Combination antifibrotic and immunosuppressive therapy in progressive fibrosing ILD

Background: Progressive fibrosing interstitial lung disease is characterized by continuous functional decline and early mortality despite conventional immunosuppressive therapy. The dual pathophysiology involves both inflammation and fibrosis and provides rationale for combination antifibrotic and immunosuppressive therapy. Objectives: To review and synthesize current clinical evidence on the efficacy, safety, and clinical positioning of combination antifibrotic and immunosuppressive therapy in progressive fibrosing interstitial lung disease. Methods: We conducted a comprehensive literature review of randomized controlled trials, observational studies, and real-world cohorts published between 2015 and 2025 that evaluated combined antifibrotic (nintedanib or pirfenidone) and immunosuppressive therapy in adults with non-IPF progressive fibrosing ILD. We synthesized evidence from randomized controlled trials, observational studies, and real-world data regarding their methodologies, patient population, therapies and outcomes. Results: Forty-one studies were identified, including 14 RCTs and 12 observational cohorts. The available evidence suggests that combination therapy demonstrates promising results across various PF-ILDs. Clinical trials and real-world data have shown improved lung function and forced vital capacity with combination therapy in PF-ILD. Evidence supports combination therapy to be well-tolerated, with manageable safety and tolerability profile consistent with individual agents rather than additive effects. Limitations of the available evidence include heterogeneity of PF-ILD populations, variable background immunosuppression, and limited long-term outcome data. Conclusions: Combination antifibrotic and immunosuppressive therapy shows meaningful efficacy in select PF-ILD patients. Evidence supports individualized combination approaches, particularly for progressive systemic sclerosis-ILD and connective tissue disease-ILD with nonspecific interstitial pneumonia pattern. Critical evidence gaps remain regarding optimal sequencing, patient selection, and long-term outcomes, requiring future investigation.