Associations between interleukin-37 gene polymorphisms and susceptibility and clinical outcomes of rheumatoid arthritis: a meta-analysis and systematic review

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting millions of people worldwide. Genetic factors, including specific polymorphisms such as the anti-inflammatory cytokine Interleukin (IL)-37, play a significant role in RA. This meta-analysis and systematic review investigated the associations between IL-37 gene polymorphisms and susceptibility and clinical outcomes of RA. A comprehensive literature search of the MEDLINE(R), Embase, and Web of Science databases was conducted on January 1, 2026. Case control studies assessing associations between IL-37 polymorphisms and RA susceptibility and/or clinical outcomes were included. Studies deviating from the Hardy-Weinberg equilibrium in controls, lacking genotype data, reviews, duplicates, or non-original studies were excluded. Study selection, data extraction, and quality assessment using the Newcastle-Ottawa Scale were independently performed by two authors, with any discrepancies resolved by a senior researcher. Data were pooled using inverse-variance weighted random-effects models under five genetic models, with heterogeneity assessed using Cochran’s Q test and the I2 statistic. Sensitivity analyses were conducted, and prediction intervals were calculated. A total of 7 studies were included in the final analysis, involving 1627 RA patients and 1722 healthy controls. No significant associations were observed between IL-37 polymorphisms (including rs3811047 and rs3811046) and RA susceptibility across genetic models. In the dominant model of rs3811047, patients carrying the AA or AG genotypes exhibit favorable clinical outcomes as compared to patients having GG genotype, including lower joint swelling index scores (MD = −1.65, 95% CI −2.53 to −0.78, p = 0.0002), reduced rest pain (MD = −1.02, 95% CI −1.52 to −0.52, p < 0.0001), lower joint tenderness index scores (MD = −2.11, 95% CI −3.96 to −0.27, p = 0.02), and improved Health Assessment Questionnaire scores (MD = −0.28, 95% CI −0.42 to −0.15, p < 0.0001). IL-37 polymorphisms do not appear to be strongly associated with RA susceptibility but may influence disease severity, highlighting a potential role in RA pathophysiology and prognosis. Limitations included a small number of included studies, moderate to high heterogeneity in some genetic models, and limited availability of genotype-stratified clinical outcome data.