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Sleep Disturbance in Children with Atopic Dermatitis and the Role and Applications of Melatonin
|Publication Year :||2017|
我們共召集72名異位性皮膚炎病童及32位健康受試者參與測量，年齡介於1至18歲之間。我們以腕動錶及多層次睡眠儀測量多項客觀的睡眠指數，並測量尿液中褪黑激素的代謝物6-sulfatoxymelatonin的量，及血清中細胞激素及免疫球蛋白E的數值。客觀睡眠量測結果顯示，異位性皮膚炎病童睡眠效率較差，需要較長的時間才能入睡，睡眠較為片段，且較少非快速動眼期睡眠。腕動錶及多層次睡眠儀量測的結果高度相關。異位性皮膚炎的嚴重度和睡眠障礙顯著相關（r = 0.55-0.7），且如果病人異位性皮膚炎嚴重度指數（SCORAD）≥ 48.7，即可預測病童會有較差的睡眠效率，其敏感性83.3%，特異度75%（P = 0.001）。異位性皮膚炎病童中，夜晚褪黑激素分泌較低者，睡眠障礙較嚴重。另外，癢，搔抓，較高的血清免疫球蛋白E值，及對於塵蟎及金黃色葡萄球菌內毒素過敏，也都和睡眠障礙有顯著相關。
這是一個隨機雙盲對照交叉試驗，於2012年8月至2013年1月間於台大醫院小兒部執行。我們召集了73位1至18歲，經醫師診斷為異位性皮膚炎且皮膚病兆面積超過5%體表面積的病童參與，其中有48位被隨機分配，而有38位（79%）完成試驗。試驗當中沒有受試者因為藥物之不良反應而退出。受試者以1:1的比例被隨機分配至兩組，ㄧ組每晚吃3毫克的褪黑激素，ㄧ組則吃安慰劑。結束後休息兩週，再交換至另一個治療。評估的主要結果為異位性皮膚炎的嚴重度（以SCORAD測量），而次要結果為腕動錶及多層次睡眠儀測量的多項客觀睡眠指數，主觀的睡眠及皮膚炎是否改善，夜晚尿液中褪黑激素的量，及血清中免疫球蛋白E及細胞激素的數值。我們發現褪黑激素治療後，入睡的時間相較於安慰劑後，縮短了21.4分鐘（95%信賴區間: -38.6至-4.2），而且皮膚炎嚴重度指數也較安慰劑減少了9.1（95%信賴區間: -13.67至-4.57）。SCORAD改善的程度及入睡時間改善的程度無顯著相關。長處和困難問卷當中的親社會行為分數，在褪黑激素治療後也有顯著改善。整個試驗過程中都沒有副作用或不良反應發生。
我們使用DNCB於Balb/c老鼠以誘發異位性皮膚炎的老鼠模型，來評估外用褪黑激素治療異位性皮膚炎是否有效。老鼠隨機分至四組：對照組，DNCB組，DNCB＋3%外用褪黑激素組，DNCB＋5%外用褪黑激素組，比較各組組織學切片的皮膚炎嚴重度，血清免疫球蛋白E數值，及皮膚細胞激素IL-4，IL-13，及IL-17的mRNA表現量。試驗結果發現，3%及5%外用褪黑激素治療後皮膚組織學嚴重度分數顯著降低（3%外用褪黑激素組相較於DNCB組P = 0.04，5%外用褪黑激素組相較於DNCB組P = 0.02）。每十個高倍顯微鏡視野下T細胞的數目，於3%及5%外用褪黑激素治療後也都顯著降低（3%外用褪黑激素組相較於DNCB組P = 0.03，5%外用褪黑激素組相較於DNCB組P = 0.0007）。血清免疫球蛋白E數值於5%外用褪黑激素治療後也顯著降低（P = 0.02）。
Sleep disturbance is common in children with atopic dermatitis (AD) and is a major factor leading to impaired quality of life. However, the pathophysiology of sleep disturbance in children with AD is poorly understood, and there is no consensus on how to manage sleep problems in these patients. The aims of this study were to determine objective characteristics of sleep disturbance in children with AD and explore contributing factors and clinical predictors, and to evaluate the effectiveness of oral or topical melatonin in treating patients with AD and their sleep disturbance.
Methods and Results
Part I. Cross-Sectional Study to Evaluate the Characteristics and Contributing Factors of Sleep Disturbance in Children with Atopic Dermatitis
Sleep parameters were measured by actigraphy and polysomnography in 72 AD patients and 32 controls aged 1 to 18 years. Urinary 6-sulfatoxymelatonin levels, serum cytokines, and total and allergen-specific immunoglobulin E (IgE) levels were also measured. The objective measurements showed that the AD patients had significantly reduced sleep efficiency, longer sleep onset latency, more sleep fragmentation, and less non-rapid eye movement sleep. Results from actigraphy correlated well with those from polysomnography. The AD disease severity was associated with sleep disturbance (r = 0.55-0.7), and a Scoring Atopic Dermatitis (SCORAD) index of ≥ 48.7 predicted poor sleep efficiency (sensitivity 83.3%, specificity 75%, area under the curve = 0.81, P = 0.001). Lower nocturnal melatonin secretion was significantly associated with sleep disturbance in the AD patients. Other correlates of sleep disturbance included pruritus, scratching movements, higher total serum IgE levels, and allergic sensitization to dust mite and staphylococcal enterotoxins.
Part II. Randomized Controlled Trial to Evaluate the Effect of Melatonin for the Treatment of Atopic Dermatitis and Sleep Disturbance
A randomized, double-blind, placebo-controlled crossover study was conducted. Seventy-three children with physician-diagnosed AD involving at least 5% of the total body surface area, aged between 1 and 18 years were recruited, 48 children were randomized, and 38 (79%) completed the study. None withdrew due to adverse effects. Participants were randomized (1:1) to melatonin 3 mg or placebo daily for 4 weeks. After a 2-week washout period, they crossed over to the alternative treatment. The primary outcome was the AD disease severity evaluated using the Scoring Atopic Dermatitis (SCORAD) index. Secondary outcomes included sleep parameters measured by actigraphy, subjective sleep and dermatitis change, the sleep parameters measured by polysomnography, nocturnal urinary levels of 6-sulfatoxymelatonin, serum immunoglobulin E levels, serum cytokine levels, and behavior analysis scores. After melatonin treatment, the sleep onset latency shortened 21.4 minutes more than placebo (95%CI: -38.6 to -4.2). Moreover, the SCORAD index decreased 9.1 more than placebo (95%CI: -13.67 to -4.57). The improvement in the SCORAD index did not significantly correlate with the change in the sleep onset latency. The scoring of prosocial behavior also significantly improved after melatonin treatment. No adverse event was reported throughout the study.
Part III. Animal Study to Evaluate the Effectiveness of Topical Melatonin for the Treatment of Atopic Dermatitis
The DNCB-induced dermatitis in Balb/c mice, the animal model for AD, was used to evaluate the effectiveness of topical melatonin for the treatment of AD. Mice were randomly assigned to one of four groups: the control, DNCB, DNCB + 3% topical melatonin, and DNCB + 5% topical melatonin. Gross and histological dermatitis severity, serum IgE levels, and skin mRNA expression of the cytokines IL-4, IL-13, and IL-17 were measured. There was significant improvement in pathology scoring in both the 3% and 5% topical melatonin treatment group (P = 0.04 for 3% melatonin compared with DNCB-stimulated, and P = 0.02 for 5% melatonin compared with DNCB-stimulated). T cell infiltration of the skin was significantly reduced after either 3% or 5% topical melatonin treatment (P = 0.03 and P = 0.0007 for 3% and 5% melatonin compared with DNCB group, respectively). Moreover, the serum total IgE level significantly reduced after 5% melatonin treatment compared with the DNCB-stimulated group (P = 0.02).
In AD patients, sleep disturbance is strongly associated with disease severity, and posslible contributing factors include lower nocturnal melatonin secretion, pruritus and scratching, and allergic sensitization to dust mite and Staphylococcal enterotoxins. Oral melatonin supplement is potentially a safe and effective way to improve the sleep onset and skin condition simultaneously. Preliminary animal studies also suggest that topical melatonin could be effective in the treatment of AD.
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