidence based DETECT algorithm is a non-invasive tool which identifies patients in risk of developing PAH and patients with subclinical PAH.

The study was designed to investigate if the DETECT algorithm would identify PAH among systemic sclerosis patient already being followed by annual echocardiography according to the international guidelines.

Material and Methods: A single-center, cross-sectional observational study among all adult SSc patients recruited during routine visit during one year (from 1.September 2016 to 31. August 2017) at the Scleroderma Team, Department of Dermatology, Aarhus University Hospital, Denmark. During the visit a clinical evaluation including Modified Rodnan Skin Score, pulmonary function test and blood test were performed All patients were referred for echocardiography. DETECT step 1 and 2 scores were calculated by the same dermatologist. Patients were referred to a diagnostic right heart catheterization (RHC) including a exercise test during the RHC if it was recommended by the DETECT step 2 –score.

Results: A total number of 90 patients have been screened and DETECT step 1 score has been calculated. Among patients that have had an echocardiography as per September 2017 21 had a DETECT step 2 score that qualified for a diagnostic RHC. Our final results including the result of the RHC will be presented at the meeting.

Conclusions: It is has been estimated, that approximately 20% of SSc patients with PAH are missed if only a routine practice of annual screening with echocardiography is performed. Our results will indicate if adding the DETECT algorithm in a Danish SSc population supports this estimate.

P.119

Mmp-10, a Novel Mediator of Vascular Remodeling Underlying Pulmonary Hypertension Associated with Systemic Sclerosis

J. Avouac¹, C. Guignabert², A.M. Hoffmann-Vold³, B. Ruiz¹, P. Dorfmuller², S. Pezet¹, O. Amiar¹, L. Tu², J. Van Wassenhove¹, J. Sadoine⁴, D. Launay⁵, M. Elhai¹, A. Cauvet¹, A. Subramaniam⁶, R. Resnick⁶, E. Hachulla⁵, O. Molberg³, A. Kahan¹, M. Humbert², Y. Allanore¹

¹ Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016 and CNRS UMR8104, Institut Cochin, Paris, FRANCE, ² Inserm UMR_S 999, Plessis Robinson, FRANCE, ³ Department of Rheumatology, Oslo University Hospital, Oslo, NORWAY, ⁴ EA 2496 Pathologie, Imagerie et Biothérapies Orofaciales, UFR Odontologie, Université Paris Descartes, Paris, FRANCE, ⁵ Médecine Interne, Hopital Huriez, Université de Lille, Lille, FRANCE, ⁶ Immune Mediated Diseases, Sanofi Genzyme, Framingham, USA

Introduction: Pulmonary hypertension (PH) is the most extreme vascular phenotype of systemic sclerosis (SSc). PH is one of the leading causes of death in patients with SSc and current therapeutic strategies remain limited. Pulmonary endothelial cell (EC) damages and dysfunctions play an integral role in the initiation and progression of pulmonary vascular remodeling associated to PH. We have studied gene expression profiles of Human ECs to decipher the role of gene candidates involved in SSc-PH.

Material and Methods: Gene candidates were identified through microarray experiments performed on Affymetrix GeneChip® Human Exon 1.0 ST Arrays in ECs derived from circulating progenitors issued from patients with SSc-PH, SSc without PH and controls. Expression of identified candidates was assessed by quantitative sandwich ELISA in the serum and by immunohistochemistry in lesional lung tissue. Their functional importance was then evaluated in vitro in ECs using siRNA and in vivo in fos-related antigen-2 (Fra-2) transgenic mice, that spontaneously develop SSc-like features associated with an intense pulmonary vascular remodeling, using neutralizing antibodies.

Results: Microarray experiments revealed that MMP10 was one of the top upregulated genes in SSc-PH ECs. Endothelial MMP10 was overexpressed in patients with SSc-PH and MMP10 produced by ECs derived from circulating progenitors was biologically active in vitro, regulating EC proliferation and matrix degradation. Circulating pro-MMP10 serum concentrations were markedly increased in a cohort of 102 patients with SSc-PH compared to 278 SSc patients without PH and 50 controls. Consistent with these observations, a strong MMP10 staining of the thickened wall of distal pulmonary arteries was found in lungs of SSc-PH patients and Fra-2 transgenic mice.

Daily treatment of Fra-2 mice with neutralizing anti-MMP10 antibodies reversed established PH. Regarding pulmonary hemodynamic parameters, a substantial reduction in values of right ventricular systolic pressure (29.3±2.2 versus 33.7±2.2 mmHg, respectively; P<0.05) and right ventricular hypertrophy (0.28±0.01 versus 0.31±0.02 %, P<0.05) was observed in MMP10-treated Fra-2 mice. Pulmonary vascular remodeling was also markedly improved upon neutralization of MMP10, with a significant reduction of percent medial wall thickness and numbers of muscularized distal pulmonary arteries. Treatment with anti-MMP10 antibodies resulted in reduced cell proliferation, cell survival and the PDGF signaling axis.

Conclusions: Gene expression profiling of ECs identified MMP10 as a novel candidate in SSc-PH. MMP10 is overexpressed in the serum and pulmonary arteries of patients with SSc-PH, and its blockade alleviates PH in the Fra-2 mouse model. MMP10 appears to be a prospective treatment target for this devastating disorder.

P.120

The Frequency of Obstructive Sleep Apnea Syndrome in Patients with Systemic Sclerosis

D. Arslan Tas¹, K. Aslan², I. Turk¹, D. Kurt Gok², C.E. Cagliyan³, I. Hanta⁴

¹ Cukurova University, Rheumatology, Adana, Turkey, ² Cukurova University, Neurology, Adana, Turkey, ³ Cukurova University, Cardiology, Adana, Turkey, ⁴ Cukurova University, Pulmonary Diseases, Adana, Turkey

Introduction: Sleep disturbances are observed to be frequent in rheumatological diseases. Patients with systemic sclerosis may be prone to sleep problems due to narrowing of the mouth, fibrosis in pharynx and esophagus and gastroesophageal dismotility. Besides, pulmonary hypertension and pulmonary fibrosis may lead to cardio-respiratory problems and subsequently may cause sleep disturbances.

One of the most common sleep disturbances in rheumatological diseases is obstructive sleep apnea syndrome. The aim of this study is to observe the sleep stages and investigate the frequency of obstructive sleep apnea syndrome in systemic sclerosis patients.

Material and Methods: The patients under the follow-up of Rheumatology Department in Cukurova University, with systemic sclerosis who were presented with sleep disturbances such as hypersomnia or insomnia and underwent polysomnographic evaluation were searched retrospectively. Age, gender, body mass index, disease age, subtype of the disease, pulmonary involvement (interstitial lung disease, pulmonary arterial hypertension), cardiac involvement, gastroesophageal involvement, digital ulcers were recorded. Obstructive sleep apnea was considered when the apnea-hypoapnea index was over 5.

Results: In this study, 23 patients (91,3 % female) were included. Mean age was 53,43±11,6 years and 73,9 % of patients were diagnosed as diffuse subtype. 95,7 % of patients were with positive ANA, 69,6 % were with positive anti-Scl70 and 13 % were with positive anti-centromere antibody. In 9 patients (39,1%), apnea-hypoapnea index was over 5. Of these 9 patients, 5 were without pulmonary hypertension and 4 were with pulmonary hypertension.

In the whole group 8 patients were diagnosed as pulmonary hypertension, so, patients with obstructive sleep apnea syndrome were 50 % of pulmonary hypertension patients. The sleep stages in whole group were as follows: stage 1: %10,41±6,46, stage 2: %60,61±11,72, stage 3: %15,66±7,82 and REM: %13,33±6,2. Most of the patients were accepted to reveal decreased effective sleep (%74,83±20,43). The mean number of arise from sleep was 8,2±4,1. Periodic leg movement index was over 5 in 17,39 % of patients.

Conclusions: The frequency of obstructive sleep apnea syndrome in patients with systemic sclerosis was found to be 39,1 %. However it is found to be 50 % in patients with pulmonary hypertension. When both prognostic and therapeutic significance of obstructive sleep apnea syndrome were considered, systemic sclerosis patiens, especially the patients with pulmonary hypertension are suggested to be evaluated for this issue.

P.121

Quantitative Chest CT Predicts 5-Years-Mortality in Systemic Sclerosis

A. Ariani¹, M. Silva², F. Girelli³, M. De Santis⁴, F. Lumetti⁵, A. Volpe⁶, M. Saracco⁷, E. Bravi⁸, S. Parisi⁹, L. Idolazzi¹⁰, F. De Gennaro¹¹, M. Mozzani¹, D. Santilli¹, G. Lucchini¹, V. Seletti², E. Bacchini², D. Giuggioli⁵, G. Paolazzi⁶, F.C. Bodini¹², E. Arrigoni⁸, E. Fusaro⁹, C. Benini¹⁰, D. Imberti⁸, C.A. Scirè¹³, N. Sverzellati²

¹ Department of Medicine, Internal Medicine and Rheumatology Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, ITALY, ² Department of Clinical Sciences, Section of Radiology, University of Parma, Parma, ITALY, ³ Rheumatology Unit, Internal Medicine Department, GB Morgagni - L Pierantoni Hospital, Forlì, ITALY, ⁴ Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, ITALY, ⁵ Rheumatology Unit. University of Modena and Reggio Emilia, Azienda Ospedaliero- Universitaria, Policlinico di Modena, Modena, ITALY, ⁶ Rheumatology Unit, Santa Chiara Hospital, Trento, ITALY, ⁷ Rheumatology Unit, Ospedale Mauriziano Umberto I di Torino, Torino, ITALY, ⁸ Department of Medicine, Internal Medicine and Rheumatology Unit, Ospedale G. Da Saliceto, Piacenza, ITALY, ⁹ Rheumatology Department, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, ITALY, ¹⁰ Rheumatology Section, Department of Medicine, University of Verona, Azienda Ospedaliero Universitaria Integrata, Verona, ITALY, ¹¹ Rheumatology Unit, Azienda Ospedaliera Istituti Ospitalieri di Cremona, Cremona, ITALY, ¹² Radiology Unit, Ospedale G. Da Saliceto, Piacenza, ITALY, ¹³ Department of Medical Sciences, Section of Rheumatology, University of Ferrara and AOU Sant’Anna, Ferrara, ITALY

Introduction: Interstitial Lung Disease (ILD) is the main cause of death in Systemic Sclerosis (SSc). In clinical practice is essential to identify those subjects with poor prognosis in order to start an aggressive treatment. The gold standard to detect the ILD is the chest Computed Tomography (CT) but there is no standardized method to assess ILD extent and severity. Only an ILD semiquantitative score (see Goh et al., 2008) has a prognostic value but it is not routinely performed for its relevant variability. Quantitative CT (QCT) is an innovative and operator independent method to assess ILD-SSc extent and severity. An increasing number of evidences confirmed that QCT can be extremely useful for detecting SSc patients with the worst prognosis. However is not well established if QCT can predict clinical worsening or death.

The main aim of this study is to verify if QCT predict 5-years mortality in SSc.

Material and Methods: Patients with a diagnosis of SSc (according to ACR/EULAR classification criteria) from ten different centers underwent a chest CT. Their clinical history in the following 60 months was carefully recorded. We post-analyzed every CT with an open source DICOM viewer in order to obtain QCT indexes. Patients were clustered in two subgroups: according to QCT indexes’ cutoff previously found (see Ariani et al., 2017). The survival time of each patient was considered the time interval between the CT date and the death or the last clinic visit.

Results: We enrolled 314 patients; 13.7% (43/314) died during the 5-years follow-up. A Kaplan-Meier survival analysis demonstrates a significantly worse survival in patients with QCT indexes above or below the previously found cutoffs. (p < 0.01) (see Figure 1). In particular the QCT index cutoff which the best performance was total lung kurtosis (tKurt) equal to 4.89 (p = 0.0001)

Conclusions: The QCT indexes’ cutoffs previously obtained (see Ariani et al., 2017) make possible to identify a subgroup of SSc subjects with an high risk of 5-years mortality. Our findings suggest that QCT could became a pivotal assessment in SSc management because its role in identifing patients with poor prognosis and who deserve an early aggressive treatment.