Abstract
The goal of this study was to elucidate the anti-pruritic and anti-inflammatory efficacy of ruxolitinib cream in experimentally-induced dermatitis. Atopic dermatitis (AD), the most common chronic relapsing inflammatory skin disease, significantly impairs patients’ quality of life, with pruritus being a common complaint. The sensation of itch results from the interplay between epidermal barrier dysfunction, upregulated immune signaling and the activation of the central nervous system. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a central role in pro-inflammatory cytokine signaling in AD. Ruxolitinib cream is a potent and selective JAK1/2 inhibitor currently undergoing clinical evaluation in adults with mild-to-moderate AD (NCT03745638, NCT03920852 and NCT03745651). The efficacy of ruxolitinib cream was tested in murine models of acute and chronic dermatitis and was also characterized in an ex vivo human skin dermatitis model. Ruxolitinib cream was highly effective at ameliorating disease symptoms in multiple murine dermatitis models through downregulation of T helper (Th)2-driven inflammation, resulting in reduced skin thickening and decreased itch. Pathway analysis of mouse ear tissue and human skin explants underscored the role for ruxolitinib in ameliorating inflammation and reducing itch via modulation of the JAK-STAT pathway. Together, the data offer a strong rationale for the use of ruxolitinib cream as a potent therapeutic agent for the clinical management of atopic dermatitis.
Highlights
Atopic dermatitis (AD) is the most common inflammatory skin disease, with intense pruritus being the major and most burdensome symptom [1, 2]
Ruxolitinib treatment resulted in a significant downregulation in pro-inflammatory and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway genes, including IL-33 (Il33), IL-4 receptor alpha chain (Il4ra), IL-7 receptor (Il7r), interferon gamma receptor 1 (Ifngr1), interferon regulatory factor 9 (Irf9), IL-1 beta (Il1b), gasdermin (Gsdmd), interferon-inducible protein Aim2 (Aim2), and Jak1, Jak3, Stat1, Stat3, Stat5a, Stat5b, and Stat6 (Figure 1F)
The JAK-STAT pathway has been implicated as a key driver of several inflammatory skin diseases, including AD [20]
Summary
Atopic dermatitis (AD) is the most common inflammatory skin disease, with intense pruritus being the major and most burdensome symptom [1, 2]. The Janus kinase (JAK) signal transducer and activator of transcription (STAT) pathway, a classical signal transduction pathway for numerous cytokines and growth factors, has been shown to play an important role in the dysregulation of immune responses in AD [5]. The JAK family is Ruxolitinib Cream Inhibits Itch, Dermatitis comprised of four types of cytoplasmic tyrosine kinases: JAK1, JAK2, JAK3, and TYK2. Multiple immune mediators present within the inflamed skin utilize class I/II cytokine receptors and are dependent on the JAK-STAT pathway for signal transduction [7,8,9,10]
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