JAK–STAT signaling pathway in the pathogenesis of atopic dermatitis: An updated review

Abstract

Atopic dermatitis (AD) is a chronic, inflammatory, pruritic form of dermatosis with heterogeneous manifestations that can substantially affect patients' quality of life. AD has a complex pathogenesis, making treatment challenging for dermatologists. The Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway plays a central role in modulating multiple immune axes involved in the immunopathogenesis of AD. In particular, Th2 cytokines, including interleukin (IL)-4, IL-5, IL-13, IL-31, and thymic stromal lymphopoietin, which contribute to the symptoms of chronic inflammation and pruritus in AD, are mediated by JAK–STAT signal transduction. Furthermore, JAK–STAT is involved in the regulation of the epidermal barrier and the modulation of peripheral nerves related to the transduction of pruritus. Targeting the JAK–STAT pathway may attenuate these signals and show clinical efficacy through the suppression of various immune pathways associated with AD. Topical and oral JAK inhibitors with variable selectivity have emerged as promising therapeutic options for AD. Notably, topical ruxolitinib, oral upadacitinib, and oral abrocitinib were approved by the U.S. Food and Drug Administration for treating patients with AD. Accordingly, the present study reviewed the role of JAK–STAT pathways in the pathogenesis of AD and explored updated applications of JAK inhibitors in treating AD.

Real‐world effectiveness of abrocitinib treatment in patients with difficult‐to‐treat atopic dermatitis

“…The different pharmacodynamic properties of JAK inhibitors and especially different selectivity for JAK isoforms may explain these findings. 17 For instance, baricitinib inhibits both JAK1 and JAK2 tyrosine kinases, while abrocitinib and upadacitinib are more selective for JAK1. [18][19][20] Different affinity for JAK1 and concomitant inhibitory activity on JAK2 and JAK3 pathways may explain why abrocitinib was effective in a subset of patients previously treated with other JAKi.…”

“…Interestingly, eight of these patients (8/14) showed good clinical response to abrocitinib treatment. The different pharmacodynamic properties of JAK inhibitors and especially different selectivity for JAK isoforms may explain these findings 17 . For instance, baricitinib inhibits both JAK1 and JAK2 tyrosine kinases, while abrocitinib and upadacitinib are more selective for JAK1 18–20 .…”

Interactions between Malassezia and New Therapeutic Agents in Atopic Dermatitis Affecting Skin Barrier and Inflammation in Recombinant Human Epidermis Model

“…Histologically, AD lesional skin shows hyperkeratosis, acanthosis, and spongiosis [ 36 ]. Studies have suggested that activating the JAK/STAT signaling pathway and producing Th2 cytokines may also contribute to developing spongiosis in AD [ 22 , 24 , 36 ]. This was also confirmed in our research results ( Figure 1 and Figure 6 ).…”

“…They can lead to the recruitment of immune cells to the site of inflammation and exacerbation of AD symptoms. Th2 cytokines also contribute to skin barrier dysfunction by activating the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway and reducing the production of skin barrier proteins [ 22 , 23 , 24 ].…”

The safety of systemic Janus kinase inhibitors in atopic dermatitis: A systematic review and meta‐analysis of randomized controlled trials

“…Recently, the FDA added a boxed warning for JAK inhibitors, including baricitinib, abrocitinib and upadacitinib, for the treatment of arthritis and other inflammatory diseases as well as atopic dermatitis to include information about risk of major adverse cardiac events (MACEs), venous thromboembolic events (VTEs) and cancers 7,8 . Recently, several meta‐analyses on the safety of JAK inhibitors have been published 9–12 .…”