The design and 1-year interim results of this PMS have been previously described [8]. Briefly, this observational, multicenter PMS (UMIN Clinical Trials Registry ID, UMIN000032807) enrolled individuals who first received dupilumab for the treatment of moderate-to-severe AD in Japanese clinical practice. For reimbursement in Japan, dupilumab is recommended for individuals not adequately controlled after ≥6 months of conventional therapies (i.e., topical anti-inflammatory medications), with Eczema Area and Severity Index (EASI) score ≥16 (or EASI head and neck sub score ≥2.4), Investigator’s Global Assessment (IGA) score ≥3 (i.e., moderate-to-severe disease), and AD lesions on ≥10% of the total body surface area [2]. The approved dosage of dupilumab for the treatment of AD in adults is 600 mg administered by subcutaneous injection for the first dose, followed by 300 mg subcutaneous injections every 2 weeks thereafter [2].

Patients were registered into the PMS between July 2018 and June 2020 (registration period) and monitored for a maximum of 2 years following dupilumab initiation (observation period).

This PMS was conducted in accordance with Japanese Ministerial Ordinance on Good Post-marketing Study Practice and the Fair Competition Code in Ethical Pharmaceutical Drugs Marketing Industry; ethics approval for the study was obtained from participating sites, and all patients provided voluntary informed consent. Only data from the sites that permitted publication of the data were included in the present analysis.

Data describing patient characteristics and the safety and effectiveness of dupilumab were obtained from electronic case report forms (CRFs) collected throughout the observation period [8]. To understand the real-world usage of dupilumab, treatment discontinuation was broadly defined as either treatment interruption (treatment stopped temporarily and restarted at a later date), deferral (treatment postponed to a later date) or true discontinuation (stopped permanently due to loss of follow-up, for reasons such as change to another hospital or death) of treatment during the observation period, at the discretion of the physicians. Two-year safety outcomes reported in this final PMS analysis include the incidence of adverse drug reactions (ADRs; defined as adverse events [AEs] for which a causal relationship to dupilumab could not be ruled out), and AEs of interest (AEIs).

AEIs are specified in the Japanese Risk Management Plan (J-RMP) for dupilumab as serious hypersensitivity reactions, serious infections, the exacerbation of symptoms associated with other allergic diseases, events associated with depression and suicidal behavior, and malignant tumors [9]. ADRs and AEs were coded using the system organ class and preferred terms according to the Japanese version of Medical Dictionary for Regulatory Activities Terminology (MedDRA/J, version 25.1). Serious events were defined based on the impact on the patient’s health, and an event is considered serious if it results in any of the following: death, life-threatening, hospitalization, disability or incapacity, congenital anomaly/birth defect, or other important medical events.

The effectiveness of dupilumab for AD was evaluated through changes in disease severity, symptoms, biomarkers, and patient-reported outcomes throughout the observation period. Disease severity outcomes included EASI, IGA, and weekly peak pruritus numerical rating scale (NRS) scores measured at baseline and at months 1, 2, 4, 6, 8, 10, 12, 18, and 24.

Additional analyses evaluated the proportion of patients with ≥50%, ≥75%, and ≥90% improvements in the EASI score from baseline (EASI-50, EASI-75, and EASI-90, respectively) over time, and the proportion of patients who achieved an IGA score ≤1 and an IGA score reduction of ≥2 at any time during the observation period. Biomarker data were collected if available, including peripheral eosinophil count and serum levels of lactate dehydrogenase (LDH), C-C motif chemokine ligand (CCL)-17/thymus and activation-regulated chemokine (TARC), and total immunoglobulin E (IgE) measured during the observation period.

Patient-reported outcomes were collected through Dermatology Life Quality Index (DLQI), EuroQol (EQ)-5D, and Work Productivity and Activity Impairment Questionnaire - atopic dermatitis (WPAI-AD) questionnaires, which were conducted at baseline, 4 months, 12 months, and after treatment discontinuation (where evaluable).

As previously described, a target sample size of 900 patients was estimated for the safety analysis set [8], which included all registered individuals who had CRFs collected, received at least one dose of dupilumab, and had data available for safety evaluation. Baseline characteristics, prior and concomitant treatments for AD, ADRs, AEIs, and treatment discontinuation during the observation period were summarized using descriptive statistics, including the means, standard deviations (SDs), medians, and/or interquartile ranges (IQRs) for continuous variables, and patient numbers and proportions for categorical variables. Kaplan–Meier analyses were additionally performed to estimate the cumulative incidence [±95% confidence interval (CI)] of ADRs over time. The effectiveness analysis set was defined as all patients in the safety analysis set, excluding those with unknown medication status, a primary disease other than AD, and no effectiveness data available for evaluation. Measures of disease severity, symptoms, biomarkers, and patient-reported outcomes over time were summarized using descriptive statistics and compared with baseline values using t tests. The proportion of patients who achieved an IGA score ≤1 and an IGA score reduction of ≥2 at any time during the observation period (herein referred to as the effective proportion) was evaluated in patients with a baseline IGA score ≥2. The effective proportion was estimated in the overall population and in subgroups stratified by baseline factors; exploratory comparisons between subgroups were performed using Fisher’s exact tests or Cochran-Armitage tests as applicable. Statistical analyses were based on observed data with no imputation for missing values and were performed using SAS version 9.1 or later (SAS Institute Inc., Cary, NC).

Between July 2018 and June 2020, 989 individuals with moderate-to-severe AD who initiated treatment with dupilumab were registered in this PMS from 184 clinical sites in Japan. Electronic CRFs were collected from 970 patients at 179 sites; after exclusions, the safety analysis set comprised 962 patients, and 892 of those were included in the effectiveness analysis set (Supplementary Figure S1). The median duration of active dupilumab treatment during the observation period was 62.3 weeks (IQR, 22.4–100.3). The median treatment interval of dupilumab, determined as the number of days since the most recent treatment at 6, 12, 18, and 24 months, was 15 days over the 2-year observation period (Supplementary Table S1).

In the safety analysis set, 679 patients (70.6%) were male, and most patients were adults (5.1% were adolescent patients aged 15–18 years; Table 1). Approximately half of the safety analysis set (527 patients; 54.8%) had one or more comorbid allergic diseases at baseline; the most common were allergic rhinitis (194 patients; 20.2%), allergic conjunctivitis (139 patients; 14.4%), and asthma (104 patients; 10.8%). Among those with available data, the EASI score (mean ± SD) was 30.1 ± 13.2 at baseline, and in line with clinical practice guidelines [2]; most patients had IGA score 3 (460/862 patients; 53.4%) and IGA score 4 (388/862 patients; 45.0%) at dupilumab initiation.

Consistent with the clinical practice guidelines, in which dupilumab is recommended as an add-on therapy to topical therapy in Japan [2], almost all patients in this PMS (951 patients; 98.9%) had previously received treatment for AD, and most (942 patients; 97.9%) continued concomitant treatment while receiving dupilumab (Table 2). The most common prior treatments for AD were topical corticosteroids (924 patients; 96.0%), moisturizers (727 patients; 75.6%), and topical calcineurin inhibitors (473 patients; 49.2%). The proportions of patients who received these treatments during the observation period (i.e., in combination with dupilumab) were similar (Table 2).

Of those who reported prior treatment with oral non-steroidal immunosuppressants (158 patients; 16.4%) and oral corticosteroids (104 patients; 10.8%), 93 (9.7%) and 60 patients (6.2%), respectively, were receiving these treatments at baseline. Of these, 75 patients (7.8%) on baseline oral non-steroidal immunosuppressants and 46 patients (4.8%) on baseline oral corticosteroids reported a period of overlapping administration of these drugs after starting dupilumab treatment. The proportion of patients receiving these treatments decreased throughout the 2-year observation period (Supplementary Figure S2).

Over 2 years, ADRs were reported in 162 patients (16.8%), including eight patients (0.8%) with serious ADRs (Table 3; Supplementary Table S2). The most common ADRs were conjunctivitis [68 patients (7.1%), including one (0.1%) with a serious ADR], allergic conjunctivitis [40 patients (4.2%), including one (0.1%) with a serious ADR], and blepharitis [eight patients (0.8%), with no serious ADRs].

When the incidence of ADRs was assessed by time of onset during the observation period, most events occurred within 120 days of initiating dupilumab (Figures 1, 2). AEIs specified in the J-RMP, regardless of causal relationship with dupilumab, are summarized in Supplementary Table S3. Serious hypersensitivity reactions were reported in four patients (0.4%; all were serious AEIs), serious infections in 11 patients (1.1%; all were serious AEIs), exacerbations of other allergic diseases in 10 patients [1.0%, including one (0.1%) with a serious AEI; eight of these patients (0.8%) experienced an exacerbation of asthma symptoms (Supplementary Table S4) and all eight patients had a history of asthma or comorbid asthma], events associated with depression and suicidal behavior in two patients [0.2%, including one (0.1%) with a serious AEI], and malignant tumors in three patients (0.3%; all were serious AEIs).

Six patients died during the course of the PMS. Causes of death were malignant neoplasm of the lung (76-year-old), cardiac death (81-year-old), aspiration pneumonia (81-year-old), renal failure (93-year-old), malignant neoplasm progression (75-year-old), and white blood cell count increased and myelodysplastic syndrome (65-year-old). For the first five patients, a causal relationship to this drug was ruled out by the investigators. For the sixth patient (with a white blood cell count increase and myelodysplastic syndrome), atypical lymphocytes were observed before dupilumab initiation and dupilumab was administered once; the event was considered causally related by the investigator.

For patients in whom dupilumab was readministered, the reasons for initial interruption, deferral, and discontinuation and the reasons for reinitiation were analyzed (Table 4). Overall, 724/962 patients (75.3%) had at least one event of either interruption, deferral, or discontinuation of dupilumab treatment during the observation period. The reasons of any such event included improvement of AD (125 patients; 17.3%), economic reasons (81 patients; 11.2%), occurrence of AEs (37 patients; 5.1%), inadequate response (20 patients; 2.8%), and other (460 patients; 63.5%; Table 4). Reasons for initial treatment reinitiation included AD flare (61 patients; 8.4%), economic reasons (40 patients; 5.5%), AE recovery (19 patients; 2.6%), and other (393 patients; 54.3%). In total, 513 patients (70.9%) reinitiated treatment at least once during the observation period; the median duration of either treatment interruption, deferral, or discontinuation was 95.0 days (IQR, 40.0–261.0). Of the 20 patients who once stopped dupilumab treatment due to inadequate clinical response, two patients (10.0%) reinitiated dupilumab. On the other hand, of the 125 patients who once stopped dupilumab due to improvement of AD, 88 patients (70.4%) reinitiated dupilumab, of which 45 patients (36.0%) reinitiated due to flare.

Among those who eventually discontinued dupilumab (n = 382), the median time to treatment discontinuation was 33.9 weeks (IQR, 15.6–64.0). Reasons for permanent treatment discontinuation included the improvement of AD (96 patients; 25.1%), economic reasons (54 patients; 14.1%), inadequate response (25 patients; 6.5%), occurrence of AEs (20 patients; 5.2%), and other (186 patients; 48.7%).

Although the primary objective of this PMS was to investigate safety aspects, some effectiveness outcomes were collected as real-world data. The EASI score (mean ± SD) improved from 30.1 ± 13.2 at baseline to 10.7 ± 10.1 at 2 months and 4.0 ± 7.0 at 24 months (both P < 0.001 vs. baseline). Similarly, the proportion of patients who achieved EASI-75 increased from 44.1% at 2 months to 85.6% at 24 months (Figure 3A). Over the same period, EASI-50 increased from 75.5% to 95.1%, and EASI-90 increased from 16.9% to 63.5%.

The mean IGA score also improved from 3.4 ± 0.5 at baseline to 2.2 ± 0.8 at 2 months and 1.4 ± 0.8 at 24 months (both P < 0.001 vs. baseline). The proportion of patients with an IGA score of 0 or 1 increased from 0.2% at baseline to 16.7% at 2 months and 58.6% at 24 months (Figure 3B). The weekly peak pruritus NRS score (mean ± SD) was 6.9 ± 2.1 at baseline, which improved to 3.1 ± 1.9 at 2 months and 1.8 ± 1.6 at 24 months (both P < 0.001 vs. baseline). This corresponded to percent changes (mean ± SD) of −53.1% ± 29.8% at 2 months and −68.5% ± 29.2% at 24 months (Figure 3C).

The proportion of patients who achieved an IGA score ≤1 and an IGA score reduction of ≥2 from baseline at any time during the observation period (effective proportion) was 47.4% (Supplementary Table S5). The effective proportion remained consistent across subgroups stratified by baseline age, age at AD onset, duration of AD, and the presence of allergic comorbidities. Female patients exhibited higher outcome achievement than male patients (55.4% vs. 44.0%).

Improvements in AD severity and symptoms with dupilumab treatment coincided with reductions in circulating biomarkers and patient-reported outcomes. The peripheral eosinophil count (mean ± SD) gradually decreased from 754.9 ± 765.9 cells/mm³ at baseline to 370.4 ± 335.5 cells/mm³ at 24 months (Supplementary Figure S3A). Apparent reductions in mean serum LDH, TARC, and total IgE from baseline were first achieved after 1 month of dupilumab treatment and continued to decrease over 24 months (P < 0.001 at all time points vs. baseline; Supplementary Figures S3B–D). Significant improvements in patient-reported DLQI, EQ-5D, and WPAI-AD scores were observed during the first 4 months after initiating dupilumab and were maintained through 1 year (Supplementary Table S6).