Antifibrotics in interstitial lung disease related to rheumatic and musculoskeletal diseases: a systematic review and meta-analysis

Objective: Interstitial lung disease (ILD) is a significant cause of morbidity and mortality in rheumatic and musculoskeletal diseases (RMDs).This systematic literature review and meta-analysis evaluated the efficacy and safety of antifibrotics (nintedanib, pirfenidone, and nerandomilast) in RMDs-ILD.Methods: We searched PubMed, Embase, CENTRAL, Web of Science, ClinicalTrials.govand conference abstracts.Outcomes included change in forced vital capacity (FVC), diffusing capacity of carbon monoxide, exercise capacity, fibrosis extent, patientreported outcomes, acute exacerbations, hospitalizations, mortality, and adverse events (AEs).Risk of bias (RoB) was assessed with RoB 2 and ROBINS-I.Quantitative synthesis was performed using ReviewManager version 5.4, with appropriate effect measures for continuous and categorical outcomes.Results: Thirty-one studies (2,638 patients; 1,790 on antifibrotics) were included; nine entered the meta-analysis.RoB was variable among randomised controlled trials and predominantly serious/critical in observational studies.Antifibrotics significantly slowed FVC decline at 52 weeks compared with placebo (mean difference [MD]: 65.87 mL; 95% confidence interval [CI]: 40.07 to 91.67; I=52%).Nintedanib and pirfenidone showed consistent benefits, while nerandomilast demonstrated a non-significant trend towards FVC preservation.A positive survival signal was observed with nerandomilast (risk ratio: 0.22; 95% CI: 0.12 to 0.40), requiring confirmation in larger trials.Gastrointestinal AEs were the most common, particularly with nintedanib and pirfenidone, whereas nerandomilast showed a more favourable tolerability profile.Conclusion: Antifibrotics slowed lung function decline in RMDs-ILD and were generally well tolerated.Larger, well-designed trials with standardised outcomes and longer follow-up are required to optimise treatment strategies.