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Hidradenitis suppurativa is an autoinflammatory keratinization disease: A review of the clinical, histologic, and molecular evidence

Open AccessPublished:June 27, 2020DOI:https://doi.org/10.1016/j.jdin.2020.05.005
      The pathogenic model of hidradenitis suppurativa is in the midst of a paradigm shift away from a disorder of primary follicular occlusion to an autoinflammatory keratinization disease. Observational, experimental, and therapeutic evidence supports the concept of hidradenitis suppurativa as a primarily inflammatory disorder, a disorder of autoimmunity, or both, in contrast to the current prevailing paradigm of primary follicular occlusion. The lack of reliable and high-fidelity disease models has limited the available experimental and mechanistic evidence to support or refute one pathogenic model over another. This scholarly review synthesizes the existing clinical, histologic, and molecular data to evaluate the extant evidence supporting the autoinflammatory paradigm and further informing the molecular mechanisms of hidradenitis suppurativa pathogenesis. Follicular hyperkeratosis/occlusion and perifollicular inflammation coexist in histologic specimens, with interleukin 1α demonstrated to stimulate comedogenesis in the infundibulum. pH elevation in occluded body sites alters the microbiome and amplifies existing T-helper cell type 17 immunoresponses. Known metabolic comorbidities and smoking are known to upregulate interleukin 1α in follicular keratinocytes. Identified genetic variants may alter epidermal growth factor receptor signaling, leading to upregulated keratinocyte inflammatory responses. The process of follicular rupture and dermal tunnel formation can be explained as secondary responses to inflammatory activation of fibroblasts and epithelial-mesenchymal transition, with antibody production associated with inflammatory amplification in advanced disease. This review aims to reevaluate and integrate the current clinical, histologic, and molecular data into a pathogenic model of hidradenitis suppurativa. This is essential to advance our understanding of the disease and identify novel therapeutic targets and approaches.

      Key words

      Abbreviations used:

      EGFR (Epidermal growth factor receptor), IL (interleukin)
      • Hidradenitis suppurativa is known as a disorder of follicular occlusion, with inflammation being a primary manifestation of disease. Clinical, histologic, and molecular evidence suggests that inflammation is central to multiple aspects of disease, but this remains poorly integrated into the existing pathogenic paradigm.
      • Histologic and molecular evidence supports the concept of inflammation as the primary driver of disease activity in hidradenitis suppurativa. It enables explanation of observed events such as follicular rupture, tunnel formation, and systemic inflammation, which are poorly described in the follicular occlusion paradigm. Hidradenitis suppurativa is an autoinflammatory keratinization disease. Reframing our pathologic and clinical understanding in the context of this paradigm is vital to identify and implement novel therapeutic strategies for this burdensome disease.

      Introduction

      The pathogenic model of hidradenitis suppurativa is in the midst of a paradigm shift
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      Autoinflammatory keratinization diseases.
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      Hidradenitis suppurativa: a systematic review integrating inflammatory pathways into a cohesive pathogenic model.
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      There is observational, experimental, and therapeutic evidence to support the concept of hidradenitis suppurativa as a primarily inflammatory disorder,
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      Autoinflammatory keratinization diseases.
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      Neutrophil extracellular traps, B cells, and type I interferons contribute to immune dysregulation in hidradenitis suppurativa.
      (in contrast to that primarily of follicular occlusion), or both (Fig 1); however, the lack of reliable disease models
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      has limited experimental and mechanistic evidence to support or refute one pathogenic model over another (Fig 1). This review aims to reevaluate and integrate the current clinical, histologic, and molecular data into a pathogenic model of hidradenitis suppurativa. This is essential to advance our understanding of the disease
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      Commentary: hidradenitis suppurativa: a systematic review integrating inflammatory pathways into a cohesive pathogenic model.
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      Figure thumbnail gr1
      Fig 1Schematic representation and comparison of the follicular occlusion paradigm (left panel) and the autoinflammatory paradigm (right panel) in the pathogenesis of hidradenitis suppurativa. In the follicular occlusion paradigm, deficient Notch signaling (1) directly results in infundibular keratinocyte proliferation and follicular occlusion (2), leading to follicular dilatation, rupture, and resultant inflammation. One deficiency of this paradigm is the lack of hypothesized mechanisms by which rupture occurs and why deep follicular rupture occurs preferentially to expulsion of the comedo. The resultant T-helper cell 1/17 inflammatory axis (3) (4) then results in the observed inflammatory profile of disease; however, no clear mechanism is hypothesized for how tunnels form and how the infiltrative proliferative gelatinous mass results. The autoinflammatory paradigm (right panel) places inflammation as the primary driver of disease, with subclinical inflammation (1) developing as a result of disparate contributing factors on a background of topographic predisposition. Dermal inflammatory infiltrates (2) then drive secondary follicular occlusion (3 and 4), with resultant tunnel formation a consequence of keratinocyte-mesenchymal interactions (5) that mimic outer-root sheath keratinocyte downgrowth in follicular development in early anagen. Chemokine gradients in epithelialized tunnels then drive neutrophil trafficking to the lumen and formation of the infiltrative proliferative gelatinous mass (6).

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      raises the possibility that these mechanisms are shared. Molecular and ex vivo evidence suggests comedo formation may be secondary to subclinical inflammation. These results may explain the diffuse scattering of comedones observed in hidradenitis suppurativa–prone areas, the presence of comedones in extraflexural sites, and their presence in previously inflamed (“burned-out”) tissue or sites distant from a follicular unit.
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      Hidradenitis suppurativa (acne inversa): early inflammatory events at terminal follicles and at interfollicular epidermis.

      Skin fold occlusion is associated with microbiome alterations and subsequent proinflammatory keratinocyte responses

      From a clinical perspective, follicular occlusion may refer to anatomic sites of disease predilection (axillary, inguinal, and submammary folds).
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      Infundibular keratinocytes produce CCL20 and antimicrobial peptides under normal physiologic conditions
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      promoting the colonization and activity of hidradenitis suppurativa–associated microbionts (eg, Porphyromonas)
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      (Fig 2). Other bacteria,
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      Indirect evidence for the role of yeasts in inflammatory activity in hidradenitis suppurativa
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      ASCA antibodies in hidradenitis suppurativa: more than a gut feeling.
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      Staphylococcus aureus lipoteichoic acid damaged the epidermal barrier through an IL-1 mediated pathway.
      Figure thumbnail gr2
      Fig 2Initiating factors in hidradenitis suppurativa. Normal control skin (first panel from the left) from hidradenitis suppurativa–associated cutaneous sites (eg, axilla) have normal colonizing microbionts (including within the follicular infundibulum), which are continuously monitored by circulating immune cells in homeostasis (circulating to and from regional lymph nodes (inset in first panel from the left). Known predisposing factors, including skin occlusion (second panel from left), predisposing genetic mutations (third panel from the left), and proinflammatory comorbidities such as obesity and insulin resistance, increase the inflammatory drive of infundibular keratinocytes (purple rectangular cells) via varied mechanisms. Skin occlusion (second panel from the left) alters the microbiological composition of the skin (red and yellow microbionts) via increases in cutaneous pH. These microbionts increase the production of CCL20 and interleukin (IL) 1α by infundibular keratinocytes. Genetic mutations in the γ-secretase complex are known to affect Notch signaling and also substrates including epidermal growth factor receptors, which are active in the follicular infundibulum. Dysregulation of EGFR signaling is known to increase CCL20 and IL-1α production by infundibular keratinocytes. Metabolic comorbidities produce increased levels of circulating tumor necrosis factor-α, IL-1β, and IL-6. These mediators stimulate CCL20 and IL-1α production.

      Inflammation in hidradenitis suppurativa: evidence from existing studies

      The inflammatory signature of established hidradenitis suppurativa has been well characterized in multiple histologic
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      Similarities and parallels with psoriasis
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      have been observed in lesional and perilesional hidradenitis suppurativa tissue,
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      Role of the complement pathway in inflammatory skin diseases: a focus on hidradenitis suppurativa.
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      Chronic long-standing disease appears autoinflammatory
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      Neutrophil extracellular traps, B cells, and type I interferons contribute to immune dysregulation in hidradenitis suppurativa.
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      NETosis,
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      Neutrophil extracellular traps, B cells, and type I interferons contribute to immune dysregulation in hidradenitis suppurativa.
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      An issue with understanding the characteristics of inflammation in hidradenitis suppurativa is that the majority of specimens isolated for studies are from individuals with severe, long-standing disease.
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      Neutrophil extracellular traps, B cells, and type I interferons contribute to immune dysregulation in hidradenitis suppurativa.
      ,
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      Enrichment of plasma cells in the peripheral blood and skin of patients with hidradenitis suppurativa.
      ,
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      • et al.
      Integrating the skin and blood transcriptomes and serum proteome in hidradenitis suppurativa reveals complement dysregulation and a plasma cell signature.
      Hence, we have limited insight into the initiating events in early and mild hidradenitis suppurativa. Additionally, until recently there were no standardized, defined biopsy sites for investigational studies.
      • Frew J.W.
      • Navrazhina K.
      • Byrd A.S.
      • et al.
      Defining lesional, perilesional and unaffected skin in hidradenitis suppurativa: proposed recommendations for clinical trials and translational research studies.
      Given that hidradenitis suppurativa is morphologically diverse, it would be erroneous to assume that a biopsy from one portion of tissue is representative of all the different epidermal (and deep dermal) morphologies present across the spectrum of hidradenitis suppurativa.
      • Frew J.W.
      • Navrazhina K.
      • Byrd A.S.
      • et al.
      Defining lesional, perilesional and unaffected skin in hidradenitis suppurativa: proposed recommendations for clinical trials and translational research studies.
      Therefore, studies that do not define the severity, treatments, sites, and lesion types of biopsies should be interpreted with caution.
      • Frew J.W.
      • Hawkes J.E.
      • Krueger J.G.
      A systematic review and critical evaluation of immunohistochemical associations in hidradenitis suppurativa.
      ,
      • Frew J.W.
      • Hawkes J.E.
      • Krueger J.G.
      A systematic review and critical evaluation of inflammatory cytokine associations in hidradenitis suppurativa.
      The mechanisms of lesion development are unclear because perilesional inflammation is of the same character (albeit less intense) as nearby lesional inflammation
      • Frew J.W.
      • Hawkes J.E.
      • Krueger J.G.
      A systematic review and critical evaluation of inflammatory cytokine associations in hidradenitis suppurativa.
      ,
      • Vossen A.R.J.V.
      • Ardon C.B.
      • van der Zee H.H.
      • Lubberts E.
      • Prens E.P.
      The anti-inflammatory potency of biologics targeting tumour necrosis factor-alpha, interleukin (IL)-17A, IL-12/23 and CD20 in hidradenitis suppurativa: an ex vivo study.
      ,
      • Vossen A.R.J.V.
      • van Straalen K.R.
      • Florencia E.F.
      • Prens E.P.
      Lesional inflammatory profile in hidradenitis suppurativa is not solely driven by IL-1.
      ; however, lesional cytokine profiles are unable to be experimentally generated from the addition of IL-1α, IL-1β, or both to perilesional tissue.
      • Frew J.W.
      • Piguet V.
      Ex-vivo models and interpretation of mechanistic studies in hidradenitis suppurativa.
      ,
      • Vossen A.R.J.V.
      • van Straalen K.R.
      • Florencia E.F.
      • Prens E.P.
      Lesional inflammatory profile in hidradenitis suppurativa is not solely driven by IL-1.
      This raises the prospect that the process of inflammation in hidradenitis suppurativa is more complex than initially thought and that the inflammatory characteristics of perilesional tissue are distinct from those of lesional tissue.
      • Frew J.W.
      • Piguet V.
      Ex-vivo models and interpretation of mechanistic studies in hidradenitis suppurativa.

      Disease initiation is associated with systemic subclinical inflammation and dysregulated infundibular keratinocytes

      Understanding of the initiating factors associated with the excessive and self-perpetuating perifollicular inflammation in hidradenitis suppurativa remains incomplete. Epidemiologic and clinical observations suggest that a number of systemic disorders (including insulin resistance, hormonal dysregulation, and obesity) may be associated with hidradenitis suppurativa
      • Porter M.L.
      • Kimball A.B.
      Comorbidities of hidradenitis suppurativa.
      and contribute to a proinflammatory state
      • Jimenez-Gallo D.
      • de la Varga-Martinez R.
      • Ossorio-Garcia L.
      • Albarran-Planelles C.
      • Rodriguez C.
      • Linares-Barrios M.
      The clinical significance of increased serum proinflammatory cytokines, C-reactive protein, and erythrocyte sedimentation rate in patients with hidradenitis suppurativa.
      ,
      • Kanni T.
      • Tzanetakou V.
      • Savva A.
      • et al.
      Compartmentalized cytokine responses in hidradenitis suppurativa.
      (Fig 2). In other inflammatory disorders, such as psoriasis,
      • Jensen P.
      • Skov L.
      Psoriasis and obesity.
      rheumatoid arthritis,
      • Romano S.
      • Salustri E.
      • Ruscitti P.
      • Carubbi F.
      • Penco M.
      • Giacomelli R.
      Cardiovascular and metabolic comorbidities in rheumatoid arthritis.
      and atherosclerosis,
      • Raggi O.P.
      • Genest J.
      • Giles J.T.
      • et al.
      Role of inflammation in the pathogenesis of atherosclerosis and therapeutic interventions.
      these factors have been found to be associated. However, the causation between disease and systemic inflammation is still a topic of contention.
      • Jemec G.B.
      • Hansen U.
      Histology of hidradenitis suppurativa.
      Guidelines
      • Alikhan A.
      • Sayed C.
      • Alavi A.
      • et al.
      North American clinical management guidelines for hidradenitis suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations: part II topical, intralesional and systemic medical management.
      ,
      • Zouboulis C.C.
      • Desai N.
      • Emtestam L.
      • et al.
      European S1 guideline for the treatment of hidradenitis suppurativa/acne inversa.
      and clinical evidence
      • Simonart T.
      Hidradenitis suppurativa and smoking.
      ,
      • Gallagher C.
      • Kirthi S.
      • Burke T.
      • O'Shea D.
      • Tobin A.M.
      Remission of hidradenitis suppurativa after bariatric surgery.
      suggest weight loss, smoking cessation, and dietary counseling as an integral part of hidradenitis suppurativa management
      • Alikhan A.
      • Sayed C.
      • Alavi A.
      • et al.
      North American clinical management guidelines for hidradenitis suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations: part II topical, intralesional and systemic medical management.
      ,
      • Zouboulis C.C.
      • Desai N.
      • Emtestam L.
      • et al.
      European S1 guideline for the treatment of hidradenitis suppurativa/acne inversa.
      through suppression of inflammation.
      • Reily S.M.
      • Saltiel A.R.
      Adapting to obesity with adipose tissue inflammation.
      • Deng T.
      • Lyon C.J.
      • Bergin S.
      • Caliguri M.A.
      • Hsueh W.A.
      Obesity, inflammation and cancer.
      • Gonçalves R.B.
      • Coletta R.D.
      • Silvério K.G.
      • et al.
      Impact of smoking on inflammation: overview of molecular mechanisms.
      Smoking, via polycyclic aromatic hydrocarbons, can directly alter follicular keratinocyte differentiation, resulting in comedogenesis.
      • Patterson A.T.
      • Tian F.T.
      • Elston D.M.
      • Kaffenberger B.H.
      Occluded cigarette smoke exposure causing localized chloracne-like comedones.
      It can also produce widespread methylation changes and systemic increases in IL-6, C-reactive protein, fibrinogen, and multiple members of the nuclear factor kappa-light-chain-enhancer of activated B cells family.
      • Gonçalves R.B.
      • Coletta R.D.
      • Silvério K.G.
      • et al.
      Impact of smoking on inflammation: overview of molecular mechanisms.
      Adipose tissue can produce proinflammatory signatures, including IL-6, IL-1β, and tumor necrosis factor-α in the setting of chronic nutrient excess.
      • Reily S.M.
      • Saltiel A.R.
      Adapting to obesity with adipose tissue inflammation.
      ,
      • Deng T.
      • Lyon C.J.
      • Bergin S.
      • Caliguri M.A.
      • Hsueh W.A.
      Obesity, inflammation and cancer.
      Additionally, adipokines can mediate both inflammation and the development of insulin resistance
      • Kwon H.
      • Pessin J.E.
      Adipokines mediate inflammation and insulin resistance.
      (Fig 2), which is also associated with hidradenitis suppurativa.
      • Porter M.L.
      • Kimball A.B.
      Comorbidities of hidradenitis suppurativa.
      Keratinocytes in the infra-infundibulum of the follicle express type 1 5-hydroxytestosterone,
      • Kumtomrut C.
      • Yamauchi T.
      • Koike S.
      • Aiba S.
      • Yamasaki K.
      Androgens modulate keratinocyte differentiation indirectly through enhancing growth factor production from dermal fibroblasts.
      modulating infundibular keratinocyte differentiation programs both directly
      • Guy R.
      • Kealey T.
      Modelling the infundibulum in acne.
      and via fibroblast activation and fibroblast-keratinocyte interactions, contributing to androgen-induced follicular changes.
      • Kumtomrut C.
      • Yamauchi T.
      • Koike S.
      • Aiba S.
      • Yamasaki K.
      Androgens modulate keratinocyte differentiation indirectly through enhancing growth factor production from dermal fibroblasts.
      Overall, these associations suggest that a systemic proinflammatory state and localized infundibular keratinocyte dysregulation are potential predisposing factors to clinical disease. There are contradictory reports
      • Sivanand A.
      • Gulliver W.P.
      • Josan C.K.
      • Alhusayen R.
      • Fleming P.J.
      Weight loss and dietary interventions for hidradenitis suppurativa: a systematic review.
      pertaining to the benefit of withdrawing these predisposing factors (eg, cessation of smoking, weight loss) during established disease. These findings appear contradictory only if one holds the assumption that the initiating and perpetuating factors of clinical disease in hidradenitis suppurativa are one and the same. As other authors have suggested,
      • Hoffman L.K.
      • Ghias M.H.
      • Lowes M.A.
      Pathophysiology of hidradenitis suppurativa.
      there may be unique factors contributing to each state (initiation of disease and perpetuation of disease); and our lack of data regarding early (subclinical) disease has not allowed us to appreciate this fact.
      • Hoffman L.K.
      • Ghias M.H.
      • Lowes M.A.
      Pathophysiology of hidradenitis suppurativa.

      T-helper cell 17 feed-forward inflammation is prominent in established disease

      The T-helper cell 17 axis is strongly implicated in established self-perpetuating clinical disease
      • Melnik B.C.
      • John S.M.
      • Chen W.
      • Plewig G.
      T helper 17 cell/regulatory T-cell imbalance in hidradenitis suppurativa.acne inversa: the link to hair follicle dissection, obesity, smoking and autoimmune comorbidities.
      ; however, the mechanisms leading to T-helper cell 17 feed-forward self-amplification in hidradenitis suppurativa are still unclear. It is assumed to be similar to the activation of the T-helper cell 17 axis in psoriasis,
      • Ogura H.
      • Murakami M.
      • Okuyama Y.
      • et al.
      Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction.
      with the predisposition of the axillae and other areas of apocrine-gland-rich skin to a T-helper cell 17 immunoresponse, as demonstrated experimentally.
      • Jenei A.
      • Dajnoki Z.
      • Medgyesi B.
      • Gáspár K.
      • Béke G.
      • Kinyó Á.
      Apocrine gland–rich skin has a non-inflammatory IL-17–related immune milieu, that turns to inflammatory IL-17–mediated disease in hidradenitis suppurativa.
      There is well-documented evidence (largely from the psoriasis literature) regarding feed-forward mechanisms between IL-1β, IL-6, and tumor necrosis factor-α by IL-17,
      • Ogura H.
      • Murakami M.
      • Okuyama Y.
      • et al.
      Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction.
      ,
      • Veldhoen M.
      Interleukin 17 is a chief orchestrator of immunity.
      leading to further IL-1β, IL-6, and tumor necrosis factor-α production, as well as downstream activation of acute phase reactants and neutrophilic and complement-mediated inflammatory responses.
      • Ogura H.
      • Murakami M.
      • Okuyama Y.
      • et al.
      Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction.
      • Veldhoen M.
      Interleukin 17 is a chief orchestrator of immunity.
      • Ramirez-Carrozzi V.
      • Sambandam A.
      • Luis E.
      • et al.
      IL-17C regulates the innate immune functions of epithelial cells in an autocrine manner.
      This is further perpetuated through leucocyte-keratinocyte interactions,
      • Ogura H.
      • Murakami M.
      • Okuyama Y.
      • et al.
      Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction.
      • Veldhoen M.
      Interleukin 17 is a chief orchestrator of immunity.
      • Ramirez-Carrozzi V.
      • Sambandam A.
      • Luis E.
      • et al.
      IL-17C regulates the innate immune functions of epithelial cells in an autocrine manner.
      further amplifying antimicrobial peptide and chemokine production (including CXCL1 and CXCL8),
      • Navrazhina K.
      • Frew J.W.
      • Krueger J.G.
      Interleukin 17C is elevated in lesional tissue of hidradenitis suppurativa.
      leading to further inflammatory cell recruitment adjacent to IL-17–activated epidermal keratinocytes (Fig 3). Such inflammatory cell localization has been observed surrounding intrafollicular and interfollicular sites adjacent to epidermal keratinocytes in early histologic specimens of hidradenitis suppurativa,
      • Von Laffert M.
      • Stadie V.
      • Wohlrab J.
      • Marsch W.C.
      Hidradenitis suppurativa/acne inversa: bilocated epithelial hyperplasia with very different sequelae.
      • von Laffert M.
      • Helmbold P.
      • Wohlrab J.
      • Fiedler E.
      • Stadie V.
      • Marsch W.C.
      Hidradenitis suppurativa (acne inversa): early inflammatory events at terminal follicles and at interfollicular epidermis.
      • Zouboulis C.C.
      • Nogueira de Costa A.
      • Fimmel S.
      • Zouboulis K.C.
      Apocrine glands are bystanders in hidradenitis suppurativa and their involvement in gender specific.
      ,
      • Jemec G.B.
      • Hansen U.
      Histology of hidradenitis suppurativa.
      with evidence of early psoriasiform hyperplasia suggestive of IL-17–induced epidermal changes. Despite that the majority of translational work focuses on IL-17A (given the body of preexisting work based on psoriasis), significant elevations of other IL-17 isoforms, including IL-17C and IL-17F, are observed in hidradenitis suppurativa tissue,
      • Navrazhina K.
      • Frew J.W.
      • Krueger J.G.
      Interleukin 17C is elevated in lesional tissue of hidradenitis suppurativa.
      ,
      • Witte-Handel E.
      • Wolk K.
      • Tsausi A.
      • et al.
      The IL-1 pathway is hyperactive in hidradenitis suppurativa and contributed to skin infiltration and destruction.
      and these may be significant contributors to disease activity that are not targeted by anti-IL-17A therapies alone.
      Figure thumbnail gr3
      Fig 3Mechanisms of tunnel formation, follicular rupture, and perpetuation of inflammation in hidradenitis suppurativa. Development of tunnels (top panel): Inflammation adjacent to the follicular outer root sheath activates fibroblasts, with stromal-keratinocyte feedback resulting in keratinocyte outgrowth from the follicular wall. The ongoing keratinocyte outgrowth results in keratinocyte-mediated inflammatory cell recruitment, further amplifying the stromally mediated keratinocyte outgrowth in a positive-feedback loop. The inflammatory cells are attracted to the keratinocyte chemokine (CXCL1/CXCL8) gradient, resulting in migration into the lumen of the tunnels. Mechanisms of follicular rupture (middle panel): The inflammatory infiltrate is associated with high levels of matrix metalloproteinases, which degrade the reticular lamina. Keratinocyte-leucocyte cross talk activated epithelial-mesenchyme-transition mechanisms, leading to degradation of the basement membrane zone, loss of hemidesmosomes and desmosomes, and keratinocytes expressing mesenchymal cell surface markers (yellow keratinocytes). Eventually, the follicular wall is disassembled, replaced by mesenchymal cells and dense inflammatory infiltrates. Mechanisms of inflammatory amplification (bottom panel): Activated keratinocytes interact with inflammatory and stromal cells via various pathways to result in activated fibroblasts, T-helper cell types 1 and 17, and infiltration of dendritic cells and neutrophils. Circulating B cells (circulating to and from regional lymph nodes; far right of lower panel), activated by the high-interferon-mediated milieu, interact with multiple cell types to amplify existing inflammatory loops, as well as recirculate in the lymphatic and vascular system, contributing to systemic inflammation. D, Desmosome; HD, hemidesmosome; MMP, matrix metalloproteinase; ORS, outer root sheath.

      The role of B cells, despite their dominance, remains unclear

      Long-standing and severe disease may have a unique inflammatory profile compared with milder or less established forms of hidradenitis suppurativa. Histologic and transcriptomic studies
      • Zouboulis C.C.
      • Nogueira da Costa A.
      • Makrantonaki E.
      • Hou X.X.
      • Almansouri D.
      • Dudley J.T.
      Alterations in innate immunity and epithelial cell differentiation are the molecular pillars of hidradenitis suppurativa.
      ,
      • Shanmugan V.K.
      • Jones D.
      • McNish S.
      • Bendall M.L.
      • Crandall K.A.
      Transcriptome patterns in hidradenitis suppurativa: support for the role of antimicrobial peptides and interferon pathways in disease pathogenesis.
      have identified a high level of B-cell
      • Byrd A.S.
      • Carmona-Rivera C.
      • O'Neil L.J.
      • et al.
      Neutrophil extracellular traps, B cells, and type I interferons contribute to immune dysregulation in hidradenitis suppurativa.
      and plasma-cell
      • Musilova J.
      • Moran B.
      • Sweeney C.M.
      • et al.
      Enrichment of plasma cells in the peripheral blood and skin of patients with hidradenitis suppurativa.
      ,
      • Hoffman L.K.
      • Tomalin L.E.
      • Schultz G.
      • et al.
      Integrating the skin and blood transcriptomes and serum proteome in hidradenitis suppurativa reveals complement dysregulation and a plasma cell signature.
      signatures, complement (specifically C5a) activation,
      • Ghias M.H.
      • Hyde M.J.
      • Tomalin L.E.
      • et al.
      Role of the complement pathway in inflammatory skin diseases: a focus on hidradenitis suppurativa.
      • Grand D.
      • Navrazhina K.
      • Frew J.W.
      Integrating complement into the molecular pathogenesis of hidradenitis suppurativa.
      • Kanni T.
      • Zenker O.
      • Habel M.
      • Riedemann N.
      • Giamarellos-Bourboulis E.J.
      Complement activation in hidradenitis suppurativa: a new pathway of pathogenesis?.
      • Giamarellos-Bouboulis E.J.
      • Argyropoulou M.
      • Kanni T.
      • et al.
      Clinical efficacy of complement C5a inhibition by IFX-1 in hidradenitis suppurativa: an open-label single-arm trial in patients not eligible for adalimumab.
      and extensive tissue remodeling via matrix metalloproteinases with subsequent destruction of follicular and glandular structures in the dermis.
      • Vossen A.R.J.V.
      • van der Zee H.H.
      • Prens E.P.
      Hidradenitis suppurativa: a systematic review integrating inflammatory pathways into a cohesive pathogenic model.
      ,
      • Zouboulis C.C.
      • Nogueira de Costa A.
      • Fimmel S.
      • Zouboulis K.C.
      Apocrine glands are bystanders in hidradenitis suppurativa and their involvement in gender specific.
      The role and characteristics of B cells in mild to moderate hidradenitis suppurativa are unclear.
      • Frew J.W.
      • Grand D.
      • Navrazhina K.
      • Krueger J.G.
      Beyond antibodies: B cells in hidradenitis suppurativa: bystanders, contributors or therapeutic targets?.
      The presence of B cells and plasma cells in skin and blood
      • Byrd A.S.
      • Carmona-Rivera C.
      • O'Neil L.J.
      • et al.
      Neutrophil extracellular traps, B cells, and type I interferons contribute to immune dysregulation in hidradenitis suppurativa.
      ,
      • Musilova J.
      • Moran B.
      • Sweeney C.M.
      • et al.
      Enrichment of plasma cells in the peripheral blood and skin of patients with hidradenitis suppurativa.
      ,
      • Hoffman L.K.
      • Tomalin L.E.
      • Schultz G.
      • et al.
      Integrating the skin and blood transcriptomes and serum proteome in hidradenitis suppurativa reveals complement dysregulation and a plasma cell signature.
      suggests the possibility that some component of severe or long-standing hidradenitis suppurativa may be an autoimmune or antibody-mediated disorder. However, to date no product has been definitively identified as an autoimmune target for the disease.
      • Frew J.W.
      • Grand D.
      • Navrazhina K.
      • Krueger J.G.
      Beyond antibodies: B cells in hidradenitis suppurativa: bystanders, contributors or therapeutic targets?.
      B cells are present in other chronic inflammatory disorders without known autoimmune targets, including psoriasis and atopic dermatitis.
      • Gauntner T.D.
      Hormonal, stem cell and Notch signaling as possible mechanisms of disease in hidradenitis suppurativa: a systems-level transcriptomic analysis.
      In these conditions, they are thought to be bystanders (secondary to combined B-cell and T-cell chemoattractants such as CXCL13 or CCL20) or secondary amplifiers of T-cell–mediated inflammation.
      • Frew J.W.
      • Grand D.
      • Navrazhina K.
      • Krueger J.G.
      Beyond antibodies: B cells in hidradenitis suppurativa: bystanders, contributors or therapeutic targets?.
      (Fig 3). Byrd et al
      • Byrd A.S.
      • Carmona-Rivera C.
      • O'Neil L.J.
      • et al.
      Neutrophil extracellular traps, B cells, and type I interferons contribute to immune dysregulation in hidradenitis suppurativa.
      demonstrated that antibodies to citrullinated peptides contribute to the development of neutrophil extracellular traps in advanced disease, with parallels to B-cell and neutrophil extracellular traps in rheumatoid arthritis.
      • Byrd A.S.
      • Carmona-Rivera C.
      • O'Neil L.J.
      • et al.
      Neutrophil extracellular traps, B cells, and type I interferons contribute to immune dysregulation in hidradenitis suppurativa.
      Case reports of rituximab ameliorating hidradenitis suppurativa disease activity are known,
      • Frew J.W.
      • Grand D.
      • Navrazhina K.
      • Krueger J.G.
      Beyond antibodies: B cells in hidradenitis suppurativa: bystanders, contributors or therapeutic targets?.
      but overall, the role of B cells as bystanders, amplifiers of existing inflammation, or central pathogenic players is unclear and requires further investigation.
      • Frew J.W.
      • Grand D.
      • Navrazhina K.
      • Krueger J.G.
      Beyond antibodies: B cells in hidradenitis suppurativa: bystanders, contributors or therapeutic targets?.

      Genetic variants in hidradenitis suppurativa may act via EGFR-associated pathways linking follicles, T-helper cell 17−mediated inflammation, and drug-induced disease

      A minority of patients with familial and spontaneous hidradenitis suppurativa have been identified with GSC mutations.
      • Duchatelet S.
      • Miskintye S.
      • Delage M.
      • et al.
      Low prevalence of gamma-secretase complex gene mutations in a large cohort of predominantly Caucasian patients with hidradenitis suppurativa.
      The precise mechanism of action of GSC mutations in the pathogenesis of hidradenitis suppurativa is unclear.
      • Frew J.W.
      • Navrazhina K.
      In silico analysis of gamma-secretase-complex mutations in hidradenitis suppurativa demonstrates disease-specific substrate recognition and cleavage alterations.
      The GSC complex cleaves more than 70 different substrates involved in cell cycle and inflammation, including epidermal growth factor receptor (EGFR), IL-1, tumor necrosis factor-α, and Notch.
      • Frew J.W.
      • Navrazhina K.
      In silico analysis of gamma-secretase-complex mutations in hidradenitis suppurativa demonstrates disease-specific substrate recognition and cleavage alterations.
      Notch is proposed as the unifying motif in hidradenitis suppurativa pathogenesis via associations with keratinocyte proliferation,
      • Xiao X.
      • He Y.
      • Li C.
      • Zhang X.
      • Xu H.
      • Wang B.
      Nicastrin mutations in familial acne inversa impact keratinocyte proliferation and differentiation through the Notch and phosphoinositide 3-kinase/AKT signaling pathways.
      smoking, and sequence variants in GSC.
      • Melnik B.C.
      • Plewig G.
      Impaired Notch signaling: the unifying mechanism explaining the pathogenesis of hidradenitis suppurativa (acne inversa).
      ,
      • Melnik B.C.
      • Plewig G.
      Impaired Notch-MKP-1 signaling in hidradenitis suppurativa: an approach to pathogenesis by evidence from translational biology.
      However, Notch dysregulation is also present in multiple other inflammatory dermatoses,
      • Frew J.W.
      • Navrazhina K.
      No evidence that impaired Notch signaling differentiates hidradenitis suppurativa from other inflammatory skin diseases.
      arguing against a unique role in hidradenitis suppurativa. In silico evidence
      • Frew J.W.
      • Navrazhina K.
      In silico analysis of gamma-secretase-complex mutations in hidradenitis suppurativa demonstrates disease-specific substrate recognition and cleavage alterations.
      has identified ERbb4 and Tie1 as differentially expressed GSC substrates that distinguish the transcriptome of hidradenitis suppurativa from familial Alzheimer disease and other inflammatory skin diseases.
      • Frew J.W.
      • Navrazhina K.
      No evidence that impaired Notch signaling differentiates hidradenitis suppurativa from other inflammatory skin diseases.
      These components of the EGFR pathway (active in the follicular infundibulum
      • Schneider M.R.
      • Paus R.
      Deciphering the functions of the hair follicle infundibulum in skin physiology and disease.
      ) are associated with SOX9 and Wnt signaling linked with hair cycle progression, IL-17A production
      • Schneider M.R.
      • Paus R.
      Deciphering the functions of the hair follicle infundibulum in skin physiology and disease.
      ,
      • He Y.
      • Li C.
      • Xu H.
      • et al.
      AKT-dependent hyperproliferation of keratinocytes in familial hidradenitis suppurativa with a NCSTN mutation: a potential role of defective miR-100-5p.
      (through shared downstream Act1 activity), and epithelial cell fate,
      • He Y.
      • Li C.
      • Xu H.
      • et al.
      AKT-dependent hyperproliferation of keratinocytes in familial hidradenitis suppurativa with a NCSTN mutation: a potential role of defective miR-100-5p.
      all mechanisms identified in transcriptomic analysis of hidradenitis suppurativa tissues.
      • Zouboulis C.C.
      • Nogueira da Costa A.
      • Makrantonaki E.
      • Hou X.X.
      • Almansouri D.
      • Dudley J.T.
      Alterations in innate immunity and epithelial cell differentiation are the molecular pillars of hidradenitis suppurativa.
      ,
      • Hoffman L.K.
      • Ghias M.H.
      • Lowes M.A.
      Pathophysiology of hidradenitis suppurativa.
      GSC knockdown results in IL-36α production,
      • Cao L.
      • Morales-Heil D.J.
      • Roberson E.D.O.
      Nicastrin haploinsufficiency alters expression of type 1 interferon stimulated genes: the relationship to familial hidradenitis suppurativa.
      alterations in EGFR signaling,
      • Yang J.
      • Wang L.
      • Zhang X.
      • et al.
      Keratin 5-Cre driven deletion of NCSTN in acne inversa-like mouse model leads to markedly increased IL36q and SPRR2 expression.
      and increased sensitivity to interferon-mediated proinflammatory pathways
      • Cao L.
      • Morales-Heil D.J.
      • Roberson E.D.O.
      Nicastrin haploinsufficiency alters expression of type 1 interferon stimulated genes: the relationship to familial hidradenitis suppurativa.
      (Fig 2). POFUT-1 (identified in cases of Dowling-Degos disease associated with hidradenitis suppurativa
      • Gonzalez-Villanueva I.
      • Guiterrez M.
      • Hispan P.
      • Betloch I.
      • Pascual J.C.
      Novel POFUT1 mutation associated with hidradenitis suppurativa–Dowling-Degos disease firm up a role for Notch signaling in the pathogenesis of this disorder.
      ,
      • Jfri A.H.
      • O'Brien E.
      • Litvinov I.
      Hidradenitis suppurativa: comprehensive review of predisposing genetic mutations and changes.
      ) is a fucosyltransferase that is active on multiple substrates, including Notch and EGFR,
      • Liu Y.
      • Yen H.
      • Chen C.Y.
      • et al.
      Sialylation and fucosylation of epidermal growth factor receptor suppresses its dimerization and activation in lung cancer cells.
      and is important for posttranslational modification of receptors.
      • Liu Y.
      • Yen H.
      • Chen C.Y.
      • et al.
      Sialylation and fucosylation of epidermal growth factor receptor suppresses its dimerization and activation in lung cancer cells.
      This suggests a role for EGFR signaling in hidradenitis suppurativa, supported by reports of hidradenitis suppurativa associated with use of EGFR antagonists in oncology.
      • Frew J.W.
      • Vekic D.A.
      • Woods J.A.
      • Cains G.D.
      Drug-associated hidradenitis suppurativa: a systematic review of case reports.

      The evidence and proposed mechanisms for follicular rupture

      Follicular rupture is proposed as the primary mechanism by which follicular occlusion leads to dermal inflammation in hidradenitis suppurativa, but the molecular mechanisms remain unclear.
      • Vossen A.R.J.V.
      • van der Zee H.H.
      • Prens E.P.
      Hidradenitis suppurativa: a systematic review integrating inflammatory pathways into a cohesive pathogenic model.
      Observational studies demonstrate the coexistence of dense perifollicular and intrafollicular inflammation and discontinuities in follicular epithelium in affected tissues
      • Von Laffert M.
      • Stadie V.
      • Wohlrab J.
      • Marsch W.C.
      Hidradenitis suppurativa/acne inversa: bilocated epithelial hyperplasia with very different sequelae.
      ,
      • von Laffert M.
      • Helmbold P.
      • Wohlrab J.
      • Fiedler E.
      • Stadie V.
      • Marsch W.C.
      Hidradenitis suppurativa (acne inversa): early inflammatory events at terminal follicles and at interfollicular epidermis.
      ,
      • Jemec G.B.
      • Hansen U.
      Histology of hidradenitis suppurativa.
      (Fig 3). Long-standing disease demonstrates a noticeable absence of follicular and adnexal structures,
      • Rongioletti F.
      Histopathology.
      consistent with profound dermal inflammation. A reduction in the thickness of the fibroreticular lamina surrounding follicles and sebaceous glands
      • Danby F.W.
      • Jemec G.B.
      • Marsch WCh
      • von Laffert M.
      Preliminary findings suggest hidradenitis suppurativa may be due to defective follicular support.
      has been observed. Occluded follicles in other conditions (such as epidermal inclusion cysts
      • Hoang V.T.
      • Trinh C.T.
      • Nguyen C.H.
      • Chansomphou V.
      • Chansomphou V.
      • Tran T.T.T.
      Overview of epidermoid cyst.
      ) are testament to the potential size intrafollicular collections may progress to before rupture. However, the early presence of inflammation in hidradenitis suppurativa lesions suggests an inflammation-related mechanism
      • Mozeika E.
      • Pilmane M.
      • Nürnberg B.M.
      • et al.
      Tumour necrosis factor-alpha and matrix metalloproteinase-2 are expressed strongly in hidradenitis suppurativa.
      that is well documented to disassemble the basement membrane zone as part of the wound-healing process.
      • Chuang Y.H.
      • Dean D.
      • Allen J.
      • Dawber R.
      • Wojnarowska F.
      Comparison between the expression of basement membrane zone antigens of human interfollicular epidermis and anagen hair follicle using indirect immunofluorescence.
      Epithelial-mesenchymal transition pathways
      • Frew J.W.
      • Navrazhina K.
      • Marohn M.
      • Lu P.C.
      • Krueger J.G.
      Contribution of fibroblasts to tunnel formation and inflammation in hidradenitis suppurativa/acne inversa.
      are part of the normal wound-healing response and have been identified in transcriptomic analysis of hidradenitis suppurativa tissues.
      • Gauntner T.D.
      Hormonal, stem cell and Notch signaling as possible mechanisms of disease in hidradenitis suppurativa: a systems-level transcriptomic analysis.
      ,
      • Coates M.
      • Mariottoni P.
      • Cocoran D.L.
      • et al.
      The skin transcriptome in hidradenitis suppurativa uncovers an antimicrobial and sweat gland gene signature which has distinct overlap with wounded skin.
      It may also explain the presence of keratin-staining cells in the dermis of hidradenitis suppurativa sections
      • Frew J.W.
      • Hawkes J.E.
      • Krueger J.G.
      A systematic review and critical evaluation of immunohistochemical associations in hidradenitis suppurativa.
      (via keratinocytes undergoing epithelial-mesenchymal transition but still expressing keratin proteins), the destruction of follicular and adnexal structures in advanced disease,
      • Rongioletti F.
      Histopathology.
      and the development of dermal tunnels
      • Frew J.W.
      • Navrazhina K.
      • Marohn M.
      • Lu P.C.
      • Krueger J.G.
      Contribution of fibroblasts to tunnel formation and inflammation in hidradenitis suppurativa/acne inversa.
      (Fig 3). Similar inductions in epithelial-mesenchymal transition-associated signaling pathways are observed in malignancy and wound healing and contribute to the metastatic potential of cancer and long-standing wounds.
      • Ge Y.
      • Fuchs E.
      Stretching the limits: from homeostasis to stem cell plasticity in wound healing and cancer.
      Hence, the concept of follicular rupture may be more appropriately described as a process of “follicular disassembly” (Fig 3) induced by the chronic inflammatory changes via epithelial-mesenchymal transition and aberrant extracellular remodeling wound-healing programs.
      • Frew J.W.
      • Navrazhina K.
      • Marohn M.
      • Lu P.C.
      • Krueger J.G.
      Contribution of fibroblasts to tunnel formation and inflammation in hidradenitis suppurativa/acne inversa.

      Dermal tunnels are active inflammatory structures and their development is orchestrated by dermal inflammation

      Dermal tunnels in hidradenitis suppurativa are unique structures comprising stratified squamous epithelia that recapitulate the structure of the overlying epidermis and produce active inflammatory mediators.
      • Navrazhina K.
      • Frew J.W.
      • Sullivan-Whelan M.
      • Gilleadeau P.
      • Garcet S.
      • Krueger J.G.
      Epithelialized dermal tunnels drive “feed-forward” inflammation and transepithelial neutrophil migration in hidradenitis suppurativa.
      This is in contrast to other tunnel-like structures in chronic inflammatory conditions such as fistulizing Crohn's disease, which do not recapitulate mucosal structures with the same degree of fidelity.
      • Scharl M.
      • Rogler G.
      Pathophysiology of fistula formation in Crohn's disease World.
      The mechanisms leading to tunnel formation are unclear; however, it is hypothesized that these tunnels derive from the aberrant keratinocyte outgrowth from the outer root sheath of the follicle
      • Frew J.W.
      • Navrazhina K.
      • Marohn M.
      • Lu P.C.
      • Krueger J.G.
      Contribution of fibroblasts to tunnel formation and inflammation in hidradenitis suppurativa/acne inversa.
      (Fig 3). Tunnels do not extend into the subcutaneous tissues or fistulize with other hollow organs (except in the context of coexistent inflammatory bowel disease), suggesting an association with signaling from the dermis.
      • Frew J.W.
      • Navrazhina K.
      • Marohn M.
      • Lu P.C.
      • Krueger J.G.
      Contribution of fibroblasts to tunnel formation and inflammation in hidradenitis suppurativa/acne inversa.
      This parallels the development of the hair follicle and early anagen downgrowth in the hair cycle,
      • Ge Y.
      • Fuchs E.
      Stretching the limits: from homeostasis to stem cell plasticity in wound healing and cancer.
      ,
      • Oh J.W.
      • Kloepper J.
      • Langan E.A.
      • et al.
      A guide to studying human hair follicle cycling in vivo.
      which are mediated via platelet derived growth factor α-derived signaling from the dermal condensate.
      • Ge Y.
      • Fuchs E.
      Stretching the limits: from homeostasis to stem cell plasticity in wound healing and cancer.
      Platelet derived growth factor α-mediated signaling has also been identified in transcriptomic data from hidradenitis suppurativa–associated fibroblasts.
      • Frew J.W.
      • Navrazhina K.
      • Marohn M.
      • Lu P.C.
      • Krueger J.G.
      Contribution of fibroblasts to tunnel formation and inflammation in hidradenitis suppurativa/acne inversa.
      Given that these fibroblast-derived signals are secondary to inflammation-mediated epigenetic modifications,
      • Frew J.W.
      • Navrazhina K.
      • Marohn M.
      • Lu P.C.
      • Krueger J.G.
      Contribution of fibroblasts to tunnel formation and inflammation in hidradenitis suppurativa/acne inversa.
      it is plausible to assume that the development of tunnels is an inflammation-driven process. However, once these tunnels are established, the CXCL1/8 gradient established across the epithelia
      • Navrazhina K.
      • Frew J.W.
      • Sullivan-Whelan M.
      • Gilleadeau P.
      • Garcet S.
      • Krueger J.G.
      Epithelialized dermal tunnels drive “feed-forward” inflammation and transepithelial neutrophil migration in hidradenitis suppurativa.
      (including tunnels) results in transepithelial neutrophil trafficking and neutrophil extracellular trap formation in tunnel lumen.
      • Byrd A.S.
      • Carmona-Rivera C.
      • O'Neil L.J.
      • et al.
      Neutrophil extracellular traps, B cells, and type I interferons contribute to immune dysregulation in hidradenitis suppurativa.
      This results in development of the infiltrative proliferative gelatinous mass
      • Kidacki M.
      • Cong Z.
      • Flamm A.
      • Helm K.
      • Danby F.W.
      • Nelson A.M.
      Invasive proliferative gelatinous mass of hidradenitis suppurativa contains distinct inflammatory components.
      and biofilm formation in hidradenitis suppurativa tunnels
      • Ring H.C.
      • Bay L.
      • Nilsson M.
      • et al.
      Bacterial biofilm in chronic lesions of hidradenitis suppurativa.
      (Fig 3). This in turn drives further inflammatory recruitment surrounding these established tunnels, leading to the ongoing cycle of severe intractable inflammation and drainage.

      Conclusions

      The available histologic and molecular evidence suggests inflammation is a central component to the pathogenesis of hidradenitis suppurativa. Placing inflammation as the primary driver of disease provides a scaffold for testable hypotheses regarding polygenic risk loci for the development of hidradenitis suppurativa, drug-induced causes of hidradenitis suppurativa, the development of dermal tunnels, and the inflammatory proliferative gelatinous mass, which are currently poorly integrated into the follicular occlusion model of hidradenitis suppurativa (Fig 1). More mechanistic and translational investigations are needed to further evaluate the role of genetics and B cells in hidradenitis suppurativa, as well as provide mechanistic evidence about the development of follicular rupture and tunnel formation. Such basic cellular and molecular investigations are vital to develop our understanding of the disease. Realigning the pathogenic paradigm with the molecular evidence is essential to enable the identification and exploration of novel targets, interventions, and therapeutics for this chronic debilitating disease.

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