Efficacy and Safety of Upadacitinib versus Dupilumab Treatment for Moderate-to-Severe Atopic Dermatitis in Four Body Regions: Analysis from the Heads Up Study

Atopic dermatitis (AD), or atopic eczema, is a common inflammatory skin condition characterized by eczematous lesions, redness (erythema), and intense itch (pruritus). While AD often presents in childhood and can persist into adulthood, it can occur at all ages and substantially impacts quality of life [1, 2]. AD is a heterogeneous condition, with multiple factors contributing to variations in lesional morphology, topography, and severity of signs and symptoms for different anatomical areas [3, 4]. These can be exacerbated by environmental stressors, leading to increased redness and itch on exposed areas, such as the head, neck, hands, and feet, with reports of increased facial redness in adulthood [5]. When inadequately controlled, AD symptoms on body regions that are highly visible and difficult to cover, such as the hands, neck, and face, can have a profound impact on quality of life [6, 7] as patients are more likely to encounter social stigma leading to significant increases in anxiety and depression scores [8‒10]. Patients attribute greater weight to the importance of complete or almost complete skin clearance for exposed body regions, such as the head and neck, as well as the hands and feet [6, 7].

Dupilumab is an inhibitor of the interleukin (IL)-4 and IL-13 receptor signaling pathways and is currently approved for the treatment of moderate-to-severe AD; however, previous studies indicate that fewer than 50% of patients treated with dupilumab achieved clear or almost clear skin after 16 weeks of monotherapy (36–38% compared with 8–10% treated with placebo) [9]. Notably, some observations of paradoxical increases in facial or neck redness with dupilumab have been reported, termed dupilumab-associated facial or neck erythema, which may lead to treatment cessation [11, 12].

Many of the proinflammatory cytokines involved in the pathophysiology of AD, including IL-4, IL-13, IL-22, IL-31, thymic stromal lymphopoietin (TSLP), and interferon γ, utilize the Janus kinase 1 (JAK1) pathway to mediate their effects on T-helper 2 cell (Th2)-mediated inflammation, skin barrier dysfunction, epidermal thickening, and itch [13, 14]. Upadacitinib is an oral, once-daily selective JAK inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 and is approved in the USA, EU, and other countries for the treatment of AD and other immune-mediated inflammatory conditions in rheumatology and gastroenterology [15]. In the phase 3b Heads Up study, 71.0% of patients receiving oral upadacitinib 30 mg once daily compared with 61.1% of patients receiving subcutaneous dupilumab 300 mg every other week achieved the primary endpoint of 75% improvement in skin clearance measured by the Eczema Area and Severity Index (EASI 75) at week 16. Additionally, at this time point, a significantly greater proportion of patients treated with upadacitinib (60.6% vs. 38.7% treated with dupilumab) achieved EASI 90 and EASI 100 (27.9% treated with upadacitinib vs. 7.6% treated with dupilumab) [16].

Given the wide variety of topographic presentations of AD, and the impact of inadequately controlled AD on quality of life, there is a need for safe and effective treatment options with long-term sustained results and robust efficacy across body regions. Here, we assess skin clearance in patients with AD in four anatomical regions (head and neck, trunk, upper limbs, and lower limbs) over 24 weeks from the Heads Up study, by comparing the efficacy and speed of response of once-daily upadacitinib 30 mg versus dupilumab 300 mg every other week, as measured by the EASI.

Full methodological details for the Heads Up study (NCT03738397) including study dates and size, inclusion/exclusion criteria, randomization and blinding, and details about the endpoints assessed have been published previously [16] and are provided in brief below.

Heads Up was a phase 3b head-to-head, multicenter, randomized, double-blind, double-dummy, active-controlled study in adults with moderate-to-severe AD. At baseline, patients were randomized 1:1 to receive an oral upadacitinib 30 mg extended-release tablet once daily or subcutaneous injection of dupilumab 300 mg every 2 weeks after a loading dose of 600 mg.

Independent Ethics Committees or Institutional Review Boards approved the study protocol, informed consent form(s), and recruitment materials before patient enrollment. The study was conducted in accordance with the International Conference for Harmonisation guidelines, applicable regulations, and the Declaration of Helsinki. Patients provided written informed consent before screening.

As a result of the coronavirus disease 2019 (COVID-19) pandemic, operational accommodations for clinical trial continuity were incorporated for temporary site disruptions and secure-in-place measures, including remote visits, local laboratory collections, and courier delivery of study drug to the patient, where allowed and in accordance with local regulations. Remote efficacy assessments of the skin were not allowed, and in-person visits were required at baseline and week 24.

Efficacy was assessed as upadacitinib superiority over dupilumab, based on the mean percent change in EASI and the achievement of 100% (EASI 100), ≥90% (EASI 90), and ≥75% (EASI 75) skin clearance of AD measured using the EASI in four body regions: (1) head and neck, (2) trunk (including genitals), (3) upper limbs, and (4) lower limbs (including buttocks) at each study visit through week 24. The EASI is a validated scoring system that grades the extent and severity of the physical signs of AD [17].

Measurements of erythema for each body region were compared to baseline at each study visit through week 24. Efficacy was also assessed using the Head and Neck Patient Global Impression of Severity (HN-PGIS) scale, which was developed specifically for this trial and asks patients to assess the severity of their AD symptoms on the head and neck on a 7-point scale ranging from “absent (0),” “minimal (1),” “mild (2),” “moderate (3),” “moderately severe (4),” “severe (5),” to “very severe (6).” The proportion of patients reporting “absent” or “minimal” on the HN-PGIS scale was compared at each study visit through week 24.

Safety was assessed as treatment-emergent adverse events (TEAEs) in all patients who received ≥1 dose of study drug. A TEAE was defined as any AE that began or worsened in severity after initiation of upadacitinib or dupilumab (30 days following the last dose of upadacitinib or 84 days following the last dose of dupilumab). All AEs presented were treatment emergent, unless otherwise noted, and have been previously published [16].

Categorical variables were analyzed using the Cochran-Mantel-Haenszel (CMH) test, stratified by vIGA-AD categories (vIGA-AD 3 or 4). Continuous variables were analyzed using a mixed-effect model with repeated measures. For categorical endpoints, the primary approach for handling the intercurrent events or missing data was nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C). NRI-C categorized any patient who did not have an evaluation during a pre-specified visit window as a nonresponder for that visit. The only exceptions were (1) when the patient was a responder both before and after the visit window, the patient was categorized as a responder for the visit and (2) missing due to COVID-19 infection or logistical restriction was handled by multiple imputation. Patients were counted as nonresponders after the start of rescue medication. For the continuous endpoints, mixed-effect model with repeated measures was used for handling the intercurrent events or missing data. As these additional, pre-specified endpoints were not multiplicity controlled, all p values are nominal.

A total of 924 patients were screened, 251 were excluded, and 673 were enrolled and treated in Heads Up (342 received upadacitinib 30 mg and 331 received dupilumab 300 mg); demographics, baseline disease characteristics, efficacy, and safety for this pivotal trial have been previously published [16].

Patients receiving upadacitinib (UPA) versus dupilumab (DUPI) had greater reductions (p ≤ 0.001) in EASI scores for all body regions beginning as early as week 1. These reductions continued for all regions through week 12, through week 16 for the upper limbs, and through week 20 for the lower limbs (Fig. 1). Reductions in head and neck redness were greater for upadacitinib versus dupilumab beginning as early as week 1 and continuing for all visits through week 20, with no statistically significant difference at week 24 (Fig. 2a). Patient reports of absent or minimal AD symptoms specific to the head and neck (HN-PGIS) continued to show greater improvement with upadacitinib at all visits from week 1 to week 24 (Fig. 2b). The percent change from baseline for all components of the EASI (redness, papulation/edema, excoriation, and lichenification) for all four body regions (head and neck, trunk, upper limbs, and lower limbs) was greater (p ≤ 0.05) for upadacitinib versus dupilumab beginning at week 1, continuing through week 8 or longer. Percent change in each EASI component for each body region through week 24 can be found in online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000542275).

Greater proportions of patients treated with upadacitinib versus dupilumab achieved clear (EASI 100) or almost clear (EASI 90) skin as early as week 1 for the head and neck, trunk, and upper limbs and week 2 for the lower limbs, which continued for all body regions through week 24. Greater proportions of patients receiving upadacitinib compared with dupilumab achieved EASI 75 as early as week 1 continuing through week 16 or longer for all body regions (p ≤ 0.05) (Fig. 3).

In the Heads Up study, the 24-week incidence rates of TEAEs were 79.2% in patients treated with upadacitinib and 69.2% in dupilumab-treated patients. The rates of serious TEAEs and AEs leading to drug discontinuation were 3.7% and 3.2% for upadacitinib and 2.0% and 1.2% for dupilumab, respectively. Specifics regarding adverse events in the Heads Up study have been previously published [16].

In this post hoc analysis of the Heads Up study, greater proportions of participants achieved higher response thresholds (EASI 90/100) with upadacitinib versus dupilumab across all body regions as early as week 1 and at all subsequent study visits. Improvements in EASI score from baseline were more rapid in patients taking upadacitinib versus dupilumab, with a 40.5–46.7% reduction in EASI score for all body regions as early as week 1 compared to rates of 18.2–25.4% improvement for patients taking dupilumab, with differences persisting through 12–20 weeks depending on the region (Fig. 1). Though upadacitinib provided greater reductions in EASI scores faster than dupilumab, improvements from baseline EASI scores were similar for both upadacitinib and dupilumab from week 16 on for the head and neck and trunk, from week 20 on for the upper limbs, and at week 24 for the lower limbs, as shown in Figure 1.

Greater proportions of patients receiving upadacitinib achieved EASI 75 earlier than patients taking dupilumab as early as week 1, which were sustained through week 16 for the trunk and upper limbs, and through week 20 for both the head and neck and lower limb regions. There were no statistically significant differences between treatments in the proportion of patients achieving EASI 75 at the week 24 visit (Fig. 3). For EASI 75, EASI 90, and EASI 100, differences at week 24 were not observed for each body region, though the week 4 response rates observed with upadacitinib were numerically greater than the response rates observed with dupilumab over the next 20 weeks through week 24. A 20-week period of improved AD symptoms across multiple body regions, including multiple weeks spent at EASI 90 or EASI 100, would provide a notable improvement in quality of life for patients who spent up to 5 months with little to no symptoms.

The proportion of patients achieving clear skin (EASI 100) was higher with upadacitinib versus dupilumab as early as week 1 for the head and neck, which persisted through week 20. The high response level achieved for the head and neck EASI scores translates to meaningful impact to patients as corroborated by the HN-PGIS. Given the high visibility of the head and neck region, and difficulty covering these areas, greater reductions in redness with upadacitinib versus dupilumab as early as week 1 suggest that patients taking upadacitinib can have impactful improvements in AD symptoms shortly after treatment with upadacitinib is initiated, which may positively impact quality of life and daily activities. While specific quality of life and daily activity endpoints were not captured in this study, a greater proportion of patients reported absent or minimal head or neck AD symptoms with upadacitinib as early as week 1, which persisted through week 24. Greater reductions in redness of the head and neck region with upadacitinib are notable given the paradoxical head and neck erythema reported with use of dupilumab, which differs from erythema accompanied by itch that is characteristic of AD [11]. Some studies have considered involvement of fungal colonization, rosacea, allergic contact dermatitis, alcohol-induced facial flushing, and drug-induced photosensitivity reaction in the pathophysiology of this paradoxical head and neck erythema, but results were not conclusive and further research on pathophysiology is needed [9, 11].

With the emergence of new therapies for AD, deeper responses with stringent skin clearance measures such as EASI 90 and EASI 100 are achievable and are clinically meaningful as they have been shown to be associated with greater improvements across multiple domains impacted by AD, including sleep, anxiety, depression, and other aspects of quality of life, demonstrating the importance of these levels of clearance [18‒21]. The heterogeneity in symptom presentation for different topographic regions in AD [3, 4] underscores the unmet need for better region-specific clearance, and findings in the current analysis suggest upadacitinib provides faster and more extensive skin clearance in all body regions compared to dupilumab. In addition to skin clearance on regions that are difficult to cover on the head and neck and upper limbs, rapid clearance of symptoms in areas of the trunk, including the genitals, and the lower limbs may similarly provide a positive impact on quality of life [6, 7], especially if accompanied by the reduction of itch, which can disrupt sleep and lead to increased symptoms of anxiety and depression [8‒10]. Further investigation of itch reduction in specific body regions is needed to elucidate this latter point.

This study has some limitations. This is a post hoc analysis of data from the Heads Up study, which had no comparison against placebo alone. Although not necessarily a limitation, the study evaluated both upadacitinib and dupilumab as monotherapy treatments, and in real-world practice, many patients use systemic treatments in combination with topical agents; separate phase 3 studies of upadacitinib [22] and dupilumab [20] combined with topical corticosteroids compared with placebo combined with topical corticosteroids in moderate-to-severe AD has previously been reported. Differences in skin color can impact clinical evaluation of AD, particularly with respect to the use of EASI components across diverse skin types. A photographic review of patients from the Heads Up study has been published to illustrate the importance of inclusion of diverse skin types in future clinical trials [23]. Analysis based on race, ethnicity, and other sociodemographic factors was not possible in the current study due to limited sample sizes.

Upadacitinib provided greater proportions of patients with moderate-to-severe AD with clear or almost clear skin across four body regions, including the head and neck, trunk, upper limbs, and lower limbs, with increased rapidity compared to dupilumab.

AbbVie and the authors thank all study investigators for their contributions and the patients who participated in this study. Medical writing support was provided by Elin M. Grissom, PhD, of AbbVie. Editorial support was provided by Angela Hadsell of AbbVie.

All authors were involved in the interpretation of the data, preparation, and critical review of the manuscript and approved the final version of the manuscript. Approvals were obtained from local Ethics Committees, and patients provided written informed consent to participate in the study. Since this study relied on aggregated data from clinical trials, additional ethical approval and patient consent for publication of the manuscript were not necessary.

Financial arrangements of the authors with companies whose products may be related to the present manuscript are listed, as declared by the authors. J. Thyssen has attended advisory boards for Sanofi-Genzyme, Union Therapeutics, and Eli Lilly and Co.; received speaker honoraria from LEO Pharma and Sanofi-Genzyme; and been an investigation for Sanofi-Genzyme, Eli Lilly and Co., LEO Pharma, and AbbVie. D. Rosmarin reports honoraria as a consultant for AbbVie, Boehringer-Ingelheim, Bristol Meyers Squibb, Celgene, Concert, Dermavant, Dermira, Incyte, Janssen, Kyowa Kirin, Lilly, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharmaceuticals, UCB, and VielaBio and research support from AbbVie, Amgen, Bristol Meyers Squibb, Celgene, Dermira, Galderma, Incyte, Janssen, Lilly Merck, Novartis, Pfizer, and Regeneron Pharmaceuticals Inc. and is a paid speaker for AbbVie, Amgen, Celgene, Janssen, Lilly, Novartis, Pfizer, Regeneron, and Sanofi. A. Costanzo has been a consultant and/or speaker for AbbVie, Almirall, Amgen, Boehringer Ingelheim, Janssen, Leo Pharma, Eli Lilly, Novartis, Pfizer, Sandoz, and UCB. R. Warren received grants from AbbVie, Almirall, Amgen, Celgene, Janssen, Lilly, LEO Pharma, Medac, Novartis, Pfizer, and UCB and consulting fees from AbbVie, Almirall, Amgen, Arena, Astellas, Avillion, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, DiCE, GlaxoSmithKline, Janssen, Lilly, LEO Pharma, Medac, Novartis, Pfizer, Sanofi, Sun Pharmaceuticals, UCB, and UNION and is supported by the Manchester NIHR Biomedical Research Centre. C.Y. Chu reports receiving personal fees from AbbVie (investigator, speaker fee, and consultant fee) during the conduct of the study; serving as an investigator for AbbVie, Amgen, Dermira, Lilly, Novartis, Oneness Biotech, Pfizer, Regeneron, Roche, Sanofi, and United BioPharma; receiving personal fees from AbbVie, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Leo Pharma, Lilly, Mylan, Novartis, Pfizer, Roche, Sanofi, United BioPharma, and Viatris; and receiving grants from Novartis, Regeneron, and Sanofi outside the submitted work. R. Chovatiya has served as an advisory board member, consultant, and/or investigator for AbbVie, Arcutis, Arena, argenx, Beiersdorf, Bristol Myers Squibb, Dermavant, Eli Lilly and Company, EPI Health, Incyte, L’Oréal, National Eczema Association, Pfizer Inc., Regeneron, Sanofi, and UCB and a speaker for AbbVie, Dermavant, Eli Lilly and Company, Incyte, LEO Pharma, Pfizer Inc., Regeneron, Sanofi, and UCB. B. Ladizinski, X. Hu, Y. Liu, B. Calimlim, C. Nduaka, and N. Vigna are full-time employees of AbbVie Inc. and may hold AbbVie stock and/or stock options. A. Armstrong has served as a research investigator and/or scientific advisor to AbbVie, BMS, Incyte, Leo, UCB, Janssen, Lilly, Novartis, Ortho Dermatologics, Sun, Dermavant, Dermira, Sanofi, Regeneron, Pfizer, and ModMed.

AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. Research was also supported by the NIHR Manchester Biomedical Research Centre (NIHR203308).

J.P.T, D.R., A.C., R.B.W., C.Y.C., R.C., B.L., X.H., Y.L., B.M.C., C.N., N.V., and A.A. participated in the interpretation of the data, preparation, and critical review of the manuscript and approved the final version of the manuscript.

Trial registration number: NCT03738397.

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