Review

Hidradenitis suppurativa: the role of immune dysregulation Genevieve Kelly1, MB, MRCPI, Cheryl M. Sweeney1, BA (Mod), PhD, Anne-Marie Tobin2, MB, PhD, MRCPI, and Brian Kirby1, MD, FRCPI

1 Dermatology Research Group, Education and Research Centre, St. Vincent’s University Hospital, and 2Department of Dermatology, Adelaide and Meath Hospital Incorporating the National Children’s Hospital, Tallaght, Dublin, Ireland

Abstract Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory disease of follicular occlusion characterized by boils, sinus tracts, fistulae, and scarring. It has a significant underestimated morbidity. Antimicrobial, immunosuppressive, anti-androgenic, and surgical approaches have been used with varying results. Knowledge of the pathogenesis of HS is fragmented, and treatment choices have hitherto been empiric without an exact

Correspondence Genevieve Kelly, MB, MRCPI Education and Research Centre St. Vincent’s University Hospital Dublin 4 Ireland E-mail: [email protected]

understanding of the scientific basis for their use. Tumor necrosis factor-a inhibitors have shown promise in the treatment of HS in recent years, and the concept of HS as an immunological condition has come to the fore. The focus of this review is to discuss the immunological abnormalities underpinning HS as elucidated to date.

Conflicts of interest: None.

Introduction

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Hidradenitis suppurativa (HS) is a chronic relapsing, inflammatory disease characterized by double comedones, painful deep recurrent nodules, and abscesses. This can progress to a chronic inflammatory state with fistula formation, odorous discharge, cribriform scarring, and dermal fibrosis with contractures.1 The prevalence of HS is estimated to be between 0.05 and 4%.2–4 Onset is often in the postpubertal period, in the second or third decades of life, and women are more commonly affected than men.4 HS has a predilection for the axillary, inguinal, perineal, mammary, and inframammary areas. Perineal HS is more often associated with men and appears to be more resistant to treatment.1 Disease severity may be measured using the Hurley classification and Sartorius system. The Hurley staging system categorizes patients into one of three groups based largely on the presence of sinus tract formation and scarring.1 The Sartorius system is a more detailed analysis of clinical severity and may be a more useful tool in a clinical trial setting.1 In addition, the serum level of soluble interleukin (IL)-2 receptor may be a valuable marker for determining HS disease staging and severity.5 Hidradenitis suppurativa has a significant impact on emotional health, well-being, and quality of life.6–11 Patients with HS often experience symptoms of depression and anxiety, and working life can be adversely International Journal of Dermatology 2014, 53, 1186–1196

affected. These adverse effects correlate with disease chronicity and severity.6,8,10,11 Hidradenitis suppurativa was defined initially as a disease of the apocrine glands, but it is now generally accepted that follicular occlusion is central to its pathogenesis.12 The cause of this occlusion is still unclear.1,12 A number of studies have reported a lack of inflammatory involvement of the apocrine gland.1 Other studies suggest that inflammatory involvement of the apocrine gland is usually in the context of a more nonspecific inflammation involving the eccrine gland, hair follicle, and other local structures.1 This suggests that inflammation of the apocrine gland is a secondary phenomenon.13,14 The proposed sequence starts with follicular plugging and occlusion, dilatation of the pilosebaceous unit, rupture, and extrusion of follicular contents, including keratin, corneocytes, bacteria, and sebaceous matter into the dermis. This is followed by a secondary inflammatory process, which includes release of cytokines and the influx of immune cells into the area.1 In general, histological findings of HS include perifolliculitis, follicular hyperkeratosis, follicular hyperplasia, and epidermal psoriasiform hyperplasia.12,15,16 Genetics Hidradenitis suppurativa inheritance can be sporadic, but up to 40% of patients with HS have an inherited form of the disease. Some of these forms follow an autosomal ª 2014 The International Society of Dermatology

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dominant pattern of inheritance.17,18 Genetic studies have identified susceptibility genes at locus 1p21.1–1q25.3.19 Wang et al.20 studied six Han Chinese families and located inactivating mutations in presenilin 1 (PSEN1), presenilin enhancer 2 (PSENEN), and nicastrin (NCSTN), genes which encode three of four subunits of c-secretase. c-secretase is a protease that catalyzes cleavage of intramembraneous proteins including amyloid precursor protein and Notch receptors.20 Both c-secretase and Notch 1 inactivation have been linked to epidermal and follicular abnormalities in animal studies.21 It is notable that many of the subjects of these studies had somewhat atypical disease with cutaneous involvement of the face, back, and abdomen. Moreover, it has been suggested that these genetic mutations may occur more frequently in patients with HS with a more severe phenotype.22 Pink et al.23 sequenced mutations in the c-secretase genes in UK patients conforming to the typical European patient with HS. They detected two further mutations in NCSTN and PSENEN in these multiplex HS pedigrees but did not detect mutations in c-secretase in five of seven families. It was postulated that there might be a downstream mutation in the c-secretase–Notch signaling pathway.22,23 The same group examined the c-secretase genes for mutations in 48 patients with HS who were sequentially recruited from their tertiary referral clinic.24 Three variants in coding regions and splice sites of NCSTN were identified. Two of these alleles displayed pathogenicity. They suggest that additional unidentified genes may play a role in the pathogenesis of HS and that mutations in c-secretase are responsible for only a small proportion of HS cases.24 As well as a genetic predisposition, other factors are associated with the development of HS. Smoking, obesity, endocrine imbalance, shearing forces, and friction are thought to predispose to HS.1 Several reports have suggested that immune dysregulation plays a significant role in this disease. Evidence for a role of the immune system in hidradenitis suppurativa Until the 1970s, HS was considered a disease of infectious etiology. Early studies examining granulocyte and cellmediated immunity suggested that there was no deficiency in host defense.25 Suggestions of an immune aberrancy in HS gradually began to appear in the literature in the 1980s. O’Loughlin et al.26 in 1988 reported lower levels of T lymphocytes in peripheral blood in a proportion of patients with moderate to severe HS. Lapins et al.,27 in 2001, suggested a role for dysfunctional neutrophils in HS. HS is associated with Crohn’s disease and pyoderma gangrenosum, which are recognized as conditions of immune dysfunction.28,29 ª 2014 The International Society of Dermatology

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In 2001, Martinez et al.30 observed an improvement of concomitant HS in a patient undergoing anti-tumor necrosis factor (TNF)-a treatment for Crohn’s disease. Subsequent case reports, case series, and clinical trials of anti-TNF-a agents in HS ensued.1 Infliximab appears to be beneficial in the treatment of HS.1 Grant et al.31 demonstrated that treatment with infliximab resulted in a 50% or greater decrease from baseline in HS severity index scores with an associated improvement in inflammatory markers. Adalimumab is also promising for the treatment of HS.1 Miller et al.32 observed a significant reduction in Sartorius score after six weeks of treatment with adalimumab compared to controls. Etanercept, however, does not appear to be effective in HS. Adams et al.33 found no improvement in HS in 20 patients treated with etanercept with no statistically significant difference in patient and physician global assessments or Dermatology Life Quality Index at 12 and 24 weeks between the treatment and placebo groups. Further research is warranted on the use of the IL-12/23 blocker ustekinumab in HS, but initial case reports suggest a positive effect. Gulliver et al.34 reported an improvement in two of three patients treated with ustekinumab with an improvement in their visual analog scale of pain, physician global assessment, and Dermatology Life Quality Index at six months. Cytokines Tumor necrosis factor-a

Tumor necrosis factor-a is a proinflammatory cytokine that has a central role in many inflammatory conditions.35 It is produced by various cell types, including mast cells, macrophages, dendritic cells (DC), and T cells.36 Successful treatment of HS with TNF-a antagonists suggests a key role for TNF-a in the pathogenesis of this disease.1 A number of studies have aimed to characterize the cytokine profile in HS skin, focusing particularly on TNF-a. van der Zee et al.37 reported that the protein expression of TNF-a is enhanced in lesional and perilesional skin of patients with HS compared to healthy controls. Levels of TNF-a were increased fivefold in HS skin compared to psoriatic skin. TNF-a showed a trend towards a positive correlation with disease severity according to the Hurley classification.37 In a separate study by Wolk et al.,38 it was noted that the mRNA expression of TNF-a in lesional HS skin was elevated and similar to that of psoriatic skin. Emelianov et al.39 demonstrated enhanced protein expression of TNF-a in the epidermis and dermis of HS skin, although it was decreased in the proximal outer root sheath of hair follicles in scarring HS skin. These findings reflect those of Mozeika et al.,40 who International Journal of Dermatology 2014, 53, 1186–1196

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demonstrated strong protein expression of TNF-a in lesional HS skin compared to healthy controls. Other studies examined the peripheral blood and serum expression of TNF-a. Matusiak et al.41 reported that the serum concentration of TNF-a was enhanced in HS but did not correlate with disease severity. In contrast, however, Giamarellos-Bouroulis et al.42 demonstrated that monocytes isolated from the blood of patients with HS produced less TNF-a in response to stimulation with lipopolysaccharide (LPS) when compared to healthy controls, suggesting a decreased innate immune response. The reason for this discrepancy is unclear, but it was hypothesized that previous exposure of macrophages in vivo to bacterial ligands may decrease their ability to produce TNF-a in response to LPS stimulation in vitro. In 2011, van der Zee et al.43 investigated the effects of the anti TNF-a treatment adalimumab. Biopsies were taken from nine patients with HS at week 0 and week 16 post-treatment with adalimumab. It was demonstrated that the protein expression of TNF-a, and its receptors, was significantly elevated in the skin of patients with HS compared with healthy controls, although the production of other cytokines, such as IL-1b, was enhanced to a greater degree. Treatment with adalimumab did not affect the expression of TNF-a. It was proposed that, as TNF-a was only mildly elevated, no marked change in TNF-a was to be expected. Adalimumab appeared to have a more pronounced effect on the production of other cytokines, and TNF-a did not appear to be the cytokine most responsive to treatment.43 This may suggest that other cytokines play a greater role in HS. While a number of studies have suggested an enhancement of TNF-a in HS, Dreno et al.44 have shown that the protein expression of TNF-a is decreased in lesional and perilesional HS skin compared to control skin. Treatment with zinc gluconate increased the expression of TNF-a to levels similar to that seen in control skin. This suggests a deficiency in cutaneous innate immunity as the expression of all cutaneous immunity markers was suppressed, with the exception of IL-10. These findings in HS skin reflect those of Giamarellos-Bourboulis et al.42 in peripheral blood samples from patients with HS. Thus, the evidence to date is somewhat conflicting. The trend appears to be towards an increased expression of TNF-a in HS, with six of the above eight studies showing enhancement of this cytokine. These differences may reflect variations in disease activity or in investigative approaches. Interleukin-1b

Interleukin-1b is an important mediator of the inflammatory response and promotes the development of T-helper (Th)17 cells.45 IL-1b is mainly produced by monocytes and macrophages but is also produced by many different International Journal of Dermatology 2014, 53, 1186–1196

cell types.36 Biologically active IL-1b is generated through the activation of caspase-1, which cleaves pro-IL-1b into its biologically active form.46 Caspase-1 is a component of the inflammasome, a multimeric protein complex that acts as a cytosolic pathogen recognition receptor to detect a variety of pathogen-associated molecular pattern molecules and endogenous damage associated molecular pattern molecules.46 It has been suggested that the release of high molecular weight cornified keratin into the dermis, resulting from follicular rupture, can also activate the inflammasome.37,47 Elevated levels of IL-1b have been reported in lesional HS skin by van der Zee et al.37 A 31-fold increase relative to control skin was found. It was shown that the protein expression of IL-1b was enhanced in perilesional normal-appearing skin compared to control skin, implying that HS inflammation extended beyond the visually inflamed border. Expression of IL-1b showed a trend towards a positive correlation with disease severity. IL1b production was noted to be higher in HS skin than in psoriatic skin.37 This would suggest that IL-1b has a prominent role in the pathogenesis of HS. The increased expression of IL-1b was more pronounced than that of TNF-a. In a separate study, van der Zee et al.43 examined cytokine levels released by lesional HS biopsies after 24 hours of culture and demonstrated that IL-1b was the most significantly elevated cytokine in HS skin. Treatment with adalimumab suppressed the production of IL-1b.43 Wolk et al.38 also demonstrated enhanced mRNA expression of IL-1b in HS skin compared with healthy controls. Moreover, the expression of IL-1b was higher in HS compared to psoriatic skin. Of note, the expression of IL-1b correlated with that of IL-10, suggesting a compensatory mechanism, with the increase in IL-10 a secondary response to enhancement of IL-1b.38 It appears that IL-1b and the inflammasome may have a prominent role in HS and warrant further investigation. In each study where it was sought, the expression of IL1b was significantly enhanced and was frequently one of the most significantly elevated cytokines in HS skin. Interleukin-10

Interleukin-10 is an anti-inflammatory cytokine and is expressed by innate and adaptive immune cells, including DC, macrophages, mast cells, natural killer cells (NK), and lymphocytes.48 IL-10 induces the differentiation of T regulatory cells49 and suppresses the development of Th1, Th2, and Th17 cells.48,50 Thus, IL-10 has an anti-inflammatory role in infection by limiting the immune response to pathogens and preventing harm to the host. It has a crucial role in preventing inflammatory and autoimmune pathologies.48 ª 2014 The International Society of Dermatology

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Several studies have demonstrated that the expression of IL-10 is enhanced in HS lesional and perilesional skin compared to healthy control skin and psoriatic skin.37,38,43,44 van der Zee et al. demonstrated a 34-fold induction of IL-10 in HS skin and a twofold induction in psoriatic skin compared to healthy control skin. A positive correlation with IL-10 and disease severity was observed.37 Dreno et al.44 noted increased protein expression of IL-10 in lesional and perilesional skin compared to controls, but the production of IL-10 in lesional skin was lower than in perilesional skin. Wolk et al.38 demonstrated that the mRNA expression of IL-10 is enhanced in HS skin compared with both psoriatic and healthy skin. IL-10 was found to correlate negatively with IL-22. It was demonstrated that IL-10 selectively inhibited the production of IL-22, but not IL17, by both T cells and cytokine-stimulated peripheral blood mononuclear cells in vitro, which was suggested to contribute to secondary infection.38 Potential mechanisms for the overexpression of IL-10 were considered.38 Fox P3+ regulatory T cells were ruled out as the source of IL-10. It is also suggested that nicotine may enhance the expression of IL-10 in HS, as cutaneous nicotine administration in humans was shown to increase LPS-induced IL-10 expression.38 Regardless of the source of IL-10, overexpression of IL-10 results in a dampening down of the immune response and ongoing propagation of skin commensal microbes.38 Targeting IL10 production or activity may be beneficial as a therapeutic option.38 Moreover, as TNF-a induces the production of IL-10, the therapeutic effects of anti-TNF-a agents may be mediated via indirect inhibition of IL-10.38 It appears, therefore, that IL-10 may play an important role in immune dysregulation in HS and was noted to be elevated in all of the aforementioned studies. Interleukin-17

Interleukin-17 is a proinflammatory cytokine, produced primarily by Th17 cells, a subset of pathogenic effector T cells.36,51 Th17 cells are central in the pathogenesis of psoriasis, Crohn’s disease, and several other autoimmune diseases.51 IL-17, or IL-17A, is a member of the IL-17 cytokine family, which plays a role in the recruitment of neutrophils and the expression of antimicrobial peptides (AMPs), in particular b-defensin 2 (BD-2).38,52 Th17 cell development is promoted by IL-23, IL-1b, and IL-6 produced by innate cells such as DC. Th17 cells also produce IL-22, IL-21, and TNF-a.36 Recent studies have indicated a role for IL-17 in HS. Studies by Schlapbach et al.53 and van der Zee et al.43 demonstrated that the mRNA and protein expression of IL-17 is enhanced in HS skin by a factor of 30- or sevenfold, respectively, when compared to control skin. Double ª 2014 The International Society of Dermatology

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immunofluorescence identified CD4+ T cells as the source of IL-17.53 As expected, the expression of IL-23 was also enhanced in HS skin compared to healthy control skin.53 Wolk et al. also demonstrated enhanced mRNA expression of IL-17 in HS skin compared to controls. IL-17 was shown to induce AMP expression (BD-2 and S100A7), which was not suppressed by IL-10.38 The IL-23/Th17 axis may play a role in driving inflammation in HS. Interleukin-12/Interleukin-23

Interleukin-12 is a proinflammatory cytokine that promotes the differentiation of Th1 cells.54 The IL-12/Th1 pathway is involved in the pathogenesis of many inflammatory conditions through its ability to induce the production of interferon gamma (IFN-c).54 IL-12 is a heterodimeric cytokine and has two subunits, p35 and p40, the latter being shared with IL-23.54 Until recently, the IL-12/Th1 pathway was thought to be largely responsible for the pathogenesis of many inflammatory diseases. This was then revised by the discovery of the IL-23/Th17 pathway, which is now known to play a central role in many autoimmune diseases.53 IL-23 is a member of the IL-12 family of cytokines, which also includes IL-12 and IL-27.54 IL-23 is a proinflammatory heterodimeric cytokine composed of two disulfide-linked subunits, p40 (which is also shared with IL-12) and p19. IL-23 is central to the development of Th17 cells.55 In animal studies of autoimmunity, IL-23p19-deficient mice were resistant to autoimmune encephalomyelitis (a mouse model of multiple sclerosis) and arthritis, suggesting that IL-23 is central to the development of autoimmunity.56 Schlapbach et al. demonstrated that the mRNA expression of IL-23p19 and IL-12p70 is elevated in HS skin, IL-23 to a greater degree than IL-12. IL-12 and IL-23 were found abundantly expressed by macrophages infiltrating the dermis of lesional HS skin.53 Wolk et al. demonstrated significantly enhanced mRNA expression of IL-12p35 in lesional HS skin compared to psoriatic skin. In contrast, however, van der Zee et al.43 found no significant protein expression of IL-12 in HS lesional skin. Thus, the relative contribution of IL-23/IL-12 in HS pathogenesis remains to be evaluated. This pathway could be targeted by the IL-12/IL-23 antagonist ustekinumab, and there are emerging reports of therapeutic benefit with this treatment.34 A recent report has suggested that IL-23 expression is enhanced in pyoderma gangrenosum, resolution of which was observed following treatment with ustekinumab.57 This may have relevance for HS, which is known to be associated with pyoderma gangrenosum, and further research is warranted. Interleukin-22/Interleukin-20

Interleukin-22 is a proinflammatory cytokine, which is produced by adaptive and innate T-cell subsets. These International Journal of Dermatology 2014, 53, 1186–1196

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include CD4+ T cells (Th1, Th17), CD8+ T cells, cd T cells, NK T cells, and lymphoid tissue inducer cells.58 IL22 has antimicrobial and proinflammatory functions and contributes to wound healing and maintenance of epithelial barrier function.38 IL-20 is produced by activated keratinocytes and DC and regulates the proliferation of keratinocytes. IL-22 induces the production of IL-20 by keratinocytes.38 Wolk et al.38 demonstrated that mRNA expression of both IL-22 and IL-20 is significantly enhanced in HS skin compared to healthy skin. In contrast, however, IL-22 and IL-20 expression is suppressed in HS skin when compared to psoriatic skin. The expression was also lower than in atopic dermatitis (AD) suggesting a relative deficiency of IL-22 and IL-20. IL-22 deficiency may contribute to a deficiency of AMPs in HS.38 It is suggested that an overexpression of IL-10 suppresses IL-22 in HS, which in turn leads to a suppression of IL-20 production by keratinocytes and decreased AMP expression. Propagation of bacteria with further cytokine release and IL-10 production results from relative IL-22 deficiency with an ongoing inflammatory cascade.38 Interleukin-6

Interleukin-6 is a pleotropic cytokine that plays a role in a wide variety of immune processes. IL-6 promotes antibody production by activated B cells, induces the expression of acute phase proteins such as C-reactive protein, and affects the function of several other cell types including megakaryocytes, hemopoietic stem cells, osteoclasts, hepatocytes, keratinocytes, and mesangial and myeloma cells.59,60 IL-6, in combination with TGF-b, IL-1b, and IL-23, promotes the development of Th17 cells, whereas IL-6 inhibits TGF-b-induced regulatory T-cell development.60 The role of IL-6 in the pathogenesis of HS is unclear. Monocytes from patients with HS were shown to produce less IL-6 compared with monocytes from healthy controls.42 Dreno et al.44 found that protein expression of IL-6 in lesional and perilesional skin of patients with HS is suppressed compared with healthy control skin. In contrast, van der Zee et al.43 found significantly increased levels of IL-6 receptor in lesional HS skin when compared to controls, with IL-6 levels non-significantly elevated. In another paper by the same authors, it was demonstrated that levels of IL-6 were above detection in all samples, including healthy controls.37 Wolk et al.,38 however, demonstrated significantly enhanced mRNA expression of IL-6 in HS compared to psoriatic skin. IL-6 is a key proinflammatory cytokine. Its relative lack in skin may imply that it is being consumed and/or being suppressed by IL-10. International Journal of Dermatology 2014, 53, 1186–1196

Interferon-c

The role of IFN-c in HS is also unclear. van der Zee et al.37,43 found levels of IFN-c to be frequently undetectable or not significantly elevated in HS skin. In contrast, Wolk et al.38 demonstrated that mRNA expression of IFN-c is enhanced in HS skin compared to healthy skin and is similar to that observed in psoriatic skin. In summary, there are several cytokines that may play a role in the pathogenesis of HS. Although there are some conflicting results, the overwhelming evidence points to a dysregulated immune profile, which represents a therapeutic target. The key results are summarized in Table 1. Further cytokines/chemokines/others There are a variety of other cytokines and chemokines that have been measured in HS in limited numbers of studies. Their role in HS pathogenesis remains unclear. These are summarized in Table 2. Antimicrobial peptides Antimicrobial peptides are produced constitutively or are induced by infection or inflammation as part of the body's innate response to pathogenic invasion. They are produced in large quantities by keratinocytes secondary to microbial threat.61 There are pro- and anti-inflammatory AMPs – the human BDs (hBD) 1, 2, 3, and 4, S100A7 (psoriasin), S100A8 (calgranulin A), S100A9 (calgranulin B), ribonuclease 7 (RNase 7), a defensins human neutrophil peptides 1, 2, and 3, lysozyme, and the cathelicidins.38,39,61,62 In addition to their antimicrobial properties, AMPs are immunomodulatory and play a role in cytokine production, chemoattraction of neutrophils, antigen presentation, and wound healing.61 An increase in AMP expression is crucial for the prevention or limitation of cutaneous infections in situations where the barrier function is disrupted.63 Several studies have examined the role of AMPs in HS. Schlapbach et al.62 demonstrated that psoriasin is overexpressed in HS skin both at an mRNA level and at protein level. Keratinocytes were identified as the source of psoriasin. The expression of hBD-2 was found to be elevated at mRNA level in lesions of HS, but protein expression was significantly lower in the epidermis of HS skin compared to normal skin.62 It was suggested that this relative deficiency of hBD-2 in the epidermis plays a role in the pathophysiology of HS by facilitating superficial colonization by bacteria and hence ongoing chronic inflammation via activation of Toll-like receptor (TLR) 2. A large number of hBD-2+ cells in the upper dermis were noted and were identified as CD68+ monocytes/macrophages, the relevance of which is unknown.62 ª 2014 The International Society of Dermatology

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Table 1 Key cytokines in hidradenitis suppurativa Cytokines

Elevated levels

Suppressed levels

Undetectable/not significant

No. of studies

TNF-a

Giamarellos-Bourboulis et al.42 Dreno et al.44

N/A

8

N/A

N/A

3

N/A

N/A

4

N/A

N/A

3

N/A N/A

Wolk et al.38 van der Zee et al.37,43

2 4

IL-22 IL-20 IL-6

van der Zee et al.37,43 Wolk et al.38 Emelianov et al.39 Mozeika et al.40 Matusiak et al.41 van der Zee et al.37,43 Wolk et al.38 van der Zee et al.37,43 Wolk et al.38 Dreno et al.44 Wolk et al.38 van der Zee et al.43 Schlapbach et al.53 Schlapbach et al.53 Wolk et al.38 Schlapbach et al. 53 Wolk et al.38 Wolk et al. 38 Wolk et al. 38

N/A N/A van der Zee et al.37,43

1 1 5

IFN-c

Wolk et al.38

N/A N/A Giamarellos-Bourboulis et al.42 Dreno et al.44 N/A

van der Zee et al.37,43

3

IL-1b IL-10

IL-17

IL-23 IL-12

IFN-c, interferon gamma. Table 2 Other cytokines reported to be abnormal hidradenitis suppurativa in limited numbers of studies Elevated levels

Suppressed levels

Not detectable/not significant levels

IL-839 IL-1143 IL-1643 IL-2438 IL-2638 CXCL943 BLC43 CCL343 CCL543 MIF39 MMP-240 ICAM-143 a-MSH39

TGF-b44 IGF-144 ICAM-144 a-MSH44

IL-237,43 IL-437,43 IL-537,43 IL-743 IL-837,43 IL-1343 IL-1543

in

BLC, B-lymphocyte chemoattractant; CCL, chemokine (C-C motif) ligand; CXCL, chemokine (C-X-C motif) ligand; ICAM-1, intercellular adhesion molecule 1; IGF, insulin-like growth factor.; IL, interleukin; MIF, macrophage migration inhibitory factor; MMP-2, matrix metalloproteinase-2; TGFb, transforming growth factor beta; a-MSH, alpha-melanocyte stimulating hormone.

Wolk et al.38 also demonstrated a relative deficiency of AMPs in HS lesions. The expression of all measured AMPs – BD-1, BD-2, BD-3, S100A7, S100A8, and ª 2014 The International Society of Dermatology

S100A9 – was enhanced in HS compared to controls, but their expression was significantly lower than those in psoriasis. Furthermore, the levels of BD-1, BD-3, and S100A7 (psoriasin) were lower than in AD. Moreover, the expression of BD-1 was even decreased compared to normal healthy skin. Thus, the expression of AMPs is suppressed in HS compared to psoriasis, and this attenuation is even broader than that associated with AD. It is suggested that the relative AMP deficiency is due to a relative deficiency of IL-22 and IL-20.38 It is postulated that the cooperation of several cytokines is required for AMP induction, but the absence of IL-22 may be responsible for the attenuation of AMP response in HS.38 Hofmann et al.61 demonstrated that the expression of hBD-3 is reduced in severe HS. It was suggested that the reduction in hBD-3 might be a predisposing factor in the pathogenesis of HS via an increased propensity for bacterial superinfection. Alternatively, a reduction in hBD-3 expression in severe HS may represent a secondary burning out phenomenon.61 hBD-3 has also been shown to inhibit the expression of TNF-a and IL-6, and therefore a reduction in levels of hBD-3 may promote an increase in these cytokines.64 The expression of RNase 7 was shown by Hofmann et al.61 to be suppressed across all severities of HS. RNase 7 is an integral part of the innate defense mechanism at the hair follicle, where the primary lesion of HS originates. The expression of psoriasin was not induced in lesional HS skin in this cohort. This paper International Journal of Dermatology 2014, 53, 1186–1196

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again highlights a relative deficiency of AMPs. This concept is further supported by Dreno et al.44 who report that the expression of BD-4 and BD-2 was suppressed in perilesional and lesional HS skin compared to control skin. Mozeika et al.40 also noted suppressed levels of BD-2 in lesional HS skin compared to healthy controls. In contrast, Emelianov et al.39 demonstrated that the expression of LL-37 (cathelicidin) is enhanced in HS skin with predominant inflammation. LL-37 immunoreactivity was significantly upregulated in the apocrine gland epithelium of HS skin with inflammation. Psoriasin was also increased in the epidermis and distal outer root sheath in HS skin. hBD-3 was increased in the epidermis and outer root sheath in HS in this study. In contrast to other AMPs in this study, the expression of lysozyme was suppressed in late stage HS. These observations raise the possibility of whether excessive cutaneous secretion of AMPs, in particular by the apocrine and follicular epithelium, actually facilitate and promote HS development. It is unclear as to whether these AMPs are involved in HS aggravation and progression or whether this upregulation is a primary, secondary, or tertiary event in response to bacterial carriage or infection. Hidradenitis suppurativa appears to be characterized by changes in AMP levels, and further research is needed.

a large percentage of the infiltrating cells in HS.15,53,66 When compared to normal appearing skin, Schlapbach et al.62 demonstrated a substantial increase in neutrophils as well as T cells, macrophages, and DCs in the epidermis and/or dermis of chronic inflamed HS lesions. The frequency of CD32 macrophages, CD68 macrophages, CD163 macrophages, and CD209 immature DC and hBD-2 expressing cells were shown to be enhanced in HS skin. Other studies have examined the influx of immune cells in perilesional vs. lesional skin. van der Zee et al. showed that perilesional skin displays psoriasiform hyperplasia, follicular plugging, and an influx of mast cells, CD3+ T cells, CD138+ plasma cells, and factor XIIIa+ DC, whereas in early lesional disease, neutrophilic abscess formation and the influx of mainly macrophages, monocytes, and DCs predominated.66 In chronic HS lesions, the infiltrate expanded with an increase in the frequencies of CD20+ and CD79a+ B cells and CD138+ plasma cells as well as CD4+, CD8+ T cells, macrophages, monocytes, and DCs. In chronic disease, the histological features also become more pronounced.66 Thus, HS skin is associated with an influx of a variety of innate and adaptive immune cells, including DC, macrophages, CD3+, CD4+, and CD8+ T cells, and B cells. Signaling

Immune cells Early studies in HS pathogenesis demonstrated a decrease in the frequency of T cells in the skin of a subset of patients with HS. The frequency of HLA antigens, particularly HLA-A1 and HLA-B8, was shown to be enhanced in patients within this subset.26 Other studies reported an increase in the frequency of HLADR+ and CD62L+ T cells and CD3+ T cells in early lesions.65 More recent studies also suggest a role for T cells in HS.15,38,43,53 van der Zee et al.43 demonstrated elevated numbers of CD3+, CD4+, and CD8+ T cells in lesional HS skin, which were significantly decreased following treatment with adalimumab. In contrast, Giamarellos-Bourboulis et al. demonstrated reduced numbers of CD3+/CD8+ cells in perineal HS but showed that patients with breast disease had increased numbers of NK cells. NK cell numbers decreased with advancing years of disease.42 Several studies have detected B cells and plasma cells in HS.15,66,67 Hunger et al.67 performed phenotypic analysis of all infiltrating immune cells in HS. Compared to normal skin, the most abundant cells in the dermal infiltrate were shown to be CD68+ macrophages, CD209+ DC, and CD3+ T cells. CD19+ B cells and CD56+ NK cells were found only in small numbers. Thus, innate immune cells, including DC and macrophages, are also present in HS skin. Other studies also demonstrate that innate cells constitute International Journal of Dermatology 2014, 53, 1186–1196

The role of bacterial infection in the initiation or propagation of HS remains under investigation. Bacteriology studies most frequently show a mixed growth of commensal microbes, suggesting that HS is not actually a disease of primary infectious etiology, despite its clinical appearance.1 TLRs are pattern recognition receptors, expressed by inflammatory cells, which play a crucial role in the innate immune response.68 Hunger et al. reported a highly increased expression of TLR2 at both mRNA and protein level. TLR2 was expressed by infiltrating macrophages. Increased expression of C-type leptin, another pathogen recognition receptor, was also noted in the epidermis and dermis.67 In contrast to this, Dreno et al. found evidence of deficient innate immune function with baseline expression of TLR4, TLR2, TLR3, TLR7, and TLR9 significantly suppressed in lesional HS skin compared to controls. When compared to non-lesional HS skin, levels of TLR4 were significantly suppressed in lesional skin.44 Impaired Notch signaling has recently been proposed as a mechanism underpinning the pathogenesis of HS.69 Mutations rendering loss of function have been identified in three of the four subunits of c-secretase, which is known to cleave the intracellular domain of Notch.20 Effective Notch signaling has a role in hair follicle differentiation and in the maintenance of the epidermal ª 2014 The International Society of Dermatology

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barrier function. Inhibition of Notch signaling has been shown to result in inhibition of the hair growth cycle, conversion of hair follicles into cysts, and impairment of sebaceous gland differentiation.69 Notch and TLR signaling cross-talk has been reported where Notch signaling suppressed TLR4-triggered proinflammatory cytokine expression by macrophages.70 Negative feedback regulation is impaired by deficient Notch signaling, and this causes excessive cytokine production.69 Deficient levels of IL-22 in lesional HS skin, as demonstrated by Wolk et al.,38 may be due to altered Notch signaling, as IL-22 secretion by CD4+ T cells is Notch dependent.69 Reduced levels of NK cells42 and an association with squamous cell carcinoma may also result from impaired Notch signaling.69 Smoking, which is highly associated with HS, has been reported to down regulate Notch signaling.69 What is the future for hidradenitis suppurativa? Clinical as well as laboratory evidence strongly suggests that HS is a disease of immune dysregulation. HS is associated with other immune-mediated diseases such as Crohn’s disease and pyoderma gangrenosum, and anti-TNF-a treatment has yielded promising results. Moreover, HS is associated with a local influx of immunocytes with associated cytokine abnormalities, including enhancement of TNF-a, IL-1b, IL-10, IL-17, IL-12, and IL-23. Typical Th1 and Th2 cytokines, such as IFN-c, IL-4, IL-5, and IL-13, do not appear to be involved in HS, hence differentiating the inflammatory profile in HS from that of psoriasis and AD. Elevated levels of IL-17 may be derived from a subset of Th17 cells. This may provide a rationale for the use of ustekinumab53 or novel IL-17 blockers. Clinical trials to further evaluate the therapeutic benefit of these therapies are warranted. The role of the inflammasome in the context of HS should be further explored. The actual pathogenic pathway, however, remains somewhat unclear. It has been suggested by van der Zee et al.47 that the pathogenic process begins as a result of environmental factors in a genetically susceptible individual. The process may begin before the first visible lesion in response to commensal microbes, resulting in aberrant production of AMPs and cytokines by keratinocytes and an influx of immune cells. Subclinical inflammation results in epidermal psoriasiform hyperplasia and hyperkeratosis of the follicular infundibulum, causing follicular plugging, cyst formation, and eventual rupture of contents into the dermis. Free keratin fibers may activate the inflammasome to generate IL-1b, which provides a potential therapeutic target. An IL-1 receptor antagonist (anakinra) and human monoclonal ª 2014 The International Society of Dermatology

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antibody to IL-1b (canakinumab) are efficacious in a variety of inflammasome-mediated auto-inflammatory diseases and warrant investigation in HS. Wolk et al.38 suggest inhibition of IL-10 production, IL-22 application, and AMP application as alternative therapeutic approaches. van der Zee et al.66 suggested targeting ectopic pseudo B-cell follicles in chronic HS. Novel therapeutic interventions aimed at depletion or blocking of B cells may be beneficial. The key to the development of targeted therapy will be a clear understanding of the relative contribution of the components of immune dysregulation observed in HS. The results to date, summarized in this review, serve to highlight the complexity of this dynamic interplay but indicate exciting opportunities for specific molecular therapies. Questions (See answers after references) 1 What is the estimated prevalence of HS? (a) 0.05–4% (b) 10% (c) 20% (d) 40% 2 Follicular occlusion is thought to be central to the development of HS. (a) True (b) False 3 What genetic mutations contribute to the development of HS? (a) Mutations in the CARD14 gene (b) Inactivating mutations in the genes which encode subunits of c-secretase (c) Mutations in the collagen VII gene (d) Mutations in the filaggrin gene 4 Which anti-TNF-a agents appear to be most effective in HS to date? (a) Infliximab, etanercept (b) Etanercept, ustekinumab (c) Infliximab, adalimumab 5 Which combination of cytokines appears to be involved in the pathogenesis of HS? (a) TNF-a, IL-1b, IL-10 (b) IL-15, TGF-b, IL-4 (c) IL-18, IL-5, IL-33 6 HS is characterized by an influx of immune cells into the skin, including dendritic cells, macrophages, T cells, and B cells. (a) True (b) False 7 Antimicrobial peptides may be involved in the pathogenesis of HS. (a) True (b) False International Journal of Dermatology 2014, 53, 1186–1196

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8 Which cell signaling pathway may be involved in HS? (a) WNT-signaling pathway (b) p53 signaling (c) c-secretase–Notch signaling pathway 9 What other factors are thought to be associated with HS? (a) Obesity (b) Cigarette smoking (c) Hormone imbalance (d) All of the above 10 What system is used to classify the severity of HS? (a) Expanded disability status scale (EDSS) (b) Hurley classification (c) ACR score References 1 Alikhan A, Lynch PJ, Eisen DB. Hidradenitis suppurativa: a comprehensive review. J Am Acad Dermatol 2009; 60: 539–561, quiz 62–63. 2 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. 3 Jemec GB, Heidenheim M, Nielsen NH. The prevalence of hidradenitis suppurativa and its potential precursor lesions. J Am Acad Dermatol 1996; 35: 191–194. 4 Cosmatos I, Matcho A, Weinstein R, et al. Analysis of patient claims data to determine the prevalence of hidradenitis suppurativa in the United States. J Am Acad Dermatol 2013; 68: 412–419. 5 Matusiak L, Bieniek A, Szepietowski JC. Soluble interleukin-2 receptor serum level is a useful marker of hidradenitis suppurativa clinical staging. Biomarkers 2009; 14: 432–437. 6 Wolkenstein P, Loundou A, Barrau K, et al. Quality of Life Group of the French Society of D. Quality of life impairment in hidradenitis suppurativa: a study of 61 cases. J Am Acad Dermatol 2007; 56: 621–623. 7 Esmann S, Jemec GB. Psychosocial impact of hidradenitis suppurativa: a qualitative study. Acta Derm Venereol 2011; 91: 328–332. 8 Matusiak L, Bieniek A, Szepietowski JC. Psychophysical aspects of hidradenitis suppurativa. Acta Derm Venereol 2010; 90: 264–268. 9 Matusiak L, Bieniek A, Szepietowski JC. Hidradenitis suppurativa markedly decreases quality of life and professional activity. J Am Acad Dermatol 2010; 62: 706–708, 8 e1. 10 von der Werth JM, Jemec GB. Morbidity in patients with hidradenitis suppurativa. Br J Dermatol 2001; 144: 809–813. 11 Onderdijk AJ, van der Zee HH, Esmann S, et al. Depression in patients with hidradenitis suppurativa. J Eur Acad Dermatol Venereol 2013; 27: 473–478. International Journal of Dermatology 2014, 53, 1186–1196

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12 Nazary M, van der Zee HH, Prens EP, et al. Pathogenesis and pharmacotherapy of hidradenitis suppurativa. Eur J Pharmacol 2011; 672: 1–8. 13 Yu CC, Cook MG. Hidradenitis suppurativa: a disease of follicular epithelium, rather than apocrine glands. Br J Dermatol 1990; 122: 763–769. 14 Attanoos RL, Appleton MA, Douglas-Jones AG. The pathogenesis of hidradenitis suppurativa: a closer look at apocrine and apoeccrine glands. Br J Dermatol 1995; 133: 254–258. 15 von Laffert M, Helmbold P, Wohlrab J, et al. Hidradenitis suppurativa (acne inversa): early inflammatory events at terminal follicles and at interfollicular epidermis. Exp Dermatol 2010; 19: 533–537. 16 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: 367–371. 17 Fitzsimmons JS, Guilbert PR, Fitzsimmons EM. Evidence of genetic factors in hidradenitis suppurativa. Br J Dermatol 1985; 113: 1–8. 18 Von Der Werth JM, Williams HC, Raeburn JA. The clinical genetics of hidradenitis suppurativa revisited. Br J Dermatol 2000; 142: 947–953. 19 Gao M, Wang PG, Cui Y, et al. Inversa acne (hidradenitis suppurativa): a case report and identification of the locus at chromosome 1p21.1–1q25.3. J Invest Dermatol 2006; 126: 1302–1306. 20 Wang B, Yang W, Wen W, et al. Gamma-secretase gene mutations in familial acne inversa. Science 2010; 330: 1065. 21 Pan Y, Lin MH, Tian X, et al. Gamma-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev Cell 2004; 7: 731–743. 22 Ingram JR. The aetiology of acne inversa: an evolving story. Br J Dermatol 2011; 165: 231–232. 23 Pink AE, Simpson MA, Brice GW, et al. PSENEN and NCSTN mutations in familial hidradenitis suppurativa (acne inversa). J Invest Dermatol 2011; 131: 1568–1570. 24 Pink AE, Simpson MA, Desai N, et al. Mutations in the gamma-secretase genes NCSTN, PSENEN, and PSEN1 underlie rare forms of hidradenitis suppurativa (acne inversa). J Invest Dermatol 2012; 132: 2459–2461. 25 Dvorak VC, Root RK, MacGregor RR. Host-defense mechanisms in hidradenitis suppurativa. Arch Dermatol 1977; 113: 450–453. 26 O’Loughlin S, Woods R, Kirke PN, et al. Hidradenitis suppurativa. Glucose tolerance, clinical, microbiologic, and immunologic features and HLA frequencies in 27 patients. Arch Dermatol 1988; 124: 1043–1046. 27 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: 96–99. 28 van der Zee HH, van der Woude CJ, Florencia EF, et al. Hidradenitis suppurativa and inflammatory bowel

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immune responses in patients with hidradenitis suppurativa. Br J Dermatol 2007; 156: 51–56. van der Zee HH, Laman JD, de Ruiter L, et al. Adalimumab (antitumour necrosis factor-alpha) treatment of hidradenitis suppurativa ameliorates skin inflammation: an in situ and ex vivo study. Br J Dermatol 2012; 166: 298–305. Dreno B, Khammari A, Brocard A, et al. Hidradenitis suppurativa: the role of deficient cutaneous innate immunity. Arch Dermatol 2012; 148: 182–186. Sutton C, Brereton C, Keogh B, et al. A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J Exp Med 2006; 203: 1685–1691. Schroder K, Tschopp J. The inflammasomes. Cell 2010; 140: 821–832. van der Zee HH, Laman JD, Boer J, et al. Hidradenitis suppurativa: viewpoint on clinical phenotyping, pathogenesis and novel treatments. Exp Dermatol 2012; 21: 735–739. Saraiva M, OGarra A. The regulation of IL-10 production by immune cells. Nat Rev Immunol 2010; 10: 170–181. Moore KW, de Waal Malefyt R, Coffman RL, et al. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001; 19: 683–765. Wilke CM, Wang L, Wei S, et al. Endogenous interleukin-10 constrains Th17 cells in patients with inflammatory bowel disease. J Transl Med 2011; 9: 217. Maddur MS, Miossec P, Kaveri SV, et al. Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies. Am J Pathol 2012; 181: 8–18. Liang SC, Tan XY, Luxenberg DP, et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 2006; 203: 2271–2279. Schlapbach C, Hanni T, Yawalkar N, et al. Expression of the IL-23/Th17 pathway in lesions of hidradenitis suppurativa. J Am Acad Dermatol 2011; 65: 790–798. Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 2003; 3: 133–146. Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005; 6: 1133–1141. Cua DJ, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003; 421: 744–748. Guenova E, Teske A, Fehrenbacher B, et al. Interleukin 23 expression in pyoderma gangrenosum and targeted therapy with ustekinumab. Arch Dermatol 2011; 147: 1203–1205. Rutz S, Eidenschenk C, Ouyang W. IL-22, not simply a Th17 cytokine. Immunol Rev 2013; 252: 116–132.

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59 Kishimoto T. Interleukin-6: from basic science to medicine–40 years in immunology. Annu Rev Immunol 2005; 23: 1–21. 60 Tanaka T, Kishimoto T. Targeting interleukin-6: all the way to treat autoimmune and inflammatory diseases. Int J Biol Sci 2012; 8: 1227–1236. 61 Hofmann SC, Saborowski V, Lange S, et al. Expression of innate defense antimicrobial peptides in hidradenitis suppurativa. J Am Acad Dermatol 2012; 66: 966–974. 62 Schlapbach C, Yawalkar N, Hunger RE. Human beta-defensin-2 and psoriasin are overexpressed in lesions of acne inversa. J Am Acad Dermatol 2009; 61: 58–65. 63 Harder J, Schroder JM. Antimicrobial peptides in human skin. Chem Immunol Allergy 2005; 86: 22–41. 64 Semple F, Webb S, Li HN, et al. Human beta-defensin 3 has immunosuppressive activity in vitro and in vivo. Eur J Immunol 2010; 40: 1073–1078. 65 Boer J, Weltevreden EF. Hidradenitis suppurativa or acne inversa. A clinicopathological study of early lesions. Br J Dermatol 1996; 135: 721–725. 66 van der Zee HH, de Ruiter L, Boer J, et al. Alterations in leucocyte subsets and histomorphology in normal-appearing perilesional skin and early and chronic hidradenitis suppurativa lesions. Br J Dermatol 2012; 166: 98–106. 67 Hunger RE, Surovy AM, Hassan AS, et al. Toll-like receptor 2 is highly expressed in lesions of acne inversa

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and colocalizes with C-type lectin receptor. Br J Dermatol 2008; 158: 691–697. 68 Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124: 783–801. 69 Melnik BC, Plewig G. Impaired Notch signalling: the unifying mechanism explaining the pathogenesis of acne inversa. Br J Dermatol 2013; 168: 876–878. 70 Gentle ME, Rose A, Bugeon L, et al. Noncanonical Notch signaling modulates cytokine responses of dendritic cells to inflammatory stimuli. J Immunol 2012; 189: 1274–1284.

Answers to questions 1 (a) 0.05–4%. 2 (a) True. 3 (b) Inactivating mutations in the genes that encode subunits of c-secretase. 4 (c) Infliximab, adalimumab. 5 (a) TNF-a, IL-1b, IL-10. 6 (a) True. 7 (a) True. 8 (c) c-Secretase–Notch signaling pathway. 9 (d) All of the above. 10 (b) Hurley classification.

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