Difficult-to-treat rheumatoid arthritis: systematic review and meta-analysis on global prevalence

Despite significant advances in targeted therapies, difficult-to-treat rheumatoid arthritis (D2T-RA) remains a major clinical challenge. This study aimed to systematically evaluate the global prevalence of D2T-RA using the European League Against Rheumatism (EULAR) definition and to quantify the proportion attributable to persistent inflammatory refractory rheumatoid arthritis (RA).

We comprehensively searched PubMed, EMBASE, and Cochrane Library (up to April 2025) for observational studies reporting the prevalence of D2T-RA according to the EULAR definition. Subgroup analyses were performed to explore heterogeneity sources. Random-effects meta-analysis of proportions using generalised linear mixed models was conducted to calculate pooled prevalence rates and 95% CI.

Twenty-three studies with 27,987 patients with RA from 13 countries were included. The global pooled prevalence of D2T-RA was 11.7% (95% CI: 9.5%-14.3%). The pooled prevalence of D2T-RA was 10.9% (95% CI: 8.2%-14.2%) in overall RA cohorts and 13.2% (95% CI: 9.1%-18.8%) in studies restricted to biologic and target synthetic disease-modifying antirheumatic drugs (b/tsDMARDs)-treated populations. D2T-RA prevalence was stable in the region, RA criteria, and study setting; significant variations only existed in the enrolled period (pre-2020 vs post-2020: 9.86% [95% CI: 7.6%-12.7%] vs 14.3% [95% CI: 10.3%-19.6%]; P = .08). Moreover, about half of patients with D2T-RA exhibited evidence of persistent inflammatory refractory RA (pooled proportion: 47.1%, 95% CI: 33.3%-61.4%). Prevalence decreased sharply with stricter definitions: D2T(3)-RA (≥3 b/tsDMARD failures): 4.3% (2.7%-6.7%) and D2T(4)-RA (≥4 failures: 1.6% (0.6%-4.3%).

Based on available global data, approximately 12% of patients with RA meet standard D2T-RA criteria, with nearly half exhibiting persistent inflammatory disease. Stricter definitions with failure of ≥3 b/tsDMARD identify the small group of patients for whom innovative treatments or strategies are needed.