Rethinking the Black Box: JAK Inhibitors Find Their Place in Dermatology

In 2021, ruxolitinib cream became the first Janus kinase (JAK) inhibitor approved by the US Food and Drug Administration (FDA) in dermatology, marking the introduction of a new class of targeted, non-steroidal immunomodulators for inflammatory skin disease.1

In succeeding years, JAK inhibitors began to see an explosion in approvals, becoming known as central players in the management of conditions such as psoriasis, alopecia areata, and atopic dermatitis. Data supporting their use grew dramatically, with many seeing JAK inhibitors as representing the future of disease management.

However, clinicians and patients alike were soon faced with black box warnings on JAK inhibitors, largely resulting from research into safety concerns such as major adverse cardiovascular events (MACE).2 However, clinicians are increasingly contextualizing such safety warnings in light of real-world dermatologic data and an evolving understanding of these drugs’ use among patients of different age cohorts.

“We need to all have respect for black box warnings,” Shawn Kwatra, MD, chair of dermatology at the University of Maryland School of Medicine, said in an interview with HCPLive. “But context matters.”

In this editorial feature, HCPLive spoke with several experts in the space to provide commentary on the evolution of JAK inhibitor perceptions in dermatology, from the initial excitement surrounding JAK inhibitors, the subsequent caution due to black box warnings, and the newfound confidence expressed in recent months, grounded in real-world data.

Early Adoption of JAK Inhibition in Dermatology

“They’ve raised the bar—they’re showing us what rapid and meaningful change looks like, not just getting you a little bit better, but restoring lives,” Kwatra explained.

JAK inhibitors, sometimes referred to as JAKis, are small-molecule drugs designed to target the intracellular signaling pathways linking cytokines to inflammatory gene expression. They act on members of the JAK family: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2).

JAKis can help to disrupt multiple pro-inflammatory signals simultaneously among patients with diseases such as alopecia areata, atopic dermatitis, and psoriasis, thereby dampening immune activity. These medications are engineered for selectivity, to balance efficacy with safety. JAK inhibitors differ from biologics in both mechanism and speed, serving effectively as “conductors” to help rebalance multiple cytokine pathways, as opposed to single targets.

Several JAKi have been approved across a spectrum of cutaneous and nondermatologic diseases in adults. Ruxolitinib was the first JAKi to earn FDA approval in November 2011 for adults with graft-versus-host disease. One year later, tofacitinib was approved for rheumatoid arthritis. Both drugs were later found to inhibit the pathways driving atopy, plaque psoriasis, alopecia areata, and vitiligo.

Other JAKi, including baricitinib, upadacitinib, abrocitinib, and deucravacitinib, have subsequently gained approval in the US for patients over the age of 18 years. Following the approval of ruxolitinib, JAK inhibitors expanded across multiple indications, and both topical and oral formulations now play roles in atopic dermatitis, alopecia areata, and vitiligo. Kwatra highlighted the expansion of JAK inhibitors across multiple dermatologic conditions, noting the expanded use of these treatments alongside the increasing amount of data on their use.

In atopic dermatitis, JAKis have allowed for meaningful relief for patients who do not respond to biologics. Among those with alopecia areata, JAK inhibitors have opened what Kwatra referred to as “the first real pathway we’ve ever had to regrow hair.” In the vitiligo space, topical ruxolitinib and emerging oral formulations have begun producing visible repigmentation in patients. Even for those suffering from hidradenitis suppurativa (HS), an area of focus in Kwatra’s Baltimore clinic, off-label utilization of JAKs led to substantial results.

Ruxolitinib was approved for mild-to-moderate atopic dermatitis for patients 12 years and older, and upadacitinib and abrocitinib received similar approvals. Baricitinib and ritlecitinib and deuruxolitinib were approved alopecia areata. In short, the armamentarium for inflammatory diseases expanded dramatically thanks to this new treatment class.

“Clinicians now have real-world patients whose lives have been changed. Patients themselves are oftentimes the most powerful advocates—they’ll tell you, ‘I can finally sleep, I can finally feel like myself again,’” Kwatra expressed.

Evolving Concerns Over Black Box Warnings

Despite the rapid expansion of research on JAKi use in dermatology and other fields, as well as a growing number of studies into their efficacy, 1 study in February 2021 dealt a major blow to JAK progress across medical fields.

At this point, preliminary safety results were released from the ORAL Surveillance trial of tofacitinib in patients with rheumatoid arthritis (RA).2,3 The analysis had explored comparisons to tofacitinib with TNF inhibitors in older patients ≥50 years living with RA who had at least a single cardiovascular risk factor. Increased rates of cardiovascular events, malignancy, and all-cause mortality in those treated with tofacitinib were highlighted, preceding the FDA decision to formally require black box warnings for tofacitinib, upadacitinib, and baricitinib.2

This caution was thereby extended to all oral systemic JAK inhibitors approved for inflammatory diseases. Given the addition of this label, patients treated with such medications were now given an overt warning of risks of MACE, cancer (particularly lymphoma and lung cancer), mortality, and blood clots.

This decision by FDA officials had the effect of shifting the landscape of JAK inhibitor perceptions, with these cardiovascular risk data being extrapolated from a high-risk RA population to much broader groups of patients given the option to use JAKis.

In an additional blow to JAKi perceptions, in November 2022, the European Medicines Agency (EMA) updated its inhibitor recommendations. The agency suggested the treatment should only be prescribed for individuals at high risk if there are no suitable alternatives available.3 Thus, another blow was struck.

Real-World Data on JAK Inhibitor Safety

In the years since the black box warnings’ announcement, however, dermatologists sought to contextualize concerns; the data leading to this decision was collected on an older cohort of patients ≥50 years with at least 1 cardiovascular risk factor at the outset.4

The need for long-term safety data on JAK inhibitors to address patients' justifiable concerns became apparent. Researchers began to explore cardiovascular safety in JAK inhibitors rapidly, seeking to expand upon these ORAL Surveillance trial data and improve patient understanding of the context of the FDA’s black box warnings.

In 1 systematic review of 43 studies on JAKi safety in those living with inflammatory skin diseases, real-world data demonstrated low incidence rates of serious adverse events.6 These events included MACE, thromboembolism, and malignancies.

New studies began to help contextualize the previous cardiovascular safety findings on JAKs. In another notable example, Christopher G. Bunick, MD, PhD, associate professor of dermatology at Yale School of Medicine, spoke with HCPLive about his team’s findings.7 These data, presented at the European Academy of Dermatology and Venereology (EADV) 2025 Congress, highlighted upadacitinib’s safety in a US atopic dermatitis population.

“These medicines are incredibly safe with very low rates of MACE, VTE, and malignancy,” Bunick noted, highlighting large-scale trial data in the Measure Up 1, Measure Up 2, and AD Up, studies on upadacitinib. Bunick et al noted the significantly low incidence of venous thromboembolism (VTE), MACE, and malignancy, even among participants with existing cardiovascular comorbidities.

Study populations included those with diabetes, hypertension, smoking history, and oral contraceptive use, each known to potentially be factors otherwise elevating patients’ risk. Yet these findings demonstrated treatment with upadacitinib did not increase cardiovascular events, reinforcing this JAK inhibitor’s favorable benefit–risk balance.

Bunick’s interpretation aligned with a growing consensus suggesting the early safety concerns surrounding JAKi use, largely derived from studies in older, high-risk individuals with RA, did not represent the whole picture. While often discussed as a single class, JAKis can differ significantly in their selectivity for JAK1, JAK2, JAK3, or TYK2. This type of selectivity can drive much of the observed differences in safety findings.

Additional data on treatments such as deucravacitinib for psoriasis, falling within the JAK family, have come to light. These findings have helped to expand dermatologists’ broader understanding of JAKs’ place in the lineup of treatment options for patients with inflammatory disease.8

Milaan Shah, MD, a dermatology resident at the Medical University of South Carolina, Charleston, took part in the Delphi-method expert consensus panel providing guidance to clinicians on deucravacitinib.9 Shah spoke with HCPLive about this panel and its review of deucravacitinib’s efficacy and adverse-event evidence, resulting in practical guidance for dermatologists.

Deucravacitinib, though technically a JAK-family agent targeting TYK2, demonstrated a strong safety profile, owing to its allosteric mechanism and extreme selectivity. The findings of this panel help to demonstrate the ways in which mechanistic refinements within the JAK family have advanced both safety and clinical confidence.

“By definition, deucravacitinib falls under the JAK inhibitor family—but there are so many differences in its safety profile that we made the statement it has a superior safety profile to traditional JAK inhibitors,” Shah said.

Shah’s commentary suggests the evolving JAK landscape has seen greater molecular precision translating into tangible clinical safety. This could potentially serve as a notable counterpoint to the lingering class-wide caution prompted by earlier, less-selective agents.

JAK Inhibitors in 2025 and Beyond

In 2025, with the emergence of real-world data, clinicians' perception has commonly become one of cautious optimism. Improved understanding of the context behind the boxed warnings is becoming increasingly widespread, and for many dermatologists, it sheds new light on this medication class.

A growing number of clinicians have come to see the notable efficacy findings resulting from research on JAKi use in dermatology. Evidence on the potential cardioprotective benefits of JAK inhibitors in patients with atopic dermatitis, stemming from the systemic anti-inflammatory properties of the drug class, has also become more widely discussed.8

As safety concerns have been increasingly addressed by a growing number of long-term analyses, JAKs have also continued to be approved for dermatologic diseases.

Most recently, ruxolitinib cream was approved by the FDA in September 2025 for children aged 2 - 11 years with moderate-to-severe atopic dermatitis.10 In the announcement, the drug is indicated for the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised children ≥ 2 years of age whose condition has not been well controlled with topical drugs, or when such medications are not recommended.

Ruxolitinib cream 1.5% had already been FDA-approved for the short-term, non-continuous treatment of those aged 12 years and older with mild to moderate atopic dermatitis. This expansion of the drug’s indication helps to reinforce the increasing acceptance of JAK pathway modulation in the field, including in younger ages and less-severe disease settings.

“If we look five, ten years ahead and beyond, I think JAK inhibitors will absolutely be part of the permanent landscape of dermatology,” Kwatra explained in his HCPLive interview. “I don’t see them disappearing. I see them finding their niche. JAK inhibitors have raised the bar; they’ve shown us what rapid and meaningful change looks like...They’re pushing our field toward therapies that aren’t just getting you a little better, but restoring lives.”

As new clinical data and real-world findings continue to converge in the dermatology space, JAK inhibitors appear primed to remain integral to dermatologic innovation, potentially helping clinicians to bridge the gap between efficacy and safety.

References

1. Incyte Announces Additional FDA Approval of Opzelura® (Ruxolitinib) Cream in Children Ages 2-11 with Atopic Dermatitis. Incyte. September 18, 2025. Accessed October 21, 2025. https://investor.incyte.com/news-releases/news-release-details/incyte-announces-additional-fda-approval-opzelurar-ruxolitinib

2. FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. FDA. January 14, 2022. Accessed October 21, 2025. https://www.fda.gov/drugs/fda-drug-safety-podcasts/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death

3. The Lancet Gastroenterology Hepatology. New restrictions on JAK inhibitors in the EU. Lancet Gastroenterol Hepatol. 2023 Jan;8(1):1. doi: 10.1016/S2468-1253(22)00397-1. PMID: 36495898.

4. Bukhari M, Bergman M, Giles JT, et al. Safety of jakinibs: lessons from ORAL Surveillance, Rheumatology, Volume 61, Issue 11, November 2022, Pages 4223–4225, https://doi.org/10.1093/rheumatology/keac166.

5. Tomelleri A, Benanti G, Dagna L. The impact of 2023 EMA recommendations on patients treated with JAK inhibitors: real-life experience from a prospective monocentric cohort. Rheumatology (Oxford). 2024 Feb 1;63(2):e39-e42. doi: 10.1093/rheumatology/kead395. PMID: 37522875; PMCID: PMC10836993.

6. Smith T. Real-World Findings on Incidence of Adverse Events Highlighted for JAK Inhibitors. HCPLive. October 6, 2025. Accessed October 21, 2025. https://www.hcplive.com/view/real-world-findings-incidence-adverse-events-highlighted-jak-inhibitors.

7. Bunick C. Cardiovascular Risk and Upadacitinib Treatment for Atopic Dermatitis, With Christopher Bunick, MD, PhD. HCPLive. September 19, 2025. Accessed October 21, 2025. https://www.hcplive.com/view/cardiovascular-risk-upadacitinib-treatment-atopic-dermatitis-christopher-bunick-md-phd.

8. Bunick C, Ackerman L. Understanding the Safety Profile of Oral JAK Inhibitors in Atopic Dermatitis. HCPLive. July 17, 2025. Accessed October 21, 2025. https://www.hcplive.com/view/understanding-the-safety-profile-of-oral-jak-inhibitors-in-atopic-dermatitis.

9. Shah M. Efficacy, Safety of Deucravacitinib for Psoriasis, with Milaan Shah, MD. HCPLive. June 13, 2025. Accessed October 21, 2025. https://www.hcplive.com/view/efficacy-safety-deucravacitinib-psoriasis-milaan-shah-md.

10. Incytye. Incyte Announces Additional FDA Approval of Opzelura® (Ruxolitinib) Cream in Children Ages 2-11 with Atopic Dermatitis. September 18, 2025. Accessed October 21, 2025. https://investor.incyte.com/news-releases/news-release-details/incyte-announces-additional-fda-approval-opzelurar-ruxolitinib.