The Multikinase Inhibitor Midostaurin Mitigates Loss of Intercellular Adhesion and Skin Blistering in Pemphigus Vulgaris.

Pemphigus is a group of autoimmune blistering diseases characterized by the presence of autoantibodies against desmogleins, which are critical components of desmosomes. These autoantibodies disrupt the adhesive function of desmosomes, leading to loss of cell-cell adhesion in the epidermis, which manifests clinically as blistering and erosions of the skin and mucous membranes. In this study, we explored the potential use of midostaurin, a multikinase inhibitor commonly employed in the treatment of FLT3-altered cancers, as a therapeutic option for pemphigus. The results demonstrated that midostaurin effectively rescued loss of adhesion and keratin retraction induced by both pemphigus vulgaris and pemphigus foliaceus IgG in cultured keratinocytes. In addition, midostaurin prevented pemphigus vulgaris IgG-mediated relocalization of desmoglein 3 within the cell membrane as well as loss of desmoglein 3 adhesion on single-molecule level as revealed by atomic force microscopy. In ex vivo human skin, midostaurin treatment successfully prevented pemphigus vulgaris IgG-induced blister formation. Ultrastructural analyses revealed that midostaurin restored the integrity of desmosomes. These findings indicate that midostaurin can counteract the pathogenic effects of pemphigus autoantibodies, suggesting its potential as a therapeutic agent for pemphigus.