Real‐world safety and effectiveness of adalimumab in patients with hidradenitis suppurativa: A 52‐week analysis of a postmarketing surveillance study in Japan

Adalimumab is a human monoclonal antibody against tumor necrosis factor‐α that was approved in Japan for the treatment of hidradenitis suppurativa (HS), a chronic recurrent inflammatory skin disease. We report the results of the final analysis of the postmarketing surveillance (PMS) study (ClinicalTrials.gov: NCT03894956), which evaluated the 52‐week safety and efficacy of adalimumab for HS treatment in real‐world clinical practice in Japan. This multicenter, prospective, open‐label, observational study (March 2019 to May 2021) included patients with HS treated with subcutaneous adalimumab at doses following the package insert. The primary endpoint was safety, and the secondary endpoints were effectiveness, including HS clinical response (HiSCR), C‐reactive protein (CRP), skin pain, and Dermatology Life Quality Index (DLQI). Of the 84 patients registered at 65 sites, 83 patients were included in the analyses. Adverse drug reactions (ADRs) were reported by 10 (12.0%) patients; two patients reported a serious ADR, including one patient with serious infection. Other safety events of special interest reported were liver disorder and dermatitis psoriasiform (one patient each). Almost all patients with ADRs were recovering or had recovered, except for one patient who experienced a serious ADR of liver disorder and died. At 12 weeks, 55.4% of patients achieved HiSCR; this increased to 60.5% and 62.8% at 24 and 52 weeks of adalimumab treatment, respectively. Significant reductions from baseline in CRP (P < 0.05), skin pain (P < 0.0001), and DLQI (P < 0.0001) were observed at all time points. The results from this PMS study demonstrated that long‐term adalimumab treatment is well tolerated and effective in patients with HS in real‐world clinical practice in Japan.

which can have a substantial impact on the patient's mental health, social functioning, and quality of life (QOL). [4][5][6][7][8] The pathogenesis of HS is not fully understood, making disease management challenging.
However, it is thought to be multifactorial, with genetic, immunological, behavioral, and endocrine factors interplaying in the development of HS. 9 In particular, pro-inflammatory cytokines, including tumor necrosis factorα (TNFα), are elevated in patients with HS 10,11 and may be involved in the excessive inflammatory responses that are observed in HS lesions. 12 Adalimumab is a human monoclonal antibody against TNFα that is approved for the treatment of HS in Europe, the USA, Canada, and Japan. Adalimumab has demonstrated efficacy and safety in patients with moderate-to-severe HS in several phase III clinical trials 13,14 and real-world observational studies. 15,16 In the PIONEER I and II studies, 13 significantly higher clinical response rates were observed at 12 weeks in patients receiving adalimumab compared with those receiving placebo; the incidence of adverse events (AEs) was similar between the treatment groups. A phase III, open-label, single-arm study of adalimumab in Japanese patients with moderate-to-severe HS also showed sustained efficacy, with 66.7% of patients achieving clinical responses at 52 weeks, with no severe or new AEs reported. 14 Furthermore, recent real-world observational studies conducted in Europe and Canada have demonstrated the efficacy of adalimumab, reporting sustained clinical responses through 52 weeks in patients with HS. 15,16 However, there are no long-term data on the effectiveness and safety of adalimumab in Japanese patients with HS in a real-world clinical setting.
A postmarketing surveillance (PMS) study of adalimumab in Japanese patients with HS was therefore conducted. 17 In the 12-week interim analysis, 57.4% of patients had achieved a clinical response at 12 weeks of adalimumab treatment, and skin pain, Creactive protein (CRP), and QOL, assessed by the Dermatology Life Quality Index (DLQI), had significantly improved from baseline; no serious infections or new safety concerns were reported. Here we report the final analysis of the PMS study and evaluate the 52-week safety and effectiveness results of adalimumab treatment in patients with HS in real-world clinical practice in Japan.

| Study design
This was a multicenter, prospective, open-label observational study conducted at 65 centers in Japan between March 11, 2019 and May 14, 2021. The study design has been described previously in the 12-week interim report. 17 Briefly, patient enrollment started in April 2019 and ended in February 2020. Patients were registered using a central registration method, and their data were collected using a case report form, which was completed by the physician in charge of the study and submitted via an internet-based electronic data capture system. The study was conducted in accordance with the GPSP Ordinance (Good Post-marketing Study Practice; Ministerial Ordinance No. 171 of the Ministry of Health, Labour and Welfare dated December 20, 2004) and was registered at Clini calTr ials.gov (identifier: NCT03894956). All patients provided informed consent prior to study participation.

| Study population
Patients included in this study were those diagnosed with HS and were prescribed adalimumab for the first time by their treating physicians per routine practice. Patients who were previously treated with adalimumab and who did not consent to participate in the study were excluded.

| Treatment protocol
Dosage and administration of adalimumab followed the description in the package insert. Adalimumab was administered subcutaneously at a dose of 160 mg as the first dose, 80 mg as the second dose (2 weeks after the initial dose), then 40 mg every week or 80 mg every 2 weeks as the third (4 weeks after the initial dose) and subsequent doses. Patients were observed for 52 weeks from the start of adalimumab treatment. If treatment was discontinued before 52 weeks, the occurrence of AEs was observed up to 70 days after treatment discontinuation.

| Survey items
Survey items in this study have been described previously. 17 Briefly, patient information collected was as follows: baseline characteristics, including age, sex, body weight, HS severity per the Hurley classification, HS family history, and affected site(s); medical history, including comorbidities and previous disease; adalimumab treatment status; previous medication and nonpharmacological therapy for HS; concomitant medication and nonpharmacological therapy for HS; occurrence of AEs, including name and seriousness of the AE; and effectiveness evaluation (described below).

| Outcome measures
Details on the outcome measures were reported previously. 17 The primary endpoint was safety. The incidence of serious infection, any adverse drug reactions (ADRs), any infection, and any safety event of special interest were assessed using the Medical Dictionary for Regulation Activities/Japanese edition (MedDRA/J) Version 24.0.
Safety events of special interest were serious infection, reactivation of hepatitis B, tuberculosis, demyelinating disorders, lupus-like syndrome, serious allergic reaction, interstitial pneumonia, serious blood disorder, liver disorder (fulminant hepatitis, liver dysfunction, jaundice, liver failure), malignant tumor, dermatitis psoriasiform (exacerbation and new onset of psoriasis), exacerbation of sarcoidosis, and immunogenicity.
The secondary endpoints assessed at 12, 24, and 52 weeks, and at adalimumab discontinuation were as follows: the proportion of patients who achieved HS clinical response (HiSCR), defined as ≥50% reduction in the number of abscesses and inflammatory nodules, and no increase in the number of abscesses and draining fistulas relative to baseline; total number of abscesses and inflammatory nodules (AN), in which AN was defined as the sum of abscess and inflammatory nodule count measured in the same examination period; the proportion of patients achieving an overall improvement of "improved", which was subjectively assessed by the physicians as "improved", "unchanged", or "impossible to evaluate"; change from baseline in CRP to evaluate the extent of inflammation; change from baseline in the patient's global assessment of skin pain, evaluated using an 11-point numeric rating scale (NRS), with 0 indicating "no pain" and 10 indicating "worst skin pain imaginable"; the proportion of patients achieving NRS30, defined as a ≥30% reduction and ≥1-unit reduction from baseline in NRS in patients whose baseline NRS value was ≥3; and change from baseline in DLQI. 18 The DLQI is a questionnaire that assesses the patient's health-related QOL; the total score is the sum of each question, with a higher score indicating greater impairment in QOL.

| Statistical analysis
As described previously, 17 the planned target sample size was 80 patients, which was based on the safety results of two phase III studies of adalimumab in patients with HS (PIONEER I and PIONEER II). 13 The CRP, and DLQI are summarized using descriptive statistics; a paired t-test was performed, and two-sided P < 0.05 was considered statistically significant. Multiplicity was not considered in the hypothesis test.
Missing data were not imputed. Statistical analyses were performed using SAS 9.3 or higher (SAS Institute Inc.).

| Demographic and baseline clinical characteristics
Of the 84 patients registered for the study, 83 patients were included in the safety analysis and the effectiveness analysis. 17 One patient was excluded from the analyses due to consent withdrawal. Patient TA B L E 1 Patient baseline demographic and disease characteristics (safety analysis population, n = 83).

| Previous and concomitant treatments before and during adalimumab administration
Before starting adalimumab treatment, most patients (84.3%, 70/83 patients) were taking medications for HS (Supporting Information

| Safety
Serious infection was reported by two (2.4%) patients, with one patient having a serious infection classified as an ADR (Table 2).
Overall, there were 39 AEs reported by 21 (25.3%) patients, and an AE of any infection was reported by 11 (13.3%) patients (  Patients with any safety events of special interest other than serious infection Liver disorder (fulminant hepatitis, liver dysfunction, jaundice, liver failure) antibacterial drugs (i.e., received previous antibacterial drugs but discontinued them and never received them at the start of and during adalimumab treatment), 60.0% and 50.0% achieved HiSCR at 12 and 52 weeks, respectively (Supporting Information Table S6).
In those who continued to receive concomitant antibacterial drugs,

| Physician-assessed overall improvement and CRP
The proportion of patients with a status of "improved" for physicianassessed overall improvement was 93.8% at 12 weeks (Supporting Information Figure S1)

| DISCUSS ION
This 52-week PMS was the first study to evaluate the long-term In this study, the incidence of any ADR with adalimumab treatment was 12.0%, which was lower than that reported in a clinical trial but higher than the incidences reported in recent observational studies. The Japanese phase III, open-label, single-arm study reported that 47% of patients had any ADR. 14 However, a multicenter post-marketing observational study of adalimumab in mainly White patients with HS (HARMONY study) reported an incidence rate of any ADR of 9.5%. 15 Moreover, in a 1-year, Canadian, prospective observational PMS (SOLACE study), 7.1% of patients reported any ADR. 16 The difference in the overall incidence rate of ADRs between the current study and previous studies may be explained by the differences in study design (clinical trials vs. observational studies). Furthermore, patient characteristics, including ethnicity, sex, and patients' comorbidity and previous disease, may also explain these differences given that the present study demonstrated that the incidence of ADRs was higher in women than in men and in patients with previous disease or comorbidity than in those without.
However, further studies are needed to confirm this because no statistical test was conducted for the subgroup analyses.
Increased risks of serious infections, malignancies, and tuberculosis have been reported previously with TNFα inhibitors, including adalimumab. 19,20 However, in this study, AE of serious infection was  HS lesions and improvements in inflammation (CRP) and skin pain through 52 weeks relative to baseline. Moreover, QOL in this study significantly improved over time (P < 0.0001 at all time points); mean DLQI score of 8.5 at baseline continued to decrease after 12 weeks and was <3 at 52 weeks of adalimumab treatment. This is similar to the results observed in the HARMONY study, 15 which reported an approximately 50% reduction in DLQI from baseline (16.9) to 52 weeks (8.6), although the mean DLQI scores at baseline and at 12 and 52 weeks were substantially lower in this study than in the HARMONY study. Health-related QOL is considerably affected by bodily pain, 8  outcomes. However, this study was limited by the absence of a control or comparator group and the exclusion of patients with a history of adalimumab use for HS and other diseases. The severity of HS was also not reported using the International Hidradenitis Suppurativa Severity Score System, and the results of some outcomes were not analyzed or were based on a small sample size due to missing patient data. Furthermore, for the subgroup analyses, no significance test was conducted and no baseline characteristics were adjusted.
Subgroup analysis of patients with and without concomitant antibacterial drugs or nonpharmacological therapy may also be subject to selection bias, therefore the clear relationship between the use of concomitant antibacterial drug or nonpharmacological therapy and the achievement of HiSCR may be lacking.
In conclusion, this PMS study demonstrated the long-term safety and effectiveness of adalimumab for the treatment of patients with HS in real-world clinical practice in Japan. No new safety concerns were observed over the 52 weeks of treatment; adalimumab was well tolerated regardless of patient demographic and clinical characteristics. Furthermore, adalimumab showed sustained improvements in clinical response, symptoms, and QOL through the 52 weeks of treatment.

ACK N OWLED G M ENTS
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.

FU N D I N G I N FO R M ATI O N
This study was sponsored by AbbVie GK, manufacturer and licensee of adalimumab. Medical writing assistance was provided by Hana Nomura, BPharm (Hons), and Prudence Stanford, PhD, CMPP, of ProScribe -Envision Pharma Group, and was funded by AbbVie GK.
ProScribe's services complied with international guidelines for Good Publication Practice. AbbVie GK was involved in the study design, data collection, data analysis, and preparation.