Treatment with baricitinib misses the noninferiority mark against tumour necrosis factor inhibitors (TNFi) in active rheumatoid arthritis (RA) patients enriched for venous thromboembolism (VTE) risk factors with high baseline disease activity, reports a study.
“Baricitinib showed a numerically higher VTE rate vs TNFi, though absolute rates were low for the enriched population studied in both groups,” said lead author Dr Peter C Taylor, The Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Windmill Road, Oxford, UK.
“No increased MACE risk was observed, while serious infecÂtions were increased in the baricitinib arm, including new onset COVID-19,” he added.
A total of 3,640 patients were included in the combined RA-BRIDGE and RA-BRANCH trials (baricitinib 2 mg: n=1,219; baricitinib 4 mg: n=1,214; TNFi: n=1,207). The median on-treatment exposure was ~3.7 years in both groups. Taylor and his team calculated incidence rates (IRs) per 100 person-years using event-specific person-time.
Treatment discontinuation rates did not significantly differ between the baricitinib and TNFi arms (55.2 percent vs 57.3 percent), with similar rates due to adverse events (~14 percent) and patient withdrawal (14 percent). [EULAR 2026, abstract LB0009]
Compared with TNFi, combined baricitinib doses had a hazard ratio of 1.61 (95 percent confidence interval [CI], 0.97‒2.66; p=0.066) for time to first adjudicated VTE (baricitinib IR, 0.79, 95 percent CI, 0.60‒1.01; 62 events; TNFi IR, 0.51, 95 percent CI, 0.31‒0.79; 20 events). The upper limit of the 95 percent CI went beyond the 1.8 prespecified margin, thus noninferiority was not met.
These findings persisted across doses of baricitinib (2 mg: HR, 1.70, 95 percent CI, 0.94‒3.08; 4 mg: HR, 1.69, 95 percent CI, 0.97‒2.94). No dose-dependent effect was seen.
Secondary endpoints
The risks for major adverse cardiovascular events (MACE; HR, 1.06, 95 percent CI, 0.64‒1.76) and malignancy, except for nonmelanoma skin cancer, (HR, 1.27, 95 percent CI, 0.85‒1.89) were similar between combined baricitinib and TNFi, with numerically higher rates in the 2-mg baricitinib group (IR, 1.28, 95 percent CI, 0.90‒1.75) vs the 4-mg group (IR, 0.94, 95 percent CI, 0.67‒1.29) and the TNFi group (IR, 0.83, 95 percent CI, 0.57‒1.15).
Patients treated with baricitinib were also vulnerable to serious infections than those who received TNFi (IR: 3.17 vs 2.46; HR, 1.32, 95 percent CI, 1.04‒1.68). COVID-19 accounted for approximately 20 percent and 13 percent of serious infections in the combined baricitinib and TNFi groups, respectively.
No between-group differences were observed for arterial thromboembolic events, opportunistic infections, and mortality.
“The enriched population studied may limit direct extrapolation of these findings to the broader RA population, where baseline VTE and infection risk is lower,” Taylor said. “These results inform the ongoing benefit-risk characterization of baricitinib and support individualized treatment decisions accounting for patient-specific VTE and infecÂtion risk factors.”
RA-BRIDGE (global) and RA-BRANCH (US-based) are randomized, open-label, active-controlled safety trials involving adults with moderate to severe RA and at least one predefined VTE risk factor (prior VTE, age ≥60 years, BMI ≥30 kg/m2 or age 50 to <60 years with BMI 25 to <30 kg/m2).
Taylor and his team randomly assigned participants in a 1:1:1 ratio to receive baricitinib 2 mg, 4 mg, or TNFi (adalimumab or etanercept). They conducted analyses on the safety population. The primary analysis was based on on-treatment exposure with censoring at treatment discontinuation. Data from the two trials were pooled based on the prespecified analysis plan.
Cox proportional hazards models, stratified by study and randomization factors, were used to estimate IRs and HRs for VTE and other safety outcomes.
“RA is a systemic autoimmune disease characterized by chronic inflammation, progressive joint damage, and substanÂtial disability,” according to Taylor and colleagues. “Patients with active RA have VTE incidence rates 50- to 100-percent higher than the general population.” [Pain Palliat Care Pharmacother 2021;35:291-299; Ann Rheum Dis 2023;82:189-197]
Janus kinase inhibitors, including baricitinib, are effective oral therapies for patients with RA, but these medications have also been associated with safety concerns related to VTE, MACE, malignancy, and serious infections. [Clin Rheumatol 2021;40:4457-4471]