Abstract & Overview
Introduction: Janus kinase (JAK) inhibitors and tumor necrosis factor (TNF) inhibitors are both recommended after methotrexate (MTX) failure in rheumatoid arthritis (RA). However, head-to-head trials are limited. This network meta-analysis (NMA) compares clinical and radiographic outcomes.Methods: NMA of RCTs (≥24 weeks) comparing any JAK inhibitor (tofacitinib, baricitinib, upadacitinib) vs TNF inhibitors (adalimumab, etanercept) in MTX-inadequate responders. Outcomes: ACR50 response rate at 24 weeks, change in modified Sharp score (mTSS), and serious infection rates.Results: Twenty RCTs (n=12,420) included. Upadacitinib 15 mg daily ranked highest for ACR50 (OR 1.48 vs adalimumab, 95% CI 1.22–1.79). Baricitinib 4 mg was similar to TNF inhibitors (OR 1.02, 95% CI 0.88–1.19). Radiographic progression (mTSS change): JAK inhibitors pooled had smaller progression (mean difference -0.38 units, 95% CI -0.61 to -0.15) vs TNF inhibitors. Serious infection rates: JAK 3.8% vs TNF 3.2% (p=0.24), but herpes zoster more common with JAKs (RR 2.8, p<0.001).Discussion: Upadacitinib shows slight superiority for ACR50, but JAKs carry higher herpes zoster risk. Cardiovascular and malignancy signals (post-hoc analyses) suggest caution in elderly with risk factors.Conclusions: JAK inhibitors are non-inferior to TNF inhibitors, with upadacitinib potentially more efficacious. Safety profiles differ, guiding personalized choice.