FormalPara Key Summary Points

Why carry out this study?

Treatments with long-term acceptable safety profiles and efficacy durability are needed for atopic dermatitis, a chronic inflammatory skin disease characterized by eczematous morphology and intense itch.

This 3-year, phase 3 clinical trial evaluated the long-term safety and efficacy of upadacitinib, an oral Janus kinase inhibitor, for the treatment of adolescents and adults in Japan with moderate-to-severe atopic dermatitis.

What was learned from the study?

Through up to 160 weeks of continuous treatment, upadacitinib 15 mg and 30 mg were well tolerated, with a safety profile similar to that of short-term studies; no new safety risks were identified for adolescents or adults in Japan.

Response rates for skin clearance and itch improvement were numerically higher with upadacitinib than with placebo at week 16 and were maintained through week 160.

These 3-year results support the favorable benefit–risk profile of upadacitinib for the long-term treatment of moderate-to-severe atopic dermatitis in adolescents and adults in Japan.

Introduction

Atopic dermatitis (AD) is a common, chronic, inflammatory skin condition characterized by eczematous morphology, intense pruritus, and impaired quality of life [1, 2]. Most (approximately 80%) AD cases begin during childhood and can persist into adulthood [1, 2]. AD is a heterogeneous disease with clinical phenotypes that vary widely on the basis of multiple factors including age, severity, and race [1, 2]. The worldwide prevalence of AD ranges from 0.2% to 24.6%, and a higher prevalence of AD has been reported in Asian populations compared with White or European populations [2,3,4]. The prevalence of AD in Japan has been estimated between 5% and 32% in children 6 months to < 18 years old [5, 6] and between 2% and 10% in adults [6, 7].

Common first-line AD treatments include local antiinflammatory therapies such as topical corticosteroids (TCS), topical calcineurin inhibitors, topical Janus kinase (JAK) inhibitors, and topical phosphodiesterase 4 inhibitors [2, 6]. If topical treatments are insufficient to control AD symptoms or improve patients’ quality of life, current guidelines (including those from the Japanese Dermatological Association) recommend systemic therapies including biologics and oral JAK inhibitors [2, 6, 8]. Multiple systemic therapies are currently approved or in development for the treatment of AD; however, further studies evaluating the benefit–risk ratio and long-term safety of systemic AD therapies are needed [2, 9].

Upadacitinib, an oral, selective JAK inhibitor with greater potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 [10, 11], is approved in multiple countries including Japan, Europe, Canada, Australia, and the USA for the treatment of moderate-to-severe AD in adolescents and adults [12, 13]. Upadacitinib demonstrated greater efficacy in skin clearance and itch reduction in phase 3 studies (with and without concomitant TCS) compared with placebo over 16 weeks of treatment in adolescents and adults with moderate-to-severe AD [14, 15].

Rising Up was a 3-year, phase 3 study evaluating the safety and efficacy of upadacitinib 15 mg and 30 mg in adolescents and adults in Japan with moderate-to-severe AD [16]. In a planned 24-week interim safety analysis [16] and 112-week interim analysis [17], an acceptable safety profile was reported for upadacitinib for the treatment of moderate-to-severe AD. Substantial improvements in skin clearance and itch reduction were reported after 24 weeks [16] or 112 weeks [17] of treatment with either upadacitinib dose. Herein we report long-term safety and efficacy data for upadacitinib 15 mg and 30 mg for the treatment of Japanese patients with AD through up to 3 years of continuous therapy.

Methods

Study Design, Patients, and Treatment

Detailed methods were previously reported [16, 17]. In brief, Rising Up (NCT03661138) was a 3-year, phase 3 study to evaluate the safety and efficacy of upadacitinib treatment for moderate-to-severe AD in adolescents (aged 12 to < 18 years, weight ≥ 40 kg) and adults (aged 18–75 years) in Japan. All 42 study sites were in Japan. Patients were randomized 1:1:1 to receive, in combination with TCS, upadacitinib 15 mg, upadacitinib 30 mg, or placebo from baseline to week 16. Randomization was stratified according to baseline disease severity [moderate (validated Investigator Global Assessment for Atopic Dermatitis, vIGA-AD™) score of 3 versus severe vIGA-AD score of 4] and age (< 18 years versus 18–40 years versus > 40 years). Patients who were randomized to placebo at baseline were rerandomized 1:1 at week 16 to receive either upadacitinib 15 mg or 30 mg; rerandomization at week 16 was stratified by ≥ 50% improvement in Eczema Area and Severity Index (EASI 50) from baseline at week 16 (“yes” versus “no”) and age at baseline (< 18 years versus 18–40 years versus > 40 years). All treatment arms were blinded from weeks 0–16 (double-blind period) and weeks 16–52 (blinded extension period) and were open label from weeks 52–160 (open-label period). All patients were required to follow a step-down regimen of concomitant TCS therapy during the double-blind period [15, 16]; briefly, application of a medium-potency TCS to areas with active lesions was required once daily for a maximum of three consecutive weeks. After 3 weeks or once the lesions were clear or almost clear, a low-potency TCS was required once daily for 7 days and then stopped if lesions remained clear. If lesions returned or persisted after 7 days of low-potency TCS, the step-down approach was repeated until lesions resolved or until local or systemic TCS toxicity was observed. Concomitant TCS use was optional (administered per investigator discretion) after week 16 through the end of the study. The study was conducted in accordance with the protocol, International Council for Harmonisation guidelines, and applicable regulations, guidelines, and ethical principles originating from the Declaration of Helsinki. The study protocol was reviewed and approved by an institutional review board [16, 17]. Patients provided written informed consent before screening or undergoing study-specific procedures [16, 17].

Assessments

Safety was assessed by monitoring adverse events (AEs), serious adverse events (SAEs), adverse events leading to discontinuation, and adverse events of special interest (AESIs) through up to 3 years (week 160) of continuous upadacitinib treatment; for comparison, 2-year (week 112 cutoff date: 11 August 2021) safety data are also presented [16, 17]. Relatedness to study drug was determined at the discretion of the investigator. Efficacy assessments included ≥ 75% and ≥ 90% improvement from baseline in EASI (EASI 75/90), achievement of clear or almost clear on the vIGA-AD (vIGA-AD 0/1) with at least two grades of reduction from baseline, and ≥ 4-point improvement (reduction) from baseline on the Worst Pruritus Numerical Rating Scale (WP-NRS) among patients with WP-NRS scores ≥ 4 at baseline.

Statistical Analysis

AEs were summarized using Medical Dictionary for Regulatory Activities system organ class and preferred terms (version 25.0). Statistical analyses were performed using SAS version 9.4 or higher (SAS Institute, Cary, NC). Exposure-adjusted incidence rates were calculated as the number of patients with at least one event divided by the total number of patient-years for patients at risk of an event (n/PY) to account for differences in upadacitinib exposure across cohorts (the exposure for PY was counted from the first dose of study drug to the time when an event occurred); incidence rates are also presented as the number of patients with events per 100 patient-years (n/100 PY) [17]. Exposure-adjusted event rates [the number of events per 100 patient-years (E/100 PY)] were also calculated through the end of the study. Efficacy data were analyzed using two approaches for handling missing data: observed cases (OC) and nonresponder imputation (NRI). The OC analysis does not impute values for missing evaluations; patients without an evaluation at a scheduled visit will be excluded from the OC analysis for that visit. The NRI analysis categorizes any patient without an evaluation during a specific visit window as a nonresponder for that visit; the exception is if the patient is a responder both before and after a specific visit window and the patient then will be categorized as a responder for that visit. The 3-year efficacy results were descriptively summarized and no hypothesis testing was performed.

Results

Patients

Of the 272 patients randomized in the study, 264 (97.1%) completed the double-blind period, and 230 (87.1%) of the 264 who entered the blinded extension/open-label periods completed the study (Fig. 1). A total of 29 adolescents were randomized; 28 adolescents completed the double-blind period, and 21 adolescents completed the study (12 in the upadacitinib 15 mg group and 9 in the upadacitinib 30 mg group). As previously reported, baseline demographics and characteristics were generally balanced across cohorts in the overall population (Table 1) and in the adolescent population (Supplementary Table 1) [16, 17]. The median exposure to upadacitinib was 3.1 years (range 0.04–3.1 years) in both of the continued upadacitinib treatment groups.

Fig. 1
figure 1

Patient disposition. aIncludes one patient who completed the study but discontinued study drug. bIncludes two patients who completed the study but discontinued study drug

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Table 1 Patient demographics and baseline characteristics
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Safety

Safety Overview

Safety profiles were generally similar for the upadacitinib 15 mg group and 30 mg group through the end of the 3-year study (Table 2); through week 160, 121 (91.0%) and 124 (91.2%) patients experienced AEs with upadacitinib 15 mg and 30 mg, respectively. The long-term exposure-adjusted incidence rate for any AE (n/100 PY) through week 160 was numerically higher with upadacitinib 30 mg (170.6 n/100 PY) than with 15 mg (122.2 n/100 PY). Long-term incidence rates (n/100 PY) for SAEs, severe AEs, and AEs leading to discontinuation were similar across upadacitinib treatment arms; incidence rates through week 160 were 4.4 n/100 PY (upadacitinib 15 mg) and 3.8 n/100 PY (upadacitinib 30 mg) for SAEs, 5.3 n/100 PY (upadacitinib 15 mg) and 5.7 n/100 PY (upadacitinib 30 mg) for severe AEs, and 2.2 n/100 PY (upadacitinib 15 mg) and 1.9 n/100 PY (upadacitinib 30 mg) for AEs leading to discontinuation. Of the 41 patients who discontinued treatment, two discontinued because of a lack of efficacy and one discontinued because of worsening of AD. The most common SAEs were herpes zoster (upadacitinib 15 mg, n = 1; upadacitinib 30 mg, n = 2), coronavirus disease 2019 (COVID-19) (upadacitinib 30 mg, n = 3), and appendicitis (upadacitinib 15 mg, n = 1; upadacitinib 30 mg, n = 1); most SAEs were considered unrelated to study drug by the investigator. Overall safety profiles were similar according to exposure-adjusted event rates (E/100 PY; Supplementary Table 2). SAEs considered possibly related to study drug are reported in Supplementary Table 3, and AEs leading to discontinuation of study drug are reported in Supplementary Table 4. No deaths occurred during the study.

Table 2 Long-term safety of upadacitinib among patients enrolled in the Rising Up studya
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Consistent with previous interim analyses, the most common AEs through week 160 were acne, nasopharyngitis, and herpes zoster; the overall rate of these events was higher with upadacitinib 30 mg compared with upadacitinib 15 mg. Long-term incidence rates through week 160 were 11.6 n/100 PY (upadacitinib 15 mg) and 22.3 n/100 PY (upadacitinib 30 mg) for acne, 12.7 n/100 PY (upadacitinib 15 mg) and 16.5 n/100 PY (upadacitinib 30 mg) for nasopharyngitis, and 8.2 n/100 PY (upadacitinib 15 mg) and 12.3 n/100 PY (upadacitinib 30 mg) for herpes zoster. All cases of acne were mild or moderate; one acne event in the upadacitinib 30 mg group led to study drug discontinuation. Acne morphology primarily consisted of inflammatory papules, pustules, and comedones. Among patients randomized to receive upadacitinib at baseline, longitudinal evaluation of patients who experienced acne events demonstrated no clear patterns regarding time to acne onset or duration of acne events during the study (Fig. 2); these findings are consistent with previous studies characterizing acne events related to upadacitinib use [18, 19]. The incidence of other common AEs was generally similar between both upadacitinib treatment groups; however, some variability was observed likely due to the small sample size. Through week 160, rates of some AEs including pyrexia, tinea pedis, and arthralgia were numerically higher in the upadacitinib 30 mg group than in the upadacitinib 15 mg group.

Fig. 2
figure 2

Longitudinal evaluation of acne events among individual patients randomized to receive upadacitinib at baseline in the Rising Up study. Data presented for adolescent and adult patients who received upadacitinib 15 mg (A) or upadacitinib 30 mg (B) during the study. Dashed line represents duration of study drug; solid line represents duration of acne event. Patients who experienced multiple acne events are represented with different colors: green (one acne event), red (two acne events), and orange (three acne events)

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In adolescent patients, the long-term incidence rate of AEs through week 160 was numerically higher with upadacitinib 30 mg than with 15 mg, and the rate of AEs considered possibly related to study drug by the investigator was higher in the upadacitinib 15 mg group than in the 30 mg group (Supplementary Table 5); however, the number of adolescents in this study was small. The most common AEs in the adolescent population were generally similar to those in the overall population. There were two AEs leading to study drug discontinuation: worsening of atopic dermatitis (upadacitinib 15 mg, considered possibly related to study drug) and lymphocyte morphology abnormal (upadacitinib 30 mg, described in further detail below). There was one SAE considered possibly related to study drug with upadacitinib 15 mg (appendicitis).

Adverse Events of Special Interest

Long-term incidence rates (n/100 PY) of AESIs were generally consistent with the previous interim analysis [17]; most AESIs were infrequent through week 160 for either upadacitinib dose (Table 3). Exposure-adjusted event rates (E/100 PY) for AESIs through week 160 are presented in Supplementary Table 6. The incidence rate of serious infections was slightly higher with upadacitinib 30 mg (2.6 n/100 PY) compared with upadacitinib 15 mg (2.0 n/100 PY). There were seven serious infections in the upadacitinib 15 mg group (one event each of appendicitis, cellulitis, eczema herpeticum, enteritis infectious, herpes zoster, Pneumocystis jirovecii pneumonia, and septic shock); all seven events were severe and resolved by the end of the study, and four events (appendicitis, enteritis infection, herpes zoster, and Pneumocystis jirovecii pneumonia) were considered possibly related to study drug by the investigators. In the upadacitinib 30 mg group, nine serious infections were reported: COVID-19 (n = 3), herpes zoster (n = 2), appendicitis (n = 1), herpes simplex (n = 1), herpes zoster cutaneous disseminated (n = 1), and herpes zoster disseminated (n = 1). All but one serious infection in the upadacitinib 30 mg group were severe (COVID-19 was moderate), and all but one serious infection were considered possibly related to study drug by the investigators (COVID-19 was unrelated). All serious infections resolved by the end of the study.

Table 3 Long-term exposure-adjusted incidence rates for AESIs among patients enrolled in the Rising Up study
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All but two opportunistic infections (excluding tuberculosis and herpes zoster) were eczema herpeticum (Kaposi’s varicelliform eruption; 3.4 n/100 PY with upadacitinib 15 mg and 1.4 n/100 PY with upadacitinib 30 mg); the exceptions were one event of esophageal candidiasis (upadacitinib 30 mg) and one event of Pneumocystis jirovecii pneumonia (upadacitinib 15 mg). The event of Pneumocystis jirovecii pneumonia was severe, considered possibly related to study drug, and led to study drug discontinuation. Most herpes zoster events were nonserious and involved one or two dermatomes; only one herpes zoster event led to treatment discontinuation. There was one case of malignancy in a 38-year-old man (rectal cancer; grade 1 and nonserious; onset 2 years after enrollment) reported in the upadacitinib 15 mg group; the event resolved after polypectomy and was considered by the investigator to be unrelated to study drug. There was one event categorized as lymphoma (lymphocyte morphology abnormal) in an adolescent who received upadacitinib 30 mg; it was an atypical lymphocyte laboratory finding that resolved in subsequent testing and thus was not considered a malignancy. A 22-year-old man experienced a cerebellar hemorrhage (adjudicated as a major adverse cardiovascular event) on study day 65; the event was considered possibly related to study drug and led to study drug discontinuation, and the patient recovered. Most hepatic disorders were elevations in transaminase levels; none of the events were serious. Incidence rates of anemia, neutropenia, and elevations in creatine phosphokinase levels remained higher with upadacitinib 30 mg than with upadacitinib 15 mg. All laboratory-related AEs were generally mild or moderate and nonserious; few led to treatment discontinuation. There were no events of nonmelanoma skin cancer, gastrointestinal perforation, renal dysfunction, active tuberculosis, or venous thromboembolic events during the study.

AESIs were reported infrequently in adolescents, with no new safety findings relative to the overall study population (Supplementary Table 7). There was one serious infection (appendicitis) and one nonserious event of eczema herpeticum reported in adolescents receiving upadacitinib 15 mg; both events were considered possibly related to study drug. Three events of herpes zoster were reported in adolescents (all with upadacitinib 30 mg); none were serious. No malignancies, adjudicated major adverse cardiovascular events, or venous thromboembolic events were reported in adolescents.

Efficacy

Among patients who were randomized to receive upadacitinib at baseline, improvement in skin clearance observed at week 16 was generally sustained through the end of the study (Figs. 3, 4). In the OC analysis, the proportion of patients achieving EASI 75 at week 160 was 72.7% with upadacitinib 15 mg and 77.0% with upadacitinib 30 mg, and the proportion of patients achieving EASI 90 at week 160 was 40.3% with upadacitinib 15 mg and 59.5% with upadacitinib 30 mg. Results for both EASI 75 and EASI 90 responses by NRI analysis were generally consistent with the OC analysis. Among patients who switched from placebo to upadacitinib at week 16, substantial improvements in EASI scores were also observed by the first visit after initiation of upadacitinib treatment; responses improved continuously until reaching a plateau that was sustained through the end of the study with either upadacitinib dose (Supplementary Figs. 1, 2).

Fig. 3
figure 3

Patients achieving EASI 75 from baseline to week 160. EASI 75 ≥ 75% improvement in Eczema Area and Severity Index, NRI nonresponder imputation, OC observed cases, PBO placebo, UPA upadacitinib. The OC analysis does not impute values for missing evaluations; patients without an evaluation at a scheduled visit will be excluded from the OC analysis for that visit. The NRI analysis categorizes any patient without an evaluation during a specific visit window as a nonresponder for that visit; the exception is if the patient is a responder both before and after a specific visit window, then the patient will be categorized as a responder for that visit

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Fig. 4
figure 4

Patients achieving EASI 90 from baseline to week 160. EASI 90 ≥ 90% improvement in Eczema Area and Severity Index, NRI nonresponder imputation, OC observed cases, PBO placebo, UPA upadacitinib. The OC analysis does not impute values for missing evaluations; patients without an evaluation at a scheduled visit will be excluded from the OC analysis for that visit. The NRI analysis categorizes any patient without an evaluation during a specific visit window as a nonresponder for that visit; the exception is if the patient is a responder both before and after a specific visit window, then the patient will be categorized as a responder for that visit

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The proportion of patients achieving vIGA-AD 0/1 was substantially higher with either upadacitinib dose than with placebo during the double-blind period, and vIGA-AD 0/1 response rates in the continued upadacitinib groups were sustained through the end of the study (Fig. 5). At week 160 by OC analysis, 39.0% and 50.0% of patients, respectively, achieved vIGA-AD 0/1 with continuous upadacitinib 15 mg and 30 mg treatment. Among patients who switched from placebo to upadacitinib at week 16, vIGA-AD 0/1 responses increased substantially within 8 weeks of initiating upadacitinib treatment and were generally maintained through the end of the study with either upadacitinib dose (Supplementary Fig. 3).

Fig. 5
figure 5

Patients achieving vIGA-AD 0/1a from baseline to week 160. NRI nonresponder imputation, OC observed cases, PBO placebo, UPA upadacitinib, vIGA-AD 0/1 validated Investigator Global Assessment for Atopic Dermatitis score of clear or almost clear. aPatients achieving vIGA-AD 0/1 with at least two grades of reduction from baseline. The OC analysis does not impute values for missing evaluations; patients without an evaluation at a scheduled visit will be excluded from the OC analysis for that visit. The NRI analysis categorizes any patient without an evaluation during a specific visit window as a nonresponder for that visit; the exception is if the patient is a responder both before and after a specific visit window, then the patient will be categorized as a responder for that visit

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Itch was also substantially reduced in patients receiving upadacitinib within 1–8 weeks of initiating treatment and remained low through the end of the study (Fig. 6). In the OC analysis, 51.3% and 55.4% of patients with WP-NRS scores ≥ 4 at baseline achieved a ≥ 4-point improvement in WP-NRS scores at week 160 with upadacitinib 15 mg and 30 mg, respectively; similar results were observed by NRI analysis. Among patients who switched from placebo to upadacitinib at week 16, rapid improvements in itch were reported by the first visit after initiation of upadacitinib treatment, and these responses remained durable through the end of the study with either upadacitinib dose (Supplementary Fig. 4).

Fig. 6
figure 6

Patients achieving WP-NRS ≥ 4-point improvementa from baseline to week 160. NRI nonresponder imputation, OC observed cases, PBO placebo, UPA upadacitinib, WP-NRS Worst Pruritus Numerical Rating Scale. aAmong patients with WP-NRS scores ≥ 4 at baseline. The OC analysis does not impute values for missing evaluations; patients without an evaluation at a scheduled visit will be excluded from the OC analysis for that visit. The NRI analysis categorizes any patient without an evaluation during a specific visit window as a nonresponder for that visit; the exception is if the patient is a responder both before and after a specific visit window, then the patient will be categorized as a responder for that visit

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Efficacy responses in the adult population were consistent with those in the overall study population (Supplementary Figs. 5, 6, 7, 8). In the adolescent population, upadacitinib treatment also led to substantial skin clearance and itch reduction, with generally similar trends as in the overall population; however, the data should be interpreted with caution as higher variability was observed owing to the small sample size.

Use of Concomitant TCS Therapy

The mean proportion of days in which patients were not receiving concomitant TCS therapy during the study was greater among patients receiving upadacitinib compared with placebo and was generally higher for patients receiving upadacitinib 30 mg versus those receiving upadacitinib 15 mg (Fig. 7A). From baseline through week 16, the mean (SD) percentage of TCS-free days was 23.7% (29.2) with upadacitinib 15 mg, 27.7% (30.9) with upadacitinib 30 mg, and 4.1% (10.0) with placebo. Among patients who received upadacitinib, the mean proportion of TCS-free days increased during the double-blind period (when the TCS regimen was required) and peaked between weeks 4 and 16 for patients who received upadacitinib 15 mg and between weeks 12 and 16 for patients who received upadacitinib 30 mg; the proportion then decreased over the next several weeks when TCS use was optional per investigator discretion. The mean proportion of TCS-free days generally remained stable from weeks 88–160 with upadacitinib 15 mg and from weeks 52–160 with upadacitinib 30 mg. Over the course of the study (up to 160 weeks of exposure), the mean (SD) percentage of TCS-free days was 13.1% (22.8) with upadacitinib 15 mg and 21.2% (32.3) with upadacitinib 30 mg.

Fig. 7
figure 7

Mean proportion of days in which patients were not receiving concomitant TCS therapy from baseline to week 160 (OC). EASI 75 ≥ 75% improvement in Eczema Area and Severity Index, OC observed cases, PBO placebo, TCS topical corticosteroids, UPA upadacitinib. A Visit window average of proportion of days in which patients were not receiving concomitant TCS therapy from baseline to week 160. B Visit window average of proportion of days in which patients achieved EASI 75 and were not receiving concomitant TCS therapy from baseline to week 160. The OC analysis does not impute values for missing evaluations; patients without an evaluation at a scheduled visit will be excluded from the OC analysis for that visit

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The mean proportion of days in which patients were TCS free and also achieved EASI 75 generally followed a similar pattern for all treatment groups (Fig. 7B). From baseline up to week 16, the mean (SD) percentage of days in which patients were TCS free and still achieved EASI 75 was 16.3% (25.4) in the upadacitinib 15 mg arm and 21.9% (27.7) in the upadacitinib 30 mg arm compared with 0.4% (1.8) in the placebo arm. Over 160 weeks of exposure, the mean (SD) percentage of days in which patients were TCS free and still achieved EASI 75 was 11.0% (20.0) with upadacitinib 15 mg and 18.5% (29.7) with upadacitinib 30 mg. Similar trends were observed among patients who switched from placebo to upadacitinib at week 16 (Supplementary Fig. 9A, B).

Discussion

Through up to 160 weeks of continuous treatment, upadacitinib was generally safe and well tolerated in Japanese patients, with a similar safety profile to those reported in previous analyses; no new safety risks were identified for adolescents or adults [16, 17]. The incidence of acne, nasopharyngitis, herpes zoster, increased blood creatine phosphokinase levels, and tinea pedis was slightly higher with upadacitinib 30 mg than with upadacitinib 15 mg; these findings are consistent with the established upadacitinib safety profile from other global studies [14, 15, 18, 20]. In the double-blind, placebo-controlled period, response rates for skin clearance and itch improvement were numerically higher for upadacitinib than for placebo at week 16 in both the overall study population and the adolescent population, and response rates with either dose of upadacitinib remained durable through 3 years of continuous treatment. These 3-year data from the Rising Up study support the favorable benefit–risk profile for upadacitinib for the long-term treatment of moderate-to-severe AD.

The chronic, relapsing nature of AD requires long-term management for both adolescents and adults to alleviate symptoms and improve quality of life [2, 21,22,23]. Although several therapies are currently approved for AD, many are focused on short-term control of disease flares, and some (e.g., oral corticosteroids) are not recommended for long-term use because of safety issues [6, 24]. Despite recent advances in therapeutic options for AD, as well as recent guidance on selecting among different systemic AD treatments, standardized measures to define long-term control for AD are lacking, and long-term head-to-head studies comparing multiple AD therapies have not yet been conducted [9, 22]. Considering the heterogeneous nature of AD and variable prevalence by ethnicity, including higher prevalence in Asian populations than in White populations [1, 3, 4], additional studies evaluating the safety and efficacy of various AD treatments within different racial and ethnic populations are also needed. AD appearance may vary based on skin color and differences in gene expression (which may affect immune responses) across White, Black, and Asian patients may also cause AD to appear molecularly and histologically distinct in different ethnic populations [3, 4]. Asian patients may have more scaling, lichenification, and well-demarcated lesions compared with White patients [3, 4]. However, data on global phenotypes of AD are limited and further research is needed to better understand racial differences in AD phenotypes. Most patients in clinical trials are White and few data on the efficacy of AD treatments in non-White patients are available, although some studies have reported no differences in treatment response between White, Black, and Asian patients [4]. Further investigation of the safety and efficacy of systemic therapies among various racial and ethnic groups is needed considering potential differences in AD disease phenotypes and pharmacokinetics across these populations [4]. Findings from the present study contribute to the totality of safety and efficacy data for upadacitinib in diverse patient populations, especially for long-term use.

The proportion of days in which patients were TCS free was generally highest around weeks 8–20 following the initiation of upadacitinib treatment, suggesting that skin clearance observed during this timeframe allowed for the discontinuation of concomitant TCS therapy according to the protocol-mandated step-down regimen. The proportion of TCS-free days declined after week 16, suggesting that the standard clinical practice in Japan [6, 8] of proactively reinitiating TCS therapy regardless of the degree of skin clearance to prevent disease flares was likely followed by many investigators in this study. These results suggest that after week 16, the clinical trial was conducted in a near-real-world setting with regard to concomitant TCS therapy, considering that Japanese dermatologists prefer to continue using TCS during systemic treatment to ensure the maintenance of efficacy and that patients can maintain the habit of applying topical treatments to promote adherence to TCS therapy.

One limitation of this study was small sample sizes. Because the number of adolescents in the study was small, interpretation of safety and efficacy data in the adolescent population should be made with caution. Additional limitations include the absence of a control group from weeks 16–160, and open-label treatment from weeks 52–160 could have introduced reporting or attribution bias. Furthermore, results may not be comparable to those of other AD treatments owing to differences in study designs. Results of this study in Japanese patients may not be generalizable to other racial or ethnic groups for AD; however, the safety and efficacy data reported from the Rising Up study are generally similar to findings from other phase 3 studies of upadacitinib with more diverse patient populations [14, 15].

Conclusions

In Japanese patients with moderate-to-severe AD, upadacitinib 15 mg and 30 mg were well tolerated and response rates for skin clearance and itch improvement were maintained for up to 3 years of continuous treatment. These results support the favorable benefit–risk profile of upadacitinib for the long-term treatment of patients with moderate-to-severe AD.