Real‐world safety and effectiveness of adalimumab in patients with hidradenitis suppurativa: 12‐week interim analysis of post‐marketing surveillance in Japan

Abstract Hidradenitis suppurativa (HS) is a painful chronic skin disease characterized by abscesses, nodules, and tunnels in the skin. Adalimumab, a monoclonal antibody against tumor necrosis factor‐α, is approved for the treatment of HS in Europe, the USA, and Japan. This multicenter, open‐label, post‐marketing, observational study (ClinicalTrials.gov: NCT03894956) evaluated the safety and effectiveness of adalimumab in routine clinical practice in Japan (March 2019–May 2021). Patients with HS were treated with s.c. doses of adalimumab according to the dosage described in the package insert. The primary end‐point was safety (data cut‐off, December 2020). Secondary end‐points assessed effectiveness, including HS Clinical Response (HiSCR), skin pain, Dermatology Life Quality Index (DLQI), and C‐reactive protein (CRP). Here, we report 12‐week interim effectiveness results. A total of 84 eligible patients from 65 sites were enrolled; 83 patients were included in this analysis. Mean age was 42.0 years, mean body mass index was 26.9 kg/m2, 78.3% of patients were male, 61.4% had Hurley stage III disease, 39.8% had a disease duration ≥10 years, and 7.2% had a family history of HS. The most common affected sites were the axilla (60.2%), buttocks (59.0%), and the inguinal and femoral regions (47.0%). Mean abscess and inflammatory nodule count was 13.0 (standard deviation, 12.0). Among patients with a comorbidity (57.8%), the most common were diabetes mellitus, hypertension, and chronic kidney disease. No patient reported a serious infection or any safety event of special interest. One patient died from a serious adverse event of cardiac failure unrelated to adalimumab. At week 12, 57.4% of patients achieved HiSCR, and significant reductions from baseline in skin pain, DLQI (both p < 0.0001), and CRP (p = 0.0029) were observed. These results support the administration of adalimumab as a well‐tolerated and effective treatment for Japanese patients with HS in real‐world clinical practice.


| INTRODUC TI ON
Hidradenitis suppurativa (HS) is a painful chronic skin disease characterized by the presence of recurrent inflammatory nodules and abscesses; a rupture of the lesion may cause a fistula and scarring.
Lesions predominantly develop in regions rich in apocrine glands, including the axilla, groin and anogenital region, and buttocks, and in the interbreast area in females. 1 Gluteal involvement has been observed more frequently in Asian than in European and US cohorts. [2][3][4][5] The prevalence rate of HS differs across geographical regions with a general consensus that the prevalence is higher in Europe than in the USA, Asia-Pacific, and South America. 6 In particular, in Europe, rates of 1-4% have been reported, 7,8 compared with 0.1-0.2% in the USA 9 and 0.06% in Korea. 10 Although no large-scale epidemiological study has been conducted to determine the prevalence of HS in Japan, a study extracting data from a health insurance claims database estimated the prevalence of HS to be 0.0039%. 11 In Europe and the USA, the prevalence of HS was estimated to be twice as high in females compared with males, but in the Asia-Pacific region the prevalence appears higher in males. 6 In epidemiological studies of Japanese and Korean patients with HS, male:female ratios of 2.69:1 and 2.5:1, respectively, have been reported. 3,5 Hidradenitis suppurativa is histopathologically characterized by severe inflammatory cell infiltration by neutrophils, lymphocytes, and histiocytes. Inflammatory cytokines including tumor necrosis factorα (TNFα), as well as activated neutrophils and lymphocytes, are considered to be involved in the onset of HS. 12 Adalimumab (Humira ® ; AbbVie) is a human monoclonal antibody that binds to TNFα and has high affinity and selectivity for human TNFα. Two multicenter, randomized, double-blind, placebocontrolled, phase 3 studies (PIONEER I and PIONEER II) evaluated the safety and efficacy of adalimumab treatment for patients (predominantly from Western countries) with moderate to severe HS. 13 Clinical response rates at week 12 were significantly higher for adalimumab-treated patients compared with placebo-treated patients (PIONEER I: 41.8% vs. 26.0%, p = 0.003; PIONEER II: 58.9% vs. 27.6%, p < 0.001), and rates of serious adverse events (AE) were similar across treatment groups. 13 A multicenter, openlabel, single-arm, phase 3 study (NCT02904902) evaluated the safety and effectiveness of adalimumab in Japanese patients with moderate to severe HS; interim analyses indicated that 86.7% of patients achieved a HS Clinical Response (HiSCR) at 12 weeks, and this was sustained through week 52 at 66.7%. 14,15 No new safety findings were reported with adalimumab weekly dosing. 15 Results of these studies led to the approval of adalimumab for the treatment of moderate to severe HS in Europe, the USA, and Japan.
The objective of this post-marketing surveillance was to evaluate the long-term safety and effectiveness of adalimumab in real-world clinical practice in Japanese patients with HS. We report the interim analysis of safety up to the date of data cut-off, and effectiveness up to 12 weeks, for patients with HS registered in 2019 and 2020 in Japan.

| Study design
This was a multicenter, open-label, post-marketing, observational study. The enrollment period was 23 April 2019 to 14 February 2020, and the study period was 11 March 2019 to 14 May 2021. Data cut-off for interim analysis was 31 December 2020. Patients were registered for the study by a central registration method at medical institutions that signed a written contract for the study. Patient data were collected by the physicians in charge of the study using case report forms and were submitted to the study sponsor at the end of the observation period using an internet-based electronic data capture system. All patients were required to provide consent to participate in the study.

| Study population
Patients who were prescribed adalimumab for the first time by their treating physician were eligible for inclusion in the study. Per routine clinical practice, patients were eligible for adalimumab treatment only after all existing treatment options (pharmacological or non-pharmacological therapy) had been proven to be ineffective for the treatment of HS.
Patients previously treated with adalimumab and patients who did not provide consent to participate in the study were excluded.

| Treatment protocol
Adalimumab was administered s.c. according to the dosage and administration described in the package insert. The first dose was 160 mg, the second dose (2 weeks after the initial dose) was 80 mg, the third (4 weeks after the initial dose) and subsequent doses were 40 mg every week or 80 mg every 2 weeks. The observation period was 52 weeks from the start of adalimumab treatment; if treatment discontinued before 52 weeks, the occurrence of AE was observed up to 70 days after the last dose. Discontinuation was defined as the time when there was no possibility of re-administration of adalimumab before 52 weeks from the start of treatment or when observation was no longer possible.

| Survey items
The following patient information was collected: age, sex, bodyweight, disease period, severity of HS (Hurley staging classification), 16 family history of HS, history of smoking, affected site (axilla, around the breast, buttocks, around the inguinal and femoral regions, perianal region, perineum, other), medical history (comorbidities and previous disease), status of adalimumab treatment, previous HS treatment (medication and non-pharmacological therapy), concomitant HS treatment (medication and non-pharmacological therapy), concomitant drugs for diseases other than HS, occurrence of AE, and effectiveness evaluation (described below).

| Outcome measures
The primary end-point was safety and included the number and per- Secondary end-points were assessed at 12, 24, and 52 weeks, and at adalimumab discontinuation. For this interim analysis, results at 12 weeks only are reported. End-points included the following: the proportion of patients achieving a HiSCR, 17 where HiSCR was defined as a ≥50% reduction in the number of abscesses and inflammatory nodules, and no increase in abscess count and no increase in draining fistula count relative to baseline; the total abscess and inflammatory nodule (AN) count, defined as the sum of the measured abscesses and inflammatory nodules in the same examination period; physicianassessed overall improvement, defined as the proportion of patients achieving a status of "improved", "not improved", or "impossible to evaluate"; the change from baseline in patient's global assessment of skin pain, evaluated on an 11-point numeric rating scale (NRS), with 0 for "no pain" and 10 for "worst skin pain imaginable", from the start of adalimumab treatment to 12 weeks; the percentage of patients achieving NRS30, where NRS30 was defined as a ≥30% reduction and ≥1-unit reduction from the baseline NRS; and changes from baseline in Dermatology Life Quality Index (DLQI) 18 and C-reactive protein (CRP; mg/dL). CRP values were measured as an inflammatory parameter, with low CRP values indicating less inflammation.

| Statistical analysis
A primary end-point of this study was to determine the incidences of ADR in patients with HS. Infection is one of the risks of TNFα inhibitors. Sample size was based on the incidences of infections in two phase 3 clinical studies in patients with HS (PIONEER I and PIONEER II), which were 24.8% (38/153) and 25.2% (41/163), respectively. 13 Accordingly, for this study, when the incidence of infections was set at 25%, and the 95% confidence interval (CI) at ±10%, the required number of patients for the safety analysis was 73; allowing for possible dropout patients, the sample size for this study was set at 80 patients. Safety was analyzed up to the data cutoff date for all consenting patients who received at least one dose of adalimumab and had at least one follow-up safety evaluation.

| Demographic and baseline clinical characteristics
A total of 84 patients registered and provided consent for the study across 65 medical institutions. One patient who withdrew consent during the observation period was excluded from the safety and effectiveness analysis populations. The demographics and characteristics of the 83 patients included in the study are presented in Table 1. Sixty-five (78.3%) patients were male, 24 (28.9%) patients were aged ≥40 to <50 years, the mean (SD) age was 42.0 (15.  Table S1. Overall, 20 (24.1%) patients had a medical history of previous disease; there was no medical history in common between patients (Table S2).

| HS disease characteristics and treatment prior to adalimumab administration
Hidradenitis suppurativa disease characteristics prior to adalimumab treatment are reported in Table 2. The majority of patients

| Safety
No patient reported a serious infection, six (7.2%) patients reported an ADR, six (7.2%) patients reported any infection, and no patients reported any safety event of special interest (Table 5). Overall, 21 AE were reported by 15 (18.1%) patients; eight were classified as ADR (Table S5). There was one serious AE, an event of cardiac failure. The most common types of AE were infections and infestations (7.2%; one each of carbuncle, folliculitis, nasopharyngitis, pneumonia, subcutaneous abscess, and incision site abscess) and skin and subcutaneous tissue disorders (6.0%; two events of asteatotic eczema and one each of hidradenitis, pruritus, and rash). One patient died from a serious AE of cardiac failure, which the physician considered was unrelated to adalimumab. Overall, six (7.2%) patients reported one or more ADR; no serious ADR were reported. Infections and infestations were reported by three (3.6%) patients and consisted of carbuncle, pneumonia, and incision site abscess (one event of each).
Other ADR were abdominal pain, hematochezia, hepatic function abnormal, rash, and back pain (one event of each). One patient discontinued adalimumab owing to an ADR of an incision site abscess.
The current status for all ADR was "recovering".

| Effectiveness
The proportion of patients to achieve HiSCR at 12 weeks of adali-    57.1%). 13 In clinical trials, the occurrence of AE is monitored more frequently and accurately followed, and this may account for the dif- Importantly, no new safety concerns were identified, and these interim results support the administration of adalimumab as a safe and effective drug for the treatment of Japanese patients with HS.
The clinical response (HiSCR) observed in this study at 12 weeks was similar to that observed in PIONEER II at 12 weeks, both of  which were greater than that observed in PIONEER I at 12 weeks (57.4% vs. 58.9% vs. 41.8%, respectively). 13 The difference in clinical response between the two PIONEER studies was attributed to the higher disease burden at baseline for patients in PIONEER I. 13 However, the baseline disease burden for patients in this study and those in PIONEER I is comparable, and the improved clinical response observed in this study may be attributable to racial differences.

TA B L E 4 Usage/dosage and administration status of adalimumab
Racial differences in HS rates have been reported. In particular, in East Asia, the prevalence of HS is higher in men compared with women, but in Western countries, the prevalence is higher in women. [2][3][4][5]21 The current Japanese study revealed that patients with HS in Japan who were treated with adalimumab were mainly male

ACK N OWLED G M ENTS
This study was sponsored by AbbVie GK, manufacturer and licensee of adalimumab. Medical writing assistance was provided by Prudence Stanford, PhD, and Rebecca Lew, PhD, CMPP, of ProScribe -Envision Pharma Group, and was funded by AbbVie GK.
ProScribe's services complied with international guidelines for Good Publication Practice (GPP3). AbbVie GK was involved in the study design, data collection, data analysis, and preparation of the manuscript. The authors would like to thank all study participants. This surveillance study was conducted at 65 institutions nationwide in Japan. We would like to thank all the physicians and medical staff members who cooperated in this surveillance.