FormalPara Key Summary Points

Although ustekinumab is used to manage hidradenitis suppurativa (HS), there is a lack of comprehensive data regarding its safety and efficacy.

In this systematic review and meta-analysis of ten articles with 88 patients, we found that the pooled response rate to ustekinumab was 67%. The majority of patients had previously failed treatment with one or more biologic agents.

Our study demonstrates the potential efficacy of ustekinumab as a secondary or tertiary treatment option for HS.

Introduction

Hidradenitis suppurativa (HS) is a chronic, oftentimes debilitating skin condition that presents with abscesses, nodules, sinus tracts, and scarring, typically in intertriginous areas [1]. The pathogenesis of HS is complex and encompasses genetic [2], epigenetic [3], immunological, hormonal, and environmental factors [4]. Though many medical and procedural therapies are used to treat the disease, the condition is often recalcitrant to treatment [5]. Despite recent advances in treatments for HS, there is a substantial unmet need for effective therapeutic solutions [6]. Adalimumab, a tumor necrosis factor (TNF)-alpha inhibitor, and secukinumab, an interleukin (IL)-17 inhibitor, are currently the only FDA-approved biologic agents for the treatment of HS. However, some patients may not have an adequate or durable response to TNF-alpha or IL-17 inhibitors [7]. Ustekinumab is an IL-12 and IL-23 inhibitor that has been utilized in patients with HS, but there is a paucity of data on its efficacy and safety for this disease [8]. The aim of this study is to systematically evaluate existing literature on the efficacy and safety of ustekinumab treatment in HS and conduct a meta-analysis. This information will be useful for clinicians as they counsel patients with HS, particularly those who have inadequate responses to previous biologic treatments, regarding treatment with ustekinumab.

Methods

Search Strategy

This study was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Fig. 1) and was preregistered on PROSPERO (CRD42022364634). On 5 October 2022, two independent reviewers (R.M. and J.S.) searched MEDLINE and Embase databases from inception to start date with the following terms: (“hidradenitis suppurativa” OR “hidradenitis” OR “acne inversa” OR “velpeau disease” OR “verneuil disease”) AND (“ustekinumab”). A total of 361 articles were identified. Articles were filtered to remove non-English-language and nonhuman studies. Duplicate articles were excluded, and the titles and abstracts of the remaining articles were screened for relevance. Full-text review was then performed on the remaining 112 articles by the two independent reviewers (R.M. and J.S.). Studies that described ustekinumab as the primary intervention for HS, contained outcome efficacy data, and had three or more patients were considered eligible for inclusion. Reviews, conference abstracts, meta-analyses, commentaries, and nonrelevant articles were excluded. Any discrepancies were discussed to consensus with a third reviewer (J.L.H.). Reference lists of articles that met the inclusion criteria were screened for additional relevant articles, and none were identified.

Fig. 1
figure 1

PRISMA flow diagram. Moher D, Liberati A, Tetziaff J, Altman DG, The PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097. https://doi.org/10.1371/journal.pmed1000097. For more information, visit www.prisma-statement.org

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This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. The databases used in this study are publicly available: MEDLINE: https://pubmed.ncbi.nlm.nih.gov/ and Embase: https://www.embase.com/search/quick.

Data Extraction

Two reviewers (R.M. and J.S.) independently completed data extraction. Each article was reviewed, and the following information was collected: study design, country of study, patient characteristics, HS severity, regions of the body affected by HS, previously failed treatments, concomitant treatments, inflammatory comorbidities, study intervention, duration of treatment/timepoint of efficacy measurement, treatment response, and adverse effects.

Meta-analysis

A meta-analysis was conducted to determine the pooled estimated response rate of HS to ustekinumab. To determine response, predetermined primary clinician reported outcome measures were used whenever available, followed by physician assessments; the HS Clinical Response (HiSCR) was prioritized if different clinician reported outcome measures were available. Forest plots were constructed using the proportion of patients with a reported response (including partial response) to ustekinumab, and standard errors/confidence intervals were computed using inverse variance weighting (Fig. 2). Cochran’s Q statistic and I squared index (the percentage of variation across studies that is due to heterogeneity rather than chance) were used to assess heterogeneity. Because significant heterogeneity was not observed, a fixed-effects meta-analytical model was utilized as opposed to a random-effects pooled estimate. Statistical analyses were performed using R version 4.1.0 (www.r-project.org). p-Values < 0.05 were considered statistically significant.

Fig. 2
figure 2

Forest plot of fixed effects meta-analysis among hidradenitis suppurativa patients treated with ustekinumab

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Results

Ten articles published between 2012 and 2022 met inclusion criteria. There were 88 patients across nine case series and one prospective trial. Study locations included Spain (n = 5), USA (n = 1), the Netherlands (n = 1), Denmark (n = 1), Ireland (n = 1), and Germany (n = 1). Study characteristics, patient characteristics, treatment regimens, previous treatments, concomitant treatments, inflammatory comorbidities, responses to treatment, adverse events, and study quality are summarized in Table 1. In terms of study quality, the prospective trial had a high risk of bias.

Table 1 Hidradenitis suppurativa and ustekinumab study characteristics
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Across all studies, patient age ranged from 20 to 70 years. The mean age of patients was reported in one prospective trial and two case series as 35, 37, and 53.2 years [9,10,11], respectively. Of the eight studies that included gender data, 64.8% (46/71) of patients were female. HS severity was reported as Hurley stage in 68 patients across eight studies, and the majority of patients had Hurley stage III disease (82.4%, 56/68) followed by stage II (17.6%, 12/68). Previously failed treatments were described in all studies and included topical resorcinol, topical or systemic antibiotics, steroids (topical, systemic, or intralesional), adalimumab, infliximab, certolizumab, etanercept, anakinra, efalizumab, methotrexate, azathioprine, cyclosporine, sulfasalazine, oral retinoids, dapsone, liraglutide, metformin, spironolactone, finasteride, interferon, intense pulsed light plus epilation, phototherapy, deroofing, incision and drainage, and surgery. The majority (80.7%, 71/88) of patients had previously failed at least one biologic treatment. Nearly three-fourths (71.6%, 63/88) had failed adalimumab, and more than one-third (36.4%, 32/88) had failed infliximab. Comorbidities were reported in 73 patients across six studies; 23.3% (17/73) had Crohn’s disease or ulcerative colitis, and 9.6% (7/73) had psoriasis. Concomitant treatments reported in four studies include topical resorcinol, systemic and intralesional steroids, incision and drainage, oral antibiotics, oral retinoids, deroofing, and surgery.

Dosing of ustekinumab was 90 mg (mg) in four studies, 45 or 90 mg in three studies, 45 mg in one study, and unspecified in two studies. Across eight studies, the frequency of the ustekinumab maintenance dosage ranged from every 4 to 12 weeks. The initial loading dose was delivered intravenously in four studies and subcutaneously in three studies. The timepoints for efficacy measurement ranged from 8 weeks to 18 months across all ten studies. Clinician-reported outcome measures used for meta-analysis of the pooled response rate included HiSCR (n = 4), physician assessment (n = 4), HS-Physician Global Assessment (n = 1), and International HS Severity Score System (IHS4) (n = 1). The overall response rate for weight-based intravenous (IV) loading dose followed by 90 mg every 8–12 weeks subcutaneously (SC) was 65.4% (17/26); the response rate for SC loading dose followed by doses ranging from 45 to 90 mg every 8–12 weeks was 56.7% (17/30).

On the basis of the meta-analysis of the ten included studies, the pooled response rate of patients with HS responding to ustekinumab was 67% (95% CI 0.57–0.76). Nonsignificant heterogeneity was observed between studies (I2 = 0%, p = 0.73) (Fig. 2). Eight out of ten studies reported a response rate greater than 50%. Adverse events were reported in 4.5% (4/88) of patients across studies. These included headache, fatigue, upper respiratory infection, urticaria, cystitis, psoriasiform dermatitis, arthritis, bacterial axillary infection, and recurrent infections.

Discussion

Our study found that ustekinumab may be an effective and safe treatment option for patients with recalcitrant, moderate−severe HS. The fixed-effects meta-analysis showed a pooled response rate of 67%, and over 80% of the patients had previously failed at least one other biologic agent. Adverse events were reported in only 4.5% of patients with HS on ustekinumab treatment.

Although the exact pathophysiology of HS remains unclear, chronic upregulation of inflammatory cytokines is believed to play a vital role in the initiation and propagation of the disease. Disproportionately high levels of IL-12 and IL-23 have been found in HS lesions, suggesting potential benefits from biologic agents that block these cytokines and reduce the downstream maturation of IL-17-producing T-helper cells [12].

The optimal dosing regimen for ustekinumab in patients with HS has not yet been established. Jiang et al.’s 2022 study demonstrated that high-dose, high-frequency ustekinumab may be effective in reducing IHS4 and pain scores in patients with HS, but the study was limited by a small sample size of six patients [11]. In a 2021 systematic review and meta-analysis by Meserve et al., increasing the frequency of doses to every 4 or 6 weeks instead of 8 weeks, and/or intravenous reinduction, led to a clinical response in 55% of 925 patients with Crohn’s disease who previously had an inadequate response to the standard ustekinumab dosing regimen [13]. Increasing the ustekinumab dosing frequency from every 12 weeks to 8 weeks has also been reported to be beneficial in patients with psoriasis [14]. More investigation is needed to understand the potential advantages of dose intensification in patients with HS who are initially nonresponders or partial responders to ustekinumab treatment. Use of ultrasonographic characteristics, such as vascularization and fibrosis [15], may also be considered in the future as adjunct tools to monitor responses to treatment.

In addition, it is currently unclear whether the IV loading dose for HS has benefits over an initial SC loading dose. One study found that ustekinumab trough levels and clinical outcomes were comparable in 17 patients with Crohn’s disease who completed SC induction compared with 249 patients with Crohn’s disease who received intravenous induction in another clinical trial [16]. At this time, SC induction of ustekinumab may be an appropriate treatment consideration for patients who have personal, financial, or logistical barriers to accessing an infusion center for intravenous induction dosing, but further studies are needed.

There is a paucity of data on the development of antidrug antibodies (ADAs) and therapeutic drug level monitoring for ustekinumab in HS. Tsakok et al.’s prospective cohort study of 491 patients with psoriasis treated with ustekinumab found that ADAs were detected in 3.5% of patients. Higher serum ustekinumab levels during early treatment were associated with better clinical responses after 6 months of treatment, suggesting that appropriate drug levels during the initial phases of treatment may be important for future clinical outcomes [17]. A 2014 systematic review by Hsu et al. reported that ADAs were detected in 3.8–6% of patients treated with ustekinumab for psoriasis compared with 5.4–43.6% of patients on infliximab, 0–18.3% on etanercept, and 6–45% on adalimumab [18]. While these results indicate that ustekinumab may not have as high a risk of ADA development as TNF inhibitors that are commonly used in HS such as adalimumab and infliximab, a more comprehensive understanding of ustekinumab’s immunogenicity and optimal serum trough levels could guide clinicians in cases of partial or nondurable response to ustekinumab.

This study contributes to the literature by providing an updated systematic review as well as a pooled response rate on ustekinumab use in HS, which supports the use of ustekinumab in recalcitrant cases of HS. A 2020 systematic review of ustekinumab in HS by Montero-Vilchez et al. found that 78% of 49 patients exhibited a response [8], though of note, case reports were included in this study, which could skew results towards a more favorable response rate. Further support for ustekinumab in HS treatment is seen in recent drug survival studies. Ring and colleagues found that, in a nationwide cohort study of patients with HS, drug survival was comparable between ustekinumab, adalimumab, and infliximab; the median time to discontinuation for ustekinumab was 26 months [19]. Larger studies on the drug survival of ustekinumab in patients with HS may shed further insight on its real-world clinical efficacy. We also found that adverse effects were mild and infrequent among patients with HS treated with ustekinumab and in line with the known side-effect profile of ustekinumab [20]. A retrospective cohort study of 21,821 patients with inflammatory bowel disease found that ustekinumab was associated with a decreased risk of infections compared with TNF-alpha inhibitors [21]. These safety findings may be a potential advantage for ustekinumab as a less immunosuppressive agent compared with TNF-alpha inhibitors.

Study limitations, shared by most systematic reviews on HS treatments, include an overall small number of studies and patients. All studies took place in the USA or Europe, limiting generalizability. Given the small number of patients, we were unable to differentiate the response rates of patients on the basis of inflammatory comorbidities or previously failed treatments. Another limitation is the risk of reporting bias with the inclusion of case series. Lastly, studies had variable dosing regimens, outcome measures, and timepoints for efficacy measurements.

Conclusions

Overall, ustekinumab may be a helpful biologic to consider for patients with recalcitrant HS who have failed first-line biologic therapies such as TNF-alpha or IL-17 inhibitors that have robust phase III trial data and, for adalimumab, post-marketing data as well. Large randomized controlled trials are needed to better understand the efficacy, safety, and optimal dosing regimen of ustekinumab in HS. Future investigations should evaluate the benefits of concomitant treatment with ustekinumab and other HS treatments. Studies that investigate patient characteristics that may predict therapeutic responses, drug survival rates, and the potential use of therapeutic drug monitoring are also warranted.