Baricitinib's equivalent to ORAL Surveillance confirms VTE and infection risk but cardiovascular signal absent.
Treating highly active rheumatoid arthritis (RA) with the oral JAK inhibitor baricitinib may not have increased cardiovascular risk, even when compared to TNF inhibitors in patients with existing metabolic and cardiovascular risk factors, based on data from a much-awaited pair of large clinical trials.
The surprise finding from regulator-mandated safety studies raises more questions than answers from a late breaking abstract presentation at the European Alliance of Associations for Rheumatology (EULAR) 2026 Annual Meeting in London.
There was also no statistically significant increase in malignancy or arterial thromboembolism with baricitinib compared to TNF inhibitors across 3640 patients with VTE risk and 11,524 patient-years of exposure in the postmarketing studies mandated by the US Food and Drug Administration.
These results sit in contrast to the similar ORAL Surveillance study in tofacitinib, which led to the regulatory warning for cancer and cardiovascular disease for all JAK inhibitors.
The study, however, did confirm the higher risk of venous thromboembolism (VTE) with baricitinib, which was the primary focus of the study, and also showed an increase rate of serious infections.
While absolute occurrence rates of blood clots remained relatively low across both treatment pathways, patients randomised to the JAK inhibitor experienced a higher number of thromboembolic events than those taking biologic disease-modifying antirheumatic drugs (bDMARDs), according to study co-author Professor Torsten Witte, a rheumatologist at Hannover Medical School in Germany.
The data further revealed that baricitinib increased a patient’s vulnerability to severe infections, including covid.
Weighing the baseline risk
Active RA patients already experience a baseline VTE risk that is 50% to 100% higher than that of the general population.
High systemic inflammation can effectively double this risk compared to patients who have achieved clinical remission.
Though oral options offer a highly effective alternative to subcutaneous or intravenous biologics, safety concerns surrounding thromboembolism, major adverse cardiovascular event (MACE), and cancers have lingered over the JAK inhibitor class.
To clarify these risks, investigators pooled data from 3640 adults across two randomised, open-label, active-controlled post-approval protocols: the global RA-BRIDGE trial and the US-based RA-BRANCH trial.
Participants selected for the trials had moderate-to-severe active disease alongside at least one established risk factor for blood clots – including obesity, an age profile of 60 years or older, or a prior personal history of VTE.
The baseline characteristics represented a highly vulnerable cohort: half of the patients were obese, half were hypertensive, 40% were current or former smokers, and 30% had diabetes. A further 4% had a history of ATE.
Patients were randomised in an equal 1:1:1 layout to receive baricitinib at a 2mg daily dose (n = 1219), baricitinib at 4mg daily (n = 1214), or an approved TNF inhibitor such as adalimumab or etanercept (n = 1207).
Over a median follow-up of 3.7 years, baricitinib could not prove non-inferiority to the biologics. The combined baricitinib arms recorded 62 clot events, compared with just 20 in the TNF inhibitor cohort. Stepping down the dosage from 4mg to 2mg did not offer protection or lower the risk profile.
Severe infection rates were similarly skewed toward the oral JAK inhibitor. COVID-19 complications accounted for roughly 20% of the severe infection pool within the baricitinib arms, compared to 13% for patients on TNF inhibitors.
However, MACE rates were nearly identical across both arms, with a hazard ratio of 1.06, and confidence intervals which did not exceed 1.8, the regulator-mandated non-inferiority threshold for the primary endpoint.
Related
Malignancy numbers (excluding non-melanoma skin cancer) were also statistically comparable (HR 1.27 (0.85-1.89)) a slightly numerically higher rate of malignancies was observed in the lower 2mg baricitinib group.
This sits in contrast to the ORAL Surveillance study, another postmarketing requirement study examining tofacitinib versus TNF inhibitors in a cardiovascular risk-enriched population, where the HR was 1.33 (0.91-1.94) for MACE and 1.48 (1.04-2.09) for malignancy.
Clinical takeaways
Clinical remission rates were maximised in the baricitinib 4mg group, outperforming both the 2mg arm and the TNF inhibitor pathway.
However, because this safety trial intentionally enriched its dataset with older, heavier patients carrying high metabolic burdens, experts caution against applying the safety warning broadly across the entire clinic.
“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,” Professor Witte told delegates.
“In these patients, we carefully have to weigh the benefits and risks of a treatment.”
Independent experts agree that clinical context is everything when looking at these outcomes.
Professor Jonathan Kay, MD, the Timothy S. and Elaine L. Peterson Chair in Rheumatology and professor of medicine at the University of Massachusetts School of Medicine in Worcester, told Rheumatology Republic that the safety profile must be weighed relative to other considerations.
He suggested that while the relative risks are clear in an enriched, vulnerable cohort, the absolute incidence remains low.
Reassuringly, the totality of the clinical data continues to demonstrate that baricitinib remains a highly viable, effective option for the vast majority of standard RA patients who do not possess these severe baseline comorbidities.
It is expected that more extensive results will be released at future conferences and in subsequent publications.
The EULAR 2026 Congress was held in London from 3-6 June.
