385 Ruxolitinib cream ameliorates a preclinical model of skin dermatitis via modulation of inflammatory T-cell subsets

Abstract

Allergic contact dermatitis, is driven by an overreaction of the body’s immune system to a normally harmless substance resulting in skin inflammation. Preclinically, topical administration of the T helper 2 (Th2) hapten fluorescein isothiocyanate (FITC) drives an immunogenic sensitization in mice and recall challenge on the ear triggers a localized inflammatory contact hypersensitivity. Pharmacological inhibition of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway has previously demonstrated efficacy in a Phase 2 clinical trial in patients with atopic dermatitis (AD) (NCT03011892). 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). The experimental goal was to evaluate the dose-dependent efficacy of ruxolitinib cream as a topical monotherapy for the modulation of experimentally induced contact dermatitis in mice. Acute and chronic dermatitis was induced in Balb/C mice via FITC sensitization and subsequent recall response. Topical administration of ruxolitinib cream was compared to steroid (Betamethasone cream, 0.05%). Efficacy was quantified via inflammatory edema, immune phenotyping, tissue histology and immune pathway analysis. Topical administration of 1.5% ruxolitinib cream (q.d. and b.i.d) dose-dependently reduced inflammatory swelling and lichenification following recall FITC challenge in both acute (p<0.05) and chronic (p<0.05) contact dermatitis. Ruxolitinib efficacy was associated with a significant (p<0.01), dose-dependent, reduction in Th2 lymphocytes within the auricular (draining) lymph node). Pathway analysis revealed downregulation of inflammatory mechanisms consistent with JAK1/2 inhibition. Ruxolitinib cream was highly effective at inhibiting contact dermatitis in mice, ameliorated pro-inflammatory mechanisms and reduced skin thickening. Together, the data suggest that ruxolitinib cream may have potential as a therapeutic agent for the treatment of contact dermatitis.