Brodalumab for moderate–severe hidradenitis suppurativa: An open‐label multicentric cohort study in real clinical practice

The use of biological therapy is becoming increasingly common in patients with hidradenitis suppurativa (HS). Levels of serum TNF‐alfa and IL17 support the role of an immune system dysregulation in the pathogenesis of HS. Brodalumab targets the receptor A of IL‐17, thus having a promising role in the treatment of HS.


INTRODUCTION
Hidradenitis suppurativa (HS) is a chronic, relapsing and debilitating inflammatory disease of the pilosebaceous unit, that affects areas rich in apocrine glands. 1 HS is an autoinflammatory disorder with dysregulation of Th17 lymphocyte response. 2Its symptoms and cutaneous lesions, consisting in nodules, abscesses and fistulae, can lead to significant sequelae. 3ecause the limited existing therapeutic options, HS supposes a therapeutic challenge and disease control is not achieved in some patients. 4Classic immunosuppressants have traditionally been used for moderate and severe cases; however, they can have serious side effects and its long-term use can carry out major complications.
The use of biological therapy is becoming increasingly common in HS patients.Levels of serum TNF-alfa and IL-17 correlating to disease severity support the role of an immune system dysregulation in the pathogenesis of HS. 1 Thus, a Th17 lymphocyte response is seen as dominant in this disease. 2t the moment, there are several drugs available that target IL17, mainly used in dermatology for the treatment of psoriasis. 5In patients with HS, these drugs may have promising benefit.Brodalumab is a fully human monoclonal antibody which targets the receptor A of IL-17 (IL17RA) with a potential role in decreasing inflammatory pathways in HS. 6 However, more clinical experience is currently needed on the use of this drug for the treatment of HS.
The aim of this study is to evaluate the effectiveness and safety of brodalumab in patients with moderate or severe HS after 16 weeks of treatment.

MATERIALS AND METHODS
A multicenter retrospective observational study was conducted in two tertiary hospitals from Andalusia (Southern Spain).Adults with moderate to severe HS (defined as Hurley stage II or III or International HS Severity Scoring system-IHS4-≥4) under treatment with brodalumab between January 2020 and February 2023 were included.Patients aged under 18 years or those who had not given their consent for participation in the study were excluded.
According to hospital protocols, patients were assessed before initiation of brodalumab (baseline or week 0) and at week 16 of treatment.Brodalumab 210 mg at week 0, 1, 2 and then every 2 weeks was the regimen of choice for the whole cohort.Variables regarding sociodemographic and clinical details, effectiveness and safety were recorded.Descriptive parameters-relative and absolute frequency distributions for nominal variables and mean and standard deviation (SD)-were calculated to describe the characteristics of the cohort.The chi-squared test or Fisher's exact test and Student's t-test were used to compare nominal and continuous variables respectively between patients who responded to treatment with brodalumab and those who did not.Database was built using Excel version 2301and statistical analyses were performed using IBM® SPSS® version 21.
This study was conducted according to the Declaration of Helsinki and has been evaluated and approved by the Ethics Committee of the Hospitales Universitarios Virgen del Rocio-Macarena.

RESULTS
A total of 16 patients (75% of them males) with moderate to severe HS under treatment with brodalumab for at least 16 weeks were identified and included (Table 1).Mean age for the cohort was 46.88 years (SD 12.43) and HS appeared at an average age of 27.56 years (SD 11.15) with a mean disease duration of 19.31 years (SD 11.57).Inflammatory phenotype was the most frequent, present in 50% of patients (8/16), followed by a mixed phenotype (5/16; 31.3%) and follicular phenotype (3; 18.8%).Family history of HS was present in 50% of patients.As for comorbidities, 12.25% patients suffered from psoriasis, 37.5% from mental health conditions and 37.5% met metabolic syndrome criteria.There were no patients with concomitant inflammatory bowel disease (IBD) in our cohort.Regarding disease severity, mean baseline IHS4 was 24.13 T A B L E 1 Sociodemographic and baseline characteristics of the cohort.(SD 10.11), presenting all patients a severe disease defined by a score higher than 10.All patients presented Hurley stage II (3; 18.8%) or III (13; 81.3%).Mean therapeutic burden, defined as the summatory of all systemic treatments used and surgical interventions was 6.56 (SD 4.30). 7ll patients had failed to previous treatment with adalimumab for a median pretreatment time of 131 weeks and 68.75% of patients had received another biological drug (secukinumab was prescribed in 10 patients and risankizumab in one patient).Concomitant treatment was prescribed in 50% of patients at the start of the treatment.Oral antibiotics were prescribed in seven patients (43.75%) and systemic corticosteroids in two patients (12.5%) in one of them both were used.No patient was submitted to surgery during the first 3 months of brodalumab treatment.

HS patients under
Regarding response to brodalumab data (Figure 1 and Table S1), after 16 weeks of treatment, 56.25% (9/16) of patients achieved Hidradenitis Suppurativa Clinical Response (HiSCR50), defined as reduction of at least 50% in nodule and abscess count, no increase in the number of abscesses nor in the count of active fistulae from baseline data.In 31.25% (5/16) a reduction ≥50% in IHS4 was observed.Mean IHS4 went from a baseline of 24.13-16.81(p = 0.002) and a reduction was reported in its three parameters.Mean nodule count decreased from 4.25 to 2.56 (p = 0.017), abscess count from 3.06 to 1.63 (p = 0.004) and active fistulae from 3.44 to 2.75 (p = 0.151).No differences were found regarding sex, age, BMI, baseline IHS4, age of onset, disease duration nor any other variables studied between patients who achieved HiSCR versus non-responders (Table 2).
Concerning safety data (Table 3), 31.25%(5/16) experienced adverse events, 60% grade 2 (3/5) and no grade 3 or higher.One patient suffered from mild oral aphtosis.One more patient developed generalized non-disabling joint pain.Finally, another three patients reported mild adverse events: pain at the injection site, decreased appetite and upper respiratory infections at the beginning of brodalumab use.Treatment discontinuation was advised in four patients (25%).Intwo patients, the reason for withdrawal was the occurrence of adverse effects: definitively by patient choice in the one who reported aphtosis and in a precautionary manner until evaluation by rheumatology in the patient who developed polyarthralgias.In the other two patients, brodalumab was ceased due to lack of efficacy.

DISCUSSION
While many medications have been used to treat patients with HS, adalimumab has been the only Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved biological drug. 8A complicated scenario arose when patients did not respond to this drug as no other was approved until months ago when secukinumab received the EMA approval. 9Even so, there are still few approved alternatives for the treatment of HS.There is no data available on clinical trials for brodalumab in HS, which increases the importance of this kind of daily practice studies to generate some useful data.Our study shows that brodalumab may be F I G U R E 1 Baseline and week 16 response parameters.a phase 2, double-blind, controlled randomized controlled clinical trial on the use of bimekizumab are also available. 11This study compares bimekizumab versus adalimumab and placebo, reporting at week 12 HiSCR values of 57.3.In this case, our population presents a lower HiSCR rate.However, the same population differences can be noted as with the SUNNY studies, which are: higher rates of Hurley III and non-naive patients.
Published evidence on the use of brodalumab for the treatment of HS is scarce.Case reports of recalcitrant cases of HS refractory to anti-TNFα but also patients naive to target therapies have been communicated with effective results. 12,13However, there are not many studies including higher number of patients.Recently, Frew et al. published the results of two open-label cohort studies. 14,15n the first study, brodalumab was administered subcutaneously at weeks 0, 1, and 2 and every 2 weeks thereafter until week 24 to a cohort of 10 patients with moderate-severe HS. 80% of them at Hurley II stage, and most of them non-naive to biological therapy. 14At 2 weeks, all the patients achieved the HiSCR response.The HiSCR response was maintained at weeks 12 and 24 in all the patients, although certain cyclical response was noted in patients with draining tunnels, the same type of lesion that responded the less in our participants specified.
The second open-label study explored the efficacy and safety of a weekly administration of brodalumab in 10 patients with a more severe HS than the previous cohort.Seven of the patients had been included in both studies and demographic characteristics are not specified. 15Even though in both studies the HiSCR response was achieved by all the subjects at 24 weeks, a greater proportion of patients of the second cohort achieved HiCSR75 and HiSCR100 responses.
In our cohort, the HiSCR response was observed in a 56.25% of patients, which is a percentage considerably lower than in the other studies.This can be explained by the complexity of the patients studied, giving our results greater realism.Furthermore, in our study, we administered brodalumab subcutaneously at week 0, 1, 2 and every 2 weeks, although intensification was not possible in patients with poor response due to our hospital's protocols.In the second cohort of Frew, which the complexity of the patients is not available, they administer brodalumab weekly, that could improve the effectiveness and could be an option of intensification in that patients who do not achieve a good response.
In addition, in our series, all the visits were carried out in person, while in the previous studies, some of them were conducted by video examination due to the COVID-19 pandemic.Frew et al. also reported in a sub-study data on the usefulness of sonographic biomarkers for the monitoring of patients with HS under brodalumab treatment, suggesting epidermal thickness and power-Doppler intensity as markers of effectiveness, which could be useful for further studies. 16egarding adverse events, IL17 inhibitors have a favourable safety profile but are linked to relatively frequent mucocutaneous candidiasis and, more rarely, neutropenia and IBD. 17 In our cohort, we observed adverse events in 31% of the patients being mild all of them.No cases of fungal infections or neutropenia were reported and, although not an exclusion criterion, no patient in our cohort had a history of IBD but no new cases were declared.Brodalumab was also in the spotlight for the possible association with severe psychiatric adverse events; however, Lebwohl et al. disproved these initial suspicions. 18As for the six patients with mental health history, no worsening of their disease nor new psychological symptoms were reported.Finally, one of our patients discontinued the treatment due to arthralgias, which has proven to be the most common side effect that led to brodalumab discontinuation in patients with psoriasis in daily clinical practice. 19ecently, female sex, lower BMI and lower therapeutic burden have been described as potential response markers in patients under secukinumab and moderate to severe HS. 7 In our study, we did not observe differences between patients who achieved HiSCR and those who did not in those variables or in any other.
Our study is limited by its small sample size, the absence of a control group and a follow-up period of only 16 weeks.

CONCLUSIONS
Biological therapy stands as an effective and safe option in patients with HS.Given the increasing evidence on the pathophysiological role of IL17 and on the efficacy of brodalumab, we consider that patients with HS should be highly benefit from the use of this monoclonal antibody.

AMERICAN TRADE NAMES
The following drugs mentioned in the manuscript respond to the following trade names as approved by the FDA: • Brodalumab: Siliq® • Secukinumab: Cosentyx® • Bimekizumab: Bimzelx®