FormalPara Key Summary Points

Why carry out this study?

Little is known about possible differences in treatment efficacy between adults with adult-onset or childhood-onset atopic dermatitis (AD).

Dupilumab, a fully human monoclonal antibody, inhibits the signaling of both interleukin (IL)-4 and IL-13, which are key drivers of type 2-mediated inflammation, a molecular signature common to AD across age groups and clinical phenotypes.

We hypothesize that dupilumab treatment responses in adults with moderate-to-severe AD would be similar, regardless of age of AD-onset.

What has been learned from this study?

Our findings show that dupilumab is efficacious in adults with moderate-to-severe AD regardless of age of AD-onset; despite possible endophenotypic differences linked to age of onset and differences in AD duration at baseline, dupilumab showed similar improvements in AD signs, symptoms, and quality of life (QoL) in adults during 16 weeks of treatment.

These findings support targeting of both IL-4 and IL-13 as an effective treatment strategy for AD across all ages of onset.

Digital Features

This article is published with digital features, including an infographic, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.20750128.

Introduction

Atopic dermatitis (AD) frequently develops during childhood and, in a proportion of patients, may remit by adolescence. There is mounting evidence that adult-onset AD occurs more commonly than previously thought [1,2,3,4,5]. Adult-onset AD is estimated to account for approximately one-quarter of AD cases among adult patients, and studies have shown that it has distinct clinical characteristics, including localized hand, head, and neck lesions [4, 6,7,8,9,10]. Laboratory characteristics also differ in adult-onset AD, with lower immunoglobulin E (IgE) responses. Furthermore, genetic analysis revealed a reduced prevalence of filaggrin loss-of-function mutations in this group [6, 11]. Adult-onset patients are less likely to report a family history of atopic conditions, show less predilection for flexural sites, and possibly have a greater frequency of associated morphologic variants [12, 13].

Dupilumab, a fully human monoclonal antibody, inhibits the signaling of both interleukin (IL)-4 and IL-13, which are key drivers of type 2-mediated inflammation [14, 15]. Although evidence is mounting of different endotypes of AD based on age, ethnicity, and race, type 2 predominant inflammatory skewing is a molecular signature common to AD across multiple age groups and clinical phenotypes [9, 16, 17]. We therefore hypothesize that dupilumab treatment responses in adults with moderate-to-severe AD would be similar regardless of age of AD onset. We evaluated dupilumab treatment efficacy by age of AD onset in adults with moderate-to-severe AD, using pooled data from the LIBERTY AD SOLO 1 and 2 studies [18].

Methods

This study was a post hoc analysis of patient characteristics and treatment efficacy from two phase 3 randomized, placebo-controlled trials of dupilumab in adults with AD (LIBERTY AD SOLO 1 [18], NCT02277743; and LIBERTY AD SOLO 2 [18], NCT02277769). Detailed methods of the studies, including full inclusion and exclusion criteria, were previously reported [18]. Briefly, patients from both studies were aged 18 years and older, with moderate-to-severe AD (Investigator’s Global Assessment [IGA] score 3 or 4) inadequately controlled by topical corticosteroids (TCS). In addition, the diagnosis had to meet American Academy of Dermatology Consensus Criteria for chronic AD, and patients were required to have had the diagnosis for at least 3 years before the screening visit and had other differential diagnoses ruled out [18]. Patients received dupilumab 300 mg or placebo once weekly (qw) or once every 2 weeks (q2w) for 16 weeks. Only patients from the approved 300 mg q2w treatment and control (placebo) groups were included in this analysis to be consistent with the approved posology in this age group [19, 20].

The studies were approved by their respective institutional review boards and conducted per the ethical principles outlined in the Declaration of Helsinki, the International Council on Harmonisation Good Clinical Practice guideline, and applicable regulatory requirements. All patients provided written informed consent before participating in the trials.

Assessments

This analysis includes results using the following disease severity metrics: IGA (0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, 4 = severe), Eczema Area and Severity Index (EASI; range 0–72), weekly peak pruritus Numerical Rating Scale (NRS; range 0–10), and Dermatology Life Quality Index (DLQI; range 0–30). For each of these metrics, higher scores represent a greater AD burden. EASI scores were also analyzed by body region: head/neck, upper extremities, lower extremities, and trunk. Treatment efficacy endpoints included EASI-50, -75, and -90, which represent the proportion of patients achieving a decrease in EASI from baseline of 50%, 75%, or 90%, respectively. The proportion of patients who achieved IGA scores of 0 or 1 were also analyzed.

Statistical Analysis

The study population was the full analysis set (FAS), including all randomized patients from the two studies. Patients were analyzed by subgroups based on patient-reported age of AD-onset as follows: 0–4 years, 5–9 years, 10–19 years, and 20 years or older. Confidence intervals (CI) and p values were based on treatment difference (dupilumab group versus placebo) of the LS (least squares) mean or LS mean percent change using an Analysis of Variance (ANOVA) model with baseline measurements as covariate and the treatment group, randomization strata, region, disease severity (IGA 3 versus IGA 4), and study identifier as fixed factors. Multiple imputation methods were used including censoring after rescue treatment for analysis of EASI scores by body region; EASI-50, -75, and -90; and achievement of IGA 0 or 1. No adjustments were made for multiple comparisons.

Results

Patient Demographics and Medical History

In total, 460 patients in the placebo group and 457 in the dupilumab 300 mg q2w group were included in this analysis. The mean age of patients at baseline was 38 years, with a mean duration of AD of approximately 28 years (Table 1). Age of AD onset (self-reported) showed a peak in early childhood, with 53.2% of patients developing AD at 0–4 years (Fig. 1, Table 1), while 18.5% of patients reported developing AD as an adult (20 years or above). For the patients included in this analysis, age of AD onset was relatively well balanced between treatment groups. Baseline demographics and disease characteristics were also relatively balanced between treatment arms and age groups, except for Patient-Oriented Eczema Measure (POEM) and DLQI, which were reported to be more severe with an earlier age of onset (Table 2).

Table 1 Overview of AD age of onset and duration
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Fig. 1
figure 1

Age of AD onset in study patients. Left: incidence; Right: cumulative incidence. AD atopic dermatitis, q2w every 2 weeks

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Table 2 Baseline characteristics by age of AD onset
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In general, a family history of atopic and allergic conditions was reported by fewer patients in the onset age of 20 years or older group, with allergic rhinitis being reported in 24–30% of the 0–4 years group compared with 10–17% of the 20 years or older group (Table 3).

Table 3 Medical history by age of AD onset
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Patient history of atopic and allergic conditions was more frequent in patients with an earlier age of AD onset, with asthma reported in 47–54% of those with onset at 0–4 years versus 23–31% in the 20 years or older age-of-onset group (Table 3). Similar trends were seen for allergic rhinitis, food allergies, atopic keratoconjunctivitis, and allergic conjunctivitis (Table 3).

Physician Assessed Efficacy Outcomes at 16 Weeks

EASI-75 was achieved in significantly more patients treated with dupilumab (LS mean range 38–54%) versus placebo (LS mean range 10–19%, p < 0.0001), irrespective of age of AD onset (Fig. 2). Dupilumab treatment also resulted in a significantly greater proportion of patients achieving EASI-50 and EASI-90 in all age-of-onset subgroups versus placebo. IGA 0 or 1 was achieved in 25–42% of patients across the dupilumab age-of-onset subgroups versus 7–14% in the placebo groups; p < 0.05 for all comparisons (Fig. 2).

Fig. 2
figure 2

Proportion of patients achieving EASI-50, -75, or -90 or IGA 0 or 1 at 16 weeks, age of AD onset. *p < 0.0001, **p < 0.05 for dupilumab versus placebo. AD atopic dermatitis, EASI Eczema Area and Severity Index, IGA Investigator’s Global Assessment Score, q2w every 2 weeks

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Lastly, EASI improvements were significantly higher in dupilumab-treated patients across all four anatomic regions, regardless of age of AD onset (Fig. 3).

Fig. 3
figure 3

LS mean EASI scores per body regions at baseline and 16 weeks by age of AD onset. AD atopic dermatitis, EASI Eczema Area and Severity Index, LS least squares, q2w every 2 weeks

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Patient-Reported Efficacy Measures

Weekly average peak pruritus NRS (baseline LS mean range across subgroups 7.1–7.6) decreased significantly by weeks 1–3, with further improvement through 16 weeks of dupilumab 300 mg q2w (LS mean range 3.9–4.0) versus placebo (LS mean range 5.3–6.0), regardless of age of AD onset (Fig. 4). Quality of Life (QoL), as measured by DLQI (baseline LS mean range across subgroups 13.5–15.6), showed a similar, consistent pattern of significant improvement irrespective of age of AD onset, with dupilumab subgroups achieving a DLQI score of 5.6–5.9 (corresponding to a small effect on QoL) versus 9.6–11.4 (a moderate or large effect on QoL) by week 16 with the placebo subgroups (Fig. 5).

Fig. 4
figure 4

Weekly average peak pruritus NRS over time, by age of AD onset. *p < 0.0001 for dupilumab versus placebo. AD atopic dermatitis, LS least squares, NRS Numerical Rating Scale, PP peak pruritus, q2w every 2 weeks

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Fig. 5
figure 5

DLQI LS mean over time, by age of AD onset. *p < 0.0001 for dupilumab versus placebo. AD atopic dermatitis, DLQI Dermatology Life Quality Index, LS least squares, q2w every 2 weeks

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Safety

The number of patients with treatment-emergent adverse events were generally balanced across treatment arms for each age-of-onset subgroup. Treatment emergent severe adverse events were either balanced or more commonly reported in the placebo group across all age-of-onset subgroups. The most commonly reported treatment-emergent adverse events (≥ 5% in any group) were consistent across age-of-onset subgroups. Adverse events leading to treatment discontinuation were rare and similar for all age-of-onset subgroups (< 2%).

Discussion

In this post hoc analysis of 917 adults with AD, dupilumab treatment resulted in significant improvements in the extent and severity of lesions, patient assessed symptoms, and QoL, irrespective of the (self-reported) age of AD onset. Proportions achieving physician assessed EASI-50, -75, and -90 increased similarly and significantly in all age-of-onset groups with dupilumab versus placebo, as did the proportion of patients attaining an IGA score of 0 or 1. Peak pruritus NRS decreased significantly with dupilumab as early as weeks 1–3 in all age-of-onset groups, with DLQI improving significantly within the first month of treatment.

Of note, in the earliest age-of-onset group (under 5 years), with correspondingly the longest mean disease duration, dupilumab-treated patients had differentiating improvements versus placebo in both pruritus NRS and DLQI at week 1. Interestingly, a recent real-world study of adolescents with moderate-to-severe AD treated with dupilumab found that early age of onset (≤ 1 year of age) may positively influence the effectiveness of dupilumab in terms of EASI-75, EASI-90, and EASI-100 [21].

The lower rate of personal and family history of allergic and atopic comorbidities observed in the older age of AD-onset group (20 years or older) is consistent with other reports in patients with adult-onset AD [4, 6,7,8,9, 11, 16, 22].

The clinical presentation of AD is complex and variable in morphology, distribution, course, and prominence and/or pattern of symptoms, with mechanistic studies revealing a diverse underlying pattern of immune disturbance and skin-barrier defects [23, 24]. Recent studies reported distinct clinical presentation in early- versus late-onset AD, based on age groupings of infant (under 6 years), child (6–11 years), adolescent (12–17 years), adult (18 years and over), and late onset (over 60 years) [4, 6,7,8,9, 11, 16, 22]. These differences include an association found between family history and other coexisting allergies and atopic disorders in patients with early-onset AD, and higher nonflexural presentation and focal hot-spots of disease on the hands, head, and neck in patients with late-onset AD [4, 7, 8, 11, 22]. In a retrospective case review study of 214 adults with AD, conducted by Ha et al. [8], an association was found between allergic asthma and rhinitis, family history of atopic disease, elevated total serum IgE, and food allergies and early-onset AD (prior to 12 years). In the same study, the late-onset group (12 years and over) was significantly associated with nonflexural involvement, with pre-/post-age 12 being another arbitrary designation of early- or late-onset AD. A further study of 356 adults revealed an association between adult-onset AD and lesions occurring predominately on the hand, neck, and face [4]. The present study did not show differences in improvement of AD by anatomic region in the different age-of-onset subgroups, as measured by EASI score per body region (head, lower extremities, trunk, upper extremities). However, the pattern of lesions in specific body areas such as hands, genitals, and flexures was not captured and could not be analyzed. The prevalence of family history of atopic conditions was found to be lower in the older age-of-onset group (20 years or older) in comparison with the younger groups. This is in agreement with findings reported in prior studies [12, 13].

Pathobiologic differences in age of AD-onset subgroups were reported, such as loss-of-function filaggrin mutations, which were strongly correlated with AD onset in infancy [13]. With regards to the immune responses detected in AD patients, several studies reported differences in IgE response or serum levels, T cell subsets, and IL-9 and IL-17 changes across age-of-onset groups [6, 24, 25]. This differing pathobiology may underscore the need for utilization of different treatments depending on characteristics of AD in each patient. However, a study analyzing AD skin biopsies from patients in different age groups (n = 54) compared with the skin of same-age controls revealed a common genomic fingerprint in all age groups of patients with AD, suggesting that type-2 mediated inflammation is present across all age-of-onset subgroups [16]. This signature included Th2 and Th22 skewing and Th2-related markers including IL-13, CCL17/TARC (thymus and activation-regulated chemokine), CCL18/PARC (pulmonary and activation-regulated chemokine), and IL-4R [16].

Previous analyses of clinical studies also showed that dupilumab significantly improved clinical signs, symptoms, and QoL across patients with AD in different life stages, for adults and adolescents with moderate-to-severe AD and for children with severe AD, with an acceptable safety profile [26,27,28,29]. These findings are supported by real-world experiences with dupilumab in children, adolescents, adults, and elderly with AD [21, 30,31,32]. The similar efficacy of dupilumab, which inhibits key drivers of type 2-mediated inflammation, in the different age-of-onset subgroups analyzed in this study confirms the high clinical relevance of dysregulated type 2 inflammation in AD among different age-of-onset groups [14, 15].

Limitations

A potential limitation of this analysis is that the sample sizes of the age-of-onset subgroups are small, and the age of AD onset is self reported, which could lead to incorrect categorization of age of onset.

Conclusion

Dupilumab is efficacious in adults with moderate-to-severe AD regardless of age of onset. Despite possible endophenotypic differences linked to age of onset and differences in AD duration at baseline, dupilumab showed similar improvements in AD signs, symptoms, and QoL in adults during 16 weeks of treatment. These findings support targeting of both IL-4 and IL-13 as an effective treatment strategy for AD across all ages of onset.