Monotherapy Versus Combination Therapy of Janus Kinase Inhibitors With Conventional Synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs) in Rheumatoid Arthritis: Evidence From a Systematic Review of Randomized Controlled Trials.

Abstract

The optimal use of Janus kinase inhibitors (JAKi) in rheumatoid arthritis (RA), either as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), remains a subject of clinical debate. While combination therapy is often standard, JAKi monotherapy presents a potential alternative for patients intolerant to csDMARDs. This systematic review aims to evaluate and compare the efficacy and safety of JAKi monotherapy versus combination therapy with csDMARDs in patients with RA. This review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search of PubMed, Scopus, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and ClinicalTrials.gov was performed for randomized controlled trials (RCTs) published between January 2020 and August 2025. Eleven RCTs, encompassing 7,421 patients, were included. Data on study characteristics, efficacy outcomes, and safety outcomes were extracted. The Cochrane Risk of Bias (RoB 2) tool was used for quality assessment. JAKi monotherapy demonstrated significant efficacy, outperforming methotrexate (MTX) and placebo in American College of Rheumatology 50% (ACR50) and American College of Rheumatology 20% (ACR20) response rates, achieving high rates of disease activity score based on 28 joints with C-reactive protein (DAS28-CRP) remission, and inhibiting radiographic progression. Efficacy was comparable to tumor necrosis factor (TNF) inhibitors. Combination therapy also showed robust efficacy, often with numerical trends favoring it over monotherapy for some endpoints, though direct comparisons were limited. The safety profile was consistent across monotherapy and combination strategies, with an increased risk of infections and a low but present risk of serious adverse events (SAEs), including malignancies and cardiovascular events. JAKi monotherapy is an effective and generally well-tolerated treatment strategy for RA, offering a viable alternative for patients intolerant to csDMARDs. Its efficacy is superior to conventional DMARDs and comparable to both TNF inhibitors and JAKi combination therapy. The choice between monotherapy and combination therapy should be individualized, weighing efficacy, tolerability, and specific patient risk factors.