Nocturnal eczema: Review of sleep and circadian rhythms in children with atopic dermatitis and future research directions
2015; Elsevier BV; Volume: 136; Issue: 5 Linguagem: Inglês
10.1016/j.jaci.2015.08.028
ISSN1097-6825
AutoresAnna Fishbein, Olivia Vitaterna, Isabel Haugh, Aakash Bavishi, Phyllis C. Zee, Fred W. Turek, Stephen H. Sheldon, Jonathan I. Silverberg, Amy S. Paller,
Tópico(s)Asthma and respiratory diseases
ResumoChildren with atopic dermatitis (AD) experience significant sleep disruption, and clinically, the disease is noted to worsen in a circadian manner at night. Epidemiologic findings highlight many negative consequences of AD, such as impaired linear growth, which is uniquely related to disturbed sleep. Clinical guidelines currently recommend assessing sleep in patients with AD as a crucial parameter of disease control with appropriate treatment. In this review we describe our current understanding of the roles of sleep cycles and circadian rhythms in the nighttime exacerbation of AD (nocturnal eczema). We present a schematic to explain the mechanism of nocturnal eczema. Treatment options for sleep disturbance and future directions for research are discussed in the context of AD. Children with atopic dermatitis (AD) experience significant sleep disruption, and clinically, the disease is noted to worsen in a circadian manner at night. Epidemiologic findings highlight many negative consequences of AD, such as impaired linear growth, which is uniquely related to disturbed sleep. Clinical guidelines currently recommend assessing sleep in patients with AD as a crucial parameter of disease control with appropriate treatment. In this review we describe our current understanding of the roles of sleep cycles and circadian rhythms in the nighttime exacerbation of AD (nocturnal eczema). We present a schematic to explain the mechanism of nocturnal eczema. Treatment options for sleep disturbance and future directions for research are discussed in the context of AD. Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com. Sleep plays an important role in promoting physical and mental health. Sleep deprivation has been shown to alter immune function.1Ozturk L. Pelin Z. Karadeniz D. Kaynak H. Cakar L. Gozukirmizi E. Effects of 48 hours sleep deprivation on human immune profile.Sleep Res Online. 1999; 2: 107-111PubMed Google Scholar Patients with chronic disease are susceptible to sleep disruption caused by poor illness control, illness-related symptoms at night, and medications used as principal treatments.2Koinis-Mitchell D. Craig T. Esteban C.A. Klein R.B. Sleep and allergic disease: a summary of the literature and future directions for research.J Allergy Clin Immunol. 2012; 130: 1275-1281Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Atopic dermatitis (AD; also called eczema) is a chronic inflammatory skin disorder affecting 10% to 20% of US children.3Shaw T.E. Currie G.P. Koudelka C.W. Simpson E.L. Eczema prevalence in the United States: data from the 2003 National Survey of Children's Health.J Invest Dermatol. 2011; 131: 67-73Abstract Full Text Full Text PDF PubMed Scopus (543) Google Scholar AD is characterized by intense nocturnal pruritus,4Wolter S. Price H.N. Atopic dermatitis.Pediatr Clin North Am. 2014; 61: 241-260Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar which can severely affect sleep continuity, sleep quality, and quality of life. Sixty percent of children with AD experience sleep disturbance caused by their disease, with 83% reporting sleep disturbance during exacerbations.5Chamlin S.L. Mattson C.L. Frieden I.J. Williiams M.L. Mancini A.J. Cella D. et al.The price of pruritus: sleep disturbance and cosleeping in atopic dermatitis.Arch Pediatr Adolesc Med. 2005; 159: 745-750Crossref PubMed Scopus (144) Google Scholar, 6Hon K.L. Leung T.F. Wong K.Y. Chow C.M. Chuh A. Ng P.C. Does age or gender influence quality of life in children with atopic dermatitis?.Clin Exp Dermatol. 2008; 33: 705-709Crossref PubMed Scopus (78) Google Scholar, 7Camfferman D. Kennedy J.D. Gold M. Martin A.J. Lushington K. 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The circadian clock controls toll-like receptor 9-mediated innate and adaptive immunity.Immunity. 2012; 36: 251-261Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar and itch exacerbation by bacterial products, such as staphylococcal superantigens, irritants, and allergens, can all promote the hallmark of inflammatory TH1, TH2, and TH22 cellular infiltrate21Novak N. Leung D.Y. Advances in atopic dermatitis.Curr Opin Immunol. 2011; 23: 778-783Crossref PubMed Scopus (68) Google Scholar in patients with AD, homing to skin secondary to diurnally mediated chemokine gradients.22Scheiermann C. Kunisaki Y. Frenette P.S. Circadian control of the immune system.Nat Rev Immunol. 2013; 13: 190-198Crossref PubMed Scopus (605) Google Scholar In this review we describe our current understanding of the roles of sleep cycles and circadian rhythms in the nighttime exacerbation of AD (nocturnal eczema, Fig 1). Treatment options for sleep disturbances and future directions for research are discussed in the context of AD. By around 3 months of age, 24-hour sleep architecture begins to become structurally more predictable and reproducible. Sleep is defined polysomnographically by 4 stages.23Kahn A. Dan B. Groswasser J. Franco P. Sottiaux M. Normal sleep architecture in infants and children.J Clin Neurophysiol. 1996; 13: 184-197Crossref PubMed Scopus (98) Google Scholar, 24Iber C. Ancoli-Israel S. Chesson A.L. Quan S.F. The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. American Academy of Sleep Medicine, Westchester (IL)2007Google Scholar, 25Sheldon S.H. Kryger M. Ferber R. Gozal D. Principles and practices of pediatric sleep medicine.2nd ed. Elsevier, Philadelphia2014Google Scholar A typical night of sleep involves multiple cycles through stages N1-N3 (nonrapid eye movement [NREM]) and rapid eye movement (REM) sleep. During the first year of life, NREM and REM sleep are equally distributed across the nocturnal sleep period. After the first year, NREM sleep is most prominent during the first third to first half of the sleep period and REM sleep during the last third to last half of the sleep period. N1 sleep is considered transitional, and arousal from this state is easiest. Arousal thresholds during N2 and REM sleep are similar. N3 sleep is the deepest stage of sleep, with characteristic slow waves on a polysomnogram, and has the highest arousal threshold. Dreaming occurs during REM sleep. Muscle tone is at its nadir during REM sleep. Sixty-minute NREM/REM cycles are seen in infants and toddlers, extending to a mature 90-minute NREM/REM cycling between 2 and 5 years of age.25Sheldon S.H. Kryger M. Ferber R. Gozal D. Principles and practices of pediatric sleep medicine.2nd ed. Elsevier, Philadelphia2014Google Scholar After each state change, brief (<1 minute) waking is normal, and most healthy children quickly fall back asleep. Multiple studies using actigraphy and polysomnography have documented that children with severe AD have decreased sleep efficiency (defined as actual sleep time divided by the total polysomnogram recording time).26Hon K.L. Leung T.F. Ma K.C. Li A.m. Wong Y. Yin J.A. et al.Resting energy expenditure, oxygen consumption and carbon dioxide production during sleep in children with atopic dermatitis.J Dermatol Treat. 2005; 16: 22-25Crossref PubMed Scopus (22) Google Scholar Children with AD also have frequent nighttime awakenings, greater difficulty falling asleep, and greater difficulty awakening for school.27Dahl R.E. Bernhisel-Broadbent J. Scanlon-Holdford S. Sampson H.A. Lupo M. Sleep disturbances in children with atopic dermatitis.Arch Pediatr Adolesc Med. 1995; 149: 856-860Crossref PubMed Scopus (145) Google Scholar Because currently available tools to assess parental and patient reports of sleep disruption and itching correlate poorly with objective measures, objective studies are critical for the assessment of sleep disturbances in children with AD.10Gupta M.A. Gupta A.K. Sleep-wake disorders and dermatology.Clin Dermatol. 2013; 31: 118-126Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar AD scratching is generally highest in transitional sleep (N1 and N2) compared with N3 sleep (N1: 0.46 ± 0.4 scratches/min)28Savin J.A. Paterson W.D. Oswald I. Scratching during sleep.Lancet. 1973; 2: 296-297Abstract PubMed Scopus (63) Google Scholar; however, the length of scratching episodes is the same throughout the sleep stage.29Savin J.A. Paterson W.D. Oswald I. Adam K. Further studies of scratching during sleep.Br J Dermatol. 1975; 93: 297-302Crossref PubMed Scopus (66) Google Scholar Although one earlier study contradicts the increased frequency of movements during stage 1 and 2 sleep,30Tantam D. Kalucy R. Brown D.G. Sleep, scratching and dreams in eczema. A new approach to alexithymia.Psychother Psychosom. 1982; 37: 26-35Crossref PubMed Scopus (20) Google Scholar children with AD generally have greater sleep disturbance during the first half of the night, resulting in decreased NREM but not REM sleep compared with control subjects.13Chang Y.S. Chou Y.T. Lee J.H. Lee P.t. Dai Y.S. Sun C. et al.Atopic dermatitis, melatonin, and sleep disturbance.Pediatrics. 2014; 134: e397-405Crossref PubMed Scopus (99) Google Scholar The significantly higher arousals and awakenings in patients with AD might only be related to scratching in part because only 15% of patients with AD had arousals related to objective scratching.31Reuveni H. Chapnick G. Tal A. Tarasiuk A. Sleep fragmentation in children with atopic dermatitis.Arch Pediatr Adolesc Med. 1999; 153: 249-253Crossref PubMed Scopus (94) Google Scholar Awakenings as a result of scratching can be brief or long,32Stores G. Burrows A. Crawford C. Physiological sleep disturbance in children with atopic dermatitis: a case control study.Pediatr Dermatol. 1998; 15: 264-268Crossref PubMed Scopus (76) Google Scholar and many children with AD have a comorbid diagnosis of restless leg syndrome apparently secondary to itch-induced movements.33Cicek D. Halisdemir N. Dertioglu S.B. Berilgen M.S. Ozel S. Colak C. Increased frequency of restless legs syndrome in atopic dermatitis.Clin Exp Dermatol. 2012; 37: 469-476Crossref PubMed Scopus (17) Google Scholar Restless leg syndrome is diagnosed clinically as an unrelenting urge at night and before sleep onset to move the legs.25Sheldon S.H. Kryger M. Ferber R. Gozal D. Principles and practices of pediatric sleep medicine.2nd ed. Elsevier, Philadelphia2014Google Scholar Children with AD are also often given a diagnosis of periodic leg movement disorder,34DelRosso L. Hoque R. Eczema: a diagnostic consideration for persistent nocturnal arousals.J Clin Sleep Med. 2012; 8: 459-460PubMed Google Scholar which is defined by the presence of repetitive limb movements that, in contrast to restless leg syndrome, only occur during sleep and not before sleep onset. Several studies have demonstrated that actigraphy is the preferred method of assessing sleep in children with AD because it reflects the home environment, is easy to use, is cost effective, and assesses the most common parameters of sleep affected in patients with AD (ie, sleep disruption secondary to nocturnal awakenings and scratching).35Sandoval L.F. Huang K. O'Neill J.L. Gustafson C.J. Hix E. Harrison J. et al.Measure of atopic dermatitis disease severity using actigraphy.J Cutan Med Surg. 2014; 18: 49-55PubMed Google Scholar Although parameters on actigraphy are not scored in a standard manner between research studies, in general, AD disease severity positively correlates with sleep disturbances by using the Wake After Sleep Onset (WASO) score,35Sandoval L.F. Huang K. O'Neill J.L. Gustafson C.J. Hix E. Harrison J. et al.Measure of atopic dermatitis disease severity using actigraphy.J Cutan Med Surg. 2014; 18: 49-55PubMed Google Scholar sleep onset latency, sleep fragmentation, time in bed, and sleep efficiency.13Chang Y.S. Chou Y.T. Lee J.H. Lee P.t. Dai Y.S. Sun C. et al.Atopic dermatitis, melatonin, and sleep disturbance.Pediatrics. 2014; 134: e397-405Crossref PubMed Scopus (99) Google Scholar Actigraphy results correlate with itch and quality of life, and actigraphy is able to discriminate movement during sleep, number of awakenings, minutes asleep, and minutes awake.36Bender B.G. Leung S.B. Leung D.Y. Actigraphy assessment of sleep disturbance in patients with atopic dermatitis: an objective life quality measure.J Allergy Clin Immunol. 2003; 111: 598-602Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar Actigraphy presents more accurate information about sleep fragmentation than self-reporting and strongly correlates with nocturnal scratch behavior when assessed with an infrared video camera. Patients with severe AD demonstrate a mean total scratch time of approximately 15% of the night.37Ebata T. Aizawa H. Kamide R. Niimura M. The characteristics of nocturnal scratching in adults with atopic dermatitis.Br J Dermatol. 1999; 141: 82-86Crossref PubMed Scopus (64) Google Scholar Furthermore, nocturnal scratch behavior assessed by actigraphy correlates with pruritus and AD severity.38Fujita H. Nagashima M. Takeshita Y. Aihara M. Correlation between nocturnal scratch behavior assessed by actigraphy and subjective/objective parameters in patients with atopic dermatitis.Eur J Dermatol. 2014; 24: 120-122PubMed Google Scholar More information on mechanisms of sleep disturbance in patients with AD can be found in Fig 1. Despite the widespread prevalence of sleep disruption in children with AD, the mechanism of this disruption is poorly understood. Given the robust literature on sleep deprivation inducing T cell–derived inflammation,39Kim J. Hakim F. Kheirandish-Gozal L. Gozal D. Inflammatory pathways in children with insufficient or disordered sleep.Respir Physiol Neurobiol. 2011; 178: 465-474Crossref PubMed Scopus (63) Google Scholar the relative contributions of the natural circadian rhythm of immune cells, AD-induced inflammation, and further T cell–mediated inflammation from AD-induced sleep deprivation all need to be considered in understanding sleep disturbance in patients with AD. Inflammatory cytokines, such as IL-6, have long been associated with sleep disturbance in multiple disease conditions39Kim J. Hakim F. Kheirandish-Gozal L. Gozal D. Inflammatory pathways in children with insufficient or disordered sleep.Respir Physiol Neurobiol. 2011; 178: 465-474Crossref PubMed Scopus (63) Google Scholar, 40Rohleder N. Aringer M. Boentert M. Role of interleukin-6 in stress, sleep, and fatigue.Ann N Y Acad Sci. 2012; 1261: 88-96Crossref PubMed Scopus (190) Google Scholar and might have the potential to drive sleep disturbance in patients with AD. Nocturnal itching might also correlate with mobilized T cells, as stimulated by nocturnal peaks in IL-2.41Lissoni P. Rovelli F. Brivio F. Brivio O. Fumagalli L. Circadian secretions of IL-2, IL-12, IL-6 and IL-10 in relation to the light/dark rhythm of the pineal hormone melatonin in healthy humans.Nat Immun. 1998; 16: 1-5Crossref PubMed Scopus (88) Google Scholar A pilot study in patients with AD performed by Bender et al42Bender B.G. Ballard R. Canono B. Murphy J.R. Leung D.Y. Disease severity, scratching, and sleep quality in patients with atopic dermatitis.J Am Acad Dermatol. 2008; 58: 415-420Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar measured plasma IL-6, IL-10, and TNF-α levels and noted that higher daytime and nighttime values of IL-6 were correlated with poor sleep efficiency.42Bender B.G. Ballard R. Canono B. Murphy J.R. Leung D.Y. Disease severity, scratching, and sleep quality in patients with atopic dermatitis.J Am Acad Dermatol. 2008; 58: 415-420Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar In general, IL-1–mediated inflammation is increased at night, with less diurnal variation to IL-10.43Petrovsky N. Harrison L.C. The chronobiology of human cytokine production.Int Rev Immunol. 1998; 16: 635-649Crossref PubMed Scopus (187) Google Scholar In addition, T cells consistently were upregulated at night, including natural regulatory T cells, which have optimal suppressive function at 2 am. However, sleep deprivation abrogates the diurnal rhythm of regulatory T-cell activity.15Bollinger T. Bollinger A. Skrum L. Dimitrov S. Lange T. Solbach W. Sleep-dependent activity of T cells and regulatory T cells.Clin Exp Immunol. 2009; 155: 231-238Crossref PubMed Scopus (116) Google Scholar Chang et al argue that increased TH2 versus TH1 inflammation is associated with sleep disturbance based on the correlation of elevated morning levels of total IgE, dust mite–specific IgE, and staphylococcal toxin (staphylococcal enterotoxin B or A)–specific IgE with pruritus and increased WASO scores in patients with AD.13Chang Y.S. Chou Y.T. Lee J.H. Lee P.t. Dai Y.S. Sun C. et al.Atopic dermatitis, melatonin, and sleep disturbance.Pediatrics. 2014; 134: e397-405Crossref PubMed Scopus (99) Google Scholar Morning blood plasma levels of IL-31 (but not IL-4, IL-10, IL-6, or IL-1β) correlated with sleep disturbance, specifically in N1 sleep. Other studies have found that circulating levels of IL-31 and CCL18/pulmonary and activation-regulated chemokine correlate with sleep loss but not pruritus.16Raap U. Weissmantel S. Gehring M. Eisenberg A.M. Kapp A. Folster-Holst R. IL-31 significantly correlates with disease activity and Th2 cytokine levels in children with atopic dermatitis.Pediatr Allergy Immunol. 2012; 23: 285-288Crossref PubMed Scopus (127) Google Scholar, 44Hon K.L. Ching G.K. Ng P.C. Leung T.F. Exploring CCL18, eczema severity and atopy.Pediatr Allergy Immunol. 2011; 22: 704-707Crossref PubMed Scopus (21) Google Scholar Although actigraphic studies correlate nocturnal eczema with increased plasma levels of AD-associated chemokines (cutaneous T cell–attracting chemokine, macrophage-derived chemokine, and thymus and activation-regulated chemokine), self-reports of pruritus/sleep loss do not correlate with increases in levels of these chemokines.45Hon K.L. Lam M.C. Leung T.F. Kam W.Y. Lee K.C. 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Impact of seasonality on conducting clinical studies in dermatology.Clin Dermatol. 2008; 26: 565-569Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Skin mast cell responses also have circadian rhythm and might contribute to timing of AD flares.61Nakamura Y. Nakano N. Ishimaru K. Hara M. Ikegami T. Tahara Y. et al.Circadian regulation of allergic reactions by the mast cell clock in mice.J Allergy Clin Immunol. 2014; 133: 568-575Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 62Reinberg A. Ghata J. Sidi E. Circadian reactivity rhythms of human skin to histamine or allergen and the adrenal cycle.J Allergy. 1965; 36: 273-283Abstract Full Text PDF PubMed Scopus (54) Google Scholar Few studies have explored circadian rhythm in human patients with AD. Most studies evaluate biomarkers of central circadian rhythm (melatonin or cortisol), but none has assessed peripheral circadian function. With regard to central circadian rhythm, total melatonin levels are increased,13Chang Y.S. Chou Y.T. Lee J.H. Lee P.t. Dai Y.S. Sun C. et al.Atopic dermatitis, melatonin, and sleep disturbance.Pediatrics. 2014; 134: e397-405Crossref PubMed Scopus (99) Google Scholar with suppressed cortisol and adrenocorticotropic hormone in some patients with AD,63Rupprecht M. Hornstein O.P. Schluter D. Schafers H.J. Koch H.U. Beck G. et al.Cortisol, corticotropin, and beta-endorphin responses to corticotropin-releasing hormone in patients with atopic eczema.Psychoneuroendocrinology. 1995; 20: 543-551Abstract Full Text PDF PubMed Scopus (33) Google Scholar and natural rhythmic secretion of melatonin might be diminished.64Schwarz W. Birau N. Hornstein O.P. Heubeck B. Schonberger A. Meyer C. et al.Alterations of melatonin secretion in atopic eczema.Acta Derm Venereol. 1988; 68: 224-229PubMed Google Scholar Heubeck et al65Heubeck B. Schonberger A. Hornstein O.P. [Are shifts in circadian cortisol rhythm an endocrine symptom of atopic eczema?].Hautarzt. 1988; 39: 12-17PubMed Google Scholar noted shifts in cortisol peaks/troughs in patients with AD compared with those in control subjects in addition to altered levels and rhythmicity, suggesting circadian misalignment.65Heubeck B. Schonberger A. Hornstein O.P. [Are shifts in circadian cortisol rhythm an endocrine symptom of atopic eczema?].Hautarzt. 1988; 39:
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