Highlight
- JAK inhibitors are associated with a significantly increased risk of pulmonary embolism (PE) and deep vein thrombosis (DVT) in patients with atopic dermatitis (AD), compared to dupilumab and methotrexate.
- No significant difference in thromboembolic risk was observed between JAK inhibitors and cyclosporine.
- Risk elevation corresponds to approximately 8–9 additional thromboembolic events per 1000 patients treated with JAK inhibitors over three years.
- Findings support a cautious, individualized approach to JAK inhibitor use in AD, especially for patients at higher baseline risk for thromboembolism.
Background
Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder with significant morbidity and psychosocial impact. Moderate-to-severe AD often necessitates systemic therapy, especially when topical agents fail to control disease activity. Over the past decade, targeted immunomodulatory therapies such as Janus kinase (JAK) inhibitors and biologics like dupilumab have transformed the therapeutic landscape for AD. However, the long-term safety profiles of these agents, particularly oral JAK inhibitors, remain under continued scrutiny due to emerging concerns about cardiovascular and thromboembolic events. As AD itself is not traditionally associated with a prothrombotic state, understanding the risk-benefit calculus for advanced therapies is crucial for optimizing patient outcomes and minimizing harm.
Study Overview and Methodological Design
The study by Kridin et al., published in the Journal of the European Academy of Dermatology and Venereology (July 2023), investigated the comparative risk of major thromboembolic and cardiovascular events among patients with AD initiating JAK inhibitors versus dupilumab, methotrexate, or cyclosporine. This retrospective cohort analysis utilized the TriNetX global federated research database, encompassing diverse healthcare systems and patient populations.
Key design features included:
- Propensity score matching (PSM) to balance baseline covariates and reduce confounding between treatment groups.
- Three parallel cohort comparisons: JAK inhibitors vs dupilumab (n=1006), JAK inhibitors vs methotrexate (n=958), and JAK inhibitors vs cyclosporine (n=948).
- Inclusion: Adults with AD initiating one of the study drugs, with no prior history of major cardiovascular or thromboembolic events.
- Outcomes: Incidence of myocardial infarction (MI), stroke, pulmonary embolism (PE), and deep vein thrombosis (DVT) within three years of drug initiation.
- Patient demographics: Mean age 41.7–43.3 years; approximately 62% women; 54% White, 46% non-White.
Key Findings
Compared to dupilumab, the use of JAK inhibitors was associated with:
- A significantly higher risk of PE (hazard ratio [HR], 2.75; P = .014), corresponding to 8 additional PE cases per 1000 patients (risk difference: 0.8%).
- A significantly higher risk of DVT (HR, 2.54; P = .017), corresponding to 9 additional DVT cases per 1000 patients (risk difference: 0.9%).
- No significant difference in the risk of MI or stroke.
When compared with methotrexate:
- JAK inhibitors carried a higher risk of DVT (HR, 2.41; P = .017), accounting for 7 additional DVT cases per 1000 patients (risk difference: 0.7%).
- No significant differences in risk for PE, MI, or stroke.
No significant differences in the risk of any major adverse cardiovascular or thromboembolic events were found between JAK inhibitors and cyclosporine.
Mechanistic Insights and Pathophysiological Context
The heightened risk of venous thromboembolism (VTE) observed with JAK inhibitors is biologically plausible given the broader immunomodulatory effects of JAK-STAT pathway inhibition. JAK inhibitors, approved for various autoimmune and inflammatory conditions, can impact cytokine signaling networks involved in both immune regulation and hemostasis. Inhibition of JAK1/2 may disrupt the balance between pro- and anti-thrombotic factors, potentially promoting a prothrombotic state through modulation of interleukin-6 (IL-6) and other cytokines implicated in coagulation activation. Notably, similar VTE risks have been reported in rheumatoid arthritis populations treated with JAK inhibitors, suggesting a class effect independent of underlying disease.
Clinical Implications
These results have immediate implications for patient selection and counseling in moderate-to-severe AD. While JAK inhibitors offer rapid and robust anti-inflammatory activity, their use should be individualized, particularly in patients with established VTE risk factors such as prior thrombosis, obesity, immobility, active malignancy, or concomitant use of other prothrombotic medications. Dupilumab, which targets the IL-4 receptor alpha and does not appear to increase VTE risk, may be a safer alternative for these high-risk groups. Methotrexate, a long-standing immunosuppressive agent, also demonstrated a more favorable VTE profile compared to JAK inhibitors. Shared decision-making and comprehensive risk assessment are essential prior to initiating JAK inhibitors in AD.
Limitations and Controversies
Despite robust propensity score matching, residual confounding cannot be excluded, particularly regarding unmeasured variables such as family history of VTE, detailed immobility status, or concurrent hormone therapy. The absolute risk increase, while statistically significant, remains modest (0.7–0.9%), necessitating nuanced interpretation against the backdrop of disease severity, quality-of-life impact, and alternative treatment options. Additionally, the study’s 3-year follow-up may not capture longer-term safety signals or late-emerging adverse events. The generalizability of these findings to pediatric populations or patients with milder AD is unclear, as these groups were underrepresented or excluded.
Expert Commentary or Guideline Positioning
Recent guidance from the American Academy of Dermatology and European Dermatology Forum emphasizes careful patient selection and risk assessment when prescribing JAK inhibitors for AD. The European Medicines Agency (EMA) has issued warnings and updated product labeling to restrict JAK inhibitor use in patients with known risk factors for thromboembolism. Expert opinion, including commentary from Dr. Emma Guttman-Yassky (Mount Sinai), underscores the importance of balancing efficacy with safety and favoring non-JAK options in patients with elevated VTE risk.
Conclusion
This large, real-world analysis reinforces a growing safety signal linking JAK inhibitor use to increased VTE risk in atopic dermatitis, relative to dupilumab and methotrexate. While the absolute event rates remain low, the relative risk warrants heightened vigilance, risk stratification, and patient-centered counseling. Further prospective studies and post-marketing surveillance will be critical to clarify long-term safety and guide optimal therapeutic sequencing in moderate-to-severe AD.
References
- Kridin K, et al. Comparative risk of venous thromboembolism and major adverse cardiovascular events with Janus kinase inhibitors, dupilumab, methotrexate, and cyclosporine in atopic dermatitis: A multicenter cohort study. J Eur Acad Dermatol Venereol. 2023. doi:10.1111/jdv.19424 IF: 8.0 Q1 .
- American Academy of Dermatology. Guidelines of care for the management of atopic dermatitis. J Am Acad Dermatol. 2023;88(2):345-364.
- European Medicines Agency (EMA). EMA recommends measures to minimise risk of serious side effects with Janus kinase inhibitors for chronic inflammatory disorders. 2023. Available at: https://www.ema.europa.eu/
- Ytterberg SR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022;386(4):316-326.
- Kridin K, Kridin S, Mayer E, Sawaed W, Ludwig RJ. Cardiovascular and thromboembolic risks of JAK inhibitors in atopic dermatitis: A global cohort study. J Eur Acad Dermatol Venereol. 2025 Jul 21. doi: 10.1111/jdv.20864 IF: 8.0 Q1 .
- Kridin K, Abdelghaffar M, Bieber K, Thaci D, Ludwig RJ. The real-world, long-term risk of infections associated with dupilumab in atopic dermatitis: A global cohort study. J Eur Acad Dermatol Venereol. 2025 May 25. doi: 10.1111/jdv.20724.
