University of Groningen. Hidradenitis suppurativa Dickinson-Blok, Janine Louise

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1 University of Groningen Hidradenitis suppurativa Dickinson-Blok, Janine Louise IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2015 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Dickinson-Blok, J. L. (2015). Hidradenitis suppurativa: From pathogenesis to emerging treatment options. [Groningen]: University of Groningen. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 1Introduction J.L. Dickinson-Blok 9

3 Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease affecting approximately 1-4% of the general population. 1 The disease is characterized by painful deep-seated nodules and abscesses. In a later stage, epitheliazed sinus tracts are formed in the dermis and subcutaneous fat. The lesions seen in HS are mainly restricted to the body folds, like the axillary, inguinal and anogenital regions. 2 These locations have several characteristics in common: 1) the skin contains apocrine glands, 2) a predisposition to mechanical friction and 3) humid conditions. Lesions commonly heal with hypertrophic fibrous scarring resulting in complete architectural loss, cosmetic disfigurement and in some cases even movement impairment. 3 Not surprisingly, patient s quality of life is impaired to a great extent. 4 In fact, it has been found that quality of life scores are worse in HS compared to other distressing chronic dermatoses like atopic dermatitis, psoriasis, Darier s disease and Hailey-Hailey disease. 5 In addition to their professional career, patient s intimate, sexual and social relationships are adversely affected by the disease. HS has also an impact on society, as it is associated with frequent and/or long-term sick leaves. 6 Due to embarrassment, ignorance and neglect of the patient, as well as a lack of knowledge of regarding HS under certain medical specialists, diagnostic delays of several years are not uncommon. 7,8 Pathogenesis The pathogenesis of HS is still largely unknown. The term hidradenitis suppurativa dates back to a time where it was assumed to be primarily a disease of the apocrine sweat glands. 3 Although, it is now generally accepted that the hair follicle is primarily involved while the associated apocrine gland is affected in only the minority of patients as a secondary event (figure 1). 9 The role of bacteria in this inflammatory process remains elusive. Fulminant discharge suggests bacterial involvement but cultures in microbiological studies have been shown to be negative or mainly revealed commensal bacteria of the skin or intestine, dependent on the investigated body location Psoriasiform hyperplasia, follicular hyperkeratosis and occlusion are early events in the disease process It has been suggested that these histopathological changes result from subclinical inflammation initiated by keratinocytes reacting to commensal skin bacteria. 16 Additionally, a recent study suggested that fragility of the sebofollicular junction (SFJ) as part of the folliculopilosebaceous unit (FPSU) could contribute to the inflammatory activity by a defect in the follicular basement membrane zone (BMZ) that allows the release of follicular content into the surrounding dermis. 17 Massive inflammation as a result of immune system activation occurs upon complete rupturing of the occluded hair follicle. 10

4 Epidermis FPSU Sebaceous gland Apocrine gland Hair follicle Dermis Subcutaneous fat Figure 1. The folliculopilosebaceous unit (FPSU) in the skin. * sebofollicular junction (SFJ) In addition, overproduction of interleukin (IL)-1b and tumor necrosis factor (TNF)-α from the innate immune system as well as IL-10, IL-12, IL-17 and IL-23 from the adaptive immune system have been demonstrated in HS skin. 18,19 Epithelialized sinus tracts may be formed from epithelial strands in the dermis in response to these cytokines. This may facilitate access for (commensal) bacteria, leading to repetitive inflammation, further extension of the disease, and subsequently a vicious circle is made with ever increasing architectural destruction. Unraveling what cytokines are predominant in the inflammatory cascade is an important step for a better understanding of the HS pathogenesis and for identifying therapeutic targets. Epidemiology The prevalence of HS varies between studies and is estimated to be 1-4% in Europe, these numbers are mostly derived from population based questionnaires. 20,21 Substantial lower prevalence rates were found in the United States, varying from to 0.078%. 22,23 Females are three times more often affected than men. 1,20,24 First symptoms typically occur in the second or third decades of life but disease onset during childhood is not exceptional

5 About 80% of HS patients has a history of smoking, making it a well-known risk factor for HS. 20,24,28,29 The exact pathogenic mechanism remains unclear, however, tobacco smoking may induce HS by promoting follicular occlusion, augmenting the innate immune system and triggering pro-inflammatory cytokine release. 30 The association between obesity and HS has also widely been recognized and may result from increased mechanical friction of the skin and inducing a pro-inflammatory state. 20,29,31 Both smoking and obesity are associated with higher disease severity. 31 The role of hormones in HS remains controversial, especially regarding androgens. Studies have shown that HS improves in women on anti-androgen therapy. 32,33 Also, HS rarely develops in postmenopausal women, a phase in life that is characterized by relative hypo-androgenism. 34 However, it has been demonstrated that free androgen levels are not consistently elevated in women with HS. 35 Multiple studies have suggested that HS is associated with several co-morbidities, including morbus Crohn, metabolic syndrome, hypertension, diabetes mellitus and polycystic ovarian syndrome (PCOS). 23,36-38 Finally, it has been recognized that HS runs in families, indicating that genetic factors are also important. (24) In fact, loss-of-function mutations in genes encoding for the g-secretase protein complex have been identified in familial HS. 39,40 Inactivation of g-secretase may result in altered Notch signaling which may promote the formation of epidermal cysts and contribute to the continuing inflammatory activity in HS by dysfunction of the innate immune system. 30 Classification and monitoring disease severity There is wide diversity in the clinical appearance of HS regarding severity, disease location and whether there is predomination of inflammatory nodules or sinus tracts and fistulas. The Hurley classification (grade I through III) is a well-known and commonly used system to express disease severity by determination of the character and the extensiveness of the lesions (figure 2)

6 Hurley I Localized disease. Single or multiple abscesses. No sinus tracts or scarring. Hurley II Recurrent abscesses. Single or multiple sinus tracts and scarring. Lesions separated by healthy skin. Hurley III Multiple interconnected abscesses and sinus tracts. Involvement of the entire affected area. Figure 2. The Hurley stages of lesions in HS. Although the Hurley classification is convenient to use in daily practice, its major disadvantage is that it is a static rather than a dynamic scoring system and therefore inappropriate for monitoring therapeutic effects over time. In recent years, several dynamic scoring systems have been developed, including the modified Sartorius score (mss) 29 and the Hidradenitis Suppurativa Clinical Response (HiSCR). 42 The recently proposed HiSCR is actually the first 13

7 score defining a validated practical clinical endpoint. 42 Unfortunately, in previous studies no uniformly applied clinical endpoint was applied to assess treatment effectiveness, making it difficult to compare these trials with each other. The identification of a specific biomarker for HS could support disease monitoring. Recent evidence suggests that the soluble IL-2 receptor (sil2r) and S100A8/A9 may be putative candidates for distinguishing HS patients from healthy controls. 43,44 However, more studies are needed to establish their usefulness in monitoring treatment efficacy and to identify other potential biomarkers. Treatment of HS Treatment of HS is a challenge as many patients are resistant to therapy. Recently Zouboulis et al. 45 developed a treatment guideline for HS. Although this guideline is of great help in ordering the currently available therapeutic options, the evidence for individual therapies remains relatively sparse. Three primary goals should be pursued in the treatment of HS: 1) to treat acute painful lesions, 2) to heal chronic lesions in the maintenance phase and 3) to prevent the development of new lesions. The main general therapeutic options are topical agents, systemic medication and surgical interventions. The strategy for achieving the treatment goals is dependent on the severity of HS and the expertise of the center of treatment. The Hurley classification is a practical tool to give direction to the choice of therapy. Topical therapies The only topical treatments that have been studied in HS are resorcin 15% cream and topical clindamycin. 46 These agents can be applied as monotherapy in Hurley stage I disease. In Hurley stage II or III disease it is mainly used as adjuvant or as maintenance therapy. Acute painful lesions may be treated with intralesional triamcinolon 0.1% acetonide 10 mg/ml. Systemic therapies Systemic agents comprise anti-inflammatory, immunosuppressive medication and retinoids. Systemic antibiotics are used for both their anti-inflammatory and anti-bacterial effect. These agents are indicated for Hurley II and III disease as well as in widely spread Hurley I disease. The choice for a specific systemic antibiotic is mainly dependent on clinical experience, as studies are still limited. Most evidence exists for oral tetracyclin and combinational therapy with clindamycin and rifampicin The systemic retinoids acitretin and isotretinoin were introduced to the therapeutic arsenal of HS based on their immunomodulatory effects and 14

8 their ability to normalize epithelial cell differentiation. Immunosuppressive therapy is indicated in severe inflammatory disease (Hurley stage II or III) and a wide variety of agents has been studied, including dapsone, methotrexate, ciclosporin and biologicals, like the TNF-α inhibitors infliximab and adalimumab. Unfortunately, the quality of performed studies is frequently poor and the number of randomized controlled trials is only limited. Therefore, consensus on what systemic agent is most effective in HS is still not achieved. Surgical treatment Surgery is required for Hurley stage II and III disease, as epithelialized cysts and sinus tracts will still remain present once inflammation has been treated. In the acute phase simple incision and drainage is appropriate for relieving pressure of acute painful abscesses. However, this is a symptomatic rather than a definite treatment, as lesions will recur. Therefore, surgical removal of all lesional tissue is the preferred approach in HS. Sparing healthy tissue to a maximum while lesional tissue is completely removed could be an appropriate surgical aim in HS. This aim may be achieved with the deroofing technique. 51,52 The so-called deroofing is a suitable technique for Hurley stage I or limited stage II disease as lesions are superficially removed. However, in severe HS deroofing does not suffice since lesions may extend into the subcutaneous fat. Furthermore, severe HS is frequently dominated by fibrotic tissue, which cannot be removed during deroofing. Removal of this tissue is of importance as it may contain skin appendages that serve as a source of recurrence, and prevent adequate wound contraction and subsequent healing. Therefore in moderate to severe HS, wide excision of the entire affected area is frequently used, especially by surgeons. 53 A disadvantage of this approach is that it causes large defects with a serious risk on contracture formation and long healing times. Surgery may be performed with cold steel, electrosurgery or a CO 2 laser. 52,54,55 Finally, several types of wound healing techniques have been proposed for HS, including healing by secondary intension or primary closure by sutures, skin grafts or flaps. 9 Exploring current and new surgical approaches in severe HS is needed to identify what techniques are superior regarding surgical outcomes in terms of radical lesional tissue removal, healing time and complications. In conclusion, treatment of HS is still difficult despite the numerous options, leading to frustration in both patients and in doctors. Studies are needed to investigate currently available treatments and to explore new systemic and surgical treatments for the development of general treatment guidelines. 15

9 AIMS AND OUTLINE OF THIS THESIS HS has a severe impact on quality of life and treatment is, despite the numerous options, in many cases still unsatisfactory. To develop new and improved treatment strategies, the fundamentals of the pathogenesis of HS need to be further unraveled. Furthermore, clinical trials are needed to investigate the effectiveness of (new) systemic and surgical treatments as well as to determine their therapeutic value in HS. The aims of this thesis are: To investigate the principles of the HS pathogenesis by focusing on histopathological changes of the hair follicle and to study the role of specific protein upregulation in the inflammatory cascade. To study the effectiveness of established and new systemic agents for the treatment of HS. To explore new surgical techniques to provide tools for clinicians dealing with HS. Chapter 2 describes the expression of the main glycoproteins at the basement membrane zone in pilosebaceous units of HS patients by performing immunofluorescence stainings on perilesional skin. In Chapter 3 an association between Down s syndrome and HS is hypothesized based on defective Notch signaling as a result of functional g-secretase deficiency. Chapter 4 describes the gene expression profile of hidradenitis suppurativa in skin and blood. In Chapter 5 we systematically review the current literature to explore the effectiveness of systemic treatment with immunosuppressive agents and retinoids in HS. In Chapter 6 the effectiveness and safety of the IL-12/IL-23 inhibitor ustekinumab is prospectively studied in HS patients. Chapter 7 and 8 focus on the skin tissue sparing excision with electrosurgical peeling (STEEP) technique as a surgical method for moderate to severe HS and describes its results over a time span of 14 years. Chapter 9 summarizes the main findings of this thesis and provides a general discussion for future studies. 16

10 REFERENCES 1. Jemec GB. Clinical practice. Hidradenitis suppurativa. N Engl J Med 2012; 366: Revuz J. Hidradenitis suppurativa. J Eur Acad Dermatol Venereol 2009; 23: Jemec G, Revuz J, Leyden J. Hidradenitis Suppurativa. Berlin: Springer-Verlag, Wolkenstein P, Loundou A, Barrau K, et al. Quality of life impairment in hidradenitis suppurativa: a study of 61 cases. J Am Acad Dermatol 2007; 56: Matusiak L, Bieniek A, Szepietowski JC. Psychophysical aspects of hidradenitis suppurativa. Acta Derm Venereol 2010; 90: Esmann S, Jemec GB. Psychosocial impact of hidradenitis suppurativa: a qualitative study. Acta Derm Venereol 2011; 91: Vazquez BG, Alikhan A, Weaver AL, et al. Incidence of Hidradenitis Suppurativa and Associated Factors: A Population-Based Study of Olmsted County, Minnesota. J Invest Dermatol 2013; 133: Mebazaa A, Ben Hadid R, Cheikh Rouhou R, et al. Hidradenitis suppurativa: a disease with male predominance in Tunisia. Acta Dermatovenerol Alp Panonica Adriat 2009; 18: Alikhan A, Lynch PJ, Eisen DB. Hidradenitis suppurativa: a comprehensive review. J Am Acad Dermatol 2009; 60:539-61; quiz Lapins J, Jarstrand C, Emtestam L. Coagulase-negative staphylococci are the most common bacteria found in cultures from the deep portions of hidradenitis suppurativa lesions, as obtained by carbon dioxide laser surgery. Br J Dermatol 1999; 140: Sartorius K, Killasli H, Oprica C, et al. Bacteriology of hidradenitis suppurativa exacerbations and deep tissue cultures obtained during carbon dioxide laser treatment. Br J Dermatol 2012; 166: Matusiak L, Bieniek A, Szepietowski JC. Bacteriology of Hidradenitis Suppurativa - Which Antibiotics are the Treatment of Choice? Acta Derm Venereol 2014;. 13. Jemec GB, Hansen U. Histology of hidradenitis suppurativa. J Am Acad Dermatol 1996; 34:

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13 39. 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: Wang B, Yang W, Wen W, et al. Gamma-secretase gene mutations in familial acne inversa. Science 2010; 330: Hurley HJ. Axiillairy hyperhidrosis, apocrine bromhidrosis, hidradenitis suppurativa, and familial benign pemphigus: surgical approach. In: Dermatologic Surgery(In: Roenigh, R.K. Roenigh, HH, ed): Marcel Dekker, New York, 1989; Kimball AB, Jemec GB, Yang M, et al. Assessing the validity, responsiveness and meaningfulness of the Hidradenitis Suppurativa Clinical Response (HiSCR) as the clinical endpoint for hidradenitis suppurativa treatment. Br J Dermatol 2014; 171: Matusiak L, Bieniek A, Szepietowski JC. Soluble interleukin-2 receptor serum level is a useful marker of hidradenitis suppurativa clinical staging. Biomarkers 2009; 14: Wieland CW, Vogl T, Ordelman A, et al. Myeloid marker S100A8/A9 and lymphocyte marker, soluble interleukin 2 receptor: biomarkers of hidradenitis suppurativa disease activity? Br J Dermatol 2013; 168: Zouboulis CC, Desai N, Emtestam L, et al. European S1 guideline for the treatment of hidradenitis suppurativa/acne inversa. J Eur Acad Dermatol Venereol 2015; 29: Clemmensen OJ. Topical treatment of hidradenitis suppurativa with clindamycin. Int J Dermatol 1983; 22: Jemec GB, Wendelboe P. Topical clindamycin versus systemic tetracycline in the treatment of hidradenitis suppurativa. J Am Acad Dermatol 1998; 39: Gener G, Canoui-Poitrine F, Revuz JE, et al. Combination therapy with clindamycin and rifampicin for hidradenitis suppurativa: a series of 116 consecutive patients. Dermatology 2009; 219: van der Zee HH, Boer J, Prens EP, Jemec GB. The effect of combined treatment with oral clindamycin and oral rifampicin in patients with hidradenitis suppurativa. Dermatology 2009; 219: Bettoli V, Zauli S, Borghi A, et al. Oral clindamycin and rifampicin in the treatment of hidradenitis suppurativa-acne inversa: a prospective study on 23 patients. J Eur Acad Dermatol Venereol 2014; 28:

14 51. van der Zee HH, Prens EP, Boer J. Deroofing: a tissue-saving surgical technique for the treatment of mild to moderate hidradenitis suppurativa lesions. J Am Acad Dermatol 2010; 63: van Hattem S, Spoo JR, Horvath B, et al. Surgical treatment of sinuses by deroofing in hidradenitis suppurativa. Dermatol Surg 2012; 38: Rompel R, Petres J. Long-term results of wide surgical excision in 106 patients with hidradenitis suppurativa. Dermatol Surg 2000; 26: Alharbi Z, Kauczok J, Pallua N. A review of wide surgical excision of hidradenitis suppurativa. BMC Dermatol 2012; 12: Madan V, Hindle E, Hussain W, August PJ. Outcomes of treatment of nine cases of recalcitrant severe hidradenitis suppurativa with carbon dioxide laser. Br J Dermatol 2008; 159:

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