Synovitis severity may influence response to JAK inhibitors versus non-TNFi-targeted biologicals in patients with difficult-to-treat rheumatoid arthritis

The management of difficult-to-treat rheumatoid arthritis (RA) largely relies on a trial-and-error approach. Patients with D2TRA are typically non-responders to TNF inhibitors and are commonly treated with bDMARDs with other mechanisms of action (OMA) or Janus kinase inhibitors (JAKi). We investigated whether synovial histopathology, including synovitis severity and pathotype, is associated with differential treatment response to JAKi versus OMA. MATRIX is a prospective, observational, multicenter cohort of RA patients undergoing ultrasound-guided synovial tissue biopsy (UGSTB). Patients fulfilling the EULAR definition of D2TRA who initiated JAKi or OMA after biopsy were included. Synovitis severity was graded using the Krenn Synovitis Score (KSS; low-grade 2–4, high-grade 5–9), and synovial pathotypes were classified as lympho-myeloid, diffuse-myeloid, or pauci-immune. The primary outcome was CDAI at six months, analysed using ANCOVA adjusting for baseline CDAI and synovitis grade. The secondary outcome was low disease activity (LDA; CDAI ≤ 10). Thirty-one patients were included (68% female, median (IQR) age 63 (12.5) years, disease duration 14 [12.5] years). Consistent with the study inclusion criteria, all patients exhibited moderate-to-high disease activity (median (IQR) CDAI 23.9 (14.5)); eleven received JAKi and twenty OMA. Baseline characteristics were comparable, although the pauci-immune pathotype was numerically more frequent in the OMA group (31.6% vs 10%, p = 0.367). At six months, CDAI was significantly lower in the JAKi group compared to OMA (median (IQR) 12.2 (10) vs 24.5 (19.2), p = 0.018). In patients with high-grade synovitis, JAKi was associated with lower CDAI compared to OMA (β -14.5; p = 0.005), whereas no difference was observed in low-grade synovitis (treatment-by-synovitis grade interaction β = 9.80, 95% CI -4.8 to 24.4; p = 0.18). Synovial pathotype was not associated with CDAI at follow-up. LDA was achieved more frequently with JAKi (45.5% vs 20%; p = 0.218). In D2TRA, synovitis severity may be associated with differential response to JAKi versus OMA. Given the observational study design and small sample size, these exploratory findings warrant confirmation in larger cohorts.