10.1038@s41572 020 0149 1

PRIMER
Hidradenitis suppurativa
Robert Sabat1 ✉, Gregor B. E. Jemec2, Łukasz Matusiak3, Alexa B. Kimball4, Errol Prens5
and Kerstin Wolk6
Abstract | Hidradenitis suppurativa (HS; also designated as acne inversa) is a chronic
inflammatory disorder, which affects the intertriginous skin and is associated with numerous
systemic comorbidities. The estimated prevalence of HS is ~1% in most studied countries.
Typically starting in early adulthood, cutaneous inflamed nodules, abscesses and pus-discharging
tunnels develop in axillary, inguinal, gluteal and perianal body sites. The comorbidities of HS
include metabolic and cardiovascular disorders, which contribute to reduced life expectancy.
A genetic predisposition, smoking, obesity and hormonal factors are established aetiological
factors for HS. Cutaneous changes seem to start around hair follicles and involve activation
of cells of the innate and adaptive immune systems, with pivotal roles for pro-inflammatory
cytokines such as tumour necrosis factor, IL-1β and IL-17. The unrestricted and chronic immune
response eventually leads to severe pain, pus discharge, irreversible tissue destruction and scar
development. HS has profound negative effects on patients’ quality of life, which often culminate
in social withdrawal, unemployment, depression and suicidal thoughts. The therapeutic options
for HS comprise antibiotic treatment, neutralization of tumour necrosis factor and surgical
intervention together with lifestyle modification. Nevertheless, there is an enormous need for
awareness of HS, understanding of its pathogenesis and novel treatments.
Hidradenitis suppurativa (HS), also known as acne infectious disease, but bacterial propagation on and in
inversa, is a debilitating inflammatory disorder that is the intertriginous skin, particularly within the occluded
1
Psoriasis Research and
Treatment Center, Charité – associated with systemic manifestations. HS is defined hair follicle units, acts as a ‘booster’ for immune activa-
Universitätsmedizin Berlin, by its chronic course and the nature and localization tion. Resident and migrated cells of the innate immune
Berlin, Germany. of skin alterations. Patients develop painful inflamed system (such as macrophages and granulocytes) and of
2
Department of Dermatology, nodules, abscesses and pus-discharging tunnels known the adaptive immune system (such as type 1 T helper
Zealand University Hospital as sinus tracts and fistulas, which typically occur in skin (TH1) cells and TH17 cells) secrete pro-inflammatory
and Health Sciences Faculty,
folds of axillary (armpits), inguinal (groin), gluteal and cytokines (such as tumour necrosis factor (TNF), IL-1β
University of Copenhagen,
Copenhagen, Denmark. perianal areas of the body1. HS usually begins in early and IL-17) to activate the tissue cells, further enhanc-
3
Department of Dermatology,
adulthood and afflicts people of both sexes for decades2. ing immune cell infiltration and inflammation5 (Fig. 1).
Venereology and Allergology, Owing to severe pain, purulent secretions that smell bad Importantly, in contrast to most other chronic skin dis-
Wrocław Medical University, and movement restrictions, HS has a profound negative orders, inflammation in HS eventually results in exten-
Wrocław, Poland. influence on the private lives of patients. Furthermore, sive pus formation, irreversible tissue destruction and
4
Department of Dermatology, cross-sectional studies imply that HS also causes sub- scar development.
Harvard Medical School and
stantial impairment in people’s professional lives, Inflammation in patients with HS is not restricted to
Beth Israel Deaconess Medical
Center, Boston, MA, USA.
affecting their economic situation3,4. Despite these cir- the skin but is systemic, affecting several other organs.
5
Department of Dermatology,
cumstances, the number of therapies approved for HS is In fact, patients frequently have metabolic syndrome
Erasmus University Medical limited, resulting in an enormous unmet medical need. (a cluster of conditions that comprises a large waist cir-
Center, Rotterdam, The aetiology of HS is multifactorial, encompassing cumference, high blood sugar, abnormal cholesterol
Netherlands. genetic and enviromental factors, lifestyle, hormonal sta- and elevated triglyceride levels, and/or high blood pres-
6
BIH Center for Regenerative tus and microbiota. These factors lead to immune activa- sure), type 2 diabetes mellitus, atherosclerosis, spondylo
Therapies, Charité – tion around the terminal hair follicles and hyperkeratosis arthritis or spondyloarthropathy (SpA), inflammatory
Universitätsmedizin Berlin,
Berlin, Germany.
(thickening of the horny layer) of the infundibulum bowel disease (IBD) and depression6–14. The conse-
✉e-mail: robert.sabat@ (the funnel-shaped opening of the hair follicle). These quences of metabolic and cardiovascular complications
charite.de changes occur in the intertriginous areas of the body include reduced life expectancy of patients.
https://doi.org/10.1038/ where the skin surfaces touch or rub together, result- In this Primer, we describe the epidemiology, patho-
s41572-020-0149-1 ing in follicular plugging and stasis (Fig. 1). HS is not an physiology, diagnosis and current treatment options
NATURE REVIEWS | DISEaSE PrIMErS | Article citation ID: (2020) 6:18 1
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a b
Epidermis
Epidermis
Psoriasiform
epidermal
thickening
Dermis
Keratin plug Dermis
Perivascular
T cell infiltration
T cell infiltration
of hair shaft Dense T cell
infiltration
500 μm
c
Dense mixed
immune cell T cell
infiltration infiltration
of hair shaft
Epithelium
Keratin debris
500 μm 1 mm
Fig. 1 | Histology of hidradenitis suppurativa lesions. Histological images showing sections of perilesional (panel a) and
lesional (panels b and c) skin of patients with hidradenitis suppurativa (HS). In panels a and b, T cells are visualized by the
pan-T cell marker CD3. In the perilesional skin, T cells are predominantly found in perivascular and perifollicular areas.
Lesional skin is characterized by massive diffuse T cell infiltration in the dermis, whereas limited infiltration is found in the
hair shaft and thickened (psoriasiform) epidermis. Panel c reveals a cross-section of a sinus tract with surrounding immune
cell infiltrate visualized using haematoxylin and eosin staining.
for HS. Furthermore, we discuss the therapeutics that are in different populations might be due to genetic or
being developed and the aspects regarding HS that need environmental factors. Studies in young adults between
to be addressed in the near future. 20 and 40 years of age have reported the highest prev-
Nodules
Firm swellings of the skin,
alence (4%), whereas the prevalence declines in those
mainly arising from the dermis Epidemiology >50 years of age21.
and subcutis. Globally, estimates of HS prevalence vary widely Two recent epidemiological studies have tried to
depending on the method of data collection15. For improve the estimate of HS prevalence. The first study, an
Abscesses
example, registry-based studies report a low prevalence Australian population-b ased cross-s ectional study,
Red, tender, pus-containing
cavities in the skin or any of <0.1%, whereas studies based on self-reported dis- was based on self-reported diagnosis. The study con-
organ, surrounded by ease, diagnosed using validated questionnaires, demon- ducted interviews with 17,050 individuals (of whom
inflammation. strate a substantially higher prevalence in the range 11,433 responded) who represented the country’s adult
1–2%15. However, current registry data from the USA population22. The interview consisted of previously val-
Sinus tracts
Linear, palpable, subcutaneous
and Norway reported an increasing incidence of idated questions including regarding previous diagnoses
tunnels draining to the skin HS13,16,17, which suggests that under-recording of mild of HS as well as corroborative general health questions.
surface via an opening. disease and misclassification in the older registries might In addition, individuals were offered a physical exami-
be the main reasons for this discrepancy. Furthermore, nation by a dermatologist to confirm the diagnosis or
Fistulas
ethnic variations cannot be ruled out as the estimated an assessment of photos of lesions by an international
Permanent, abnormal tunnels
between two hollow organs or prevalence in, for example, Japan (0.03–0.40%) and the expert. The study indicated a prevalence of 0.67%
from a hollow organ to the skin Republic of Korea (0.06%) are even lower18,19. Likewise, (95% CI 0.53–0.84%)22. In the second study, an extended
surface. registry data from the USA demonstrated that HS is registry analysis was performed using the UK Clinical
notably more common in African Americans (0.30%) Practice Research Datalink with data on hospital epi-
Plugging
The occlusion of a hair follicle
than white individuals (0.09%), and prevalence in bira- sode statistics2. Previously diagnosed and coded cases
or sweat gland pore by a cial individuals is at an intermediate level (0.22%)20. were supplemented by cases with at least five records
keratin mass. This finding implies that the difference in prevalence of painful, erythematous papules, nodules or abscesses
2 | Article citation ID: (2020) 6:18 www.nature.com/nrdp
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in flexural skin sites. The UK prevalence was 0.77% inhibition of γ-secretase in clinical trials in patients
(95% CI 0.76–0.78%). Importantly, ~30% of HS patients with advanced solid tumours and Alzheimer disease34,
were previously unrecognized2. Additionally, 18,417 which are associated with tumour cell survival facili-
cases had a history of one to four flexural skin boils, tating Notch receptor hyperactivity and cervical gen-
potentially increasing the prevalence to 1.19%2. These eration of the neurodegenerative amyloid-β peptide,
results are broadly in agreement with HS prevalence respectively. In patients with HS, the pathogenetically
data that were collected in western European countries relevant effect of impaired γ-secretase activity might
using self-reported disease diagnosed using validated be the reduced cleavage and, therefore, reduced activa-
questionnaires15. Furthermore, the UK study suggests tion of the Notch receptor. In fact, transgenic mice with
that peak prevalence occurs in young adults2. Notch receptor deficiency develop follicular cysts similar
Further aspects of HS epidemiology are also likely to those observed in γ-secretase-deficient mice, thereby
to be influenced by selection and classification bias supporting such a link33. Mechanistically, Notch signal-
as data are heavily dependent on information gath- ling controls the fate of hair follicle stem cells by prevent-
ered in secondary-level and tertiary-level health care ing their differentiation to keratinocytes35 and supports
institutions. Most patients with HS seem to have an the immunosuppressive function of regulatory T cells36
onset in their twenties23. In fact, HS is very rare before and the regulatory T cell-mediated constitutive renewal
menarche (first occurrence of menstruation), although of the hair37. Attenuation of Notch signalling leads to
paediatric cases have been reported24. The majority an alteration in the proliferation and differentiation
of patients reported in western countries are women, of keratinocytes38, resulting in an increased number of
whereas reports from Asia predominantly describe keratinocytes in the hair follicle, alteration of their dif-
men2,6,18,22,25. Although social bias can be hypothesized ferentiation, disruption of the normal hair follicle cycle
as the underlying cause for these sex differences, genetic and formation of follicular cysts containing cell debris.
or environmental differences cannot be ruled out. Interestingly, Notch signalling is also essential for the
Comparatively little is known about the long-term production of IL-22 (a key cytokine involved in anti
evolution of the disease. Long-term follow-up using microbial defence in the epidermis) by T cells39–41.
self-reported real-world data revealed remission in However, most patients with HS with a positive family
approximately one-third of treated patients, which was history (>90% in cases of white inviduals42–44) do not
more common in patients without obesity than in those harbour γ-s ecretase mutations and the genetic fea-
with obesity26. The disease was either unaffected or tures contributing to disease development in these
worsened in another one-third of treated patients, but patients remains unknown. Furthermore, the identified
the remaining one-third reported amelioration, which γ-secretase mutations have not been found in sporadic
might be the result of improved coping over time26. cases of HS42–44, which is the common form. First efforts
A broad range of comorbidities have been observed are being made to identify the genetic predisposition,
in patients with HS. Most importantly, HS is associated including single nucleotide polymorphisms, of genes in
with a substantially increased mortality (mean incidence these patients with HS45,46.
ratio of 1.35 (95% CI 1.15–1.59)), in particular due to
cardiovascular events (mean incidence ratio of 1.95 Lifestyle. The role of lifestyle in the development of HS is
(95% CI 1.42–2.67))27. well accepted. Approximately 90% of patients with HS are
current or former smokers13,47,48 and smoking, and spe-
Mechanisms/pathophysiology cifically nicotine, might contribute to disease onset and
Risk and trigger factors progression in various ways. Nicotine induces epidermal
As with most chronic inflammatory diseases, a genet- hyperplasia49 (an increase in the number of cells within
ically based predisposition and external or lifestyle the epidermis) which might lead to infundibular hyper-
factors seem to contribute to disease development. keratosis and occlusion. Nicotine might also influence
Moreover, the particular nature of the intertriginous bacterial propagation and biofilm formation, for exam-
skin might play a part. ple, by promoting the initial attachment and intercellular
accumulation of these microorganisms50,51. Furthermore,
Genetics. A positive family history is observed in ~30% nicotine increases the production of IL-10 by activated
of patients with HS28,29. Mutations in genes encoding immune cells, a cytokine relevant to HS pathogenesis
γ-secretase, an intramembrane multisubunit protease (see below)52. In addition, 50% of patients with HS have
complex, were identified in several members of Chinese obesity and ~40% of patients with HS have metabolic
families with severe HS30. γ-Secretase cleaves several syndrome6. Obesity might contribute to HS pathogene-
transmembrane proteins (for example, Notch receptor sis through subclinical inflammation, metabolic changes
or β-amyloid precursor protein) that are involved in var- and increased friction in skin folds. In people with meta
ious signalling cascades31. So far, 36 mutations have been bolic syndrome, the abdomen and waist are more often
described in three of the four components of γ-secretase affected in patients with HS who have obesity than in
in patients with HS, most concerning the nicastrin sub patients with HS who are lean53. However, in contrast to
unit32. The majority of these mutations seemingly impair earlier dogma, shaving and the use of chemical depilato-
γ-secretase activity32. Interestingly, genetic targeting ries, deodorants and talcum powder were shown to have
of γ-secretase components in mice resulted in the trans- no role as causative factors in the pathogenesis of HS54.
formation of hair follicles into cysts33. Similar alterations A contribution of sex hormones to disease development
in hair follicles were observed upon pharmacological is also suspected55,56. In this regard, microarray analysis
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suggested androgen receptor pathway activation in the bacteria such as Prevotella and Porphyromonas spp.
skin of patients with HS57. as well as Streptococcus anginosus, which typically
reside in different mucosal sites of the body, and the
Localization and microbiota. Intertriginous skin areas facultative skin pathogen Staphylococcus aureus61–63.
show increased mechanical friction, especially in In parallel, a reduced abundance of skin commensals
patients with obesity. The influence on HS development was detected in these studies. HS lesions frequently show
of higher temperature, moisture, a specific microbiota large bacterial biofilms compared with corresponding
composition or a possibly increased number of den- skin areas from healthy donors, whereas clinically unin-
dritic cells and T helper cells58 that are generally present volved hair follicles in matched skin areas revealed less
in intertriginous areas requires further investigation. biofilm64–66. The abundance of apocrine glands typi-
Interestingly, in patients with HS, the number and vol- cally found in intertriginous areas does not seem to
ume of sebaceous glands in optically healthy skin of be essential for lesion development, as lesions can also
affected areas seems to be reduced59; this finding might develop in submammary areas, the upper buttocks or
result in less lubrication of the skin surface, thereby in newly developed skin folds (for example, around
intensifying local mechanical friction with epidermal a hernia)1,67.
micro-injury and hyperplasia.
Bacteria are relevant not only in HS lesions but also Pathogenesis
in HS-prone skin (for example, after skin micro-injury) The underlying mechanisms in HS are complex and
owing to their immunostimulatory effects60 and being include immune activation and progression to chronic
unrelated to infection. The cutaneous micro-injury rate inflammation. For ease of reading, we divide the patho
might be elevated in intertriginous sites through friction, genic events into ‘initial pathogenetic events’ and
especially in patients with obesity. Chronic HS lesions ‘progression to advanced disease’, although current
show increased and polybacterial colonization, includ- knowledge is still limited and mainly based on studies
ing high enrichment of strictly anaerobic Gram-negative with restricted numbers of patients.
Infundibular
Nicotine Mechanical Bacterial
occlusion and
stress components
follicular
Corneal dilatation Keratinocyte
layer
CXCL8
Epidermis CXCL11
CCL2
CCL20
Dendritic
Bacteria TNF cell
Sebaceous Cytokines IL-10
T17 cell
gland Cell IL-1β
debris
Hair T22 cell
follicle
Fibroblast Monocyte
T17 cell T1 cell
CXCL1 B cell
Dermis TNF
IL-6 Cytokines TLR CXCL6
IL-1β Blood Granulocyte
vessel Chemokines
NLRP3 NF-κB
Adipose AP-1
tissue Macrophage
Fig. 2 | Pathogenesis of HS — initial pathogenetic events. To conceptualize and hyperkeratosis are further supported by nicotine present in the high
the pathogenesis of hidradenitis suppurativa (HS), which is still poorly proportion of cigarette-consuming patients. Follicular occlusion in turn
elucidated in a temporal sense, we plausibly separate initial pathogenetic induces intrafollicular stasis and propagation of resident bacteria with
events and those associated with advanced disease. Skin alterations in HS dilatation of the hair follicle. The intrafollicular content further activates
develop in intertriginous areas around hair follicles. Local cell damage innate immune cells, strengthening the production of tumour necrosis
caused by mechanical friction within the skin fold, which is strengthened by factor (TNF) and IL-1β. These cytokines activate the endothelium of local
the reduced number of sebaceous glands in respective areas, leads to blood vessels and induce the expression of a broad range of chemokines
release of cellular damage-associated molecular patterns (DAMPs) such as such as CXCL8, CXCL11, CCL2 and CCL20 in keratinocytes and CXCL1 and
IL-10 and penetration of microbial components into the skin. DAMPs and CXCL6 in fibroblasts. Together, these signals boosts further infiltration of
microbial components activate resident immune cells and induce immune cells into the tissue, including granulocytes, T cells, B cells and
production of cytokines and chemokines, leading to perivascular and monocytes, which locally differentiate into macrophages and dendritic
perifollicular immune cell infiltration. Subclinical inflammation present in cells. T cells involved in HS pathogenesis mainly comprise IL-17-producing
the subcutaneous adipose tissue of patients with obesity is also associated T17 cells and interferon-γ-producing T1 cells; T cells include both helper T
with the release of cytokines that support perifollicular immune cell (TH) cells and cytotoxic T (TC) cells. AP-1, activator protein 1 (heterodimeric
infiltration and activation. Specific mediators of the perifollicular immune transcription factor); NLRP3, NACHT, LRR and PYD domain-containing
cells subsequently induce hyperplasia and hyperkeratosis of the protein 3 (inflammasome component, also known as cryopyrin); NF-κB,
infundibular epithelium of the hair, causing follicular occlusion. Hyperplasia nuclear factor-κB (transcription factor); TLR, Toll-like receptor.
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Initial pathogenetic events. The first histologically skin demonstrates high mRNA levels of interferon-γ
detectable events in developing HS lesions are perivas- (IFNγ) and IL-17, similar to the levels observed in
cular and perifollicular immune cell infiltration as well patients with psoriasis5. High IFNγ and IL-17 levels are
as hyperkeratosis and hyperplasia of the infundibular in line with a study that showed enrichment of CD4+
epithelium68–72 (Fig. 1). The exact underlying causes are T cells able to secrete IFNγ and IL-17 ex vivo, suggesting
unknown, although these might be linked to the trigger that T helper cells are the source of these mediators89,90.
factors described above. Alterations of the infundibular Importantly, IL-12 and IL-23, cytokines that support
epithelium lead to follicular ‘plugging’ and subsequent the function of TH1 and TH17 cells, respectively, and are
stasis of follicular content, propagation of resident bacte- mainly produced by dendritic cells or macrophages91,
ria and dilatation of the hair follicle unit (Fig. 2). Bacterial are also clearly present in the HS skin5.
components and danger-associated molecular patterns In the HS lesion, IFNγ, which is the predominant
(DAMPs) might activate local macrophages, leading to cytokine of TH1 cells, also activates dermal endothe-
secretion of pro-inflammatory cytokines such as IL-1β lial cells allowing infiltration of immune cells from the
and TNF5,73. Bacterial sensing might be strengthened bloodstream92 (Fig. 3). IFNγ induces the secretion of
owing to increased expression of Toll-like receptor 2 by TH1-attracting chemokines such as CXCL10, thereby
local macrophages or dendritic cells as observed in HS creating a positive feedback loop93. In fact, homogen-
skin74. Furthermore, the inflammasome system, which ates of skin lesions of patients with HS demonstrated
is necessary for sensing of DAMPs and subsequent post- elevated levels of CXCL10 (ref. 94) . IFNγ also acti-
translational activation of IL-1β, is also elevated in HS vates macrophages and tissue cells. The consequently
skin75–77. Notably, upregulation of IL-1β is not accom- strengthened antigen presentation of these cells might
panied by a counteracting induction of the natural IL-1 be important for local activation of T cells92. IL-17,
receptor antagonist IL-1RA75. secreted predominantly by TH17 cells, stimulates the
IL-1β and TNF are pleiotropic cytokines that act production of selected chemokines (such as CCL20
on several cell types and have partially overlapping and neutrophil-attracting chemokines that include
effects78,79. Among skin cells, the highest levels of the CXCL1 and CXCL8), cytokines (such as G-CSF and
receptor for IL-1β were found in fibroblasts75. IL-1β pro- IL-19 (which amplifies the actions of IL-17)) and epi-
vokes the production of chemokines, with those attract- dermal antimicrobial proteins (AMPs) 95–99 (Fig. 3) .
ing neutrophilic granulocytes (for example, CXCL1 and Although causing only moderate cell responses on its
CXCL6) being the most prominent (Fig. 2). TNF induces own, IL-17 mainly exerts these functions synergistically
a wide range of chemokines (for example, CXCL8, with other tissue-active cytokines such as TNF, IL-22
CXCL11, CCL20 and CCL2 in keratinocytes) that attract and IFNγ96,98–101.
neutrophils, subsets of T cells and monocytes into the In contrast to IL-17 and IFNγ, expression of IL-22
skin80 (Fig. 2) . Moreover, TNF activates endothelial (the lead cytokine of TH22 cells but also produced by
cells, resulting in strengthened expression of adhesion other lymphocytic cells) in HS lesions is lower than in
molecules. The significance of TNF in HS is supported psoriatic lesions5, which might be due to reduced infil-
by patient response to anti-TNF therapy81. Together, tration of IL-22 secreting cells89,90 and impaired produc-
chemokine induction and endothelial cell activation tion of IL-22 by these cells5. IL-10 was demonstrated
lead to profound immune cell infiltration of the devel- to inhibit the lymphocytic production of IL-22 but not
oping lesions (Fig. 2). Consequently, HS lesions contain IL-17 (ref.5). By contrast, no evidence suggests reduced
massive immune cell infiltrates (Fig. 1). Attracted mono- expression of IL-6 or TNF, cytokines that support TH22
cytes develop into macrophages and dendritic cells. cells5. In addition to reduced levels of IL-22, the activity
Neutrophilic granulocytes, macrophages, dendritic of IL-22 might also be reduced in HS, as deduced from
cells and T cells are the most abundant cells found in the increased expression of the natural IL-22 inhibitor,
HS lesions. Additionally, mast cells, natural killer cells, IL-22 binding protein102,103, in HS lesions5. IL-22 is a
B cells and plasma cells are found72,74,82,83, but the role of major inducer of AMPs41, in particular in the presence
these cells in the pathogenesis of HS is unclear. of IL-17. The reduced expression and action of IL-22
In contrast to other immune-mediated skin disin HS lesions (even in the presence of high IL-17) can,
orders (such as psoriasis), HS skin highly expresses therefore, cause low AMP levels in HS skin compared
not only pro-inflammatory cytokines but also the with psoriatic skin5,104, which results in insufficient inhi-
anti-inflammatory mediator, IL-10 (ref.5). In macro bition of bacterial propagation in HS. IL-22 also pro-
phages, IL-10 is induced by the autocrine action of tects tissue cells against cellular damage105–107 and is a
pro-inflammatory cytokines including TNF. In patients counter-regulator of inflammation-induced metabolic
with HS who are smokers, nicotine increases intra alterations108. Indeed, IL-22 decreases triglyceride syn-
cellular cAMP levels, which might further support cuta- thesis in the liver and triglyceride levels in the blood as
neous IL-10 production52,84,85. IL-10 dampens immune well as improves insulin sensitivity and increases glucose
responses by suppressing pro-inflammatory cytokine uptake in brown adipose tissue108,109. Thus, the lack of an
production by monocytes and macrophages and, directly IL-22 action might also be related to skin destruction
and indirectly, limiting T cell activation86–88. as well as to systemic metabolic changes observed in
patients with HS.
Progression to advanced disease. The diverse immune The intrafollicular bacterial propagation and mas-
cell types that infiltrate the skin secrete specific sive immune cell infiltration both lead to rupture of the
cytokines. Regarding cytokines produced by T cells, HS dilated hair follicle (Fig. 3), which might be facilitated by
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Follicular rupture, inflammatory nodule Keratinocyte Fistula formation

Corneal layer and abscess formation Pus
Epidermis
Dermis T17 cell IL-36
IL-23 IL-17 Cell Epidermal
debris IL-17 IL-26 acanthosis
Bacteria TNF CXCL1
CXCL2
T1 cell
AMPs Lipocalin 2
IL-12
Blood Pus
Dendritic formation
cell vessel
IFNγ
IL-22
TNF IL-6 G-CSF
IL-10 IL-32 MMP1
MMP3 Tissue
T22 cell MMP10 destruction
Macrophage IL-1β B cell
Fibroblast
Granulocyte
Adipose
tissue
Fig. 3 | Pathogenesis of HS — progression to advanced disease. thinning of the underlying basement membrane and genetically based
To conceptualize the pathogenesis of hidradenitis suppurativa (HS), which disturbance of the follicular stem cells. Release of immunostimulatory
is still poorly elucidated in a temporal sense, we plausibly separate initial content from the ruptured follicle further amplifies skin inflammation.
pathogenetic events and those associated with advanced disease. The When surrounded by immune cells, the dilated and ruptured hair follicle
dendritic cell mediators IL-23 and IL-12 support the T17 cells and T1 cells, unit clinically manifests as an inflamed nodule or abscess. Extracellular
respectively , to produce their specific cytokines (IL-17 and interferon-γ matrix-degrading enzymes (matrix metalloproteinases (MMPs)), which are
(IFNγ)). The presence of T22 cells and their main effector cytokine, IL-22, is mainly produced by activated fibroblasts, induce tissue destruction.
rather limited in HS lesions (denoted by dotted arrows). T cells involved in Massive granulocyte infiltration and activation, supported by lipocalin 2 and
the pathogenesis include both T helper (TH) cells and cytotoxic T (TC) cells. granulocyte colony-stimulating factor (G-CSF), result in pus formation.
IL-10, strongly produced by macrophages in HS skin, inhibits the production Mediators of activated T cells and keratinocytes contribute to epithelial
of IL-22 by T cells. The deficiency of IL-22 leads to insufficient levels of hyperplasia, which also develops in the interfollicular areas of HS skin.
antimicrobial protein (AMPs), which are needed to restrict microbial growth Extracellular matrix degradation, accumulating pus and seeding of follicular
in the inflamed skin. Further dilatation of the hair follicle results in its stem cells into the dermal skin layer eventually results in formation of
rupture, a process that is supported by damage of the follicular epithelium, pus-draining tunnels (sinus tracts and fistulas). TNF, tumour necrosis factor.
a thinned basement membrane surrounding the hair specific cytokines (for example, IL-1β and IL-36γ) and
follicle unit (ref.110). This rupture boosts inflammation AMPs116,117. The actual contribution of IL-36 cytokines to
via the release of follicular content comprising immuno HS pathogenesis should be clarified in further studies, as
stimulatory DAMPs, keratin fragments and bacterial their expression is clearly lower in HS than in psoriasis75.
products into the tissue. Once attracted to the lesion, neutrophils contribute to
In this stage, TNF mRNA expression reaches levels inflammatory cytokine production and pus formation
similar to those observed in the inflamed skin of patients in HS. One of the cytokines produced by these cells in
with psoriasis5,75, a disease that responds strongly to HS lesions is lipocalin 2 (ref.118) (Fig. 3). Apart from its
anti-TNF therapy111. The IL-1β upregulation in HS skin function in metabolic control and inducing inflamma-
clearly exceeds even levels in psoriatic skin75. TNF and tory pain, both of which are applicable in HS, lipocalin
IL-1β, as mentioned above, induce various immune 2 stimulates further neutrophil tissue infiltration, creat-
cell-attracting chemokines and activate endothelial ing another vicious cycle119,120. Neutrophils also produce
cells, leading to immune cell infiltration into the skin. the cathelicidin-derived peptide LL37, which has been
This increased immune cell infiltration contributes to postulated to be involved in the proliferation of T cells
subsequent formation of subcutaneous inflammatory in HS lesions121.
nodules and dermal abscesses. IL-1β also provokes the Accumulating pus and seeding of follicular stem
production of extracellular matrix-degrading enzymes cells into the disintegrated tissue110 might promote the
such as matrix metalloproteinases (MMPs) (Fig. 3) formation of pus-draining epithelialized sinus tracts
in addition to inducing the production of selected and fistulas (Fig. 1). Apart from inflammatory nodules,
cytokines such as IL-6 and IL-32 (ref.75) that are abun- abscesses and tunnels, HS lesions also contain areas with
dant in HS lesions5,75,112. MMPs can facilitate the rup- thickened interfollicular epidermis, which is typical of
ture of neighbouring dilated hair follicles and promote psoriatic lesions71,72,82,122.
final destruction of the skin with abscess and tunnel Overall, the immunopathogenesis of HS seems to be
formation. complex, simultaneously showing characteristics of a
HS lesions also show increased expression of IL-36 neutrophilic dermatosis (inflammasome-driven domi-
cytokines75,113–115 that are mainly localized to the keratino nance of IL-1β), the presence of a strong anti-inflammatory
cytes and induce neutrophil-attracting chemokines, component (IL-10), a possible involvement of B cells and
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Open comedones a clear contribution of TH1 or TH17 cells. These activated or gluteal cleft (the groove between the buttocks) are
Wide skin pores, plugged with immunological pathways lead to insufficient anti more affected in men13,135,136. Additional, nonpatho
a mass of black keratin debris. microbial defence, extracellular matrix degradation and gnomonic clinical signs, which support the diagnosis
pus formation, finally leading to pyogenic progressive of HS, include a familial history of HS in first-degree
Double-ended
pseudocomedones
tissue destruction. and second-degree relatives, recurrent atypical lesions
Two interconnected dilated (such as folliculitis and open comedones) in intertrig-
pores with a plug of black Systemic inflammation inous areas, the presence or history of a pilonidal sinus,
keratin debris at each end. Some of the cytokines and the molecules induced in HS and occurrence of typical HS lesions in atypical locations
lesions by these cytokines reach the circulation and might (for example, areas with pressure or mechanical friction
Pilonidal sinus
A recurrent nodule or abscess contribute to the comorbidities seen in these patients. such as the inner thighs or the belt region of the abdo-
draining via a sinus in the cleft For example, IL-1β and IL-6, found to be increased in the men)53,136. Key symptoms of typical HS lesions include
between the buttocks near the patients’ blood75,123, induce a pro-atherogenic and insulin purulent, malodorous discharge, pain and discomfort
tailbone. resistance-promoting adipokine pattern124 that has been during daily life activities1.
Furuncle
recently detected in HS125. Early HS lesions often mimic other disorders (Box 1)
An abscess or nodule arising IL-1β and IL-6 also induce the hepatic produc- such as a simple abscess or a furuncle and, therefore, diag-
from a hair follicle, caused by tion of serum amyloid A (SAA)75, a multifunctional nosis of HS is frequently missed, leading worldwide to
infection with Staphylococcus acute-phase protein. Elevated blood SAA levels increase a mean diagnostic delay of ~7 years137. Early identifica-
aureus.
the risk of atherosclerosis and might lead to amyloid A tion of HS is important as early treatment minimizes the
Pyoderma gangrenosum amyloidosis, a rare but life-threatening complication of risk of progression and associated comorbidities.
Rare skin disease characterized HS126,127. Systemically increased IL-32 levels, which are
by growing painful ulcers with also observed in HS112, have been associated with the Additional diagnostics
undermined borders. risk of cardiovascular disease in other chronic inflam- A skin biopsy is usually not required for the diagnosis of
matory diseases128. Elevated levels of lipocalin 2 in the HS. The histopathological characteristics of HS depend
blood of patients with HS might further contribute to on the type of alteration, which can range from an early
metabolic alterations in these patients118. In addition, an cyst, nodule or abscess to an inflamed sinus tract or a
increased blood level of MMP8, a protease that, among rope-like scar71 (Fig. 4). In the case of a ruptured cyst,
others, degrades the apolipoprotein A-I component of keratin fragments or debris are dispersed in the dermis
HDL, has been linked to metabolic alterations in HS129. and can be visualized using regular haematoxylin and
Apart from metabolic changes, systemically availa- eosin staining, but are often more easily identified using
ble pro-inflammatory cytokines might contribute to pan-keratin immunostaining82. Nevertheless, in uncer-
other comorbidities such as Crohn’s disease and SpA in tain cases a biopsy might be useful to exclude other
patients with HS. For example, the elevated blood lev- disorders such as pyoderma gangrenosum, squamous cell
els of TNF130 and IL-17 (ref.131) might contribute to the carcinoma or lymphomas.
development and persistence of HS-associated SpA132,133. Although routine bacterial cultures are also not indi-
Cutaneous inflammation, extracutaneous inflammation cated in HS, these can be useful in cases in which clinical
and metabolic alterations are thought to mutually stimu- findings (for example, fever) are suggestive of infection
late each other124, supporting ‘chronification’ and further rather than HS, or in cases of secondary infection in
disease progression. HS. Ultrasonography is also typically not required for
the diagnosis of HS, although sometimes (for example,
Diagnosis, screening and prevention in patients with obesity) clinically undetectable lesions
Clinical diagnosis might be discovered 138,139. Similarly, MRI might be
HS is clinically diagnosed based on the nature and helpful in preoperative assessment of fistulation in the
localization of skin lesions and the disease course, anogenital area to exclude the occurrence of fistulas that
which can be persistent (presence of lesions for at least communicate with the rectum or anal canal140.
6 months) or recurrent (>2 skin lesions occurring or Laboratory blood tests are not used for establishing
recurring within 6 months)1,134. The typical lesions a diagnosis as the various proteins that are elevated in
in patients with HS include inflammatory nodules, the blood of patients with HS are not disease-specific.
abscesses, inflamed and draining sinus tracts or fistulas,
and rope-like scarring134 (Fig. 4). Recurrent or persistent Severity classifications
disease can lead to the formation of other lesions such A total body skin examination is required to assess
as open comedones, bridged scars and postinflamma- the extent and severity of HS. The Hurley staging that
tory double-ended pseudocomedones (which resemble introduced the first severity score for HS in 1989 (ref.141)
a ‘tombstone’)134. Patients with HS often present with is widely known and useful for rapid classification of
multiple types of lesions simultaneously. In addition to regional disease severity (Table 1). However, it is static
intertriginous areas, lesions might appear in other areas, and not sensitive enough in the clinical trial setting and
including the nape of the neck, the trunk, extremities for treatment follow-up. The Sartorius system142 repre-
or in the retroauricular area (that is, behind the ear). The sents a universal, detailed and dynamic score, detecting
involvement of different body sites in HS is influenced changes in disease severity over time and in response
by sex. For example, the groin, specifically the upper to treatment. However, owing to its laborious nature,
inner thigh, and submammary and inframammary it is not routinely used in clinical practice. Alternative
regions are frequently affected in women, whereas tools include the Physician Global Assessment Tool
armpits, the perineal or perianal regions, and buttocks for HS (Table 1), which is validated and easy to use143.
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a b c
d e f
Fig. 4 | Typical skin lesions of hidradenitis suppurativa. Representative c | Vulnerability of the skin over inflammatory nodules can lead to
images of the various lesions that are typically found in patients with incomplete or complete loss of the epidermis referred to as erosions and
hidradenitis suppurativa (HS). a | Generally, the first HS lesion is a solitary, ulcerations, respectively. Postinflammatory hyperpigmentation can occur
painful, deep-seated inflamed nodule (1–2 cm in diameter), usually in an as a result, which tends to affect darker skinned patients with greater
intertriginous area. New nodules can develop overnight with a mean frequency and severity. d | Closed comedones can develop in HS. They are
duration of 1–2 weeks. Patients develop a median of two nodules or small cysts that occur as a result of follicular occlusion. In long-standing HS,
abscesses per month, which might recur in the same location. Prodromal open comedones and double-ended pseudocomedones frequently appear
symptoms such as fatigue, localized pruritus or paraesthesia can occur prior (arrows). e,f | Long-affected skin areas can appear as pitted hypertrophic
to disease flares. b | Sinus tracts are typical lesions in HS that persist for scars, fibrotic bands or indurated, thick, scarred plaques that affect an entire
months or years. The development of multiple recurrent inflammatory anatomical area. Scars are often colocalized with inflammatory nodules,
nodules within a limited area can predispose the individual to the formation abscesses or pus-discharging tunnels (panel e) and erosions or ulcers
of intercommunicating sinuses. Patients with sinus tracts often experience (panel f). Scar formation might also lead to impaired function (for example,
intermittent release of blood-stained, sero-purulent, malodorous discharge. impaired arm elevation due to contracture formation) and deformities
Occasionally , pyogenic granulomas develop at sinus tract openings. owing to lymphoedema.
Even though it is slightly rigid (distinguishing only medical treatment. However, most clinical scores are not
six stages), it is suitable for observing changes during detailed enough for precise descriptions of disease sever-
treatment and, therefore, is frequently used in both ity or for therapy outcomes, hampering the comparison
clinical trials and daily practice. The latest tool is the of study results in HS. In addition, scores based on lesion
International Hidradenitis Suppurativa Severity Score counts might not be useful for patients who have lesions
System (IHS4), which is a composite score based on that are extensively inflamed and contain indurated areas
counts of inflammatory nodules, abscesses and drain- lacking clear, individual, countable nodules (frequently
ing tunnels, translating into ‘mild’, ‘moderate’ or ‘severe’ found in patients with Hurley stage III disease). Because
disease23 (Table 1). The IHS4 score is useful for severity of these limitations, several additional scores, including
assessment at baseline, which helps determine the type of the refined Hurley score, have been suggested144–146.
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Box 1 | Differential diagnoses of HS the Hidradenitis Suppurativa Global Assessment

scale, the Hospital Anxiety and Depression Scale151,
Clinically, hidradenitis suppurativa (HS) may resemble the Work Ability index and Work Productivity and
several conditions; the most prominent are infections Activity Impairment152.
arising from hair follicles.
The NRS is a segmented numerical version of the
Bacterial infection VAS in which patients select a whole number (from
• Folliculitisa,b 0 to 10 or from 0 to 100) that best reflects the inten-
• Furunclea,b sity of their pain or itch. Sometimes the improvement
• Carbunclea,b obtained is not captured by objective counts of lesions,
• Abscessa,b but patients experience significantly less pain or itch,
which is of utmost importance to the patient.
• Nocardiosisc,d
As inflammation in HS extends to deep skin regions
• Atypical mycobacterial abscesses
it cannot be reliably assessed visually by physicians.
• Granuloma inguinalee,f
Thus, blood biomarkers have garnered considerable
• Lymphogranuloma venereumg,f interest to objectively reflect the activity of inflammatory
• Noduloulcerative syphilish,f processes. Accordingly, the levels of several proteins are
Deep fungal infection increased in the blood of patients with HS131,153. These
proteins include chitinase-3-like protein 1 (YKL-40;
• Blastomycosisi
a protein with largely unknown function)154, MMP8
• Sporotrichosisj
(ref.129), lipocalin 2 (ref.118), IL-6 (refs75,123), C-reactive
• Chromoblastomycosisk protein123 and SAA75, the expression levels of which cor-
• Mycetomal relate with the extent of inflammatory skin alterations.
Cysts Furthermore, classic markers of inflammation, such as
• Pilonidal cyst erythrocyte sedimentation rate, might also be altered in
patients with HS155.
• Epidermoid cyst
• Bartholin’s cyst
Associated conditions and syndromes
• Steatocystoma multiplex The most frequently reported conditions associated with
• Sebaceous or trichilemmal cysts HS skin alterations are metabolic syndrome, depression,
Other conditions SpA and IBD (Crohn’s disease and ulcerative colitis).
• Giant comedonesb Whether skin alterations or extracutaneous inflam-
matory alterations occur first is currently unknown.
• Acne keloidalis nuchae
Interestingly, some of the conditions (for example, obe-
• Acne fulminans
sity and metabolic syndrome) have been extensively
• Rosacea fulminans linked to the pathogenesis of HS. Increased prevalence of
• Cutaneous Crohn’s disease metabolic syndrome (in up to 50% of patients), based on
• Strangulated inguinal hernia concomitant obesity, dyslipidaemia, hyperglycaemia and
• Pyoderma gangrenosum hypertension, has been noted in patients with HS6,156.
• Amicrobial pustulosis of the folds Together with a high rate of smoking in patients with HS,
• Scrotal, vulvar, anal or vulvovaginal fistulas metabolic syndrome might contribute to the increased
risk of cardiovascular-associated death27. Approximately
a
Caused by Staphylococcus aureus. bCommon differential
50% of patients also seem to have SpA and/or arthrop-
diagnosis. cCaused by Nocardia asteroides. dCaused by
Nocardia brasiliensis. eCaused by Klebsiella granulomatis. athies including osteoarthrosis7–9. The prevalence of
f
Sexually transmitted infections. gCaused by Chlamydia IBD among patients with HS is 2.8–3.3% (0.8–2.5%
trachomatis. hCaused by Treponema pallidum. iCaused by for Crohn’s disease; 0.8–1.3% for ulcerative colitis)10,11.
Blastomyces dermatitidis. jCaused by Sporothrix schenckii. These data reveal that patients with HS have a higher
k
Caused by e.g., Phialophora verrucosa. lCaused by e.g.,
Madurella mycetomatis.
risk of developing IBD compared with the general popu
lation, who show a prevalence of up to 0.3% and 0.5%
for Crohn’s disease and ulcerative colitis, respectively157.
The refined Hurley score captures the extent of inflam- Conversely, the prevalence of HS in patients with Crohn’s
Acne conglobata
mation and enables distinction of severity within a single disease or ulcerative colitis has been reported to be up
A rare and severe form of acne Hurley category146. Which new scoring systems will be to 25%158. Finally, a subset of patients with severe HS
presenting with interconnected incorporated into routine clinical practice remains to have chronic fatigue, which might be a symptom of a
nodules, abscesses and be determined. secondary, inflammation-induced anaemia159,160.
sometimes sinus tracts, mostly
As well as scoring tools used by physicians, patient- HS is part of the follicular occlusion tetrad consisting
in the neck, back and chest.
reported outcome measures (PROMs) have attracted of HS, acne conglobata, dissecting cellulitis of the scalp and
Dissecting cellulitis of the increased attention. PROMs gather information directly pilonidal sinus. Although developing in different ana-
scalp from patients about their symptoms, condition and tomical locations, these clinical entities share follicular
A rare condition of the scalp overall quality of life. Commonly used PROMs include occlusion as the key pathogenetic event and might occur
associated with hidradenitis
suppurativa, with pus-filled or
the Dermatology Life Quality Index (DLQI) and Visual in conjunction with each other in individual patients.
indurated lumps, scarring and Analogue Scale (VAS) or Numeric Rating Scale (NRS) Furthermore, acne vulgaris is often seen on its own in
permanent hair loss. for pain and itch147–150. Less common PROMS comprise association with HS, especially in men and in patients
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Table 1 | Scores of hidradenitis suppurativa disease severity development of Hurley stage III HS and, therefore, a
sign of a poor prognosis. Finally, inadequate treatment
Severity or stage Description and/or lack of lifestyle improvements seem to counteract
Hurley stage 141
any remission26,163.
Stage I Abscess formation, single or multiple, without sinus tracts The persisting inflammation in HS leads to several
or cicatrization complications. In areas such as the axilla or groin, scar-
Stage II Recurrent abscesses, single or multiple, and widely ring can result in thick, linear, rope-like cutaneous bands.
separated lesions, with tunnel formation and/or scarring Severe scarring in the axilla might result in reduced mobil-
Stage III Diffuse or near-diffuse involvement or multiple ity of the arm or cause lymphatic obstruction, leading to
interconnected tunnels and abscesses across the entire lymphoedema164. Groin involvement might also lead
area to lymphoedema of the pubis, labia and vulva in women or
The Physician Global Assessment Tool for hidradenitis suppurativa (HS-PGA)a penile and/or scrotal lymphoedema in men164. Long-term
systemic effects of chronic inflammation include anae-
Clear No abscesses, draining tunnels, inflammatory nodules or
noninflammatory nodules mia, hypoproteinaemia, amyloidosis and infectious
complications such as lumbosacral epidural abscess
Minimal No abscesses, draining tunnels or inflammatory nodules
and sacral bacterial osteomyelitis7,159,165,166. Furthermore,
and the presence of noninflammatory nodules
there is an increased prevalence of lymphomas (non-
Mild No abscesses or draining tunnels and 1–4 inflammatory Hodgkin lymphoma, Hodgkin lymphoma and cutane-
nodules, or 1 abscess or draining tunnel and no
inflammatory nodules ous T cell lymphoma) in patients with HS167. In addition,
fistulas into the urethra, bladder, rectum and peritoneum
Moderate No abscesses or draining tunnels and ≥5 inflammatory
are reported complications of HS168. However, confusion
nodules, or 1 abscess or draining tunnel and ≥1
inflammatory nodule, or 2–5 abscesses or draining tunnels with Crohn’s disease or coexistence of HS with Crohn’s
and <10 inflammatory nodules disease might be partly responsible for these reports.
Severe 2–5 abscesses or draining tunnels and ≥10 inflammatory Squamous cell carcinoma, mostly arising in gluteal or
nodules perianal locations, has been described as a rare compli-
cation and seems to be more common in men, possibly
Very severe >5 abscesses or draining tunnels
related to more severe perianal involvement in men166.
International Hidradenitis Suppurativa Severity Score System (IHS4)b
Mild ≤3 points (number of inflammatory nodules ×1 and number Preventive measures and lifestyle
of abscesses ×2) It is not known whether primary prevention of disease
Moderate 4–10 points (number of inflammatory nodules ×1, number is possible. Accordingly, a recommendation for a regular
of abscesses ×2 and number of draining tunnels ×4) body inspection of individuals with a strong familial pre-
Severe ≥11 points (number of inflammatory nodules ×1, number of disposition seems prudent. Secondary prevention through
abscesses ×2 and number of draining tunnels ×4) lifestyle changes is often needed in addition to medical
a
Score development based on 154 patients143. bScore development and validation based on and/or surgical treatment. Strong evidence supports
236 patients23. weight reduction for improvement of the disease.
In a study involving patients with HS who showed a
with familial HS. HS might also occur as part of a syn- reduction of >15% in BMI over 2 years after bariatric sur-
drome such as PASH (pyoderma gangrenosum, acne and gery (n = 35), 50% reported a substantial reduction in HS
suppurative hidradenitis) or PAPASH (pyogenic arthritis, disease severity163. These results are further supported by
pyoderma gangrenosum, acne, and suppurative hidra case reports of patients achieving disease remission after
denitis)161. These syndromes combine different but extensive weight loss169. However, attempting to lose
closely associated diseases in one patient, with subse- weight by active involvement in sports might be difficult
quent increased morbidity. Other conditions, including because of the pain caused by friction during exercise.
genetic disorders and malignancy have been associated Furthermore, extensive weight loss might create loose
with HS (Box 2). skin, resulting in increased friction. Thus, reconstructive
plastic surgery might be needed in concerned patients.
Natural course and complications Some evidence supports that cessation of smoking might
HS is one of the most distressing dermatological dis- improve the disease course of HS26. However, patients
eases owing to its monthly flares of painful lesions and often find it extremely difficult to quit smoking as this
decades-long chronicity26. Our knowledge about the can be accompanied by weight gain. Finally, both the
natural history of HS and the factors that influence design and fabric of undergarments might influence
disease progression is, however, limited. Onset of HS the evolution of HS lesions by reducing mechanical stress,
before 13 years of age has been shown to be associated humidity, heat and microbial colonization170, but further
with a positive family history of HS and involvement clinical testing is needed before firm recommendations
of an increased number of body sites24. Furthermore, can be made.
patients with current Hurley stage III HS are described
as having a faster and more aggressive disease course Management
Pyogenic arthritis compared with patients with current Hurley stage II162. Patients with HS generally have a high, unmet medi-
Arthritis caused by invasion of
a joint by an infectious agent
This finding might mean that rapid disease progression cal need because of a long delay in diagnosis, the lim-
resulting in painful joint (within several months to a few years) from Hurley ited range of evidence-based therapies and the absence
inflammation. stage I to Hurley stage II is a predictive factor for the of curative treatments. Nevertheless, several national
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guidelines and one international guideline exist that seemingly healthy-looking regional skin. Pharmacological
describe the various options available to manage therapies are therefore potentially needed for targeting
HS171–174. Adapting the treatment to disease severity these lesions and should be a core element of disease
and the patient situation is generally advised175 (Fig. 5). management. Although there is a flurry of ongoing
Treatment options comprise pharmacological thera- trials in HS (Table 2), only comparatively few, often
pies and surgery and should be provided together with small, randomized controlled trials (RCTs) have, as
supportive care and lifestyle-modification measures1. yet, been published. The pharmacological manage-
A low socioeconomic status might affect the resil- ment of HS generally follows either an antibiotic or
ience of patients, and general supportive care might be of an anti-inflammatory approach, although most anti
particular benefit in this group of patients. In addition to biotics used are characterized by having an independent
the psychosocial effects of the disease, the lack of proper anti-inflammatory effect.
treatment represents an additional burden. Thus, parti
cipation in structured patient education that provides Antibiotic therapy
information on appropriate dressings, supports tobacco Topical antibiotic treatment can be used in mild or mod-
abstinence and encourages weight reduction might be erate disease of limited extent (Fig. 5). By contrast, sys-
helpful, as these factors can improve disease severity and temic treatment is necessary in the large proportion of
prognosis176. In addition, these measures can reduce the patients with advanced disease, which is frequently asso-
likelihood of complications after surgery and might fur- ciated with systemic inflammation and comorbidities.
ther help reduce symptoms and risks associated with A small RCT (n = 30) showed that topical application of
comorbidities such as metabolic syndrome, diabetes clindamycin to involved regions improved widely spread
mellitus and arthritis. Supportive care should ideally also mild disease, but is associated with increased risk of pro-
provide professional pain management and treatment moting bacterial clindamycin resistance179,180. Another
of superinfections that potentially occur in HS lesions. small RCT (n = 46) comparing topical clindamycin with
Pain management can include an initial classification of systemic tetracycline found no difference in pain or
pain177 and subsequent treatment according to current lesion counts, but was not powered for equipotency181.
WHO guidelines for the management of nonmalignant Furthermore, various open studies and case series sug-
pain178. Superinfections, evident by an erythematous peri gest that tetracycline-like drugs such as doxycycline
lesional halo, increased oozing, marked heat and ten- and minocycline are effective in the management of
derness, are managed with microbiological identification mild HS182,183.
of the pathogen, characterization of its susceptibility to The use of systemic antibiotics to treat HS is largely
treatment and targeted antibiotic therapy. Topical disin- based on cohort studies or open case series. In particular,
fectants might minimize the bacterial load on the skin, several studies have evaluated the effect of a combination
influence odour and prevent superinfections, even if of rifampicin and clindamycin, which was usually given
they are unlikely to affect the disease course. for 10–12 weeks. The studies demonstrated a reduction
In addition to clinically obvious lesions, preclinical in pain, lesion counts and suppuration, although the
or subclinical inflammatory lesions can be found in contribution of clindamycin to the overall effect has
been questioned184–186. The studies reported mild gastro
intestinal upset and only rare severe adverse effects in
Box 2 | Selected diseases associated with hidradenitis suppurativa patients treated with rifampicin and clindamycin187. More
Inflammatory disorders extensive antibiotic regimens such as 6-week ertapenem
• Metabolic syndrome monotherapy with subsequent 6 weeks of rifampicin–
• Spondyloarthritis and/or spondyloarthropathy moxifloxacin–metronidazole, followed by 6 weeks of
• Crohn’s disease
rifampicin–moxifloxacin188, or, alternatively, the com-
bination rifampicin–moxifloxacin–metronidazole189
• Ulcerative colitis
have also been described as partially effective. Dapsone,
• Acne conglobata alone or as the follicular occlusion tetrad
an antibiotic with immunomodulatory effects, has
• PASH syndrome (pyoderma gangrenosum, acne, suppurative hidradenitis), PAPASH similarly been described as partially effective in
syndrome (pyogenic arthritis, pyoderma gangrenosum, acne, suppurative
case series190.
hidradenitis), SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis)
Genetic disorders Anti-inflammatory therapy
• Dowling–Degos disease A second possibility for pharmacological therapy
• Down syndrome for HS is to directly counteract inflammation (Fig. 5).
• Keratitis–ichthyosis–deafness Intralesional application of the glucocorticoid triamci-
• Pachyonychia congenita syndrome
nolone has been shown to rapidly alleviate pain in a case
series191. Similar to antibiotic therapies, the effects of tra-
Malignancy ditional immunosuppressive drugs such as cyclosporine
• Squamous cell carcinoma are shown only in small case series29. However, evidence
• Lymphoma (non-Hodgkin lymphoma, Hodgkin lymphoma and cutaneous T cell based on large RCTs (phase II and III) support the use
lymphoma) of adalimumab, a human anti-TNF antibody (given
as weekly subcutaneous injections)81,143. Two phase III
Other
trials, PIONEER I and PIONEER II, included a total of
• Depression
633 patients (n = 307 and n = 326, respectively) who
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Patient education and coaching

Pain management
Patients with nodules and abscesses only Patients with tunnels, scars or contractures
≤4 Nodules and abscesses 5–10 Nodules and abscesses ≥11 Nodules and abscesses
and DLQI ≤10 or DLQI 11–20 or DLQI ≥21
• Local therapy with antiseptics • Local therapy with antiseptics

• Local therapy with antibiotics • Local therapy with antibiotics • Local therapy with antiseptics
• Intralesional steroids • Systemic antibiotics • Systemic antibiotics and/or
• Zinc gluconate • If needed, anti-TNF mAb (adalimumab) anti-TNF mAb (adalimumab)
Patients with medical therapy-resistant nodules or abscesses
Low inflammatory activity High inflammatory activity
• De-roofing • Systemic antibiotics and/or

• Laser surgery anti-TNF mAb (adalimumab)
• Excision • Excision
Consider long-term systemic anti-inflammatory therapy (for example, adalimumab)

Lifestyle changes
Diagnosis Treatment
Fig. 5 | Hidradenitis suppurativa management. Therapy decisions for hidradenitis suppurativa should consider the
severity of disease as well as the patient’s perception of disease symptoms. Supportive care and patient coaching should
be offered. Patients with only nodules and abscesses should be subgrouped into mild, moderate or severe disease, and
treated with antibiotics and/or anti-inflammatory drugs in a subgroup-specific manner. Subgrouping and treatment
options according to skin alterations (based on the number of nodules and abscesses145) and quality of life (based on the
Dermatology Life Quality Index (DLQI)) are shown. It should be noted that other patient subgroupings were published
(for example, based on the International Hidradenitis Suppurativa Severity Score System (IHS4)23, or the refined Hurley
score146). In the event of an indication for surgery (for example, presence of tunnels, scars or contractures) patients with
low inflammatory activity should undergo surgery promptly, whereas those with high inflammatory activity should
undergo surgery after treatment with systemic antibiotics and/or adalimumab. In some patients, long-term systemic
anti-inflammatory therapy should be considered. With the improvement of the patient’s health status, further efforts
should focus on lifestyle changes, especially on weight reduction and, if applicable, cessation of smoking. mAb,
monoclonal antibody; TNF, tumour necrosis factor.
received placebo or loading doses of adalimumab for the meaningful improvement was generally observed dur-
first 2 weeks (induction period) and a weekly lower dose81 ing the 2-week induction period, and was sustained
thereafter. The design of the two trials was almost identi- during 3 years of investigation194. The primary outcome
cal; the main difference was the concomitant oral tetra of the trial was also mirrored in secondary outcomes in
cycline class antibiotics permitted in PIONEER II (for PIONEER II; adalimumab was markedly efficacious for
19% of participants). The primary efficacy end point was the reduction of pain (measured with the Patient’s Global
the Hidradenitis Suppurativa Clinical Response (HiSCR), Assessment of Skin Pain), disease severity (with modified
which was developed based on the underlying phase II Sartorius score and Hurley stage) and number of lesions,
trial of adalimumab and validated against meaningful as well as for an improvement in DLQI. The proportions
changes in pain score and DLQI192,193. The achievement of patients experiencing adverse events including infec-
of HiSCR is defined as a ≥50% reduction in acute lesion tion or serious adverse events were similar between
count (sum of inflammatory nodules and abscesses) placebo-treated and adalimumab-treated groups in
with no increase in abscesses or draining tunnels com- PIONEER I and PIONEER II 81. Furthermore, the
pared with baseline. A significantly greater proportion of safety profile during 3 years of investigation was similar
adalimumab-treated patients achieved HiSCR compared to the profiles observed in the PIONEER studies194.
with placebo-treated controls in the PIONEER I trial Infliximab, a chimeric monoclonal antibody, is
(41.8% versus 26%; P = 0.003) and in the PIONEER II another anti-T NF antibody recommended for the
trial (58.9% versus 27.6%; P < 0.001). The clinically treatment of HS173, but the recommendation is based
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on a small phase II RCT comprising only 38 patients155. series and two exploratory small RCTs (both involving
Patients were treated with infliximab as single intrave- 20 patients) demonstrated an effect of apremilast198–200,
nous injections in weeks 0, 2 and 6. At 8 weeks, ~27% of a selective inhibitor of phosphodiesterase 4 with
patients treated with infliximab demonstrated at least a immunosuppressive effects.
50% decrease in the Hidradenitis Suppurativa Severity
Index (HSSI) compared with the placebo group (~5%). Surgery
The HSSI is an unvalidated composite score in which the In patients with severe chronic lesions that do not
size of the body surface area involved and the number respond to antibiotic or anti-inflammatory therapy, or
of skin lesions are combined with the patient’s assess- in patients with irreversible skin lesions such as tunnels,
ments of purulent secretion and pain severity. A simi- distinct scars and contractures, surgical intervention
lar effect was observed in patients who switched from should be considered (Fig. 5). A wide range of surgical
placebo to infliximab in the second phase of the study. techniques have been used in the management of HS
The improvement in HS severity was further supported lesions. The general consensus is that incision and
by a reduction in the DLQI, pain VAS, static Physician drainage of individual lesions is associated with an
Global Assessment scores and classic inflammation unacceptably high recurrence rate and should, there-
markers such as the erythrocyte sedimentation rate fore, be reserved as an emergency measure for very
and CRP155. Open case series and smaller exploratory painful abscesses174. If the disease is localized (for exam-
RCTs indicate that targeting of other cytokines such as ple, a draining tunnel) more limited surgery such as
IL-1 and those involved in the IL-12 and IL-23 path- de-roofing of tunnels or simple local excisions can be
ways might be useful in the management of HS and performed. De-roofing is defined as surgical removal
should be considered195–197. Similarly, an open case of the skin covering a tunnel, laying open the partially
Table 2 | Systemic drugs being under development for hidradenitis suppurativa

Target Drug name Structure Sponsor Study start Phase Estimated Statusa Trial number
enrolment
G-CSF CSL324 Monoclonal CSL Behring July 2019 I 40 Recruiting NCT03972280
antibody
IL-23 p19 Risankizumab Monoclonal AbbVie June 2019 II 190 Recruiting NCT03926169
antibody
IL-17RA Brodalumab Monoclonal Florida Academic May 2019 II 20 Not yet NCT03910803
antibody Dermatology Centers recruiting
Cannabinoid Cannabis oil Olive oil TO Pharmaceuticals May 2019 II 40 Not yet NCT03929835
receptors extract recruiting
CD40 Iscalimab Monoclonal Novartis February 2019 II 90 Recruiting NCT03827798
antibody
Unknown LYS006 Unknown Novartis February 2019 II 90 Recruiting NCT03827798
IL-17A Secukinumab Monoclonal Novartis February 2019 III 471 Recruiting NCT03713632
antibody
IL-17A Secukinumab Monoclonal Novartis January 2019 III 471 Recruiting NCT03713619
antibody
C5a receptor Avacopan (C5aR Small ChemoCentryx December 2018 II 391 Recruiting NCT03852472
antagonist) molecule
JAK1 INCB054707 Small Incyte corporation September 2018 II 36 Completed NCT03607487
molecule
IL-23 p19 Guselkumab Monoclonal Janssen Research & September 2018 II 184 Active, not NCT03628924
antibody Development, LLC recruiting
IL-1α Bermekimab Monoclonal XBiotech June 2018 II 20 Recruiting NCT03512275
antibody
C5a IFX-1 Monoclonal InflaRX GmbH February 2018 II 175 Active, not NCT03487276
antibody recruiting
IL-17A and Bimekizumab Monoclonal UCB Biopharma September 2017 II 157 Completed NCT03248531
IL-17F antibody S.P.R.L.
Inflammation, Hydroxychloroquine Small Elena Gonzales Brant, September 2017 I and II 17 Active, not NCT03275870
protozoa molecule MD recruiting
PDE4 Apremilast Small M.B.A. van Doorn, February 2017 II 20 Completed NCT03049267
molecule Erasmus Medical
Center
PDE4 Apremilast Small Florida Academic July 2016 II 20 Completed NCT02695212
molecule Dermatology Centers
As of 23 January 2020. G-CSF, granulocyte colony-stimulating factor ; IL-17RA , IL-17 receptor A ; PDE4, phosphodiesterase 4.
a
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Box 3 | Patient experiences The size of the intervention is often associated pos-
itively with complications but inversely with recur-
Randomly selected patients were interviewed about living with hidradenitis rence rates; that is, smaller surgical procedures such
suppurativa. They were asked to spontaneously and briefly sum up their struggle and as de-roofing or simple excisions are associated with
how they cope with the disease on three separate levels: perception of their own body,
lower complication rates and higher recurrence rate,
social relations and self-esteem.
whereas the reverse is true for wide excisions. However,
The statements provided have not been edited and the patients’ emphases remain
in place. reporting of these crucial surgical parameters is ham-
pered by a lack of consensus on definitions regarding
Body recurrence and complications. Furthermore, the fact that
• ‘As I have it under my armpit, the pain disturbs absolutely in EVERYTHING during the the different surgical techniques are used for different
day, because I just cannot move my limb. When I move, it hurts me so much that I feel degrees of disease severity (for example, de-roofing for
my brain is going to be ripped out. So it is in everything, from cooking to writing’.
a recalcitrant draining tunnel versus wide excision
• ‘I do not even shave my armpits anymore. Come on! In the summer, well, you need a for very severe Hurley stage III disease) adds to the com-
little bit. But I had also an impression that it was worse [when I was shaving]. But come
plexity and hinders direct comparison of data. The most
on, the woman with unshaven armpits?! Well, here I am… I am already trying to buy
some blouses with the long sleeves’.
commonly reported complications of surgery include
anaesthesia or paraesthesia of the scars, wound infec-
• ‘I have to watch out what I wear, no artificial materials, everything made from cotton,
natural. Airy in summer. And I wear leggings because of that, they do not have thick
tion, pain, scarring, necrosis of flaps and grafts, wound
seams, they do not chafe the infected body sites, they are quite thin and only cotton’. dehiscence, a restricted range of motion due to scar
contracture, haematoma, failure of the skin graft and
Social relations hypertrophic scars.
• ‘Since I was very weak, I had to give up with a lot of things, right? I do not know…, for As well as surgical approaches, laser therapy can be
instance from any meetings or everything else. And then?… how to explain it? “Why used in the treatment of HS. In an RCT (n = 22), appli-
did not you come?” “Well, because I was sick.” “How were you sick, again?” “And how cation of nonablative 1,064‐nm neodymium‐doped
would you explain it?”’
yttrium aluminium garnet (Nd:YAG) laser that leads to
• ‘Home, sweet home. I can walk here, I can ventilate myself. I will create some photothermolysis of hair follicles has shown utility206.
conditions to survive it somehow. I can go to the backstage, wash up myself.’ Affected regions were treated with a single-pulse tech-
Self-esteem nique, whereas individual nodules were treated with
• ‘So, how do I look like? And when I was changing my clothes…, they gave me a double pulsing in 3-month laser sessions. The outcome
half-wall mirror in the room, and take a look at you, man… Although it is better, but it was assessed 1 month after the completion of treat-
still does not look nice.’ ment using the Hidradenitis Suppurativa Lesion, Area,
• ‘I have a depression. It means…, I had. I really do not want to get out of my bed. and Severity Index, which was based on a modified
Man wonders — why should I get out of bed? It hurts me all the same. When I get up, Sartorius score expanded by an investigative assessment
sit down, it is going to rupture. There is black despair, yes, there is. There are black of erythema, oedema, purulent discharge and pain.
thoughts that nobody shakes hands with you… It is easy to fall down, easy to get lost’. Overall, there was a 65.3% reduction in the score in the
Nd:YAG-treated anatomical sites, indicating a substan-
tial beneficial effect. Case series suggest that a similar
epithelialized tunnel floor for secondary intention heal- effect is also likely with intense pulsed light devices207.
ing (spontaneous healing without attempting closure of In addition, CO2 laser ablation of chronic lesions can
the wound), whereas simple local excisions include the also be used in more widespread disease.
removal of the entire tunnel and can be closed directly.
These approaches are often performed in an office Quality of life
setting with a quick recovery201. When planning more HS substantially reduces the quality of life of patients
extensive surgery or if perineal/perianal lesions occur, (Box 3), which has been demonstrated by the elevated
preoperative MRI or ultrasonography is necessary to rule DLQI score142,208,209, a validated ten-question question-
out anal fistulas, which should be managed by colorectal naire. The categories ‘symptoms and feelings’ and ‘daily
surgeons. On the basis of expert opinion, inflammation activities’ revealed the strongest negative effect. With
should be minimized before larger surgery (Fig. 5). reference to single questions, pain assessment, discom-
Ablation of lesions can also be achieved using fort and embarrassment142,209,210 provided the highest
electrosurgery (namely, diathermy), which uses a scores. Chronic pain is the most bothersome symptom
heat-generating electrical device to vaporize tissue. The in HS, with ~97% of patients reporting mild to moder-
common paradigm is to remove diseased tissue only, ate intensity of pain211–213. Moreover, the pain intensity
thereby minimizing the postsurgical wound, which is correlated positively with disease severity, assessed with
most often left for secondary intention healing202,203. the modified Sartorius score, HSSI and Hurley staging211.
These procedures might be an alternative to wide exci- However, the pain was particularly pronounced during
sion, which involves the complete removal of all affected disease flares and abscess formation. In contrast to other
lesions including a 1–2 cm lateral margin of healthy dermatoses, HS pain, evaluated with the NRS-11 (NRS
skin204. The resulting wounds can be left for secondary ranging from 0 to 10) was of higher intensity (mean
intention healing, but particularly large wounds are score 3.6–4.9)210–213. Moreover, pain was reported as the
often closed with meshed split-thickness skin grafts or main cause of insomnia and deterioration of sleep qual-
flaps to shorten healing time. A small study (n = 10) has, ity among patients with HS, considerably affecting sleep
however, implied that patients possibly prefer secondary duration and daytime dysfunction214. Various research-
healing over skin grafting205. ers have postulated that itch might also reduce the
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quality of life211,215. Two cross-sectional studies reported Despite this immense development, fundamental questions
an itch prevalence of 41.7% and 67.3%, respectively, remain to be answered, including the initiating causal
among all examined patients with HS and obtained con- factors, genetics, the microbiome and immunology that
vergent results with regard to many aspects, including underlie the disease. It will be exciting to see how the
itch intensity (NRS-11 mean of 4.3 and 5.4 for patients progress in HS research will validate, refine or refute
reporting any itch) and its association with increased our current hypotheses about its pathogenesis. Without
pain severity, high number of affected skin areas, Hurley a doubt, this is a time of tremendous momentum that
stage III and active smoking habit211,215. will greatly improve our understanding of HS and the
The profound disturbance of sexual health also con- possibilities for its treatment.
tributes to reduced quality of life in patients with HS216.
Sexual distress was greater in women than men, and Mechanisms
correlated with the extent of quality of life reduction but Genetics. Although there have been several attempts to
not disease severity216. The impairment to sexual life is identify the genetic basis for the predisposition to HS,
higher in patients with HS compared with patients with to date the patterns remain largely uncovered. Thus,
other dermatoses such as psoriasis217. The reduced inti- larger cohorts of patients, whose disease state has been
mate relationships might contribute to the reduced birth well characterized, will likely be needed for genome-
rates reported among women with HS218. wide association studies to evaluate involved genes and
HS also drastically impairs a patient’s professional this will require substantial coordinated efforts.
life; absenteeism from work was reported for 50–58%
of patients (mean number of HS-related sick days was Pathogenesis. A few studies have expanded beyond the
14.2–33.6 workdays per year)3,4. Furthermore, a Danish description of immune mediators present in HS lesions
study demonstrated a relatively high unemployment rate and have elucidated their cellular effects and poten-
in patients with HS (25.1%) compared with the general tial role in HS pathogenesis5,75,223. Although immune
population (6.2%)3. mediators have been identified that underlie the typ-
Considering the huge overall burden caused by HS, ical purulent secretion and skin structure disruption
patients unsurprisingly experience psychological disin HS5, little is known about the mechanisms leading
turbances such as depression (with a prevalence up to to the debilitating cutaneous scarring. Our knowledge
42.9%), which was demonstrated by two independent regarding the exact immune cell subpopulations that are
studies13,14 and subsequently confirmed by numerous involved in specific aspects of HS pathogenesis is even
observational and registry studies219. Indeed, the Danish more limited90,224, in contrast to other chronic inflamma-
registry reported an increased intake of antidepressants tory diseases like psoriasis225. Much work is also needed
or anxiolytics by patients with HS compared with the to understand the cellular origin of the immune medi-
age-adjusted and sex-adjusted general population (OR ators and the specific factors that activate these cells in
2.02–2.19)220. The same study reported a substantially HS. Beyond these issues, understanding whether the
elevated risk of suicide among patients with HS versus key immune pathways described in HS inflammation
the general population, which remained increased even are present in all patients with HS or whether there are
after adjustment for confounding factors such as age, different immune subtypes among patients is crucial.
sex, socioeconomic status, smoking, alcohol abuse and Enhancing our knowledge of the immunopathogene-
health care use (HR 2.42)220. The reasons for depression sis of HS is fundamental for the identification of novel,
in patients with HS could be manifold and, besides a more effective therapeutic targets. With that knowl-
reduction in quality of life because of pain, impaired edge, future studies can be directed at the develop-
sexual health and limitations in professional life, could ment of monospecific and multispecific therapies that
also include the systemic inflammation as mentioned might be suited for the majority of patients or specific
above. A further element of the psychosocial burden subpopulations.
for patients with HS is an impaired personal body
image, which includes aspects such as ‘self-acceptance’ Microbiota and hormonal impact. An important ques-
and ‘acceptance of one’s body by others’221. Accordingly, tion to answer is the mechanisms by which factors such
patients feel stigmatized 222 . The extent of body as the microbiota or hormones boost cutaneous inflam-
image impairment shows a strong correlation with mation in HS. The connection between HS and the
depression, suggesting an important link between microbiota is particularly interesting because the areas
these aspects221. affected by HS tend to have a different microbial compo-
sition from other regions of the skin. Several microbiome
Outlook studies have demonstrated that the dominant organisms
Even though HS was described ~200 years ago by in patients with HS are different from those in patients
the French anatomist and surgeon Alfred-Armand- with other dermatoses or normal skin226. The hypothesis
Louis-Marie Velpeau, it was neglected for a long period that the microbiota in deeper skin areas might trigger
of time. Fortunately, research over the past decade has innate immune reactions and subsequently affect wound
made considerable progress in understanding the aetiol- healing needs to be further evaluated. Similarly, epide-
ogy and pathogenesis of this disease, with a first medica- miological data showing hormonally related disease state
tion (adalimumab) approved by the FDA and European changes (for example, obesity, pregnancy or menses)
Medicines Agency, with several RCTs in progress and with suggest that hormonal manipulation could be an impor-
hundreds of new insights into HS published each year. tant factor in controlling HS227,228. It will be important to
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understand the mechanisms by which these hormones Disease severity

affect follicular inflammation and/or the microbiota. To better address patient needs, our aim should be to
establish methods to quantify disease severity, taking
Delayed diagnosis into account the clinical assessment, objective laboratory
Worldwide, an average of 7 years passes between the parameters and/or imaging parameters, as well as the
onset of the first symptoms of HS and the correct diag- self-assessment of the patient. Imaging methods can help
nosis137. Surprisingly, this delay seems to be even greater to delineate the full extent of the disease that needs to be
in some developed European countries229. This diagnos- managed procedurally. Ultrasonography is a very useful
tic delay and, therefore, the delay in starting therapy have tool but might not be always available in dermatological
devastating effects owing to the progressive and destruc- practice. As technology becomes increasingly available,
tive course of the skin changes. The delay not only adds the use of mobile devices and other technologies such as
to patient frustration but also unnecessarily increases thermography (temperature-guided imaging that indi-
the costs of patient care. Thus, it is crucial to analyse the cates the extent of the inflammation) could be helpful to
circumstances and consequences of the diagnostic delay discern the true extent of lesions. Specific PROMs have
in detail to achieve its minimization. been tested to also acknowledge the patient’s perspective
on their disease severity231. Accordingly, the Hidradenitis
Disease phenotypes Supportive Core Outcomes Set International Collab
Phenotypic classifications in the literature have largely oration (HISTORIC) group is working towards an
been developed based on categorization of descriptive evidence-based and consensus-driven core outcome
characteristics230. The next step is to validate previous set for clinical trials in HS, incorporating both scoring
categories or define novel categories to correlate with systems of quality of life and PROMS232.
genetic patterns and/or pathophysiology. For exam-
ple, a comedonal phenotype may correspond to some Treatment options
of the follicular differentiation defects associated with The number of ongoing clinical trials in HS is increas-
the relatively rare familial forms of HS. A hormonally ing (Table 2) and might also uncover some aspects of
sensitive follicle-based phenotype might resemble acne HS pathogenesis. In a reversal of the bench-to-bedside
and a third, inflammatory phenotype pathophysiolog- model, clinical observation from studies targeting
ically resembling Crohn’s disease might be revealed. IL-17 or the p19 subunit of IL-23 will help us under-
These different phenotypes might also have differ- stand the role of these pathways in the pathogenesis.
ent natural courses. The next generation of classifi- Furthermore, emerging new therapies will expand
cations should bring us closer to phenotypes that are treatment options and decision-making233. A clear algo-
more likely to influence clinical decision-making. rithm for the interdisciplinary treatment of patients with
If clinical, anamnestic and/or genetic characteris- HS is clearly needed, which, in addition to considering
tics are insufficient to define therapy response-based the stage-dependent therapy of the skin lesions, should
phenotypes, blood biomarkers might enable stratifica- include lifestyle-modification measures and take into
tion of patients with HS with respect to their immuno- consideration the systemic aspects of HS.
logical phenotype and, accordingly, prediction of the
most effective therapy. Published online xx xx xxxx
1. Saunte, D. M. L. & Jemec, G. B. E. Hidradenitis 7. Shlyankevich, J., Chen, A. J., Kim, G. E. & Kimball, A. B. 15. Jemec, G. B. & Kimball, A. B. Hidradenitis
suppurativa: advances in diagnosis and treatment. Hidradenitis suppurativa is a systemic disease with suppurativa: epidemiology and scope of the
JAMA 318, 2019–2032 (2017). substantial comorbidity burden: a chart-verified problem. J. Am. Acad. Dermatol. 73, S4–S7
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identify the true burden of hidradenitis suppurativa. 8. Schneider-Burrus, S. et al. High prevalence of back suppurativa in the Norwegian patient registry during a
Br. J. Dermatol. 178, 917–924 (2018). pain and axial spondyloarthropathy in patients with 5-year period may describe professional awareness of
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their pathways and their consequences in the skin 13. Vazquez, B. G., Alikhan, A., Weaver, A. L., Wetter, D. A. 20. Garg, A., Kirby, J. S., Lavian, J., Lin, G. & Strunk, A.
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This paper is a comprehensive prospective case– 14. Kurek, A., Johanne Peters, E. M., Sabat, R., Sterry, W. 21. Jemec, G. B., Heidenheim, M. & Nielsen, N. H.
control study that first reported the high prevalence & Schneider-Burrus, S. Depression is a frequent The prevalence of hidradenitis suppurativa and its
of the metabolic syndrome in patients with HS, an co-morbidity in patients with acne inversa. J. Dtsch. potential precursor lesions. J. Am. Acad. Dermatol.
observation most striking among young patients. Dermatol. Ges. 11, 743–750 (2013). 35, 191–194 (1996).
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22. Calao, M. et al. Hidradenitis suppurativa (HS) sporadic hidradenitis suppurativa (acne inversa). patient with a monster hernia. Acta Dermatovenerol.
prevalence, demographics and management pathways Br. J. Dermatol. 168, 874–876 (2013). Croat. 26, 260–261 (2018).
in Australia: a population-based cross-sectional study. 45. Giatrakos, S. et al. Haplotypes of IL-12Rbeta1 impact 68. Yu, C. C. & Cook, M. G. Hidradenitis suppurativa:
PLoS One 13, e0200683 (2018). on the clinical phenotype of hidradenitis suppurativa. a disease of follicular epithelium, rather than apocrine
This paper is a comprehensive study describing the Cytokine 62, 297–301 (2013). glands. Br. J. Dermatol. 122, 763–769 (1990).
prevalence of HS in the general population. 46. Vural, S. et al. Association of pyrin mutations This paper describes an early histopathological
23. Zouboulis, C. C. et al. Development and validation of and autoinflammation with complex phenotype study that suggests that HS develops upon
the international hidradenitis suppurativa severity hidradenitis suppurativa: a case-control study. dilatation and rupture of hair follicles.
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to assess HS severity. Br. J. Dermatol. 177, 47. Revuz, J. E. et al. Prevalence and factors associated The pathogenesis of hidradenitis suppurativa: a closer
1401–1409 (2017). with hidradenitis suppurativa: results from two look at apocrine and apoeccrine glands. Br. J. Dermatol.
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which has the potential to become the gold 596–601 (2008). 70. Boer, J. & Weltevreden, E. F. Hidradenitis suppurativa
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Correlation of early-onset hidradenitis suppurativa suppurativa. Dermatology 198, 261–264 (1999). 71. Jemec, G. B. & Hansen, U. Histology of hidradenitis
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26. Kromann, C. B. et al. Risk factors, clinical course and production. Cell Host Microbe 7, 277–289 (2010). 73. van der Zee, H. H. et al. Elevated levels of tumour
long-term prognosis in hidradenitis suppurativa: a 51. Wu, Y. et al. Nicotine enhances Staphylococcus necrosis factor (TNF)-alpha, interleukin (IL)-1beta and
cross-sectional study. Br. J. Dermatol. 171, 819–824 epidermidis biofilm formation by altering the IL-10 in hidradenitis suppurativa skin: a rationale for
(2014). bacterial autolysis, extracellular DNA releasing, targeting TNF-alpha and IL-1beta. Br. J. Dermatol.
27. Egeberg, A., Gislason, G. H. & Hansen, P. R. Risk of and polysaccharide intercellular adhesin production. 164, 1292–1298 (2011).
major adverse cardiovascular events and all-cause Front. Microbiol. 9, 2575 (2018). 74. Hunger, R. E., Surovy, A. M., Hassan, A. S.,
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JAMA Dermatol. 152, 429–434 (2016). human responses to endotoxin. Clin. Exp. Immunol. is highly expressed in lesions of acne inversa and
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Dermatol. Clin. 34, 23–28 (2016). 53. Boer, J. Should hidradenitis suppurativa be included in 158, 691–697 (2008).
29. von der Werth, J. M. & Williams, H. C. The natural dermatoses showing Koebnerization? Is it friction or 75. Witte-Handel, E. et al. The IL-1 pathway is hyperactive
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30. Wang, B. et al. Gamma-secretase gene mutations in suppurativa: a comprehensive review. J. Am. Acad. 1294–1305 (2019).
familial acne inversa. Science 330, 1065 (2010). Dermatol. 60, 539–561; quiz 562–563 (2009). This paper elucidates the role of IL-1β in cutaneous
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function mutations in genes encoding γ-secretase, The role of androgens and estrogens in hidradenitis analyses, stimulation studies with skin-derived cells
cumulatively found among members of Chinese suppurativa — a systematic review. Acta and ex vivo cytokine neutralization of HS skin.
families with severe HS. Dermatovenerol. Croat. 24, 239–249 (2016). 76. Kelly, G. et al. Dysregulated cytokine expression in
31. Haapasalo, A. & Kovacs, D. M. The many substrates of 56. Karagiannidis, I., Nikolakis, G., Sabat, R. lesional and nonlesional skin in hidradenitis suppurativa.
presenilin/gamma-secretase. J. Alzheimers Dis. 25, & Zouboulis, C. C. Hidradenitis suppurativa/acne Br. J. Dermatol. 173, 1431–1439 (2015).
3–28 (2011). inversa: an endocrine skin disorder? Rev. Endocr. 77. Manfredini, M. et al. The P2X7 receptor is
32. Frew, J. W., Vekic, D. A., Woods, J. & Cains, G. D. Metab. Disord. 17, 335–341 (2016). overexpressed in the lesional skin of subjects affected
A systematic review and critical evaluation of 57. Gauntner, T. D. Hormonal, stem cell and Notch by hidradenitis suppurativa: a preliminary study.
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suppurativa. Br. J. Dermatol. 177, 987–998 (2017). hidradenitis suppurativa: a systems-level (2019).
33. Pan, Y. et al. γ-Secretase functions through Notch transcriptomic analysis. Br. J. Dermatol. 180, 78. Dinarello, C. A., Simon, A. & van der Meer, J. W.
signaling to maintain skin appendages but is not 203–204 (2019). Treating inflammation by blocking interleukin-1 in a
required for their patterning or initial morphogenesis. 58. Jenei, A. et al. Apocrine gland-rich skin has a broad spectrum of diseases. Nat. Rev. Drug. Discov.
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Theut Riis, P. & Jemec, G. B. Pain perception in mild-to-moderate hidradenitis suppurativa in a 220. Thorlacius, L., Cohen, A. D., Gislason, G. H.,
patients with hidradenitis suppurativa. Br. J. prospective, open-label, phase 2 study. J. Drugs Jemec, G. B. E. & Egeberg, A. Increased suicide
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178. WHO. Scoping document for WHO guidelines 200. Vossen, A., van Doorn, M. B. A., van der Zee, H. H. & J. Invest. Dermatol. 138, 52–57 (2018).
for the pharmacological treatment of persisting Prens, E. P. Apremilast for moderate hidradenitis This paper reports on a registry-based study that
pain in adults with medical illnesses. https:// suppurativa: results of a randomized controlled trial. clearly demonstrates the increased risk of suicide
www.who.int/medicines/areas/quality_safety/ J. Am. Acad. Dermatol. 80, 80–88 (2019). among patients with HS compared with the general
Scoping_WHO_GLs_PersistPainAdults_webversion. 201. van der Zee, H. H., Prens, E. P. & Boer, J. Deroofing: population.
pdf?ua=1 (2012). a tissue-saving surgical technique for the treatment 221. Schneider-Burrus, S. et al. Association of hidradenitis
179. Clemmensen, O. J. Topical treatment of hidradenitis of mild to moderate hidradenitis suppurativa lesions. suppurativa with body image. JAMA Dermatol. 154,
suppurativa with clindamycin. Int. J. Dermatol. 22, J. Am. Acad. Dermatol. 63, 475–480 (2010). 447–451 (2018).
325–328 (1983). This paper introduces a practical surgical technique 222. Esmann, S. & Jemec, G. B. Psychosocial impact of
180. Fischer, A. H., Haskin, A. & Okoye, G. A. Patterns of of great clinical use in the management of HS. hidradenitis suppurativa: a qualitative study. Acta
antimicrobial resistance in lesions of hidradenitis 202. Lapins, J., Marcusson, J. A. & Emtestam, L. Surgical Derm. Venereol. 91, 328–332 (2011).
suppurativa. J. Am. Acad. Dermatol. 76, 309–313 treatment of chronic hidradenitis suppurativa: CO2 223. Scala, E. et al. A new Th-17 cytokine in hidradenitis
(2017). laser stripping-secondary intention technique. Br. J. suppurativa: antimicrobial and pro-inflammatory role
181. Jemec, G. B. & Wendelboe, P. Topical clindamycin Dermatol. 131, 551–556 (1994). of IL-26. Br. J. Dermatol. https://doi.org/10.1111/
versus systemic tetracycline in the treatment of This paper gives detailed insight into a useful bjd.17854 (2019).
hidradenitis suppurativa. J. Am. Acad. Dermatol. 39, management technique for HS of intermediate 224. Lima, A. L. et al. Keratinocytes and neutrophils are
971–974 (1998). severity. important sources of proinflammatory molecules in
182. Matusiak, L., Bieniek, A. & Szepietowski, J. C. 203. Blok, J. L., Spoo, J. R., Leeman, F. W., Jonkman, M. F. hidradenitis suppurativa. Br. J. Dermatol. 174,
Bacteriology of hidradenitis suppurativa — which & Horvath, B. Skin-Tissue-sparing Excision with 514–521 (2016).
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Primer
225. Witte, K. et al. Increased presence and differential (Erasmus University Medical Center) and J. Triebus (Charité of Dermatovenereologists, the Hungarian Society of
molecular imprinting of transit amplifying cells in – Universitätsmedizin Berlin) for their help with this manu- Dermatology, the Baltic Association of Dermatovenerologists,
psoriasis. J. Mol. Med. 98, 111–122 (2020). script. The authors also acknowledge the support by the the Finnish Society of Dermatology and the Latvian Society
226. Ring, H. C. et al. The follicular skin microbiome in German Federal Ministry of Education and Research (http:// o f D e r m a to l o g y a n d Ve n e re o l o g y. G . B. E . J . i s t h e
patients with hidradenitis suppurativa and healthy www.bmbf.de/; grant 01ZX1312A to K.W. and R.S.). Editor- i n- c hief of Dermatology, commissioning editor of
controls. JAMA Dermatol. 153, 897–905 (2017). Clinical Problems in Dermatology, associate editor of Clinical
227. Clark, A. K., Quinonez, R. L., Saric, S. & Sivamani, R. K. Author contributions Dermatology and Acta Dermatovenerologica Adriatica,
Hormonal therapies for hidradenitis suppurativa: Introduction (R.S.); Epidemiology (G.B.E.J.); Mechanisms/ Pannonica et Alpina, and an editorial board member of Acta
review. Dermatol. Online J. 23, 13030/qt6383k0n4 pathophysiology (K.W.); Diagnosis, screening and prevention Dermatovenerologica Croatica and Frontiers in Medicine.
(2017). (E.P.); Management (G.B.E.J.); Quality of life (Ł.M.); Outlook G.B.E.J. has received research grants and grants for partici-
228. Golbari, N. M., Porter, M. L. & Kimball, A. B. (A.B.K. and R.S.); Overview of Primer (R.S.). R.S. and pation as an investigator from Abbvie, Astra-Zeneca, Inflarx,
Antiandrogen therapy with spironolactone for the G.B.E.J. contributed equally and are co-first authors. E.P. Janssen-Cilag, Leo Pharma, Novartis, Regeneron and Sanofi.
treatment of hidradenitis suppurativa. J. Am. Acad. and K.W. contributed equally and are co-last authors. He has also received unrestricted departmental grants from
Dermatol. 80, 114–119 (2019). Abbvie, Leo Pharma, and Novartis. G.B.E.J. has received hon-
229. Loget, J. et al. Misdiagnosis of hidradenitis Competing interests oraria from AbbVie, Chemocentryx, Coloplast, Incyte, Inflarx,
suppurativa continues to be a major issue. The R-ENS R.S. is a member of Arbeitsgemeinschaft Dermatologische Novartis, Pierre Fabre and UCB for participation on advisory
Verneuil study. Ann. Dermatol. Venereol. 145, Forschung (ADF; Consortium for Dermatological Research), boards, and has received speaker honoraria from AbbVie,
331–338 (2018). the German Society of Allergy and Clinical Immunology Boehringer-Ingelheim, Galderma, MSD and Novartis. Ł.M. is
230. Canoui-Poitrine, F. et al. Identification of three (DGAKI), the German Society of Immunology (DGfI), the a founding member of the EHSF and a member of the
hidradenitis suppurativa phenotypes: latent class American Association of Immunologists (AAI), the International European Academy of Dermatology and Venereology and
analysis of a cross-sectional study. J. Invest. Dermatol. Psoriasis Council (IPC) and the European Hidradenitis Polish Dermatological Society. Ł.M. has received research
133, 1506–1511 (2013). Suppurativa Foundation (EHSF), and is the spokesman of the grants, travel grants, consulting honoraria or lecturer’s hono-
231. Kimball, A. B., Sundaram, M., Banderas, B., Foley, C. ADF Psoriasis Group. R.S. has received research grants and raria from AbbVie, Amgen, Behringer Ingelheim, InfraRX,
& Shields, A. L. Development and initial psychometric scientific awards or honoraria for participation on advisory Janssen, Leo Pharma, Medac, Menlo Therapeutics, Pfizer,
evaluation of patient-reported outcome questionnaires boards, clinical trials or as speaker for one or more of the Pierre Fabre, Polpharma, Regeneron, Novartis, Trevi, UCB
to evaluate the symptoms and impact of hidradenitis following: AbbVie Inc., AbbVie Deutschland GmbH & Co. KG, and Valeant. A.B.K. is a consultant and investigator for
suppurativa. J. Dermatol. Treat. 29, 152–164 (2018). Bayer Schering Pharma AG, Biogen IDEC GmbH, Boehringer Novartis, Abbvie, UCB, Pfizer, Lilly and Janssen. A.B.K. has
232. Thorlacius, L. et al. Towards global consensus on core Ingelheim Pharma GmbH & Co. KG, Celgene GmbH, Celgene received fellowship funding from Janssen and Abbvie. K.W.
outcomes for hidradenitis suppurativa research: an International II Sàrl, Charité Research Organization GmbH, has received research grants, travel grants, consulting hono-
update from the HISTORIC consensus meetings I and II. Dr. Willmar Schwabe GmbH & Co. KG, Flexopharm GmbH & raria or lecturer’s honoraria from AbbVie, Bayer Schering
Br. J. Dermatol. 178, 715–721 (2018). Co. KG, Generon Corporation Ltd., Janssen-Cilag GmbH, Pharma, Biogen IDEC, Celgene, Dr. Willmar Schwabe GmbH
233. Porter, M. L., Golbari, N. M., Lockwood, S. J. & La Roche-Posay Laboratoire Dermatologique Deutschland, & Co. KG, Flexopharm, Generon Corporation, Janssen-Cilag,
Kimball, A. B. Overview and update on biologic Novartis Pharma GmbH, Parexel International GmbH, Johnson & Johnson, Novartis, Pfizer, Sanofi-Aventis, TFS Trial
therapy for moderate-to-severe hidradenitis Pfizer Deutschland GmbH, Sanofi-Aventis Deutschland Form Support and UCB. E.P. declares no competing
suppurativa. Semin. Cutan. Med. Surg. 37, 182–189 GmbH, TFS Trial Form Support GmbH, UCB Pharma GmbH. interests.
(2018). G.B.E.J. is the vice president and a founding member of the
EHSF, a board member of the Nordic Association of Publisher’s note
Acknowledgements Dermatology and an honorary member of the British Springer Nature remains neutral with regard to jurisdictional
The authors thank A. Vossen (Erasmus University Medical Association of Dermatologists. G.B.E.J. is also a member of claims in published maps and institutional affiliations.
Center), G. Kokolakis (Charité – Universitätsmedizin Berlin), the European Academy of Dermatology and Venereology, the
I. Chlebicka (Wrocław Medical University), K. van Straalen American Academy of Dermatology, the Serbian Association © Springer Nature Limited 2020
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PRIMER

NATURE REVIEWS | DISEaSE PrIMErS | Article citation I­D:­ (2020) 6:18 ­ 1

2 | Article citation ID: (2020) 6:18 www.nature.com/nrdp

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4 | Article citation ID: (2020) 6:18 www.nature.com/nrdp

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Follicular rupture, inﬂammatory nodule Keratinocyte Fistula formation

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NATURE REVIEWS | DISEaSE PrIMErS | Article citation I­D:­ (2020) 6:18 ­ 7

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Box 1 | Differential diagnoses of HS the Hidradenitis Suppurativa Global Assessment

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Patient education and coaching

• Local therapy with antiseptics • Local therapy with antiseptics

Patients with medical therapy-resistant nodules or abscesses

Low inﬂammatory activity High inﬂammatory activity

• De-rooﬁng • Systemic antibiotics and/or

Consider long-term systemic anti-inﬂammatory therapy (for example, adalimumab)

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Table 2 | Systemic drugs being under development for hidradenitis suppurativa

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understand the mechanisms by which these hormones Disease severity

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