Acne and hidradenitis suppurativa

BJD

British Journal of Dermatology

S C H O L A R L Y R E V IE W

Acne and hidradenitis suppurativa A. Pink,1 F. Anzengruber2 and A.A. Navarini2 1 2

St John’s Institute of Dermatology, Division of Genetics and Molecular Medicine, Guy’s Hospital, King’s College, London SE1 9RT, U.K. Department of Dermatology, University Hospital Zurich, Zurich 8091, Switzerland

Summary Correspondence Alexander A. Navarini. E-mail: [email protected]

Accepted for publication 26 September 2017

Funding sources None.

Conflicts of interest None declared. DOI 10.1111/bjd.16231

Acne and hidradenitis suppurativa (HS) both centre on hair follicles. They often occur together as part of the acne tetrad, but are found in distinct localizations. Acne is primarily defined by the presence of comedones and inflammatory lesions. However, in HS the intertriginous localization and chronicity play equally important roles for the diagnosis to the inflammatory lesions. Genetics, bacteria, environmental factors and innate inflammation have all been found to play a role in acne and/or HS. Surprisingly, there is little overlap between the findings so far. The genetics of acne and HS are distinct, bacteria have not been shown convincingly to play a role in HS, and the important risk factors obesity and smoking in HS cannot be easily translated to acne. The one driving factor central to both diseases is innate inflammation, most strikingly involving interleukin-1. Hence the interleukin-1 family, as already shown in autoinflammatory conditions associated with acne, could represent attractive treatment targets.

What’s already known about this topic?

• •

Acne and hidradenitis suppurativa often occur together and have a related pathogenesis. The innate immune system is involved in both conditions.

What does this study add?

• • •

Hidradenitis suppurativa has no seborrhoea and the role of bacteria is not clear. There may be no association of acne and high body mass index. Both conditions show involvement of interleukin-1, which could be a rationale for treatment.

Acne (acne vulgaris, OMIM 604324) and hidradenitis suppurativa (HS, acne inversa; OMIM 142690) are chronic and debilitating inflammatory dermatoses centred on hair follicles. They often occur together clinically and are important features of the acne tetrad, which also includes sinus pilonidalis on the coccygeal region, and dissecting cellulitis of the scalp. The initial pathogenetic event in acne is known to occur in the pilosebaceous unit. In HS, the apocrine glands were suspected to be at the centre of the pathogenesis, because HS is found largely in apocrine-gland-bearing regions of skin. In contrast to acne, HS was only described in 1839,1 and was named ‘hidrosadenite phlegmoneuse’ in 1854.2 More recently, pathogenetic models of both acne and HS have converged closer, centring on the pilosebaceous unit’s biology. © 2018 British Association of Dermatologists

HS has been defined as ‘a chronic, inflammatory, recurrent, debilitating, follicular skin disease that usually presents after puberty with painful deep seated, inflamed lesions in the apocrine gland-bearing areas of the body, most commonly, the axillary, inguinal and anogenital regions’ (Dessauer definition, 2006, as modified at the 2nd International HS Research Symposium, San Francisco, 2009). A diagnosis of HS requires (i) typical lesions (painful nodules, abscesses, sinus tracts, bridged scars or open comedones) in (ii) typical sites (axillae, groin, perineal region, perianal region, infra- and intermammary folds or buttocks) and (iii) the disease must be chronic and recurrent.3 Acne is defined as a ‘chronic inflammatory dermatosis notable for open or closed comedones (blackheads and British Journal of Dermatology (2018)

1

2 Acne and hidradenitis suppurativa, A. Pink et al.

whiteheads) and inflammatory lesions, including papules, pustules, or nodules (also known as cysts)’.4 The regions of the body most usually affected by acne are the face and upper torso.

Epidemiology The onset of acne usually occurs at the age of 10–14 years and it regresses by the age of 20–25 years.5 Men and women develop acne with equal frequency. A number of studies have examined the prevalence of this condition in different populations.6–9 Although acne occurs in all races and ethnicities, worldwide prevalence studies show conflicting data, because the methods of diagnosis and classification vary between centres, as we still lack an international consensus system for the classification of acne.7 In some patients acne persists into the fourth or fifth decade of life, with irreversible scarring occurring in up to 20% of patients.10–12 The resulting disfigurement is important socially and economically as acne can cause difficulties in finding employment, low self-esteem and depression.13,14 Both sexes are about equally affected. Evidence suggests there is a substantial genetic component to acne pathogenesis. Twin and family studies indicate that a family history doubles the risk of significant acne, and heritability estimates vary from 75% to 82%.12,15 HS develops at an average age of 22 years and persists for an average of 19 years.16,17 There is a female predominance, with reported female-to-male ratios as high as 5 : 1.17 The 1-year prevalence is estimated to be 1–4% in European populations.18,19 The disease incidence is 6 in 100 000 in the U.S.A., and this has significantly increased over the last 40 years (from 43 to 96 per 100 000).20 However, this increase should be interpreted with caution given that higher presentation rates and more accurate diagnosis may have influenced the statistics.20 Body mass index (BMI) and smoking have been associated with disease development and progression.18 Overall, 43–77% of patients with HS are overweight (BMI 25–30 kg m 2) or clinically obese (BMI > 30 kg m 2),18,21–23 and disease severity appears to correlate with BMI.21 Up to 937% of patients with HS are current or former cigarette smokers, compared with 46% of controls.24 The average disease severity is highest in current smokers and reduces through ex-smokers and nonsmokers.21,25 Genetic factors appear to play an important role in HS, given that up to 42% of patients report a family history of the condition,26 and that it can follow autosomal dominant inheritance in some kindreds.27,28

Clinical presentation Acne lesions progress through different stages. Initially, blockage of the pilosebaceous outflow tract by keratinocytes leads to accumulation of sebum and keratinous material. This results in closed comedones that can only be detected by manual stretching of the skin. Continued obstruction leads to such British Journal of Dermatology (2018)

amounts of material contained in the outflow tract that the follicular orifice is bulged towards the skin surface again, resulting in presentation of the keratinous plug and subsequent oxidation. This, together with melanin, leads to the formation of blackheads. When this process eventually leads to superinfection by opportunistic bacteria such as Propionibacterium acnes and leakage of material from the follicular structure, inflammation ensues and produces an inflammatory papulopustule. The maximal form is the formation of cysts and scarred tissue regions, largely comparable with HS lesions in Hurley stage II and III. In HS there are no comedones like in acne vulgaris but the characteristically paired pseudocomedones that are actually superficial microfistulae, whereas paired blackheads are microfistula openings. HS also produces polymorphic lesions combining papules, pustules, nodules, cysts, abscesses, sinus tracts and fistulae in flexural areas.29 The condition is associated with significant pain, tenderness, burning, stinging, pruritus, chronic discharge (serous, purulent or blood stained) and a persistent malodour.30 Long-standing disease can result in fibrosis, dermal contractures, scarring and a consequent reduction in mobility. The disease targets flexural areas, notably the postauricular region, axillae, submammary region, abdominal fold, groin, perineum, buttocks and medial thighs. Rarer sites include the scalp, face, neck, back and legs. Complications include fistula formation (affecting the urethra, bladder or rectum), lymphoedema and the development of squamous cell carcinoma (SCC). SCC development is rare in HS (five of 2119 cases retrospectively analysed in one study) and arises predominantly in the context of long-standing perianal disease.31 Metabolic syndrome has more recently been associated with HS, and this appears independent of patient age, disease severity or disease duration.32

Histopathological features Acne produces collections of neutrophils and fibrin within the infundibulum, and lymphocytes and plasma cells surround the follicle. Subsequently, focal abscesses form that contain debris, and the follicular epithelium bursts. This leads to a granulomatous, foreign-body reaction. The features of HS are closely related to those of acne. Common histopathological features include follicular hyperkeratosis, follicular hyperplasia and follicular occlusion with an associated spongiform infundibulofolliculitis.33 These changes may be associated with follicular dilatation, follicular rupture and the formation of keratin-containing cysts (lined by stratified squamous epithelium), abscesses, sinus tracts, granulomas, fibrosis and scarring. Other features include hyperplasia of both the interfollicular epidermis and the intrafollicular epithelium, sebaceous gland involution and apocrine gland hyperplasia, which is often associated with a periglandular inflammatory infiltrate.34–36 Subepidermal, dermal and subcutaneous inflammation is observed in 82%, 76% and 31% of cases, respectively, and the inflammatory infiltrate comprises predominantly lymphocytes in the early stages followed by neutrophils, multinucleated © 2018 British Association of Dermatologists

Acne and hidradenitis suppurativa, A. Pink et al. 3

foreign-body giant cells and granulomas as the disease progresses.37 In HS the intra- und interfollicular epidermis is hyperplastic, partly oedematous, and no parakeratosis can be seen. In acne the hyperplasia occurs intrafollicularly. In either disease, characteristically a mixed infiltrate consisting of neutrophils, lymphocytes/histiocytes, plasma cells and multinucleated giant cells occurs. Also fistulae, sinus tracts, intraepidermal pustules and scarring are seen in both diseases. Clinically, no closed comedones are seen in HS, while seborrhoea occurs only in acne vulgaris. In HS, follicular occlusion occurs at the terminal hair follicle, while acne vulgaris mainly manifests in sebaceous follicles (Fig. 1). Sites of maximal sebaceous gland density, like the face, are the locations where acne vulgaris occurs (Table 1).38

products by bodybuilders, for example. Chloracne Herxheimer, an acneiform dermatosis, is due to polyaromatic substances, nowadays better understood as MADISH (metabolizing acquired dioxin-induced skin hamartoma).40,41 Finally, acne excoriee des jeunes filles, another acneiform disease, is a psychiatric disease that arises due to an inability of impulse control and produces multiple excoriations.42 Likewise, for HS, the significant interindividual variability regarding the site of disease, the type of lesions present and the associated systemic symptoms (such as fever, general malaise and arthralgia) during disease flares indicate that there may be multiple, as yet poorly defined, phenotypes within HS. Three broad phenotypic groups have recently been proposed: axillary–mammary, follicular and gluteal.43

Phenotypic variation

Treatment

In acne, multiple phenotypes exist that are not all due to the same pathogenetic processes.39 Acne neonatorum and acne infantum are the earliest types. Acne vulgaris encompasses the subtypes comedonica, papulopustulosa and conglobata. Acne venenata is due to occlusive topicals, and hormonal acne can occur due to endocrinological problems or abuse of hormone

Strategies to control acne4 are focused on removal of follicular occlusion, sebaceous hyperactivity and bacterial overgrowth. Benzoyl peroxide and retinoids5 improve comedones but can irritate, and thus must be started gradually. Newer retinoids such as adapalene also have anti-inflammatory effects.5 Topical antibiotics are useful; however, resistance occurs regularly in monotherapy. Therefore, they are usually combined with topical antiseptic agents. Systemic fat-soluble antibiotics are of even higher efficacy, but can have mainly gastrointestinal sideeffects. The best results are ultimately achieved with isotretinoin, which is used in the great majority of cases of severe acne. Due to its potential to shrink sebaceous glands, it can lead to stable remission of symptoms.5 However, 4–6 weeks after the beginning of treatment, acne can flare, especially in large closed comedones,44 and additional steroids are necessary. Very rarely, acne fulminans can develop. Table 1 Acne vulgaris and hidradenitis suppurativa/acne inversa: differences and similarities Acne vulgaris

Hidradenitis suppurativa

Focus of pathology Seborrhoea Closed comedones Fistulas Location

Sebaceous follicles Yes Yes

Terminal hair follicles

Age at onset Duration

Puberty Remission after puberty Unknown, possibly androgens No

Risk factors

Fig 1. The current histopathological model of acne and hidradenitis suppurativa (HS). While the focus of pathology in acne vulgaris is the sebaceous gland, it is the terminal hair follicle in HS (acne inversa). BMZ, basement membrane zone. © 2018 British Association of Dermatologists

Malignant transformation Therapeutic response

No No

Seldom Face, chest, back

Good

Common Common sites: armpits, genitoanal area, submammary ~23 years In some cases lifelong Nicotine abuse, overweight, hormones, friction, hyperhidrosis Possibly; squamous cell carcinoma Often frustrating

British Journal of Dermatology (2018)


For HS, treatment is difficult but the evidence gets better,45 even though few treatments have been rigorously validated in blinded, randomized and placebo-controlled trials. Mild disease can be managed with topical clindamycin.46 More severe disease is more often treated with systemic therapy including antibiotics (tetracyclines, clindamycin, rifampicin), retinoids, dapsone, ciclosporin and oral steroids. Clindamycin and rifampicin in combination (both 300 mg twice daily) can significantly improve both disease severity and quality of life.47,48 Retinoids appear to be of mixed benefit. Acitretin confers a long-lasting improvement in disease severity in up to 75% of cases, whereas isotretinoin is only minimally effective but may alleviate mild forms of the disease.49,50 Immunosuppressants including prednisolone, dapsone and ciclosporin can be effective.51,52 Antitumour necrosis factor (anti-TNF) agents can be of significant benefit in HS; adalimumab and infliximab are the best studied so far.53,54 An interesting new option could be interleukin (IL)-1a blockade, which has been trialled recently and showed 36% numerical reduction of inflammatory lesions after 6 weeks of an open-label study.55 In a randomized clinical trial with 20 patients,56 the disease activity score was decreased in 67% (six of nine) of the anakinra arm at 12 weeks, but in only 20% of placebo-treated patients (P = 004). In addition, a prolongation of the time to new HS exacerbations was found in the anakinra arm by log-rank test (log rank 614, P = 001). No serious adverse events occurred. Other treatment options include radiotherapy, psoralen and ultraviolet A phototherapy, photodynamic therapy, laser therapy (neodymium–yttrium aluminium garnet, and carbon dioxide lasers) and surgery.57–61 All therapies except ablative surgery lead to only temporary remission in HS, and inflammation quickly returns upon stopping treatment.

Pathogenesis Follicular occlusion HS was once considered a disease of the apocrine gland, but newer evidence firmly implicates direct follicular involvement in disease pathogenesis. Over 95% of early lesions (< 3 days old) include hyperkeratosis, occlusion of the follicular unit and an associated perifolliculitis. These are often accompanied by dilatation of the hair follicle and subsequent stasis in both the apocrine and eccrine glands.33 While apocrine stasis, hyperplasia and a periglandular inflammatory infiltrate are observed in and around the apocrine glands in 33–90% of cases of HS, they are universally accompanied by extensive inflammation of the hair follicle, eccrine gland and cystic structures,33,34,36 and are thought to be a secondary phenomenon.33 It has recently been observed that there is a thinning of the basement membrane zone around the sebofollicular junction (neck of the ductus seboglandularis) in HS skin. This area of weakness may predispose to spillage of follicular contents into the dermis and a subsequent inflammatory response.62 The British Journal of Dermatology (2018)

identification of free keratin filaments in the dermis supports that mechanism and is consistent with follicular rupture playing a key role in disease pathogenesis.63 Also in acne, follicular obstruction has long been known to play a crucial role in the pathogenesis. The histology of acne has previously been thought to be related to HS, and it was suggested to rename HS as ‘acne inversa’. However, there are multiple differences between the two diseases, for example the role of seborrhoea seems to be distinct, as sebum production in HS in normal.64 Taken together, these studies suggest that follicular plugging, dilatation and rupture underlie the development of HS and acne (Fig. 1), the latter of which is further supported by seborrhoea. The driving forces behind these characteristic histological changes remain unclear; however, a number of endogenous and exogenous factors have been implicated in the development and propagation of the condition. This section further aims to summarize the involvement of genetics, the immune system, hormones, bacteria, and smoking and obesity. Genetics HS has not been associated with any specific human leucocyte antigen type.65 Until about 10 years ago, only one putative genetic locus had been reported in HS (a 80-cM locus on chromosome 1, 1p211–1q253).66 In 2010, heterozygous mutations were reported in the c-secretase genes PSENEN, PSEN1 and NCSTN in six Chinese multiplex kindreds, all showing full cosegregation.67 One of these genes, NCSTN, lies within the previously reported region of linkage on chromosome 1.66 Mutations have since been reported in two British, six Chinese, one Japanese and three French multiplex kindreds, as well as four apparently sporadic cases.68–74 To date, eighteen mutations have been reported in NCSTN, three in PSENEN and one in PSEN1,67,70–73,75 of which four are nonsense mutations, seven result in frameshifts, seven result in altered splicing and four are missense mutations. c-Secretase is an aspartyl intramembrane protease complex capable of hydrolysing and cleaving in excess of 50 type 1 transmembrane proteins including amyloid precursor protein, Notch receptors, N-cadherin, E-cadherin, neuregulin, Erb4 and nectin-1a.76–78 The complex has traditionally been viewed as playing two key roles. The first is to catalyse cleavage of the potentially biologically relevant intracellular portions of substrates (e.g. Notch intracellular domain in the context of Notch signalling), a process known as regulated intramembrane proteolysis.79 The second is to remove intramembranous proteins from the cell membrane and thus maintain healthy cell cycling and homeostasis.80 c-Secretase also plays a role in cellular mechanisms including endocytosis (including receptor-mediated endocytosis), protein trafficking (e.g. amyloid precursor protein) and phagocytosis.81–84 The overall nature of the mutations reported in HS and the available functional data would suggest that they are loss-offunction variants. Some of the mutations have been shown to result in haploinsufficiency of their respective © 2018 British Association of Dermatologists


components.85,86 Given that mutations have been reported in three of the four c-secretase enzyme complex components it has been hypothesized that these mutations may affect enzyme activity, but this has not been proven in studies performed to date.86 The recent genetic findings are supported by in vivo data showing that knockdown of individual c-secretase components in mouse skin (PSEN1 PSEN2 , PSEN1 and NCSTN) results in follicular keratinization, follicular atrophy and the formation of epidermal cysts.87–89 The fact that knockdown of the Notch proteins Notch 1, 2 and 3 results in similar phenotypic changes87 has led to speculation that it is an effect on the c-secretase–Notch signalling pathway that may result in disease development, but this is yet to be proven. A recent study examining the effects of four missense mutations reported in HS showed that only one mutation affected Notch cleavage.90 Interestingly, that effect was negated when the respective mutant transcript was expressed alongside the wildtype nicastrin transcript (representing heterozygosity). Recently, interesting findings identified the b-defensin cluster to be associated with HS and its clinical course.53 In acne, several twin studies showed high heritability. In one study, 930 pairs of twins of the Kaiser Permanente Twin Registry had high concordance of acne in monozygotic twins, although acne status was assessed from nonstandardized medical records by retrospective questioning.13,91 An Australian twin registry also demonstrated high heritability estimates for acne in adolescent twins.92 Moreover, the comparison of the family history of acne between 220 twins with acne and 1358 twins without acne showed that 47% of the twins with acne had a family history of acne, compared with 15% in those without acne (P < 0001).13 Several candidate gene studies were performed in genes of known factors involved in acne. These successfully identified a higher than expected rate of mutations in the genes of TNFa93–97 or the TNF receptor,67 Toll-like receptor (TLR)2,67 IL-1a and IL-6.98 Also identified were genes involved in metabolism, genes in the cytochrome P450 family and those affecting hormone metabolism, such as the androgen receptor.99–101 Subsequently, two genome-wide studies investigating genetic signals in acne were performed. The first was a genome-wide association study (GWAS) including 1860 patients with acne and 3660 healthy controls in a Chinese Han population. Three single-nucleotide polymorphisms in two genomewide significant susceptibility loci (1q242 and 11p112) were found.102 Those loci contain genes related to androgen metabolism, inflammation processes and scar formation, such as the damage-specific DNA binding protein 2 (DDB2) and selectin L (SELL).102 The second was a European study. With 1893 cases of severe acne and 5132 controls from the U.K., 73 million singlenucleotide polymorphisms were tested in a GWAS.103 Three genome-wide significant loci were discovered, on 11q131, 5q112 and 1q41. All three loci contain genes linked to the transforming growth factor (TGF)-b cell signalling pathway, namely OVOL1, FST and TGFB2.103 The study has since been extended and the loci further confirmed (unpublished data). © 2018 British Association of Dermatologists

However, no overlap between the Chinese and the European loci was found, which is unusual in GWAS studies. So far, no rare damaging variants have been found in families of patients with severe acne. Thus, current data on genetic drivers of disease suggest a role of rare variants in a some cases of HS, and common genetic variants in severe acne. GWASs have yet to be performed in HS, or studies sequencing familial forms of severe acne. Aberrant immune responses The intense inflammation observed in HS has led many to speculate that aberrant immune responses may play a role in disease pathogenesis.104 This is supported by the efficacy of immunomodulatory agents such as oral steroids, ciclosporin and more recently anti-TNF-a therapy in treating HS.105 The latter (infliximab and adalimumab) specifically imply the involvement of the cytokine TNF-a in disease pathogenesis. Indeed, TNF-a levels are elevated in the skin and circulation of patients with HS,106,107 and TNF-a receptor 1 and TNF-a receptor 2 expression is increased in affected skin.104 TNF-a is capable of recruiting and activating lymphocytes and neutrophils, both of which are prominent in early HS infiltrates, and of stimulating the production of a wide array of other proinflammatory cytokines.108 One such cytokine, IL-1b, is overexpressed in the skin and circulation of patients with HS, and levels appear to correlate with disease severity.104 IL-1b is produced by monocytes and macrophages and is activated by the inflammasome. This is an innate immune sensor situated within the cytosol that can be triggered by a variety of danger signals including pathogenassociated molecular patterns and damage-associated molecular pattern molecules (DAMPs). In the context of HS, these signals may originate from bacterial sequences, free keratin or DAMPS produced as a result of tissue destruction and scarring. Macrophages and dendritic cells initially recognize these danger signals through pattern recognition receptors situated within the cell membrane such as TLR2. Macrophages and dendritic cells harvested from affected HS skin have correspondingly been shown to overexpress TLR2.109 IL-10 expression is also elevated in HS skin; however, in contrast to IL-1b, IL-10 is an anti-inflammatory cytokine capable of limiting the response to bacteria and thus reducing overall tissue damage.104 It can be produced by cells of both the innate and adaptive immune systems, including macrophages, which are prominent in HS infiltrates.104 In acne, the overproduced sebaceous lipids are broken down by lipase-producing bacteria, such as P. acnes. It dominates the microflora after puberty and is considered the stimulus for inflammation in acne, activating TLR2110–112 among other receptors. This leads to a T helper 17 adaptive response. The sebum composition can initiate acne lesions,39 and comedones also contain inflammatory cytokines such as IL-1a,113 which attracts neutrophils releasing enzymes that digest the follicular wall. In addition, P. acnes is hard to degrade and persists for many weeks in the skin, in contrast to Staphylococcus British Journal of Dermatology (2018)


aureus, which can be lysed into its soluble components within hours. The above evidence suggests that innate inflammatory mechanisms initiate the inflammatory response observed in HS and acne,114 and that they can be considered primary inflammatory skin disorders.115 However, cytokine profiles are not consistent across studies, which may in part be due to the exact skin compartments studied and the methods by which expression levels were analysed. A study that focused explicitly on the expression of cytokines in the epidermis corroborated the finding that IL-10 expression is raised. It also found that expression of TNF-a, TLR2, TLR3, TLR7, TLR9, b-defensins 2 and 4, intercellular adhesion molecule-1, IL-6, insulin-like growth factor-1, a-melanocyte-stimulating hormone and TGFb was reduced in affected and unaffected epidermis vs. control epidermis and epidermis from patients with other inflammatory dermatoses including psoriasis and acne vulgaris. The apparent downregulation of these innate markers led the authors to postulate that HS may be a disease of deficient innate immunity.116 In support of this, monocyte responses to bacteria are reduced in HS and the number of circulating natural killer cells diminishes over time.31,117 Furthermore, IL-20 and IL-22 receptor expression is reduced in HS skin, and expression of the natural antagonist to those receptors, IL-22binding protein, is increased.118 The involvement of the innate immune system in disease pathogenesis is further supported by the association of HS with Crohn disease (17% of patients with Crohn disease have HS).119 Like HS, Crohn disease was once thought of as a direct consequence of bacterial infection. However, recent genetic advances suggest that Crohn disease arises as a result of subtle defects in mucosal immunity. NOD2 was the first susceptibility gene to be identified, and encodes an innate intracellular pattern recognition receptor.120 The NOD2 receptor recognizes bacterial peptides and, in turn, enhances intestinal epithelial cell barrier function and mediates chemokine production.121 In animal models the loss-of-function variants observed in Crohn disease disable the function of that receptor, resulting in a defective barrier, bacterial invasion and a chronic inflammatory response (colitis).122 Further variants have now been identified in more pattern recognition receptor genes (TLR4 and NLRP3), genes involved in autophagy (ATG16L1 and IRGM) and genes important in mucosal barrier function such as DLG5.123,124 Antimicrobial peptides (AMPs) represent another mechanism of innate immunity in the skin. They confer antimicrobial, immunomodulatory and proinflammatory properties and can promote keratinocyte proliferation and differentiation. Examples include the b-defensins, cathelicidin, psoriasin, ribonuclease 7 and dermcidin.66,125,126 In acne, intriguing data showed recently that increased human b-defensin 2 in the T-zone (sebaceous regions of the face) leads to a lower number of inflammatory lesions than in the cheeks, even though the number of lesions is much higher in the T-zone.127 AMPs are strongly expressed in sebocytes,128–130 which supports a role of sebum in innate defence – allowing British Journal of Dermatology (2018)

them to kill P. acnes with cathelicidin.131 The AMPs can be upregulated by free fatty acids. The role of AMPs in HS is a subject of ongoing investigation. Human b-defensins 2 and 3, cathelicidin (LL-37) and psoriasin have been reported to be overexpressed in HS skin (cathelicidin appears particularly upregulated in apocrine epithelium), ribonuclease 7 is reduced and there is no discernible difference in the level of dermcidin.126,132–134 These data provide an insight into the immune response underlying acne and HS. Epidermal studies and the association with Crohn disease potentially implicate aberrant innate immunity as a causative factor, but the consequential effects on the adaptive response and the exact mechanisms by which any such immune deficiency could result in the severe inflammatory responses observed are yet to be elucidated. It remains unclear as to whether immune dysregulation is a primary event, somehow resulting in the characteristic follicular occlusion noted on histology, or in some way a consequence of the cascade of events that follow initial follicular plugging. Many subtle mechanisms by which the hair follicle contributes to cutaneous immunity and inflammation have been characterized and may be of direct relevance in the pathogenesis of HS. The hair follicle is considered ‘immune privileged’ as, at certain times in the hair cycle, it can protect itself from immune recognition and inflammatory responses via a loss of major histocompatibility complex class I and II expression, and by expressing CD200, a-melanocyte-stimulating hormone, TGF-b2, macrophage migration inhibitory factor and indoleamine-2,3-dioxygenase.131,135 The role of TGF-b2 may be especially interesting because a confirmed genome-wide significant signal was found close by in patients with acne, and the authors also found TGF-b2 to be downregulated in fresh acne biopsies.136 Multiple immune cells, including Langerhans cells, T cells (CD4+ and CD8+), macrophages and mast cells are commonly located in and around the hair follicle.135 Langerhans cells have been a particular focus of recent study. They form an important bridge between the innate and adaptive immune responses and are integral in stimulating cells such as T helper 17 and T helper 2 lymphocytes to react against fungal and bacterial infections.137,138 Keratinocyte subsets within the hair follicle have been reported to play an integral role in facilitating the migration of Langerhans cell precursors into the epidermis. Specific expression of the chemokine ligands CCL2 and CCL20 appears promigratory and CCL8 inhibitory.139 This recent advance has led some to speculate that the hair follicle acts as the ‘gatekeeper’ to the epidermis.140 The emerging immune function of the hair follicle, or indeed any malfunction thereof, may be of direct relevance in HS and acne, prompting further investigation. Hormonal influence Acne activity closely correlates with the onset of androgens. Early-onset acne is associated with elevated serum dehydroepiandrosterone, which underscores the importance of © 2018 British Association of Dermatologists


hormones in acne. High 17a-hydroxyprogesterone levels were associated with acne severity in a Chinese cohort,102 and patients with acne have lower serum estradiol and sex-hormone-binding globulin levels than controls. On the other hand, androgen-insensitive persons have low sebaceous activity and do not develop acne. In female patients with acne, antiandrogen therapy is a mainstay of treatment. It would probably also work well in men, but naturally it would perturb the male hormonal homeostasis. Also in HS, the female predominance, postpubertal onset, premenstrual flares (57% of affected women)22 and clinical improvement often observed during pregnancy and postmenopause imply a role for hormones in HS pathogenesis.141 Given the role of androgens in acne vulgaris it has been proposed that they may also play a role in HS. In concordance with this, female patients often have premenstrual flares (when progesterone levels are high) and are more likely to present with other androgen-related sequelae such as acne, hirsutism and irregular menses (although data were never replicated in larger cohorts).142,143 Case reports lend further evidence to the involvement of androgens in HS, documenting that progestogens (androgens) within oral contraceptive agents may induce disease flares. Furthermore, in vivo mouse models indicate that androgens may induce a proinflammatory state by increasing TLR-mediated monocyte expression of TNF-a.144,145 Some very interesting findings suggest that in skin, sebocytes regulate androgen homeostasis. They show expression of aromatase and steroidogenic acute regulatory protein but none of the sex-hormone-inactivating enzymes. Therapeutically, antiandrogens (cyproterone acetate) combined with oestrogens were no more beneficial than oestrogens alone,142 and plasma testosterone, dehydroepiandrosterone and apocrine-gland androgen-converting enzyme levels are no different in patients with HS.146,147 Furthermore, the female predominance and the fact that the disease often starts many years after puberty are also not consistent with androgen involvement in HS. However, finasteride, another antiandrogen, has shown beneficial effects in several case series.148–151 Overall, the impact of androgens remains uncertain and the mechanism of hormonal involvement in HS requires further clarification.152

excluding superficial colonizing bacteria, revealed no growth in 51% of cases. In the remaining 49% of cases, S. aureus, coagulase-negative staphylococci and occasional anaerobes were detected.155 Two further studies employed CO2 laser to dissect through deeper tissue planes. One study focused on patients with an acute exacerbation,156 whereas the other looked at patients with chronic disease.157 Coagulase-negative staphylococci were found to be the most abundant organisms in superficial and deep planes in both acute and chronic lesions. Corynebacterium and anaerobes were the next most abundant organisms in acute lesions158 (S. aureus was not present at any level in the 10 individuals studied), whereas S. aureus and anaerobes were the next most abundant organisms in chronic disease. Polymicrobial growth was noted in at least one tissue plane in all patients studied, and deep-tissue cultures were positive in 22 of 25 patients.157 Taken together it would appear that bacteria are found within the majority of, but not all, HS lesions. There was considerable interindividual variation in the number and type of organisms present, although coagulase-negative staphylococci were most common. Also, studies on the microbiome of HS, somewhat surprisingly, detected fewer bacteria in preclinical lesions than in normal skin.159 The lack of consistent organisms, the failure of patients to develop infectious complications such as cellulitis, the normal appearance of regional lymph nodes and the efficacy of oral steroids in HS support a secondary rather than primary role for bacteria in disease pathogenesis.160 One mechanism by which they may confer such a role is by, upon follicular rupture, being recognized by pattern recognition receptors and triggering an immune response. Eradication of these bacteria may therefore be one mechanism by which antibiotics alleviate symptoms in HS. That said, it remains a matter of debate as to whether antibiotics act via their antibacterial actions or through independent anti-inflammatory mechanisms in this context. Taking all the evidence into account, a pathogenic role of bacteria has not been established, and an analysis of several prospective studies implies involvement of impaired innate immunity triggered by microbial factors.153

Bacterial involvement

Obesity and smoking

Bacteria are deeply involved in causing acne. One of their many roles is activation of the innate immune system on the level of microcomedones. However, in HS, the role of bacteria is controversial.153 Studies using superficial sampling techniques have shown that a wide variety of bacteria overlay HS lesions, including aerobes (S. aureus, S. viridans), Corynebacterium spp. and anaerobes.154 However, the reliability of these results is questionable, given that many bacteria on the skin surface are likely to be colonizers rather than directly involved in the disease process. Furthermore, there was very little consistency in the bacterial strains identified across the different studies. One study involving deep-needle aspiration of lesions, thus

The role of obesity in acne is controversial. Even though acne is a feature of polycystic ovarian syndrome, few studies have explored the association of a high BMI with acne, and some studies even suggest that patients with high BMI have a lower risk of acne.161 For HS, the association with BMI is much clearer.162,163 Obesity may have an impact on HS by mechanically increasing friction at flexural sites (thus potentially damaging follicular outlets), increasing sweat retention or increasing the circulating level of proinflammatory cytokines (IL-1b and TNF-a are both secreted by macrophages within visceral fat).17 Circulating mononuclear cells reportedly exhibit a proinflammatory state in obese individuals (IL-6 and TNF-a

© 2018 British Association of Dermatologists



gene expression is upregulated).164 Furthermore, elevated circulatory levels of palmitate in obese individuals may also predispose to inflammation by interacting with TLRs and activating innate immune mechanisms.165 Alterations to the microbiome in regions of opposed skin may also predispose to disease development.166 Smoking is associated with HS;162,167 however, for acne the influence of smoking is still controversial. The exact mechanisms by which smoking contributes to HS pathogenesis are unclear; however, nicotine has been shown to induce epidermal hyperplasia and follicular plugging.168 Further mechanisms by which smoking may confer an impact on the disease are that it appears to cause an initial overstimulation and eventual reduction of glandular secretion,169 it results in the secretion of noxious metabolites in sweat and stimulates neutrophil chemotaxis,154 and it increases the expression of proinflammatory cytokines such as IL-1b and TNF-a.170 Furthermore, smoking has been shown to reduce cutaneous blood flow, reduce tissue oxygenation and impair wound healing, all of which may be detrimental to the healing of HS lesions.171,172 Reactive oxygen species within tobacco smoke confer immunomodulatory effects by detrimentally affecting phagocytosis, potentially facilitating any infective involvement in disease pathogenesis.173 Effects on fibroblast migration and activation174,175 and an upregulation of matrix metalloproteinase 1 and 3 activity may have a significant impact on the supporting structure in the skin, such as collagen, elastin and proteoglycan,176 and consequently impact on the histopathological evolution of the disease.

Associated conditions and overlap conditions Both acne and HS can arise as part of a follicular occlusion tetrad comprising HS, acne conglobata, dissecting cellulitis of the scalp and pilonidal cysts or abscesses.177–189 In total 23–70% of patients with HS report a history of acne vulgaris; however, there appears to be no correlation between the severity of the two conditions.20,26,180 It has also been associated with conditions including Dowling–Degos disease, Jackson–Lawler pachyonychia congenita, keratitis–ichthyosis–deafness syndrome, Crohn disease, Fox–Fordyce disease and SAPHO syndrome (see below). Some rarer but more specific phenotypic subgroups have been described. Acne is a feature of the pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, which has also been associated with HS (a combination referred to as PAPASH),181,182 and can occur secondarily to heterozygous mutations in the PSTPIP1 gene.183 A related phenotypic group comprises individuals with pyoderma gangrenosum, acne and suppurative hidradenitis (PASH syndrome),182 and a mutation has recently been reported in NCSTN in one pedigree.184 As the PSTPIP1 gene is associated with the inflammasome pathway, IL-1b blockade has been a successful therapy for PAPA syndrome. Recently, isolated pyoderma gangrenosum was also found to have increased IL-1b and was treated successfully in an investigator-initiated trial with anti-IL-1b blockade, resulting in an 80% response rate.185 British Journal of Dermatology (2018)

SAPHO syndrome encompasses a variety of clinical presentations including sterile osteomyelitis, osteitis or arthritis and pustular psoriasis, acne or HS.186 Two further phenotypic groups have been reported, one with HS and keratitis, the other with HS, spondyloarthropathy and acne conglobata.187,188 Keratitis was observed in four of 62 patients with HS in one case series (HS preceded the development of keratitis by an average of 7 years) and has been reported in several case reports since.189,190

Conclusions Acne and HS are both complex disorders with many contributing factors. Even though the roles of occlusion, bacteria and seborrhoea have been shown, we are unable as yet to explain why some lesions are inflamed and some remain innocuous. We are faced with large lesions that have been spared by inflammation, as well as microcomedones surrounded by erythematous oedema. Possibly, the local presence or absence of autoinflammatory cytokines could be responsible for this baffling paradox. It is interesting that also in classic autoinflammatory diseases, inflammation arises seemingly spontaneously, which may just indicate that we have not yet found the triggering event. It seems that IL-1 and the inflammasome play an important role in both conditions, even though acne and HS are clearly not autoinflammatory diseases in the strict sense. It will be very interesting to determine whether blockade of cytokines in the IL-1 family will cause acne-like conditions to yield, as has been shown by case reports recently.191,192 Altogether, in the acne and HS disease family, much progress has been made on the genetic, microbiological and inflammatory levels. It is now the community’s task to combine these findings to reach an integrated understanding of these conditions and better address them with effective treatments.

References 1 Velpeau A. Dictionnaire de Medecine, ou Repertoire Generale des Sciences Medicals sous le Rapport Theorique et Pratique. Paris: Bechet Jeune, 1839. 2 Verneuil A. Etudes sur les tumeurs de la peau et quelques maladies de glandes sudoripares. Arch Gen Med 1854: 693–705. 3 Zouboulis CC, Del Marmol V, Mrowietz U et al. Hidradenitis suppurativa/acne inversa: criteria for diagnosis, severity assessment, classification and disease evaluation. Dermatology 2015; 231:184–90. 4 Zaenglein AL, Pathy AL, Schlosser BJ et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol 2016; 74:945–73. 5 Gollnick H. Current concepts of the pathogenesis of acne. Drugs 2003; 63:1579–96. 6 Freyre EA, Rebaza RM, Sami DA et al. The prevalence of facial acne in Peruvian adolescents and its relation to their ethnicity. J Adolesc Health 1998; 22:480–4. 7 Ghodsi SZ, Orawa H, Zouboulis CC. Prevalence, severity, and severity risk factors of acne in high school pupils: a communitybased study. J Invest Dermatol 2009; 129:2136–41. 8 Purvis D, Robinson E, Watson P. Acne prevalence in secondary school students and their perceived difficulty in accessing acne treatment. N Z Med J 2004; 117:U1018.


Acne and hidradenitis suppurativa, A. Pink et al. 9 9 Shen Y, Wang T, Zhou C et al. Prevalence of acne vulgaris in Chinese adolescents and adults: a community-based study of 17,345 subjects in six cities. Acta Derm Venereol 2012; 92:40–4. 10 Degitz K, Placzek M, Borelli C et al. Pathophysiology of acne. J Dtsch Dermatol Ges 2007; 5:316–23. 11 Shalita AR. Acne: clinical presentations. Clin Dermatol 2004; 22:385–6. 12 Williams HC, Dellavalle RP, Garner S. Acne vulgaris. Lancet 2012; 379:361–72. 13 Bataille V, Snieder H, MacGregor AJ et al. The influence of genetics and environmental factors in the pathogenesis of acne: a twin study of acne in women. J Invest Dermatol 2002; 119:1317–22. 14 Cunliffe WJ. Acne and unemployment. Br J Dermatol 1986; 115:386. 15 Bataille V, Lens M, Spector TD. The use of the twin model to investigate the genetics and epigenetics of skin diseases with genomic, transcriptomic and methylation data. J Eur Acad Dermatol Venereol 2012; 26:1067–73. 16 von der Werth JM, Williams HC. The natural history of hidradenitis suppurativa. J Eur Acad Dermatol Venereol 2000; 14:389–92. 17 Nazary M, van der Zee H, Prens E et al. Pathogenesis and pharmacotherapy of hidradenitis suppurativa. Eur J Pharmacol 2011; 672:1–8. 18 Revuz JE, Canoui-Poitrine F, Wolkenstein P et al. Prevalence and factors associated with hidradenitis suppurativa: results from two case–control studies. J Am Acad Dermatol 2008; 59:596–601. 19 Jemec GB, Heidenheim M, Nielsen NH. The prevalence of hidradenitis suppurativa and its potential precursor lesions. J Am Acad Dermatol 1996; 35:191–4. 20 Vazquez BG, Alikhan A, Weaver AL et al. Incidence of hidradenitis suppurativa and associated factors: a population-based study of Olmsted County, Minnesota. J Invest Dermatol 2013; 133:97–103. 21 Sartorius K, Emtestam L, Jemec GB et al. Objective scoring of hidradenitis suppurativa reflecting the role of tobacco smoking and obesity. Br J Dermatol 2009; 161:831–9. 22 Harrison BJ, Read GF, Hughes LE. Endocrine basis for the clinical presentation of hidradenitis suppurativa. Br J Surg 1988; 75:972–5. 23 Rompel R, Petres J. Long-term results of wide surgical excision in 106 patients with hidradenitis suppurativa. Dermatol Surg 2000; 26:638–43. 24 Konig A, Lehmann C, Rompel R et al. Cigarette smoking as a triggering factor of hidradenitis suppurativa. Dermatology 1999; 198:261–4. 25 Simonart T. Hidradenitis suppurativa and smoking. J Am Acad Dermatol 2010; 62:149–50. 26 Pink AE, Simpson MA, Desai N et al. Mutations in the gammasecretase genes NCSTN, PSENEN, and PSEN1 underlie rare forms of hidradenitis suppurativa (acne inversa). J Invest Dermatol 2012; 132:2459–61. 27 Fitzsimmons JS, Guilbert PR. A family study of hidradenitis suppurativa. J Med Genet 1985; 22:367–73. 28 von der Werth JM, Williams HC, Raeburn JA. The clinical genetics of hidradenitis suppurativa revisited. Br J Dermatol 2000; 142:947–53. 29 Jemec GBE. Hidradenitis suppurativa. N Engl J Med 2012; 366:158–64. 30 Brunsting HA. Hidradenitis suppurativa; abscess of the apocrine sweat glands. a study of the clinical and pathologic features, with a report of twenty-two cases and a review of the literature. Arch Derm Syphilol 1939; 39:108–20. 31 Lapins J, Asman B, Gustafsson A et al. Neutrophil-related host response in hidradenitis suppurativa: a pilot study in patients with inactive disease. Acta Derm Venereol 2001; 81:96–9.


32 Sabat R, Chanwangpong A, Schneider-Burrus S et al. Increased prevalence of metabolic syndrome in patients with acne inversa. PLOS ONE 2012; 7:e31810. 33 Boer J, Weltevreden EF. Hidradenitis suppurativa or acne inversa. A clinicopathological study of early lesions. Br J Dermatol 1996; 135:721–5. 34 von Laffert M, Stadie V, Wohlrab J et al. Hidradenitis suppurativa/acne inversa: bilocated epithelial hyperplasia with very different sequelae. Br J Dermatol 2011; 164:367–71. 35 Kamp S, Fiehn AM, Stenderup K et al. Hidradenitis suppurativa: a disease of the absent sebaceous gland? Sebaceous gland number and volume are significantly reduced in uninvolved hair follicles from patients with hidradenitis suppurativa. Br J Dermatol 2011; 164:1017–22. 36 Yu CC, Cook MG. Hidradenitis suppurativa: a disease of follicular epithelium, rather than apocrine glands. Br J Dermatol 1990; 122:763–9. 37 Revuz J. Hidradenitis suppurativa. J Eur Acad Dermatol Venereol 2009; 23:985–98. 38 Patterson J. Weedon’s Skin Pathology, 4th edn. Amsterdam: Elsevier, 2015. 39 Gollnick HP, Zouboulis CC. Not all acne is acne vulgaris. Dtsch Arztebl Int 2014; 111:301–12. 40 Saurat JH, Sorg O. Chloracne, a misnomer and its implications. Dermatology 2010; 221:23–6. 41 Saurat JH, Kaya G, Saxer-Sekulic N et al. The cutaneous lesions of dioxin exposure: lessons from the poisoning of Victor Yushchenko. Toxicol Sci 2012; 125:310–17. 42 Anzengruber F, Ruhwinkel K, Ghosh A et al. Wide range of age of onset and low referral rates to psychiatry in a large cohort of acne excoriee at a Swiss tertiary hospital. J Dermatolog Treat 2017; in press. 43 Canoui-Poitrine F, Le Thuaut A, Revuz JE et al. Identification of three hidradenitis suppurativa phenotypes: latent class analysis of a cross-sectional study. J Invest Dermatol 2013; 133:1506–11. 44 Bottomley WW, Cunliffe WJ. Severe flares of acne following isotretinoin: large closed comedones (macrocomedones) are a risk factor. Acta Derm Venereol 1993; 73:74. 45 Gulliver W, Zouboulis CC, Prens E et al. Evidence-based approach to the treatment of hidradenitis suppurativa/acne inversa, based on the European guidelines for hidradenitis suppurativa. Rev Endocr Metab Disord 2016; 17:343–51. 46 Clemmensen OJ. Topical treatment of hidradenitis suppurativa with clindamycin. Int J Dermatol 1983; 22:325–8. 47 Gener G, Canoui-Poitrine F, Revuz JE et al. Combination therapy with clindamycin and rifampicin for hidradenitis suppurativa: a series of 116 consecutive patients. Dermatology 2009; 219:148– 54. 48 van der Zee HH, Boer J, Prens EP et al. The effect of combined treatment with oral clindamycin and oral rifampicin in patients with hidradenitis suppurativa. Dermatology 2009; 219:143–7. 49 Boer J, Nazary M. Long-term results of acitretin therapy for hidradenitis suppurativa. Is acne inversa also a misnomer? Br J Dermatol 2011; 164:170–5. 50 Boer J, van Gemert MJ. Long-term results of isotretinoin in the treatment of 68 patients with hidradenitis suppurativa. J Am Acad Dermatol 1999; 40:73–6. 51 Yazdanyar S, Boer J, Ingvarsson G et al. Dapsone therapy for hidradenitis suppurativa: a series of 24 patients. Dermatology 2011; 222:342–6. 52 Rose RF, Goodfield MJ, Clark SM. Treatment of recalcitrant hidradenitis suppurativa with oral ciclosporin. Clin Exp Dermatol 2006; 31:154–5.


10 Acne and hidradenitis suppurativa, A. Pink et al. 53 Kimball AB, Okun MM, Williams DA et al. Two phase 3 trials of adalimumab for hidradenitis suppurativa. N Engl J Med 2016; 375:422–34. 54 Blok JL, van Hattem S, Jonkman MF et al. Systemic therapy with immunosuppressive agents and retinoids in hidradenitis suppurativa: a systematic review. Br J Dermatol 2013; 168:243–52. 55 Belinchon I, Ramos JM, Carretero G et al. Adverse events associated with discontinuation of the biologics/classic systemic treatments of moderate-to-severe plaque psoriasis: data from the Spanish Biologics Registry, Biobadaderm. J Eur Acad Dermatol Venereol 2017; 31:1700–8. 56 Tzanetakou V, Kanni T, Giatrakou S et al. Safety and efficacy of anakinra in severe hidradenitis suppurativa: a randomized clinical trial. JAMA Dermatol 2016; 152:52–9. 57 Frohlich D, Baaske D, Glatzel M. [Radiotherapy of hidradenitis suppurativa – still valid today?]. Strahlenther Onkol 2000; 176:286– 9 (in German). 58 Trombetta M, Werts ED, Parda D. The role of radiotherapy in the treatment of hidradenitis suppurativa: case report and review of the literature. Dermatol Online J 2010; 16:16. 59 Tierney E, Mahmoud BH, Hexsel C et al. Randomized control trial for the treatment of hidradenitis suppurativa with a neodymiumdoped yttrium aluminium garnet laser. Dermatol Surg 2009; 35:1188–98. 60 Lapins J, Marcusson JA, Emtestam L. Surgical treatment of chronic hidradenitis suppurativa: CO2 laser stripping-secondary intention technique. Br J Dermatol 2006; 131:551–6. 61 Schweiger ES, Riddle CC, Aires DJ. Treatment of hidradenitis suppurativa by photodynamic therapy with aminolevulinic acid: preliminary results. J Drugs Dermatol 2011; 10:381–6. 62 Danby FW, Jemec GBE, Marsch WC et al. Preliminary findings suggest hidradenitis suppurativa may be due to defective follicular support. Br J Dermatol 2013; 168:1034–9. 63 Ellebaek E, Engell-Noerregaard L, Iversen TZ et al. Metastatic melanoma patients treated with dendritic cell vaccination, interleukin-2 and metronomic cyclophosphamide: results from a phase II trial. Cancer Immunol Immunother 2012; 61:1791–804. 64 Jemec GBE, Gniadecka M. Sebum excretion in hidradenitis suppurativa. Dermatology 1997; 194:325–8. 65 Lapins B AJ. Neutrophil-related host response in hidradenitis suppurativa: a pilot study in patients with inactive disease. Acta Derm Venereol 2001; 81:96–9. 66 Chen X, Niyonsaba F, Ushio H et al. Antimicrobial peptides human b-defensin (hBD)-3 and hBD-4 activate mast cells and increase skin vascular permeability. Eur J Immunol 2007; 37:434– 44. 67 Tian L, Xie H, Yang T et al. TNFR2 M196R polymorphism and acne vulgaris in Han Chinese: a case–control study. J Huazhong Univ Sci Technolog Med Sci 2010; 30:408–11. 68 Wang B, Yang W, Wen W et al. c-Secretase gene mutations in familial acne inversa. Science 2010; 330:1065. 69 Pink AE, Simpson MA, Brice GW et al. PSENEN and NCSTN mutations in familial hidradenitis suppurativa (acne inversa). J Invest Dermatol 2011; 131:1568–70. 70 Liu Y, Gao M, Lv YM et al. Confirmation by exome sequencing of the pathogenic role of NCSTN mutations in acne inversa (hidradenitis suppurativa). J Invest Dermatol 2011; 131:1570–2. 71 Miskinyte S, Nassif A, Merabtene F et al. Nicastrin mutations in French families with hidradenitis suppurativa. J Invest Dermatol 2012; 132:1728–30. 72 Zhang C, Wang L, Chen L et al. Two novel mutations of the NCSTN gene in Chinese familial acne inverse. J Eur Acad Dermatol Venereol 2012; 27:1571–4.


73 Nomura Y, Nomura T, Sakai K et al. A novel splice site mutation in NCSTN underlies a Japanese family with hidradenitis suppurativa. Br J Dermatol 2012; 168:206–9. 74 Jiao T, Dong H, Jin L et al. A novel nicastrin mutation in a large Chinese family with hidradenitis suppurativa. Br J Dermatol 2013; 168:1141–3. 75 Li CR, Jiang MJ, Shen DB et al. Two novel mutations of the nicastrin gene in Chinese patients with acne inversa. Br J Dermatol 2011; 165:415–18. 76 Chavez-Gutierrez L. Dissecting c-secretase function. J Neurochem 2013; 125:1–3. 77 Tolia A, De Strooper B. Structure and function of c-secretase. Semin Cell Dev Biol 2009; 20:211–18. 78 Kimberly WT, LaVoie MJ, Ostaszewski BL et al. c-Secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci U S A 2003; 100:6382–7. 79 Kopan R, Ilagan MX. Gamma-secretase: proteasome of the membrane? Nat Rev Mol Cell Biol 2004; 5:499–504. 80 Schenk D. Alzheimer’s disease. A partner for presenilin. Nature 2000; 407:34–5. 81 Jutras I. c-Secretase is a functional component of phagosomes. J Biol Chem 2005; 280:36310–17. 82 Neely KM, Green KN, LaFerla FM. Presenilin is necessary for efficient proteolysis through the autophagy–lysosome system in a csecretase-independent manner. J Neurosci 2011; 31:2781–91. 83 Tamboli IY, Prager K, Thal DR et al. Loss of c-secretase function impairs endocytosis of lipoprotein particles and membrane cholesterol homeostasis. J Neurosci 2008; 28:12097–106. 84 Vetrivel KS, Zhang YW, Xu H et al. Pathological and physiological functions of presenilins. Mol Neurodegener 2006; 1:4. 85 Yang JQ, Wu XJ, Dou TT et al. Haploinsufficiency caused by a nonsense mutation in NCSTN underlying hidradenitis suppurativa in a Chinese family. Clin Exp Dermatol 2015; 40:916–19. 86 Pink AE, Dafou D, Desai N et al. Hidradenitis suppurativa: haploinsufficiency of c-secretase components does not affect c-secretase enzyme activity in vitro. Br J Dermatol 2016; 175:632–5. 87 Pan Y, Lin MH, Tian X et al. c-Secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev Cell 2004; 7:731–43. 88 Xia X, Qian S, Soriano S et al. Loss of presenilin 1 is associated with enhanced b-catenin signaling and skin tumorigenesis. Proc Natl Acad Sci U S A 2001; 98:10863–8. 89 Li T, Wen H, Brayton C et al. Epidermal growth factor receptor and Notch pathways participate in the tumor suppressor function of c-secretase. J Biol Chem 2007; 282:32264–73. 90 Zhang X, Sisodia SS. Acne inversa caused by missense mutations in NCSTN is not fully compatible with impairments in Notch signaling. J Invest Dermatol 2015; 135:618–20. 91 Friedman GD. Twin studies of disease heritability based on medical records: application to acne vulgaris. Acta Gen Med Gemellol (Roma) 1984; 33:487–95. 92 Kirk KM, Evans DM, Farthing B, Martin NG. Genetic and environmental influences on acne in adolescent twins. Twin Res Hum Genet 2001; 4:190. 93 Al-Shobaili HA, Salem TA, Alzolibani AA et al. Tumor necrosis factor-a 308 G/A and interleukin 10–1082 A/G gene polymorphisms in patients with acne vulgaris. J Dermatol Sci 2012; 68:52–5. 94 Baz K, Emin Erdal M, Yazıcı AC et al. Association between tumor necrosis factor-a gene promoter polymorphism at position 308 and acne in Turkish patients. Arch Dermatol Res 2008; 300:371–6. 95 Grech I, Giatrakos S, Damoraki G et al. Impact of TNF haplotypes in the physical course of acne vulgaris. Dermatology 2014; 228:152–7.


Acne and hidradenitis suppurativa, A. Pink et al. 11 96 Sobjanek M, Zabłotna M, Nedoszytko B et al. Lack of association between the promoter polymorphisms at positions 238 and 308 of the tumour necrosis factor alpha gene and acne vulgaris in Polish patients. J Eur Acad Dermatol Venereol 2009; 23:331–2. 97 Szabo K, Kemeny L. Studying the genetic predisposing factors in the pathogenesis of acne vulgaris. Hum Immunol 2011; 72:766–73. 98 Younis S, Javed Q. The interleukin-6 and interleukin-1A gene promoter polymorphism is associated with the pathogenesis of acne vulgaris. Arch Dermatol Res 2015; 307:365–70. 99 Pang Y, He CD, Liu Y et al. Combination of short CAG and GGN repeats in the androgen receptor gene is associated with acne risk in North East China. J Eur Acad Dermatol Venereol 2008; 22:1445–51. 100 Sawaya ME, Shalita AR. Androgen receptor polymorphisms (CAG repeat lengths) in androgenetic alopecia, hirsutism, and acne. J Cutan Med Surg 1998; 3:9–15. 101 Yang Z, Yu H, Cheng B et al. Relationship between the CAG repeat polymorphism in the androgen receptor gene and acne in the Han ethnic group. Dermatology 2009; 218:302–6. 102 He L, Wu W-J, Yang J-K et al. Two new susceptibility loci 1q24.2 and 11p11.2 confer risk to severe acne. Nat Commun 2014; 5:2870. 103 Maul JT, Djamei V, Kolios AGA et al. Efficacy and survival of systemic psoriasis treatments: an analysis of the Swiss registry SDNTT. Dermatology 2016; 232:640–7. 104 van der Zee HH, de Ruiter L, van den Broecke DG et al. Elevated levels of tumour necrosis factor (TNF)-a, interleukin (IL)-1b and IL-10 in hidradenitis suppurativa skin: a rationale for targeting TNF-a and IL-1b. Br J Dermatol 2011; 164:1292–8. 105 van Rappard DC, Leenarts MFE, Meijerink-van‘t Oost L et al. Comparing treatment outcome of infliximab and adalimumab in patients with severe hidradenitis suppurativa. J Dermatolog Treat 2011; 23:284–9. 106 Ahmed AA, Nordlind K, Schultzberg M et al. Immunohistochemical localization of IL-1a-, IL-1b-, IL-6- and TNF-a-like immunoreactivities in human apocrine glands. Arch Dermatol Res 1995; 287:764–6. 107 Matusiak L, Bieniek A, Szepietowski JC. Increased serum tumour necrosis factor-a in hidradenitis suppurativa patients: is there a basis for treatment with anti-tumour necrosis factor-a agents? Acta Derm Venereol 2009; 89:601–3. 108 Marzano AV, Cugno M, Trevisan V et al. Role of inflammatory cells, cytokines and matrix metalloproteinases in neutrophilmediated skin diseases. Clin Exp Immunol 2010; 162:100–7. 109 Hunger RE, Surovy AM, Hassan AS et al. Toll-like receptor 2 is highly expressed in lesions of acne inversa and colocalizes with C-type lectin receptor. Br J Dermatol 2008; 158:691–7. 110 Contassot E, French LE. New insights into acne pathogenesis: Propionibacterium acnes activates the inflammasome. J Invest Dermatol 2014; 134:310–13. 111 Kistowska M, Gehrke S, Jankovic D et al. IL-1b drives inflammatory responses to Propionibacterium acnes in vitro and in vivo. J Invest Dermatol 2014; 134:677–85. 112 Kistowska M, Meier B, Proust T et al. Propionibacterium acnes promotes Th17 and Th17/Th1 responses in acne patients. J Invest Dermatol 2015; 135:110–18. 113 Ingham E, Eady EA, Goodwin CE et al. Pro-inflammatory levels of interleukin-1a-like bioactivity are present in the majority of open comedones in acne vulgaris. J Invest Dermatol 1992; 98:895–901. 114 Kircik LH. Advances in the understanding of the pathogenesis of inflammatory acne. J Drugs Dermatol 2016; 15:s7–10. 115 Zouboulis CC. Is acne vulgaris a genuine inflammatory disease? Dermatology 2001; 203:277–9.


116 Dreno B, Khammari A, Brocard A et al. Hidradenitis suppurativa: the role of deficient cutaneous innate immunity. Arch Dermatol 2012; 148:182–6. 117 Giamarellos-Bourboulis EJ, Antonopoulou A, Petropoulou C et al. Altered innate and adaptive immune responses in patients with hidradenitis suppurativa. Br J Dermatol 2007; 156:51–6. 118 Wolk K, Warszawska K, Hoeflich C et al. Deficiency of IL-22 contributes to a chronic inflammatory disease: pathogenetic mechanisms in acne inversa. J Immunol 2011; 186:1228–39. 119 van der Zee HH, van der Woude CJ, Florencia EF et al. Hidradenitis suppurativa and inflammatory bowel disease: are they associated? Results of a pilot study. Br J Dermatol 2010; 162:195–7. 120 Quaglietta L, te Velde A, Staiano A et al. Functional consequences of NOD2/CARD15 mutations in Crohn disease. J Pediatr Gastroenterol Nutr 2007; 44:529–39. 121 Hiemstra IH, Bouma G, Geerts D et al. Nod2 improves barrier function of intestinal epithelial cells via enhancement of TLR responses. Mol Immunol 2012; 52:264–72. 122 Rubino SJ, Selvanantham T, Girardin SE et al. Nod-like receptors in the control of intestinal inflammation. Curr Opin Immunol 2012; 24:398–404. 123 Cooney R, Jewell D. The genetic basis of inflammatory bowel disease. Dig Dis 2009; 27:428–42. 124 Lees CW, Satsangi J. Genetics of inflammatory bowel disease: implications for disease pathogenesis and natural history. Expert Rev Gastroenterol Hepatol 2009; 3:513–34. 125 Braff MH, Hawkins MA, Nardo AD et al. Structure–function relationships among human cathelicidin peptides: dissociation of antimicrobial properties from host immunostimulatory activities. J Immunol 2005; 174:4271–8. 126 Emelianov VU, Bechara FG, Glaser R et al. Immunohistological pointers to a possible role for excessive cathelicidin (LL-37) expression by apocrine sweat glands in the pathogenesis of hidradenitis suppurativa/acne inversa. Br J Dermatol 2012; 166:1023–34. 127 Choi DK, Li ZJ, Chang IK et al. Regional difference of inflammatory acne lesions according to b-defensin-2 expression. J Invest Dermatol 2014; 134:2044–6. 128 Nakatsuji T, Kao MC, Zhang L et al. Sebum free fatty acids enhance the innate immune defense of human sebocytes by upregulating b-defensin-2 expression. J Invest Dermatol 2010; 130:985–94. 129 Dahlhoff M, Zouboulis CC, Schneider MR. Expression of dermcidin in sebocytes supports a role for sebum in the constitutive innate defense of human skin. J Dermatol Sci 2016; 81:124–6. 130 Lee DY, Yamasaki K, Rudsil J et al. Sebocytes express functional cathelicidin antimicrobial peptides and can act to kill Propionibacterium acnes. J Invest Dermatol 2008; 128:1863–6. 131 Meyer KC, Klatte JE, Dinh HV et al. Evidence that the bulge region is a site of relative immune privilege in human hair follicles. Br J Dermatol 2008; 159:1077–85. 132 Schlapbach C, Yawalkar N, Hunger RE. Human b-defensin-2 and psoriasin are overexpressed in lesions of acne inversa. J Am Acad Dermatol 2009; 61:58–65. 133 Hofmann SC, Saborowski V, Lange S et al. Expression of innate defense antimicrobial peptides in hidradenitis suppurativa. J Am Acad Dermatol 2012; 66:966–74. 134 Bechara FG, Sand M, Skrygan M et al. Acne inversa: evaluating antimicrobial peptides and proteins. Ann Dermatol 2012; 24:393. 135 Christoph T, Muller-Rover S, Audring H et al. The human hair follicle immune system: cellular composition and immune privilege. Br J Dermatol 2000; 142:862–73.


12 Acne and hidradenitis suppurativa, A. Pink et al. 136 Jungo P, Maul JT, Djamei V et al. Superiority in quality of life improvement of biologics over conventional systemic drugs in a Swiss real-life psoriasis registry. Dermatology 2016; 232:655– 63. 137 Nagao K, Ginhoux F, Leitner WW et al. Murine epidermal Langerhans cells and langerin-expressing dermal dendritic cells are unrelated and exhibit distinct functions. Proc Natl Acad Sci U S A 2009; 106:3312–17. 138 Igyarto BZ, Haley K, Ortner D et al. Skin-resident murine dendritic cell subsets promote distinct and opposing antigen-specific T helper cell responses. Immunity 2011; 35:260–72. 139 Nagao K, Kobayashi T, Moro K et al. Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin. Nat Immunol 2012; 13:744–52. 140 Heath WR, Mueller SN. Hair follicles: gatekeepers to the epidermis. Nat Immunol 2012; 13:715–17. 141 Cornbleet T. Pregnancy and apocrine gland diseases: hidradenitis, Fox-Fordyce disease. Arch Dermatol 1952; 65:12. 142 Mortimer PS, Dawber RP, Gales MA et al. Mediation of hidradenitis suppurativa by androgens. BMJ 1986; 292:245–8. 143 Jemec GB. The symptomatology of hidradenitis suppurativa in women. Br J Dermatol 1988; 119:345–50. 144 Jain S, Stephens CJM. Successful treatment of disseminated granuloma annulare with topical tacrolimus. Br J Dermatol 2004; 150:1042–3. 145 Lai JJ, Lai KP, Chuang KH et al. Monocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-a expression. J Clin Invest 2009; 119:3739–51. 146 Barth JH, Layton AM, Cunliffe WJ. Endocrine factors in pre- and postmenopausal women with hidradenitis suppurativa. Br J Dermatol 1996; 134:1057–9. 147 Barth JH, Kealey T. Androgen metabolism by isolated human axillary apocrine glands in hidradenitis suppurativa. Br J Dermatol 1991; 125:304–8. 148 Domenech C, Matarredona J, Escribano-Stable JC et al. Facial hidradenitis suppurativa in a 28-year-old male responding to finasteride. Dermatology 2012; 224:307–8. 149 Randhawa HK, Hamilton J, Pope E. Finasteride for the treatment of hidradenitis suppurativa in children and adolescents. JAMA Dermatol 2013; 149:732–5. 150 Joseph MA, Jayaseelan E, Ganapathi B et al. Hidradenitis suppurativa treated with finasteride. J Dermatolog Treat 2005; 16:75–8. 151 Khandalavala BN, Do MV. Finasteride in hidradenitis suppurativa: a ‘male’ therapy for a predominantly ‘female’ disease. J Clin Aesthet Dermatol 2016; 9:44–50. 152 Riis PT, Ring HC, Themstrup L et al. The role of androgens and estrogens in hidradenitis suppurativa – a systematic review. Acta Dermatovenerol Croat 2016; 24:239–49. 153 Nikolakis G, Join-Lambert O, Karagiannidis I et al. Bacteriology of hidradenitis suppurativa/acne inversa: a review. J Am Acad Dermatol 2015; 73:S12–18. 154 Alikhan A, Lynch PJ, Eisen DB. Hidradenitis suppurativa: a comprehensive review. J Am Acad Dermatol 2009; 60:539–61. 155 Jemec GBE, Faber M, Gutschik E et al. The bacteriology of hidradenitis suppurativa. Dermatology 1996; 193:203–6. 156 Sartorius K, Killasli H, Oprica C et al. Bacteriology of hidradenitis suppurativa exacerbations and deep tissue cultures obtained during carbon dioxide laser treatment. Br J Dermatol 2012; 166:879– 83. 157 Lapins J, Jarstrand C, Emtestam L. Coagulase-negative staphylococci are the most common bacteria found in cultures from the deep portions of hidradenitis suppurativa lesions, as obtained by carbon dioxide laser surgery. Br J Dermatol 1999; 140:90–5.


158 Guet-Revillet H, Jais JP, Ungeheuer MN et al. The microbiological landscape of anaerobic infections in hidradenitis suppurativa: a prospective metagenomic study. Clin Infect Dis 2017; 65:282–91. 159 Ring HC, Bay L, Nilsson M et al. Bacterial biofilm in chronic lesions of hidradenitis suppurativa. Br J Dermatol 2017; 176:993–1000. 160 Wortsman X, Revuz J, Jemec GBE. Lymph nodes in hidradenitis suppurativa. Dermatology 2009; 219:22–4. 161 Wake DJ, Strand M, Rask E et al. Intra-adipose sex steroid metabolism and body fat distribution in idiopathic human obesity. Clin Endocrinol 2007; 66:440–6. 162 Andrade T, Vieira BC, Oliveira AMN et al. Hidradenitis suppurativa: epidemiological study of cases diagnosed at a dermatological reference center in the city of Bauru, in the Brazilian southeast state of Sao Paulo, between 2005 and 2015. An Bras Dermatol 2017; 92:196–9. 163 Fabbrocini G, De Vita V, Donnarumma M et al. South Italy: a privileged perspective to understand the relationship between hidradenitis suppurativa and overweight/obesity. Skin Appendage Disord 2016; 2:52–6. 164 Ghanim H. Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation 2004; 110:1564–71. 165 Huang S, Rutkowsky JM, Snodgrass RG et al. Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways. J Lipid Res 2012; 53:2002–13. 166 Faergemann J, Aly R, Wilson DR et al. Skin occlusion: effect on Pityrosporum orbiculare, skin PCO2, pH, transepidermal water loss, and water content. Arch Dermatol Res 1983; 275:383–7. 167 Dessinioti C, Zisimou C, Tzanetakou V et al. A retrospective institutional study of the association of smoking with the severity of hidradenitis suppurativa. J Dermatol Sci 2017; 87:206–7. 168 Hana A, Booken D, Henrich C et al. Functional significance of non-neuronal acetylcholine in skin epithelia. Life Sci 2007; 80:2214–20. 169 Parks RW, Parks TG. Pathogenesis, clinical features and management of hidradenitis suppurativa. Ann R Coll Surg Engl 1997; 79:83–9. 170 Jeong SH, Park JH, Kim JN et al. Up-regulation of TNF-a secretion by cigarette smoke is mediated by Egr-1 in HaCaT human keratinocytes. Exp Dermatol 2010; 19:e206–12. 171 Mosely LH, Finseth F. Cigarette smoking: impairment of digital blood flow and wound healing in the hand. Hand 1977; 9:97– 101. 172 Leow Y. Cigarette smoking, cutaneous vasculature, and tissue oxygen. Clin Dermatol 1998; 16:579–84. 173 Sorensen LT, Nielsen HB, Kharazmi A et al. Effect of smoking and abstention on oxidative burst and reactivity of neutrophils and monocytes. Surgery 2004; 136:1047–53. 174 Wong LS, Green HM, Feugate JE et al. Effects of ‘second-hand’ smoke on structure and function of fibroblasts, cells that are critical for tissue repair and remodeling. BMC Cell Biol 2004; 5:13. 175 Arredondo J, Hall LL, Ndoye A et al. Central role of fibroblast a3 nicotinic acetylcholine receptor in mediating cutaneous effects of nicotine. Lab Invest 2003; 83:207–25. 176 Yin L, Morita A, Tsuji T. Alterations of extracellular matrix induced by tobacco smoke extract. Arch Dermatol Res 2000; 292:188–94. 177 Plewig G, Kligman A. Acne. Morphogenesis and Treatment. Berlin: Springer, 1975. 178 Scheinfeld NS. A case of dissecting cellulitis and a review of the literature. Dermatol Online J 2003; 9:8. 179 Chicarilli ZN. Follicular occlusion triad: hidradenitis suppurativa, acne conglobata, and dissecting cellulitis of the scalp. Ann Plast Surg 1987; 18:230–7.


Acne and hidradenitis suppurativa, A. Pink et al. 13 180 Conway H, Stark RB, Climo S et al. The surgical treatment of chronic hidradenitis suppurativa. Surg Gynecol Obstet 1952; 95:455– 64. 181 Marzano AV, Trevisan V, Gattorno M et al. Pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PAPASH): a new autoinflammatory syndrome associated with a novel mutation of the PSTPIP1 gene. JAMA Dermatol 2013; 149:762. 182 Braun-Falco M, Kovnerystyy O, Lohse P et al. Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH): a new autoinflammatory syndrome distinct from PAPA syndrome. J Am Acad Dermatol 2012; 66:409–15. 183 Wise CA. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet 2002; 11:961–9. 184 Duchatelet S, Miskinyte S, Join-Lambert O et al. First nicastrin mutation in PASH (pyoderma gangrenosum, acne and suppurative hidradenitis) syndrome. Br J Dermatol 2015; 173:610–12. 185 Kolios AG, Maul JT, Meier B et al. Canakinumab in adults with steroid-refractory pyoderma gangrenosum. Br J Dermatol 2015; 173:1216–23.


186 Kahn MF, Chamot AM. SAPHO syndrome. Rheum Dis Clin North Am 1992; 18:225–46. 187 Bergeron JR. Interstitial keratitis associated with hidradenitis suppurativa. Arch Dermatol 1967; 95:473. 188 Leybishkis B, Fasseas P, Ryan KF et al. Hidradenitis suppurativa and acne conglobata associated with spondyloarthropathy. Am J Med Sci 2001; 321:195–7. 189 Alzaga Fernandez AG, Demirci H, Darnley-Fisch DA et al. Interstitial keratitis secondary to severe hidradenitis suppurativa: a case report and literature review. Cornea 2010; 29:1189–91. 190 Blanco R, Gonzalez-Vela MC, Gonzalez-L opez MA et al. Interstitial keratitis secondary to severe hidradenitis suppurativa responding to adalimumab. Cornea 2012; 31:206. 191 Zarchi K, Dufour DN, Jemec GBE. Successful treatment of severe hidradenitis suppurativa with anakinra. JAMA Dermatol 2013; 149:1192. 192 Faleri S, Feichtner K, Ruzicka T. [Severe acne in autoinflammatory diseases]. Hautarzt 2016; 67:897–901 (in German).
