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

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 2nd 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.