Multi-target Therapy with Rituximab plus Mycophenolate Mofetil versus Rituximab Monotherapy in Systemic Sclerosis–Associated Interstitial Lung Disease

Abstract

Objective To compare the effectiveness and safety of rituximab (RTX) plus mycophenolate mofetil (MMF) versus RTX monotherapy in patients with SSc-ILD. Methods We performed a retrospective comparative analysis among adults with radiologically confirmed SSc–ILD treated with rituximab monotherapy or RTX + MMF (MTT) as rituximab-based treatment strategy. The primary outcome was improvement in percent-predicted forced vital capacity (FVC%) of more than 5 percentage points at the end of 2 nd year (ΔFVC>+5). Secondary outcomes included longitudinal FVC trajectories over three years, skin involvement, and safety. Longitudinal analyses used linear mixed-effects models, with additional sensitivity analyses using inverse probability of treatment weighting. Results Among 109 patients (MTT n=42; RTX n=67), baseline FVC% was lower in MTT group (50.6 vs 61.0). At the end of two years ΔFVC>+5 occurred in 69% of patients receiving MTT compared with 33% receiving rituximab alone. Over 3 years, the adjusted mean increase in FVC% was greater in the MTT group than in the monotherapy group (+12.9% vs +4.4%) with early separation of lung-function trajectories that was sustained throughout follow-up. The association between MTT and greater FVC improvement remained consistent across prespecified subgroups, including patients with severe baseline restriction (FVC% <45%). Herpes zoster occurred more frequently in the MTT group, while serious infections were uncommon in both groups. Conclusion In this real-world study, RTX plus MMF was associated with favourable longitudinal FVC% trajectories compared with RTX monotherapy in a non-randomised cohort, despite greater baseline disease severity in the MTT group. These findings support prospective evaluation of MTT particularly in high-risk patients.