Hidradenitis suppurativa is an autoinflammatory keratinization disease: A review of the clinical, histologic, and molecular evidence

Abstract

The pathogenic model of hidradenitis suppurativa is in the midst of a paradigm shift away from a disorder of primary follicular occlusion to an autoinflammatory keratinization disease. Observational, experimental, and therapeutic evidence supports the concept of hidradenitis suppurativa as a primarily inflammatory disorder, a disorder of autoimmunity, or both, in contrast to the current prevailing paradigm of primary follicular occlusion. The lack of reliable and high-fidelity disease models has limited the available experimental and mechanistic evidence to support or refute one pathogenic model over another. This scholarly review synthesizes the existing clinical, histologic, and molecular data to evaluate the extant evidence supporting the autoinflammatory paradigm and further informing the molecular mechanisms of hidradenitis suppurativa pathogenesis. Follicular hyperkeratosis/occlusion and perifollicular inflammation coexist in histologic specimens, with interleukin 1a demonstrated to stimulate comedogenesis in the infundibulum. pH elevation in occluded body sites alters the microbiome and amplifies existing T-helper cell type 17 immunoresponses. Known metabolic comorbidities and smoking are known to upregulate interleukin 1a in follicular keratinocytes. Identified genetic variants may alter epidermal growth factor receptor signaling, leading to upregulated keratinocyte inflammatory responses. The process of follicular rupture and dermal tunnel formation can be explained as secondary responses to inflammatory activation of fibroblasts and epithelial-mesenchymal transition, with antibody production associated with inflammatory amplification in advanced disease. This review aims to reevaluate and integrate the current clinical, histologic, and molecular data into a pathogenic model of hidradenitis suppurativa. This is essential to advance our understanding of the disease and identify novel therapeutic targets and approaches.

Angiogenesis in Chronic Inflammatory Skin Disorders

“…Increased TNF-α from the keratocytes and activated dendritic cells and IL-17 from the Th17 cells are key cytokines in HS [ 116 ]. Furthermore, IL-1α was demonstrated to stimulate comedogenesis in the follicular infundibulum [ 117 ]. Because IL-1α is a potent inducer of the production of VEGF [ 118 ], it can be inferred that angiogenesis may play a role in the pathogenesis of HS.…”

The Microbiome in Hidradenitis Suppurativa: A Review

“…The role of the microbiome in the pathogenesis of HS remains unclear. There is evidence that inflammation is the triggering event to follicular occlusion and subsequent follicular rupture and fistula formation [ 62 ]. Whether the dysbiosis and alternations in the local microbiome are pathogenic and a driver in the underlying inflammatory processes, or a result, remains to be elucidated.…”

Clinical considerations in the management of hidradenitis suppurativa in women

“…In recent years, there has been increasing observational, experimental, and therapeutic evidence that HS has features of a chronic, autoinflammatory, keratinization disorder ( Frew, 2021 ). Hormone dysfunction is thought to play a role in the underlying pathogenesis given the association of HS with hormonal acne vulgaris, polycystic ovarian syndrome (PCOS), and fluctuations in HS disease severity associated with the menstrual cycle ( Riis et al, 2016 ).…”

“…The existing HS pathogenic paradigm holds that end-organ (follicular) activity of sex hormones may play a role in disease pathogenesis ( Frew, 2021 ). However, studies have not shown immunohistochemical evidence of dysregulated sex hormone receptors in the lesional skin of patients with HS when compared with healthy controls ( Frew et al, 2018 ).…”