Rheumatoid arthritis may induce ILD development

Rheumatoid arthritis (RA) appears to contribute to the development of interstitial lung disease (ILD), as shown by genetic evidence from a Mendelian randomization (MR) study.

“This MR study provides robust genetic evidence supporting a potential causal relationship between RA and increased risk of ILD,” the researchers said. “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.”

A two-sample MR analysis was conducted to determine whether RA has a causal effect on ILD, utilizing genetic variants related to RA as instrumental variables to infer causality and minimize confounding.

The research team obtained genetic instruments for RA from a large European genome-wide association study (GWAS) and derived ILD outcome data from FinnGen, excluding auto-immune codes to minimize phenotypic overlap. They performed MR analyses using inverse variance weighting (IVW), MR-Egger regression, weighted median, mode-based methods, and MR-PRESSO.

Fifty-two RA-related single nucleotide polymorphisms (SNPs; p<5 x 10^-8) arose from the MR analysis and served as instrumental variables. The IVW method shed light on a significant causal effect of RA on the risk of ILD (odds ratio, 1.155, 95 percent confidence interval, 1.083‒1.232; p=1.04E-05). [Respirology 2026;31:162-173]

Directionally consistent results were also obtained from weighted median and mode-based methods, while the MR-Egger regression found no evidence of directional pleiotropy (intercept, 0.014; p=0.147), and the Cochran’s Q test did not detect significant heterogeneity (IVW Q, 45.424; p=0.694).

Moreover, horizontal pleiotropy was not observed in the MR-PRESSO global test, and no outlier SNPs were detected. In leave-one-out analysis, no single SNP disproportionately impacted the overall estimate. Finally, the funnel plot exhibited a symmetrical distribution, indicating no evidence of directional pleiotropy or influential bias.

“These findings highlight the need for heightened clinical vigilance for lung involvement in RA patients and provide a foundation for future mechanistic studies and personalized treatment strategies,” the researchers said. “Elucidating the shared immunogenetic pathways between RA and ILD may ultimately lead to improved outcomes for patients suffering from these debilitating conditions.”

Mechanisms

The causal association seen in the MR analysis may have been driven by the shared immunopathogenic mechanisms of RA and ILD.

“Chronic systemic inflammation, autoantibody production (such as RF and anti-CCP), and shared HLA genetic risk factors contribute to both synovial and pulmonary manifestations,” the researchers said.

Specifically, patients with RA-ILD have lung tissues that normally show citrullinated proteins and ectopic lymphoid structures. This supports the assumption that the lungs could function as a site of “initial immune priming in RA” prior to the involvement of the joints. [Thorax 2016;71:1082-1090]

“Genetic variants, such as HLA-DRB1 shared epitope alleles, are implicated in both articular and extra-articular (including pulmonary) autoimmunity,” the researchers said. [PLoS One 2012;7:e33133]

“Moreover, persistent immune activation and release of pro-fibrotic cytokines (such as TGF-β, IL-6, and TNF-α) may contribute to progressive interstitial fibrosis through fibroblast activation and extracellular matrix deposition,” they added. [Rheumatology (Oxford, England) 2025;64:3989-3995]

RA, a systemic autoimmune disease, is often complicated by ILD, one of its most severe extra-articular manifestations, according to the researchers.