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Patient-Reported Ocular Disorders and Symptoms in Adults with Moderate-to-Severe Atopic Dermatitis: Screening and Baseline Survey Data from a Clinical Trial

Abstract

Introduction

Patients with atopic dermatitis (AD) have a greater risk of conjunctivitis and other ocular surface disorders than the general population. We evaluated the burden of ocular surface disorders and related symptoms prior to treatment initiation in adults with moderate-to-severe AD.

Methods

Patients were enrolled in a randomized, placebo-controlled, double-blinded, phase 3 trial of dupilumab administered with concomitant topical corticosteroids. At the beginning of the screening period, all enrolled patients completed a survey of ocular disorder diagnoses received in the past year; at baseline, patients completed a survey of frequency and severity of ocular symptoms (discomfort, itching, redness, and tearing) experienced in the past month.

Results

A total of 712 of 740 patients enrolled in the trial provided responses to the survey. At screening, 286 of 740 patients (38.6%) reported having at least one ocular disorder in the past year. At baseline, 499 of 712 respondents (70.1%) reported having at least one symptom within the past month. Of these patients, 4.4%, 6.0%, 5.5%, and 4.4%, respectively, reported having discomfort, itching, redness, and tearing all of the time. Mild discomfort, itching, redness, and tearing were reported by 26.1%, 33.7%, 30.8%, and 31.6% of patients, respectively, while 7.3%, 7.7%, 6.2%, and 4.2%, reported severe discomfort, itching, redness, and tearing, respectively.

Conclusions

These data demonstrate a high burden of ocular surface disorders and related symptoms in a population of adults with moderate-to-severe AD. Dermatologists should be aware of increased incidence of these disorders in AD and query their patients for signs and symptoms of eye disease.

ClinicalTrials.gov Registration Number

NCT02260986.

FormalPara Key Summary Points
Why carry out this study?
Patients with atopic dermatitis (AD) have a greater risk of conjunctivitis and other ocular surface disorders than the general population.
We evaluated the burden of ocular surface disorders and related symptoms prior to treatment initiation with dupilumab in adults with moderate-to-severe AD enrolled in a randomized, placebo-controlled, double-blinded phase 3 trial of dupilumab administered with concomitant topical corticosteroids.
What was learned from the study?
These data demonstrate a high burden of ocular surface disorders and related symptoms in a population of adults with moderate-to-severe AD.
Dermatologists should be aware of increased incidence of these disorders in AD and query their patients for signs and symptoms of eye disease.

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Introduction

Patients with atopic dermatitis (AD) have a greater risk of conjunctivitis and other ocular surface disorders (e.g., atopic keratoconjunctivitis [AKC], keratoconus, herpetic eye disease, and dry eye) than the general population [1,2,3,4,5,6,7,8,9,10,11,12]. The prevalence rates of ocular surface disorders in patients with AD are high, with studies showing up to 32–42% of patients with AD reporting eye disease or prescriptions for eye disorders in the past 12 months [1, 5, 6]. Some of these disorders, such as AKC, may lead to serious eye problems, impaired vision, or even vision loss [3, 4, 9]. Incidence of ocular surface disorders increases with AD severity and factors related to AD severity, including elevated circulating levels of IgE, thymus and activation-regulated chemokine, and eosinophils [1, 6, 13].

To provide further information on the prevalence and severity of these disorders, particularly in patients with moderate-to-severe AD, we evaluated the burden of ocular surface disorders and related symptoms prior to treatment initiation in adults with moderate-to-severe AD enrolled in a phase 3 trial of dupilumab.

Methods

LIBERTY AD CHRONOS (NCT02260986) was a randomized, placebo-controlled, double-blinded, phase 3 trial of dupilumab administered with concomitant topical corticosteroids [14]. Detailed patient eligibility criteria were previously published [14]. In brief, patients were eligible to enroll in CHRONOS if they were at least 18 years of age, and had chronic moderate-to-severe AD, inadequate response to medium- to high-potency topical corticosteroids (with or without concomitant topical calcineurin inhibitors) within 6 months before screening, an Investigator’s Global Assessment Score of at least 3 (on a scale of 0–4, where 3 was moderate and 4 was severe), and an Eczema Area and Severity Index score of at least 16 at screening and baseline.

At the beginning of the 35-day screening period, patients completed a survey of ocular disorder diagnoses received in the past year. At baseline, they completed a survey of frequency and severity of ocular symptoms (itching, tearing, redness, and discomfort) experienced in the past month.

The number and proportion of patients at screening who reported ocular disorder diagnoses in the past year, and the number and proportion of patients at baseline reporting frequency and severity of symptoms, were analyzed using descriptive statistics, based on the number of patients who provided responses to the survey.

The study was conducted in accordance with the provisions of the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice guideline, and applicable regulatory requirements. The protocol was reviewed and approved by institutional review boards/ethics committees at all study sites. An independent data monitoring committee monitored patient safety. All patients provided signed written informed consent.

Results

Of the 740 patients enrolled in CHRONOS, 712 provided responses to the survey. At screening, 286 of 740 patients (38.6%) reported having at least one ocular disorder in the past year. Among the 712 respondents to the survey, the most common ocular disorder reported in the past year was dry eye (20.5% of patients), while the least common disorder reported was keratoconus (2.1% of patients) (Table 1). Eighty-seven patients (12.2%) reported AKC, a potentially serious ocular disorder, in the past year (Table 1).

Table 1 Screening: ocular surface disorders during the past year

Of the 712 respondents to the survey, 499 patients (70.1%; comprising 67.4% of all enrolled patients) reported having at least one symptom within the past month at baseline. A total of 47.9%, 65.0%, 53.8%, and 49.9% of survey respondents, respectively, reported symptoms of discomfort, itching, redness, and tearing in the past month (Table 2). Of these patients, few reported having symptoms all of the time (4.4% [discomfort], 6.0% [itching], 5.5% [redness], and 4.4% [tearing]) (Table 2). Mild symptoms of discomfort, itching, redness, and tearing were reported by 26.1%, 33.7%, 30.8%, and 31.6% of patients, respectively (Table 2). Fewer patients (15.0%, 22.6%, 15.3%, and 12.5%, respectively) reported moderate symptoms of discomfort, itching, redness, and tearing; and only 7.3%, 7.7%, 6.2%, and 4.2%, respectively, reported severe symptoms (Table 2).

Table 2 Baseline: frequency and severity of ocular symptoms during the past month

Discussion

This survey demonstrated a substantial burden of ocular surface disorders within the past year in patients with moderate-to-severe AD that was inadequately controlled with topical medications. Most patients reported having at least one ocular symptom within the past month at baseline, and a substantial proportion of symptoms were moderate to severe. The burden of ocular surface disorders in this patient population is consistent with other studies demonstrating a substantially greater incidence of ocular surface disorders among patients with type 2 inflammatory disorders, such as AD, asthma, and rhinosinusitis, compared with the general population [1,2,3,4,5,6,7,8,9,10,11,12].

Previous studies have demonstrated an association of AD severity with increased risk of ocular disorders [1, 6, 13]. Although the burden of ocular disorders has been demonstrated to be high in patients with AD compared with the general population [1,2,3,4,5,6,7,8,9,10,11,12], there is also an association of AD with other type 2 inflammatory comorbidities such as allergies, asthma, and rhinitis, and in turn these type 2 inflammatory diseases are also associated with increased incidence of ocular disorders [15, 16]. Therefore, it is difficult to identify the relative contributions of AD and other associated type 2 inflammatory disorders to comorbid ocular diseases.

Some ocular disorders associated with AD, such as AKC, are potentially serious and may have an impact on vision, and, therefore, require ophthalmic assessment and treatment [1, 3, 4, 9]. Given the demonstrated association of ocular diseases with AD, it is important to increase awareness of the burden, signs and symptoms, and management guidelines for ocular disease associated with AD among dermatologists [17, 18].

Limitations of this survey include a population comprised of patients who were screened and enrolled in a clinical trial, which may not be representative of all patients with moderate-to-severe AD; however, this is a limitation of all randomized clinical trials. The survey is a non-validated instrument, and it is possible that some patients may not have understood the medical terms of the questionnaire. Survey data for diagnoses are subject to recall bias; symptom data may be more reliable, as they reflect patient experience within the previous month.

Conclusion

These data demonstrate a high burden of ocular surface disorders and related symptoms in a population of adults with moderate-to-severe AD. Dermatologists should be aware of increased incidence of these disorders in patients with AD and query their patients for signs and symptoms of eye disease.

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Acknowledgements

The authors thank the patients and their families for their participation in this study; their colleagues for their support; and Linda Williams (Regeneron Pharmaceuticals, Inc.), and Adriana Mello and El-Bdaoui Haddad (Sanofi Genzyme) for their contributions.

Funding

Research sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. ClinicalTrials.gov Identifier NCT02260986. The study sponsors have funded the Journal’s Rapid Service fee for this paper.

Medical Writing and Editorial Assistance

Medical writing/editorial assistance provided by Vicki Schwartz, PhD, of Excerpta Medica, funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc.

Prior Presentation

Content included in this manuscript was previously accepted for a poster presentation at the Society for Investigative Dermatology (SID) 2020 Annual Meeting; May 13–16, 2020. However, the meeting was held virtually, and no posters were presented. The abstract was published in the SID 2020 Meeting Abstract Supplement of the Journal of Investigative Dermatology (J Invest Dermatol. 2020;140[7Suppl]:S53[Abstract 407]).

Disclosures

Jonathan Weyne, Zhen Chen, Brad Shumel are employees and shareholders of Regeneron Pharmaceuticals, Inc. Andrew Blauvelt is a scientific adviser, clinical study investigator for AbbVie, Aclaris, Almirall, Arena, Athenex, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Dermira, Eli Lilly, Forte, Galderma, Janssen, LEO Pharma, Novartis, Ortho Derm, Pfizer, Rapt, Regeneron Pharmaceuticals, Inc., Sandoz, Sanofi Genzyme, Sun Pharma, UCB; and a paid speaker for AbbVie. Marjolein de Bruin-Weller is a Principal Investigator, advisory board member, consultant for Regeneron Pharmaceuticals, Inc., Sanofi Genzyme; Principal Investigator, advisory board member for AbbVie, Pfizer; and an advisory board member for Eli Lilly, and UCB. Errol Prens has received honoraria and/or research grants from AbbVie, Amgen, Celgene, Eli Lilly, Galderma, Janssen-Cilag, Novartis, Pfizer, Regeneron Pharmaceuticals Inc., Sandoz, Sanofi Genzyme, and UCB. Penny Asbell is an advisory board member and consultant for Regeneron Pharmaceuticals, Inc. Debra Sierka is an employee, and may hold stock and/or stock options in Sanofi Genzyme.

Compliance with Ethics Guidelines

The study was conducted in accordance with the provisions of the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice guideline, and applicable regulatory requirements. The protocol was reviewed and approved by institutional review boards/ethics committees at all study sites. An independent data monitoring committee monitored patient safety. All patients provided signed written informed consent.

Author Contributions

All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Data Availability

Qualified researchers may request access to study documents (including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan) that support the methods and findings reported in this manuscript. Individual anonymized participant data will be considered for sharing once the product and indication has been approved by major health authorities (e.g., FDA, EMA, PMDA, etc), if there is legal authority to share the data and there is not a reasonable likelihood of participant re-identification. Submit requests to https://vivli.org/.

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Correspondence to Jonathan Weyne.

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Weyne, J., Blauvelt, A., de Bruin-Weller, M. et al. Patient-Reported Ocular Disorders and Symptoms in Adults with Moderate-to-Severe Atopic Dermatitis: Screening and Baseline Survey Data from a Clinical Trial. Dermatol Ther (Heidelb) 10, 1415–1421 (2020). https://doi.org/10.1007/s13555-020-00456-x

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Keywords

  • Atopic dermatitis
  • Burden
  • Ocular disorders
  • Symptoms
  • Survey