J Cutan Pathol 2008: 35: 795–797doi: 10.1111/j.1600-0560.2008.01108.xBlackwell Munksgaard. Printed in Singapore

Copyright # Blackwell Munksgaard 2008

Journal of

Cutaneous Pathology

Erratum

What causes acne inversa (or hidradenitissuppurativa)? – The debate continuesSellheyer K, Krahl D. J Cutan Pathol 2008; 35: 701.

The Journal Reviews published was incomplete. TheJournal Reviews should have read as follow:

What is the utility of critical evaluation ofour lexicon? As our understanding ofpathogenesis evolves, we become betterable to reappraise and reclassify diseases.One may argue that as long as weunderstand the disease process, there isno harm in allowing misnomers tocontinue. However, misnomers conveya false impression of pathophysiology, thushampering our ability to communicateeffectively with colleagues in other spe-cialties. As our understanding of medicineand the interconnection of diseasesdeepen, clarity of communication isimperative. The following discussion re-views several publications on hidradenitissuppurativa, one of which is an in-depthdiscussion of the pathogenesis. Knowingthe pathogenesis also allows for a propernomenclature.

– ar.

‘Hidradenitis suppurativa’ is a devastating disease.The term conveys that the primary pathogenic eventis centered on the (apocrine) sweat glands, a conceptdating back to the original description of the diseasebyVerneuil1 in 1854 (quoted by Sellheyer andKrahl1)and supported by an early experimental study byShelley and Cahn2 in 1955, who applied perforatedbelladonna adhesive tape to manually depilatedaxillary skin. The authors observed lesions at the tapeside clinically resembling ‘hidradenitis suppurativa’ in3 of 12 volunteers. Histologically, they noted pluggingand dilatation of the apocrine sweat duct associatedwith severe inflammation limited to a single apocrinesweat gland. In this study, which one may consider tobe flawed, the authors interpreted their findings asevidence of the apocrine nature of the disease.How far have we come in our understanding of the

disease more than five decades after the study of

Shelley and Cahn? In the following, we will reviewa compiled paper from a group of 14 authorspublished in the most recent series of Controversies inExperimental Dermatology.3 The authors were asked bythe section editor Ralf Paus to share their viewpointsof what causes ‘hidradenitis suppurativa’. There wasno consensus, and while – in the midst of the differentviewpoints – it may appear that we have not evolvedmuch beyond the knowledge available 50 years ago,there are some silver linings on the horizon. These‘silver linings’ are discussed in the compiled paper3

and are also published in three studies,4–6 two ofwhich were conducted by contributors to theControversies series. These three studies will bereviewed, albeit briefly, because they are alsodiscussed in the Controversies series.

Is ‘hidradenitis suppurativa’ a disease of the hairfollicle and, if so, which portion: cycling (stem) or non-cycling (follicular infundibulum or isthmus)? In eithercase, the term ‘hidradenitis suppurativa’ would makeno sense. Or, is it a process initiated by or centered onthe sweat glands in which case the terminology wouldbe adequate? Intertwined with the issue of theanatomical target from which the process starts isthe even more pressing question of what precipitatesthe changes at the morphological substrate, whateverthat may be.

It is well known that ‘hidradenitis suppurativa’affects primarily obese women7 in their 30s to 40s. Inview of the anatomical predilection of the diseaseprimarily in intertriginous areas, many of the authorswho contributed to the Controversies in ExperimentalDermatology3 favor shearing forces and constantfriction originating in the large skin folds, especiallyof obese patients, as one of the precipitating factors.The emphasis is on one because one would expectmore patients suffering from the disease, if bio-mechanical factors enhanced by obesity were the soleculprit. One author from the Controversies series,Jemec,3 speculated that microtears of the hair folliclemay represent the primary event. We ourselves viewmicrocomedones – essentially dilatations of thefollicular infundibulum – as one of the earliest

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pathogenic events and have documented theirpresence with rupture sites histopathologically,1 ashave others.8,9 Once microcomedones have devel-oped, the ‘fire of HS [hidradenitis suppurativa]becomes a bit bigger’, as stated by a group of authors(Emtestam et al.)3 participating in the Controversiesseries. The microcomedones, preceded by hyperker-atosis of the follicular infundibulum, enlarge exten-sively over time because their content – keratin – ismore resistant to being broken down than in non-intertriginous acne. Subsequent rupture, bacterialcolonization, sinus tract formation and scars evolve, atwhich time the process is difficult to contain. Theabove scenario would make the follicular infundibu-lum the prime anatomical target, thus rendering theterm ‘hidradenitis suppurativa’ illogical.

Inviewof ‘hidradenitis suppurativa’ as a ‘playgroundfor the high priests of nomenclature’, as paraphrased inthe abstract of theControversies series,3 it is not surprisingthat not every author participating in the compiledpaper agreed with the above viewpoint. Jean Revuzconcluded his contributions with the statement that‘Any pathogenesis scenario, however, that completelydiscards apocrine glands and their specific distributionas key elements in the development ofHS [hidradenitissuppurativa]may soon turn out to have to be discardeditself !’ This author speculates that an abnormalsecretion of a substance in the apocrine gland may bea triggering factor in the disease leading to morpho-logically recognizable effects in the acroinfundibulum‘with the responsible gland disguising itself as aninnocent bystander upon histology – a perfectlymasked ‘‘criminal’’ ’. There are currently no papersvalidating this viewpoint.

If the follicular infundibulum is the substrate in thepathogenesis of ‘hidradenitis suppurativa’, couldendocrine factors apart from biomechanical shearingforces play a role in the disease? This would link thenarrow age spectrum of patients suffering from thedisease and the frequent obesity into a commonpathogenic scenario. Zouboulis pointed out in hiscontribution to the Controversies series3 that studiesestablishing a relationship between ‘hidradenitis sup-purativa’ and hyperandrogenism often did not controlfor body mass index and the results are contradictory.However, the association of ‘hidradenitis suppurativa’with Cushing’s syndrome and acromegaly mayindicate a role of hormonal factors in the diseaseprocess.More controlled studies, however, aremissing.

What is the contribution of genetic factors in thedisease? Kurzen briefly mentions in the Controversiesseries3 that an initial attempt byGao et al.10 to localizethe susceptibility locus for ‘hidradenitis suppurativa’to chromosome 1q has not been confirmed by othergroups (unpublished observations according to per-sonal communication by Uppala Radhakrishna toKurzen).3 Studies reporting a link between genetic

factors and ‘hidradenitis suppurativa’ refer to theoccasional familial clustering of the disease.11,12

However, these studies are not controlled for otherfactors likely relevant, at least indirectly for the disease,such as obesity. To date, no convincing and irrefutableevidence of a genetic predisposition to ‘hidradenitissuppurativa’ has been presented.Could ‘hidradenitis suppurativa’ be infectious in

etiology?While a bacterial infection is not the primarycause, Kurokawa in the Controversies series3 proposesan abnormal immune response against bacteria mayplay a role in the disease process in that patients with‘hidradenitis suppurativa’ may respond abnormallyto the residential bacterial flora. In acne vulgaris,bacterial superinfection activates the immune systemin the lesions via stimulation of Toll-like receptors.13

Toll-like receptors are a part of the innate immuneresponse to bacteria. Hunger et al.4 describe theoverexpression of Toll-like receptor 2 within infiltrat-ing macrophages and dendritic cells in lesions of‘hidradenitis suppurativa’. In addition, the authorsalso report an increased expression of different C-typelectin receptors including the mannose receptor,CD209, a endritic cell-specific lectin receptor, andlangerin, which represent constituents of the innateimmune response to bacteria. C-type lectin receptorsengage very effectively in antigen capture and uptakeby macrophages and dermal dendritic cells. Theauthors speculate that the bacterially inducedenhanced expression may contribute to the patho-genesis of the disease, comparable with acne vulgaris.They emphasize a possible cross talk between C-typelectin receptors and Toll-like receptor 2; both areexpressed onmacrophages anddermal dendritic cells,and the authors speculate that this may contribute tothe chronic state of the disease. Bacteria stimulatethe production of proinflammatory cytokines in acnevulgaris, and it has been shown that interleukin-1alpha causes hypercornification of the infundibulumsimilar to that seen in acne comedones, which can beblocked by the addition of an interleukin-1 receptorantagonist.14 Thus, bacterial colonization of thefollicular infundibulum, facilitated by the occlusiveconditions of microcomedones and later sinus tracts,may be crucial in the initial events leading to‘hidradenitis suppurativa’.Could a disturbed immune systemplay a key role in

the pathogenesis of ‘hidradenitis suppurativa’? Thiswas suggested by another contributor, Giamarellos-Bourboulis,5 who reported a reduction in thepercentage of natural killer cells and a lower mono-cyte response to triggering by bacterial components inpatients with ‘hidradenitis suppurativa’, who alsospeculated that these changes might be connected toan autoimmune mechanism. Using flow cytometryand enzyme immunoassays, Giamarellos-Bourbouliset al.5 reported lower numbers of CD3/CD8

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lymphocytes in patients with involvement of theperineum compared with controls in contrast topatients with involvement of the breast, which showedhigher levels of natural killer cells in the peripheralblood than controls. How relevant these findings arefor a possible autoimmune mechanism leading to‘hidradenitis suppurativa’ remains to be seen. How-ever, this publication represents one of only a fewexperimental studies available in the field.The viewpoint posted by Kurzen in the Controversies

in Experimental Dermatology3 is quite interesting as itreferences the first study presenting supportiveexperimental data explaining why ‘hidradenitissuppurativa’ is so closely linked to smoking.6 In thishighly recommended article, Kurzen et al. used tissuecultures to study the effects of nicotine on skin frompatients with ‘hidradenitis suppurativa’ and com-pared the effects to skin from normal subjects. Theynoted a significantly thicker epidermis in the presenceof nicotine, which correlated with the production ofnon-neuronal acetylcholine in the skin, as suggestedby an increased expression of acetylcholine receptors.In the epidermis from patients with ‘hidradenitissuppurativa’, the highest expression of acetylcholinereceptors was found around the follicular infundibu-lum,while in the sinus epithelia, it was only weak, thusproviding a possible linkwith nicotine.While it cannotexplain all pathogenic aspects of ‘hidradenitis suppu-rativa’, it is an example of a study extending beyonda mere descriptive approach, which yields valuableinsight into the diseasemechanismby highlighting therole of the non-neuronal cholinergic system inpromoting infundibular epithelial hyperplasia andthus follicular plugging.Do we indeed have to conclude that we have not

advanced our knowledge on ‘hidradenitis suppura-tiva’ beyond the study of Shelley and Cahn2 from1955? The majority of the contributors to theControversies in Experimental Dermatology3 view thedisease not as a disease of the apocrine sweat gland.In that sense,wehave advanced our knowledge butwehave not advanced it enough and to the extent that itbecomes clinically applicable in the sense of a thera-peutic breakthrough. Nevertheless, a continuouseffort for the correct understanding of the pathogenicevents leading to this devastating disease will have animpact on therapeutic decision making. It is thepersonal opinion of the authors of this journal reviewthat the still established belief (in our view incorrect)that ‘hidradenitis suppurativa’ is a disease of theapocrine glands misguided the clinicians (which we asdermatopathologists serve to guide in the diagnosticapproach). Hopefully, further research with possiblegene expression profiling, as suggested by Zouboulis,

will shed more light into the pathogenesis of thisenigmatic disease.

Klaus Sellheyer1

Dieter Krahl21Department of Dermatology, University of Alabama

at Birmingham, Birmingham, AL, USAE-mail: ksellheyer@uab.edu and

2Institut fur Dermatohistologie, Heidelberg, Germany

References

1. Sellheyer K, Krahl D. ‘Hidradenitis suppurativa’ is acne

inversa! An appeal to (finally) abandon a misnomer. Int J

Dermatol 2005; 44: 535.

2. Shelley WB, Cahn MM. The pathogenesis of hidradenitis

suppurativa in man. Arch Dermatol 1955; 72: 562.

3. Kurzen H, Kurokawa I, Jemec GB, et al. What causes

hidradenitis suppurativa? Exp Dermatol 2008; 17: 455;

discussion 457.

4. Hunger RE, Surovy AM, Hassan AS, Braathen LR,

Yawalkar N. Toll-like receptor 2 is highly expressed in lesions

of acne inversa and colocalizes with C-type lectin receptor. Br

J Dermatol 2008; 158: 691.

5. Giamarellos-Bourboulis EJ, Antonopoulou A, Petropoulou C,

et al. Altered innate and adaptive immune responses in

patients with hidradenitis suppurativa. Br J Dermatol 2007;

156: 51.

6. Hana A, Booken D, Henrich C, et al. Functional significance of

non-neuronal acetylcholine in skin epithelia. Life Sci 2007; 80:

2214.

7. Meixner D, Schneider S, Krause M, Sterry W. Acne inversa.

J Dtsch Dermatol Ges 2008; 6: 189.

8. Jemec GB, Heidenheim M, Nielsen NH. The prevalence of

hidradenitis suppurativa and its potential precursor lesions.

J Am Acad Dermatol 1996; 35: 191.

9. Plewig G. Acne inversa, Acne keloidalis nuchae, abszedierende

Follikulitis der Kopfhaut: ein verbindendes Konzept. In Plewig

G, Prinz J, eds. Fortschritte der praktischen Dermatologie und

Venerologie 2002. Berlin: Springer; 192.

10. Gao M, Wang PG, Cui Y, et al. Inversa acne (hidradenitis

suppurativa): a case report and identification of the locus at

chromosome 1p21.1-1q25.3. J Invest Dermatol 2006; 126:

1302.

11. Fitzsimmons JS, Guilbert PR, Fitzsimmons EM. Evidence of

genetic factors in hidradenitis suppurativa. Br J Dermatol 1985;

113: 1.

12. Von Der Werth JM, Williams HC, Raeburn JA. The clinical

genetics of hidradenitis suppurativa revisited. Br J Dermatol

2000; 142: 947.

13. Kim J, Ochoa MT, Krutzik SR, et al. Activation of toll-like

receptor 2 in acne triggers inflammatory cytokine responses.

J Immunol 2002; 169: 1535.

14. Guy R, Green MR, Kealey T. Modeling acne in vitro. J Invest

Dermatol 1996; 106: 176.

We apologize for this error.

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