Real-World Safety and Effectiveness of JAK Inhibitors in Systemic Sclerosis: A Propensity-Matched Study from the EUSTAR Cohort.

Abstract

JAK inhibitors (JAKis) have shown promising effects in early-phase studies of SSc. We aimed to assess the safety and explore effectiveness of JAKis compared to conventional immunosuppressants in SSc. A longitudinal retrospective study of the EUSTAR cohort was performed. JAKi treated patients were compared to patients receiving Mycophenolate Mofetil (MMF), Rituximab (RTX), and Methotrexate (MTX) using nearest-neighbour propensity score matching. Primary outcomes were safety and drug survival. Secondary outcomes included changes in Forced Vital Capacity (FVC), modified Rodnan Skin Score (mRSS) in diffuse SSc patients, swollen joint count, digital ulcer (DU) recurrence, and a composite disease progression endpoint. Comparative analyses were performed using generalized linear models and time-to-event methods, including Kaplan-Meier and restricted mean survival time analyses. Thirty-six JAKi-treated patients from 19'601 were included (median drug exposure 37 months). Median disease duration was 7 years and 33% had diffuse cutaneous SSc. For 98.7 patient-years, 23 adverse events (AEs) were recorded, including 12 infections, 7 laboratory abnormalities, and 3 malignancies. Treatment was permanently discontinued in 39% and transiently in 19%. At 12 months, lung function remained stable (mean FVC% +1.7%, p=0.530) during follow up and skin fibrosis showed a numerical improvement (mean mRSS -1.8) in dcSSc. These results were comparable to those observed in MMF, RTX, and MTX groups. Swollen joint counts decreased in patients with baseline synovitis (median change -1, p=0.052). DU recurrence rates and disease progression events were comparable to matched immunosuppressive arms. No new calcinotic burden was observed. JAKi's showed similar effectiveness compared to standard of care immunosuppressants. However, drug persistence and safety concerns may be a limiting factor in SSc patients.