New ways to tackle itch in atopic dermatitis

Traditional and popular treatments aimed at calming the often intense pruritus that accompanies atopic dermatitis might not be optimal therapeutic options, according to a review published August 2019 in the Journal of Allergy and Clinical Immunology.

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“Classically, it was widely believed that treatment of atopic dermatitis with anti-inflammatory agents was the only manner in which itch could be alleviated. In other words, inflammation in the skin was inextricably linked to itch. This article highlights new and emerging pathways in atopic dermatitis-associated itch, such that itch can be selectively and potently targeted with newer therapeutics. These include existing therapies like dupilumab, or emerging therapies like [interleukin-] IL-13 and IL-31 antagonists as well as [Janus kinase] JAK inhibitors,” says review author Brian S. Kim, MD, MTR, associate professor dermatology and co-director, Center for the Study of Itch, at Washington University School of Medicine, in St. Louis.

Researchers have traditionally thought itch mechanisms revolved around the canonical IgE-mast-cell-histamine axis, yet therapies focused on blocking the histaminergic itch pathway have been in large part ineffective against atopic dermatitis associated itch, the authors write.

Today, there’s new emphasis on targeting nonhistaminergic itch pathways.

Atopic dermatitis patients exhibit systemic immune dysregulation and increased serum IgE levels. Like other atopic disorders, such as asthma and food allergy, atopic dermatitis is associated with increased expression of epithelial cell-derived cytokines, as well as enhanced adaptive TH2 cell and innate basophil, eosinophil, mast cell and group 2 innate lymphoid cell responses, the authors write.

These processes, which increase production of effector cytokines IL-4, IL-5 and IL-13, set the stage for the allergic cutaneous immune atopic dermatitis response.

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Recent studies suggest there’s more to itch than skin inflammation and point to the immune system interacting with the sensory nervous system to arouse itch. So, researchers are studying things like the effects of H4 antihistamines to treat the itch of atopic dermatitis, according to the authors.

“Notwithstanding this, the first cytokine to be identified as a pruritogen was found to be produced by TH2 cells in the context of atopic dermatitis, namely IL-31," they write.

A phase 2b randomized study published in August in the Journal of Allergy and Clinical Immunology of nemolizumab treatment in adults with moderate-to-severe atopic dermatitis and severe pruritus found nemolizumab treatment resulted in rapid and sustained improvements of cutaneous signs of inflammation and pruritus, with an acceptable safety profile.

Dr. Kim and colleagues “recently identified that IL-4 receptor alpha is expressed on sensory neurons and critically regulates itch responses in vivo in a murine model of AD-like disease,” according to the paper in the Journal of Allergy and Clinical Immunology.

It seems IL-4 and IL-13 promote neuronal hypersensitivity to pruritogens, therefore regulating itch, they write.

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While IL-4 is the target of dupilumab, which is FDA approved for atopic dermatitis treatment, research is underway for anti-IL-13 drugs. Among those: tralokinumab and lebrikizumab. Tralokinumab has significantly improved itch related to atopic dermatitis in trials, according to the paper.

In a review published August 2019 in the Journal Pediatric Drugs, the authors report: While the aryl hydrocarbon receptor modulating agent tapinarof, the IL-4/IL-13 antagonists lebrikizumab and tralokinumab, and the IL-31Rα antagonist nemolizumab have potential in atopic dermatitis treatment. Janus Kinase- (JAK)-STAT inhibitors (baricitinib, upadacitinib, PF-04965842, ASN002, tofacitinib, ruxolitinib, and delgocitinib) have the most promise among emerging therapies.

Dr. Kim and colleagues write they have in recent studies identified neuronal JAK1 signaling as an important regulator of atopic dermatitis itch in vivo and JAK inhibitors probably have neuromodulatory properties.

Disclosures:

Dr. Kim has served as a consultant for AbbVie, Cara Therapeutics, Concert Pharmaceuticals, Incyte, Menlo Therapeutics, and Pfizer; has served on advisory boards for Celgene, Kiniksa Pharmaceuticals, Menlo Therapeutics, Regeneron Pharmaceuticals, Sanofi, and Theravance Biopharma; and is founder, chief scientific officer and stockholder of Nuogen Pharma.