Dear Editor,

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease originating in the hair follicle. The etiopathogenesis is not yet fully understood, but there appears to be consensus that infundibular hyperkeratosis is an important element. The question, however, remains: is keratosis a primary or secondary phenomenon?

Genetic predisposition, the microbiome, inflammation, and mechanical stress have all been postulated to play a role in the development and progression of the disease. Mechanical stress may cause HS-like lesions, and lesions have been observed to co-localize with changes (striae distensae) that influence the mechanical properties of the dermis. A role for simple mechanical forces in the pathogenesis of HS is also supported by the statistical association between HS and diseases that affect the functional properties of collagen in general, such as Marfan’s syndrome and Ethers-Danlos syndrome [1]. These clinical and epidemiological observations, however, need further exploration. Here we hypothesize the role of mechanical forces in HS development and evolution.

Histopathological features of early HS include follicular occlusion, hyperplasia of the follicular epithelium, and an initial lymphocytic perifolliculitis [2, 3]. This has led to the suggestion that follicular occlusion plays a crucial role and may trigger cyclic inflammation in HS-prone individuals. One recent article indicated that HS arises from the infundibular epithelium of both terminal and vellus hairs [2]. It was further noticed that several publications described distorted keratinocyte proliferation in the hair follicle [2]. Van der Zee et al. [4] described follicular occlusion, hyperplasia, and a mild leucocytic proliferation in perilesional skin which may suggest a structural abnormality existing prior to inflammation. IL-1β stimulation of the outer root sheath keratinocytes in HS has been shown to secrete significantly more IL-6, IL-8, TNF-α, IP-10, and CCL5 compared to healthy controls [5].

Hair removal improves HS by an unknown mechanism, but it may involve a mechanical element. The interaction between the rapidly growing hair and the epithelium of the surrounding follicle is a dynamic, carefully monitored process that allows the hair to grow along the relatively immoveable follicular epithelium. It may be speculated that the persistent sear forces within the follicle that occur between the growing hair and the root sheet furnish the initial steps of the HS pathogenesis.

If the presupposition is correct, we expect cell-cell communication and differentiation abnormalities to occur, either on a genetic or environmental level, and cause functional changes in the hair growth of HS patients. The GJB-2 gene encodes Connexin-26 which is found in human hair follicles and eccrine sweat glands, and mutations in the gene have been linked to HS [6]. Connexin 26 is a member of the gap junction proteins, which allow cellular communication and maintain homeostasis, growth, and development. Mutations in this gene have been linked to disorders of keratinization [5]; moreover, these defects may cause hyperproliferation of the epidermis or follicular hyperkeratosis. Furthermore, associations with HS have been found in genes encoding keratinization genes and gamma secretase complex. Some gene mutations of the subunits of gamma secretase complex, namely NCSTN, PSEN1, PSEN2, seem to result in defective Notch signaling which may play a role in the development of cysts and comedones as well as altering keratinocyte proliferation [7].

The functional characteristics of keratinocytes in the uninflamed hair follicle and its epithelium may therefore play a central role in HS. Testing this hypothesis involving the intra-follicular shear forces is further complicated by the dynamic characteristics of the hair follicle.

GBE Jemec has received honoraria from AbbVie, ChemoCentryx, Coloplast, Incyte, InflaRx, Novartis, Pierre Fabre, and UCB for participation on advisory boards; grants from AbbVie, AstraZeneca, Inflarx, Janssen-Cilag, Leo Pharma, Novartis, Regeneron, and Sanofi for participation as an investigator; speaker honoraria from AbbVie, Boehringer Ingelheim, Galderma, and MSD; and unrestricted departmental grants from AbbVie, Leo Pharma, and Novartis. B. Hrvatin Stančič received honoraria for lectures and consultancies by AbbVie and Eli Lilly and support for attending meetings by Janssen and AbbVie. J. Boer and M. Dolenc Voljč had no conflicts of interest to declare.

The authors received no financial support for the research, authorship, or publication of this article.

Bor Hrvatin Stancic, Jurr Boer, Mateja Dolenc-Voljč, and Gregor B.E. Jemec contributed equally in the conception, discussion, and preparation of this article. Bor Hrvtain Stancic and Gregor B.E. Jemec prepared the final version of the manuscript. The final version of the article was approved by all the above mentioned authors, prior to submission.

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