FormalPara Key Summary Points

Why carry out this study?

Acne was the most common treatment-emergent adverse event as reported in the primary upadacitinib trials in patients with moderate-to-severe atopic dermatitis.

This study evaluated the incidence, possible associated medications, clinical characteristics, and management of acne events in Japanese patients with moderate-to-severe atopic dermatitis who were receiving upadacitinib in the first year of the Rising Up study.

What was learned from this study?

Approximately 17–32% of Japanese patients with atopic dermatitis treated with upadacitinib experienced acne events that were mild or moderate, had a mean (range) onset time of 135.4 (7–465) days after initiation of therapy, lasted 3–4 months on average, and were readily managed with topical treatments.

Patients and clinicians should be aware that acne is a potential side effect associated with upadacitinib treatment for atopic dermatitis; however, no special precautionary measures for potential acne development are needed before starting upadacitinib.

Introduction

Atopic dermatitis (AD) is a chronic, itchy skin disease characterized by inflammation and eczematous morphology [1, 2]. Skin inflammation and symptoms in AD are driven by epidermal skin barrier dysfunction, environmental factors, changes in the skin microbiota, and T lymphocyte infiltration in affected areas [3]. Common treatment options for AD include topical therapies, phototherapy, and systemic or topical immunosuppressants [3]. Recently developed AD treatments include biologic therapies and small-molecule inhibitors targeting cytokines and intracellular signaling molecules related to AD pathology. [4] Multiple cytokines—including interleukin (IL)-4, IL-13, and IL-31—contribute to inflammation and symptoms in AD by signaling via cell surface receptors coupled to cytoplasmic Janus kinases (JAKs) [3]. IL-31 produced by T cells in affected skin also signal to sensory neurons via JAK signaling, leading to the sensation of itchy skin [5]. Together, the relevance of JAK signaling in AD suggests that JAK inhibition is a promising therapeutic strategy to treat the underlying pathophysiology and symptoms of chronic, itchy, eczematous skin in patients with AD.

Upadacitinib is an orally administered, selective, small-molecule JAK inhibitor with greater potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 [6, 7]. Upadacitinib is approved in Japan, Europe, and the USA for the treatment of moderate-to-severe AD in adolescents and adults [8, 9]. Acne was reported as one of the most common treatment-emergent adverse events in phase 3 placebo-controlled trials of upadacitinib in patients with moderate-to-severe AD (Measure Up 1, NCT03569293; Measure Up 2, NCT03607422; and AD Up, NCT03568318) [1, 2, 10]. In an integrated analysis of these three phase 3 studies up to 16 weeks of follow-up, the incidence of acne was 9.8% with upadacitinib 15 mg, 15.2% with upadacitinib 30 mg, and 2.2% with placebo [11]. Although acne was also reported with upadacitinib treatment in clinical trials for other indications, acne incidence was lower (≤ 7%) than that observed in the AD studies [12]. Despite studies characterizing the incidence of acne associated with upadacitinib treatment in patients with AD [11], little is known about the severity, clinical characteristics, and effective management of acne with upadacitinib treatment in global patient populations including Japanese patients.

Here, we report the incidence, severity, duration, clinical features including possible associated medications, and management of treatment-emergent acne events associated with upadacitinib therapy in Japanese patients who had moderate-to-severe AD during the first year of treatment in the phase 3 Rising Up study.

Methods

Patients

Eligible patients were adolescents (aged 12 to younger than 18 years, body weight ≥ 40 kg) and adults (aged 18–75 years) in Japan who had moderate-to-severe AD [Eczema Area and Severity Index score ≥ 16, validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score ≥ 3, AD affecting at least 10% of body surface area (BSA), and weekly average of daily Worst Pruritis Numerical Rating Scale score of ≥ 4] with symptoms for at least 3 years or longer per Hanifin and Rajka criteria [13] and were candidates for systemic therapy. Excluded patients had previous exposure to JAK inhibitors or dupilumab, had AD lesions on at least 30% of BSA that could not be safely treated with topical corticosteroids (TCS), were unable or unwilling to discontinue current AD treatments, and/or required prohibited medications during the study.

Study Design and Treatment

Rising Up (NCT03661138) was a phase 3, randomized, multicenter, double-blinded study conducted at 43 sites in Japan to evaluate the safety and efficacy of upadacitinib for the treatment of moderate-to-severe AD [14]. The study consisted of a 35-day screening period; a 16-week placebo-controlled, double-blind treatment period; a 36-week blinded extension period (from week 16 to week 52 of treatment); and an open-label extension period (from week 52 to week 160 of treatment), followed by a 30-day follow-up period.

Patients were randomized 1:1:1 to orally receive upadacitinib 15 mg once daily, upadacitinib 30 mg once daily, or placebo (all in combination with concomitant TCS) at baseline of the double-blind treatment period. At the end of 16 weeks, patients who received placebo were re-randomized 1:1 to either upadacitinib 15 mg or upadacitinib 30 mg. After week 16, the use of any concomitant topical medication for AD was optional per investigator discretion. Randomization occurred using an interactive response technology system and a randomization schedule generated by statisticians at AbbVie. Randomization at baseline was stratified by AD severity [moderate (vIGA-AD = 3) versus severe (vIGA-AD = 4)] and by age (< 18 vs 18–40 versus > 40 years); re-randomization at week 16 was stratified by clinical response (“yes” versus “no” achievement of 50% improvement in Eczema Area and Severity Index) and by age.

The Rising Up study was conducted in accordance with Good Clinical Practice Guidelines as defined by the International Conference on Harmonisation and the Declaration of Helsinki. Before participating in the study, all adult patients and parents or legal guardians of adolescent patients provided written informed consent. Independent institutional review boards at each study site reviewed and approved the protocol and informed consent forms before patients were enrolled and treated.

Assessments

Our post hoc analysis assessed the incidence, severity, duration, clinical characteristics, and management of treatment-emergent acne events from baseline (17 November 2018) to week 16 and up to the 52-week cutoff date (18 June 2020).

Acne severity was evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Mild acne (grade 1) was defined as papules and/or pustules covering less than 10% BSA, which may or may not be associated with symptoms of pruritus or tenderness. Moderate acne (grade 2) was defined as papules and/or pustules covering 10–30% BSA, which may or may not be associated with symptoms of pruritus or tenderness but having psychosocial impact and limiting instrumental activities of daily living, or papules and/or pustules covering more than 30% BSA with or without mild symptoms. Severe acne (grade 3) was defined as papules and/or pustules covering more than 30% BSA with moderate-to-severe symptoms that limit self-care activities of daily living and are associated with local superinfection with oral antibiotics indicated. For each reported acne event, relevant information was collected using a supplemental case report form completed by investigators. The time of onset, duration, severity, location/distribution, morphology, and recurrence of treatment-emergent acne events were recorded. Medications used to manage acne events were also recorded. Descriptive data for all patients randomized at baseline of the double-blind treatment period and who received at least one dose of study drug and all observed cases of acne were reported.

Results

Patients

A total of 272 patients were enrolled and randomly assigned at baseline to receive either upadacitinib 15 mg plus TCS (n = 91), upadacitinib 30 mg plus TCS (n = 91), or placebo plus TCS (n = 90). At week 16, 87 placebo-treated patients were re-randomized to receive upadacitinib 15 mg (n = 42) or upadacitinib 30 mg (n = 45). Including those patients who received placebo and switched to upadacitinib, a total of 133 patients received upadacitinib 15 mg and 136 patients received upadacitinib 30 mg. Eight (2.9%) patients discontinued treatment during the first 16 weeks and 16 (6.1%) patients receiving upadacitinib discontinued treatment in the blinded-extension period up to the 52-week cutoff date.

The baseline demographics and characteristics were well balanced across treatment groups (Table 1). The overall mean [standard deviation (SD)] age was 35.6 (12.8) years (13–66 years), 22.4% were female, and 100% were Asians residing in Japan at the time of enrollment in the study. The mean (SD) duration of AD since diagnosis was 22.8 (14.3) years (0.03–51.9 years).

Table 1 Baseline patient demographics and disease characteristics
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Acne Events

Placebo-Controlled Period Up to Week 16

During the first 16 weeks of treatment, acne was experienced by 13.2% of patients treated with upadacitinib 15 mg, 19.8% of patients treated with upadacitinib 30 mg, and 5.6% of patients receiving placebo (Table 2). Baseline demographics among patients who experienced acne events during the placebo-controlled period are reported in Supplementary Table 1. The mean (SD) age of patients experiencing acne was 28.8 (10.5) years. All acne cases were mild or moderate in intensity and none led to discontinuation of the study drug. Higher rates of acne were reported among female patients than male patients in the upadacitinib 30 mg group, but not in the upadacitinib 15 mg group.

Table 2 Incidence of acne events by severity, sex, and age (16-week placebo-controlled period)
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Adults aged 18 to younger than 30 years generally had the highest incidence of acne, followed by adolescents aged younger than 18 years, then adults aged 30 to younger than 65 years (Table 2). Among patients in the placebo group, the incidence of acne was highest in adolescents aged younger than 18 years. No adults aged 65 years or older reported acne events; however, there were limited numbers of patients enrolled in this age group. Most patients treated with upadacitinib experienced events of facial acne, followed by acne on the trunk and/or extremities (Table 3). The most common morphology for acne was inflammatory papules, pustules, and comedones.

Table 3 Acne event involvement and morphology (16-week placebo-controlled period)
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Long-Term Treatment Up to Week 52 Cutoff Date

Acne was experienced by 17.3% of patients receiving upadacitinib 15 mg and 32.4% of patients receiving upadacitinib 30 mg up to the week 52 cutoff date (Table 4). Baseline demographics among patients who experienced acne events through the week 52 cutoff date are reported in Supplementary Table 2. The mean (SD) age of patients experiencing acne was 31.2 (11.6) years. All acne cases were mild or moderate in intensity and nonserious; no cases of acne led to discontinuation of the study drug. Similar to the first 16 weeks of treatment, through the week 52 cutoff date, rates of acne were higher in female patients receiving upadacitinib 30 mg than in male patients, most acne events occurred on the face, and the most common morphology was inflammatory papules.

Table 4 Incidence, severity, involvement, and morphology of acne events (up to the week 52 cutoff date)
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Among all patients who experienced acne during the study, the average time to onset (SD, range) of the first acne event (in days) was similar in patients treated with upadacitinib 15 mg [137.9 (138.0, 7–465) days] compared with upadacitinib 30 mg [134.1 (101.3, 11–364) days]. The first acne event lasted an average (SD, range) of 128.8 (133.9, 20–406) days in the upadacitinib 15 mg group and 106.6 (80.9, 8–307) days in the upadacitinib 30 mg group. Six (4.5%) patients treated with upadacitinib 15 mg and 2 (1.5%) patients treated with upadacitinib 30 mg experienced multiple acne events. Among patients who were randomized to receive upadacitinib at baseline, longitudinal evaluation of patients who experienced acne events demonstrated variable onset time within the study period (Fig. 1). 

Fig. 1
figure 1

Longitudinal assessment of acne events among individual patients randomized to receive upadacitinib at baseline in the Rising Up study. a Data presented for adolescent and adult patients who received upadacitinib 15 mg or b upadacitinib 30 mg during the placebo-controlled period and blinded extension period. Patients who experienced acne events beyond day 365 are not shown. b The discontinuation was unrelated to acne (due to peripheral edema). 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 (1 acne event) and red (2 acne events)

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Most patients who experienced acne events had their acne clinically managed with topical medications (82.6% and 77.3% of patients in the upadacitinib 15 mg and 30 mg groups, respectively), such as anti-infectives (Table 5). Approximately 21% of the patients with acne events were treated with oral medications (e.g., macrolides, tetracyclines) in both upadacitinib treatment groups. No medical treatment was given to manage the acne events in 13.0% of patients receiving upadacitinib 15 mg and 15.9% of patients receiving upadacitinib 30 mg. Of the 80 acne events that began by the week 52 cutoff date, 41.3% (n = 33) had resolved as of the cutoff date.

Table 5 Acne treatments (up to the week 52 cutoff date)
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Among those patients who developed acne while taking upadacitinib, the most common predisposing risk factors (in the upadacitinib 15 mg and upadacitinib 30 mg groups, respectively) were the use of concomitant medications associated with acne (87.0%, 84.1%), family history of acne (30.4%, 27.3%), and a medical history of acne (30.4%, 25.0%). Examples of concomitant medications used by patients who experienced acne and thought to contribute to acne onset included topical corticosteroids, heparinoid cream, white petrolatum, tacrolimus ointment, and adapalene.

Discussion

Upadacitinib therapy was associated with an increased risk of acne in Japanese patients with AD who were enrolled in the Rising Up study. Less than 20.0% of patients treated with upadacitinib 15 mg and about one-third of patients treated with upadacitinib 30 mg reported acne events that occurred at various times with long-term treatment of upadacitinib. The results in this Japanese study were similar to findings in other phase 3 AD clinical trials of upadacitinib [2, 11], which supports a dose-dependent association between upadacitinib and acne development. Importantly, all events of acne in upadacitinib-treated patients were mild or moderate in severity, nonserious, and did not result in discontinuation of upadacitinib treatment.

No clear pattern of time to acne onset was observed. The mean time to onset of the first acne event was over 3 months. In addition, not all acne events started within 1 month of administration (when improvements in skin clearance and pruritus are observed), and many events occurred after 4 months of upadacitinib treatment, which makes it difficult to explain whether these events were directly related to upadacitinib treatment. Most events occurred once and typically lasted for 3–4 months; multiple acne events in individual patients were uncommon. No patient discontinued because of acne and no patient required oral administration of isotretinoin for the treatment of acne. In addition, acne was readily manageable with topical acne treatments such as topical anti-infectives, retinoids, and/or peroxides. Taken together, these findings suggest that acne in upadacitinib-treated patients can be managed per the Japanese acne treatment guidelines for acne vulgaris [15].

Acne prevalence is highest among adolescents and young adults aged 16–20 years and in adult women in the general population [16]. Patients with AD also have a higher prevalence of acne than do individuals observed in the general population [17]. In this study, the incidence of acne observed in adolescent patients is consistent with acne prevalence in the general population and in patients with AD [16, 17]. When compared with patients in trials investigating upadacitinib for rheumatoid arthritis (mean age 55–56 years) [18] or psoriatic arthritis (mean age 53 years) [19], the younger population (mean age 36 years) may partly account for the higher frequency of acne observed in this study. The higher incidence of acne among female patients of all ages treated with upadacitinib 30 mg is consistent with findings that acne is generally more common among female patients with AD compared with male patients [17]; overall, acne severity was similar for male and female patients in this study.

The most common risk factor for developing acne was the use of concomitant medications that have previously been associated with acnegenic potential. Topical corticosteroids, which were required for all patients from baseline through week 16 and optional per investigator discretion after week 16, have been associated with the development of steroid acne [20]. White petrolatum, a common ingredient in topical medications and cosmetics, has moderate comedogenicity that can lead to acne [21]. Tacrolimus cream is also formulated with wax and white petrolatum, which may contribute to acne development [22]. Further research is required to determine the underlying causes of acne in patients treated with both upadacitinib and other concomitant medications with known comedogenic potential.

Acne has also been reported with other systemic (abrocitinib and baricitinib) and topical (delgocitinib) JAK inhibitors approved for the treatment of AD in Japan. Abrocitinib is associated with an acne incidence rate of 2–5% of patients based on an integrated analysis of six studies in predominantly White and Asian patients with AD [23]. Baricitinib is associated with acne incidence rates of 5–15% in Japanese patients with AD who received up to 105 weeks of treatment [24]. In a 52-week open-label study of topical 0.5% delgocitinib ointment in Japanese patients with AD, acne was reported in 4.8% of patients [25]. Overall, little is known about the mechanism leading to different rates of acne events with upadacitinib compared with other systemic and topical JAK inhibitors in patients with AD.

The underlying pathogenesis for upadacitinib-associated acne in patients with AD is not currently understood. AD is characterized by secretion of inflammatory cytokines, activation of JAK signaling, and T-cell infiltration [3]. In addition, JAK1 and JAK3 mRNA levels are increased in inflammatory acne lesions, but not in non-lesional skin [26]. JAK inhibition is thought to reduce JAK activation and inflammation in patients with AD resulting in lower risk of acne development, which is not observed in the upadacitinib AD studies. Further research into the mechanism underlying acne development in JAK inhibitor-treated patients is warranted.

A limitation of this study is the small patient sample size, especially for adolescents, which makes it difficult to predict patients who may be at a higher risk of developing acne with upadacitinib treatment. The results for Japanese patients may not be generalizable to other global populations. Finally, this study did not include a head-to-head comparison with other JAK inhibitors for AD treatments.

Conclusion

Overall, although acne is one of the most common treatment-emergent adverse events seen with upadacitinib treatment in adolescents and adults with moderate-to-severe AD, the events are readily manageable with standard acne treatment. Physicians and patients should be aware that acne may occur with upadacitinib treatment; however, most physicians considering upadacitinib for the treatment of AD are likely to have experience with acne management, so no precautionary measures are necessary. The mechanism behind JAK inhibitor-associated acne requires further research.