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The unprecedented number of targeted systemic therapies for moderate-to-severe refractory atopic dermatitis (AD) is revolutionizing treatment and elevating the standard of care, experts said.

"It's really been a breakthrough with the introduction of dupilumab [Dupixent] and these newer therapies in terms of bringing greater depths of symptom control, as well as better long-term disease control," Lawrence F. Eichenfield, MD, of the University of California San Diego in La Jolla, told MedPage Today.

Dupilumab, an interleukin (IL)-4/IL-13-directed biologic approved by the FDA in 2017 for use in adults with moderate-to-severe AD, provides a highly efficacious alternative to the traditional broad systemic immunosuppressant therapies. In clinical trials, more than half of adults reported a 75% reduction in AD symptoms after 16 weeks of therapy. The FDA has since expanded the biologic's indication for use in children as young as 6 months.

"Dupilumab has revolutionized how we can treat severe disease early on in young children who are not responding to topical steroids, and can turn AD around in the majority of children," Amy S. Paller, MD, of Northwestern University Feinberg School of Medicine in Chicago, said in an interview.

In 2022, FDA approval of the selective oral Janus kinase (JAK) inhibitors upadacitinib (Rinvoq) and abrocitinib (Cibinqo) added two small-molecule inhibitors to the treatment algorithm, further elevating the standard of treatment for moderate-to-severe AD.

"The treatment of severe AD has been extremely challenging until recently," said Cameron Rokhsar, MD, of Mount Sinai Hospital in New York City. "I think that with the advent of the JAK inhibitors, the treatment of severe AD has been revolutionized and the entire atopic triad gets treated. These patients really get better in 4 to 8 weeks and stay better."

Last June, an of the comparative efficacy of six targeted systemic therapies as monotherapy showed that the most efficacious for moderate-to-severe AD after 12 to 16 weeks was upadacitinib 30 mg, generally followed by abrocitinib 200 mg, upadacitinib 15 mg, dupilumab 300 mg, and either the selected IL-13 inhibitor lebrikizumab 250 mg (currently unapproved) or abrocitinib 100 mg.

"We've really seen miraculous responses with the JAK inhibitors, even at low doses," said lead author Jonathan Silverberg, MD, PhD, MPH, of George Washington University School of Medicine and Health Sciences in Washington, D.C. "If you look at the efficacy data, upadacitinib at the 30-mg dose has really set the standard for treatment in moderate-to-severe AD," he told MedPage Today.

Chris Bunick, MD, PhD, of the Yale School of Medicine in New Haven, Connecticut, noted that "the JAK inhibitors are bringing a level of efficacy that we haven't seen before in AD. The data on the long-term efficacy and safety of JAK inhibitors show strong, durable response by patients, with very low rates of adverse events up to 4 years' duration of therapy."

In the meta-analysis, upadacitinib and abrocitinib were the only targeted therapies for moderate-to-severe AD that achieved an Eczema Area and Severity Index (EASI) score of 90 in more than 40% of patients, and an EASI score of 75 in more than 50% of patients, Bunick noted. "If you look at EASI response in Olympic terms, the gold, silver, and bronze medals all go to the JAK inhibitors: upadacitinib 30 mg and abrocitinib 200 mg, and then upadacitinib 15 mg."

"The narrative is shifting," he added. "Now, we're talking about a score of EASI90 or EASI100 instead of EASI50 or EASI75, and an itch score of 0 or 1 instead of 5, 6, or 7, where our patients are so itchy, they can't sleep, and it's affecting their work."

Even so, many dermatologists remain wary of using the JAK inhibitors, especially after the FDA put a black box warning on the class of drugs in 2021. This followed the release of data from the ORAL Surveillance study of tofacitinib (Xeljanz) in arthritis. The evidence indicated that this potent inhibitor of JAK1, JAK2, and JAK3 was associated with a higher risk of cancer, venous thromboembolism (VTE), and major adverse cardiovascular events (MACE) compared with tumor necrosis factor inhibitors.

"I think the apprehension [on the part of some dermatologists] is appropriate," said Brett King, MD, PhD, also of the Yale School of Medicine. "The JAK inhibitors are a new class of medicines in dermatology and there is a warning."

Silverberg agreed, noting that "there are definitely dermatologists who are not going to use JAK inhibitors any time soon." As more real-world data become available, the use of JAK inhibitors will increase "slowly but surely," he predicted.

"A lot of the FDA decision-making around the boxed warning had to do with patients using a pan-JAK inhibitor that inhibits a lot more than the JAK-STAT [signal transducer and activator of transcription] signaling," Bunick said. "Tofacitinib is not as specific as the JAK inhibitors we use in dermatology."

So how safe are upadacitinib and abrocitinib in moderate-to-severe AD?

of integrated data from three ongoing phase III studies -- Measure Up 1 and Measure Up 2, and -- examined the safety of upadacitinib 15 mg and 30 mg compared with placebo. The results revealed no new safety signals. In fact, the low rates of VTE, MACE, and cancer seen at 1 year remained consistently low 4 years later. Half of the study population had one or more cardiovascular risk factors, 30% were current or former tobacco users, 20% had a body mass index ≥30, and 20% of women were on oral contraceptives.

These findings "continue to support a favorable benefit-risk profile of upadacitinib in the treatment of adults and adolescents with moderate-to-severe AD for up to 4 years of treatment," wrote Silverberg and co-authors.

These 4-year safety data "are representative of modern-day Americans," said Bunick. "For better or for worse, it can be applied to the average dermatology patient walking in the door."

Similarly, a of the safety of all oral JAK inhibitors, including abrocitinib and upadacitinib, as well as oral baricitinib (Olumiant), a JAK1/2 inhibitor, and deucravacitinib (Sotyktu), a TYK2 inhibitor, showed very low rates of VTE, MACE, and malignancy compared with placebo. The most common treatment-emergent adverse events, observed in 5% or more of patients, included upper respiratory tract infection, nasopharyngitis, nausea, headache, and acne.

"A comprehensive evaluation of a patient's baseline risk factors for complications and comorbid diseases is critical in assessing the net benefit of JAK inhibitors on a case-by-case basis," advised the review authors.

Using data from the ongoing JADE EXTEND trial, an integrated in adolescents demonstrated no new safety signals. The dataset included 635 patients ages 12 to 17 with more than 1,000 patient-years of exposure. The authors, led by Paller, concluded that abrocitinib 200 mg has an acceptable long-term safety profile in adolescents with moderate-to-severe AD.

Perhaps not surprisingly, comparing the safety data on the JAK1 inhibitors for AD with methotrexate, cyclosporine, azathioprine, and oral corticosteroids showed that the older immunosuppressive therapies were associated with equal or higher rates of malignancy, MACE, and VTE per 100 patient-years. Notably, oral prednisone was associated with the highest risk of malignancy and adverse cardiac events of any of the therapies.

"These findings indicate that JAK inhibitors should be positioned, at least based on safety, ahead of traditional systemic therapies for atopic dermatitis treatment," the authors noted.

How does the efficacy and safety of upadacitinib and abrocitinib compare with dupilumab?

A of data from the phase III JADE COMPARE trial compared the efficacy of once-daily oral abrocitinib 200 mg or 100 mg, dupilumab 300 mg, or placebo with concomitant topical corticosteroids in adults with severe and/or difficult-to-treat AD. The results showed that by week 16, abrocitinib 200 mg appeared more effective than dupilumab. However, at the 100-mg dose, the JAK inhibitor was slightly less effective than the biologic, and while abrocitinib had faster onset of efficacy at both doses, dupilumab had the best safety profile overall.

"I don't think we can say that one drug is 'better' than another," said Silverberg. "But there are pros and cons to both."

King summed it up this way: "In light of the fact that there's a discussion about the boxed warning and lab monitoring with the JAK inhibitors, I think most physicians are going to reach for dupilumab first. But if dupilumab doesn't get the patient to disease-free or nearly so, we should be reaching for abrocitinib and upadacitinib. We want to push the envelope towards being 'clear,' not just 'better.'"

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