Upadacitinib in rheumatoid arthritis: progress and challenges

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by progressive joint destruction and systemic inflammation, imposing a substantial global health burden, with an estimated 31.7 million cases projected by 2050. Despite advances in therapy, limitations of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologic DMARDs (bDMARDs) persist, including adverse effects, high costs, and inadequate responses in certain patient subgroups. Upadacitinib (UPA), a selective Janus kinase (JAK) 1 inhibitor, represents a breakthrough in targeted synthetic DMARDs (tsDMARDs), offering rapid symptom relief and structural preservation. Clinical trials, including the SELECT-COMPARE study, have demonstrated that UPA outperforms adalimumab in achieving higher 12-week American College of Rheumatology (ACR) 20 (71% vs. 63%), ACR50 (45% vs. 29%), and ACR70 responses, with sustained efficacy extending beyond 5 years. Real-world evidence from the Canadian post-marketing observational CLOSE-UP study corroborated these findings, showing that 63.5% of patients achieved DAS28-CRP ≤2.6 at 6 months. Compared with pan-JAK inhibitors such as tofacitinib, the JAK1 selectivity of UPA may reduce off-target effects; however, safety concerns remain, including an increased risk of herpes zoster (particularly in Asian populations), liver enzyme abnormalities, and potential cardiovascular events. Cost remains a major barrier, with annual expenses exceeding USD 60,000 for uninsured patients, although partially alleviated by insurance coverage. Future directions highlight combination strategies, personalized treatment approaches, and broader applications in psoriatic arthritis and ankylosing spondylitis. While UPA enhances RA management through its oral convenience and robust efficacy, addressing long-term safety monitoring, affordability, and mechanisms underlying refractory RA remains imperative for optimizing global patient outcomes.