Abstract
Objective
The present study aimed to investigate serum levels of B cell activation factor (BAFF) and chemokine C-X-C ligand 13 (CXCL13) in SSc patients with/without lung involvement and correlation with clinical parameters.
Methods
Serum samples were collected from four groups: SSc patients with progressive/in remission/without lung involvement (n = 21 for each group) and healthy controls (n = 32). Progressive interstitial lung disease (ILD) was defined based on the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society and Asociación Latinoamericana de Tórax (ATS/ERS/JRS/ALAT) guidelines. ELISAs were used to measure BAFF and CXCL13 levels.
Results
The results revealed significantly elevated serum CXCL13 levels in SSc patients with progressive lung involvement compared with other SSc groups and healthy controls (311 ng/ml vs 273, 282 and 231 ng/ml; P = 0.013). Moreover, a positive correlation was observed between modified Rodnan skin score (MRSS), pulmonary artery pressure (PAP) and CXCL13 levels (P = 0.029 for PAP, P = 0.001 for MRSS). Serum BAFF and CXCL13 were independently associated with MRSS, PAP and European League Against Rheumatism Scleroderma Trials and Research group disease activity scores.
Conclusion
These findings suggest that increased serum CXCL13 levels are associated with progressive pulmonary involvement in SSc patients. Serum BAFF levels were also related to SSc but not associated with ILD.
Keywords: BAFF, CXCL13, MRSS, pulmonary involvement, systemic sclerosis
Lay Summary
What does this mean for patients?
Systemic sclerosis (SSc) is a rare disease that causes skin thickening and painful fingertip sores. In some cases the disease can also affect the lungs, leading to symptoms like coughing and difficulty breathing. Detecting lung involvement early is essential because treating it before the lung tissue is damaged can prevent long-term complications. Doctors currently use breathing tests and imaging such as chest computed tomography to diagnose lung problems in these patients. However, having a simple and practical blood test could make diagnosis faster and easier. Our research focuses on a blood marker called chemokine C-X-C motif ligand 13. This marker may help identify active lung disease and distinguish between patients with and without lung involvement. This is especially useful for those with a history of lung damage, as it can clarify whether worsening symptoms are due to old damage or new disease activity. Early identification and management of lung issues in SSc can improve the quality of life for patients. While our findings are promising, further studies are needed to confirm and expand upon these results.
Graphical abstract
Key messages.
A practical approach to distinguish between damage and activity in SSc-ILD is still lacking.
A serum-based biomarker may play a crucial role in identifying active SSc-ILD and facilitating treatment.
According to our findings, serum CXCL13 may serve as a promising biomarker for active SSc-ILD.
Introduction
SSc, or systemic scleroderma, is a chronic autoimmune disorder characterized by fibrosis and vascular dysfunction in multiple organs, including the lungs. Pulmonary involvement in SSc is a significant contributor to morbidity and mortality in affected patients [1, 2]. Emerging research has focused on understanding the role of B cell–associated markers in developing and progressing SSc-associated lung disease [3, 4].
B cells play a crucial role in the pathogenesis of autoimmune disorders, including SSc, through autoantibody production and immune dysregulation [5–7]. An increase in B cell–associated markers was previously documented in the skin lesions, lamina propria of the digestive tract, parenchyma and bronchoalveolar fluid of patients with SSc [8–10]. Earlier studies suggest the disorganization of B cell homeostasis, which is caused by dysregulation of B cell receptor (BCR) signalling, causes the tendency to increase the production of B cell survival signals like B cell activating factor (BAFF), a proliferation inducing ligand (APRIL) and chemokine signalling pathways [5].
Chemokine C-X-C motif ligand 13 (CXCL13) is a B cell chemokine essential in lymphoid neogenesis, lymphoid organization and immune responses with receptor CXCR5 [11]. This molecule also effectively organizes ectopic lymphoid-like structures, an integral part of many autoimmune diseases [12, 13]. This marker is also associated with tissue fibrosis and vasculopathy in SSc [14].
BAFF [as B lymphocyte stimulator (BlyS)] also plays a substantial role in the priming and organization of B lymphocytes [15]. The BAFF/BAFF receptor family plays a primary role in the maturation stages of B cell differentiation, ranging from primary B cells to the maintenance of long-lived bone marrow plasma cells [16, 17]. Excessive production of BAFF causes a decrease in anergy to B cells and promotes autoimmunity [18]. Previously, serum BAFF levels were reported as associated with myositis, gastrointestinal system involvement and skin fibrosis in patients with SSc [19–21]. Also, in one report [22], BAFF inhibition attenuated skin fibrosis. Controversially, belimumab, a BlyS inhibitor monoclonal antibody, did not prove efficacious in reducing the modified Rodnan skin score (MRSS) [23].
We hypothesize that BAFF and CXCL13 may contribute to pulmonary involvement and correlate with clinical activity and severity of pulmonary involvement in SSc. Understanding the role of these markers in SSc-associated lung disease may contribute to improved diagnosis, prognosis and targeted therapeutic interventions.
Materials and methods
Study design and patient selection
This cross-sectional study was performed in the Gazi University Rheumatology Outpatient Clinic between April and December 2022. The study group was selected from patients consecutively admitted to the clinic. Age- and sex-matched controls were included among the relatives of the patients diagnosed with SSc who applied to the hospital. Individuals without any chronic diseases and not using any medication were recruited for the study. Informed consent was obtained from all participants. The Ethics Committee of Gazi University approved the study (approval 79).
Assessment of clinical activity
Demographics, clinical status and current treatments were recorded during clinic interviews. SSc patients fulfilling the 2013 EULAR/ACR classification criteria were enrolled in the study [24]. All patients were evaluated for sclerodactyly, fingertip lesions, RP, telangiectasia, nail fold capillaries, joint involvement, interstitial lung disease (ILD), pulmonary artery hypertension (PAH), oesophagus motility and muscular involvement. The severity of skin involvement was assessed by the MRSS, which is obtained by clinical palpation of 17 different body areas (fingers, hands, forearms, upper arms, face, chest, abdomen, thighs, lower legs and feet), with a maximum total score of 51.
The definition of progressive ILD was based on both the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society and Asociación Latinoamericana de Tórax (ATS/ERS/JRS/ALAT) guidelines and the definition used in the SpO2 and arthritis model [25, 26]. The disease was classified as stable or progressive based on specific criteria. These included a relative decrease in forced vital capacity (FVC; ≥15%) or an FVC ≥10% decrease combined with a ≥15% reduction in diffusing capacity for carbon monoxide, worsening respiratory symptoms or an increased extent of high-resolution CT involvement that could not be attributed to pulmonary infection, concurrent pulmonary hypertension or airflow obstruction within 12 months despite standard treatment.
The study group was dichotomized into four subgroups: SSc patients without lung involvement (n = 21), SSc-ILD patients with stable disease (n = 21), SSc-ILD patients with progressive disease (n = 21) and healthy controls (n = 32).
The clinical activity of SSc was evaluated with the European Scleroderma Trials and Research Group (EUSTAR) Disease Activity Score, with a range of 0–10 points [27]. The physiologic capacity of the lungs was evaluated with a pulmonary function test and carbon monoxide diffusion capacity.
Blood sampling
Venous blood samples were taken from all participants after overnight fasting. Blood samples collected for analysis were centrifuged at 4000 rpm for 10 min. Serum BAFF and CXCL13 levels were detected with ELISA kits (double antibody sandwich method) according to the manufacturer’s instructions (BT Lab Sciences, Shanghai, China). All assays were performed at the Gazi University Biochemistry Laboratory according to the manufacturer’s instructions, with results in ng/ml.
Statistical analysis
SPSS version 17.0 (SPSS, Chicago, IL, USA) was used for the statistical data analysis. Results were expressed as mean (s.d.) or median and interquartile range (IQR) levels according to the distribution properties of the data. The normality of numerical variables was examined with the Kolmogorov–Smirnov test. Because serum BAFF and CXCL13 levels were not normally distributed, the Kruskal–Wallis analysis compared levels between study groups. A post hoc analysis of subgroups was performed using the Mann–Whitney U test. Pearson’s or Spearman’s tests were used for correlation analysis as appropriate. A P-value <0.05 was considered statistically significant. Receiver operating characteristics (ROC) curve analysis was used to identify optimal cut-off values of serum BAFF and CXCL13 levels. While evaluating the area under the curve (AUC), a 5% type I error was used to accept a statistically significant predictive value of test variables. A multiple linear regression model was used to identify independent serum BAFF and CXCL13 level predictors. The model fit was assessed using appropriate residual and goodness-of-fit statistics. A 5% type I error level was used to infer statistical significance.
Results
A total of 95 participants were enrolled in the study with a mean age of 45.3 years (s.d. 9.55) [84 female (88%)/11 male (12%)]. All patients with SSc were grouped according to the presence and progressivity of ILD. Twenty-one of the patients had progressive ILD involvement, 21 had SSc-ILD in the remission period and 21 patients were without ILD. Results were compared with 32 healthy controls. A comparison of clinical and laboratory parameters between study groups is provided in Table 1.
Table 1.
Comparison of clinical and laboratory parameters between study groups
| Characteristics | Patients with active lung involvement (n = 21) | Patients with inactive lung involvement (n = 21) | Patients without lung involvement (n = 21) | Healthy controls (n = 32) | P-value |
|---|---|---|---|---|---|
| Age, years, median (IQR) | 48 (8.5) | 48 (8) | 43 (12.5) | 42 (15.5) | 0.088 |
| BMI, kg/m2, median (IQR) | 28 (9.53) | 27.6 (10.15) | 26.25 (12.6) | 24.5 (8.75) | 0.113 |
| Sex (female ratio), % | 100 | 95.3 | 95.3 | 93.75 | 1 |
| Cigarette (smoker/non-smoker), % | 9.5 | 4.7 | 9.5 | 9.37 | 0.612 |
| ALT, U/l, median (IQR) | 16 (10.5) | 16 (8) | 18.5 (10.25) | 17 (12) | 0.925 |
| ESR, mm/h, median (IQR) | 27 (37) | 23 (18.5) | 13.5 (16) | 12 (12) | 0.001 a |
| CRP, mg/l, median (IQR) | 3 (4.2) | 4 (5.6) | 2.4 (2) | 3 (2.5) | 0.056 |
| BAFF, ng/ml, median (IQR) | 654 (735) | 540 (248) | 528 (193) | 476 (232) | 0.001 b |
| CXCL13, ng/ml, median (IQR) | 311 (807) | 273 (119) | 282 (211) | 231 (78) | 0.013 a |
| Haemoglobin, g/dl, median (IQR) | 12.4 (1.4) | 12.5 (0.9) | 13.1 (2.3) | 13.1 (2.5) | 0.001 c |
| WBCs, cells/ml×104, median (IQR) | 6300 (3940) | 6100 (3850) | 6200 (3900) | 6000 (1850) | 0.838 |
| PLTs, cells/ml×104, median (IQR) | 293 000 (890) | 264 000 (895) | 255 000 (1095) | 267 000 (785) | 0.343 |
| AST, U/l, median (IQR) | 20 (8.5) | 21 (11.5) | 20 (8.2) | 22 (18) | 0.832 |
| GFR, ml/min, median (IQR) | 90 (8.5) | 90 (2) | 90 (4) | 90 (3.5) | 0.185 |
ALT: alanine transaminase; WBCs: white blood cells; PLTs: platelets; AST: aspartate transaminase; GFR: glomerular filtration rate.
Bold text indicates significant P-values <0.05.
Patients with lung involvement had significantly higher levels of median ESR regardless of activity when compared with patients without lung involvement and healthy controls.
Patients with active lung involvement had significantly higher levels of BAFF and CXCL13 than other groups. Also, all patients with SSc had higher BAFF and CXCL13 levels when compared with controls. BAFF levels did not change according to the clinical activity of lung involvement, but CXCL13 levels were significantly higher in patients with active lung involvement when compared with patients with lung involvement but in remission.
Patients with lung involvement, regardless of activity, had lower haemoglobin levels when compared with other groups.
A history of digital ulcers was recorded in 38 patients. Patients with ILD involvement, regardless of activity, had significantly more attacks of digital ulcer, arthritis and contracture when compared with patients without ILD (P = 0.008, P = 0.018 and P = 0.028, respectively). The number of patients with oesophagus involvement was similar for all groups (P = 0.358). The frequencies of RP and cardiac and renal involvement were not significantly different between patient groups (P > 0.05). Comparison of autoantibody types, clinical manifestations and activity markers between the patient groups are presented in Table 2.
Table 2.
Comparison of autoantibody types, clinical manifestations and activity markers between the patient groups.
| Characteristics | Patients with active lung involvement (n = 21) | Patients with inactive lung involvement (n = 21) | Patients without lung involvement (n = 21) | P-value |
|---|---|---|---|---|
| ANA antibody type, n (%) | ||||
| Fine granular | 19 | 17 | 14 | 0.4 |
| Homogeneous | 0 | 1 | 0 | |
| Centromere | 2 | 2 | 6 | |
| SCL antibody positivity, n (%) | 12 | 13 | 9 | 0.436 |
| ACA positivity, n (%) | 2 | 8 | 8 | 0.3 |
| Systemic involvement, n (%) | ||||
| Oesophagus | 13 (61.9) | 13 (61.9) | 9 (42.8) | 0.358 |
| Renal crisis | 1 (4.7) | 1 (4.7) | 1 (4.7) | 1 |
| RP | 1 (4.7) | 3 (14.2) | 1 (4.7) | 0.41 |
| Contracture | 10 (47.6) | 9 (42.8) | 3 (14.2) | 0.021 a |
| Arthritis | 15 (71.4) | 12 (57.1) | 6 (28.5) | 0.018 a |
| Myositis | 6 (28.5) | 7 (33.3) | 0 | 0.002 a |
| Cardiac involvement | 3 (14.2) | 2 (9.5) | 0 | 0.106 |
| History of active digital ulcer | 16 (76.1) | 15 (71.4) | 7 (33.3) | 0.008 a |
| Telangiectasia | 10 (47.6) | 8 (38) | 8 (38) | 0.01 a |
| MRSS, median (IQR) | 14 (8.5) | 10 (9.5) | 4 (8) | 0.001 a |
| PAP, mmHg, median (IQR) | 30 (24.5) | 25 (11.5) | 25 (9.75) | 0.055 |
| FEV-1, %, median (IQR) | 86.5 (22.75) | 89 (37.5) | 105 (19.5) | 0.002 b |
| FVC, %, median (IQR) | 91 (17) | 87 (38.5) | 110 (28.75) | <0.001 b |
| FEV1:FVC ratio, %, median (IQR) | 98.5 (22.75) | 99 (29.5) | 100 (20.75) | 0.94 |
| DLCO, %, median (IQR) | 62 (26.75) | 62 (26.5) | 92 (26.25) | <0.001 b |
Significant P-values <0.05 in bold.
Differences were caused by patients without lung involvement. This group had a lower incidence of contracture, arthritis, myositis, history of digital ulcer, telangiectasia and MRSS.
Differences were caused by patients without lung involvement. This group had a higher ratio of FEV-1, FVC and DLCO when compared with patients with lung involvement.
Patients with progressive ILD involvement had significantly higher MRSSs when compared with patients without ILD involvement (median levels 13.5 vs 4; P = 0.002). Also, patients with ILD involvement, regardless of progressivity, had higher EUSTAR disease activity scores than those without ILD involvement (median levels of two ILD-involvement groups were 3.25 vs 2.25; P = 0.001).
Healthy participants had significantly lower serum BAFF levels (654 ng/ml; P = 0.001), but subgroups of SSc patients were not significantly different (540, 528 and 476 ng/ml; P > 0.05; Fig. 1). ROC analysis showed a cut-off level of 575.8 ng/ml for SSc [0.962 (IQR 0.924–1), P < 0.001; sensitivity 50%, specificity 50%; Fig. 2A].
Figure 1.
Comparison of serum CXCL13 and BAFF levels between study groups.
Figure 2.
ROC analyses for (A) serum levels of BAFF for diagnosis of SSc, (B) serum CXCL13 levels for diagnosis of SSc and (C) serum CXCL13 levels for diagnosis of progressive ILD associated with SSc.
Serum CXCL13 levels significantly differed when overall groups were compared (311, 273, 282 and 231 ng/ml; P < 0.001; Fig. 1). When the study group was divided based on the presence of ILD (patients with ILD, patients without ILD and controls), both patient groups showed higher serum CXCL13 levels compared with controls (P < 0.001 for both comparisons). However, serum CXCL13 levels were similar between the two patient groups (P = 0.312 for patients with ILD vs those without ILD).
Patients with progressive ILD had significantly higher levels of serum CXCL13 when compared with those with in-remission ILD (P = 0.002), patients without ILD (P = 0.008) and healthy controls (P < 0.001). Patients without ILD and those with ILD in remission had similar CXCL13 levels when compared with each other (P = 0.703), but both groups had higher levels compared with healthy controls (P = 0.004 and P = 0.001, respectively).
Serum levels of CXCL13 were positively correlated with pulmonary artery pressure (PAP) (R = 0.3272, P = 0.029) and ESR (R = 0.221, P = 0.042) and inversely correlated with FVC (R = −0.25, P = 0.048; Table 3). ROC analysis showed a cut-off level of 233.45 ng/ml for serum CXCL13 in SSc [AUC 897 (IQR 837–956), P < 0.001; sensitivity 79.4%, specificity 81.3%; Fig. 2B] and 545 ng/ml for progressive ILD [AUC 0.931 (IQR 0.864–0.998), P < 0.001; sensitivity 90.5%, specificity 91.9%; Fig. 2C].
Table 3.
Correlation of serum CXCL13 and BAFF levels with other numeric variables
| Variables | CXCL13 | BAFF | |
|---|---|---|---|
| CXCL13 (ng/ml) | R | 1 | |
| P | |||
| BAFF (ng/ml) | R | 0.704 | 1 |
| P | <0.001 | ||
| Age (years) | R | 0.131 | 0.05 |
| P | 0.2 | 0.6 | |
| BMI (kg/m2) | R | 0.173 | 0.354 |
| P | 0.1 | 0.1 | |
| CRP (g/dl) | R | −0.12 | −0.03 |
| P | 0.9 | 0.7 | |
| ESR (mm/h) | R | 0.221 | 0.15 |
| P | 0.04 | 0.1 | |
| PAP (mmHg) | R | 0.272 | 0.2 |
| P | 0.029 | 0.19 | |
| MRSS (points) | R | 0.216 | 0.08 |
| P | 0.09 | 0.5 | |
| DLCO (%) | R | −0.13 | −0.09 |
| P | 0.305 | 0.4 | |
| FVC (%) | R | −0.25 | −0.13 |
| P | 0.04 | 0.3 | |
| EUSTAR score (points) | R | 0.035 | −0.22 |
| P | 0.7 | 0.1 |
Significant P-values <0.05 in bold.
Linear regression analyses showed that serum BAFF and CXCL13 levels were independent predictors of EUSTAR score and MRSS and diffusing capacity for carbon monoxide (DLCO). Serum CXCL13 levels were also independent predictors of PAP (Table 4).
Table 4.
Linear regression analysis of BAFF and CXCL13 levels with other clinical parameters
| Variables | β | Standard error | β coefficient | P-value | 95% confidence interval |
|---|---|---|---|---|---|
| CXCL13a | |||||
| MRSS | 49.4 | 13.8 | 0.569 | 0.001 | 21.5, 77.3 |
| DLCO | 9.8 | 4.7 | 0.33 | 0.044 | 0.28, 19.4 |
| PAP | 11.1 | 4.3 | 0.34 | 0.023 | 1.6, 20.6 |
| EUSTAR | 151.6 | 70.7 | 0.35 | 0.037 | 9.2, 294.01 |
| BAFFb | |||||
| MRSS | 94.61 | 36.6 | 0.41 | 0.013 | 20.92, 168.3 |
| DLCO | 32.3 | 12.6 | 0.41 | 0.014 | 6.8, 57.7 |
| EUSTAR | 377.1 | 187.2 | 0.334 | 0.05 | 0.24, 754 |
Significant P-values <0.05 in bold.
R2 = 0.591, P = 0.002.
R2 = 0.351, P = 0.002.
Discussion
Our study revealed that serum CXCL13 and BAFF levels are significantly higher in patients with SSc when compared with healthy controls. Moreover, serum CXCL13 levels are considerably higher in patients with overall pulmonary involvement and progressive ILD. Also, serum BAFF and CXCL13 levels are independent predictors of MRSS, EUSTAR score and DLCO. Serum CXCL13 levels are independently associated with PAP. The frequency of digital ulcer attacks, arthritis and contracture is observed significantly more in patients with ILD involvement regardless of clinical activity.
B cells display a diverse population that includes different subgroups characterized by their cytokine secretion profile. Many reports have revealed that both naïve B cells and switched memory cells are increased in patients with SSc and associated with lung involvement [4, 28]. In another study, CD19-deficient mice showed a lesser extent of lung fibrosis when compared with CD19+ littermates, and this difference was referred to as the difference in B cell activity [29]. Additionally, in the same report, the migration of B cells into the inflamed lungs was associated with the up-regulation of CXCR3 and IL-6 secretion.
CXCL13 is a B cell chemokine expressed in the B cell follicles of secondary lymphoid organs [30, 31]. This chemokine is essential in lymphoid neogenesis, lymphoid organization and immune responses. Overexpression of CXCL13 is associated with various cancers [32], infectious diseases [33, 34] and autoimmune conditions like RA, SS and SLE [11]. Moreover, the association of molecular lung diseases was demonstrated in a transgenic mouse study. The presence of lymphoid follicles in the lung during early stages and elevated CXCL13 levels have been associated with an increased risk of chronic lung disease [35]. Effects of CXCL13 in autoimmune diseases may be associated with local antibody production, ectopic lymphatic structures and B cell expansion [11]. Aberrant activation of B cells is also a potential predisposing factor for the pathogenesis of SSc [7, 36, 37]. In a recent clinical study, serum CXCL13 levels and Th2 cytokine pathway interleukins were evaluated in SSc patients with ILD involvement. While a significant association was observed between CXCL13 and SSc involvement, no association was found between CXCL13 and the fibrotic area of ILD involvement as assessed by Computer-Aided Lung Informatics for Pathology Evaluation and Ratings software [38]. However, it should be noted that ILD activity may be more related to the level of inflammation rather than the degree of fibrosis. In the same study, a significant relationship was observed between Th2 pathway cytokines and the degree of fibrosis, highlighting their role in SSc-ILD.
Gaydosik et al. [39] identified a cluster of recirculating CXCL13+ T cells that promote B cell responses within the lesioned skin in SSc. Also, in a recent report, CXCL13 and BAFF levels were studied in patients with primary RP, lcSSc, limited SSc and progressive SSc. They showed significantly increased levels with dcSSc, which were higher in those with limited SSc compared with controls and patients with primary RP. However, they showed no association with the course of the disease, autoantibody profile or organ involvement [40]. They also reported that CXCL13 levels correlate with higher EUSTAR activity scores, digital ulcers and dysphagia. This concurs with data reported by Matsushita et al. [20, 21], who showed that an increase in BAFF is not associated with a specific disease subset. In another study, serum CXCL13 levels were evaluated in dermal cultures of 56 patients with SSc. They showed an association with tissue fibrosis and the presence of ILD and digital ulcers [14]. The originality of our study is that we evaluated serum CXCL13 levels according to the activity of ILD involvement. Taniguchi et al. [14] also showed that SSc patients with higher serum levels of CXCL13 had a higher frequency of PAH and impaired pulmonary function tests, which is compatible with our study. Serum levels of CXCL13 are independently associated with MRSS, PAP and DLCO in regression analysis. Thus serum CXCL13 levels may be important in the severity of SSc cutaneous and lung involvement.
Studies in TSK/+ mice have demonstrated elevated BAFF levels, and after BAFF inhibition is performed with BAFF-R-Ig, a decrease in hypodermal thickness and dermal collagen was observed. Moreover, BAFF inhibition decreases topoisomerase 1 antibody and levels of IL-6, IL-10 and TGF-β [28]. Also, median BAFF levels were significantly higher in patients with diffuse SSc than those with the limited form [20] and correlated with MRSS [21]. A randomized placebo-controlled study of belimumab was conducted in patients with early diffuse SSc, demonstrating a significant reduction in the expression of B cell signalling and profibrotic genes and pathways among those in the belimumab group who showed improvement in MRSS. The median difference in the MRSS was also more significant in the belimumab group, but did not achieve statistical significance in this small pilot study [23]. There was no relationship between BAFF levels and the presence of lung involvement in previous reports [20, 21]. Our results were also compatible with previous reports.
Our study showed for the first time that patients with progressive ILD have significantly higher CXCL13 levels compared with the in-remission group. CXCL13-targeted treatments may provide therapeutic effects in SSc-ILD patients in the future. The study has some limitations. First, assessing serum CXCL13 levels in the same patient group at the progressed and remission states could give more reliable information. Second, immunohistochemical studies on cutaneous and lung tissues may provide accurate information about the site-specific quantity of this marker. Larger-scale studies may elucidate this relationship.
Acknowledgements
We extend our sincere appreciation to Alessandra Della Rossa and Marco di Battisti, from Pisa University, for their valuable insights and contributions.
Contributor Information
Derya Yildirim, Rheumatology Clinic, Sincan Education and Research Hospital, Ankara, Turkey; Department of Rheumatology, Gazi University Faculty of Medicine, Ankara, Turkey.
Abdulsamet Erden, Department of Rheumatology, Gazi University Faculty of Medicine, Ankara, Turkey.
Ibrahim Vasi, Department of Rheumatology, Gazi University Faculty of Medicine, Ankara, Turkey.
Aslihan Avanoglu Guler, Rheumatology Clinic, Bilkent State Hospital, Ankara, Turkey.
Rahime Duran, Department of Rheumatology, Gazi University Faculty of Medicine, Ankara, Turkey.
Riza Can Kardas, Department of Rheumatology, Gazi University Faculty of Medicine, Ankara, Turkey.
Burcugul Kaya, Department of Rheumatology, Gazi University Faculty of Medicine, Ankara, Turkey.
Gizem Tugce Alp, Department of Internal Medicine, Gazi University Faculty of Medicine, Ankara, Turkey.
Hamit Kucuk, Department of Rheumatology, Gazi University Faculty of Medicine, Ankara, Turkey.
Nilgun Yilmaz Demirci, Department of Chest Disease, Gazi University Faculty of Medicine, Ankara, Turkey.
Berna Goker, Department of Rheumatology, Gazi University Faculty of Medicine, Ankara, Turkey.
Mehmet Akif Ozturk, Department of Rheumatology, Gazi University Faculty of Medicine, Ankara, Turkey.
Data availability
The datasets used in this study are available from the corresponding author upon valid request.
Authors’ contributions
H.K., A.T. and M.O. contributed to the conception and design of the study. I.V., B.K., R.K., H.K., A.A. and R.D. were involved in clinical evaluation. B.G. and A.E. interpreted the results. F.E. and G.A. performed the statistical analysis. D.Y. drafted the manuscript. N.Y.D. supervised the study. All authors read and approved the final manuscript.
Funding
No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.
Disclosure statement: The authors declare no conflicts of interest.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used in this study are available from the corresponding author upon valid request.