There are various treatment options for hidradenitis suppurativa (HS), a recurrent and suppurative disease, but none is wholly satisfactory or effective. There have been many reports on the efficacy of biologic drugs for the treatment of HS; this article is an in-depth review of the published evidence on this topic. Because the current evidence is limited, randomized, double-blinded, placebo-controlled trials are needed to better elucidate the future of these drugs for the treatment of HS.
Hidradenitis suppurativa (HS) is a recurrent and suppurative disease with an insidious onset. It is characterized by deep furuncles, abscesses, fistulas, sinus tracts, and scarring and has a prevalence of 0.3% to 4% of the general population. The average age of onset is 23 but may fall anywhere between postpubertal age to middle age. HS is more prevalent in women than men by a ratio of between 2:1 and 5:1, with genitofemoral lesions found more often in women and anogenital lesions found more often in men. The most commonly affected site, the axilla, is involved in an equal proportion of men and women. Other affected areas may include the areola, inframammary folds, periumbilical skin, scalp, zygomatic and malar face, buttocks, thighs, popliteal fossa, ear canal, and eyelids. Patients with active disease generally develop 2 furuncles per month with an average disease duration of 19 years.
The initial symptoms of HS are localized erythema, pruritus, and hyperhidrosis followed by the spontaneous development of painful and tender red nodules and abscesses with incessant purulent drainage, open comedones, sinus tracts, and scarring. The pathologic event that culminates in full-blown HS is hyperkeratosis of the terminal hair follicle that leads to an occlusive keratin plug. Eventual rupture of the lower end of the occluded follicle leads to an acute inflammatory infiltrate. This inflammation can be confined to the hair follicle leading to a granulomatous reaction and limited disease. If the inflammation is not confined or if nearby perifollicular inflammatory nodules coalesce, however, a large abscess forms, extends to, and destroys the adnexal apocrine glands. Follicular epithelium may proliferate in an attempt to confine the inflammation and form sinus tracts, which can secondarily become infected with bacteria. Multiple abscesses and sinus tracts in the dermis and subcutaneous tissues form a reticulated network that can extend to the fascia and muscle. HS is thus a misnomer, because the pathogenesis does not involve sweat gland dysfunction as originally thought. Because of the similarities in their development, HS, dissecting cellulitis, acne conglobata, and pilonidal sinus are known as the follicular occlusion tetrad. Other names for HS include apocrinitis, hidradenitis axillaries, and acne inversa, with the latter rapidly gaining in popularity and acceptance. Although 1 study found 34% of first-degree relatives of probands had HS, a specific genetic locus or specific HLA association has yet to be elucidated.
- 1.
HS is
- A.
Is a recurrent disease
- B.
Is a suppurative disease
- C.
May have an insidious onset
- D.
All of the above
- A.
- 2.
Which treatment modality for HS is most likely to result in decreased activity of HS?
- A.
Oral antibiotics
- B.
Antiandrogens
- C.
Incision and drainage
- D.
Surgical excision
- A.
- 3.
Adalimumab is
- A.
Chimeric monoclonal antibody to TNF-α
- B.
The oldest TNF-α inhibitor on the market
- C.
Approved for treatment of HS
- D.
Administered via weekly or bimonthly self-injections
- A.
- 4.
Patients taking adalimumab
- A.
Often develop drug-induced lupus
- B.
May have reactivation of latent TB
- C.
Do not have to worry about effects of the drug on their CHF
- D.
Have an increased risk of developing psoriasis
- A.
- 5.
Alefacept
- A.
Has been proved an effective treatment of HS
- B.
Is a TNF-α inhibitor
- C.
May cause lymphopenia
- D.
Prevents B-cell activation
- A.
- 6.
Etanercept
- A.
Is a competitive inhibitor of TNF-α
- B.
Is a fusion protein of IgG and TNF-α
- C.
Is administered intravenously
- D.
As a treatment of HS is inefficacious based on evidence to date
- A.
- 7.
Which of the following is true of etanercept?
- A.
Injection site reactions are fairly common
- B.
Necrotizing vasculitis due to cryoglobins has been reported as an adverse effect of treatment
- C.
May result in a demyelinating process
- D.
All of the above
- A.
- 8.
Which of the following is correct?
- A.
Both infliximab and etanercept induce apoptosis of TNF-α bound cells in vitro
- B.
Infliximab is a less specific agent for TNF-α than etanercept
- C.
Complete resolution is the rule for treatment of HS with infliximab
- D.
The concomitant administration of other medications in many of these studies and cases makes judgment on the efficacy of infliximab difficult
- A.
- 9.
Infusion reactions caused by infliximab are attributable to
- A.
Anaphylactic/anaphylactoid reactions
- B.
Serum-sickness–like reactions
- C.
Antibody formation against infliximab
- D.
Any or all of the above
- A.
- 10.
All of the following are true except:
- A.
Grade A and B recommendations for treatment of HS with biologics are justified by the available evidence
- B.
Biologics can be considered as treatment for patients with HS who have failed conventional therapy
- C.
The use of biologic drugs as treatment of HS has proved to have variable long-term results
- D.
Randomized, double-blinded, placebo-controlled trials are needed to better determine the role of biologic drugs for the treatment of HS
- A.
The diagnosis of HS is based on clinical findings and is substantiated by a history of recurrence, onset after puberty, poor response to antimicrobials, and overall disease duration greater than 6 months. Biopsy may be performed to exclude cutaneous Crohn disease or the development of squamous cell carcinoma. Laboratory findings, such as elevated erythrocyte sedimentation rate, leukocytosis, decreased serum iron, and alterations in the serum protein electrophoresis, are reflective of chronic inflammation and thereby nonspecific. Complications include anemia of chronic disease, septicemia, decreased mobility from scars, anal strictures, urethral fistulas, disfiguring genital edema, amyloidosis, locally aggressive squamous cell carcinoma, and malignancy in general. These complications, along with the significant morbidity related to pain and disability from the disease, emphasize the urgent need for reliably effective treatment.
Traditional therapies for HS
Although there are various treatment options for HS, none of the traditional therapies is wholly satisfactory or uniformly effective. Therapy varies based on the severity of disease, although there is considerable overlap between treatment groups. Mild HS consists of solitary nodules and abscesses, and treatment is generally conservative. Mainstays of treatment are nonsteroidal anti-inflammatory drugs for pain and inflammation, antiseptics, antibacterial soaps, warm compresses, hydrotherapy, and antibiotics. Bacteria may lead to secondary infection but this is not likely central to the pathogenesis of the disease. Staphylococcus aureus and coagulase-negative Staphylococci are the 2 most commonly cultured organisms, although Streptococcus, gram-negative rods, and anaerobes are also frequently isolated. Antimicrobial treatment generally consists of topical clindamycin or oral antistaphylococcal agents for axillary disease, whereas more broad-spectrum coverage is called for in those with perineal disease. The average duration of a HS nodule is 6.9 days, which is approximately the same duration as a course of antibiotics, making it difficult to determine if antibiotics are rally effective. Oral contraceptive pills with a high estrogen:progesterone ratio as well as immunosuppressive drugs, such as cyclosporine, azathioprine, and prednisone, are occasionally successful. Single nodules may be injected with intralesional triamcinolone (3–5 mg/mL) to decrease inflammation. Topical and oral retinoids inhibit keratinization and have been used with some success in mild to moderate HS. Acitretin and isotretinoin are more often used to decrease inflammation before surgery than as definitive treatments. Although there is no definitive evidence linking hyperandrogenism and HS, antiandrogens, such as cyproterone acetate and the 5α-reductase inhibitor, finasteride, also have been used with varying degrees of success. Incision and drainage of abscesses is not recommended because it is only transiently beneficial and does nothing to halt progression of the disease. On an individual basis, however, incision and drainage might be indicated to relieve excessive lesional pain. Weight loss and avoidance of heat and humidity can help reduce maceration and irritation of the affected sites. Other measures, such as avoidance of shaving affected areas, eliminating tight synthetic clothing, lowering stress, and smoking cessation, have only anecdotally been associated with amelioration of the disease.
Moderate disease is characterized by multiple nodules and abscesses with purulent discharge. It can be treated with similar therapies as for mild disease with the addition of limited excision if needed. Unroofing and marsupialization of individual nodules or tracts may also be performed, although such limited extent surgical intervention is less beneficial in the long term than en bloc excision. Carbon dioxide laser treatment is a less-invasive method of removing affected skin than traditional scalpel surgery. Disadvantages of carbon dioxide laser treatment and cryotherapy, another modality used to treat mild to severe HS, are substantial increases in healing time and pain. Radiotherapy has also been used for HS, but the long-term side effects make it less popular and probably less safe.
Severe HS is comprised of multiple sites of draining abscesses and sinuses with associated scarring. In this case as well as some moderate cases of HS, local excision with wide margins has traditionally been the only effective therapy. Nevertheless, there is still a risk of recurrence adjacent to the excision site or even at a distant site.
Screening for depression and psychological support is an important dimension of treatment, because patients with moderate to severe HS become progressively unable to interact socially or maintain employment due to pain, odor, and shame. It is important to stress to patients that HS is neither caused by poor hygiene nor contagious. Because surgical intervention can be disfiguring and not entirely curative, clinicians have pursued alternative treatment modalities. Biologic drugs, although not yet approved for treatment of HS, offer a potentially promising solution.
Evidence-based grading of biologic drugs
Many of the studies discussed in this review use scoring systems to measure the efficacy of the drug being discussed. The Sartorius scale, one of the most commonly used scoring systems for HS, tallies points based on the number of regions involved, lesion types (ulcers, fistulas, nodules, or scars), and number, size of individual lesions, and separation of affected tissue from normal tissue. The Dermatology Life Quality Index (DLQI) assesses the effect of the disease on 6 separate categories, including daily activities, work and school, leisure activities, and personal relations. Another often-mentioned tool is the visual analog scale (VAS), which is used by patients to grade their own perception of disease severity.
Although many reports on the efficacy of biologic drugs for off-label treatment of HS have surfaced, to the authors’ knowledge, this is the first in-depth review of the published evidence on this topic. The authors compiled data via a PubMed search of each of the 5 biologic agents and HS. Then a systematic review was performed of the evidence and each relevant article assigned an evidence level based on the type of study and its quality. Evidence levels range from 1 to 4 with stratification standards borrowed from Harbour and Miller’s system of evidence-based grading. The endpoint was a final recommendation as to the efficacy of each drug for the treatment of HS based on the amassed evidence. A grade A recommendation corresponds to studies rated as 1 (randomized controlled trials and meta-analyses); a grade B recommendation is based on evidence characterized as level 2+ (case-control studies, cohort studies, and systematic review of anything other than a randomized controlled trial); a grade C recommendation is reserved for level 2 evidence (open-label clinical trials, retrospective analyses, and extrapolated evidence from level 2+ studies); and finally, a grade D recommendation is conferred on level 3 studies (case reports and case series) and level 4 studies (anecdotal evidence and expert opinion). This grading system was chosen to clearly and consistently judge the strength of the available evidence and transparently display how recommendations were arrived at.
Evidence-based grading of biologic drugs
Many of the studies discussed in this review use scoring systems to measure the efficacy of the drug being discussed. The Sartorius scale, one of the most commonly used scoring systems for HS, tallies points based on the number of regions involved, lesion types (ulcers, fistulas, nodules, or scars), and number, size of individual lesions, and separation of affected tissue from normal tissue. The Dermatology Life Quality Index (DLQI) assesses the effect of the disease on 6 separate categories, including daily activities, work and school, leisure activities, and personal relations. Another often-mentioned tool is the visual analog scale (VAS), which is used by patients to grade their own perception of disease severity.
Although many reports on the efficacy of biologic drugs for off-label treatment of HS have surfaced, to the authors’ knowledge, this is the first in-depth review of the published evidence on this topic. The authors compiled data via a PubMed search of each of the 5 biologic agents and HS. Then a systematic review was performed of the evidence and each relevant article assigned an evidence level based on the type of study and its quality. Evidence levels range from 1 to 4 with stratification standards borrowed from Harbour and Miller’s system of evidence-based grading. The endpoint was a final recommendation as to the efficacy of each drug for the treatment of HS based on the amassed evidence. A grade A recommendation corresponds to studies rated as 1 (randomized controlled trials and meta-analyses); a grade B recommendation is based on evidence characterized as level 2+ (case-control studies, cohort studies, and systematic review of anything other than a randomized controlled trial); a grade C recommendation is reserved for level 2 evidence (open-label clinical trials, retrospective analyses, and extrapolated evidence from level 2+ studies); and finally, a grade D recommendation is conferred on level 3 studies (case reports and case series) and level 4 studies (anecdotal evidence and expert opinion). This grading system was chosen to clearly and consistently judge the strength of the available evidence and transparently display how recommendations were arrived at.
Biologic drugs
The 5 biologic drugs included in this review are adalimumab (Humira), alefacept (Amevive), efalizumab (Raptiva), etanercept (Enbrel), and infliximab (Remicade). Adalimumab, etanercept, and infliximab are tumor necrosis factor (TNF)-α inhibitors whereas alefacept and efalizumab are T-cell–specific agents. To date, the data on the efficacy of the latter 2 drugs for treatment of HS are sparse. Efalizumab was recently withdrawn from the marketplace due to perceived increased risk of progressive multifocal leukoencephalopathy, making the usefulness of this agent a moot point.
Although mostly produced by monocytes and macrophages, TNF-α is also produced in the skin by keratinocytes, melanocytes, Langerhans cells, activated T cells, natural killer cells, and mast cells in response to infection or keratinocyte death. Soluble TNF-α monomers form a trimer, which binds to the TNF-α receptor 1 or TNF-α receptor 2, entities found in most cells of the body excluding erythrocytes and unstimulated lymphocytes. Cross-linked receptors induce signal transduction cascades that ultimately influence cell differentiation, mitogenesis, regulation of cytotoxic responses, inflammation, immunomodulation, and wound healing. Specifically, TNF-α receptor activation upregulates vascular cell leukocyte adhesion molecule 1, intercellular adhesion molecule 1 (ICAM-1), E-selectins, and metalloproteinases 1 and 3, all of which promote cellular infiltration. It also increases vascular endothelial growth factor, increases production of proinflammatory cytokines, increases keratinocyte production of transforming growth factor α causing epidermal proliferation, inhibits melanocyte activity, promotes growth of fibroblasts, and releases acute phase reactants from hepatocytes.
Most available data on the TNF-α inhibitors are related to studies of rheumatoid arthritis, but use for dermatologic conditions is increasingly common. TNF-α, via its induction of proinflammatory cytokines and accretion of an inflammatory infiltrate, is necessary for granuloma development and maintenance. Although HS is not primarily a granulomatous disease, granulomas have been observed in histologic examination of the skin surrounding HS sites. Inhibiting TNF-α is also thought to inhibit the keratinocyte activation cycle and to downregulate keratin 6, thereby preventing hyperkeratinization. High levels of TNF-α often go hand in hand with interleukin-1α, which has been shown to cause hypercornification of the follicular infundibulum and may be involved in the perpetuation of HS in its chronic state. Some of the current treatments of HS are also immunosuppressive or anti-inflammatory drugs, lending further credence to the hypothesis that immune dysregulation is at least partially responsible for the development of this disorder.
Side effects of TNF-α inhibitors include injection site reactions, reactivation of latent tuberculosis (TB), increased risk of sundry bacterial and fungal infections, demyelinating disease, worsening of congestive heart failure, hepatotoxicity, reactivation of hepatitis B virus, hypersensitivity reactions, pancytopenia and aplastic anemia, and autoimmune diseases. Although the most common infections associated with biologic treatment are upper respiratory tract infections, bronchitis, and urinary tract infections, deep fungal infections and TB are also documented. Contraindications to treatment are active TB, known active and serious infections, hepatitis B, and heart failure classified as New York Heart Association (NYHA) level III or level IV. Caution is advised for patients with latent TB, malignancy, heart failure classified as NYHA level I or II, or a hematologic disorder.
Adalimumab (Humira)
Adalimumab is a monoclonal immunoglobulin G1 antibody to soluble and membrane-bound TNF-α. Because it is fully human, it is hoped it will prove less immunogenic than the other TNF-α inhibitors on the market. Adalimumab is administered subcutaneously and is absorbed slowly, reaching peak concentration in approximately 5 days with a mean half-life of 2 weeks. It is delivered via an autoinjectable pen device or prefilled syringe, thus allowing for home administration. Adalimumab is currently approved by the Food and Drug Administration for treatment of rheumatoid arthritis, psoriatic arthritis and psoriasis, polyarticular juvenile idiopathic arthritis, ankylosing spondylitis, and Crohn disease. There are no dosage guidelines for the off-label use of adalimumab in the treatment of HS, but 40 mg per week to 40 mg every other week is the norm. Adalimumab has the fewest data available of all the TNF-α inhibitors because it is the newest, available on the commercial market only since 2003.
A review of the data on use of adalimumab for the treatment of HS yielded the following: 2 case reports, 1 case series, and 1 open-label clinical trial (summary in Table 1 ). The first report was published in 2005 by Scheinfeld and showed improved ambulation and decreased flocculence of axillary nodules within 2 months of treatment with adalimumab. When treatment was halted for insurance reasons, the patient experienced a flare; when the medication was later restarted, symptoms abated. The next case was reported by Moul and Korman in 2006. This report describes severe HS in a patient with inflammatory bowel disease who had resolution of all pain and significant improvement of HS severity after 1 month of treatment with adalimumab. He improved further with continued treatment at the 4-month follow-up visit. Lastly, in 2009, a small case series was published by Yamauchi and Mau pertaining to patients with HS successfully treated with adalimumab. All 3 cases showed significant improvement 1 year after initiation of adalimumab therapy with the first 2 cases showing 70% to 80% improvement from baseline. Unfortunately, due to the confounding administration of other drugs in the third patient in this series, it is difficult to ascribe resolution of the patient’s condition to any 1 particular medication.
| Name | Number of Patients | Age range | Dosage Regimen | Success Rate | Comments |
|---|---|---|---|---|---|
| Scheinfeld | 1 | 41 | 40 mg EOW for 2 mo, 40 mg QW thereafter | Significant improvement | |
| Moul | 1 | 67 | 40 mg EOW | Significant improvement | IBD |
| Yamauchi | 3 | 34–44 | 40 mg EOW (2 patients required increase to 40 mg QW) | 70%–80% improvement | Concomitant IL steroids, MTX, and levofloxacin |
| Sotiriou | 3 | Mean age 35.3 | 40 mg EOW for 3 mo | Over 50% decrease in disease severity within 2 mo |
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