C104-14 Mycophenolate Mofetil Versus Rituximab in Non-IPF Interstitial Lung Disease With or Without Concomitant Corticosteroids: A Target Trial Emulation Study

Rationale Non-idiopathic pulmonary fibrosis (IPF) interstitial lung disease (ILD) is a heterogeneous entity; among its autoimmune subsets (connective tissue disease [CTD]-ILD or interstitial pneumonia with autoimmune features [IPAF]), immunosuppressants are routinely used as therapy, though response to therapy can be widely variable. Mycophenolate mofetil (MMF) and rituximab (RTX) are frequently selected as first-line options, either with or without concomitant systemic corticosteroids. However, superiority as an initial treatment option between these two agents has never been established. Therefore, we aimed to compare MMF versus RTX as initial immunosuppressive therapy in non-IPF ILD and to assess which strategy is associated with better clinical outcomes. Methods We emulated a target trial to evaluate the comparative effectiveness of MMF versus RTX, using ILD registries from the Mass General Brigham hospital network. Eligible participants were adults (≥18 years) with a diagnosis of non-IPF ILD who initiated MMF or RTX for ILD management between January 2015 and August 2025; concomitant systemic corticosteroids were permitted. Time zero was the date of MMF or RTX initiation. To address confounding, we applied overlap weighting to balance baseline covariates (age, sex, smoking history, ILD subtype, UIP pattern, FVC, DLCO, systemic corticosteroid use, antifibrotic use, and calendar year). The outcome was a composite of first ILD hospitalization, lung transplantation, or all-cause mortality. We estimated hazard ratio (HR) with 95% confidence intervals (CIs) using weighted Cox proportional hazards model. Results We included 353 new users of MMF (n = 300) and RTX (n = 53). Mean (Q1, Q3) age was 68 (60, 75) years and 55% were female. ILD subtypes were as follows: IPAF (n = 174, 49%), CTD-ILD (n = 88, 25%), hypersensitivity pneumonitis (n = 32, 9%), and idiopathic ILD (n = 59, 17%). Over a median follow-up of 25.8 months, component outcomes for MMF vs. RTX were as follows: ILD hospitalization 50 (17%) vs 12 (23%); lung transplantation 23 (8%) vs 2 (4%); and death 68 (23%) vs 15 (28%). After overlap weighting, an estimated HR for the composite outcome (MMF vs RTX [reference]) was 0.78 (95% CI, 0.47 to 1.30). In subgroup analyses by concomitant corticosteroids at time zero, HRs (MMF vs RTX) were 0.79 (95% CI, 0.42 to 1.50) with corticosteroids and 0.75 (95% CI, 0.32 to 1.72) without corticosteroids. Conclusion In this target trial emulation of non-IPF ILD patients, we found no clear evidence that ILD event-free survival differed between patients using MMF vs. RTX. This abstract is funded by: Sidney and Deanna Wolk Family Foundation