Background Improvement of skin fibrosis over time is part of the “natural history” of diffuse cutaneous systemic sclerosis (dcSSc). However, in individual patients, the pattern of change in skin fibrosis varies widely. The extent of skin fibrosis measured by the modified Rodnan skin score (mRSS) is the major outcome measure in clinical trials (CT) in dcSSc. Understanding the factors behind the improvement of skin fibrosis in dcSSc could avoid unnecessary use of therapy and medical resources. Moreover, it could improve cohort selection in CT with skin fibrosis as a major outcome.
Objectives Identification of predictors for improvement of skin fibrosis over a 1 year follow-up in dcSSc patients.
Methods We performed a longitudinal analysis on the EUSTAR registry. The inclusion criteria were: dcSSc, fulfillment of ACR criteria, baseline mRSS ≥7, available data for mRSS at 12±2 months. The primary outcome was skin improvement, defined as decrease in mRSS of >5 points AND ≥25% within 1 year. Variables with p<0.2 in univariate analysis were selected for multivariable analysis using nominal group technique. Multiple imputation for missing data was used. Multiple logistic regression with a stepwise forward and backward model selection was applied to each of the imputed datasets. Variables included in >50% of the models were re-tested in the available dataset. The final model was validated in a second temporal cohort from the EUSTAR database.
Results Out of 11228 EUSTAR patients, 704 fulfilled the inclusion criteria and 155/704 (22%) patients had skin improvement. In univariate analysis, high baseline mRSS (Figure 1), a high modified skin fibrosis progression rate at baseline, cardiac involvement (defined as presence of at least one of conduction blocks, diastolic dysfunction or left ventricular ejection fraction <45%), immunosuppression and ESR <25 mm/h were associated with skin improvement after 1 year. In multivariable logistic regression, the variables present in >50% of the models from the imputed datasets were baseline mRSS (100%), Anti Scl-70 positive (97%), ESR >25mm/h (88%), DLCO ≥70% (61%). These were tested again in the available dataset. The final model revealed high mRSS at 1st visit and ESR <25mm/h as independent predictors of skin improvement after 1 year. The predictive value of high baseline mRSS was confirmed in the validation cohort (N=47).
Conclusions These results show that patients with already advanced skin fibrosis are more likely to regress under standard of care in the next 12 months than patients with milder skin fibrosis. Thus, focus for treatment intervention and recruitment in CT aiming at skin fibrosis should shift from these patients with high baseline mRSS to at risk patients characterized by low to moderate skin fibrosis.
Disclosure of Interest R. Dobrota Grant/research support from: Articulum Fellowship (Pfizer), Actelion, B. Maurer: None declared, N. Graf: None declared, C. Mihai Speakers bureau: Actelion, Pfizer, MSD, Roche, UCB and Abbvie, O. Kowal-Bielecka Consultant for: Abbvie, Actelion, Pfizer, Speakers bureau: Abbvie, Actelion, Pfizer, Y. Allanore Grant/research support from: Bayer Pharma, Actelion, Pfizer, Sanofi-Aventis, CSL Behring, Roche, Consultant for: Bayer Pharma, Actelion, Pfizer, Sanofi-Aventis, CSL Behring, Roche, O. Distler Grant/research support from: 4D Science, Actelion, Active Biotec, Bayer-Schering, Biogen, Biovitrium, BMS, Boehringer Ingelheim Pharma, EpiPharm, Ergonex, GSK, Inventiva, Medac, Novartis, Pfizer, Pharmacyclics, Roche/Genentech, Sanofi/Genzyme, Serodapharm, Sinoxa and United BioSource Corporation, Consultant for: 4D Science, Actelion, Active Biotec, Bayer-Schering, Biogen, Biovitrium, BMS, Boehringer Ingelheim Pharma, EpiPharm, Ergonex, GSK, Inventiva, Medac, Novartis, Pfizer, Pharmacyclics, Roche/Genentech, Sanofi/Genzyme, Serodapharm, Sinoxa and United BioSource Corporation