Mycophenolate mofetil (MMF) and rituximab (RTX) are recommended as first-line therapies for skin and interstitial lung disease (ILD) involvement in systemic sclerosis (SSc). However, data on their combined use remain limited. This study evaluated the efficacy and safety of MMF/RTX combination therapy compared to each drug alone.

We conducted a retrospective multicenter French study including SSc patients treated with MMF, RTX, or MMF/RTX combination for ≥12-months. Primary outcomes were changes in modified Rodnan skin score (mRSS) and predicted forced vital capacity (FVC) at 12 months. Secondary outcomes included factors associated with improvement in skin or ILD and adverse events.

Forty-seven patients received MMF/RTX combination, 30 received RTX, and 50 received MMF. At 12 months, intra-group analyses showed significant mRSS improvement with MMF/RTX combination and MMF (p = 0.002 and p = 0.04, respectively). FVC increased significantly only with combination group (p = 0.003). In multivariate inter-group analysis, MMF/RTX combination was independently associated with greater mRSS improvement versus RTX (OR 0.07, 95 % CI [0.007–0.67], p = 0.02) and greater skin and/or lung improvement compared to RTX (OR 0.27 [0.08–0.89], p = 0.03) or MMF (OR 0.24 [0.07–0.81], p = 0.02). Adverse events were not significantly increased with MMF/RTX combination. In subgroup analyses restricted to MMF/RTX combination group, patients with upfront initiation significantly improved their FVC compared to patients with sequential introduction. Upfront initiation of MMF/RTX was associated with ILD improvement in multivariate analysis.

In SSc, MMF/RTX combination is well-tolerated and improves skin and ILD involvement, particularly when MMF and RTX are introduced simultaneously.