Background In clinical trials of systemic sclerosis (SSc), there is an unmet need for better inclusion criteria to enrich for patients with progressive skin fibrosis [1,2]. Recent trials on skin fibrosis frequently used active skin disease at baseline as an enrichment parameter. However, there is little data available supporting such an approach.
Objectives To investigate the relationship between active skin disease at baseline and progression of skin fibrosis after one year in patients with diffuse cutaneous SSc (dcSSc).
Methods A longitudinal analysis of the EUSTAR registry was performed. The inclusion criteria were: dcSSc, fulfillment of ACR criteria, baseline mRSS≥7, available data for mRSS at 12±2 months. Skin progression was defined as increase in mRSS of >5 points AND ≥25% within 1 year . Activity of skin fibrosis was assessed by patient-reported parameters (worsening of skin within the past month), by using a modified skin thickness progression rate (defined as MRSS at baseline visit/disease duration (years)) and by following patients with progression of mRSS in the recent 12 months for another 12 months. Additionally, non skin specific activity parameters such as the Valentini index, elevated serum inflammatory markers, and other patient reported activity parameters were also analyzed. The Mann-Whitney and the Chi-square tests were used.
Results From the 637 patients included, 9.7% had progressive skin fibrosis after 1 year. The patient-reported worsening of skin fibrosis within the past month prior to baseline was not significantly associated with progressive skin disease after 1 year (p=0.774). Similarly, the modified skin progression rate at baseline did not differ between progressive and non-progressive patients at 1 year follow up (p=0.323). Most interestingly, patients with progression of skin fibrosis in the previous year were not significantly more likely to show progression of skin fibrosis in the following year (p=0.385, none of the initially progressive patients at one year showed further progression). In addition, other more general activity parameters at baseline including the Valentini activity index (p=0.673) and inflammatory markers (Erythrocyte sedimentation rate, p=0.287; C-reactive protein p=0.358) were also not associated with progression of skin fibrosis after one year (Figure 1).
Conclusions dcSSc patients with recently active skin disease have a similar or even lower likelihood to show further progression of skin fibrosis in a 12 months trial – most likely because they have reached their peak skin score already. Recently active skin disease should not be used as an enrichment criterion in clinical trials targeting skin fibrosis.
Maurer B, Graf N, Michel BA, et al. Prediction of worsening of skin fibrosis in patients with diffuse cutaneous systemic sclerosis using the EUSTAR database. Ann Rheum Dis. 2015;74(6):1124–31.
Allanore Y, Distler O. Systemic sclerosis in 2014: Advances in cohort enrichment shape future of trial design. Nature Rev Rheumatol. 2015;11(2):72–4.
Disclosure of Interest R. Dobrota: None declared, B. Maurer: None declared, N. Graf: None declared, O. Kowal-Bielecka Consultant for: Abbvie, Actelion, Bayer, Biogen, Pfizer, Roche, Speakers bureau: Abbvie, Actelion, Bayer, Biogen, Pfizer, Roche, M. Matucci-Cerinic: None declared, P. Airò: None declared, P. Caramaschi: None declared, P. Carreira: None declared, G. Riemekasten: None declared, E. Rosato: None declared, Y. Allanore Grant/research support from: Bristol-Myers Squibb, Roche/Genentech, Inventiva, Pfizer, Sanofi, and Servier, Consultant for: Actelion, Bayer, Roche/Genentech, Inventiva, Medac, Pfizer, Sanofi, Servier, and UCB, O. Distler Grant/research support from: Bayer, Sanofi, Ergonex, Boehringer Ingelheim, Actelion, Pfizer, Consultant for: 4 D Science, Actelion, Active Biotec, Bayer, BiogenIdec, BMS, Boehringer Ingelheim, EpiPharm, Ergonex, espeRare foundation, Genentech/Roche, GSK, Inventiva, Lilly, medac, MedImmune, Pharmacyclics, Pfizer, Serodapharm, Sinoxa