Th2/Th17 Inflammation: Pathogenic Drivers and Therapeutic Targets in Darier and Hailey‐Hailey Diseases

Abstract

ABSTRACT Background The inherited acantholytic dermatoses Darier disease (DD) and Hailey‐Hailey disease (HHD) are characterized by a barrier dysfunction of the epidermis susceptible to inflammation and microbial infections. Objectives This study aimed at investigating the expression of inflammatory and epithelial barrier markers in DD and HHD in order to identify potential targets for novel treatment strategies. Methods In this retrospective study, 6 DD and 4 HHD patients were included, of which three (1 DD, 2 HHD) have received targeted anti‐inflammatory therapies. To visualize inflammatory and barrier markers, immunofluorescence techniques were applied on skin biopsies. Gene expression patterns were analyzed in skin specimens of DD and HHD patients (each n = 2). Results A mixed interleukin (IL)‐13/IL‐17 expression was observed in both DD and HHD. The numbers of IL‐13+ cells were significantly higher in HHD compared with DD ( p = 0.0143; 2.27, CI 95% (0.73, 3.74)). The analysis of gene expression patterns revealed a mixed Th17/Th2/eosinophil signature in lesional skin of DD, and a Th17 signature in HHD. Thymic stromal lymphopoietin was noticed in DD and HHD skin, while an aberrant, weak or missing expression of E‐cadherin, filaggrin and cathelicidin was observed. Treatment with dupilumab or secukinumab was effective in all three patients; however, the latter had to be stopped because of skin infections. Limitations Limitations of the study are the retrospective design, lack of genetic results, low numbers of patients and tissue samples, as well as the preliminary results on the efficacy of biologics in DD and HHD. Conclusions DD and HHD are characterized by Th2 and Th17 immune responses that might result in further epidermal barrier disruption. Thus, reducing the inflammation seems a worth treatment approach, even though the efficacy and safety of targeted therapies have to be proven in larger patient cohorts.