Multitarget 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) vs RTX monotherapy in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD).

Methods: We performed a retrospective comparative analysis among adults with radiologically confirmed SSc-ILD treated with RTX monotherapy or RTX plus MMF (a multitarget approach [MTT]) as an RTX-based treatment strategy. The primary outcome was improvement in percent predicted forced vital capacity (FVC%) > 5 percentage points at the end of the second year (ΔFVC > +5). Secondary outcomes included longitudinal FVC trajectories over 3 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 the MTT group (50.6 vs 61.0). At the end of 2 years, ΔFVC > +5 occurred in 69% of patients receiving MTT compared with 33% receiving RTX 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, whereas serious infections were uncommon in both groups.

Conclusion: In this real-world study, RTX plus MMF was associated with favorable longitudinal FVC% trajectories compared with RTX monotherapy in a nonrandomized cohort, despite greater baseline disease severity in the MTT group. These findings support prospective evaluation of MTT, particularly in high-risk patients.