Elevated IL ‐4 and IL ‐13 Expression in Hailey‐Hailey Disease: Evidence for Th2‐Mediated Pathogenesis and Targeted Treatment

Background Hailey‐Hailey disease (HHD) is a rare autosomal dominant blistering disorder caused by mutations in the ATP2C1 gene, which impair keratinocyte adhesion through disrupted calcium signaling. While traditionally considered a structural defect, recent studies suggest that Th2‐mediated inflammation may exacerbate disease pathology. Interleukin (IL)‐4 and IL‐13, central mediators of type 2 inflammation, have been implicated in barrier dysfunction in other dermatoses, yet their role in HHD remains poorly defined. Methods This retrospective study employed immunohistochemistry to assess IL‐4 and IL‐13 expression in lesional skin from patients with HHD ( n = 7) compared to age‐, sex‐, and site‐matched atopic dermatitis (AD) controls ( n = 6) and healthy control samples ( n = 4). Results IL‐4 expression was significantly elevated in the epidermis of HHD compared to negative control tissue (mean 3966 cells/mm 2 vs. 808 cells/mm 2 , p = 0.0219), whereas IL‐13 expression was markedly increased in the dermis (mean 5288 cells/mm 2 vs. 629 cells/mm 2 , p < 0.0001), relative to healthy controls. No statistically significant difference was observed between AD and HHD samples. Conclusions These findings highlight a potential role for IL‐4 and IL‐13 in the pathogenesis of HHD, supporting the therapeutic relevance for targeting type 2 cytokines. Agents such as dupilumab and potentially JAK inhibitors may offer new avenues for effective disease management.