what causes hidradenitis suppurativa?€¦ · pathogenesis, which can only be achieved by a...

Section Editor: Ralf Paus, Lubeck

What causes hidradenitis suppurativa?

H. Kurzen, I. Kurokawa, G. B. E. Jemec, L. Emtestam, K. Sellheyer, E. J. Giamarellos-Bourboulis,

I. Nagy, F. G. Bechara, K. Sartorius, J. Lapins, D. Krahl, P. Altmeyer, J. Revuz and C. C. Zouboulis

Abstract: Hidradenitis suppurativa (HS) – a rather common, very

chronic and debilitating inflammatory skin appendage disorder

with a notoriously underestimated burden of disease – has long

been a playground for the high priests of nomenclature: Ask a

bunch of eminent dermatologists and skin pathologists to publicly

share their thoughts on what causes HS, and they will soon get

entrenched in a heated debate on whether this historical term is

a despicable misnomer. Fortunately, the recently founded

Hidradenitis Suppurativa Foundation (HSF; http://www.

hs-foundation.org), to which EXP DERMATOL serves as home

journal, has broken with this unproductive tradition and has

encouraged publication of the current CONTROVERSIES feature.

This is exclusively devoted to discussing the pathobiology of this

chronic neutrophilic folliculitis of unknown origin. Although

traces of terminological bickering remain visible, it does the HS

experts in our virtual debate room credit that they engage in a

constructive and comprehensive dissection of potential

pathogenesis pathways that may culminate in the clinical picture

we know under the competing terms HS or acne inversa. These

experts sketch more often complementary than mutually exclusive

pathogenesis scenarios, and the outlines of a conceivable

consensus on the many open pathobiology questions begin to

emerge in these CONTROVERSIES. Hopefully, this heralds a

welcome new tradition: to get to the molecular heart of HS

pathogenesis, which can only be achieved by a renaissance of solid

basic HS research, as the key to developing more effective HS

therapy.

Please cite this paper as: What causes hidradenitis suppurativa?. Experimental Dermatology 2008.

Prelude

Apocrine or not, that is the question……In the context of HS, it has become foolhardy to speak of

apocrine sweat glands ever since pathologists have demon-

strated that the primary histological event was in the follic-

ular duct, like in acne. It was then simple, if not to say

simplistic, for many dermatologists to forget any major dif-

ferences between acne and HS, and to rename the disease

‘acne inversa’, thus replacing one possible misnomer (HS)

with another – and leading investigators to a dead end,

and practitioners to use ineffective treatments.

Any hypothesis about HS must take two paradoxons into

account:

1 Hidradenitis suppurativa lesions have a very specific

topography which is a copy of the anatomical distribution

of apocrine sweat glands: axillae and groin as the main

areas; breast, perineum and buttocks as accessory regions.

YET

Apocrine glands are not the primary target of the patholog-

ical process.

2 Hidradenitis suppurativa is not primarily an infectious

disease, and yet drugs that are conducive to infection, such

as corticosteroids, immunosuppressive drugs and ⁄ or anti-

TNF agents, may improve the disease

YET

One of the most useful drug regimens in cases of active

inflammatory lesions is a combination of two antibiotics:

rifadin and clindamycin (1).

Paradoxon 1The topography of involvement may be explained by two –

not mutually exclusive – hypotheses: (a) the distribution of

apocrine glands; and (b) shearing forces, which originate in

large skin folds, especially of overweight patients.

Obesity and overweight are frequent in HS and could be

a risk factor (2). However, HS is not infrequent in inter-

mammary folds and on the buttocks, where such shearing

forces are absent. Moreover, individuals with low or nor-

mal body mass index also do develop HS. Thus, while

obesity and overweight are strongly associated with severity

in HS, they are insufficient to explain the specific topogra-

phy of the disease.

So, what about apocrine sweat glands? The rejection of

apocrine glands as a main factor in the pathogenesis of HS

originates in the clear demonstration that they are spared

DOI:10.1111/j.1600-0625.2008.0712.x

www.blackwellpublishing.com/EXDControversies in Experimental Dermatology

ª 2008 The Authors

Journal compilation ª 2008 Blackwell Munksgaard, Experimental Dermatology 1

by the initial inflammatory and destructive process. The

primary event is a follicular hyperkeratosis with plugging

and dilatation of the hair follicle ensuing in inflammation,

abscess and sinus tract formation. Apocrine involvement

appears as a secondary phenomenon resulting from the

diffusion of the granulomatous inflammation in deep

structures of the skin.

The mechanism by which follicular plugging occurs in

acne is not known; various candidates are hypersecretion of

sebum, proliferation of P. Acnes favoured by an alteration

of innate immunity and ⁄ or of inflammatory reactions, and

possibly several others.

Here, the specific anatomical relationship of the apocrine

gland with the follicular canal has to be taken into account:

In contrast to eccrine glands, whose ducts open onto the

skin surface, apocrine glands empty their content into the

follicular canal, just above the sebaceous gland duct. In HS,

hyperseborrhoea is definitely absent but the other factors

may be at work:

An abnormal secretion – excess or absence – of a sub-

stance that is present in apocrine gland secretion under

physiological conditions may therefore, after all, be the

triggering factor of HS! Its morphologically recognizable

effect could be in the acro infundibulum of the follicle,

with the responsible gland disguising itself as an innocent

bystander upon histology – a perfectly masked ‘criminal’.

Paradoxon 2Hidradenitis suppurativa is a disease in which numerous

bacteria are present and active (3), and in which various

antibiotic regimens have definitely improved the condition

in patients with severe inflammatory involvement (2). Sur-

prisingly, numerous pro-infectious drugs have also been

used with good results: corticosteroids, immunosuppressive

drugs, anti-tumour necrosis factor (4,5). The coexistence of

these two seemingly contradictory phenomena calls for a

closer look at the properties of anti bacterial molecules

which play a key role in innate and acquired immunity: the

so-called anti-microbial peptides (6).

They are known to exert both pro- and anti-inflamma-

tory functions; they alarm and activate the adaptive

immune system and the keratinocytes that produce them.

They induce keratinocytes migration, proliferation – a role

in follicular occlusion? They are part of a complex network

of cytokine and chemokine production. The absence or

abnormality of one of these anti-microbial peptides would

be a good candidate for explaining the infectious and

inflammatory features of HS. Cathelicidins and defensins

are the main representatives of this family identified today.

New ones, psoriasin (7), are under consideration. Some of

these peptides are produced by mature keratinocytes

spontaneously or after stimulation, some are produced by

eccrine sweat glands, and some are prominently subject to

modulation by antibiotics (7–9).

However, until now, nothing is known about anti-micro-

bial peptides that are specifically produced in apocrine

sweat glands. This is where we need to search.

ConclusionHidradenitis suppurativa is as multifactorial as any chronic

disease and probably heterogeneous. Here, I have only con-

sidered the role that apocrine glands may have, a role that

might well be central – no matter, how much this gland

has fallen out of fashion in HS research. The role of other

factors – e.g. hair follicle anatomical ⁄ structural abnormali-

ties (highly probable at least in a subset of HS patients),

the role of obesity, the role of cigarette smoking – all

deserve careful exploration. Any pathogenesis scenario,

however, that completely discards apocrine glands and their

specific distribution as key elements in the development of

HS may soon turn out to have to be discarded itself!

Jean Revuz

Department of Dermatology, Henri Mondor Hospital,

94000 Creteil, France;

E-mail: [email protected]

References1 Mendonca C O, Griffiths C E M. Br J Dermatol 2006: 154: 977–978.

2 Naldi L. Epidemiology. In: Jemec G, Revuz J, Leyden J, eds. Hidrade-

nitis suppurativa, Chap. 8. Springer Verlag, 2006: 58–64.

3 Faye O, Poli F, Gabison G, Pouget F, Wolkenstein P, Revuz J. Associa-

tion rifampicine ⁄ clindamycine dans l’hidradenite suppuree. Ann Der-

matol Venereol 2005: 132: 68–69.

4 Oprica C, Nord C E. Bacteriology of hidradenitis suppurative. In:

Jemec G, Revuz J, Leyden J, eds. Hidradenitis suppurativa, Chap. 11.

Berlin: Springer Verlag, 2006: 86–94.

5 Nybaek H, Jemec G B E. Immunosuppressive therapy. In: Jemec G,

Revuz J, Leyden J, eds. Hidradenitis Suppurativa, Chap. 18. Berlin:

Springer Verlag, 2006: 136–140.

6 Jacob S E, Kerdel F A. Biologic for hidradenitis suppurativa (Verneuil’s

disease in the Era of biologics). In: Jemec G, Revuz J, Leyden J, eds.

Hidradenitis suppurativa, Chap. 20. Berlin: Springer Verlag, 2006:

145–149.

7 Schauber J, Gallo R L. Expanding the roles of antimicrobial peptides

in skin: alarming and arming keratinocytes. J Invest Dermatol 2007:

127: 510–512.

8 Glaser R et al. Antimicrobial psoriasin (S100A7) protects human skin

from Escherichia coli infection. Nat Immunol 2005: 6: 1–57.

9 Tokura Y et al. Epidermal chemokines and modulation by antihista-

mines, antibiotics and antifungals. Exp Dermatol 2007: November 22

[Epub ahead of print].

Kurzen et al.

ª 2008 The Authors

2 Journal compilation ª 2008 Blackwell Munksgaard, Experimental Dermatology

Viewpoint 1

The scientific mind should view things without prejudice.

Hidradenitis suppurativa (HS) is a common dermatosis,

which significantly affects the lives of patients and which is

notoriously difficult to treat. It is a well-defined clinical

entity, consisting of recurrent crops of inflammatory lesions

in inverse areas (1). It looks infectious, but it is not.

The lesions are initially transient, but gradually become

intransigent and associated with significant scarring. Histo-

logically, it is a disease of the hair follicle; associated with

lympho-histiocytic inflammation, granulomatous reactions,

sinus tracts and scarring (2–5). It looks like acne – but it

is not.

Treatment is often disappointing, and has significant

negative impact on the patient’s quality of life (6–8).

Anti-inflammatory, immunosuppressive, antiandrogenic,

antibiotic and surgical treatments have been described as

effective, although few randomized, controlled trials exist

that convincingly support these claims (1,9–11).

So, what then is HS?

Disease hallmarksOne of the most obvious hallmarks of the disease is the

restriction to the skin areas affected. The disease is essen-

tially limited to inverse areas, although aberrant lesions

may occur. This lead to the original proposition that

apocrine glands are involved in the disease. It is good to

suggest theories – but these can be rejected later.

The inverse areas are indeed rich in apocrine glands –

although the overlap between HS lesions and apocrine-rich

regions of the integument is not good within an affected

skin territory (3). The inverse areas are, however, also char-

acterized by skin–skin contact and subsequent shear forces

affecting the skin; increased moisture and bacterial flora, all

of which may play a role.

Within the affected regions, hair follicles are invariably

involved (2). The deep part of the follicle appears to be

involved, rather than its superficial compartments, as seen

with acne affecting convex skin surfaces (12). Clinically,

closed comedones are not seen.

Although a range of bacteria may be retrieved from HS

lesions, these frequently appear to be sterile (13–15). Of

the bacteria identified, only a small minority are recognized

pathogens, and no consistent IgG response to staphylococ-

cal antigens is found (13). Hormones are unlikely players

in the pathogenesis of HS: increased sebum excretion and

other signs of cutaneous virilization are not seen, although

single cases have been published to suggest this (16–19).

Similarly, the use of depilatories and other cosmetics are

not associated with the disease (20,21). Scarring is promi-

nent, but often overlooked in this disease. The fully devel-

oped disease is characterized by significant scarring and

may cause contractures, and far-reaching sinus tracts, the

latter often growing in a pseudo-invasive manner into the

surrounding tissue.

AetiologyThe wide range of clinical HS presentations, and of occa-

sionally successful HS treatments, invites the speculation

that HS aetiology does not arise from a single external

factor, but rather represents a reaction pattern within the

afflicted patient. This concept is supported by genetic

observations (22,23).

The effectiveness of antimicrobial drugs such as clinda-

mycin suggest that bacteria may occasionally be responsible

for starting the process (9,11). Similarly, the use of anti-

inflammatory treatment such as corticosteroids or TNF-

blockers, suggest a role for the immune system (24), while

tobacco or physical trauma (described in convincing indi-

vidual cases or epidemiological studies as trigger or aggra-

vation factors) suggest that these factors may be involved

(25). Most likely, however, they are only temporarily

involved (or of secondary importance) as there is no evi-

dence to suggest that their removal invariably cures HS.

Hypothetically, identical HS lesions can therefore be

produced by bacterial, immunological, chemical or physical

factors affecting the predisposed hair follicle.

PathophysiologyThere is consensus that the pathophysiology of the disease

involves hair follicle rupture and subsequent inflammation,

sinus tract formation and scarring. Most likely, folliculitis

is one of the most common pathological events in the

human skin – and yet this leads to HS only in a minority

of individuals. Why?

One possibility is the special biomechanical conditions in

the affected follicles and concave skin regions. It has been

suggested that the biomechanics of the predominant kera-

tin found in the lesions is suboptimal, leading to repeated

ruptures and development of lesions. The process may be

further supported by the local biomechanical forces affect-

ing the concave surface of, e.g. the axillae. It may be specu-

lated that micro-tears of the hair follicle of predisposed

individuals could be the primary event. Clinical observa-

tions support such a mechanism. If unspecific factors

induce inflammation, the subsequent control of the inflam-

matory process may offer an alternative explanation. Either

an excess of pro-inflammatory signals, or a lack of inflam-

mation containing signals may lead to the development of

HS. Indeed, studies have pointed to abnormalities in the

immunity of HS patients (26,27).

Finally, the ‘containment’ or wound healing mechanisms

of the host may play a role. The wound healing mecha-

Controversies in Experimental Dermatology

ª 2008 The Authors


nisms responsible for the scarring and sinus tract formation

may depend on which cells from the damaged hair follicles

are recruited. A group of stem cell-like cells have been

identified in sinus tracts of HS lesions, and may provide

the dynamic impetus for development of characteristic

lesions (28). A better characterization of the specific wound

healing-related characteristics of the hair follicles in indi-

viduals affected by HS may not only provide better insight

into HS pathogenesis, but may also promote our under-

standing of the clinically challenging problem of fistula

formation in general, not only in HS patients.

The scientific mind must be without prejudice, fertile

and prepared to reject the ideas it has fostered. It will be

interesting to see which of the ideas outlined here will

survive.

Gregor B.E. Jemec

Department of Dermatology, Roskilde Hospital, University

of Copenhagen, DK-4000 Roskilde, Denmark;


References1 Jemec G B. J Cutan Med Surg 2003: 7: 47–56.

2 Yu C C, Cook M G. Br J Dermatol 1990: 122: 763–769.

3 Jemec G B, Hansen U. J Am Acad Dermatol 1996: 34: 994–999.

4 Jemec G B, Thomsen B M, Hansen U. APMIS 1997: 105: 378–383.

5 Boer J, Weltevreden E F. Br J Dermatol 1996: 135: 721–725.

6 Jemec G B et al. Clin Exp Dermatol 1996: 21: 419–423.

7 von der Werth J M, Jemec G B. Br J Dermatol 2001: 144: 809–813.

8 Wolkenstein P et al. J Am Acad Dermatol 2007: 56: 621–623.

9 Clemmensen O J. Int J Dermatol 1983: 22: 325–328.

10 Mortimer P S et al. Br J Dermatol 1986: 115: 263–268.

11 Jemec G B, Wendelboe P. J Am Acad Dermatol 1998: 39: 971–

974.

12 Jemec G B, Gniadecka M. Arch Dermatol 1997: 133: 967–970.

13 Jemec G B et al. Dermatology 1996: 193: 203–206.

14 Sartorius K et al. Dermatology 2006: 213: 305–312.

15 Lapins J et al. Br J Dermatol 1999: 140: 90–95.

16 Jemec G B, Gniadecka M. Dermatology 1997: 194: 325–328.

17 Jemec G B. Br J Dermatol 1988: 119: 345–350.

18 Barth J H et al. Br J Dermatol 1996: 134: 1057–1059.

19 Harrison B J et al. Br J Surg 1988: 75: 972–975.

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2000: 14: 389–392.

22 Fitzsimmons J S, Guilbert P R. J Med Genet 1985: 22: 367–373.

23 Gao M et al. J Invest Dermatol 2006: 126: 1302–1306.

24 Alexis A F, Strober B E. J Cutan Med Surg 2005: 9: 296–302.

25 Konig A et al. Dermatology 1999: 198: 261–264.

26 Ginder P A et al. J Clin Immunol 1982: 2: 237–241.

27 Giamarellos-Bourboulis E J et al. Br J Dermatol 2007: 156: 51–56.

28 Gniadecki R, Jemec G B. Exp Dermatol 2004: 13: 361–363.

Viewpoint 2

I Fell Into A Burning Ring Of Fire

I Went Down, Down, Down

And The Flames Went Higher

And It Burns, Burns, Burns

The Ring Of Fire

June Carter Cash, 1962

After a cigarette is lit with a match, the match is perhaps

thrown into the corner of the room. The glowing match is

lying in the corner among dust, dirt, hair, microbes and

grease. Slowly a fire starts. This tiny fire resembles the

starting point of hidradenitis suppurativa (HS). The central

question, then, is: What started the fire…?

Recently, it has been shown that that the primary event,

the smallest fire of HS, is follicular retention by keratinized

stratified squamous epithelium. HS would therefore appear

to be a disorder of follicular rather than apocrine occlusion

(1–6). Regardless of disease duration, follicular occlusion is

an early and important feature in the pathogenesis of the

disease. Three types of phenotypes on the basis of the

expression of cytokeratins of the epithelial cells of the HS

lesions have been suggested (7). Type I epithelium is corni-

fying, type II is non-cornifying, type III is non-cornifying

and strongly inflamed. The three phenotypes are charac-

terized as pathologically stratified squamous epithelia

reflecting the dynamic process of inflammation, prolifera-

tion and stratification taking place in HS (7). Hyperkerato-

sis of the infundibular follicular epithelium occurs in

response to androgenic stimulation.

As the fire of HS becomes a bit bigger, the plug becomes

larger and then is invaded by bacteria from the skin com-

mensal bacterial population, usually staphylococci. Hyper-

keratosis of the follicular infundibulum forms comedo-like

impactions which occlude the pilosebaceous apparatus. The

keratincyte–keratin complex is not easily broken down or

resolved. This is followed by rupture of the follicular canal,

and the extrusion of foreign material – e.g. corneocytes,

bacteria, sebaceous matter and hairs – into the connective

tissue induces the formation of an inflammatory infiltrate,

which consists initially of granulocytes, followed by mono-

nuclear cells and the formation of a foreign body-like gran-

uloma. Epithelial strands develop and produce keratin.

Squamous epithelium-lined sinuses, fistulas and secondary

comedones are typical features (Fig. 1).

The leakage of the follicular content of bacteria and

keratin into the perifollicular space causes more inflam-

mation and an abscess develops. After emptying or

absorption of the abscess contents the follicular epithelial

cells line the lumen of the abscess and form sinusoids.

These cells that line the sinuses and fistulae form masses

of keratin harbouring a bacterial flora that lives in balance

Kurzen et al.

ª 2008 The Authors


with the local immune system in this foreign body-like

milieu. When the bacterial overgrowth in the epithelial

keratin debris favours a vigorous chemotactic response

with an inflammatory cellular infiltrate consisting of neu-

trophils, lymphocytes and histiocytes, abscess formation

develops, the even bigger fire of HS, leading to the

destruction of the pilosebaceous unit and eventually the

other adnexal structures in the vicinity. Epithelial strands

are generated possibly from ruptured follicular epithelium

to form sinus tracts. If keratin-forming epithelial cells are

left in the wound after surgery, the process can be set off

again from this living cell remnant. This chronic inflam-

matory process causes severe deformation and fibrotic scar

tissue (Fig. 1) with subsequent functional defects, repre-

senting the largest fire of HS.

Treatment of HS should aim to remove the causes of

hyperkeratosis of the infundibular follicular epithelium.

Thus, the follicular mass of the apoptotic keratinocyte–ker-

atin complex can be eliminated, and bacterial overgrowth

reduced, thereby inhibiting the formation of and promot-

ing destruction of the epithelial strands in the abscess. Sur-

gery is recommended early in the disease process and it has

to be as radical as possible to minimize recurrence risk (8–

22). The main features of the recently described carbon

dioxide laser technique are in the blood-less surgical field,

stepwise vaporization, radical removal of the inflamed tis-

sues of HS, including its content of follicular epithelial cells

all of which obviate local recurrences, with minimal

destruction of healthy tissues (23–26).

Friction and small trauma might start the little fire, as

well as the use of deodorants and depilatory products and

shaving, which leads to minor primary lesions, boils, of HS

that normally heal spontaneously in a week. Small balls of

keratin are found in the openings of the boils. In the

largest fire, i.e. when fistulas are formed, swelling of the

keratinocytes occurs.

Overweight is unlikely to be causal but may be an exac-

erbating factor (27–31). Its importance in HS is probably

due to shearing forces of skin and ⁄ or androgen effects.

Weight loss may help control the disease. Keratin hydration

is increased in sweat gland-rich regions of the body, and

this has been shown to favour occlusion.

Genetics and endocrine factors may also contribute.

Patients frequently report cases among their relatives (32–

35). There appears to be an autosomal dominant inheri-

tance with single gene transmission. One study supports

the concept of a familial form of HS with autosomal domi-

nant inheritance. A genome-wide scan was performed in a

four-generation Chinese family to map the chromosome

location of the responsible gene (36).

The apparent strong influence of sex hormones on HS is

emphasized by an association with acne vulgaris comedones

and hirsutism, development postpuberty, general decline in

disease activity seen at the climacteric and improvement

often seen during pregnancy (1,30,37–45). However, not all

authors agree. Most HS patients have normal androgen

profiles and apocrine glands, and unlike sebaceous glands,

are not androgen sensitive. Nevertheless, there have been

anecdotes of symptomatic improvement after the use of

antiandrogens.

Finally, coming back to fire and cigarettes, smoking in

patients with HS has been reported to be more frequent

compared with that in controls (46–48). Smoking induces

altered chemotaxis of polymorhic neutrophils which may

play a role, similar to that in palmoplantar pustulosis. It

seems reasonable that smoking cessation should therefore

be strongly encouraged in patients with HS.

Lennart Emtestam, Karin Sartorius, Jan Lapins

Section of Dermatology, Department of Medicine,

Karolinska Institutet, Karolinska University Hospital

Huddinge, SE 141 86 Stockholm, Sweden;


Figure 1. Middle, right – a reddish brown ‘beefy’ ball, which is a

Hidradenitis suppurativa sinus-surrounded inflammatory active

connective tissue. The fat tissue close to the sinus has turned white due

the inflammation.


ª 2008 The Authors


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27 Edlich R F et al. J Emerg Med 1986: 4: 369–378.




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Viewpoint 3

According to the ‘Dessau definition’ of hidradenitis suppu-

rativa ⁄ acne inversa (HS), this is a chronic, inflammatory,

recurrent, debilitating skin disease that usually presents

after puberty with painful, deep-seated, inflamed lesions in

the apocrine gland-bearing areas of the body, most com-

monly the axillary, inguinal and anogenital regions (First

International Conference on Hidradenitis suppurativa,

March 30–April 1, 2006, Dessau, Germany1).

Its prevalence ranges from one per 600 to four per 100

in the general population (1,2). HS affects more women

than men, with a female-to-male predominance as high as

4:1. The majority of the patients are obese and smoke. The

disease occurs almost always after puberty and before the

age of 40 years. The apparent ‘rarity’ of HS in daily clinical

practice may be explained by the prevalence of mild forms

for which no consultation is sought, the weariness of HS

patients discouraged by previous treatment results to seek

further medical help, and by the generally poor level of

education in the medical community on the proper recog-

nition and management of HS (this is manifest from the

often very late time at which the correct diagnosis is made,

in the long run). The latter is particularly regrettable, as

the psychological impact on affected patients can be very

substantial, encompassing major social, personal and occu-

pational challenges. Together with the sequelae of the

disease, including dermal contraction, keloid formation,

restricted limb mobility, lymphoedema and fistula forma-

tion, this dominates the long-term burden of disease and

greatly diminishes a patient’s quality of life.

Aetiology and pathogenesis of HS are still unknown.

Current theories implicate hyperkeratosis of the follicular

epithelium as the morphological hallmark of HS patho-

genesis, leading to occlusion of the apocrine glands with

subsequent follicular rupture, inflammation and possible

secondary infection (3,4). From the genetic point of view,

the group of experts who participated at the First Interna-

tional Symposium has accepted that HS must be a poly-

genic disease, with sporadic cases having defects in a

number of critical genes involved in its pathogenesis and

familial cases with a probably highly penetrant defect(s) in

one of these genes.1

Hidradenitis suppurativa has given rise to a number of

lively clinical debates, such as the discussion on the exact

skin appendage involved (eccrine sweat glands, apocrine

glands or terminal hair follicles) and the discussion on the

pathogenetic background, namely a genetic, hormonal, bac-

terial, genuine inflammatory, environmental or physical

one. The significance of gender, body mass and smoking on

disease prevalence is still under investigation. The major

therapeutic challenge in HS is the optimal choice between

antibiotics, retinoids, corticosteroids, incision and drainage,

local wound care, limited versus radical local excision, radi-

ation, laser therapy and modern drugs, such as biologics, all1Abstracts from the First International Hidradenitis Suppurativa

Research Symposium, Exp Dermatol 2006: (15) 6: 478–482.

Kurzen et al.

ª 2008 The Authors


of which have been proposed – and whose relative impor-

tance and usefulness have been controversially debated.

Which is the exact skin appendage involved?One of the major debates in HS is the determination of the

exact skin appendage involved. Although initially accused,

the apocrine gland is probably ‘innocent’: neither exist sig-

nificant differences in the size and density of the apocrine

glands in HS patients compared with normal controls (5),

nor significant morphological abnormalities of the apocrine

glands in diseased skin areas (6,7). No primary apocrine

involvement is detected; and the one-third of HS cases that

present inflammatory changes involving the apocrine

glands represents cases of very extensive inflammation

that also engulf other structures such as the eccrine glands

and hair follicles.

A consistent finding in histological studies of HS is a fol-

licular occlusion regardless of disease duration (8). The

majority of specimens (50–85%) contain poral occlusion,

sinus tracts or cysts (7). The histopathology of HS supports

its classification to the follicular diseases. Newly formed

nodules show an occluding spongiform infundibulofollicu-

litis with secondary involvement of apocrine glands (9), i.e.

a disease of the follicular epithelium in the terminal hair

follicle.

Different from acne vulgaris, HS is localized in non-

facial regions, where there are terminal, pigmented, coarse

hairs, as in the axillae, groins, anal fold, mons pubis and

scalp. These regions affected by acne inversa tend to be rich

in apocrine glands, which are part of the apocrine-piloseba-

ceous unit and can be engulfed in the inflammatory

process. The sebum excretion rate is not increased in HS.

The earliest inflammatory event in acne inversa is a

segmental rupture of the follicular epithelium, followed by

spilling of foreign body material, such as corneocytes,

bacteria, sebum products and hairs, into the dermis. The

dumping of foreign products initiates an inflammatory

response provoking foreign body granuloma, and epithelial

strands try to encapsulate the necrotic tissue. Once rupture

of the follicular epithelium has occurred, the disease spreads

rapidly. The draining sinus is a late complication of HS.

Hidradenitis suppurativa and geneticpredispositionGenetic factors may contribute to HS susceptibility.

Patients frequently report HS cases among their relatives.

In one study, 18 of 70 patients with HS (26%) had a posi-

tive family history, whereas in 96 control subjects matched

for age and sex, who did not have HS, only two of their

relatives suffered from HS (10). There appears to be auto-

somal dominant inheritance with single gene transmission

(10,11). A variable degree of gene penetrance and possibly

hormonal influence on gene expression may explain the

reduced risk to first-degree relatives, which falls short of

the expected 50% found in the study.

Hidradenitis suppurativa and autoimmunityClinical improvement with the application of therapies tar-

geted against tumour necrosis factor (TNF)-a may be com-

patible with the above theory of pathogenesis, as TNF-a is

a major proinflammatory cytokine. In these studies, mono-

clonal anti-TNF-a etanercept receptors (12,13) or soluble

TNF-a infliximab antibodies (14) were administered in a

small number of patients. Positive responses with anti-

TNF-a therapies have also addressed the question of

whether any probable autoimmune predilection might con-

tribute to the pathogenesis of HS (12). Based on the above

probability for the existence of some derangement of the

activity of the host immune function, a current study has

shown a reduction in the percentage of natural killer cells

over time and a lower monocyte response to triggering by

bacterial components in patients with HS (15).

The role of hormones in hidradenitis suppurativapathogenesisThe occurrence of HS in a narrow age spectrum and in

obese individuals as well as the female predominance have

led to the theory that a hormonal component may be

involved in the pathogenesis of HS (16). Flare-ups have

been linked with menses (17); shorter menstrual cycles and

longer duration of menstrual flow are associated with the

disease (18). Onset after menopause is rare (19). Sex hor-

mones may influence HS; association with acne vulgaris,

comedones and hirsutism, development post puberty, gen-

eral decline in disease activity seen at the climacteric, and

improvement seen during pregnancy have been reported

(20–22). On the other hand, although most HS patients

have normal androgen profiles (23), there have been

reports of symptomatic improvement with the use of anti-

androgen therapy (23–25). Indeed, HS has been regarded

as an androgen-dependent disorder (26). HS is rarely a

presenting feature of premature adrenarche, leading sup-

port to the view that it is androgen-dependent (27).

It has been suggested that enhanced peripheral conver-

sion of androgens by apocrine glands plays a critical part

in its pathogenesis (26). However, equivalent activity of

three peripheral androgen-converting enzymes in axillary

apocrine glands of subjects with HS was similar with those

of controls (28). A relationship between HS and

hyperandrogenism is largely based on the finding of an

increased free androgen index (testosterone ⁄ sex hormone

binding globulin, SHBG) due to a low SHBG, but the sub-

jects were not controlled for body mass index (BMI) (20).

This finding is compromised, as many subjects are signifi-

cantly overweight (21) and SHBG is negatively correlated

with BMI (29). Another study could only demonstrate


ª 2008 The Authors


hyperandrogenism in a subgroup of women who did not

experience a premenstrual flare in their disease (21) but no

supporting evidence for hyperandrogenism or suppression

of SHBG has been found in women with HS compared

with age-, weight- and hirsutism-matched controls (19).

Hidradenitis suppurativa has also been reported to be

associated with classical endocrine disorders, such as

Cushing’s syndrome (30) and acromegaly (31). This may

be interpreted as further indication that hormonal factors

may play a significant role in HS pathobiology.

OutlookIn the era of molecular genetics, new diagnostic possibilities

are emerging: gene expression profiling can be applied to

compare the gene expression pattern in the apocrine gland-

bearing areas of the body of HS patients versus healthy

individuals. Bioinformatics will help to identify the most

relevant among the differentially expressed genes. This may

provide valuable insights into the basic pathologic processes

occurring in HS and may identify genes and biochemical

pathways that could act as new targets for classical drugs in

the treatment of HS.

Christos C. Zouboulis

Departments of Dermatology, Venereology, Allergology and

Immunology, Dessau Medical Center, D-06847 Dessau,

and Laboratory for Biogerontology, Dermato-Pharmacology

and Dermato-Endocrinology, Institute of Clinical Pharma-

cology and Toxicology, Charite Universitaetsmedizin Berlin,

Berlin, Germany;


References1 von der Werth J M, Jemec G B E. Br J Dermatol 2001: 144: 809–

813.

2 Jansen T et al. J Eur Acad Dermatol Venereol 2001: 1: 532–540.

3 Slade D E M et al. Br J Plast Surg 2003: 56: 451–461.

4 Wiseman M C. Dermatol Ther 2004: 17: 50–54.

5 Morgan W P, Hughes L E. Br J Surg 1979: 66: 853–856.

6 Yu C C W, Cook M G. Br J Dermatol 1990: 122: 763–769.

7 Jemec G B E et al. APMIS 1997: 105: 378–383.

8 Attanoos R L et al. Br J Dermatol 1995: 133: 254–258.

9 Boer J, Weltevreden E F. Br J Dermatol 1996: 135: 721–725.

10 Fitzsimmons J S, Guilbert P R. Br J Dermatol 1985: 113: 1–8.

11 von der Werth J M et al. Br J Dermatol 2000: 142: 947–953.

12 Sullivan T P et al. Br J Dermatol 2003: 149: 1046–1049.

13 Rosi Y L et al. J Dermatol Ther 2005: 16: 58–61.

14 Cusack C, Buckley C. Br J Dermatol 2006: 154: 726–729.

15 Giamarellos-Bourboulis E J et al. Br J Dermatol 2007: 156: 51–

56.

16 Shah N. Am Fam Phys 2005: 72: 1547–1552.

17 Von der Werth J M, Williams H C. J Eur Acad Dermatol Venereol

2000: 14: 389–392.

18 Jemec G B. Br J Dermatol 1988: 119: 345–350.


20 Mortimer P S et al. Br Med J 1986: 292: 245–248.


22 Harrison B J. Br J Surg 1985: 22: 1002–1004.

23 Sawers R S et al. Br J Dermatol 1986: 115: 269–274.

24 Goldsmith P C, Dowd P M. J R Soc Med 1993: 86: 729–730.

25 Camisa C et al. J Reprod Med 1989: 34: 543–546.

26 Ebling F J G. Br J Dermatol 1986: 115: 259–262.

27 Lewis F et al. Br J Dermatol 1993: 129: 447–448.

28 Barth J H, Kealey T. Br J Dermatol 1991: 125: 304–308.

29 Franks S et al. J Steroid Biochem Mol Biol 1991: 39: 835–838.

30 Curtis A C. Arch Dermatol Syphilol 1950: 62: 329–330.

31 Chalmers R J G et al. Br Med J 1983: 287: 1346–1347.

Viewpoint 4

Greek methodology has created the term ‘labyrinth’ for the

convoluted indoor maze (Fig. 1a) that, according to legend,

was constructed for King Minos of Crete (after the design

by Daedalus) to hold the Minotaur (1), a creature half-

man, half-bull.

Ranging from its clinical and histological presentation to

the many open questions posed by its pathobiology, hid-

radenitis suppurativa (HS), in many respects, represents

such a labyrinth. Clinically (Fig. 1b), and on histological

analysis (Fig. 1c), the undermined sinus tracts in HS indeed

resemble a labyrinth (2). Despite intensive studies of HS

(3), the aetiology of HS still remains unclear, and we are

still trapped in a maze of possibilities and conflicting

hypotheses.

Let us walk, then, through this labyrinth, searching for

the Minotaur around which it may have been built.

This is best performed by considering selected key ques-

tions in HS research. The most pressing ones arise immedi-

ately, if one more carefully contemplates on: (a) the clinical

signs and symptoms presented by HS patients; and (b) the

proposal by Plewig et al. (4) that the term ‘HS’ should be

changed to ‘acne inversa’.

What are the differences in clinical manifestationbetween HS and acne vulgaris?The characteristic lesions in HS are deep-seated subcutane-

ous nodules or abscess (2,5). In acne vulgaris, the primary

lesions are either open or closed comedones (2,6). In HS,

closed comedones are never present, and open comedones

can be found as secondary lesions, but they are absent in

early lesions of HS (2). They may appear in long-standing

HS. Thus, the clinical appearance of HS and acne vulgaris

is quite distinct, and it adds little to our understanding of

HS pathogenesis to adopt the ‘acne inversa’ terminology.

Kurzen et al.

ª 2008 The Authors


Are terminal hair follicles really the main theatreof HS action?Plewig and Kligman stated that HS occurs in the terminal

follicle bearing pilosebaceous unit (2,4). If this were so, we

should find multiple thick hair shafts in HS. However, this

is not really the case, and at least clinically (as opposed to

histologically) terminal hair follicles actually are not the

primary target in HS. In fact, despite some overlap, the

areas of predilection for HS and the skin regions richest in

terminal hair follicles seem to be rather distinct territories.

In men, the buttock, a commonly affected site of HS

lesions, bears hardly any terminal hair follicles at all. In

addition, if terminal hair follicles were the key targets of

HS, multiple tufted terminal hair shafts from the follicle

should be observed in HS, as is characteristically seen in

folliculitis decalvans (Fig. 2), dissecting folliculitis and peri-

folliculitis abscedens and suffodiens (Hoffman). Instead,

multiple thick long terminal hairs are features one fails to

notice in the characteristic fistulae of HS (Fig. 3).

Thus, from a clinical perspective, it is quite dubious

whether HS really occurs, as frequently claimed and

reverberated uncritically, in terminal (rather than in vellus)

hair follicles.

But what about the apparent histopathological evidence

for a predilection of HS for terminal hair follicles? Plewig

and Kligman describe three types of hair follicles: vellus

hair follicle, sebaceous follicle and terminal hair follicle (2).

Well, in my personal experience, it is very difficult (if at all

possible) to histologically detect terminal hair follicles in

HS. Even in standard textbooks (2,4,7), the classical charac-

teristics of terminal hair follicles (thick, medullated hair

shafts and large sebaceous gland), as described so beauti-

fully in Plewig’s book (2), are essentially absent in HS.

Instead, Layton et al. (7) have observed tiny vellus hairs in

follicular canals in HS. The lower part of hair follicles and

sebaceous gland are uninvolved in HS. Taken together,

Opening of fistelsUndermined sinus tracts

Rupture of the epithelium

Retention hyperkeratosis

Formation ofsinus tract

Exudate and pus discharging

Commuicating of sinus tract

Leaf-like structureSubcutaneous abscessForeign body granuloma

(a)

(b)

(c)

Figure 1. Classical labyrinth (a) and clinical (b) and histological

labyrinth (c) in hidradenitis suppurativa.

Figure 2. Tufted hairs from one hair pouch in folliculitis decalvans.

Figure 3. Undermined fistulae in axilla in HS. Terminal hair follicles

are not clinically affected in HS lesions.


ª 2008 The Authors


therefore, it is very dubious that HS predominantly affects

terminal hair follicles.

Thus, even from the perspective of histopathology, HS is

not a disorder of the terminal hair follicle. The fundamen-

tal change in HS is the retention hyperkeratosis of the

infundibulum (2,4,7,8). More likely, HS predominantly

occurs in the infundibulum of vellus hair follicles, whose

tiny shafts can be observed in the follicular canal of

affected pilosebaceous units.

The keratin expression pattern in HS has been studied

immunohistologically (9,10). Among cytokeratins, CK17 is

neither expressed in the cyst wall in most cases of HS (9)

nor is found in the pilonidal sinus of HS (11). CK 14 is

more pronounced in the protruding epithelium in HS (9)

(Fig. 4) In terminal hair follicles, CK 16 is detectable in the

lower portion of hair follicle below the opening of seba-

ceous duct (9–12). The fact that CK16 was only found in

two of 16 HS cases (9); therefore, further argues against

terminal hair follicles as key targets in HS pathogenesis.

However, as these immunohistological results illustrate, HS

is definitely associated with abnormalities in keratinization.

The next questions, then, are as follows.

What causes retention hyperkeratosis, and howdoes this lead to the characteristic, labyrinthicsinus tracts of HS?Based on the above keratin expression patterns and the

unconvincing evidence that terminal hair follicles are the

key organ where HS manifests itself, I propose the follow-

ing hypothesis.

The sinus epithelium in HS is not a late, but a very early

event and does not primarily arise from the hair follicle

epithelium, but by invagination from the epidermis

(Fig. 1c). This invagination of the epidermis may result in

the formation of infundibulum-like epithelium that pro-

trudes into the deep dermis as epidermal cysts. Resident

microflora may cause the adherence of the epithelium.

Coagulase-negative Staphylococcus (CNS), in normal flora

on the skin, is the most common bacterium isolated from

HS lesions (13). CNS is also the most common bacterium

isolated from epidermal cysts (14). Therefore, CNS may

tend to adhere to the adjacent, closed serrated epidermis in

the intertriginous area, resulting in infundibular-like epi-

thelium (cyst formation) in both HS and epidermal cyst.

An alternative explanation may be that HS patients exhibit

an altered immunologic response to CNS antigens,

compared with normal individuals. Another possibility is

that anaerobic bacteria (15) play a key role in retention

hyperkeratosis, resulting in both sinus and cyst formation.

Often, the protruding epithelium that forms from the

wall of HS cysts shows a leaf-like structure, as shown in

Fig. 4. Why do such leaf-like structures arise? Formation of

the epithelial and mesenchymal interactions might be

related to undifferentiated keratin expression (CK14). In

addition, anastomosing epithelium that links sinus tracts

into a complex maze of tracts is frequently found in HS

(Fig. 1c). Kurzen et al. (10) studied desmoplakin and des-

mocollin in epithelia in HS, and demonstrated their differ-

ences between three types of epithelium (10). Altered

epithelial adhesion properties in HS might also result from

abnormalities in e-cadherin expression.

Is the clinical phenotype of HS determined by anabnormal immune response against bacteria?It is clear that bacterial infection is not the primary cause

of HS. However, bacteria, their products, and immune

responses raised against bacterial antigens may well greatly

influence the clinical phenotype of HS lesions as well as the

course of HS in any given patient. From normal skin

microflora, CNS, Staphylococcus aureus, Stereptococcus,

Peptostreptococcus, etc. are isolated in HS, e.g. in perirectal

and vulvovaginal lesions (16,17). However, it is unclear

whether these clinical isolates are involved in the pathogen-

esis of HS or not. CNS obstructs the intra-epidermal sweat

duct, resulting in miliaria formation (18). Thus, it is con-

ceivable that sinus formation in HS involves a similar

mechanism.

In terms of natural immunity, patients with HS may

respond abnormally to these bacteria (e.g. Propionibacteri-

um acnes), whose products stimulate Toll-like receptors

(19), producing pro-inflammatory cytokines such as IL-1a,

and giving rise to abnormal keratinization (20). The hair

follicle was recently recognized as one of the immune

organs of skin (21). In particular, the infundibulum, which

belongs to the distal arm of the human hair follicle

immune system, appears to represent a special organ

involved in immune response (22). These areas are the

preferred sites for perifollicular inflammatory cells in der-

matoses such as lichen planopilaris, systemic lupus erythe-

matosus, scleroderma and folliculitis decalvans (23).

Figure 4. CK 14 is expressed in the protruding epithelium in a leaf-

like structure.

Kurzen et al.

ª 2008 The Authors


Therefore, HS may just represent a certain clinical pheno-

type that reflects a disturbed hair follicle immune system.

Important studies that remain to be performed inHS researchIn consequence, infundibular immunology, therefore, needs

to be systematically dissected in future. For example, Toll-

like receptors may be related to the initiation of inflamma-

tion in the infundibulum. In this context, the impact of

pro-inflammatory cytokines on abnormal keratinization in

HS should also be carefully investigated.

Other important areas for future HS research include

for example the precise mechanism by which new epithe-

lium is formed in the process of sinus drainage (in HS

and other diseases where this occurs). Scar formation

involves a cell-mediated response that deserves study to

clarify the pathogenesis of HS, like in acne vulgaris (24).

With regard to possibly increased carcinogenesis in HS,

the CK expression in well-differentiated SCC arisen from

HS epithelium is similar to that in normal infundibulum

(25). By contrast, poorly differentiated SCC in HS con-

tained simple epithelial keratins (CK7, 8, 18, 19). Thus, it

deserves to be carefully studied whether CK expression

patterns reflect the clinical prognosis. Finally, the terminal

stage of keratinization is related to filament-aggregating

protein (filaggrin), a major component of keratohyaline

granules (26). Filaggrin expression has been linked to the

pathogenesis of acne vulgaris (27), epidermal cyst (28)

and nevus comedonicus (29). Therefore, an immunohisto-

chemical study of filaggrin expression should be under-

taken. As comprehensive ultrastructural studies of HS

remain to be performed, this should be complemented by

electron microscopy.

In the long run, at least the ‘floor plan’ of the HS laby-

rinth is becoming better defined, defined scenarios can be

developed on how it is being constructed and evidence is

emerging that its epithelial walls show distinct abnormali-

ties of keratinization.

But what is the Minotaur it may contain?

Is ‘altered epithelial adhesion’ and ⁄ or ‘altered immune

response against bacteria’ the answer…?

Ichiro Kurokawa

Department of Dermatology, Mie University Graduate

School of Medicine, 2-174, Edobashi, Tsu,

Mie 514-8507, Japan


References1 Penelope Reed Dob, The Idea of the Labyrinth: From Classified

Antiquity Through the Middle Ages. New York: Cornell University

Press, 1992.

2 Plewig G et al. Acne and Rosacea. Berlin: Springer-Verlag, 2006:

309–341.

3 Jemec G B. J Cutan Med Surg 2003: 7: 47–56.

4 Plewig G et al. Acne and Related Disorders. London: Martin Dunitz,

1988: 345–347.

5 Poli F et al. Hidradenitis Suppurativa. Berlin: Springer-Verlag, 2006:

11–24.

6 Cunliffe W J et al. Acne – Diagnosis and Management. London:

Martin Dunitz, 2001: 49–67.

7 Layton A M. Hidradenitis Suppurativa. Berlin: Springer-Verlag, 2006,

25–33.

8 Jansen T et al. Int J Dermatol 1998: 37: 96–100.

9 Kurokawa I. J Int Med Res 2002: 30: 131–136.

10 Kurzen H et al. Br J Dermatol 1999: 141: 231–239.

11 Kurokawa I et al. Br J Dermatol 2002: 146: 409–413.



14 Nishijima S et al. Jpn J Dermatol (in Japanese) 2003: 113: 165–168.

15 Brook H S et al. J Med Microbiol 1999: 48: 103–105.

16 Leach R D et al. Br J Med 1979: 2: 5–7.

17 Brook I. Arch Dermatol 1989: 25: 1658–1661.

18 Mowad C M et al. J Am Acad Dermatol 1995: 33: 729–733.

19 Kim J et al. J Immunol 2002: 169: 1535–1541.

20 Guy R et al. J Invest Dermatol 1996: 136: 166.

21 Paus R et al. Trends Immunol 2005: 26: 32–40.

22 Christoph T et al. Br J Dermatol 2000: 142: 862–873.

23 Paus R et al. J Invest Dermatol Symp Proc 1999: 4: 226–234.

24 Holland D B et al. Br J Dermatol 2004: 150: 72–81.

25 Kurokawa I et al. J Cutan Pathol 2007: 21: 675–678.

26 Dale B et al. J Invest Dermatol 1979: 72: 257–261.

27 Kurokawa I et al. J Invest Dermatol 1988: 91: 566–571.


29 Kurokawa I et al. J Cutan Pathol 2007: 34: 338–341.

Viewpoint 5

Before you read these comments, the authors want you to

know that we have a ‘conflict of interest’ – we do not

believe in ‘hidradenitis suppurativa’! While we will not be

engaging in a terminological debate, in our opinion ‘acne

inversa’ is the appropriate term for this often devastating

disease (1). It is a term which – in a nutshell – already puts

forth part of our answer to the introductory question

posed by the editor: What causes hidradenitis suppurativa?

‘Acne inversa’ indicates that this is a disease of follicular

occlusion similar to acne vulgaris. Pathogenetically, how-

ever, more can be said about what does not cause ‘hidrade-

nitis suppurativa’ than what causes it.

Similar to other forms of acne, apocrine glands have no

role in acne inversa; the glands are guilty by association

only and as such are merely ‘innocent bystanders’ (Fig. 1).

This is documented in numerous studies (1–6). The early

experimental model for ‘hidradenitis suppurativa’, pub-

lished in 1955 by Shelley and Cahn (7), was designed to


ª 2008 The Authors


recapitulate the changes seen in patients with ‘hidradenitis

suppurativa’ and relied on the application of belladonna

adhesive tape to manually depilated axillary skin. It was

one of the most important papers emphasizing the central

role of apocrine glands in the disease process but was pla-

gued with flaws and assumptions, although the conclusions

derived from it were considered dogma – at least for many

years. In our opinion, the paper did not deserve the

attention it got and the attention was uncritical.

Knowing that at centre stage in ‘hidradenitis suppurati-

va’ is follicular occlusion, the question remains what causes

it or – more specifically – what causes it in the axillae and

in the groin area, the predominant anatomical locations

(hence the term acne inversa). It is well documented that

obese females are most commonly affected (8–11). Normal

axillary skin displays already a ruffled appearance under the

microscope (Fig. 1a) as opposed to the even epidermal sur-

face observable in biopsies, e.g. from facial skin. We specu-

late that constant friction in the axillae and in the groin,

enhanced by obesity, is the major biomechanical factor

contributing to microcomedo formation from which the

subsequent cascade of pathogenetic events initiates. Micro-

comedones are part of the histopathological spectrum of

early disease (1,12). Especially the folds observable in the

skin of obese individuals contribute mechanically to the

retention of corneocytes, hair shafts and sebaceous secre-

tory products within the microcomedones, leading to their

enlargement and later rupture. The hair follicles in ‘hid-

radenitis suppurativa’ exhibit an abnormal shape, are wider

in the deep dermis and are also larger in the axilla (13).

We interpret this finding as corroborating our biomechani-

cal theory.

A close relative of ‘hidradenitis suppurativa’ and part of

the acne tetrad (14), the pilonidal sinus, is equally caused

in our opinion by biomechanical factors. Known also as

‘jeep disease’ (15), it has a predilection for soldiers sub-

jected to long-term occlusive sitting conditions (16,17).

Outside the intertriginous areas, the human body employs

clever mechanisms to combat mechanical retention. A good

example is the external auditory canal, where a peculiar pat-

tern of keratinocyte migration occurs for the sole purpose of

keeping the meatus free from desquamation products (18).

The epidermal front of the mucocutaneous junction of the

tympanic membrane simply expresses hyperproliferation-

associated cytokeratins and such keratinocytes migrate, thus

preventing their accumulation and allowing also cerumen to

be disposed to the outside.

Epidemiologically, it is known that most patients with

‘hidradenitis suppurativa’ are smokers (19–21). A recent

intriguing paper by Hana et al. (22), one of the few experi-

mental studies in the field, convincingly demonstrated the

induction of infundibular epithelial hyperplasia by nicotine

(a)

(d) (e) (f)

(c) (b)

Figure 1. (a) In the early stage of the disease, microcomedones are characteristic (arrowhead). Note that the apocrine glands are unremarkable

(arrow) and that the epidermal surface of the axillary skin is thrown into folds. (b) A comedo has ruptured (arrow) and the body initially tries to

contain the acute inflammation by surrounding granulation tissue. (c) If unsuccessful in confining the disease, the inflammatory response following

rupture of the comedo is more florid. Note that the apocrine glands to the right of the ruptured nodule are not involved. (d) Apocrine glands,

however, become secondarily affected when they are close to the focus of inflammation (arrow). (e) Naked hair shafts (arrowheads) may be the only

indication that the process started from the hair follicle. Note that the apocrine glands outside of the area of inflammation are not affected (arrow).

(f) In the later stage of the disease sinus tracts, often surrounded by prominent inflammation, are the predominant feature. [All sections stained with

haematoxylin–eosin; original magnification: (a) 16·; (b) 200·; (c) 25·; (d) 25·; (e) 50·; (f) 16·]. With permission from Sellheyer, K., Krahl, D.

‘Hidradenitis suppurativa’ is Acne inversa! An appeal to (finally) abandon a misnomer. Int. J. Dermatol 2005; 44: 535–540.

Kurzen et al.

ª 2008 The Authors


as a prerequisite for follicular plugging. The authors

employed organotypic cultures and suggested the non-neu-

ronal acetylcholine receptors, prominent around the follic-

ular infundibulum, as the nicotine-mediating effector

system (22). This would be the first logical explanation of

why mostly smokers are predominantly affected by the dis-

ease and also confirms our findings of microcomedones as

an early pathogenetic event. While we do not think that

nicotine is the inducing factor, it certainly is a major

contributing factor of ‘hidradenitis suppurativa’. In later

disease stages, nicotine seems to be less important, as the

non-neuronal cholinergic system is not prominent in sinus

tracts (22). By then, however, the disease has already devel-

oped a life of its own. Nicotine is also secreted in apocrine

and eccrine sweat (23), which may play a direct role in

‘hidradenitis suppurativa’. It remains speculative if, in addi-

tion to nicotine, tar products in cigarette smoke are

secreted via sweat and find their way to the follicular

infundibula, thereby exerting their well-documented

comedogenic effects.

From the above, it is obvious that we are in dire need of

more basic science data on this enigmatic disease, foremost

to help our patients. They may otherwise fall into the

trap of alternative or holistic medicine using the lack of

knowledge about ‘hidradenitis suppurativa’ to its commer-

cial advantage by selling products with no therapeutic

benefits, such as algae (http://www.akne-inversa.de/projekt/

spiru-studie/index.htm), thereby extending the ordeal of the

patients and preventing them to seek adequate treatment.

Reflecting on ‘What causes hidradenitis suppurativa?’ we

are still astounded that even the current fragmented level

of knowledge on ‘hidradenitis suppurativa’ cannot be com-

prehended by many representatives of allopathic medicine.

An especially baffling example is that of a well-known

cosmetic dermatologist from Nashville, TN, who asked for

copyright permission for histological photographs from our

own paper on acne inversa (1). After reproduction of

the photomicrographs, he elaborates in his review on the

application of photodynamic therapy for ‘hidradenitis sup-

purativa’: ‘Because HS [= hidradenitis suppurativa] is an

apocrine disorder, and not a sebaceous gland problem

[…]’ (24). This is the exact opposite of what we have

hoped to rectify with our histological pictures. We

hope the reader of this commentary is not a cosmetic

dermatologist!

Klaus Sellheyer

Department of Dermatology, University of Alabama at

Birmingham, Birmingham, AL 35294, USA


Dieter Krahl

Institut fur Dermatohistologie, D-69120 Heidelberg,

Germany;


References1 Sellheyer K, Krahl D. Int J Dermatol 2005: 44: 535–540.

2 Yu C C-W, Cook M G. Br J Dermatol 1990: 122: 763–769.

3 Felding C, Moesgaard J, Clevin L, Fischer S. Ambulat Surg 1995: 3:

3–6.

4 Jemec G B E, Hansen U. J Am Acad Dermatol 1996: 34: 994–999.

5 Jemec G B E, Thomsen B M, Hansen U. APMIS 1997: 105: 378–

383.

6 Heller D B, Haefner H K, Hameed M, Lieberman R W. J Reprod

Med 2002: 47: 695–700.

7 Shelley W B, Cahn M M. Arch Dermatol 1955: 72: 562–565.

8 Edlich R F, Silloway K A, Rodeheaver G T, Cooper P H. J Emerg

Med 1986: 4: 369–378.

9 Harrison B J, Read G F, Hughes L E. Br J Surg 1988: 75: 972–975.

10 Barth J H, Layton A M, Cunliffe W J. Br J Dermatol 1996: 134:

1057–1059.

11 Yosipovitch G, DeVore A, Dawn A. J Am Acad Dermatol 2007: 56:

901–906.

12 Plewig G. Acne inversa, Acne keloidalis nuchae, abszedierende Fol-

likulitis der Kopfhaut: ein verbindendes Konzept. In: Plewig G, Prinz

J, eds. Fortschrritte der Praktischen Dermatologie und Venerologie

2002. Berlin: Springer, 2003: 192–203.

13 Jemec G B, Gniadecka M. Arch Dermatol 1997: 133: 967–970.

14 Plewig G, Steger M. Acne inversa (alias acne triad, acne tetrad or

hidradenitis suppurativa). In: Marks R, Plewig G, eds. Acne and

Related Disorders. London: Martin Dunitz, 1989: 345–357.

15 Patey D. Nurs Times 1971: 67: 534–536.

16 Clothier P R, Haywood I R. Ann R Coll Surg Engl 1984: 66: 201–

203.

17 Chijiwa T, Suganuma T, Takigawa T et al. Mil Med 2006: 171:

650–652.

18 Vennix P P, Kuijpers W, Peters T A, Tonnaer E L, Ramaekers F C.

Laryngoscope 1996: 106: 470–475.

19 Konig A, Lehmann C, Rompel R, Happle R. Dermatology 1999:

198: 261–264.

20 Bassukas I D, Hundeiker M. J Am Acad Dermatol 1997: 36: 1029.

21 Freiman A, Bird G, Metelitsa A I, Barankin B, Lauzon G J. J Cutan

Med Surg 2004: 8: 415–423.

22 Hana A, Booken D, Henrich C et al. Life Sci 2007: 80: 2214–2220.

23 Balabanova S, Buhler G, Schneider E, Boschek H J, Schneitler H.

Hautarzt 1992: 43: 73–76.

24 Gold M H. Dermatol Clin 2007: 25: 67–73.

Commentary 1

Hidradenitis suppurativa (HS) is a devastating chronic skin

disorder affecting areas rich in apocrine glands. HS is in

most cases recalcitrant to therapy (1). Therapy decision

making largely depends on the impression of the physician

about pathogenesis of HS. This may be connected to the

high rate of treatment failure (2). HS was initially con-

ceived as an infectious disease process or as a form of acne.

Patients run a life of exacerbations and remissions with


ª 2008 The Authors


heavy purulent discharge from the affected areas. The pres-

ence of pus creates the impression of an infectious disease

which is compatible with the traditional theory of patho-

genesis. In that theory, follicular hyperkeratosis leads to

occlusion of the apocrine glands with secondary infection

from bacterial skin flora (3). As a consequence, antibiotics

are prescribed. Even though antibiotics may offer relief of

symptoms, cessation of treatment is usually accompanied

by flare-ups (4). This creates serious doubts if HS is indeed

an infectious process or not. The fate of treatment with

retinoids is similar (5).

Surgical excision of the affected areas is accompanied by

high recurrence rates (6,7). Carbon dioxide laser locally

applied for the management of 35 patients with Hurley II

lesions ended in recurrence in 25 patients. Surprisingly,

relapse supervened in another anatomical region, different

from the one which was operated (8). Re-appearance in

another site after immune triggering is a characteristic of

auto-immune disorders which creates the hypothesis if HS

is an autoimmune disorder. This is compatible with the

coexistence of HS with other auto-inflammatory disorders

like Crohn’s disease (1).

In a recent study of our group (8), peripheral blood

monocytes were isolated from 53 patients with active HS

and stimulated with bacterial endotoxin (LPS) for the pro-

duction of pro-inflammatory cytokines, namely tumour

necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6).

Cells isolated from six healthy volunteers were controls. It

was found that monocytes of patients with HS were weaker

producers of cytokines compared with healthy controls. In

the same study, it was shown that percentages of natural

killer (NK) cells were decreased in parallel with the natural

history of HS (Fig. 1). These findings favour the existence

of significant alterations of innate immune functions of HS

patients. They also support indirectly an auto-immune aeti-

ology as antigen presentation is based on the integrity of

the innate immune system.

The concept of HS as an autoimmune disorder is also

based on the favourable responses of patients to targeted

therapies against TNF-a. Infliximab, a chimeric anti-TNF-amonoclonal antibody, and etanercept, a soluble receptor of

TNF-a, have been administered in case-studies with limited

number of patients and at a variety of dose regimens.

Results of infliximab were contradictory in terms of safety

and efficacy in case-studies of five and seven patients each

(9,10), whereas etanecept was effective and well tolerated in

a series of six patients (11).

The only open-label prospective study on the safety and

efficacy of a specific regimen of etanercept has been

published by our group (12) (EudraCT: 2004-004555-19,

http://www.clinicaltrials.gov, NCT00329823).

Etanercept was administered at a dose of 50 mg once

weekly for 12 weeks in 10 patients. A more than 50%

decrease in the Sartorius score was found in six patients at

week 12 and in seven patients at week 24. A considerable

decrease in the total number of fistulas from the baseline

was seen over all weeks of follow-up. Eight patients reported

recurrence of drainage of pus from the affected areas within

4–8 weeks after the end of administration of etanercept.

There is accumulating indirect evidence for a key role of

the immune system in HS pathogenesis. Derangements of

the innate immunity, favourable responses to therapy with

etanercept and exacerbations upon cessation of anti-TNF-atreatment, support auto-immunity as the underlying cause

of HS.

Evangelos J. Giamarellos-Bourboulis

Fourth Department of Internal Medicine, ‘‘Attikon’’

University General Hospital, University of Athens

Medical School, Athens, Greece;


References1 Shah N. Am Fam Physician 2005: 72: 1547–1552.

2 Jemec G B E. Expert Opin Pharmacother 2004: 5: 1767–1770.

3 Wiseman M. Dermatol Ther 2004: 17: 50–54.


5 Krbec A C. J Am Acad Nurs Pract 2007: 19: 228–234.

6 Kagan R J et al. Surgery 2005: 138: 734–741.

7 Lapins J et al. J Am Acad Dermatol 2002: 47: 280–285.

8 Giamarellos- Bourboulis E J et al. Br J Dermatol 2007: 156: 51–56.

9 Fardet l et al. J Am Acad Dermatol 2007: 56: 624–628.

10 Sullivan T P et al. Br J Dermatol 2003: 149: 1046–1049.

11 Cusack C, Buckley C. Br J Dermatol 2006: 154: 726–729.

12 Giamarellos-Bourboulis E J et al. Br J Dermatol 2008: 158: 567–572.

HS Controls

TN

Fα

(pg/

1000

0 ce

lls, m

edi

an +

/– 9

5% C

I)

1000

750

500

250

0

P<0.0001

Figure 1. Release of TNF-a by monocytes isolated from 53 patients

with hidradenitis suppurativa (HS) after stimulation with endotoxin (LPS)

of Escherichia coli O111:B4 compared with six healthy volunteers.

Kurzen et al.

ª 2008 The Authors


Commentary 2

Although recognized more than 150 years ago, hidradenitis

suppurativa (HS) is still a mysterious disease. Ever since

inflammation of the apocrine glands was recognized as a

secondary event in the pathogenesis of the disease, it has

been speculated that comedonal and ⁄ or poral occlusion(s)

and bacterial infection play a crucial role. Even though this

concept has been questioned almost immediately, there is

some consensus regarding the role of immunity and infec-

tion. Thus, even if I cannot provide an answer to the ques-

tion posed by the editor, let me elaborate on the issues of

skin immune response and infection in HS pathogenesis.

The involvement of immune response in HS remains

controversial. Immunological investigations of patients with

HS suggested no abnormalities of the immune system (1).

By contrast, other authors showed increased peripheral

suppressor T-cell activity (2), indicative of a cellular

immune response. This is further supported by the

presence of activated, HLA-DR-positive as well as Leu-8-

positive immunoregulatory lymphocytes (3). These results

indicate that the lymphocytic infiltrate is definitely the

result of in vivo activation of lymphoid cells. Indeed, the

significant fall of the T-helper ⁄ suppressor and NK cell ratio

over time after the initiation supports the existence of a

precipitating, cell-mediated immune response with only a

short eliciting period (3,4). More recent studies have shown

that dysfunctional neutrophils and monocytes may also be

involved in the pathogenesis of HS, still, no primary abnor-

malities of the innate or acquired immune system can be

held to be causal in every case (3–6).

Because of increasing evidence suggesting that keratino-

cytes (KCs) not only participate in cutaneous immune

responses but may in fact play key initiation roles (7),

one must also consider the contribution of KCs to HS

pathogenesis. KCs are able to recognize a wide variety of

micro-organisms through their pattern recognition recep-

tors (PRRs) and have evolved mechanisms to distinguish

between skin commensals and pathogens. Signalling

through specific PRR combinations provides selectivity and

specificity to immune response. As a result, KCs produce a

wide range of antimicrobial peptides, proinflammatory

cytokines ⁄ chemokines and inducible enzymes (8). The

secretion of antimicrobial peptides is indeed crucial, as skin

lesions characterized by low levels of such host-defence

peptides are more susceptible to infections. By exhibiting

chemoattractant activity, KC-derived cytokines ⁄ chemokines

and antimicrobial peptides can recruit T cells, neutrophils

and dendritic cells into sites of infection, thus providing an

improved immune response against pathogens (7,8). These

findings indicate a close interdependence of KCs and

inflammatory infiltrate as well as a balance between the

innate and acquired immune systems. Any perturbation in

this system, for example dysregulation and abnormal

expression of inflammatory mediators or their receptors in

KCs, can lead to the pathogenesis of chronic inflammatory

skin diseases, such as HS.

The significance of bacterial involvement in the patho-

genesis of HS is also controversial. It is likely that chronic

inflammation is because of secondary bacterial colonization

(5). This is further supported by the fact that routine cul-

tures from the surface of the lesions are often negative.

Still, bacteria are likely to be involved in the pathogenesis

of the disease as numerous species are most frequently iso-

lated from lesions (6,9). Most of bacteria identified in HS

lesions, such as Propionibacterium acnes and coagulase-neg-

ative staphylococci, are part of the normal microflora, but

have also gained attention as pathogens. These findings

highlight a possible polymicrobial nature and predomi-

nance of anaerobic bacteria, supporting the role of bacterial

infections as a possible pathogenic event in HS. However,

interpreting the results of previous studies is difficult, as

potential differences amongst recently discovered phyloge-

netic groups and ⁄ or ecotypes have not been taken into

account. Notably, the existence of philogenetically distinct

P. acnes clusters have recently been demonstrated (10).

Importantly, these clusters differ in the production of

secreted proteins (11), and induce different immune

responses in KCs and sebocytes (12,13).

These findings challenge our current understanding of

the pathogenic nature of bacteria involved in HS pathogen-

esis and raise the exciting possibility that bacterial strains,

or group of strains, with greater potential to cause oppor-

tunistic infection in HS may exist. This may explain, in

part, the apparent controversy with respect to the role of

bacterial infection in HS.

Istvan Nagy

Institute for Plant Genomics, Human Biotechnology and

Bioenergy, Bay Zoltan Foundation for Applied Research,

Szeged, Hungary;


References1 Dvorak V C et al. Arch Dermatol, 1977: 113: 450–3.

2 McDaniel D H, Welton W A. Arch Dermatol, 1984: 120: 437.

3 Boer J, Weltevreden E F. Br J Dermatol, 1996: 135: 721–5.

4 Giamarellos-Bourboulis E J et al. Br J Dermatol, 2007: 156: 51–6.

5 Jansen I P et al.. J Eur Acad Dermatol Venereol, 2001: 15: 532–40.

6 Lapins J, J C et al. Br J Dermatol, 1999: 140: 90–5.

7 Schroder J M et al. Exp Dermatol, 2006: 15: 913–29.

8 Pivarcsi A et al. Curr Immunol Rev, 2005: 1: 29–42.

9 Jemec G B et al. Dermatology, 1996: 193: 203–6.

10 McDowell A et al. J Clin Microbiol, 2005: 43: 326–34.

11 Valanne S et al. Microbiology, 2005: 151: 1369–79.

12 Nagy I et al. Microbes Infect, 2006: 8: 2195–205.

13 Nagy I et al. J Invest Dermatol, 2005: 124: 931–8.


ª 2008 The Authors


Commentary 3

Hidradenitis suppurativa (HS) has originally been consid-

ered a disorder of the apocrine glands.(1) However, over the

years more and more authors suggested HS to be a misno-

mer as the disease seems to start rather with follicular occlu-

sion than with a primary involvement of apocrine sweat

glands. Since 1989, the term acne inversa (AI) is commonly

used instead of HS to underline that this disorder is actually

a defect of follicular epithelium (2–4). This concept does,

however, not explain sufficiently the causes of follicle

involvement and possible subsequent follicle rupture.

When discussing with colleagues of different medical dis-

ciplines, we often are under the impression that the experts

treating this disease have split in two camps – rigorous

supporters of the term HS, and equally stern supporters of

the term AI. The ongoing conflict between these two hos-

tile camps may actually have put basic HS research into a

kind of ‘hibernation’, rather than having promoted scien-

tific breakthroughs in this obscure, but very important

chronic inflammatory disease.

As a provocative approach to possible causes of HS or

AI is favoured on these pages, we therefore would like to

modify the question raised by the editor into one that

often rises in clinical routine: Do all patients that we treat

for HS ⁄ AI really suffer from the same disease?

From the point of view of daily clinical routine, we

have long wondered about the extremely different patient

populations that are referred to our clinic with a diagno-

sis of HS or AI. Some of our patients report acne vulgaris

to have occurred in their medical history. Theses patients

often show clinical signs or remnants of a previous severe

acne, most often presenting as typical scarring of the face

and back. Others still have active acne lesions. These

patients often do not show obesity (which has been

claimed to be a characteristic of HS patients). Instead,

they usually present comedones within or surrounding the

inflammatory lesions. Interestingly, in our experience,

these patients frequently respond to retinoid treatment,

whereas the majority of HS patients do not benefit from

retinoid.

By contrast, there are the classical obese smoking

HS ⁄ AI patients with chronic inflammatory lesions, which

support the concept that nicotine and obesity present a

significant risk factor. (5) Compared with the normal-

weight patients, we rarely notice any comedones in this

patient population at all, even in early lesions or healthy

surrounding skin.

A third type of patient, although less frequently encoun-

tered, presents with typical HS ⁄ AI lesions in conjunction

with granulomatous colitis (Crohn’s disease). We have

never seen comedones in this collective. Are theses patients

really suffering from the same type of HS or AI as is

present in slim patients with a prominent history of acne

vulgaris, or the obese smoking female patients?

Based on clinical observation and experience, we hypoth-

esize that we do not deal with the same pathobiological

entity in all patients that meet currently accepted diagnostic

criteria for HS or AI. Further studies with an accurate and

refined definition of distinct patient subcollectives is likely

to also provide new answers to the central question that

drives these CONTROVERSIES.

Falk G. Bechara, Peter Altmeyer

Department of Dermatology and Allergology, Ruhr-Univer-

sity Bochum, Germany; St Josef Hospital, Gudrunstr. 56, D

44791 Bochum, Germany;


References1 Brunsting H A. Arch fur Dermatol Syph (Berlin) 1939: 39: 108–120.

2 Plewig G, Steger M. Acne inversa (alias acne triad, acne tetrad or

hidradenitis suppurativa). In: Marks R, Plewig G, eds. Acne and

Related Disorders. London: Martin Dunitz, 1989: 345–57.


4 Wiseman M C. Dermatol Ther 2004: 17: 50–54.

5 Jansen T et al. J Eur Acad Dermatol Venereol 2001: 15: 532–540.

Viewpoint 6

Hidradenitis suppurativa (HS) is a chronic inflammatory,

disabling disease that has been shown to emerge from the

pilosebaceous unit of the intertriginous areas and is hence

preferentially called acne inversa in the European literature

(1). HS is certainly a multifactorial disease based on a

genetic background with different triggering factors. The

genetic background that predisposes the individual for HS

has so far escaped elucidation. First attempts to localize the

HS susceptibility locus to chromosome 1q (2) have not

been confirmed by other groups (U. Radhakrishna, Omaha,

USA). By contrast, different triggering factors are well

known, amongst which tobacco smoking, sweating, obesity

and colonization with Staphylococcus aureus seem to be the

most important (3).

In the following, I would like to place full emphasis on

what I consider a still insufficiently appreciated aspect of

HS, i.e. why and how tobacco-smoking is involved in HS

pathogenesis:

1 Between 80–90% of HS patients are active smokers,

which designates HS, together with, e.g. pustular palmopl-

antar psoriasis, a clearly tobacco-related skin disease (3,4).

In a questionnaire-based study, we have noticed that HS

Kurzen et al.

ª 2008 The Authors


patients develop new lesions after surgical therapy only if

they continued smoking (4).

2 Nicotine is the main toxin in cigarette smoke and

reaches serum levels of 50–500 nm (5), while in axillary

sweat nicotine concentrations of up to 150 nm have been

measured (6). After smoking one cigarette, nicotine can be

detected for up to 7 days in axillary sweat, indicating a

slow metabolization rate (7). Thus, due to the density of

sweat glands and the occlusive milieu in the intertriginous

areas, nicotine is present on the surface in relevant phar-

macological concentrations, higher than elsewhere on the

skin. This observation would explain the distribution of HS

lesions and the interdependency to sweating, provided

nicotine really is a major pathogenic factor in HS.

3 As a natural alkaloid occurring in plants, nicotine has

a selective antimicrobial activity. An important exception in

this is S. aureus, the growth of which is actually favoured by

nicotine (8). Consequently, HS patients are, like smokers in

general, heavily colonized with S. aureus (4,9). This vicious

circle is closed by the fact that S. aureus has been shown

to stimulate the expression of choline-acetyltransferase

(ChAT), the rate-limiting enzyme in the synthesis of acetyl-

choline (ACh) (10). ACh, in turn, can stimulate S. aureus

growth – analogous to nicotine (Fig. 1a,b).

4 Indeed, the production of ACh in human skin (as

suggested by ChAT immunoreactivity) is limited to kerati-

nocytes, sebocytes, endothelial cells, lymphocytes and neu-

trophilic granulocytes, finding its peak in peri-infundibular

basal keratinocytes of HS patients (blue line in Fig. 1a,b)

(11).

5 The natural ligands of nicotine are nicotinic acetylcho-

line receptors (AChR) that can be found in a highly complex

composition on all cells putatively participating in the path-

ogenesis of HS: keratinocytes, sebocytes, mast cells, neutro-

philic granulocytes, lymphocytes and macrophages (12).

6 Despite their somewhat misleading name, not all

nAChR are stimulated by nicotine. While nicotine leads to

calcium influx in homopentameric a7 nAChR and to

sodium and ⁄ or potassium flux after binding a3* nAChR

(a)

(b)

(c)

(d)

Figure 1. Proposed sequence of events in the pathogenesis of acne

inversa: Nicotine fuels the vicious circle of ACh production and

Staphylococcus aureus growth (a) promoting chemotaxis of neutrophilic

granulocytes and degranulation of mast cells (b). In addition the

infundibular epidermis becomes increasingly hyperplastic leading to

follicular obstruction (b). Influx of neutrophilic granulocytes and mast

cell degranulation promote a spongiotic infundibulitis. The acute phase

is followed by a chronic phase characterized by the appearance of

lymphocytes and macrophages (c) culminating in the rupture of the hair

follicle (d). Draining sinus are formed in an attempt to eliminate residual

hair-shafts. ACh Acetylcholine, ASG apokrine sweat gland, ChAT

choline acetyl transferase, ESG eccrine sweat gland, GC foreign body

giant cell, HF hair follicle, LC lymphocyte, MC mast cell, NG neutrophilic

granulocyte, Mph macrophage.


ª 2008 The Authors


(13), in both a9 and a10 nAChR, ion flux is actually inhib-

ited after nicotine exposure. Therefore, in the presence of,

e.g. both a7 and a10 nAChR the dominating effect is hard

to predict and may be determined by AChR subunit

density (remains to be determined) (12).

7 Nicotine has been shown to promote inflammatory

reactions, especially in the presence of mast cells and neutr-

ophilic granulocytes, both of which have been shown to be

present in early lesions of HS, causing a spongiotic infun-

dibulitis (1). Specifically, nicotine provokes mast cell

degranulation (14) and enhances chemotaxis and survival

of neutrophilic granulocytes (15,16).

8 To terminate an inflammatory reaction induced by

micro-organisms, cell debris or by ‘foreign’ material (hair

keratin!) in the chronic phase of HS lesions, both lympho-

cytes and macrophages secrete and need proinflammatory

cytokines like TNF-a, IL-4, Il-2 or IL6 (Fig. 1c,d). Nicotine

has been shown to suppress the LPS-induced secretion of

these cytokines (10,17). In addition, chemotaxis of macro-

phages is diminished in the presence of cigarette smoke

extract, an effect attributed to nicotine (18).

9 Nicotine is a highly potent inducer of epidermal

hyperplasia as we could show in an in vitro model. This

corresponds to the prominent, approximately threefold

increase in epidermal thickness observed in HS specimens

(compare Fig. 1a–d). At the same time, the density of

nAChR is most pronounced at the place where HS patho-

genesis is thought to originate from: the hair follicle infun-

dibulum (11).

Altogether, there is overwhelming evidence for a crucial

role of nicotine and the non-neuronal cholinergic system

in the pathogenesis of HS, providing a molecular mecha-

nism especially for early events in HS pathogenesis, which

is follicular obstruction and infundibulitis. Late events are

more complex, but even those may still be prominently be

influenced by nicotine, e.g. by impairment of macrophage

and lymphocyte functions.

Clearly, further studies are needed to verify the presented

novel hypothesis of HS as a disorder of over-stimulation of

defined nicotinergic AChR, and to test the new therapeutic

strategy that is invited by this HS pathogenesis scenario:

the systematic use of anticholinergic agents in the manage-

ment of HS.

Hjalmar Kurzen

Department of Dermatology, Venerology and Allergology,

Medical Faculty of Mannheim, University of Heidelberg,

Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany;

E-mail: [email protected];

[email protected]

References1 Sellheyer K, Krahl D. Int J Dermatol 2005: 44: 535–540.


3 Jansen I et al. J Eur Acad Dermatol Venereol 2001: 15: 532–540.

4 Kurzen H et al. Int J Coloproct 2000: 22: 76–80.

5 Alkondon M et al. Neuropharmacology 2000: 39: 2726–2739.

6 Kintz P et al. J Chromatogr B: Biomed Sci Appl 705: 357–361.

7 Balabanova S, Krupienski M. Hautarzt 1995: 46: 255–258.

8 Pavia C S et al. J Med Microbiol 2000: 49: 675–676.

9 Durmaz R et al. New Microbiol 2001: 24: 143–147.

10 Kawashima K et al. Life Sci 2003: 74: 675–696.

11 Hana A et al. Life Sci 2007: 25: 2214–2220.

12 Kurzen H et al. Horm Metab Res 2007: 39: 125–135.

13 Millar N. Biochem Soc Trans 2003: 31: 869–874.

14 Blandina P et al. J Physiol 1980: 301: 281–293.

15 Aoshiba K et al. J Lab Clin Med 1996: 127: 186–194.

16 Sorensen L T et al. Surgery. 2004: 136: 1047–1053.

17 Pavlov V A et al. Mol Med 2003: 8: 125–134.

18 Ortega E et al. Comp Immunol Microbiol Infect Dis 1994: 17:

77–84.

Kurzen et al.

ª 2008 The Authors


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