Should HS/acne inversa best be renamed as “dissecting terminal hair folliculitis”?
Hidradenitis suppurativa/acne inversa is a diverse, enigmatic and distressful disease that has aroused growing interest in specialists from different disciplines. Both names describe its classical manifestations in the intertriginous regions and reflect the historical view of the disease definition, but cause confusions in the understanding of its pathogenesis and classification. In the light of the advance in clinical, histopathological and pathophysiological findings, we propose the term “dissecting terminal hair folliculitis” (DTHF) to characterize its disease nature as folliculitis instead of acneiform disease or apocrine gland disorder. DTHF attacks exclusively the terminal hair follicles in an overwhelming majority of adults, initiating from the fragile acroinfundibulum leading to a non‐infectious overreaction of innate immunity system with inflammation that may fiercely dissect and engulf all the surrounding tissues accompanied by secondary bacterial infections. Evidence indicates that perifolliculitis capitis abscedens et suffodiens and pilonidal disease are very likely regional variants of DTHF with the same pathogenesis. Treatment of DTHF remains frustrating. The benefit of biologics in targeting inflammation is so far non‐specific, palliative and inconsistent. Hair epilation and photodynamic therapy in treatment of the disease is questionable in consideration of the pathogenesis. Genetic and dtranslational research, especially on the Notch signalling pathways, will yield breakthrough in the development of novel treatment modalities.
1 Introduction: Times of Confusion
First described in 1839 by Velpeau in a patient with abscesses in the axillary, mammary and perianal regions (s1), association between HS/AI and sweat glands was noted by Verneuil in 1854 (s2). The term hidradenitis destruens suppurativa was first proposed by Pollitzer in 1894 (s3). Kierland reported the concurrence of acne conglobata (AC), HS and perifolliculitis capitis abscedens et suffodiens in 1951 (s4), which was later coined as follicular occlusion triad by Pillsbury, Shelley and Kligman (s5). In 1989, Plewig and Steger suggested to use AI to cover the whole spectrum of acne tetrad, namely AC, HS/AI, perifolliculitis capitis abscedens et suffodiens and pilonidal disease (s6). In 2006, an international group of experts presented the first monograph on HS/AI (s7). In 2010, gene mutations encoding essential components of the γ‐secretase multiprotein complex were identified in Chinese patients with the autosomal dominant familial form of HS/AI.1 In spite of the advance in the understanding of its pathogenesis and publication of many national or international guidelines for disease classification and management (s8,s9), the aetiology of this group of diseases remains incompletely understood, and no standard treatment has been established. Through a critical re‐evaluation of the taxonomical changes and a better stratification of the clinical manifestations, this work is aimed to clarify the confusion in disease categorization, explain the difference in therapeutic response and shed light on new research pathways.
2 Anatomy, Physiology and Pathology
Three kinds of human hair follicles are recognized: sebaceous, vellus and terminal, which differ significantly in their fine structure and distribution.2 Acne occurs in sebaceous follicles and never in terminal hair follicles. Sebaceous follicles are widely distributed over the entire skin except on the palms and soles. The apocrine sweat glands are mainly found in axillae, pubis, labia majora, scrotum, perineum, perianal regions and areola of the breast, but lacking in other intertriginous regions like submammary, antecubital or popliteal. Unlike eccrine sweat glands, apocrine sweat glands are innervated by the adrenergic nerve fibres, and their long excretory ducts open into the acroinfundibulum of the terminal hair follicles (Fig. S1A).
The earliest pathologic change of HS/AI was observed in the junction between apocrine sweat duct and terminal hair infundibulum, with two major findings (Fig. S1B): (i) microcomedones in the ampulla of the apocrine sweat duct draining into the hair acroinfundibulum;2 (ii) mild hyperplasia and segmental spongiosis of the epithelium in the acroinfundibulum (Fig. S1C,D), which is speculated to be caused by the epithelial instability associated with impaired Notch‐MKP‐1 signalling.3 It is unclear whether they happen concurrently or which event comes first. The subsequent breakage of the infrainfundibulum with rupture of the follicular epithelium initiates the inflammatory cascade (Fig. S2A), sometimes with violent and stormy progression to cause a tsunami‐like damage, whereby the apocrine and eccrine sweat glands are passively engulfed by the flooding inflammation rampaging everywhere (Fig. S2C–E). At this stage, the sebaceous follicles and sebaceous glands of terminal hair follicles are affected as innocent bystanders. This observation has been shared and supported by many subsequent studies, showing that the terminal hair infundibulum is the primary site of defect.4-6 Mechanical stress can act as a possible trigger in the disease development (s10,s11).
It is unclear whether the reduced number and volume of sebaceous glands in uninvolved hair follicles from patients with HS/AI is in a causal link or is the result of a common pathogenic process (s12). This is observed in the lesions of HS/AI, but does not apply to the uninvolved terminal hair follicles in the unaffected regions of these patients. All terminal hair follicles have more or less attached sebaceous lobules, smaller or bigger in size, which can modulate during the hair cycle.2 In both human and animals, it is known that with irritation, including inflammation, the sebaceous glands regress in size or virtually disappear temporarily.
3 Hidradenitis Suppurativa (HS), Acne Inversa (AI) and Dissecting Terminal Hair Folliculitis (DTHF): Three Names for the Same Disease
Based on the above discussion, one of the authors (GP) first proposed the term dissecting terminal folliculitis in 2009 (s13), now more precisely termed as dissecting terminal hair folliculitis (DTHF), to replace HS and AI. These three synonyms can be redefined as follows:
We suggest to abandon the term HS, which is incorrect in terms of pathogenesis and misleading for the patients. Infectious or non‐infectious aetiology should be specifically designated in the inflammation of eccrine or apocrine sweat glands associated with suppurative changes. Due to the expression of innate defense antimicrobial peptides in both eccrine and apocrine sweat glands (s14, s15), infectious eccrine hidradenitis is a rare presentation (s16), while infectious apocrine hidradenitis has not yet been confirmed. The single case reports about a complete remission of the disease caused by rare pathogens suggest the possible existence of an infectious apocrine hidradenitis which can mimic DTHF clinically (s17).
The nomenclature of AI and acne tetrad was based on their common pathogenesis of abnormal keratinization in the follicular infundibulum. However, acne is a disease sui generis with a wide spectrum of clinical manifestations occurring exclusively in sebaceous follicles. DTHF is also a unique disease of its own originating from terminal hair follicles, with the attached sebaceous glands being secondarily involved. Although rare, AC can be observed in the intertriginous regions and should be distinguished from DTHF. Vice versa, DTHF can occur on the sebaceous gland‐rich, acne‐prone regions like beard and chest and can be confused with AC.
As a distinct entity beginning from the acroinfundibulum of terminal hair follicles, dissecting process in DTHF can be understood in two aspects: (i) clinically the involved regions are cut through with undermining and communicating draining sinuses and fistulae, leading to extensive interwoven scars; (ii) histologically the fragile hyperproliferative follicular acroinfundibulum becomes dissected and the subsequent fierce inflammation makes its way through various directions of the dermis destroying all anatomic structures (Fig. S2A,B).2 Apocrine sweat glands or sebaceous glands are secondarily attacked. DTHF can be further labelled as axillary, submammary, inguinal, gluteal or facial DTHF, according to the site of involvement.
4 Clinical Impact of the Redefinitions
Synchrony and metachrony between AC and DTHF: Acne and its massive expression AC usually begin from teenage and most of the patients never develop DTHF later in life. On the other hand, DTHF is a disease of adults and very rare in children, runs relentlessly, often ad infinitum, with most of the patients never experiencing severe acne or AC in early life (Table ST1). AC and DTHF do not develop in parallel (no synchrony), but it may start in certain patients initially with AC accompanying puberty, and being attacked by DTHF later (metachrony). The statistics about natural intersection or concurrence of both diseases is unknown. In our own experience, it is uncommon. Differentiation between DTHF and AC in the regions abundant with both terminal hair and sebaceous follicles can be challenging, such as chest, back and beard. A careful histological examination in the early stage can help.
As compared to AC, the non‐hereditary, non‐syndromic DTHF affects mainly Caucasian women (female to male ration 3‐4 to 1) with a close association with smoking and obesity (s18–s20). The seemingly low prevalence of DTHF in China,7 Japan (s21), Korea and Taiwan might be explained by a generally lower prevalence of hirsutism, obesity, smoking and the use of contraceptives in women from these regions. Moreover, more men are affected than women in these regions, based on the case series reported to date (s22).7
DTHF can occur in prepubertal age, estimated to account for 1% or lower of all affected patients (s23, s24). Most of the reported cases have certain endocrine or hormonal abnormalities, while girls already show visible terminal hair growth in the pubic or axillary areas (s25). Successful treatment with oral finasteride lends support to our observation (s26).
DTHF and AC mostly occur in an isolated non‐hereditary, non‐syndromic pattern. The pyogenic arthritis–pyoderma gangrenosum–acne (PAPA) syndrome is an autosomal dominant disease entity with well‐defined genetic mutations and usually showing severe nodular/conglobate acne . Observations demonstrate significant overlapping between acne fulminans and the synovitis–acne–pustulosis–hyperostosis–osteitis (SAPHO) syndrome. In less clear syndromes like the pyoderma gangrenosum–acne–suppurative hidradenitis (PASH) syndrome and pyogenic arthritis–pyoderma gangrenosum–acne–suppurative hidradenitis (PAPASH) syndrome, acne manifests to a variable degree and severe acne occurs much more uncommonly (s27–s29). Cases showing nodulocystic lesions in the beard and chest should be differentiated from DTHF in histology. As acne is a very common disease, it raises the question whether acne is an essential component of these syndromes.
DTHF and AC respond very differently to treatment. Oral isotretinoin has been demonstrated to be an effective treatment for AC but not for DTHF (s30, s31). The efficacy of TNF‐α inhibitors or interleukin (IL)‐1β blockers on DTHF, especially the non‐syndromic type, has so far been inconsistently demonstrated (s32–s35).8 Given the rarity of controlled studies, biologics seem to benefit more the arthritis and pyoderma gangrenosum in diverse associated rare syndromes, their effect on acne is muss less convincing and long‐term efficacy remains to be confirmed (s36, s37).
Laser hair epilation has been proposed to be a promising treatment for DTHF, so far with scanty evidence (s38). In theory, therapy should aim to normalize or stabilize the follicular infundibulum but not to inhibit hair growth. Further understanding on the possible working mechanisms of laser treatment is required.
Perifolliculitis capitis abscedens et suffodiens (Hoffmann disease) and pilonidal disease both share many clinical, histological and immunohistological characteristics with DTHF (s39).9 Many similarities also exist in their treatment options and disease course. They are definitely the disease of terminal hair follicles in the category of “folliculitis” and no longer belong to acne based on the redefinition.
5 Conclusion
Terminal hair follicles and sebaceous follicles are two different hair follicles of distinctive natures. In pathophysiology, DTHF is neither hidradenitis nor acne; instead, it is folliculitis of terminal hair follicles. Inconsistency in the description of DTHF reflects multifacetedness of the disease. The terms Velpeau or Verneuil disease, HS, AI and many others will remain of historical interest but can be replaced with DTHF in the future in favour of medical advances. Instability of acroinfundibular epithelium is very likely the aetiology, whereby mechanical stress can trigger the disease initiation. A pivotal role of Notch signalling and innate immunity has been demonstrated in pathogenesis, while antimicrobial or anti‐inflammatory treatment cannot cure the disease. The use of acne triad or acne tetrad is misleading while follicular occlusion triad is less accurate and differentiating because occlusion is not the primary event observed. The proposal of DTHF will pave and lead the way for a better understanding of pathogenesis and future design of novel treatment modalities.
Acknowledgements
Figures S1A,B and S2B–D have been published in Plewig G, Kligman AM. Acne and Rosacea. Springer, Heidelberg 2000. Copyright of all illustrations Gerd Plewig, Munich.
Both authors have fulfilled the requested criteria for ethical guidelines. Both authors performed the research, analysed the data, drafted and wrote the paper and revised it critically and approved the submitted and final versions.