Hidradenitis Suppurativa as a Potential Subtype of Autoinflammatory Keratinization Disease

Abstract

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition, clinically characterized by boiled cysts, comedones, abscesses, hypertrophic scars, and/or sinus tracts typically in the apocrine-gland-rich areas such as the axillae, groin, and/or buttocks. Although its precise pathogenic mechanisms remain unknown, I herein emphasize the importance of the following three recent discoveries in the pathogenesis of HS: First, heterozygous loss-of-function mutations in the genes encoding γ-secretase, including NCSTN, PSENEN, and PSEN1, have been identified in some patients with HS. Such genetic alterations result in hyperkeratosis, dysregulated hair follicle differentiation, and cyst formation via aberrant Notch signaling. Furthermore, Psen1-/Psen2-, Psen1-, Ncstn+/-, and Notch1-/Notch2-mice share common phenotypes of human HS, suggesting a role of aberrant keratinization in the development of HS. Second, upregulation of interleukin 1β, interleukin-36, caspase-1, and NLRP3 and dysregulation of the Th17:Treg cell axis have been demonstrated in HS samples, suggesting that autoinflammation is a key event in the pathophysiology of the disease. Notably, HS may be complicated with other autoinflammatory diseases such as inflammatory bowel diseases and pyoderma gangrenosum, again highlighting the importance of autoinflammation in HS. Last, biologics such as adalimumab, infliximab, anakinra, ustekinumab, and secukinumab are reportedly effective for moderate-to-severe HS. These findings collectively suggest that HS is closely linked with aberrant keratinization and autoinflammation, raising the question whether it represents an autoinflammatory keratinization disease, a recently proposed disease entity. In this mini review, I introduce the concept of autoinflammatory keratinization disease and attempt to address this clinically important question.

Notch Signaling Regulation in Autoinflammatory Diseases

“…Moreover, mutations in POFUT1 and POGLUT1 genes, encoding, respectively, for GDP-fucose protein O-fucosyltransferase 1 protein and protein O-glucosyltransferase 1, two proteins associated with Notch signaling, have been described in patients suffering with HS and Dowling–Degos disease, an autosomic dominant inherited skin disease that can occur alone or in association with HS in which patients present flexural hyperpigmentation [ 53 ].…”

Development of In-Situ Spray for Local Delivery of Antibacterial Drug for Hidradenitis Suppurativa: Investigation of Alternative Formulation

“…There has yet to be a consideration on the design of the formulation where the treatment of early-stage HS could be more effective by enhancing bioadhesive property and retention of the formulation at the site of action. In this regard, using an in situ gel with a prolonged contact time and a sustained drug release effect could improve the therapeutic efficacy as the inflammation is mainly found at the epidermis and upper dermis skin layer [ 8 ]. In situ gels are viscous liquids which have a unique characteristic of undergoing sol-to-gel transitions by the influence of various stimuli, namely pH, temperature, and electrolytes [ 9 ].…”

Hidradenitis suppurativa and amyloidosis: a possible association with the pyrin inflammasome

“…Secondary AA‐type amyloidosis may be encountered throughout the long‐standing course of various inflammatory diseases, including HS, but the association of amyloidosis and HS is intriguing considering the autoinflammatory nature of HS itself. We would like to draw attention to the pathogenic mutations in the genes encoding the components of the pyrin inflammasome and its associated proteins, ME diterranean F e V er ( MEFV ) and P roline– S erine‐ T hreonine P hosphatase I nteracting P rotein 1 ( PSTPIP1 ), as a relevant topic 2,3 …”

“…HS is regarded as an autoinflammatory keratinization disorder, and syndromic forms of HS involve several different mutations of the inflammasome complex 2 . HS may present with a severe phenotype in patients with FMF, and we previously investigated the role of autoinflammation in a relatively large cohort of Turkish patients with HS with a complex inflammatory phenotype 3 .…”

“…HS is regarded as an autoinflammatory keratinization disorder, and syndromic forms of HS involve several different mutations of the inflammasome complex. 2 HS may present with a severe phenotype in patients with FMF, and we previously investigated the role of autoinflammation in a relatively large cohort of Turkish patients with HS with a complex inflammatory phenotype. 3 We found that the odds ratio for carrying a pathogenic MEFV allele was 2.8, and that the M694V and M680I variants, the most amyloidogenic FMF mutations, were associated with the highest risk of HS.…”