From the Journals

Understanding AD as immune-driven disease has opened the door to new therapies



– The “therapeutic drought” in available therapies for atopic dermatitis (AD) is “finally ending,” in part because understanding of the pathogenesis of the disease has grown, Emma Guttman-Yassky, MD, PhD, said during a presentation at the annual meeting of the American Academy of Dermatology.

Dr. Emma Guttman-Yassky

Dr. Emma Guttman-Yassky

“It’s due to the increased understanding we now have in atopic dermatitis,” Dr. Guttman-Yassky, professor and vice chair for research in the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, said in her presentation.

According to Dr. Guttman-Yassky, therapeutic development was prevented in AD because of the abnormalities present in the disease immune responses and barrier abnormalities. “Frankly, pharma[ceutical] companies didn’t know what they should go after,” she said. “Should they go after the immune abnormalities, or should they go after the barrier? I think that’s why we’re so far behind psoriasis – but don’t worry, we are catching up quite fast because now ... we understand what we need to go after.”

It was when researchers began to look at AD in the same way as psoriasis that they realized the two were “polar” immune diseases, with psoriasis having Th17/interleukin-17 involvement while atopic dermatitis had Th2/IL-13 involvement. The same approach of “bedside-to-bench pathogenic dissection and translational testing of therapeutics” that led to successful advancements in therapies for psoriasis can also be applied to AD, Dr. Guttman-Yassky said.

To create a translational approach to AD, researchers need to have a well-defined molecular phenotype and understanding of inflammatory pathways, good baseline biomarkers of disease activity and treatment responses, and drugs that would selectively target the immune system. Th2-type cytokines such as IL-4 and IL-13 could help link the barrier and immune defects in AD. In addition, all variations of AD subtypes across white, black, Asian, and pediatric populations have “robust Th2 activation” but differ in other areas. “We’ll need to stratify biomarkers specific to different atopic dermatitis phenotypes to really develop a personalized medicine approach in atopic dermatitis,” she said.

High-level systemic immune activation shows that AD is emerging as a systemic disease that leads to atopic comorbidities such as allergy and asthma, as well as cardiovascular and infectious comorbidities. “We need to think about it when we treat our patients, because we really need to give them systemic treatment approaches when they have this moderate to severe disease,” Dr. Guttman-Yassky said. “When adult patients have moderate to severe disease, what is nonlesional today may be lesional tomorrow, and to treat them effectively, you have to offer them some systemic approaches.”

There is evidence that dupilumab, a human monoclonal antibody that targets IL-4 receptor alpha, is “proving the immune hypothesis” of AD, Dr. Guttman-Yassky said. She cited a recent study from her own group that found use of dupilumab to inhibit IL-4/IL-13 signaling improved disease activity for patients with AD, including reducing the expression of genes that caused type 2 inflammation, epidermal hyperplasia, T cells, dendritic cells, and Th17/Th22 activity (J Allergy Clin Immunol. 2019 Jan;143(1):155-72).

“We could postulate it before, but we couldn’t prove it,” she said. “Basically, this opened the door to all the therapy that we now have in atopic dermatitis.”

According to Dr. Guttman-Yassky, the future of AD will be in creating personalized treatments for patients by stratifying biomarkers specific to different AD phenotypes.

“It’s a very hopeful time in atopic dermatitis with this growing knowledge that we have of the biology of [the disease],” she said. “We have many more agents to treat our patients, and I think the future will be about personalized medicine so we really are treating the disease very well.”

Dr. Guttman-Yassky reported relationships with AbbVie, Allergan, Almirall, Anacor Pharmaceuticals, Asana BioSciences, Celgene, Dermira, Eli Lilly, Escalier Biosciences, Galderma Research & Development, Glenmark Generics, Janssen, Kyowa Hakko Kirin, Leo Pharma, Medimmune, Novartis, Pfizer, Regeneron, Sanofi-Aventis, Sanofi/Regeneron, Stiefel, Theravance Biopharma, and Vitae Pharmaceuticals.

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