Selective JAK1 Inhibitors for the Treatment of Atopic Dermatitis: Focus on Upadacitinib and Abrocitinib

Sandra Ferreira; Emma Guttman-Yassky; Tiago Torres

Disclosures

Am J Clin Dermatol. 2020;21(6):783-798. 

In This Article

Abstract and Introduction

Abstract

Atopic dermatitis is a common, chronic, immune-mediated disease associated with several comorbidities. Elevated levels of T helper (Th)2, Th22, and also some Th1 and Th17 cytokines are found in atopic dermatitis skin lesions. Similar to psoriasis, there is a tendency towards increased use of more targeted therapies. However, there are still several unmet needs in the treatment of atopic dermatitis concerning long-term efficacy, tolerability, safety, route of administration, and cost. The increased knowledge of atopic dermatitis pathogenesis and the role of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways has allowed the development of new compounds to inhibit this intracellular signaling pathway implicated in atopic dermatitis-related immune responses. Currently, JAK inhibitors are an important focus of therapeutic research for atopic dermatitis. Upadacitinib and abrocitinib are oral small molecules that inhibit the JAK/STAT pathway by selectively blocking JAK1. Data from phase II and III trials are encouraging, revealing that JAK1 inhibitors are effective and well-tolerated agents for moderate-to-severe atopic dermatitis. Selective JAK1 inhibitors may represent an important therapeutic option to be included in the treatment algorithm of atopic dermatitis, owing to oral administration and a favorable safety and tolerability profile. In this article, we review the current evidence on the efficacy and safety of oral selective JAK1 inhibitors for the treatment of atopic dermatitis.

Introduction

Atopic dermatitis (AD) is a common inflammatory skin disease, with an increasing prevalence worldwide, affecting 15–20% of people in developed countries.[1,2] It is mainly characterized by skin barrier dysfunction and pruritus, leading to recurrent eczematous lesions and a negative impact on the quality of life of these patients.[3,4] Presently, treatment options include topical therapy, phototherapy, and systemic immunotherapies. Topical therapy is usually sufficient to control the disease in most patients; however, moderate-to-severe AD is often refractory to first-line topical treatments and may require systemic conventional immunosuppressant agents, which are potentially associated with several side effects and toxicities, and new targeted therapies.[4–8]

To date, dupilumab, an interleukin (IL)-4 receptor-α inhibitor, is the only biologic agent approved for the treatment of moderate-to-severe AD in adults.[9] Although dupilumab has demonstrated high efficacy and safety in phase II and III trials, only 40% of patients achieved clear or almost clear skin with and without a background of topical corticosteroids.[10–12]

Therefore, the treatment of AD remains challenging and limited, with a large unmet need for alternative and more effective therapies with a good safety profile for long-term use. Several targeted topical and systemic immunotherapies targeting pathways directly responsible for AD are being evaluated in clinical trials, including Janus kinase (JAK) inhibitors.[13]

This article reviews the role of the JAK and signal transducer and activator of transcription (JAK-STAT) pathway in AD pathogenesis and summarizes the data on the efficacy and safety of upadacitinib and abrocitinib, two selective JAK1 inhibitors, in the treatment of moderate-to-severe AD. A search in the PubMed database (up until May 2020) for articles with the specific keywords "atopic dermatitis; JAK inhibitors; upadacitinib; abrocitinib" present in the title, abstract, or body was performed. The reference lists of those articles were examined to retrieve other studies that were considered relevant and contributed to the scientific purpose of the present review but had not been retrieved by the database search.

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