Danny Barlev, MD1; Daniel B. Eisen, MD2; Ali Alikhan, MD1
1Department of Dermatology, University of Cincinnati, OH, USA
2Department of Dermatology, University of California Davis, CA, USA
Hidradenitis suppurativa (HS) is a chronic disease of the follicular unit that often leads to marked impairment of quality of life and usually affects the axillary, perineum and inframammary regions resulting in tender subcutaneous nodules, abscesses, fibrosis and sinus tract formation. New updates on HS underscores the role of various genes as well as the innate and adaptive immune response in its pathogenesis. Although every patient requires an individualized approach to treatment, topical therapy and antibiotics are mainly used for mild to moderate disease, whereas various systemic immune modulators and/or surgical approaches play a pivotal role in moderate to severe disease. New treatments using various immune modulators, laser modalities and other novel agents provide clinicians with better ways of managing HS.
hidradenitis suppurativa, antibiotics, biologics, immune modulators, lasers, surgery
Hidradenitis suppurativa (HS) is a chronic disease of the follicular unit that results in significant impairments to quality of life and increases emergency room visits and inpatient hospitalizations.1-3 It most commonly occurs in the axillary, inguinal, and anogenital regions in post-pubertal females.3 HS may result in sinus tract formation and severe scarring, and is difficult to treat, with many patients never achieving complete clearance of lesions. Ongoing research and new insights into pathogenesis and treatment will hopefully improve the management of HS patients.
Prevalence of HS is a matter of debate, with estimates ranging from 0.052% to 1% of the population, likely reflecting differences in research methodology and populations studied.1,3-12 A recent population-based study in Olmsted County, Minnesota, found an overall annual age- and sex-adjusted incidence of 6 per 100,000, supporting that HS is an uncommon diagnosis.7 Incidence appears significantly higher in women, particularly in those aged 18 to 44 years. HS may occur more commonly in certain races, but this is still unclear.13
A review of 846 Dutch patients identified that male sex, disease duration, obesity, pack-year smoking, and lesions in axillary, perianal, and mammary regions are significant factors for more severe disease.8
About one-third of HS patients report a family history of the disease, and families with an autosomal dominant mode of inheritance have been identified.14 There may be a strong association between HS and Crohn’s disease – in a recent patient questionnaire of 1,093 patients with inflammatory bowel disease, 23% of patient responded to having signs and symptoms of HS.15 Other diseases that may occur concomitantly include acne conglobata, dissecting cellulitis, pilonidal cysts, spondyloarthritis,
pyoderma gangrenosum, and synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome.4,16,17
Hypertension, metabolic syndrome, depression, anxiety, obesity and smoking are important co-morbidities among HS patients.1,18-20 Furthermore, smoking and obesity are not only predictive of disease severity but are also correlated with lower rates of disease remission.20,21
The pathogenesis of HS is complex. Although it was previously believed to be a disorder of apocrine glands, HS is now thought of as a disorder of follicular occlusion. Whether immune dysregulation precedes or follows follicular occlusion remains to be determined, but it is evident that both play a role.22-36
Of note, recent data demonstrates that many familial cases of HS show mutations in gamma secretase, a protease that cleaves intramembrane receptors and regulates follicular keratinization, elucidating further the role of follicular occlusion in the disorder.37-40
Both innate and adaptive immune dysregulation has been demonstrated via decreased expression of epithelial-derived antimicrobial peptides (such as ribonuclease, human beta-defensin 3 and toll like receptor 4), which may result in excessive inflammatory response, as well as overexpression of pro-inflammatory cytokines (e.g., interleukin (IL)-1, IL-10, tumor necrosis factor (TNF)-alpha, IL-17, IL-22) in HS lesions.22-24,26-28,33 Additional factors that contribute to HS include bacterial biofilms, abnormal secretion of apocrine glands, abnormal invaginations of the epidermis leading to sinus tract formation, and deficient numbers of sebaceous glands.35,41-44 Hyperandrogenism and/or vitamin D deficiency may be involved, although their role is unclear at this time.45,46
HS is characterized by recurrent inflammatory nodules, cysts, abscesses and sinus tracts in apocrine gland-bearing sites such as the axilla, groin, perianal and/or inframammary areas.47 The lesions are frequently accompanied by chronic drainage. The clinical presentation of HS is highly variable in terms of cutaneous features, distribution, presence of complications (fistula formation, lymphedema, scrotal elephantiasis), extracutaneous features (arthritis, interstitial keratitis) and associated constitutional symptoms (i.e., fever and malaise).47
HS affecting the anogenital region may be difficult to differentiate from Crohn’s disease, especially given the strong association between the two disorders and that they can both present clinically as fistulas and sinuses, and histologically as granulomas.48 Since HS is a chronic inflammatory disease, anemia and hypoproteinemia may develop. Furthermore, HS lesions can form fistulae to the rectum, vagina, urethra, peritoneum and/or bladder. Reactive arthritis and SAPHO syndrome has been described in HS patients.49 Additionally, aggressive squamous cell carcinoma may form in areas of chronic scarring and carry a morbid prognosis.50
HS can be staged by either the Hurley staging system (Table 1) or the newer Sartorius system (Table 2). The Hurley system is more clinically applicable while the Sartorius system is used primarily for research.51
Search for biomarkers that help diagnose HS and/or correlate its severity have been undertaken. Analogous to Sartorius clinical staging, these tests remain largely for research use, since diagnosis is generally achievable via clinical findings and disease location.52-55
|I||Abscess formation, single or multiple, without sinus tract and scarring|
|II||One or more widely separated recurrent abscesses with sinus tracts and scarring|
|III||Multiple interconnected tracts and abscesses throughout an entire area|
|Table 1. Hurley staging of HS|
|The Sartorius Hidradenitis Suppurativa Score|
|Anatomic region involved|
(3 points per region)
Other inflammatory region
|Number and score of lesions||2 points for each nodule|
4 points for each fistula
1 point for each scar
1 point each for “other”
|Longest distance between|
2 relevant lesions
|Less than 5 cm (2 points)|
Less than 10 cm (4 points)
More than 10 cm (8 points)
|Lesions clearly separated by normal skin in each region||Yes (0 points)|
No (6 points)
|Table 2. The Sartorius Hidradenitis Suppurativa Score is comprised of counting involved regions, nodules and sinus tracts|
Treatment of HS varies widely depending on disease severity, with many treatments supported by weak scientific evidence. Topical, systemic, and surgical therapies are available and are often used in combination. The authors list their treatment ladder in Table 3. Non-pharmacologic therapies include avoidance of tight-fitting clothing, reassurance, smoking cessation, management of underlying depression and anxiety, support group referral, and weight loss.
Pain is a common problem expressed by HS patients and must be addressed.56 Given the chronicity of HS, opioid dependence is a significant concern. Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are good initial therapies,57 while pregabalin, gabapentin, selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) may be considered as second-line agents.58
Both topical and systemic antibiotics have been widely used for patients with HS. A randomized controlled study of 30 patients treated with topical clindamycin 1% solution found the
clindamycin group did significantly better than the placebo group at 3 months.59 In another randomized trial, Jemec et al. suggested that topical clindamycin has similar efficacy to systemic tetracycline (500 mg twice daily for 3 months).60
Tetracyclines are often used for mild to moderate HS, although published data (in the form of trials) regarding their efficacy is limited. We commonly prescribe doxycycline 100 mg orally once to twice daily for our HS patients, and may taper down after several months based on patient response and tolerance.58 Two prospective trials that looked at combination treatment with systemic rifampin and clindamycin suggest this treatment might be beneficial.61,62 However, another series reported a large proportion of patients needed to discontinue this regimen due to gastrointestinal side effects.63
|Hidradenitis Suppurativa Treatments by Hurley Stage|
|Hurley Stage I to II||Topical, injectable and intralesional|
|Surgical and physical options|
|Hurley Stage II to III||(includes Stage I to II approaches)|
|Table 3. Treatment summary for HS by Hurley Stage|
Dapsone is considered relatively ineffective for HS. A study of 24 patients treated with dapsone reported improvement in 9 (38%), while 15 (62%) did not experience any improvement.64
Although data supporting their efficacy is limited, antimicrobial cleansers such as chlorhexidine and benzoyl peroxide are often applied daily to affected areas.43,57,65
Anti-androgens such as spironolactone and cyproterone acetate, as well as oral contraceptives, may be considered in female patients who have a history of hormonal abnormalities or are not responding to conventional treatment(s).66,67 A randomized controlled trial of 18 female patients who received either daily ethinyloestradiol 50 mg/norgestrel 500 mg or ethinyloestradiol 50 mg/cyproterone acetate 50 mg for 6 months demonstrated improvement in 5 patients, no change in 4, and worsening in 2.66
Finasteride has been suggested as another treatment option in HS. A series of 3 pediatric patients receiving finasteride for HS showed marked reduction in the amount and severity of flares.68 A similar trial of 7 patients showed complete healing of lesions in 3 patients and reduction in suppuration and inflammation in the remaining 4 patients.6
Tumor Necrosis Factor-Alpha (TNF-a) Inhibitors
Biologic agents are increasingly utilized in the management of moderate to severe HS (Table 3). Among TNF-a inhibitors, infliximab is one of the better studied medications. A randomized double-blind, placebo-controlled trial, in which 38 subjects received infliximab (5 mg/kg) infusions at 0, 2 and 6 weeks compared to placebo, showed that 60% of patients in the infliximab group compared to 5.6% of patients in the placebo group achieved 25-50% decrease in their severity scores at 8 weeks.70 A long-term study of 10 patients who received infliximab every 8 weeks after an initial loading regimen found 2 patients (20%) had no response to treatment after five doses and 5 (50%) patients experienced disease recurrence after a median treatment period of 37 weeks.71 Another prospective cohort trial with more frequent dosing (every 4 weeks) found that 9 of 11 patients (mean follow-up of 60.3 months) had measurable improvement after undergoing treatment. Two patients failed treatment at 12 and 19 months.65
Adalimumab, unlike infliximab, is self-administered by the patient.72,73 In a double-blind, randomized, controlled trial, 15 patients received adalimumab 80 mg subcutaneously (SC) at baseline followed by 40 mg SC every other week for 12 weeks. A significantly better reduction in Sartorius score was seen at 12 weeks in the treatment group compared to placebo.74 A recent large multicenter study demonstrated that weekly dosing of adalimumab achieved better clinical outcomes than bi-monthly dosing.75
Etanercept is considered inefficacious for HS. A double-blind, placebo-controlled study of 20 patients in which etanercept 50 mg was administered twice weekly for 3 months, followed by open-label etanercept 50 mg twice weekly for an additional 3 months found no significant difference in outcomes between groups.76
Ustekinumab, an IL-12/IL-23 antibody, may also be efficacious for moderate to severe HS. In a small prospective trial, 3 patients received three 45 mg SC injections at 0, 1 and 4 months. At 6 months, 1 patient had remission of disease, the second patient improved, and the third had no response.77
Most recently, 5 patients receiving anakinra, an antibody directed against IL-1, showed mean decrease in modified Sartorius score of 34.8 points.78 A report of the related agent, canakinumab, also demonstrated good response.79
Cyclosporine has been used in severe HS recalcitrant to other therapies, though data is scant and mostly case reports.80 Two case reports suggest that prednisone may be used in those patients who have concomitant pyoderma gangrenosum or arthritis.81,82 Methotrexate is of limited value in the management of HS.83
In our experience, intralesional triamcinolone at concentrations ranging from 5 mg/cc to 10 mg/cc can help with acutely inflamed nodules and cysts, as well as with scar formation. It is important to be confident that these are not injected into infectious abscesses prior to administration.58
Isotretinoin has demonstrated mixed results for the management of HS. In a retrospective trial of 68 patients, only 48 actually completed the trial (29.4% dropped out due to side effects and/or lack of efficacy). Sixteen patients (23.5%) had clearance of lesions, 14 patients (20.6%) had marked improvement, 11 (16.2%) patients improved, and 7 (10.3%) experienced no change in their disease.84 A later retrospective report with 88 patients found that only 14 patients (16.1%) noted improvement, 67 patients (77%) had no change, and 6 patients (6.9%) experienced disease worsening.85
Many providers feel acitretin is more effective than isotretinoin in the treatment of HS, probably based upon initially favorable reports. Boer et al. found in their retrospective trial of 12 patients that 10 had marked improvement or complete disease resolution and the remaining 2 improved from baseline. However, Mutasiak et al. reported less favorable results in a prospective trial of 17 patients. Eight patients exhibited a 50% reduction in HS severity index. However, 8 patients (47%) dropped out of the study due to lack of efficacy or adverse effects.86
Alitretinoin has a similar pharmacologic mechanism to acitretin, but a much shorter half-life and, thus, may carry a lower teratogenic risk. In one trial, 14 female patients of childbearing age received alitretinoin (10 mg daily) for 24 weeks with significant improvement in Sartorius and Dermatology Life Quality Index (DLQI) scores recorded in 78.5% of cases.87
Surgery is frequently performed to control moderate and severe HS. The type of surgery depends on the severity and location of the disease and can be limited or extensive.88 In one trial, 73 patients underwent a deroofing procedure (in which the roof of a lesion is surgically removed and the floor of the lesion is left exposed to heal by second intention) and were followed for a median of 34 months; 83% of patients showed no recurrence.89
A study comparing recurrence rates of HS after incision and drainage (limited excision and wide radical excision) found that all cases recurred (median time = 3 months), 42.8% recurred in the local excision (median time = 11 months), and 27% recurred in the wide excision group (median time = 20 months).90
Alharabi et al. conducted a retrospective analysis of 50 operative procedures for 32 patients who underwent wide surgical excision. Twenty six patients (81.25%) showed no recurrence after surgery.91
Lasers and Lights
Various laser and light treatments, alone or in combination with surgery and/or systemic therapy, have been suggested in the management of HS. Photodynamic therapy (PDT) has been reported several times. The range of results have been described as good92-94 to mediocre95,96 in terms of efficacy. In general, evidence regarding PDT for HS is of such limited or poor quality that meaningful conclusions are not ascertainable.
Bath psoralen + ultraviolet A (PUVA) was undertaken in a retrospective trial with 13 patients receiving bath PUVA twice weekly. Five patients had clearance or near clearance of their
lesions, 4 patients had moderate clearance, and 4 had minimal to no response. Among the 5 patients in which clearance or near clearance was documented, the response was sustained for at least a 3-month follow-up period.97 Long-pulsed neodymium:yttrium-aluminum-garnet laser (Nd:YAG) has demonstrated promising results in a randomized trial. Mahmoud et al. enrolled 22 subjects who received monthly Nd:YAG laser sessions for 4 months and reported a 72.7% mean improvement on the laser-treated side compared to 22.9% on the control side.98 A subsequent trial of 19 patients showed a mean 31.6% reduction in Lesion Area and Severity Index (LASI) over all anatomic sites 2 months following treatment.99
Intense pulse light has also been used. In a prospective trial, 18 patients were randomized to treatment on one side of the axillae, groin, or inframammary region two times per week for 4 weeks. There was significant reduction in Sartorius score of 55% after completion of treatment compared to 10% on the untreated side. Patients maintained a 33% reduction in their Sartorius score compared to 3% on the untreated side at 12 months.100
Lastly, several studies show that carbon dioxide (CO2) laser ablation is an efficacious treatment in HS.101-103 In a trial by Hazen et al., all (61) patients who underwent CO2 laser ablation followed by marsupialization had clearance of treated areas. Of note, 17 patients (28%) experienced postsurgical hypertrophic granulation tissue appearing approximately 5 weeks after surgery.104
Cryoinsufflation, a modified spray cryotherapy performed by injecting liquid nitrogen through a needle directly into HS tracts, has been recently described. Results are restricted to a single patient experience.105
One case report of a patient with moderate HS who underwent four treatments of 50 units of botulinum toxin type A (100 units dissolved in 4 mL of 0.9% sodium chloride solution) injected to each axilla (administered over 3 years) achieved lesion clearance following the second treatment (6 months) with maintenance of remission 1 year after completion of treatment.106
|Biologics||Author and Trial Design||N||Dose/Frequency||Followup from Treatment Initiation||Result|
|Adalimumab||Miller et al. (2011), double-blind randomized controlled trial||15||Adalimumab 80 mg SC at|
baseline followed by 40 mg
|12 weeks||Reduction in Sartorius score of 10.7|
points at 6 weeks and 11.3 points at
12 weeks was seen in the treatment
group compared to 7.5 points and
5.8 points in the placebo group,
|Kimball et al. (2012), phase 2, parallel, randomized, placebo-controlled trial consisting of a blinded 16-week period (period 1) and an open-label|
36-week period (period 2)
|154||Adalimumab, 40 mg/wk; adalimumab, 40 mg EOW; or placebo. All patients received adalimumab, 40 mg EOW, at the beginning of period 2 but switched to weekly dosing if the response was suboptimal at weeks 28 or 31||16 weeks||At week 16, 3.9% of patients receiving placebo (2 of 51), 9.6% of patients receiving adalimumab EOW (5 of 52), and 17.6% of patients treated weekly (9 of 51) achieved minimal or mild HS-PGA score by week 16|
|Infliximab||Paradela et al. (2012), prospective trial||10||Infliximab 5mg/kg every 8 weeks after initial standard loading dose||37 weeks||2 patients (20%) had no response to treatment after 5 doses; 5 (50%) patients experienced disease recurrence|
|Grant et al. (2010), randomized double-blind placebo-controlled crossover trial||38||Infliximab 5mg/kg infusions at 0, 2 and 6||8 weeks||60% of patients in the infliximab group compared to 5.6% of patients in the placebo group achieved 25%-50% decrease in in their severity scores|
|Moriarty et al. (2014), prospective cohort trial||11||Infliximab 5mg/kg infusion every 4 weeks after initial standard loading dose||60.3 months||9 patients had measurable improvement after undergoing treatment; 2 had treatment failure at 12 and 19 months|
|Ustekinumab||Gulliver (2012), prospective cohort trial||3||Ustekinumab 45 mg SC injections at 0, 1 and 4 months||6 months||1 patient had remission of disease, the second patient improved, and the third had no response|
|Etanercept||Adams et al. (2010), double-blind, placebo-controlled study||20||Etanercept 50 mg SC was administered twice weekly for 3 months, followed by open-label etanercept 50 mg SC, twice weekly for an additional 3 months||6 months||No statistically significant difference among PGA, patient global assessment, and DLQI at 12 or 24 weeks between treatment and placebo groups|
|Anakinra||Leslie (2014), prospective cohort||5||Anakinra 100 mg SC daily||8 weeks||Mean decrease in modified Sartorius score of 34.8 points|
|Table 4. Summary of trials for biologics used in HS|
N = number of patients, SC = subcutaneous, DLQI = dermatologic quality of life Index, PGA = physician global assessment, EOW = every other week dosing
A study of 22 patients with mild to moderate HS receiving zinc gluconate (90 mg/day) for at least 6 months (with a mean follow-up of 23.7 months) demonstrated a positive response in all patients with complete remission in 8 and partial remission in 14 patients.107
Eighteen of 25 (72%) patients who received metformin (500 mg daily to 500 mg three times daily) had a mean reduction in their Sartorius sore of 12.7 at 24 weeks of treatment. Seven patients had no response.108
HS is associated with significant morbidity and health care costs. Many treatments are available to meet the needs of these patients, though more data is warranted to determine optimal management algorithms. Care needs to be individualized to each patient’s situation and preferences, with a strong emphasis on improving quality of life and management of related comorbidities.
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