392 Ruxolitinib cream ameliorates spontaneous atopic dermatitis in the IL-33 transgenic mouse model

Abstract

Atopic dermatitis (AD) is characterized by intense itch and recurrent eczematous lesions. Interleukin (IL)-33 is constitutively produced from the structural and lining cells, including skin epithelial cells, which are exposed to the environment. Extracellular IL-33 binds to ST2 on T helper 2 (Th2) cells and various innate immune cells including mast cells, eosinophils and innate lymphoid cells. In AD patients, IL-33 overexpression in the epidermis, infiltration of ST2-positive cells and elevated serum IL-33 levels has been implicated in disease pathogenesis. Transgenic mice with constitutive epidermal-specific IL-33 expression (IL-33tg) spontaneously develop a progressive, AD-like skin inflammation and pruritis. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is involved in AD-related cytokine signaling, including IL-33, mediating downstream inflammation and barrier alterations. Ruxolitinib cream, a topical JAK1/2 inhibitor, is currently being evaluated in clinical trials for the treatment of mild-to-moderate AD (NCT03745638 & NCT03538041 and NCT03745651). Our goal was to evaluate Ruxolitinib cream as a monotherapy for the treatment of pruritis in the spontaneous onset IL-33 transgenic mouse model of AD. Animals were randomized to four treatment groups; vehicle cream (bid), ruxolitinib cream 1.5% (bid), topical steroid (clobetasol 0.05%) and vehicle treated (bid) non-transgenic littermates. Scratching and grooming analysis was performed at 14 and 24 weeks of age. Skin inflammation and mast cell frequency were quantified by histology. Tissue biopsies were analyzed for JAK-STAT pathway modulation and disease pathogenesis markers. Ruxolitinib cream treatment (1.5% bid) demonstrated sustained amelioration of pruritus (p<0.05) and abnormal grooming behaviors (p<0.001) at 14 and 24 weeks of age. Chronic topical administration of ruxolitinib cream was well tolerated in the IL-33tg mice. Together, these data support the scientific rationale that ruxolitinib cream, a topical JAK1/2 inhibitor, may have potential as a therapeutic agent for the treatment of atopic dermatitis.