Efficacy and safety of upadacitinib in the treatment of rheumatoid arthritis: a systematic review and meta-analysis.

Background: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by persistent synovial inflammation, leading to progressive joint destruction and functional impairment. Although conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), particularly methotrexate, remain the first-line therapy, a substantial proportion of patients exhibit inadequate responses and require escalation to biologic or targeted synthetic therapies. Upadacitinib, a selective Janus kinase 1 (JAK1) inhibitor administered orally, has demonstrated promising efficacy in phase III trials; however, a comprehensive evaluation of its dose-dependent efficacy and safety across different patient populations remains lacking. Methods: This systematic review and meta-analysis was conducted in accordance with the PRISMA guidelines. Electronic databases, including PubMed, Web of Science, and Embase, were systematically searched from inception to July 2025 for randomized controlled trials evaluating upadacitinib in patients with RA. The primary outcome was the proportion of patients achieving an American College of Rheumatology 20% improvement (ACR20) response at 12 weeks. Secondary outcomes included safety endpoints such as overall adverse events, serious infections, herpes zoster, and laboratory abnormalities. Meta-analyses were performed using RevMan 5.4, with fixed- or random-effects models applied based on heterogeneity. The study protocol was registered with PROSPERO under identifier CRD420251134541. Results: Nine randomized controlled trials involving 5,237 participants were included. Both 15 mg and 30 mg once-daily upadacitinib significantly improved ACR20 response rates at 12 weeks compared with control treatments (15 mg: OR=4.09, 95% CI 3.51-4.76; 30 mg: OR=3.61, 95% CI 2.88-4.52; both P < 0.00001). No significant difference in efficacy was observed between the two dosage regimens (OR=1.00, P=0.98). In terms of safety, upadacitinib was associated with an increased risk of adverse events, with a dose-dependent trend observed (15 mg: OR=1.30; 30 mg: OR=1.42). The incidence of specific adverse events, including serious infections, herpes zoster, and elevated liver enzymes, was higher in the 30 mg group. Conclusion: Upadacitinib demonstrates superior efficacy compared with control treatments in patients with RA, with both 15 mg and 30 mg doses providing comparable clinical benefits. However, the higher dose is associated with an increased risk of adverse events, suggesting that the 15 mg regimen may offer a more favorable benefit-risk balance. Further studies are warranted to evaluate long-term outcomes and safety in specific patient populations. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=1134541, identifier CRD420251134541.