JAKi and IL-4/-13i Show Similar Safety Profiles in AD

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Janus kinase inhibitors (JAKi) have emerged as an effective systemic therapy for moderate to severe atopic dermatitis (AD), offering rapid and substantial symptom relief for many patients. However, long-standing safety concerns—particularly regarding cardiovascular events and malignancies—have persisted since an elevated risk of these outcomes was observed in the ORAL Surveillance trial involving patients with rheumatoid arthritis (RA).¹ Importantly, the AD population differs from the RA population in key demographic and clinical aspects, raising questions about whether such risks are generalizable.²

AD itself is independently associated with increased risks of both cardiovascular disease and cancer, which complicates risk attribution.2 Given the therapeutic overlap and different mechanisms of action between JAKi and interleukin-4 and interleukin-13 inhibitors (IL-4/-13i), such as dupilumab, researchers aimed to assess whether treatment choice modifies these underlying risks.³

“In this large real-world study evaluating JAKi safety among adults with AD, we found no evidence of increased cardiovascular or cancer risk compared to IL-4/-13i,” researchers stated. “These findings are reassuring and align with AD trials and a substantial body of observational evidence from RA.”

Methods and Materials

To address this question, investigators conducted a large, retrospective cohort study using electronic health records from North American health care systems. The study population included adults (aged ≥18 years) diagnosed with AD and newly initiating either JAKi therapy (tofacitinib, upadacitinib, or abrocitinib) or IL-4/-13i therapy (dupilumab, lebrikizumab, or tralokinumab). The primary outcomes were incidence of coronary artery disease or stroke and any cancer. Secondary endpoints included individual analysis of coronary events, stroke, skin cancer, and 2 control outcomes—herpes zoster and conjunctivitis—to test the specificity of associations.

To reduce bias, 1:1 propensity score (PS) matching was used, balancing a comprehensive list of covariates such as age, sex, ethnicity, body mass index (BMI), inflammatory markers (e.g., CRP), cardiovascular risk factors, preexisting cancer, and proxies for AD severity. Patients were followed from drug initiation until the earliest of outcome occurrence, loss to follow-up, or study end. Those switching between the treatment groups during follow-up were excluded.

Results

A total of 1,978 patients starting JAKi were matched to an equal number initiating IL-4/-13i therapy. Across multiple time points—1, 3, and 5 years—researchers noted no statistically significant difference between the 2 groups in the incidence of cardiovascular events (hazard ratio [HR] 1.41; 95% confidence interval [CI], 0.78–2.56), overall cancer (HR 0.81; 95% CI, 0.60–1.08), or skin cancer (HR 1.07; 95% CI, 0.61–1.89). These findings remained consistent across sensitivity analyses excluding patients with prior outcomes and omitting events occurring in the first month of treatment.

Interestingly, JAKi users exhibited a higher risk of herpes zoster, an expected finding aligned with prior studies, while IL-4/-13i users had a greater incidence of conjunctivitis—again, consistent with established drug profiles. These control outcomes reinforce the reliability of the analytical approach.

Although this is the largest real-world comparative safety analysis of JAKi in AD to date, the limited number of adverse events constrains the statistical power to detect small differences in rare outcomes. Furthermore, as with any observational study, residual confounding cannot be entirely ruled out, and administrative data limitations—such as unclear treatment discontinuation dates—pose challenges.

Conclusion

Nonetheless, the use of an active comparator (IL-4/-13i) and rigorous methodological adjustments lend credibility to the conclusion. In this study, JAK inhibitors did not confer a higher risk of cardiovascular events or cancer in adults with AD compared to IL-4/-13 inhibitors. These results are consistent with clinical trial data and real-world evidence from other disease settings, offering a degree of reassurance for clinicians and patients considering JAKi therapy for AD.

Want to hear more pearls and expert insights on AD? Join us at the annual Revolutionizing Atopic Dermatitis Conference this June in Nashville, TN. Use code DT40 for 40% off your RAD 2025 registration.

References

1. Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022;386(4):316-326. doi:10.1056/NEJMoa2109927
2. Mansfield KE, Schmidt SAJ, Darvalics B, et al. Association between atopic eczema and cancer in England and Denmark. JAMA Dermatol. 2020;156(10):1086-1097. doi:10.1001/jamadermatol.2020.1948
3. Zhao SS, Hernandez G, Alam U. Risk of cardiovascular disease and cancer in patients initiating JAK versus IL-4/-13 inhibitors for atopic dermatitis. Int J Dermatol. Published online April 28, 2025. doi:10.1111/ijd.17815