Classification of skin transcriptome reveals two molecular subtypes in hidradenitis suppurativa

Abstract

Background and AimsHidradenitis suppurativa (HS) is an understudied chronic inflammatory skin disease that is characterized by painful bumps and abscesses. Adalimumab and secukinumab are the only two approved biologics for the treatment of HS. Despite these advances in the treatment of disease, there remains significant unmet medical need, with many patients only achieving moderate improvements in disease, or continuing to experience flares. This suggests that there may be distinct patient subsets with unique molecule drivers of disease. The aim of this study is to identify and characterize the molecular subtypes of HS patients to further understand its heterogeneity. MethodsSix public datasets with a total of 100 skin lesional samples were integrated to identify molecular subtypes and build a 36-gene classifier, which was validated by three independent lesional skin datasets. Two out of six training datasets generated from patients treated with adalimumab were used to identify the relationship between subtypes and response status. ResultsTwo molecular subtypes were identified from the training datasets, in which subtype S1 had a higher response rate of adalimumab than subtype S2 in the two adalimumab treatment datasets. Subtype S1 was characterized by three gene modules associated with keratinization, development, and metabolism, and six cell types related to sebocytes, smooth muscle cells, endothelial cells, schwann cells, basal cells, and proliferating cells. Subtype S2 was associated with three modules related to immune response, wound healing, keratinization, and cell cycle, and three cell types related to T lymphocytes, dendritic cells, and fibroblasts. The two subtypes were replicated in three additional independent datasets. ConclusionsThis study discovered and validated two HS subtypes with different molecular mechanisms and drug response, which may aid interpretation of heterogeneous molecular and clinical information in HS patients.