Janus Kinase (JAK) Inhibitors in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a progressive autoimmune disease with systemic involvement and is characterized by synovial inflammation, unremitting joint destruction, and systemic involvement. While biologic disease-modifying antirheumatic drugs (bDMARDs) and conventional synthetic DMARDs (csDMARDs) form the foundation of treatment, limitations such as incomplete efficacy, parenteral administration, and adverse events highlight the need for alternative strategies. Janus kinase inhibitors (JAKis), a newer class of targeted synthetic DMARDs (tsDMARDs), offer the advantages of oral administration, rapid onset, and broad cytokine modulation, thereby potentially offering advantages over established therapies. This review utilizes synthesized data from peer-reviewed clinical trials, systematic reviews, meta-analyses, regulatory documents, and international guidelines. Only studies involving adult patients with RA treated by approved JAKis (baricitinib, tofacitinib, upadacitinib, peficitinib, and filgotinib) were included. Both real-world observational studies and randomized controlled trials were assessed for efficacy, safety, drug interaction, and long-term outcomes. JAKis consistently demonstrated superior responses compared with placebo and methotrexate, with higher American College of Rheumatology 20% response rates, improved disease activity scores, reduced radiographic progression, and enhanced patient-reported outcomes. In head-to-head comparisons, baricitinib and upadacitinib demonstrated advantages over adalimumab across multiple efficacy domains. However, safety concerns emerged, particularly regarding major adverse cardiovascular events, herpes zoster, and malignancy. While randomized controlled trials showed low absolute event rates, observational studies revealed higher risks compared with tumor necrosis factor inhibitors, especially among older patients, smokers, and those with cardiovascular comorbidities. JAKis represent a highly effective and convenient therapeutic option in RA management, offering significant improvements over csDMARDs and certain biologic agents. Nonetheless, their use requires individualized, risk-stratified decision-making, with particular caution in patients at elevated cardiovascular or malignancy risk. Ongoing long-term studies and real-world data remain essential to further define their benefit-risk profile and optimize their integration into personalized RA care.