FormalPara Key Summary Points

Why carry out this study?

In the RELIEVE-AD study, adult patients with moderate-to-severe atopic dermatitis reported that effectiveness of dupilumab was maintained during 1 year of follow-up.

Since longer-term data can inform the durability of this response from the perspective of patients in clinical practice settings, patients in the RELIEVE-AD study were recontacted 30–36 months after dupilumab initiation to determine if the treatment effects were maintained from the patient perspective.

What was learned from the study?

In this prospective, longitudinal, real-world study, patients reported maintenance of disease control and treatment satisfaction after 30–36 months of treatment, with a magnitude of improvement from baseline that was better than or comparable to the 12-month evaluation in all outcomes, including symptoms, flares, sleep problems, health-related quality of life, work/activity impairment, disease control, and treatment satisfaction.

Survey respondents reported long-term effectiveness of dupilumab for treatment of moderate-to-severe atopic dermatitis, with benefits observed after 12 months of therapy that were maintained up to 36 months.

Digital Features

This article is published with digital features, including a video abstract, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.23790879.

Introduction

Moderate-to-severe atopic dermatitis (AD) is associated with substantial clinical morbidity, and patients report a negative impact on function, health-related quality of life (HRQoL), and work productivity [1,2,3]. While topical and conventional systemic therapies are typically used for first-line treatment, these strategies still result in high rates of uncontrolled disease [4, 5].

Dupilumab, a fully human monoclonal antibody, is approved in the US for the treatment of adult and pediatric patients aged 6 months and older with moderate-to-severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable [6]. Since AD is a chronic condition, it is important to determine whether long-term treatment results in sustained benefits, especially from the patient’s perspective. While an open-label extension of a clinical trial showed that the efficacy and safety of dupilumab were maintained for up to 4 years [7], few prospective real-world studies have comprehensively evaluated the long-term patient experience with dupilumab [8], with these studies having either a small sample size or a 1- to 2-year follow-up.

RELIEVE-AD (EaRly REal WorLd PatIent EValuation for DupixEnt in Atopic Dermatitis) was a prospective observational study that used patient-reported outcomes (PROs) to evaluate the effectiveness of dupilumab over a 1-year period in adults with moderate-to-severe AD in clinical practice settings [9]. Patients in RELIEVE-AD achieved rapid and sustained improvements in disease control, HRQoL, and daily activities (including work productivity) through 1 year of treatment and reported reductions in flares, itch, non-itch skin symptoms, and sleep problems; use of other AD therapies was reduced while patient satisfaction with treatment improved. RELIEVE-AD Recontact is a long-term follow-up of the original participants to further evaluate the effectiveness of treatment over an extended timeframe. Patients in RELIEVE-AD were recontacted 30–36 months after initiating dupilumab, and here we report the results of the approximate 3-year follow-up.

Methods

Ethics

The RELIEVE-AD study received institutional review board approval. Patients provided informed consent, and data were anonymized in compliance with the Health Insurance Portability and Accountability Act (HIPAA).

Study Design and Patient Population

Adults with moderate-to-severe AD who were prescribed dupilumab were enrolled in the US dupilumab manufacturer patient support program and consented to participate in questionnaires via an online portal before (baseline) and at prespecified timepoints after dupilumab initiation. Details of the study design and the complete methods used and results obtained over the first 12-month assessment period have previously been published [9]. All participants were recontacted 30–36 months after initiation of dupilumab treatment and were asked to complete the same questionnaire as during previous assessments, regardless of current dupilumab use.

Patient-Reported Outcomes

The questionnaire included validated PRO measures of disease control, HRQoL, and work and activity impairment. Disease control was assessed using the Atopic Dermatitis Control Tool (ADCT; total score range 0–24, with higher scores indicating poorer control and adequate disease control validated as a total score  of < 7) [10, 11]. HRQoL was evaluated using the Dermatology Life Quality Index (DLQI), which has a total score range of 0–30, with higher scores indicating a more adverse impact on HRQoL and threshold bands for defining the magnitude of the effect on the patient’s life [12, 13]; a change of 4 points or greater in total score is considered clinically meaningful. The effects of AD on self-reported productivity and activity over the past week were assessed among patients who were employed for pay using the Work Productivity and Activity Impairment Questionnaire specific for AD (WPAI:AD) [14]. Other assessments included questions on whether the patient was taking dupilumab as prescribed; use of concomitant therapies for AD in the past 4 weeks; non-itch skin symptoms over the past week (skin pain or soreness, skin feeling hot or burning, skin sensitivity to touch) using numerical rating scales (NRS) of 0–10 (10 = worst score); effects on sleep that included the sleep item from the ADCT and a stand-alone question on sleep problems over the past week (“Over the past week, did you experience sleep problems because of your atopic dermatitis”); and flares, as previously defined [9], over the past 4 weeks. The Recontact survey also included a stand-alone question on global change in itch compared with before the initiation of dupilumab (“Please choose the response below that best describes the overall change in your itching now compared to just before you started taking dupilumab”), with responses on a 7-point Likert scale ranging from “very much better” to “very much worse.” Another stand-alone question queried patient satisfaction with their current treatment (“How satisfied are you with your current treatment(s) for atopic dermatitis?”), with responses that ranged from “extremely satisfied” to “extremely dissatisfied.”

Statistical Analysis

All survey responses at 30–36 months were evaluated. As in the original analysis [9], outcomes were compared vs. baseline using generalized estimating equations to account for correlated data from the same patients responding at each follow-up. A sensitivity analysis was conducted using pattern-mixture modeling (PMM) for imputation of missing values for selected outcomes [15], adjusted as previously described for demographic and clinical covariates [9]. All structured outcome data that were collected (including data that may overlap with safety-related concepts) are presented in this analysis. Analyses were conducted using SAS Enterprise Guide version 7.1 (SAS Institute, Cary, NC).

Results

Of the 698 patients who initiated dupilumab and completed the baseline assessment, 425 (60.9%) completed the questionnaire at 30–36 months. This population does not include 1 participant who completed the original RELIEVE-AD study but was misdiagnosed and did not have AD. Demographic and clinical characteristics of the Recontact respondents were similar to those who completed the baseline and month-12 surveys (Table 1). Additionally, the baseline demographic and clinical characteristics of patients who completed the survey at 30–36 months were similar to those for the 273 patients who did not (data not shown).

Table 1 Demographic and clinical characteristics
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A total of 127 patients (18.2%) permanently discontinued dupilumab. Among those who discontinued, the most common reasons were lack of efficacy and adverse effects, in 33 (26%) and 26 (20%) patients, respectively, followed by cost issues and insurance coverage in 23 (18%) and 19 (15%) patients, respectively. Additionally, 25 patients discontinued dupilumab and subsequently restarted treatment at least once. Across all timepoints, > 97% of patients said they were adhering to the prescribed injection schedule.

At long-term recontact, more than half of the patients (231 of 425; 54.4%) reported not using any medication for AD other than dupilumab in the past 4 weeks vs. 12.8% who were not using any other AD therapies at the time of dupilumab initiation (Fig. 1a). The proportion of patients using other AD therapies at 30–36 months was significantly lower than baseline across all medication categories, including any prescription topical agents, topical steroids, systemic steroids, and systemic immunosuppressants (all P < 0.05; Fig. 1b). At baseline, 82.8% of participants reported using over-the-counter emollients, which decreased to 58.8% by month 30–36.

Fig. 1
figure 1

Medications for AD used in the previous 4 weeks other than dupilumab. a Number of concomitant medications. b Class of concomitant medications. AD atopic dermatitis, PMM pattern-mixture model. *P < 0.05 and ***P < 0.001 vs. baseline

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Approximately three-quarters of the Recontact respondents (320 of 425; 75.3%) reported a global change in itch that was “very much better” relative to before dupilumab initiation (Fig. 2a), and 59.1% of respondents had no days of intense episodes of itching over the past week, compared with 3.2% of patients at baseline (P < 0.001; Fig. 2b). Consistent with the 12-month results, 45.9% of patients had no flares over the past 4 weeks, compared with 3.0% of patients at baseline (Table 2).

Fig. 2
figure 2

Itch symptoms. a Global change in itch at the 30–36-month recontact assessment relative to itch before initiation of dupilumab treatment. b Patients with no days of intense episodes of itching over the past week based on item 2 of the Atopic Dermatitis Disease Control Tool. PMM pattern-mixture model. ***P < 0.001 vs. baseline

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Table 2 Patient-reported outcomes of flares, skin symptoms, sleep, quality of life, and work and activity impairment
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Results for all other PROs were similar to or incrementally better than at the 12-month timepoint and showed significant improvements vs. baseline (all P < 0.001; Table 2 and Figs. 2, 3). The NRS scores for the non-itch skin symptoms of skin pain, skin feeling hot/burning, and skin sensitivity (Table 2) represent reductions from baseline of 74.6%, 76.9%, and 78.2%, respectively. Patients also continued to report less sleep disturbance in the previous week, as indicated by the low proportion (13.4% vs. 77.5% at baseline) of patients with sleep problems and the high proportion (81.6% vs. 15.3% at baseline) who had no trouble falling/staying asleep (Table 2).

Fig. 3
figure 3

Disease control and satisfaction with treatment. a Disease control assessed using the patient-reported ADCT. b Satisfaction with current treatment based on a stand-alone question. ADCT Atopic Dermatitis Control Tool, PMM pattern-mixture model. ***P < 0.001 vs. baseline

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On the DLQI, the mean total score ± standard deviation of 3.2 ± 4.8 at the long-term assessment was significantly lower than at baseline (14.4 ± 7.3), and most patients (84.9%) had a change from baseline of ≥ 4 points, which is clinically meaningful (Table 2). More than half the patients (52.5%) also reported DLQI scores of 0–1, which indicated no effect of AD on their life, vs. 1.1% at baseline. These long-term effects on HRQoL were similar to those at 12 months (Table 2). Scores for all subscales of the DLQI (symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment) showed trends that were similar to the total score (i.e., changes from baseline were statistically significant [all P < 0.001] and scores that were at least as good as at 12 months [data not shown]). Additionally, significant reductions from baseline reported by patients for both work and activity impairment on the WPAI:AD at 12 months were further maintained at the long-term assessment (Table 2). Among the 278 patients who were employed for pay at long-term recontact and had worked in the previous week, impairment of work was 8.6% and impairment of daily activities was 9.4%, and these values were lower than the 40.3% and 45.6% impairment, respectively, reported at baseline (both P < 0.001).

Consistent with the improvement in clinical symptoms and other PROs, the mean total ADCT score (Fig. 3a) was indicative of adequately controlled AD and reflected an incremental benefit of 13.6% from month 12 and a 75.9% improvement from baseline; all individual items of the ADCT showed improvements from baseline, ranging from 64% for severity of eczema-related symptoms to 86% for trouble falling or staying asleep (all P < 0.001; data not shown). Adequately controlled AD was reported by 80.7% of patients, similar to month 12 (77.4%) and higher than baseline (5.9%; Fig. 3a). Patients also reported greater satisfaction with treatment than at baseline (Fig. 3b); 75.5% of patients were “extremely” or “very” satisfied with treatment, vs. 2.8% at baseline.

The PMM ranges representing the sensitivity analysis were generally consistent with the primary analysis, albeit the wide ranges for some outcomes were reflective of the higher number of missing values at this extended timepoint (Figs. 1, 2b, 3, and Table 2).

Discussion

This real-world analysis of patients who were recontacted 30–36 months after initiating treatment with dupilumab extends the 1-year results of the RELIEVE-AD study. Among patients with moderate-to-severe AD who completed the survey, patient-reported benefits achieved at 12 months were maintained at 30–36 months. Most of these patients considered their AD to be adequately controlled while also reporting significant reductions in use of concomitant medications for AD. Sensitivity analyses that accounted for missing values confirmed the robustness of the results. These results also expand on previous reports of the real-world effectiveness of dupilumab by providing a substantially longer follow-up and using a broader range of outcomes relevant to the daily life of patients than studies that mainly focused on clinical measures of disease activity and HRQoL [16,17,18,19,20,21].

While itch is the predominant symptom, AD is associated with a multidimensional burden [2, 3] and, similarly, the benefits of long-term dupilumab treatment were multidimensional. These benefits not only encompassed substantial improvements in itch and other patient-reported symptoms (flares, non-itch skin symptoms), but also in functional outcomes, HRQoL, and simplification of treatment. Improvements in the clinical symptoms over the first year of dupilumab treatment were sustained or improved through long-term follow-up. The sustained improvements in itch, in particular, were supported by the responses to the global change in itch question, which, although only collected at the Recontact survey, indicate the magnitude of the patient’s perception of the improvement relative to before dupilumab initiation.

Continued improvement at 30–36 months was also observed for measures of AD-related sleep disturbance and HRQoL, where 85% of patients achieved a clinically meaningful improvement in DLQI score and more than half (53%) reported that AD had no effect on their lives. It has been reported that, in patients with AD, the longitudinal course of itch, sleep disturbances, and HRQoL are heterogeneous, with these symptoms manifesting fluctuating patterns over time [22,23,24]. However, the sustained benefits in these outcomes that were reported by patients over the entire assessment period suggest that the improvements relative to baseline likely result from treatment effects rather than fluctuation in symptom presentation. The low rates of work and activity impairment, which were substantially reduced from baseline, not only demonstrate improved daily function from the patient’s perspective but are also relevant from the societal perspective, as improved work productivity may reduce the economic burden of AD [25, 26].

The effectiveness of dupilumab treatment for these patient-reported clinical and functional outcomes is consistent with the high proportion of patients who also reported adequate disease control and satisfaction with treatment. It is important to note that disease control was maintained even with decreasing use of concomitant therapies for AD. While uncontrolled AD has previously been shown to be associated with a higher patient-reported disease burden, disease control in those studies was based on clinical measures or a physician’s report [4, 27, 28], whereas the current study relied on the patient-reported ADCT score.

The main limitation of this analysis is that it reflects a self-selected population, as those who maintain long-term efficacy and safety may be more likely to participate in such a survey. However, the baseline characteristics of patients who responded at 30–36 months were similar to those of the non-respondents. Furthermore, discontinuations appeared to be consistent with other real-world studies with follow-up periods of 1–2 years [29,30,31]. A similar limitation is that participants were recruited through the dupilumab patient support program, which may influence patient perceptions of treatment benefit. To mitigate the risk of bias, patients were assured that their survey responses were confidential, reported in aggregate for research purposes, and would not affect their care. Recall bias represents another potential limitation. However, other than the global change in itch and use of concomitant therapies, the other outcomes had a maximum recall period of 1 week.

Conclusions

This prospective observational study demonstrated continued improvements in clinical symptoms, function and activity, and HRQoL through 30–36 months of follow-up in adults with moderate-to-severe AD who were treated with dupilumab in clinical practice. Improved outcomes reported by patients included flares, itch and non-itch skin symptoms, and sleep. These improvements were reflected by patients reporting adequate disease control and a reduced impact of AD on their lives. All improvements were observed in the context of decreased use of other AD medications and increasing patient-reported satisfaction with their AD treatment.

These findings on the long-term, real-world outcomes of dupilumab add to the evidence from clinical trials and other real-world studies of patients receiving dupilumab for moderate-to-severe AD.