Experts Herald “Year of the JAK Inhibitor” in Dermatology

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A symposium at the American Academy of Dermatology 2023 Annual Meeting convened speakers who presented current data on the use of Janus kinase (JAK) inhibitors in dermatology, including in atopic dermatitis (AD) and vitiligo.

Brett Andrew King, MD, PhD, of Yale School of Medicine, kicked off the session by announcing “the year of the JAK inhibitor”: After 3 or 4 years of symposia touting JAK inhibitors as the future, they are now here, with 6 FDA approvals in the past 18 months. He promised a lineup of speakers who would present not only clinical trial results but also pearls about treatment algorithms and important safety information, because if dermatologists do not feel comfortable prescribing JAK inhibitors for their patients, “we’re never going to enjoy watching countless patients get better in ways that only JAK inhibitors provide the ability to do.”

King set the stage for the speakers to follow by summarizing what makes JAK inhibitors so effective for so many inflammatory skin diseases. JAK inhibitors, which are small-molecule drugs that can be oral or topical, modulate the cytokines that signal through the JAK/STAT pathway, many of which are drivers of skin disease.

In a presentation peppered with clips from Quentin Tarantino films, Raj J. Chovatiya, MD, PhD, of Northwestern University Feinberg School of Medicine, likened the intriguing promise of JAK inhibitors for AD to the tantalizing contents of the briefcase in Pulp Fiction. AD is driven by a complex interplay of immune dysregulation and barrier dysfunction, he explained, and traditional treatment pathways have involved steroids, which carry safety concerns, and biologics, which don’t work well for everyone and must be refrigerated before injection.

Enter the JAK inhibitors, Chovatiya announced, set to a shot of the criminals from Reservoir Dogs strolling down the street. One such therapy, ruxolitinib 1.5% cream, kicked off the wave of JAK inhibitor approvals when it was green-lit in 2021, bolstered by phase 3 trial findings showing that the majority of patients achieved the primary end point of a 75% improvement in Eczema Area and Severity Index score. Participants reported a rapid reduction in itching, with encouraging safety signals, and long-term response appeared durable.

He also covered the oral JAK inhibitors upadacitinib and abrocitinib, both approved in January 2022, which have yielded similar efficacy and appear superior to dupilumab, with abrocitinib provoking response in patients who did not respond to prior treatment with dupilumab. These oral therapies are ideal for patients with severe, flaring disease who require rapid control of symptoms, he noted, and patients like the convenience of oral therapy.

JAK inhibitors can’t exactly be called new anymore, Chovatiya concluded, “but they’re a great new tool in our armamentarium and a really welcome addition.”

Another setting where JAK inhibitors are making a splash is in treatment of vitiligo, according to Amit G. Pandya, MD, of University of Texas Southwestern Medical Center and Palo Alto Foundation Medical Group. In his 30 years of practice, this is the most exciting time of his career, he said, because never before has there been an approved medication for vitiligo. Now, with the July 2022 approval of ruxolitinib 1.5% cream, the entire vitiligo community is excited.

Vitiligo differs from other skin diseases like psoriasis and AD because removing the inflammatory infiltrate is not sufficient; skin affected by vitiligo requires stimulation of melanocytes to recover. The 3 pillars of vitiligo treatment are reducing triggers, increasing melanocytes, and lessening the immune attack on skin, and the latter pillar is where JAK inhibitors have come to outshine the mainstays of corticosteroids, tacrolimus, and pimecrolimus.

Pandya cited findings from a phase 2 trial of topical ruxolitinib among patients with severe vitiligo, on which he was a coauthor.¹ After 1 year, more than half had achieved at least a 75% improvement in facial Vitiligo Area Scoring Index (F-VASI) score—an important end point, as patients generally believe repigmentation of 75% to 80% to be clinically relevant.

He showed the dramatic improvement in one of his own patients who participated in the trial, narrating, “I held her hand for 6 months,… she hung in there, she went on the higher dose, and she was delighted with this 93% improvement.… It changes a person’s life.”

The need for patience was a common theme across several of the JAK inhibitors Pandya discussed, as he noted that a trial of oral ritlecitinib showed that only 11.7% of participants achieved a 75% or greater improvement in F-VASI at 24 weeks, but there was much more improvement in the extension period that followed, culminating in a mean 66% reduction in F-VASI from baseline to 48 weeks.²

Another recurring theme was the power of phototherapy (narrow-band UV-B light) to really “rev up the melanocytes” and provoke a greater response than with a JAK inhibitor alone. In summary, Pandya said, “the JAK inhibitors inhibit these pathogenic T cells, their use shows promise in the treatment of vitiligo, it is very much likely optimized when you use UV light exposure, and multiple studies are currently underway to determine the optimal inhibitor method of delivery, dosing, and use of combination therapy.”

He closed by acknowledging all those who had worked together for years to help the vitiligo community, and he suggested that attendees direct their patients with vitiligo to trusted resources like the Global Vitiligo Foundation website for information.

References

1. Rosmarin D, Pandya AG, Lebwohl M, et al. Ruxolitinib cream for treatment of vitiligo: a randomized, controlled, phase 2 trial. Lancet. 2020;396(10244):110-120. doi:10.1016/S0140-6736(20)30609-7

2. Ezzedine K, Peeva E, Yamaguchi Y, et al. Efficacy and safety of oral ritlecitinib for the treatment of active nonsegmental vitiligo: a randomized phase 2b clinical trial. J Am Acad Dermatol. 2023;88(2):395-403. doi:10.1016/j.jaad.2022.11.005