Atopic dermatitis (AD) is a common relapsing inflammatory skin condition characterized by pruritus, erythema, and lichenified skin lesions [1]. AD usually appears in childhood and, in most cases, improves with age. However, in about one in five patients, it persists into adulthood [1]. AD is thought to be caused by skin barrier dysfunctions that lead to increased immune reactions and inflammation [1, 2].
The intense itching associated with AD often causes patients to experience severe sleep disturbance, leading to daytime sleepiness and sleep-related impairment [1, 3,4,5]. Compared to patients with AD who do not report sleep disturbance, those who report sleep disturbance more often miss work, have doctor visits, and experience difficulties performing daily tasks [6, 7]. Sleep disturbance is reported by 33% to 87% of patients with AD [3], and as few as one in five patients report having good or very good sleep quality [5].
Although sleep disturbance is a significant problem for patients with AD, clinical trials examining AD treatments have usually focused on physician-assessed outcomes [3, 8]. Reliable tools for assessing sleep disturbance from the patient perspective are lacking [3]. Simple concepts such as itch or pain are often assessed using single-item questionnaires, whereas complex concepts such as sleep disturbance require a more detailed approach to capture the multidimensionality and daily variability of the concept. Thus, a single-item scale, such as a single NRS administered daily, is not sufficient to adequately capture the multidimensionality of the sleep disturbance concept. However, combined with a multi-item diary, it could be an appropriate approach for assessing the benefit of an intervention.
Actigraphy and polysomnography have been used to quantitatively measure objective aspects of sleep [9, 10], but they do not capture how individuals feel or function in daily life, cannot examine the effect of an intervention from the patient perspective, often do not correlate well with subjective assessments of sleep using diaries, and, in the case of actigraphy, have limited usefulness for assessing sleep onset latency and duration of awakenings [8, 11]. Several patient-reported outcomes (PROs) for assessing sleep are available. These include the Pittsburgh Sleep Quality Index for adults [3] and the PROMIS Sleep Disturbance and sleep-related impairment item banks [5]. Several other instruments are available for assessing sleep quality in children, adolescents, and adults [12, 13]. However, these instruments were not developed in consultation with AD patients, and, therefore, cannot be assumed to be fit-for-purpose or adequate for them.
Participants were identified and recruited across six clinical sites in the US (California, Florida, New York, and Texas). Participants had to be aged ≥12 years; have a clinical diagnosis of moderate-to-severe AD, as defined by an Eczema Area and Severity Index (EASI) ≥12 within 2 weeks of study enrollment [11]; and have a score ≥ 4 on the SCORing Atopic Dermatitis (SCORAD) sleep loss visual analog scale (VAS) [18] within 2 weeks of study enrollment. Participants also had to be able to read and understand English sufficiently to participate in a telephone interview and complete the assessments. Participants were excluded if they had a significant speech impairment, cognitive impairment, hearing difficulty, visual impairment, or severe psychopathology in the opinion of the site’s clinical staff. Efforts were made to recruit a diverse sample of patients that included adolescents (12–17 years), young adults (18–30 years), middle-aged adults (31–45 years), and mature adults (≥46 years).
The EASI is a clinician-reported scale designed to measure the severity and extent of AD [19]. The EASI is a composite score based on the total area affected and intensity of redness, thickness, scratching, and latensification on the head/neck, trunk, upper limbs, and lower limbs. The score ranges from 0 to 72, with a higher score indicating more severe AD.
SCORAD is a hybrid clinician- and self-reported tool that includes the extent, intensity, and symptoms of AD [18]. The SCORAD total score ranges from 0 to 103, with a higher score indicating more severe AD. Included in SCORAD are VASs in which sleeplessness and pruritus are scored from 0 for “none” to 10 for “worst possible.”
Interviews
The interviews followed the methodology of the US Food and Drug Administration and ISPOR for developing PRO instruments [15, 16, 20]. All interviews were conducted in US English by trained qualitative researchers. Clinical site investigators were responsible for ensuring that all participants fully understood the nature and purpose of the interview. Potential participants received a consent form describing the details of the study, which they reviewed with the site’s clinical staff, and were given the opportunity to ask questions about the study.
Experienced and trained staff conducted interviews by telephone using semi-structured interview guides. Interviewers were trained in study-specific objectives and the sponsor’s adverse event reporting requirements.
All identifying information was removed from the transcripts to maintain the confidentiality of all protected health information. Interviews lasted approximately 90 min and were audio recorded.
Data management and quality control
Audio-recorded data collected during the interviews were transcribed by third-party professional transcription services. Audio files from the interviews were reviewed by the scientific staff for quality assurance purposes to remove public health information and correct obvious transcription errors. Quantitative sociodemographic and clinical data were transmitted using a secure file transfer portal directly into the electronic system database. An electronic image of the case report form was then entered into the database and reviewed by project scientific staff. Data discrepancies were identified and resolved.
The scientific staff was responsible for the overall direction and supervision of the data collection, as well as for monitoring the study progress and quality control of data. All work was subject to quality control, as well as documentation procedures to ensure that the data were accurate, and the analyses could be reproduced.
Data analysis
Sociodemographic and clinical characteristics collected in phase I were characterized using descriptive statistics for the entire participant sample. Quantitative analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA) [21].
Qualitative data collected in transcripts were analyzed using a content analysis approach. The coding process was driven by the objectives of the study and consisted of tagging codes to segments of textual data to facilitate the comprehension of a large amount of data. Concept codes were used to capture the participants’ descriptions of their experiences with sleep problems, and the impact on their everyday life. Specific codes related to comprehension, relevance, and acceptability of the items, instructions, response options, recall periods, and ease of use/completion of the measures were also used. All qualitative analyses were performed using ATLAS.ti, version 7.0 or higher (Scientific Software Development GmbH, Berlin, Germany) [22]. Coding dictionaries were developed to aid with the coding. Relevant concepts mentioned in the interviews were tracked to monitor the saturation of concepts. Saturation was defined as the point at which no substantially new information or concepts continued to emerge beyond what had been mentioned in previous interviews [23, 24]. Saturation was documented with the help of saturation grids, where concepts (spontaneously reported or probed) endorsed by participants were listed vertically, and study participant identification numbers representing each individual interview were listed horizontally [14]. The qualitative interviews in phase I were also used to identify thresholds for a meaningful change, and the thresholds for “no or minimal” sleep disturbance in the SD NRS.
Ethics
Prior to participant recruitment, institutional review board approval (Advarra, Columbia, MD) of the study protocol was obtained. All recruitment procedures complied with current Health Insurance Portability and Accountability Act regulations in the US. Adult participants had to provide written informed consent prior to study procedures. Adolescent participants had to provide informed assent, and their parent or legal guardian had to provide written permission for their child to participate beforehand. All participants also had to consent to being audio recorded during the discussions.
Results
Phase I
Participants
In phase I, 20 adult and 10 adolescent participants were enrolled between December 2018 and April 2019 across six clinical sites in the US. The mean age of the adult participants was 33.5 years, and the majority were female (n = 12). The mean age of the adolescent participants was 14.1 years, and equal numbers were male and female (n = 5 each) (Table 2). Most participants were White or Asian, and most identified themselves as not Hispanic. According to the site’s clinical staff, pruritus was severe for most participants (n = 13 adults, n = 7 adolescents); all other patients were described as having moderate pruritus. The mean ± standard deviation (SD) Eczema Area and Severity Index (EASI) score was 25.7 ± 11.5 (median [range] = 22.5 [12.0–50.9]) for adults and 26.3 ± 8.9 (median [range] = 25.0 [12.2–38.5) for adolescents. The mean ± SD SCORing Atopic Dermatitis (SCORAD) score was 72.5 ± 11.0 (median [range] = 70.8 [57.0–97.4]) for adults and 78.6 ± 15.6 (median [range] = 75.0 [52.0–95.8]) for adolescents. The EASI and SCORAD scores indicate that all patients had moderate to severe AD [25].
Table 2 Participant Demographics and Clinical Characteristics
The mean ± SD SCORAD VAS for pruritus was 7.7 ± 1.6 (median [range] = 8.1 [4.0–9.8]) for adults and 7.6 ± 1.7 (median [range]: 8.0 [5.4–10.0]) for adolescents. The mean ± SD SCORAD VAS for sleep loss was 7.2 ± 1.6 (median [range] = 7.5 [4.0–9.7]) for adults and 6.7 ± 1.9 (median [range] = 6.5 [4.3–10.0]) for adolescents. Thus, all patients had moderate to very severe pruritus and sleep loss.
Concept elicitation
Data saturation was assessed following an inductive thematic approach after all interviews had been completed [23, 24]. Figure 1 shows the saturation grids that summarize the concepts that emerged during the interviews with adults and adolescents, as well as the number of participants who mentioned sleep disturbance concepts spontaneously versus when probed. Saturation was reached after four adult participant interviews and two adolescent participant interviews.
Fig. 1
Saturation Concepts by Individual Adult and Adolescent Participants
Overall, the most frequent sleep-related issue reported was nighttime awakening (87% overall: 80% of adults and 60% of adolescents), followed by trouble falling asleep (73% overall: 90% of adults and 80% of adolescents), feeling unrested (53% overall: 60% of adults and 40% of adolescents), daytime fatigue or sleepiness (53% overall: 55% of adults and 50% of adolescents), and feeling as though they had not gotten enough sleep (33% overall: 30% of adults and 50% of adolescents) (Fig. 1 and Table 3). Early morning awakening was mentioned by 40% of adolescents, but reported by only 5% of adults.
Sleep disturbance was daily for 70% of adults and 30% of adolescents, less than daily for 20% of adults and 70% of adolescents, and not specified for 10% of adults. How sleep disturbance varied was obtained from 19 adults and 10 adolescents. For several patients (32% of adults and 20% of adolescents), variation in sleep disturbance was related to whether they were experiencing a flare up. Several others (16% of adults and 20% of adolescents) indicated the sleep disturbance depended upon whether or not they had used their medication for AD that day, and one adult participant (5%) stated that their sleep disturbance depended on the weather. Other participants (26% of adults and 60% of adolescents) described the extent of variation in sleep disturbance but did not provide reasons. A few adults (16%) indicated that the severity of their sleep disturbance did not vary from day to day.
Duration of sleep disturbance
The duration of total daily sleep varied between participants. One adult (5%) reported sleeping as little as three to 4 h per day, while another (5%) reported sleeping eight to 9 h per day. One adolescent (10%) described sleeping as little as 4 h per day, while another (10%) slept eight to 10 h. All other participants reported durations of total daily sleep between these extremes.
Description of nighttime awakenings
The number of awakenings each night varied greatly, although most adult and all adolescent participants reported 1–10 awakenings per night. Two adult participants (10%) reported waking up 1–2 times per night, and one (5%) reported that they did not usually wake up during the night because of being too tired. On the extreme end, another adult (5%) estimated waking up as many as 10 times per night. A few adolescents (30%) reported waking up 2–3 times per night; others reported waking up 1–2 times per night (20%), two times per night (20%), or five times per night (20%).
The duration of awakenings also varied. One adult (5%) reported being awake for as little as a few seconds, while another (5%) would be awake for an hour. Some adults (15%) noted that the amount of time they were awake would vary from a couple minutes to an hour. One adolescent participant (10%) reported being awake for 10–15 min, while another (10%) would be awake for an hour. Another adolescent (10%) noted that the amount of time awake varied, as it would sometimes be for 15 min and other times for “hours.”
Of 16 adults asked about the ease of falling back asleep after a nighttime awakening, 44% noted that they could fall asleep easily or quickly and 31% reported difficulty falling back asleep. Some (31%) explained that it varied depending on how tired they were, how bad the itch was, or whether they got out of bed to use medication, use lotion, or to shower. Of six adolescents asked this question, most (67%) reported that they could fall back to sleep easily or quickly.
Causes of sleep disturbance
Several adults (37%) and adolescents (43%) attributed their sleep disturbance solely to itching from AD. The remaining participants attributed the sleep disturbance to a combination of AD-related symptoms (e.g., itching, burning sensations, inflammation, or pain) and other non-AD causes (e.g., consuming caffeinated beverages, asthma, stress, anxiety, or panic attacks).
Impact of sleep disturbance on quality of life
Several adults (63%) and adolescents (56%) mentioned feeling tired, fatigued, or drowsy during the day. Some adult participants (32%) discussed an impact on work, and most adolescents (67%) reported an impact on school. Some adults (11%) reported that sleep disturbance affected their mood, reporting feeling “impatient,” “snappy,” “irritable,” or not “cheery;” other effects included increased stress levels or being lazier during the day (5% each).
All participants understood the SD NRS question; most found it easy or very easy to understand (100% of adults and 90% of adolescents), and most understood the anchors as intended (95% of adults and 100% of adolescents) (Table 4). A few adults (25%) and adolescents (10%) provided suggestions for improving the item. Suggestions included replacing the abbreviation “AD” with “atopic dermatitis” (15% of adults and 10% of adolescents), adding “eczema” in parenthesis next to “atopic dermatitis” (10% of adults), reducing the scale from 1 to 10 to 1–5 (5% of adults), adding “getting better” next to the anchor description of “no sleep loss” (5% of adults), and adding a description under the response option for five on the scale (10% of adolescents).
Meaningful change in SD NRS
If sufficient time was available during the interviews, participants were queried about what they considered a meaningful change. Of participants (n = 19 adults and n = 9 adolescents) asked about the smallest improvement they would be satisfied or content with on the SD NRS, most (69% of adults and 88% of adolescents) indicated a change of one to three points, with a two-point change being the most frequent response (32% of adults and 44% of adolescents) (Table 5). Of participants (n = 17 adults and n = 10 adolescents) probed about the levels of improvement that would be meaningful, most (94% of adults and 90% of adolescents) indicated that they would consider a change of one or two points in the SD NRS a meaningful change. Of participants (n = 18 adults and n = 10 adolescents) asked about what they considered no or minimal sleep disturbance, the most frequent response was score of two (41% of adults and 40% of adolescents), followed by one (29% of adults and 30% of adolescents) and three (24% of adults and 10% of adolescents).
Changes made to the SD NRS following phase I interviews
Based on the recommendations made during the cognitive interviews during phase I, the abbreviation “AD” in the SD NRS was replaced with “atopic dermatitis” or “your skin disease,” and the anchor “I cannot sleep at all” was changed to “I did not sleep at all” (Table 1).
This qualitative study supports the importance and relevance of sleep disturbance in adolescents and adults with moderate-to-severe AD and pruritis. We found that AD-associated sleep disturbance is a multidimensional concept, and that nighttime awakenings, trouble falling asleep, and feeling unrested are experienced by most participants. Other common issues included daytime fatigue or sleepiness, a feeling of not having had enough sleep, and an early-morning awakening. The current study also revealed that the degree of sleep disturbance varies substantially from day to day in patients with AD due to varying extents of itching and flares, medication use, and changes in the weather.
Our findings agree with a recent systematic literature review, which reported that adults with AD frequently experience sleep disturbance (prevalence of 33% to 87.1%), difficulty falling asleep, frequent/extended awakenings, and shorter sleep durations, which result in daytime sleepiness, fatigue, and reduced functioning [3]. The current results also agree with studies showing that a sleep disturbance is one of the most important components of the burden of chronic itch [26], that pruritus and scratching are a principal cause of sleep disturbance in patients with AD [27], and that the degree of sleep disturbance and sleep loss corresponds with the severity of AD [4, 5].
To support the potential use of the SD NRS as an endpoint in AD clinical trials for evaluating the meaningful treatment effects on this population, we also investigated thresholds for meaningful change. Although data on meaningful change are often collected using quantitative approaches (especially anchor- and distribution-based methods) [28], we evaluated thresholds using a qualitative approach to reflect the direct patient perspective, which is increasingly valued by regulators [29]. Most participants considered a one-point improvement to be a meaningful change, although they most frequently reported that they would be satisfied or content with a two-point change. This information will be used to inform the responder definition threshold estimates assessed quantitatively using anchor- and distribution-based methods.
The data that support the findings of this study are available from Galderma, but restrictions apply to the availability of these data and, so, are not publicly available. Data are however available from the authors upon reasonable request and with permission of Galderma.
Change history
29 December 2020
An amendment to this paper has been published and can be accessed via the original article.
Abbreviations
AD:
Atopic dermatitis
CSD-AD:
Consensus Sleep Diary, atopic dermatitis version
EASI:
Eczema Area and Severity Index
PRO:
Patient-reported outcome
SCORAD:
SCORing Atopic Dermatitis
SD NRS:
Sleep disturbance numerical rating scale
VAS:
Visual analogue scale
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The authors thank: Phillip Leventhal, PhD (Evidera) for medical writing; Fatoumata Fofana and Danielle Rodriguez for reviewing the article; Andrea Schutz for analyzing the results and reporting; and the interviewers and coders for conducting the interviews and coding the transcripts. Medical writing was paid for by Galderma.
Funding
The study was funded by Galderma.
Author information
Authors and Affiliations
Evidera, The Ark, 201 Talgarth Road Hammersmith, London, W6 8BJ, UK
Carla Dias-Barbosa
Evidera, 7101 Wisconsin Avenue, Suite 1400, Bethesda, MA, 20814, USA
Rodolfo Matos & Margaret Vernon
Ryerson University, 350 Victoria Street, Toronto, ON, M5B 2K3, Canada
Colleen E. Carney
University of California, San Francisco, Weill Institute for Neurosciences, 401 Parnassus Avenue, San Francisco, CA, 94143-0984, USA
Andrew Krystal
Galderma, World Trade Center, Avenue Gratta-Paille 2, 1018, Lausanne, Switzerland
CDB designed the study, and was involved in the analysis, results interpretation, and reporting. RM was involved in the development of study documents, data collection, analyses and reporting. MV was involved in the study design and results interpretation. AK and CEC were involved in the results interpretation, and reviewed the manuscript. And JP was involved in the study design, results interpretation, and reporting. The author(s) read and approved the final manuscript.
Adult participants had to provide written informed consent prior to study procedures. Adolescent participants had to provide informed assent, and their parent or legal guardian had to provide written permission for their child to participate beforehand. All participants also had to consent to being audio recorded during the discussions. All recruitment procedures complied with current Health Insurance Portability and Accountability Act regulations in the US. Evidera obtained institutional review board approval of the study protocol in the US prior to participant recruitment.
Consent for publication
Not applicable.
Competing interests
AK reports research funding from the National Institutes of Health (NIH), Patient-Centered Outcomes Research Institute (PCORI), Janssen, Jazz, Axsome and Reveal Biosensors, as well as consulting fees from Eisai, Ferring, Galderma, Harmony Biosciences, Idorsia, Jazz, Janssen, Takeda, Merck, Neurocrine, Pernix, Sage, and Evecxia. CDB, RM, and MV are employees of Evidera, a firm contracted by Galderma to conduct the research. JP is an employee of Galderma.
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Dias-Barbosa, C., Matos, R., Vernon, M. et al. Content validity of a sleep numerical rating scale and a sleep diary in adults and adolescents with moderate-to-severe atopic dermatitis.
J Patient Rep Outcomes4, 100 (2020). https://doi.org/10.1186/s41687-020-00265-y
