Characterising subgroups of difficult-to-treat rheumatoid arthritis in real-world clinical settings

ABSTRACT: Objectives: To evaluate the proportion of persistent inflammatory refractory rheumatoid arthritis (PIRRA) and noninflammatory refractory rheumatoid arthritis (NIRRA) of difficult-to-treat rheumatoid arthritis (D2T-RA) using musculoskeletal ultrasound (MSUS) and to compare clinical characteristics across PIRRA, NIRRA, and disease-controlled refractory rheumatoid arthritis (RA) subgroups. Methods: A retrospective single-centre cohort study identified patients (May 2021 to December 2022) with inadequate response to ≥2 different mechanism of action biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) and disease activity score in 28 joints-erythrocyte sedimentation rate (ESR) of >3.2 as European Alliance of Associations for Rheumatology-defined D2T-RA. MSUS classified this group into PIRRA (power Doppler present) or NIRRA (no power Doppler synovitis). A comparator group of controlled refractory RA (≥2 b/tsDMARD failures but sustained low disease activity) was also assessed. Clinical data were collected and analysed. Results: Of the 85 patients, 45 had D2T-RA (25 [56%] PIRRA; 20 [44%] NIRRA), and 40 had controlled refractory RA. PIRRA subgroup had higher C-reactive protein (CRP), but NIRRA subgroup higher ESR. Fibromyalgia was more prevalent in PIRRA and NIRRA than that in controlled refractory RA (48%, 40%, and 17.5%, respectively; P = .02). Nearly half of patients in the controlled refractory group (17/37 [46%]) had subclinical synovitis on MSUS. Rates of radiographic erosions were similar across PIRRA, NIRRA, and controlled refractory groups. Conclusions: MSUS-based stratification of D2T-RA into PIRRA and NIRRA reveals distinct associations to CRP and ESR and comparable chronic pain. Subclinical inflammation is present even in ostensibly controlled disease, suggesting risk of re-falling into an active D2T-RA state. Identifying such subphenotypes can inform on monitoring strategies, support mechanistic investigation, and enable more targeted treatments to improve outcomes of D2T-RA.