Introduction
Atopic dermatitis (AD), commonly known as eczema, is a chronic relapsing inflammatory skin disease characterized by pruritus, erythema, and lichenified lesions of the skin. The pathogenesis of AD is complex and involves genetic predisposition, a hyperactive immune system, and environmental factors [
1]. While AD most frequently affects children, it is a disease that can persist into adulthood or have adult onset. The prevalence in US adults is estimated to be 7.2% [
2,
3].
Pruritus is an early characteristic symptom of AD, so much so that AD is known as “the itch that rashes” [
4]. AD is commonly associated with intense nocturnal pruritus, which can affect sleep and quality of life (QoL) [
5,
6]. Sleep insufficiency can lead to excessive daytime sleepiness, mood disturbance, and impaired cognition [
7], which can then have an impact on work or school productivity, accidents, and adverse health outcomes including metabolic, endocrine, and immune dysregulation such as type 2 diabetes, hypertension, and infection [
8‐
12].
Both qualitative and quantitative analyses of sleep disturbance in patients with AD are valuable for the evaluation of disease activity and response to therapy. Much of the current literature focuses on sleep disturbance in pediatric patients with AD using qualitative assessments based on subjective surveys [
13]. In general, discrepancies between subjective and objective measurements of sleep have been previously reported [
14,
15]. For example, adults with nocturnal asthma reported reduced overall sleep quality compared to control subjects but not increases in frequency of awakenings (subjective) even though polysomnographic measurement revealed differences in sleep latency, efficiency, and awakenings (objective) [
16]. The topic of sleep disturbance in adult AD patients is not well studied. We reviewed the literature for studies that have investigated the relationship between AD and its effect on sleep in adults.
Discussion
A comprehensive review of the literature showed that there is a high prevalence (33–87.1%) of sleep disturbance in adults with AD [
17,
18,
20]. The likelihood of sleep disturbance is much higher in patients with AD compared to healthy controls [
2,
17]. Sleep disturbance appears to worsen with AD severity [
19,
20,
24,
26,
29]. Although various studies showed mixed results, overall, adults with AD experience lower sleep quality as evidenced by difficulty falling asleep, greater frequency and duration of waking episodes, and shorter sleep duration. Such disturbances can consequently lead to daytime sleepiness, fatigue, and dysfunction. Adult patients with AD and associated sleep disturbance can experience difficulties with IADLs and may have more missed workdays, days in bed, and doctor visits [
2,
17,
26,
27], which may contribute to decreased QoL. These findings illustrate the importance of addressing sleep disturbances in patients with AD as part of routine disease management.
The current literature review found pruritus and scratching to be a large contributor to sleep disturbance in adult patients with AD. Pruritus appears to be associated with lower quality of sleep [
24] with more frequent and longer duration of awakenings. Scratching also brings one to a more superficial stage of sleep. Scratching mainly occurs in N1 and N2 stages of NREM sleep [
26,
31], which have the lowest arousal threshold but are essential for “restorative” sleep. Pruritus in AD is associated with a negative impact on QoL as measured by validated instruments such as the DLQI and EuroQoL-5 dimensions visual analog scale (EQ-5d VAS) [
23]. A better understanding of the mechanism of pruritus and therapies may improve QoL in adult patients with AD and sleep disturbance.
Small numbers of studies suggest that sleep disturbance is associated with increased type 2 T helper (Th2) cell pathway activation in AD patients, which can worsen skin disease, leading to a self-perpetuating cycle of itch-scratch-sleep loss. However, current evidence does not clearly describe the extremely complex relationship between sleep disturbance and cytokines in AD. Many cytokines have been implicated in the pathogenesis of AD, and a small number of studies show that these cytokines may overlap or interact with those that regulate or influence sleep. Bender et al. [
26] found that the morning-evening change of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-10 produced by peripheral mononuclear cells and stimulated by anti-CD3 correlates with sleep efficiency as measured by actigraphy in adults with AD. This suggests that higher levels of inflammatory cytokines are associated with poor sleep efficiency, a finding that is also seen in other diseases such as rheumatoid arthritis and inflammatory bowel disease [
54,
55]. Other studies have found that the ratio of interferon (IFN)-γ to IL-4 is lower in children with AD experiencing poor sleep efficiency and that morning blood plasma levels of IL-31 correlated with sleep disturbance, specifically in N1 sleep [
56,
57].
Interestingly, inflammation and sleep are linked by central and peripheral circadian mechanisms [
58], which not only regulate melatonin and sleep-wake cycles, but also affect inflammatory cells, cytokines [
59,
60], and intrinsic skin properties such as pH, water loss, and permeability [
61‐
63]. In AD, cyclical changes in melatonin and cortisol release may promote inflammation and exacerbate itch [
41]. Nighttime changes in skin physiology and inflammatory cytokines can, in turn, exacerbate atopic inflammation, pruritus, and sleep disturbance [
58,
61,
64].
Several environmental factors have also been associated with sleep disturbance in AD. For example, serum IgE antibodies specific for dust mite allergens, Derf and Derp, were significantly correlated with reduced sleep efficiency, longer sleep onset latency, increased sleep fragmentation, and decreased non-REM sleep in children with eczema [
65]. High concentrations of dust mite allergen are found on beds and may be a source of exposure during sleep. In children with AD from the German LISAplus cohort, exposure to mold or visible dampness was also associated with increased risk of sleep problems, including difficulty falling asleep, difficulty staying asleep, and decreased overall sleep time [
66]. Currently, there is a lack of studies examining the impact of environmental factors on sleep in adults with AD. Future research in this area may identify modifiable aspects of the living environment that can improve sleep and QoL in adults.
Despite the obvious importance of evaluating sleep, there is currently no reliable tool designed specifically for AD patients to assess sleep in the clinical setting. It is important to note that sleep disturbance is a parameter that is included in the calculation of total points on the SCORAD; this can give rise to bias in favor of reported correlations between both sleep disturbance and AD activity in the clinical and research settings. PSG and actigraphy are not practical for utilization in a dermatology practice. Widely used, validated dermatology QoL surveys such as DLQI [
67] identify sleep disturbance only as a secondary measure and do not focus on assessing the degree of sleep disturbance or offer much insight into treatment options. Furthermore, available patient QoL measurement scales are considered less practical and are not recommended for routine clinical practice [
68]. However, administering a brief sleep questionnaire (e.g., PSQI) prior to the first visit in all new patients and then on subsequent follow-up visits may be worthwhile to follow improvement with management of AD [
69]. At a minimum, clinicians should evaluate the patients’ severity of AD and ask general questions about itch, sleep, impact on daily activities, and persistence of disease. If a patient complains of sleep disturbance, clinicians can take a basic sleep history focusing on the five major domains of sleep: sleep onset, latency, quality, efficiency, snoring, or difficulty breathing. A useful mnemonic used as a screening tool in children is BEARS (B = bedtime problems, E = excessive daytime sleepiness, A = awakenings during the night, R = regularity and duration of sleep, S = snoring or difficulty breathing), which can be useful to quickly assess different domains of sleep [
70]. Furthermore, it may also help rule in or out other possible causes that may be contributing to sleep disturbance, such as an unhealthy sleep hygiene or an underlying sleep disorder, and make appropriate recommendations if necessary. A referral to a specialist for sleep evaluation can be considered when a patient regularly has trouble with sleep disturbance despite addressing one or more of these factors.
Optimal management of sleep health in AD requires a multidisciplinary approach. One aspect of improving sleep involves targeting pruritus, which can drive sleep disturbance in AD. Generally, the least invasive treatments should be tried first. Patient education on breaking the itch-scratch cycle has been used to address sleep disruption [
71]. Topical emollients can significantly improve itch and consequently sleep quality [
35]. Addition of chlorhexidine-soaked dressing “wet wrap” may also be helpful [
37]. Similarly, topical corticosteroids with or without use of emollients and systemic agents for AD such as methotrexate [
46] and azathioprine [
47] are also shown to be beneficial for improving itch and sleep in AD patients. Dupilumab is a new biologic agent that also has been shown to significantly improve pruritus and sleep during clinical trials [
18]. Antihistamines used to treat pruritus have sedative effects and can therefore also improve sleep [
40,
42‐
44,
50]. On the other hand, the use of benzodiazepines is not well studied and may not improve sleep in adult AD patients [
51]. Other interventions focus directly on sleep disturbance itself. For example, psychological therapy aimed at improving sleep hygiene, promoting relaxation, and establishing behavior plans for addressing sleep problems may reduce loss of sleep in chronic itch [
72,
73]. In addition to behavioral interventions, melatonin has been shown to be a safe and effective way to improve sleep-onset latency in pediatric patients with AD [
49].
Acknowledgements
No funding or sponsorship was received for this study or publication of this article. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.