|Year : 2018 | Volume
| Issue : 2 | Page : 48-59
Hidradenitis suppurativa: A comparison of guidelines
Verena Isak, Steve R Feldman, Rita O Pichardo
Department of Dermatology, Wake Forest University, Winston-Salem, North Carolina, USA
|Date of Web Publication||21-Sep-2018|
Dr. Rita O Pichardo
Department of Dermatology, Wake Forest University, Winston-Salem, North Carolina
Source of Support: None, Conflict of Interest: None
Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the folliculopilosebaceous unit (FPSU) in the intertriginous skin areas, especially axilla, groin, perineum, and peri- or sub-mammary fold in women, with secondary inflammation of eccrine and apocrine glands. HS disease activity and severity can be divided into three different stages according to the Hurley staging system. Stage I disease consists of single or multiple abscesses, while in Stage II, additional sinus tract formation or scarring can be seen, and in Stage III, interconnected tracts and abscesses have developed over a complete anatomic area. Due to its high disease burden, the extent to which HS negatively impacts patients' quality of life is higher than that of most other chronic dermatological conditions. Pain is considered one of the worst aspects of HS. In this article, we compare different guidelines for the management of HS between hospitals in Europe and the U.S. for Hurley Stage I, II, and III. Existing treatment guidelines were identified through systematic review of medical databases, including PubMed, using the search terms “hidradenitis suppurativa treatment guidelines” as well as “acne inversa treatment guidelines” for the European and German treatment guidelines, as well as American hospital-specific treatment algorithms, including Henry Ford Hospital, Detroit, Michigan, and Mayo Clinic, Rochester, Minnesota. In the German S1 guidelines, the goal is an improvement of one Hurley stage and/or a 25% improvement of the Sartorius score or the dermatology life quality index within 12 weeks. Radical surgical or laser excision, oral combination therapy of clindamycin and rifampin, or alternatively tetracycline, topical clindamycin, and hormonal therapy are recommended, while topical resorcinol, dapsone, finasteride, zinc gluconate, and acitretin are the treatment options that can be taken into consideration. Unlike the European or German S1 guidelines or the algorithm proposed by the Henry Ford Hospital, more systemic antibiotic therapy options are suggested in the Mayo Clinic algorithm before the addition of immunosuppressive therapy. Evaluation for efficacy happens every 3 months, and in case of treatment failure, the antibiotic regimen is changed and reevaluated 3 months later. Options include Trimethoprim-sulfamethoxazole, amoxicillin-clavulanate, fluoroquinolones, clindamycin, and rifampin, as well as rifampin plus moxifloxacin plus metronidazole. If none of the proposed antibiotic therapies help, acitretin, dapsone, or cyclosporine may be used instead. In refractory HS, infliximab or adalimumab is added to the regimen. For Stage III disease or in case of treatment failure so far, wide local excision as an addition to medical therapies can be considered. With the literature of the existing treatment options mostly being low evidence, scarce new randomized controlled trials, and the existing guidelines leaving room to interpretation, a gold standard for the treatment of HS does not yet exist. Further large-scale, randomized studies are necessary to continue treatment exploration and improve treatment regimens.
Keywords: Guidelines, hidradenitis suppurativa, Hurley stage, treatment
|How to cite this article:|
Isak V, Feldman SR, Pichardo RO. Hidradenitis suppurativa: A comparison of guidelines. J Dermatol Dermatol Surg 2018;22:48-59
| Introduction|| |
Hidradenitis suppurativa (HS), formerly acne inversa, is a chronic inflammatory disease of the folliculopilosebaceous unit (FPSU) in the intertriginous skin areas, especially axilla, groin, perineum, and peri-or sub-mammary fold in women, with secondary inflammation of eccrine and apocrine glands.,, Typical clinical features include primary lesions such as painful follicular papules or pustules, nodules, and abscesses, as well as secondary lesions such as cysts, fistulas, double pseudocomedones, or scars. Diagnosis of HS is made clinically if recurrent lesions appear more than twice per 6 months in predilection sites.,,
Differential diagnosis includes folliculitis, abscesses, and bacterial infections, as well as cutaneous Crohn's disease, especially if lesions are perianal., If a fistula connects to an organ, Crohn's disease should be suspected. Acute complications, such as bacterial superinfections, are rare. Chronic complications include scarring, contractures, fistulas, and lymphedema, as well as squamous cell carcinoma (SCC). When SCC occurs, it is usually after long-standing Stage II and III disease over decades, with a 5:1 male-to-female ratio. The majority of SCC arises in gluteal, perianal, and perineal, but not in the axilla, which might be due to HPV being a causative factor.
Without treatment, disease duration is about 18.8 years, with an average of 4.6 flares per year and a duration of 6.9 days per flare. The prevalence is estimated to be 98/100,000 people in the US population (0.10%), with a 2:1 female-to-male ratio and a 2–3:1 African-American or biracial to White ratio. This is in accordance with two other studies that found a prevalence of 0.07% and 0.08%, respectively., Other, especially European, studies however, have suggested a higher average prevalence of 1%., This difference might be due to different study designs, due to patients being misdiagnosed, or due to only a fraction of patients seeking medical help for the disease.
HS disease activity and severity can be divided into three different stages according to the Hurley staging system. Stage I disease consists of single or multiple abscesses, while in Stage II, additional sinus tract formation or scarring can be seen, and in Stage III, interconnected tracts and abscesses have developed over a complete anatomic area. More dynamic scores include the Sartorius and modified Sartorius score, which counts the number of individual lesions, and the physician global assessment score, which is frequently used in trials and is divided into six stages that range from “clear” to “very severe.”,,, Another score used in the clinical trials is the HS clinical response (HiSCR), which is defined as a reduction of the number of lesions of over 50% and is more sensitive to changes.,,
Hyperkeratosis and lymphocytic perifolliculitis are the typical histological findings in early pathogenesis. These subsequently cause occlusion, which then results in inflammation of the follicular duct. This weakens follicular walls, eventually leading to rupture and sinus tract formation., Up to date, the pathogenesis has not yet been fully understood but is suggested to be multifactorial. Melnik and Plewig propose loss of function mutations of y-secretase and subsequent deficient Notch signaling to play a central role in the pathogenesis of HS, by leading to both an immunologic dysregulation through deficient interleukin (IL)-22 and increased IL-23 secretion, as well as having a disturbing effect on the terminal hair follicles' keratinization and sebaceous gland differentiation. In a study of 21 HS patients, sebaceous glands were reduced in volume or absent in unaffected skin due to obliteration, suggesting inflammation in HS before the formation of lesions.
Although conventional microbiological tests yield negative results, the exact role of the dermal microbiome in HS has yet to be determined. The amount of bacteria in the dermal microbiome is decreased, and biofilm is present in HS patients compared with healthy controls. In a case–control study of 30 HS patients and 24 controls, lesional skin contained mostly Corynebacterium as well as Porphyromonas and Peptoniphilus species, while Propionibacterium was more abundant in the skin of healthy controls, and neither Porphyromonas nor Peptoniphilus was found.
HS is associated with higher rates of overweight and smoking.,, Both smoking and obesity downregulate the Notch signal pathway, consistent with it being an aggravating factor in predisposed patients. This would explain higher HS remission rates in nonsmokers and nonobese patients. Smoking pack-years and obesity were the indicators of disease severity in a study of 846 patients, just as male sex and disease duration were. In addition, predilection areas for HS undergo greater friction in obese patients, leading to mechanical disturbances.,, Alternatively, other possibilities, such as patients with HS being more likely to smoke to cope with the disease, need to be considered as well. Reported higher rates of alcohol and drug dependence might fall into the same category of coping with this often disfiguring disease. Higher rates of comorbidities such as metabolic syndrome and diabetes, polycystic ovary syndrome (PCOS), dyslipidemia, or hypertension in HS patients are still found after adjusting for obesity., Patients with HS also have a higher prevalence of autoimmune diseases such as the inflammatory bowel diseases, Crohn's disease, and ulcerative colitis, as well as arthropathies, such as spondyloarthritis.,,
Due to its high disease burden, the extent to which HS negatively impacts patients' quality of life (QOL) is higher than that of most other chronic dermatological conditions., Pain is considered one of the worst aspects of HS. A combination of fear of stigmatization and rejection due to the look and smell of lesions, low self-esteem, and pain leads to social isolation of patients, diminished sexual health in especially women, and higher rates of depression, anxiety, and substance dependence, as well as lower productivity and attendance.,,,, Numerous sick leaves due to HS thus have a socioeconomic impact on patients, which further leads to a downward spiral of depression and social isolation, and the inability to afford appropriate care.
There is no generally used HS-specific QOL measuring tool as exists for more common diseases such as psoriasis. The recently developed HS symptom assessment and HS impact assessment might be an addition to the currently used scores such as the DLQI and the visual analog scale (VAS) pain score in the assessment of HS patients' QOL.
Early diagnosis and the appropriate treatment are crucial for HS patients. New randomized controlled trials (RCTs) are scarce; thus, treatment options are often lacking high-grade evidence. Treatment varies based on the stage of the disease among various topical and systemic medications, as well as surgical options, with pain management as an important cornerstone in all stages of the disease. Additional measures such as smoking cessation and weight loss, among others, are important in controlling disease activity. The use of biologics has evolved as an effective treatment option for refractory disease. Several guidelines have been developed to help guide HS treatment planning. In this review, we compare guidelines for the management of HS from Europe and U.S.
| Methods|| |
Existing treatment guidelines were identified via systematic review of medical databases, including PubMed, using the search terms “hidradenitis suppurativa treatment guidelines” as well as “acne inversa treatment guidelines” for the European and German treatment guidelines, as well as American hospital-specific treatment algorithms, including Henry Ford Hospital, Detroit, Michigan, and Mayo Clinic, Rochester, Minnesota.
Both the European and German treatment guidelines are classified as S1; thus, they are formed on the expert recommendations without a systematic literature review. In the German guidelines, which are partially based on the 2010 2SK guidelines for the treatment of acne, treatment options were classified into one of the following five categories: strong recommendation, weak recommendation, open (unbound?) recommendation, recommendation against an intervention, and absolute recommendation against an intervention. The guidelines were determined to be effective until December 2017; an updated version is planned to be completed by the end of June 2018.
Gulliver et al. classified therapy options in the European guidelines into first-, second-, and third-line treatments based on the category of evidence and the strength of recommendation, as well as the results of a benefit–risk ratio analysis. The first-line treatment options ranged from Category Ib for adalimumab and Category Ia/IIa for reconstruction with flap as well as Category Ib for laser treatments to Category III for oral clindamycin/rifampin and Category IV for deroofing and Intense pulse laser treatment. Apart from infliximab as a second-line biologic, evidence for second- and third-line treatments was weak, with no RCTs or controlled studies.
| Results|| |
In the German S1 guidelines, the goal is an improvement of one Hurley stage and/or a 25% improvement of the Sartorius score or the DLQI within 12 weeks. Radical surgical or laser excision, oral combination therapy of clindamycin and rifampin, or alternatively tetracycline, topical clindamycin, and hormonal therapy are recommended, while topical resorcinol, dapsone, finasteride, zinc gluconate, and acitretin are the treatment options that can be taken into consideration. Both severity of the disease and the personal disease burden determine the chosen regimen.,
According to the German S1 treatment algorithm, systemic antibiotic treatment with rifampin 300 mg BID and clindamycin 300 mg BID or minocycline 50 mg orally over 4–12 weeks is the first step in the treatment for all stages of the disease and oral antiandrogenic therapy for women with signs of hyperandrogenism. Clindamycin 300–600 mg 2–3/day intravenous (i.v.) for the first 5 days can be administered. The next step in Hurley Stage II and III, respectively, is local surgical excision or CO2 ablation of recurring lesions and wide surgical excision of involved areas or the addition of infliximab or adalimumab to the regimen, followed by wide surgical excision. Adjunctive therapy in all stages is topical clindamycin. The algorithm based on the European guidelines is similar; however, pain management and lifestyle modifications are included for all stages of the disease, and the combination of clindamycin and rifampin is prescribed if topical clindamycin and oral tetracycline 500 mg BID for 4 months have failed.
We did not find any comparable American guidelines; however, the Henry Ford Hospital and Mayo Clinic have published algorithms for the treatment of HS., The algorithm proposed by the Henry Ford Hospital is Hurley stage-dependent. The text is intended to differenciate localized vs generalized Hurley stage I. In localized disease, the first line treatment option is topical therapy with 10% benzoyl peroxide wash and clindamycin 1% solution. The second line treament is 1-6 month course of oral doxycycline, combined with intralesional triamcinolone for acute flares, second line in localized disease, whereas in generalized Hurley Stage I, the first line is a combination of both topical and oral above-mentioned measures. The next step for both localized and generalized stage I disease is up to three monthly Nd: YAG treatments. In localized HS refractory to treatment, plastic surgery or urology can be consulted for radical excision.
Hurley Stage II is treated with a combination of systemic antibiotics (300 mg clindamycin BID plus 300 mg rifampin BID) for 8–10 weeks and up to three monthly Nd:YAG laser treatments. In females with flares associated with menstruation, spironolactone can be added. In refractory HS, addition of the tumor necrosis factor (TNF)-α adalimumab as the first line, or, as alternatives, infliximab or i.v. ertapenem, can be considered. The second-line antibiotic regimen consists of levofl oxacin 500 mg daily and rifampin 300 mg BID up to 8 weeks, plus metronidazole 500 mg three times per day for 2 weeks. In addition, localized deroofing procedures or CO2 laser excision can be taken into consideration. In Hurley Stage III or refractory disease, consultation of radiation oncology, plastic surgery, or reconstructive urology is recommended.
The algorithm suggested in the Mayo Clinic guidelines is similar for mild disease, with a topical maintenance regimen of clindamycin plus the decolonization with chlorhexidine gluconate or benzoyl peroxide solution, or bleach baths as the first-line therapy for mild disease, and reevaluation at 3 months. If treatment failed, or in case of moderate (Stage II) disease, an oral antibiotic such as doxycycline 100 mg BID or erythromycin 250–500 mg BID is added, plus an oral contraceptive pill in females. Concurrent surgical management with deroofing or local excision is recommended or alternatively CO2 or Nd:YAG laser.
Unlike the European or German S1 guidelines or the algorithm proposed by the Henry Ford Hospital, more systemic antibiotic therapy options are suggested in the Mayo Clinic guidelines before the addition of immunosuppressive therapy. Evaluation for efficacy happens every 3 months, and in case of treatment failure, the antibiotic regimen is changed and reevaluated 3 months later. The options include TMP-SMX, amoxicillin-clavulanate, fluoroquinolones, clindamycin, and rifampin, as well as rifampin plus moxifloxacin plus metronidazole. If none of the proposed antibiotic therapies help, acitretin, dapsone, or cyclosporine may be used instead. In refractory HS, infliximab or adalimumab is added to the regimen. For Stage III disease, or in case of treatment failure so far, wide local excision as an addition to medical therapies can be considered [Table 1], [Table 2], [Table 3].
Adjuvant therapy mainly consists of lifestyle modifications, pain management, and treatment of superinfections., As mentioned above, obesity and smoking are significantly more prevalent in HS. In a study of 127 patients, treatment in nonsmokers and nonobese patients was more successful with significant higher remission rates. In one case, bariatric surgery and subsequent weight loss led to the resolution of lesions despite previous treatment failure with antibiotics and retinoids. Therefore, a multidisciplinary approach in the treatment of HS is required as HS patients should be counseled for both smoking cessation and weight loss.
Pain related to HS is often debilitating in its nature and consequently has a negative impact on the patients' QOL and emotional state. Exacerbating factors are friction, e.g., due to tight clothes, heat, and psychological stress. Nevertheless, pain management of HS is vastly left out in the literature.,,, Therefore, no guidelines for pain management in HS specifically exist. Pain control differs for acute pain related to flares, and chronic pain, with a combination of both systemic and topical analgesics being most effective in pain management. In addition, intralesional corticosteroids or incision with drainage can result in pain relief., The German S1 guidelines recommend avoiding the incision of lesions due to a 100% recurrence rate but do not consider pain management. While Horváth et al. have considered anti-inflammatory medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen as the first line in the treatment of flaring lesions, according to the European S1 guidelines, no clinical evidence for the use of NSAIDs exists., In a study of 50 patients, Ring et al. have found a low level of pain relief from NSAIDs alone but the additional need of tramadol or morphine in some patients to adequately control pain. Due to the risk of dependence and misuse, caution is warranted, and the prescription of opioids should be reserved for selected cases in which other pain medications have failed.,
Anticonvulsants such as pregabalin or gabapentin have proven to be effective in several conditions in the long-term control of chronic neuropathic pain, including HS. Scheinfeld has preferred pregabalin over gabapentin except for its higher cost. In patients with concomitant depression and anxiety, especially serotonin and norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors, but also tricyclic antidepressants, might be a good choice for pain control. Appropriate wound care with cleansers, antiseptics, and dressings is crucial to prevent bacterial colonization and subsequent superinfections in both HS lesions and the postoperative management of radical surgical excisions.
As the only curative treatment, surgery is an important pillar in the treatment of HS. Local in toto excision of nodules and abscesses is recommended for Hurley Stage I or mild Stage II disease, while Stage II–III requires wide excision with subsequent wound healing by secondary intention, with or without split skin grafts.
Danby et al. have distinguished five surgical approaches such as local destruction, incision and drainage, mini-unroofing, standard deroofing, and wide surgical excision. Mini-unroofing, or punch debridement, is conducted with a 5–8 mm punch biopsy. It completely removes the FPSU; thus, no recurrences develop. Deroofing is the removal of the roof of an abscess, nodule, or sinus tract with scissors, CO2 laser, or electrosurgery. The use of a probe to explore the connections of underlying sinus tracts is recommended., Cryoinsufflation and electrosurgical peeling are other options for the local destruction of lesions., Deroofing is indicated for Hurley Stage I and mild Stage II disease as it is too superficial in the extensive Stage II and III disease. Those cases are an indication for the skin-tissue-sparing excision with electrosurgical peeling (STEEP) procedure. The advantages of STEEP are its skin-sparing effect and subsequently lower risk of contractures, favorable cosmetic outcomes and high patient satisfaction, shorter healing times, good hemostasis during the procedure, and low recurrence rates due to the complete removal of the lesion as well as fibrotic tissue.,, Therefore, Blok et al. have preferred STEEP over wide excisions or deroofing for the surgical treatment of Hurley Stage II/III. However, in a case series of 16 patients conducted by Janse et al., the recurrence rate was 50%.
Wide excision of the complete affected area may be necessary in addition to medical treatment in managing chronic extensive disease. Disadvantages associated with wide excisions are longer healing times, scarring with contractures, and limited range of motion. Postoperative wound management is crucial. Due to high complication rates such as infections or wound dehiscence, primary closure is inferior to healing by secondary intention. Negative pressure wound therapy can be helpful as an addition in severe cases that required wide debridement to improve healing and lower the infectious risk, followed by reconstruction with split-thickness skin grafts or primary delayed closure.,,
Wide excision yields lower recurrence rates than less invasive procedures, with rates of 15% for primary closure, 8% for flaps, and 6% for grafts, compared to 22% for local excision and 27% for deroofing. However, Mehdizadeh et al. have pointed out that the high heterogenicity as well as no standard outcome measurement does not allow for the direct comparison of the surgical techniques included in this meta-analysis. In a retrospective study of 590 patients, the overall postoperative recurrence rate was 24.4%, with higher rates among younger patients and patients with multiple surgical sites, as well as drainage-type procedures. Sex, Hurley stage, extent of the excision, surgery site, and unroofing procedure type did not affect recurrence rates. Patient satisfaction is high after surgical procedures due to good cosmetic outcomes and significant improvement in patients' QOL.
Ablative CO2 laser therapy is an alternative to surgery. However, clinical trials directly comparing laser to surgery are lacking. CO2 laser is especially useful for deeper lesions that reach into the subcutis, and in thick, fibrotic areas of recurrence, where other techniques such as deroofing would be too superficial. The advantages are the local hemostasis and remodeling of scars. Just as in surgical procedures, toluidine-blue or methylene-blue can be used to display sinus tracts during the procedure., Hair removal with Nd: YAG laser or intense-pulsed-light therapy has led to the improvement in patients with HS by destroying the hair follicles, but long-term data are lacking.
Further studies are necessary to determine the possible role of currently experimental therapies, such as intralesional photodynamic therapy (PDT) or brachytherapy. Superficial brachytherapy was reported to be successful in one case so far. Literature on PDT yields mixed results, with better outcomes in early, superficial lesions. This might be due to topically applied photosensitizers such as 5-aminolevulinic acid (ALA) or methylene-blue (MB) not being absorbed deep enough into especially thick tissue. Different forms of application could potentially elude this limitation. Fadel and Tawfik found deeper penetration into the dermis if MB was delivered in niosomes. A case series of 38 patients treated with PDT with intralesional 5-ALA showed promising results: Of the 29 patients who had a complete response, 18 only needed one treatment, and only one patient experienced a recurrence.
Despite bacteria not playing a pathogenic role in HS, an abnormal immune response to local skin flora as well as an altered microbiome in both lesional and nonlesional skin of HS patients has been postulated to play a role in HS.,,, Nevertheless, topical clindamycin as well as systemic tetracyclines or a combination of clindamycin and rifampin is considered the first-line treatment in HS., The anti-inflammatory potency of said antibiotics presumably is what makes them effective.
Only one double-blinded randomized trial for topical antibiotics, specifically clindamycin 0.1%, exists, showing it to be significantly superior to placebo in especially superficial lesions. For deep or scarred lesions, however, deep enough penetration cannot be achieved. Thus, topical clindamycin is recommended for localized Hurley Stage 1 and mild Stage 2 disease BID as well as addition to systemic or surgical therapy in severe HS., Scheinfeld has reevaluated patients after 2–4 weeks and had added oral antibiotics to the regimen if no improvement has been seen. Topical dapsone is an another topical agent that has been reported to be used, either alone or in combination with topical clindamycin. Topical resorcinol as a peeling can also be considered in mild HS: In an open prospective study of 32 patients, a single, nonfistulous lesion was treated with 15% resorcinol BID for 30 days, achieving a significant drop in lesion size from 13.8 m to 8.4 mm at day 7 and 1.7 mm at day 30, as well as a decrease of pain from 4.6 to 1.8 to 0.5 on the VAS scale. Interestingly, in six of 27 resolved lesions, only clinical remission was achieved, but not resolution on ultrasound.
Oral tetracycline 500 mg BID is recommended in more widely spread Stage I or mild Stage II disease. Alternatively, a combination of rifampin and clindamycin (both 300 mg BID) or minocycline (50 mg BID) is prescribed if topical treatment alone fails, with efficacy in all stages of the disease.,,, While adverse gastrointestinal effects have been reported, none of them were related to Clostridium difficile., This might be due to rifampin's effects against C. difficile. Furthermore, rifampin shows good tissue penetration and is effective against granulomas as well as biofilms. However, risk for hepatic damage requires regular monitoring of liver function tests.
In an open, prospective pilot study, 20 patients were treated with tetracycline and colchicine, achieving a significant improvement or complete remission. Over the course of 9 months, 21 patients had a good (50%–75%) or excellent (75%–100%) response according to the patient global assessment scale; the remaining patient had a fair response (PGA score 25%–50%). The European and German guidelines, however, do not recommend colchicine for the treatment of HS.,
Other antibiotics that have been reported to be successful are i.v. linezolid and meropenem and i.v. ertapenem in the initial treatment of severe HS. The combination of rifampin, moxifloxacin, and metronidazole was reported to lead to complete remission in 16 of 28 patients, with disease severity being a significant prognostic factor of response to treatment.
An important factor in long-term antibiotic treatment is the development of resistance. Fischer et al. found in a study of 239 patients significantly higher rates of clindamycin-resistant Staphylococcus aureus, ciprofloxacin-resistant Methicillin-resistant Staphylococcus aureus, and TMP/SMX-resistant Proteus species, respectively, in patients using said antibiotic compared to patients not using antibiotics. Oral clindamycin and tetracyclines, however, did not yield higher antimicrobial resistance.
Due to lack of efficacy in HS trials, isotretinoin is not recommended in the treatment of HS, oral acitretin 0.3–0.5 mg/kg/day, though, can be considered over the course of 3–4 weeks., In a prospective study of 17 patients with previous unresponsive HS, improvement, measured by the HS severity index and DLQI, occurred after the 1st month of acitretin monotherapy. However, half of the patients dropped out over the full course of 9 months due to ineffectiveness or adverse events, and only one patient had a long-lasting remission. Of the five patients with a body mass index within the normal range, all responded to treatment. Another study of 14 patients showed treatment failure when acitretin was used as monotherapy, but an improvement in 87.5% of patients in whom acitretin was added to a standard regimen. In addition to adverse events, the teratogenicity and long half-life make acitretin a suboptimal choice for especially women of child-bearing age. A possible alternative would be alitretinoin, a retinoid with a shorter half-life. In a small study of 14 patients, improvement was seen in 11 patients after 6 months of 10 mg alitretinoin daily. Larger clinical trials would be necessary to determine if retinoids might be effective for a certain subgroup of patients.
Certain epidemiological features of HS such as onset after puberty, a predominance in women and premenstrual flares, as well as an association with obesity and hormonal disorders such as metabolic syndrome and PCOS suggest endocrinological dysfunction to either play a role or be a confounding factor in the pathogenesis of HS; this theory is controversial., There may be altered expression of estrogen and androgen receptors in the apocrine glands of HS patients, with a lack of estrogen receptors, based on 33 skin biopsies.
An antiandrogenic therapy with estrogens and cyproterone acetate as an add-on for women with medium-to-severe HS unresponsive to systemic antibiotics and concomitant hormonal and menstrual abnormalities/PCOS is recommended., The type II 5α-reductase inhibitor finasteride as well as spironolactone has also been reported to be effective in HS both as monotherapy and in combination with other medications, with finasteride also being effective in the pediatric population; however, high-grade evidence is lacking.,,,,
In a pilot study of 25 patients with recalcitrant HS treated with metformin at doses of 500 mg/day in the 1st week, 500 mg BID in the 2nd week, and 500 mg three times per day from the 3rd week onward, yielding improvement in 12 of the patients at week 12 and 24, while six showed no response. The exact mechanism of metformin in HS is unknown, but an antiandrogenic effect is postulated. In one case report, the glucagon-like peptide-1 agonist liraglutide led to improvement of HS despite previous treatment failure.
Both intralesional and systemic corticosteroids are considered the second-line therapy. Intralesional triamcinolone 5–10 mg/ml is useful in the treatment of acute flares, mostly in combination with antibiotics., Its quick anti-inflammatory effect also helps in the reduction of pain related to acute flares. In a prospective study of 36 patients, pain significantly decreased 3.2 points on the VAS scale within the first 24 h and dropping from 5.5 to 1.1 on the VAS scale within a week of treatment. Due to atrophic properties, treatment every 2 weeks can lead to scarring of open tracts and sinuses. Systemic corticosteroids only play a very minor role in the treatment of HS and are rather used in HS associated with rheumatologic diseases. In an analysis of 164,000 patient visits for HS annually in the US, systemic steroids were prescribed on 1% of visits. Although reports show improvement of acute flares with systemic steroids, rebound flares after discontinuation are common. Given the chronicity of HS and the frequent recurrence of flares, high-dose systemic corticosteroids are not a suitable choice in the long-term treatment. In a study of 13 patients with previously treatment-resistant HS, 11 improved when low-dose corticosteroids were added to the regimen.
The European S1 guidelines recommend dapsone as a third-line treatment option for Hurley Stage I or II if other therapies failed., In the Mayo Clinic treatment algorithm, dapsone can be considered as part of maintenance therapy in patients refractory to various systemic antibiotic regimens. Treatment shows mixed results. In a study of 24 patients, only six patients improved considerably, while 15 did not show any improvement at all. The anti-inflammatory effect was short-lived, with rapid recurrence after discontinuation of the drug. In two older studies of five patients each, dapsone led to an improvement of HS in all 10 patients., Dapsone seems to be effective in the treatment of pyogenic granuloma type HS.
The calcineurin inhibitor cyclosporine A was successful in a small number of patients with severe, recalcitrant HS and can be considered as a last resort if all other treatment options have failed., Colchicine is not effective in the treatment of HS and therefore not recommended., Methotrexate, just as systemic corticosteroids are, is prescribed in HS associated with rheumatological diseases and can be helpful as concomitant treatment with infliximab to reduce antibody formation.
Tumor necrosis factor-α inhibitors
The TNF-α inhibitor adalimumab is a first-line medication in moderate and severe HS., Unless previously discussed treatment options, new RCTs were performed to assess the efficacy of adalimumab. In two parallel multicenter phase 3 RCTs, 633 patients with moderate-to-severe HS were assigned to 40 mg of adalimumab or placebo weekly for 12 weeks and then for adalimumab at a 1- or 2-week interval or for placebo for 24 weeks. Clinical response rates, defined as at least 50% reduction of baseline abscess and nodule count, were higher in the adalimumab group in both studies (41.8% vs. 26.0% in Group 1, 58.9% vs. 27.6% in Group 2). Greater improvement in the secondary outcomes such as a nodule count of maximum 2, at least 30% reduction of skin pain, and improvement of the Sartorius score was seen in the adalimumab-treated patients in only one of the two studies, in which patients continued their baseline antibiotic therapy throughout the trial. In a phase 2 RCT with 154 patients with previously antibiotic-resistant HS who were randomized to 40 mg adalimumab weekly or bi-monthly or placebo for 16 weeks, adalimumab provided greater clinical response (17.6% of weekly, 9.6% of biweekly adalimumab, 3.9% of placebo patients), as well as a reduction in pain and depressive symptoms.,, An initial loading dose of 160 mg s.c. plus 80 mg s.c. 1 week later can be administered as a conditioning measure before curative surgical treatment. For long-term treatment, patients receive 40 mg weekly.,
If patients show no response to adalimumab, infliximab is recommended as the second-line therapy. In the only RCT assessing the efficacy of infliximab, there was no significant difference between infliximab and placebo in the number of subjects with a reduction of more than 50% of HS severity, but more patients treated with infliximab did achieve 25%–50% improvement. Unlike with adalimumab, dosing varies among different studies. Monthly administration of infliximab controlled the disease in nine of 11 patients with previously refractory HS.
Based on a study of 13 patients, high levels of IL-6 and high-sensitivity C-reactive protein at baseline may be negative predictors for the response to infliximab. Further similar investigations lead to a more individually tailored approach to successfully treat HS.
Response to infliximab in HS patients may be weaker with concomitant systemic inflammatory diseases. However, there are reports of successful treatment with infliximab of HS associated with pyoderma gangrenosum, Crohn's disease, and systemic amyloidosis. In one case, pyoderma gangrenosum, acne HS was successfully treated with a combination of infliximab, cyclosporine, and dapsone. While infliximab is effective in the treatment of concomitant arthritis, three patients developed arthritis while receiving infliximab for HS. In one case report, a patient developed metastatic SCC after three doses of infliximab.
In contrast to adalimumab and infliximab, etanercept 50 mg twice per week was not effective in a randomized, double-blind, cross-over HS trial.
In a prospective, open study of 12 patients, the IL-12 and 23 inhibitors ustekinumab given at doses of 45 mg or, for patients over 100 kg, 90 mg, at weeks 0, 4, 16, and 28, resulted in an improvement of the modified Sartorius score in 35% and a moderate-to-marked improvement in 82% of patients at week 40. Ustekinumab showed better responses in patients with milder disease and lower expression of the pro-inflammatory leukotriene A4-hydrolase, suggesting these to be positive predictors in response to ustekinumab. In two further case reports, ustekinumab controlled disease activity of long-standing HS after failure of previous treatment, including TNF-α inhibitors, adalimumab and infliximab, and concomitant psoriasis and Behcet's disease, respectively.
In a small RCT of 19 patients, daily administration of 100 mg of the IL-1 receptor antagonist anakinra for 12 weeks reduced disease severity and yielded a higher HiSCR when compared to placebo (67% vs. 20% and 78% vs. 30%, respectively). Time to a new exacerbation was longer in patients who received anakinra. HS treatment with anakinra was also successful in an open-label study of five patients over the course of 8 weeks as well as in a case report. In other case reports, however, treatment with anakinra led to no improvement or deterioration of the disease.,, Whether anakinra can be an alternative treatment in a subset of HS patients who failed therapy with TNF-α inhibitors still requires more research. While anakinra might play a role in the treatment of refractory HS in the future, a possible reduced compliance due to its daily administration compared to other biologics with less frequent dosing must be considered as well.
IL-17 is higher in the serum of patients with HS compared to healthy controls. The IL-17 inhibitor secukinumab was effective for HS in two case reports., In a case series of nine patients with refractory HS, the s-4 inhibitor apremilast decreased pain on the VAS scale and improved QOL measured by the DLQI. However, long-term data are lacking. Ongoing phase I and II trials on a number of agents such as apremilast, IL-17A inhibitors, anti-C5a, anti-IL-1 receptor, and anti-IL-1α-antibodies might point toward a bigger role of these treatments in the future treatment of HS.
In two retrospective studies, outcomes of the combination of biologics and surgery showed promising results. While patients who received biologics alone had a significant better outcome compared to those who never received biologics, their effect was significantly increased if used as an adjunctive therapy to surgery. Recurrence rates in patients receiving combination therapy were lower, with longer disease-free intervals while on biologic therapy and fewer new lesions. RCTs with larger patient samples would be required to evaluate whether a combination therapy of surgery for the treatment of existing lesions plus biologics for both the treatment of current disease and the prevention of future lesions is a possible regimen for the long-term management of HS.
High-dose oral zinc gluconate with initial doses of 90 mg/day can be considered as part of the regimen in mild HS., In a retrospective study of 66 patients, the combination of zinc gluconate and topical triclosan 2% BID improved HS. However, one in five patients reported adverse gastrointestinal effects. Botulinum toxin A is not recommended but may be a possible experimental therapy for mild (Hurley Stage I or II) HS as it was effective in a few case reports.,,, A possible mechanism is the prevention of follicular rupture and subsequent inflammation and sinus tract formation.
| Discussion|| |
HS is a debilitating and painful disease that has a negative impact on patients' QOL. Early diagnosis and appropriate treatment to control disease activity are crucial. The treatment of HS consists of a combination of topical and systemic medications, as well as surgery and laser, and varies based on the disease severity. Topical and systemic antibiotics and more localized surgical procedures are used in milder disease. Topical clindamycin 1% is recommended by all mentioned guidelines for Hurley Stage I. There are differences between the guidelines about which systemic antibiotics are preferred. In Stage 2, recommendations vary more, with the Mayo guidelines advocating the trial of different antibiotics after treatment failure of one class of antibiotics before adding biologics, while the other algorithms recommend moving to biologics after one treatment failure of antibiotics. Extensive, refractory disease often requires wide excisions and treatment with biologics. Although pain is one of the worst aspects of the disease, no specific guidelines for the treatment of pain in HS exist; thus, it is vastly dependent on a physician. Therefore, the development of an HS-specific algorithm for pain management would be helpful.
Biologics, especially when combined with surgery, is an effective way of treating extensive HS. Recurrence rates, as well as new disease activity, suggest that although surgery can be helpful in the management of existing lesions, future lesions cannot be prevented. Thus, it would be interesting to explore whether continued immunosuppressive or other treatment after the clearance of existing lesions with a subsequent taper could keep patients in remission.
With the literature of the existing treatment options mostly being low evidence, scarce new RCTs, and the existing guidelines leaving room to interpretation, a gold standard for the treatment of HS does not yet exist. Further large-scale, randomized studies are needed to continue treatment exploration and improve treatment regimens.
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Conflicts of interest
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[Table 1], [Table 2], [Table 3]