Arthritis Res Ther. 2026 Jan 26. doi: 10.1186/s13075-026-03746-5. Online ahead of print.
ABSTRACT
BACKGROUND: Rheumatoid arthritis (RA) and gout are traditionally considered distinct diseases with differing pathogenic mechanisms, making their coexistence controversial. Emerging evidence suggests this overlap may be underestimated. This study aimed to evaluate their epidemiological association, genetic causality, and intersecting molecular features.
METHODS: Epidemiological analyses used National Health and Nutrition Examination Survey (NHANES; 2007 ~ 2018, n = 19,705) data. Propensity score matching and weighted multivariate logistic regression assessed gout prevalence, temporal trends, and risk factors in RA. Restricted cubic spline (RCS) analysis examined nonlinear serum urate (SUA)-gout associations within RA. Mendelian randomization (MR) analyses based on genome-wide association study (GWAS) data evaluated causal effects of overall RA, Seronegative RA (SNRA), and Seropositive RA (SPRA) on gout and SUA, with multiple testing controlled by Bonferroni correction. Transcriptomic analyses from the Gene Expression Omnibus (GEO) used differential expression and weighted gene co-expression network analysis (WGCNA). Results were integrated with disease-related genes from the Comparative Toxicogenomics Database (CTD), Online Mendelian Inheritance in Man (OMIM), and GeneCards databases for enrichment and pathway analyses.
RESULTS: NHANES data indicated higher gout prevalence among RA patients compared to matched controls (10.3% vs. 4.8%, P < 0.001), with an increasing trend over time (P = 0.006). Weighted logistic regression supported RA as an independent risk factor for gout (OR: 2.67; 95% CI: 1.95 to 3.67; P < 0.001). RCS analysis revealed a nonlinear SUA-gout association in RA (P < 0.05). MR supported a causal effect of RA on gout, strongest for SNRA (OR = 1.132; 95% CI: 1.044 to 1.227; P = 0.003) after Bonferroni correction, whereas no effect was found for SPRA on gout or for RA, SNRA, and SPRA on SUA. Bioinformatics analysis identified 207 shared RA-gout genes enriched in interferon signaling, immune activation, and antiviral defense pathways, highlighting five hub genes (RSAD2, DDX60, IFIT1, IFIT3, XAF1) central to a convergent interferon-driven mechanism.
CONCLUSIONS: RA and gout may overlap more than previously recognized, with stronger genetic evidence in SNRA. No causal effect on SUA suggests the link may not primarily involve urate pathways. Transcriptomic overlap in interferon signaling indicates potential molecular intersections, warranting further investigation.
PMID:41582139 | DOI:10.1186/s13075-026-03746-5
