JAKi for Atopic Dermatitis Comparable to IL-4, IL-13 Inhibitors in Cancer, Heart Disease Risk

Individuals with atopic dermatitis who initiate systemic Janus kinase (JAK)-inhibitors are not at greater risk of developing cardiovascular disease or cancer compared to those initiating interleukin (IL)-4 or IL-13 inhibitors, recent data suggest.¹

These data comparing rates of risk between these 2 patient groups were the result of a recent study authored by investigators such as Sizheng Steven Zhao, MBChB, PhD, a clinical senior lecturer and consultant rheumatologist at the University of Manchester’s Centre for Musculoskeletal Research.

Zhao and colleagues highlighted the well-known efficacy of JAK inhibitors (JAKi) for patients living with atopic dermatitis. They added, however, that cardiovascular and cancer risk concerns have remained persistent, given a prior study pointing to increased risk among patients with rheumatoid arthritis (RA).²

“While the RA and [atopic dermatitis] populations likely differ, [atopic dermatitis] is independently associated with an increased risk of cardiovascular disease and cancer compared with the general population,” Zhao and coauthors wrote.^1,3 “We aimed to compare the risk of cardiovascular disease and cancer between individuals starting systemic JAKi versus IL-4/-13 inhibitors (IL-4/-13i).”

The investigative team used electronic health record data from healthcare systems primarily located in North America to conduct this cohort study. Those deemed eligible to be participants were required to be adults aged ≥18 years and to have an ICD-10 diagnosis code for atopic dermatitis. They also had to have initiated treatment with either a JAKi such as upadacitinib, tofacitinib, or abrocitinib or to have initiated an IL-4/IL-13 inhibitor such as lebrikizumab, dupilumab, or tralokinumab.

The main outcomes Zhao et al assessed were the occurrence of coronary artery disease or stroke, and the incidence of any form of cancer among patients. In their evaluation of secondary endpoints, outcomes included coronary artery disease alone, skin cancer, stroke alone, and 2 control outcomes—herpes zoster and conjunctivitis.

The investigative team applied 1:1 propensity score (PS)-matched Cox proportional hazards models to draw comparisons of time-to-event outcomes between treatment cohorts in their analysis. Zhao and colleagues included matching variables such as participants’ sex, age at initiation of treatment, sex, and ethnicity. The team assessed other covariates within the 12 months before initiation of these medications, including C-reactive protein (CRP) levels, ischemic heart disease, body mass index (BMI), cerebrovascular disease, cardiovascular risk factors, proxies for atopic dermatitis severity, and cancer history.

Zhao and coauthors’ follow-up period continued until the last available record or the conclusion of the study period, whichever occurred first. Individuals involved in the analysis who shifted to 1 drug from another treatment class during follow-up were not included. The analyses were repeated for 1-, 3-, and 5-year follow-up intervals, with investigators hoping to address potential differences in exposure duration. They also conducted sensitivity analyses, excluding participants who reported a prior history of the outcome of interest. They would also remove events that took place within the first month of follow-up to limit reverse causation.

In total, there were 1978 subjects who began using a JAK inhibitor and were successfully matched to 1978 IL-4/IL-13 inhibitor initiators. Mean follow-up duration was shown by the investigative team to have been slightly longer for IL-4/IL-13 inhibitor users (e.g., 291 days versus 264 days at the 1-year timepoint). All covariates at the point of baseline were well-balanced across the different cohorts of patients. Overall, the team found no statistically significant differences observed between drug classes in risk of any cancers (HR 0.81; 95% CI 0.60–1.08), cardiovascular events (HR 1.41; 95% CI 0.78–2.56), or skin cancers specifically (HR 1.07; 95% CI 0.61–1.89).¹

Zhao et al’s findings in this study were consistent across 1-, 3-, and 5-year follow-up periods and across their sensitivity analyses. However, JAKi therapy was linked with a decreased risk of conjunctivitis and an increased risk of herpes zoster. Nevertheless, this large real-world study’s findings indicate that, among adult patients with atopic dermatitis, JAK inhibitors do not appear to raise their risk of developing cardiovascular disease or cancer when compared with IL-4/IL-13 inhibitors.¹

Such conclusions may allow for reassurance among patients and clinicians, and the findings were consistent with both atopic dermatitis clinical trial data and previous observational research in RA. The investigators did acknowledge, however, the relatively limited number of outcome events and the consequent constraint on the data’s statistical power, highlighting the value of continued monitoring and replication in future studies.

“The main limitation is the inability to accurately ascertain the drug cessation date using administrative data and the differences in follow-up time between exposure groups,” Zhao et al concluded.¹ “However, results were similar across different durations of follow-up. As with all observational studies, residual confounding may bias our results. Nonetheless, reassurance comes from using IL-4/-13i as an active comparator and from the use of control outcomes.”

References

1. 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. 2025 Apr 28. doi: 10.1111/ijd.17815. Epub ahead of print. PMID: 40293104. Accessed September 5, 2025.

2. Ytterberg SR, Bhatt DL, Mikuls TR, Connell CA, et al; ORAL Surveillance Investigators. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med. 2022 Jan 27;386(4):316-326. doi: 10.1056/NEJMoa2109927. PMID: 35081280. Accessed September 5, 2025.

3. Silverwood RJ, Forbes HJ, Langan SM, et al. Severe and predominantly active atopic eczema in adulthood and long term risk of cardiovascular disease: population based cohort study. BMJ. 2018 May 23;361:k1786. doi: 10.1136/bmj.k1786. PMID: 29792314; PMCID: PMC6190010. Accessed September 5, 2025.