Hidradenitis Suppurativa (Acne Inversa): Management of a Recalcitrant Disease

STATE-OF-THE-ART REVIEW Editor: Bernard A. Cohen, M.D. Pediatric Dermatology Vol. 24 No. 5 465–473, 2007

Hidradenitis Suppurativa (Acne inversa): Management of a Recalcitrant Disease

Joseph Lam, M.D.,* Andrew C. Krakowski, M.D.,* and Sheila F. Friedlander, M.D.

*Rady Children’s Hospital, University of California, Departments of Pediatrics and Medicine (Dermatology), San Diego School of Medicine, University of California, San Diego, California

Abstract: Hidradenitis suppurativa is a chronic relapsing disorder of follicular occlusion that is often recalcitrant to therapy. Topical and systemic antibiotics, hormonal therapies, oral retinoids, immunosuppressant agents, and surgical treatment are some of the therapeutic alternatives used for this often recalcitrant and frequently troublesome disorder. This article reviews the pathophysiology of hidradenitis suppurativa, an evidence-based analysis of standard treatments, and recent advances in the therapy of this disorder.

Hidradenitis suppurativa (HS) is a disease of the (2,3), with the inflammation of apocrine glands that oc- apocrine gland-bearing areas of the body that commonly curs likely representing a secondary phenomenon affects the intertriginous areas. Although it may initially resulting from follicular plugging (3). It is now believed present in a mild form, recurrent abscesses with the that HS is primarily an inflammatory disorder of the hair development of sinus tracts and scarring generally en- follicle and, therefore, is included in the follicular occlu- sues. Rather than a distinct disease entity, it may repre- sion tetrad along with acne conglobata, dissecting cellu- sent the severe end of a spectrum of disease that includes litis, and pilonidal sinuses (4) (Table 1). As well, the acne. Hidradenitis suppurativa has a prevalence estimate ‘‘suppurativa’’ may be inappropriate, as HS is likely not of 1:300 (1). Not surprisingly, HS may have a severe initiated by infection. A more appropriate term may be deleterious psychosocial impact on the patient, due to ‘‘acne inversa,’’ a label preferred by some experts (4,5). both its chronic nature and lack of response to standard therapeutic options. Side effects of therapy often nega- Histopathology of the Disease tively impact on the patient’s well-being. In a review in 2005 by Sellheyer and Krahl (4), serial histologic specimens show progression from follicular PATHOPHYSIOLOGY AND NATURAL hyperkeratosis and comedo formation to rupture of the HISTORY follicular infundibulum, with resultant inflammation of The term hidradenitis suppurativa derives from the the surrounding dermis. Over time, a granulomatous Greek words hidros for sweat and adne for gland. infiltrate is seen, with further local inflammation causing However, this term may be a misnomer, as it appears that abscess formation and apocrinitis as the inflammation HS may not be a primary disorder of the apocrine glands spreads. Of note, early specimens only show the follicular

Address correspondence to Dr. Sheila Fallon Friedlander, Clinical Professor, 8010 Frost Street, Suite 602, San Diego, CA 92123, or e-mail: [email protected].

DOI: 10.1111/j.1525-1470.2007.00544.x

2007 The Authors. Journal compilation 2007 Blackwell Publishing, Inc. 465 466 Pediatric Dermatology Vol. 24 No. 5 September ⁄ October 2007

TABLE 1. Follicular Occlusion Tetrad

Dissecting cellulitis of the scalp Acne conglobata Hidradenitis suppurativa (acne inversa) Pilonidal sinus occlusion with sparing of the apocrine glands. The authors present a convincing argument for apocrinitis as a secondary eﬀect caused by extension of the inﬂammatory process.

Clinical Presentation Clinically, HS usually presents as tender subcutaneous nodules in the intertriginous areas, which include the axillae, inguinal, anogenital, and mammary areas. It has been noted in association with Crohn disease (6,7), Dowling-Degos disease (8–10), and arthropathy (11,12). Although the exact pathophysiologic mechanisms are still unknown, genetics (13–15), hormones (16–18), obesity (18), bacterial infection (19), and smoking (20) Figure 1. A patient with mild hidradenitis suppurativa. may play a role. With time, the follicular occlusion leads to dilatation and rupture of the structure, which sets oﬀ a chain of events including inﬂammation, abscess formation and, in established disease, sinus tract formation, which are classically resistant to treatment. Squamous cell carcinoma is a rare complication of chronic, severe, hidradenitis suppurativa (21–23).

STAGING OF HIDRADENITIS SUPPURATIVA Mild HS is usually noted early in the course of the disease, and consists of solitary nodules with minimal pain and no abscess formation (Fig. 1). Moderate HS can be classified as multiple recurrent nodules affecting the patient’s daily activities due to pain, discharge or drainage. Abscess formation occurs at this stage (Fig. 2). Severe HS develops late in the course of the disease and involves Figure 2. A patient with moderate hidradenitis suppurativa. diffuse abscess formation with chronic draining sinus tracts. Chronic inflammation is evident in multiple areas depilation, and deodorants. Warm compresses and top- of scarring (Fig. 3). Fortunately, not all patients progress ical antiseptic or antibacterial soaps can be used for in- to severe disease. flamed lesions. Although no controlled trials of these general measures have occurred, the consensus among MEDICAL TREATMENT practitioners is that general preventative measures can help with the symptoms of mild HS. General First line therapy consists of conservative management, Antibiotics which is subsequently often used in conjunction with other treatment modalities. Initial measures include Conservative measures may not be enough to control the cessation of smoking, weight loss, and avoidance of disease and systemic and ⁄or topical antibiotics can be irritation in the affected area. Patients should wear loose- added to the treatment regime. Topical clindamycin (24) fitting cotton clothing and avoid heat, humidity, shaving, is a good choice for initial therapy. A double-blind Lam et al: Hidradenitis Suppurativa Management 467

two agents best studied are cyproterone acetate and finasteride. In a study, using 50 lgofethinyloestra- diol ⁄50 mg of cyproterone acetate daily, 50% of the women showed improvement, with approximately 30% having complete remission for 18 months (27). Another report demonstrated clinical control using 100 mg⁄day of cyproterone acetate in four women with long-standing HS (28); unfortunately this drug is not available in the US due to its potential hepatotoxicity (29–31) and theo- retical concerns regarding feminization of male fetuses (33,34). Data are lacking on the use of other oral contraceptives in HS, and the rationale for their use is largely based on anecdotal reports and clinical data confirming that oral contraceptives are useful in the treatment of acne. Recently, a few case series demonstrated clinical improvement in both male and female HS patients following the use of finasteride, a selective inhibitor of type-II 5-a-reducatase (34,35). However, finasteride is associated with a number of side-effects, including teratogenicity, decreased libido, erectile dysfunction, decreased ejaculatory volume, gynecomastia, and breast enlargement in women (36). Nonetheless, because of its rapid and almost complete elimination, some have sug- Figure 3. A patient with severe hidradenitis suppurativa. gested that it may be safer than retinoids for women of childbearing age (34). placebo controlled study showed that topical clindamycin for 3 months resulted in significant improvement, Oral Retinoids and a recent double-blind trial showed that topical clindamycin was just as efficacious as systemic tetracycline. Isotretinoin is a useful medication in the treatment of (25). However, concern regarding the emergence of acne and has been used in HS as well. However, despite resistant bacteria following prolonged therapy is a rea- earlier reports of success with isotretinoin (37,38), a re- sonable factor impacting on treatment plans. cent retrospective study of 68 patients showed that less Of the systemic antibiotics, tetracycline, mino- than a quarter (23.5%) had clearing with a 4–6 month cycline, and erythromycin are among those commonly course of low-dose isotretinoin and only 16.2% showed used for chronic treatment of HS. Most information maintenance of improvement on follow-up (39). In this comes from anecdotal evidence and case reports. study, the mean daily dose was 0.56 mg ⁄kg ⁄day. No However, a recent small retrospective study showed large studies with standard doses of isotretinoin have remission of HS using a 10-week course of combina- been performed. However, success with acitretin and tion 300 mg of clindamycin twice daily and 300 mg of etretinate, including in patients who have failed courses rifampicin twice daily (26). In this study, the major of isotretinoin, has been reported (40–42). side-effect was diarrhea, which necessitated discontin- uation of the medication in four patients. The Dapsone remaining 10 patients were maintained in remission up until the time of the report, for a symptom-free Dapsone has been found to be helpful in a small number duration of 1 to 4 years. of HS patients and is a reasonable therapeutic alternative for recalcitrant disease (43). In a recent series of five patients, clinical improvement was noted in all five within 4 Hormonal to 12 weeks, utilizing doses between 25 and 150 mg daily Although most patients with HS have normal androgen (44). No significant adverse effects were noted. As with all profiles, improvement of HS with the use of anti- patients on dapsone, it is important to monitor the androgens has been reported. The mechanism may be hemoglobin levels and to screen for glucose-6-phospha- due to altered end-organ sensitivity to androgens. The tase deficiency. 468 Pediatric Dermatology Vol. 24 No. 5 September ⁄ October 2007

Immunosuppressive Therapy SURGICAL TREATMENT Systemic and intralesional corticosteroids may be used Although medical treatments are often used in early for their nonspecific anti-inflammatory effects. Sys- stages of HS, once scarring develops, surgical interven- temic steroids carry with them a higher risk of side tions become the preferred mode of treatment. The goal effects including hypertension, cushingoid features, in surgery is to remove the scarred tracts and draining and adrenal axis suppression. Although initial control abscesses. Although the best mode of surgical therapy may occur, many patients will flare as steroid therapy has yet to be determined, consensus has been reached is tapered or discontinued. Intralesional steroids are of regarding several general principles. First, incision and benefit to patients in the short term, although evidence drainage of an inflammatory lesion is of limited value is lacking to support this as a long-term form of dis- and should be avoided (19,67). However, marsupiali- ease control. A total of four patients have been zation of recurrent lesions may aid with local control reported, documenting improvement with cyclosporin (68). Second, the surgical literature suggests that surgical (45–47).Onemustkeepinmindtherisk–benefitratio removal of the involved tissue is the treatment of choice when using this drug, and long-term use is probably (69–71). However, depending on the extent of disease not warranted in most instances, given the risks of involvement, this may not be feasible. Unfortunately hypertension and renal impairmentthatincreasewith recurrences happen even following wide surgical exci- prolonged treatment. sion. A recent study showed 100% recurrence after drainage, 42.8% after limited, and 27% after radical excision (67). As well, a series of 82 patients with 118 Biologics radical excisions showed high recurrence rates for Considerable interest exists in the possible benefits of biologic agents for HS. The most experience has accrued with infliximab, a chimeric monoclonal antibody with TABLE 2. Stepwise Approach to Management of HS high affinity for tumor necrosis factor-alpha. The initial Consider related or associated diseases report involved a patient with Crohn disease and axillary Crohn (especially if perineal disease), acne conglobata, dissecting HSwhoreceivedinfliximabfor her Crohn disease (48). folliculitis, pilonidal sinus, arthropathy, Dowling-Degos The HS showed significant improvement after one dose disease, hyperandrogenism General measures and cleared completely after the second dose. Subse- Education and counseling quently, nine patients with HS who responded to inflix- Avoid irritation (Deodorant, razor shaving, depilation, loose imab have been reported (49–53). Success with clothing, cotton underwear, losing weight, avoid heat and humidity) etanercept and adalimumab has also been described Cessation of smoking (54,55). However, treatment with any of these agents Warm compresses carries significant risks. Side effects include infusion Topical antiseptic Antibacterial soap ⁄ wash reactions, serum-sickness reaction, reactivation of latent First-line agents (mild–moderate disease) tuberculosis (TB), immunosuppression, exacerbation of Topical clindamycin; if ineffective, consider demyelinating diseases, lupus-like reactions, and the Oral clindamycin and rifampin Oral tetracycline, minocycline, doxyxycline or erythromycin potential development of late lymphomas (56–58). Intralesional corticosteroids A fatal occurrence of epidermoid carcinoma has been Oral contraceptives reported following treatment with infliximab (59). Second-line agents (recalcitrant or severe disease) Systemic retinoids (isotretinoin, acitretin) Although the use of biologics is promising, the decision Dapsone must be made with serious consideration for the potential Finasteride severe side effects. Biologic therapy (primarily infliximab) Cyproterone acetate (if available) Surgical excision Unproven therapies Other Medical Treatments Cryotherapy Methotrexate Other modalities that have been used for HS include Botulinum toxin A radiotherapy (60), ALA-PDT (61,62), botulinum toxin Radiotherapy A (63), granulocyte–macrophage colony-stimulating ALA-PDT Cyclosporin factor (GM-CSF) (64), cryotherapy (65), and metho- GM-CSF trexate (66). Unfortunately the data supporting the use of CO2 laser these agents consist of isolated case reports with atten- HS, hidradenitis suppurativa; GM-CSF, granulocyte–macrophage dant selection bias. colony-stimulating factor. Lam et al: Hidradenitis Suppurativa Management 469 inguinoperineal and submammary disease (72). A large designed (Table 2). Unfortunately, no level-1 high- study of 106 patients and 143 excisions showed a recur- quality data from appropriately designed trials of sig- rence rate of almost 70% following primary closure in nificant size are available, and recommendations are patients with mild to severe HS (73). However, all vari- therefore limited by this shortcoming. eties of flaps and grafts have been used for more extensive For the purposes of examining the levels of evidence, diseasewithnomajorrecurrences(70). three methods for evaluating and grading were consid- Various modalities of surgery have been used, from ered. The first method was that of the Oxford Centre for the traditional scalpel to the use of CO2 laser (74–78). Evidence-based Medicine Levels of Evidence (http:// While surgical excision is definitely a treatment option www.cebm.net/levels_of_evidence.asp). We found this for chronic and intractable disease, it carries the risk of method quite extensive and comprehensive. The advan- additional scarring. Although curative surgery is possi- tages were the strict definitions of each category and the ble, the chance of recurrence is a real and potential out- inclusion of grades of recommendation. However, this come. Other complications include contractures and method has drawbacks. The level of complexity makes functional loss or limitation of mobility, secondary to the system difficult to access for the practitioner (i.e., fibrosis and scarring (79). level-1 evidence is split into a, b, or c depending on further qualifications to the evidence). As well, there is no weight placed on clinically relevant outcome versus STEPWISE APPROACH TO purely numerical outcomes (i.e., reduction in deaths MANAGEMENT OF HS versus lowering of cholesterol numbers). For this reason, In light of our current understanding of this disease, and an attempt was made to identify another method of the quality of evidence in support of the various therapies evaluation. A second method considered was that of the available, a stepwise approach to management has been US Preventive Services Task Force (USPSTF).

TABLE 3. Levels of Evidence for Select Medications in the Treatment of HS

Quality of Grade of Agent Dose evidence recommendation

Topical antibiotics Clindamycin 1% solution 2 B Systemic antibiotics Clindamycin ⁄ Rifampin Clindamycin 300 bid 2B Rifampin 300 bid for 12 wks Other antibiotics Variable 3 C Hormonal therapy Cyproterone 100 mg ⁄ d2B Other oral contraceptives Variable 3 C Finasteride 5 mg ⁄ day 3 C Oral retinoids Isotretinoin Variable (low dose, 0.7–1.2 mg ⁄ kg ⁄ day) 3 C Acitretin Variable 3 C Immunosuppressants Corticosteroids (intralesional) Variable 3 C Cyclosporin 2–4.5 mg ⁄ kg ⁄ day 3 C Biologics Inﬂiximab 5 mg ⁄ kg repeated at 2 wks and 6 wks 3 C Etanercept 25 mg s.c. twice weekly 3 C Adalimumab 40 mg s.c. every other week 3 C Other (medical) Dapsone 25–150 mg ⁄ day 3 C ALA-PDT N ⁄ A3C MTX 12.5–15 mg weekly 3 C Radiotherapy N ⁄ A3C Botox 250 U Dysport as for hyperhidrosis 3 C GM-CSF 450 lg in 10 mL of 0.9% NaCl solution 3 C Cryotherapy N ⁄ A3C Surgical therapy Local excision N ⁄ A3C Radical excision N ⁄ A3C CO laser N ⁄ A3C HS, hidradenitis suppurativa; GM-CSF, granulocyte–macrophage colony-stimulating factor. 470 Pediatric Dermatology Vol. 24 No. 5 September ⁄ October 2007

TABLE 4. Side-Eﬀect Proﬁle of Select Medications in the Treatment of HS

Medication Side-eﬀect proﬁle

Clindamycin and rifampin Discoloration of body fluids (rifampin), pseudomembranous colitis (clindamycin), selection of resistant organisms, vulvovaginal candidiasis Finasteride Teratogenicity, decreased libido, erectile dysfunction and gynecomastia (males), breast enlargement (females) Isotretinoin Mood lability, pseudotumor cerebri, hypertriglyceridemia, pancreatitis, hepatic transaminitis, myalgias, xerosis Infliximab Serum sickness reaction, reactivation of latent tuberculosis, immunosuppression, exacerbation of demyelinating diseases, lupus-like reactions, latent lymphoma (potential) Dapsone Hemolytic anemia, methemoglobinemia, blood dyscrasias, hepatitis, peripheral neuropathy, lupus-like reaction, mood lability, erythema multiforme Cryotherapy Local pain, scarring, prolonged healing time, posttreatment infection Methotrexate Myelosuppression, hepatotixicity, nausea, nephropathy, interstitial pneumonitis Botulinum toxin A Pain at infection site Cyclosporine Hypertension, pancreatitis, blood dyscrasias, immunosuppression, hepatotoxicity, hypomagnesemia, hirsutism, gingival hyperplasia, hypertrichosis, nephrotoxicity ALA-PDT Local pain and irritation GM-CSF Transaminitie, fluid retention, venous thrombosis, ‘first dose’ reaction (fever, hypotension, tachycardia, rigors, flushing, nausea, vomiting, dyspepsia) Radiotherapy Carcinogenic risk, myelosuppression HS, hidradenitis suppurativa; GM-CSF, granulocyte–macrophage colony-stimulating factor.

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Gold M, Bridges TM, Bradshaw VL et al. ALA-PDT and blue light therapy for hidradenitis suppurativa. J Drugs Dermatol 2004;3(Suppl. 1):S32–S35. APPENDIX 1: REFERENCES FOR QUALITY OF 63. O’Reilly DJ, Pleat JM, Richards AM. Treatment of EVIDENCE AND GRADING OF RECOMMEN- hidradenitis suppurativa with botulinum toxin A. Plast DATIONS Reconstr Surg 2005;116:1575–1576. 64. Sharon-Guidetti A, Ziv Y, Kummer E et al. Granulocyte- macrophage colony-stimulating factor for perianal hidradenitis suppurativa: report of a case. Dis Colon Rectum Strength of recommendation taxonomy (SORT) 2006;49:682–684. Study quality Definition (for treatment) Level 1 SR ⁄ meta-analysis of RCT with 65. Bong JL, Shalders K, Saihan E. Treatment of persistent consistent findings painful nodules of hidradenitis suppurativa with cryother- High-quality individual RCT* apy. Clin Exp Dermatol 2003;28:241–244. All-or-none study 66. Jemec GB. Methotrexate is of limited value in the Level 2 SR ⁄ meta-analysis of lower quality treatment of hidradenitis suppurativa. Clin Exp Dermatol clinical trials or of studies with 2002;27:528–529. inconsistent findings 67. Ritz JP, Runkel N, Haier J et al. Extent of surgery and Lower quality individual RCT* recurrence rate of hidradenitis suppurativa. Int J Colo- Cohort study rectal Dis 1998;13:164–168. Case-control study Level 3 Consensus guidelines, 68. Brown SC, Kazzazi N, Lord PH. Surgical treatment of extrapolations from bench perineal hidradenitis suppurativa with special reference to research, usual practice, opinion, recognition of the perianal form. Br J Surg 1986;73: disease-oriented evidence 978–980. (intermediate or physiologic 69. Weyandt G. Surgical management of acne inversa. outcomes only), or case series for Hautarzt 2005;56:1033–1039. studies of diagnosis, treatment, 70. Mandal A, Watson J. 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B Recommendation based on inconsistent or limited quality patient-oriented evidenceà C Recommendation based on consensus, usual practice, disease- oriented evidenceà or case series for studies of diagnosis, treatment, prevention or screening Adapted from Ebell et al (80) *High-quality RCT: allocation concealed, blinding if possible, intention-to-treat analysis, adequate statistical power, adequate follow-up (>80%). In an all-or-none study, the treatment causes a dramatic change in outcomes, such as antibiotics for meningitis or surgery for appen- dicitis, which precludes study in a controlled trial. àPatient-oriented evidence measures outcomes that matter to patients: morbidity, mortality, symptom improvement, cost reduction, and quality of life. Disease-oriented evidence measures intermediate, physiologic, or surrogate end points that may or may not reflect improvements in patient outcomes (e.g., blood pressure, blood chemistry, physiologic function, pathologic findings). Consistent: Most studies found similar or at least coherent con- clusions (coherence means that differences are explainable) or if high-quality and up-to-date systematic reviews or meta-analyses exist, they support the recommendation. Inconsistent: Considerable variation among study findings and lack of coherence or if high-quality and up-to-date systematic reviews or meta-analyses exist, they do not find consistent evidence in favor of the recommendation.