Janus kinase inhibitor monotherapy was associated with improved clinical, functional, and radiographic outcomes compared with methotrexate or placebo in patients with rheumatoid arthritis, although evidence directly comparing monotherapy with combination therapy remained limited, according to a systematic review published in Cureus.
Researchers reviewed 11 randomized controlled trials published from 2020 to 2025 that included 7,421 patients with rheumatoid arthritis. The trials evaluated upadacitinib, baricitinib, and filgotinib as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs, primarily methotrexate. Because of heterogeneity in patient populations, treatment regimens, comparators, follow-up duration, and outcome reporting, the researchers conducted a narrative synthesis rather than a meta-analysis, meaning comparisons across trials should be interpreted as indirect rather than head-to-head evidence.
In SELECT-EARLY, upadacitinib monotherapy was associated with higher American College of Rheumatology 50% response rates at week 12 compared with methotrexate monotherapy among methotrexate-naive patients. Response rates were 52% with upadacitinib 15 mg and 56% with upadacitinib 30 mg vs 28% with methotrexate. Disease Activity Score 28-C-reactive protein remission at week 24 occurred in 48% and 50% of patients receiving upadacitinib 15 mg and 30 mg, respectively, vs 19% of patients receiving methotrexate.
Long-term data from SELECT-MONOTHERAPY showed that approximately 42% of patients receiving upadacitinib monotherapy maintained low disease activity through 260 weeks.
Baricitinib also improved outcomes compared with placebo among patients with inadequate response to methotrexate. In one phase 3 trial, American College of Rheumatology 20% response rates at week 12 were 58.6% with baricitinib vs 28.3% with placebo.
Another randomized study found that baricitinib monotherapy produced higher response rates than conventional disease-modifying antirheumatic drugs and outcomes comparable to tumor necrosis factor inhibitors. However, that study was judged to have a high overall risk of bias, largely because of its nonblinded design, and the findings should be interpreted cautiously.
Filgotinib showed efficacy as both monotherapy and combination therapy. In the FINCH 3 trial, filgotinib monotherapy and filgotinib plus methotrexate both performed favorably vs methotrexate alone, although some endpoints numerically favored combination therapy. In the separate phase 3 FINCH 2 trial, filgotinib 200 mg plus methotrexate achieved an American College of Rheumatology 20% response rate of 76.6% at week 12 and was noninferior to adalimumab plus methotrexate.
Across studies, infections were the most commonly reported adverse events. Herpes zoster was more frequent in Asian populations; an integrated analysis of baricitinib studies in Japanese patients reported 6.5 events per 100 patient-years, a finding that may not be directly generalizable to US or European populations. Serious infections were reported at 2.4% over 12 weeks in one upadacitinib study and 3.6 events per 100 patient-years in the Japanese baricitinib analysis.
Malignancies, major adverse cardiovascular events, and venous thromboembolism were uncommon, but the review was not designed to definitively characterize rare long-term safety risks. The researchers noted that safety interpretation should account for broader Janus kinase inhibitor class concerns, including findings from ORAL Surveillance, in which tofacitinib was associated with higher risks of major adverse cardiovascular events and malignancy compared with tumor necrosis factor inhibitors among high-risk patients.
The researchers identified several limitations, including variability in trial design, populations, treatment regimens, follow-up duration, and outcome measures. Most studies did not directly compare Janus kinase inhibitor monotherapy with Janus kinase inhibitor combination therapy, and older patients and those with elevated cardiovascular risk were underrepresented. The researchers also noted that most included trials were industry-sponsored, which may have introduced reporting bias.
Although the findings supported Janus kinase inhibitor monotherapy as an option for selected patients, the researchers emphasized individualized decision-making. The review noted that current guideline approaches generally favor combination therapy with conventional synthetic disease-modifying antirheumatic drugs when tolerated but allow monotherapy among patients who cannot use methotrexate or other conventional agents.
“JAKi monotherapy is an effective and generally well-tolerated treatment strategy for patients with RA,” wrote lead study author Razaz Galal Mirghani Idris, MBBS, of Sligo University Hospital in Ireland, and colleagues.
Disclosures: The researchers reported no financial support and no relevant financial relationships or conflicts of interest.
Source: Cureus
