University of Groningen

Hidradenitis suppurativaDickinson-Blok, Janine Louise

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Citation for published version (APA):Dickinson-Blok, J. L. (2015). Hidradenitis suppurativa: From pathogenesis to emerging treatment options.University of Groningen.

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9

1INTRoDUcTIoN

J.L. Dickinson-Blok

10

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.10-12 Psoriasiform hyperplasia, follicular hyperkeratosis and occlusion are early

events in the disease process.13-15 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.

11

Figure 1. The folliculopilosebaceous unit (FPSU) in the skin.

* sebofollicular junction (SFJ)

In addition, overproduction of interleukin (IL)-1β 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 0.053 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.25-27

Sebaceous gland

Apocrine gland

Hair follicle

FPSU

Epidermis

Dermis

Subcutaneous fat

12

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).41

13

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

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.

14

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.47-50 The systemic retinoids acitretin and isotretinoin were

introduced to the therapeutic arsenal of HS based on their immunomodulatory effects and

15

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 CO2 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.

16

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 1.

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.2.

To explore new surgical techniques to provide tools for clinicians dealing with HS. 3.

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.

17

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