The possible effectiveness of difamilast in improving barrier dysfunction in patients with atopic dermatitis and in mouse model

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritus and impaired skin barrier function. Although difamilast, a topical phosphodiesterase-4 (PDE4) inhibitor, has demonstrated clinical efficacy in AD, its role in restoring barrier function remains incompletely understood. This study aimed to investigate the barrier-improving effects of topical difamilast in patients with AD and in an MC903-induced mouse model of AD-like dermatitis. We conducted a retrospective study involving seven Japanese adult patients with mild-to-moderate AD who received 1% difamilast ointment twice daily for 1 week. Transepidermal water loss (TEWL) was measured before and after treatment. Animal experiment was performed using MC903-induced AD-like dermatitis model, followed by treatment with difamilast or vehicle. Dermatitis scores, TEWL, histological changes, immunofluorescence for filaggrin and CD4, and mRNA expression of filaggrin, IL-4, IL-13 and TSLP were evaluated. Topical difamilast reduced TEWL in six out of seven AD patients. In the mouse model, difamilast markedly attenuated dermatitis severity and reduced TEWL. Histological analysis revealed suppression of epidermal thickening and inflammatory cell infiltration. Difamilast restored filaggrin expression and decreased mast cell and CD4 + T-cell infiltration in lesional skin. Quantitative PCR demonstrated that difamilast normalized the MC903-induced decrease in filaggrin and increase in IL-4 mRNA expression. Our findings suggest that difamilast improves skin barrier dysfunction in both human AD and an experimental AD-like mouse model. However, large-scale controlled studies are required to validate its barrier-improving efficacy in real-world clinical settings.