Two major real-world studies presented at the 2025 EULAR congress in Barcelona provide reassuring safety data for JAK inhibitors in rheumatoid arthritis patients, addressing longstanding concerns about cancer and cardiovascular risks that emerged from the pivotal ORAL Surveillance trial.
Cancer Risk Analysis Shows No Significant Increase
Romain Aymon and colleagues conducted a comprehensive analysis using data from 13 international registries to assess cancer incidence in RA patients treated with JAK inhibitors compared to biologic disease-modifying anti-rheumatic drugs (bDMARDs). The study identified 53,169 treatment initiations in 33,127 patients, with cancers linked to treatments within 5 years of cessation or until follow-up loss, death, or study end.
The analysis revealed 219 non-melanoma skin cancers and 638 non-NMSC cancers across all treatment groups. The crude incidence of non-NMSC cancer was 2.2 per 1,000 patient-years for TNF inhibitors, 2.9 for JAK inhibitors, and 3.1 for bDMARDs with other mechanisms of action. However, statistical analysis found no significant difference in the incidence of either cancer type between JAK inhibitors and TNF inhibitors, nor between JAK inhibitors and other bDMARDs.
A sub-analysis focused on patients aged 50 and older with at least one cardiovascular risk factor—mimicking the ORAL Surveillance inclusion criteria—comprised 39.4% of treatment courses. This high-risk cohort showed higher cancer incidence rates of 3.2, 4.2, and 4.1 per 1,000 patient-years for TNF inhibitors, JAK inhibitors, and other bDMARDs, respectively. Despite the elevated baseline risk, no significant difference in cancer incidence was observed between JAK inhibitors and either bDMARD group.
Keratinocyte Cancer Risk Remains Elevated
While overall cancer risk appeared comparable, a separate Swedish study of 21,121 RA patients revealed increased keratinocyte cancer risk with JAK inhibitors. The analysis identified 94 keratinocyte cancers in patients starting JAK inhibitors, 407 with other bDMARDs, and 628 with TNF inhibitors.
Compared to TNF inhibitors, the hazard ratio for keratinocyte cancer was 1.72 with JAK inhibitors and 0.81 with other bDMARDs. Among RA patients with a history of keratinocyte cancers, the hazard ratio for a second diagnosis was 2.76 for JAK inhibitors versus TNF inhibitors.
Viking Huss, presenting the work, noted: "These findings suggest that people with RA treated with a JAK inhibitor have a higher incidence of a first keratinocyte cancer, primarily driven by basal cell carcinoma. Additionally—although based on a limited number of events—we saw a higher incidence of a second cancer of this type with JAK inhibitors compared to TNF inhibitors."
Cardiovascular Safety Profile Appears Favorable
A separate cardiovascular safety analysis of 51,233 patients from 15 international registries provided additional reassurance. The study included patients with a mean age of 58.4 years who received 73,008 treatment courses with a median follow-up of 1.3 years. Among the cohort, 16,417 patients were treated with JAK inhibitors, 35,373 with TNF inhibitors, and 21,218 with other biologic DMARDs.
The analysis documented 828 major cardiovascular complications across all patients. JAK inhibitors demonstrated a major cardiovascular complication rate of 6.97 per 1,000 person-years, compared to 7.57 for TNF inhibitors and 11.77 for other biological DMARDs.
After adjusting for baseline covariations, researchers found no differences in major cardiovascular complications for JAK inhibitors compared with TNF inhibitors (within-registry adjusted incidence rate ratio = 0.96; 95% CI 0.6-1.54). However, other biologic DMARDs were associated with increased major cardiovascular complications compared to TNF inhibitors (within-registry aIRR = 1.35; 95% CI 1.1-1.66).
GLP-1 Agonists Show Cardioprotective Potential
An intriguing finding emerged from a retrospective analysis examining whether GLP-1 receptor agonists might offer cardiovascular protection in RA patients. Asmaa Beltagy presented data from 2,449 RA patients over age 40, all receiving JAK inhibitors, with one group subsequently initiating GLP-1 receptor agonists while the other did not.
The study assessed primary outcomes within 5 years, including acute coronary syndromes, cerebral infarction, acute peripheral arterial thrombosis, deep venous thrombosis, and overall arterial events. Patients taking GLP-1 receptor agonists had significantly lower risk of acute coronary syndromes and deep venous thrombosis, with trends toward lower risk of acute cerebral infarction and peripheral arterial disease events, though these differences were not statistically significant.
Clinical Implications and Future Directions
The collective findings provide important real-world context for JAK inhibitor safety in RA treatment. While the cancer data appear reassuring overall, the elevated keratinocyte cancer risk supports recommendations for regular skin examinations in patients receiving JAK inhibitors.
The cardiovascular safety profile appears more favorable than suggested by ORAL Surveillance, particularly within the first two years of therapy. The potential cardioprotective effects of GLP-1 receptor agonists warrant further investigation as a possible risk mitigation strategy.
The authors note that additional analyses are planned, including incorporation of more registries to enhance statistical power and evaluation of cancer incidence across different exposure periods. These ongoing efforts will continue to refine understanding of JAK inhibitor safety in real-world clinical practice.
