© Borgis - Postępy Nauk Medycznych 10/2012, s. 811-816
Hidradenitis suppurativa/Acne inversa – etiopatogeneza, obraz kliniczny i możliwości terapeutyczne
Hidradenitis suppurativa/Acne inversa – etiopathogenesis, clinical presentation and therapeutic options
Chair and Department of Dermatology, Venerology and Pediatric Dermatology, Medical University of Lublin
Head of Department: prof. Grażyna Chodorowska, MD, PhD
Hidradenitis suppurativa/Acne inversa (HS) jest przewlekłą nawrotową zapalną chorobą skóry zajmującą głównie okolice wyprzeniowe. Zasadniczymi klinicznymi objawami choroby są skórne guzki, ropnie, prowadzące do rozlanego głębokiego stanu zapalnego, powstawanie zatok/kanałów i przetok uwalniających cuchnącą ropną wydzielinę. Etologia HS jest wieloczynnikowa i niejasna, a palenie papierosów i otyłość są uznanymi czynnikami prowokującymi. Patogeneza nie została całkowicie wyjaśniona. Pierwotnym zjawiskiem jest okluzja mieszków włosowych z wtórnie rozwijającym się zapaleniem, infekcją i zniszczeniem jednostki włosowo-łojowej oraz rozprzestrzenieniem zapalenia na otaczające tkanki. Leczenie zależy od klinicznego stadium choroby. Znane są różne metody terapeutyczne, w tym antybiotyki, retinoidy, leki przeciwandrogenowe, ogólne kortykosteroidy, inhibitory TNF, leki immunosupresyjne/przeciwzapalne, wszystkie przynoszą tylko ograniczoną poprawę. Najskuteczniejszą metodą leczenia jest rozległe radykalne wycięcie chirurgiczne całej zmienionej okolicy. Z powodu przewlekłego, nawrotowego charakteru i szczególnej, kłopotliwej dla pacjenta lokalizacji, HS jest chorobą fizycznie, psychologicznie i społecznie upośledzającą, ze znacznym pogorszeniem jakości życia.
Hidradenitis suppurativa/acne inversa (HS) is a chronic recurrent inflammatory skin disease affecting mainly the intertriginous areas. Cutaneous nodules, abscesses, subsequent widespread deep inflammation, sinus tract and fistulas formation with foul-smelling purulent discharge are the main clinical features of the disease. Etiology of HS is believed multifactorial and not clear, but the cigarette smoking and obesity are the established triggering factors.
Pathogenesis is not well understood yet. The primary event is a follicular occlusion with secondary inflammation, infection and destruction of the pilosebaceous unit and extension of inflammation to the adjacent subcutis. Treatment depends upon the clinical stage of the disease. There are various therapeutic options known, including antibiotics, antiandrogens, retinoids, systemic corticosteroids, TNF inhibitors, inmmunosupresive/anti-inflammatory agents, all of them used with limited results. The most effective treatment is the radical wide excision of the affected area. Due to its chronicity, recurrent character and specific multifocal embarrassing location HS is physically, psychologically and socially disabling condition with considerable impairment of the quality of life.
Hidradenitis suppurativa/Acne inversa (HS) is a chronic recurrent, inflammatory skin disease affecting mainly the intertriginous areas. The disease involving the apocrine – gland – bearing skin areas may be mild and limited or severe, causing widespread deep infection and resulting in abscesses, sinus tract formation, fistulas releasing malodorous discharge and subsequently in excessive scarring (1-4). Due to its chronicity, recurrent character and specific multifocal location of the lesions, HS is a physically, psychologically and socially disabling condition associated with considerable impairment of the quality of life (5).
There are some controversies about the epidemiology of HS. Despite the common opinion of HS being a rare disease, the exact prevalence is uncertain and probably different in various populations and groups of age. Literature data report the prevalence rate raging between 0.03-0.06 and 4%, but most authors suggest 1% in general population (1, 2, 4, 6). The onset of the disease is usually observed between 11 and 30 years of life (1, 4). Postmenopausal onset is rare, its prevalence among the subjects older than 55 years of age is about 5 times lower than in younger patients (1, 2, 4). What is interesting, some locations have distinct sexual predisposition, thus the perianal HS seems to affect male more than female patients (1, 7). Although the disease occurs in all human races, a higher prevalence is observed in black people than in Caucasians (1, 2).
Genetic background is being taken into consideration, although genetic studies conduce to conflicting results (4, 8). Clinical data, indicate that, 30-40% of HS patients have a family history, but the HLA association seems to be not significant (4, 8). An autosomal dominant pattern has been suggested with locus for the disease on chromosome 1p21.1-1q25.3, but a specific gene was not identified (1, 4).
Understanding of the HS pathogenesis has changed considerably over time, but still remains unclear. Due to the specific anatomical distribution of the disease, HS was initially believed to be a disorder of the apocrine glands (1, 2, 4). It is well known, that the apocrine sweat glands, mainly distributed in the axillary and anogenital skin, are evolutional analogues of an odour-producing organ found in lower animals (2). Early data suggested that the apocrine gland involvement is the primarily event leading to the development of the widespread inflammation in the skin and subcutis (1). In 1955, Shelley and Cahn evidenced that the primary event was a keratinous plugging of the apocrine sweat duct leading to the follicular occlusion, which eventually resulted in inflammation of the apocrine glands and neighbouring periglandular tissue (1). Further data suggested that inflammation of apocrine glands is not basic to HS pathogenesis, being only the secondary phenomenon (1). Pillsbury et al confirmed follicular occlusion as cause of HS, and what is more, the authors included this disease, together with acne conglobata and perifolliculitis capitis abscendens et suffodiens/dissecting cellulitis of the scalp, to so called “acne triad” or “follicular triad” (6). From this time, the similarity between the pathogenic mechanisms of acne and HS is being discussed. Plewig and Kligman added pilonidal sinus to “acne triad” and coined the term “acne tetrad” (9). In 1989 Plewig and Steger introduced the term “acne inversa” for the hidradenitis suppurativa, emphasizing a follicular origin of the disease (10).
The results of histologic study published by Yu and Cook in 1990 considerably influenced the contemporary understanding of the HS pathogenesis (1). The researchers showed that follicular occlusion and the dilated follicles were the most constant and probably primary feature and concluded that HS was a disease of follicular epithelium rather than a disease of apocrine glands.
Hidradenitis suppurativa is currently considered as an inflammatory disease of terminal hair follicles manifesting in intertriginous skin sites (2, 8). The accepted belief is that the initiating event is occlusion of the follicular ducts by keratinous plugging, leading to ductal dilatation and stasis in the pilosebaceous unit (1, 2, 3, 11). Bacteria entering the apocrine gland through the hair follicle, are entrapped under the keratinous plug and multiply rapidly (2). Subsequent follicular rupture leads to extrusion of follicular contents, into the dermis inducing a chemotactic inflammatory response (1). The resulting influx of neutrophils, lymphocytes and histiocytes lead to inflammation of the surrounding tissue and abscess formation (1, 2). Bacterial infection results in further local inflammation, suppuration, tissue destruction and skin damage (1, 2). Numerous recurrences and presence of ruptured epithelium lead to development of sinus tracts and fistulas (1, 2).
Last years studies have brought new data concerning the extent of skin inflammation in HS. In 2011 van der Zee et al (12) investigated the cytokine profile in lesional and perilesional HS skin and have shown that TNF-α, IL-1β and IL-10 levels are elevated in HS skin. Moreover, it was also demonstrated that HS inflammation extend beyond the visibly affected inflammatory lesions, and that likely can be the cause of recurrences. These results are in agreement with those obtained earlier by Matusiak et al. (13), who evidenced the elevated TNF-α level in the peripheral blood of HS patients. Recently, alterations in leukocyte subsets in normal-appearing perilesional skin and in HS lesions have been found (14). Moreover, psoriasiform hyperplasia, follicular plugging and mild mixed infiltration consisted of T cells, plasma cells dendritic cells and mast cells, was observed in perilesional “normal” skin (14).
A variety of etiologic factors is suspected of a causal relationship in the pathogenesis of HS. First of all, the role of hormones, especially androgens in HS is still being investigated, but with conflicting results provided by many studies (1). Some researchers present opinion of the disorder being androgen dependent in adults, but others believe that hyperandrogenism probably does not play a role in HS (2). It is worth to stress, that the influence of androgens on the formation of terminal hair follicles in the axillae and anogenital regions may be important in the development of HS, as it is primarily an inflammatory disease of terminal hair follicles (8). A relationship between onset of hidradenitis and androgen levels is strongly suggested by clinical observations of the disease occurring with puberty and its persisting in females up to menopause, rarity of onset thereafter (1, 2). What is more, HS may decline substantially following menopause, also suggesting a hormonal role (1, 8). However, there is no substantial evidence to support hyperandrogenism in women with HS (2). No change in the peripheral blood hormone levels, including testosterone and dehydrotestosterone was observed in HS patients (1, 4). Revuz considering the etiopathogenesis of HS stresses that some important facts concerning the role of androgens remain still unexplained, among them the high female prevalence, the frequent improvement during pregnancy, and the termination of the disease in post-menopausal women (4).
Bacterial infection was suggested as a important etiologic factor contributing to HS pathogenesis. Various aerobic and anaerobic species have been cultured from samples taken from the HS lesions, among them Streptococcus viridans, Staphylococcus aureus, Staphylococcus milleri, Staphylococcus epidermidis, Peptostreptococcus spp., Bacteroides melaninogenicus and Bacteroides corrodens, coryneform bacteria (1, 4). In perineal and perianal locations of HS the Gram-negative bacteria are more commonly found, such as Escherichia coli, Klebsiella, and Proteus (1, 4). Very heterogeneous spectrum of pathogens indicates that the disease is not associated with the presence of a specific pathogen because no single species is dominant (1, 8). Most researchers believe that the bacteria implicated in HS are the secondary colonizers, which may exacerbate the disease, but should not be regarded as the primary etiologic factors (1, 4, 8).
The possible role of numerous exogenous factors in HS development are also taken into consideration. Among them, the mechanical and chemical irritation of the local skin in the areas typically involved, especially caused by shaving and friction (1, 2, 4). The use of chemical irritants, such as deodorants, depilatory chemicals, antiperspirants, talcum powder have been suggested as triggering or exaggerating factors (1, 2, 4, 8).
The role of pharmacological agents is also being considered and it seems that it can not be completely ruled out as yet. Onset or exacerbation following lithium therapy has been reported (1, 4). The suggested mechanism is not only the known lithium ability to induce inflammation but also to facilitate follicular plugging through its direct effect on follicular keratinocytes (1).
Results of many studies indicate smoking and obesity as the established risk factors of HS. High prevalence (70 – up to 90%) of heavy cigarette smokers among patients with HS suggests that cigarette smoking can be a major triggering factor (1, 2, 4, 6, 15). Revuz et al (4, 6) showed a strong association with current smoking in HS patients, but they failed to observe this association for ex-smokers. Much stronger relationship than with smoking exists between obesity and HS (2, 4, 6, 8). It is worth to stress that a significant association with body mass index in HS patients was found (4, 6, 7). Some authors have observed above 75% of HS patients to be overweight and obese (1). Moreover, there is dose/effect relationship between the overweight/obesity and severity of HS (6, 7). Obesity may affect disease not only through the sweat retention, maceration, and occlusion in the skin folds but also through its connection with the abnormal hormonal metabolism, including changed production and activity of the sex hormone binding globulin, estrogens and androgens, resulting in the relative androgen excess (1). It is believed that this androgen surplus may be involved in coarsening of the hair shaft with further follicular plugging (1).
Consideriong the chronic, inflammatory course of HS, defects in the immunological response mechanisms are suggested as a possible etiologic factors (1, 12). Some studies do not confirm any abnormalities of the immune system (1). Other investigators, however, have found the defected neutrophilic function, decreased percentage of NK cells with the progression of the disease, and lower monocyte responses to bacterial compounds (4, 16). Moreover, the increased expression of Toll-like receptors 2 within infiltrating macrophages and dendritic cells of the HS inflammatory lesions has been observed (16, 17).
HS often begins insidiously with non-specific early symptoms, such as pain, burning, erythema, pruritus, local warmth and hyperhidrosis (1, 2, 4).
The primary lesions are single firm palpable nodule or few solitary painful nodules which are deep-sited and rounded (1, 2, 8). Approximately 50% of all patients have above mentioned subjective prodromal symptoms 12-48 h before consecutive nodule recurs (4). The subcutaneous nodules may persist for weeks with recurrent episodes of inflammation, or may spontaneously rupture after 7-15 days or coalesce into deep, painful abscesses (1, 4). Spontaneous resolving of the single nodule is possible, but the most frequent evolution observed is to form abscesses with an external rupture and draining purulent discharge (1, 2, 4). The numerous recurrences of inflammatory nodules may lead to the development of chronic secondary lesions. Multiple abscesses release purulent malodorous material due to the anaerobic colonization (1, 4, 8). Formation of sinus tracts results with generating deep interconnected network and progressive tissue inflammation and destruction which may extend deep into muscles and fascia (1, 2). Healing occurs with extensive fibrosis and hypertrophic scars making the rope-like dermal contractures (1, 2, 4, 11). The double or multiporous giant comedones can be often observed and are regarded as characteristic feature of HS (1, 4, 8). What is interesting, despite the chronic extensive inflammation, there is no regional lymphadenopathy (4).
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