Treatment Outcomes Associated With Dupilumab Use in Patients With Atopic Dermatitis: 1-Year Results From the RELIEVE-AD Study

Key Points

Question  What are the benefits of treatment with dupilumab in the clinical practice setting from the perspective of patients with moderate-to-severe atopic dermatitis?

Findings  In this prospective, longitudinal study in the clinical practice setting, 699 patients with atopic dermatitis who initiated dupilumab treatment were administered a survey over the 12-month study duration that included measures of disease control, treatment satisfaction, symptoms, health-related quality of life, and work and activity impairment. Patients reported adequate disease control, treatment satisfaction, and improvement in other outcomes that were significant vs baseline at the earliest evaluated assessment (1 month; 632 patients), and these improvements were maintained over the study period (12 months; 483 patients).

Meaning  This cohort study found that use of dupilumab for the treatment of atopic dermatitis was associated with early (1 month) of patient-reported benefits that were maintained after 12 months of therapy.

Importance  Clinical trial populations may not reflect clinical practice: knowledge generated in other settings can inform clinical decision-making.

Objective  To evaluate self-reported disease control and quality of life after initiating dupilumab treatment in patients with atopic dermatitis (AD) in the the clinical setting.

Design, Setting, and Participants  This cohort study using an online survey administered prior to (baseline) and at 1, 2, 3, 6, 9, and 12 months after dupilumab initiation included adults with moderate-to-severe AD who initiated treatment with dupilumab through the US patient support program and agreed to participate in the study. Data were collected between January 2018 and January 2020 and the analysis was completed in May 2020.

Interventions  Clinically driven treatment with dupilumab.

Main Outcomes and Measures  Disease control measured by the Atopic Dermatitis Control Tool (ADCT); concomitant AD therapies; satisfaction with therapy; skin symptoms (skin pain/soreness, hot/burning feeling, sensitivity to touch) assessed using numerical rating scales; flares; health-related quality of life assessed using the Dermatology Life Quality Index; sleep problems assessed using the ADCT item and a stand-alone question; and the AD-specific Work Productivity and Activity Impairment Questionnaire.

Results  Of 699 patients who initiated dupilumab (431 [61.7%] female, 515 [73.7%] White), 632 and 483 completed the survey at months 1 and 12, respectively. As-observed results showed that most patients achieved adequate disease control (ADCT total score) at month 1 with further improvement at month 12 (385 of 632 patients [60.9%] and 374 of 483 [77.4%] for the 2 time points, respectively, vs 41 of 699 [5.3%] at baseline; both P < .001). Use of other AD therapies was reduced at each follow-up vs baseline, including topical and systemic corticosteroids, which were reduced at month 12 to 40.4% (195 of 483 patients) and 6.2% (30 of 483 patients), respectively, from 68.1% (476 of 699) and 34.9% (244 of 699), respectively, at baseline (both P < .001 vs baseline). Patient satisfaction with AD treatment was higher than baseline (120 of 699 [17.7%]) at each follow-up to 85.1% (411 of 483) at month 12 (P < .001). At each follow-up, patients reported reductions in flares, itch, skin symptoms, and improved sleep, health-related quality of life, and daily activities vs baseline. Results were consistent based on observed data and imputed data using pattern mixture models for missing data.

Conclusions and Relevance  Consistent with patient-reported outcomes in clinical trials, this cohort study found that dupilumab treatment was associated with rapid and sustained disease control for up to 12 months as demonstrated by statistically significant improvements relative to baseline on all patient-reported outcomes including treatment satisfaction.

Patients with atopic dermatitis (AD) commonly complain of a triad of symptoms including itch, skin pain, and sleep disturbances,¹ which increase with disease severity and reduce health-related quality of life.² Despite the use of topical therapies and immunosuppressants, many patients with moderate-to-severe AD experience uncontrolled disease,^3,4 and there is an unmet need for an appropriate treatment that provides long-term disease management. Dupilumab, a fully human monoclonal antibody that targets interleukin (IL)-4Rα and modulates the downstream pathways,⁵ is approved in the US for patients aged 6 years or older with moderate-to-severe AD not adequately controlled with topical therapies.⁶ In clinical trials of patients with moderate-to-severe AD, dupilumab significantly reduced itch and improved clinical and patient-reported outcomes relative to placebo, with demonstration of long-term efficacy and safety.^7-16 Characterization of real-world effectiveness from the patient perspective can provide greater understanding of outcomes and may help improve overall AD management. Although the efficacy of dupilumab in clinical practice has been reported,^17-26 many of these studies focused on measures of clinical disease activity. The objective of the RELIEVE-AD (EaRly Real-WorLd PatIent EValuation for DupixEnt in Atopic Dermatitis) study is to evaluate the patient experience in the clinical setting with regard to disease control and quality of life during the first year following dupilumab initiation to determine potential benefits beyond those seen in the clinical trial setting.

The RELIEVE-AD study was a prospective, longitudinal cohort survey designed to characterize the patient experience in the clinical practice setting with dupilumab over a 12-month treatment period. The study received approval from the New England independent review board (Needham, Massachusetts); all patients provided informed consent, and data were anonymized prior to analysis in compliance with the Health Insurance Portability and Accountability Act of 1996 (HIPAA).

Patients invited to participate were adults with AD who were prescribed dupilumab in routine clinical practice in the US and then enrolled in the dupilumab patient support program. This program was designed to help patients gain access to dupilumab as quickly as possible and provide services such as copay assistance programs, nurse educator support, and supplemental injection training. Outreach to patients for participation was initiated January 2018, and the final completed survey at the 12-month time point was in January 2020. Patients were required to be 18 years or older, able to speak and read English, had not previously participated in a dupilumab trial or been treated with dupilumab.

Eligible patients completed questionnaires via an online portal before (baseline) and after dupilumab initiation at months 1, 2, 3, 6, 9, and 12.

Sociodemographic, disease characteristics, and prior AD treatment history were collected at baseline, as was medical history, including atopic comorbidities of asthma, eosinophilic esophagitis, nasal polyps, and nonseasonal allergies. Disease control was assessed using the Atopic Dermatitis Control Tool (ADCT),^27,28 a validated patient-reported outcome measure that includes 6 questions evaluating severity of overall AD symptoms, number of days experiencing intense itch, and the degree to which AD was bothersome and affected sleep, daily activities, and mood over the past week. Total score ranges from 0-24 with higher scores indicating poorer control; adequate disease control can be defined as a total score of less than 7.²⁸

Patient satisfaction with treatment was evaluated using the stand-alone question “How satisfied are you with your current treatment(s) for atopic dermatitis?” with responses on a 7-point Likert scale from “extremely satisfied” to “extremely dissatisfied.” Nonitch skin symptoms (skin pain or soreness, skin feeling hot or burning, and skin sensitivity to touch) were assessed using 0 to 10 numerical rating scales (NRS; 10 = worst score) with a 1-week recall period. Effects on sleep were evaluated using the sleep item on the ADCT and a stand-alone question on sleep problems over the past week.

Patients reported the number of flares over the past 4 weeks, and the proportion of patients with no flares was used as the outcome. Flares were defined as any one of the following: increased itching beyond what is normally experienced, increased redness beyond what is normally experienced, appearance of new lesions (spots or sores), or spreading of lesions (increased body surface area affected).

The Dermatology Life Quality Index (DLQI)²⁹ was used to evaluate health-related quality of life (HRQoL) over the previous week. Total score range is 0 to 30; higher scores indicate greater effect, and threshold bands for effect on patient’s life are 0 to 1 (no effect); 2 to 5 (small effect); 6 to 10 (moderate effect); 11 to 20 (very large effect); and 21 to 30 (extremely large effect). A change of 4 points or more in total score is considered clinically meaningful.³⁰

The Work Productivity and Activity Impairment Questionnaire specific for AD (WPAI:AD),^31,32 which was collected only for patients who were employed for pay, evaluated the effects of AD on self-reported productivity and activity over a recall period of the past week. The WPAI:AD includes subscales for absenteeism (absence from work), presenteeism (impairment while at work), overall work impairment, and impairment of nonwork-related activities, with subscales scored from 0% to 100% and higher scores indicative of greater work or activity impairment.

Patient characteristics and observed outcomes were summarized, and comparisons of outcomes vs baseline were conducted using generalized estimating equations (GEEs) to account for correlated data from the same patients responding at each follow-up; normal distributions with identity link functions were used for continuous outcomes, and binomial distributions with logit link function were used for categorical outcomes. As a sensitivity analysis, pattern mixture modeling (PMM) was conducted for imputation of missing values for selected outcomes.^33-35 These models used multiple imputation based on different patterns of distribution to provide a range of values for all patients who completed the baseline survey as an estimate of the validity and robustness of the observed data. Each missing outcome was imputed 20 times per patient per visit, and the estimated range is expressed around the mean follow-up value. Analyses were conducted using SAS Enterprise Guide (version 7.1; SAS Institute, Inc). The analysis was completed in May 2020.

A total of 699 patients who completed the baseline survey and confirmed initiating dupilumab were followed and included in the PMM sensitivity analysis. Of these patients, 632 (90.4%) completed the survey at month 1 and 483 (69.1%) completed at month 12. Discontinuation of dupilumab was reported by 93 (13.3%) patients, of whom 17 subsequently restarted therapy, resulting in an overall discontinuation rate of 10.9%. Although adverse effects and lack of efficacy were the most common reasons for discontinuation, 22 (3.1%) and 25 (3.6%) patients, respectively, cost issues and insurance coverage were also cited by 16 (2.3%) and 12 (1.7%) patients, respectively. One adverse event was reported by a patient outside of the structured data collection from the patient-reported measures included in the survey. All structured data that were collected (including data that may overlap with safety-related concepts) are presented in this analysis.

The patient population at baseline included 431 (61.7%) women, 515 (73.7%) were White, with a mean (SD) age of 46.2 (15.5) years, and 354 (50.6%) had at least 1 atopic comorbidity including nonseasonal allergies and asthma (Table 1). The demographic and clinical characteristics of patients who completed the survey at month 12 were similar to baseline (Table 1), as were the characteristics of respondents at 3, 6, and 9 months (eTable 1 in the Supplement).

The mean (SD) total ADCT score at baseline was 15.8 (5.4), and was reduced at each follow-up relative to baseline (Table 2). Similar patterns vs baseline were observed for the individual ADCT items (eTable 2 in the Supplement).

At baseline, 41 of 699 patients (5.9%) had adequately controlled disease based on ADCT total score (Figure 1). The majority of patients achieved adequate disease control at month 1 with further improvement at each follow-up through month 12 (Figure 1).

At baseline, 610 of 699 patients (87.3%) were using 1 or more AD therapies including topical (476 [68.1%]) and systemic corticosteroids (244 [34.9%]). After initiating treatment with dupilumab, use of topical and systemic corticosteroids therapies was lower at every follow-up to 40.4% (195 of 483 patients) and 6.2% (30 of 483 patients), respectively, at month 12 (both P < .001 vs baseline) (eTable 2 in the Supplement). Similar results were observed for other AD therapies (eTable 2 in the Supplement).

At baseline, only 21 of 699 (3.0%) patients reported no flares in the past 4 weeks (Table 2). One month after initiating dupilumab treatment, 213 of 632 (33.7%) patients reported no flares, which increased to 43.5% at month 12 (210 of 483; both P < .001 vs baseline) (Table 2).

Scores on the ADCT item for days with intense periods of itching were improved relative to baseline at each follow-up (eTable 2 in the Supplement). In addition, the proportion of patients reporting no days of intense itch in the past week improved at each follow-up from 3.1% (22 of 699) at baseline to 53.2% (257 of 483) at month 12 (P < .001) (eFigure 1 in the Supplement).

Mean (SD) skin symptom NRS scores at baseline ranged from 5.2 (2.9) for hot/burning skin to 5.9 (2.5) for skin pain. These scores were reduced vs baseline at month 1 to 2.2 (2.4) and 2.7 (2.3), respectively (both P < .001) with additional reductions at each follow-up (Table 2).

On the ADCT sleep item, 107 of 699 (15.3%) patients at baseline reported no trouble falling or staying asleep. The proportion increased at month 1 with further improvements at each subsequent follow-up to 77.6% (375 of 483 patients) at month 12 (P < .001 vs baseline) (eFigure 2A in the Supplement). Responses to the stand-alone question on sleep problems in the past week due to AD showed that 542 of 699 (77.5%) patients had problems at baseline, with reductions at each follow-up to 14.1% (68 of 483) at month 12 (eFigure 2B in the Supplement).

The mean (SD) baseline DLQI total score was 14.4 (7.3) out of 30, indicating a very large effect of AD on patients’ lives (Table 3). One month after initiating dupilumab, patients reported a mean DLQI score of 5.9 (5.8) (P < .001 vs baseline) that continued to improve to month 12 (Table 3). More than three-quarters of the patients at each follow-up had a clinically meaningful change (ie, ≥4-point reduction) (Figure 2A). Although 8 of 699 (1.1%) patients reported a baseline score that indicated “no effect” (Figure 2B), the effect of AD on patients’ lives at each follow-up was reduced: at month 12, 223 of 483 (46.2%) patients reported scores indicating no effect (Figure 2B).

On all DLQI subscales, improvements relative to baseline were observed at month 1 and were maintained at month 12 (Table 3).

At baseline, patients reported a mean (SD) AD-related total work impairment of 40.2% (28.1%) that was primarily driven by presenteeism (Table 3). This impairment was reduced at month 1 after dupilumab initiation (14.9% [19.7%]; P < .001) and was maintained to month 12; both absenteeism and presenteeism were reduced at each follow-up relative to baseline. Mean impairment of activity other than work at baseline was reduced at each follow-up relative to baseline (Table 3).

Few patients reported satisfaction with treatment at baseline (120 of 699 [17.7%]) (eFigure 3 in the Supplement). After initiating dupilumab, satisfaction improved at each follow-up to 85.1% (411 of 483) at month 12 (eFigure 3 in the Supplement).

When missing data were imputed using PMM, the resulting ranges were generally consistent with the primary analysis. However, wider ranges were obtained at later follow-up time points that were indicative of the greater amount of missing values.

This large-scale, 12-month study of dupilumab in the US provides evidence of patient-reported benefits of dupilumab for controlling AD and its symptoms in the clinical practice setting. From the patient’s perspective, AD was adequately controlled in substantial proportions of patients after initiating dupilumab based on the ADCT total score. Although 22.6% of patients had an ADCT score of 7 or higher (not controlled) at month 12, a substantially smaller proportion of patients (10.3%) who completed the survey were “somewhat dissatisfied,” “very dissatisfied,” or “extremely dissatisfied” with AD treatment. Disease control was also demonstrated by early onset of benefits across a broad array of patient-reported outcomes that were maintained after 12 months of therapy. Although there has not been consensus for defining AD disease control,³⁶ the Harmonising Outcome Measures in Eczema (HOME) initiative identified disease control as a core outcome^37,38 and recommends using the ADCT to measure long-term control as part of core disease outcomes.³⁹ The ADCT, a validated measure that incorporates symptoms and effects of the disease on daily life, is particularly appropriate because disease control should include psychological and social factors as well as daily function.^40,41

Control of AD was supported by significant reductions in flares, skin symptoms, and sleep problems. Disease control with dupilumab treatment not only resulted in substantial reduction in use of concomitant therapies, including topical and systemic corticosteroids, but was also paralleled by significant improvement in patient satisfaction with their current treatment. Sensitivity analysis further demonstrated that these results were robust even when accounting for missing values.

All observed effects were statistically significant and substantial at 1 month, the first survey time point after dupilumab treatment initiation, and were maintained across all subsequent time points up to 12 months. The effects observed at month 1 are consistent with clinical trials that have reported a rapid onset of reduced symptoms and improved patient-reported outcomes.^7-11,42,43 Of additional importance, the 12-month outcomes appeared to be consistent with those of 52 weeks in the dupilumab CHRONOS trial, including a change of 4 or more points in DLQI scores in 83% of patients at month 12 in the current study relative to 80% in the CHRONOS trial at week 52.⁴⁴

Itch, the hallmark symptom of AD and the primary complaint of patients, frequently affects daily function and sleep.^1,45 Both itch and sleep were significantly improved after initiation of dupilumab, and improvements were sustained over time, consistent with what has been reported in clinical trials.^{7-11,42,43,46}

The stand-alone sleep question and the ADCT sleep item provide complementary evidence supporting the effects of dupilumab for improving sleep. Sleep disturbances are an especially frequent and bothersome complaint among patients with AD,¹ resulting in fatigue, excessive daytime sleepiness, and reductions in daily activities such as difficulties at school or work and falling asleep while driving.^47,48 Sleep improvements may be related to the effects of dupilumab on reducing nocturnal itch, which is significantly associated with insomnia and sleep quality.⁴⁹

In addition to itch, skin symptoms of pain/soreness and burning sensation were markedly and significantly reduced relative to baseline. Skin pain is increasingly recognized as an important AD symptom that may overlap with itch with regard to presentation and mechanisms.^50-52 Although dupilumab reduces pain/discomfort,⁵³ that study was not specific to skin pain. Thus, the current data on skin symptoms add to the existing evidence on the broad benefits of dupilumab from the patient perspective.

Improvements in daily function were further supported by reductions in work and activity impairment assessed using the WPAI:AD. Work productivity has economic implications from multiple perspectives (individual, employer, society), and increased productivity may partly offset drug acquisition costs.

Overall, these results are consistent with other studies of dupilumab in the clinical practice setting that reported improvements from baseline and subsequent maintenance of treatment benefits,^17-20,25,54 and expands on those findings by assessing patient-reported disease control and satisfaction through 12 months of treatment. In all studies in clinical practice, including the current analysis, the most marked improvements were observed between baseline and the first assessment at 1 month. These results support the rapid onset of efficacy, generally 1 to 2 weeks after initiating treatment, that have been reported in clinical trials of dupilumab.^7-11,42,43 These early effects are additionally sustained over 12 months, providing benefits consistent with a previous 52-week clinical trial.⁴⁴

Study limitations include lack of a contemporary control group. However, dupilumab’s efficacy has been supported by randomized controlled clinical trials, and thus the current prepost study design may be considered appropriate in terms of providing supplemental data in the clinical setting to support the efficacy observed in clinical trial settings. Another limitation is that patients who continue in long-term studies may represent a population that self-selects for efficacy and safety, therefore potentially biasing the outcomes in a more positive direction. In this regard, it should be noted that the baseline characteristics of those who remained in each assessment appeared to be similar to the initial sample, and that results of the sensitivity analysis using PMM to impute missing data consistently demonstrated the effectiveness of dupilumab treatment. Furthermore, although patient perceptions of the benefits of dupilumab may be influenced by other factors, including participation in the patient support program, this bias was mitigated in the current study by efforts to assure patients that their survey responses would not affect their care. Although there was also the potential for recall bias because outcomes were patient-reported, such bias may be minimal considering that most of the included patient-reported outcomes have a recall period of 1 week.

This 1-year study of adult patients with AD initiated on dupilumab in clinical practice demonstrates rapid and sustained disease control using the ADCT. Patients experienced sustained benefits over the study duration from multiple aspects of disease control including reductions in patient-reported flares and symptoms (eg, itch, pain, and sleep); improvements in function, HRQoL, productivity; and reduction in concomitant use of other AD treatments, including topical and systemic corticosteroids. These results are consistent with those observed in clinical trials and expand on the sustained benefits that may be expected with dupilumab over the course of long-term treatment.

Accepted for Publication: October 3, 2021.

Published Online: December 15, 2021. doi:10.1001/jamadermatol.2021.4778

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2021 Strober B et al. JAMA Dermatology.

Corresponding Author: Bruce Strober, MD, PhD, Central Connecticut Dermatology, 1 Willowbrook Rd, Suite 2, Cromwell, CT 06416 (brucestrober30@me.com).

Author Contributions: Dr Strober had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Strober, Mallya, Yang, Gadkari, Wang, Delevry.

Acquisition, analysis, or interpretation of data: Mallya, Yang, Ganguli, Gadkari, Wang, Sierka, Delevry, Kimball.

Drafting of the manuscript: Mallya, Wang, Sierka, Delevry.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Yang, Ganguli, Wang.

Obtained funding: Yang, Ganguli, Gadkari.

Administrative, technical, or material support: Mallya, Yang, Ganguli, Wang, Sierka, Delevry.

Supervision: Strober, Mallya, Yang, Gadkari, Wang, Delevry.

Conflict of Interest Disclosures: Dr Strober reported receiving honoraria for serving as a consultant, advisory board member, and/or speaker for AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dermavant, Dermira, Janssen, Eli Lilly and Company, LEO Pharma, Medac, Meiji Seika Pharma, Sebela Pharmaceuticals, Menlo Therapeutics, Novartis, Pfizer, GlaxoSmithKline, UCB Pharma, Sirtris, Sun Pharma, Ortho Dermatologics/Valeant, Regeneron Pharmaceuticals, Inc, and Sanofi-Genzyme. Drs Mallya and Ganguli were employees of and stockholders in Sanofi at the time of study. Dr Sierka reported being an employee of, and stockholder in, Sanofi. Drs Yang and Wang reported being employees of Analysis Group, Inc, Boston, Massachusetts, which received research funds from Sanofi/Regeneron Pharmaceuticals, Inc, during the conduct of the study. Dr Gadkari was an employee of and stockholder in Regeneron Pharmaceuticals at the time of the study; he is a current employee of Boehringer Ingelheim Corporation. Dr Delevry is an employee of, and stockholder in, Regeneron Pharmaceuticals, Inc. Dr Kimball reported consulting for Novartis, AbbVie, Dermira, UCB, Eli Lilly and Company, and Janssen, and has received fellowship funding from Janssen and AbbVie.

Funding/Support: The work was supported by funding from Sanofi and Regeneron Pharmaceuticals, Inc.

Role of the Funder/Sponsor: Sanofi and Regeneron Pharmaceuticals, Inc, contributed to the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript.

Additional Contributions: We thank the patients who participated in this study. The authors also acknowledge the following individuals for their valuable input during the conduct of this study: Jingdong Chao, PhD; Mandeep Kaur, MD; Susan Boklage, MPH; Christina X. Chamberlain, PhD; and Miriam C. Fenton, PhD. Medical writing support in the preparation of this publication was provided by E. Jay Bienen, PhD, and funded by Sanofi and Regeneron Pharmaceuticals, Inc.