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

OBJECTIVE

JAK inhibitors (JAKi) have shown promising effects in early-phase studies of systemic sclerosis (SSc). We aimed to assess the safety and explore the effectiveness of JAKi compared to conventional immunosuppressants in SSc.

METHODS

A longitudinal retrospective study of the European Scleroderma Trials and Research Group (EUSTAR) cohort was performed. JAKi-treated patients were compared to patients receiving mycophenolate mofetil (MMF), rituximab (RTX), and methotrexate (MTX) using nearest-neighbor propensity score matching. Primary outcomes were safety and drug survival. Secondary outcomes included change in forced vital capacity (FVC), change in modified Rodnan skin scores (mRSS) in patients with diffuse cutaneous SSc (dcSSc), improvement in 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.

RESULTS

Thirty-six JAKi-treated patients from 19,601 were included (median drug exposure 37 months). Median disease duration was seven years, and 33% had dcSSc. For 98.7 patient-years, 23 adverse events were recorded, including 12 infections, 7 laboratory abnormalities, and 3 malignancies. Treatment was discontinued permanently 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 patients with 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 those in matched immunosuppressive groups. No new calcinotic burden was observed.

CONCLUSION

JAKi showed similar effectiveness compared to standard-of-care immunosuppressants. However, drug persistence and safety concerns may be a limiting factor in patients with SSc.