New and Emerging Biologics for Atopic Dermatitis

Wenelia Baghoomian; ChanHo Na; Eric L. Simpson

Disclosures

Am J Clin Dermatol. 2020;21(4):457-465. 

In This Article

Abstract and Introduction

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by complex pathophysiology involving both skin barrier dysfunction and aberrant type 2 inflammation/immune responses. AD can be a debilitating condition that drastically impairs quality of life, especially in patients with moderate-to-severe disease. Currently, topical therapies such as corticosteroids and non-steroidal immunomodulatory therapy provide limited efficacy for patients with moderate-to-severe AD; limitations include inadequate response, cutaneous toxicity from overuse, and poor tolerance due to stinging and burning. Historically, the development of targeted therapies has been challenging due to the complex and multifaceted etiology of AD. Recent progress in understanding the immunopathology of AD reinforces the development of newly targeted therapeutics. The successful launch of dupilumab, a monoclonal antibody targeting the interleukin (IL)-4α receptor subunit, for AD in 2017 spurred the development of a number of biologics targeting novel cytokine and receptor targets that are now in phase II and III of development. This review aims to explore the rationale behind these novel biological therapies and to summarize current clinical studies of these agents.

Introduction

Atopic dermatitis (AD) is a systemic inflammatory disease that is prevalent worldwide, often developing in childhood and persisting into adulthood for many patients. Up to 10% of adults and 13% of children in the US have AD, and it affects approximately 5% of the population worldwide with significant geographical variation.[1] Clinical features of AD include pruritus, erythema, lichenification, and excoriation.[2] These chronic signs and symptoms are associated with reduced quality of life and impair both social and physical functioning.[3] With a seemingly ever-increasing number of patients with AD having moderate to severe disease, novel targeted therapies hold promise for improved efficacy and safety over conventional oral immunosuppressive systemic treatments. Along with topical steroids, there are currently only three Food and Drug Administration (FDA)-approved topical treatments for AD—pimecrolimus and tacrolimus, both topical calcineurin inhibitors, and crisaborole, a topical phosphodiesterase-4 inhibitor. These topical treatments often have more limited efficacy in moderate-to-severe disease and do not address systemic inflammation or allergic comorbidities.[4]

In conjunction with genetic susceptibility from epidermal barrier defects such as FLG mutations, our current understanding of AD includes the involvement of several different inflammatory pathways contributing to the varying phenotypic expression of the disease.[5] Transcriptomic analysis of lesional and non-lesional skin reveal type 2 cytokine-driven inflammatory infiltrates in both acute and chronic skin lesions. Keratin 16 (K16) expression is upregulated, which is consistent with epidermal hyperproliferation and down regulation of several skin barrier genes including filaggrin (FLG) and loricrin (LOR).[6] Several additional cytokine and chemokine transcripts show upregulation in lesional skin including genes related to Th22, Th17, and Th1 pathways including interleukin (IL)-22, IL-23, IL-31, IL-33, IL-17, and several others.[7] The relative expression of some cytokine pathways appear enhanced in certain disease phenotypes such as Asian AD (IL-17) and African American AD (IL-22).[8,9] The significant beneficial effects of dupilumab, an inhibitor of IL-4 and IL-13, prototypical type 2 cytokines, reinforces the central role of type 2 inflammation in AD pathogenesis. Blockade of type 2 cytokines with dupilumab decreases the expression of not only type 2 cytokines, but also cytokines and chemokines of the Th1, Th22, and Th17 pathway, suggesting that type 2 cytokines are the key drivers of inflammation in AD.[6] The clinical importance of the additional cytokine pathways is difficult to determine. Clinical trials blocking these additional cytokine pathways, unfortunately, remain the best way to determine the clinical relevance of these additional cytokine pathways. This review will aim to cover the scientific basis behind new targeted biological therapies and to summarize any new clinical research or therapies in development. Table 1 summarizes the commonly used assessment tools for atopic dermatitis studies.

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