Mycophenolate and Azathioprine in Fibrotic Interstitial Lung Disease

RATIONALE: Immunosuppression is routinely used for non-idiopathic pulmonary fibrosis (IPF) interstitial lung diseases (ILDs), despite limited trial evidence and unclear impact on long-term outcomes. OBJECTIVES: To evaluate whether mycophenolate or azathioprine improves three-year transplant-free survival and lung function trajectory in fibrotic ILD, including non-IPF idiopathic interstitial pneumonia (IIP), fibrotic hypersensitivity pneumonitis (fHP), and connective-tissue disease (CTD) associated ILD. METHODS: We employed a clone-censor-weighting framework to emulate a randomized controlled trial in this multi-center retrospective study. Each patient was cloned and assigned to immunosuppression initiation within 6 months of enrollment or no initiation strategies, and censored when the assigned strategy deviated from observed treatment. Stabilized inverse probability treatment and censoring weights were used. MEASUREMENTS: The primary endpoint was three-year transplant-free survival assessed with weighted Cox models across treatment strategies. Weighted generalized estimating equations were used to model lung function trajectory. MAIN RESULTS: Among 2,270 included patients, 18% (186/1022) with non-IPF IIP, 30% (162/544) with fHP, and 31% (221/704) with CTD-ILD were initiated on immunosuppression within 6-months. Immunosuppression was not associated with improved survival within any ILD subtype but was associated with worse survival in non-IPF IIP (HR 1.38, 95% CI 1.04-1.84) and fHP (HR 1.62, 95% CI 1.09-2.40). Immunosuppression was not associated with differential lung function trajectory within any ILD subtype. CONCLUSIONS: In this study, immunosuppression initiation showed no evidence of benefit for three-year transplant-free survival or lung function and was associated with higher mortality in select fibrotic ILD subtypes. Prospective randomized controlled trials are needed to inform patient care.