Chapter 9 Nosology and Classification 9 Jean Revuz, Gregor B.E. Jemec and James Leyden

Key points classifying biological phenomena, we structure our understanding of the underlying biological Q Classification should be based complexity, and thereby make it possible for us on explicit criteria, e.g., etiology, not only to ask meaningful positivist scientific or even therapy questions, but also offer help to our patients. Two threats exist in all classification systems, Q The current understanding of HS splitting and lumping, and both are equally se- identifies it as a unique , rious. Splitting occurs when the same disease clearly different from acne or folliculitis entity is split into numerous diagnoses depend- for example ing on, for example, location, a good example being pityriasis amientacea and scalp psoriasis. Q A better future understanding of the This overwhelms the reader with diagnoses that etiology and pathogenesis may resolve are not essentially different, but that have been HS’s current nosological impasse classified as different because of an essentially random aspect of the disease, e.g., location or clinical appearance. This does not allow a mean- ingful use of existing knowledge by direct trans- fer, and therefore erodes the understanding of #ONTENTS the underlying pathogenic process as well as ac- cumulation of clinically relevant knowledge. 9.1 Introduction ...... 65 The other extreme is lumping, where all dis- 9.2 Morphology ...... 66 eases are lumped together pell-mell in large cat- 9.2.1 ...... 66 egories, where little consideration is given to 9.2.2 Clinical Features ...... 66 significant etiological, pathogenic, and clinical 9.3 Etiology; Pathogenesis ...... 67 differences between disease entities. It may be 9.3.1 ...... 67 speculated that several of the more common 9.3.2 Inflammation ...... 68 9.3.3 Hormones ...... 68 dermatological fall into this trap, as 9.3.4 Treatments ...... 68 clinical experience suggests significant inter-in- dividual differences in regard to treatment re- 9.4 Conclusion ...... 69 sponse or prognosis. Nosology should be based on defined param- eters, e.g., anatomy (gross and microscopic), eti- 9.1 Introduction ology, pathogenesis or therapy. It should provide clinically meaningful distinctions between dis- Dermatologists are clever classifiers. We master ease entities in order not only to promote the a repertoire of approximately 2000 different di- understanding of the disease and accumulation agnoses, which can be classified and structured. of knowledge, but also to help practical manage- Classification of diseases is very important. By ment. 66 Jean Revuz, Gregor B.E. Jemec and James Leyden

9.2 Morphology tention and subsequent infection and inflam- mation in the apocrine sweat gland. Follicular 9.2.1 Anatomy abnormalities may be a key factor of HS: they are apparent in histological as well as ultrasono- Hidradenitis suppurativa (HS) was originally graphic studies of hair follicles in HS patients classified according to location, and this re- (see Chaps. 4, 5). There is also clinical evidence mains a hallmark of the disease. Shortly after suggesting a relationship between HS and an the diagnosis was established, an erroneous as- anatomical anomaly of the pilosebaceous duct sociation with apocrine glands was made and in the high prevalence of pilonidal cysts in HS the name created. A classification according to patients. In one series (Faye O, Bastuji-garin S, topography alone obviously does not improve Poli F, Revuz J. Hidradenitis suppurativa: a clin- the understanding of pathogenesis and hence is ical study of 164 patients; manuscript in prepa- of little help. The erroneous classification ac- ration) 30% of 164 patients are reported to have cording to an incorrect deduction based only on co-existing pilonidal sinus ducts. simple co-localization obviously delayed the de- HS is clearly a follicular disease located to re- velopment of knowledge This mistake comes stricted areas of the body. The pathogenic pro- from a paradox: the lesions of HS are predomi- cess in the hair follicle may be elucidated from nantly or exclusively situated in the regions of histology, and appears to be rupture of the deep- apocrine sweat glands, yet the histological pic- er parts of the follicle, with spillage of the fol- ture is one of follicular obstruction like that licular contents into the dermis and subsequent seen in acne lesions, and sweat gland involve- inflammation (see Chap. 4). The exact cause of 9 ment is usually absent from early lesions. The the rupture is however not established. So even apocrine sweat gland’s excretory canal opens if HS can be classified as a folliculitis, just as into the follicular duct immediately above the acne vulgaris, this classification does not aid sebaceous duct (see Fig. 9.1). This distinctive our understanding significantly, and additional anatomical characteristic may explain the re- aspects of the diseases must therefore be consid- percussions of follicular obstruction, with re- ered.

9.2.2 Clinical Features

The clinical characteristics of HS, i.e., deep- seated lesions and topography, are very specific and the hallmark of the disease; however, they are not explained by the histological pictures which form the main evidence for establishing a connection with acne and the so-called follicu- lar obstruction diseases. Exceptional case re- ports of an association of HS with dissecting folliculitis of the scalp, acne conglobata, large epithelial cysts and pilonidal cysts have focused attention on a possible common mechanism shared by these diseases and their grouping to- gether under the term “follicular obstruction diseases.” Some case reports of an association with Dowling–Degos pigmentation of the flex- ure also point to a follicular obstruction. In spite of these anecdotal reports, the prevalence of acne in HS patients is identical to the prevalence Fig. 9.1. The anatomy of the hair follicle in controls. The rarity of these reports and the Nosology and Classification Chapter 9 67

Table 9.1. Similarities and differences between acne vulgaris, acne conglobata, hidradenitis suppurativa (HS), and fol- liculitis. Etiology reflects known mechanisms such as inflection in simple folliculitis, morphology describes similari- ties in clinical morphology, pathogenesis describes similarities in known pathogenesis, e.g., seborrhea, and treatment describes response to similar treatments, e.g., response to isotretinoin Similarities between follicular diseases

Acne conglobata Acne vulgaris Acne conglobata HS Etiology – ? Morphology – no Pathogenesis – ? Treatment – yes HS Etiology – no Morphology – no Etiology – ? Pathogenesis – no Morphology – ? Treatment – ? Pathogenesis – ? Treatment – ? Folliculitis Etiology – no Etiology – no Etiology – no Morphology – no Morphology – yes Morphology – yes Pathogenesis – no Pathogenesis – no Pathogenesis – no Treatment – yes Treatment – yes Treatment – yes

potential for positive reporting bias therefore made in Table 9.1. As can be seen from this, all raise questions about the validity of this as- these diseases have similarities and differences, sumption. which can reasonably be said to influence their As for individual lesions the differences be- classification. tween acne and HS are significant: the deep- seated nodules and the absence of closed come- dones – hallmark of acne – are characteristics of 9.3 Etiology; Pathogenesis HS. Open comedones – black heads – are regu- larly observed in old lesions of HS, frequently as The etiology of HS is not known. double or multiple comedones, but these are secondary lesions, i.e., tombstone comedos. Scarring is also more prominent in HS than in 9.3.1 Infection acne. In particular, the hypertrophic cicatrizing process, which leads to the formation of highly There are no convincing data to suggest that HS specific rope-like scars, is another characteristic is primarily an infectious disease (see Chap. 11). of HS, very rarely seen in acne. Finally the time- The polymicrobial infection (or colonization) span of the diseases differ. The long-lasting evo- of HS – Staphylococcus aureus,Gram-negative lution of HS over decades is in sharp contrast rods, anaerobic – is quite different from with the usually self-healing nature of acne. The the usual colonization of acne by Propionibacte- reclassification of the disease as acne inversa rium acnes and coagulase-negative staphylococ- does not adequately reflect the unique features ci. The role of bacteria in HS may therefore be of HS and carries a serious risk of drawing either secondary to some as yet unknown mech- incorrect analogies to acne. anism, or purely secondary once anatomical Looking at four key factors of clinical rele- disruptions are established. HS is not a primary vance which may be used for classification of infectious disease; yet the initial inflammatory diseases (etiology, morphology, pathogenesis, changes can be produced by a bacterial coloni- and treatment) a comparison between acne zation of the follicular area similar to the trig- vulgaris, acne conglobata, HS and folliculitis is gering event of acne. The amount of inflamma- 68 Jean Revuz, Gregor B.E. Jemec and James Leyden

tion and related pain is however quite different of HS, the efficacy of anti-inflammatory drugs, from what is observed in acne, even in the nod- of anti-tumor necrosis factor (TNF) drugs, and ular variety. This may be due to the localization the significant association with Crohn’s disease of the lesions but may also point to either a spe- all point to an abnormality of immune and/or cific non-infectious inflammatory phenome- inflammatory mechanisms in HS. The number non, or a sequential series of events in which of “candidates“ is large, including abnormalities bacterial involvement occurs at specific points. of innate immunity, e.g., NOD, TLR, and defi- Early involvement of pathogenic bacteria may ciencies of natural antibacterial substances such be responsible for establishing inflammation, as defensins and cathelicidins (see Chaps. 6, 12). which leads to destructive scarring and exten- The potential usefulness of anti-inflammatory sion of the disease independently of bacteria. and immunosuppressive therapy in HS may Eventual secondary bacterial superinfections therefore have a broader scope than is reflected would then maintain the inflammatory process in existing literature. without the need for permanent colonization with pathogenic bacteria. The dramatic im- provement observed in some patients with se- 9.3.3 Hormones vere HS following a 3-month course of clinda- mycin–rifampicin treatment suggests a role for The absence of any significant hormonal abnor- infection in advanced disease (see Chap. 15). mality (see Chap. 12) and above all the normal However, it does not rule out the possibility that sebum excretion rate in HS areas as well as in this polymicrobial infection is only a secondary seborrhea-prone areas clearly put HS apart from 9 phenomenon, or that these antibiotics exert a the acne spectrum. predominantly anti-inflammatory effect. A spe- cific anti-inflammatory role of some antibiotics – including tetracyclines, clindamycin and ri- 9.3.4 Treatments fampicin – has been demonstrated in in vitro experiments. Whether this action is relevant in Classification can also be made along purely vivo and independent from any anti-infectious practical lines, i.e., from the therapy. To classify activity remains to be established. diseases according to their response to stan- dardized therapies may appear non-academic but is useful in practice and allows more spe- 9.3.2 Inflammation cific speculations to be made about the etiology and pathogenesis when the therapeutic princi- The exact cause of the rupture of the follicle is ple of the drug is known. In HS, clindamycin– not established, although a lymphocytic inflam- rifampicin, anti-TNF biologics, sometimes cor- matory infiltrate appears to be present in early ticosteroids and even immunosuppressive drugs lesions (see Chap. 4). There is some evidence may be helpful, while they are not useful in acne. of infundibular epithelial hyperproliferation as In contrast, the retinoids, which are the most ef- well. In older lesions, sinus tract formation pre- fective drugs in the treatment of acne, appear dominates the histopathology. It is speculated generally ineffective in HS (see Chap. 17). Thus that the introduction of follicular material into the terminology acne inversa may lead to an er- the dermis as well as secondary colonization of roneous management. The lack of efficiency of sinus tracts cause flares of HS. These mecha- retinoids is in good agreement with the absence nisms suggest that HS can be classified as a fol- of local seborrhea and supports the classifica- liculitis of unknown origin affecting the deeper tion of HS as a follicular disease different from end of the hair follicle and not involving the se- the acnes. baceous glands. The polymicrobial colonization Nosology and Classification Chapter 9 69

9.4 Conclusion

W HS is multifactorial. Follicular occlusion and disruption are predisposing factors, but other factors, including bacterial colonization and an as yet unknown pro-inflammatory mecha- nism, are at work. HS can be described as in- verse recurrent suppuration according to to- pography, clinical evolution, and morphology. Looking at the parameters of etiology, mor- phology, pathogenesis, and therapy, HS can be differentiated from the acnes and from simple folliculitis.