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Hidradenitis suppurativa: A practical review of possible medical treatments based on over 350 hidradenitis patients

  • Author(s): Scheinfeld, Noah
  • et al.
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Hidradenitis suppurativa: A practical review of possible medical treatments based on over 350 hidradenitis patients
Noah Scheinfeld MD
Dermatology Online Journal 19 (4): 1

Weil Cornell Medical College, New York, New York

Abstract

Hidradenitis suppurativa (HS), a pathological follicular disease, impacts patients’ lives profoundly. HS most commonly involves cutaneous intertriginous areas, such as the axilla, inner thighs, groin and buttocks, and pendulous breasts, but can appear on any follicular skin. Protean, HS manifests with variations of abscesses, folliculitis, pyogenic granulomas, scars (oval honeycombed), comedones, tracts, fistulas, and keloids. The pathophysiology might involve both defects of the innate follicular immunity and overreaction to coagulase negative Staphylococcus. Treatment depends on the morphology, extent, severity, and duration. Topical clindamycin and dapsone are often adequate for treating mild HS. For Stage 1 and 2 HS, first line treatment combines rifampin with either oral clindamycin or minocycline. Other HS treatments include: fluoroquinolones with metronidazole and rifampin, oral dapsone, zinc, acitretin, hormone blockers (oral contraceptive pills, spironolactone, finasteride, and dutasteride), and oral prednisone. For severe HS, cyclosporine, adalimumab, or infliximab (used at double psoriatic doses) and intravenous carbapenems or cephalosporins are often required. Isotretinoin, etanercept, isoniazid, lymecycline, sulfasalazine, methotrexate, metformin, colchicine, clarithromycin, IVIG, and thalidomide are less favored treatments. The role of botulinum toxin is uncertain. The most important life style modification is weight loss. De-roofing fluctuant nodules and injection of intralesional corticosteroids ameliorates the disease and perhaps, if done at regular intervals, improves HS more permanently. Surgical excision and CO2 laser ablation are more definitive treatments. The 1064 nm laser for hair removal aids in the treatment of HS. This article centers on medical therapies and will only passingly mention surgical and laser treatments. This article summarizes my treatment experience with over 350 HS patients.



Introduction

Hidradenitis suppurativa (HS) [1-132], also called acne inversa (AI) [88], has long confounded dermatologists. Originally, when first described, HS was thought to be a disease of the apocrine gland because HS most commonly occurs in apocrine gland-rich intertriginous areas. HS has more recently been shown to be a disease that centers on the hair follicular unit, resulting in follicular occlusion and inflammation. I find that AI seems a poor term for HS [87]. Whereas isotretinoin cures acne, isotretinoin works only sporadically for HS and, unlike acne, HS can occur on almost any body area.

HS can and does occur on any part of the body with follicles. HS has been noted on the legs, back, ears, penis, chest, and other atypical areas that seem to break the rule that HS is an intertriginous disease that occurs only where there are apocrine glands. I have seen over 350 individual patients since 2006 with HS. This paper will take both practical and evidence based approaches toward the medical treatment of HS. Each patient who has HS is an individual. Whereas trials are useful, treatment must be tailored to the individual patient and this article takes this approach.

This will be the first article in a series of articles and will address the medical treatment of HS in a practical fashion with a review of the evidence for each treatment. Future articles will address (1) the etiology of HS including the relationship of HS to arthritis and inflammatory bowel disease (IBD) with attention to whether primary HS that occurs in isolation is different from HS that occurs in the context of inflammatory bowel disease and other diseases including the follicular occlusion tetrad and arthritis; (2) surgical treatment of HS; (3) pain control and HS; (4) the psychosocial impact of HS; (5) use of biologic agents for HS in a comprehensive fashion; (6) the epidemiology of HS; and (7) the clinical and histological manifestations of HS. As such, herein, surgery, laser (hair removal and ablative), and pain control, which are key parts of the treatment of HS, will only be touched on in brief. Limited, too, will be the discussion of the role of biologics, the psychosocial impact of HS, and the clinical and histological manifestations of HS, which will be dealt with in future issues [54].


Etiology

The etiology of HS has yet to be fully defined. Familial clusters of HS exist and both the genetics and pattern of inheritance of most patients with HS require more definition and further explication. Loss-of-function mutations in the γ-secretase genes [103] NCSTN, PSENEN, and PSEN1 have recently been reported to underlie a subset of familial hidradenitis suppurativa (HS) in Chinese, Japanese, and European kindreds [86]. γ-secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. γ-secretase is also critical in the related processing of the Notch protein, which some have suggested is the key to the etiology of HS [101]. Proteases of this type are known as intramembrane proteases. The most well known substrate of γ-secretase is amyloid precursor protein, a large integral membrane protein. When it is cleaved by both γ-secretase and β-secretase it is involved with amyloid formation that occurs in Alzheimer disease [102]. Amyloid is not a common finding in HS although reports exist of amyloid in HS patients [97]. Patients without a family history of HS (sporadic HS) have infrequently shown γ-secretase defects [1].

Insight into the etiology of HS can be gleaned by assessing its treatment effectiveness. Antibiotics can ameliorate HS, suggesting that bacteria are involved. Notably, deep tissue samples of HS have always demonstrated coagulase-negative staphylococci (CONS) [2, 3]. It is interesting to speculate if HS involves aberrant innate cutaneous cellular immunity to commensal CONS or some other bacteria, just as seborrheic dermatitis involves an over reaction of the immune system to commensal skin yeast. Streptococcus milleri [104, 105] was implicated in reports now decades old and does not seem to be a central trigger for aberrant innate immunity. A combination of Streptococcus milleri, Staphylococcus aureus, anaerobic streptococcus, or Bacteroides species was noted as pathogenic is in one report in 1988 [106]. Whereas it is also possible that other bacteria besides CONS including Staphylococcus aureus (SA) are involved with HS as well, CONS seems to be a central target for the immune system. The abscesses of HS are mostly “sterile” when cultured and devoid of normal pathogenic bacteria like SA. In addition, IVIG does not abate HS, implying that B cells and immunoglobulin are not likely to be involved with the pathophysiology [54]. The binding of leukocyte function-associated-1 to intercellular adhesion molecule-1 does not appear to be involved in HS because efalizumab, which inhibits this adhesion, fails to ameliorate HS. Some tumor necrosis factor alpha (TNFa, TNFα) blockers (TNFaB) treat HS, implying that TNFa is involved with HS. IVIG does not work well for HS, implying that B-Cells and immunoglobulin are not actors in HS. It is possible like in neophogenic system fibrosis and pseudoxanthoma elasticum, cutis laxa, and lipoid proteinosis cutis [107], the kidney is involved somehow with HS. One patient’s HS cleared with a kidney transplant [108] and several patients with HS have been noted to have nephritic syndrome [109].

Because there are usually no true infections with pathologic bacteria like SA in HS, even HS stage 3 almost never results in a fever, sepsis, or swollen lymph nodes. It is also interesting to speculate whether or not a particular distribution of HS depends on which of the 30-45 species of CONS localized to a body region is “pathogenic” to defective innate cellular immunity.

CONS can be a pathogen if present on indwelling devices in debilitated hospitalized patients [4, 5], but it is likely that such CONS infections are different in nature to the CONS role in HS. It is possible that HS patients’ hairs or scars themselves play the role of foreign body and that the CONS can latch onto the scarred skin, especially if HS manifests with honeycombs of scarred skin or in scarred interconnected subcutaneous tracts and fistulas. Aberrant responses to commensal bacteria likely occur in other diseases. It is interesting to note that both Crohn disease (CD) and HS, diseases that can infrequently overlap, occur primarily in areas rich in bacteria. They have wholly different histopathology, but share a common treatment – TNFaB.

The basis for follicular occlusion in HS has yet to be fully defined. It is clear that HS is a follicular disease and some defect in keratin clearance exists with resultant follicular occlusion. This occlusion could be part of the defective innate cellular immunity discussed above or an independent effect. Danby compared axillary sebofollicular junctional skin of HS patients; the HS skin was found to be almost devoid of PAS positive material (0/1+) in both the border and center lesions of HS, whereas sinus tract and interfollicular epidermis showed uniformly 2-3+ positivity irrespective of inflammation; controls showed no such changes [120]. The sebaceous glands, which contribute to the occlusion of the follicles in acne, are not present in HS [26], suggesting that other structures and biochemical mediators underlie the pathology of HS-related follicular occlusion. Several partly effective therapies might be useful because they resolve the follicle occlusion and allow for restoration of proper follicular functioning.

Keratinocytes can make “antimicrobial peptides” (“AMP”) possessing both pro-inflammatory and anti-inflammatory functions. AMPs can activate the adaptive immune system. The peptides produced might induce keratinocyte migration and proliferation — providing a basis for the development of follicular occlusion. AMPs are part of a complex production network of cytokines and chemokines. The presence, absence, or abnormality of one of any of the AMPs could explain the infectious and inflammatory features of HS. The AMPs, cathelicidins, defensins, TNFα, and psoriasin might underpin, at least in part, the pathophysiology of HS. Some AMPs are produced by mature keratinocytes spontaneously or after stimulation and some AMPs are produced by eccrine sweat glands. Other AMPs are prominently subject to modulation by antibiotics (hence the anti-inflammatory mode of action for antibiotics in acne and rosacea). Also because sebaceous glands are miniaturized or absent in HS skin [26], their diminished size might stop them from producing or modulating AMPs and nullifying their role in the innate immunity of the skin. Soluble interleukin-2 receptor seems to play some role in the pathophysiology of HS [121, 122]. Vemurafenib (Zelboraf®), a B-Raf enzyme inhibitor, which causes cutaneous eruptions in > 50 percent of its users [123], and lithium [124, 125] have both been found to induce HS, raising the possibility that B-RAF and increasing the number of neutrophils (a side effect of lithium that also worsens acne and psoriasis) might be involved in the pathophysiology of HS.

Numerous antibiotics are active against CONS including: carbapenems, intravenous cephalosporins, betalactamins, lincosamides, rifampicin, aminoglycosides, tetracyclines, and fluoroquinolones. Macrolides do not seem to ameliorate HS. It is not clear why. Why antibiotics work best in combination against HS remains unclear; it has yet to be defined whether the antibiotics play an anti-bacterial role or anti-inflammatory role or both.

HS affects the sexes differently. HS appears to be more common in women, at least in the United States [79]. Sexual incidence differences might be related to shaving, follicular trauma, hormones, or the fact that women seek medical care more often than men in the United States. These questions remain to be answered. In some countries, like Tunisia, HS is more common in men than in women [80]. I will address life style issues below that might explicate sexual differences and other aspects of HS care.

HS almost always occurs after the onset of puberty. This supports the conception that adult skin and the adult immune system for reasons of hormonal influences or other factors is different from that of children. The courses of HS and acne through aging are different. Acne almost always starts during puberty and is equal in the sexes if not more common in males. Males seem to have more extreme cases of acne involving the back and chest. Acne’s persistence after puberty, however, is more common in women than in men and more fixed in location to the face. With HS, women are more likely to have axillary HS involvement, whereas men are more likely to have perineal or perianal HS. Most reports of HS occurring in especially atypical locations like the ear and back heavily occur in males. HS, however, can occur in any body area in men and women. Does obesity, the differing hormone levels, the bacterial florae of mature skin, or the sites of adipose tissue define these differences? We do not know.


Staging

HS is most easily staged using the 3 part Hurley Staging system: Stage 1 shows isolated HS; Stage 2 HS shows some confluence of HS lesions; Stage 3 HS shows full confluence of HS lesions (Table 1). It is estimated that ~75 percent of patients have stage 1 HS, ~24 percent have stage 2 HS, and ~1 percent have stage 3 HS.

The Sartorius score is a more complex scoring system now used in clinical trials (Table 2).

Pain control might also alter the course of HS. We do not fully understand the feedback loops that link the nervous system to the cutaneous system and dermatological disease. Reflex sympathetic dystrophy, a syndrome involving increased pain, exacerbates hidradenitis suppurativa [126]. Nerve fibre-marker protein gene product 9.5 (PGP 9.5) expression is altered in HS. We do not know if these findings are primary or secondary [127]. We do not understand how depression impacts the severity of HS, i.e., being in a better mood and feeling less pain might make HS better. I have had patients with stage 3 HS, however, who showed no signs of depression, but were in extreme and almost constant pain. All that we do know is that most patients with HS have a higher incidence of depression and pain [89].


Treatment

Medically, HS can be treated in at least 7 ways: (1) decrease the load of the “pathogenic” HS bacteria; (2) decrease the immune response; (3) alter the hormonal balance; (4) reduce follicular occlusion; (5) help the skin to heal; (6) reduce pain; and (7) improve psychological state.

Stage 2 and stage 3 HS seldom remit permanently. However, in mild stage 1 cases or after treatment (significant weight loss, removal of the axillary tissue, or sustained courses of combination antibiotics), HS can abate leaving only scars in its wake. The course of all diseases has a quality of random, stochastic drift; they get better and worse for no apparent reason and HS is no exception. Therefore, optimal treatment varies over time particularly in Stage 1 HS. Stage 2 and 3 HS usually require continuous or at least intermittent therapy – even surgery often only abates the disease for a time (sometimes, however, permanently in the axillae). A combination of medical management, pain management, and psychological and surgical interventions can aid HS patients [6, 7].


Topical HS Treatments-Topical Clindamycin, Dapsone, 15 percent Resorcinol, Gentamicin

Topical clindamycin is the first treatment that should be prescribed to HS patients. The reasons for this are (1) few side effects, (2) efficacy for stage 1 HS, (3) ease of use, (4) low cost, and (5) good insurance coverage for topical clindamycin. Topical clindamycin was the historical standard of care in 1980s, 1990s, and early 2000s as a result of studies done up to that time (stage 2 and stage 3 HS were treated by surgery in this period). When a clinical trial using 1064 nm laser for HS was performed at Henry Ford Hospital, the investigational review board insisted that the researcher use topical clindamycin as the placebo to be compared to topical clindamycin and 1064 nm laser because study patients could not be deprived ethically of the standard of care for the previous decades. One report notes the use of topical genatmycin for HS [110] and another fusidic acid for HS [111]. I have used gentamicin sulfate on rare occasions with some additive effect reported by patients but I am afraid of gentamicin sulfate’s systemic absorption and ototoxicity, so use gentamicin sulfate only as a bridge to oral therapy.

Topical antibiotics can still help HS patients. I commonly prescribe topical clindamycin gel and less commonly (because of cost and insurance coverage) topical dapsone gel to be used each once a day. Either can be used twice a day and work within weeks. I usually find topical clindamycin or dapsone may be effective alone, sometimes, in milder stage 1 HS. However, when I see no improvement after 2-4 weeks, I combine them with oral antibiotic combinations. Stage 2 patients ask for topical antibiotics even when on an antibiotic combination therapy and receiving regular intralesional corticosteroid injections. Sometimes, patients do not want oral agents and topical alternatives are useful alone, but usually work better with intralesional injections of triamcinolone. Some patients prefer topical clindamycin, some dapsone, and many want both. Generally, the gel formulation of clindmycin is used, but this is not to say clindamycin lotion should not be used and some of my patients prefer the lotion. No study has yet formally assessed the utility of topical dapsone for HS patients; topical dapsone costs $200 for 30 grams. Similarly, no studies have looked at the role of topical metronidazole, a therapy that I seldom have found useful. Benzoyl peroxide (in particular as a wash), while irritating, might help patients as well, and was used in one study discussed below [20].

Three articles on topical clindamycin have been published and other articles have mentioned its use in passing. One investigated the efficacy of topical clindamycin alone and the other compared oral tetracycline to topical clindamycin. The last compared topical clindamycin to itself and without 1064 nm laser. With the advent of antibiotic combinations including rifampin, the importance of topical clindamycin has faded but in mild disease or maintenance therapy after a successful course of oral antibiotics or surgery it remains useful.

In a randomized double blind controlled trial [18], Clemmenson studied 30 patients with mild to moderate HS who received topical clindamycin twice daily or placebo. Clemmenson assessed patients after 12 weeks of therapy. Clemmenson measured patient assessment (and validated this approach) and the number of inflammatory papules, pustules, and nodules. The topical clindamycin group did better than the placebo group (+350 versus -90, p < 0.01). In a secondary analysis papules and pustules decreased significantly, but not inflammatory nodules or abscesses (a penetration issue perhaps). Of those studied, 5 patients noted mild side effects and transient burning after application (3 in treatment and 2 controls). However, none of those patients discontinued the treatment. The 10 percent drop out rate, especially with the small sample size of the Clemmenson study, must be noted.

Jemec and Wendelboe [19] conducted a randomized controlled double blind trial comparing topical clindamycin twice daily to oral tetracycline 500 mg bid in 46 HS patients and found the two equivalent. The outcomes were patient and physician global assessments (PGA) using visual analogue scales (VAS). With 3 months of treatment, patients in both groups showed significant improvement. However, there was no statistical difference in improvement between treatment arms. Although both groups were comparable at baseline, there was a large unbalanced dropout rate (26%). Two-thirds of the patients who dropped out (8/12) were in the tetracycline group. Of the 12 patients who dropped out; 7 patients did not show up for scheduled visits; 2 patients discontinued treatment because of gastrointestinal upset; the rest discontinued because of lack of effect, concomitant treatment with another antibiotic, or suspected allergic reaction to topical medication. Those patients were not included in the analysis.

In 2010, Mahmoud [20] in 22 Hurley Stage 2 patients with Fitzpatrick type 3-6 skin, compared topical therapy in the form of benzoyl peroxide wash 10 percent and clindamycin 1 percent lotion to benzoyl peroxide wash 10 percent and clindamycin 1 percent lotion with once monthly ndYAG 1064 laser hair removal. They reported that there was progressive improvement in disease activity, most significantly during the 4 months of treatment, which was maintained during the 2-month post-treatment follow-up period. Averaged over all anatomic sites, the percent improvement was 72.7 percent on the laser treated side and 22.9 percent on the control side, suggesting that topical treatments do ameliorate HS, albeit less well than when the ndYAG 1064 nm laser hair removal and topical medications were combined.


Resorcinol and Hibiclens

Boer and Jemec have reported the use of 15 percent resorcinol, a peeling agent, for the treatment of HS [21]. Boer and Jemec treated 12 women with stage 1 or 2 HS with topical resorcinol and followed up for at least 1 year. The patients rated the efficacy of treatment by the global maximum pain of nodules and abscesses on a VAS and by self-report of the mean duration (days) of a painful lesion. All patients experienced a significant decrease in pain as assessed by VAS and reported a reduction in mean duration of painful inflammatory nodules. It might be an interesting option to try Rezumid® (Summer Laboratories) an acne treatment, but that contains 5 percent sulfur and 2 percent resorcinol (a much lower concentration than Jemec used).

It is not surprising that standard cleansers, such hibiclens, are not effective for HS because CONS produces a biofilm [73]. In the intensive care setting, CONS is controlled by indwelling devices embedded with antibacterial agents and strict sterile protocols. When an actual CONS infection occurs, the use of strong intravenous antibiotics is necessary. It is possible that 15 percent resorcinol breaks up the biofilms of CONS and removes follicular occlusion. A barrier to the use of 15 percent resorcinol is that it must be obtained from a compounding pharmacy and likely is not covered by insurance.


Combinations of Oral Rifampin and Clindamycin or Minocycline

The first line of treatment of stage 1 painful HS, not responsive to topical clindamycin or dapsone, is the combination oral rifamipin 300mg BID and clindamycin 300mg BID or minocycline 50-100mg BID (or the expensive extended release minocycline at a weight adjusted dose once a day). Minocycline, owing to its side effects, is the second choice of oral agents to combine with rifampin. Concerns with this drug include: (1) increased side effects versus clindamycin, (2) lack of study as compared to clindamycin, (3) pregnancy category, and (4) drug interactions. Clindamycin in the treatment of HS provides a very safe agent, causing much less diarrhea in the community patients who use it versus hospitalized patients who commonly suffer Clostridium difficile associated diarrhea-pseudomembranous colitis. Clindamycin seems to cause fewer vaginal yeast infections owing to narrower antibotic effect spectrum than minocycline. In addition, clindamycin costs less than generic minocycline or extended release minocycline. Lower doses and different frequencies do work and are used based on an individual patient’s status (rifampin 150 mg bid with clindamycin 150 mg bid or even used once in combination daily). The 300 mg bid dose of both medications is preferred for reasons of efficacy and side effect profile. Lower doses can work, if side effects stand in the way of full doses.

The safety of these medications deserves further discussion. The pregnancy category of clindamycin is a B; rifampin is a C; minocycline is a D. Because these drugs might be used in women who may not use birth control and might get pregnant, I do query female HS patients whether they intend to get pregnant while they are on therapy and let their answers shape the therapy that I prescribe them.

Clindamycin has been linked in particular to skin rashes, abdominal pain, esophagitis, diarrhea, and Clostridium difficile associated diarrhea-pseudomembranous colitis, but I have only seen abdominal pain in HS patients who have used the medication. Rifampin changes body secretions, such as urine, to orange red, so patients should be warned about this. It can cause hepatitis and interacts with many drugs. Rifampin decreases the effectiveness of oral contraceptive pills (OCP) and this must be considered if female patients are using OCPs for birth control. Rifampin has many drug interactions and HS patients may be taking a variety of other medications because of their co-morbidities such as metabolic syndrome [92]. Minocycline can cause headaches, dizziness, malaise, vertigo, chest and joint pain, a lupus erythematosus-like reaction, and a hypersensitivity reaction (e.g. Drug Reaction with Eosinophilia and Systemic Symptoms-DRESS), dyspigmentation, and other rare side effects. Mincocycline has more drug interactions and package insert warnings than clindamycin. However, minocycline seems to have more immunomodulatory effects than other tetracyclines; it even shows occasional success in the treatment of sarcoidosis. Therefore, I believe that it is the most effective companion antibiotic of the tetracyclines to use with rifampin.

For the simple side effects that accompany therapy, there are steps that can be taken. Fluconazole 150 mg intermittently or even in rare cases every week can be given with the rifampin/clindamycin combination if a woman is prone to vaginal yeast infections. The incidence of yeast infections and stomach upset seems lower with lower doses of antibiotics. Sometimes, cimetidine or agents for irritable bowel syndrome can calm the gastrointestinal side effects related to antibiotic use. If clindamycin fails to ameliorate HS with rifampin, minocycline 50-100 mg BID with rifampin can be substituted. I find that extended release minocycline (Solodyn®) given daily at a dose of 55, 65, 80, or 90 mg in thinner patients and 105, 115, or 135 in heavier patients with rifampin 300 mg BID can be the most effective double antibiotic combination. I sometimes even dose extended release minocycline twice a day. Sometimes, I give the patients one pill of the extended release type and one pill of regular minocycline 12 hours a part. The use of doxycyline with rifampin has not been reported and perhaps for some patients this might be an option because minocycline’s side effect profile is complex. Lymecycline, a tetracycline class antibiotic available in the United Kingdom has not been found to be effective for HS. It is important to determine the combination of treatments that ameliorate the individual’s HS and recall that study data is only a jumping off point for treating an individual patient.

I have found these combinations effective to varying in degrees in between 250-300 patients and have found some success in at least 75 percent of the patients with Stage 1 and mild-moderate Stage 2 HS. I find them to have synergistic affect with biologics for patients with Stage 2 or Stage 3 HS. Some patients cannot tolerate these antibiotics owing to gastrointestinal upset. Other factors can affect medication tolerance. Two patients that I have treated with stage 3 HS (one whom was on adalimumab 80 mg twice a week), which had improved with treatment, stated that rifampin induced depression. I am not sure of the basis of this (the patient tolerated the clindamycin or minocycline well once the rifampin was stopped). I have not seen mood changes with clindamycin or minocycline. If side effects that are not true allergies are encountered, doses as low as minocycline extended release 55 mg daily or 50 mg BID of generic minocycline and rifampin 150 mg BID can still be helpful, albeit sometimes less effective. I also combine these agents with other topical, oral, and injectable corticosteroids.

Strong data supports the combination use of rifampin and clindamycin for at least stage 1 HS and for mild stage 2 HS. The first report of combination use was noted in 2006 [8]. Fourteen patients with HS had received treatment with oral rifamipin 300 mg BID and clindamycin 300 mg BID combination therapy. Of these patients, 8 achieved remission and a further 2 achieved remission when minocycline was substituted for clindamycin. Four patients were unable to tolerate therapy. The combination of clindamycin and rifampin has been found effective in a series of 116 patients [10] with 10 weeks of treatment; the Sartorius score dramatically improved at the end of treatment, (median = 29, inter-quartile range = 14.5, vs. median = 14.5, inter-quartile range = 11; p < 0.001), as did other parameters of severity including the quality of life score. Eight patients (6.9%) stopped the treatment because of side effects [9]. In a retrospective study in 34 HS patients, 28 of 34 patients (82%) experienced at least partial improvement and 16 (47%) showed a total remission [10]. The maximum effect of treatment appeared within 10 weeks. Following total remission, 8 of 13 (61.5%) patients treated as mentioned above experienced a relapse after a mean period of 5.0 months. Non-responders were predominantly patients with severe stage 2 or stage 3 HS.

Some of my patients (10-30%) with stage 1 and mild stage 2 HS have stopped treatment after 10-12 weeks with remission (estimated this number at 10-20% at one year). Sometimes, I leave patients on this combination treatment for longer periods, or leave them on topical indefinitely; the persistence of HS and the tolerance of medications informs the best manner in which to treat the individual HS patient. Rarely, patients with milder HS do get relief from monotherapy with minocycline (in particular its extended release form) or clindamycin. It should be noted that older reports of HS dating from the 1980s state that tetracycline 500 mg bid was equal in effect to topical clindamycin (mentioned above), and thus antibiotic monotherapy has been shown to help some HS patients. A study, yet unreported, but noted in clinicaltrials.gov, is now comparing oral rifampin and clindamycin to oral rifampin, oral clindamycin, and 1064 nm laser hair removal.

If combinations of clindamycin or minocycline and rifampin fail, other combination antibiotic treatments can be considered. A combination of metronidazole 500 mg BID (or extended-release 750 mg daily), rifampin 300 mg BID, and moxifloxcin 400 mg daily [11] has helped HS patients. The regimen induced a remission when used over 2.4 months (range 0.9-6.5) and 3.8 months in stage 1 patients and 6.2 and 12 months in the 2 stage 3 patients. The triple regimen has been reported as effective, but significant side effects have been reported that include: gastrointestinal disorders (64% of patients), vaginal candidiasis (35% of females), reversible tendinopathy (14% of patients), and hepatitis (3.5% of patients). No frank tendon rupture was reported.

The combination of moxifloxcin, rifampin, and metronidazole is not to be undertaken lightly. I prefer to use a shorter course of the treatment with generic levofloxacin (Levaquin®) 500 mg daily for one month with metronidazole and/or rifampin as rescue therapy when clindamycin/minocycline and rifampin are not working. I first try adding on low dose dapsone, before using a fluoroquinolone. The toxicity of fluoroquinolones and metronidazole increases with extended use and these medications have their own complex side effect profiles. I have not used ciprofloxin for HS because its efficacy for treating skin bacteria is the lowest of the fluoroquinolones, but its side effect profile might be better than later generation fluoroquinolones; perhaps I should consider it more regularly. The risk of tendon rupture (while infrequent) and CNS alterations increases with the duration of fluoroquinolone use, obesity, and corticosteroid use (among other factors) and thus should be considered carefully in HS patients. Metronidazole, useful in a number of other hard to treat HS cases, discussed here and below, might be combined with rifampin and clindamycin and minocycline as well but this has not been studied. Finally, it should be emphasized that the mechanism of action of antibiotics – antibiotic or anti-inflammatory – is not known. In this regard, oral linezolid, a protein synthesis inhibitor, which is very expensive (but available orally at a cost of over $1000 for a 10 day course, usually only with the approval of an infectious disease specialist) is effective against CONS, MRSA, and other bacteria that might have a role in the treatment of HS. Its use for HS is noted below in one patient in combination with other antibiotics with excellent effect.


Dapsone

If rifampin combinations do not work, another antibiotic to consider is dapsone (which has a role in treating dermatitis herpetiformis and leprosy). Before initiating this therapy, first check a G6PD, complete blood cell count (CBC), and basic blood chemistries and perform a neurological examination. I have found dapsone effective. Dapsone can have a variety of hematological effects and these should be monitored clinically and with regular CBCs. Dapsone should be started at 25 mg daily and can be titrated to 100 mg BID (although 75 mg BID is usually sufficient) as tolerated. Cimetidine (200-400 mg daily) should be given with dapsone to decrease dapsone’s hematolytic side effects. I have found that in a subset of patients, dapsone can be quite effective, particularly in patients with pyogenic granuloma-type (PG) HS lesions. In one thin patient, with PG like lesions in the groin, clindamycin and rifampin did not work, but 4 months of dapsone with monthly intralesional kenalog 2.5 mg/cc abated her disease. In one of my obese female patients, 6 months of oral dapsone at 50 mg BID achieved a 6 month remission with relapse that was partially controlled with 25 mg of dapsone daily. I have combined dapsone with clindamycin and rifampin, which has resulted in a greater effect than if these agents are used alone.

Several studies involving oral dapsone have been published with mixed results. Early studies yielded positive results [14]. In 2006[15], in a retrospective series of 5 patients, physicians noted improvement in all five patients within 4-12 weeks, at doses ranging between 25 and 150 mg/day. All patients required maintenance therapy with dapsone at doses between 50 and 150 mg/day to sustain their disease control. All patients reported symptoms improved after dapsone initiation, supporting physician observed clinical improvement. All patients tolerated dapsone well. The patients did not note any significant adverse effects. The median follow-up period was 24 months. In 2011, a total of 24 HS patients were prospectively treated with dapsone [16]. Improvement was seen in 9 out of 24 (38%) treated patients, whereas 15 out of 24 (62%) did not experience any improvement. None of the 4 cases with severe disease experienced improvement. Side effects leading to discontinuation of the treatment occurred in 2 of 24 patients (8%). Rapid recurrence of disease at the cessation of treatment occurred. A recent report of the combination of infliximab with dapsone did not find dapsone to be a very effective add-on-agent [17]. Thus, it seems that dapsone is best used in Stage 1 or sometimes in stage 2 patients, but not in stage 3 patients or in combination with other agents. Ultimately, dapsone is a second line treatment but it is a low risk option for treating HS with close monitoring. In sum, I have found dapsone can induce remissions in stage 1 and stage 2 patients who have failed combination antibiotics, but other reports have not found its response to be durable. Dapsone is not a medication for treating stage 3 HS.


Intravenous Antibiotics

Because bacteria appear to play a role in HS, powerful intravenous or intramuscular antibiotics hold promise for HS treatment, although case reports are few and often exhibit confounding factors. The need for intravenous access and their cost complicates the use of intravenous antibiotics. Interestingly, I had a patient with HS who said that when piperacillin/tazobactam (Zosyn®), and vancomycin was administered for a possible SA infection, improvement HS occurred, independently of any benefit to controlling SA. Notably, a 4 patient case study [12] (based on the compassionate usage of combination antimicrobial treatment) found powerful intravenous antibiotics in combination with oral antibiotics to be highly effective for Stage 2 HS. Two patients with severe stage 2 HS took ertapenem (a carbapenem class drug), which has its antimicrobial through inhibiting cell wall synthesis, but does not treat MRSA, and had a complete remission; one of these patients also took oral metronidazole, rifampin, and linezolid 1200 mg each daily for a month, then moxifloxin, and amoxicillin [12]. Two other severe stage 2 HS patients took intravenous ceftriaxone with excellent results; one of these patients also took rifampin, moxifloxacin, and metronidazole. All 4 patients achieved complete remission with the absence of any inflammatory lesions. This report was prefigured by a report in 2009 that noted an HS patient given intravenous ceftriaxone (BID x 2 g / day x 21 days) and linezolid (BID x 600 mg / day x 28 days) that was initiated upon the diagnosis of acute bacterial meningitis; eventual successful management of the HS patient’s fistulas was noted [112]. I should note that some imipenems can be given IM, which would simplify their use, but I have not attempted such use.

The exact timing and length of use of intravenous ertapenem or ceftriaxone and which oral or intravenous antibiotics must be combined with IV agents still needs to be determined. It is possible that other intravenous antibiotics such as vancomycin, cefepime, ceftaroline, combination piperacillin/tazobactam, and others might also help to decrease the burden of CONS or have other affects, thereby improving HS. Similarly, as stated above, intravenous or oral antibiotics like linezolid are likely useful for the treatment of HS.

In sum, powerful antibiotics with wide bacterial coverage including coverage for CONS may have a role in the treatment of severe stage II and perhaps stage III HS [13]. Again, the need for intravenous access and daily dosing, along with high cost complicates their use. The issue of resistance that will be generated with continuous use of these powerful antibiotics must be considered as well. Finally, the fact that the scars and strictures of HS will be left behind even if there is no inflammation should make patients consider quiescence of the HS after strong antibiotic treatment as a possible bridge to surgery.


Triamcinolone acetonide injections with drainage of HS abscesses

In most patients who see me, I actively use triamcinolone acetonide injectable suspension (Kenalog®) diluted to 1.25–10 mg/cc, for injection with an 18, 22, 25, tuberculin or 30 gauge syringe into HS lesions (ILK). This is done to decrease pain and inflammation to and to (1) extract pus out of the needle incision site or (2) de-roof active lesions [94]. I find that triamcinolone acetonide injections typically exert an anti-inflammatory effect for two weeks on average. However, I find that a series of injections at 2-week intervals is helpful because it can collapse or transform some sinuses and tracts into scar tissue. In fact, injections appear to have a cumulative affect. I think of this in the same way that a series of botulinum toxin treatments in the gabellar area can have a semi-permanent effect once the gabellar muscle is left to atrophy. If the inflammation is pummeled by constant (catabolic) local corticosteroid, sometimes the body’s natural scarring process can proceed to close fistulas, tracts, and abscesses. In many cases, however, the injections are palliative, decreasing pain, shrinking abscesses and tracts, but not curative. Corticosteroid injections also ameliorate the painful fibrosis and keloids related to HS. I have never noted adrenal suppression in HS patients receiving ILK.

I also will freeze and/or use silver nitrate on HS pyogenic granuloma-type lesions and sinus tracts to try to cauterize them. All this is done in combination with oral and topical antibiotics. I must note that some HS patients cannot tolerate silver nitrate application and that treatments must fit the patient’s needs and tolerance. Most references for the use of triamcinolone acetonide injections and silver nitrate for HS exist in textbooks [22, 71, 72] or as passing references in journal articles [81], but triamcinolone acetonide injections for HS is a common practice that should be studied more rigorously.


Retinoids-Isotretinoin

Isotretinoin is discussed in the treatment section of this article for historical reasons (it was a mainstay of treatment in the 1980s and 1990s) and has in fact has been used to treat HS with poor success. A trial done in 86 HS patients found that only 17 percent responded to oral isotretinoin at standard acne doses [23]. In a retrospective study of 358, 14 patients (16.1%) declared an improvement, 67 patients (77%) no effect, and 6 patients (6.9%) worsened [24]. Other studies have shown that isotretinoin is an ineffective treatment for HS [25].

Isotretinoin’s failure is not surprising because HS is a disease of the follicular unit and CONS/immune system interactions. In fact, in most HS patients, the sebaceous glands are already decreased in size [26]. Interestingly, one of the main effects of isotretinoin is to shrink sebaceous glands, an affect already accomplished by HS without pharmacological intervention.

One problem with studies of HS is that HS is only now being stratified into types [93] and we need to find which subtype of HS is retinoid responsive. It is possible that HS that manifests mostly the follicular plugs and comedones, true AI, may respond well to isotretinoin. I avoid isotretion and treat advanced HS with antibiotics, TNaB, 1064 nm laser, or hormones, allowing patients’ responses to define therapeutic course. The clinical findings of HS and previous courses of treatments define whether isotretinoin has any place in the treatment of an individual patient’s HS, but with other treatments available, istotretinoin can no longer be recommended as a primary therapy for HS.


Retinoids-Acitretin

Acitretin has been a more promising agent than isotretinoin for the treatment of HS. Acitretin’s efficacy has only been reported in small HS studies. I found it ineffective in 3 patients. One case notes the successful use of etretinate [113] for retroauricular acne (likely HS as acne does not occur behind the ear and HS does) an agent that is off the US market even though etretinate was more effective for psoriasis than acitretin. No studies have assessed topical or oral tretinoin, topical or oral tretinoin, topical or oral panretin, or topical tazarotene; the utility of oral tazarotene, which never made it to market, for HS in unknown.

Oral alitretinoin (approved for use in UK in 2009) has been found effective for hand dermatitis unresponsive to other agents and might have promise in HS. In an abstract in the Journal of the American Academy of Dermatology (jaad.org) in April 2013, oral alitretinoin demonstrated efficacy as measured by DLQI and Sartorious scoring in 4 patients aged 30 to75 years of age. Average depression scores as measured by the DLQI at week 0, 12, and 24 were 19.7, 8.0, and 6.7, respectively, achieving an average reduction of 13 at week 24. Indeed, similar results were achieved using the Sartorious scale, with an average reduction of 15.7 [128].

A positive report [27] has been noted regarding the use of acitretin rather than isotretinoin for HS accompanied by nodulocystic acne. Hogan [28] found that acitretin was effective in 5 HS patients. In 2011, Boer and Nazary [29] performed a retrospective study of 12 patients and treated patients with acitretin (mean dose, 0.59 mg/kg/d) for a mean period of 10.8 months. Nine patients saw marked or complete remission after 1 course of treatment and 3 patients showed mild to moderate improvement of their condition. Significant adverse effects were seen in all patients, including cheilitis (in all patients), dermatitis, hypertrichosis at the chin, sticky skin, depression, fatigue, buzzing in the ears, and photosensitivity.

Acitretin is poorly tolerated, in particular when the dose is above 25 mg daily [132]. Boer and Nazary [29] reported that half of the treated group was unwilling to undergo a second course of treatment with acitretin (a finding that I find to be important as well). There still might be a role for acitretin in HS because a study of surgery with subsequent use of acitretin noted that the recurrence rate was low. The recurrence rate was only 20 percent in group 2 patients who received both acitretin and surgical excision as compared with 40 percent of patient who used acitretin alone [30].


Hormone Therapy – Female Hormone therapy

A subset of female patients has some aspect of endocrine dysfunction or menstrual variation in their HS. In particular they note that their HS waxes and wanes with their menstrual cycles. In females with HS a relationship with endocrine abnormalities is not clear. In a study of 32 women with HS, testosterone and dehydroepiandrosterone sulphate levels were normal with one being 6 years post menopause at time of HS onset and 8 being menopausal at age of HS onset [114]. The validity of the previous study was questioned by others [115]. Some HS patients likely suffer from endocrine irregularities or “metabolic syndrome” [92]. It is important to establish if a patient with HS has irregular periods, irregular hormone levels, or PCOS. Female patients have noted that oral birth control pills (OCP) and spironolactone 25–75 mg QD-BID have helped to ameliorate their disease. Spironolactone is a synthetic 17-lactone drug that is a renal competitive aldosterone antagonist in a class of pharmaceuticals called potassium-sparing diuretics. The potassium should be checked because spironolactone can cause hyperkalemia. Spironolactone, which is pregnancy category C, should be accompanied by an OCP when possible to prevent pregnancy related complications, such as feminization of a male fetus. I have had a few patients who have benefited from spironolactone at the higher end of dosing. Published reports of the use of spironolactone for HS do not exist.

Another hormone blocker, cyproterone acetate, can be used in the EU. Most studies have shown that spironolactone and cyproterone acetate are equivalent in effect in various contexts [77, 78]. Cyproterone acetate is not available in the United States, thus making spironolactone, the hormonal therapeutic option of choice. Cyproterone acetate and ethinyloestradiol (Diane 35®, approved in the EU) might be another treatment, but reports regarding its use are sparse. Only one article notes it as a failure in patients who eventually were put on infliximab [130]. The side effects of spironolactone must be discussed and are mentioned in brief in Table 4.

Isolated case reports note that anti-androgen therapy can be effective in women with HS. Bogers noted successful HS treatment with a gonadotropin-releasing hormone agonist and by total abdominal hysterectomy with bilateral salpingo-oophorectomy [116]. Camisa [31] noted a 33-year-old woman with severe familial hidradenitis suppurativa of the vulva and perineum who was treated with a combination of dexamethasone and leuprolide acetate (discussed below). The clinical improvement paralleled the adrenal and ovarian suppression, as demonstrated by falling blood levels of testosterone, dehydroepiandrosterone sulfate, androstenedione, and estradiol. Another case report [32] noted that combinations of minocycline with cyproterone acetate and ethinyloestradiol given at different times of a woman’s 28 day cycle helped her HS.

OCPs can help treat HS [33]. It is not clear which OCP is optimal for HS. For the treatment of acne in women who want to use birth control, several OCPs are FDA approved. These agents might be the best OCPs for females with HS, but this has not yet been defined. However, those with drospirenone might be best because it has effects similar to spironolactone. OCPs indicated for acne include: estrogen combined with a progestin called norgestimate in Ortho Tri-Cyclen®, differing doses of estrogen combined with a progestin in Estrostep®, and drospirenone and ethinyl estradiol in Yaz®. An OCP with drospirenone, appears to increase the risk of stoke more than other ingredients in OCPs. Other brands of OCP containing drospirenone include Beyaz®, Gianvi®, Loryna®, Ocella®, Safyral®, Syeda®, Yasmin®, and Zarah®. Mini OCPs likely do not have a role in the treatment of HS. Drospienone (which is a molecule resembling spironolactone) is particularly complicated to use in HS patients who smoke, because smoking and using drospirenone increases the risk of stroke even more than drospienone used without smoking. A trial with drospirenone and ethinyl estradiol (Yaz®) was undertaken at Massachusetts General Hospital, but its findings have not been published and clinicalstudies.gov in February of 2013 notes that that this trial was terminated.

Mortimer [33] enrolled 24 females in a study comparing ethinyloestradiol 50 μg/cyproterone acetate 50 mg to ethinyloestradiol 50 μg/norgestrel 500 μg in a reverse sequential regimen given on days 5-25 in the menstrual cycle. The researcher divided HS patients into two groups matched for age and disease duration. The treatments were given sequentially for 12 months with cross over at 6 months. The two treatment regimens both ameliorated HS showing no difference. Mortimer reported that seven patients who had had continuously active disease for 20 years cleared. For the other patients, five improved, four remained the same, and two deteriorated. The dropout rate was 20 percent. Of the six patients who dropped out, four dropped because of inability to tolerate the treatment (2 in each group) and two because of lack of efficacy.

In a retrospective cohort study studying 64 women with HS, Kraft and Searles [34] compared the efficacy of anti-androgen therapy to systemic antibiotics in a heterogeneous group of 52 female patients. Researcher collected data from HS patients’ charts. The response to anti-hormonal therapy was superior to that of antibiotics (55% verus 25%, p < 0.04). They found isotretinoin and metformin to be ineffective and kenalog injection to be short lasting. Kraft and Searles haphazardly used several modalities of antiandrogen and antibiotic therapy. A combination pill of ethinyl estradiol 35 μg/cyproterone acetate 2 mg and cyproterone acetate alone were the most commonly used anti-androgens. Ineffective antibiotics included doxycycline, minocycline, azithromycin, trimethoprim/sulphamethoxazole, and tetracyclines. Kaft and Searles did not compare rifampin/clindamycin to antiandrogen therapy.


Metformin

If hormones do not work in women, there is another hormonal approach to their treatment in women--metformin. It probably works best in obese patients as an add-on medication. Metformin is an FDA oral anti-diabetic drug in the biguanide class, also used in PCOS and obese women with hormonal irregularity, off label. The most serious potential side effect of metformin use is lactic acidosis resulting in an FDA black box warning. Lactic acidosis is very rare and the vast majority of these cases seem to be related to co-morbid conditions, such as impaired liver or kidney function, rather than to the metformin itself. Metformin has also been reported to decrease the blood levels of thyroid-stimulating hormone in people with hypothyroidism and testosterone in men. The clinical significance of these changes is still unknown. A once a day extended release form of metformin exists. Metformin has been assigned to pregnancy category B by the FDA. Close monitoring for lactic acidosis is prudent when using metformin.

In some HS patients with abnormal hormone levels, diabetes, or PCOS, it is not surprising that metformin has helped. Verdolini [39] studied 25 HS patients who had failed other therapies (including hormones and antibiotics). They were treated with metformin and after 24 weeks, 18 patients clinically improved with a significant average reduction in their Sartorius score of 12.7. The number of monthly workdays lost reduced from 1.5 to 0.4. DLQI also showed a significant improvement in 16 cases, with a drop in DLQI score of 7.6. Arun and Loffeld [40] reported a woman with a family history of PCOS, who lost weight from 209 kg to 146 kg during metformin treatment, 500 mg TID. Her type 2 diabetes resolved and the metformin was discontinued. After this her HS flared, initially, lymecycline (a tetracycline not available in the US) helped her somewhat, but it was discontinued and metformin 500 mg daily was re-started, decreasing her HS flares. Doctors increased the metformin to 500 mg BID, which greatly decreased the pain of her remaining HS. I have not been able to replicate this result in 3 patients who were obese but not diabetic in whom I tried metformin 1000 mg daily. In patients who are obese or who have diabetes, metformin should be considered as a treatment option. These finding suggest that HS might be like psoriasis, a metabolic syndrome-related disease [92]. In obese patients metformin is a good agent to combine with antibiotic owing to its different mechanism of action of action and side effects.


Hormonal Therapy of Men

Hormones appear to sometimes play a role in male HS patients [95]. Finasteride 5 mg daily (which blocks 5α-reductase isoenzyme blocking the production of dihydrotestosterone (DHT-2), has been reported as an effective HS treatment. I have found finasteride can help obese male HS patients with stage II or III HS already taking TNFaB or antibiotics. An alternative is dutasteride 0.5 mg, which blocks DTH-2 isoenzyme (more so than finasteride) and the DTH-1 isoenzyme, which finasteride does not block. Finasteride 5 mg and dutasteride 0.5 mg (together DTHB) are approved for treatment of benign prostatic hypertrophy. DHT-1 is most active in the skin. DTHBs appear most useful in obese patients who seem to have more hormone pathology than patients with appropriate weight. DTHBs have negative effects on sexual function and can enlarge the male breast. Finasteride was used effectively in a study as monotherapy (5 mg/d) in 7 patients [35]. Six patients [36] showed significant improvement and 3 patients demonstrated complete healing. Two patients with follow-up periods continuing longer than 1 year reported remissions lasting 8 to 18 months. One report showed finasteride’s utility in a patient with facial HS [37]. No formal reports of the use of dutasteride (I have used it with good effect), an agent more potent that finasteride, for HS have been noted in Pubmed (US National Library of Medicine National Institutes of Health, PubMed.gov as of February of 2013.

Other hormone blockers exist and might have utility in for severe stage II or III HS including: leuprolide acetate (Lupron(LA)), flutamide, and degarelix. Flutamide is an oral anti-androgen drug that primarily competes with testosterone and dihydrotestosterone for binding to androgen receptors. Flutamide is a treatment for prostate cancer and can be dosed as 300 mg TID. It is only for stage 2 or 3 disease and can be combined with other agents. Leuprolide acetate (LA) is a synthetic form of gonadotropin-releasing hormone used in the treatment of prostatic cancer, endomtriosis, and precocious puberty. In these conditions, LA is dosed at 3.75 mg/month and combined with other anti-hormonal agents. Degarelix (INN) or degarelix acetate (USAN) is a hormonal therapy used in the treatment of prostate cancer. Degarelix has an immediate onset of action to bind to gonadotropin-releasing hormone (GnRH) receptors in the pituitary gland and blocking their interaction with GnRH. This induces a rapid and profound reduction in luteinizing hormone (LH), follicle-stimulating hormone (FSH), and in turn, testosterone suppression. Sometimes, these agents are used in women for a variety of purposes and might have a role in both sexes in severe cases of HS. Camisa noted a woman successfully treated in part with LA [31].


Tumor necrosis alpha blockers (TNFaB) adalimumab or infliximab

If hormones, retinoids, and antibiotics do not work and surgery is not undertaken, adalimumab or infliximab are the next treatments for HS. TB testing with PPD or Quantiferon Gold TB test must be performed before using TNFaB. Although I will discuss them more extensively in a future article, they merit a brief summary herein. It is important to keep in mind that they do not erase the scars, tunnels, fistulas, or honeycombed tissue of HS; they can stop the immune response abating pus collection and inflammation. Dormant tracts and fistulae can evolve into scars, which does improve HS. Importantly, because severe cases of HS (Hurley Stage 3) can evolve into squamous cell cancer (SCC) after 15-20 years duration, particularly in the perianal region (on their own without treatment), and TNFaB can lead to an increase in SCCs, the use of TNFaB must be considered carefully and patients must be closely monitored. I had a patient with Stage 3 HS who developed metastatic SCC after 3 doses of infliximab. How much this drug contributed to the metastatic SCC after so few doses cannot be determined.

The use of biologics for HS has a biochemical basis because TNFa is an inflammatory substance of the immune response of HS that includes innate immunity markers (toll-like receptors 2, 3, 4, 7, and 9, intercellular adhesion molecule 1, IL-6 and IL-10, tumor necrosis factor, α melanocyte stimulating hormone, transforming growth factor β, β-defensin 2 and 4, and insulin-like growth factor 1) [55]. Similarly van der Zee [56] found that the pro-inflammatory cytokines, interleukin (IL)-1β and TNF-α, as well as the anti-inflammatory cytokine IL-10 were significantly elevated in HS skin. Elevated levels of these cytokines were also found in perilesional HS skin. Increases relative to control skin of IL-1β, TNF-α, and IL-10 in HS were 31, 5, and 34 fold, respectively, compared with psoriasis, which showed 4, 1, and 2 fold increases, respectively. Levels of all three cytokines showed a trend towards a positive correlation with disease severity. IL-2, IL-4, IL-5, and interferon-γ were hardly detectable in HS or healthy control skin. The work of van der Zee and Dréno [57] provides a basis for the usefulness of antibodies that block TNF-α in the skin. Interestingly, IL-12 and IL-23 are found to be abundantly expressed by macrophages infiltrating the papillary and reticular dermis of HS lesional skin, providing a basis for the use of IL12/23 blockers [57]. Interestingly, zinc does down regulate all innate immunity markers except for TNFa.

I reported the first case of the use of adaliumab for HS in 2006 [58], in an obese male with stage III HS and arthritis. This patient continues to derive benefit from an 80 mg biweekly dose of the medication combined with rifampin 300 mg BID and minocycline 100 mg BID. I will review some of my patients who used adaliumab for HS. All but one have benefited for months at a time. In one thin, 70-year-old male, the administration of adulimumab, 40 mg weekly with 5 mg of finasteride daily worked for two years, then stopped working. In a young 18-year-old male, the use of 80 mg of adulimumab twice a week with minocycline 100 mg BID and rifampin 300 mg BID with regular intralesional triamcinolone injections and periodic incision and drainage has allowed the young man to attend college and live a normal life. In a female patient with total scarring and marsuplization of her genital and vulvar areas, adulimumab 40 mg weekly had no impact on her disease. Basically, the less severe the scarring and the shorter the duration of disease, the better adulimumab works. Multiple other reports have found that adaliumab at doses 2 or 4 times psoriatic doses can be an effective treatment for HS [59, 60, 61, 62].

In December 2012, the results of a phase 2 study of adalimumab in 154 patients were published. The study compared placebo, adalimumab QOW, and adalimumad QW. At 16 weeks the response rate was 3.9 percent, 9.6 percent, and 17.6 percent, respectively [82]. This study shows that QW dosing of adalimumab 40 mg can be effective in some patients with HS. It might be that dosing should be weight based. I find even higher doses up to 80 mg BIW are needed in obese patients. Patients, in the aforementioned study, were not separated by duration of their disease, an important factor determining degree of scarring, tracts, and fistulae possessed by a patient with HS.

Studies have also found that infliximab is an effective treatment for HS [63, 64]. Furthermore, some studies suggest that infliximab is superior to adalimumab with certain set dosing schedules [65]. However, one patient with PG and co-morbid HS, eventually responded to adalumimab therapy after failure of infliximab therapy. Combination with intravenous methylprednisolone followed by thalidomide (100 mg / 200 mg) and oral prednisolone has been noted [49]. As is true in psoriasis and rheumatoid arthritis, if one TNFaB fails, another might work. One advantage of infliximab is that insurance coverage is better because patients who are hospitalized to undergo surgical removal of lesions or for other reasons can receive infliximab as part of their hospital treatment. Finally, it seems that the IL12/23 blocker ustekinumab [66, 67] might be an effective treatment for HS, but its use has not been compared to TNFa blockers. Ustekinumab is currently in a proof of concept study at University Medical Centre Groningen as noted at clinicalstudies.gov in Feburary of 2013.

I have not had good luck with infliximab as a treatment for HS. One 50-year-old male with stage III HS developed metastatic squamous cell cancer after 3 doses of infliximab and died. A 35-year-old female developed drug induced lupus and had to stop therapy after 6 doses. Another HS patient developed multiple sclerosis-like symptoms after 5 doses of infliximab and stopped therapy.


Cyclosporine

Older literature suggests that strong immune suppression with agents such as corticosteroids and cyclosporine (CSA) can be helpful for HS patients with severe disease, but it is not used commonly and requires close monitoring. Rose [41] noted 2 cases in which cyclosporine ameliorated HS. One 38-year-old female patient with a 20-year history of HS, was initially treated with controlled release minocycline 100 mg twice daily together with a tapering course of oral steroids, starting at prednisolone 30 mg daily. The disease flared when the corticosteroids were discontinued and the patient received a pulse of 500 mg of intravenous methyl-prednisolone. Despite this, she required surgery to excise areas of inflammation on the right thigh and labia majora. She subsequently received oral clindamycin, clarithromycin, and intralesional corticosteroids without improvement. Cyclosporine started at 4 mg / kg daily for 3 months then was reduced to 2 mg / kg daily for 4 months. After cyclosporine was stopped, the patient had no severe episodes of HS during this period. Rose [41] also noted a 31-year-old man with a 16-year history of severe nodulocystic acne that had failed to respond to 6 months of oral minocycline and surgery, with a normal CBC and blood chemistries. He had severe back acne but also inflammatory lesions with HS scarring and sinus formation in the axillae and groin. He began taking 20 mg isotretinoin (0.25 mg / kg daily) and prednisolone 20 mg daily, the latter reduced by 5 mg weekly. Over the subsequent 18 months he had four prednisolone tapers with daily lymecycline without achieving HS control. He started cyclosporine at 3 mg / kg daily with appropriate monitoring. Within 8 weeks he was weaned off prednisolone, with HS abatement and the residual acne cleared completely. Cyclosporine was well tolerated and was discontinued after 4 months with HS abatement. The patient remained in remission for 4 months and his subsequent relapse was much milder than his pretreatment HS. The patient then elected to restart cyclosporine and had another rapid response. For HS with pyoderma gangrenosum (PG), cyclosporine works well [42]. Not all reports are positive as researchers observed a poor response for HS to 10 mg prednisone daily in conjunction with cyclosporine (2.5 mg / kg) and minocycline (100 mg BID) [49].

Cyclosporine HS reports do not discuss the difference between generic cyclosporine (Sandimmune) and microemulsion cyclosporine (Neoral). It is important to give magnesium supplements when using cyclosporine because cyclosporine causes the kidneys to release magnesium into the urine. Buckley [42] noted a 48-year-old patient with PG and HS who had resolution of the PG and the HS with cyclosporine 4.5/mg/kg and antibiotics 15 months after the cyclosporine was begun. Gupta [43] treated a 60-year-old man with 6 mg/kg daily for 6 weeks and described a moderate response. The use of cyclosporine has many side effects and the rise in the use of TNFaB, which require less monitoring than cyclosporine, has complicated cost benefit analysis for the use of cyclosporine for HS. Long standing lesions of HS can evolve into SCC, which increases concerns about the use of cyclosporine long term. The affects on blood pressure and kidney function have not been assessed over the long term in HS patients using cyclosporine. Some stage 3 HS patients show signs of anemia and chronic organ stress, again complicating the use of cyclosporine in stage 3 HS patients who need cyclosporine most. Cyclosporine is likely best used in younger patients without co-morbid conditions.


Zinc, B12, Niacinamide

Weak data supports use of Zinc, B12, Niacinamide, and growth factors in HS.

Reports have assessed the use of zinc supplements to treat HS. In a pilot study by Brocard [38] 22 patients with stage 1 HS were prescribed zinc gluconate (90 mg/d). Brochard reported 8 complete remissions and 14 partial remissions; gastrointestinal symptoms were the most commonly reported adverse effect. Dréno [54] studied 12 patients (HS stage 1 or 2) in whom the disease had progressed for at least 6 months and who had a minimum of 2 closed nodules in typical sites. Two biopsies were performed at baseline: one in a closed inflammatory nodule and one in healthy adjoining skin. Patients were treated for 3 months with zinc gluconate at a dosage of 90 mg/d. A new biopsy was then performed in the same nodule.

The biochemical findings of the study are interesting. Innate immunity markers (toll-like receptors 2, 3, 4, 7, and 9, intercellular adhesion molecule 1. interleukin [IL] 6 and 10, tumor necrosis factor, α melanocyte stimulating hormone, transforming growth factor β, β-defensin 2 and 4, and insulin-like growth factor 1) were studied by immunohistochemical analysis. Dréno observed significantly decreased expression (P < .001) of all the innate immunity markers studied except IL-10 in non-lesional and lesional HS skin. The down-regulation of innate markers was significantly greater in lesional HS skin compared with normal skin except for tumor necrosis factor. Dréno noted that 3 months of zinc treatment induced a significant increase in the expression of all the markers involved in innate immunity. In over 20 patients in whom I added zinc to antibiotic regimens, I found little difference in their HS. Because high dose zinc used alone can cause copper deficiency and related skin pathology, it is always advisable to take copper along with zinc. On the other hand, zinc seems a low risk treatment for HS and zinc should be considered more seriously.

Vitamins may have a role in the treatment of HS. B12 [68] was used effectively in patients with inflammatory bowel disease and suppurative dermatoses; further study needs to be done is this regard. Nicotinamide (niacinamide) has been used to treat patients with acne (sometimes bullous pemphigoid with tetracycline) and might have use in HS. It is interesting to speculate that combinations of nicotinamide, zinc, and copper or nicotinamide, zinc, copper, and azelaic acid might be helpful in a limited fashion for HS because these minerals and vitamins are occasionally useful for the treatment of acne. I have, however, have not found short courses of these combinations to be effective for HS.


Treatments of HS that are not supported by the literature


Oral Corticosteriods

The data for the use of oral corticosteroids in HS is not compelling as Rose’s cases demonstrate [41]. Marquardt [44] made a presumptive diagnosis of reactive arthritis associated with hidradenitis suppurativa and initially prescribed prednisone with good response. After that was tapered, he was started on sulfasalazine, but suffered recurrence of his HS and arthritis. He was then started on 10 mg of methotrexate weekly; after several months of therapy, his symptoms improved. Bhalla [45] noted 9 cases of HS with reactive arthritis treated with NSAIDs, prednisone, and isotretinoin, with varying success. It is interesting to speculate about which forms of HS with arthritis respond to prednisone or methotrexate. HS without associated findings of arthritis or PG might not respond as well. Fearfield presented a case of a 34-year-old woman with severe vulvar “apocrine acne.” She was successfully treated initially with prednisolone and then maintained on long-term isotretinoin suggesting that the patient had acne not HS [46]. Corticosteriods combined with thalidomide does not seem useful for treatment for HS combined with PG [49].


Methotrexate

As is the case with prednisone, methotrexate (MTX) may be more effective in HS linked with another disease than it is in primary isolated HS. De Souza [47] noted that SAPHO syndrome associated with hidradenitis suppurativa was successfully treated with infliximab and methotrexate. Jemec [48] reported 3 patients who were treated with either 12.5 mg (two patients) or 15 mg (one patient) in weekly doses of MTX for 6 weeks for 4 months or 6 months, respectively. Two-weekly blood samples were taken to monitor signs of possible toxicity. After treatment with MTX, patients and dermatologists were asked to assess frequency of pustular or nodular eruptions and severity of inflammation separately on the scale: – (worse), 0 (unchanged), + (marginally better), ++ (better), +++ (substantially better). This was then compared to standard treatment (topical clindamycin). Results showed minimal changes in the HS as assessed by the patient and the dermatologist. Specifically, HS lesions and flares were unaffected by treatment with MTX. Prednisolone and azathioprine in one patient with HS and Crohn disease only yield a partial response that did eventually respond better to biologics [131].


Colchicine

Colchicine is efficacious in the IL-1β- and inflammatory-mediated diseases: gout, familial Mediterranean fever, and Behçet disease. However, van der Zee conducted an open prospective pilot study in which 8 HS patients were treated with the accepted gout maintenance regimen of 0.5 mg colchicine BID orally up to 4 months [50]. Patients treated with colchicine failed to improve their HS by PGA.


Isoniazid

Isoniazid is an anti-tuberculosis drug with antibacterial, anti-granulomatous, and immunomodulatory effects. Jemec [51] assessed the case records of four HS patients (three women, one man) with a minimum of Hurley 2 stage who had previously unsuccessfully tried topical treatment and at least one kind of systemic treatment. These patients were offered oral isoniazid 300 mg daily for 3 months in an open study. In addition, three of the patients were offered oral pyridoxine 20 mg daily to prevent any neurological side effects of isoniazid. Jemec assessed a modified Sartorius score before and after the isoniazid treatment and recorded patients’ subjective assessment of the treatment effect. None of the patients felt any subjective improvement in their skin condition during isoniazid treatment. A clinically insignificant reduction in the Sartorius score (36 to 32 and 75 to 68) was seen in two patients treated for 1 and 3 months, respectively. In one patient treated for 3 months, the Sartorius score slightly worsened (51 to 53).


Etanercept

Etanercept is a fusion protein produced through expression of recombinant DNA. That is, it is a product of a DNA "construct" engineered to link the human gene for soluble TNF receptor 2 to the gene for the Fc component of human immunoglobulin G1 (IgG1). Expression of the construct produces a continuous protein “fusing” TNF receptor 2 to IgG1. The data on the efficacy of etanercept for HS is conflicting. A 2006 study of 4 patients published in the British Journal of Dermatology found it very effective [69]. Lee [52] conducted a phase II clinical trial of etanercept (50 mg/wk subcutaneously) in patients with moderate to severe HS. Efficacy was measured using a PGA and several secondary physician- and patient-reported outcome measures at least a 50 percent reduction on the PGA score at week 12 compared with baseline defined response. Only 3 of the 15 patients who entered the study were classified as responders (response rate of 20%; 95% confidence interval: 4.3-48.1) based on the intention-to-treat analysis. DLQI scores improved slightly from a median of 19 to 15 (P = .02). Comparison of baseline with week-12 PGA scores and secondary outcome measures of lesion counts and patient pain scores failed to show statistically significant improvement. Whereas other studies have noted that etanercept is effective for HS, Lee’s study seems to be the best controlled study. Hence because of the high cost and superiority of other TNFa inhibitors, etanercept cannot be recommended for HS. Possibly, higher doses of etanercept might work for HS, but these studies have not been performed or contemplated.


Efalizumab

Efalizumab, which is no longer marketed in the United States, is a once weekly, self-injected humanized monoclonal antibody that inhibits the binding of leukocyte function-associated-1 to intercellular adhesion molecule-1. This interaction contributes to the activation of T lymphocytes, the adhesion of T lymphocytes to endothelial cells, and the migration of T lymphocytes to sites of inflammation. Strober [53] conducted a single center, prospective, open-label clinical trial using efalizumab, and found it ineffective for the treatment of adult women with treatment-refractory HS.


Intravenous Immunoglobulin and Anakinira

Forms of intravenous immunoglobulin (IVIG) have been used in HS. In a review of 63 cases [54] of the use of intramuscular immunoglobulin for recalcitrant suppurative diseases of the skin, five cases of HS were noted and only 1 of 5 HS patients had an improvement, an 80 percent improvement. In a patient with PG and HS, IVIG did not abate either condition [98]. Thus, IVIG is not likely to be a useful treatment for HS. One article [70] noted that in a patient with pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) – a new autoinflammatory syndrome distinct from PAPA syndrome, treatment with the interleukin (IL)-1 receptor antagonist, anakinra, produced improvement, although without complete remission. Anakinra is currently being studied at the University of Athens for the treatment of HS in a Phase 2 study as noted at clinicalstudies.gov in Feburary of 2013.

In sum, isotretinoin, thalidomide, entanercept, cochicine, isonizid, efalizumab and intramuscular immunoglobulin, which have been reported as primary or incidental treatments of HS, have not been particularly successful treatments.


Life style modification to alter the course of disease

More patients with HS as compared with case controlled patients smoke and are obese. Therefore, life style modification appears to have role in controlling HS. Whether such life style factors correlate with or are causal in HS still needs further examination. This question also needs assessment if we consider HS to be a disease that falls under the umbrella of metabolic syndrome. Life style modifications suggested by various authorities include: (1) weight reduction, (2) mild antiperspirant agents, (3) smoking cessation, (4) soap (local hygiene and ordinary hygiene), (5) wearing of loose-fitting clothing, and (6) application of warm compresses with sodium chloride solution or Burow’s solution. It is not clear which of these modifications have true impact on HS.

I will assess my experience with life style modifications. Of these, weight loss, which decreases the friction in body folds, seems the best founded. Women have more body fat than men and this might account for sexual differences in HS. Obesity often accompanies HS, but could be merely an aggravating factor in increasing friction and occlusion in intertriginous areas rather than an independent risk factor. On the other hand, obesity affects hormone levels and can be associated with depression, both of which factors might influence HS. I have found that weight loss can decrease the severity of HS. Thus, the importance of weight reduction cannot be understated. I have had several patients who experienced HS in early puberty when they were heavier, then lost weight, and by their early 20s had only the residual characteristic scars of HS (whether this is due to changes in hormone levels complicates this analysis). Nevertheless, I find that at least 50 percent of my Hurley Stage 3 patients are already at their ideal body weight and that the HS itself in these patients is a chronic disease state in which patients experience some degree of cachexia. Cachexia with anemia in stage 3 HS patients has been noted by others [99, 100].

I do not think that antiperspirant choice (even oral ones) affects HS or that warm compresses with saline change the course of HS. Some have stated that antiperspirants can worsen HS [117]. I do agree with others that razor removal of the axillary hair with a safety razor may worsen axillary HS [118] and that 1064 nm laser is the best way of removing axillary HS hair. Anything that soothes the HS should be contemplated for use in HS with the patients’ reports acting as the physician’s guide. The sweat itself might be a breeding ground for CONS and other bacteria, so it is possible that reducing sweat in a way that does not irritate the patient might have a role in the overall control of HS. Because the apocrine gland is not the initial site of HS and HS is related to follicular occlusion with hyperkeratosis of the follicle, the use of an anti-antiperspirant such as aluminum chloride 20 percent, which is irritating, can not be advocated. A few reports note that botulinum toxin has ameliorated HS [74, 75, 76], but this needs to be demonstrated in clinical trials. Botulinum toxin’s utility might be to decrease sweating (making it harder for bacteria to propagate) or to change nerve function that is involved in immunity. Thus, the basis for the off label use of botulinum toxin for HS needs definition.

It is certain that HS patients smoke more than controls and most authorities advocate smoking cessation as a means of decreasing the severity of HS [79]. I think that the role of smoking in HS remains to be defined. I am not convinced that smoking aggravates HS. I think that smoking might be a means of self medicating for pain control. However, it might constrict the blood vessels, which might in turn affect the innate immunity of the skin, particularly if subcutaneous tracts and scarring are present. Nevertheless, smoking is toxic and has been reported to worsen several skin conditions (some diseases might be ameliorated by smoking including pemphigus vulgaris, pyoderma gangrenosum, aphthous ulcers, and Behçet disease) [96], However, for many health-related reasons it is advisable in all patients for physicians to advocate smoking cessation and this should be done in HS patients. Smoking cessation is even more important when a patient is considering surgery because smoking undermines healing and significantly worsens surgical outcomes [90, 91, 129].

Choice of soap does seem to affect the course of HS. In all cases irritating soaps should be avoided. The use reported above with a 10 percent BP wash is interesting and can be suggested to patients to be combined with other treatments. Interestingly, CONS produces biofilm that is resistant to conventional cleaners (including hibiclens). Whereas, HS may be thought of as partly a biofilm disease [73], soaps do not dissolve this biofilm and strong soaps are irritants that might make the HS worse. In sum, I do not think that soaps such as hibiclens aid HS patients. Thus, an unmet medical need is finding an agent that will, in fact, reopen occluded follicles and reduce the quantity of bacteria in the skin that are perpetuating the HS. Local hygiene and ordinary hygiene seem to have only mild impact on HS because it is not a disease caused by dirt.

Loose fitting cotton clothes, which have a place in the care of atopic dermatitis might have a place in the care of HS patients because they decrease friction. As I have discussed above, finding ways to keep absorbent material in place on top of oozing or open HS lesions (tubular net bandages) without causing the irritation that tape induces can help HS patients. The role of mechanical friction thus seems important in HS but remains to be defined. Psoriasis, another disease in which the innate immunity of the skin strikes wrong notes, does koebnerize, but HS does not appear to do this. It spreads follicular unit to follicular unit. Interestingly, inverse psoriasis, only 2-3 percent of all psoriasis, manifests in intertrigous skin subject to constant friction.


Topical wound care and Hyperbaric Oxygen to alter the healing of HS


Figure 1

Wound dressing is also an important aspect of the medical care of HS. The severity of disease in patients with stage 2 and 3 HS is sometimes assessed by how many dressings (pads) they use daily. Dressings made of highly absorbent cotton fabric bonded on both sides with perforated non-adherent film (e.g., Telfa®) are often used for the erosions and oozing abscesses of HS. Xeroform contains bacitracin (neosporin/bactracin), the second most common allergen in North America, complicating its long-term use for HS patients. Whereas simple cotton gauze can be used too, gauze sticks more than dressings with non-adherent film, although it is cheaper. It might be best to keep the wound dressing in place with tubular net bandages (Figure 1) because taping down wound dressings can irritate areas of HS, in particular when patients have to go through multiple wound dressing changes in a day. Even use of paper tape can generate irritation. It might be interesting to speculate that platelet derived growth factor (PDGF) gels approved for diabetic ulcers could help HS patients, but they are expensive and I have never used them. For chronic ulcers in patients with longstanding stage 2 and 3 disease, which maybe gravitating toward the development SCC, PDGF should certainly be avoided. Granulocyte-macrophage colony-stimulating factor combined with surgery was reported effective for treating perianal hidradenitis suppurativa [85].

Other wound healing modalities exist and might be considered for HS patients. Hyperbaric oxygen therapy might be an option for HS ulcerations that will not heal. Hyperbaric oxygen treatment has been reported as effective for healing the wounds of HS [83, 84]. Hyperbaric oxygen is expensive and does not affect the inflammation framework, the foundation of HS, but has been advocated. Surgical excision is perhaps a better option for ulcers of HS that will not heal. I have never used hyperbaric oxygen therapy for HS.


Topical pain control for HS

For topical pain control, I use lidocaine 5 percent ointment BID-QID, diclofenac 1 percent gel BID-TID, and ice packs. Compounding pharmacies have more complex formulations using such agents as ketamine, doxepin, gabapentin, and bupivacaine, which I will discuss in my future discussion of HS and pain control. I have not encountered problems related to systemic absorption of lidocaine or diclofenac but their use for the pain of HS is off label. Again, a challenge remains in combining their utilization with other topical agents like topical antibiotics and wound repair preparations. Patients report that diclofenac gel seems to be more effective than lidocaine ointment. Micronized creams of 4 and 5 percent lidocaine cream (e.g., LMX4® or LMX5®) also seem to be more effective than lidocaine 5 percent ointment but are much more expensive and lack insurance coverage. I have not found that topical steroids or topical calcineurin inhibitors help HS patients’ pain or lesion control.

Oral medications are the true backbone of pain control for HS. NSAIDs, atypical anticonvulsants (e.g., gabapentin and pregabalin) that treat neuropathic pain, serotonin-norepinephrine reuptake inhibitors (SNRI) (e.g. Duloxetine) that treat depression and pain, and opiates have a role in the treatment of HS related pain. It is also useful to have the patient see a pain specialist if the pain from the HS is severe. Also, if depression accompanies the HS, seeing a mental health care professional and use of appropriate psychotropic medications can help the patient as well.


Further work that needs to be done

Some agents for HS are very promising yet little validated trial data exists for their use. These include acitretin and cyclosporine and clinical trials are needed. Generic cyclosporine would be a much cheaper alternative to TNFaB but cyclosporine requires closer medical monitoring. We need to know whether TNFaB are inflammatory salvage agents like oral corticosteroids or if they can alter but not stop the course of HS (like they do with psoriasis) with an acceptable side effect profile. Adalimumab is now in Phase 3 trials and that data will be crucial to determining if it receives an FDA indication for HS. If this happens it would: (1) allow its maker to promote the drug for HS, (2) induce the company to promote more awareness of the disease, (3) improve insurance coverage for the medication. The status of phase 3 trials for infliximab for HS is unclear at this time. Because HS is a complex disease, combination therapies are needed and trials for agents like ILK and surgery with medication need to be done. We need to know more about combining hormonal agents and antibiotics. It would be interesting to know if topical dapsone is useful for HS and which are the best topical pain and wound healing medications for HS.


Conclusion

HS continues to be a complex disease to treat. Like most dermatological disease it is likely not one disease but a reaction pattern to many factors that fall under one rubric for the sake of categorization simplicity. We refer to 5 kinds of psoriasis: plaque, guttate, erythrodermic, pustular and inverse, but we now are going to be able to stage HS. In particular, a French group defined three phenotypes of (“axillary-mammary,” “follicular,” and “gluteal”) HS by phenotype and this typing might be used to tailor treatment and shape clinical trials [93]. Another group defined 2 groups of HS patients: one with hyperplasia of the follicular epithelium causing sinus formation and one with psoriasiform hyperplasia of the interfollicular epidermis with subepidermal inflammatory infiltrate but no sinus formation [119]. Treatment must be tailored both by the HS patient’s individual disease and by staging the disease. A summary in Table 3 summarizes how a physician might choose to treat HS based on the morphology of HS lesions and stage of the HS. In Table 4, I compare the advantages and disadvantages of medical treatments for HS. Few studies have assessed whether early intervention for HS at the time of puberty can change the course of the disease. Thus, we cannot compare all HS patients easily. As patients age with HS the scarring can take on a life of its own, thwarting medical treatment. In this way, HS is more like psoriatic arthritis (inducing permanent damage) than it is like psoriasis, which can disappear with continuous effective treatment. Weight loss can help some HS patients, but thin patients have HS, too. In particular stage 3 patients can be thin, anemic, and even cachectic. Whereas smoking may not worsen or cause HS, patients with HS should be counseled to stop smoking because it may be an aggravating factor.

Again, I stress that HS is a heterogeneousness disease that is more a reaction pattern with various genetic factors and inflammatory mediators playing out differently in the skin in different patients. This realization is the first step to tailoring therapy to the individual suffering from HS.

There seems to be a movement away from the term “hidradenitis suppurativa,” because the apocrine glands are innocent bystanders. The term “acne inversa” is becoming popular. This largely relates to histopathologic studies. However, one must remember that just because the follicle is involved does not mandate that we call HS acne, which centers in the follicle. Whereas I do not like naming games, perhaps a better name for HS/AI could be autoimmune follicular inflammatory disease.

It is crucial to sort out which factors (e.g., endocrine status, age of onset, duration, and/or associated inflammatory disorders) determine natural course and effective therapies. As HS progresses, combinations of therapies TNFaB with antibiotic and ILK must be in the armamentarium of clinicians. Combining hormonal and antibiotic treatment with ILK can be a useful tool for patients who do not solely reply on OCPs for their birth control but use hormonal agents to control their HS. Nothing should stop a physician who is dealing with seemingly intractable stage III HS from using TNFaB with antibiotics as bridge to pain control and/or surgery. Defining the etiology of HS remains an important project for future research in the field of HS. Better understanding about the use of antibiotic and anti-inflammatory drug combinations and integration with surgical modalities is an important goal for the future.

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