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

Rheumatoid 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.

We 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.

The MR analysis identified 52 RA-related single nucleotide polymorphisms (SNPs) (p < 5 × 10^-8), which were selected as instrumental variables. The IVW method revealed a significant causal effect of RA on ILD risk, with an odds ratio (OR) of 1.155 (95% confidence interval [CI]: 1.083-1.232, p = 1.04E-05). Directionally consistent results were obtained from weighted median and mode-based methods. The MR-Egger regression showed no evidence of directional pleiotropy (intercept = 0.014, p = 0.147), and Cochran's Q test detected no significant heterogeneity (IVW Q = 45.424, p = 0.694). Furthermore, the MR-PRESSO global test did not detect horizontal pleiotropy (p = 0.26), and no outlier SNPs were identified. Leave-one-out analysis indicated that no single SNP disproportionately influenced the overall estimate. The funnel plot showed a symmetrical distribution, suggesting no evidence of directional pleiotropy or influential bias.

This 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.