JAK Inhibitors Offer Hope for Hard-to-Treat Atopic Dermatitis but Carry Black-Box Warnings

Esther Landhuis

November 07, 2021

Just a few years after the successful launch of dupilumab (Dupixent), new biologics are expanding the treatment arsenal for serious cases of atopic dermatitis. Yet as these topical and oral JAK inhibitors pave the way to more personalized care, safety concerns and screening considerations make it challenging for doctors to discuss these new treatment options with patients.

"It's a hard conversation," said Jonathan Silverberg, MD, PhD, MPH, associate professor of dermatology at the George Washington University School of Medicine and Health Sciences in Washington, DC. "You need to know the data well and you need to really present everything as comprehensively as possible."

Emerging treatments for atopic dermatitis were a key focus at this year's American College of Allergy, Asthma & Immunology (ACAAI) meeting in New Orleans. The conference kicked off with a dermatology program in which Silverberg and others gave a rundown of the fast-evolving science and real-world use of these biologics.

Dupilumab is a monoclonal antibody that blocks signaling of two key cytokines (IL-4 and IL-13) implicated in multiple atopic diseases. The injectable is now approved for uncontrolled atopic dermatitis and asthma down to 6 years of age, and for adults with chronic rhinosinusitis with nasal polyposis. Additional approvals are expected in 2022 for atopic dermatitis in younger children (aged 6 months to 5 years) and for eosinophilic esophagitis, Mark Boguniewicz, MD, pediatric allergist and immunologist at National Jewish Health in Denver, told ACAAI attendees.

In September, the topical cream ruxolitinib (Opzelura) became the first JAK inhibitor to gain approval for atopic dermatitis (ages 12 and up). This class of drugs targets the JAK/STAT intracellular pathway, which transmits signals through various cytokines including the ones blocked by dupilumab. In pivotal trials of patients with mild to moderate eczema affecting up to 20% of body surface area, ruxolitinib was well-tolerated and showed clear efficacy on skin lesions, itch, and pain and outperformed the go-to topical steroid, triamcinolone 0.1% cream. Itch relief was "significant already by 12 hours after the initial application," Silverberg said, so "from the efficacy standpoint this starts to look like the Holy Grail of topical nonsteroidal medications for atopic dermatitis."

The bigger issue is safety. JAK inhibitors have FDA black-box warnings because they were found associated with rare but serious side effects including blood clots and cancer. "So it becomes a complicated shared decision-making conversation," said Silverberg, who has served as an investigator, advisory board member, or speaker for companies that develop JAK inhibitors. "On paper, this is the best topical we have. But when it comes to these rare safety concerns in the FDA labeling, it makes it look worse than all the others." Dupilumab has no black-box warnings.

Given these considerations, Silverberg said he has prescribed ruxolitinib mainly for eczema in sensitive areas such as the face, eyelids, genitals — areas where "we don't expect there to be very much systemic absorption."

On the heels of ruxolitinib, three oral JAK inhibitors — baricitinib, abrocitinib, and upadacitinib — await FDA approval for atopic dermatitis, showing similar promise and safety concerns.

In a systematic review and meta-analysis of nonsteroidal targeted therapies for moderate to severe atopic dermatitis, baricitinib (Olumiant) looked "a little bit less effective at the doses studied, compared to dupilumab," Silverberg said. The analysis, presented initially at the "Revolutionizing Atopic Dermatitis" virtual meeting in June, compared the therapies' impact on skin lesions and itch.

Abrocitinib (Cibinqo) was compared against the tried-and-true dupilumab in a phase 3 trial published this spring in the New England Journal of Medicine. At the 100-mg dose, it worked about as well as dupilumab but showed greater efficacy at 200 mg, particularly on itch relief at 2 weeks. The once-daily JAK inhibitor also showed safety and efficacy in 12-17 year-olds with moderate to severe eczema, and recently got licensed for this indication (ages 12 and up) in Great Britain.

Upadacitinib (Rinvoq) worked well, both alone and with topical steroids, in two phase 3 studies, and cleared eczema symptoms faster than dupilumab in a head-to-head comparison. In the meta-analysis, the lower dose of upadacitinib (15 mg) looked comparable to 200 mg abrocitinib but it outperformed all other biologics at the higher dose (30 mg). Upadacitinib "really seems to set the bar in terms of efficacy," Silverberg said. "We haven't seen numbers like this."

"It's a really exciting time for atopic dermatitis," Marcella Aquino, MD, pediatric allergist at Hasbro Children's Hospital in Providence, Rhode Island, told Medscape Medical News. "There are so many options for patients now — many more systemic options than were available even 5 years ago."

Silverberg is a speaker, advisory board member, and/or investigator for AbbVie, Afyx, Aobiome, Arena, Asana, BioMX, Bluefin, Bodewell, Boehringer Ingelheim, Celgene, Dermavant, Dermira, Eli Lilly, Galderma, GlaxoSmithKline, Incyte, Kiniksa, Leo, Luna, Menlo, Novartis, Pfizer, RAPT, Regeneron, and Sanofi-Genzyme. Boguniewicz is an investigator for Regeneron and Incyte and has served on advisory boards for Regeneron, Sanofi-Genzyme, AbbVie, Leo, Lilly, Pfizer, and Janssen. Aquino has disclosed no relevant financial relationships.

American College of Allergy, Asthma & Immunology (ACAAI) 2021 Annual Scientific Meeting. Presented November 4, 2021.

Esther Landhuis is a freelance science journalist in the San Francisco Bay Area. She can be found on Twitter  @elandhuis .

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