576 Difamilast, a new topical PDE4 inhibitor, ameliorates not only chronic allergic dermatitis but also idiopathic dermatitis induced by psychological stress in mice

Abstract

Difamilast is a novel PDE4 inhibitor with the strongest inhibitory activity against PDE4B among the four PDE4 subtypes. Moizerto® ointment (0.3%, 1% difamilast) has been recently approved for treatment of atopic dermatitis (AD) in Japan. Exogenous antigen stimulation or psychological stress can trigger or exacerbate AD symptoms. In this study, we evaluated the therapeutic effects of difamilast, tacrolimus, and betamethasone valerate on two different mice models of dermatitis: one was chronic contact hypersensitivity (CCH) induced by repeated application of hapten every 2 days for 52 days, the other was idiopathic dermatitis due to persistent self-scratching induced by application of hapten three times a week for 16 weeks, followed by individual housing (social isolation) for 6 months. Efficacy was assessed by repeated topical application of each drug for 4 or 6 weeks after each dermatitis established. In the CCH model, difamilast ointment group significantly improved skin hyperplasia from 0.03% to 3% dose-responsibly with inhibition of inflammatory cell infiltration such as T cells, eosinophils, and neutrophils. Betamethasone valerate ointment (0.12%) improved skin hyperplasia more strongly than 3% difamilast ointment. Tacrolimus ointment (0.1%) temporarily improved skin symptoms, but eventually had no effect. In the idiopathic dermatitis model, difamilast (1%, 3%) significantly improved skin symptoms with a decrease in MIP-1 alpha and MIP-2 content. Tacrolimus (0.1%) slightly improved skin symptoms, while betamethasone valerate (0.1%) exacerbated it. Notably, difamilast ameliorates both CCH and psychological stress-induced idiopathic dermatitis. Betamethasone valerate worsened the idiopathic dermatitis probably due to skin atrophy as steroid’s side effect and tacrolimus had weak effects in both models. Therefore, difamilast is expected to be a possible treatment for AD symptoms such as chronic allergic dermatitis and psychological stress-exacerbated idiopathic dermatitis.