Clinics in Dermatology (2014) 32, 397–408

Hidradenitis suppurrativa (acne inversa) as a systemic disease Clio Dessinioti, MD ⁎, Andreas Katsambas, MD, Christina Antoniou, MD Department of Dermatology, A. Syggros Hospital, University of Athens, Athens, Greece

Abstract Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic follicular occlusive skin disorder characterized by recurrent abscesses, draining sinuses, and scarring, with a multifactorial pathogenesis. The answer to the question whether HS may be considered a systemic disease relies on the presence of accompanying systemic manifestations, on the proof of association with other diseases or conditions, and on the occurrence of systemic implications. We address these questions based on a systemic review of the existing literature. There are several reports in the literature of the coexistence of HS with other diseases, including pyoderma gangrenosum, PASH syndrome, Adamantiades-Behcet’s disease, spondylarthropathy, Crohn’s disease, SAPHO, pachyonychia congenita, Dowling-Degos disease, and the keratitis-ichthyosis-deafness (KID) syndrome. Case series exist only for Crohn’s disease, while most other reports are anecdotal, thus, not providing high-quality scientific evidence. Based on well-designed studies, HS has been associated with the metabolic syndrome and with excess body weight or obesity. The link between HS and systemic associations may be attributed to common genetic or environmental factors or shared inflammatory pathways. © 2014 Elsevier Inc. All rights reserved.

Introduction The term hidradenitis is derived from the Greek words hidros meaning sweat and adenas meaning gland. The German philosopher Karl Marx was thought to be affected by HS1. In 1839, the first clinical description of hidradenitis suppurativa (HS), as a distinct disease, was made by Velpeau, and in 1854, the French surgeon Verneuil coined the term hidradenitis suppurativa, relating the disease to the apocrine sweat glands. Apocrine sweat glands empty their content into the follicular canal, just above the sebaceous gland duct, in contrast to eccrine sweat glands that empty their ducts directly onto the skin surface. In 1989, Plewig and Steger proposed the term acne inversa.2 The term acne inversa is based on the infundibular ⁎ Corresponding author. Tel.: 00302107265259; fax: 00302107258476. E-mail address: [email protected] (C. Dessinioti). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.006

hyperkeratosis seen in terminal follicles in HS that parallels the infundibular hyperkeratosis of the pilosebaceous unit in acne vulgaris3; however, HS is not a type of acne. In HS, there are no closed comedones, as it is the deep and not the superficial part of the follicle that is affected.4 Also, hyperseborrhea and/or sebum lipid changes are not noted in HS, whereas they have prominent roles in the pathogenesis of acne. Similar frequency, density, and pattern of active sebaceous glands were found in HS patients and controls, and there was no significant facial, axillary, or genital seborrhea.5 Hidradenitis suppurativa (acne inversa) is a chronic inflammatory skin disorder characterized by recurrent, painful nodules, abscesses, and draining sinuses, with resultant scarring.6 Hidradenitis suppurativa mainly affects the intertriginous body areas including the axillae, the inguinal folds, the anogenital, the perineum, the inframammary regions, and the nape. Although HS was considered a rare disease in the past, its prevalence has

398 been estimated to be 1% to 4%.6 HS presents as a sporadic or familial form. It typically presents after puberty with an average age of onset in the second or third decade of life.5 The man:woman ratio is 1:2.7 to 1:3.3.7,8 A populationbased study in Omsted County, Minnesota, reported an overall annual age- and sex-adjusted incidence of HS of 6.0 per 100,000 person-years [95% confidence interval (CI): 5.2–6.7] during 1968–2008. The incidence was significantly higher among women than among men, with 8.2 per 100,000 (95% CI: 7.0–9.3) and 3.8 per 100,000 (95% CI: 3.0–4.7), respectively (P b .001).9 The answer to the question whether HS may be considered a systemic disease relies on the presence of accompanying systemic manifestations, on the proof of association with other diseases or conditions, and on the occurrence of systemic implications. We address these questions based on a critical appraisal of the existing literature. We have searched the English literature in MEDLINE, EMBASE, and Cochrane libraries for publications, from 1950 to May 2013, with the terms hidradenitis suppurativa and acne inversa in association with the following terms: comorbidities, systemic disease, Crohn’s disease, and inflammatory bowel disease. Based on existing literature, we included in our search the terms Fox-Fordyce disease, Adamantiades-Behcet disease, Complex regional pain syndrome type 1, pachyonychia congenita, SAPHO syndrome, PASH syndrome, spondyloarthropathy, follicular tetrad, Interstitial keratitis, KID syndrome, Dowling-Degos disease, and SCC, to search for updated reports for these possible associations. Results are discussed in the following sections.

Cutaneous characteristics The predilection of HS for hair-bearing skin sites and, especially, for body regions with apocrine sweat glands, as well as the histopathologic observation that the earliest involvement of HS occurs in and around of the distal hair follicle (HF) outer root sheath (ORS) have led to the suggestion that HS is a disease arising from the distal HF epithelium. 10 Histologically, HS is characterized by hyperkeratosis, follicular occlusion, perifolliculitis, apocrinitis and/or sinus tract formation, fibrosis, and a dense inflammatory cell infiltrate with neutrophils in the acute phase of the disease11; however, during the diagnostic approach of an HS patient, a biopsy and histology are not necessary, except for excluding another suspected disease. The diagnosis of HS is based exclusively on clinical grounds, and the following three criteria must all be met for establishing diagnosis: (1) the presence of typical lesions, including deep-seated painful nodules, and/or abscesses, and/or draining sinuses, and/or bridged scars; (2) typical topography, with predominant involvement of

C. Dessinioti et al.

Fig. 1 Hurley stage I: Single or multiple nodules/abscesses without sinus tracts or cicatrization. Characteristic pseudocomedones are noted in this patient.

the axillae and groin; and (3) chronic course with multiple recurrences.4,12 The primary HS lesions include painful nodules and/or abscesses (Figures 1-3). The secondary lesions include chronic sinus formation with intermittent release of serous, foul smelling (due to anaerobic colonization) discharge, hypertrophic scars, and open pseudocomedones. There are no closed comedones.13 The distribution pattern of HS corresponds with the “milk line” distribution of apocrinerelated mammary tissue in mammals.5 The disease severity is determined with the Hurley stage14 and/or the Sartorius score.15 There is no fever or significant associated laboratory findings.5 There is considerable clinical intrapatient heterogeneity as far as the predominant lesions or the sites of involvement are concerned and locations appear to have sexual predilection. Axillary, upper torso, groin, or thigh involvement is more common in women, while perianal or perineal disease is more frequent in men.9 The ratio of man:woman differs by body region, with women presenting most commonly having involvement of the axillary or inguinal areas (2:5) and the mammary area (1:14), while perianal HS is more common in

Fig. 2 Hurley stage II: Recurrent abscesses with tract formation and cicatrization. Widely separated lesions.

Hidradenitis suppurativa as a systemic disease

Fig. 3 Hurley stage III: Diffuse involvement, multiple interconnected tracts and abscesses across entire area.

men (5:1).16 A cross-sectional study of 618 patients with a median age of 31 years old, reported that the median age of HS onset was 20 years old and the median HS duration was 9 years. The majority of patients were smokers, either current (72.8%) or past smokers (10.4%). Patients were classified in three HS phenotypes (classes) with distinct characteristics. In particular, the axillary-mammary class was the more common type (48%) with high prevalence of breast and axillae involvement and of hypertrophic scars. The follicular class (26%) was characterized by all lesion types and mainly by follicular lesions, mainly epidermal cysts, pilonidal sinus, and by severe acne. The gluteal class was characterized by gluteal involvement, follicular papules, and folliculitis. In comparison with the axillary-mammary class, the follicular class was characterized by higher proportions of men

399 (OR:4.6, 95% CI: 3–7, P b .001), current/former smokers (OR:2.2, 95% CI:1.3–3.9, P = .005), greater disease severity (Sartorius and Hurley), earlier disease onset, and longer disease duration. The gluteal class was characterized by patients that were more often smokers, had lower body mass index (BMI) values and less severe disease despite a longer disease duration compared to the “axillary-mammary” class. The question remains whether these distinct phenotypes are associated with distinct biological, physiological, or genetic patterns.7 The frequency of disease appearing at specific anatomical sites might be likely to reflect the absolute number or density of apocrine sweat glands. Apocrine glands are densely located in the axilla, sparser in the groin and perineum, and least evident in perianal and mammary regions. The male predilection for perianal disease may be attributed to gender differences in the density of perianal apocrine glands, although other local factors may also be implicated.16

Pathophysiology and pathology of HS The pathogenesis of HS is complex and it remains unclear. Genetic factors, hormones, smoking, obesity, bacterial infection, and alteration of antimicrobial peptides (AMPs) that regulate cutaneous innate immunity, have been implicated in the multifactorial pathogenesis of HS (Figure 4).17 In HS, the primary event is increased outer root sheath (ORS) keratinocyte proliferation with subsequent

Fig. 4 Schematic pathophysiology of HS. KC, Keratinocyte; HF, Hair follicle; ASG, Apocrine sweat gland; hBD, Human b-defensin; dashed lines, Possible implication, still in hypothesis; solid line, Reported implication in published studies.

400 follicular occlusion and occlusion of the apocrine sweat gland.4,18 This is followed by rupture of the follicular canal and extrusion of contents, including corneocytes, bacteria, sebum, and hair follicles, into the surrounding connective tissue, and the development of an inflammatory infiltrate.17,10 In a total of 94 operative specimens from 60 patients with HS, hyperkeratosis of the terminal follicles was found in 82% (77⁄94) of the cases. Hyperplasia of follicular epithelium was evident in 77% (72⁄94), and pronounced perifolliculitis was observed in 68% (64⁄94) of the cases. Follicle ruptures, in contrast, were only found in 28% (26⁄94) of the tissue samples.3 The mechanism by which follicular plugging occurs in acne is not known; various candidates are genetic alterations in the γ-secretase/Notch pathway, and alterations of innate immunity. Decreased Notch signaling, due to loss-of-function mutations in the γ-secretase genes, is hypothesized to play a key role in the pathogenesis of familial and nonfamilial HS via aberrant trichilemmal keratinization. Familial HS [Online Mendelian Inheritance in Man (OMIM) 142690] is an autosomal dominant disease with genetic heterogeneity. An autosomal dominant inheritance in UK patients was first reported by Fitzsimmons et al, in 1985,19 a finding that was later confirmed by von der Werth et al.20 Thirty-four percent of first-degree relatives of probands also had HS.19 The genetic locus responsible for HS was located at chromosome 1p21.1-1q25.3 by genome-wide linkage scan in a fourgeneration Chinese family.21 This is a 73-Mb chromosome region containing nearly 900 genes. Mutations in the NCSTN gene (1q22-23) has been identified in Chinese families with HS, and familial HS in Japanese patients while it was not found in nonfamilial HS.6,22,10,23 NCSTN encodes Nicastrin, which is an essential subunit of γ-secretase complex. γSecretase is a transmembrane protease that mediates intramembranous cleavage of Notch. Notch is a highly conserved and ubiquitous signaling system that regulates cell fate determination and alterations in the Notch pathway lead to epidermal and follicular abnormalities in mouse skin that are histopathologically similar to those observed in human HS. A study of seven London families with HS that showed an autosomal dominant inheritance pattern failed to detect any pathogenic γ-secretase mutations in five of the seven families.24 It is still unclear whether the phenotype of familial cases differs from apparently sporadic cases of AI, some of which may be accounted for by incomplete penetrance. Among 48 UK HS patients, three variants in NCSTN were detected in three patients with nonfamilial HS. The authors proposed that germ line mutations of γsecretase are confined in a minority of patients and additional, and as yet unknown, genes may predispose to HS.25 Further research will investigate the genetics of HS in the European patient population and genotype–phenotype studies are important to associate disease phenotypes with potential mutations in the whole γ-secretase–Notch pathway.26

C. Dessinioti et al. The role of smoking was studied in a population-based case-control study (67 self-reported HS patients, 200 ageand sex-matched controls) and a clinic-based case-control study (302 HS patients, and 906 age- and sex-matched controls). Compared to controls, in self-reported patients and in multivariate analysis, current smoking remained significantly associated with HS (OR:4.16, 95% CI: 2.99-8.69). Compared to controls, in the medically assessed patients, HS was significantly associated with current smokers (OR:12.55, 95% CI:8.58-18.38).27 A total of 251 HS patients were included in the study and among them 99 patients with HS were clinically evaluated. Of the 249 patients who answered the question about smoking 173 (70%) were smokers, 37 (15%) former smokers, and 39 (16%) nonsmokers. Only one of 34 men was a nonsmoker compared with 38 of 215 women. On average, the patients were overweight, with a mean ± SD BMI of 28.3 ± 6.5 kg m- 2). There was more severe HS in smokers compared to nonsmokers (P = .032), as evaluated by the Hidradenitis Suppurativa Score.28 The effect of nicotine on the skin of HS patients compared to controls showed a significantly thicker epidermis in the presence of nicotine. This finding correlated with the production of nonneuronal acetylcholine in the skin, as suggested by an increased expression of acetylcholine receptors found around the follicular infundibulum in the epidermis of HS patients.10 Hormonal factors have been implicated in the pathogenesis of HS. One study found no difference in androgenism (acne, hirsutism, and irregular menstrual periods) between 70 woman HS patients and 100 healthy controls.29 It has been stated that the usual absence of clinical signs of virilism, the normal levels circulating androgens, the absence of hyperseborrhea, and the limited effect of antiandrogen treatments rule out a key role of hyperandrogenism.13 Although the verdict is still out, it has been proposed that bacteria play a secondary rather than a primary role in HS.5 The observation of many bacterial species, including Streptococcus viridans, Staphylococcus aureus, S milleri, anaerobes ( Peptostreptococcus species, Bacteroides melaninogenicus, and B corrodens), coryneform bacteria, and Gram-negative bacteria, such as Escherichia coli, Klebsiella, and Proteus, and no dominant single species, suggests that bacteria found on the surface of HS lesions are secondary colonizers rather than etiologic agents.5 A study involving an aspiration technique to sample deeper parts of early HS lesions clearly showed negative cultures in 51% of the cases, suggesting that HS is primarily a disease of the follicular epithelium that is secondarily colonized and infected by bacteria30; however, the persistence of bacteria frequently found in chronic and relapsing HS may contribute to flares of the disease.31 A disturbance of the cutaneous innate immune system has been implicated in the follicular occlusion and the inflammation of HS. Innate immunity provides the first line of defense against foreign microorganisms. AMPs exhibit antimicrobial and immunomodulatory functions, and they

Hidradenitis suppurativa as a systemic disease promote keratinocyte differentiation and/or proliferation.32 The majority of AMPs is expressed by epithelial cells, such as keratinocytes (human β–defensin [HBD]-3, ribonuclease [RNase] 7, and psoriasin) or by epithelial appendages, such as eccrine sweat glands (dermcidin), whereas α–defensins human neutrophil peptides 1 to 3 and human cathelicidin LL37 are contained within or secreted by circulating leukocytes.31 Innate immune markers were studied with immunohistochemistry in biopsies from 12 patients with HS, from both normal (uninvolved) skin and from inflammatory nodules. Skin biopsies from non-HS individuals were used as controls. The expression of TLR-2, -3, -4, -7, and -9, IL-6, TGF-β, α-MSH, β-defensin 2, β-defensin 4, and IGF-1, was suppressed in involved and uninvolved skin of HS patients compared to controls. Compared to control skin, TNF-α was suppressed in nonlesional HS skin (P b .001), while there was no difference in lesional HS skin (P = .08). Defensins also have antiinfectious properties, and a decrease in defensins may enable the development of bacteria. 18 Similarly, defective immune response was found in the blood of HS patients in another study. Monocytes isolated from healthy controls (n = 6) were more active for the secretion of TNF-α compared to those isolated from HS patients (n = 53).33 Contradictory results have reported significantly increased IL-1β, TNF-α, and IL-10 levels in lesional and perilesional HS skin compared with healthy control skin and psoriatic skin, suggesting that the inflammation is strong in HS skin and providing a rationale for anti-TNF therapy in HS patients.34 The in situ expression of proinflammatory cytokines TNF-α, IL-8, as well as, α-MSH, a potent antiinflammatory neuropeptide, and antimicrobial peptides, such as psoriasin, lysozyme, cathelicidin (LL-37), and hBD3, was studied with immunohistochemistry in biopsies from lesional skin from 18 HS patients compared to 12 controls. There was increased immunoreactivity for LL-37 in the apocrine sweat gland and distal ORS epithelium of inflammatory HS skin (P ≤ .01), psoriasin was increased in the epidermis and distal outer root sheath in inflammatory HS skin, hBD-3 was increased in the epidermis and the distal ORS in HS skin and α-MSH was significantly increased in the epidermis of inflammatory HS skin (P ≤ .01). Compared to controls, TNF-α was increased in the epidermis and the dermis of inflamed HS skin but decreased in the proximal ORS. IL-8 was increased in the epidermis and the ORS of inflamed HS skin.17 It is unclear if the up regulation of AMPs is a primary or a secondary event due to bacterial superinfection.17 The epidermis of HS patients shows signs of hyperplasia35 is well in line with the concept that excessive LL-37 secretion can lead to epithelial hyperproliferation. The observed up regulation of psoriasin and hBD-3 in HS epidermis may also be of relevance to stimulate keratinocyte proliferation and/or differentiation and could, thus, induce follicular hyperkeratinization and subsequent follicular occlusion. Psoriasin stimulates α-defensin and TNFα transcription.17 Up regula-

401 tion of IL-8 expression in HS skin may lead to a vicious circle that promotes neutrophil, mast- and T-cell chemotaxis, activation of NF-κB in neutrophils, macrophages, and neutrophils, are induced by IL-8 to produce more LL-37.17 Elevated levels of tumor necrosis factor (TNF-α) have been found in HS skin.17,34 The expression of AMPs, hBD-3, ribonuclease 7 (RNase 7), psoriasin, and dermcidin, were studied in skin biopsies in 33 patients with HS and in axillary or inguinal biopsy specimens from normal-appearing skin of 6 patients with melanoma undergoing lymphadenectomy. Immunohistochemistry showed increased immunoreactivity of HBD-3 in HS lesions compared to controls. Realtime reverse transcription-polymerase chain reaction (RTPCR) showed HBD-3 mRNA levels were increased in HS of lower severity (grades I and II) compared with controls (P = .046). Interestingly, lesional skin of patients with severe HS (Hurley grade III) clearly showed no significant induction of HBD-3 mRNA expression compared with healthy skin. Also, compared to controls, RNase 7 mRNA levels were significantly lower in HS skin, while there was no difference for psoriasin expression. The authors proposed that reduced HBD-3 inducibility may represent a predisposing factor for severe HS and, therefore, be present in these patients independent of the duration of the disease, or be the result of a secondary inhibition of AMP production due to longstanding disease.31 Another study also recently reported increased HBD-2 and HBD-3 in patients with HS (n = 7) compared with healthy control subjects (n = 8) (P b .0001 and P = .004, respectively)36; however, there were reports of an overexpression of psoriasin in lesional HS skin compared with normal-appearing skin of different locations, ie, of submammary origin or trunk.36,37 These conflicting findings may be explained in part by the fact that psoriasin secretion is dependent on the body location with highest levels secreted on head, hands, and axillae.31 It is tempting to speculate that the recently described deficiency of IL-22 in HS may explain the low psoriasin expression, because IL-22 strongly induces expression of cutaneous AMPs, including psoriasin in vivo.36

Is hidradenitis suppurativa a systemic disease? The answer to the question whether HS could be considered a systemic disease relies on the presence of accompanying systemic manifestations, on the association with other diseases or conditions, and on the occurrence of systemic implications. Not long ago, HS was a neglected, understudied disease. Identified reports on the association of HS with other diseases are summarized in Table 1. Most reports investigating HS rely on isolated case reports or involve a small number of patients providing only descriptive statistics, and

402 Table 1 Disease associated with HS

C. Dessinioti et al. Association of HS with other diseases or syndromes Type of study

Fox-Fordyce disease Case reports Case report Complex regional pain syndrome type 1 Pachyonychia congenita Case series Case report Crohn’s disease Case series Case report Case reports Interview-based pilot study SAPHO syndrome Multicenter study of 12 SAPHO patients Case report Case report PASH syndrome Case report PAPASH syndrome Case reports Pyoderma Case series Case series gangrenosum Interstitial keratitis Case series of 62 HS patients KID syndrome Case reports Dowling-Degos Case reports disease AdamantiadesCase reports BehcSet ́ disease

Number of patients with HS and associated disease 338 139

540 141 2445 246 347 2548 749

150 151 152 253,54 1155 656 457

258,59 860–63,42–44,64 565–69

without having analyzed results for statistical significance. As a result, there are a very small number of studies that may be used for drawing evidence-based conclusions.

Accompanying systemic manifestations Accompanying systemic manifestations that have been described in the context of HS include obesity and hormonal disturbances. Obesity has been associated with HS in more than 75% of cases, and it is considered to participate in the pathophysiology of the disease, as there is more friction and skin contact with adjacent skin surfaces in patients with excessive body weight.5,16 There were a population-based case-control study (67 self-reported HS patients, 200 age- and sexmatched controls) and a clinic-based case-control study (302 HS patients, and 906 age- and sex-matched controls). In selfreported patients, the association with BMI was nearly significant (OR 1.05 for every increase of 1 U of BMI). Compared to controls, in the medically assessed patients, HS

was significantly associated with each increase of 1 U of BMI (OR = 1.12 [1.08-1.15]). The multivariate OR was 2.08 (1.40-3.08) for being overweight and 4.42 (2.82-6.93) for obese.27 Obesity also has been associated with alterations in the hormonal milieu, such as changes in the production, metabolism, and biological activity of androgens and oestrogens.16 A hormonal dependence has been implicated in the pathogenesis of HS based on the observation of a female preponderance and of a HS decline following menopause, the association with polycistic ovary syndrome, and reported hormonal abnormalities.16,70 A disturbance of feedback signaling from peripheral hormones was reported in13 patients, with an exaggerated prolactin and TSH response to TRH71; however, the prevalence of acne, hirsutism, and irregular menses are not more common in HS patients compared to controls13 and most HS patients have normal hormone levels.16

Association of HS with other diseases or conditions There are several reports in the literature of the coexistence of HS with other diseases, including pyoderma gangrenosum, PASH syndrome, Adamantiades-BehcSet ́ disease, spondylarthropathy, Crohn’s disease, SAPHO, pachyonychia congenita, Dowling-Degos disease, and the keratitis-ichthyosis-deafness (KID) syndrome (Table 1)4; however, this does not establish that HS is characterized by systemic involvement, as they could be a serendipitous finding. Isolated case reports of patients with HS and another disease do not provide scientific-based evidence of a link between the two conditions. Association of HS with other diseases should be based on large studies including a large number of patients. Several case reports and studies have suggested an association between HS and CD.72–82,45,83,84,47,85,46 An interview-based study of 158 patients with inflammatory bowel disease (CD or UC), showed that 25 patients (16%) reported a history of “painful boils in the axillae and/or groin,” of whom 17 patients had CD and 8 patients had UC. The authors mentioned that this study was underpowered and so a higher prevalence of HS and IBD in these patients could not established.48 In the largest of these reports, 24 of 61 (39%) HS patients also had a CD diagnosis.45 In most of these cases, CD affected only the large bowel, and its diagnosis preceded that of HS, while diagnosis of HS preceding that of CD has also been reported.45,46 HS affected the perineal and perianal area in all patients and secondary sites in 83% of patients.45 Possible shared pathogenetic factors have been reported in HS and Crohn’s disease. Both are chronic diseases of epithelia, which are inhabited by commensal flora, and common key factors include genetic predisposition, smoking, fistula formation,

Hidradenitis suppurativa as a systemic disease

403

Fig. 5 Association of HS with Crohn’s disease. (A) Numerous fistulas in the inguinal folds in a patient with Crohn’s disease, (B) Hidradenitis suppurativa of the axilla with abscess, fistula, and hypertrophic scarring.

and clinical response to anti-TNF-α therapy.48 Decreased levels of intestinal hBD-2 have also been established as a risk factor for Crohn’s disease, and the protein expression of hBD-2 was significantly lower in the epidermis of HS lesions than in the control skin samples.37 It is important to differentially diagnose cutaneous Crohn’s disease from HS coexisting with Crohn’s disease, although diagnosis may be difficult in cases of HS affecting the perineal region. Additional involvement of the axilla favors a diagnosis of HS (Figure 5) as metastatic Crohn's disease of the skin usually affects the lower extremities.46 When diagnosis is not certain, a colonoscopy should be performed even in the absence of overt digestive symptoms.13 Pyoderma gangrenosum (PG) has been reported in 17 patients with HS. The authors proposed that PG and HS may represent variant manifestations of cytokine dysregulation by the innate immune system with common etiology.55,56 PAPA syndrome (OMIM 604416) was first described in 1997 as the clinical triad of pyogenic sterile arthritis, pyoderma gangrenosum, and acne. Mutations in the gene of CD2-binding protein 1 (CD2BP1, also called proline-serine-threonine-phosphatase-interactive protein 1, PSTPIP1) (chromosome 15q24-q25.1), have been identified.86,87 Two unrelated patients have been reported with a symptom triad of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH syndrome)52, but with no identified mutations in the PSTPIP1 gene.52 Pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PAPASH syndrome) has been described54,53 and associated with a novel mutation of the PSTPIP1 gene.53

It has been proposed that HS belongs to the group of autoinflammatory diseases that are characterized by noninfectious recurrent inflammatory episodes, the absence of autoantibodies and antigen-specific T cells, and the presence of polymorphonuclear cell infiltrates. These disorders include Crohn’s disease (CD), pyoderma gangrenosum, acnelike syndromes, familial Mediterranean fever, tumor necrosis factor-receptor associated periodic syndrome, cryopyrin-associated periodic syndrome, pyogenic sterile arthritis, recurrent multifocal osteomyelitis, and Adaman5 tiades-BehcSet ́ disease. HS of the head and neck has been classified as a member of the follicular triad, together with acne conglobata and dissecting cellulitis of the scalp (perifolliculitis capitis). The follicular occlusion tetrad defines the aforementioned three diseases together with the pilonidal cyst.88 A given patient may have two or more disorders within the tetrad.89,90 Acne conglobata is a rare but severe form of acne comprised of multiple grouped comedones, inflammatory papules, tender, suppurative nodules that commonly coalesce to form sinus tracts on the trunk and arms. Perifolliculitis capitis is a chronic and progressive infection of the hair follicles of the scalp presenting with subcutaneous abscesses. At least eight reports have described the association of HS and Dowling-Degos disease that is a genetic syndrome characterized by acquired, reticulated, symmetric pigmentary macules of the flexural areas.60–63,42–44,64 Two case reports have reported an association of keratitis-icthyosisdeafness (KID) syndrome and HS.58,59 A single case series reported four patients with interstitial keratitis (IK)

404 among 62 HS patients. HS preceded IK by a mean of 7.2 years.57 The association of HS, spondyloarthropathy, and acne conglobata is well described.91–94,54,95–98 This association is seen predominantly in African American men and equally affects the axial and appendicular joints. It has a chronic course, with temporal concurrence between cutaneous and arthritic flare-ups.93 SAPHO syndrome is an acronym for synovitis, acne, pustulosis, hyperostosis, and osteitis. There are three proposed diagnostic criteria: (1) chronic recurrent multifocal noninfectious osteomyelitis with or without skin manifestations; (2) acute or chronic sterile arthritis associated with (a) pustular psoriasis or palmoplantar pustulosis, (b) acne, or (c) HS; (3) sterile osteitis in the presence of the aforementioned skin manifestations. Any of these three presentations is sufficient for diagnosis.87,49,99 In one study, 12 patients with SAPHO from three hospitals were analyzed, with seven having HS as part of the syndrome. Of the seven patients with HS six were African American, suggesting a possible predisposition in that population. HS in the presence of SAPHO may have more severe clinical manifestations compared to HS alone.49 Two additional case reports have been reported.50,51 An association between reflex sympathetic dystrophy or complex regional pain syndrome type 1 and HS has been reported in one patient.39 Five of six family members with Jackson-Lawler type pachyonychia congenita have reported to have a history of HS, with three of them having evidence of nodules, sinus tract formation, and scarring in the axillae. Pachyonychia congenita (PC) is a rare genodermatosis affecting ectodermal development. The Jackson-Lawler subtype is characterized by natal teeth presence, steatocystoma multiplex, and multiple epidermoid cysts on the trunk, axillae, neck, and scalp, in addition to pachyonychia. Palmar and plantar hyperkeratosis and blister development, hyperhidrosis and follicular hyperkeratosis, may also be present.40 A woman with PC and HS has been reported.41 Fox-Fordyce disease (FFD) is a rare pruritic disorder characterized by eruptions of small, discrete, flesh-colored papules located in the axillary, areolar, pubic, and sternal regions. Concurrent HS and FFD has been described in three African American women.38 The association of HS with inflammatory, peripheral oligoarthritis and seronegative spondyloarthropathy has been reported.93 It is hypothesized that the arthropathy may represent a reaction to chronic skin infection. There is a close association between flares of HS and exacerbation, as well as, severity of arthritis. Conversely, improvement of arthritis follows surgical therapy for HS.4 Isolated case reports of patients with Adamantiades65–69 BehcSet ́ disease and HS have been reported. The metabolic syndrome increases the risk of cardiovascular disorders, such as arteriosclerosis, coronary heart disease, myocardial infarction, and stroke. Its diagnosis

C. Dessinioti et al. is based on the presence of three or more of the following criteria, according to the United States National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III)100: (i) central obesity: Waist circumference ≥ 102 cm (men), ≥ 88 cm (women), (ii) hypo-HDL-cholesterolemia: Plasma HDL-cholesterol b 40 mg/dL (men), b 50 mg/dL (women), (iii) hypertriglyceridemia: Plasma triglyceride ≥ 1.695 mmol/l (≥ 150 mg/dL), (iv) hypertension: Blood pressure ≥ 130/85 mmHg or use of medication for hypertension, (v) hyperglycemia: Fasting plasma glucose ≥ 6.1 mmol/L (≥ 110 mg/dL) or use of medication for hyperglycemia. A hospital-based case-control study of 80 HS patients and 100 age- and sex-matched controls, showed that the average waist circumference, plasma TG levels, fasting plasma glucose levels, as well as the systolic and diastolic blood pressure were significantly higher in HS patients than in controls. The prevalence of central obesity (OR:5.88, 95% CI:2.93-11.91, P b .001), hypertriglyceridemia (OR:2.24, 95% CI: 1.11-4.54, P b .014), hypo-HDL-cholesterolemia (OR: 4.56, 95% CI: 2.21-9.46, P b .001), and hyperglycemia (OR:4.09, 95% CI: 1.59-10.84, P b .001) in HS patients were significantly higher than in controls. The metabolic syndrome was significantly more common in the patients than in controls (40.0% versus 13.0%, OR: 4.46, 95% CI: 2.02-9.96, P b .001).101 These results raise the question about the mechanisms underlying the increased frequency of the metabolic syndrome in HS patients. An hypothesis is that chronic inflammation promotes and enhances metabolic alterations; however, the severity and/or duration of disease were not associated with the metabolic parameters or metabolic syndrome in this study, suggesting that the magnitude of inflammation in HS is not associated with the metabolic syndrome. The authors proposed that the metabolic alterations might be the primary rather than a secondary pathologic event in these patients, ie, that they might trigger HS. In fact, the metabolic alterations can lead to poor blood circulation of respective skin areas. Hypoxia in turn induces IL-10 production in CD4 + T-cells, and IL-10 inhibits the production of IL-22, an important inducer of keratinocyte IL-20 production. Since IL-22 and IL-20 are major inducers of antibacterial proteins in epithelia, poor blood circulation would eventually lead to enhanced cutaneous bacterial persistence and the outbreak of AI.101 The link between HS and systemic associations may be attributed to common genetic or environmental factors, or shared inflammatory pathways.102 Having psoriasis, a wellstudied condition, as a paradigm, it has been reported that well established factors for cardiovascular disease (CVD) originate from inflammation in other tissues. Undeniably, inflammation is a risk factor for progressive development of atheroma and other vascular alterations. The profile of

Hidradenitis suppurativa as a systemic disease

405

cytokines in the skin of HS patients has not been well characterized, but there is evidence for overexpression of proinflammatory cytokines such as TNF-α17,34 and IL-8.17. The obesity of psoriasis has emerged as a key link with increased diabetes risk, with the metabolic syndrome, and increase cardiovascular risk. In addition to energy storage and lipid synthesis production, adipose tissue is an active endocrine organ with many secretory products, including adipocyte-derived hormones, adipokines (leptin, adiponectin), and a variety of proinflammatory cytokines, including IL-6 and TNF-α. Although the actions of TNF on adipocytes and monocytes are complex with respect to metabolic regulation, there is experimental evidence that TNF directly regulates insulin secretion and disrupts lipid synthesis, which are the central features of type 2 diabetes and obesity.102 The “obesity of HS” is yet to be unraveled, but the beneficial effect of anti-TNFα therapies in HS suggests an intriguing key role for TNFα in HS as well.

significant malignant associations included buccal cancer and primary liver cancer, but these findings were attributed to confounding by smoking and alcohol abuse.104 There are reports of 65 cases of SCC complicating HS.105 There is a need for studies with vigorous follow-up of HS patients for SCC development to provide data regarding the rate of SCC in these patients. HS has been shown to have a substantial negative impact on the patients’ quality of life and sexual health.106 An association of HS with an impact to the quality of life as assessed by the Dermatology Quality of Life Index (DLQI) has been reported. The basis for this association has been attributed to a combination of painful eruptions, malodorous discharge, stigma due to the location of lesions in intimate sites, and, until recently, the lack of medical care related to incorrect diagnosis or the hesitancy of patients to disclose the symptoms or signs of HS.107 Several studies have mentioned not only physical but also social and economic disabilities resulting from HS.5 One study found that patients with HS lost an average of 2.7 work days per year because of HS.108 A self-administered questionnaire study of 44 patients diagnosed with HS showed a significant impairment in sexual health compared to 41 age- and BMI-matched controls.106 A diagnosis of depression was found in 115 of 268 (42.9%) HS patients in a population-based U.S. study.9 A population-based study in Omsted County, Minnesota, investigated the potential association with other medical disorders. 268 confirmed HS patients were identified using the Rochester Epidemiology Project resources. The majority of these patients had mild HS, with 59.7% patients having Hurley stage I disease, 38.1% had Hurley stage II disease, and 2.2% had Hurley stage III disease. There were no significant associations identified between disease severity and BMI, depression, acne, or pilonidal disease. 9

Occurrence of systemic implications in HS

Conclusions

HS may have systemic implications on the physical, psychological, or sexual health of afflicted patients. There is a risk of serious infection depending on the location of lesions.5 It should be kept in mind that men with perineal fistula, bowel disease, scrotal or penile trauma, or past procedures are generally at increased risk for Fournier gangrene, a localized variant of necrotizing fasciitis caused by facultative and anaerobic organisms.103 Urethral fistulas and massive scrotal and vulvar lymphedema have also been reported in patients with HS.5 In addition, lymphedema of the pubis may develop (Figure 6). A large retrospective study with more than 2,000 subjects revealed that those with HS had a 50% increased risk in overall incidence of malignancy. A 4.6-fold increase in cutaneous SCC was observed in these patients. Other

The question if hidradenitis suppurativa could be considered as a systemic disease remains to be answered. The association of HS with other diseases is mostly based on isolated case reports or small case series failing to provide robust data for such an association. To quote Dr Roger Brinner, “the plural of anecdote is not data.” Based on welldesigned studies, HS has been associated with the metabolic syndrome and with excess body weight or obesity. The link between HS and systemic associations may be attributed to common genetic or environmental factors, or shared inflammatory pathways. HS has systemic implications, as it has been shown to have a substantial negative impact on the patients’ quality of life and sexual health.106 The answer to the question of whether HS is a systemic disease continues to elude us; however, it is a disease with

Fig. 6 Secondary lymphedema of the pubis in a patient with HS stage III.

406 considerable systemic implications for the afflicted patients. Further research in the context of well-designed, controlled studies in adequate number of HS patients is warranted to shed further light on this still understudied condition.

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