IN-DEPTH REVIEW Combination Treatment for Hidradenitis Suppurativa

a chronic,

severity and other patient factors. 5,6ncreasingly it is thought that combination therapy may be more adept in meeting the challenges of treatment of this multimodal disorder.
We aim to provide a comprehensive review of the of the combination therapies used in the treatment of HS.Electronic searches were performed using Ovid Medline, Cochrane Central Register of Controlled Trials, PubMed, ACP Journal Club, Cochrane Database of Systemic Reviews (CDSR), and the Database of Abstracts of Review of Effectiveness (DARE) from their dates of inception to May 2023.We combined the terms: combination, treatment, therapy and hidradenitis suppurativa as key words of MeSH headings in order to maximize the search strategy.Reference lists of all retrieved articles were also assessed for any relevant articles using the exclusion and inclusion criteria.
Eligible studies for the present review included case reports, case series, cohort studies or clinical trials in which patients with hidradenitis suppurativa were treated with a combination treatment.Combination was defined as two or more systemic, medical treatments.
Procedural and surgical treatments were excluded.Language was restricted to English and only human subjects were included.
Nineteen articles met the search criteria and are presented in the Table 1.
There is significant heterogeneity in reported outcomes.Most studies reported clinical outcomes including Hurley score, Sartorius score, complete remission, and hidradenitis suppurativa clinical response (HiSCR).Some studies, included psychological outcome measures such as the Dermatology Life Quality Index (DLQI) and Skindex questionnaire.
The primary outcomes varied across the studies.Complete remission was reported in 3 studies and ranged from 1-57%. 9,11,14owever, partial remission was only reported by van der Zee et al. and observed in 35% of patients. 14In 3 studies, the primary clinical outcome was the HiSCR, defined as at least, a 50% reduction in inflammatory lesion count and no increase in abscesses or draining fistulas.Dessinoiti et al used a similar, novel clinical response score, defined as at least 50% clinical improvement from baseline.The proportion of patients achieving these measures was a range of 33-57% and 73% respectively. 10,12,13,15Four studies reported Sartorius score or the modified Sartorius score as a primary outcome measure, with mean reductions of 16%-68.5% and a median reduction of 50% amongst the studies. 7,10,11,17Yao et al. reported the Hidradenitis Suppurativa Score (HSS) as their primary endpoint and demonstrated a

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12 point improvement in median score with therapy. 16 terms of side effects across the pooled cohort, a total of 17% reported diarrhea, and 10% other gastrointestinal symptoms including nausea, vomiting, abdominal pain and digestive discomfort.There were only two patients experiencing candida vaginitis across the literature.
Rates of relapse after cessation of treatment was reported in only 4 of the studies. 9,12,13,15endoca et al reported no relapse in 8/14 (57%) patients that responded to treatment.Dessinoiti et al had 10/26 (38%) patients relapse after a mean of 4.2 months whereas Caro et al. reported 15/30 (50%) patients with relapse after a mean of 12.4 weeks and 68% of patients after a mean of 24.9 weeks in two separate studies.

Rifampicin-moxifloxacin-metronidazole
We found 2 studies investigating the efficacy of a combination of rifampicin-moxifloxacinmetronidazole (RMoM). 19,20In a retrospective review by Join-Lambert et al. of 28 patients treated with a 3-week course of IV ceftriaxone and oral metronidazole as induction therapy before RMoM, clinical remission was observed in 16 people. 19owever, only 2 of these patients had severe, Hurley stage 3 disease.Gastrointestinal side effects including nausea and diarrhea occurred in 64% of patients.Vaginal candidiasis and moxifloxacin tendinitis were seen in 25% and 14% of patients, respectively.
In the same study site, Delage et al. conducted a prospective study of 28 patients in 2020, and clinical remission was seen in 21 patients. 20Adverse events including mild digestive discomfort, mucosal candidiasis, and asthenia was observed in 96%, 64% and 79% of patients, respectively.The treatment protocol between both studies also varied as the latter substituted pristinamycin, cotrimoxazole or doxycycline in the case of adverse drug reactions.

Combinations with at least one antibiotic
Several other combination treatments that included an antibiotic were found in our literature search.Armyra et al. conducted a prospective study of 20 patients with HS treated with a combination minocycline and colchicine for 6 months, followed by a maintenance regimen of 0.5mg oral colchicine twice per day for 3 months. 21linical improvement was observed in all patients and only 15% of patients experienced nausea and diarrhea after 9 months of treatment.Delaunay et al. conducted a retrospective audit of 65 patients treated with a combination of clindamycin and ofloxacin. 22A complete response was observed clinically in 34% of patients and a partial response in 25% of patients.Eighteen patients reported secondary adverse events, including 12% with clinical or biological symptoms such as worsening renal function and anemia, and 8% of patients experienced intermittent diarrhea.Eleven of these patients had to cease treatment due to side effects.Fania et al. completed a prospective study of 37 patients using intralesional ultrasoundguided injections of triamcinolone plus lincomycin, at baseline and after 2 weeks. 23here was a statistically significant reduction in mean, clinical (12.2 to 6.8), pain VAS (4.6-1.5), and skindex (60.3 to 49.6) scores.There was 1 case each of fever, increased acanthosis nigricans, and a delayed menstrual cycle in 3 different patients.However, 15 patients were on concomitant therapy including adalimumab, doxycycline, clindamycin, oral acitretin and dapsone.
There has also been a single case report of a patient taking a combination of intravenous linezolid and meropenem for one month with complete remission observed during treatment, however relapse occurred shortly afterwards.

Other Combination treatments
There were 3 retrospective studies which included combination therapies that did not include antibiotics.One study, by Hessam et al., looked at 66 patients treated with a combination of oral zinc gluconate and 2% topical triclosan. 24They reported a mean reduction mHSS score from 32.5-25 and a statistical improvement in clinical and quality of life scores.
Mcphie et al looked 31 patients that had received various combination treatment. 25he best clinical outcomes included CCR for mild disease, spironolactone & dapsone gel for moderate disease, and isotretinoin/adalimumab, adalimumab/tetracycline, isotretinoin/spironolactone, and intralesional steroid/tetracycline for severe HS.[3][4][5][6] Literature regarding combination treatment that include biologics have also been very limited, despite the emerging evidence for its efficacy for HS. 26 Brunasso et al. described a small case series of 7 patients with HS treated with a combination of infliximab and methotrexate. 27Data was documented from the two years following treatment (114-122 weeks).Short term results were promising with a mean reduction of pain in 96.2%, quality of life improved in 52%, and a 7% reduction of affected area.However, at the 2-year follow-up, pain was reduced only by 34.8%, quality of life improvement was in 14.7%, and a 1.25% reduction in the affected area.A single case report of dapsone and infliximab in combination has also been trailed in a patient with HS with significant clinical improvement of lesions. 28Another case series of sirolimus used as a rescue therapy in combination to tumor necrosis factor inhibitors demonstrated improvement in 78% of patients with severe refractory HS. 29 HS is primarily a chronic inflammatory disease affecting apocrine glands.Several treatment modalities have been recommended for HS including medical and surgical interventions.In mild to moderate HS, topical and systemic antibiotics including clindamycin, rifampicin and tetracycline tend to be the first line treatments. 30e rationale for antibiotic therapy in HS is based on the idea that bacteria is linked to the pathogenesis of the disease.Recent studies investigating the skin microbiome of HS patients with and without lesions, have demonstrated the presence of Staphyloccus lugdunesis, polymorphous anaerobic flora and skin commensals, including prophyromonas and poptoniphilus species, as the most commonly observed bacteria. 31,32Antibiotic combinations in the literature were developed on a basis of their wide coverage for this broad spectrum of bacteria present in HS lesions in addition to prevention of resistance seen with monotherapy and their anti-inflammatory effects. 33,346][37] CCR was first trialled in patients with HS on the background of its established effectiveness in patients with other follicular disorder such as folliculitis delcalvans. 38Across all studies investigating the efficacy of CCR in HS, clinical improvement has been observed in reported outcomes measures including complete remission in some patients. 9,11,14However, there is a paucity of randomized controlled trials and significant heterogeneity in reported outcomes, making it difficult to combine results.The safety profile is varying with the most commonly reported adverse event being gastrointestinal symptoms, including diarrhea and nausea.][9][10][11][12][13][14][15][16][17][18] Furthermore, patients using CCR experienced varying relapse rates, demonstrating that this intervention is not curative but feasible for use in symptom relief.Only one study has investigated longer term use of CCR for 6 months demonstrating sustained results during the course of treatment, however, did not include any follow up results after ceasing treatment. 16cently it has been demonstrated that rifampicin significantly reduces the clindamycin concentration, and the clinical relevance of this in CCR treatment of HS needs to be elucidated. 39The gastrointestinal side effects of CCR are an important area for future consideration as clindamycin is related to Clostridium difficile infection and there has been one report of the infection arising from CCR treatment in HS. 40,41 Rifampicin monotherapy is linked to antibiotic resistance and recommended for use in association with another antistaphylococcal agent. 42Caro et al. demonstrated that clindamycin monotherapy was slightly more effective than CCR.However, the evidence for this is limited and the risk of antibiotic resistance with clindamycin monotherapy needs to be taken into account. 12e combination RMoM was developed in response to issues of antibiotic resistance and diminishing clindamycin concentrations with CCR. 20To provide similar coverage to CCR, the same study site previously identified bacteria including, Staphyloccus lugdunesis, polymorphous anaerobic flora and skin commensals from bacterial isolates of their HS patient cohort, before selecting antibiotic agents. 32,43The effectiveness of combination therapy of RMoM for HS is comparable to CCR, however RMoM is most suitable for Hurley stage 1 disease.However, there is a relatively high prevalence of adverse events such as mild abdominal discomfort and mucosal candidiasis.Most of these side effects are mild and, in the context of its efficacy, increase its value as an intervention.Unlike CCR, patients treated with RMoM had a relatively lower relapse rate at year follow-up.This may be related to the pharmacokinetics and lesser interaction between rifampicin and moxifloxacin.Rifampicin is an inducer of cytochrome P450 which metabolises clindamycin, diminishing its plasma levels over time. 39Combination ofloxacin and clindamycin is another alternative to CCR and RMoM, sparing rifampicin use for MSSA and MRSA severe infections.This combination demonstrates significant clinical improvement; however, the sample size is extremely low and the prevalence of side effects is relatively high.Some researchers have investigated the effect of combination therapies which more directly target the inflammatory pathway in HS.Combination minocycline/colchicine and triamcinolone/lincomycin for the treatment of

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HS have demonstrated significant reduction in disease with minimal side effects. 21,23owever both studies are observational in nature, thereby limiting the gravity of the results.Colchicine works primarily via tubulin disruption with the effect of downregulating several inflammatory pathways, making it a potential treatment for HS, due to its overall, anti-inflammatory and immunomodulating effects. 44In the study conducted by Armyra et al., investigating a combination therapy of minocycline and colchicine, patients also undertook maintenance treatment with colchicine, which may have affected the results at their 3 month follow up after ceasing combination treatment.

Hessam et al. have investigated unique
combinations such as zinc gluconate with topical triclosan demonstrating some clinical and quality of life improvement, however further studies are required to provide stronger evidence for its efficacy. 24Zinc's effect on HS is related to its anti-inflammatory properties and the intimate link to the immune system, similar to its already established use in acne patients. 45In combination with the involvement in the antibacterial properties of triclosan, the use of zinc gluconate presents as an alternate therapy for HS.
Biologics have an important role in many inflammatory diseases due to their immunosuppressive properties and are fast emerging as forerunners in the treatment of HS. 46 Currently, adalimumab is the only food and drug administration (FDA) approved drug for the treatment of HS.Infliximab monotherapy has also been reported in several studies as an effective treatment for HS.However, reports on combination therapy using biologics is extremely limited and reported only in a case report with combination infliximab/dapsone and a small case series using infliximab/methotrexate. 47,48 In both studies, the therapy demonstrated significant efficacy.However, the infliximab/methotrexate combination was associated with a poor safety profile and long-term outcomes as many patients relapsed.This is in keeping with previous literature related to infliximab monotherapy for HS which was associated with a high rate of adverse events.The use of biological treatments in combination with other therapies may be useful for severe disease or HS that is unresponsive to other agents and requires further investigation.
The body of literature related to combination treatment in HS is subject to significant limitations.The quantity of studies investigating each intervention is small, with a maximum of 6 for CCR and 1-2 for other interventions.Another limitation is that the outcome studied between reports are all different, which limits comparability.The evidence is also low quality due to being primarily composed of retrospective studies, case series and case reports.Furthermore, the nature of these studies being retrospective or unblinded makes them subject to significant observer bias.Other forms of bias include selection and publication bias, which was significant in the present review as it is likely that only positive results are being published.
The current evidence depicts combination therapy as a potentially beneficial treatment modality for HS.However, the current literature is composed mostly, of observational studies and case reports and thus, further research in the form of randomized controlled trials comparing

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September 2023 Volume 7 Issue 5 (c) 2023 THE AUTHORS.Published by the National Society for Cutaneous Medicine.
2023 THE AUTHORS.Published by the National Society for Cutaneous Medicine.

971 Table 1 .
Characteristics of included studies.

Combinations with at least one antibiotic
PGA: physician's global assessment, IHS4: International Hidradenitis Suppurativa Severity Score System, DLQI: Dermatology Quality of Life Index, VAS: visual analogue scale, HiSCR: Hidradenitis suppurativa clinical response, MSS: modified Sartorius score, SF-36: 36-Item Short Form Health Survey questionnaire, mHSS: Modified Hidradenitis Suppurativa Score, CRP: C-reactive protein.AISI (acne inversa severity index).* Level of evidence is defined according to the National and Medical Research Council guidelines .47^Median and range.
SKINSeptember 2023 Volume 7 Issue 5 (c) 2023 THE AUTHORS.Published by the National Society for Cutaneous Medicine.SKIN September 2023 Volume 7 Issue 5 (c) 2023 THE AUTHORS.Published by the National Society for Cutaneous Medicine.