Follicular Occlusion and Inflammation

Introduction

The pathogenic model of hidradenitis suppurativa (HS) may be in the midst of a paradigm shift, balancing the initial model of a disorder of (primary) follicular occlusion with consideration as an autoinflammatory keratinization disease (AiKD). There is observational, experimental, and therapeutic evidence to support the concept of HS as a primarily inflammatory disorder and/or a disorder of autoimmunity (in contrast to that primarily of follicular occlusion); however, the lack of reliable disease models has limited experimental/mechanistic evidence to support or refute one pathogenic model over another ( Fig. 10.1 ). Continual re-evaluation and integration of current clinical, histological, and molecular data into our pathogenic model of HS is essential in order to advance our understanding of the disease. Challenging existing paradigms through observation, hypothesis, and experimentation (while maintaining an open mind) is a core component of the scientific process, and is essential to enable accurate identification of novel therapeutic targets and treatment strategies. It is also vital to the understanding of differential treatment response in different individuals and exploring the potential role of variations in inflammatory endotypes (disease subtypes defined by a distinct functional or pathological mechanism) in the disease, in a similar way to how this has been identified in atopic dermatitis. This review aims to synthesize existing knowledge from clinical observation, classical histology, as well as modern molecular biology techniques to evaluate the evidence for HS as either a disorder of follicular occlusion or an AiKD.

The Evolving Pathogenic Paradigm(s) of Hidradenitis Suppurativa

Historically, HS has been proposed to be a disorder of apocrine gland inflammation, although multiple independent histological studies have demonstrated that inflammatory involvement of apocrine glands is a secondary phenomenon, and that the primary inflammatory driver of the disease exists adjacent to keratinocytes of the follicular infundibulum and interfollicular epidermis. It is now widely accepted that the primary driver of disease activity centers upon the follicular infundibulum. Additionally, other disorders such as pilonidal sinus disease and dissecting cellulitis of the scalp share many clinical, histological, and inflammatory features with HS and are beginning to be considered as uni-localized variants of disease. Melnik’s seminal 2013 paper began to shift the pathogenic paradigm of HS away from an apocrine-gland based inflammatory or infectious disorder, to a disorder of follicular occlusion and proposed dysregulated Notch signaling as the unifying feature of HS pathogenesis.

Emerging evidence as to the role of the inflammasome, complement, and IL-1 isoforms has led to the suggestion of HS as an AiKD. Evidence of systemic inflammation, activation of B cells, and plasma cells have raised the possibility of HS having an autoimmune or antibody-mediated component. However, follicular occlusion is still considered the “primem movens” of HS preceding the inflammatory drive of disease.

The Problem(s) with Animal and Ex-Vivo Models in Hidradenitis Suppurativa

The development of animal models in HS dates from the identification of gamma secretase associated polymorphisms in familial HS. Gamma secretase and Notch-1 null mice were incompatible with life due to the vital role of notch signaling in body segment development; however, post-natal knockdown of Notch-1 results in hyperproliferative epidermis, hair loss, and epidermal cyst formation in adult mice. Combined Notch-1 and Notch-2 knockdown results in an atopic-dermatitis-like epidermal disorder and a rapidly fatal myeloproliferative disorder in adult mice. When interpreting these results through the follicular occlusion paradigm, it is reasonable to assume that epidermal cyst formation is consistent with the proposed initial steps in HS pathogenesis; however, the lack of inflammation, cyst rupture or tunnel development argue against Notch-1 knockdown being a high fidelity animal model for HS.

One possible explanation for the lack of comparable dermal inflammation and tunnel formation in Notch-1 knockdown murine models may be the difference in dermal thickness between human and murine skin and the differential localization of the follicular unit in the dermis (human) and subcutis (murine). In order to overcome these potential issues, a murine xenotransplantation model was developed involving direct transplantation of lesional HS tissue to immunosuppressed mice. The most recent model developed involves a transwell ex-vivo model, which overcomes the structural and morphological issues of dermal thickness and follicular insertion of murine models and has relatively less infection risk than xenotransplantation models. However, given the overlapping limitations of existing models, only translational studies of interventions in human subjects give the greatest fidelity in both mechanistic and clinically relevant responses to pharmacological interventions in HS in order to explore the pathogenic mechanisms of disease.

Follicular Occlusion: Comedones are Clinically and Experimentally a Product of Inflammation, Rather Than a Cause

Histological studies illustrate the prominent roles of comedogenesis, follicular hyperkeratosis, and comedogenesis in HS tissues. However, in each instance, the coexistence of perifollicular inflammation is comparably prominent. Clinically, comedones (both open and closed), as well as typical double-sided comedones, are present in diseased areas, inflamed tissues, and also in scarred, non-inflamed tissues. They are also present in areas not exposed to flexural occlusion.

Von Laffert et al. report comedones as more common in end stage fibrotic and scarred lesions and independent of the follicular unit. These comedones are more likely to be those of the double-ended variety which were once considered to be pathognomonic of HS. From these clinical observations, it can be concluded that comedones are associated with HS; however, the establishment of causation requires mechanistic evidence. Such mechanistic evidence is available thanks to investigations into comedogenesis in acne research. Recent findings have identified subclinical inflammation as preceding comedogenesis in acne prone skin, disrupting the longstanding assumption that follicular occlusion is the primary initiating factor in acne. The molecular mechanisms of comedogenesis involve follicular keratinocytes, producing a number of pro-inflammatory mediators (including antimicrobial peptides, microbial associated proteins including lipotechoic acid, CCL20, and IL-1α). Ex-vivo studies of the follicular infundibum isolated in vitro are able to recapitulate the formation of comedones with addition of IL-1α and prevent formation with the addition of IL-1RA. It is acknowledged that the in vitro studies performed are based on highly sebaceous follicular units which have distinct differences from apocrine bearing skin ; however, the similarities in immunological milieu between sebaceous and apocrine skin in Th17 associated mediators (central to inflammation in HS) raise the theoretical possibility of these mechanisms being shared between body sites. Reproduction of these experiments using follicular infundibular from apocrine gland bearing regions would hopefully be definitive in confirming or refuting these findings.

Therefore, it can be concluded that molecular and ex-vivo evidence suggests comedone formation is possible secondary to subclinical inflammation, rather than inflammation being the result of comedone formation and follicular rupture. The precise mechanisms that have been demonstrated in human skin, however, require validation in apocrine gland bearing skin given the unique immunological milieu of these sites. These results may explain the diffuse scattering of comedones seen in HS prone areas, the presence of comedones in extra-flexural sites, and the presence of comedones in previously inflamed (“burnt out”) tissue or sites distant from a follicular unit. It also raises the additional question of what differentiates conditions in which subclinical inflammation and diffuse flexural comedone formation (such as Dowling-Degos disease ) exist, from highly inflammatory HS lesions. Direct molecular comparisons of these conditions may further inform the differences in subclinical inflammation that leads to the development of one condition over another (or the coexistence of both conditions at different timepoints).