今日の臨床サポート

アトピー性皮膚炎(小児科)

著者: 渋谷紀子 総合母子保健センター愛育クリニック 小児科

監修: 渡辺博 帝京大学老人保健センター

著者校正/監修レビュー済:2019/09/06
参考ガイドライン:
日本皮膚科学会、日本アレルギー学会、アトピー性皮膚炎診療ガイドライン作成員会編:アトピー性皮膚炎診療ガイドライン2018.日皮会誌:128(12),2431-2502. 2018
患者向け説明資料

概要・推奨   

  1. アトピー性皮膚炎とは増悪・寛解を繰り返す、掻痒のある湿疹を主病変とする疾患であり、病態的には角層の異常に起因する皮膚の乾燥とバリアー機能異常を伴う。
  1. アトピー性皮膚炎の薬物治療として、その有効性と安全性が科学的に立証されている薬剤は、ステロイド外用薬とタクロリムス軟膏(カルシニューリン阻害外用薬)である(推奨度2)。
  1. ステロイド外用薬の経皮吸収による副腎皮質抑制はほとんどないと考えられるが、長期の使用の際には外用薬の選択や塗布回数などに注意する必要がある(推奨度2)。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧に
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となり
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契
閲覧にはご契
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
渋谷紀子 : 特に申告事項無し[2021年]
監修:渡辺博 : 特に申告事項無し[2021年]

改訂のポイント:
  1. アトピー性皮膚炎診療ガイドライン2018 に基づき、診断方針(指標)、薬剤情報を改訂した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. アトピー性皮膚炎とは、増悪・寛解を繰り返す、瘙痒のある湿疹を主病変とする疾患であり、患者の多くはアトピー素因を持つ[1]。湿疹は、特徴的な左右対称性の分布を示し、年齢により好発部位や湿疹の性状が異なる。
  1. 病態的には、角層の異常に起因する皮膚の乾燥とバリアー機能異常という皮膚の生理学的異常を伴い、多彩な非特異的刺激反応および特異的アレルギー反応が関与して生じる。
  1. 近年フィラグリン遺伝子異常が発症に関与している可能性が示唆されている[2][3]
  1. 有病率は3歳頃で最も高く、小児全体ではおおむね10%と報告されている[4]
 
アトピー性皮膚炎の年齢別有症率

アトピー性皮膚炎の有症率は3歳、次いで乳児に多く、小児全体でおおむね10%と報告されている。

 
  1. 日本には今まで、日本皮膚科学会と、厚生労働省研究班および日本アレルギー学会による2つのアトピー性皮膚炎診療ガイドラインが存在したが、2018年のガイドライン改訂にあたり、これらが統合された。定義および診断基準については、従来の日本皮膚科学会のものが採用されている。
 
アトピー性皮膚炎の定義・診断基準

①瘙痒、②特徴的皮疹と分布、③慢性・反復性経過の3つを満たすものを、症状の軽重を問わず、アトピー性皮膚炎と診断する。皮疹には急性および慢性病変があり、皮疹の分布には年齢による特徴が認められる。

 
アトピー性皮膚炎の診断の手引き

日本皮膚科学会の診断基準と異なり、対象を乳児から小児のアトピー性皮膚炎に限定しており、乳児、および幼児・学童にそれぞれ別の診断基準を設けている。

 
問診・診察のポイント  
  1. 最も重要な臨床症状は、①瘙痒、②特徴的皮疹と分布、③慢性・反復性の経過、である。
  1. 乳児では2カ月以上、その他では6カ月以上を慢性とする。

今なら12か月分の料金で14ヶ月利用できます(個人契約、期間限定キャンペーン)

11月30日(火)までにお申込みいただくと、
通常12ヵ月の使用期間が2ヶ月延長となり、14ヵ月ご利用いただけるようになります。

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文献 

著者: Colin N A Palmer, Alan D Irvine, Ana Terron-Kwiatkowski, Yiwei Zhao, Haihui Liao, Simon P Lee, David R Goudie, Aileen Sandilands, Linda E Campbell, Frances J D Smith, Gráinne M O'Regan, Rosemarie M Watson, Jo E Cecil, Sherri J Bale, John G Compton, John J DiGiovanna, Philip Fleckman, Sue Lewis-Jones, Gehan Arseculeratne, Ann Sergeant, Colin S Munro, Brahim El Houate, Ken McElreavey, Liselotte B Halkjaer, Hans Bisgaard, Somnath Mukhopadhyay, W H Irwin McLean
雑誌名: Nat Genet. 2006 Apr;38(4):441-6. doi: 10.1038/ng1767. Epub 2006 Mar 19.
Abstract/Text Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.

PMID 16550169  Nat Genet. 2006 Apr;38(4):441-6. doi: 10.1038/ng1767. E・・・
著者: I Nemoto-Hasebe, M Akiyama, T Nomura, A Sandilands, W H I McLean, H Shimizu
雑誌名: Br J Dermatol. 2009 Dec;161(6):1387-90. doi: 10.1111/j.1365-2133.2009.09406.x. Epub 2009 Aug 7.
Abstract/Text BACKGROUND: Mutations in the gene encoding filaggrin (FLG) have been shown to predispose to atopic eczema (AE).
OBJECTIVES: Further to establish population genetics of FLG mutations in the Japanese population and to elucidate effects of FLG mutations to filaggrin biosynthesis in skin of patients with AE.
METHODS: We searched for FLG mutations in 19 newly recruited Japanese patients with AE. We then screened 137 Japanese patients with AE and 134 Japanese control individuals for a novel mutation identified in the present study. In addition, we evaluated FLG mRNA expression by real-time reverse transcription-polymerase chain reaction and profilaggrin/filaggrin protein expression by immunohistochemical staining in the epidermis of the patients carrying the novel mutation.
RESULTS: We identified a novel FLG nonsense mutation c.12069A>T (p.Lys4021X) in one patient with AE. Upon further screening, p.Lys4021X was identified in four patients with AE (2.9% of all the patients with AE). In total, there are at least eight FLG variants in the Japanese population. Here we show that about 27% of patients in our Japanese AE case series carry one or more of these eight FLG mutations and these variants are also carried by 3.7% of Japanese general control individuals. There is a significant statistical association between the eight FLG mutations and AE (chi(2) P = 6.50 x 10(-8)). Interestingly, the present nonsense mutation is in the C-terminal incomplete filaggrin repeat and is the mutation nearest the C-terminal among previously reported FLG mutations. Immunohistochemical staining for filaggrin revealed that this nonsense mutation leads to remarkable reduction of filaggrin protein expression in the patients' epidermis.
CONCLUSIONS: We clearly demonstrated that FLG mutations are significantly associated with AE in the Japanese population. The present results further support the hypothesis that the C-terminal region is essential for proper processing of profilaggrin to filaggrin.

PMID 19663875  Br J Dermatol. 2009 Dec;161(6):1387-90. doi: 10.1111/j.・・・
著者: T Kakinuma, K Nakamura, M Wakugawa, H Mitsui, Y Tada, H Saeki, H Torii, A Asahina, N Onai, K Matsushima, K Tamaki
雑誌名: J Allergy Clin Immunol. 2001 Mar;107(3):535-41. doi: 10.1067/mai.2001.113237.
Abstract/Text BACKGROUND: Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease characterized by the predominant infiltration of TH2-type cells in lesional skin. Thymus and activation-regulated chemokine (TARC/CCL17) is a chemokine that attracts CC chemokine receptor 4-positive (CCR4+) or CCR8+ cells.
OBJECTIVE: The purpose of this study was to investigate the participation of TARC in AD.
METHODS: We measured serum TARC levels in 40 patients with AD, 20 healthy control subjects, and 20 patients with psoriasis. We also examined disease activity by using SCORAD score; serum soluble E-selectin, soluble IL-2 receptor, IgE, and GM-CSF levels; and eosinophil numbers in peripheral blood, as well as correlations between TARC levels and these factors. The positivity of CCR4 of CD4+CD45RO+ cells in PBMCs was examined by using FACS analysis. Immunohistochemical staining of TARC and GM-CSF was performed in the lesional skin of patients with AD.
RESULTS: The serum TARC levels of patients with AD were significantly higher than those of healthy control subjects and patients with psoriasis. The serum TARC levels significantly correlated with eosinophil number (r = 0.61), SCORAD score (r = 0.60), and serum soluble E-selectin levels (r = 0.58) and weakly correlated with serum soluble IL-2 receptor levels (r = 0.34) in patients with AD. The TARC levels of patients with AD decreased after the treatment in accordance with the improvement of clinical symptoms. The CCR4 positivity of CD4+CD45RO+ cells in PBMCs of patients with AD was also higher than that of healthy control subjects. Immunohistochemical staining revealed that TARC was positive in keratinocytes in the epidermis and in vascular endothelial cells, T cells, and dendritic cells in the dermis.
CONCLUSION: Serum TARC levels are associated with disease activity of AD, and TARC may play an important role in the pathogenesis of AD.

PMID 11240957  J Allergy Clin Immunol. 2001 Mar;107(3):535-41. doi: 10・・・
著者: Mizuho Nagao, Shinichiro Inagaki, Toshiki Kawano, Yoshinori Azuma, Noriko Nomura, Yasuhiko Noguchi, Shoichiro Ohta, Atsushi Kawaguchi, Hiroshi Odajima, Yukihiro Ohya, Takao Fujisawa, Kenji Izuhara
雑誌名: J Allergy Clin Immunol. 2018 May;141(5):1934-1936.e11. doi: 10.1016/j.jaci.2018.01.021. Epub 2018 Feb 5.
Abstract/Text
PMID 29421276  J Allergy Clin Immunol. 2018 May;141(5):1934-1936.e11. ・・・
著者: Sabina Illi, Erika von Mutius, Susanne Lau, Renate Nickel, Christoph Grüber, Bodo Niggemann, Ulrich Wahn, Multicenter Allergy Study Group
雑誌名: J Allergy Clin Immunol. 2004 May;113(5):925-31. doi: 10.1016/j.jaci.2004.01.778.
Abstract/Text BACKGROUND: Atopic dermatitis (AD) is considered to be one of the first manifestations in the atopic march. However, few prospective studies on AD and its association with childhood asthma exist.
OBJECTIVE: The aim of this study was to prospectively investigate the natural course of AD to determine factors influencing its prognosis and to analyze the relationship of AD with childhood asthma.
METHODS: The Multicenter Allergy Study, a German birth cohort, followed 1314 children from birth to age 7 years. Physical examinations, parental interviews on atopic symptoms and diagnoses, and determination of specific IgE levels were performed regularly.
RESULTS: The cumulative prevalence of AD in the first 2 years of life was 21.5%. Of these children with early AD, 43.2% were in complete remission by age 3 years, 38.3% had an intermittent pattern of disease, and 18.7% had symptoms of AD every year. Severity (adjusted cumulative odds ratio, 5.86; 95% CI, 3.04-11.29) and atopic sensitization (adjusted cumulative odds ratio, 2.76; 95% CI, 1.29-5.91) were major determinants of prognosis. Early wheeze and a specific sensitization pattern were significant predictors for wheezing at school age, irrespective of AD. Early AD without these cofactors constituted no increased risk of subsequent wheeze (adjusted odds ratio, 1.11; 95% CI, 0.56-2.20) or bronchial hyperreactivity.
CONCLUSION: AD is a common condition in infancy but disappears around age 3 years in a significant proportion of children. The prognosis is mostly determined by the severity and the presence of atopic sensitization. Early AD is associated with asthma at school age, but in many of these asthmatic children, wheezing manifests before or with the onset of AD. Children with AD and wheeze have a marked loss in lung function, suggesting a distinct phenotype rather than a progressive development from AD to asthma.

PMID 15131576  J Allergy Clin Immunol. 2004 May;113(5):925-31. doi: 10・・・
著者: Giampaolo Ricci, Annalisa Patrizi, Elena Baldi, Giuseppe Menna, Michela Tabanelli, Massimo Masi
雑誌名: J Am Acad Dermatol. 2006 Nov;55(5):765-71. doi: 10.1016/j.jaad.2006.04.064. Epub 2006 Jun 27.
Abstract/Text BACKGROUND: The association of atopic dermatitis (AD) with other allergic diseases has been extensively studied; however, there is a lack of reports focusing on long-term studies of the clinical and allergometric evaluations observed during the course of AD in respect to its evolution and association with allergic responses in affected patients.
OBJECTIVE: The aim of this study was to evaluate, with defined criteria of clinical diagnosis, severity assessment, and objective allergometric test at the time of inclusion, the natural course of AD, the factors influencing its healing or persistence, and the appearance of other allergic diseases with particular focus on asthma and the presence of specific immunoglobulin E at first observation.
METHODS: This study included only children, aged between 6 and 36 months, whose first clinical examination was made between 1981 and 1989. A total of 252 children satisfied these criteria. A semistructured interview was performed by the physician using a preformed questionnaire, which was completed for 205 children (104 boys and 101 girls).
RESULTS: AD had completely disappeared in 124 cases (60.5%). Other allergic manifestations that appeared included asthma in 70 cases (34.1%) and rhinoconjunctivitis (RC) in 118 cases (57.6%). Generally the average age of patients recovering from AD was higher in severe AD (6.0 +/- 3.5 years) than in its moderate or mild forms (5.8 +/- 4.5 and 5.5 +/- 3.9 years, respectively). This phenomenon was particularly evident in children with hen's egg sensitization, who show a longer persistence of the condition (Student t = 2.462 and P < .02). The initial severity score of AD was found to be associated with a high frequency of asthma appearance (Pearson chi2 = 14.225 and P < .001). Hen's egg sensitization was significantly related to the appearance of asthma (Fisher's exact test P < .007) and RC (Fisher's exact test P < .05). A retrospective analysis of related risks factors and their association with concomitant allergic diseases in our case studies shows that the egg sensitization, severity of AD, and onset of RC were positively related to the occurrence of asthma. In addition, our analysis shows that, although the appearance of RC was proportional to the incidence of atopy and asthma, it was inversely related to the persistence of AD (corrected odds ratio confidence intervals <1).
LIMITATIONS: The study includes children referred to the hospital. However, it is the practice of local national health pediatricians to send all patients with suspected AD, whatever the severity grade, to hospital specialists to perform allergometric assessment.
CONCLUSION: The use of defined criteria of clinical diagnosis for the determination of the condition's severity, along with the performance of objective allergometric tests at the time of inclusion, shows that the course of AD is significantly related to egg sensitivity. In addition, the average healing time is higher in egg-sensitive patients affected by the most severe form of AD than in mild or moderate cases.

PMID 17052480  J Am Acad Dermatol. 2006 Nov;55(5):765-71. doi: 10.1016・・・
著者: Yusei Ohshima, Akiko Yamada, Masahiro Hiraoka, Kenji Katamura, Setsuko Ito, Takao Hirao, Hiroshi Akutagawa, Naomi Kondo, Akihiro Morikawa, Mitsufumi Mayumi
雑誌名: Ann Allergy Asthma Immunol. 2002 Sep;89(3):265-70. doi: 10.1016/S1081-1206(10)61953-9.
Abstract/Text BACKGROUND: Bronchial asthma (BA) often develops in children with atopic dermatitis (AD). Identification of factors that could predict the development of asthma in children with AD is useful for early intervention.
OBJECTIVE: We undertook a 4-year followup study to clarify the factors involved in the development of BA in infants with AD.
METHODS: We registered 169 infants with AD who were free of BA at registration and examined the prevalence and characteristics of the subsequent development of BA among these patients.
RESULTS: Among the patients followed for 4 years, approximately 45% experienced asthma-like respiratory symptoms, and 35% were diagnosed as asthmatic patients by pediatric allergologists. Patients who developed BA showed early appearance of house dust mite (HDM)-specific immunoglobulin E (IgE) and persistently high levels of food-specific IgE. Male sex, a positive family history of BA, and the appearance of HDM-specific IgE were identified as significant risk factors for the early development of BA, but the significance of these parameters decreased thereafter. A positive family history of AD, the outcome of skin lesions, and keeping furred pets were also identified as risk factors in a part of the followup period. Among the parameters examined, the early appearance of HDM-specific IgE was the most significant risk factor.
CONCLUSION: Appearance of HDM-specific IgE antibodies in early childhood, which seems to be mainly influenced by genetic factors, is a major risk factor for the subsequent development of BA in children with AD, but the influence decreases after longer followup.

PMID 12269646  Ann Allergy Asthma Immunol. 2002 Sep;89(3):265-70. doi:・・・
著者: M Lebwohl
雑誌名: Cutis. 1996 Feb;57(2 Suppl):62-8.
Abstract/Text The clinical efficacy and safety of fluticasone propionate ointment, 0.005%, were compared with those of its vehicle in the treatment of moderate-to-severe eczema of long duration in two multicenter, double-blind, vehicle-controlled, randomized studies. One of the two study medications (up to 100 gm/week) was applied topically to the affected areas of the body twice daily for up to four consecutive weeks. Drug efficacy was measured in terms of three variables: the physician's gross assessment of clinical response of the target lesion, severity scores of individual signs and symptoms, and the patient's subjective assessment of treatment effects. Efficacy and safety were evaluated after seven, fourteen, twenty-one, and twenty-eight days of treatment. The total number of patients in the two studies was 372 (203 in study 1 and 169 in study 2). Fluticasone propionate ointment, 0.005%, was more effective than vehicle at all postbaseline visits in both studies (study 1 P < or = 0.015, study 2 P < or = 0.018). In study 1, approximately 80% of the patients on fluticasone were rated as cleared, excellent, or good by the investigators at treatment endpoint, compared with 38% of those receiving vehicle. In study 2, the sum of 80% of the fluticasone-treated patients was rated as cleared, excellent, or good by the investigators at the end of the study, compared with 34% of those receiving vehicle. The beneficial effect of fluticasone ointment, 0.005%, was early and sustained and was particularly noticeable for pruritus, erythema, and skin thickening. In study 1, no drug-related adverse events were reported in the fluticasone group. Four patients (4.3%) in the vehicle group experienced a total of four drug-related adverse events. The most common was burning/stinging, reported by two patients. In study 2, two patients (2.4%) in the fluticasone-treated group and three (4.1%) in the vehicle group reported a total of five drug-related adverse events, the most common event being pruritus (fluticasone group one patient, vehicle group two patients). These findings show that fluticasone propionate ointment, 0.005%, applied twice daily, is therapeutically superior to the vehicle and is well tolerated.

PMID 8646873  Cutis. 1996 Feb;57(2 Suppl):62-8.
著者: H W Sears, J W Bailer, A Yeadon
雑誌名: Clin Ther. 1997 Jul-Aug;19(4):710-9. doi: 10.1016/s0149-2918(97)80095-1.
Abstract/Text This multicenter, double-masked, placebo-controlled, randomized study evaluated the efficacy, safety, tolerability, and cosmetic acceptability of hydrocortisone buteprate 0.1% cream in the treatment of patients with atopic dermatitis. One hundred ninety-four adults with clinically diagnosed atopic dermatitis were randomized to treatment with hydrocortisone buteprate 0.1% cream or placebo (the cream base of the medication) applied topically once daily for 14 days. Investigators assessed the severity of dermatitis signs on a four-point scale at baseline and on days 3, 7, and 14. Overall improvement was also assessed at each study visit using a seven-point scale. In addition, overall treatment efficacy, tolerability, and cosmetic acceptability of both treatments were evaluated at the last study visit. At each study visit, patients treated with hydrocortisone buteprate showed significant improvement in mean total lesion scores and overall improvement compared with those receiving placebo. Investigators and patients rated hydrocortisone buteprate significantly more effective and significantly more tolerable than placebo at the end of the treatment period. In general, most adverse effects were mild to moderate, with a burning sensation (4% of patients using placebo, 2% of patients using hydrocortisone buteprate) being the most commonly reported. Patients judged both hydrocortisone buteprate and placebo cosmetically acceptable for daily use.

PMID 9377615  Clin Ther. 1997 Jul-Aug;19(4):710-9. doi: 10.1016/s0149・・・
著者: N Doss, M-R Kamoun, L Dubertret, F Cambazard, A Remitz, M Lahfa, Y de Prost
雑誌名: Pediatr Allergy Immunol. 2010 Mar;21(2 Pt 1):321-9. doi: 10.1111/j.1399-3038.2009.00895.x. Epub 2009 Jun 26.
Abstract/Text Tacrolimus 0.03% ointment is licensed for second-line treatment of children with atopic dermatitis (AD). Although data are available from clinical trials, no study has enrolled only second-line patients. This double-blind, non-inferiority study compared tacrolimus 0.03% and fluticasone 0.005% ointments in children with moderate-to-severe AD, who had responded insufficiently to conventional therapies. Children (aged 2-15 yr) were randomized to tacrolimus ointment (n = 240) or fluticasone ointment (n = 239), twice daily until clearance or for a maximum of 3 wk and, if lesions remained, once daily for up to 3 wk further. Primary end-point was week 3 response rate (improvement of >or=60% in modified Eczema Area and Severity Index and not withdrawn for lack of efficacy). Secondary end-points included pruritus and sleep quality, global assessment of clinical response, incidence of new flares and safety. Response rates were 86.3% with tacrolimus ointment and 91.5% with fluticasone. Lower limit of the 95% confidence interval was -11.8%, exceeding the non-inferiority limit of -15% and meeting the primary end-point. Moderate or better improvement on the physicians' global assessment occurred in 93.6% and 92.4% of patients in the tacrolimus ointment and fluticasone arms, respectively, while median pruritus scores improved by 84.0% and 91.5%. Sleep quality improved by approximately 92% in both treatment arms. After day 21, new flare-up occurred in 5.5% and 11.3% of patients receiving tacrolimus ointment and fluticasone, respectively; mean times to new flares were 6.5 +/- 5.0 and 8.6 +/- 5.2 days. Adverse events were similar between the two arms, with the exception of application-site skin burning sensation in the tacrolimus ointment group. In conclusion, efficacy of tacrolimus 0.03% ointment as second-line treatment was not inferior to that of fluticasone 0.005% ointment, with similar benefits on global disease improvement and quality of sleep.

PMID 19563466  Pediatr Allergy Immunol. 2010 Mar;21(2 Pt 1):321-9. doi・・・
著者: Jon M Hanifin, Amy S Paller, Lawrence Eichenfield, Richard A Clark, Neil Korman, Gerald Weinstein, Ivor Caro, Eileen Jaracz, M Joyce Rico, US Tacrolimus Ointment Study Group
雑誌名: J Am Acad Dermatol. 2005 Aug;53(2 Suppl 2):S186-94. doi: 10.1016/j.jaad.2005.04.062.
Abstract/Text OBJECTIVE: This study was designed to evaluate the long-term safety and efficacy of 0.1% tacrolimus ointment in adult and pediatric patients with atopic dermatitis (AD).
METHODS: A total of 408 adult and 391 pediatric patients with AD who had participated in a previous clinical trial of tacrolimus ointment were enrolled in this long-term, open-label, noncomparative trial. Tacrolimus ointment 0.1% was applied twice daily either intermittently or continuously to the affected areas. Efficacy and safety assessments included percent body surface area affected, Eczema Area and Severity Index score, individual signs of AD, and the incidence of adverse events.
RESULTS: A total of 799 patients were evaluated, of whom 300 (37.5%) were followed for more than 3 years (maximum 49 months). Improvements in efficacy parameters were observed within 1 week of treatment and continued for the duration of the study. Common adverse events included skin burning, pruritus, skin infection, skin erythema, flu-like symptoms, and headache. The incidence of adverse events, including cutaneous infections, did not increase with time on study.
CONCLUSION: Tacrolimus ointment therapy is a rapidly effective and safe treatment for the management of AD in pediatric and adult patients for up to 4 years.

PMID 16021174  J Am Acad Dermatol. 2005 Aug;53(2 Suppl 2):S186-94. doi・・・
著者: S Reitamo, M Rustin, J Harper, K Kalimo, A Rubins, F Cambazard, E E A Brenninkmeijer, C Smith, J Berth-Jones, T Ruzicka, G Sharpe, A Taieb, 0.1% Tacrolimus Ointment Long-term Follow-up Study Group
雑誌名: Br J Dermatol. 2008 Sep;159(4):942-51. doi: 10.1111/j.1365-2133.2008.08747.x. Epub 2008 Jul 15.
Abstract/Text BACKGROUND: For the treatment of a chronic disease like atopic dermatitis, sustained tolerability and efficacy of the applied medication are essential.
OBJECTIVES: The present open-label, noncomparative study was conducted to obtain information on the long-term safety and efficacy of 0.1% tacrolimus ointment.
METHODS: Patients aged 2 years or older with an affected body surface area of more than 5%, who previously participated in a clinical trial on tacrolimus ointment, were eligible for this study. The treatment area was defined by the investigator at study entry. Both children and adults applied continuously or intermittently 0.1% tacrolimus ointment twice daily during episodes of active disease plus an additional week after remission over a follow-up period of up to 4 years.
RESULTS: The intent-to-treat population comprised 782 patients, with a median age of 22 years (range 2-72). Patients remained in the study for up to 4 years. Approximately half of the patients discontinued the study prematurely; the median follow-up was 1422 days. Median tacrolimus ointment use was 31.2 g during the first week; ointment use decreased during the first year and then remained stable for the remainder of the study. The median cumulative tacrolimus use was 271.5 g at month 6, 462.5 g at month 12, 739.9 g at month 24, 1029.3 g at month 36 and 1320.8 g at month 48. Altogether 51.8% of patients discontinued the study prematurely; the main reasons were withdrawal of consent (13.3%), loss to follow-up (11.3%) and lack of efficacy (9.4%). Adverse events led to study discontinuation in 3.7% of the patients. The most frequent application site events were skin burning and pruritus. These events were most often reported in adult patients during the initial treatment period; prevalence decreased after the first week and remained at a low level throughout the study. Nonapplication site events occurred with stable incidences throughout the study period. In general, calculated daily hazard rates did not indicate an increased risk of adverse events with prolonged treatment. The total affected body surface area decreased substantially upon onset of treatment and efficacy of treatment was maintained until the end of the study with smaller but continuous improvements throughout the follow-up period. Overall, 75% of the patients and 76% of the investigators rated their satisfaction with the treatment as excellent, very good or good at the end of the study or at the time of premature discontinuation.
CONCLUSIONS: The safety profile of intermittent or continuous long-term application of 0.1% tacrolimus ointment for up to 4 years was consistent with that which has been established from shorter studies and gave no reason for concern. In addition, 0.1% tacrolimus ointment demonstrated sustained efficacy as reflected by the expression of high satisfaction with treatment by both patients and investigators.

PMID 18637898  Br J Dermatol. 2008 Sep;159(4):942-51. doi: 10.1111/j.1・・・
著者: Felix M Arellano, Charles E Wentworth, Alejandro Arana, Carlos Fernández, Carle F Paul
雑誌名: J Invest Dermatol. 2007 Apr;127(4):808-16. doi: 10.1038/sj.jid.5700622. Epub 2006 Nov 9.
Abstract/Text Systemic use of immunosuppressant agents increases the risk of lymphoma in transplantation. We performed a nested case-control study in the PharMetrics database to evaluate the association between topical immunosuppressants and lymphoma in a cohort of patients with atopic dermatitis. We identified cases of lymphoma and randomly selected four controls for each case, matched by length of follow-up. We used conditional logistic regression to calculate odds ratio (OR) and 95% confidence intervals (CIs) of the association between topical immunosuppressants and lymphoma. Two hundred and ninety-four cases of lymphoma occurred in 293,253 patients, 81 in patients younger than 20 years. The adjusted analysis yielded the following OR (95%CI) for: severity (OR 2.4; 95% CI 1.5-3.8), oral steroids 1.5 (1.0-2.4), "super potent" topical steroids 1.2 (0.8-1.8) , "low potency" topical steroids OR 1.1 (0.7-1.6); pimecrolimus 0.8(0.4-1.6), tacrolimus OR 0.8 (0.4-1.7), and concomitant topical steroids, pimecrolimus, and tacrolimus 1.0 (0.3-4.1). We did not find an increased risk of lymphoma in patients treated with topical calcineurin inhibitors. It is difficult to disentangle the effects of severity of disease on outcome versus the true effects of drugs. However, in the adjusted analysis, severity of AD was the main factor associated with an increased risk of lymphoma.

PMID 17096020  J Invest Dermatol. 2007 Apr;127(4):808-16. doi: 10.1038・・・
著者: David J Margolis, Ole Hoffstad, Warren Bilker
雑誌名: Dermatology. 2007;214(4):289-95. doi: 10.1159/000100879.
Abstract/Text BACKGROUND: Two topical calcineurin inhibitors (TCI) are available for the treatment of atopic dermatitis and there has been concern that their use could be associated with an increased risk of nonmelanoma skin cancer (NMSC).
OBJECTIVE: To determine if TCI exposure is associated with an increased risk of NMSC in adults.
METHODS: A case-control study using a questionnaire mailed to 5,000 adults with dermatitis.
RESULTS: We received responses from 70.7% of those surveyed by mail. Overall, 25.7% reported exposure to TCI. TCI exposure was 14.4% for the cases and 30.7% for the controls. Our primary analysis was a comparison between those with NMSC and those without. The unadjusted odds ratio was 0.38 (0.31-0.47) and the adjusted (age, gender, previous NMSC, history of atopic dermatitis) was 0.54 (0.41-0.69). The odds ratio of association for NMSC decreased as the number of tubes used and the potency of the agent increased.
CONCLUSION: This early study shows that TCI use is not associated with an increased risk of NMSC in adults.

2007 S. Karger AG, Basel
PMID 17460399  Dermatology. 2007;214(4):289-95. doi: 10.1159/000100879・・・
著者: S S Bleehen, A C Chu, I Hamann, C Holden, J A Hunter, R Marks
雑誌名: Br J Dermatol. 1995 Oct;133(4):592-7.
Abstract/Text The aim of this study was to compare the efficacy and safety of once-daily with twice-daily application of a 0.05% cream formulation of fluticasone propionate in the treatment of atopic eczema in adults and children. Two hundred and seventy patients with moderate to severe atopic eczema were enrolled in the study, and randomized to receive either once-daily or twice-daily fluticasone propionate 0.05% cream for 4 weeks. Patients randomized to the once-daily group also received the vehicle cream to ensure that the study remained blinded. The clinical response of a preselected target area of affected skin was assessed by investigators at weekly intervals and compared with the baseline. Analysis of the investigators' overall assessment of the response of the target area for both the 'intent-to-treat' population and the per protocol population showed that 79-85% of patients were judged a clinical success. For both populations, there was no statistically significant difference between the response to once-daily and twice-daily active treatment (intent-to-treat; P = 0.35; 95% confidence interval for difference -14.2 to +5.0 percentage points: per protocol; P = 0.42; 95% confidence interval for difference -14.7 to +6.2 percentage points.) The improvement in the signs and symptoms was judged a success in 95-97% of patients. There was an equal reduction in severity scores for disease activity in both groups, and the speed of symptom relief was similar.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 7577590  Br J Dermatol. 1995 Oct;133(4):592-7.
著者: C Green, J L Colquitt, J Kirby, P Davidson
雑誌名: Br J Dermatol. 2005 Jan;152(1):130-41. doi: 10.1111/j.1365-2133.2005.06410.x.
Abstract/Text BACKGROUND: Topical corticosteroids remain the mainstay of treatment for atopic eczema, yet there is uncertainty over the frequency of their use in terms of clinical and cost effectiveness.
OBJECTIVES: To assess the clinical and cost effectiveness of once-daily vs. more frequent use of same-potency topical corticosteroids in atopic eczema.
METHODS: A systematic review of the clinical and cost-effectiveness literature was undertaken, together with a cost-minimization analysis.
RESULTS: The review identified a sparse literature, comprising one previous systematic review and 10 randomized controlled trials (RCTs). No published cost-effectiveness studies were identified. RCTs were focused on potent topical corticosteroids (eight RCTs), with no trials (RCTs/controlled clinical trials) identified on mild potency products. There was broad heterogeneity in trial methods, and therefore we considered outcomes according to: (i) at least a good response or 50% improvement, and (ii) eczema rated as cleared or controlled. Studies found little difference between once-daily and more frequent use of topical corticosteroids. The literature on moderately potent and potent corticosteroids offered no basis for favouring once-daily or more frequent use, although some significant differences favouring twice-daily treatment were identified. One RCT on very potent products favoured three times daily use on the basis of clinical response, but reported no difference in the numbers with at least a good response. Given the similar outcomes seen in clinical effectiveness a cost-minimization approach was adopted to consider cost effectiveness, in order to identify the least-cost option. However, cost-minimization analysis proved complex due to wide variations in product price, with the relative cost of product comparisons by frequency proving the most important factor in determining the least-cost alternative.
CONCLUSIONS: This review has not identified any clear differences in outcomes between once-daily and more frequent application of topical corticosteroids. We would encourage prescribing clinicians to consider the once-daily use of topical corticosteroids when making treatment decisions for patients with atopic eczema. However, we find that the literature on clinical effectiveness is limited and a broader understanding of compliance and phobia associated with topical steroids is needed to inform on this issue.

PMID 15656813  Br J Dermatol. 2005 Jan;152(1):130-41. doi: 10.1111/j.1・・・
著者: Lawrence F Eichenfield, Sarmistha Basu, Barry Calvarese, Ronald J Trancik
雑誌名: Pediatr Dermatol. 2007 May-Jun;24(3):289-95. doi: 10.1111/j.1525-1470.2007.00405.x.
Abstract/Text Desonide, a low potency corticosteroid, has been used widely as a topical treatment for inflammatory dermatoses for over 30 years. A recent formulation advance has enabled the development of desonide 0.05% into a novel moisturizing aqueous gel (hydrogel) that is free of alcohol and surfactants. This multicenter, open-label study evaluated the hypothalamic-pituitary-adrenal axis suppression potential, tolerability, and efficacy of this new Class VI topical steroid formulation in pediatric subjects with moderate-to-severe atopic dermatitis (mean body surface area = 51%). Forty children, aged 6 months to 6 years were enrolled and treated twice daily for 4 weeks. Desonide hydrogel 0.05% was well tolerated and no treatment-related adverse events were reported. No suppression of adrenal function was observed in subjects who completed the study without protocol violations related to cosyntropin administration or cortisol testing (n=34). Of the subjects who completed the study with complications in cortisol testing (n=3), there was one subject (1/37=3%) who had a low poststimulation cortisol level at week 4. Efficacy was demonstrated by marked improvement in overall disease state and in the signs and symptoms of atopic dermatitis. This study validates the systemic safety of a novel desonide hydrogel formulation in young pediatric patients and confirms the longstanding tolerability and efficacy profile of desonide.

PMID 17542883  Pediatr Dermatol. 2007 May-Jun;24(3):289-95. doi: 10.11・・・
著者: Adelaide A Hebert, Sheila Fallon Friedlander, David B Allen
雑誌名: J Pediatr. 2006 Sep;149(3):378-82. doi: 10.1016/j.jpeds.2006.05.008.
Abstract/Text OBJECTIVE: To establish the absence of adrenal suppression of fluticasone propionate (FP) 0.05% lotion when applied extensively to children (3 months to 6 years), with moderate to severe atopic dermatitis (AD).
STUDY DESIGN: Open-label, conducted at 6 US centers; 44 subjects (3 to 71 months) with widespread AD (mean body surface area treated, 65%) received FP lotion twice daily for up to 4 weeks.
RESULTS: No significant differences in mean cortisol levels were detected before or after treatment. At baseline, mean (+/-standard deviation) cortisols before and after cosyntropin (CST) stimulation were 13 +/- 6 microg/dL and 35 +/- 6 microg/dL, respectively. End-treatment, pre-CST, and post-CST cortisols were 12 +/- 6 microg/dL and 33 +/- 8 microg/dL, respectively. All 42 subjects with end-treatment post-CST cortisols demonstrated a normal adrenal response to CST (>18.0 microg/dL). FP lotion was well tolerated. Subjects who had blood drawn for bioavailability showed no correlation between FP levels and end-treatment post-CST cortisols.
CONCLUSIONS: In patients as young as 3 months, FP lotion had no effect on HPA axis function and did not cause skin thinning even when used extensively over widespread, severe inflammatory disease. These results, together with others from studies using cream and ointment, provide further evidence of the safety of FP.

PMID 16939752  J Pediatr. 2006 Sep;149(3):378-82. doi: 10.1016/j.jpeds・・・
著者: Amy S Paller, Sai Nimmagadda, Lawrence Schachner, Susan B Mallory, Teri Kahn, Isaac Willis, Lawrence F Eichenfield
雑誌名: J Am Acad Dermatol. 2003 Apr;48(4):569-77. doi: 10.1067/mjd.2003.174.
Abstract/Text BACKGROUND: Fluocinolone acetonide 0.01% in a blend of refined peanut and mineral oils has been used as treatment for scalp psoriasis for several years, but only more recently for atopic dermatitis.
OBJECTIVE: We sought to study the effectiveness for atopic dermatitis, potential for adrenal axis suppression, and safety of the fluocinolone acetonide 0.01% in oil in children with atopic dermatitis, including children with atopic dermatitis and peanut allergic sensitivity.
METHODS: Three separate studies were performed in children aged 2 to 12 years with atopic dermatitis: multicenter double-blind, randomized, and vehicle-controlled trial; cortisol stimulation testing; and prick testing, patch testing, and monitored medication use in children with peanut allergic sensitivity.
RESULTS: Improvement of >/=50% was demonstrated within 2 weeks in 81% to 87% of 81 patients treated with active medication versus 39% of 45 children treated with vehicle oil alone. No adrenal suppression occurred after 4 weeks of therapy in 32 patients. None of 9 patients who were peanut sensitive reacted to either the full formulation or vehicle in prick or patch testing; 20 children who were peanut sensitive showed no allergic reactions after application of the medication.
CONCLUSION: Fluocinolone 0.01% in peanut oil is an effective alternative to the use of topical corticosteroid agents in ointment, cream, and lotion forms in children. No evidence of adrenal suppression or adverse local effects were demonstrated in these studies. The medication was well tolerated in patients with peanut allergic sensitivity.

PMID 12664021  J Am Acad Dermatol. 2003 Apr;48(4):569-77. doi: 10.1067・・・
著者: J A Ellison, L Patel, D W Ray, T J David, P E Clayton
雑誌名: Pediatrics. 2000 Apr;105(4 Pt 1):794-9.
Abstract/Text OBJECTIVES: Topical glucocorticoids (GCs) fail to produce a clinical response in some children with atopic dermatitis (AD), suggesting that GC resistance may be present. To determine whether such resistance is generalized or specific to diseased skin, hypothalamic-pituitary-adrenal (HPA) axis function has been assessed in children with moderate to severe AD, who showed a variable response to treatment with topical GC.
STUDY DESIGN: Thirty-five patients (.7-18.7 years old; median: 9.3 years) with AD requiring topical GCs from infancy underwent a low-dose adrenocorticotrophin hormone (ACTH; Synacthen) test (LDST) (500 ng/1.73 m(2) ACTH). Groups 1 (7 patients), 2 (17 patients), and 3 (4 patients) used mild, moderate, or potent/very potent topical preparations, respectively. Group 4 (7 boys with severe, treatment-resistant disease) had received GC in at least 1 form (inhaled +/- intranasal +/- oral) in addition to varying potencies of topical GC. Fourteen healthy subjects (3.8-17.3 years old) served as control subjects. Group 4 patients had a daytime plasma cortisol profile and 08.00 hours measurement of plasma ACTH and its precursors.
RESULTS: The response to ACTH for groups 1 and 2 did not differ from that of control subjects. Group 3 had lower peak, increment, and area under curve cortisol responses than those in controls, whereas group 4 had lower baseline, peak, and area under curve cortisol responses. Eight patients failed the LDST (peak cortisol <500 nmol/L and increment <200 nmol/L): controls = 0/14, group 1 = 0/7, group 2 = 1/17, group 3 = 4/4, and group 4 = 3/7. Treatment score (based on GC potency, area treated, and duration) was the only factor to influence peak cortisol response on LDST (r(2) = 24%). In group 4, only 1 of 7 patients had a cortisol profile within the normal range but he failed the LDST. In the 5 subjects with an 08.00 hours cortisol <300 nmol/L, the matched ACTH level was inappropriately low.
CONCLUSIONS: HPA suppression was rarely found in children or adolescents with moderate to severe AD who used mild or moderately potent topical GCs over many years. However, HPA suppression was common in those receiving potent topical GC preparations or a combination of GC routes of administration. In those with severe AD, evidence of HPA suppression but lack of clinical response to GC treatment excluded significant generalized GC resistance. This would suggest that localized resistance to GCs within the diseased skin may be part of the aetiopathogenesis of severe AD.

PMID 10742322  Pediatrics. 2000 Apr;105(4 Pt 1):794-9.
著者: Joel Schlessinger, Bruce Miller, Richard D Gilbert, R Todd Plott, Vanos Study Group
雑誌名: Arch Dermatol. 2006 Dec;142(12):1568-72. doi: 10.1001/archderm.142.12.1568.
Abstract/Text OBJECTIVE: To assess the potential of a superhigh-potency 0.1% fluocinonide cream to suppress the hypothalamic-pituitary-adrenal (HPA) axis in pediatric patients with atopic dermatitis.
DESIGN: A multicenter, multiple-dose, open-label safety study in 4 age cohorts with 0.1% fluocinonide cream applied once or twice daily for 2 weeks.
SETTING: Clinical outpatient setting.
PATIENTS: Patients with moderate to severe atopic dermatitis with 20% or more of the body surface area involved were included in the study. Each cohort began only after evaluation of the preceding cohort: ages 12 to younger than 18 years (cohort 1); 6 to younger than 12 years (cohort 2); 2 to younger than 6 years (cohort 3); and 3 months to younger than 2 years (cohort 4).
MAIN OUTCOME MEASURES: Assessment of HPA axis suppression, local and systemic adverse events, and change in disease status from baseline.
RESULTS: Suppression of the HPA axis was not observed in any patient treated once daily for the 2 youngest cohorts. Suppression was observed in 1 (7%) of 15 and 2 (12%) of 16 patients in the fluocinonide twice-daily group in cohorts 1 and 2, respectively. In all 4 cohorts, more than 90% of patients in the fluocinonide once-daily and twice-daily groups showed improvement in their disease status.
CONCLUSIONS: Once-daily treatment with 0.1% fluocinonide cream for 2 weeks does not result in HPA axis suppression under the conditions of this study. Once-daily applications provided similar or better efficacy as twice-daily applications with a lower risk of HPA axis suppression. The frequency of HPA axis suppression is no greater in younger children than in older children.
TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN71227633.

PMID 17178982  Arch Dermatol. 2006 Dec;142(12):1568-72. doi: 10.1001/a・・・
著者: M Kawashima, T Tango, T Noguchi, M Inagi, H Nakagawa, S Harada
雑誌名: Br J Dermatol. 2003 Jun;148(6):1212-21.
Abstract/Text BACKGROUND: Fexofenadine, a nonsedating, H1-receptor selective antihistamine, exhibits consistent efficacy and safety in the treatment of allergic rhinitis and urticaria. The pruritus associated with atopic dermatitis is considered to be induced, in part, by histamine. Therefore, we thought that fexofenadine may be useful in the relief of pruritus associated with atopic dermatitis.
OBJECTIVE: To compare the efficacy of twice-daily fexofenadine hydrochloride (HCl) 60 mg vs. placebo in reducing the pruritus associated with atopic dermatitis.
METHODS: In this randomized, multicentre, double-blind, placebo-controlled study, patients (aged >or= 16 years) with atopic dermatitis underwent a 1-week placebo lead-in period, followed by randomization to fexofenadine HCl 60 mg twice daily or placebo for 1 week. All patients also received topical treatment with 0.1% hydrocortisone butyrate twice daily throughout the study. The primary efficacy endpoint was mean change in pruritus score from baseline. Patients reflectively recorded pruritus scores twice daily (day and night) using a five-point scale (0 = none; 4 = very severe).
RESULTS: Fexofenadine (n = 201) significantly decreased the severity of pruritus compared with placebo (n = 199) (mean change in score -0.75 (unadjusted 95% confidence interval [-0.88, -0.62]) vs. -0.5 [-0.62, -0.38], respectively; P = 0.0005). This improvement was seen after just 1 day of treatment (P = 0.039) and was maintained throughout the treatment period (P = 0.019). Compared with placebo, fexofenadine significantly improved both diurnal (P = 0.0001) and nocturnal pruritus (P = 0.013). In addition, significantly more patients in the fexofenadine group experienced a reduction in the ratio of pruritus area to body surface area compared with those in the placebo group (P = 0.007). The incidence of adverse events was low and similar across all treatment groups.
CONCLUSIONS: Fexofenadine HCl 60 mg twice daily demonstrated a rapid, significant improvement in the pruritus associated with atopic dermatitis, with a safety profile equivalent to that of placebo.

PMID 12828751  Br J Dermatol. 2003 Jun;148(6):1212-21.
著者: T Zuberbier, C Bindslev-Jensen, W Canonica, C E H Grattan, M W Greaves, B M Henz, A Kapp, M M A Kozel, M Maurer, H F Merk, T Schäfer, D Simon, G A Vena, B Wedi, EAACI/GA2LEN/EDF
雑誌名: Allergy. 2006 Mar;61(3):321-31. doi: 10.1111/j.1398-9995.2005.00962.x.
Abstract/Text This guideline is the result of a consensus reached during a panel discussion at the second International Consensus Meeting on Urticara, Urticaria 2004, a joint initiative of the EAACI Dermatology Section and GA2LEN. Urticaria has a profound impact on the quality of life, and effective treatment is therefore required. The recommended first line treatment are nonsedating H1 antihistamines. They have proven to be effective in double-blind controlled studies, but dosages increased up to fourfold over the recommended doses may be necessary. However, for different urticaria subtypes and in view of individual variation in the course of the disease and response to treatment, additional or alternative therapies may be required. Immunosuppressive drugs like cyclosporin A and corticosteroids are not recommended for long-term treatment due to unavoidable severe adverse effects. This guideline was, in addition, accepted by the European Dermatology Forum (EDF) and formally approved by the European Union of Medical Specialists (UEMS).

PMID 16436141  Allergy. 2006 Mar;61(3):321-31. doi: 10.1111/j.1398-999・・・
著者: Kirsi Laitinen, Marko Kalliomäki, Tuija Poussa, Hanna Lagström, Erika Isolauri
雑誌名: Br J Nutr. 2005 Oct;94(4):565-74.
Abstract/Text Current research into dietary factors contributing to the development of allergic diseases is directed towards new active approaches instead of passive elimination diets. The present study aimed to investigate the explanatory role of the diet in a probiotic intervention study on the appearance of atopic eczema (AE) in childhood and the safety of perinatal supplementation with probiotics (Lactobacillus rhamnosus strain GG; ATCC 53 103). A prospective follow-up study from birth to 48 months of children (n 159) with a family history of allergic disease was carried out. Outcome measures included growth, dietary intake assessed with 4 d food diaries and their association with AE by logistic regression models. Increased intakes of retinol, Ca and Zn, with perinatal administration of probiotics, reduced the risk of AE, whilst an increase in intake of ascorbic acid increased the likelihood of AE. Perinatal administration of probiotics was safe, as it did not influence the height (mean difference 0.04 (95 % CI -0.33, 0.40) sd scores, P=0.852) or the weight-for-height (mean difference -3.35 (95 % CI -7.07, 0.37)%, P=0.077) of the children at 48 months with and without perinatal administration of probiotics. Up to 48 months, AE did not affect height (mean difference -0.05 (95 % CI -0.42, 0.33) sd scores, P=0.815), but mean weight-for-height in children with AE was -5.1 % (95 % CI -8.9, -1.2 %) lower compared with children without (P=0.010). The joint effects of nutrients and probiotics need to be considered in active prevention and management schemes for allergic diseases.

PMID 16197582  Br J Nutr. 2005 Oct;94(4):565-74.
著者: Matthias Volkmar Kopp, Isabell Hennemuth, Andrea Heinzmann, Radvan Urbanek
雑誌名: Pediatrics. 2008 Apr;121(4):e850-6. doi: 10.1542/peds.2007-1492. Epub 2008 Mar 10.
Abstract/Text BACKGROUND: The value of probiotics for primary prevention is controversial. Published trials vary considerably in study design and the applied probiotics, thereby limiting comparability of the results.
OBJECTIVE: The purpose of this trial was to study the preventive effect of the probiotic Lactobacillus GG on the development of atopic dermatitis.
METHODS: In a double-blind, placebo-controlled prospective trial, 105 pregnant women from families with > or = 1 member (mother, father, or child) with an atopic disease were randomly assigned to receive either the probiotic Lactobacillus GG (American Type Culture Collection 53103; 5 x 10(9) colony-forming units of Lactobacillus GG twice daily) or placebo. Ninety-four families (89.5%) completed the trial. The supplementation period started 4 to 6 weeks before expected delivery, followed by a postnatal period of 6 months. The primary end point was the occurrence of atopic dermatitis at the age of 2 years. Secondary outcomes were severity of atopic dermatitis, recurrent episodes of wheezing bronchitis, and allergic sensitization at the age of 2 years.
RESULTS: Atopic dermatitis was diagnosed in 14 (28%) of 50 in the Lactobacillus GG group and in 12 (27.3%) of 44 in the placebo group. The risk of atopic dermatitis in children on probiotics relative to placebo was 0.96 (confidence interval 0.38-2.33). Severity of atopic dermatitis was comparable between the 2 groups. Notably, children with recurrent (> or = 5) episodes of wheezing bronchitis were more frequent in the Lactobacillus GG group (26%; n = 13), as compared with the placebo group (9.1%; n = 4). No difference was observed between both groups in total immunoglobulin E concentrations or numbers of specific sensitization to inhalant allergens.
CONCLUSIONS: Supplementation with Lactobacillus GG during pregnancy and early infancy neither reduced the incidence of atopic dermatitis nor altered the severity of atopic dermatitis in affected children but was associated with an increased rate of recurrent episodes of wheezing bronchitis. Therefore, Lactobacillus GG cannot be generally recommended for primary prevention.

PMID 18332075  Pediatrics. 2008 Apr;121(4):e850-6. doi: 10.1542/peds.2・・・
著者: Mikael Kuitunen, Kaarina Kukkonen, Kaisu Juntunen-Backman, Riitta Korpela, Tuija Poussa, Tuula Tuure, Tari Haahtela, Erkki Savilahti
雑誌名: J Allergy Clin Immunol. 2009 Feb;123(2):335-41. doi: 10.1016/j.jaci.2008.11.019. Epub 2009 Jan 8.
Abstract/Text BACKGROUND: Less microbial exposure in early childhood is associated with more allergic disease later. Allergic children have a different fecal microflora, with less lactobacilli and bifidobacteria. Beneficial effects regarding the development of allergy have been suggested to come through probiotic supplementation.
OBJECTIVE: We sought to study the effect of probiotic and prebiotic supplementation in preventing allergies.
METHODS: In a double-blinded, placebo-controlled study we randomized 1223 mothers with infants at high risk for allergy to receive a probiotic mixture (2 lactobacilli, bifidobacteria, and propionibacteria) or placebo during the last month of pregnancy and their infants to receive it from birth until age 6 months. Infants also received a prebiotic galacto-oligosaccharide or placebo. At 5 years, we evaluated the cumulative incidence of allergic diseases (eczema, food allergy, allergic rhinitis, and asthma) and IgE sensitization.
RESULTS: Of the 1018 intent-to-treat infants, 891 (88%) attended the 5-year visit. Frequencies of allergic and IgE-associated allergic disease and sensitization in the probiotic and placebo groups were similar: 52.6% versus 54.9% and 29.5% versus 26.6%, respectively, and 41.3% in both. No significant difference appeared in frequencies of eczema (39.3% vs 43.3%), atopic eczema (24.0% vs 25.1%), allergic rhinitis (20.7% vs 19.1%), or asthma (13.0% vs 14.1%) between groups. However, less IgE-associated allergic disease occurred in cesarean-delivered children receiving probiotics (24.3% vs 40.5%; odds ratio, 0.47; 95% CI, 0.23% to 0.96%; P = .035).
CONCLUSIONS: No allergy-preventive effect that extended to age 5 years was achieved with perinatal supplementation of probiotic bacteria to high-risk mothers and children. It conferred protection only to cesarean-delivered children.

PMID 19135235  J Allergy Clin Immunol. 2009 Feb;123(2):335-41. doi: 10・・・
著者: S E Soh, M Aw, I Gerez, Y S Chong, M Rauff, Y P M Ng, H B Wong, N Pai, B W Lee, L P-C Shek
雑誌名: Clin Exp Allergy. 2009 Apr;39(4):571-8. doi: 10.1111/j.1365-2222.2008.03133.x. Epub 2008 Dec 9.
Abstract/Text BACKGROUND: The role of probiotics in allergy prevention remains uncertain but has been shown in some studies to have a possible protective effect on eczema.
OBJECTIVE: We aimed to assess the effect of probiotic supplementation in the first 6 months of life on eczema and allergic sensitization at 1 year of age in Asian infants at risk of allergic disease.
METHODS: A double-blind, placebo-controlled randomized clinical trial involving 253 infants with a family history of allergic disease was carried out. Infants received at least 60 mL of commercially available cow's milk formula with or without probiotic supplementation [Bifidobacterium longum (BL999) 1 x 10(7) colony forming unit (CFU)/g and Lactobacillus rhamnosus (LPR) 2 x 10(7) CFU/g] daily for the first 6 months. Clinical evaluation was performed at 1, 3, 6 and 12 months of age, with serum total IgE measurement and skin prick tests conducted at the 12-month visit. The primary and secondary end-points were eczema and allergen sensitization, respectively.
RESULTS: The incidence of eczema in the probiotic (22%) group was similar to that in the placebo group (25%) (P=0.53). The median Scoring Atopic Dermatitis score at 12 months was 17.10 (9.74) in the probiotic group and 11.60 (8.40) in the placebo group (P=0.17). The prevalence of allergen sensitization showed no difference (probiotic=24% vs. placebo=19%, P=0.26). The total IgE geometric mean (95% confidence interval) was 18.76 (12.54-24.98) kU/L in the probiotic group and 23.13 (16.01-30.24) kU/L in the placebo group (P=0.15). Atopic eczema (with sensitization) in the probiotic (7.3%) group was comparable to the placebo group (5.8%) (P=0.86).
CONCLUSION: Early life administration of a cow's milk formula supplemented with probiotics showed no effect on prevention of eczema or allergen sensitization in the first year of life in Asian infants at risk of allergic disease. Further work is needed to determine whether timing of supplementation, dose and probiotic strain are important considerations.

PMID 19134020  Clin Exp Allergy. 2009 Apr;39(4):571-8. doi: 10.1111/j.・・・
著者: S Weston, A Halbert, P Richmond, S L Prescott
雑誌名: Arch Dis Child. 2005 Sep;90(9):892-7. doi: 10.1136/adc.2004.060673. Epub 2005 Apr 29.
Abstract/Text BACKGROUND: The aim of the study was to investigate the effects of probiotics on moderate or severe atopic dermatitis (AD) in young children.
METHODS: Fifty six children aged 6-18 months with moderate or severe AD were recruited into a randomised double blind placebo controlled trial in Perth, Western Australia; 53 children completed the study. The children were given a probiotic (1x10(9)Lactobacillus fermentum VRI-033 PCC; Probiomics) or an equivalent volume of placebo, twice daily for 8 weeks. A final assessment at 16 weeks was performed.
RESULTS: The main outcome measures were severity and extent of AD at the end of the study, as measured by the Severity Scoring of Atopic Dermatitis (SCORAD) index. The reduction in the SCORAD index over time was significant in the probiotic group (p = 0.03) but not the placebo group. Significantly more children receiving probiotics (n = 24, 92%) had a SCORAD index that was better than baseline at week 16 compared with the placebo group (n = 17, 63%) (p = 0.01). At the completion of the study more children in the probiotic group had mild AD (n = 14, 54%) compared to the placebo group (n = 8, 30%).
CONCLUSION: Supplementation with probiotic L fermentum VRI-003 PCC is beneficial in improving the extent and severity of AD in young children with moderate or severe disease.

PMID 15863468  Arch Dis Child. 2005 Sep;90(9):892-7. doi: 10.1136/adc.・・・
著者: D Sistek, R Kelly, K Wickens, T Stanley, P Fitzharris, J Crane
雑誌名: Clin Exp Allergy. 2006 May;36(5):629-33. doi: 10.1111/j.1365-2222.2006.02485.x.
Abstract/Text BACKGROUND: Probiotics have previously been shown to reduce the severity of atopic dermatitis (AD) in infants and children.
OBJECTIVE: To examine the effect of two probiotics (Lactobacillus rhamnosus and Bifidobacteria lactis) on established AD in children.
SUBJECTS AND METHODS: Atopic children with current dermatitis received 2 x 10(10) colony forming units/g of probiotic (n=29) or placebo (n=30). Both were given daily as a powder mixed with food or water. SCORing Atopic Dermatitis (SCORAD; developed by the European Task Force on Atopic Dermatitis) a measure of the extent and severity of AD, was assessed at baseline, 2 and 12 weeks after starting treatment and 4 weeks after treatment was discontinued.
RESULTS: SCORAD geometric mean score at baseline was 26.0 (21.9-30.8) in the probiotic group and 35.1 (28.9-42.8) in the placebo group (P=0.02). After adjustment for these between-group baseline differences there was no significant improvement in AD at 12 weeks, SCORAD geometric mean ratio: 0.80 (95% confidence level (CI) 0.62-1.04, P=0.10). Among the food sensitized children, there was an improvement in those treated with probiotics, SCORAD geometric mean ratio: 0.73 (95% CI 0.54-1.00, P=0.047).
CONCLUSION: In this study a combination of Lactobacillus rhamnosus and Bifidobacteria lactis improved AD only in food sensitized children.

PMID 16650048  Clin Exp Allergy. 2006 May;36(5):629-33. doi: 10.1111/j・・・
著者: M Viljanen, E Savilahti, T Haahtela, K Juntunen-Backman, R Korpela, T Poussa, T Tuure, M Kuitunen
雑誌名: Allergy. 2005 Apr;60(4):494-500. doi: 10.1111/j.1398-9995.2004.00514.x.
Abstract/Text BACKGROUND: Probiotic bacteria are suggested to reduce symptoms of the atopic eczema/dermatitis syndrome (AEDS) in food-allergic infants. We aimed to investigate whether probiotic bacteria have any beneficial effect on AEDS.
METHODS: Follow-up of severity of AEDS by the Severity Scoring of Atopic Dermatitis (SCORAD) index in 230 infants with suspected cow's milk allergy (CMA) receiving, in a randomized double-blinded manner, concomitant with elimination diet and skin treatment, Lactobacillus GG (LGG), a mixture of four probiotic strains, or placebo for 4 weeks. Four weeks after the treatment, CMA was diagnosed with a double-blind placebo-controlled (DBPC) milk challenge in 120 infants.
RESULTS: In the whole group, mean SCORAD (at baseline 32.5) decreased by 65%, but with no differences between treatment groups immediately or 4 weeks after the treatment. No treatment differences were observed in infants with CMA either. In IgE-sensitized infants, however, the LGG group showed a greater reduction in SCORAD than did the placebo group, -26.1 vs-19.8 (P=0.036), from baseline to 4 weeks after the treatment. Exclusion of infants who had received antibiotics during the study reinforced the findings in the IgE-sensitized subgroup.
CONCLUSION: Treatment with LGG may alleviate AEDS symptoms in IgE-sensitized infants but not in non-IgE-sensitized infants.

PMID 15727582  Allergy. 2005 Apr;60(4):494-500. doi: 10.1111/j.1398-99・・・
著者:
雑誌名: Ann Allergy Asthma Immunol. 2014 Aug;113(2):217-26. doi: 10.1016/j.anai.2014.05.021. Epub 2014 Jun 20.
Abstract/Text
PMID 24954372  Ann Allergy Asthma Immunol. 2014 Aug;113(2):217-26. doi・・・
著者:
雑誌名: J Eur Acad Dermatol Venereol. 2015 Feb;29(2):232-42. doi: 10.1111/jdv.12496. Epub 2014 Apr 4.
Abstract/Text
PMID 24698503  J Eur Acad Dermatol Venereol. 2015 Feb;29(2):232-42. do・・・
著者:
雑誌名: J Allergy Clin Immunol. 2014 Oct;134(4):818-23. doi: 10.1016/j.jaci.2014.08.005.
Abstract/Text
PMID 25282563  J Allergy Clin Immunol. 2014 Oct;134(4):818-23. doi: 10・・・
著者:
雑誌名: J Allergy Clin Immunol. 2014 Oct;134(4):824-830.e6. doi: 10.1016/j.jaci.2014.07.060.
Abstract/Text
PMID 25282564  J Allergy Clin Immunol. 2014 Oct;134(4):824-830.e6. doi・・・
著者: Debra Breneman, Alan B Fleischer, William Abramovits, Joshua Zeichner, Michael H Gold, Robert S Kirsner, Toni F Shull, Andrew W Crowe, Eileen Jaracz, Jon M Hanifin, Tacrolimus Ointment Study Group
雑誌名: J Am Acad Dermatol. 2008 Jun;58(6):990-9. doi: 10.1016/j.jaad.2008.02.008. Epub 2008 Mar 21.
Abstract/Text BACKGROUND: Intermittent dosing of a topical calcineurin inhibitor for preventing atopic dermatitis (AD) disease relapse in patients with stabilized AD has not been evaluated.
OBJECTIVE: We sought to evaluate the long-term efficacy and safety of 3-times-weekly use of tacrolimus ointment in preventing AD disease relapse.
METHODS: Adult and pediatric patients with moderate to severe AD who were clear of disease after up to 16 weeks of treatment with tacrolimus ointment were randomized in a double-blind fashion to 3-times-weekly treatment with either tacrolimus ointment (0.03% or 0.1%) or vehicle for 40 weeks. The primary end point was the number of flare-free treatment days.
RESULTS: A total of 125 patients were randomized to tacrolimus and 72 patients to vehicle. The mean number of flare-free treatment days was 177 for tacrolimus and 134 for vehicle (P = .003). Median time to first relapse was 169 days for tacrolimus and 43 for vehicle (P = .037).
LIMITATIONS: Generalizability to all patients seen in clinic may be limited because only patients who responded to tacrolimus ointment in the stabilization phase were randomized into the maintenance phase of the trial.
CONCLUSIONS: Maintenance therapy with tacrolimus ointment was associated with significantly more flare-free days compared with vehicle, and a significantly longer time until first disease relapse.

PMID 18359127  J Am Acad Dermatol. 2008 Jun;58(6):990-9. doi: 10.1016/・・・
著者: A Wollenberg, S Reitamo, G Girolomoni, M Lahfa, T Ruzicka, E Healy, A Giannetti, T Bieber, J Vyas, M Deleuran, European Tacrolimus Ointment Study Group
雑誌名: Allergy. 2008 Jul;63(7):742-50.
Abstract/Text BACKGROUND: Long-term treatment for atopic dermatitis (AD) using low dose, intermittent, topical anti-inflammatory agents may control acute disease and prevent relapses. This 12-month, European, multicentre, randomized study investigated whether the proactive use of 0.1% tacrolimus ointment applied twice weekly can keep AD in remission and reduce the incidence of disease exacerbations (DE).
METHODS: During the initial open-label period, 257 adults with AD applied 0.1% tacrolimus ointment twice daily (b.i.d.) for up to 6 weeks to affected areas. When an Investigator Global Assessment (IGA) score of RESULTS: Proactive tacrolimus 0.1% ointment application significantly reduced the number of DEs requiring substantial therapeutic intervention (median difference 2; P < 0.001; Wilcoxon rank sum test), the percentage of DE treatment days (median difference: 15.2%; P < 0.001; Wilcoxon rank sum test) and increased the time to first DE (median 142 vs 15 days; P < 0.001; stratified log-rank test). The adverse event profile was similar for the two treatment approaches.
CONCLUSION: A 12-month, twice weekly proactive tacrolimus ointment application was an effective treatment in most study patients which prevented, delayed and reduced the occurrence of AD exacerbations

PMID 18592619  Allergy. 2008 Jul;63(7):742-50.
著者:
雑誌名: Br J Dermatol. 2011 Feb;164(2):415-28. doi: 10.1111/j.1365-2133.2010.10030.x. Epub 2010 Nov 23.
Abstract/Text
PMID 20819086  Br J Dermatol. 2011 Feb;164(2):415-28. doi: 10.1111/j.1・・・
著者: Marie Lodén, Anna-Carin Andersson, Chris Anderson, Ing-Marie Bergbrant, Thomas Frödin, Hans Ohman, Mari-Helen Sandström, Tore Särnhult, Ewa Voog, Berndt Stenberg, Eva Pawlik, Anna Preisler-Häggqvist, Ake Svensson, Magnus Lindberg
雑誌名: Acta Derm Venereol. 2002;82(1):45-7.
Abstract/Text Moisturizing creams have beneficial effects in the treatment of dry, scaly skin, but they may induce adverse skin reactions. In a randomized double-blind study, 197 patients with atopic dermatitis were treated with one of the following: a new moisturizing cream with 20% glycerin, its cream base without glycerin as placebo, or a cream with 4% urea and 4% sodium chloride. The patients were asked to apply the cream at least once daily for 30 days. Adverse skin reactions and changes in skin dryness were assessed by the patient and a dermatologist. Adverse skin reactions such as smarting (a sharp local superficial sensation) were felt significantly less among patients using the 20% glycerin cream compared with the urea-saline cream, because 10% of the patients judged the smarting as severe or moderate when using glycerin cream, whereas 24% did so using urea-saline cream (p < 0.0006). No differences were found regarding skin reactions such as stinging, itching and dryness/irritation. The study showed equal effects on skin dryness as judged by the patients and the dermatologist. In conclusion, a glycerin containing cream appears to be a suitable alternative to urea/sodium chloride in the treatment of atopic dry skin.

PMID 12013198  Acta Derm Venereol. 2002;82(1):45-7.

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