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Systematic review of immunomodulatory therapies for hidradenitis suppurativa

Authors Lim SYD, Oon HH

Received 29 December 2018

Accepted for publication 22 March 2019

Published 13 May 2019 Volume 2019:13 Pages 53—78

DOI https://doi.org/10.2147/BTT.S199862

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Cristina Weinberg

Peer reviewer comments 2

Editor who approved publication: Dr Doris Benbrook


Shi Yu Derek Lim,1 Hazel H Oon2

1Internal Medicine Residency, National Healthcare Group, Singapore, Singapore; 2Department of Dermatology, National Skin Centre, Singapore, Singapore

Background: Greater understanding of the roles of tumor necrosis factor-α, IL-1β, IL-10, and the IL-23/T-helper (Th) 17 and IL-12/Th1 pathways in immune dysregulation in moderate/severe hidradenitis suppurativa (HS) has helped in developing new regimens. We aim to review the use of different immunomodulatory therapies used to manage HS.
Methods: A comprehensive literature search was conducted on the PubMed and Clinicaltrials.gov databases from 1 January 1947 to 31 December 2018. Only clinical trials, case reports, case series and retrospective analyses published in the English language were included.
Results: Our search yielded 107 articles and 35 clinical trials, of which 15 are still ongoing. The tumor necrosis factor-α inhibitors adalimumab and infliximab were the most comprehensively studied agents. Published data from clinical trials support the efficacy of adalimumab, infliximab, anakinra, ustekinumab, bermekimab and apremilast but not etanercept and MEDI8968. Clinical trials for CJM112 have been completed, with results awaiting publication. Trials are underway for secukinumab, IFX-1, INCB054707 and bimekizumab. Biologics used in smaller cohorts include canakinumab, golimumab and rituximab. Most agents are well tolerated and demonstrate a good safety profile, with the most commonly reported adverse event being infections.
Discussion and conclusions: To date, adalimumab is the only biologic which has been approved by the United States Food and Drug Administration for HS. However, other agents also show promise, with further trials underway to evaluate their efficacy, tolerability and safety profiles. Different clinical measurement scores and endpoints used to make direct comparison difficult. Longitudinal surveillance and pooled registry data are paramount to evaluate the long-term safety profile and efficacy of therapy.

Keywords: Hidradenitis suppurativa, biologics, tumor necrosis factor, adalimumab, infliximab, secukinumab

Introduction

Hidradenitis suppurativa (HS), which has an estimated worldwide prevalence of 1%, is a chronic inflammatory follicular occlusive disease predominantly involving the intertriginous areas.1 Clinically, its manifestations vary from inflammatory nodules and abscesses to the formation of sinus tracts and scarring.2 It has a profound adverse impact on patients’ quality of life, and has been closely linked with physical and psychiatric co-morbidities including obesity, hypertension, dyslipidemia, diabetes mellitus, thyroid disorders, polycystic ovarian syndrome, arthropathies and depression.3

Pathophysiology of HS

Histopathological examination of early lesions in HS demonstrates terminal follicular hyperkeratosis, hyperplasia of the follicular epithelium and perifolliculitis. The occlusion of the terminal hair follicle results in dilation and cyst formation, followed by rupture of the hair follicle. The introduction of follicular contents to the surrounding dermis induces an inflammatory response and subsequent formation of abscess, sinus tracts, fibrosis and scars. This is worsened by biofilm formation and secondary infection.4,5

The inflammatory response in HS has in recent years been better characterized, although there are many components that remain to be elucidated. In particular, tumor necrosis factor (TNF)-α, IL-1β, IL-10, and the IL-23/T-helper (Th) 17 and IL-12/Th1 pathways play key roles in immune dysregulation in HS.6,7 In studies of HS skin, significantly increased frequencies of CD4 T cells expressing Th17-associated cytokines and TNF were found infiltrating HS skin.7 Treatment with TNF inhibitors was also related with a significant decrease in IL-17 expressing CD4 T cells in HS skin.7

Staging of HS and implications on therapy

HS has traditionally been staged according to the Hurley staging system, first proposed in 1989 (Table 1).8

Table 1 Hurley staging of HS

The Hurley staging system remains useful for determining the severity of disease in individual patients but is limited in monitoring the dynamic characteristics of disease in clinical trials.9 Hence, alternative scoring systems have been developed to better evaluate the efficacy of the intervention, as shown in Table 2.

Table 2 Scoring systems used in grading HS severity

Conventional medical therapy, involving oral antibiotics and topical treatments, is suitable for treatment of mild to moderate HS. However, there are patients where HS remains resistant to conventional treatment. With the discovery of the key inflammatory mediators in HS, the role of biologics and other immunomodulatory therapies in the targeted treatment of moderate-to-severe HS has been closely studied. Of these, adalimumab remains the only Food and Drug Administration (FDA)-approved biologic for the treatment of HS.10

We present a review of all biologics and immunomodulatory therapies that have been reported in the treatment of HS.

Methods

A review of the literature was conducted by multiple PubMed searches using the keywords “hidradenitis suppurativa“ or ”acne inversa”; with publication date limits from 1 January 1947 to 31 December 2018. Retrieved references were critically appraised. The inclusion criteria were original articles, reports and letters in the English language reporting the treatment of HS with biologic or other immunomodulatory agents, either alone or in combination with conventional drugs or surgery. Articles which were judged to be irrelevant based on the title, abstract or full text, were excluded from the review.

A search of the website Clinicaltrials.gov for planned, in-progress, terminated and completed clinical trials with the terms “hidradenitis suppurativa“ and ”acne inversa” was also performed up to 31 December 2018.

Results

A total of 2,088 articles were retrieved by multiple PubMed searches conducted until 31 December 2018 using the keywords “hidradenitis suppurativa” or “acne inversa”. A total of 107 relevant articles were included in the analysis. A total of 47 case reports, 29 case series, 3 retrospective analyses, 4 cohort studies and 24 articles based on clinical trial data, were selected (Figure 1).

Figure 1 Selection of articles identified by PubMed search.

A total of 65 clinical trials were retrieved by a search of the Clinicaltrials.gov database conducted on 31 December 2018, of which 35 were related to immunomodulatory treatment. Twenty of these studies were completed or terminated. To access the results of these trials, the articles retrieved from the PubMed searches were reviewed and matched to their respective clinical trials, using the National Clinical Trial identifier, and the PubMed database was again searched using the terms (“hidradenitis suppurativa“ OR ”acne inversa”) and the medication name. Fourteen of the completed or terminated studies had published articles on PubMed (Figure 2). When trial results were not available in PubMed, results posted on Clinicaltrials.gov were used. In five cases, the trials were listed as “completed” on Clinicaltrials.gov, but neither PubMed indexed journal articles nor posted study results on Clinicaltrials.gov were found. A World Wide Web search was then performed to retrieve any study results available.

Figure 2 Selection of articles identified by Clinicaltrials.gov search.

Biologic and other immunomodulatory therapies

A total of 19 biologic and other immunomodulatory agents reported in the treatment of HS were identified and categorized according to their mode of action (Table 3). Of these, efalizumab has been withdrawn and was thus excluded from this review. Information from individual published articles included in this review is available in Table 4.

Table 3 Biologics and other immunomodulatory therapies reported in the treatment of HS

Table 4 Articles included in systematic review

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Table 4 (Continued).

TNF-α inhibitors

Adalimumab

Adalimumab is a recombinant human anti-TNF-α IgG1 monoclonal antibody. When used for HS, it is given subcutaneously as an initial dose of 160 mg, followed by a dose of 80 mg 2 weeks later, and a maintenance dose of 40 mg weekly thereafter.10 In 2015, it became the first and, to date, only FDA-approved biologic agent for the treatment of moderate/severe HS.10

A Phase II study by Kimball et al in 2012 first demonstrated that a significantly greater proportion receiving adalimumab weekly (17.6%) compared to placebo (3.9%) achieved the primary clinical endpoint of a HS-PGA score of clear, minimal or mild with at least a two-grade improvement relative to baseline scores at week 16. This effect was not significantly demonstrated in the group of patients receiving adalimumab every other week (9.6%) (weekly vs placebo difference 13.7%, p=0.025; every other week vs placebo difference 5.6%, p=0.25).11 After changing from weekly to every other week dosing, a decreased proportion of patients showed a clinical response.11

The subsequent PIONEER I and II Phase III trials involved a total of 633 patients with moderate-to-severe HS with an inadequate response to oral antibiotics. A significantly higher proportion of patients given adalimumab achieved HiSCR, compared to patients given placebo after 12 weeks of treatment (PIONEER I: 41.8% vs 26.0%, p=0.003; PIONEER II: 58.9% vs 27.6%, p<0.001).12 Most adverse events observed were mild or moderate in severity. Of note, in the group of patients treated with adalimumab, there were new psoriasiform eruptions and psoriasis in ten patients, one case of squamous cell carcinoma of the nose, and one death from cardiorespiratory arrest 42 days after the last dose of adalimumab in a 35-year-old man with a history of diabetes mellitus, smoking and a family history of ischemic heart disease.12 Secondary efficacy data also showed a greater proportion of subjects achieving a ≥30% reduction in the Patient’s Global Assessment of Skin Pain (PGA-SP) in both PIONEER I (adalimumab vs placebo [24.9%]; OR=2.03, p=0.004) and PIONEER II (adalimumab [61.2%] vs placebo [24.8%]; OR=4.78, p<0.001).13,14

An open-label extension trial of the PIONEER I and II trials also confirmed that patients who continued to receive weekly adalimumab maintained a long-term response with a HiSCR rate of 52.3% at week 168 and a decrease in the Dermatology Life Quality Index (DLQI) of 5.1–6.8 points at week 72, with no new safety risks identified.15

In a study by Ryan et al that analyzed the safety data of adalimumab in HS, there were no new safety concerns identified with the weekly dosing of adalimumab compared with every other week dosing.16

In case reports, adalimumab has also shown effectiveness in treating HS associated with pyoderma gangrenosum, acne and psoriatic arthritis.1719 However, some case reports and series have drawn caution to the use of adalimumab, reporting adverse events such as erythroderma, melanoma, demyelinating disorders and drug-induced lupus.2022

There are currently post-marketing surveillance trials of adalimumab underway, assessing quality of life, effectiveness of treatment and safety profile.2327 In addition, the safety, efficacy and cost-effectiveness of adalimumab in conjunction with surgery are currently under investigation by two Phase IV trials.28,29

Infliximab

Infliximab is a chimeric mouse/human anti-TNF-α monoclonal antibody. It is currently FDA-approved for use in inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis;30 and has been used as an off-label treatment in patients with HS resistant to adalimumab.9,31,32 It is currently dosed as an intravenous infusion 5 mg/kg body weight on week 0, 2, 6 and thereafter every 8 weeks.30 However, reports suggest that the dosing regimen for HS requires further refinement.31

In a descriptive single-center study involving 10 patients, no long-term curative effect was uniformly seen.33 In another study evaluating the efficacy of a single course (three infusions) of infliximab in 10 patients, three patients did not have a recurrence at 2 years, whereas the other seven had an average time of 8.5 months to recurrence of lesions (4.3–13.4 months).34

In a Phase II randomized study comprising a double-blind placebo-controlled treatment phase, an open-label crossover treatment phase and an observational phase, 38 patients with moderate-to-severe HS as defined by a HSSI score >8 were selected. More patients treated with regular infliximab responded with a 25% to <50% decrease in HSSI compared to placebo (60% vs 5.6%), whereas most patients treated with placebo had a <25% decrease in HSSI compared with infliximab (88.9% vs 13.3%, p<0.001).9 After 8 weeks of treatment, there were significant improvements in the infliximab group compared to the placebo group in terms of mean DLQI change (−10 vs −1.6, p=0.003) and mean PGA scores (1.8 vs 4.7, p<0.001).9 Most adverse events were mild and none were considered unexpected.9

In case reports, infliximab demonstrated efficacy in treating HS associated with pyoderma gangrenosum, acne, Crohn’s disease and systemic amyloidosis.3542

However, infliximab has also in cases been associated with paradoxical worsening of facial acne vulgaris, demyelinating neuropathies, metastatic cutaneous squamous cell carcinoma and a case of Gemella morbillorum bacteremia complicated by brain abscesses.20,4345

Etanercept

Etanercept is a dimeric TNF-α inhibitor. It is approved for use in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, plaque psoriasis and psoriatic arthritis.46

After showing mixed results in open-label trials,4750 it was examined under a double-blind, placebo-controlled study in 20 patients with moderate-to-severe HS. In patients given etanercept 50 mg twice weekly for 24 weeks, no significant improvement in HS was found.51

Golimumab

Golimumab is an anti-TNF-α human monoclonal antibody, approved for use in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and ulcerative colitis.52

To date, it has been used in two case reports in the treatment of HS. In a case of a patient with concomitant Hurley Stage 3 HS and psoriatic arthritis, the use of subcutaneous golimumab 50 mg once weekly did not result in clinical improvement of HS (after adalimumab and anakinra had failed).53 However, in a later case report published in 2016 of a 42-year-old female with Hurley Stage 2 HS and pyostomatitis vegetans on a background of ulcerative colitis, golimumab subcutaneously 200 mg once followed by 100 mg every 4 weeks, together with amoxicillin-clavulanate, resulted in complete and sustained remission of HS, pyostomatitis vegetans and ulcerative colitis.54

There are no clinical trials underway to further assess golimumab in HS.

Certolizumab

Certolizumab is a PEGylated Fab fragment of a humanized TNF-α monoclonal antibody that is FDA-approved for the treatment of Crohn’s disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and plaque psoriasis.55 Its use in HS was described briefly in a case series, where it was used in two patients but found to be ineffective.56

IL-1 inhibitors

Anakinra

Anakinra is a recombinant IL-1 receptor inhibitor which is FDA-approved for use in rheumatoid arthritis and neonatal-onset multisystem inflammatory disease.57 It has been given as a 100 mg subcutaneous daily dose in HS.57

It has been studied in a double-blind, randomized, placebo-controlled Phase II clinical trial involving 20 patients. There were significantly more patients with a decreased disease activity score in the anakinra group compared to the placebo group after 12 weeks of treatment (78% vs 20%, p=0.02) and achieving HiSCR at the end of 12 weeks (78% vs 30%, p=0.04).58 However, at 24 weeks, the difference in patients achieving HiSCR was not statistically significant (10% vs 33%, p=0.28).58

In later case reports, there were also experiences of failure of anakinra therapy, or even worsening of HS related to anakinra use, suggesting the need for further clinical trials.59 Painful injection site reactions are also commonly reported with the use of anakinra, limiting its tolerability for some patients.60 It was also linked with drug-induced sarcoidosis in one case report.13

Canakinumab

Canakinumab is a human monoclonal anti-IL-1β antibody which is FDA-approved for use in cryopyrin-associated periodic syndromes and systemic juvenile idiopathic arthritis.61 It has been given up to 150 mg subcutaneous weekly dose in the treatment of HS. To date, it has shown mixed results in case reports and series.6265

Bermekimab

Bermekimab (MABp1) is an anti-IL 1α human monoclonal antibody. In a recent Phase II trial involving 20 patients with moderate-to-severe HS either randomized to bermekimab or placebo for 12 weeks, 60% of patients on bermekimab achieved HiSCR at week 12 compared to 10% on placebo (P=0.035).66 Twelve weeks after cessation of treatment, 40% of patients on bermekimab had a positive HiSCR compared to 0% of patients on placebo.66 No adverse events related to bermekimab were reported.66

MEDI8968

MEDI8968 is a fully human immunoglobulin monoclonal antibody that selectively binds to the IL-1R1 receptor to inhibit activation by IL-1α and IL-1β. It has been studied for use in osteoarthritis, rheumatoid arthritis and chronic obstructive pulmonary disease.6769 A Phase IIa study evaluating the safety, tolerability and efficacy of MEDI8968 for the treatment of subjects with moderate-to-severe HS was terminated early due to a lack of efficacy.70

IL-12/-23 inhibitors

Ustekinumab

Ustekinumab is a human monoclonal antibody that acts by binding to and inhibiting the p40 subunit on IL-12 and IL-23. It is FDA-approved for use in plaque psoriasis, psoriatic arthritis and Crohn’s disease.71 Patients weighing 100 kg and below receive 45 mg per dose, and those weighing above 100 kg receive 90 mg per dose.71

In a Phase II open-label study involving 17 patients on ustekinumab, the majority of patients showed moderate to marked improvement, as defined by a significant decrease in the mSS and modified HS Lesional Area Severity Index.72 Forty-seven percent of patients achieved HiSCR.72 Adverse events were mild and temporary, most commonly headache, fatigue and upper respiratory tract infections. The authors of the Phase II study suggested that the dosing regimen in HS may have to be further intensified.72

IL-17 inhibitors

Secukinumab

Secukinumab is a human IgG1k monoclonal antibody that acts as an IL-17A inhibitor. It is FDA-approved for moderate-to-severe plaque psoriasis, psoriatic arthritis and ankylosing spondylitis.73 Given at 300 mg subcutaneously weekly for 1 month followed by 4-weekly maintenance dosing, it has shown dramatic improvement in case reports of patients in whom other biologic therapies failed.74,75 An exploratory pilot study on the safety and feasibility of secukinumab in HS patients is currently underway,76 and there are two randomized double-blind multicenter trials to compare the efficacy, safety and tolerability of 2-weekly and 4-weekly secukinumab 300 mg in patients with moderate-to-severe HS.77,78

CJM112

CJM112 is a human monoclonal anti-IL-17A antibody. A Phase II study involving 66 patients with moderate-to-severe chronic -HS has been completed, but results are not available at present.79

Bimekizumab

Bimekizumab is a humanized anti-IL17A and IL-17F monoclonal antibody which has been studied and found to be effective in patients with psoriasis.80,81 A Phase II trial is currently underway to investigate its use in moderate-to-severe HS, with no results available at the time of writing.82

IL-23 inhibitors

Guselkumab

Guselkumab is an anti-IL-23 monoclonal antibody that has been FDA-approved for use in adults with moderate-to-severe plaque psoriasis. It is given subcutaneously 100 mg at week 0, week 4 and every 8 weeks thereafter.83 A case series involving three patients with severe HS, given guselkumab, found significant reductions in the IHS4, VAS for pain and (DLQI for all three patients.84 Another retrospective chart review of eight patients with moderate-to-severe HS given guselkumab found that 63% of patients reported improvements, with suggestions to further intensify the dosing regimen.85 No adverse events were documented in both articles. A Phase II multicenter randomized double-blind placebo-controlled trial has been initiated to evaluate its efficacy in the treatment of moderate-to-severe HS.86

Selective PDE-4 inhibitors

Apremilast

Apremilast is an orally administered PDE-4 inhibitor which is FDA-approved for use in patients with moderate-to-severe plaque psoriasis and active psoriatic arthritis. It is titrated to a target dose of 30 mg twice daily.87

In a reported case series of nine patients with Hurley stages II–III HS who had responded poorly to other treatments, five of six patients who persisted with treatment showed a good clinical response, with a significant improvement in the Sartorius score (73.17±67.76 to 56.17±44.89, p=0.028), VAS (7.17±0.98 to 2.00±2.10, p=0.026) and DLQI (21.33±8.91 to 9.33±5.85, p=0.027).88

In a double-blind, randomized, placebo-controlled trial involving 20 patients with moderate HS, 8 of 15 patients (53.3%) given apremilast achieved a positive HiSCR at week 16 compared to zero of five in the placebo group (p=0.055). Patients receiving apremilast also showed a significantly lower abscess and nodule count (mean difference −2.6; 95% CI −6.0 to −0.9; p=0.011), numerical rating scales for pain (mean difference −2.7; 95% CI −4.5 to −0.9; p=0.009), itch (mean difference −2.8; 95% CI −5.0 to −0.6; p=0.015) and disease burden (mean difference −1.8; 95% CI −3.7 to −0.01; p=0.049) compared to placebo. There were no major adverse events documented.89

Another Phase II open-label trial involving 20 patients has been completed, with no results available at present.90

Complement 5a inhibitors

IFX-1

IFX-1 is a human C5a-specific monoclonal antibody. Preliminary data from an open-label clinical study involving 12 patients, 75% of patients achieved HiSCR at day 50 (95% CI 0.43–0.95) and 83% at day 134 (95% CI 0.52–0.98).91,92

Another Phase II study is currently underway to determine its efficacy and safety.93

CD-20 inhibitors

Rituximab

Rituximab is a chimeric monoclonal antibody against the CD20 protein. It is FDA-approved for use in non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis and pemphigus vulgaris.94

In one case report in a kidney transplant recipient with idiopathic carpotarsal osteolysis who suffered chronic active antibody-mediated rejection and also developed HS, low-dose rituximab with two courses of 200 mg each were given with dramatic improvement of HS without remission of rejection.95

There are no further studies underway to evaluate the efficacy of rituximab.

JAK-1 inhibitors

INCB054707

INCB054707 is an orally administered inhibitor of the Janus kinase 1 pathway. There are currently two Phase II trials underway, with no other information available at the time of writing.96,97

Discussion

The increased understanding of the inflammatory pathways in HS provides many exciting therapeutic opportunities for patients with HS resistant to conventional methods of therapy. As more molecular targets are identified, immunomodulatory therapies can be developed, and their dosing regimens further refined. The efficacy, or lack thereof, of individual therapies also provides key insights into disease pathophysiology.

TNF-α inhibition in HS has been demonstrated to be useful. Adalimumab is presently the only FDA-approved biologic for use in HS and should thus be the drug of choice in moderate-to-severe HS where conventional treatment has proven ineffective. It is worth noting from our systematic review that where HS is associated with pyoderma gangrenosum, acne, Crohn’s disease or systemic amyloidosis, infliximab may also be considered as an effective off-label treatment.

Etanercept and MEDI8968 have already proven to be ineffective. Other therapies, involving smaller cohorts, have shown partial or mixed responses, with larger trials underway to further assess their efficacy in HS. The varying clinical measurement scores and endpoints used in these trials to determine treatment responsiveness potentially complicate direct comparison between different agents.

Most biologics and immunomodulatory therapies exhibit a generally well-tolerated safety profile. However, long-term safety concerns, including infection risks, especially latent tuberculosis reactivation, demyelinating disorders, and the development of malignancy from chronic immunosuppression will need to be evaluated through longitudinal surveillance and pooled registry data.98 These issues are especially pertinent in the treatment of HS, where the dosing regimen for biologics is typically more intensive compared to other inflammatory diseases, such as psoriasis. Patient selection remains important, as complete response is not the norm, not all patients with HS tolerate or respond well to immunomodulatory therapy, and may benefit from other modes of treatment, such as surgery.

In patients with severe HS that does not fully respond even to biologic treatment, we may consider biologics as an adjunct to surgery, where biologics are used to debulk disease to minimize the area required for surgical resection. Results from Phase IV trials to assess the combination of adalimumab with surgery will help refine the treatment approach for this category of severe HS.28,29

Ultimately, it is hoped that the use of immunomodulatory therapies will help overcome some of the challenges in treating severe HS, alleviating the impact on sufferers’ quality of life and morbidity associated with the disease. However, more quality data is required on their efficacy, safety and use in specific sub-populations before we can achieve truly targeted treatment of HS.

Disclosure

Hazel H Oon is a clinical investigator for Janssen, Novartis and Pfizer. She has also served as a speaker and advisory board member for AbbVie, Janssen, Novartis and Eli Lilly. Hazel H Oon reports grants and personal fees from AbbVie, Eli Lilly, Janssen, Novartis, and Pfizer outside the submitted work.The authors report no other conflicts of interest in this work.

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