FormalPara Key Points

Recent studies add support for the use of intralesional corticosteroids for hidradenitis suppurativa (HS) flares and localized lesions.

A recent study suggests that monotherapy with tetracyclines may be as effective as the clindamycin/rifampicin combination.

Non-biologic drugs may be useful adjuncts to the biologic therapy of HS.

1 Introduction

Hidradenitis suppurativa (HS) is a chronic inflammatory disorder involving intertriginous areas. Inflammation in patients with HS is not restricted to the skin but is systemic, affecting several other organs [1]. Patients with HS are not only affected by recurrent painful draining skin lesions but also with associated comorbidities, including, but not limited to, metabolic syndrome and mood disorders [2, 3]. The earlier implementation of proper treatment is associated with better outcomes. Not uncommonly, patients with HS are faced with late diagnosis and undertreatment, and in dermatology we face patients suffering from both inflammation and fibrosis. The management of HS requires multiple modalities and a team approach to include the management of inflammation (amenable to medical treatment), scarring (amenable to surgery). and comorbidities (to involve a multidisciplinary approach). Biologics remain the treatment of choice for moderate to severe disease and surgical intervention is the treatment of choice for addressing permanently damaged tissue. There remains an adjunctive role for non-biologic therapies to be used in conjunction with biologics and surgical interventions in moderate to severe disease or as monotherapy for mild disease. Even though approval of the first anti-tumor necrosis factor (TNF) inhibitor in the management of HS shed light on this disease, with many more targeted therapies currently in the pipeline [4, 5], non-biologic therapies play a key role in managing HS [6]. We searched PubMed for studies and selected case reports from 2019 to 2021 for the current non-biologic therapies, which encompass antimicrobial, hormonal, anti-inflammatory, and retinoid drugs. This paper provides an update on the medical management of HS (excluding biologics and Janus kinase (JAK) inhibitors and phosphodiesterase inhibitors). A summary of recently published studies of these agents can be found in Table 1.

Table 1 Recent studies of non-biologic medical treatments for hidradenitis suppurativa (2019–2021)
Full size table

2 Antimicrobial Washes

The use of antiseptic washes in the management HS is supported by anecdotal evidence. Chlorhexidine wash, bleach baths, pyrithione zinc shampoo, and benzoyl peroxide (BPO) are commonly used in the management of HS as adjunctive therapy for their anti-inflammatory properties and ability to reduce antibacterial resistance [7,8,9]. Choice of specific agent is often empiric and guided by expert opinion [10]. A cross-sectional study looking at adherence to antimicrobial washes use among HS patients found that 30% of the 54 patients who had been recommended to use washes were using them on a daily basis, which raises questions about the practicality of whole-body washes and barriers to accessing washes [11].

3 Topical Therapies

Current North American clinical management guidelines for HS support clindamycin use in HS [10]. The use of topical antibiotics such as clindamycin is associated with a high risk of bacterial resistance, as shown in one cross-sectional study, which showed that HS patients using topical clindamycin were more likely to grow clindamycin-resistant Staphylococcus aureus [12]. For this reason, concomitant use of antiseptic washes, such as BPO, are recommended to help reduce resistance.

The efficacy of topical ichthammol 10% ointment, also known as ammonium bituminosulfonate, which is prepared by distillation of bituminous shale and ammonium sulfate, in HS patients has been reported [13]. Ichthammol is suggested as a local treatment in the Swiss practice recommendations for the management of HS [14]; however, these results are based largely on case series and expert opinion.

Resorcinol 15% cream, a compound structurally similar to phenol, with keratolytic, antimicrobial, and anti-inflammatory properties, is also used in the management of HS. In a case series studying the efficacy of topical resorcinol treatment among patients with stage I–II HS, all patients self-reported a reduction in pain from nodules [15]. In one study conducted by Molinelli et al., there was a significant reduction in mean pain and size and number of nodules and abscesses after treatment with topical 15% resorcinol cream [16]. Another study reported that HS patients treated with resorcinol 15% were satisfied with the treatment and 84.8% of patients responded to a questionnaire that they would recommend this treatment [17]. These studies suggest the long-term safety and efficacy of topical resorcinol use in the management of mild-to-moderate HS, although resorcinol is not available as a commercial formulation in the US and has to be compounded by a pharmacist.

4 Intralesional and Systemic Steroids

Recent studies provide more evidence for the use of intralesional steroids for flares and localized active lesions [18]. Intralesional corticosteroid therapy is an option for isolated HS nodules, likely through activation of intralesional glucocorticoid receptors and subsequent blockage of proinflammatory cytokine production [19, 20]. However, in a recent randomized controlled trial comparing intralesional triamcinolone and normal saline (NS), there was no statistically significant difference between the two concentrations of triamcinolone and NS in the treatment of acute HS lesions, although a low concentration of intralesional steroid (0.1 mL) was delivered to each inflammatory lesion [21].

In an interventional prospective study looking at the treatment of HS using intralesional ultrasound-guided triamcinolone plus lincomycin injections at baseline and at 2 weeks, there was a statistically significant improvement in pain, clinical improvement, and overall patient satisfaction at the week-4 follow-up [22]. In a follow-up study conducted by Caposiena Caro et al., there was also a statistically significant improvement in moderate–severe HS patients who were treated with intralesional ultrasound-guided triamcinolone and lincomycin injection. These studies offer promising hope for the use of intralesional corticosteroid injections in conjunction with an antibiotic in the management of acute HS flares and as a neoadjuvant therapy prior to surgery [23, 24]. García-Martínez et al. reported that high-frequency cutaneous ultrasound examination prior to intralesional corticosteroid injection improved clinical outcomes in all lesion types, including fistulous tracts and fluid collections [25].

In an interesting case of recalcitrant Crohn’s disease and Hurley stage III HS, tumescent anesthesia and 120 mg of triamcinolone in the form of a 40 mg/mL solution mixed into a saline bag were prepared and delivered intralesionally with significant clinical improvement 48 h after the procedure, with sustained results for 7 months after the procedure. Further studies are needed to study the efficacy and practicality of this drug delivery method for the treatment of recalcitrant HS [26]. In a recent study, the effectiveness of adjunctive therapy with systemic or intralesional corticosteroids to adalimumab among 38 patients with stage II–III HS with recurrence on biologics was evaluated. After stratification of the patients into two treatment arms (intralesional methylprednisolone, and oral prednisone), 88% of patients in the oral prednisone group and 85% of patients in the intralesional group showed improvement in the International Hidradenitis Suppurativa Severity Score System (IHS4), Dermatology Life Quality Index (DLQI), and pain visual analog scale (VAS) [27]. This demonstrates the importance of considering combination therapy, especially for managing acute HS flares.

5 Antibiotic Therapy

Systemic antibiotics are the first line of therapy in HS. HS lesions are colonized by bacteria, and biofilms have been found in the tunnels of HS lesions. Antibiotic therapy is often used due to both its antimicrobial and anti-inflammatory properties [28]. A case-control study comparing the skin microbiome of HS patients and healthy controls revealed variation in the amount and type of bacteria according to HS severity and lesion morphology, with dominant bacteria within HS lesions including Actinobacter and Moraxella species, Staphylococcus epidermidis, and anaerobes such as Porphyromonas and Peptoniphlius species, and a significantly higher abundance of Propionibacterium acnes in healthy controls, suggesting reduced Proprionibacterium colonization could contribute to HS pathogenesis [29].

In a recent study looking at the duration of antibiotic treatment, the authors found that the majority of oral antibiotic courses for HS have durations of < 12 weeks in an attempt to avoid emergence of antibiotic resistance [30]. Systemic tetracycline antibiotics, often used as first-line treatment for Hurley stage I and II HS, work by blocking the 30S subunit of the bacterial ribosome and also by blocking cytokine production. Common tetracycline antibiotics used for HS management include tetracycline 500 mg twice daily, doxycycline 100 mg twice daily, and minocycline 100 mg once daily [31] One study demonstrated the efficacy of combination therapy with colchicine and minocycline in HS [32]. In a recent Danish study evaluating the clinical efficacy of tetracycline, doxycycline, and lymecycline for the management of 108 HS patients, the greatest clinical improvement was observed in the tetracycline treatment group. Furthermore, response to treatment was significantly associated with lower body mass index (BMI), Hurley stage III, higher disease severity at baseline, and higher number of boils in the preceding month at baseline. Moreover, almost all secondary outcomes, including quality of life, overall disease-related distress, and number of boils in the preceding month, improved significantly in all groups [33].

Clindamycin, an antibiotic with anti-staphylococcal and anti-streptococcal coverage that works by inhibiting bacterial protein synthesis and suppressing neutrophil chemotaxis, is also used in the management of HS [34]. Rifampicin, a broad-spectrum antibiotic, can also be used in HS management for both its antimicrobial and immunomodulatory properties [34, 35]. The clindamycin/rifampicin combination has been well-studied in the management of HS with favorable success rates, especially in less-severe disease [36]. One study of 54 patients receiving oral clindamycin 300 mg and rifampicin 300 mg twice daily reported that a total 80% of the patients showed improvement in Hidradenitis Suppurativa Score (HSS) to some extent, including 37% achieving an improvement in HSS of ≥ 50% from baseline and 13% achieving full remission (100% improvement in HSS) at the 6-month follow-up. Conversely, 11% of the patients showed worsening in disease and 9% showed no change in HSS or were lost to follow-up. In this study, adverse effects were reported by 56% of the patients and the most commonly occurring adverse effect was diarrhea (12 patients, 22%) [37]. One study of 20 pediatric patients treated with a 10-week combination of oral clindamycin and rifampicin found that 60% of patients achieved a Sartorius score improvement ≥ 50% [38]. In a recent prospective, cohort study assessing the 12-week efficacy of oral tetracyclines (tetracycline, doxycycline, and minocyline) and a clindamycin/rifampicin combination, there was a significant reduction in the IHS4 from baseline among patients in both treatment groups. Interestingly, no significant difference was observed between patients in the two treatment groups, regardless of the disease severity [39]. A 52-patient retrospective study showed that lymecycline monotherapy and clindamycin plus rifampicin combination are both effective treatments for patients with moderate–severe HS. This study suggests that nodular-type HS may respond better to lymecycline, whereas the abscess/tunnel type may respond better to clindamycin plus rifampicin [40].

In another study evaluating the efficacy of oral clindamycin versus that of a clindamycin/rifampicin combination among 60 HS patients, both groups had a similar, statistically significant improvement in IHS4 scores, possibly indicating that clindamycin alone may be a useful treatment, regardless of disease severity [41]. A retrospective study of 31 HS patients treated with oral clindamycin showed a mean Sartorius score reduction of 42.5% and complete remission in three patients. The severity of HS increased in only one patient, which also indicates the efficacy of oral clindamycin monotherapy compared with the rifampicin/clindamycin combination in a selected group of patients [42]. Although the efficacy of clindamycin against HS has been shown, it should be noted that the use of clindamycin carries the highest risk of community-associated Clostridium difficile infection, and combination with rifampin reduces the risk [43].

One prospective cohort study with 28 patients showed the efficacy of the oral combination of rifampin, moxifloxacin, and metronidazole (RMoM) in patients with severe Hurley stage HS. The median Sartorius score dropped from 14 to 0 at week 12, with 75% of patients reaching clinical remission [44].

Metronidazole, an antimicrobial agent with strong anaerobic coverage against Prevotella and Porphyromonas species and immunomodulatory effects of T cells, has also been studied in the management of HS [29]. Treating patients with Hurley stage I and II HS with metronidazole 500 mg three times daily for 2 weeks may be helpful in reducing anaerobic bacterial load, especially Prevotella, which is resistant to clindamycin [30]. Topical metronidazole may be more effective than clindamycin in the eradication and prevention of colonization by Prevotella and Porphyromonas species and may possess a more robust anti-inflammatory profile, although this has yet to be studied in HS [45].

Ertapenem is a broad-spectrum carbapenem antibiotic used intravenously for the treatment of skin and soft tissue infections and HS [46]. In a retrospective study of 30 patients with severe HS treated with ertapenem for 6 weeks, disease relapse was common after treatment cessation. Ertapenem might be used to achieve rapid improvement of disease as a bridge to surgery or other maintenance therapies, such as biologic therapy, in order to prevent relapses [47, 48].

Dapsone is a sulfone drug with antimicrobial, bacteriostatic, and anti-inflammatory properties that can be used for Hurley stage I and II HS. In a retrospective study of 24 HS patients treated with dapsone, clinical improvement was seen in 38% of patients, suggesting that dapsone therapy may be possible for mild HS, but that rapid recurrence after treatment cessation is a concern [49]. In a recent study looking at 25 patients with mild-to-moderate disease, there was clinical improvement in 64% of patients and no clinical improvement in patients with Hurley stage III HS. In spite of the decreased efficacy with dose reduction, dapsone can serve as an option for stage I–II HS while bridging to maintenance therapy [50].

Despite the extensive use and evidence on efficacy of antibiotics, the emergent evidence on bacterial resistance limits the use of these treatments.

6 Hormonal Therapies

Androgen and estrogen levels play a role in HS, as patients may often experience premenstrual flares. HS is more common in women of child-bearing age, with the incidence dropping after menopause [51, 52]. Small sample sizes, variable outcome measures and methods, and reporting bias all limit the evidence for the use of hormonal therapy in HS [52]. The only reported randomized controlled, double-blinded, crossover trial of hormonal therapy in HS compared ethinylestradiol/noregestrol on days 5–25 of the menstrual cycle with ethinylestradiol on days 5–25 and cyproterone acetate on days 5–14 of the menstrual cycle. Both groups had decreased plasma testosterone levels and similar improvement in HS, but there was no clinically significant difference between the two treatment groups [53].

Spironolactone is a potassium-sparing diuretic that exerts anti-androgen properties through its ability to block mineralocorticoid receptors [54]. In a retrospective study on oral spironolactone (75 mg daily), there was a statistically significant improvement in pain score, number of inflammatory lesions, and Physician Global Assessment (PGA) score, indicating that anti-androgen therapy may be useful in the management of HS among females who report menstrual flares [52, 55]. A retrospective chart review of 26 women patients taking spironolactone 100 mg or 50 mg daily revealed it was well-tolerated and effective, with a reduction in DLQI of >5, however further studies are needed to identify optimal dosing and efficacy [56].

Metformin is an antihyperglycemic agent that improves insulin receptor sensitivity and reduces insulin resistance through improved glucose uptake, and may also possess anti-androgen properties. Since HS patients may have hyperandrogenism, co-occurring polycystic ovarian syndrome (PCOS), and low glucose tolerance, metformin is another treatment option. In a retrospective study of Hurley stage I–III HS patients treated with metformin, clinical response was seen in 68% of patients, with the majority being stage II patients [57]. In another study, 75% of patients had features of insulin resistance, but this did not predict response to treatment [58]. One retrospective chart review with 16 pediatric HS patients treated with metformin as adjunctive therapy showed improvement in five patients with decreased frequency of flares, whereas five patients had no improvement. Six patients were lost to follow-up or data were not available [59].

Overall, hormonal agents are considered a good therapeutic option in females with HS who report menstrual flares or who have features of PCOS [60].

7 Retinoid Therapy

Retinoids have been historically used for HS, likely due to similarities between HS and acne vulgaris pathogenesis [61]. Results from isotretinoin studies have been mixed. In a recent retrospective study of 209 HS patients with a prior history of isotretinoin use, no response to treatment was reported among 64.1% of patients. Responders were more likely to have a history of pilonidal cysts than non-responders. Having a concomitant history of acne did not enhance HS treatment response to isotretinoin [62]. In another retrospective study of 31 HS patients, combination therapy with isotretinoin and adalimumab led to a positive clinical response [63]. Acitretin is a retinoic acid derivative often used in the management of psoriasis that works by inhibiting epidermal growth and differentiation [64]. In addition to disorders of keratinization, it may be useful for the management of nodulocystic acne and HS that are not adequately suppressed by isotretinoin [65].

8 Other Therapies

Zinc has been used in HS patients for its anti-inflammatory effects, and showed a positive response clinically. A retrospective study with 92 patients receiving 90 mg of zinc gluconate and 30 mg of nicotinamide reported the efficacy of oral zinc plus nicotinamide [66]. However, long-term pharmacologic doses of zinc compete with copper absorption and can cause anemia [67].

Although robust evidence is needed, there is one case report each for verapamil [68] and thalidomide [69], suggesting their potential efficacy.

9 Conclusions

The management of HS is complex and often requires a combination of medical and surgical treatments in order to achieve promising results for disease sufferers. Non-biologic and non-procedural treatments are often used as monotherapy for mild disease and can be used in conjunction with biologic therapy and surgery for moderate to severe disease. Recent studies highlighted in this review add support for the use of intralesional corticosteroids for HS flares and localized lesions, and there is evidence that monotherapy with tetracyclines may be as effective as the clindamycin/rifampicin combination. There is hope for the potential efficacy of add-on drugs to biologics to increase drug survival of the limited biologics available for HS.

HS treatment continues to remain a challenge and a refined understanding of disease pathogenesis will lead to more efficacious therapies in the armamentarium of therapeutic options. This review aims to assist clinicians in their decision making in the management of HS patients, which often requires multimodal, individualized approaches to address both the medical and psychiatric impacts of disease. With ongoing clinical trials with biologic and other immunomodulatory treatment options and stronger data supporting evidence-based guidelines, practicing dermatologists will have access to a greater variety of resources to support their HS patients that combine both medical and surgical approaches for optimal disease control.