Hidradenitis Suppurativa: A Systematic Review Integrating Inflammatory Pathways Into a Cohesive Pathogenic Model

Abstract

Background: The pathogenesis of hidradenitis suppurativa (HS) is not fully understood. This systematic review examined the latest evidence for molecular inflammatory pathways involved in HS as a chronic inflammatory skin disease.Methods: A systematic literature search was performed in PubMed/Medline and EMBASE from January 2013 through September 2017, according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA). Findings on HS pathogenesis were also compared with those of other immune-mediated inflammatory diseases (IMIDs) in a non-systematic review. In addition, current therapeutic options for HS are briefly discussed on the basis of the findings for the inflammatory pathways involved in HS.Results: A total of 32 eligible publications were identified by the systematic search; these were supplemented with three additional publications. The extracted data indicated that four key themes underlie the pathogenesis of HS and related syndromic conditions. First, nicastrin (NCSTN) and PSTPIP1 mutations are directly associated with auto-inflammatory disease. Secondly, the up-regulation of several cytokines including tumor necrosis factor-α and T helper-17/interleukin-23 are connected to auto-inflammatory mechanisms in the pathogenesis of HS. Thirdly, the microbiome of lesional skin differs significantly vs. normal-appearing skin. Fourthly, HS risk is enhanced through physiological and environmental factors such as smoking, obesity, and mechanical friction. There is significant overlap between the pathogenesis of HS, its syndromic forms and other IMIDs, particularly with respect to aberrations in the innate immune response.Conclusions: The evidence presented in this review supports HS as an auto-inflammatory skin disorder associated with alterations in the innate immune system. Based on these most recent data, an integrative viewpoint is presented on the pathogenesis of HS. Current management strategies on HS consist of anti-inflammatory therapies, surgical removal of chronic lesions, and lifestyle changes such as smoking cessation and weight loss. As large gaps remain in the understanding of the pathogenesis of HS, further research is warranted to ultimately improve the management and treatment of patients with HS and related syndromic conditions.

Alterations in innate immunity and epithelial cell differentiation are the molecular pillars of hidradenitis suppurativa

“…Inflammation plays an important role in the pathogenesis of HS. In LS, cytokines and chemokines, such as TNFα, IL1, IL6, IL10, IL12, IL17, IL23, interferon (IFN)γ, phosphodiesterase‐4, complement 5α, uteroglobulin, chemokine (C‐X‐C motif) ligand (CXCL)6, CXCL9, CXCL11, CX3CL1, CC‐chemokine ligand (CCL)2, CCL18, TLR2, soluble IL2 receptor are upregulated, as described in proteome studies . Especially IL23 has been shown to induce IL17‐producing T helper cells (Th17), which infiltrate the dermis in HS lesions .…”

Integrating complement into the molecular pathogenesis of Hidradenitis Suppurativa

“…Other inflammatory mediators have been identified as compartmentalized between HS serum and lesional tissue by Kanni et al, [16] and it would be valuable to ascertain whether this also holds true for C5a. [17] This begs the question as to whether complement is a central component of the pathophysiology of HS alongside Th17 activation, or a secondary consequence (ie bystander) of inflammatory pathway activation and neutrophil activity. Based upon the serological results of Kanni et al, [15] complement inhibition has been identified as a potential therapeutic target in HS.…”

“…[17] Given the dual expression of C5aR1 and C5aR2 on dermal fibroblasts and mast cells, [29] complement dysregulation may also contribute to the activation of fibroblasts. Pruritus is also a common manifestation, which often goes under-reported.…”

No evidence that impaired Notch signalling differentiates hidradenitis suppurativa from other inflammatory skin diseases

“…However, Notch dysregulation has also been identified in keratinocytes of other inflammatory dermatoses including psoriasis and atopic dermatitis . Animal knockout models of components of the GSC with resultant Notch dysregulation result in the development of dermal cysts and histological features of follicular occlusion, suggesting that aberrant Notch signalling is linked to the unique clinical and histological manifestations of HS . However, these models also rapidly develop multiple squamous cell carcinomas, which is not consistent with the typical progression of HS.…”

“…Animal knockout models of components of the GSC with resultant Notch dysregulation result in the development of dermal cysts and histological features of follicular occlusion, suggesting that aberrant Notch signalling is linked to the unique clinical and histological manifestations of HS . However, these models also rapidly develop multiple squamous cell carcinomas, which is not consistent with the typical progression of HS. The precise role of Notch dysregulation as the primary driver in the molecular pathogenesis of HS is unclear.…”