University of Groningen
Hidradenitis suppurativaDickinson-Blok, Janine Louise
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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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