University of Groningen
Hidradenitis suppurativaDickinson-Blok, Janine Louise
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HIDRADENITIS SUPPURATIVA FROM PATHOGENESIS TO EMERGING
TREATMENT STRATEGIES
Janine Louise Dickinson-Blok
ISBN: 978-90-367-8142-8
ISBN: 978-90-367-8141-1 (e-version)
© 2015 by J.L. Dickinson-Blok, Groningen, The Netherlands
Financial support for the publication of this thesis was provided by:
AbbVie BV, ALK-Abelló BV, Almirall, Celgene BV, Fagron BV, Flen Pharma, Galderma Benelux
BV, Janssen-Cilag BV, La Roche-Posay, Leo Pharma BV, Molnlycke Health Care, Rijksuniversiteit
Groningen, Studiefonds Dermatologie, Universitair Medisch Centrum Groningen, Will Pharma.
Design and layout: Arjan Veening, Id Graficus, Assen, The Netherlands
Printing: GVO drukkers & vormgevers B.V., Ede, The Netherland
HIDRADENITIS SUPPURATIVA FROM PATHOGENESIS TO EMERGING
TREATMENT STRATEGIES
PRoEfScHRIfT
ter verkrijging van de graad van doctor aan de
Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. E. Sterken
en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op
woensdag 30 september 2015 om 11.00 uur
door
Janine Louise Blok
geboren op 11 juli 1984
te Deventer
Promotor
Prof. dr. M.F. Jonkman
Copromotor
Dr. B. Horváth
Beoordelingscommissie
Prof. dr. B. van der Lei
Prof. dr. E.P. Prens
Prof. dr. G.B.E. Jemec
Paranimfen
Katarzyna Gostyńska
Ineke Janse
coNTENTS
List of abbreviations 7
Chapter 1. Introduction 9
Chapter 2. Increased expression of integrin α6β4 at the basement membrane 23
zone lining the sebaceous glands in hidradenitis suppurativa
Chapter 3. The possible association of hidradenitis suppurativa and Down 37
syndrome: are impaired Notch signaling and immunological
abnormalities the missing links?
Chapter 4. Gene expression profiling in skin and blood in hidradenitis 45
suppurativa
Chapter 5. Systemic therapy with immunosuppressive agents and retinoids 51
in hidradenitis suppurativa: a systematic review
Chapter 6. Ustekinumab in hidradenitis suppurativa: a clinical open label 79
study with analyses of the protein expression profile in serum
Chapter 7. Skin-tissue-sparing excision with electrosurgical peeling (STEEP): 97
a surgical treatment option for severe hidradenitis suppurativa
Hurley stage II/III
Chapter 8. Surgery under general anesthesia in severe hidradenitis 107
suppurativa: a study of 363 primary operations in 113 patients
Chapter 9. General discussion and future perspectives 125
Chapter 10. Dutch summary / Nederlandse samenvatting 137
Appendices List of publications 145
Dankwoord
Curriculum vitae
LIST of ABBREVIATIoNS
AE adverse event
BMZ basement membrane zone
DLQI daily life quality index
FPSU folliculopilosebaceous unit
HiSCR hidradenitis suppurativa clinical response
HS hidadenitis suppurativa
IF immunofluorescence
IFE interfollicular epidermis
IL interleukine
m-HSLASI modified hidradenitis suppurativa-lesion area and severity index
mSS modified Sartorius scale
PAS periodic acid–schiff
PGA physician’s global assessment
SFJ sebofollicular junction
STEEP skin tissue sparing excision with electrosurgical peeling
Th-cells T-helper cells
TNF-α tumor-necrosis-factor-α
VAS visual analogue scale
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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21
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23
2INcREASED ExPRESSIoN of INTEgRIN α6β4 AT THE BASEMENT MEMBRANE zoNE LININg THE SEBAcEoUS gLANDS IN HIDRADENITIS SUPPURATIVA
J.L. Blok, I.C. Janse, B. Horváth, M.F. Jonkman
Department of Dermatology, University Medical Center Groningen, University of Groningen,
Groningen, the Netherlands
Acta Derm Venereol. 2015 Jun 30. doi: 10.2340/00015555-2186. [Epub ahead of print]
24
ABSTRAcTThe pathogenesis of hidradenitis suppurativa (HS) is still elusive. A recent study of the
folliculopilosebaceous unit (FPSU) in HS patients showed that the basement membrane zone
(BMZ) of the sebofollicular junction was almost devoid of periodic acid–schiff (PAS) positive
material, a staining method for glycoproteins. By performing PAS and immunofluorescence
stainings for type XVII collagen, type VII collagen, laminin-332 and integrin α6β4 on skin
biopsies from body folds of patients and controls, we aimed to identify whether these
glycoproteins are differently expressed in HS. We found normal PAS staining along the
sebofollicular junction in HS, and could therefore not confirm any weakening of the BMZ.
Conversely, we demonstrated increased expression of integrin α6β4 lining the sebaceous
glands in HS patients. The other BMZ components were normally expressed. Enhanced
expression of integrin α6β4 along sebaceous glands in HS could result from alterations in the
skin microbioma and enhance inflammation.
25
INTRoDUcTIoNHidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent
painful nodules, abscesses, sinus tracts and scarring. The disease is primarily located at the
apocrine gland bearing skin, including the armpits and groins.1 Quality of life in HS patients is
severely affected due to the appearance of the skin, associated pain and the filthy odor that is
often secreted from the inflammatory lesions.2
The pathogenesis of HS has not been clarified yet. Several histological studies have shown
that the hair follicle is involved at an early stage of the disease process.3-6 These studies
demonstrated that follicular occlusion is present in the majority of patients, an event that
eventually results in rupturing of the hair follicle with subsequent inflammation and sinus
tract formation. However, the question remains what the driving mechanism behind this
follicular occlusion is. In a recent study, diminished periodic acid schiff (PAS) staining was
found at the basement membrane zone (BMZ) of the sebofollicular junction (SFJ) at the
folliculopilosebaceous units (FPSU) of HS patients.3 Since this deficiency was also found in
perilesional skin, the authors suggest that the PAS-negative gaps represent primary defects
in the BMZ leading to fragility of the hair follicle. Consequently there is release of follicular
contents into the dermis, triggering an inflammatory reaction. Diminished expression in one of
the glycoproteins in the BMZ of the SFJ might explain the PAS-gaps. However, there was not
stained for specific glycoproteins. The aim of this study was to document the expression of the
most important BMZ components, including type XVII collagen, type VII collagen, laminin-332,
and integrin α6β4, of the follicular epidermis relative to the interfollicular epidermis in HS, and
to compare the expression ratio with healthy controls.
26
MATERIAL AND METHoDS Design and setting
This study was performed at the department of Dermatology at the University Medical Center
Groningen. The local institutional review board approved the study.
Patients
Patients who were scheduled for surgical treatment of HS with the deroofing technique or
the STEEP procedure4,5 were included after written informed consent was obtained. Healthy
volunteers were considered eligible for participation when they had no skin disease at the
armpits and had given written informed consent. The age of all individuals was 18 years or
older.
Collection procedure
Up to 17 perilesional samples were obtained from axillary or inguinal HS skin by four mm
punch biopsy, immediately frozen in liquid nitrogen, and subsequently stored at -80 degrees
Celsius. Additionally, after injection with local anaesthesia consisting of 1cc 1% lidocaine/
adrenaline (1: 200.000), four mm punch biopsies were obtained from axillary skin of eight
healthy volunteers that served as controls. Skin samples lacking an associated sebaceous gland
with the hair follicle were excluded.
Staining procedure
PAS staining of the skin samples was performed. Briefly, after periodic acid solution oxidation,
tissue sections were immerged in Schiff’s reagent and counterstained with hematoxylin.
Immunofluorescence (IF) staining for type XVII collagen, type VII collagen, laminin 332,
integrin α6 and β4 was performed. The procedures for IF staining and image collection
have been described in detail previously.6 The following monoclonal antibodies were used:
VK1 against type XVII collagen (dr. H. H. Pas, Groningen, The Netherlands), LH7:2 against
collagen type VII (gift from Dr I. Leigh, London, UK), K140 against laminin β3 (gift from
dr. M. Marinkovich, Stanford, U.S.A.), 58xβ4 against integrin β4 (gift from dr. Sonnenberg,
Amsterdam, Netherlands) and GOH3 against integrin α6 (gift from dr. Sonnenberg,
Amsterdam, Netherlands). Fluorescein-conjugated goat anti rat IgG (Southern Biotechnology
Associates, Birmingham, U.S.A) and Alexa 488-conjugated goat anti mouse IgG (Molecular
Probes, Eugene, U.S.A) were used as secondary steps.
27
Assessments and statistical analysis
The intensity of the stainings was measured at the 6 segments of the FPSU: 1) the interfolliclar
epidermis (IFE), 2) the superior segment (SS) of the hair follicle, 3) the inferior segment (IS) of
the hair follicle, 4) the sebofollicular junction (SFJ) and 5) the sebaceous gland (SG). The SS was
defined as the part of the hair follicle extending from the IFE to the SFJ. The IS was defined as
the part extending from the SFJ to the bulb. The SFJ was defined as the transition zone from
the hair follicle to the sebaceous gland. The SFJ of skin samples stained with IF was identified
by the presence of fat globules characteristic of the sebaceous gland and by comparison of the
skin sample with the PAS staining of that same biopsy. For each skin sample the intensity of
all performed PAS and IF stainings at the aforementioned individual segments were analyzed
using Image J software. Subsequently, the ratio of individual segments to the IFE was calculated
for both the PAS and IF stainings, with the IFE serving as an internal control for each skin
sample. The Mann-Whitney U test was performed to compare the differences in these ratios
between patients and controls.
28
RESULTS Skin biopsies were obtained from a total of 17 HS patients and eight controls. Biopsies of ten
patients and two controls were excluded due to the lack of an associated sebaceous gland.
Eventually, biopsies of seven HS patients (two women, five men) and six controls (three
women, three men) were studied.
PAS staining
As previously described by Danby et al.3 the IFE showed a continuous and regular PAS staining
pattern in all biopsies with a mean intensity of 143.8 pixels (SD 11.6) in controls and 150.0
pixels (SD 10.5) in patients. Therefore, the IFE served as a suitable internal control. There
were no statistically significant differences between the ratios of the mean intensity of the PAS
staining at the individual segments of the FPSU to the IFE in patients and controls (figures.
1-2).
Type VII collagen, type XVII collagen, laminin 332
For these IF stainings no statistically significant differences were found between patients and
controls in the ratios of the mean staining intensity at the individual FPSU segments to the IFE.
Integrin β4 and α6
At the sebaceous gland, the mean intensity of integrin β4 declined compared to the IFE in
both patients and controls (figures. 1-2). The ratio of the mean intensity of integrin β4 at the
sebaceous gland to the IFE was significantly higher in patients (0.41) compared to controls
(0.14) (p=0.004). This implicates that integrin β4 expression at the sebaceous gland was
relatively higher in patients. IF-staining for integrin α6 also revealed a significantly (p=0.011)
higher level of expression at the sebaceous gland in HS compared to controls (figures. 1-2). It
is plausible that the expression patterns of integrin α6 en β4 followed the same pattern, since
they are dimerized in the integrin α6β4-complex. The relative expression of integrin α6β4 was
not altered at the remaining FPSU segments in HS compared to controls.
29
Figure 1. PAS and IF staining of the IFE and SFJ/SG in control and patient skin.
There were no differences in the intensity of the PAS staining between the IFE and the SFJ/SG
in both controls and patients. The ratio of the staining intensity of integrin α6 and β4 of the
SG to the IFE is higher in patients than in controls. Scale bar = 20 µm.
Control skin
Patient skin
IFE
SS
IS
SFJSG
PAS Integrin β4 Integrin α6
Integrin α6PAS Integrin β4
IFE
SS
SFJSG
IS
30
Figure 2. Ratio of PAS and integrin α6β4 expression compared to the IFE.
The bars represent the ratio of the mean PAS and integrin α6β4 staining intensities of the
individually assessed folliculopilosebaceous segments to the IFE.
IFE: interfollicular epidermis; SS: superior segment; SFJ: sebofollicular junction; SG: sebaceous
gland; IS: inferior segment. *statistically significant difference
1,1 1
0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1
0
Rat
io s
egm
ent
to IF
E
FPSU segment
PAS PatientControls
1,1 1
0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1
0
Rat
io s
egm
ent
to IF
E
FPSU segment
Integrin β41,1
1 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1
0
Rat
io s
egm
ent
to IF
E
FPSU segment
Integrin α4
31
DIScUSSIoN This study demonstrates that integrin α6β4 was relatively upregulated along the BMZ of the
sebaceous glands in HS patients. In contrast to Danby et al,3 reduced PAS positivity at the
SFJ in HS was not observed, neither did we find any differences in PAS positivity within the
remaining hair follicle segments. Therefore, we cannot confirm that BMZ fragility at the SFJ is
responsible for leakage of follicular content into the surrounding dermis.
One can speculate about the cause and consequences of integrin α6β4 upregulation in HS.
Integrins are a family of heterodimeric glycosylated transmembrane receptors. They come
primarily to expression in organs lined with stratified epithelium, like the skin and lungs. In
human epidermis, integrin expression is restricted to the basal layer.7 The β4 integrins are
primarily found at the basement membrane zone where they are located transmembranous
in hemidesmosomes. In addition to an adhesive function, integrins are important signaling
molecules that have bidirectional actions. Integrins show affinity to several extracellular proteins
and are therefore involved in a variety of pathological processes, including oncogenesis,
immune responses and inflammatory reactions.8,9 In HS integrines possibly have a cell
signaling function. For instance, previous studies on pulmonary tissue have demonstrated
that integrin β4 expression increased upon binding with pathogenic microorganisms.8,10 It has
been hypothesized that integrines, just as toll-like receptors, function as pattern recognition
receptors (PRRs) that upon interaction with bacteria induce cellular responses that acitivate
the innate immune system and inflammation.8 The role of bacteria in the pathogenesis of HS
is still elusive, as previous microbiological studies found a wide range of bacteria associated
with HS.11-13 However, new molecular techniques using a genomic approach revealed that
there is greater bacterial diversity in the skin than previously assumed based on results of
culturing methods.14 Van der Zee et al,15 hypothesized that alterations in the microbioma
of HS skin stimulate keratinocytes to produce antimicrobial peptides and pro-inflammatory
cytokines, resulting in the typical histological changes observed early on in the disease process.
Additionally, alterations in the microbioma could explain why HS lesions are mainly localized
at the body folds, as the bacterial community is different in these moist areas compared to the
relatively dry areas of the body.14,16 Similar to lung tissue, changes in the bacterial community
are possibly responsible for the integrin α6β4 upregulation we found in HS patients and may
contribute to activation of the immune system. Finally, increased expression of α6β4 may also
contribute to the development of squamous cell carcinoma (SCC), a well-known complication
of HS.17,18 In fact, mice with aberrant α6β4 expression showed a greater infiltration of
immunosuppressive cells during tumor promotion, a phenomenon that may contribute to the
susceptibility of SCC formation.18
32
In conclusion, in this study we demonstrate that integrin α6β4 is upregulated in sebaceous
glands of HS patients. This upregulation could result from alterations in the skin microbioma
and may contribute to the inflammatory reaction seen in HS as well as to the increased risk of
SCC development in HS. Integrin α6β4 could therefore be a putative treatment target for HS in
the future. Characterization of the skin microbioma in more detail could provide further insight
in the role of bacteria in HS and may provide a rationale for specific antibiotic treatments.
33
REfERENcES
Jemec GB. Clinical practice. Hidradenitis suppurativa. 1. N Engl J Med 2012; 366:158-164.
Matusiak L, Bieniek A, Szepietowski JC. Psychophysical aspects of hidradenitis suppurativa. 2.
Acta Derm Venereol 2010; 90:264-268.
Danby FW, Jemec GB, Marsch WC, von Laffert M. Preliminary findings suggest hidradenitis 3.
suppurativa may be due to defective follicular support. Br J Dermatol 2013;168:1034-1039.
Blok JL, Spoo JR, Leeman FW, Jonkman MF, Horvath B. Skin-Tissue-sparing Excision with 4.
Electrosurgical Peeling (STEEP): a surgical treatment option for severe hidradenitis suppurativa Hurley
stage II/III. J Eur Acad Dermatol Venereol 2015; 29:379-382.
van Hattem S, Spoo JR, Horvath B, Jonkman MF, Leeman FW. Surgical treatment of sinuses by 5.
deroofing in hidradenitis suppurativa. Dermatol Surg 2012; 38:494-497.
Vodegel RM, Jonkman MF, Pas HH, de Jong MC. U-serrated immunodeposition pattern differentiates 6.
type VII collagen targeting bullous diseases from other subepidermal bullous autoimmune diseases.
Br J Dermatol 2004;151:112-118.
Oldak M, Smola-Hess S, Maksym R. Integrin beta4, keratinocytes and papillomavirus infection.7.
Int J Mol Med 2006;17:195-202.
Ulanova M, Gravelle S, Barnes R. The role of epithelial integrin receptors in recognition of pulmonary 8.
pathogens. J Innate Immun 2009; 1:4-17.
Berman AE, Kozlova NI. Integrins: structure and functions. 9. Membr Cell Biol 2000;13:207-44.
Gravelle S, Barnes R, Hawdon N, Shewchuk L, Eibl J, Lam JS, et al. Up-regulation of integrin 10.
expression in lung adenocarcinoma cells caused by bacterial infection: in vitro study. Innate Immun
2010;16:14-26.
Lapins J, Jarstrand C, Emtestam L. Coagulase-negative staphylococci are the most common bacteria 11.
found in cultures from the deep portions of hidradenitis suppurativa lesions, as obtained by carbon
dioxide laser surgery. Br J Dermatol 1999; 140:90-95.
Sartorius K, Killasli H, Oprica C, Sullivan A, Lapins J. Bacteriology of hidradenitis suppurativa 12.
exacerbations and deep tissue cultures obtained during carbon dioxide laser treatment. Br J Dermatol
2012; 166:879-83.
34
Matusiak L, Bieniek A, Szepietowski JC. Bacteriology of Hidradenitis Suppurativa - Which Antibiotics 13.
are the Treatment of Choice? Acta Derm Venereol 2014; 94:699-702.
Grice EA, Segre JA. The skin microbiome. 14. Nat Rev Microbiol 2011; 9:244-53.
van der Zee HH, Laman JD, Boer J, Prens EP. Hidradenitis suppurativa: viewpoint on clinical 15.
phenotyping, pathogenesis and novel treatments. Exp Dermatol 2012; 21:735-39.
SanMiguel A, Grice EA. Interactions between host factors and the skin microbiome. 16. Cell Mol Life Sci
2015; 72:1499-1515.
Lavogiez C, Delaporte E, Darras-Vercambre S, et al. Clinicopathological study of 13 cases of 17.
squamous cell carcinoma complicating hidradenitis suppurativa. Dermatology 2010; 220:147-53.
Maalouf SW, Theivakumar S, Owens DM. Epidermal alpha6beta4 integrin stimulates the influx of 18.
immunosuppressive cells during skin tumor promotion. J Dermatol Sci 2012; 66:108-18.
35
37
3THE PoSSIBLE ASSocIATIoN of HIDRADENITIS SUPPURATIVA AND DowN SyNDRoME: ARE IMPAIRED NOTCH SIGNALING AND
IMMUNOLOGICAL ABNORMALITIES THE MISSING
LINKS?
J.L. Blok1, M.F. Jonkman1, B.Horváth1
1Department of Dermatology, University of Groningen, University Medical Center Groningen,
Hanzeplein 1, 9700 RB Groningen, the Netherlands
Published in the British Journal of Dermatology, 2014; 170:1375-77
38
ABSTRAcTHidradenitis suppurativa (HS) is an inflammatory skin disease of unknown origin. Recently, it
has been demonstrated that mutations in several genes encoding for the protease g-secretase
(GS), including presenilin-1 (PSEN1), probably play a major role in the pathogenesis through
impairment of the Notch signaling pathway. Mutations in PSEN1 are also associated with
Alzheimer’s disease (AD), a condition that is strongly related to Down syndrome (DS). HS
occuring in patients with DS has been described in only five patients so far. Here we describe
five new cases. An association between HS and DS is reasonable since trisomy of chromosome
21 leads to overexpression of the amyloid precursor protein (APP) resulting in a change of the
substrate pool for GS processing at the expense of the Notch receptors. Consequently, Notch
signaling is impaired in DS predisposing these individuals to HS. APP itself may also directly
influence keratinocytes resulting in the typical histopathological features seen in HS. Finally,
the relatively high prevalence of obesity amongst DS patients as well as alterations in their
immune system could underlie the possible association between both conditions. To confirm
our hypothesis, further studies are needed investigating the expression of Notch receptors and
APP in the epidermis of DS patients.
39
Hidradenitis suppurativa (HS) is an inflammatory skin disease that usually arises after puberty
and severely impairs quality of life. Smoking, obesity, genetics and abnormalities of the immune
system are important risk factors for the development of HS.(1) The latter makes that the
disease is generally responsive to immunosuppressive agents, including to tumor-necrosis-factor
(TNF)-α inhibitors.1 Our knowledge regarding the pathogenesis, risk factors and treatment may
be further enhanced by studying conditions that tend to co-occur with HS. Here, we describe
five cases where HS occurred in Down syndrome (DS). The cases are summarized in table 1
and figure 1. The disease characteristics and course of patients 1-3 have several similarities:
they have therapy resistant disease located at the (ano)genital area and a pre-pubertal onset.
Patients 4 and 5 are monozygotic twins whose other family members were not affected by HS.
DS is caused by trisomy of chromosome 21 and occurs in approximately 1 of 1000 newborns.
The co-occurrence of HS and DS has previously been described in three men and two
women.2-4 The phenotype of DS is complex and includes a broad range of cognitive and
neurological deficits. Two hypotheses have been proposed regarding the cause of the DS
phenotype: the “developmental instability hypothesis” states that developmental pathways
are disrupted through a general genetic imbalance whereas the “gene-dosage theory” implies
that increased expression of certain genes on chromosome 21 is responsible. We think that the
genetic abnormalities of DS might also predispose these individuals to the development of HS.
Previously, loss-of-function mutations in the genes encoding for the g-secretase (GS) complex
have been identified in familial HS, including nicastrin (NCSTN), presenilin-1 (PSEN1) and
presenilin enhancer 2 (PSENEN).5 GS is a transmembranous enzyme complex that enhances
intracellular Notch signaling by cleavage of the Notch receptor (figure. 2). Humans have four
Notch receptors of which Notch-1 and Notch-2 are predominantly expressed in the epidermis.6
GS-deficiency and inhibition of Notch-1 and -2 in mice causes replacement of hair follicles
by epidermal cysts and diminished sebaceous gland differentiation, which are typical features
of HS.5 Impaired Notch signaling also inhibits the generation of natural killer cells and causes
an insufficient suppression of the innate immune system once it is activated, resulting in a
compromised defense mechanism and continuing inflammatory activity, respectively.5 GS is
also a key player in the development of Alzheimer’s disease (AD). By the fourth decade of life
characteristic β-amyloid (Aβ) brain plaques start to develop in DS that eventually give rise to
AD. Aβ is a product resulting from GS-cleavage of the amyloid precursor protein (APP). APP
is also strongly expressed in the human epidermis.7 The gene encoding for APP has shown to
be located on chromosome 21 and its expression is therefore, in accordance with the “gene
dosage hypothesis,” probably increased in DS. APP and one of its other cleavage products
sAPPα (secretory N-terminal ectodomain of APP) stimulate keratinocyte adhesion, migration
40
and proliferation.7 This makes DS patients prone to keratinocyte hyperproliferation and
follicular plugging, which are major histopathological features of HS. Furthermore, Berezovska
et al.8 demonstrated that APP and the Notch receptor are competitive substrates for GS and
that Notch-1 signaling was diminished in primary neurons overexpressing APP. The increased
amounts of APP that need to be processed by GS in DS might therefore occur at the expense
of Notch processing. The genes encoding for the Notch receptors and GS are in contrast to APP
not located on chromosome 21. Thus, increased APP expression might represent the missing
link between HS and DS by enhancing keratinocyte activity as well as by being a competitive
substrate for Notch receptors, leading to impairment of Notch-1 and -2 signaling (figure. 2).
Finally, obesity and a dysregulated immune system might also contribute to an association
between DS and HS. The majority of the patients in our case series were overweight or obese
(four out of five patients). Indeed, the prevalence of obesity is higher in children with DS
compared to healthy children, making them more prone for the development of HS as well
as to a more severe course of the disease. Additionally, DS patients are more susceptible to
the development of infections and autoimmune disorders, like celiac disease, due to intrinsic
immunological defects.9 With five new cases we strengthen the thought that DS and HS are
associated. We hypothesize that this results from increased APP expression, an altered immune
system and increased prevalence of obesity in DS. Further studies comparing the expression of
Notch receptors and APP in the epidermis of DS patients and controls are needed to confirm
our hypothesis.
Patient 1 Patient 2 Patient 3 Patient 4a Patient 5a
Seks Female Female Male Female Female
Age (years) 14 16 13 24 24
Age at disease onset (years) 9 10 13 20 20
BMI (kg m-2) 33.1 22.9 27.1 35.2 37.2
Family history Negative Negative Negative Negativeb Negativeb
Location affected by HS Genital area Anogenital area Genital area and upper
legs
Armpits and groins Armpits and groins
Treatment history SA, anti-androgens,
prednisone,
etanercept, infliximab,
surgery
SA, i.l. Corticosteroids,
surgery
TA, SA SA, surgery SA, surgery
Current treatment infliximab 5 mg kg-2
every 4 weeks
i.l. Corticosteroids Doxycycline 100 mg
daily
None None
aMonozygotic twin sisters; bexcept for the monozygotic twin sister no other family members were affected. BMI, body mass index; HS,
hidradenitis suppurativa; i.l., intralesional; SA, systemic antibiotics; TA, topical antibiotics.
Table 1. Characteristics of the patients with Down syndrome
41
Figure 1. (a) Patient 1 with erythematous nodules, fistulae and scarring located on the genital area, before treatment
with infliximab. (b) Four months later after four infusions of infliximab; the hidradenitis suppurativa has improves to some
extent but there are still multiple active nodules and fistulae present.
Figure 2. (a) Normal situation: amyloid precursor protein (APP) and the Notch receptor are both processed by g-secretase
(GS). APP is cleaved by GS whereupon β-amyloid (Aβ) is released. The Notch receptor is also cleaved by GS leading
to the release of the nuclear intracellular domain (NICD). NICD enters the nucleus where it activates the transcription
factor for the Notch target genes that enhance epidermal differentiation and immune regulation. (b) patients with Down
syndrome: increased expression of APP changes the substrate pool of GS. Increased amounts of GS are required for APP
processing occurring at the expense of the Notch receptor. This leads to a “functional GS deficiency” for Notch processing
whereupon the release of the NICD is prevented resulting in impaired intracellular Notch signaling.
GS GS
Notchreceptor
Notchreceptor
NICD
NICD
NICD
NICD
NICD
extracellular
intracellular
Nucleus
NICD
extracellular
intracellular
Nucleus
Aβ
Aβ
Aβ
(a) (b)
(a) (b)
42
REfERENcES
Alikhan A, Lynch PJ, Eisen DB. Hidradenitis suppurativa: a comprehensive review. 1.
J Am Acad Dermatol 2009; 60:539-61; quiz 562-3.
Borbujo Martinez J, Bastos Amigo J, Olmos Carrasco O, et al. Suppurative hidradenitis in Down’s 2.
syndrome. Apropos of three cases. An Esp Pediatr 1992; 36:59-61.
Mebazaa A, Ben Hadid R, Cheikh Rouhou R, et al. Hidradenitis suppurativa: a disease with male 3.
predominance in Tunisia. Acta Dermatovenerol Alp Panonica Adriat 2009; 18:165-72.
Mengesha YM, Holcombe TC, Hansen RC. Prepubertal hidradenitis suppurativa: two case reports and 4.
review of the literature. Pediatr Dermatol 1999; 16:292-96.
Melnik BC, Plewig G. Impaired Notch-MKP-1 signalling in hidradenitis suppurativa: an approach to 5.
pathogenesis by evidence from translational biology. Exp Dermatol 2013; 22:172-77.
Massi D, Panelos J. Notch signaling and the developing skin epidermis. 6. Adv Exp Med Biol
2012; 727:131-41.
Herzog V, Kirfel G, Siemes C, Schmitz A. Biological roles of APP in the epidermis. 7. Eur J Cell Biol
2004; 83:613-24.
Berezovska O, Jack C, Deng A, et al. Notch1 and amyloid precursor protein are competitive substrates 8.
for presenilin1-dependent gamma-secretase cleavage. J Biol Chem 2001; 276:30018-23.
Kusters MA, Verstegen RH, Gemen EF, de Vries E. Intrinsic defect of the immune system in children 9.
with Down syndrome: a review. Clin Exp Immunol 2009; 156:189-93.
43
45
4gENE ExPRESSIoN PRofILINg IN SKIN AND BLooD IN HIDRADENITIS SUPPURATIVA
J.L. Blok1, K. Li2; C. Brodmerkel2; B. Horváth1, M.F. Jonkman1
1. Department of Dermatology, University Medical Center Groningen, University of Groningen,
Groningen, the Netherlands 2. Janssen Research & Development, LLC, Spring House, PA, U.S.A.
Submitted
46
Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by recurrent
abscesses, nodules and sinus tract formation that is mainly localized in the body folds.
The pathogenesis of HS is poorly understood. Mutations in genes encoding for essential
compounds of the transmembrane protease g-secretase, including NCSTN, PSEN1 and PSENEN,
have been identified in familial HS.1,2 These mutations may result in impaired Notch signaling
promoting cyst formation and continuing inflammatory activity.3 Additionally, certain single
nucleotide polymorphisms (SNPs) at the promoter region of the tumour necrosis factor - alpha
(TNF-α) gene were found to be associated with a greater susceptibility for the development
of HS as well as to influence the natural course of the disease.4 Furthermore, elevated levels of
IL-1, TNF-α and IL-10 were demonstrated in both lesional and perilesional skin of HS patients,5
and increased expression of the IL-23/Th-17 pathway was found in lesional skin.6 However, the
mechanism behind these pro-inflammatory changes in HS is still largely unknown.
To acquire a better understanding of the molecular pathogenesis of HS, we performed mRNA
microarray studies to compare gene expression in lesional skin to healthy skin of HS patients.
Also, the gene expression profile in whole blood of patients and unaffected individuals was
determined.
Seventeen HS patients were included. Whole blood was collected from all subjects and ten
healthy controls. Skin biopsies of 3 mm were obtained from inflammatory lesions in all 17
patients. Additionally, an extra biopsy from clinically healthy skin of the upper arm or leg was
obtained from 13 patients. The skin samples were immediately frozen in liquid nitrogen and
subsequently stored at -80 degrees Celsius. mRNA was extracted from skin samples using the
Qiagen RNeasy Fibrous Tissue Mini Kit (Qiagen Inc., Valencia, CA) and from whole blood with
the Qiagen PAXgene blood RNA kit according to the manufacturer’s instructions. RNA was
hybridized to the GeneChip HT HG-U133+ PM Array (Affymetrix, Santa Clara, CA). Pathway
analyses were conducted with QIAGEN’s Ingenuity Pathway Analysis (IPA®, www.qiagen.com/
ingenuity). Array Studio software version 8.0 (OmicSoft Corp., St. Morrisville, NC) was used
to analyze microarray data. Dysregulated genes were identified using a general linear model.
Expression modulation with a fold change >2 or <-2 and an FDR-adjusted p-value < 0.05 were
considered significant.
A significant difference was observed in mRNA expression between lesional and clinically
healthy skin of HS patients, with over 1145 probe sets representing over 800 genes having
at least a two-fold change (p <0.05). Patients with the most dysregulated gene profile were
more likely to have longstanding disease (>15 years) (figure 1a). Pathway analyses of the
modulated genes were mostly related to inflammation, including cell adhesion, diapedesis and
47
extravasation as well as immune cell signaling and communication pathways (figure 1b). An
interesting finding is involvement of the atherosclerosis signaling pathway in lesional HS skin
as it supports the current thought that the inflammatory response in HS is associated with
metabolic syndrome.7 Expression of NCSTN, PSEN1 and PSENEN was not modulated in lesional
compared to clinically healthy skin of patients. No significant differences were identified in
whole blood mRNA expression between patients (N=17) and healthy controls (N=10) (data not
shown).
In summary, we demonstrated significant altered gene expression in lesional HS skin compared
to clinically healthy skin of patients. This, in addition to the finding that whole blood RNA
expression did not differ between HS patients and healthy subjects, implicates that activated
cells in HS reside in affected tissue. This may be due to migration of leucocytes from the
circulation into skin tissue in response to released inflammatory chemokines. Our results
implicate that the inflammatory reaction is restricted to the skin of specific anatomical areas
and HS may therefore be considered as a localized rather than a generalized skin disease.
However, our results must be interpreted with caution as the sample size was relatively
small. Regardless whether local dysregulation of the atherosclerotic pathway is caused by the
inflammatory process or a secondary event due to an unhealthy lifestyle, the clinician should
be aware of metabolic syndrome in HS patients as early detection and treatment may prevent
cardiovascular complications. As perilesional skin of HS patients already shows histological
abnormalities,8 one may hypothesize that the skin type of HS patients in general is genetically
different from normal human skin, making patients prone to the development of HS lesions
under certain mechanical and lifestyle triggers. Therefore, investigating differences in gene
expression between clinically healthy skin from predilection sites of HS patients and skin of
unaffected individuals from the same sites would be an interesting additional study.
48
Skin typeDisease duration
-3.00 3.00
5 15
0 2 4 6 8 10 12 14 16 18
- log (p-value)
Granulocyte Adhesion and Diapedesis
Agranulocyte Adhesion and Diapedesis
Atherosclerosis Signaling
Hepatic Fibrosis /Hepatic Stellate Cell Activation
Primary Immunodeficiency Signaling
Communication between Innate and Adaptive Immune Cells
Dendritic Cell Maturation
Complement System
Systemic Lupus Erythematosus Signaling
Leukocyte Extravasation Signaling
Non lesional Lesional
Figure 1. (a) The heat-map of differentially expressed genes in HS skin based on mRNA microarray analysis. A significant
difference was observed in mRNA expression between lesional (grey boxes) and non-lesional patient skin (red boxes).
Patients with the most dysregulated gene profile were more likely to have longstanding disease.
(b) The top ten canonical pathways involved in the disease profile of patient skin.
(a)
(b)
49
REfERENcES
Wang B, Yang W, Wen W, et al. Gamma-secretase gene mutations in familial acne inversa. 1. Science
2010; 330:1065.
Pink AE, Simpson MA, Brice GW, et al. PSENEN and NCSTN mutations in familial hidradenitis 2.
suppurativa (Acne Inversa). J Invest Dermatol 2011; 131:1568-70.
Melnik BC, Plewig G. Impaired Notch-MKP-1 signalling in hidradenitis suppurativa: an approach to 3.
pathogenesis by evidence from translational biology. Exp Dermatol 2013; 22:172-77.
Savva A, Kanni T, Damoraki G, et al. Impact of Toll-like receptor-4 and tumour necrosis factor gene 4.
polymorphisms in patients with hidradenitis suppurativa. Br J Dermatol 2013; 168:311-17.
van der Zee HH, de Ruiter L, van den Broecke DG, et al. Elevated levels of tumour necrosis factor 5.
(TNF)-alpha, interleukin (IL)-1beta and IL-10 in hidradenitis suppurativa skin: a rationale for targeting
TNF-alpha and IL-1beta. Br J Dermatol 2011; 164:1292-98.
Schlapbach C, Hanni T, Yawalkar N, Hunger RE. Expression of the IL-23/Th17 pathway in lesions of 6.
hidradenitis suppurativa. J Am Acad Dermatol 2011; 65:790-98.
Gold DA, Reeder VJ, Mahan MG, Hamzavi IH. The prevalence of metabolic syndrome in patients with 7.
hidradenitis suppurativa. J Am Acad Dermatol 2014; 70:699-703.
van der Zee HH, de Ruiter L, Boer J, et al. Alterations in leucocyte subsets and histomorphology in 8.
normal-appearing perilesional skin and early and chronic hidradenitis suppurativa lesions.
Br J Dermatol 2012; 166:98-106.
51
5SySTEMIc THERAPy wITH IMMUNoSUPPRESSIVE AgENTS AND RETINoIDS IN HIDRADENITIS SUPPURATIVA: A SYSTEMATIC REVIEW
J.L. Blok1, S. van Hattem1, M.F. Jonkman1, B.Horváth1
Department of Dermatology1, University of Groningen, University Medical Center Groningen,
Groningen, The Netherlands
Published in the British Journal of Dermatology, 2013;168:243-52
52
ABSTRAcTHidradenitis suppurativa (HS) is a difficult disease to treat. Although the pathogenesis of
this inflammatory skin disease is largely unknown, the important role of the immune system
has been demonstrated in both experimental and clinical studies. Clinicians are therefore
increasingly prescribing systemic treatments with immunosuppressive agents, but the more
traditional systemic retinoids, especially isotretinoin, also remain relatively common therapies.
In order to provide an overview of all currently available systemic immunosuppressive agents
and retinoids for the treatment of HS, a systematic search was performed using MEDLINE and
EMBASE databases. All published papers concerning systemic retinoids or immunosuppressive
treatment for HS in adults were included. The primary endpoint was the percentage of
significant responders, moderate responders and non-responders. Other endpoints were the
relapse rate and adverse events. In total 87 papers were included, comprising 518 patients
with HS who were treated with systemic retinoids, biologic agents or other immunosuppressive
agents including colchicine, ciclosporin, dapsone or methotrexate. The highest response rates
were observed with infliximab, adalimumab and acitretin. Overall, the quality of evidence was
low and differed between the agents, making direct comparisons difficult. However, based on
the amount of evidence, infliximab and adalimumab were the most effective agents. Acitretin
was also effective in HS, although the quality of the evidence was low. The therapeutic
effect of isotretinoin is questionable. Randomized controlled trials are needed to confirm the
effectiveness of acitretin as well as to identify the most effective immunosuppressive agent in
HS.
53
INTRoDUcTIoNHidradenitis suppurativa (HS), also known as acne inversa, is a chronic inflammatory skin
disease characterized by recurrent, painful, deep-seated nodules and abscesses. In an advanced
stadium sinus tracts are formed, eventually leading to fibrotic scars, dermal contractures and
induration of the skin.1,2 Lesions typically occur on inverse, apocrine gland-bearing skin, like
the axillary, inguinal and anogenital regions. Quality of life is greatly impaired in HS.3,4 In
addition to lifestyle changes, therapeutic options include topical and systemic antibiotics, anti-
androgens, systemic retinoids, immunosuppressive agents, laser treatment, and surgery.5-7
Since an effective monotherapy is lacking, it is often required to combine different treatment
modalities to achieve some improvement.
Although the pathogenesis of HS is largely unknown, follicular hyperkeratinisation followed
by follicular occlusion is a primary feature of HS.8-11 Several factors probably contribute to
these histological changes, including smoking, sweating, obesity and hormonal changes.12
The important role of the immune system in HS has been underlined in recent studies, where
several observations have been observed, including involvement of the interleukin (IL)-12/
Th1 IL-23/Th17 pathways, and increased TNF-α in the skin and serum.13-15 In addition, there
is a deficiency of IL-22 and IL-20 in lesional HS skin leading to decreased antimicrobial protein
(AMP) levels, making the skin prone to bacterial infection.16
In conclusion, both clinical and experimental studies support the use of anti-inflammatory
drugs and retinoids in the treatment of HS and several different types of these agents are
currently available. However, there is no consensus on which agent is most effective for HS.
Therefore, this review aims (i) to evaluate all existing evidence to date for the use of systemic
immunosuppressive agents and systemic retinoids in HS and (ii) to assess their current position
in the treatment of HS.
54
PATIENTS AND METHoDS Inclusion and exclusion criteria
Included in the study were all fully published papers that reported on the clinical effects of any
systemic immunosuppressive agents or systemic retinoids in HS localized at the typical inverse.
Patients had to be 18 years or older. Studies not exclusively dealing with HS were excluded,
unless data for HS could be extracted separately. Studies were excluded if insufficient details
were given on treatment regime in respect of dosing, treatment duration and concomitant
immunosuppressive medication. There were no language restrictions.
Types of outcome measures
The efficacy of treatment was classified for each patient as “significant response”, “moderate
response” or “nonresponse.” A significant response was defined as a reduction of the Sartorius
score with ≥50%, improvement in quality of life of >50% or if stated so by the authors. A
moderate response comprised score reductions <50% or if stated so by the authors. The
primary endpoint comprised the percentage of significant responders, moderate responders
and nonresponders. If a study did not report individual results, all patients of that study were
categorized corresponding to the reported mean results. Dropouts were considered to be
nonresponders. The secondary endpoint was the percentage of responders that relapsed during
or after discontinuation of treatment, and the tertiary endpoint comprised adverse events
(AEs).
Identification of studies
Databases were systematically searched by two independent authors (SvH and JLB) for studies
dated up to May 2012. A search was conducted using EMBASE (search terms: ‘hidradenitis
suppurativa’/exp OR ‘hidradenitis suppurativa’ OR (hidraden* AND suppurativ*) OR ‘acne
inversa’ OR ‘inverse acne’) and Medline (search terms: “Hidradenitis Suppurativa”[MeSH]
OR (hidraden* AND suppurativ*) OR “acne inversa” OR “inverse acne”). Reference lists of
included papers and relevant reviews were manually searched to identify additional papers.
Data extraction
Two authors (JLB and SvH) independently conducted data extraction by using standardized
forms. Discrepancies between the researchers were resolved through discussion. Authors were
not contacted for missing data. Data were analysed by means of descriptive statistics.
55
Quality assessment
The quality of evidence was assessed by grading as follows: A, systematic review or meta-
analysis, randomized controlled trial with consistent findings, or all-or-none observational
study; B, lower quality clinical trial or study with limitations and inconsistent findings, cohort
study or case-control study; C, consensus guidelines, usual practice, expert opinion, or case
series.17
56
RESULTSFigure 1 shows the process of study selection, at the end of which 87 papers were included,
comprising a total of 518 patients. The immunosuppressive therapies evaluated in these
papers were biologics, colchicine, ciclosporin, methotrexate and dapsone. Treatment with
systematic retinoids included the use of acitretin and isotretinoin. Two papers dealt with
two immunosuppressive agents and these studies are therefore discussed in subheadings
of the Results section.18,19 The level of evidence of included papers is described for each
immunosuppressive agent in Table 1. A summary of the results is described in Figure 2.
57
Figure 1. Study selection
58
Biologics Adalimumab
Studies: We identified 15 papers studying a total of 68 patients.18-32 One study had a
randomized double-blind placebo-controlled design (evidence level A).31 In one retrospective
cohort study, the effectiveness of adalimumab was compared to infliximab (evidence level
B).19 Four other studies had an evidence level of B,20,21,23,32 and the remaining 9 studies had
level C.18,22,24-30 Dosing regimes varied from 40-80 mg in a frequency ranging from weekly
to every other week. The treatment duration was ≥1 year in three studies,21,24,26 ≤6 months
in six studies18,20,22,27,31,32 and unclear in six studies.19,23,25,28-30 One patient was simultaneously
to adalimumab treated with methotrexate for the first 2 months.26 The follow-up time varied
between studies, ranging from 13 weeks-29 months.
Primary endpoints: in total, 30/68 patients (44%) showed a significant response to
adalimumab, 24 patients (35%) had a moderate response and 14 patients did not respond
(21%). (Figure 2)
Secondary endpoints: one paper reported that the majority of the seven responding patients
showed recurrence of HS after 1 year of follow-up; however, individual numbers could not be
extracted.19 Occurrence of relapse was described for 35 of the remaining 42 responders: 22/35
(66%) relapsed within 3-10 months after discontinuation of treatment.21,23,25,26,28,31 Seven of the
35 responders (20%) relapsed during treatment, but symptoms improved in all when the dose
of adalimumab was increased.23,26,28
Tertiary endpoints: Adverse events (AEs) are described in Table 2. Six papers did not report on
AEs.22,24,27-30,32
59
Immuno-suppressive agent
(total nr of papers)
Nr of level A evidence
(% within group)
Nr of level B evidence
(%within group)
Nr of level C evidence
(% within group)
% of responders
% of non responders
Biologicals 66 3 5 17a 24 48b 71
Adalimumab 15 1 7 5 33 9 60 79 21
Etanercept 9 1 11 5 56 3 33 56 44
Infliximab 42 1 2 7 17 34 81 89 11
Ustekinumab 2 2 100 75 25
Retinoids 13 6 46 7 54
Acitretin/etretinate 6 2 33 4 67 95 5
Isotretinoin 7 4 57 3 43 36 64
Other 8 2 25 6 75
Ciclosporin 3 3 100 100 0
Dapsone 3 3 100 100 44
Colchicine 1 1 100 75
Methotrexate 1 1 100 100
a one paper compared adalimumab with infliximab, and is included as level B for both adalimumab and infliximab.19
b One paper describes the efficacy of adalimumab and etanercept; therefore it has been included as level C for both adalimumab and
etanercept.18
Table 1. Level of evidence for all included studies
Etanercept
Studies: nine papers comprising 54 patients evaluated the effect of etanercept on HS.18,33-
40 One study had a randomized double-blind placebo controlled design (evidence level A);
however, after 12 weeks all patients received open-label etanercept.33 We included only those
10 patients who were initially allocated to etanercept group. Five papers had evidence level
B34,35,37,39,40 and 3 papers level C.(18,36,38) Dosing schedules varied from 25 mg to 50 mg once or
twice weekly to 100 mg weekly. Treatment duration was 3 months in two papers,34,35 6 months
in two33,39 and around 1 year or longer in four papers.18,36-38 The follow up time was 17-144
weeks. Long term results of the patients described by Giarmellos et al.35 were reported in a
separate paper.41
Primary endpoints: a significant response to etanercept was observed in 21/54 patients (39%),
whereas nine patients (17%) had moderate improvement and 24 patients (44%) did not
respond to the treatment. (Figure 2)
Secondary endpoints: in total 18/30 responders (60%) relapsed after treatment was
discontinued. The time to relapse ranged from immediately after stopping of treatment until 8
months thereafter, but the majority had recurrence of HS lesions within 2 months.
Tertiary endpoint: Table 2 describes the tertiary endpoints. One study did not report on AEs.18
60
Infliximab
Studies: the efficacy of infliximab was evaluated in 42 papers, comprising 147 patients.
One study had a randomized double-blind placebo controlled design (evidence level A) but
after 8 weeks all patients received infliximab.42 Only those 15 patients who were initially
allocated to infliximab were included. Evidence levels B and C were found in seven19,43-48
and 34 studies49-82 respectively. One study compared the effect of infliximab with another
treatment, namely adalimumab.19 Almost all 147 patients received intravenous infliximab
5 mg/kg at weeks 0, 2 and 6. In 10 studies treatment was discontinued after these three
administrations.19,46,57,61,63,65-67,70,82 However, the majority of patients received maintenance
therapy every 6-8 weeks. Dosing schedules were not clear in five papers.50,69,71,74,75 The duration
of treatment was >1 year in nine studies.45,48,49,53,56,60,64,79,80 In four papers patients, in addition to
infliximab, patients received methotrexate, which might have prevent the formation of auto-
antibodies.45,49,60,64 Simultaneously to infliximab, patients were treated with azathioprine in two
studies,70,72 prednisolone in one study,77 prednisolone and ciclosporin in one study,68 and with
oral azathioprine and methylprednisolone in one study.71
Primary endpoints: a significant improvement was seen in 74/147 patients (50%); 57 patients
(39%) showed moderate improvement and 16 patients (11%) had no response (Figure 2)
Secondary endpoints: Only 10/131 responders (8%) experienced recurrence of HS during
treatment,48,49,55,60,68,79 and 26 responders (20%) relapsed within 2 weeks to 3 years after
discontinuation of therapy.42,46,52-54,57,62,63,67,73,75 One paper reported that the majority of patients
had recurrence of HS one year after discontinuation of treatment, however, individual numbers
could not be extracted.19
Tertiary endpoints: Fourteen studies did not report on AEs.50,52,55,59-61,65,66,69-71,74,78,82 AEs were
observed in 19 studies (Table 2).19,42-48,57,63,64,68,72,73,75,76,79-81
Ustekinumab
Studies: Two papers comprising a total of four patients, evaluated the effect of ustekinumab
(both evidence level C).83,84 The patients received 45 mg ustekinumab at weeks 0, 4 and 12.
Subsequently, one patient received injections every 3 months,84 and three patients every 2
months.83 Three patients were treated for at least 6 months and two of them were probably
still on treatment at the time the paper was written.83
Primary endpoints: two of the four patients (50%) showed a significant response, one patient
had a moderate response (25%) and one patient (25%) did not respond. (Figure. 2)
Secondary endpoints: one responding patient had temporary relapses every 2 weeks prior to
61
his next injection, but after administration.84 In another responding patient lesions recurred
after 6 months.83 The dose ustekinumab was therefore increased to 90 mg and his disease has
improved ever since. The remaining one responding patient did not relapse during treatment.83
Tertiary endpoint: AEs were reported in one paper (Table 2).83
Retinoids
Isotretinoin
Studies: seven papers evaluated the effect of oral isotretinoin, and comprised a total of 174
patients. Level B evidence was found in four papers85-88 and level C in three.89-91 The daily
dosages of isotretinoin were 0.5-1.2 mg/kg and treatment duration was 4-12 months. One
patient was pretreated with prednisone and erythromycin, followed by the gradual introduction
of isotretinoin.89
Primary endpoints: significant improvement was observed in 32/174 patients (18%), moderate
improvement in 30/174 patients (17%) and no response was observed in 112 patients (64%)
(Figure 2).
Secondary endpoints: one study comprising 14 responders did not mention whether
recurrences occurred after cessation of therapy.85 Of the remaining 48 responders, six patients
(13%) relapsed within a couple of months after discontinuation of treatment.
Tertiary endpoint: Two studies did not report on AEs.85,89 All remaining 18 patients experienced
AEs (Table 2).
Acitretin and etretinate
Studies: Acitretin is a metabolite of etretinate and has replaced treatment with etretinate in a
variety of disorders, as it has a much shorter elimination half-life and is equally effective. Six
papers reported on the treatment of HS with these retinoids, and comprised 22 patients.92-97
The level of evidence was B in two studies;92,96 the remaining papers were level C. Patients
treated with etretinate received daily doses of 0.35-1.1 mg/kg and the daily doses for acitretin
ranged from 0.25-0.88 mg/kg. The duration of treatment was 3-39 months.
Primary endpoints: significant improvement was seen in 16 of 22 patients (73%), five patients
(23%) improved moderately and one patient (5%) did not respond to the therapy (Fig. 2).
Secondary endpoints: No relapses during therapy were described. Acitretin or etretinate
treatment was eventually discontinued in 17 patients. Within six months after cessation of
therapy, six of 17 patients (35%) had recurrence. Eight patients (47%) relapsed >1 year after
discontinuation of treatment.
62
Tertiary endpoint: The AEs that were reported are shown in table 2. Two studies did not report
on AEs.93,97 For one study, data on AEs could not be extracted separately for HS.96
other therapies Dapsone
Studies: the effect of dapsone was described in three papers all with evidence level C.98-100
In total 34 patients were treated with doses of 25-200 mg daily during 0.5-48 months. The
majority of patients was still on treatment at the time of study closure.
Primary endpoints: A significant improvement was seen in 12/34 patients (35%) showed a
significant response, seven patients (21%) had a moderate response and 15 patients (44%) did
not respond (Figure 2).
Secondary endpoints: Two studies reported that discontinuation of therapy led to a rapid
recurrence of HS lesions in all patients, and that dapsone treatment could therefore not be
terminated.99,100 Two out of nine responders in the study of Yazdanyar et al.98 also rapidly
relapsed after cessation of treatment; however, re-introduction of dapsone led to rapid
improvement.
Tertiary endpoint: Adverse events are shown in table 2.
Colchicin
Studies: we identified one paper (evidence level B) describing eight patients who were treated
with colchicine 0.5 mg twice daily during 4 months.101
Primary endpoints: Two out of eight patients (25%) had a moderate respons and six out of
eight patients (75%) did not respond to colchicines (Figure 2).
Secondary endpoints: these were not stated.
Tertiairy endpoint: The observed AEs are shown in Table 2.
Ciclosporin
Studies: we identified three papers (evidence level C) on ciclosporin.102-104 Four patients were
treated with ciclosporin 2-6 mg/kg daily for 4-15 months. Two patients were concomitantly
treated with prednisolone and oral antibiotics.102,103
Primary endpoints: a significant response was observed in two of four patients (50%) and the
remaining two patients had a moderate response (Figure 2).
63
Secondary endpoints: in one patient ciclosporin was discontinued after 4 months, leading to
a recurrence 4 months later.102 Two patients were still on treatment at the time the paper was
published and did not experience any relapses. It was not reported whether the last patient
experienced relapse.104
Tertiary endpoint: These were not reported in any of the studies.
Methotrexate
Studies: we identified one paper that reported on the effectiveness of methotrexate in HS.105
It concerned an open study in which two patients received a weekly dose of 12.5 mg and one
patient received 15 mg. Treatment duration was 6 weeks, 4 months or 6 months.
Primary endpoints: none of the three patients responded to the treatment with methotrexate
(Figure 2).
Secondary endpoints: since none of the patients showed a response to the treatment, time to
relapse was not applicable.
Tertiary endpoint: Adverse events were not reported.
64
SI = significant responders. M
I = m
oderate responders. NR
= non-responders. N
= num
ber of patients.
Figure 2. Overview
of total number of papers and treated patients for each agent, including response rates.
65
Immunosuppressive agent (number of treated patients)
Observed adverse events (frequency) Nr of patients that discontinued treatment due to adverse events
Adalimumab (68) Painful injection site,a mild infections (10), non-specific gastrointestinal symptoms
(3), non-specific rash (3), fatigue (3), elevated liver enzymes (2), reactivation of
Epstein-Barr virus (1), severe infusion reaction urticaria (1), facial cellulitis (1),
irritation ears (1), hoarseness (1), headache (1), dry eyes (1), muscle chest pain (1),
dry skin (1), hay fever (1),
1(23)
Etanercept (54) Injection site reaction,a upper respiratory tract infection (4), nausea (3), paresthesias
(2), chest pain (2), cellulitis (2), muscle cramps (1), flu-like symptoms (1),
hypertension (1), elevated cholesterol (1)
3 (34)
Infliximab (147) Non-specific side effects (14), headache (7), acute arthritis/myalgia (8),
hypersensitivity reactions (5), influenza-like illness (4), dizziness (3), asthenia
(3), numbness in legs/neuropathy (3), skin rash (3), anaphylactic shock (1),
pneumococcal sepdis (1), localized tuberculosis infection (1), pustular lesions lower
limbs (1), fever (1), hypertension (1), herpes zoster (1), colon cancer (1), cervical
abscess (1), dyspnoea (1), lupus like reaction (1)
31 (43-46,48,57,63,68,72,73,75,76,78-80)
Ustkeinumab (4) Cystitis (1), psoriasiform dermatitis (1), HS lesion infected by staphylococcus aureus
(1)
None
Isotretinoin (174) Cheilitis/xeorsis (15), usual side efectsb (3), arthralgia (1), headache (1) 10 (86)
Acitretin/etretinate
(22)
Cheilitis/xerosis (13), alterations in lipids (4), altered triglyceride levels (3),
hypertrichosis/photosensitivity (2), alopecia (2), depression/fatigue (1), headache (1),
loss of concentration (1), elevated cholesterol (2), buzzing ears (1), joint pain (1)
2 (92,95)
Dapsone (34) Anemia/hemolysis (4), nausea (3), dizziness (2), tiredness (2), headache (2), elevated
bilirubine (1), rash (1), gloomy mood (1), malaise (1)
None
Colchicine (4) Nausea (3), diarrhea (3) 1 (101)
Methotrexate (3) Adverse events not stated none
Ciclosporin (4) Adverse events not stated none
a some studies reported that this event occurred in 'several patients', without mentioning exact numbers.
b Probably xerosis/cheilitis
66
DISCUSSION To the best of our best knowledge, this is the first systematic review specifically aimed to
analyze all currently available evidence of immunosuppressive agents and systemic retinoids for
the treatment of HS. In total 518 patients were analysed, divided over 87 papers. The majority
of patients (n = 273) was treated with a biological agent. Overall, the quality of the included
papers was low; only three randomized controlled trials were identified, all on biologics.31,33,42
The majority of papers were case reports or series, bringing along a risk of publication bias.
Two papers were not identified by our search strategy due to the fact that they were not
incorporated in Medline or EMBASE.96,97
Based on our results, the most effective agents for HS were infliximab, adalimumab and
acitretin with respectively 89%, 79% and 96% of patients, respectively, responding to
treatment. However, as the results of acitretin were based on far fewer patients and were of a
lower level of evidence than the results for infliximab and adalimumab, caution must be taken
when directly comparing the efficacy of these agents. The positive results of infliximab and
adalimumab are in accordance with the findings of Van Rappard et al.106 Acitretin for HS is
barely mentioned in the literature, however, its positive effect is pharmacologically reasonable,
as the primary event in HS is follicular occlusion and acitretin induces normalization of the
epithelial cell proliferation and differentiation.107,108 Not surprisingly, isotretinoin is ineffective
for HS as this agent primarily works on sebaceous glands, which are not involved in the
pathogenesis of HS.109,110 The observation that 35% of treated patients still responded to
isotretinoin, is more likely to be due to the immunomodulatory effects of this retinoid.111
The highest quality of evidence was identified for etanercept, which enables us to conclude
that the efficacy (56% responders) was relatively low. Only a few patients have been treated
with ustekinumab, ciclosporin, dapsone, methotrexate and colchicine. It has been shown that
the IL-12/IL-23 pathway is upregulated in HS, therefore there is a rationale for the efficacy
of ustekinumab (an inhibitor of this pathway), and the first results of this agent are indeed
promising.83,84 However, clinical trials are needed to confirm its effect. The same applies for
ciclosporin; although all patients responded to treatment, this agent has been studied in only
four patients, making it impossible to draw any definite conclusions. The efficacy of dapsone is
doubtful, methotrexate as a monotherapy seems of little value and colchicine is not effective in
HS.
Although long-term results and relapse rates were not available for many papers on biologics,
recurrence of HS occurred frequently during therapy or within a couple of months after
cessation of biologic therapy. In contrast, Boer and Nazary92 achieved long-term remission (i.e.
>1 year) in a majority of patients treated with acitretin, indicating that this is probably also
67
effective on the long term. However, this observation needs to be confirmed in bigger trials
since only 12 patients were included.
Adverse events were observed with all agents, except for ciclosporin and methotrexate, where
it was not stated. The highest number of withdrawals due to AEs occurred with infliximab and
isotretinoin. Other reviews also showed that the risk of withdrawal is higher during infliximab
therapy compared with adalimumab and etanercept therapy.106,112 The most common AE
during acitretin therapy is cheilitis which can be very disturbing for patients. Moreover, the
most important disadvantage of acitretin is that it has extremely teratogenic side effects.113
Therefore, this agent should mainly be reserved for men and sterilized or postmenopausal
women.
A limitation of this review, and any other review on HS treatment, is heterogeneity between
the studies in respect of study design, number of included participants, the severity of HS and
the timing and methods for outcome assessments. Therefore, caution must be taken in directly
comparing the different treatment options of HS.
In conclusion, this review indicates that, based on the evidence today, infliximab and
adalimumab are the most effective immunosuppressive agents for HS. Additionally, acitretin is
a promising agent and definitely worth considering in men and sterilized or postmenopausal
women, although high quality evidence is lacking for its administration in HS. Also, these data
strongly indicate that there is a need for randomized controlled clinical trials in order to identify
the most effective treatment targets and the most effective therapy for HS.
68
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79
6USTEKINUMAB IN HIDRADENITIS SUPPURATIVA: A CLINICAL OPEN LABEL STUDY WITH ANALYSES
OF THE PROTEIN EXPRESSION PROFILE IN SERUM
Janine L. Blok, MD1; Katherine Li, MS2; Carrie Brodmerkel, PhD2; Péter Horvátovich PhD3,
Marcel F. Jonkman, MD PhD1; Barbara Horváth, MD PhD1
1Department of Dermatology, University Medical Center Groningen, University of Groningen,
Groningen, the Netherlands 2Janssen Research & Development, LLC, Spring House, PA, U.S.A. 3 Department of Pharmacy, Analytical Biochemistry, Faculty of Mathematics and Natural
Sciences, University of Groningen, Groningen, The Netherlands
Submitted
80
ABSTRAcTIntroduction
Treatment of hidradenitis suppurativa (HS) is difficult and the search for effective therapies
continues.
Objectives
To evaluate the efficacy of ustekinumab in HS.
To discover a potential biomarker.
Material and methods
Seventeen patients were included in this open label study and treated with 45 to 90 mg
ustekinumab at weeks 0, 4, 16 and 28. Proteomic technology and enzyme-linked assay
analysis (ELISA) was applied on serum.
Results
Twelve patients completed the protocol. Moderate to marked improvement of the modified
Sartorius Score was achieved in 82% of patients at week 40 and the hidradenitis suppurativa
clinical response (HiSCR-50) in 47%. There was significant modulation in the expression of 54
serum proteins in patients at baseline compared to normal controls. Involved pathways were
related to inflammation, immune cell signaling, and tissue morphology and development. Four
of these (FSH, LH, HCG and LTA4H) were significant modulated at the end of treatment. Good
responders had milder disease and lower expression of leukotriene A4-hydrolase (LTA4H). IL-
2R, TNF-α, IL17A and IL-17F were not elevated in patient serum and did not change during
treatment.
Conclusion
The majority of patients showed improvement with ustekinumab. Although no biomarker was
discovered, low LTA4H concentrations with mild disease severity may be predictive for the
effectiveness of ustekinumab.
81
INTRoDUcTIoN Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by recurrent
abscesses and sinus tract formation.1 The clinical severity of HS is commonly classified
according to the Hurley stages.2 HS is painful and disfiguring, impairing quality of life to a
great extent.3,4 Genetic susceptibility, smoking and obesity are important risk factors for the
development of HS.5
A dual approach is usually adopted in the treatment of HS. First, the inflammatory reaction
is inhibited with systemic anti-inflammatory or immunosuppressive agents. Lesions resistant
to systemic therapy, like sinus tracts, are subsequently surgically removed.6 Commonly used
immunosuppressive agents are tumor-necrosis-factor-α (TNF-α) inhibitors, like infliximab and
adalimumab.7 However, in a substantial number of patients TNF-α inhibitors are ineffective or
cause adverse events requiring discontinuation of therapy.7,8 Therefore, there is still a need for
new effective immunosuppressive agents in HS.
The pathogenesis of HS has not been clarified yet. It has been suggested that follicular
plugging followed by the release of follicular material into the dermis are primary events that
activate the immune system.9 Unraveling what cytokines are involved has been the main
objective of several studies. Recently, it has been shown that the interleukin-23/ T-helper 17
cells (IL-23/Th17) and IL-12/Th1 pathways come to expression in HS skin.10,11
Ustekinumab is a human IgG1k monoclonal antibody that binds with high affinity to the
p40 subunit of IL-12 and IL-23. Thereby, these cytokines are prevented from interacting
with their IL-12Rβ1 receptor protein that is expressed on the surface of T-cells and natural
killer cells.12 Certain genetic variations within the gene encoding for the common IL-12βR1
subunit of the IL-12/IL23 receptor have shown to be associated with a more severe course of
HS.13 Ustekinumab has been approved for the treatment of psoriasis.14-16 The effectiveness of
ustekinumab in HS has been retrospectively studied in a total of seven patients with conflicting
results.17-20 With this open label prospective study we investigated the efficacy and safety of
ustekinumab in a group of 20 patients with moderate to severe HS. To identify candidate
biomarkers for HS we performed proteomics and immunoassays on serum of patients and
healthy volunteers.
82
MATERIAL AND METHoDS The manuscript was approved by the institutional review board.
Study patients
Subjects were recruited from May 2012 until March 2013. Patients with moderate to severe
HS (Hurley stage II-III) with a treatment history of at least one systemic anti-inflammatory/
immunosuppressive agent or surgery were eligible for participation. The diagnosis of HS was
made by a dermatologist.
Design and intervention
The trial had a prospective uncontrolled open-label design. The washout period for systemic
immunosuppressive medication was at least 3 months. All patients received ustekinumab
according to the psoriasis dosing regimen.(14) Subcutaneous injections were administered at
weeks 0 and 4 (induction phase) and week 16 and 28 (maintenance phase). Each injection
contained 45 mg ustekinumab, with subjects weighing >100 kg receiving 90 mg per injection.
The intervention period was set to 40 weeks, consisting of the treatment phase (weeks 0-28)
followed by a post-treatment phase of 12 weeks. Topical resorcinol 15% cream or incision
and drainage of acutely painful were the only allowed escape treatments. Assessments were
performed by the same investigator at baseline (week 0) and weeks 4, 10, 16, 22, 28, 34
and 40. The study was approved by the local institutional review board and registered with
ClinicalTrials.gov (NCT01704534).
Assessments of disease severity
At every visit, the modified Sartorius scale (mSS) and modified hidradenitis suppurativa-lesion
area and severity index (mHSLASI) were assessed. The mSS is a dynamic scoring system
for HS and includes the number of involved anatomical regions, the type and number of
lesions, the extent of involvement and the Hurley stage.21 The mHSLASI reflects the degree of
inflammatory activity by assessing the level of experienced pain, redness, edema and lesional
discharge.22 A ≥50% reduction in these scores was considered as a marked response; 25-<50%
reduction as moderate; >0-<25% reduction as mild and ≤0 as non-response.
A visual analogue scale (VAS) to determine the degree of experienced pain ranging from 0
mm (no pain) to 100 mm (maximum pain), the Dermatology Life Quality Index (DLQI) and
Skindex-29 questionnaires were used to investigate patient-reported outcomes.
83
outcomes and follow-up
The primary endpoint was the proportion of patients with marked improvement (≥50%
reduction) of the mSS and mHSLASI scores at week 40. Secondary outcomes included the
mean change in patient’s reported pain, Skindex-29 and DLQI. Regarding the Skindex-29, the
cut-off scores as proposed by Prinsen et al.23 were applied. Improvement of the Skindex-29
was considered as clinically meaningful if the score of a specific domain went at least one scale
down compared to week 0. A DLQI of 0-1 corresponds to no effect on patient’s quality of life,
an index of 2-5 to a small effect, 6-10 to a moderate effect, 11-20 to a very large effect and
21-30 to an extremely large effect on patient’s quality of life.24 A reduction of ≥5 points on the
DLQI was considered as clinically meaningful improvement.25
We performed a post-hoc analysis using the Hidradenitis Suppurativa Clinical Response
(HiSCR), which is a recently validated endpoint for assessing HS treatment effectiveness.26
Responders (HiSCR achievers) are defined as patients with at least 50% reduction in the
number abscesses or inflammatory nodules, without an increase in draining fistulas (HiSCR-50).
This endpoint was added to support our clinical scores as the mSS and mHSLASI may not be
optimal in assessing inflammatory manifestations.27
Sample collection and analyses
Protein analyses from serum:
A total of 1129 proteins were measured in serum by somalogics (high content proteomics)
using “SOMAscan” (SomaLogic Inc. Boulder, CO) at baseline and at week 40.
Pathway analyses:
Pathway analyses were conducted with QIAGEN’s Ingenuity Pathway Analysis (IPA®, www.
qiagen.com/ingenuity).
Immunoassays: Enzyme-linked Immunosorbent Assay (ELISA) was performed on serum at baseline, week 4,
16, 28 and 40 for TNF-α (MesoScale Discovery, Rockville, MD) and the soluble IL-2 receptor
(sIL2R) (Alpco, Salem, NH) according to the manufacturer’s instructions. Serum IL17A and
IL17F were measured by the Erenna® Immunoassay system according to the manufacturer’s
84
instructions (Singulex, Alameda, CA). Based on the protein Somalogics data measured at
week 0 and 40, additional ELISA analyses were performed for leucotriene A4-hydrolase
(LTA4H), follicle stimulating hormone (FSH), luteinizing hormone (LH) and human chorionic
gonadotropin (HCG) at weeks 0, 4, 16 28 and 40.
Safety assessments
Serious adverse events were reported to the competent Health Authorities and the ethics
committee within 24 hours in addition to completion of a Suspected Unexpected Serious
Adverse Reaction form. A Data Safety Monitoring Board gathered every six months.
Statistical analysis
Descriptive statistics (mean, percentages, minimum and maximum) were performed for the
outcome variables. Efficacy analyses were conducted on the intention-to-treat (ITT) population
that included all patients who received at least one dose of study medication. If a patient
dropped out it was attempted to obtain further patient assessments for the primary outcomes,
if not the missing data were handled by carrying the last observation forward. The Wilcoxon
rank test was used to analyze the efficacy of treatment. The criterion for statistical significance
was p<0.05. Analyses were performed with SPSS Statistics 22.
Array Studio software version 8.0 (OmicSoft Corp., St. Morrisville, NC) was used to analyze
proteomics data. Blood samples from healthy volunteers were used as controls for serum
proteomics. Expression modulation was analyzed using a general linear model. A >1.5 fold
change and an FDR-adjusted p-value < 0.05 were considered significant. Scatter plots were
made with Matlab version 8.3.0.532 (R2014a).
85
RESULTSPatients and drop-outs
A total of 26 patients were screened for entering the study. Seventeen (four men, 13 women)
instead of the initially planned 20 patients were included, as the trial medication expired due to
a slower recruitment rate than expected. Patient’s characteristics are described in table 1. Five
subjects dropped out prematurely. The mean age was 35 years (range 20-53), mean BMI 28.3
kg/m2 and mean disease duration was 18 years.
Primary endpoints (mSS and mHSLASI)
At week 40 improvement of the mSS was marked in six of 17 patients (35%), moderate in
eight patients (47%), mild in one patient (6%) and in two patients (12%) there was no change
or worsening. The mean mSS of the ITT population significantly reduced from 112.12 at
baseline to 60.18 at week 40 (46.33% improvement; p=0.001) (fig. 1a).
Improvement of the mHSLASI at week 40 was marked in three of 17 patients (18%), moderate
in six patients (35%), mild in three patients (18%) and in five patients (29%) there was no
change or worsening. The mean mHSLASI of the ITT population significantly reduced from
26.29 at baseline to 19.59 at week 40 (25.5% improvement; p=0.011) (fig. 1a).
Secondary endpoints (Skindex-29, VAS, DLQI)
At week 40 clinically meaningful improvement on the Skindex-29 overall domain was
observed in six of 17 subjects (35%), on the functioning domain in eight subjects (47%), on
the emotions domain in four subjects (24%) and on the symptoms domain in three subjects
(18%) (fig. 1c). At baseline, the DLQI indicated that HS had a very large or extremely large
effect on daily life in 71% of subjects, at week 40 this was 59% (fig. 1d). At week 40 clinically
meaningful improvement of the DLQI had occurred in seven patients (41%). The mean
reported pain on a VAS was 5.8 out of 10 at the start of treatment and 4.6 at week 40.
Post-hoc analysis with HiScR
The number of HiSCR-50 achievers increased from the induction phase through to week 22. At
week 40, eight out of 17 patients (47%) were HiSCR50 achievers (fig. 1b).
86
Escape treatments
Resorcinol 15% cream was used for troublesome inflammatory lesions by four patients and
incision and drainage in one patient. The protocol was violated in two patients who received
intralesional corticosteroids for painful lesions that were not suitable for incision and drainage.
Safety assessments
The most common adverse events were headache, fatigue and upper respiratory tract
infections. All events were mild and temporary.
Protein expression in the serum
Fifty-four proteins were significantly differentially expressed in serum of patients (n=17)
at baseline compared to healthy controls (n=10) (fig. 2a). The top involved dysregulated
pathways were related to inflammation, immune cell signaling, as well as tissue morphology
and development (fig. 2b). Significant modulation of the leucotriene A4-hydrolase (LTA4H),
follicle stimulating hormone (FSH), luteizing hormone (LH) and human chorionic gonadotropin
(HCG) were identified at week 40 in the four best responders (subjects 6, 12, 14, 15).
Serum ELISA for LTA4H, fSH, LH and Hcg
As LTA4H, FSH, LH and HCG were identified as potential biomarkers with protein microarray
analysis, these were further analyzed with ELISA. No linear correlation between clinical disease
severity and serum concentrations was identified, making these proteins not suitable as
biomarkers for treatment effectiveness. However, good responders showed a trend towards
having a relatively less severe clinical phenotype as well as lower concentrations of LTA4H
(fig. 3).
Serum ELISA for sIL-2R, TNf-α, IL17A and IL-17f
There were no significant differences in serum concentrations of sIL-2R, TNF-α, IL17A and
IL-17F between patients and controls, nor did we identify a significant decrease in any of these
cytokines during ustekinumab treatment (data not shown).
87
Subj
ect
num
ber
Gen
der
Age
His
tory
BM
I (kg
/m2)
Smok
ing
stat
usD
isea
se
dura
tion
**m
SSTr
eatm
ent
hist
ory
1F
37Ec
zem
a, h
ypot
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odis
m, h
yper
tens
ion
32.0
Form
er18
39T.
and
i.l.
cort
icos
tero
ids,
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ibio
tics,
der
oofin
g
2F
48A
sthm
a, d
epre
ssio
n37
.0Fo
rmer
4024
1R
esor
cine
15%
, ant
ibio
tics,
isot
retin
oin,
der
oofin
g
3M
23C
ongl
obat
e ac
ne23
.0A
ctiv
e7
91Pr
edni
solo
ne, i
sotr
etin
oin,
ant
ibio
tics,
infli
xim
ab
4F
51D
iabe
tes
34.4
Act
ive
2617
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cine
15%
, ant
ibio
tics,
pre
dnis
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flixi
mab
, der
oofin
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xcis
ion
5F
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n38
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100
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, ant
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me
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130
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ne25
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146
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nd i.
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a22
.0A
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ortic
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15%
, ant
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sion
/dra
inag
e,
exci
sion
11F
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ssio
n26
.0A
ctiv
e5
63I.l
. cor
ticos
tero
ids,
res
orci
ne 1
5%, a
ntib
iotic
s, in
cisi
on a
nd d
rain
age,
dero
ofing
, IPL
-EPI
***
12F
44K
idne
y st
ones
, hyp
erte
nsio
n32
.0A
ctiv
e34
121
Res
orci
ne15
%, t
opic
al a
nd in
tral
esio
nal c
ortic
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roid
s, a
ntib
iotic
s,
dero
ofing
, exc
isio
n
13M
33D
epre
ssio
n23
.1A
ctiv
e7
144
Ant
ibio
tics,
isot
retin
oin,
infli
xim
ab, e
xcis
ion
14F
40A
sthm
a, d
epre
ssio
n, h
yper
lipid
emia
23.9
Act
ive
2411
9R
esor
cine
15%
, ant
ibio
tics
15F
43H
yper
chol
este
role
mia
24.9
Act
ive
599
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ibio
tics,
res
orci
ne15
% in
cisi
on a
nd d
rain
age,
der
oofin
g
16F
20C
rohn
’s di
seas
e, d
epre
ssio
n32
.7A
ctiv
e9
52To
pica
l res
orci
ne15
%, d
eroo
fing
17F
33Ec
zem
a, h
eter
ozyg
ous
sick
le c
ell a
nem
ia40
.6Fo
rmer
1679
I.l. c
ortic
oste
roid
s, a
ntib
iotic
s, in
cisi
on/d
rain
age,
der
oofin
g
*at
the
star
t of
the
stu
dy in
yea
rs;*
*in
year
s
IPL-
EPI =
Inte
nse
puls
e lig
ht e
pilia
tion;
mSS
= m
odifi
ed S
arto
rius
Scor
e; T
. = t
opic
al; i
.l.=
intr
ales
iona
l
Tabl
e 1.
Pat
ient
cha
ract
eris
tics
88
Figure 1. Clinical scores during ustekinumab treatment
(a) Percentual reduction of the mSS and mHSLASI during ustekinumab treatment.
(b) The number of patients achieving >50% improvement of HiSCR during ustekinumab treatment.
(c) Improvement in Skindex-29 occurred for each domain with worsening of the scores during the post-treatment phase.
(d) The impact of HS on daily life as measured by the DLQI. The number of patients is presented within the bars.
Arrows represent ustekinumab administration points
(a) (c)
(b) (d)
89
Natural Killer Cell Signaling
Fc Epsilon RI Signaling
Insulin Receptor
Ephrin Receptor
T Cell Receptor Signaling
HGF Signaling
Pancreatic Adenocarcinoma Signaling
Role of Tissue Factor in Cancer
Ovarian Cancer Signaling
PI3K Signaling in B Lymphocytes
0 1 2 3 4 5 6
- log (p-value)
Disease
-3.00 3.00
Controls HS patients
Figure 2. Disease profile in serum
(A) The heat-map of the HS disease profile in serum based on somalogics. The expression of 54 proteins was significantly
different between HS (red boxes) and healthy controls (grey boxes) at baseline.
(B) The top 10 involved canonical pathways in serum of HS patients.
90
Figure 3. Scatter plot for the correlation between LTA4H and the absolute HiSCR.
There is no linear correlation between the concentration of LTA4H and the HiSCR. Note that good responders (green
circle) have lower HiSCR combined with lower LTA4H concentrations compared to non-responders (red circle).
91
DIScUSSIoNThis is the first prospective study investigating the efficacy of ustekinumab in HS. Both
primary outcomes (mSS and mHSLASI) showed a significant reduction of the mean at week
40. Additionally, moderate to marked improvement of the mSS and mHSLASI was seen in
the majority (82% and 53% respectively) of patients. This suggests that ustekinumab may
be applied for the treatment of HS as the reduction in mSS is comparable to studies on
adalimumab and infliximab.8,28
The mSS reduced >50% in 35% of patients. Other studies considered reductions of 30% to
40% as therapeutic responses.29,30 The HiSCR-50 was achieved in 47%. Considering ≥50%
improvement of the mSS as clinically meaningful in HS is therefore probably too strict. The
psoriasis dosing regimen may not have been sufficient for HS, further explaining why only
a minority met the primary endpoint. Indeed, inflammatory marker levels are higher in HS
than in psoriasis.10 Increasing the administration frequency, as has been shown to improve the
results of adalimumab in HS, as well as increasing the dosage, which has been safely applied in
Crohn’s disease, may therefore improve the effectiveness of ustekinumab.8,31
Almost half of the patients showed clinically meaningful improvement on the functioning
domain of the Skindex-29 at week 40. Quality of life scores worsened at the post-treatment
phase, suggesting that longer treatment duration may lead to prolonged effectiveness.12
Upper respiratory tract infections were one of the most common adverse events. The
increased infection risk during ustekinumab treatment is caused by suppression of Th-17 cell
differentiation, as IL-17 provides immunity against microbes like staphylococcus and candida.
We could not confirm the potential of sIL2R as a serum biomarker in HS.32,33 Neither could
we put IL-17A, IL-17F and TNF-α forward as potential biomarkers. However, HS patients
had a significant different serum protein profile compared to controls, indicating that several
proteins are secreted towards the circulation by cells present in inflammatory skin. The
significant modulation in LH, FSH and HCG after treatment in the best responders, who were
all female, is difficult to interpret as these hormones naturally fluctuate during the menstrual
cycle. In psoriasis no correlation was found between disease severity and concentrations of
FSH and LH in male patients.34 However, estradiol concentrations were associated with milder
disease severity, confirming the potential protective role of estrogen in inflammatory diseases.
Therefore, the role of sex hormones in HS also remains an interesting topic for future studies.
We show significant modulation in the expression of LTA4H in the best ustekinumab
responders. LTA4H is an intracellular enzyme released by epithelial cells and macrophages.
It converts leukotriene A4 (LTA4) into leukotriene B4 (LTB4), a pro-inflammatory mediator
capable of recruiting and activating a wide range of immune cells, including neutrophils.
92
The subsequent LTA4H release from neutrophils counteracts the inflammatory reaction by
degradation of neutrophilic attractant peptides.35 This dual effect may be responsible for the
lack of a clear linear correlation between LTA4H serum concentration and clinical disease
severity. However, the LTA4H concentration in combination with disease severity (HiSCR) may
be used to predict the effect of ustekinumab: low concentrations with a relatively mild clinical
disease severity may be associated with a good response.
Limitations of this study include the small number of patients and the lack of a control group.
Furthermore, there was a relatively high dropout rate, increasing the risk of bias. This was
restricted to a minimum by analyzing the ITT population.
In summary, this study shows that ustekinumab is well tolerated and that the standard psoriasis
dosing schedule improved HS in the majority of patients. The dosing schedule may need to be
intensified for HS to achieve sufficient immune suppression. Modulated pathways in serum of
HS patients were related to inflammation, immune cell signaling, as well as tissue morphology
and development. A biomarker for measuring treatment effects in HS was not identified.
However, low LTA4H serum concentrations in combination with relatively mild disease severity
may be predictive for the efficacy of ustekinumab.
93
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Giatrakos S, Huse K, Kanni T, et al. Haplotypes of IL-12Rbeta1 impact on the clinical phenotype of 13.
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Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human 14.
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Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human 15.
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double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 371:1675-84.
Griffiths CE, Strober BE, van de Kerkhof P, et al. Comparison of ustekinumab and etanercept for 16.
moderate-to-severe psoriasis. N Engl J Med 2010; 362:118-28.
Sharon VR, Garcia MS, Bagheri S, et al. Management of recalcitrant hidradenitis suppurativa with 17.
ustekinumab. Acta Derm Venereol 2012; 92:320-21.
Gulliver WP, Jemec GB, Baker KA. Experience with ustekinumab for the treatment of moderate to 18.
severe hidradenitis suppurativa. J Eur Acad Dermatol Venereol 2012; 26:911-14.
Baerveldt EM, Kappen JH, Thio HB, et al. Successful long-term triple disease control by ustekinumab 19.
in a patient with Behcet’s disease, psoriasis and hidradenitis suppurativa. Ann Rheum Dis
2013; 72:626-27.
Martin-Ezquerra G, Masferrer E, Masferrer-Niubo M, et al. Use of biological treatments in patients 20.
with hidradenitis suppurativa. J Eur Acad Dermatol Venereol 2015; 29:56-60.
Sartorius K, Emtestam L, Jemec GB, Lapins J. Objective scoring of hidradenitis suppurativa reflecting 21.
the role of tobacco smoking and obesity. Br J Dermatol 2009; 161:831-39.
Xu LY, Wright DR, Mahmoud BH, et al. Histopathologic study of hidradenitis suppurativa following 22.
long-pulsed 1064-nm Nd:YAG laser treatment. Arch Dermatol 2011; 147:21-28.
Prinsen CA, Lindeboom R, de Korte J. Interpretation of Skindex-29 scores: cutoffs for mild, moderate, 23.
and severe impairment of health-related quality of life. J Invest Dermatol 2011; 131:1945-47.
Hongbo Y, Thomas CL, Harrison MA, et al. Translating the science of quality of life into practice: 24.
What do dermatology life quality index scores mean? J Invest Dermatol 2005; 125:659-64.
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Basra MK, Fenech R, Gatt RM, et al. The Dermatology Life Quality Index 1994-2007: 25.
a comprehensive review of validation data and clinical results. Br J Dermatol 2008; 159:997-1035.
Kimball AB, Jemec GB, Yang M, et al. Assessing the validity, responsiveness and meaningfulness 26.
of the Hidradenitis Suppurativa Clinical Response (HiSCR) as the clinical endpoint for hidradenitis
suppurativa treatment. Br J Dermatol 2014; 171:1434-42.
van der Zee HH, Laman JD, Boer J, Prens EP. Hidradenitis suppurativa: viewpoint on clinical 27.
phenotyping, pathogenesis and novel treatments. Exp Dermatol 2012; 21:735-39.
van Rappard DC, Leenarts MF, Meijerink-van ‘t Oost L, Mekkes JR. Comparing treatment outcome of 28.
infliximab and adalimumab in patients with severe hidradenitis suppurativa. J Dermatolog Treat
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Savva A, Kanni T, Damoraki G, et al. Impact of Toll-like receptor-4 and tumour necrosis factor gene 29.
polymorphisms in patients with hidradenitis suppurativa. Br J Dermatol 2013; 168:311-17.
Fardet L, Dupuy A, Kerob D, et al. Infliximab for severe hidradenitis suppurativa: transient clinical 30.
efficacy in 7 consecutive patients. J Am Acad Dermatol 2007; 56:624-28.
Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and maintenance therapy in refractory 31.
Crohn’s disease. N Engl J Med 2012; 367:1519-28.
Matusiak L, Bieniek A, Szepietowski JC. Soluble interleukin-2 receptor serum level is a useful marker 32.
of hidradenitis suppurativa clinical staging. Biomarkers 2009; 14:432-37.
Wieland CW, Vogl T, Ordelman A, et al. Myeloid marker S100A8/A9 and lymphocyte marker, soluble 33.
interleukin 2 receptor: biomarkers of hidradenitis suppurativa disease activity? Br J Dermatol
2013; 168:1252-58.
Cemil BC, Cengiz FP, Atas H, et al. Sex hormones in male psoriasis patients and their correlation with 34.
the Psoriasis Area and Severity Index. J Dermatol 2015; 42:500-03.
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Thorax 2011; 66:550-51.
97
7SKIN-TISSUE-SPARINg ExcISIoN wITH ELEcTRoSURgIcAL PEELINg (STEEP): A SURGICAL TREATMENT OPTION FOR SEVERE
HIDRADENITIS SUPPURATIVA HURLEY STAGE II/III
J.L. Blok1, MD; J.R. Spoo1, MD PhD; F.W.J. Leeman2, MD; M.F. Jonkman1, MD PhD; B.
Horváth1, MD PhD
1Department of Dermatology, University of Groningen, University Medical Center Groningen,
Hanzeplein 1, 9700 RB Groningen, the Netherlands2Department of Dermatology, Antonius Hospital, 8601 ZK Sneek, The Netherlands
Published in the Journal European of the Academy of Dermatology and Venereology,
2015;29:379-82
98
ABSTRAcT Background: Surgery is the only curative treatment for removal of the persistent sinus tracts in
the skin that are characteristic of severe hidradenitis suppurativa (HS). Complete resection of
the affected tissue by wide excision is currently regarded as the preferred surgical technique in
these cases. However, relatively large amounts of healthy tissue are removed with this method
and suitable skin-tissue saving techniques aiming at creating less extensive surgical defects are
therefore needed in severe HS.
Method: We describe a skin-tissue saving surgical technique for HS Hurley stage II-III disease:
the Skin-tissue-sparing Excision with Electrosurgical Peeling (STEEP) procedure.
Discussion: In contrast to wide excisions that generally reach into the deep subcutaneous
fat, the fat is maximally spared with the STEEP procedure by performing successive tangential
excisions of lesional tissue until the epitheliazed bottom of the sinus tracts has been reached.
From here secondary intention healing can occur. In addition, fibrotic tissue is completely
removed in the same manner since this also serves as a source of recurrence. This tissue sparing
technique results in low recurrence rates, high patient satisfaction with relatively short healing
times and favorable cosmetic outcomes without contractures.
99
INTRoDUcTIoNHidradenitis suppurativa (HS) is an inflammatory skin disease characterized by painful deep-
seated nodules and abscesses that mainly occur on apocrine gland bearing skin.1 In a later
stage, sinus tracts surrounded by extensive fibrosis are formed in the dermis that in severe
cases even extend into the deep subcutaneous fat. These sinus tracts serve as a source for the
characteristic chronically recurring inflammation in HS. The Hurley classification is frequently
used to reflect disease severity by determination of: (i) the character of the lesions (solitary
nodules or abscesses correspond to stage I disease while stage II/III disease is characterized
by sinus tract formation); and (ii) the extensiveness of the lesions (differentiation of stage II
from stage III disease is made by determining whether or not there is healthy skin between the
lesions).2
Despite the numerous therapeutic options it is still difficult to treat HS, especially in severe
cases (Hurley stage II or III disease). Severe HS is characterized by both inflammation and a
permanent destruction of the normal skin architecture by the epithelialized sinus tracts and
fibrotic scars. Therefore, treatment requires a combined approach in order to be successful.
First, inflammatory activity needs to be improved. This can be achieved by systemic anti-
inflammatory or immunosuppressive treatment. However, (non-inflammatory) sinus tracts and
fibrotic scars will remain present after systemic therapy. The only way to permanently remove
these sinus tracts and fibrotic tissue is by means of surgery.
Currently, the classic deroofing technique and wide excision are regarded as the preferred
surgical methods for treating HS Hurley stage I/II and stage II/III respectively.3,4 However,
Hurley stage II/III disease remains a surgical challenge and the surgical treatment has dual
aspects. On the one hand, the goal of surgery is to achieve complete removal of lesional tissue.
On the other hand, it is important to spare as much healthy tissue as possible to prevent the
formation of serious contractures and to promote wound healing. The latter is not achieved
with wide excision. To meet both goals to a maximum we have developed a surgical technique
for severe HS where the advantages of both wide excision and the deroofing technique are
combined: the Skin-Tissue-sparing Excision with Electrosurgical Peeling (STEEP) procedure.
100
TEcHNIQUEThe STEEP procedure is performed under general anesthesia. The procedure starts with
palpation of the affected area to localize inflammatory nodules and fibrosis. Visible sinus
tracts are then sondaged with a probe to investigate their extensiveness. The sinus roof is
subsequently electrosurgically incised with a wire loop tip coupled to an Erbotoom (Erbe
USA Inc. Surgical Systems). This method is similar to the deroofing technique as described
previously for Hurley stage I/II disease.(3,4) Subsequently all lesional tissue, including fibrosis
that is identified by palpation, is removed from the incision on to the deeper skin layers by
successive tangential electrosurgical transsections (figure 1). The epithelialized sinus floors
and subcutaneous fat are left intact where possible. This procedure of incising sinuses and
tangential peeling off affected tissue is continued until the whole area is clear of lesional
tissue and fibrosis. Finally, the wound margins are meticulously checked with a probe for
the presence and removal of any residual sinus tracts. Hemostasis is achieved by using the
coagulation mode of the Erbotoom. The wound margins (i.e. healthy tissue) are injected with
triamcinolonacetonide 10-20mg and bupivacaine 0.5%(10ml) to prevent hypergranulation.
Wounds are left open to heal by secondary intention. Post-operative wound care consists
of twice daily irrigation followed by alginate and silicone dressings. Pain is managed with
acetaminophen, non-steroidal anti-inflammatory drugs or, in severe cases, opiates. Generally,
patients can leave the hospital on the day of surgery.
Figure 2 illustrates an example of the satisfying cosmetic results we achieve with the STEEP
procedure. This 46-year old woman with severe therapy resistant HS in the genital area was
initially treated with intravenous infliximab for six months. After five infusions, inflammatory
activity had improved and the STEEP procedure was then successfully performed in two
separate sessions. Currently (i.e. three years later), the disease is still in remission. Additionally,
her quality of life has significantly improved, as reflected in a reduction of her Dermatology Life
Quality Index (DLQI) from 28 points (maximum: 30) at the beginning of infliximab treatment
to 3 points at eight months after the final STEEP procedure.
101
Figure 1. Wide excision (a): red dotted line represents the cutting surface. Healthy tissue is removed and resection reaches
into the subcutaneous fat. STEEP-procedure (b): inflammatory nodules, sinus tracts and scar tissue are localized by a
probe or with palpation. Affected tissue is then peeled off layer by layer by means of multiple tangential transsections (red
dashed lines). The epithelial lining is spared in non-inflammatory sinus tracts but is totally excised in inflammatory sinus
tracts (blue dashed lines). The procedure is repeated until a plane has been obtained that is free of lesional tissue. The
result is that the final defect is smaller compared to wide excision.
Figure 2. Right groin before treatment with the STEEP procedure. Sondage with a tissue forceps demonstrates the depth
of the sinus tract (a). The right groin 24 weeks after the STEEP procedure (b).
Epidermis
Subcutaneous fat
Dermis
Sinus tract (non-inflammatory) Inflammatory nodule
(a) (b)
(a) (b)
102
DIScUSSIoNTreatment of HS is a challenge for both physicians and patients due to its complex and largely
unknown pathogenesis. It is generally accepted that in order to achieve satisfying results in
severe cases (Hurley stage II/III disease), a dual therapeutic approach is required.5 Usually, the
first step is inhibition of inflammatory activity with anti-inflammatory or immunosuppressive
agents, including infliximab.5,6 However, systemic treatment will not restore the skin’s
original architecture, meaning that epithelialized cysts and sinus tracts will remain present
in the affected skin once the inflammation has been treated. This may facilitate access for
(commensal) bacteria, leading to repetitive inflammation and further extension of the disease,
with ever-increasing architectural destruction.7 This vicious circle can only be interrupted by
surgical removal of these residual lesions.
The STEEP procedure is a promising tissue-saving surgical technique for HS Hurley stage II/III.
Tissue-saving surgical techniques are importance to HS for two main reasons: (i), HS especially
occurs in the body folds, which are areas prone to the formation of contractures after surgery
and (ii) large interconnected skin areas are frequently involved, making it even more important
to reduce the size of the already large surgical defects to a minimum. A suitable tissue-saving
surgical technique for Hurley stage I or limited stage II disease is the deroofing technique.3,4
However, in case of extensive Hurley stage II/III disease dominated by fibrotic tissue, the
deroofing technique is ineffective since fibrosis is not removed. Removal of fibrotic tissue is
important because it may contain skin appendages that serve as a source for recurrence and
also prevent adequate wound contraction and subsequent healing. In addition, the deroofing
technique is too time-consuming in severe HS. Surgical intervention by means of wide excision
is therefore often considered as the most effective treatment in these cases.8 However, the
STEEP procedure has several advantages over both wide excision and the deroofing technique
in severe HS. First, wide excisions always reach into the healthy deep subcutaneous fat, while
the STEEP procedure with its successive tangential transsections leaves the epithelialized
bottoms of the sinus tracts and a large extent of the subcutaneous fat intact, leading to more
superficial and smaller defects (fig 2). This results in relatively shorter healing times and fewer
complications, such as contracture formation. Furthermore, recurrence rates around the
operated area are reduced to a minimum since at the end of the STEEP procedure residual
affected tissue is identified and removed by sondaging the final wound margins with a probe
and extensive palpation. Tissue-sparing surgery in HS can also be accomplished with the use
of a CO2 laser, as previously demonstrated.9-13 The main advantage of CO2 laser incision is that
proper hemostasis is achieved allowing adequate visualization of remaining lesional tissue.
During the STEEP procedure prompt cauterization of bleeding vessels can be easily achieved
103
as well by switching between the surgery and electrocautery mode of the electrosurgical unit
using a foot pedal. For the performance of multiple transversal sections as we describe for our
surgical technique, electrosurgery has some important advantages over CO2 laser, namely:
(i) the depth of vertical incisions with transversal electrosection is more easily controlled and
adjusted by the surgeon. This leaves the epithelialized sinus bottom intact and warrants deep
excision of fibrotic and inflammatory tissue at the same time while a CO2 laser removes a
continuous horizontal plane of one depth, making it less precise and less tissue-sparing; (ii)
laser treatment is more expensive in terms of purchasing the device, the need for a special
room to perform the treatment and safety notices; and (iii) a basically trained dermatosurgeon
can perform electrosurgery, while laser treatment requires more experience and skills.
In our clinic, we have performed the STEEP procedure under general anesthesia in 156
patients with Hurley stage II/III disease between 2004 and 2013. The feedback from the
patients is generally very positive. Patients with extensive disease at multiple locations were
usually operated in several sessions. The wounds are allowed to heal by secondary intention
since in our experience, and that of others, it is time-efficient and leads to good cosmetic and
functional results.14,15 Furthermore, it allows prolonged wound drainage, diminishing the risk of
wound infection.14
In conclusion, we consider the STEEP procedure with electrosurgery superior over wide
resections and deroofing in Hurley stage II/III disease for several reasons: (i) recurrence rates
are low as it specifically aims at complete removal of lesional and fibrotic tissue; (ii) it saves
healthy tissue to a maximum which leads to rapid healing, satisfying cosmetic results and
prevention of contractures; (iii) healing time is further improved by allowing re-epithelization
of the defects from the intact epitheliazed sinus floors and dermal tissue where possible
rather than from subcutaneous fat; and (iv) in contrast to laser surgery the procedure can be
performed by basically trained dermatologic surgeons.
104
REfERENcES
Revuz J. Hidradenitis suppurativa. 1. J Eur Acad Dermatol Venereol 2009; 23:985-98.
Hurley HJ. Axiillairy hyperhidrosis, apocrine bromhidrosis, hidradenitis suppurativa, and familial benign 2.
pemphigus: surgical approach. In: Dermatologic Surgery (Roenigh R.K, Roenigh HH,eds). New York:
Marcel Dekker, 1989; 729-39.
Van der Zee HH, Prens EP, Boer J. Deroofing: a tissue-saving surgical technique for the treatment of 3.
mild to moderate hidradenitis suppurativa lesions. J Am Acad Dermatol 2010; 63:475-80.
van Hattem S, Spoo JR, Horvath B, Jonkman MF, Leeman FW. Surgical treatment of sinuses by 4.
deroofing in hidradenitis suppurativa. Dermatol Surg 2012; 38:494-97.
Van Rappard DC, Mekkes JR. Treatment of severe hidradenitis suppurativa with infliximab in 5.
combination with surgical interventions. Br J Dermatol 2012; 167:206-8.
Blok JL, van Hattem S, Jonkman MF, Horvath B. Systemic therapy with immunosuppressive agents 6.
and retinoids in hidradenitis suppurativa: a systematic review. Br J Dermatol 2013; 168:243-52.
van der Zee HH, Laman JD, Boer J, Prens EP. Hidradenitis suppurativa: viewpoint on clinical 7.
phenotyping, pathogenesis and novel treatments. Exp Dermatol 2012; 21:735-39.
Alikhan A, Lynch PJ, Eisen DB. Hidradenitis suppurativa: a comprehensive review. 8.
J Am Acad Dermatol 2009; 60:539-61.
Jain V, Jain A. Use of lasers for the management of refractory cases of hidradenitis suppurativa and 9.
pilonidal sinus. J Cutan Aesthet Surg 2012; 5:190-92.
Lapins J, Marcusson JA, Emtestam L. Surgical treatment of chronic hidradenitis suppurativa: CO2 laser 10.
stripping-secondary intention technique. Br J Dermatol 1994; 131:551-56.
Madan V, Hindle E, Hussain W, August PJ. Outcomes of treatment of nine cases of recalcitrant severe 11.
hidradenitis suppurativa with carbon dioxide laser. Br J Dermatol 2008; 159:1309-14.
Hazen PG, Hazen BP. Hidradenitis suppurativa: successful treatment using carbon dioxide laser 12.
excision and marsupialization. Dermatol Surg 2010; 36:208-13.
Bratschi HU, Altermatt HJ, Dreher E. Therapy of suppurative hidradenitis using the CO2-laser. Case 13.
report and literature review. Schweiz Rundsch Med Prax 1993; 82:941-45.
105
Bieniek A, Matusiak L, Chlebicka I, Szepietowski JC. Secondary intention healing in skin surgery: our 14.
own experience and expanded indications in hidradenitis suppurativa, rhinophyma and
non-melanoma skin cancers. J Eur Acad Dermatol Venereol 2013; 27:1015-21.
Wollina U, Tilp M, Meseg A, Schonlebe J, Heinig B, Nowak A. Management of severe anogenital acne 15.
inversa (hidradenitis suppurativa). Dermatol Surg 2012; 38:110-17.
107
8SURgERy UNDER gENERAL ANESTHESIA IN SEVERE HIDRADENITIS SUPPURATIVA: A STUDY OF 363 PRIMARY OPERATIONS IN 113
PATIENTS
J.L. Blok, MD1; M. Boersma, MD1; J.B. Terra, MD PhD1; J.R. Spoo, MD PhD1; F.W.J. Leeman,
MD2; E.R. van den Heuvel, MD PhD3; J. Huizinga, MSc, RN1; M.F. Jonkman, MD PhD1; B.
Horváth, MD PhD1
1Department of Dermatology, University of Groningen, University Medical Center Groningen,
Hanzeplein 1, 9700 RB Groningen, the Netherlands 2Department of Dermatology, Antonius Hospital, 8601 ZK Sneek, The Netherlands 3Department of Epidemiology, University of Groningen, University Medical Center Groningen,
Hanzeplein 1, 9700 RB Groningen, the Netherlands
Published in the Journal of the European Acadamy of Dermatology and Venereology,
2015 doi: 10.1111/jdv.12952
108
ABSTRAcT Background: Treatment of hidradenitis suppurativa (HS) is a difficult undertaking, especially
since there is no consensus on what surgical technique is preferred. At our center severe HS
(Hurley II/III) is operated under general anesthesia, mostly with the STEEP-procedure.
Objectives: To investigate characteristics, surgical outcomes and patient satisfaction of HS
patients who underwent deroofing or STEEP under general anaesthesia.
Methods: A clinical records-based retrospective analysis was conducted of all patients who
had surgery under general anesthesia between 1999 and 2013. Patient satisfaction was
retrospectively investigated with questionnaires.
Results: A total of 482 operations (363 primary operations and 119 re-operations) was
performed during the study period. The proportion of women in the included population
was 68%. The median diagnostic delay (patient’s and doctor’s delay) was 6.5 years. Relapses
occurred after 29.2% of primary operations. Women had higher relapse rates than men (odds
ratio 2.85 [1.07;7.61]). Hypergranulation of the wound was the most common complication
and occurred in 7% of all operations. The median score patients attributed to the medical
effect of surgery was 8 out of 10 (zero corresponding to very dissatisfied and 10 to very
satisfied).
Conclusion: The diagnostic delay in HS is long due to a lack of knowledge in both patients
and health care professionals, indicating that there is a need for education. Deroofing and
the STEEP are effective surgical procedures in severe cases of HS and lead to a relatively high
patient satisfaction. The post-operative relapse risk is higher in women. Prospective studies are
required for the development of clear guidelines on the appropriate choice of surgery.
109
INTRoDUcTIoN Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with varying phenotypes.
The clinical severity is often classified according to the Hurley stages.1 Stage I is characterized
by abscesses and nodules while in stage II and III sinus tracts have been formed. The presence
of healthy skin between the lesions differentiates Hurley stage II from III disease. Several
treatment modalities are available for HS and usually a combination of different treatment
modalities is required. An effective topical treatment is resorcinol 15%.2 However, severe cases
require systemic and surgical treatment. Systemic treatment options include acitretin, antibiotics
and tumour-necrosis-factor-α (TNF-α)-inhibitors.3-6 Though these systemic agents may be able
to improve the inflammatory component, the architectural skin destructions that may have
been formed as a consequence of HS remain. Therefore, surgery is mandatory in the treatment
of severe HS.
There is no consensus on the most suitable surgical technique for HS. Optional methods
are (i) treatment of each individual lesion with deroofing,7,8 carbon dioxide laser treatment
or excision;9 (ii) radical excision of the entire affected area with wide margins;10 and (iii)
excision of the entire area encompassing all lesions with the “skin-tissue-saving excision with
electrosurgical peeling” (STEEP) technique;11 A detailed description of the STEEP technique
was recently published by our group.11 In short, the STEEP aims at removing all lesional tissue
by performing subsequent tangential transections (fig. 1, chapter 7). In contrast to wide
excision, which serves the same goal, the STEEP technique saves healthy tissue to a maximum.
Regardless of the applied surgical technique, wound closure for HS may be achieved with
sutures, skin grafts or flaps, or by secondary intention.12 Surgery is performed under local or
general anesthesia, a choice usually depending on the extensiveness of HS.
At our specialized day care center, we are able to perform surgery in HS patients under general
anesthesia. The use of general anesthesia enables us to treat large surface areas without
being limited by the maximum allowed amount of local anesthetics. There is an indication for
the STEEP procedure when patients have extensive stage II or III disease. In these cases the
deroofing technique is too superficial and therefore not sufficient as fibrotic scar tissue that may
serve as a source of relapsing disease, is not being removed. When patients with Hurley stage
I or limited stage II disease refuse to be operated with the deroofing technique under local
anesthesia, general anesthesia is also applied. In both, the STEEP and the deroofing technique
the wounds heal by secondary intention.
In this retrospective study we describe the characteristics of HS patients who underwent
deroofing or the STEEP-procedure under general anesthesia. Furthermore, we evaluate the
characteristics, outcomes and patient satisfaction regarding these treatments.
110
MATERIAL AND METHoDS Study design and subjects
The medical charts of all patients who underwent surgical treatment under general anesthesia
between May 1999 and January 2013 at our day care center were retrospectively analyzed by
two authors (J.L.B and M.B). Our day care center applies strict criteria regarding body mass
index (BMI): patients with a BMI ≥35 kg/m2 are refused for operation. The data were stored in
a database (SPSS Statistics 20 IBM, Armonk, New York, USA). The authors randomly checked
each other’s data extraction.
Primary parameters:
Characteristics of patients and surgeries
Patients’ characteristics included gender, age, smoking status, BMI and family history. Disease
severity was defined as the Hurley stage at the first visit to our department. Diagnostic history
included the diagnostic delay (sum of patient’s and doctor’s delay) and the number of visited
doctors before referral to our specialized center was achieved. The use of co-medication for HS
was only recorded if it had been used ≥2 months post-operatively.
Secondary parameters:
Surgical outcomes
These included the percentage of remissions, post-operative general disease activity, relapses
due to irradical surgery, natural disease progression and complications. Surgeries were divided
into primary operations and re-operations. Primary operations were surgeries performed for
the first time in a specific anatomical area. Any subsequent surgical procedures within that
anatomical area were defined as re-operations. General disease activity was defined as post-
operative inflammatory activity (abscesses, nodules or fistulas) occurring within the operated
anatomical area after a primary operation and was further subdivided into relapses due to
irradical surgery and natural progression of the disease. Relapses due to irradical surgery were
defined as inflammatory activity occurring within or at the border of the surgical scar and
considered unknown when the post-operative follow-up period was <8 weeks. Inflammation
in the operated anatomical area occurring outside the surgical scar was considered as natural
disease progression. Complications were recorded for all surgeries, including re-operations.
111
Factors influencing the risk of relapse
It was investigated whether disease location, gender, age, smoking status, BMI, and the use of
co-medication were associated with the occurrence of relapses.
Tertiary parameters:
Patient reported outcomes
Patients’ opinion about their surgical treatment was assessed with questionnaires. Patients who
were <18 years, mentally retarded or deceased were excluded. Patients were asked to name
the best treatment they ever had for HS and to rate their satisfaction regarding the cosmetic
and medical outcomes of the surgery on a scale from 0 (very dissatisfied) to 10 (very satisfied).
Medical ethical committee
In the Netherlands, retrospective studies of patient records and short questionnaires do not
need to be reviewed by a medical ethical committee.
Statistical analysis
Patients’ and surgical characteristics and outcomes were analyzed with descriptive statistics.
The chi-square test was used to compare differences between groups. A p-value <0.05 was
considered significant. A generalized linear mixed model (GLMM) was selected to investigate
whether the aforementioned variables influenced the relapse risk. A logit link function and a
random intercept were applied to address for repeated measurements in subjects (in multiple
subjects >1 anatomical area was operated). First, the variables were individually put into the
model. If the P-value of the fixed effect or the interaction effect with disease location was
below 0.25, the variable was selected for a multivariable model. In the second part of the
analysis a multivariable model was created containing all variables including their interaction
with location. Backward elimination was applied at the significance level of 0.05. The least
significant terms were eliminated one by one, keeping the model hierarchical. The analyses
were conducted with the procedure GLIMMIX of SAS institute.
112
RESULTS Primary outcomes
Characteristics of patients and surgeries
We included 113 HS patients in this study (male: female ratio = 1:2.1) (Table 1). Hurley stage
I disease was present in 11.5% of patients, stage II in 77.9% and stage III in 10.6%. In 23
patients the first symptoms appeared at the age of 16 years or younger and in five patients
before the age of 11. The median diagnostic delay was 6.5 years. On average, patients had
seen 2.35 doctors before they were referred to our specialized center and in 27.4% an accurate
diagnosis of HS had not been made until then. The median time between disease onset and
surgery under general anesthesia was 12.0 years (IQR seven-18 years). The groins and armpits
were affected in 85.8% and 62.8% of patients respectively (table 2). The buttocks were
significantly more often involved in men compared to women (69.4% vs. 41.6% respectively,
P=0.008). The main indication for general anesthesia was the extensiveness of disease
(64.6%), followed by request of the patient (30.1%), mental retardation since consciousness
during surgery may be traumatic for these patients and might hinder the procedure (2.7%) and
location of the disease (2.7%).
Secondary parameters
Surgical outcomes
A total of 482 regions were operated under general anesthesia in 113 patients (363 primary
operations and 119 re-operations). The mean number of locations treated within a single
surgical procedure was 2.4. Most primary operations were performed in the groins (40.5%),
followed by the armpits (22.9%), buttocks (19.8%) and genital area (10.2%) (table 3).
Complications developed in 16% of the 482 operations with the highest percentage occurring
in the armpits (33.7%). Hypergranulation of the wound was the most common complication
and occurred in 7.2% of all operations, followed by wound infections and post-operative
bleeding which both occurred in 1.8% of operations. Remission at the operated anatomical
area was achieved in 132 of 363 primary operations (Fig. 2). Disease activity at the operated
anatomical area eventually developed after 230 of 363 primary operations of which 124 were
considered as natural disease progression and 106 as true relapses due to irradical surgery.
113
Factors influencing the risk of relapse
For the first screening the variables “disease location” (P = 0.113), “gender” (P = 0.037)
and “smoking” (P = 0.141) were selected for the multivariable model (GLMM). The second
screening for variables investigating a possible interaction effect with location, indicated
that both gender (P = 0.111) and smoking (P = 0.061) should be selected. After backward
elimination the final model only contained the variable “gender” (P = 0.0369). The odds ratio
[95% CI] for gender was 2.85 [1.07; 7.61], indicating that women have a significant higher
risk of relapses after surgery.
Tertiary outcomes
Patient satisfaction
The questionnaire was sent to 105 of 113 patients. Home addresses were missing in three
patients, three patients had been deceased and two patients were mentally retarded. A total
of 66 of 105 patients responded. There were no significant differences between responders
and non-responders with respect to gender (P = 0.93) and relapses due to irradical surgery
(p=0.42). Surgery under general anesthesia was the best treatment for HS according to 76%
of responders. The median satisfaction scores for the medical and cosmetic effects of surgery
were, respectively, 8.0 and 6.0 out of 10.
114
n %
Sex Men 36 31.9
Women 77 68.1
Smoking status Never smoked 13 12.5
Missing: 3 Current/former smoker 91 87.5
BMI (kg/m2) Normal weight (≤24) 46 41.8
Missing: 3 Overweight (>24-29) 36 32.7
Obesity (≥30) 28 25.5
Hurely stage I 13 11.5
II 88 77.9
III 12 10.6
Age at onset of disease Mean (SD) 23.1 (8.2)
Missing: 6 ≤16 years 22 20.6
>16-39 years 81 75.7
≥40 years 4 3.7
Previously visited doctors Mean number of visited doctors (range)* 2.35 (0-7)
Missing: 50 Specialist who made diagnosis:
-General practitioner 12 19
-Dermatologist 43 68.3
-Surgeon 5 7.9
-Gastroenterologist 1 1.6
-Other 2 3.2
Median diagnostic delay in years (IQR**)
Missing: 59
6.5 (2.8-13.5)
Median time between disease onset and surgery under general anesthesia in years (IQR***)
Missing: 6
12.0 (7.0-18.0)
Previous treatments Incision/drainage 63 55.8
Wide excision 33 29.2
Deroofing under local anesthesia 28 24.8
Systemic antibiotics 110 97.3
Isotretinoin 22 19.5
Biologicals 7 7.2
*Before referral to our centre; **Standard deviation; ***Interquartile range
Table 1. Patient characteristics
115
Location Total, n=113 Men, n=36 Women, n=77 P-value1
n % n % n %
Armpits 71 62.8 26 72.2 45 58.4 0.210
Groins 97 85.8 28 77.8 70 90.9 0.074
Genital area2 57 50.4 21 58.3 37 48.1 0.322
Buttocks 57 50.4 25 69.4 32 41.6 0.008*
Submammary area 16 14.2 - - 16 28.6 -
Abdominal fold 14 12.4 8 22.2 6 7.8 0.062
Retroauricular/neck 9 8.0 5 13.9 4 5.2 0.141
Other areas3 29 25.7 16 44.4 13 16.9 0.003*
1Chi-square test; 2mons pubis, scrotum or labia; 3cheeks (n=1), upper legs (n=14), chest (n=5), underneath stoma pouch (n=1), popliteal
space (n=3), back (n=2) rump bone (n=5)
*Significant difference
Table 2. Affected locations
116
Armpits Groins Genital area Buttocks Other areas* Total
Number of operations
Primary operations 83 147 37 72 24 363
Re-operations 15 58 14 30 2 119
Total 98 205 51 102 26 482
Hurley stage, n (% of primary operations)
I 12 (14.5) 19 (12.9) 11 29.7) 25 (34.7) 11 (45.8) 78 (21.4)
II/III 71 (85.5) 126 (85.7) 22 (9.4) 44 (61.1) 13 (54.2) 276 (76.0)
Unknown - 2 (1.4) 4 (10.8) 3 (4.2) - 9 (2.5)
Co-medication, n
Tetracyclines 12 34 9 22 4 81
Clindamycine/rifampicin - - - - - -
Erythromycin - 4 2 2 1 9
Other antibiotics - 2 2 - - 4
Steroids - - 1 3 3 7
Biologicals 1 5 2 3 - 11
Complications, n (% of total operations)
None 65 (66.3) 183 (89.3) 48 (94.1) 88 (86.3) 21 (80.8) 406 (84.0)
Wound infection 2 (2.0) 4 (2.0) 1 (2.0) 1 (1.0) 1 (3.8) 9 (1.9)
Nervce irritation 4 (4.1) - - - 1 (3.8) 5 (1.0)
Bleeding 1 (1.0) 3 (1.5) 1 (2.0) 3 (2.9) 1 (3.8) 9 (1.9)
Stricture 3 (3.0) - - - - 3 (0.6)
Pain >4 weeks 1 (1.0) 1 (0.5) 1 (2.0) 2 (2.0) - 5 (1.0)
Other** 22 (22.4) 14 (6.8) - 6 (5.9) 2 (7.7) 44 (9.1)
Follow-up in months
Median 31.0 47.0 29.0 48.0 33.5 43.0
(IQR) (9-89) (14-93) (11-67) (17-91) (21-79) (14-87.5)
*Mammary region (n = 5), chest (n = 2), upper legs (n = 4), abdomen (n = 7), neck (n = 1), retroauricular area (n = 1), popliteal stump (n
= 1), sacrum (n = 3). **Hypergranulation (n = 35), hypertrophic scar (n = 4), hyperpigmentation (n = 2), delayed wound healing (i.e. >3
months; n = 3).
Table 3. Characteristics of surgery in each location
117
Figure 2. Outcomes of primary operations for each anatomical area.
118
DIScUSSIoN With a total of 482 operations performed in 113 patients and a median follow-up time
of 43 months this is one of the largest studies on surgical treatment for HS so far. The
percentage of men in our severely affected population was higher compared to the general
HS population.13,14 In agreement with other studies,14,15 men had significantly more often
involvement of the buttocks which is probably due to a higher density of terminal hair follicles.
The low percentage (10.6%) of Hurley stage III disease is probably an underestimation as
it was frequently impossible to discriminate between stage II and III from the description in
the medical charts. Although HS is regarded as a post-pubertal disease,16 20% of patients
were 16 years or younger at the onset of disease suggesting that a (pre-)pubertal onset is
not uncommon in severely affected patients. Similar to studies conducted in relatively milder
affected HS populations, 32% of our patients had a positive family history for HS.14,17 This
supports the finding that a positive family history is not associated with a more severe course
of the disease.14 The mean BMI of our patients was similar to another Dutch population,7 but
lower compared to studies from other countries.15,18 The difference could be explained by
demographic factors as well as by the selection bias in our study where patients with a BMI
≥35kg/m2 were excluded. Of our patients 80% were current/former smokers, underlining once
again the important role of tobacco in HS.13-15,18,19
Early diagnosis and proper treatment are crucial as HS tends to get more severe over time and
the risk of complications increases with longstanding disease.20 The median diagnostic delay in
our study was 6.5 years, others demonstrated delays of 3.3-12 years.15,21 In our study, surgery
under general anesthesia was performed after a median disease duration of respectively 12
years. Rompel et al.22 reported the results of surgery in patients with a mean disease duration
of 7 years, Kagan et al.23 in patients with a mean disease duration of 6.7 years (0.5-40 years)
and Mandal et al.24 in patients with a median disease duration of 6 years (range 1-30 years).
This illustrates that our population had substantial longstanding HS, making it difficult to
directly compare our results to others. The majority of our patients was previously operated
under local anesthesia by deroofing or wide excision (Table 1). Unfortunately we were not able
to determine the time between the first onset of symptoms and the first surgical intervention
in our study population, however, many patients report that it took several years. The mean
period between disease onset and the first surgical intervention in the patients described
by Bieniek et al.25 was 7.6 (±7.1) years. Therapeutic delays are thus substantial in HS. It is
therefore important that patients are referred to a dermatologist on a short notice for proper
diagnosis and treatment with systemic agents and surgery. Educating general physicians is thus
crucial.
119
Relapses due to irradical surgery occurred in 29% of the 363 primary operations. Studies on
radical excision with varying closing techniques showed relapse rates of 2.5-70%.10,22,25-29 None
of the 57 patients that were retrospectively studied by Kagan et al.23 had relapses after wide
excision, however, the mean follow-up time was relatively short (8.5 months). Van der Zee et
al.7 described a relapse rate of 17% after deroofing for Hurley stage I/II. The bottom line is that
studies on surgical treatments are very heterogeneous with respect to patient numbers, disease
severity, disease location, surgical techniques, definitions of surgical outcomes (e.g. relapses
and natural disease progression) and follow-up times, making direct comparisons impossible.
A new finding is that women had significantly higher relapse rates than men. It could be that
the pathogenesis of HS is more subjected to the influence of sex hormone levels (including
androgens and estrogens) in women, resulting in a more fluctuating and chronic course of
the disease. The female hormone estrogen has indeed an effect on the immune system:30
it attenuates amongst others neutrophilic inflammatory responses and the release of pro-
inflammatory cytokines such as TNF-α, IL-1β and IL-17 which are key players in HS.31,32
Clinically, this is reflected in the observation that exacerbations are frequently reported during
relatively hypo-estrogenic states (e.g. post-partum and during the premenstrual period) and
improvement during the use of estrogen containing contraceptive pills.33,34 Estrogens may thus
have a protective role during the course of HS. However, despite a fall in estrogen levels HS
usually improves after the fourth decade. This possibly results from a simultaneous decline in
androgen levels.35 To our surprise age, smoking, disease location and the use of co-medication
did not have a statistically significant effect on the risk of relapse. Natural disease progression
occurred frequently after surgery suggesting that the effectiveness of surgery stays limited to
the operated area. Obviously, the question then arises whether saving as much healthy tissue
as possible is actually a proper aim in HS. The main focus of future studies should therefore be
whether wide excision alone or the use of minimal invasive surgical techniques (e.g. the STEEP)
with perioperative immunosuppression should be preferred to prevent natural progression of
the disease. Similar to other studies, complications occurred in 16% of the operations.(10,22,25,29)
When operating the armpits, caution should be taken for the brachial plexus since this nerve
plexus is prone to iatrogenic injuries.36
Patients were satisfied regarding the medical effect of surgery under general anesthesia. Less
severely affected patients attributed the same median score to the deroofing technique under
local anesthesia.7 The cosmetic effect was rated lower than the medical outcomes in our study
which is understandable since the wounds always heal with scar tissue. Van Rappard et al.37
retrospectively studied the cosmetic results in a group of patients who were treated with
local excision and primary closure. In this study 83% of patients rated the cosmetic results
120
as reasonable or good, however, it is hard to directly compare these results to our study since
their patient population had less severe disease (Hurley stage I or II) and different outcome
measurements were used. A significant majority of our patients reported that surgery was the
best treatment they ever had for HS. This indicates that medical rather than cosmetic effects
are most important to patients, which was also pointed out by Van Rappard et al.37 Still, these
scores reflect that further improvement of surgical techniques is required in terms of both
medical and cosmetic outcomes.
Limitations
This study has a selection bias since patients with a BMI ≥35 kg/m2 are excluded for surgery.
Missing data due to the retrospective character of the study make some percentages less
reliable. Difficulties in distinguishing Hurley stage II from stage III made it impossible to
determine whether the relapse risk after surgery is affected by disease severity. The mean time
to wound healing could not be extracted from our data. A response rate to the questionnaires
of 63% indicates a risk of bias, even though there were no differences between responders and
non-responders in terms of gender and relapses.
conclusion
This study suggests that male gender and early onset of HS are risk factors for developing
severe HS. There are still long diagnostic and therapeutic delays for HS underlining the
importance of educating patients and primary health care physicians. Deroofing and STEEP
under general anesthesia lead to good medical and cosmetic results and should be performed
at an early stage of the disease. Deroofing should be reserved for Hurley stage I or limited
II disease whereas STEEP is indicated in extensive stage II and III disease. The risk of post-
operative relapses is significantly higher in women, possibly as a result of hormonal differences.
Prospective studies on surgical techniques with predetermined outcomes and validated patient
reported outcomes are required to develop guidelines for the appropriate choice of surgery.
121
REfERENcES
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; 729-39.
Boer J, Jemec GB. Resorcinol peels as a possible self-treatment of painful nodules in hidradenitis
suppurativa. Clin Exp Dermatol 2010; 35:36-40.
Boer J, Nazary M. Long-term results of acitretin therapy for hidradenitis suppurativa. Is acne inversa also a
misnomer? Br J Dermatol 2011; 164:170-75.
Matusiak L, Bieniek A, Szepietowski JC. Acitretin treatment for hidradenitis suppurativa: a prospective series
of 17 patients. Br J Dermatol 2014; 1:170-74.
Matusiak L, Bieniek A, Szepietowski JC. Bacteriology of Hidradenitis Suppurativa - Which Antibiotics are
the Treatment of Choice? Acta Derm Venereol 2014; 6:699-702 .
Blok JL, van Hattem S, Jonkman MF, Horvath B. Systemic therapy with immunosuppressive agents and
retinoids in hidradenitis suppurativa: a systematic review. Br J Dermatol 201; 2:243-52.
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; 63:475-480.
van Hattem S, Spoo JR, Horvath B, et al. Surgical treatment of sinuses by deroofing in hidradenitis
suppurativa. Dermatol Surg 2012; 38:494-97.
Lapins J, Sartorius K, Emtestam L. Scanner-assisted carbon dioxide laser surgery: a retrospective follow-up
study of patients with hidradenitis suppurativa. J Am Acad Dermatol 2002; 47:280-85.
Alharbi Z, Kauczok J, Pallua N. A review of wide surgical excision of hidradenitis suppurativa.
BMC Dermatol 2012; 12:9-5945-12-9.
Blok JL, Spoo JR, Leeman FW, et al. Skin-Tissue-sparing Excision with Electrosurgical Peeling (STEEP): a
surgical treatment option for severe hidradenitis suppurativa Hurley stage II/III.
J Eur Acad Dermatol Venereol 2014; 2: 379-82.
Ather S, Chan DS, Leaper DJ, Harding KG. Surgical treatment of hidradenitis suppurativa: case series and
review of the literature. Int Wound J 2006; 3:159-69.
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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.
Canoui-Poitrine F, Revuz JE, Wolkenstein P, et al. Clinical characteristics of a series of 302 French patients
with hidradenitis suppurativa, with an analysis of factors associated with disease severity.
J Am Acad Dermatol 2009; 61:51-57.
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; 133:97-103.
Alikhan A, Lynch PJ, Eisen DB. Hidradenitis suppurativa: a comprehensive review. J Am Acad Dermatol
2009; 60:539-61; quiz 562-3.
Canoui-Poitrine F, Le Thuaut A, Revuz JE, et al. Identification of Three Hidradenitis Suppurativa
Phenotypes: Latent Class Analysis of a Cross-Sectional Study. J Invest Dermatol 2013; 6:1506-11.
Sartorius K, Emtestam L, Jemec GB, Lapins J. Objective scoring of hidradenitis suppurativa reflecting the
role of tobacco smoking and obesity. Br J Dermatol 2009; 161:831-39.
Matusiak L, Bieniek A, Szepietowski JC. Hidradenitis suppurativa and associated factors: still unsolved
problems. J Am Acad Dermatol 2009; 61:362-65.
Lapins J, Ye W, Nyren O, Emtestam L. Incidence of cancer among patients with hidradenitis suppurativa.
Arch Dermatol 2001; 137:730-34.
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; 18:165-72.
Rompel R, Petres J. Long-term results of wide surgical excision in 106 patients with hidradenitis
suppurativa. Dermatol Surg 2000; 26:638-43.
Kagan RJ, Yakuboff KP, Warner P, Warden GD. Surgical treatment of hidradenitis suppurativa: a 10-year
experience. Surgery 2005; 138:734-40; discussion 740-1.
Mandal A, Watson J. Experience with different treatment modules in hidradenitis suppuritiva: a study of
106 cases. Surgeon 2005; 3:23-26.
Bieniek A, Matusiak L, Okulewicz-Gojlik D, Szepietowski JC. Surgical treatment of hidradenitis suppurativa:
experiences and recommendations. Dermatol Surg 2010; 36:1998-2004.
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Ritz JP, Runkel N, Haier J, Buhr HJ. Extent of surgery and recurrence rate of hidradenitis suppurativa.
Int J Colorectal Dis 1998; 13:164-68.
Tanaka A, Hatoko M, Tada H, et al. Experience with surgical treatment of hidradenitis suppurativa.
Ann Plast Surg 2001; 47:636-42.
Menderes A, Sunay O, Vayvada H, Yilmaz M. Surgical management of hidradenitis suppurativa.
Int J Med Sci 2010; 7:240-47.
Wollina U, Tilp M, Meseg A, et al. Management of severe anogenital acne inversa (hidradenitis
suppurativa). Dermatol Surg 2012; 38:110-17.
Nadkarni S, McArthur S. Oestrogen and immunomodulation: new mechanisms that impact on peripheral
and central immunity. Curr Opin Pharmacol 2013; 13:576-81.
Schlapbach C, Hanni T, Yawalkar N, Hunger RE. Expression of the IL-23/Th17 pathway in lesions of
hidradenitis suppurativa. J Am Acad Dermatol 2011; 65:790-98.
van der Zee HH, de Ruiter L, van den Broecke DG, et al. Elevated levels of tumour necrosis factor (TNF)-
alpha, interleukin (IL)-1beta and IL-10 in hidradenitis suppurativa skin: a rationale for targeting TNF-alpha
and IL-1beta. Br J Dermatol 2011; 164:1292-98.
Mortimer PS, Dawber RP, Gales MA, Moore RA. Mediation of hidradenitis suppurativa by androgens.
Br Med J (Clin Res Ed) 1986; 292:245-48.
Harrison BJ, Read GF, Hughes LE. Endocrine basis for the clinical presentation of hidradenitis suppurativa.
Br J Surg 1988; 75:972-75.
Davison SL, Bell R, Donath S, et al. Androgen levels in adult females: changes with age, menopause, and
oophorectomy. J Clin Endocrinol Metab 2005; 90:3847-53.
Shveiky D, Aseff JN, Iglesia CB. Brachial plexus injury after laparoscopic and robotic surgery.
J Minim Invasive Gynecol 2010; 17:414-20.
van Rappard DC, Mooij JE, Mekkes JR. Mild to moderate hidradenitis suppurativa treated with local
excision and primary closure. J Eur Acad Dermatol Venereol 2012; 26:898-902.
125
9gENERAL DIScUSSIoN AND fUTURE PERSPEcTIVE
J.L. Dickinson-Blok
126
HS is evolving from a relative orphan disease towards being a renewed scientific topic.
Originally, HS was regarded as a disease of the apocrine sweat glands, hence the term
“hidradenitis suppurativa”. In 1952 it was dr. Brunsting who proposed, for the first time,
that the initial inflammation occurrs in the hair follicle with apocrine involvement occurring
only upon extension of the inflammatory process to deeper skin layers.1 Ever since, several
histological studies found that follicular hyperkeratization followed by occlusion are central
pathogenic events, rather than involvement of the sweat glands.2-5 Since no specific pathogenic
bacteria have been identified in HS, it has been suggested that aberrant immunity rather than
bacteria are responsible for the inflammatory reaction in HS6-8 The suspected association of HS
with other immune mediated diseases further supports a key role of aberrant immunity in its
pathogenesis.9
Many questions remain regarding the pathogenesis of HS and therefore the identification of
appropriate treatment targets is challenging. Although a wide arsenal of systemic agents and
surgical interventions have been described for HS, many patients are refractory to treatment.
Consequently, HS is a frustrating disease for both patients and clinicians. In this thesis we
aimed at gaining more insight in the pathogenesis of HS and explored both current and new
treatment options, including systemic and surgical therapies. The following chapter will discuss
the main findings of this thesis, combined with perspectives for future research.
To further investigate the histopathogenesis of HS we studied the morphology of the basement
membrane within the folliculopilosebaceous unit (FPSU), as shown in chapter 2. This was done
by performing periodic-acid Schiff (PAS) and immunofluorescence (IF) staining for the main
BMZ glycoproteins of perilesional HS skin and comparing this to skin of healthy volunteers.
We demonstrated relative upregulation of integrin α6β4 at the sebaceous glands of HS
patients. Integrin α6β4 is an important signaling molecule and its upregulation has also been
described in pulmonary tissue upon infection with pathogenic micro-organisms.10,11 It has
been hypothesized that integrins function as pattern recognition receptors (PRP’s) in lungs
that upon interaction with bacteria induce cellular responses that activate the innate immune
system and inflammation.10 This may also be true for upregulated integrins in HS. Although
bacterial cultures from HS lesions are often negative or only show commensal bacteria,
DNA-based analyses have revealed that the skin’s microbiome is much wider than previously
assumed.12 An aberrant composition of the skin’s microbiome has been linked to several other
inflammatory mediated skin diseases, including psoriasis and atopic dermatitis.13 Interestingly,
a relative deficiency of antimicrobial peptides (AMP’s) was demonstrated in HS lesions that
may promote bacterial propagation.14 Pathogenic changes in the skin’s microbiome may result
127
in chronic exposure of keratinocytes and Langerhans cells to pathogen-associated molecular
patterns (PAMPs), resulting in upregulation of PRPs and therefore also integrins.15 Several
clinical and histological findings further support a role for the microbiome in HS, namely: 1)
the microbiome composition in body folds differs from other areas, explaining the predilection
of HS lesions at these locations12 2) life style factors (smoking and diet) associated with HS as
well as hormonal factors influence the composition of the microbiome12 3) the composition of
the microbiome is largely determined by inherited factors,12 explaining the familial occurrence
of HS 4) sebaceous glands have shown to be diminished in volume and number in clinically
uninvolved skin of HS patients.16 The latter may promote increased infundibular friction due
to dimished sebum secretion but may also result in a diminished production of AMP’s by
sebocytes, further promoting bacterial colonization. Whether changes in the microbiome have
a causal effect in skin diseases or occur secondarily to an altered skin biology remains elusive.13
It would be interesting to investigate whether there are differences between sebocyte derived
AMP’s in HS patients and controls to determine the possible role of sebaceous glands in
bacterial colonization. Genome based techniques, like 16S RNA gene clone sequencing, may
be applied to study the microbiome in HS. In case an important role of the microbiome in HS is
identified, restoring its composition would be an interesting future therapeutic strategy.
An important finding was that we could not confirm the presence of the so called “PAS-gaps”
at the sebofollicular junction (SFJ) in HS skin as described by Danby et al.17 Neither did we find
diminished expression of specific glycoproteins (including type XVII collagen, type VII collagen,
laminin-332, and integrin α6β4) in the BMZ. Therefore we have strong doubts about the
primary importance of hair follicle fragility in the HS pathogenesis.
There is increasing evidence that HS is an immune mediated disease as the dysregulated
immune system plays a critical role in both the development and progression of HS. Therefore,
immunosuppressive agents have been recognized as a cornerstone treatment. In HS
overproduction of cytokines from both the innate (including IL-1β and TNF-α) and adaptive
immune system (including IL-10, IL-12, IL-17 and IL-23) has been observed in skin tissue.14,18-20
Additionally, diminished expression of IL-22 has been demonstrated, probably resulting from
increased IL-10 production. This may contribute to the relative deficiency of AMP’s in HS
skin.14 As the predominant cytokines driving the inflammatory reaction in HS have yet to be
determined and consensus is lacking, the choice for a specific immunosuppresive agent is
mainly based on the clinicians’ experience.
HS is associated with genetic predisposition. Heterozygote mutations in the g-secretase genes
have been identified in familial HS with an autosomal dominant inheritance pattern.21,22 In
128
our clinic we encountered five HS patients who were also diagnosed with Down syndrome
(DS), suggesting that an association between these two conditions is possible. In chapter 3 we
formulated a hypothesis that may link Down syndrome (DS) to HS via functional deficiency
of g-secretase. Dysfunctional or deficient g-secretase may induce HS by impairing Notch
signaling pathways. Notch signaling controls epidermal cell proliferation and differentiation
and is therefore involved in hair follicle and sebaceous gland maintenance.21 Furthermore, it
may promote epidermal cyst formation and impaired production of sebaceous glands, both
important characteristics of HS. Whether DS and HS are truly associated requires investigation
in a larger group of DS patients. Further work should focus on the role of g-secretase in the
skin and the hair follicle specifically. Furthermore, gene mapping techniques, including next-
generation sequencing, may be applied to identify relevant mutations in genes encoding for
other proteins in the g-secretase complex or proteins involved in the Notch signaling pathway.
Chapter 4 describes the gene expression profile of HS affected tissue. Here we show significant
upregulation of genes involved in pathways comprising amongst others leucocyte migration,
inflammatory and immune responses as well as atherosclerosis signaling in lesional HS skin
compared to clinically uninvolved skin. These results have yet to be confirmed with for
instance quantitative real-time polymerase chain reaction (PCR) analyses and on protein level.
No differences were observed in whole blood mRNA expression between HS patients and
healthy subjects. This implicates that activated cells in HS reside in affected tissue, probably
because leucocytes migrate from the circulation into skin tissue by an as yet unknown trigger.
Inflammation in HS is thus restricted to the skin of specific anatomical areas and therefore it
may be considered as a localized rather than a generalized skin disease. However, an increased
frequency of metabolic syndrome has been shown in HS, implicating that it actually may be
a systemic disease.23 It remains unclear whether these metabolic changes occur secondary
to the chronic inflammation and adverse lifestyle habits associated with HS or whether
primary metabolic alterations trigger HS. Either way, systemic immunosuppressive and anti-
inflammatory agents are important for preventing progression of HS to other skin regions.
Future studies should also establish the role of topically applied agents like topical resorcine
15% cream,24 topical antibiotics and zinc glucoanate,25,26 especially in disease phenotypes
where only one or two anatomical areas are involved.
Chapter 5 describes a systematic review on the effectiveness of systemic immunosuppressive
agents and retinoids in HS. Here we show that the quality of performed studies, to date,
129
is generally poor, making it difficult to make any therapeutic recommendations. The best
clinical results were found for the TNF-α-inhibitors adalimumab and infliximab, confirming
the importance of TNF-α in HS. Additionally, promising results were identified for the retinoid
acitretin as it was effective in 95% of the 22 described patients. Isotretinoin showed a poor
response. This may be explained by the reduction in sebaceous glands in HS, as sebaceous
glands are important targets of isotretinoin.27 Although colchicine is a potent IL-1β inhibitor
and suppressor of neutrophils,28 it was not effective in HS. In conclusion, better studies are
needed to determine the effect of other immunosuppressive agents showing promising results
in small studies, like dapsone and cyclosporine.
As mentioned above, IL-12 and IL-23 have been found to be abundantly expressed by
macrophages in lesional HS skin.19 Additionally, Th-17 cell upregulation has been observed
in HS tissue.19 Similar to psoriasis, Th-17 cells are known to produce IL-17 and IL-21 which
can lead to proinflammatory cytokine (IL-1β, IL-6 and TNF-α) production by keratinocytes,
resulting in neutrophil, macrophage and lymphocyte attraction.29 Targeting the IL-23/Th17 axis
with the biologic agent ustekinumab could therefore be effective in treating HS.
In chapter 6 we show in an open label study, for the first time, that ustekinumab can be
applied in HS, as the majority of patients showed improvement. The results were not inferior to
the results found for adalimumab in a large randomized controlled trial,30 nor compared to the
IL-1 receptor antagonist anakinra in a small open label study.31 As inflammatory marker levels
are higher in HS compared to psoriasis (where ustekinimab is an approved treatment option18)
we would recommend to adjust the standard psoriasis schedule by increasing administration
frequency and dosage. Eventually, clinical trials are warranted to compare IL-12/IL-23
inhibition to the current gold standard of TNF-α-inhibition in HS. Furthermore, it is important
to investigate in larger studies whether certain clinical characteristics are predictive for a
response to ustekinumab, including HS phenotype (for instance wide spread Hurley II disease
versus localized Hurley III disease), life style factors (smoking and obesity) and co-morbidities.
Besides treatment effect, chapter 6 also describes protein expression in serum of patients at
baseline and during the study. At baseline, a significant difference was detected between
healthy controls and HS patients in the expression of 54 serum proteins. These proteins are
probably produced by activated cells present in skin tissue. Further investigation of these
protein levels could possibly lead to putative biomarkers for diagnostic purposes or monitoring
disease progression. Although we did not discover a specific biomarker reflecting the
therapeutic effect of ustekinumab, low levels of enzyme leukotriene A4-hydrolase (LTA4H) in
patients combined with relatively mild clinical disease severity may be prognostic for a good
effect of ustekinumab.
130
Surgery is an important part of HS Hurley stage II/III treatment as systemic therapy alone is
never sufficient for heal previously formed sinus tracts and scarring. These sinus tracts provide
access for bacteria to invade the dermis, leading to repetitive inflammation and further
extension of the disease. Several surgical - as well as closure techniques have been previously
proposed for HS.9 General anesthesia is preferred when large areas require surgical intervention
or in cases where patients refuse local anesthetics.
In chapter 7 we describe a new surgical technique to approach moderate to severe HS Hurley
stage II/III: the skin tissue-sparing excision with electrosurgical peeling (STEEP) procedure.
By performing tangential excisions and exploring the wound beds with a probe, all lesional
tissue can be removed with minimal excision of healthy skin. This can lead to a shorter healing
time and less post-surgical complications, (e.g contractures), compared to the traditional wide
excision. The wounds are healed by secondary intention allowing continuous wound drainage
and therefore the risk of post-operative inflammation is diminished. In chapter 8 long term
results (median follow-up time of 43 months) of the STEEP procedure and deroofing under
general anesthesia were retrospectively studied. Here we show that natural progression of the
disease outside the surgical scar but within the operated anatomical region occurred in 34%
of patients. True relapses due to irradical surgery were seen in 29% of patients. However, in a
subsequent prospective case series of 27 patients with a follow up time of 12 months by our
group, relapses were observed in only one patient (Janse et al.; unpublished data). Due to the
relatively high percentage with natural progression of the disease, future studies should focus
on proper planning of surgery, whether the use of perioperative immunosupressiva improves
surgical outcomes (time to wond closure, relapse rate, natural progression of the disease)
and whether tissue saving procedures are superior to wide excision regarding these surgical
outcomes. Also, ultrasound imaging prior to the operation may help the surgeon in estimating
the extensiveness of fistulas and therefore assist in the choice for a specific technique.32
Finally, as many closure techniques have been proposed in HS, studies should be performed to
investigate the type of indications where wound closure with grafts or flaps should be preferred
over secondary intention healing. The choice will mainly depend on experience of the surgeon,
the location of the disease, the size of the wound and patient’s ability to take care of an open
wound.
131
coNcLUSIoNS AND fINAL coNSIDERATIoNSThe multifactorial pathogenesis of HS remains elusive, complicating the development of new
treatment strategies. Follicular occlusion may be caused by a primary keratinization disorder or
may result from an overactive innate immune system, with a possible causative or secondary
role of the skin’s microbiome. The contribution of hormones, genetics and environmental
factors requires further investigation. Consensus should be reached on what the treatment
goal should be in HS and on what outcome measures must be applied in future clinical trials
focusing on topical, systemic and surgical treatments. The ultimate goal would be to develop
individualized treatment strategies for HS.
132
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137
10NEDERLANDSE SAMENVATTINg
J.L. Dickinson-Blok
138
Hidradenitis suppurativa (HS) is een chronische huidziekte die gekenmerkt wordt door
inflammatoire noduli, nodi en abcessen. Deze ontstekingen zijn met name gelokaliseerd in de
plooien van het lichaam, zoals de liezen, oksels en de billen en genezen vaak met littekens.
De ziekte komt bij ongeveer 1-4% van de bevolking voor en treft relatief meer vrouwen dan
mannen.
De primaire afwijking bij patiënten met HS is dat de haarfollikels/haarzakjes verstopt
raken (folliculaire plugging) waardoor deze zich geleidelijk gaan vullen met talg en pus.
Uiteindelijk barsten de haarfollikels open waardoor de inhoud zich naar het huidoppervlak
beweegt, alsmede zich horizontaal verspreidt naar het omliggende weefsel (de dermis
ofwel de lederhuid). Als reactie op dit lichaamsvreemde materiaal in de dermis komt een
ontstekingsproces op gang die vervolgens verstopping van omliggende haarzakjes en de
vorming van zogenaamde fistelgangen stimuleert. Deze fistelgangen vormen onderhuidse
verbindingen tussen de ontstekingen en bestaan uit cellen die de oorspronkelijke haarzakjes
bekleedden. Dit onderhuidse gangenstelsel staat in open verbinding met de oppervlakte van de
huid waardoor ze een relatief eenvoudige toegangsweg voor bacteriën naar het onderhuidse
weefsel vormen, wat weer leidt tot verdere ontstekingen. De fistelgangen leveren daardoor een
belangrijke bijdrage aan de chroniciteit van de ziekte.
De oorzaak van HS is grotendeels onbekend. Genetische aanleg lijkt een rol te spelen
aangezien het vaak meerdere mensen binnen een familie treft. Daarnaast blijkt uit onderzoek
dat roken en overgewicht belangrijke risicofactoren zijn voor zowel het krijgen van HS als
voor een ernstiger verloop van de ziekte. De hormoonhuishouding lijkt ook een rol te spelen
aangezien HS meestal na de puberteit ontstaat, bij sommige vrouwen voor de menstruatie
opvlamt en de ontstekingsactiviteit af kan nemen door het gebruik van orale anticonceptiva
(‘de pil’).
Acute ontstekingen kunnen zeer pijnlijk zijn waardoor patiënten gehinderd worden in
hun dagelijks leven en soms zelfs arbeidsongeschikt raken. De pus die vrijkomt kan een
onaangename geur afscheiden wat leidt tot veel schaamte bij patiënten. Daarnaast zijn de
littekens cosmetisch storend en kunnen zelfs leiden tot bewegingsbeperkingen. Het is daarom
niet verwonderlijk dat HS de kwaliteit van leven vaak ernstig beïnvloedt.
HS is momenteel niet te genezen en daarom is de behandeling gericht op bestrijding van acute
ontstekingen, het opheffen van chronische ontstekingen en het zoveel mogelijk voorkomen
van nieuwe ontstekingen. Deze doelen kunnen bereikt worden met lokale therapie (o.a.
antibiotische crème/zalf/lotion, retinoïden of lokale corticosteroiden), systemische therapie
(antibiotica of middelen die het immuunsysteem remmen) of chirurgische ingrepen. Vaak
worden deze behandelingen gecombineerd om een optimaal resultaat te bereiken.
139
Om tot betere behandelingen te komen is het noodzakelijk dat er meer kennis komt over de
ontstaanswijze (pathogenese) van HS en zijn er studies nodig om nieuwe behandelingen te
onderzoeken. In dit proefschrift hebben we ons daarom gericht op zowel de pathogenese als
op de effectiviteit van bestaande en nieuwe behandelingen voor HS.
In hoofdstuk 2 hebben we haarfollikels van patiënten met HS vergeleken met de haarfollikels
van gezonde mensen. In deze studie konden wij met periodic acid-Schiff (PAS) en
immunofluorescentie (IF) kleuringen niet bevestigen dat de basaalmembraan ter hoogte van
de overgang van de talgklier naar de haarfollikel bij HS patiënten fragieler is dan bij gezonde
mensen. We toonden wel met IF-kleuringen aan dat patiënten met HS een hogere expressie
van het eiwit integrine α6β4 langs de basaalmembraan van de talgklieren hebben dan
gezonde mensen. Hypothetisch zou deze verhoogde expressie veroorzaakt kunnen worden
door veranderingen in de bacteriële samenstelling van de huid bij patiënten, het zogenaamde
microbioom. Deze integrines zouden een bijdrage kunnen leveren aan activatie van het
immuunsysteem en een rol kunnen spelen bij het vaker voorkomen van plaveiselcelcarcinomen
bij patiënten met HS.
In hoofdstuk 3 hebben we een hypothese geformuleerd die verklaart waarom HS mogelijk
vaker voorkomt bij patiënten met het syndroom van Down. Hierbij staat het enzym g-secretase
centraal. Mutaties in dit enzymcomplex zijn beschreven bij familiare HS en kunnen via
verstoring van de zogenaamde ‘Notch signaling pathway’ leiden tot de vorming van de
karakteristieke huidafwijkingen bij HS. Bij patiënten met het syndroom van Down is het
mogelijk dat deze ‘Notch signaling pathway’ verstoord is door een tekort aan g-secretase.
Dit tekort zou bij patiënten met het syndroom van Down kunnen ontstaan doordat het
beschikbare g-secretase verbruikt wordt om de vehoogde hoeveelheid amyloid precursor
protein (APP) die bij dit syndroom tot expressie komt te verwerken. Daarnaast kunnen
verhoogde concentraties APP folliculaire plugging bevorderen. Tot slot hebben patiënten met
het syndroom van Down vaker overgewicht en zijn immunologische stoornissen een bekend
verschijnsel bij dit syndroom. Al deze factoren vergroten het risico op de ontwikkeling van HS
bij het syndroom van Down.
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Hoofdstuk 4 beschrijft het genetische expressie profiel van HS in zowel de huid als het bloed
van patiënten. Met behulp van ‘mRNA microarray analyses’ laten we zien dat in klinisch
gezonde HS huid andere genen tot expressie komen dan in de ontstoken HS huid. Zoals
verwacht betreft dit met name genen die betrokken zijn bij ontstekingsprocessen. Tevens werd
betrokkendheid van atherosclerotische processen aangetoond in de aangedane huid, een
bevinding die de associatie tussen HS en het metabool syndroom ondersteunt. Er was geen
verschil aantoonbaar tussen genexpressie van HS patiënten en gezonde mensen in het bloed.
De resultaten van deze studie suggereren daarom dat de ontstekingscellen die betrokken zijn
bij HS zich beperken tot de aangedane huid en niet door het bloed circuleren. Ondanks dat de
inflammatie zich lokaal manifesteert zijn systemische middelen belangrijk om te voorkomen
dat de ontstekingsactiviteit van HS zich uitbreidt naar andere regio’s van het lichaam. Het blijft
onduidelijk of de met HS geassocieerde metabole veranderingen secundair aan de chronische
inflammatie en ongezonde levensstijl van veel HS patiënten ontstaan, of dat metabole
veranderingen primair aanwezig zijn en het risico op het ontwikkelen van HS verhogen.
In hoofdstuk 5 wordt in een systematisch review de effectiviteit van alle beschikbare
immuunsuppressieve therapieën en retinoïden voor HS onderzocht. We laten zien dat de
studies die verricht zijn naar deze behandelingsmogelijkheden vaak van lage kwaliteit zijn. De
beste resultaten werden geboekt met de tumor necrosis alpha (TNF-α) remmers adalimumab
en inflximab. TNF-α remmers behoren tot de zogeheten biologicals. Biologicals zijn
medicijnen die specifieke signaaleiwitten, zoals cytokines of receptoren, die betrokken zijn bij
ontstekingsprocessen uitschakelen en zo een ziekteproces gericht kunnen beïnvloeden. Naast
de TNF-α remmers werden ook goede resultaten behaald met het orale retinoïd acitretine.
De effectiviteit van isotretinoine, een ander soort retinoïd, was echter teleurstellend. Dit kan
worden verklaard uit het feit dat het belangrijkste werkingsmechanisme van isotretinoine
gericht is op reductie van de acitviteit van talgklieren, terwijl uit eerdere studies en uit onze
bevindingen in hoofdstuk 2 blijkt dat de talgklieren bij HS patiënten juist vaak afwezig of
verkleind zijn. Ook colchicine, een potente IL-1β en neutrofiele granulocyten remmer, blijkt
weinig effectief te zijn. Klinische studies van goede kwaliteit zijn nodig om de effectiviteit van
andere immuunsuppressieve middelen, zoals ciclosporine en dapson, alsmede van nieuwe
middelen verder te onderzoeken.
In eerdere studies werden aanwijzingen gevonden dat betrokkenheid van de IL-23/Th-17 as
een belangrijke rol zou kunnen spelen in de ontstekingscascade van HS. In hoofdstuk 6
141
onderzoeken wij in een open label studie of remming van deze IL-23/Th-17 as met de
biological ustekinumab leidt tot klinische verbetering van HS in 17 patiënten. Bij 83% van
de patiënten verbeterde de belangrijkste klinische score, de zogenaamde modified Sartorius
score (mSS), met 25-50%. Het primaire eindpunt van 50% afname van de score werd gehaald
in 35% van de patiënten. Ustekinumab zou dus een potentiële behandelingsoptie voor HS
kunnen zijn. De effectiviteit zou vergroot kunnen worden door intensievere doseringsschema’s
toe te passen bij HS. Uiteraard zijn gerandomniseerde dubbelblinde studies nodig om de
effectiviteit van ustekinumab te bevestigen.
In dezelfde studie werd middels microarray analyses op serum geen diagnostische biomarker
voor HS geïdentificeerd, noch werd er een biomarker gevonden die de activiteit van de
ziekte reflecteert. Een trend werd echter waargenomen dat patiënten met een goede respons
op ustekinumab relatief lagere concentraties van leukotriene A4-hydrolase, een enzym dat
betrokken is bij ontstekingsprocessen, in het serum tot expressie brachten en dat ze klinisch
minder ernstige HS hadden dan patiënten met een slechte respons op ustekinumab. Derhalve
zouden lage concentraties van leukotriene A4-hydrolase in combinatie met een relatief milde
klinische ziekteactiviteit voorspellend kunnen zijn voor een goede respons op ustekinumab.
Chirurgie is een belangrijk onderdeel bij de behandeling van HS, met name bij de ernstige
gevallen waar zich reeds fistelgangen hebben gevormd. Het doel van chirurgie is om al het
aangedane weefsel te verwijderen aangezien dit een bron van terugkerende ontstekingen
is. Verschillende chirurgische technieken zijn beschreven bij HS, waarvan ruime excisie de
meest bekende techniek is. Een nadeel is dat hierbij ook relatief veel gezond weefsel wordt
weggehaald. Chirurgische behandelingen kunnen, afhankelijk van de uitgebreidheid van het
ziektebeeld, zowel onder lokale als algehele anesthesie worden uitgevoerd.
In hoofdstuk 7 wordt een nieuwe chirurgische techniek beschreven voor matige tot
ernstige HS, de zogenaamde ‘Skin Tissue-sparing Excision with Electrosurgical Peeling’
(STEEP) procedure. Deze chirurgische techniek heeft als doel al het aangedane weefsel te
verwijderen, waarbij tegelijkertijd zoveel mogelijk gezond weefsel wordt gespaard. Er worden
opeenvolgende horizontale excisies verricht die steeds dieper het weefsel ingaan totdat gezond
weefsel te voorschijn komt. Door met een sonde de wondranden nauwkeurig te checken op
resterende ontstekingen en fistelgangen, wordt het risico op resterend ‘ziek’ weefsel beperkt
tot een minimum. Doordat de wondoppervlaktes zo klein mogelijk worden gehouden is het
risico op complicaties minder groot dan bij ruime excisies. De wonden worden na de operatie
open gelaten zodat er mogelijkheid is tot continue drainage van het wondbed.
142
De langetermijn resultaten van de STEEP procedure worden in hoofdstuk 8 beschreven.
Tussen 1999 en 2013 werden er op de afdeling Dermatologie in het UMCG 113 mensen een
of meerdere keren behandeld middels deze techniek, waarbij in totaal 482 operaties werden
uitgevoerd. Na een mediane follow-up van 43 maanden werd natuurlijke progressie van
de ziekte buiten het geopereerde gebied in 34% van de patiënten gezien. Daadwerkelijke
recidieven na een operatie traden uiteindelijk op in 29% van de patiënten. Toekomstige
studies zijn nodig om te bepalen of gelijktijdig gebruik van ontstekingsremmende of
immuunsuppressieve middelen de kans op het terugkeren van de ziekte na een operatie
verlagen. Daarnaast moet er meer duidelijkheid komen of de effectiviteit van weefselsparende
operaties gelijk is aan die van ruime excisies.
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coNcLUSIES De oorzaak van HS blijft grotendeels onduidelijk, wat de ontwikkeling van nieuwe
behandelingsstrategieën bemoeilijkt. De rol van hormonen, genetische aanleg en
omgevingsfactoren dient nader onderzocht te worden. Het is belangrijk om consensus te
bereiken over de te gebruiken uitkomstmaten in toekomstige studies zodat verschillende
behandelingen beter met elkaar vergeleken kunnen worden. Het ultieme doel is om
geïndividualiseerde behandelingsstrategieën voor HS te ontwikkelen.
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APPENDIcES
J.L. Dickinson-Blok
146
DANKwooRDEen promotietraject is een persoonlijke reis vol uitdagingen. De mensen om me heen, die me
op welke manier dan ook stimuleerden en/of ondersteunden, waren goud waard en daar wil ik
graag nog even bij stilstaan.
Mijn promotor Prof. Dr. M.F. Jonkman. Beste Marcel, tijdens mijn eerste jaar bood je me dit
promotietraject aan. Je gaf me je vertrouwen en de vrijheid om zelfstandig te werken maar
stond daarnaast altijd laagdrempelig klaar om me verder te helpen met ideeën voor projecten.
Je snelle en creatieve denkwijze werkt ontzettend stimulerend en heeft me laten inzien hoe
leuk wetenschap is. Bedankt voor alles!
Mijn co-promotor dr. Horváth. Beste Barbara, jouw bevlogenheid, intelligentie en enthousiasme
maken dat je altijd weer met fantastische ideeën voor nieuwe projecten komt en hebben ons
gebracht waar we vandaag staan. Ondanks alle taken die er op je schouders rusten ben je er
altijd als het nodig is. Jouw steun, warmte en vertrouwen zijn van onschatbare waarde voor me
geweest.
Dear members of the reading committee, Prof. dr. B. van der Lei, Prof. dr. E.P. Prens and Prof.
G.B.E. Jemec. Thank you for reading and reviewing my thesis.
Mijn paranimfen Kasia en Ineke. Dat jullie me bijstaan op deze belangrijke dag betekent veel
voor me. Lieve Kasia, de laatste jaren hebben we alle highs and lows gedeeld. We hoeven
elkaar maar aan te kijken om te weten wat de ander denkt. Je hebt een groot hart en onze
vriendschap is een van de mooiste dingen die ik heb gekregen tijdens dit promotietraject.
Lieve Ineke, illustrator heldin. Jouw warme persoonlijkheid gecombineerd met je aanstekelijke
gedrevenheid maakt werken met jou ontzettend leuk. Bedankt voor je onmisbare bijdrage
aan de BMZ en je input tijdens de voorbereiding op de verdediging. Ik hoop dat we nog
veel onderzoeken gaan uitvoeren om HS beter te begrijpen en vooral ook gezellige dingen
daarbuiten blijven ondernemen!
147
Katherine Li and Carrie Brodmerkel. It was a pleasure working with you. Thank you for your
important contribution to chapters 4 and 6. Peter Horvátovich, thank you for sharing your
knowledge with us and your contribution to chapter 6.
Dr. J.R. Spoo. Beste Julia, we delen onze interesse voor hidradenitis suppurativa en je bent een
expert op het gebied van de STEEP. Bedankt voor jouw belangrijke bijdrage aan en de prettige
samenwerking tijdens de totstandkoming van hoofdstuk 7 en 8. De STEEP staat nu definitief
op de kaart!
Dr. J.B. Terra. Beste Jorrit, jij was degene die me liet inzien dat de wetenschap de juiste weg
was voor mij. Ik kan je daarvoor niet genoeg bedanken. Jouw wetenschappelijke en klinische
ervaring waren onmisbaar voor hoofdstuk 8. Daarnaast heeft jouw voortreffelijke PR ervoor
gezorgd dat de term STEEP helemaal ingeburgerd is op onze afdeling!
Janneke Huizinga, bedankt voor je enthousiasme en de fijne samenwerking. Je bent onmisbaar
voor onze patienten en in ons HS team!
Drs. S. van Hattem. Lieve Simone, ook jouw bijdrage was zeer belangrijk. Bedankt voor de fijne
samenwerking en je oprechte interesse. Ik mis je in Groningen.
Marieke Boersma, je hebt heel wat uren gespendeerd in ons retrospectieve onderzoek. Bedankt
voor je bijdrage en veel succes met je carrière!
Prof. Dr. P.J. Coenraads. Beste Pieter-Jan, mijn eerste stappen op wetenschappelijk en
dermatologisch gebied zette ik onder jouw begeleiding en mede door jouw steun en
vertrouwen werd ik aangenomen voor de opleiding. Ik ben je hier ontzettend dankbaar voor.
De overige stafleden: Sylvia Kardaun, Marie-Louise Schuttelaar, Marja Oldhoff en Emöke
Rácz. Bedankt voor de fijne samenwerking. Marie-Louise en de dames van het roosterbureau,
dank voor het realiseren van een aantal onderzoeksdagen in de afrondende fase van mijn
proefschrift.
148
De steun vanuit de gehele AIOS groep tijdens de laatste maanden van de afronding van mijn
proefschrift was geweldig. Jullie collegialiteit gaf me het laatste beetje lucht dat ik nodig had.
Hierbij wil ik Susanne, Marjolein, Ruud en Christiaan, partners in crime vanaf het begin van
de opleiding, nog speciaal noemen. Lieve Suus en Marjo, we are so good together! Met zijn
drieën vormen we een perfect team en ik ben ontzettend blij met onze vriendschap. Jullie zijn
geweldige dermatologen en ik ben heel trots op jullie! Ruud en Chris, de perfecte ingrediënten
voor humor of juist een goed gesprek . “Liefde is alles wat er is”, een beter cadeau hadden
jullie op dat moment niet kunnen geven, heel veel dank.
Daarnaast wil ik Piet Toonder bedanken voor de vele foto’s die hij heeft gemaakt en zijn ICT
ondersteuning. En alles altijd met een lach!
De mensen van het laboratorium. Hendri Pas, voor vragen over IF kon ik altijd bij je terecht.
Bedankt dat ik al mijn serum en biopten kon opslaan in het lab. Janny en Gonnie, hartelijk
bedankt voor het snijden en kleuren van de biopten!
Dr. A.M.G. Pasmooij. Beste Marjon, bedankt voor de discussies en je hulp in genetica land!
“Echte vrienden zie je niet omdat ze achter je staan”
Lieve Maike, dank voor het vertalen van de Spaanse artikelen in hoofdstuk 5 en voor alles
daarbuiten! Marije, Monique, Saskia en Iris, jullie maken Groningen nog steeds een “feestje”!
Ellen, je bent er altijd in elk opzicht, dank je wel! Maeyke en Sebastiaan, jullie gezeligheid en
culinaire kunsten geven me altijd weer energie. Ewout en Maria, onze vakanties en weekendjes
zijn de beste manier om op te laden. Maria, bedankt voor het lezen van de Nederlandse
samenvatting in je verlof! Ijsbrand, Martzen, Warner, Sophie, Thomas, Ianthe, Edwin D, Helma,
Dionne en Edwin S. bedankt voor alle gezelligheid! Linda, Marike, Henrike, Jan Wendel,
Willem, Imre, Lieke en Maike: het is altijd weer thuiskomen bij jullie, bedankt voor jullie
interesse en betrokkenheid.
Lieve Annemarie, wat heb ik het met jou getroffen. Bedankt voor de fijne gesprekken, je
humor en je adviezen.
149
Dear Bill, despite the long distance between us you have always managed to stay actively
involved in our lives. Thank you so much for your emotional support and thoughtfulness.
Lieve Thomas, broederliefde kent geen grenzen. Je bent altijd actief betrokken geweest bij alles
wat ik doe en bereid je steentje bij te dragen. Ik bewonder de manier waarop jij in het leven
staat waarbij je je dromen volgt en je talent gebruikt. Mensen voelen zich thuis bij jou en dat is
niet voor niets. Je hebt een groot hart en ik ben ontzettend trots op je.
Lieve zus, Suzanne. Onze telefoons zijn van onschatbare waarde, dat zal de hele familie
beamen. Ondanks de fysieke afstand ben je namelijk altijd dichtbij en heel belangrijk voor
me. Als ik het even niet zag zitten bood je altijd een luisterend oor en dat heeft veel voor
me betekend. Michiel, ik ben zo blij dat mijn zus zo’n leuke man heeft als jij! Mijn geweldige
neefjes Jules, Jesse en Joël, wat ben ik trots op jullie!! Als ik bij jullie ben kan ik alleen maar
genieten en vooral heel veel lachen.
Lieve papa en mama, zonder jullie was ik nooit zo ver gekomen. Jullie liefde, steun en
vertrouwen in mij lijken geen grenzen te kennen. Ik vind het fantastisch hoe jullie ons alle drie
de ruimte en vrijheid hebben gegeven om ons leven in te richten zoals we wilden en ons te
ontwikkelen tot de personen die we zijn. Een betere basis had ik mij niet kunnen wensen en
daar ben ik jullie oneindig dankbaar voor.
En tot slot mijn fantastische man. Lieve Michael, dat ik mijn leven met jou mag delen is mijn
grootste geluk. Je hebt me altijd gestimuleerd het beste uit mezelf te halen en niet aan mezelf
te twijfelen. Jouw aandeel in dit proefschrift is dan ook niet in woorden uit te drukken. Je bent
een prachtig persoon en samen met jou ga ik alle uitdagingen in het leven vol vertrouwen
tegemoet!
150
LIST of PUBLIcATIoNS J.L.Blok, K.Li, C. Brodmerkel, P. Horvátovich, M.F. Jonkman, B. Horváth. Ustekinumab in
hidradenitis suppurativa: a clinical open label study with analyses of the protein expression
profile in serum. Submitted.
J.L. Blok, K. Li, C. Brodmerkel, B. Horváth, M.F. Jonkman. Gene expression profiling of skin and
blood in hidradenitis suppurativa. Submitted.
J.L. Blok, I.C. Janse, B. Horváth, M.F. Jonkman. Increased expression of integrin α6β4 at the
basement membrane zone lining the sebaceous glands in hidradenitis suppurativa. Acta Derm
Venerol. 2015. doi: 10.2340/00015555-2186. [Epub ahead of print]
J.L. Blok, M. Boersma; J.B. Terra, J.R. Spoo, F.W.J. Leeman, E.R. van den Heuvel, J. Huizinga,
M.F. Jonkman, B. Horváth, MD PhD. Surgery under general anesthesia in severe hidradenitis
suppurativa: a study of 363 primary operations in 113 patients. J Eur Acad Dermatol Venereol
2015 doi: 10.1111/jdv. 12952
Blok JL, Jonkman MF, Horvath B. The possible association between hidradenitis suppurativa
and Down syndrome: is increased APP expression resulting in impaired Notch signaling the
missing link? Br. J. Dermatol. 2014; 170:1375-1377
Blok JL, Spoo JR, Leeman FW, Jonkman MF, Horvath B. Skin-tissue sparing excision with
electrosurgical peeling (STEEP): a surgical treatment option for severe hidradenitis suppurativa
Hurley stage II/III. J Eur Acad Dermatol Venereol. 2015: 29:379-382
Blok JL, van Hattem S, Jonkman MF, Horvath B. Systemic therapy with immunosuppressive
agents and retinoids in Hidradenitis suppurativa: a systematic review. Br J Dermatol
2013;168:243-252
151
Blok JL, Reesink-Peters N, Diercks GF, Reyners AK, Terra JB. Vulvair basaalcelcarcinoom met
destructieve gevolgen. Ned Tijdschr Geneeskd 2012;156:A5391
JL Blok, PJ Coenraads. Orale retinoïden bij chronisch handeczeem: de effectiviteit van
alitretinoïne. Nederlands Tijdschrift voor Dermatologie en Venereologie 2010;20:680-4
JL Blok, JR Spoo, MF Castellanos-Nuijts, KF van Duinen. Impetigo herpetiformis. Nederlands
Tijdschrift voor Dermatologie en Venereologie 2010;20:401-4
De Groot AC, Blok J, Coenraads PJ. Relationship between formaldehyde and quaternium-15
contact allergy. Influence of strength of patch test reactions. Contact Dermatitis
2010;63:187-91
152
cURRIcULUM VITAE Janine Dickinson-Blok werd geboren op 11 juli 1984 te Deventer. In 2002 behaalde zij haar
VWO diploma aan de Scholengemeenschap “De Waerdenborch” te Holten en koos zij
voor de studie Bewegingswetenschappen aan de Rijksuniversiteit Groningen nadat zij was
uitgeloot voor de studie Geneeskunde. In 2003 was het lot haar beter gezind en kon zij
starten met Geneeskunde in Groningen. Nadat zij in 2008 haar artsen bul behaalde kreeg ze
een aanstelling als arts-onderzoeker op de afdeling Dermatologie in het Universitair Medisch
Centrum Groningen. Tijdens deze onderzoeksperiode richtte zij zich onder begeleiding van
Prof. P.J. Coenraads op handeczeem en allergisch contacteczeem. In juli 2010 begon zij met de
opleiding Dermatologie in het Universitair Medisch Centrum Groningen. Tijdens de opleiding
bleef zij belangstelling houden voor wetenschappelijk onderzoek. In januari 2012 onderbrak
zij derhalve de opleiding om te starten met haar promotietraject naar hidradenitis suppurativa
onder begeleiding van haar promotor Prof. M.F. Jonkman en co-promotor Dr. B. Horváth. In
juli 2014 hervatte zij haar opleiding en deze zal zij naar verwachting afronden in januari 2017.
Janine trouwde in mei 2013 met Michael Dickinson, met wie zij in Groningen woont.