What causes hidradenitis suppurativa ?
15 years of continuous learning
Substantial advances have been made in our understanding of hidradenitis suppurativa/acne inversa (HS) in the last 15 years. A global appreciation of the symptomatic impact of HS has emerged, along with a quantitative understanding of the associated systemic comorbidities. The dysregulated gene pathways in lesional HS skin have been mapped, and the involvement of genetic factors and the microbiome to HS pathogenesis have been explored. Convincing evidence that pro-inflammatory cytokines play a central role opens the possibility of targeted treatment and has led to clinical trials and regulatory approval of adalimumab for treatment of HS. In turn, this has spurred a flurry of new trials with different drugs. Trials need endpoints, and with fortuitous premonition a structured search for evidence-based outcome variables has been performed by the European Hidradenitis Suppurativa Foundation (EHSF) e.V.
Infection, autoimmunity or both?
The role of bacterial infections as the primary cause of HS has attracted a lot of controversy evolving knowledge as to the underlying pathogenesis. A wide range of bacteria, including Staphylococcus aureus, coagulase-negative staphylococci, Corynebacterium species and anaerobic agents, such as Porphyromonas, Prevotella and Fusobacterium, have been isolated from deep HS lesions. Indeed, bacteria may act in HS as pathogen-associated molecular triggers of inflammation by creating patterns linking their receptors, including the transmembrane Toll-like receptors and NOD-like receptors. A downregulation of the alarmins/antimicrobial peptides S100A7 and S100A9 as well as an increased expression of antimicrobial cathelicidine LL-37 have been detected in HS lesional skin, suggesting an innate immunity dysfunction leading to an altered host-microbiome crosstalk.
Reports on the coexistence of HS with autoimmune diseases, such as systemic lupus erythematous, and autoinflammatory conditions, such as SAPHO syndrome, support the role of autoimmunity/autoinflammation in HS pathogenesis.
As a consequence, the inflammasome activates the autoinflammatory process through an uncontrolled release of several pro-inflammatory cytokines, such as IL-1, IL-17, IL-23 and TNF-α, which are overexpressed in HS lesional skin.
Mutations and HS: what is valid?
Mutations of γ-secretase complex (GSC) genes PSENEN, PSEN1, and NCSTN were first described in familial HS 10 years ago. Mutations, mostly in NCSTN, have since been reported in a few patients or families world-wide. Similarly, GSC gene mutations only occur in around 6% of non-familial HS patients. In HS patients with NCSTN mutations, remarkable findings are the male predominance (1.7:1 vs 1:3 in regular HS) and the characteristic phenotype. Several other mutations have been associated with syndromic HS, including MEFV, POFUT1, PSTPIPP1 and FGFR2. The question whether there are functional consequences of these mutations and their causality is still unanswered. Loss‐of‐function mutations would result in abnormal follicular differentiation, keratinization, occlusion, and cyst formation. However, no signiﬁcant differential expression of the reported genes was identiﬁed in HS lesional skin.
One large scale study using one Greek cohort and another German cohort identified that carriers of more than six copy numbers of the β-defensin gene cluster of chromosome band 8p.23.1 had a 7-fold greater risk for the acquisition of HS.
Skin transcriptome in HS
Great strides have been achieved through HS skin transcriptomic studies initiating an in-depth investigation of the molecular events of HS. The analysis of the HS transcriptome has provided signatures of inflammatory, epithelial, hair follicle, and sweat gland signaling molecules: Early innate immune responses including the upregulation of the alarmins S100A7, S100A7A, and S100A8/A9; downregulation of the eccrine sweat gland-specific antimicrobial peptide dermcidin and induction of proinflammatory cytokines IL-1, IL-17, TNF-α and interferons. Aberrant adaptive immunity with marked increase in T and B cells and plasma cell signatures in HS could point to autoimmune causes or simply reflect the result of chronic inflammation in late-stage HS.
Racial background and HS
The role of race in HS pathogenesis is still poorly understood. In the United States, those of African American and biracial ancestry are disproportionately affected by HS and this difference is even greater among adolescents. In Brazil, Amerindians are less likely to develop HS compared to other racial groups.
Several studies have highlighted racial differences in the clinical characteristics of HS. In western Europe and America, HS is more common in women compared to men. However, studies from eastern nations including Singapore, South Korea, Malaysia and Japan as well as Turkey, Malta and Tunisia have observed higher prevalence in men. Gluteal distribution has been observed more frequently in Asian than in European and American HS cohorts, possibly related to male predominance among Asian patients.
Skin microbiota and HS
Although HS was considered for many years to be purely inflammatory, recent extensive microbiology studies demonstrated the constant presence of commensal opportunistic bacterial flora within lesions. In the majority of Hurley stage I lesions, skin pathogens are not identified and when identified, they are isolated alone, e.g. Staphylococcus lugdunensis or Cutibacterium spp. In Hurley stages II and III lesions, the flora is polymicrobial, with predominance of strictly anaerobic species but also aero-tolerant anaerobes. Flora variety and richness increase with severity, indicating that HS is not an infection but a disease in which bacteria may play a significant role, introducing a new concept of host-microbiome disease for HS, leading to a strictly cutaneous immune dysregulation.
Complement and HS
Complement split products, like complement 5a (C5a), mediate neutrophil chemotaxis and may play some role in HS pathogenesis. Indeed, C1q, C2, and factor B were found to be upregulated and factor H, factor D and C7 downregulated in HS. C5a was significantly increased in the plasma of patients with HS. Surprisingly, C5a was lower among patients with Hurley stage III HS than Hurley stage I, driving the hypothesis that C5a is consumed as HS worsens.
Tissue T and B cells in HS
Observational studies in moderate-to-severe HS have identified up-regulated numbers of Th1, Th17, B cells, plasma cells, monocytes, dendritic cells and neutrophils in lesional HS tissue. Inflammatory cell trafficking cytokines including CXCL13, IL-6 and IL-8 are consistently upregulated in HS tissue. HS patients have been shown to also have autoantibodies against citrullinated and extracellular matrix proteins. Immunoglobulin producing plasma cells and B cells are major producers of IgD, IgG, IgM, ASCA, and anti-CCP antibodies characterized in HS. The chemokine signature of HS lesional tissue and dermal inflammatory architecture is suggestive of the possibility of tertiary lymphoid organs developing in chronic HS lesions.
Cytokines, chemokines and HS
Cytokines play a crucial role in HS. Several studies showed that T cells and dendritic cells are responsible for the secretion of IL-23 and IL-12, leading to a Th17 predominant immune response and keratinocyte hyperplasia. Especially IL-23 has been shown to induce IL-17 producing T helper cells, which infiltrate the dermis in HS lesions. During disease progression many different cytokines have been shown to be expressed in increased levels. Especially TNF-α has been shown to be elevated. As HS progresses, increased levels of TNF-α, IL-1, IL-17, S100A8, S100A9, caspase-1, and IL-10 appear in the tissue accompanied by a recruitment of neutrophils, mast cells and monocytes. Recent evidence further points to autoinflammatory mechanism in HS. HS skin shows increased formation of neutrophil extracellular traps (NET). Intriguingly, immune responses to neutrophil and NET-related antigens have been linked to enhanced immune dysregulation and inflammation. In combination with the strong type I interferon (IFN) signature in HS skin, these findings suggest a key involvement of the innate immune system in HS pathogenesis. As healing from the inflammatory process moves on, tissue scarring progresses. The development of scarring and sinus tracts is associated with metalloproteinase-2, tumor growth factor-β and ICAM-1, with possible augmentation of TGF-β and ICAM-1 signaling via specific components of the microbiome.
Sex hormones and HS
Sexual hormones and particularly androgens seem to play a role in the pathogenesis of the disease. HS related-premenstrual flares, rare postmenopausal occurrence, improvement during pregnancy, post-partum flare-ups and association of the disease with contraceptive pills with low estrogen/progesterone ratio suggest an endocrine pathophysiologic possibility for the disease. However, the currently existing data do not provide the evidence level for wide use of hormonal treatment for HS, which remains limited to female patients with menstrual abnormalities, signs of hyperandrogenism (seborrhea, acne, hirsutism, androgenetic alopecia) and/or increased serum androgens.
Obesity is one of the cardinal factors which predispose to HS and there seems to be an endocrine background fueling a latent proinflammatory state. Childhood BMI has been positively and significantly associated with risk of HS development in adult age. Returning to normal weight before puberty was found to reduce risks of HS to levels of not overweight children. Insulin resistance is common in HS. The antidiabetic drug metformin, which exhibits an anti-inflammatory effect potentially reducing IL-6, TNF-α and IL-17 through decrease of Th17 cells, Treg and suppression of the NFκB complex, has been shown to be effective in HS.
Cardiovascular risk factors and their potential contribution to the pathomechanism of HS
There is strong epidemiologic evidence that cardiovascular risk factors appear at a significantly higher rate in HS patients as compared to healthy individuals. Among those risk factors, which are also commonly associated with metabolic syndrome, are obesity and in particular central obesity, insulin resistance, diabetes and dyslipidemia. HS is significantly related to presence of carotid plaques and increased frequency of subclinical atherosclerosis and is associated with a significantly increased risk of adverse cardiovascular outcomes and all-cause mortality independent of measured confounders. Notably, the risk of cardiovascular death is higher in patients with HS than in patients with other inflammatory diseases. High systemic inflammatory burden may cause a state of insulin resistance in inflamed tissues which is causally linked to endothelial dysfunction and atherosclerosis. As a result, reduced adiponectin and increased resistin serum levels have been identified as surrogate biomarkers for insulin resistance in patients with HS.
Smoking and HS
HS is a tobacco-related skin disease, however, the role and mechanisms of cigarette smoke (CS) in HS remains speculative. Many HS patients are heavy smokers. The natural ligands of nicotine are the nicotinic acetylcholine receptors (nAChRs), which are identified in skin keratinocytes, sebocytes and immune cells constituting the non-neuronal cholinergic system. Variability in genes that encode nAChR subunits are associated with multiple smoking phenotypes and could explain a certain profile of HS smokers. In epidermis of patients with HS, there is a strong expression of nAChR around the pilosebaceous unit leading to infundibular epithelial hyperplasia and follicular plugging. In addition, CS appears to further stimulate the dysbiosis-driven aberrant activation of the innate immune system in HS. Smokers in comparison with non-smokers exhibit higher serum levels of pro-inflammatory cytokines and TNF-α. Exposure to extremely high concentrations of dioxins, included in cigarette smoke, induces hyperkeratinization of the pilosebaceous unit and a metaplastic response of the sebaceous glands producing clinical lesions of chloracne, whose clinical features are highly similar to the “smokers’ boils” in HS.
(From: Zouboulis CC, Benhadou F, Byrd A, Chandran N, Giamarellos-Bourboulis E, Fabbrocini G, Frew J, Fujita H, González-López MA, Guillem P, Gulliver W, Hamzavi I, Hyran Y, Horváth B, Hüe S, Hunger R, Ingram J, Jemec G, Ju Q, Kimball A, Kirby J, Konstantinou M, Lowes M, MacLeod A, Martorell-Calatayud A, Marzano A, Matusiak Ł, Nassif A, Nikiphorou E, Nikolakis G, Nogueira da Costa A, Okun MM, Orenstein LAV, Pascual JC, Paus R, Perin B, Prens E, Röhn TA, Szegedi A, Szepietowski JC, Tzellos T, Wang B, van der Zee HH. What causes hidradenitis suppurativa? 15 years after. Exp Dermatol 29:1154-1170, 2020)