Aetiology and Pathogenesis of Hidradenitis Suppurativa

K. Wolk; O. Join-Lambert; R. Sabat


The British Journal of Dermatology. 2020;183(6):999-1010. 

In This Article

Predisposing Factors

Genetic Factors

The importance of the genetic background was first noticed when Fitzsimmons and Guilbert observed disease clustering in 14 of 23 patient families.[8] In fact, around 30% of the patients reported a positive family history for HS.[9] A very limited number of patients with mostly severe HS disease with associated severe acne bear mutations in genes encoding the subunits of γ-secretase (γ-S),[10] a protease situated in the cell membrane.[11] Thirty-six different γ-S mutations have been described in HS, most of them in the gene for the nicastrin subunit.[12] The link between γ-S impairment and HS is supported by skin alterations that arise in young mice with genetic deficiency of γ-S components. In these mice, hair follicle disintegration and impaired sebaceous gland formation led to epidermal cyst development.[13] Interestingly, this occurred without relevant inflammation. When growing older, these mice developed squamous cell carcinomas.[13,14] Furthermore, therapeutic targeting of γ-S outside the dermatology field provoked follicular alterations and cyst formation in intertriginous skin areas.[15] Respective mutations in human γ-S may lead to hyperproliferation of keratinocytes.[16]

The long list of γ-S substrates includes amyloid-β protein precursor, interleukin (IL)-1 receptor 1, interferon (IFN)-αR2, CXCL16, RAGE and notch 1–4·[11] Interestingly, mice deficient in notch or notch ligand show a skin phenotype similar to that of γ-S mice.[13,17] The cleavage and consequent activation of notch are crucial for the development and homeostatic cycling of hair follicles.[18] Moreover, notch signalling is crucial for the function of regulatory T cells and IL-22 production by effector T cells,[19,20] which are both impaired in HS.[21] As described above, the prevalence of γ-S mutations among patients with HS is very low.[10] Moreover, it has not been proven so far that γ-S mutations in HS lead to notch deficiency.

Beside γ-S mutations, variations in further genes were identified in patients with HS.[22,23] One of these genes (MEFV) encodes the pattern-recognition receptor (PRR) pyrin,[23] a critical component of the inflammasome system. Activation of the inflammasome leads to production of IL-1β, a cytokine with an important role in HS pathogenesis (see below).

However, extensive studies are needed to investigate which genetic features contribute to the development of the disease in the majority of patients with HS with a positive family history. Several efforts including genome-wide association studies are under way.[23,24]

Lifestyle Factors

There are two major lifestyle factors that, although not present in every individual patient, have accepted roles in HS disease development: obesity and tobacco smoking.

Central obesity has been found in approximately 60% of patients.[2] It is one of the factors defining the metabolic syndrome, a combination of medical conditions including central obesity, hyperglycaemia, dyslipidaemia and/or hypertension.[25] Approximately 40% of patients with HS have metabolic syndrome.[2] Investigating more than 400 hospitalized patients, Shalom et al. found that of the different metabolic syndrome components, obesity preceded the diagnosis of HS by an average of 5 years.[26] In line with this, central obesity had the highest frequency among metabolic syndrome criteria.[2] Importantly, there was a 4·5-fold increased risk of recurrence of skin alterations after laser-based surgical removal of skin lesions in obese vs. nonobese patients with HS.[27]

Obesity is supposed to favour HS skin alteration in two ways (Figure 1). Firstly, it enlarges the skinfolds in the body and, consequently, increases the mechanical stress, maceration and anaerobic conditions within those folds (see below). Secondly, it induces a low level of systemic inflammation and metabolic changes in respective individuals. In fact, inflammatory cells present in the hypertrophic adipose tissue produce proinflammatory cytokines and induce a dysregulated pattern of adipokines, all of which may have negative effects on skin cells.[28] Beside obesity, insulin resistance/hyperglycaemia/type 2 diabetes mellitus might be an independent factor for HS.[29] The altered proliferation and differentiation of insulin-resistant keratinocytes may be one of the mechanisms underlying this association (Figure 1).[30] In turn, skin disease may favour obesity and metabolic syndrome, for example by induction of adipokines, insulin resistance and dyslipidaemia.[28]

Figure 1.

Predisposing factors in hidradenitis suppurativa (HS). The mechanisms of HS lesion formation centre around the pilosebaceous–apocrine units in the intertriginous skin areas. These areas differ from other skin areas by the higher temperature, higher moisture and reduced oxygen availability and, linked to these factors, a specific, anaerobe-enriched microbiome. Moreover, they show increased mechanical stress. The mechanical stress may induce cutaneous microinjuries that provoke release of cellular damage-associated molecules (DAMPs) and entry of microbiome components into the skin, both favouring local inflammation. The aetiopathophysiology involves both genetics and factors associated with patients' lifestyles. Although one-third of patients report a positive family history for HS, the responsible genetic features are unknown in most cases. A minority of patients with positive family history for HS show alterations in γ-secretase (γ-S) genes, which may contribute to follicular instability. The lifestyle factors involved in HS disease development are obesity and insulin resistance, as well as tobacco smoking. Central obesity (found in up to 60% of patients) is one of the factors defining the metabolic syndrome, which is found in a large proportion of patients with HS. Obesity enlarges the skinfolds in the body and, consequently, increases the mechanical stress, maceration and anaerobic conditions within those folds. Obesity also induces subclinical inflammation in the adipose tissue, with secretion of inflammatory cytokines (including interleukin-1β and tumour necrosis factor-α), which can reach the skin from the underlying subcutis or via the blood flow. Insulin resistance may alter the growth of keratinocytes. Inducing endothelial activation and chemokine production, inflammatory cytokines provoke the infiltration of immune cells from the blood, further supporting the inflammatory process in the skin. Smoking (found in up to 90% of patients with HS) induces nicotine exposition, which may favour infundibular acanthosis and dysbiosis, two of the initial events observed in HS pathogenesis. [Colour figure can be viewed at]

Smoking is very common among patients with HS. Reports show up to 90% of patients currently or formerly smoking.[31] In line with that, the adjusted odds of developing HS among people who smoke compared with those who do not was 1·9.[32] Nicotine may induce epidermal hyperplasia and dysbiosis.[33–35] In monocytic cells, especially when exposed to bacterial components, nicotine may increase intracellular cAMP levels and strengthen the production of IL-10,[36–38] a cytokines that plays a role in HS (see below).

Apart from these factors, contribution of sex hormones is suspected.[39] This is based on the frequently observed onset of HS after puberty and the decreased disease severity during pregnancy.[39,40] In female patients, efficacy of antiandrogen therapy was suggested.[41]

Special Features of Skin Areas Predisposed to Hidradenitis Suppurativa

The specific nature of skin areas predisposed to HS alterations may give hints to factors that favour disease development. These areas (i.e. skinfolds in mostly axillary, inguinal, genital, gluteal and perianal body areas) contain a high density of pilosebaceous–apocrine units. They further differ from other areas by the higher temperature and moisture, reduced oxygen availability and, linked to that, the microbiome composition. In the skinfolds of healthy individuals, predominant taxa are Gram-positive aerobic and facultative anaerobic bacteria such as coagulase-negative Staphylococcus ssp. and Corynebacterium ssp., while strict anaerobes such as Propionibacterineae are detected with a low abundance (Figure 2).[42–44] Gram-negative anaerobic rods such as Prevotella, which are typical for mucosal sites, were also detected in very low numbers.[42,45] Interestingly, compared with matched areas in healthy individuals, the microbiome of clinically unaffected, HS-typical areas of patients with HS showed an increase in the relative abundance of Prevotella and other anaerobes and a decreased abundance of skin-surface-typical species like Staphylococcus epidermidis.[45] Pathogenetically, these resident anaerobic bacteria may support initial hair follicle inflammation in HS.

Figure 2.

Bacterial skin dysbiosis in hidradenitis suppurativa (HS). Bacterial skin dysbiotic features of HS are presented, from the preclinical state to severe lesions, based on 16S rRNA gene amplicon sequencing data. Only representative taxa are shown. Staphylococcus epidermidis and Corynebacterium spp. are the main bacterial taxa of the normal skinfold microbiome. At the preclinical stage, the skin-surface microbiome of HS skinfolds is characterized by a decreased abundance of the skin commensals Staphylococcus epidermidis and Cutibacterium and by a moderate increase of Prevotella, a Gram-negative anaerobic rod. These dysbiotic features are more pronounced in HS lesions. Early modifications of the hair follicle microbiome are observed in HS with abnormal colonization with the Gram-negative anaerobic rod Porphyromonas. Prevotella and Porphyromonas are associated with chronic HS lesions. Some pathogens are associated with a specific form of HS: Staphylococcus lugdunensis, associated with acute mild HS nodules, and Fusobacterium, associated with chronic severe HS. The association level of the indicated bacterial taxa with the disease state is represented by blue–white (nonpathogenic bacteria) and red–white (pathogenic bacteria) gradients. H, skinfolds of healthy donors; nL, nonlesional HS skin. [Colour figure can be viewed at]

Being intertriginous, body areas predisposed for HS are also subject to skin friction, especially in obese patients. Mechanical stress induces skin microinjuries with release of cellular damage-associated molecules (also called DAMPs or alarmins) and cutaneous entry of microbiome components. DAMPs include nucleic acids, LL37, heat shock proteins, S100A15 and HMGB1,[46] some of which have been associated with HS lesions.[47,48] DAMPs and bacterial components stimulate local macrophages, dendritic cells and keratinocytes via their various PRRs[49–51] to produce inflammatory cytokines. Bacterial components are also recognized by and activate the complement pathway.[52] In fact, the constitutive subclinical inflammation in intertriginous areas is supported by recently suggested increased numbers of dendritic cells and Th cells with constitutive IL-17 expression at these sites.[53]

It should be noted that HS lesions can also develop in intertriginous areas that do not bear apocrine glands, such as submammary folds.[54,55] Thus, apocrine glands do not appear to be necessary for the development of HS lesions. Inflammation of these glands was demonstrated to be a secondary phenomenon.[56–58]