Mendelian Randomization Analysis of the Causal Link Between Rheumatoid Arthritis and Interstitial Lung Disease.

BACKGROUND AND

objectivesRheumatoid arthritis (RA) is a systemic autoimmune disease that is often complicated by interstitial lung disease (ILD), one of its most severe extra-articular manifestations. However, whether RA causally contributes to ILD development remains unclear.

methodsWe conducted a two-sample Mendelian randomization (MR) analysis to investigate whether RA has a causal effect on ILD. MR uses genetic variants associated with RA as instrumental variables to infer causality and minimize confounding. Genetic instruments for RA were obtained from a large European GWAS (ebi-a-GCST002318; 14,361 cases and 42,923 controls). The ILD outcome data were derived from FinnGen (finn-b-ILD, 1969 ILD cases and 196,986 controls), and autoimmune-related codes were explicitly excluded to minimize phenotypic overlap. MR analyses were performed using inverse variance weighting (IVW), MR-Egger regression, weighted median, mode-based methods, and MR-PRESSO to assess causality, heterogeneity, and pleiotropy.

resultsThe MR analysis identified 52 RA-related single nucleotide polymorphisms (SNPs) (p < 5 × 10

conclusionThis MR study provides robust genetic evidence supporting a potential causal relationship between RA and increased risk of ILD. These findings highlight the need for increased clinical vigilance, including early respiratory screening and monitoring in RA patients-particularly those at high risk-to facilitate timely detection and management of ILD.