There is increasing interest regarding the role markers of inflammation in patients with HS or other syndromic forms. A study in 14 patients with HS reported TNF-α-positive inflammatory cells in the dermis of patients but not in healthy controls (35). A study comparing the presence of different inflammatory cytokines in wound fluid specimens demonstrated elevated levels of IFN-γ and TNF-β in HS lesions compared with samples from age-matched chronic wound patients (5).

A retrospective study of HS outpatient medical files found a significant association between C-reactive protein (CRP) levels and neutrophil count with HS disease severity (36). A second study reported elevated serum CRP levels in patients with HS compared with healthy volunteers (38). A number of studies have reported elevated mRNA and/or protein levels of interleukins in the skin or serum. Alterations in the skin have been reported for IL-1β (33), CXCL-8/IL-8 (33, 37), IL-17/IL-17A (33), IL-32 (42), and IL-36/IL-36α/IL-36β/IL-36γ (37, 41). Alterations in the serum have been reported for IL-1β (38), IL-6 (38), CXCL-8/IL-8 (38), IL-10 (38), IL-12p70 (38), and IL-17/IL-17A (38, 39).

Keratinocytes isolated from non-lesional skin of patients with HS exhibited a pro-inflammatory profile in addition to an enhanced production of AMPs such as hBD-2, psoriasin (S100A7), and calgranulin (S100A8) (44), indicating that the skin immune system is already activated in the steady state.

A number of studies investigated bacterial cultures from HS lesions and generated evidence implicating the involvement of microbes in disease pathogenesis. A histologic study of 42 patients with chronic HS identified bacterial aggregates (biofilms) in 67% of chronic lesion samples and in 75% of perilesional samples (47). The same author group conducted a case-control study of punch biopsy specimens and demonstrated that the microbiome in patients with HS differs significantly from that in healthy controls in both lesional and non-lesional skin (48). A microbial analysis of lesional vs. unaffected skin from 65 patients with HS identified anaerobic microbes in 83% lesions vs. 53% control samples, and the microbiome varied with disease severity (45). These bacteria were associated with low pathogenicity. An extensive prospective microbiological study identified two opportunistic bacterial pathogens associated with HS lesions (S. lugdunensis and anaerobic actinomycetes) (43). These pathogens can cause abscesses and severe infections. A cross-sectional study of 50 patients reported that bacterial colonization was correlated with severity and localization of HS lesions (46). Over two-thirds (68.8%) of patients with both aerobic and anaerobic bacteria had the most severe grade of HS (Hurley stage III).

Findings from the literature review supported the involvement of previously suggested physiological and environmental risk factors, such as smoking and obesity, in HS (36, 49, 51). A postal follow-up survey study (n = 212) found the chance of remission from HS may be improved in non-smokers vs. smokers, and in non-obese (body mass index [BMI] < 30) vs. obese patients (49). In contrast, a retrospective study of inflammatory serum markers in HS outpatients found no association between smoking status and HS severity but smoking was associated with increased neutrophil counts (36). This study did find an association between increased BMI and HS severity, whereas there was no correlation between BMI and neutrophil counts.

Related to obesity, an analysis of 14 obese patients with HS described the role of mechanical stress (for example on the abdomen at the level of the waistband) in promoting the “Koebner phenomenon” in HS (51). The development of lesions at sites of traumatized but previously uninvolved skin highlights the importance of localized environmental factors in HS development. A hospital-based cross-sectional study conducted in the Netherlands reported a significantly higher average BMI in 106 patients with HS vs. 212 general dermatological patients (21). Among those patients identified as obese, bodyweight distribution was more peripheral in patients with HS than those without, consistent with enhanced friction due to overlapping skin folds.

Kromann and colleagues reported no clear effect of pregnancy or menopause on HS symptoms (49). However, in a cross-sectional survey based study, a substantial subset of women did experience HS-related alterations, with deterioration of HS around menses and amelioration of symptoms during pregnancy reported in 43% (n = 80) and 30% (n = 29) of the respondents, respectively (52).

To consider the above findings in relation to the pathogenesis of other established IMIDs, an informal literature review was conducted. Inflammatory bowel disease (CD and UC), AS, psoriasis, PsA, PG and Behçet's disease are characterized by different pathogeneses but they also share common immunological, genetic and risk factors (Table 2).

Several cytokines are systemically-raised in many of these IMIDs, particularly those implicated in the Th1 and Th17 responses, including TNF-α, IL-12/23, IL-17, IL-12, IFN-γ, IL-1β, and the IL-1 family including IL-36 (33, 37, 60, 67, 73). Several of the inflammatory cytokines have also been shown to be upregulated in HS [e.g., IFN-γ (5), IL-2, TNF-α (33, 35) and TNF-β (5)] are produced by Th1 cells, implicating the Th1 response in the pathogenesis of HS. Furthermore, the IL-36 family, also found to be upregulated in HS (37, 41), plays an important role in the modulation of Th1 and Th17 immune responses.

Data also support the notion of shared genetic pathways of inflammation. For example, NOD2 mutations in CD are identified in PG and PASH (33) but conflicting evidence concerns their association with psoriasis and PsA (63, 75). MEFV mutations are found in FMF as well as PG and PASH; co-occurrence of FMF and HS is not uncommon (33, 76). Other genes conferring susceptibility in CD, such as OCTN, are associated with PsA (63).

In addition to shared genetic factors, the overlap in risk factors observed for different IMIDs also highlights the similar mechanisms that account for them. For example, smoking may confer a protective role in the pathogenesis of UC, PG and Behçet's disease but increases susceptibility in CD, AK, psoriasis and PsA (Table 2). With the exception of AK and conflicting evidence for Behçet's disease (56, 74), the pathogenesis of most IMIDs appears unrelated to sex-specific factors. Understanding the distinct and shared genetic, immunologic and risk factor profiles of IMIDs will aid the development of effective treatments to target the pathogenic mechanisms involved and modify the disease course.

It has previously been proposed that the link between HS and other conditions with demonstrated systemic pathology may be attributed to common genetic or environmental factors and/or shared inflammatory pathways (77).The data identified in this review demonstrate the significant overlap between the pathogenesis of HS and the aforementioned IMIDs. The most striking similarity among these diseases is that of aberrations in the innate immune response, particularly the IL-23/Th17 pathway (Table 2).

By identifying the latest publications on the pathogenesis of HS and evaluating it in the context of more established pathogenic mechanisms for known IMIDs, this review has collated substantial evidence that HS is a chronic immune-mediated auto-inflammatory disease with a multifactorial pathogenesis.

Four key themes have emerged from this review. First, genetic factors play a key role in causing HS. Mutations in a range of genes, including NCSTN mutations in the γ-secretase complex and PSTPIP1 mutations, are directly associated with auto-inflammatory disease (26, 27, 29, 31). However, the majority of HS cases appear to be non-familial, suggesting the existence of separate subsets and the need for stratification within patients diagnosed with HS (25). Secondly, the up-regulation of cytokines including TNF-α and a range of cytokines (predominantly Th17-related) are connected to auto-inflammatory mechanisms in the pathogenesis of HS (5, 35, 38). Thirdly, there is an alteration in the local microbiome of normal-appearing vs. lesional skin (43, 45, 47, 48). Data also suggest that bacterial aggregates are associated with inflammation of chronic HS lesions, and it is proposed that they most likely occur as a secondary event, possibly due to predisposing local anatomical changes such as sinus tracts (tunnels), keratinous detritus and dilated hair follicles (47). Finally, enhancement of HS risk occurs via a range of physiological and environmental factors such as smoking, obesity and mechanical friction (21, 36, 49, 51).

On the basis of the evidence reviewed here, we are able to take a cohesive view and to propose a three-stage sequence of events that contribute to the pathogenesis of HS. This integrated viewpoint is illustrated schematically in Figure 2.

The first event is follicular occlusion with subsequent dilation. This may be driven by endogenous factors in individuals harboring a genetic predisposition for an enhanced risk of infundibular keratinisation and cyst formation. Exogenous factors such as smoking, mechanical friction and metabolic changes such as obesity—which is associated with acanthosis—also contribute to occlusion of the follicular isthmus. Furthermore, occlusion of the hair follicle may lead to a dysregulation of the homeostatic keratinocyte symbiosis and microbial dysbiosis, making the skin prone to a Th1/Th17-driven inflammatory disease.

The second event is rupture of the dilated follicle. The scattering of follicle content in the dermis including keratin fibers, commensal flora or pathogen- and damage-associated molecular patterns (PAMPs/DAMPs) triggers an acute and severe immune response. The anatomical location, i.e., the inverse body areas, and enhanced mechanical friction at these predilection sites facilitates the inward rupture and extension of inflammation. We argue that release of the follicular debris into the dermis results in simultaneous activation of multiple inflammatory pathways, particularly Th17/IL-23, the (NLRP) inflammasomes and innate receptors (toll-like receptors, TLRs such as TLR2). Activation of the inflammasome in HS and related syndromes including PASH and PAPA(SH) is illustrated schematically in Figure 3. This is accompanied by histological alterations with a diverse cell infiltrate characterized by the mixed participation of monocytes, neutrophils, multinucleated giant cells, B-cells, plasma cells, T-cells, and natural killer cells, leading to an erythematous nodule or fluctuating abscess.

The third event is chronic inflammation with sinus tract or tunnel formation. Following follicular rupture, sequestered proliferating Ki-67+ epithelial strands promote continuous activation of the immune system. The presence of epithelial strands in the dermis, in addition to an imbalance in matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs), and increased activity of fibrotic factors such as tissue growth factor (TGF)-ß 1-2-3, may lead to scarring and the development of sinuses/tunnels or fistulae, a hallmark of chronic HS. These intracutaneous (partly) epithelialized cavities provide an excellent habitat for biofilm-producing bacteria, which are able to continuously trigger inflammation with associated purulent drainage. Furthermore, we hypothesize that circulating pro-inflammatory cytokines and chemokines from chronic lesions may activate the immune system of the hair follicle in distant predilection sites.

HS management usually consists of the combination of both medical therapies and surgical interventions. The main treatment goal, to improve patients' quality of life, can be achieved by reducing the inflammation-related pain and purulent discharge, limiting the incidence and duration of flares, and removing chronic lesions using surgical techniques (78). A short overview of current treatment options including the therapeutic target and/or the suggested pathophysiological link(s) is depicted in Table 3. These data summarize anti-inflammatory therapies in addition to surgery and lifestyle changes such as smoking cessation and weight loss. First-line treatment options include the use of antibiotics with anti-inflammatory properties, e.g., the tetracyclins and the combination of clindamycin and rifampicin (80, 87). The anti-TNF-α agents adalimumab and infliximab should be considered, respectively, as first- and second-choice biologics for moderate-to-severe HS after failure of systemic antibiotics (14, 90). Ustekinumab (anti-IL-12/23p40) is potentially effective in the treatment of HS (89), whereas the results of two randomized controlled trials investigating IL-17 antagonists are awaited (ClinicalTrials.gov Identifiers NCT02421172 and NCT03248531). Other promising treatment options are MABp1, targeting IL-1α for HS patients not eligible for adalimumab, and apremilast for patients with moderate HS (92, 94).

HvdZ: advisory board member for AbbVie, InflaRX, and Galderma. EP: consultant, speaker, principal investigator or received grants from: AbbVie, Amgen, Biogen, Celgene, Eli Lilly, Janssen-Cilag, Novartis, Pfizer, and UCB. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.