DENVER — It is still wise to consider the safety of JAK inhibitors when prescribing these agents in dermatology. However, real-world and other evidence have emerged since a rheumatoid arthritis study prompted the addition of a stronger boxed warning for tofacitinib and the rest of this drug class in 2021.

Experts say these agents are generally safer in dermatology and can be prescribed appropriately to the right candidates screened to identify those who need closer monitoring because of elevated cardiovascular, malignancy, and other risks. 

A quick review of what prompted the concern: Researchers compared participants taking the JAK inhibitor tofacitinib to others taking a TNF inhibitor in the Oral Rheumatoid Arthritis Trial (ORAL) Surveillance trial, published in 2022, and found that tofacitinib was associated with an elevated rate of major adverse cardiovascular events (MACE) and did not meet noninferiority criteria compared with TNF inhibitors. Tofacitinib was also associated with a higher rate of malignancies, infections, and venous thrombotic events. 

Not an Apples-to-Apples Comparison

However, the ORAL Surveillance study population does not reflect most real-world dermatology patients, said Eingun James Song, MD, director of clinical research and co-chief medical officer for Frontier Dermatology in Mill Creek, Washington.

ORAL Surveillance evaluated patients with active rheumatoid arthritis whose mean age was 61, with one or more cardiovascular risk factors, including hypertension in about two thirds. In addition, a post hoc analysis revealed that most of the elevated risk in ORAL Surveillance was driven by the highest-risk patients: those aged 65 years or older who have ever smoked.

“The take-home here is this was not a typical dermatology population,” Song said here during a session on JAK inhibitors at the American Academy of Dermatology (AAD) 2026 Annual Meeting.

The biggest adverse event concerns were the three Cs: cardiac events, clots, and cancers, Song said. “But the risk is context-dependent” and not an absolute contraindication for JAK inhibitors.

“I never tell a patient these things cannot happen to you. These are important adverse effects, but they are rare,” Song added.

Start a simple conversation, recommended Diego Ruiz Dasilva, MD, director of the AAD session and assistant professor at Eastern Virginia Medical School in Norfolk, Virginia. For example, you can say, “There are a few situations where I have to be more careful with these medications. Do you have a history of clots, heart attack/stroke, or cancer?”

Baseline factors drive most of the risk, Song said, including age, smoking, and comorbidities. For a clearer picture, research should be adjusted for the incidence of a particular adverse event in the general population and among those treated and not treated with a JAK inhibitor.

What Dermatology Research Indicates

In a Danish registry and Danish Skin Cohort study, published in 2024, investigators found risks for adverse events already exist among more than 20,000 people with atopic dermatitis (AD) not exposed to treatment with a JAK inhibitor. Nonmodifiable risk factors included cancer in 5.6%, MACE in 2.6%, venous thromboembolism (VTE) in 2.0%, smoking history in 15.6%, and an age of 65 or older in 12.4%.

Experts evaluating the ORAL Surveillance findings suggest that extrapolating safety risks in an active rheumatoid arthritis population enriched for cardiovascular risks should not be extrapolated to dermatology. A 2024 systematic review and meta-analysis supports this, for example. Researchers included 12,996 patients with AD, alopecia areata, psoriasis, vitiligo, lichen planus, and hidradenitis suppurativa across 45 randomized controlled trials. They found no significant increase in MACE (relative risk [RR], 0.47) or VTE (RR, 0.46) between placebo and JAK inhibitor cohorts. Furthermore, they found no significant differences in serious adverse events or discontinuations between groups. 

Incidence rates of MACE, VTE, and malignancy —except for nonmelanoma skin cancer — in patients with moderate-to-severe AD who received up to 6 years of upadacitinib treatment “remained low and consistent with those observed in the overall population of patients with AD, regardless of cardiovascular risk category,” revealed a study by authors including Christopher G. Bunick, PhD, MD, associate professor of dermatology, at Yale University, New Haven, Connecticut, who also presented during the JAK inhibitor session.

“Across real-world cohorts, there is no consistent increase in MACE vs TNF inhibitors,” Song said. “The MACE risk is low in atopic dermatitis and differs from rheumatoid arthritis.”

In addition, another trial conducted after ORAL Surveillance, a 2023 report in patients with rheumatoid arthritis, found no signal for increased MACE, malignancy, VTE, or serious infections — with the exception of herpes zoster — with the JAK inhibitor upadacitinib vs the TNF blocker adalimumab. Again, the risk was greatest among older participants.

An increased risk for herpes zoster is a class effect of JAK inhibitors, Song said. “I always recommend the shingles vaccination.” Limiting corticosteroids, recommending smoking cessation, and checking blood pressure and lipid levels are additional strategies to reduce risk.

Very few patients with inflammatory skin diseases are poor candidates for JAK inhibition, Dasilva said. “JAKs are much safer than you think,” he added. “Do not hear black box and be scared.”

However, he advised, reconsidering JAK inhibitors in patients with a history of unprovoked VTE not taking anticoagulation; people with a history of MACE who are unable or unwilling to modify their risk factors; and those with active malignancy or a high risk for cancer recurrence.

Song reported being a member of the advisory board for Arcutis Biotherapeutics, Bristol Myers Squibb (BMS), Castle Biosciences Inc., and Dermavant Sciences; a consultant for Alphyn Biologics, Apogee Therapeutics, Boehringer Ingelheim, and Novartis; an investigator for AbbVie, Amgen, Apogee Therapeutics, Arcutis Biotherapeutics, ASLAN Pharmaceuticals, BMS, DermBiont, Incyte Corporation, Janssen, LEO Laboratories, Pfizer, Sun Pharmaceutical Industries, and Timber Pharmaceuticals; and a speaker or faculty educatorforAbbVie, Amgen, Eli Lilly, Galderma, Incyte Corporation, Janssen Biotech, Pfizer, Sanofi/Regeneron, Sun Pharmaceutical Industries, and UCB.

Dasilva disclosed being an advisory board member for Janssen; a speaker for Arcutis Biotherapeutics, Dermavant Sciences, Eli Lilly, Galderma, Leo Pharma, Pfizer, Sanofi/Regeneron, UCB, and Verrica Pharmaceuticals; and having a speaker/faculty education role for AbbVie.

Damian McNamara is a freelance contributor to Medscape Medical News. He worked full-time for Medscape and WebMD from 2018 to 2024. Damian has a BA in chemistry and an MA in science, health, and environmental reporting/journalism.