Genetic Study Establishes Causal Link Between RA and Interstitial Lung Disease Risk

A new Mendelian randomization (MR) study published in Respirology provides new evidence supporting a causal relationship between rheumatoid arthritis (RA) and the development of interstitial lung disease (ILD).¹

Researchers analyzed genetic data from more than 57,000 individuals with RA to determine if it directly contributes to the development of ILD. The analysis drew on large-scale genome-wide association studies (GWAS), with data from 14,361 RA cases and 42,923 controls of European ancestry, and then examined their relationship with 1969 ILD cases and 196,986 controls from the FinnGen consortium. The authors note that excluding RA-related diagnostic codes from the FinnGen ILD phenotype further reinforces the analysis's validity by preventing overlap between the exposure and outcome.

Using 52 independent single nucleotide polymorphisms (SNPs) associated with RA as instrumental variables, the study found that genetic predisposition to RA increased ILD risk by 15.5% (OR, 1.155; 95% CI, 1.083-1.232; P = 1.04 × 10⁻⁵). The MR approach relies on these genetic variants to serve as instrumental variables to estimate causality, contingent on meeting 3 core criteria: a strong association with the exposure, independence from confounders, and an effect on the outcome solely through the exposure itself. Because these variants are fixed at conception, MR helps reduce bias from factors such as smoking history, age, disease severity, and treatment patterns, key limitations of traditional observational studies.

Sensitivity analyses consistently reinforced the direction and magnitude of the causal association between RA and ILD. The weighted median and simple mode approaches yielded ORs of 1.098 and 1.196, respectively, which align with the primary estimate, whereas MR-Egger regression yielded a more conservative OR of 1.074 and showed no evidence of directional pleiotropy (P = .147). Additional tests, including Cochran's Q statistic (IVW Q = 45.424; P = .694), which indicated no significant heterogeneity, and MR-PRESSO (P = .26), which detected no horizontal pleiotropy or outlier variants, further supported the validity of the findings. Leave-one-out analyses demonstrated that no single genetic instrument disproportionately influenced the overall estimate, and symmetrical funnel plot patterns confirmed the absence of influential bias. "Collectively, these sensitivity analyses provide convergent evidence that the observed causal relationship between RA and ILD is unlikely to be explained by horizontal pleiotropy, outliers or outlier effects, or single-­SNP influence," the authors explain.

The investigators note that RA and ILD share several immunopathogenic mechanisms that may explain this causal association. Persistent systemic inflammation, the generation of autoantibodies such as rheumatoid factor and anti-cyclic citrullinated peptide antibodies, and common HLA genetic susceptibility factors all contribute to both joint and lung manifestations of the disease. Previous research has documented the presence of citrullinated proteins and ectopic lymphoid structures in lung tissue from patients with rheumatoid arthritis-associated interstitial lung disease, supporting the hypothesis that pulmonary tissue may serve as an initial site of immune activation in the disease process.² The MR findings are consistent with this emerging model and support the interpretation that ILD may represent an organ-specific extension of the systemic autoimmune process underlying RA.

"Our approach improves upon earlier work by using updated summary statistics, stringent pleiotropy control (such as MR-PRESSO), and exclusion of overlapping autoimmune phenotypes from the ILD outcome dataset. We also utilized the Finn-b-ILD phenotype, which is broader than IPF-focused datasets and may better represent the clinical spectrum of ILD in RA," the authors note. However, limitations include the predominantly European ancestry of study populations, potential heterogeneity within the ILD phenotype, and the inability to conduct reverse MR analysis due to insufficient genome-wide significant variants for ILD.

"Our findings provide robust genetic evidence supporting a causal effect of RA on the development of ILD," the researchers concluded. Clinically, the results reinforce the need for earlier respiratory evaluation in patients with RA, particularly those with longstanding, seropositive disease or other known risk factors for ILD. Although the study did not stratify risk across patient subgroups, the authors suggest that integrated genetic, serologic, and clinical risk stratification tools could enhance risk prediction and may help identify patients who warrant closer pulmonary monitoring before irreversible fibrotic damage occurs.

References

1. Zhang M, Chen X, Zhang W, Yang G, Yin Y, Qu Y. Mendelian randomization analysis of the causal link between rheumatoid arthritis and interstitial lung disease. Respirology. Published online October 31, 2025. doi:10.1002/resp.70156
2. Bernstein EJ, Barr RG, Austin JHM, et al. Rheumatoid arthritis-associated autoantibodies and subclinical interstitial lung disease: the Multi-Ethnic Study of Atherosclerosis. Thorax. 2016;71(12):1082-1090. doi:10.1136/thoraxjnl-2016-208932