Background Spontaneous stabilization and regression of skin fibrosis in patients with diffuse cutaneous SSc (dSSc) is a major limitation in clinical trials, and enrichment strategies for patients with progressive skin fibrosis have been insufficient.
Objectives To identify predictive parameters for the progression of skin fibrosis in dSSc patients to enable 1) risk-stratification in clinical practice and 2) improved cohort enrichment in clinical trials with skin fibrosis as the primary endpoint.
Methods We performed an observational prospective study using the EUSTAR database which comprises 10019 SSc patients from 179 centers. Worsening of skin fibrosis was defined as increase in MRSS>5 points and ≥25% from the 1st to the 2nd visit. Patients with the following inclusion criteria were enrolled: dSSc, ACR criteria fulfilled, MRSS>7 at 1st visit, valid data for MRSS at 2nd visit, period in between visits 12±3 months. All variables collected in the EUSTAR database were included for the analysis. In the univariate analysis, patients with progressive fibrosis were compared to non-progressive patients. Nominal variables were tested with the chi-square-test, continuous variables with the Mann-Whitney U test or t-test. Predictors with p<0.2 in the univariate analysis were included in the logistic regression analysis. Additionally, the ROC curve for the respective regression model was calculated.
Results A total of 637 patients were eligible of which 62 (9.7%) had progressive skin disease. Univariate analysis showed that progressive skin fibrosis was more frequently in patients with joint synovitis (15.9%) than in patients without joint synovitis (8.0%) (p=0.009). Moreover, disease duration was shorter in patients with progressive skin fibrosis (mean±SD 60.4±82.9 vs. 72.9±78.2 months; p=0.02). In 58.6% of progressive patients, disease duration was less than 36 months, and of those, 70.6% had a disease duration of less than 18 months. Stratification by gender revealed that the association between disease duration and progression of skin fibrosis was only present in female patients. In the multivariate logistic regression analysis including disease duration (≤18 or >18 months), joint synovitis, gender, and the interaction between disease duration and gender, joint synovitis (OR=1.82, 95% CI=1.01-3.29) and the interaction between female gender and short disease duration (OR=6.12, 95% CI=1.36-27.52) were significant predictors. Prediction success overall was 87.7% (95.3% for no progression, 17.2% for progression) when classification cut-off was set at 0.18. Thus, of the 35 cases predicted through the regression model to have MRSS progression, 10 (28.6%) indeed had progressive skin fibrosis. A test of the full model against a constant only model was statistically significant, but the low Nagelkerke’s R2 of 0.061 indicated the need for further explanatory variables. The area under the ROC curve was 0.64 (95% CI=0.56-0.72).
Conclusions The identified prediction markers of progressive skin fibrosis enable the enrichment of clinical cohorts of dSSc patients from 9% to nearly 30%. However, our study also indicates a need for further explanatory variables, e. g. biomarkers.
Acknowledgements Data collection was supported by EUSTAR.
Disclosure of Interest: B. Maurer: None Declared, N. Graf: None Declared, B. Michel: None Declared, D. Khanna Grant/research support from: Actelion, Gilead, Pfizer, BMS, Sanofi-Aventis, United BioSource Corporation, United Therapeutics, Roche/Genentech, DIGNA., Consultant for: Actelion, Gilead, Pfizer, BMS, Sanofi-Aventis, United BioSource Corporation, United Therapeutics, Roche/Genentech, DIGNA., O. Distler Grant/research support from: Actelion, Pfizer, Ergonex, BMS, Sanofi-Aventis, United BioSource Corporation, Roche/Genentech, medac, Biovitrium, Boehringer Ingelheim Pharma, Novartis, 4 D Science, Active Biotec and Sinoxa., Consultant for: Actelion, Pfizer, Ergonex, BMS, Sanofi-Aventis, United BioSource Corporation, Roche/Genentech, medac, Biovitrium, Boehringer Ingelheim Pharma, Novartis, 4 D Science, Active Biotec and Sinoxa.