Q The current understanding of HS identifies it as a unique disease,

Nosology and Classification

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

Key points

Q Classification should be based on explicit criteria, e.g., etiology, pathogenesis or even therapy

Q The current understanding of HS identifies it as a unique disease,

clearly different from acne or folliculitis for example

Q A better future understanding of the etiology and pathogenesis may resolve HS’s current nosological impasse

#ONTENTS

9.1 Introduction . . . 65

9.2 Morphology . . . .66

9.2.1 Anatomy . . . .66

9.2.2 Clinical Features . . . .66

9.3 Etiology; Pathogenesis . . . 67

9.3.1 Infection . . . 67

9.3.2 Inflammation . . . .68

9.3.3 Hormones . . . .68

9.3.4 Treatments . . . .68

9.4 Conclusion . . . 69

9.1 Introduction

Dermatologists are clever classifiers. We master a repertoire of approximately 2000 different di- agnoses, which can be classified and structured.

Classification of diseases is very important. By

classifying biological phenomena, we structure our understanding of the underlying biological complexity, and thereby make it possible for us not only to ask meaningful positivist scientific questions, but also offer help to our patients.

Two threats exist in all classification systems, splitting and lumping, and both are equally se- rious. Splitting occurs when the same disease entity is split into numerous diagnoses depend- ing on, for example, location, a good example being pityriasis amientacea and scalp psoriasis.

This overwhelms the reader with diagnoses that are not essentially different, but that have been 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 the underlying pathogenic process as well as ac- cumulation of clinically relevant knowledge.

The other extreme is lumping, where all dis- eases are lumped together pell-mell in large cat- egories, where little consideration is given to significant etiological, pathogenic, and clinical differences between disease entities. It may be speculated that several of the more common dermatological diseases fall into this trap, as clinical experience suggests significant inter-in- dividual differences in regard to treatment re- sponse or prognosis.

Nosology should be based on defined param-

eters, e.g., anatomy (gross and microscopic), eti-

ology, pathogenesis or therapy. It should provide

clinically meaningful distinctions between dis-

ease entities in order not only to promote the

understanding of the disease and accumulation

of knowledge, but also to help practical manage-

ment.

9

9.2 Morphology 9.2.1 Anatomy

Hidradenitis suppurativa (HS) was originally classified according to location, and this re- mains a hallmark of the disease. Shortly after the diagnosis was established, an erroneous as- sociation with apocrine glands was made and the name created. A classification according to topography alone obviously does not improve the understanding of pathogenesis and hence is of little help. The erroneous classification ac- cording to an incorrect deduction based only on simple co-localization obviously delayed the de- velopment of knowledge This mistake comes from a paradox: the lesions of HS are predomi- nantly or exclusively situated in the regions of apocrine sweat glands, yet the histological pic- ture is one of follicular obstruction like that seen in acne lesions, and sweat gland involve- ment is usually absent from early lesions. The apocrine sweat gland’s excretory canal opens into the follicular duct immediately above the sebaceous duct (see Fig. 9.1). This distinctive anatomical characteristic may explain the re- percussions of follicular obstruction, with re-

tention and subsequent infection and inflam- mation in the apocrine sweat gland. Follicular abnormalities may be a key factor of HS: they are apparent in histological as well as ultrasono- graphic studies of hair follicles in HS patients (see Chaps. 4, 5). There is also clinical evidence suggesting a relationship between HS and an anatomical anomaly of the pilosebaceous duct in the high prevalence of pilonidal cysts in HS patients. In one series (Faye O, Bastuji-garin S, Poli F, Revuz J. Hidradenitis suppurativa: a clin- ical study of 164 patients; manuscript in prepa- ration) 30% of 164 patients are reported to have co-existing pilonidal sinus ducts.

HS is clearly a follicular disease located to re- stricted areas of the body. The pathogenic pro- cess in the hair follicle may be elucidated from histology, and appears to be rupture of the deep- er parts of the follicle, with spillage of the fol- licular contents into the dermis and subsequent inflammation (see Chap. 4). The exact cause of the rupture is however not established. So even if HS can be classified as a folliculitis, just as acne vulgaris, this classification does not aid our understanding significantly, and additional aspects of the diseases must therefore be consid- 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 in controls. The rarity of these reports and the

Fig. 9.1. The anatomy of the hair follicle

potential for positive reporting bias therefore raise questions about the validity of this as- sumption.

As for individual lesions the differences be- tween acne and HS are significant: the deep- seated nodules and the absence of closed come- dones – hallmark of acne – are characteristics of HS. Open comedones – black heads – are regu- larly observed in old lesions of HS, frequently as double or multiple comedones, but these are secondary lesions, i.e., tombstone comedos.

Scarring is also more prominent in HS than in acne. In particular, the hypertrophic cicatrizing process, which leads to the formation of highly specific rope-like scars, is another characteristic of HS, very rarely seen in acne. Finally the time- span of the diseases differ. The long-lasting evo- lution of HS over decades is in sharp contrast with the usually self-healing nature of acne. The reclassification of the disease as acne inversa does not adequately reflect the unique features of HS and carries a serious risk of drawing incorrect analogies to acne.

Looking at four key factors of clinical rele- vance which may be used for classification of diseases (etiology, morphology, pathogenesis, and treatment) a comparison between acne vulgaris, acne conglobata, HS and folliculitis is

made in Table 9.1. As can be seen from this, all these diseases have similarities and differences, which can reasonably be said to influence their classification.

9.3 Etiology; Pathogenesis The etiology of HS is not known.

9.3.1 Infection

There are no convincing data to suggest that HS is primarily an infectious disease (see Chap. 11).

The polymicrobial infection (or colonization) of HS – Staphylococcus aureus, Gram-negative rods, anaerobic bacteria – is quite different from the usual colonization of acne by Propionibacte- rium acnes and coagulase-negative staphylococ- ci. The role of bacteria in HS may therefore be either secondary to some as yet unknown mech- anism, or purely secondary once anatomical disruptions are established. HS is not a primary infectious disease; yet the initial inflammatory changes can be produced by a bacterial coloni- zation of the follicular area similar to the trig- gering event of acne. The amount of inflamma-

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

9

tion and related pain is however quite different from what is observed in acne, even in the nod- ular variety. This may be due to the localization of the lesions but may also point to either a spe- cific non-infectious inflammatory phenome- non, or a sequential series of events in which bacterial involvement occurs at specific points.

Early involvement of pathogenic bacteria may be responsible for establishing inflammation, which leads to destructive scarring and exten- sion of the disease independently of bacteria.

Eventual secondary bacterial superinfections would then maintain the inflammatory process without the need for permanent colonization with pathogenic bacteria. The dramatic im- provement observed in some patients with se- vere HS following a 3-month course of clinda- mycin–rifampicin treatment suggests a role for infection in advanced disease (see Chap. 15).

However, it does not rule out the possibility that this polymicrobial infection is only a secondary phenomenon, or that these antibiotics exert a predominantly anti-inflammatory effect. A spe- cific anti-inflammatory role of some antibiotics – including tetracyclines, clindamycin and ri- fampicin – has been demonstrated in in vitro experiments. Whether this action is relevant in vivo and independent from any anti-infectious activity remains to be established.

9.3.2 Inflammation

The exact cause of the rupture of the follicle is not established, although a lymphocytic inflam- matory infiltrate appears to be present in early lesions (see Chap. 4). There is some evidence of infundibular epithelial hyperproliferation as well. In older lesions, sinus tract formation pre- dominates the histopathology. It is speculated that the introduction of follicular material into the dermis as well as secondary colonization of sinus tracts cause flares of HS. These mecha- nisms suggest that HS can be classified as a fol- liculitis of unknown origin affecting the deeper end of the hair follicle and not involving the se- baceous glands. The polymicrobial colonization

of HS, the efficacy of anti-inflammatory drugs, of anti-tumor necrosis factor (TNF) drugs, and the significant association with Crohn’s disease all point to an abnormality of immune and/or inflammatory mechanisms in HS. The number of “candidates“ is large, including abnormalities of innate immunity, e.g., NOD, TLR, and defi- ciencies of natural antibacterial substances such as defensins and cathelicidins (see Chaps. 6, 12).

The potential usefulness of anti-inflammatory and immunosuppressive therapy in HS may therefore have a broader scope than is reflected in existing literature.

9.3.3 Hormones

The absence of any significant hormonal abnor- mality (see Chap. 12) and above all the normal sebum excretion rate in HS areas as well as in seborrhea-prone areas clearly put HS apart from the acne spectrum.

9.3.4 Treatments

Classification can also be made along purely practical lines, i.e., from the therapy. To classify diseases according to their response to stan- dardized therapies may appear non-academic but is useful in practice and allows more spe- cific speculations to be made about the etiology and pathogenesis when the therapeutic princi- ple of the drug is known. In HS, clindamycin–

rifampicin, anti-TNF biologics, sometimes cor- ticosteroids and even immunosuppressive drugs may be helpful, while they are not useful in acne.

In contrast, the retinoids, which are the most ef-

fective drugs in the treatment of acne, appear

generally ineffective in HS (see Chap. 17). Thus

the terminology acne inversa may lead to an er-

roneous management. The lack of efficiency of

retinoids is in good agreement with the absence

of local seborrhea and supports the classifica-

tion of HS as a follicular disease different from

the acnes.

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.