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LONDON — The JAK inhibitor baricitinib failed to demonstrate noninferiority to TNF inhibitors for risk of venous thromboembolism (VTE) in patients with active rheumatoid arthritis (RA) who had preexisting cardiovascular and metabolic risk factors, according to a pooled analysis of two postmarketing safety trials presented at the European Alliance of Associations for Rheumatology (EULAR) 2026 Annual Meeting. 

Although the absolute incidence of VTE remained low in both study arms, patients treated with the JAK inhibitor had a higher rate of thromboembolic events than those who received biologic disease-modifying antirheumatic drugs, study coauthor Torsten Witte, MD, PhD, a rheumatologist at Hannover Medical School, Germany, explained at the meeting.

The findings also revealed a significantly increased risk of serious infections, including COVID-19, among patients taking baricitinib. On the other hand, these patients were not at higher risk for major adverse cardiovascular events (MACE), arterial thromboembolism, or malignancy.

Investigating a Known Safety Concern 

The baseline risk of VTE is known to be 50%-100% higher in patients with active RA than in the general population, with high disease activity roughly doubling that risk compared to clinical remission. JAK inhibitors offer an effective oral alternative to injectable biologics, but they are associated with safety concerns about thromboembolism, MACE, and malignancy.

Researchers pooled data from two randomized, open-label, active-controlled post-approval trials: the global RA-BRIDGE and the US-based RA-BRANCH.

The analysis included 3640 adults with moderate to severe RA and at least one predefined VTE risk factor, such as a history of VTE, age 60 years or older, or obesity. The study population also carried a heavy burden of baseline metabolic and cardiovascular risk factors: approximately 50% of patients were obese, 50% had hypertension, 40% were current or former smokers, and 30% had diabetes. Additionally, about 4% had a history of arterial thromboembolism (ATE).

Participants were randomized 1:1:1 to baricitinib 2 mg daily (n = 1219), baricitinib 4 mg daily (n = 1214), or a TNF inhibitor (adalimumab or etanercept; n = 1207).

Patients were followed for a median of about 3.7 years, a period during which baricitinib could not be proven to be as safe as the TNF inhibitors when it came to blood clots.

In total, there were 62 blood clot events in the combined baricitinib groups and 20 events in the TNF inhibitor group. Changing the baricitinib dose from 4 mg to 2 mg did not change or lower the risk.

Serious infections were also more common in patients taking baricitinib. A significant portion of these infections stemmed from COVID-19-related complications, accounting for about 20% of severe infection cases in the baricitinib group and 13% in the TNF inhibitor group.

The risk of MACE was nearly identical between the combined baricitinib and TNF inhibitor cohorts. The risk of malignancies (excluding nonmelanoma skin cancer) was statistically similar between groups, with higher rates at the 2-mg than the 4-mg baracitinib dose or TNF inhibitor. Rates of ATE, opportunistic infections, and overall mortality did not differ significantly between treatments.

Clinical Practice Takeaways 

Despite the safety signals, an exploratory efficacy analysis from RA-BRIDGE replicated earlier clinical trial data, demonstrating that the highest clinical remission rates occurred in the baricitinib 4-mg daily group — outperforming both the TNF inhibitor arm and the lower baricitinib 2-mg dose. 

The absolute rate of VTE events remained low in both arms of the study. “The cautionary tale is [that], for someone who is at increased risk of VTE, you need to be careful,” Subhashis Banerjee, MD, a rheumatologist and chief medical officer at Artiva Biotherapeutics in San Diego, California, told Medscape Medical News. However, this conclusion cannot be generalized to all JAK inhibitors, he said.

Because the study specifically selected older, heavier patients with elevated baseline risks, the findings may not directly translate to the broader, younger RA population whose baseline VTE and infection risks are inherently lower. “We have to bear in mind this is not normal rheumatoid arthritis; this is highly active rheumatoid arthritis with [enriched] VTE risk factors, in particular obesity, and in these patients, we carefully have to weigh the benefit and risk assessment for a treatment,” Witte said.

The RA-BRIDGE and RA-BRANCH studies were funded by Eli Lilly, which manufactures baricitinib. Many authors declared financial relationships with Eli Lilly and other pharmaceutical companies. Banerjee is chief medical officer at Artiva Biotherapeutics. 

Manuela Callari is a freelance science journalist specializing in human and planetary health. Her work has been published in The Medical Republic, Rare Disease Advisor, New Scientist, The Guardian, MIT Technology Review, and others.