Pharmacodynamics of Janus kinase inhibitors for the treatment of atopic dermatitis

ABSTRACT

Introduction

Atopic dermatitis (AD) is the most common inflammatory skin disorder. Despite the high disease burden, the therapeutic options are limited and their efficacy in controlling AD might be partially satisfactory.

Areas Covered

Most of the key mediators in AD pathogenesis act through the JAK/STAT signaling pathway, which represents a valid therapeutic target. The first generation of JAK inhibitors, namely tofacitinib and ruxolitinib, inhibit multiple JAKs, whereas newer JAK inhibitors show more selective inhibitory effects for specific JAKs. The aim of this review was to discuss the role of the JAK/STAT pathway in AD and its inhibition, with a special focus on pharmacodynamic properties.

Expert opinion

JAK inhibitors have different selectivity for various JAK molecules, which influences their pharmacodynamics, efficacy, and safety profile. Since many key cytokines in AD signal through JAK1, the selective JAK1 inhibition may be effective, avoiding the concomitant inhibition of JAK2- and JAK3-dependent pathways could be associated with additional safety issues. Therefore, selective JAK1 inhibitors may represent promising therapeutic agents for AD, as they might prevent off-target effects of JAK inhibitors, especially related to the hematologic profile.

KEYWORDS:

• Abrocitinib
• atopic dermatitis
• baricitinib
• delgocitinib
• pharmacodynamics
• ruxolitinib
• upadacitinib

Article highlights

• JAK inhibitors are small molecules targeting one or more members of the JAK family. Blocking these intracellular transcription factors, JAK inhibitors can exert multiple anti-inflammatory, immunosuppressive, and antiproliferative properties.

• JAK inhibitors are traditionally classified into two classes: the first-generation JAK inhibitors (pan-JAKs), which inhibit multiple JAKs and newer JAK inhibitors, with a more selective mode-of-action.

• The different pharmacodynamic properties of JAK inhibitors and, particularly, their different selectivity for JAK isoforms have important implications in terms of efficacy and safety profile of each pharmaceutical agent.

• Several JAK inhibitors have already proven efficacy for the treatment of atopic dermatitis. Some of these agents, such as ruxolitinib and delgocitinib, are applied topically, whereas others are administered orally, namely baricitinib, upadacitinib, and abrocitinib, or both (i.e. tofacitinib).

• As many key cytokines in atopic dermatitis signal through JAK1 for signal transmission, selective JAK1 inhibitors, rather than pan-JAKs or JAK1/2 inhibitors, avoid useless inhibition of other signaling pathways, obtaining high efficacy for AD treatment and a more favorable safety profile.

• Selective JAK1 inhibitors, such as upadacitinib and abrocitinib, may represent promising therapeutic agents for the treatment of atopic dermatitis in the near future.

Declaration of interest

A Chiricozzi served as an advisory board member and consultant and has received fees and speakers honoraria or has participated in clinical trials for AbbVie, Almirall, Leo Pharma, Lilly, Janssen, Novartis, Sanofi Genzyme, Pfizer and Incyte. C De Simone has received consulting fees or honorarium from AbbVie, Amgen, Novartis, Celegene, Sanofi, UCB Pharma, Janssen, and Lilly and payment for lectures from AbbVie, Lilly, Novartis, UCB Pharma and Celgene. K Peris has served as advisory board, received honoraria for lectures and/or research grants from AbbVie, Almirall, Lilly, Galderma, Leo Pharma, Pierre Fabre, Novartis, Sanofi, Sun Pharma and Janssen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed receiving research, speaking and/or consulting support from Eli Lilly and Company, GlaxoSmithKline/Stiefel, AbbVie, Janssen, Alovtech, vTv Therapeutics, Bristol-Myers Squibb, Samsung, Pfizer, Boehringer Ingelheim, Amgen Inc, Dermavant, Arcutis, Novartis, Novan, UCB, Helsinn, Sun Pharma, Almirall, Galderma, Leo Pharma, Mylan, Celgene, Valeant, Menlo, Merck & Co, Qurient Forte, Arena, Biocon, Accordant, Argenx, Sanofi, Regeneron, the National Biological Corporation, Caremark, Advance Medical, Suncare Research, Informa, UptoDate and the National Psoriasis Foundation; this reviewer is also the founder and majority owner of www.DrScore.com [drscore.com] and founder and part owner of Causa Research. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.