Clinical application of synovial biopsy in noninflammatory and persistent inflammatory refractory rheumatoid arthritis.

Abstract

We aimed to characterise the synovial pathology of refractory rheumatoid arthritis (RA) by comparing two hypothesised clinical phenotypes-persistent inflammatory refractory RA (PIRRA) and noninflammatory refractory RA (NIRRA)-against nonrefractory RA (NORRA). We conducted a prospective, observational cohort study at two academic rheumatology centres. Adult patients with established RA and active disease (Clinical Disease Activity Index >10) underwent ultrasound-guided synovial tissue biopsies in accordance with European Alliance of Associations for Rheumatology-Outcome Measures in Rheumatology guidelines. Based on the Physician Global Assessment (>2/10) and C-reactive protein (>5 mg/L) thresholds, biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs)-inadequate responders patients were classified as PIRRA or NIRRA, whereas b/tsDMARD-naïve were designated NORRA. Histopathological assessments included the Krenn Synovitis Score (KSS) and immunohistochemistry pathotype evaluation (lympho-myeloid, diffuse-myeloid, pauci-immune/fibroid). Of the 93 biopsied patients, 43 were PIRRA, 21 NIRRA, and 29 NORRA. NIRRA had lower KSS (P = .012), lymphoid aggregates (P < .001) and predominantly pauci-immune/fibroid pathotype (n = 21/43, 47.6%), whereas PIRRA displayed more lympho- and diffuse-myeloid pathotypes, coupled with higher inflammatory markers and ultrasound-power Doppler scores. The relative risk of having pauci-immune fibroid synovitis for NIRRA was 1.6 (95% CI 1.2 to 2.9, P = .006), indicating a statistically significant increase in risk compared to PIRRA. Despite having similar overall disease activity scores, NIRRA patients reported significantly greater pain (P = .005) and higher opioid use (P = .015) than PIRRA, and worse health-related quality of life than PIRRA or NORRA, underscoring noninflammatory mechanisms. Our findings demonstrate distinct synovial and clinical phenotypes in refractory RA. Although PIRRA appears driven by active synovial inflammation and immune cell infiltration, NIRRA involves predominantly pauci-immune/fibroid histology with significant noninflammatory contributors to disease burden.