Expert Review of Dermatology
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Current and future treatments of hidradenitis suppurativa Shiva Yazdanyar & Gregor BE Jemec To cite this article: Shiva Yazdanyar & Gregor BE Jemec (2010) Current and future treatments of hidradenitis suppurativa, Expert Review of Dermatology, 5:3, 335-343, DOI: 10.1586/ edm.10.23 To link to this article: http://dx.doi.org/10.1586/edm.10.23
Published online: 10 Jan 2014.
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Current and future treatments of hidradenitis suppurativa Expert Rev. Dermatol. 5(3), 335–343 (2010)
Shiva Yazdanyar†1 and Gregor BE Jemec1 Department of Dermatology, Roskilde HospitalKøgevej 7–13, DK-4000 Roskilde, Denmark † Author for correspondence: Fax: +45 4732 2698
[email protected] 1
Hidradenitis suppurativa is a chronic disease characterized by chronic or recurrent abscesses, sinus tracts and scarring of apocrine gland-bearing skin. Key areas of different treatment options for hidradenitis suppurativa have been addressed and outlined in this review. Management should be individualized according to the extent of the disease, frequency of exacerbation and risk status. The treatment consists of medical (local or systemic), surgical and laser therapy. New treatments, such as TNF-a inhibitors, have provided clinicians with more options against this difficult disease. Keywords : clindamycin • hidradenitis suppurativa • laser therapy • off-label use • rifampicin • tetracycline • topical administration • TNF-a
Medscape: Continuing Medical Education Online This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Expert Reviews Ltd. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this educational activity for a maximum of 0.5 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at http://www.medscapecme.com/journal/expertderm; (4) view/print certificate. Learning objectives Upon completion of this activity, participants should be able to: • Recognize the typical presentation and appropriately evaluate patients with suspected hidradenitis suppurativa, and construct an effective treatment strategy for patients with hidradenitis suppurativa that appropriately incorporates surgical management
Financial & competing interests disclosure
CME Author: Charles P Vega, MD, Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships. Editor: Elisa Manzotti, Editorial Director, Future Science Group. Disclosure: Elisa Manzotti has disclosed no relevant financial relationships. Authors Shiva Yazdanyar, MD, Department of Dermatology, Roskilde HospitalKøgevej, Roskilde, Denmark Disclosure: Shiva Yazdanyar has disclosed no relevant financial relationships. No writing assistance was utilized in the production of this manuscript. Gregor BE Jemec, MD, Department of Dermatology, Roskilde HospitalKøgevej, Roskilde, Denmark Disclosure: Gregor BE Jemec has disclosed the following relevant financial relationships: Received unrestricted grants for clinical research from: UpJohn; Abbott Laboratories; Wyeth Pharmaceuticals Inc. Acted as principal investigator in hidradenitis suppurativa studies for: Abbott Laboratories Served as a member of advisory boards for: Abbott Laboratories; Pfizer Inc.; MSD/Schering Plough Other: member of the Hidradenitis Suppurativa Foundation Board
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10.1586/EDM.10.23
© 2010 Expert Reviews Ltd
ISSN 1746-9872
335
Review
Hidradenitis suppurativa (HS) is a disease characterized by chronic recurrent inflamed and suppurating lesions located in apocrine gland-bearing skin, for example that of the axillae and groin (Figure 1) [1–3] . A consensus definition was adopted by the second congress organized by the Hidradenitis Suppurativa Foundation (San Francisco, CA, USA, March 2009) [101] : “HS is a chronic, inflammatory, recurrent, debilitating, skin follicular disease that usually presents after puberty with painful deep-seated, inflamed lesions in the apocrine gland-bearing area of the body, most commonly, the axillary, inguinal and anogenital regions”. The definition includes only clinical features, with no biological or pathological test available to help. Diagnostic criteria (adopted by the second congress organized by the Hidradenitis Suppurativa Foundation) relies on the presence of: • Typical lesions, specifically deep-seated painful nodules: ‘blind boils’ in early lesions; abscesses, draining sinus, bridged scars and ‘tombstone’ open comedones in secondary lesions • Typical topography, specifically, axillae, groin, perineal and perianal region, buttocks, infra- and inter-mammary folds; • Chronicity and recurrences [101] . These three criteria must be met for establishing the diagnosis. Based on these clinical criteria, the diagnosis is comparatively uncomplicated and a good diagnostic accuracy can be obtained through the simple question: have you had recurrent boils during the last 6 months? If yes, have these been located to the armpits or groin? [4] . The clinical presentation of HS is classified into primary and secondary lesions [5] . The primary lesions are solitary painful nodules persisting for weeks or months. These early lesions are not characteristic for HS, and are frequently considered as boils or abscesses. The secondary lesions result from repetitive attacks, leading to chronic suppurative sinus and scar formation, which persist for months or years. The main differential diagnoses of HS are abscess, carbuncles, furunculosis, infected Bartholin’s gland, infected or inflamed epidermal cysts, lymphogranuloma venereum, scrofuloderma, actinomycosis, developmental fistulae, nodular acne and pilonidal cyst and cutaneous manifestation of Crohn’s disease [3,5] . The disease is not uncommon, with a prevalence in the general population of approximately 1% [6–9] . Although cases have been described in children, the disease most often appears after puberty and is rare among the aged. It causes considerable morbidity, both as seen through an associated increase in sick leave, as well as through much reduced quality of life [10–13] . The prognosis of HS is poor, as the hallmark of HS is the chronicity. The main complications of HS include: acute infections [3,14,15] ; lymphatic obstruction and lymphedema [3] ; squamous cell car cinoma [3,16] ; fistula formation into urethra, bladder or peritoneum [3,17] ; anemia [18] ; chronic malaise; and depression [3] . Moreover, a retrospective study with more than 2000 cases found a 50% increased risk of overall incidence of malignancy in HS patients [19] . The etiology of the disease is unknown. Several hypotheses have been proposed [2] , although conclusive evidence is, as yet, 336
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lacking. It has been suggested that structural anomalies of the pilosebaceous unit may be responsible under conditions of physical stress and strain of the skin; that the disease represents an immunological dysregulation within the hair follicle; and that scarring and migration of stem-cell-like cells may be responsible for the development of characteristic lesions. Nevertheless, the world literature on this disease is limited, and it remains an orphan disease, a secret scourge of the patients and an unmet challenge to physicians [20] . A number of risk factors have been suggested. By performing a case–control study of 302 HS patients, Revuz et al. confirmed that smoking and overweight are the two main nongenetic factors associated with HS [9] . The rate of active smokers was found to be significantly higher (>70%) among cases with HS compared with controls, and the odds ratio for risk of HS was estimated to be 1.12 (95% CI: 1.08–1.15) for each increase of one unit of BMI. Bacterial infections have been regarded as playing an important role in the clinical manifestation of HS, although they are most likely not the initial causative factor. Routine cultures in HS patients are often negative, but numerous bacteria have been recovered from lesions of HS, for example streptococci, staphylococci, gram-negative rods and anaerobic bacteria [21,22] . Finally, a series of observations, such as premenstrual flare-ups, female preponderance, frequent occurrence after menarche and improvement during pregnancy have pointed towards a role of hormonal factors in the etiology of HS [1,6,23–26] . However, the absence of clinical signs of virilism and the normal blood level of androgens rules out a key role of hyperandrogenism [6,23,25,27] . Severity assessment of HS
Clinically relevant staging and disease severity assessment are prerequisites for the development of evidence-based treatments. Staging of HS is carried out through the use of the Hurley stages, describing the degree of inflammation and fibrosis [28] : • Hurley stage I – abscess formation (single or multiple) without sinus tracts and cicatrization; • Hurley stage II – single or multiple, widely separated recurrent abscesses with tract formation and cicatrization; • Hurley stage III – multiple interconnected tracts and abscesses throughout an entire area (Box 1) . This relevant staging system is, however, not sufficiently dynamic for the description of treatment outcomes. The Sartorius score, which is composed of counts of involved regions, nodules and sinus tracts, has therefore been proposed for the severity assessment (Box 2) [29] . It is based on the salient clinical features of the disease, and allows a more dynamic description of disease severity. Its main restriction is that it is primarily designed to document the treatment outcomes following surgery, and, therefore, may not adequately reflect changes following medical therapy, which does not completely remove lesions, but primarily controls inflammation. Useful modifications have, therefore, been proposed to the original Sartorius score [3,30] . Expert Rev. Dermatol. 5(3), (2010)
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inflammatory nodules and pustules was significantly less in the clindamycin group than in the placebo group at each monthly evaluation. In another randomized controlled trial, the topical clindamycin was found to be as effective as systemic tetracycline (500 mg twice daily for 3 months) in the treatment of HS [33] . Resorcinol peels have traditionally been used for the treatment of follicular occlusion disease, and were extensively used in acne prior to the development of antibiotics and retinoids. There is anecdotal evidence to suggest that the use of 15% resorcinol peels may be of use to patients with HS [34] . The effect appears to be early spontaneous draining and resolution of lesions. The main effect of the treatment is, therefore, patient empowerment, as it provides patients with a certain degree of control over the flares of the disease. However, additional studies are needed to establish the exact role of this treatment modality. Intralesional triamcinolone in small doses of 2–5 mg is often useful in the control of single lesions. The intralesional therapy represents an intermediate stage between medical and surgical therapy [5] . The treatment is empirically developed and the published literature is correspondingly scant, with no formal trials having been carried out. However, this does not detract from the advantages of the technique, which has been in use for decades. It is also one of the first examples of a nonantibiotic therapy that has gained some prominence, and thereby an early suggestion that the underlying disease mechanisms are more complex than simple infection. Systemic options
Figure 1. Chronic hidradenitis suppurativa of the axilla with multiple scarring interconnected tracts and abscesses throughout an entire area; Hurley stage III.
Disease severity scores that are exclusively based on physicians’ assessment of morphological features of a disease may not adequately reflect the disease’s impact on the patient. In particular, high-impact diseases, such as HS, involve significant soreness and loss of quality of life [10,12,13] , which suggests that physician assessment may benefit from additional patient-supplied data on, for example, current soreness, number of flares since last visit or general dermatologic quality of life tools, such as the Dermatology Life Quality Index, Skindex or other validated questionnaires. Treatments General interventions
Smoking and overweight are the two main risk factors associated with HS [5,31] . The patients should therefore be encouraged to stop smoking and/or undertake a weight loss program as nonpharmological therapies. Medical therapies Topical options
In one randomized controlled trial, patients were treated with either topical clindamycin or a placebo [32] . The number of abscesses, www.expert-reviews.com
It has been suggested that folliculitis decalvans and HS are related diseases, based on the histopathology of the lesions [5] . In 2006, Mendonca and Griffiths introduced a combination therapy for folliculitis decalvans using clindamycin and rifampicin [35] . This treatment has been anecdotally reported to be successful in HS, and two case series have described the positive effects of this treatment in a total of 190 patients [36,37] . Treatment is originally prescribed using clindamycin 300 mg twice-daily and rifampicin 300 mg twice-daily for at least 3 months, but reported cases suggest that this may not be the only effective dosage [37] . These observations await further confirmation within a randomized controlled trial comparing combination treatment with, for example, tetracycline monotherapy. The treatment may potentially have associated gastrointestinal side effects limiting its use. In the published cases, 38% reported side effects and 26% stopped treatment due to the side effects. Specific dose-finding studies and pharmacological developments in the drug delivery are therefore necessary to avoid drop outs due to side effects. In order to examine the effect of anti-androgen therapy, in one double-blind, controlled, cross-over study, cyproterone actetate associated with estrogens was compared with ethinyloestradiol, a ‘classical contraceptive pill’ [38] . The results showed improvements in disease activity with both treatments, and no difference was observed between the two products. Based on the clinical confusion regarding the relationship between HS and acne, isotretinoin was expected by many to be an effective treatment option for HS, and is often tried. However, 337
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Dapsone has partial antibiotic and partial immune-regulating effects. Case series have Stage I suggested that the drug may be useful in the • Abscess formation, single or multiple without sinus tracts and cicatrization/scarring treatment of HS [49,50] . The exact mechanism Stage II of action is not described, but in histological • Recurrent abscesses with sinus tracts and scarring studies of HS the neutrophilocyte is a late• Single or multiple widely separated lesions comer in the lesions, suggesting that either the Stage III drug is only suited to treat established lesions, • Diffuse or almost diffuse involvement or multiple interconnected tracts and abscesses or that another mechanism is involved. In recent years, biological agents, such the available data suggests this is not the case. Boer et al. per- as TNF-a inhibitors, have produced favorable outcomes in formed a retrospective chart review of 68 HS patients treated with HS [5,51,52] . TNF-a is a pleiotropic pro-inflammatory cytokine isotretinoin, but unfortunately found no significant effect of the produced primarily by monocytes and macrophages. When drug [39] . These results were confirmed by another study based TNF-a is activated, it induces a cascade of inflammatory reacon patients’ ‘outcome assessment’ [40] . tions that leads to excessive inflammation. Therefore, inhibition Systemic immunosuppressants are generally useful in the treat- of TNF-a may play an important role in the therapy of a number ment of HS [5] . The concept of HS as an inflammatory disease of disparate inflammatory disorders. Matusiak et al. performed allows the use of traditional immunosuppressants in the treatment the first study demonstrating elevated levels of TNF-a in a HS of more severe cases [41] . Systemic steroids are often used with patient [53] . Infliximab was the first TNF-a inhibitor shown to have initial benefit through a reduction in inflammation and pain, a beneficial effect in HS patients with associated Crohn’s disease although formal studies are also lacking here. They may be useful [52] . ���������������������������������������������������������� In a recently published review, the authors found 20 studin acute exacerbations, but because of the high risk of flares when ies with a total of 52 HS patients examining the effect of inflixdosage is reduced and the risk of systemic side effects, it should imab [52] . Improvement with infliximab was reported in 45 out of only be used in shorter periods of time and/or in conjunction with 52 patients. However, only 17 patients showed long-term improveother therapies [42,43] . Limited evidence suggests that cyclosporine ment. The initial favorable outcome of infliximab treatment of HS is useful [44,45] , and in the experience of the authors similar effects has recently been confirmed in a randomized controlled study, can be obtained using systemic corticosteroids [46] . The immune suggesting that the majority of patients experience a significant regulation achieved with these drugs offers similar disease control improvement during therapy. Long-term effects were also studied in HS as in other inflammatory skin diseases, and is supported in a small group, where two out of five patients experienced longby histological studies suggesting an early role for lymphocytes term remission after infliximab therapy [51] . The treatment has and activation of innate immune responses [47] . In contrast, the been associated with significant adverse events, including lupus-like use of methotrexate appears to have very limited effect on the reactions, hypersensitivity reactions, abdominal pain secondary to disease activity [48] . colon cancer, multifocal motor neuropathy with conduction block, TB and anaphylactic shock [16] . Box 2. Sartorius score. Etanercept (Enbrel®) and adalimumab (Humira®) are other TNF-a inhibitors that have recently been documented as useAnatomical region involved (three points per region involved) ful for HS treatment, with no severe side effects reported so far [16,52,54,55] . Switching between TNF-a inhibitors has been • Axilla reported to be successful in cases of treatment failure [56] . • Groin Currently, the level of evidence describing the effects of TNF-a • Gluteal inhibitors in HS is limited to a few small trials and cases, and • Intramammary left/right further studies therefore need to be conducted to determine the • Other effect, side effects and long-term evaluation of these drugs. In Number and scores of lesions particular, the reports of the long-term effect of these treatments • 2 points for abscesses/nodules are of great interest [57,58] . • 4 points for fistulae Box 1. Hurley’s classification.
• 1 point for scars • 1 point for others The longest distance between two relevant lesions • 2 points if
