Symptoms of anxiety or depression were reported more frequently by patients with moderate/severe AD relative to those with mild AD (A), and by patients with inadequate disease control relative to those with controlled AD (B). AD indicates atopic dermatitis.
aP < .001 vs mild.
Patients with moderate/severe AD and those with inadequately controlled disease had poorer quality of life relative to patients with mild AD and controlled disease, respectively, as indicated by the total DLQI score (A) and percentage of patients who reported a DLQI total score higher than 10, which is indicative of a very large effect (B). AD indicates atopic dermatitis.
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Simpson EL, Guttman-Yassky E, Margolis DJ, et al. Association of Inadequately Controlled Disease and Disease Severity With Patient-Reported Disease Burden in Adults With Atopic Dermatitis. JAMA Dermatol. 2018;154(8):903–912. doi:10.1001/jamadermatol.2018.1572
What is the association of atopic dermatitis severity and disease control with the patient-reported disease burden in clinical practice?
Among 1519 adults in this cross-sectional study, patients reported a multidimensional burden that is higher with greater disease severity and inadequate disease control.
For patients with moderate to severe dermatitis, there is a need for more effective therapies and for greater incorporation of the patient’s perspective into clinical assessment.
Real-world data are limited on the patient-reported burden of adult atopic dermatitis (AD).
To characterize the patient-reported burden of AD with regard to impact of disease severity and inadequate control in adults from clinical settings.
Design, Setting, and Participants
In this cross-sectional study using data from 6 academic medical centers in the United States collected by a self-administered internet-based questionnaire, 1519 adult patients with AD were stratified by AD severity as mild or moderate/severe using the Patient-Oriented Scoring Atopic Dermatitis (PO-SCORAD). Patients with moderate/severe disease using systemic immunomodulators/phototherapy were further stratified as having adequate or inadequate disease control. Strata were compared for all outcomes.
Main Outcomes and Measures
Outcomes included validated measures and stand-alone questions assessing itch (pruritus numerical rating scale; PO-SCORAD itch visual analog scale), pain (numerical rating scale), sleep (PO-SCORAD sleep visual analog scale; sleep interference with function), anxiety and depression (Hospital Anxiety and Depression Scale), and health-related quality of life (Dermatology Life Quality Index).
Among the 1519 adult patients with AD, relative to mild AD (n = 689, 64% women; mean [SD] age, 46.5 [18.0] years), patients with moderate/severe AD (n = 830, 66.8% women; mean [SD] age, 45.1 [16.9] years) reported more severe itching and pain, greater adverse effects on sleep, higher prevalence of anxiety and depression (417 [50.2%] vs 188 [27.3%]), and greater health-related quality-of-life impairment. The 103 patients with moderate/severe AD with inadequate disease control despite treatment with systemic immunomodulators or phototherapy (55.7%) reported higher burdens of itch and sleeping symptoms vs patients with controlled disease including more days per week with itchy skin (5.7 vs 2.7) and higher proportions with itch duration greater than half a day (190 [22.8%] vs 20 [2.9%]). Sleep symptoms included trouble sleeping (3.9 vs 1.1 on the PO-SCORAD VAS), longer sleep latency (38.8 vs 21.6 minutes), more frequent sleep disturbances (2.6 vs 0.4 nights in past week), and greater need for over-the-counter sleep medications (324 [39%] vs 145 [21%]).
Conclusions and Relevance
Inadequate disease control was common among patients with moderate/severe AD, and was associated with a higher patient-reported burden than patients with controlled disease. Regardless of disease control, the burden of moderate/severe AD was higher than mild AD, suggesting a need for more effective therapies for moderate/severe disease.
Onset of atopic dermatitis (AD) most often begins in early childhood with a variable disease course and symptoms persisting into adulthood for many patients.1,2 There remain substantial gaps in our understanding of the impact of AD on the lives of adults with this disease,3 especially those with moderate-to-severe disease. Moderate AD has been reported in 20% to 37% of adult patients and severe AD in 10% to 34%.4,5 A recent clinical trial conducted in adults with moderate-to-severe AD reported the presence of a multidimensional baseline disease burden that included substantial disease activity, symptoms, and a variety of comorbid conditions with a significant impact on health-related quality-of-life (HRQoL).6 A similarly broad burden was observed based on self-report among adults with AD in the general population participating in the National Health and Wellness Survey.7,8 Although these results reflect a population-based sample, they may not be generalizable to patients encountered in clinical practice.
The Adults With Atopic dermatitis Reporting on their Experience (AD-AWARE) study, a cross-sectional burden-of-illness study in adult patients with AD from clinical practices in the United States, presented the opportunity to assess the patient burden across multiple domains in a large, well-characterized sample in a real-world setting. The objectives of this study were to characterize the association of patient-reported burden of AD with regard to disease severity and patient assessment of AD control.
The AD-AWARE study was conducted in clinical practices at 6 US academic medical centers via a self-administered internet-based questionnaire among adult patients with AD who agreed to participate: University of California, San Diego; Brown University, Rhode Island; Wake Forest Baptist Health, North Carolina; Icahn School of Medicine at Mount Sinai, New York; University of Pennsylvania, Pennsylvania; and the Oregon Health and Science University, Oregon. The protocol received institutional review board approval from each study center. Participants provided written informed consent and data collection was performed in accordance with the Health Insurance Portability and Accountability Act of 1996.
Adult patients (≥18 years) with 1 or more visits to any clinic in the facility associated with AD (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] 691.8) between January 1, 2013, and December 31, 2014, were identified for inclusion and initially contacted by postal letters, which included the URL and sign-in information to access the online consent form and questionnaire. Initial contact letters included a preincentive ($5 bill), and eligible patients who completed the questionnaire received a post-incentive ($35 mailed check or Visa gift card) as recommended by the Tailored Design Method for surveys.9 Reminders were sent via postal letters if the quota of 200 patients per site had not been met. Inclusion criteria were amended if necessary to meet site quotas by allowing participation of patients diagnosed with International Classification of Diseases, Ninth Revision (ICD-9) 692.9 (ie, contact dermatitis and other eczema, unspecified cause) if they also had 1 or more prescriptions for a systemic agent. The AD was confirmed by patients self-reporting that they had received a diagnosis by a health care provider in response to a screening question at the beginning of the online questionnaire. Paper versions of the screening questions, consent form, and full questionnaire were mailed to patients upon request.
Patients were stratified by AD severity using the Patient-Oriented Scoring Atopic Dermatitis (PO-SCORAD) that was included in the survey instrument,10 with scores less than 25 and 25 or more considered mild and moderate/severe disease, respectively.11 Treatment patterns were evaluated based on patient-reported use of medications within the past 7 days, including topical agents (corticosteroids and calcineurin inhibitors), systemic steroids, immunomodulatory therapy (Im-tx), and phototherapy. Patients with moderate/severe AD receiving Im-tx (azathioprine, cyclophosphamide, cyclosporine, methotrexate, mycophenolate, tacrolimus) or phototherapy within the past 7 days (with/without topical agents) were further categorized as having controlled or inadequately controlled AD. Inadequately controlled AD was defined as patients who somewhat or completely disagreed with the statement “I feel my current treatments are effective in controlling my atopic dermatitis”; all other responses were considered controlled AD.
The pruritus numerical rating scale (NRS; 0 = no itch to 10 = worst imaginable itch) assessed worst itch within the past 24 hours,12 and the PO-SCORAD itch visual analog scale (VAS; 0 = no itching, 10 = unbearable itching) assessed average itch over the past 3 days.10 Standalone questions evaluated days in the past week and hours per day with itchy skin. Worst pain within the past 24 hours was assessed using an NRS (0 = no pain, 10 = worst imaginable pain).
Sleep outcomes included trouble sleeping over the past 3 days using the PO-SCORAD sleep VAS (0 = no insomnia, 10 = total insomnia),10 and standalone questions on hours of sleep per night, nights with sleep disturbance during the past week, and sleep interference with function during the past week using a Likert scale (1 = not at all to 5 = very much).
The presence of anxiety and depression symptoms was evaluated using the Hospital Anxiety and Depression Scale (HADS), which consists of anxiety (HADS-A) and depression (HADS-D) subscales. Scores range from 0 to 21 on each subscale, with scores of 8 or more indicative of anxiety or depression symptoms.13 Participant HRQoL was evaluated using the Dermatology Life Quality Index (DLQI),14 which evaluates the impact of skin conditions on HRQoL over the past week (score range, 0-30; higher scores indicate greater impact).
Outcomes were compared for patients with moderate/severe vs mild AD, and patients who self-reported having controlled disease vs inadequately controlled on their current therapy (among patients with moderate/severe AD who were treated with Im-tx or phototherapy in the past 7 days). χ2 tests were used for categorical variables, and for continuous variables, equality of variances was tested first and, based on the results, pooled variances or Satterthwaite variances were used in the student t test; P < .05 was considered significant. Analyses were performed using SAS statistical software (version 9.3, SAS Institute).
Of 6737 patients who were contacted, 1519 agreed to participate and completed the questionnaire (22.5% response rate); 160 of these, at a single site (University of California San Diego), were identified using the amended criteria. A total of 997 (65.7%) of respondents were women, 1028 (67.7%) were white non-Hispanic, with a mean (SD) age of 45.7 (17.4) years; 830 (54.6%) had moderate/severe AD (Table 1). Significant differences between patients with mild AD and moderate/severe AD were observed for age distribution, race/ethnicity, education, body mass index (calculated as weight in kilograms divided by height in meters squared), education, and family income (Table 1).
Although most patients in both severity groups were diagnosed with AD as adults, moderate/severe patients were characterized by a higher proportion of patients diagnosed during childhood or adolescence (385 [46.4%] vs 232 [34.0%]; P < .001), and had been living with AD for a longer time since diagnosis than patients with mild disease (20.5 vs 15.7 years; P < .001) (Table 1). The proportion of patients with at least 1 systemic therapy or systemic/phototherapy within the past 7 days was higher among those with moderate/severe AD, but use of topical agents was similar between groups (Table 1).
A total of 185 (22.3%) patients with moderate/severe disease received Im-tx or phototherapy, of whom 103 (55.7%) assessed themselves as inadequately controlled (Table 1). Patients with inadequately controlled AD were younger than those with controlled AD (44.6 vs 49.8 years; P = .04). There were no differences between patients with controlled and inadequately controlled disease for age of onset, disease duration, or use of topical therapies and any systemic therapies (Table 1).
All measures of itch showed greater severity and duration among patients with moderate/severe disease relative to mild (all P < .001) (Table 2), including more days per week with itchy skin (5.7 vs 2.7) and higher proportions with itch duration greater than half a day (190 [22.8%] vs 20 [2.9%]). Itch intensity and frequency were higher among patients with inadequately controlled disease relative to controlled (Table 2). Pain severity was higher among moderate/severe vs mild, and inadequately controlled vs controlled disease (Table 2).
Patients with moderate/severe AD reported more sleep problems vs those with mild AD (all P < .001) (Table 2), including trouble sleeping (3.9 vs 1.1 on the PO-SCORAD VAS), longer sleep latency (38.8 vs 21.6 minutes), more frequent sleep disturbances (2.6 vs 0.4 nights in past week), and greater need for over-the-counter sleep medications (324 [39%] vs 145 [21%]) (Table 2). These sleep problems “much” or “very much” interfered with daily function in a higher proportion of patients with moderate/severe AD (202 [24.3%] vs 47 [6.8%]; P < .001).
Greater sleep problems were generally observed among the patients with inadequately controlled relative to those with controlled disease. However, only for the sleep VAS and sleep latency were the differences significant (Table 2).
Symptoms of anxiety or depression were reported by 417 (50.2%) patients with moderate/severe AD vs 188 (27.3%) with mild (P < .001) (Figure 1A). The proportion of patients with scores of 8 or higher (indicating symptoms) on the individual anxiety and depression subscales was higher among patients with moderate/severe AD relative to those with mild disease (all P < .001), with anxiety more frequent than depression, regardless of AD severity.
Anxiety and depression symptoms trended consistently higher among patients with inadequately controlled AD relative to those with controlled disease (Figure 1B).
Mean DLQI scores were higher among patients with moderate/severe vs those with mild disease (9.2 vs 2.9; P < .001), and among patients with inadequately controlled vs controlled disease (13.4 vs 9.3; P < .001) (Figure 2A). Higher proportions of patients with moderate/severe and those with inadequately controlled disease reported that AD had a very large effect on their HRQoL (DLQI >10) relative to their respective comparator categories (Figure 2B). Higher proportions of patients with moderate/severe disease also reported that AD had substantial impacts on all individual DLQI items (all P < .001); patients with inadequately controlled disease reported a greater impact across items except for “influence clothes worn” and “sexual difficulties” (Table 3). In particular, item 7 on the DLQI, which elicits information on prevention of work or study, was reported by 116 (14.0%) and 18 (2.6%) patients with moderate/severe and mild disease, respectively (P < .001), and by 28 (27.2%) and 15 (18.3%) patients with inadequately controlled and controlled disease, respectively (P < .001).
This study, which reflects real-world clinical settings and included a large sample size, describes the impact of moderate-to-severe AD on patients’ daily lives. In addition, the high proportion of patients with inadequate control among those with moderate/severe AD on Im-tx or phototherapy highlights the needs and challenges associated with treating AD, especially given that therapy had been escalated in these patients to include systemic agents not currently indicated for AD treatment.
In contrast to studies that have reported few differences in the burden between mild and moderate/severe AD,7,8 the current study reported a significantly greater burden of moderate/severe AD across all outcomes compared with mildly affected patients. This difference between studies may be owing to sample size limitations of the other studies, and may also reflect differences in severity assessment; whereas the current study used an objective, validated, patient-reported measure to assess disease activity based on specific signs and symptoms, other studies asked patients to self-rate their AD severity. Lack of a standardized measure of AD severity increases the challenge of severity assessment in clinical settings,15,16 as exemplified by previously reported discordance, where one-third of physician- and patient-rated AD severity ratings were not in agreement.17,18
A novel aspect of this study was the exploration of patients’ perceptions of disease control among patients with moderate/severe disease for whom therapy has been escalated beyond topicals to include Im-tx or phototherapy. This group likely represents the more severe end of the spectrum given the escalation of therapy to include off-label use of systemic Im-tx medications, which lack a strong evidence base for long-term use.19-21 Despite use of these guideline-recommended therapies, the results suggest many of these patients do not experience good disease control. Not surprisingly, patients with inadequately controlled disease reported higher burdens relative to controlled patients, although not all of the differences were statistically significant, suggesting some burdens are similar to those of patients with uncontrolled disease. For example, patients with “controlled” AD still reported a high frequency of itch, sleep problems that interfere with daily activities, psychosocial issues, and impaired HRQoL. Thus, even so-called “controlled” disease still profoundly affects the lives of patients.
Atopic dermatitis is often considered a disease of childhood, yet 59.2% of patients reported diagnosis during adulthood, similar to a previous study that found that approximately 40% of patients were diagnosed as adults.6 However, age at diagnosis does not necessarily reflect age at onset, and some adults may not recall having AD as a child.22 Regardless of onset, patients were living with AD for more than half of their lives, supporting an associated long-term burden.23
Patients reported frequent, almost daily, itching. Itch drives the burden of AD because it is the primary complaint of patients,24 and affects sleep (the second most common complaint),24 as well as daily activities as indicated by the DLQI total score and its subscales.
In addition to itch, pain was also reported by patients. Although mean scores for pain were lower than for itch, the large standard deviations suggest wide variability in presence or perceptions of pain. Because use of pain medications was not specifically queried, the possibility of concomitant medications to manage pain cannot be excluded. Pain has rarely been evaluated in patients with AD, and this lack has been identified as an important gap in characterizing the burden of the disease.3 However, recent reports, including this study, highlight pain as an important dimension in moderate-to-severe AD,6,25 and support pain as a relevant outcome in determining AD-related treatment response.26 Future studies should assess use of pain medications in patients with AD, characterize different dimensions of AD-related pain, and explore associations of pain with other signs and symptoms of AD.
As previously reported in clinical trials and cross-sectional population-based studies,6,27,28 AD had profound effects on sleep, including sleep disturbances, longer sleep latency, and interference with function. These effects were greater in patients with moderate/severe AD and among those with inadequately controlled disease, and are consistent with the described relationship between itch and sleep.29,30 These results also support the association of sleep problems with fatigue and daily activities,28 with implications for greater work absenteeism and more clinician visits in addition to poorer overall health.27
The mental health burden was significantly higher among those with moderate/severe AD but only numerically higher in inadequately controlled relative to controlled AD, suggesting a similarly high psychosocial burden regardless of disease control. This burden appeared to be driven by the presence of anxiety, which was greater than depression, consistent with previous reports.6,8 These results emphasize the need for mental health assessment and support because suicidal ideation is also a feature associated with AD, especially among those with more severe disease.31-33
Results from the DLQI indicated greater HRQoL impairment at higher AD severity and when inadequately controlled. The DLQI subscales provide further indication of the substantial effects on patients’ daily lives, especially with regard to participatory activities, including preventing or interfering with school/work. In addition, high proportions of patients with moderate/severe and inadequately controlled AD reported being embarrassed/self-conscious, which may potentially exacerbate psychological distress through stigmatization.24,34
In addition to potential recall bias because the data are based on patient self-report, this study may be subject to several different types of selection biases: patients who agreed to participate may have characteristics different from those who did not agree; a survey conducted through the internet may reflect a population and perspective different from a survey conducted by other methods (eg, phone); and the patients may not necessarily reflect community practice since they were recruited from academic medical centers. Although it is also possible that some patients did not have AD, studies have suggested that report of a physician diagnosis of AD through use of a targeted question designed to elicit such information (as used in this study) may accurately identify patients with the disease.35,36 The definition that was used to characterize disease control may also be considered a limitation because other definitions may provide different results. Finally, this study is cross-sectional and causal inferences cannot be made.
This study provides real-world evidence of the multidimensional patient burden present in adults with AD. Patients with moderate/severe AD reported a significantly greater burden than mild patients on all outcomes. Inadequate disease control among patients with moderate/severe AD despite treatment with Im-tx or phototherapy is high. These results highlight the need for more effective therapies to better control AD, and support the importance of incorporating the patient perspective into assessment of AD beyond using measures of disease activity. It should be noted that this study characterized the patient-reported burden before the introduction of the first biologic agent approved for the treatment of patients with moderate-to-severe AD.37
Corresponding Author: Eric L. Simpson, MD, Department of Dermatology (CH16D), Oregon Health & Science University, 3303 SW Bond Ave, Portland, OR 97239-4501 (firstname.lastname@example.org).
Accepted for Publication: April 26, 2018.
Published Online: July 3, 2018. doi:10.1001/jamadermatol.2018.1572
Open Access: This article is published under the JN-OA license and is free to read on the day of publication.
Author Contributions: Mr Vekeman had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Simpson, Guttman-Yassky, Margolis, Mastey, Wei, Eckert, Arnold, Yu, Gadkari.
Acquisition, analysis, or interpretation of data: Simpson, Guttman-Yassky, Feldman, Hata, Mastey, Eckert, Chao, Arnold, Yu, Vekeman, Suárez-Fariñas, Gadkari.
Drafting of the manuscript: Simpson, Guttman-Yassky, Margolis, Arnold, Yu, Gadkari.
Critical revision of the manuscript for important intellectual content: Simpson, Guttman-Yassky, Margolis, Feldman, Hata, Mastey, Wei, Eckert, Chao, Arnold, Yu, Vekeman, Suárez-Fariñas, Gadkari.
Statistical analysis: Arnold, Vekeman, Suárez-Fariñas, Gadkari.
Obtained funding: Wei, Arnold, Gadkari.
Administrative, technical, or material support: Arnold, Yu.
Study supervision: Simpson, Guttman-Yassky, Mastey, Wei, Chao, Arnold, Gadkari.
Conflict of Interest Disclosures: Ms Mastey and Drs Wei, Gadkari, and Chao, are employees of and stockholders in Regeneron Pharmaceuticals Inc. Dr Eckert is an employee and stockholder in Sanofi. Dr Arnold and Ms Yu are employees of Quorum Consulting, Inc, which received research funding for the current study. Mr Vekeman is an employee of StatLog Econometrics, which received research funding for the current study. Dr Simpson has received grants/research support from Amgen, Celgene, Chugai, Galderma, and Regeneron Pharmaceuticals Inc, and is a consultant for Anacor, Asubio, Celgene, Galderma, Genentech, Medicis, and Merck. Dr Guttman-Yassky has acted as a consultant for and received grants/honoraria from AbbVie, Anacor, Celgene, Celsus Therapeutics, Dermira, Galderma, Glenmark, Janssen Biotech, LEO Pharmaceuticals MedImmune, Novartis, Pfizer, Regeneron, Sanofi, Stiefel/GlaxoSmithKline, Vitae, Mitsubishi Tanabe, Eli Lilly, Asana Biosciences, and Kiowa Kirin; has acted as an investigator for Celgene, Glenmark, Leo Pharmaceuticals, MedImmune, Regeneron, Eli Lilly; and has participated in advisory boards for Celgene, Celsus Therapeutics, Dermira, Galderma, Glenmark, MedImmune, Novartis, Pfizer, Regeneron, Sanofi, Stiefel/GlaxoSmithKline, Vitae, and Asana Biosciences. Dr Margolis has received research grants from Valeant and the National Institutes of Health (NIH) for studies on atopic dermatitis and consulting monies from Valeant, Regeneron, Sanofi, Astellas, and Anacor with respect to atopic dermatitis. Dr Feldman has received consulting support from Regeneron; research, speaking and/or consulting support from Galderma, Stiefel/GlaxoSmithKline, Almirall, Leo Pharmaceuticals, Baxter, Boeringer Ingelheim, Mylan, Celgene, Pfizer, Valeant, Abbvie, Cosmederm, Anacor, Astellas, Janssen, Lilly, Merck, Merz, Novartis, Qurient, National Biological Corporation, Caremark, Advance Medical, Suncare Research, Informa, UpToDate, and National Psoriasis Foundation; is founder and majority owner of http://www.DrScore.com and founder and part owner of Causa Research, a company dedicated to enhancing patients’ adherence to treatment. Dr Qureshi has acted as an investigator for Sanofi/Regeneron Pharmaceuticals Inc and Amgen, and as a consultant for Abbvie, Amgen, Centers for Disease Control, Janssen, Merck, Novartis, and Pfizer. Dr Hata has received research grants from Galderma, Novartis and Sanofi, and the NIH for studies on atopic dermatitis, and has served as an investigator for Asubio, Celgene, Pfizer, Regeneron, Allergan, Chugai, Tigercat, and Roche/Genentech. Dr Suarez-Farinas received research funding for the current study. No other disclosures are reported.
Funding/Support: This study was supported by Regeneron Pharmaceuticals Inc and Sanofi.
Role of the Funder/Sponsor: Regeneron Pharmaceuticals Inc and Sanofi played no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: Medical writing support in the preparation of this publication was provided by E. Jay Bienen, PhD, and funded by Sanofi and Regeneron Pharmaceuticals Inc.
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