Intrinsic factors in the pathogenesis of hidradenitis suppurativa: Genetics, hormones, and the microbiome.

The pathogenesis of hidradenitis suppurativa is complex and multifaceted. Our understanding of disease mechanisms is in constant flux with new genetic, inflammatory, and microbiological insights upending previous paradigms and enlightening us as to the complex connections between different drivers of disease. This updated review integrates novel genetic insights from genome wide association studies, along with novel basic science data from single cell transcriptomic studies and recent interventional translational work to inform our evolving understanding of the disease. The overarching premise is that hidradenitis suppurativa is a chronic autoinflammatory disorder characterized by inflammatory dysregulation in a background of stem cell fate aberrations highly responsive to hormonal and metabolic changes. Genetic drivers are linked to both hair follicle stem cell fate and cellular response to androgen signaling. The complex mixed inflammatory circuits involve both innate and adaptive immunity, with activation of inflammatory fibroblast subsets and tertiary lymphoid organs in chronic disease. Interplay between inflammation, the cutaneous and gut microbiomes are observed both pre- and posttherapy, however causality remain unclear. Metabolic syndrome, sex hormones and insulin resistance are all interlinked, with adipose tissue being a hormonally active organ able to modulate endogenous sources of sex hormones. Future enquiry regarding factors contributing to disease progression and the identification of novel therapeutic targets will aid in more effective therapeutic strategies for management of this burdensome disease.