Targeting the Aryl Hydrocarbon Receptor to Address the Challenges of Atopic Dermatitis

February 2024 | Volume 23 | Issue 2 | 23 | Copyright © February 2024


Published online January 18, 2024

Lawrence F. Eichenfield MDa,b, Jonathan I. Silverberg MD PhD MPHc, Adelaide A. Hebert MDd, Raj Chovatiya MD PhDe, Philip M. Brown MD JDf, Kimberly A. McHale PhDf, David S. Rubenstein MD PhDf, Anna M. Tallman PharmDf

aUniversity of California San Diego School of Medicine, San Diego, CA
bRady Children’s Hospital, San Diego, CA
cSchool of Medicine and Health Sciences, The George Washington University, Washington, DC
dUTHealth McGovern Medical School and Children’s Memorial Hermann Hospital, Houston, TX
eNorthwestern University Feinberg School of Medicine, Chicago, IL
fDermavant Sciences, Inc., Morrisville, NC

Abstract
Atopic dermatitis (AD) is a chronic relapsing–remitting disease with a multifactorial etiology involving epidermal barrier and immunologic dysfunction. Topical therapies form the mainstay of AD treatment, but options are limited by adverse effects and restrictions on application site, duration, and extent of use. Tapinarof (VTAMA; Dermavant Sciences, Inc.) is a first-in-class, non-steroidal, topical aryl hydrocarbon receptor (AhR) agonist approved for the treatment of plaque psoriasis. AhR is a ligand-dependent transcription factor with wide-ranging roles, including regulation of homeostasis and immune response in skin cells. AhR expression and signaling are altered in many inflammatory skin diseases, and clinical trials with tapinarof have validated AhR as a therapeutic target capable of delivering significant efficacy. Tapinarof cream 1% once daily demonstrated efficacy versus vehicle in adults and adolescents with AD and is being investigated in the ADORING trials for the treatment of AD in adults and children down to 2 years of age.

J Drugs Dermatol. 2024;23(2):23-28.  doi:10.36849/JDD.8026

INTRODUCTION

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor regulating gene expression in various cells, including immune and epithelial cells.1 AhR is expressed ubiquitously throughout the body, has roles in many physiologic processes, and is activated by a wide range of ligands.2-5 AhR also affects signaling through interaction with other proteins, such as the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2).1

Atopic dermatitis (AD) is an inflammatory skin disease associated with changes in AhR signaling, reduced Nrf2 activity, abnormal immune responses, impaired skin barrier function, and oxidative stress.1,6-8 Increased T helper (Th)2 cell cytokine expression, particularly interleukin (IL)-4, IL-5, IL-13, and IL-31, has been implicated in AD pathogenesis.9-11 Management of AD includes reducing symptoms and improving the quality of life for patients and caregivers.12 

There is a need for efficacious and well-tolerated therapies that can be used by children and adults, without restrictions on the duration or extent of use, or sites of application.13 Clinical trials with tapinarof (VTAMA; Dermavant Sciences, Inc.) validate AhR as a therapeutic target in inflammatory skin diseases. Tapinarof is an AhR agonist that downregulates cytokines, promotes skin-barrier normalization, and reduces oxidative stress.1,14,15 Tapinarof cream 1% once daily (QD) is approved for the treatment of adults with plaque psoriasis,16 and is under investigation for the treatment of psoriasis in children down to 2 years of age and for the treatment of AD in adults and children down to 2 years of age, having demonstrated efficacy in adults and adolescents with moderate to severe AD in previous trials.17,18

This review discusses the rationale for targeting AhR in the treatment of AD based on the current understanding of the role of tapinarof in the treatment of inflammatory skin disease.

Rationale for Targeting AhR
Overview of AhR
AhR is a ligand-dependent transcription factor expressed in most cell types, including skin, immune, and epithelial cells,3 and acts as a master regulator of homeostasis in healthy cells, mediating responses to low-molecular-weight ligands from endogenous, 
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