A systematic review and critical evaluation of inflammatory cytokine associations in hidradenitis suppurativa

Abstract

Background: The pathogenesis of hidradenitis suppurativa (HS) remains unclear. In order to develop effective treatment strategies, a deeper understanding of pathophysiology is needed. This is impaired by multiple small studies with inconsistent methodologies and the impact of co-occurring pro-inflammatory conditions such as smoking and obesity. Methods: This systematic review aimed to collate all published reports of cytokine studies in tissue, blood, serum and exudate. It was registered with PROSPERO (Registration number CRD42018104664) performed in line with the PRISMA checklist. Results: 19 studies were identified comprising 564 individual HS patients and 198 control patients examining 81 discrete cytokines. Methodology was highly varied and the quality of studies was generally low. There was a large degree of variance between the measured levels of cytokines. 78.2% of cytokines demonstrated heterogeneity by the chi-squared test for homogeneity and hence meta-analysis was not deemed appropriate. However, a strong and significant IL-17 signalling component was identified. Conclusions: Cytokines consistently elevated in lesional, peri-lesional and unaffected tissue are identified and discussed. Areas for further investigation include the role of dendritic cells in HS; the contribution of obesity, smoking, diabetes and the microbiome to cytokine profiles in HS; and examining the natural history of this disease through longitudinal measurements of cytokines over time.

Keywords: Cytokines; Hidradenitis Suppurativa; IL-17; Inflammation; Pathogenesis; TNF-alpha.

Figure 1.. PRISMA Flowchart.

Figure 2.. Inflammatory pathways in hidradenitis suppurativa, a schematic representation of the results identified in this systematic review.

Immunological ‘priming’ occurs due to the contribution of adipose tissue, genetic susceptibility, smoking-related inflammatory mediators and obesity related pro-inflammatory signals and the composition of the microbiome. Increased activity of cDC1, cDC2 and T cells lead to both keratinocyte hyperplasia via the actions of IL-12 and IL-23, as well as a Th17 predominant immune response. Alterations of antimicrobial peptides (AMP’s) also occur throughout the epidermis. The dermal inflammation interacting with the hyperplastic epidermis result leads to a self-perpetuating inflammatory feed forward mechanism mediated by IL-36, Il-1B and TNF-a. The development of scarring and sinus tracts is associated with MMP2, ICAM-1 and TGF-Beta, with possible augmentation of ICAM-1 and TGF-B signaling via specific components of the microbiome. TNF-a, PGE2 and CXCL2 then lead to additional feed forward mechanisms perpetuating the inflammatory cycle.

Figure 3.. Funnel plot of selected cytokine in lesional and control samples of hidradenitis suppurativa.

IL-1a = Red, IL-10 = Blue, IL-12p70 = Green, hBD1 = Purple, hBD2 = light purple, hBD3 = Black, S100A9 = White, GMCSF = Yellow.