ABCs in Dermatology: Rethinking JAK Inhibitor Safety in Atopic Dermatitis

Boxed warnings drawn from a rheumatoid arthritis trial still shape Janus kinase (JAK) inhibitor prescribing in atopic dermatitis, even as long-term dermatology data show few new safety signals.

In this episode of ABCs in Dermatology, hosts Lindsay Ackerman, MD, and Chris Bunick, MD, PhD, examined how far ORAL Surveillance findings extend to JAK inhibition in atopic dermatitis.

ORAL Surveillance randomized patients with rheumatoid arthritis aged 50 years or older with at least 1 cardiovascular risk factor to tofacitinib (Xeljanz) or a tumor necrosis factor inhibitor.¹ Tofacitinib missed noninferiority for major adverse cardiovascular events (MACE; HR, 1.33; 95% CI, 0.91-1.94) and cancer (HR, 1.48; 95% CI, 1.04-2.09).¹ The open-label design lacked a placebo arm, and post hoc analyses tied risk to age 65 years or older, smoking, and baseline cardiovascular burden.²

Tofacitinib inhibits all 4 JAK family enzymes, whereas upadacitinib (Rinvoq) and abrocitinib (Cibinqo) selectively target JAK1, which carries IL-4 and IL-13 signaling. Concomitant methotrexate and systemic corticosteroid use in ORAL Surveillance further separates its population from typical atopic dermatitis patients.

Across 6 years of phase 3 data, adjudicated MACE rates with upadacitinib were 0.2 and less than 0.1 per 100 patient-years at 15 mg and 30 mg, respectively.³ Venous thromboembolism occurred at 0.1 per 100 patient-years with both doses, and malignancy excluding nonmelanoma skin cancer at 0.3 and 0.5.³ Herpes zoster, hepatic disorders, neutropenia, and creatine phosphokinase elevation proved dose-dependent.³

In the phase 3b TRuE-AD4 trial, 241 adults with moderate disease on 10% to 20% of body surface area, after topical corticosteroid and calcineurin inhibitor failure, applied ruxolitinib cream (Opzelura) 1.5% or vehicle twice daily. At week 8, Investigator's Global Assessment success reached 61.3% vs 13.6%, with no serious treatment-related adverse events.⁴

Plasma ruxolitinib concentrations stayed well below levels associated with JAK-mediated myelosuppression and declined between weeks 2 and 8, consistent with barrier recovery limiting absorption. Herpes zoster remains the most consistent oral JAK signal, likely reflecting interferon gamma inhibition, and recombinant zoster vaccination offers a modifiable safeguard.

Risk rises with age, so screening for clotting, cancer, cardiovascular disease, and broader clinical context helps individualize decisions. Prior thrombosis managed with anticoagulation need not exclude a patient. Retrospective database analyses warrant methodological scrutiny before shaping practice.

Collectively, the evidence suggests JAK inhibitor risk in atopic dermatitis tracks more closely with patient age and comorbidity than with drug class. Continued long-term surveillance will show whether class-wide labeling fits dermatology.

Relevant disclosures for Bunick include AbbVie, South Beach Symposium, Almirall, Apogee Therapeutics, Arcutis Biotherapeutics, Daiichi Sankyo, Eli Lilly, LEO Pharma, US, Novan, Novartis, Ortho Dermatologics, Palvella Therapeutics, Pfizer Inc., Sanofi, Sun Pharmaceutical Industries Ltd., Timber Pharmaceuticals, and UCB. Relevant disclosures for Ackerman include AbbVie, Alumis, Amgen, Arcutis, Beiersdorf, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Galderma, L'Oréal, Novartis, Sun Pharmaceutical, and UCB.

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. Szekanecz Z, Buch MH, Charles-Schoeman C, et al. Efficacy and safety of JAK inhibitors in rheumatoid arthritis: update for the practising clinician. Nat Rev Rheumatol. 2024;20(2):101-115. doi:10.1038/s41584-023-01062-9

3. Bunick CG, Irvine AD, Silverberg JI, et al. Safety of upadacitinib in atopic dermatitis in randomized clinical trials across 6 years. J Eur Acad Dermatol Venereol. 2026;40(5):856-866. doi:10.1111/jdv.70172

4. Carrascosa JM, Prajapati VH, Hong HC, et al. Ruxolitinib cream in adults with moderate atopic dermatitis after failure of other topicals: a randomized trial. J Eur Acad Dermatol Venereol. Published online July 20, 2026. doi:10.1111/jdv.70595