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Peer Reviewed

Review

Hidradenitis Suppurativa: A Review With an Emphasis on Treatment

Volume 56 - Issue 8 - August 2016

AUTHORS:
Brooke Rothstein, BA; Noah Scheinfeld, MD; William W. Huang, MD, MPH; and Steven R. Feldman, MD, PhD

CITATION:
Rothstein B, Scheinfeld N, Huang WW, Feldman SR. Hidradenitis suppurativa: a review with an emphasis on treatment. Consultant. 2016;56(8):693-700.

 

ABSTRACT: This article gives an overview of the etiology, diagnosis, staging, and treatment of hidradenitis suppurativa (HS), a chronic skin disorder characterized by the presence of recurrent inflammatory nodules resulting in sinuses, fistulas, and scarring, commonly in the intertriginous areas. Treatment comprises topical and oral antibiotics, hormonal therapy, immunosuppressants, zinc gluconate, biologic therapy, phototherapy, laser therapy, and surgical therapy. Despite these therapies, few randomized, controlled trials have been performed, and no standard of care exists. As our understanding of HS improves, better methods of diagnosis and more effective treatments have emerged, including the recent US approval of adalimumab for HS. However, more research is needed.

KEYWORDS: Hidradenitis suppurativa, follicular occlusion, adalimumab, retinoids, antibiotics, hormone blockers, immunosuppressants, biologics, laser therapy, light therapy, or surgical therapy

Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic, inflammatory skin disorder with a worldwide prevalence of approximately 1% to 4%,1,2 although it may be a rare disease affecting fewer than 200,000 persons in the United States.3,4

While HS mistakenly had been thought to originate in the apocrine gland, it instead is a disease of the follicle, defined by initial follicular occlusion and subsequent inflammation.5 HS manifests as chronically occurring abscesses, sinus tract formation, and scarring that may be painful and malodorous. Lesions often occur in the intertriginous areas, such as the groin and axillae, but also can occur on the buttocks and in the inframammary area.6 The lesions of HS can involve any area of the body where follicles are present. Even limited cases of HS can be debilitating, causing psychosocial and physical dysfunction.7 Persons with HS can experience sexual distress and work disability, and 6% to 39% of affected persons experience depression.7-10

HS is a challenging disease for both patients and practitioners given its debilitating nature, its comorbidities, and the complex nature of effective treatment options. Treatments range from topical and oral antibiotics to biologic agents, laser therapy, and surgical procedures, although there is no universally effective treatment, nor is there a cure. Few randomized controlled trials (RCTs) have been performed, and treatment often is based on clinical experience. However, as understanding of the disease has evolved in recent years, more available and effective therapies have surfaced. In September 2015, adalimumab became the first medication approved by the US Food and Drug Administration (FDA) for the treatment of HS.

This review covers the etiology, diagnostic criteria, staging, and treatment options for HS.


Figure 1. Stage III HS on the abdomen.

 

METHODS

Literature searches were performed using PubMed and the Cochrane Library from January 1983 to December 2015 using the key search terms hidradenitis suppurativa and acne inversa. Studies written in English and involving at least 2 adult patients with HS were included. Additional articles were identified using the reference sections of initial papers. Further information was gathered using targeted searches in PubMed and Google Scholar. Information was extracted from 1 Cochrane Review, 12 RCTs, and numerous case reports, retrospective/prospective cohort studies, and systematic reviews, and was classified based on the strength of the evidence provided. RCTs are highlighted below in the treatment section; however, there is a scarcity of well-designed, adequately powered clinical trials for HS.

ETIOLOGY

The pathogenesis of HS is not yet completely understood, although it is likely multifactorial. Up to 40% of patients with HS have a familial form of the disease, with some of these forms following an autosomal dominant pattern of inheritance.11 Heterozygous mutations in γ-secretase, a multi-subunit protease involved in the Notch signaling pathway, occur in HS patients with familial disease.12 Defined genetic defects have not been found in Hurley stage 1 HS.

Follicular occlusion is a key pathologic aspect of HS pathogenesis. This has been attributed to primary defects in the support structure of the sebofollicular junction of the folliculopilosebaceous unit (FPSU) in HS-affected skin.13 The lack of support structure may cause hyperkeratosis of the follicle and susceptibility of the FPSU to leakage and damage, resulting in the release of keratin fragments and other materials that trigger the migration of inflammatory mediators. Smoking, obesity, and hormones are factors that are associated with HS, which may be due to their role in stimulating follicular occlusion.14 Interestingly, sebaceous glands are absent in lesional skin of HS.

Additionally, compared with nonlesional skin, HS lesions have higher levels of toll-like receptor 2 expressing infiltrating macrophages (CD68+) and dermal dendrocytes (CD209+),15 as well as increased levels of perifollicular and subepidermal CD3+, CD4+, CD68+, CD79+, and CD8+ cells.16 The increased level of immunologic cells in the skin of HS lesions, along with the clinical improvement observed after treatment with biologics, strongly supports the key role of the immune response in HS pathogenesis.

Bacteria are crucial in HS pathophysiology, which is suggested by the efficacy of antibiotics in HS treatment. In particular, intravenous (IV) antibiotics can cease all HS activity.17 Coagulase-negative staphylococci (CoNS) are a dominating microbe in HS lesions, but other bacteria can stimulate the immune system, as well. It is unknown if the role of CoNS in HS is a primary cause of disease or if their presence in HS skin lesions is a secondary inflammatory event.18 The deposition of keratin fragments into the dermis may cause a primary foreign-body reaction, and the bacteria may subsequently colonize onto the skin in a secondary process.19 Thus, the efficacy of antibiotics for the treatment of HS may be due to their antibacterial properties in addition to possible immunomodulatory effects.18,20 Antibiotics also might shift the bacterial florae that live on the skin to less–immune-stimulatory bacteria.


Figure 2. Stage I HS on the axilla.

 

DIAGNOSIS

HS is a clinical diagnosis that can be a challenge. Three diagnostic criteria must be present for definitive diagnosis21-23:

  1. The presence of typical lesions of deep-seated painful nodules (known as “blind boils” without a purulent point) in early lesions and abscesses, sinuses, bridged scars, and “tombstone” open comedones (pseudocomedones) in secondary lesions.
  2. Lesions occurring in at least 1 typical body location such as the axillae, groin, perineal and perianal region, buttocks, and inframammary and intermammary folds.
  3. Chronic nature of disease, relapses, and recurrences.

The mean time to diagnosis of HS is 7 years,24 and the disease may present in various different phenotypes, making diagnosis confusing and difficult. Skin biopsy, bacterial culture, and imaging may be used to eliminate other potential diagnoses.25 However, HS is primarily a clinical diagnosis, and biopsy is not necessary to establish the diagnosis, unlike with other diseases related to HS such as acne conglobata or dissecting cellulitis, where a biopsy is needed to exclude other conditions. In a review of HS histologic findings, all biopsy samples sent with a clinical suspicion for HS were given a dermatopathologist-confirmed HS diagnosis.25

STAGING

Two major classification systems are used to stage the severity of HS. The Hurley staging system is the older of the 2 and is still used in practice today (Table). It classifies HS into 3 stages and initially was designed to aid in treatment selection of specific body regions.26 Hurley stage I involves abscess formation without confluence of lesions; stage II involves more broadly dispersed, recurrent abscesses with some confluence and tract formation; and stage III is defined by widespread skin involvement with full confluence of abscess and sinus tracts (Figures 1-3). According to this classification system, stage I disease correlates with medical therapy, stage II with local surgery, and stage III with widespread surgical excision.27

 

The Sartorius system was created to offer a more dynamic and detailed staging process for HS. The system takes into account (1) the body region involved, (2) the number and types of lesions, (3) the longest distance between 2 lesions, and (4) whether all lesions are clearly separated by normal unaffected skin.28 Points are given in each category to give a regional and total score. The Sartorius system is used primarily for research purposes, whereas the Hurley staging system more often is used in the clinical setting.28

Other clinical tools used to measure HS disease severity include the HS Physician’s Global Assessment (HS-PGA) and the Hidradenitis Suppurativa Clinical Response (HiSCR).29,30 The HS-PGA is a 6-point scale ranging from clear (score = 0) to very severe (score = 5); however, it has been faulted for failing to detect clinically important improvement in patients with severe disease.29 The HiSCR is a novel clinical endpoint used to assess the inflammatory signs and symptoms of HS, and is defined as a 50% or greater reduction in inflammatory lesion count and no increase in abscesses or draining fistulas compared with baseline. It is determined by counting the number   of inflammatory nodules, abscesses, and draining fistulas before and after an intervention.29 The HiSCR was found to be more responsive to detecting change following treatment than the HS-PGA, with 54.5% of patients who received weekly adalimumab achieving a HiSCR response compared with only 20.5% of patients who received weekly adalimumab achieving a HS-PGA response.30,31


Figure 3. Stage III HS on the axilla.

 

TREATMENT

Treatment of HS varies and depends on the patient and his or her individual disease factors. Mild disease typically is treated with topical and oral antibiotic therapies, hormone blockers, or oral immunosuppressants. More severe disease may require IV antibiotics, biologics, laser therapy, light therapy, or surgical therapy. Recommending weight loss, smoking cessation, and loose-fitting clothing to patients also may be beneficial.32 Determining the appropriate treatment for HS patients can be difficult, since there is no consistently effective treatment option or cure. Research into HS treatment consists mainly of case reports and poorly powered cohort studies due to the disease prevalence and the difficult task of diagnosing patients with HS. Only 12 RCTs were identified in our study. With the lack of reliable treatment options, many patients continue to struggle with the pain, malodor, ensuing embarrassment, and physical impairment that accompany this disease process.6,20

Topical agents

Topical therapies typically are first-line treatment for HS. Topical agents may be prescribed for daily use and can be combined with oral antibiotic therapy if improvement is not achieved with topical agents alone.

Topical clindamycin phosphate, 1%, is considered the standard of care in stage I HS due to its few adverse effects, efficacy, low cost, and ease of use, but this conclusion is based on old studies.20 In an RCT of 27 patients, topical clindamycin was statistically superior to placebo in terms of patient assessments and the number of abscesses, inflammatory nodules, and pustules following treatment.33 Unfortunately this effect was short-lived; after 2 to 3 months of treatment, abscesses and inflammatory nodules were no longer improved. However, another RCT demonstrated that topical clindamycin provided levels of improvement in disease activity similar to those of twice-daily oral tetracycline 600 mg in patients with stage I or II HS, suggesting that topical clindamycin has similar efficacy to systemic antibiotic therapy.34

Resorcinol, 15%, is a nonantibiotic topical agent used for chemical peels that was studied in a group of 12 women with stage I or II HS.35 After a year of once-daily application to active abscesses, the patients experienced decreased pain and shortening of the duration of HS flares. Resorcinol can be compounded with other agents, including clindamycin and gentamycin.

Oral and IV antibiotics

For more severe disease or stage I disease not responding to topical treatments, the next step often is adding a combination oral antibiotic regimen. Most of the recommendations for oral antibiotics are based on clinical experience, although some studies support their use.36-38 First-line oral antibiotic treatment for HS traditionally consists of a combination of oral rifampicin and clindamycin, 300 to 600 mg twice daily, with a 71% to 86% improvement in 4 available studies.36-39 Both clindamycin and rifampicin have anti-inflammatory properties, which may contribute to their efficacy.38 When given together, these 2 antibiotics also have a synergistic bactericidal action.40

Another antibiotic combination with efficacy in a retrospective study is oral rifampin (10 mg/kg once daily)-moxifloxacin (400 mg daily)-metronidazole (500 mg 3 times daily) triple therapy, which enabled complete remission of refractory HS after a median of 2.4 months and 3.8 months of treatment in patients with stage I and stage II disease, respectively.41 Hurley staging was a prognostic factor of response when treating patients with this combination, and prolonged treatment was suggested for lasting results.

Tetracyclines34 and oral dapsone (50-200 mg/d)42-44 have been used in HS treatment with limited success compared with other antibiotics, including rifampin. Dapsone has not been evaluated in an RCT. Currently, monotherapy with dapsone or tetracyclines cannot be recommended. In particular, there is no evidence that doxycycline ameliorates HS, and it should not be used as treatment.

IV antibiotics with broad bacterial coverage, typically in combination with oral antibiotics, may be implemented for treatment of severe HS, often in patients who are not surgical candidates. In case reports and cohort studies, ertapenem, ceftriaxone, and other combination IV antibiotics were found effective.17,45,46 However, IV antibiotics may be an impractical, debilitating, and costly therapy for many patients. IV antibiotics can be seen as a bridge to surgery or other treatments.

Retinoids

Systemic retinoids (vitamin A analogues), typically used for acne, have been used in the treatment of HS with some success.47-51 A recent systematic review52 reported that 73% of patients who received etretinate (not available in the United States) and/or its metabolite acitretin experienced significant improvement of their HS lesions. Isotretinoin had dubious efficacy in the review—only 18% of patients who received it experienced a significant response. The significant adverse and teratogenic effects, as well as high relapse rates after discontinuation, make retinoids difficult for long-term use.6

Hormonal Therapy

HS has been associated with high rates of polycystic ovary syndrome (PCOS), irregular menstruation, hirsutism, and acne vulgaris, along with significantly higher total testosterone levels than in control subjects.53 Some patients notice variations in disease severity with their menstrual cycle and disease improvement following menopause, suggesting a possible hormonal influence.54 Consequently, oral contraceptive pills and antiandrogen therapies have demonstrated efficacy in patients with HS.55-58 A 12-month crossover study of 24 women participants with moderate to severe HS compared 50 µg ethinyl estradiol and 500 µg norgestrel daily on days 5 to 25 of each menstrual cycle with 50 µg ethinyl estradiol and 50 mg cyproterone acetate on days 5 to 14 of each menstrual cycle.55 Both treatment regimens were effective, with statistically significant improvement compared with baseline disease status. Additionally, finasteride, a 5α-reductase inhibitor, prescribed at 5 mg daily has been reported to improve lesions and provide remission up to 18 months in both men and women with HS.57,58 Spironolactone, a synthetic steroid with antiandrogenic activity, was effective at doses of 100 to 125 mg daily after 3 to 6 months of treatment in patients with mild to moderate HS.59 Metformin also has been used in HS patients with some success,60 but no clear data show that it helps.

Ultimately, hormonal manipulation may be considered in HS patients, and a workup for underlying PCOS and insulin resistance may be beneficial in women with the condition.56

Immunosuppressants

Several immunosuppressive agents have been utilized for the treatment of HS. Case studies report clinical success with cyclosporine dosed at 2 to 6 mg/kg/d, although no RCTs have been performed.61 In the largest case series identified, which included 18 patients, 50% of patients with recalcitrant HS who received cyclosporine dosed at 2 to 4 mg/kg/d improved with treatment.62

Corticosteroids, both systemic and intralesional, are used primarily for symptomatic flares as opposed to maintenance treatment for HS.63 Corticosteroids have not been extensively studied in HS, and the literature on their use is limited to single-patient case reports, and they are not feasible for long-term treatment due to the increased risk of adverse effects.

Methotrexate has limited efficacy as monotherapy for HS treatment. In an open study, no response was observed in 3 patients who received a weekly dose of methotrexate at 12.5 to 15 mg for a duration ranging from 6 weeks to 6 months.64 Azathioprine, 50 to 100 mg daily, also lacked efficacy in a retrospective study in patients with moderate to severe HS.65

Miscellaneous Oral Agents

In a prospective study, oral zinc gluconate, 90 mg once daily, enabled 36% of HS patients to achieve complete remission and 63.5% to achieve partial remission, with minimal adverse gastrointestinal tract effects. Treatment with zinc gluconate was considered suppressive in nature, since recurrences occurred after discontinuation.66

Biologics

More-aggressive treatments are needed for patients with moderate to severe HS who do not improve using traditional medical therapies. Biologic agents that target aberrant immune responses have become an option for patients with difficult to control disease. Adalimumab, a tumor necrosis factor α (TNF-α) inhibitor, in September 2015 became the first and only FDA-approved medication for the treatment of severe (stage II) HS.67 It also was approved for this indication by the European Union in July 2015.68 Phase 2 and 3 studies of adalimumab in patients with moderate to severe HS demonstrated that following loading dosing, adalimumab 40 mg delivered subcutaneously once weekly provided statistically significant disease improvement and a good adverse effect profile compared with biweekly dosing and placebo.30,69-71 Adalimumab was approved for HS at this dosing regimen, which entails higher loading and maintenance dosing compared with that used for the treatment of psoriasis.

Other TNF-α inhibitors, including infliximab and etanercept, also have been investigated for HS treatment. IV infliximab demonstrated encouraging results in 10 cohort studies and 1 RCT.72 In the RCT, 26% of HS patients who received infusions of 5 mg/kg of infliximab at weeks 0, 2, and 6 experienced a 50% or greater improvement in disease severity compared with only 5% of patients who received placebo.73 Infliximab was well-tolerated and provided significant improvement in quality of life and decreased pain from baseline.

Conversely, the use of etanercept for the treatment of HS has shown conflicting results.74-82 Ultimately, its lack of efficacy in HS was confirmed in a double-blind RCT in which etanercept 50 mg administered twice weekly for 24 weeks did not provide statistically significant improvement of disease activity or health-related quality of life compared with placebo.76

The use of ustekinumab, a human monoclonal antibody against the p40 subunit of interleukins 12 and 23, has been reported only in a limited number of HS patients.83 It is difficult to draw conclusions from these studies, and more large-scale clinical trials are needed to better assess the role of ustekinumab in HS treatment.

The use of anakinra, an interleukin 1 receptor antagonist that is FDA-approved for the treatment of rheumatoid arthritis, has been described in several case studies for HS treatment with conflicting results.84,85 It was more formally evaluated in an RCT comparing once-daily anakinra injections with placebo.86 After 12 weeks of treatment, the disease activity score was decreased in 67% of patients in the anakinra group compared with 20% of patients in the placebo group (P = .04). Anakinra was deemed effective, with no serious adverse events reported.

Laser and Light Therapy

Laser and light therapy are commonly used in the management of HS to provide longer-lasting disease remission and to prevent disease progression. These treatments work by ablative debulking of chronic lesions and by decreasing the number of hair follicles, sebaceous glands, and bacteria in lesional areas.87 The carbon dioxide laser is used for invasive laser surgery,88-95 whereas the 1064-nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser, intense pulsed light (IPL),96 and photodynamic therapy (PDT)97-100 provide noninvasive disease control.

The efficacy of the Nd:YAG laser has been confirmed in 1 prospective study101 and 2 randomized half-body controlled studies in patients with Fitzpatrick skin types III to VI.102,103 In the 2 randomized studies, patients experienced statistically significant improvement in Sartorius scores, ranging from 65.3% to 72.7%, at sites treated with Nd:YAG plus topical benzoyl peroxide and clindamycin compared with control sites treated only with topicals.102,103

A study was noted at ClinicalTrials.gov (NCT01063270) comparing clindamycin and rifampin alone or combined with the Nd:YAG laser but its results were not reported, implying that the addition may not have been effective compared with clindamycin and rifampin alone.104

The efficacy of IPL was demonstrated in an RCT in which twice-weekly IPL provided a 33% improvement in HS lesions after 4 weeks of treatment (P < .001).96 In an additional RCT, IPL plus methylene blue used as a photosensitizer delivered as niosomal gel provided patients with an even greater reduction in disease severity compared with delivery with non-niosmal gel (P < .01).100

Ultimately, studies suggest that laser and light therapies enable significant local disease improvement with few adverse effects, but repeated treatments are needed to prevent recurrences.

Surgical Therapy

When medical therapies have failed to control established HS or prevent the occurrence of new lesions, surgery typically is the next best treatment. HS surgical procedures, including local destruction, incision and drainage, mini-unroofing by punch debridement, standard unroofing (deroofing) to all margins, and surgical excision beyond all clinically apparent margins, have been performed with varying degrees of success.105 Options for wound healing after a surgical procedure include primary closure, secondary intention wound healing, skin grafting, and skin flaps. Surgical treatment should be individualized based on disease history and severity, and concurrent medical therapy often is essential.105

Conservative treatment and incision and/or surgical removal of abscesses and fistulas often are ineffectual, and operative excision is considered the only curative treatment.106 Excision with wide margins and adequate depth, and reconstruction with appropriate methods, can enable adequate disease control and remission.106 A systematic review and meta-analysis of 22 articles noted a 13% recurrence rate for wide excision, 22% for local incision, and 27% for deroofing.107 For wide excision, recurrence rates were 15% for primary closure, 8% for flaps, and 6% for grafting.107

The only RCT that identified evaluating surgery as a treatment for HS determined that the use of a gentamicin sulfate sponge following primary closure of surgical incisions resulted in shorter mean time of wound healing and fewer postoperative infections.108 While numerous surgical techniques have been described in the literature, no standardized surgical procedure has been recognized. The shortage of RCTs, varying consensus of treatment goals, and inter-individual differences between patients and surgeons has made this task difficult.109 However, studies suggest recurrence rates may be lower following more-aggressive surgical procedures, and a new emphasis has been made to offer these procedures earlier in the disease course.109

CONCLUSION

HS is a potentially devastating disease of the hair follicle that can have a major impact on patients’ quality of life. For physicians, it can be a difficult diagnosis to make and an even more challenging disease to treat. The only treatments substantiated by evidence from RCTs include topical clindamycin 1%, oral tetracycline, oral contraceptive and antiandrogen therapy, biologic agents (ie, adalimumab, infliximab, anakinra), Nd:YAG laser, IPL, PDT, and a gentamicin sponge following primary surgical closure.

Ultimately, there are few well-designed and adequately powered studies with a uniform patient population supporting the use of these and other treatments. While the FDA and European approval of adalimumab for the treatment of HS marked a major milestone in the management of HS, more RCTs are needed to better characterize HS and the efficacy of available treatment options.

As HS becomes a more widely recognized disease, we anticipate that more dedicated research will enable the emergence of a universally effective treatment.

 

Brooke Rothstein, BA, is at the Tufts University School of Medicine in Boston, Massachusetts.

Noah Scheinfeld, MD, is in the Department of Dermatology at Weill Cornell Medical College in New York, New York.

William W. Huang, MD, MPH, is in the Department of Dermatology at Wake Forest School of Medicine in Winston-Salem, North Carolina.

Steven R. Feldman, MD, PhD, is in the departments of dermatology, pathology, and public health sciences at Wake Forest School of Medicine in Winston-Salem, North Carolina.

Disclosures:

Brooke Rothstein, BA, has no conflicts of interest to disclose.

Noah Scheinfeld, MD, is a speaker and has served on the advisory board for AbbVie.

William W. Huang, MD, MPH, has no conflicts of interest to disclose.

Steven R. Feldman, MD, PhD, is a consultant and speaker for Galderma, Stiefel/GlaxoSmithKline, Abbott, Warner Chilcott, Janssen, Amgen, PhotoMedex, Genentech, Biogen Idec, and Bristol-Myers Squibb. He has received grants from Galderma, Astellas, Abbott, Warner Chilcott, Janssen, Amgen, PhotoMedex, Genentech, Biogen Idec, Coria/Valeant, PharmaDerm, Ortho, Aventis, Roche Dermatology, 3M, Bristol-Myers Squibb, Stiefel/GlaxoSmithKline, Novartis, Medicis, Leo, HanAll Pharmaceutical, Celgene, Basilea, and Anacor. He has received stock options from PhotoMedex. He is the founder of and holds stock in Causa Research.

The Center for Dermatology Research is supported by an unrestricted educational grant from Galderma Laboratories, LP.

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