今日の臨床サポート

アトピー性皮膚炎

著者: 加藤則人 京都府立医科大学 皮膚科学

監修: 戸倉新樹 掛川市・袋井市病院企業団立 中東遠総合医療センター 参与/浜松医科大学 名誉教授

著者校正/監修レビュー済:2022/03/30
参考ガイドライン:
  1. 日本皮膚科学会:アトピー性皮膚炎診療ガイドライン 2021
患者向け説明資料
薬価収載情報:
2022年5月25日 ミチーガ 皮下注用60mgシリンジ(ネモリズマブ(遺伝子組換え) ヒト化抗ヒトIL-31受容体Aモノクローナル抗体)

2022年5月25日 モイゼルト 軟膏1%(ジファミラスト アトピー性皮膚炎治療剤)

概要・推奨   

  1. アトピー性皮膚炎の湿疹病変に対して、ステロイド外用は推奨される。顔面への使用については、初期の薬剤は可能な限り弱いステロイド外用薬を短期間使用する(推奨度2)
  1. 2歳以上のアトピー性皮膚炎の湿疹病変に対して、タクロリムス(プロトピック)外用は推奨される(推奨度2)
  1. 2歳以上のアトピー性皮膚炎の湿疹病変に対して、デルゴシチニブ(コレクチム)軟膏は推奨される(推奨度2)
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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。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※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、実際の保険適応の査定において保険適応及び保険適応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応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:
加藤則人 : 未申告[2022年]
監修:戸倉新樹 : 講演料(マルホ,サノフィ,協和キリン),原稿料(医学書院)[2022年]

改訂のポイント:
  1. 治療の手順を新しく公表された診療ガイドラインに沿ったものにした。
  1. 新しく承認されたJanus kinase(JAK)阻害内服剤を追加した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. アトピー性皮膚炎は、2002年の厚生労働省の調査によると小学生の11%、大学生の8%にみられる、ありふれた皮膚疾患である。
 
乳児アトピー性皮膚炎の顔面の皮疹

頬部、口囲、眼瞼などにびらんを伴う湿疹病変がみられる。

出典

img1:  著者提供
 
 
 
成人アトピー性皮膚炎の皮疹

慢性期の皮疹。苔癬化を伴う紅斑と掻破痕がみられる。

出典

img1:  著者提供
 
 
 
  1. 皮膚のバリアー機能低下による易刺激性と、アレルギー炎症を起こしやすい(アトピー素因)という遺伝的素因に加えて、さまざまな悪化因子が重なり、慢性に湿疹を繰り返す疾患である。
  1. 接触皮膚炎や疥癬、リンパ腫など鑑別すべき疾患は多岐にわたるが、年齢とともに推移する典型的な左右対称性の皮疹から、診断は一般に容易である。
  1. 治療は、ステロイドやタクロリムス(プロトピック)などの抗炎症外用薬による薬物療法が基本であるが、副作用に関する誤った認識のために、標準的治療が行われずに悪化する例が少なくない。
  1. 一般に慢性に経過するが、適切な治療により症状がコントロールされた状態に維持されると、自然寛解も期待される疾患である[1]
  1. 小児、成人とも、年齢が進むにつれて寛解していく傾向がある(根拠となる論文 ①1歳未満でアトピー性皮膚炎と診断された169人の乳児を4年間追跡したところ、症状は51%で改善、34%で消失していた[2]。 ②成人2,123名を対象とした調査では、有病率は20歳代 9.8%、30歳代 8.7%、40歳代 4.4%、50~60歳代 2.6%と年齢が進むにつれて低下した。また、軽症:中等症:重症:最重症の比率は20歳代(76.9%:17.9%:2.6%:2.6%)、30歳代(72.2%:21.5%:5.1%:1.3%)、40歳代 (82.4%:17.6%:0.0%:0.0%)、50~60歳代 (100%:0.0%:0.0%:0.0%)と年齢が進むにつれて軽快していくことが示唆された[3])。
病歴・診察のポイント  
  1. アトピー性皮膚炎の皮疹は、痒みを伴う左右対称性の湿疹病変である。

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文献 

Yusei Ohshima, Akiko Yamada, Masahiro Hiraoka, Kenji Katamura, Setsuko Ito, Takao Hirao, Hiroshi Akutagawa, Naomi Kondo, Akihiro Morikawa, Mitsufumi Mayumi
Early sensitization to house dust mite is a major risk factor for subsequent development of bronchial asthma in Japanese infants with atopic dermatitis: results of a 4-year followup study.
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
Hidehisa Saeki, Yuichiro Tsunemi, Hideki Fujita, Shinji Kagami, Kiyo Sasaki, Hanako Ohmatsu, Aya Watanabe, Kunihiko Tamaki
Prevalence of atopic dermatitis determined by clinical examination in Japanese adults.
J Dermatol. 2006 Nov;33(11):817-9. doi: 10.1111/j.1346-8138.2006.00187.x.
Abstract/Text
PMID 17074002
J M Maloney, M R Morman, D M Stewart, M D Tharp, J J Brown, R Rajagopalan
Clobetasol propionate emollient 0.05% in the treatment of atopic dermatitis.
Int J Dermatol. 1998 Feb;37(2):142-4.
Abstract/Text A 4-week, double-blind, randomized clinical trial, comparing the efficacy and safety of clobetasol propionate emollient cream 0.05% and its vehicle, was conducted at four private dermatology clinics in 81 non-hospitalized patients (> or = 12 years old) with moderate-to-severe atopic dermatitis covering 2% or more of their body surface. All patients had at least one lesion 2 cm or more in diameter. Three signs/symptoms of target lesions (erythema, pruritus, and induration/papulation) were scored by investigators on a scale of 0-3 (in 0.5-point increments; 0 = absent, 1 = mild, 2 = moderate, and 3 = severe); the total of the three scores had to be > or = 6 for patients to qualify for study entry. Patients were excluded if they were immunocompromised, pregnant, or nursing; had skin atrophy, telangiectasia or striae in skin areas to be treated; or had received topical treatments for atopic dermatitis within 1 week prestudy, intramuscular triamcinolone within 6 weeks prestudy, or long-term systemic corticosteroid usage within 6 months prestudy. Patients were randomized in a 1:1 ratio to receive either clobetasol propionate emollient 0.05% twice daily (n = 41), or the emollient vehicle twice daily (n = 40), for 4 weeks. A fingertip unit, equaling approximately 0.5 g in males and 0.43 g in females (enough to cover approximately 2% of the body), was used to measure and apply a thin film of study drug to the affected areas. The efficacy was evaluated by investigators and patients on days 4, 8, 15, and 29 after initiation of therapy, and 2 weeks after the end of treatment (day 43). Investigators performed a physician's gross assessment based on the percentage improvement of the target lesion. They also rated changes from baseline in mean severity scores for six individual signs/symptoms (erythema, pruritus, induration/papulation, lichenification, erosion/oozing/crusting, and scaling/dryness) and for total signs/symptoms according to the severity scoring system described above. Patients rated their response to treatment as excellent, good, fair, poor, or worse. Laboratory assessments were made on days 15, 29, and (if necessary) day 43.

PMID 9542676
John Berth-Jones, Robert J Damstra, Stefan Golsch, John K Livden, Oliver Van Hooteghem, Fulvio Allegra, Christine A Parker, Multinational Study Group
Twice weekly fluticasone propionate added to emollient maintenance treatment to reduce risk of relapse in atopic dermatitis: randomised, double blind, parallel group study.
BMJ. 2003 Jun 21;326(7403):1367. doi: 10.1136/bmj.326.7403.1367.
Abstract/Text OBJECTIVE: To explore the efficacy and safety of fluticasone propionate, cream and ointment, applied twice weekly in addition to maintenance treatment with emollients, in reducing the risk of relapse of chronic recurrent atopic dermatitis.
DESIGN: Randomised, double blind, parallel group study of 20 weeks' duration.
SETTING: Dermatology outpatient clinics (6 countries, 39 centres).
PARTICIPANTS: Adult (aged 12-65) patients with moderate to severe atopic dermatitis who were experiencing a flare.
METHODS: Participants applied fluticasone propionate (0.05% cream or 0.005% ointment; once or twice daily) regularly for four weeks to stabilise their condition. The patients whose disease was brought under control then continued into a 16 week maintenance phase, applying emollient on a daily basis with a bath oil as needed and either the same formulation of fluticasone propionate or its placebo base (emollient alone) twice weekly to the areas that were usually affected.
MAIN OUTCOME MEASURE: Time to relapse of atopic dermatitis during maintenance phase.
RESULTS: 376 patients entered the stabilisation phase, and 295 continued into the maintenance phase. After 16 weeks in the maintenance phase, the disease remained under control in 133 patients (87 using fluticasone propionate twice weekly, 46 using emollient alone), 135 (40 fluticasone propionate, 95 emollient) had experienced a relapse, and 27 had discontinued. Median time to relapse was six weeks for emollient alone compared with more than 16 weeks for additional fluticasone propionate. Patients who applied fluticasone propionate cream twice weekly were 5.8 times less likely (95% confidence interval 3.1 to 10.8, P < 0.001) and patients using fluticasone propionate ointment 1.9 times less likely (1.2 to 3.2, P=0.010) to have a relapse than patients applying emollient alone. The groups showed no differences in adverse events.
CONCLUSION: After atopic dermatitis had been stabilised the addition of fluticasone propionate twice weekly to maintenance treatment with emollients significantly reduced the risk of relapse.

PMID 12816824
K Wirén, C Nohlgård, F Nyberg, L Holm, M Svensson, A Johannesson, P Wallberg, B Berne, F Edlund, M Lodén
Treatment with a barrier-strengthening moisturizing cream delays relapse of atopic dermatitis: a prospective and randomized controlled clinical trial.
J Eur Acad Dermatol Venereol. 2009 Nov;23(11):1267-72. doi: 10.1111/j.1468-3083.2009.03303.x. Epub 2009 Jun 8.
Abstract/Text BACKGROUND: Standard treatment of atopic dermatitis (AD) is based on topical glucocorticosteroids or calcineurin inhibitors to treat flares combined with moisturizer treatment to alleviate dry skin symptoms. Patients with AD have an abnormal skin barrier function, and strategies for reducing the risks for eczema would be to repair the barrier or prevent barrier dysfunction.
OBJECTIVES: The objective of this study was to explore the time to relapse of eczema during a 26-week maintenance treatment with a urea containing moisturizer compared to no treatment (neither medical nor non-medicated preparations) after successful clearing of atopic lesions. The moisturizer has previously been shown to improve skin barrier function.
METHODS: Patients applied betamethasone valerate (0.1%) on eczematous lesions during a 3-week period. Those with cleared eczema entered a 26-week maintenance phase, applying the moisturizer or left the previously affected area untreated. Upon eczema relapse, patients were instructed to contact the clinic and to have the relapse confirmed by the investigator.
RESULTS: Fifty-five patients entered the study and 44 patients were included in the maintenance phase (22 using moisturizer twice daily and 22 using no treatment). Median time to relapse for patients treated with moisturizer was > 180 days (duration of the study) compared with 30 days for the no-treatment group. Sixty-eight per cent of the patients treated with the moisturizer and 32% of the untreated patients remained free from eczema during the observation period.
CONCLUSIONS: Maintenance treatment with a barrier-improving urea moisturizer on previous eczematous areas reduced the risk of relapse to approximately one third of that of no treatment.

PMID 19508310
Philippe Msika, Clarence De Belilovsky, Nathalie Piccardi, Nathalie Chebassier, Caroline Baudouin, Bernard Chadoutaud
New emollient with topical corticosteroid-sparing effect in treatment of childhood atopic dermatitis: SCORAD and quality of life improvement.
Pediatr Dermatol. 2008 Nov-Dec;25(6):606-12. doi: 10.1111/j.1525-1470.2008.00783.x.
Abstract/Text Emollients are commonly used for their effectiveness on atopic skin, supported by a few clinical studies suggesting their potential role as corticosteroid sparing agents. We investigated the effect of a new natural emollient on corticosteroid sparing and quality of life of young atopic children and their family. Eighty-six patients (4-48 mos) with moderate atopic dermatitis were randomized by 20 pediatricians to five groups for 21 days: corticosteroids (from twice daily to one application every other day) combined or not with the studied cream (twice daily), and evaluated by SCORAD and specific quality of life questionnaires. At the end of the study, all five groups were statistically improved in terms of SCORAD and quality of life index. Thus, application of a topical corticosteroid every other day in addition to the studied cream was as effective as a once or twice daily application of the steroid alone. The studied cream had a significant impact on lichenification, excoriation and quality of life. A twice daily application of a new natural emollient provided a major corticosteroid sparing, improved lichenification and excoriation and improved the quality of life in children and their parents.

PMID 19067864
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
J Munday, R Bloomfield, M Goldman, H Robey, G J Kitowska, Z Gwiezdziski, A Wankiewicz, R Marks, F Protas-Drozd, M Mikaszewska
Chlorpheniramine is no more effective than placebo in relieving the symptoms of childhood atopic dermatitis with a nocturnal itching and scratching component.
Dermatology. 2002;205(1):40-5.
Abstract/Text BACKGROUND: Childhood atopic dermatitis (AD) is a common disorder affecting 15% of children aged over 18 months. AD is associated with intense nocturnal itching. The central sedative effect of antihistamines is thought to be useful in interrupting the itching cycle and may prevent exacerbations.
OBJECTIVE: A multi-centred, double-blind, placebo-controlled study was carried out in 155 children to evaluate chlorpheniramine in alleviating symptoms of AD.
METHODS: Assessments were carried out over a 4-week study period consisting of 3 visits to out-patient clinics. During the visits the severity of AD and itching was rated using a series of visual analogue scale (VAS) and 5-point rating scales.
RESULTS: The use of chlorpheniramine resulted in no greater alleviation of AD symptoms than placebo.
CONCLUSIONS: The findings contradict conventional wisdom that the sedative effect of earlier-generation antihistamines alleviates symptoms of AD. The study also indicates that the use of antihistamines in AD does not affect the amounts of topical treatment used over the short term.

Copyright 2002 S. Karger AG, Basel
PMID 12145433
R Garside, K Stein, E Castelnuovo, M Pitt, D Ashcroft, P Dimmock, L Payne
The effectiveness and cost-effectiveness of pimecrolimus and tacrolimus for atopic eczema: a systematic review and economic evaluation.
Health Technol Assess. 2005 Jul;9(29):iii, xi-xiii,1-230.
Abstract/Text OBJECTIVES: To consider the effectiveness and cost-effectiveness of pimecrolimus for mild to moderate atopic eczema and tacrolimus for moderate to severe atopic eczema compared with current standard treatment in adults and children.
DATA SOURCES: Electronic databases. Experts and the manufacturers of these agents were also approached for information.
REVIEW METHODS: The systematic review was carried out using standard methodological guidelines and a stringent quality assessment strategy. A state transition (Markov) model was developed to estimate cost--utility of tacrolimus and pimecrolimus separately, compared with current standard practice with topical corticosteroids, (a) as first-line treatment and (b) as second-line treatment. Pimecrolimus was also compared to emollients only.
RESULTS: The pimecrolimus trial reports were of varying quality; however when compared with a placebo (emollient), pimecrolimus was found to be more effective and to provide quality of life improvements. There is very little evidence available about pimecrolimus compared with topical corticosteroids. Compared with a placebo (emollient), both 0.03% and 0.1% tacrolimus were found to be more effective. Compared with a mild corticosteroid, 0.03% tacrolimus is more effective in children as measured by a 90% or better improvement in the Physician's Global Evaluation (PGE). Compared with potent topical corticosteroids, no significant difference in effectiveness is seen with 0.1% tacrolimus as measured by a 75% or greater improvement in the PGE. Minor application site adverse effects are common with tacrolimus. However, this did not lead to increased rates of withdrawal from treatment in trial populations. The PenTag economic model demonstrates a large degree of uncertainty, which was explored in both deterministic and stochastic analyses. This is the case for the cost-effectiveness of pimecrolimus and tacrolimus in first- or second-line use compared with topical steroids. In all cases immunosuppressant regimes were estimated to be more costly than alternatives and differences in benefits to be small and subject to considerable uncertainty.
CONCLUSIONS: There is limited evidence from a small number of randomised controlled trials (RCTs) that pimecrolimus is more effective than placebo treatment in controlling mild to moderate atopic eczema. Although greater than for pimecrolimus, the evidence base for tacrolimus in moderate to severe atopic eczema is also limited. At both 0.1% and 0.03% potencies, tacrolimus appears to be more effective than the placebo treatment and mild topical corticosteroids. However, these are not the most clinically relevant comparators. Compared with potent topical corticosteroids, no significant difference was shown. Short-term adverse effects with both immunosuppressants are relatively common, but appear to be mild. Experience of long-term use of the agents is lacking so the risk of rare but serious adverse effects remains unknown. No conclusions can be confidently drawn about the cost-effectiveness of pimecrolimus or tacrolimus compared with active topical corticosteroid comparators. Areas for further research should focus on the effectiveness and safety of the treatments through good-quality RCTs and further economic analysis.

PMID 16022804
Mohammad Maged Y El-Batawy, Manal A-W Bosseila, Heba M Mashaly, Vanessa Suzan G A Hafez
Topical calcineurin inhibitors in atopic dermatitis: a systematic review and meta-analysis.
J Dermatol Sci. 2009 May;54(2):76-87. doi: 10.1016/j.jdermsci.2009.02.002. Epub 2009 Mar 20.
Abstract/Text OBJECTIVES: To build a critical appraisal of the available literature to evaluate the effectiveness of topical calcineurin inhibitors in treatment of atopic dermatitis (AD), in comparison to topical corticosteroids (TCs) and/or placebo.
REVIEW METHODS:
DESIGN: systematic review and meta-analysis.
DATA SOURCES: electronic search of MEDLINE Pubmed along the last 10 years (1997-2006).
STUDY SELECTION: randomized control trials of TCIs reporting efficacy outcomes, in comparison to TCs or vehicle (placebo) or both.
DATA SYNTHESIS: of 210 articles, 19 studies were included, 10 for tacrolimus and 9 for pimecrolimus, involving 7378 patients of whom 2771 applied tacrolimus, 1783 applied pimecrolimus, and 2824 were controls. Both drugs were significantly more effective than a vehicle. However, two long-term trials comparing demonstrated the value of pimecrolimus in reduction of flares and steroid-sparing effect after 6 months. Compared to TCs, both 0.1% and 0.03% tacrolimus ointments were as effective as moderate potency TCs, and more effective than a combined steroid regimen. Tacrolimus was more effective than mild TCs.
CONCLUSIONS: TCIs in AD are more effective than placebo. Although less effective than TCs, pimecrolimus has its value in long-term maintenance and as a steroid-sparing agent in AD, whenever used early enough, at first appearance of erythema and/or itching. In treatment of moderate to severe AD, topical tacrolimus is as effective as moderately potent TCs, and more effective than mild preparations. Chronic AD lesions of the face and flexures are the most justified indication for topical calcineurin inhibitors.

PMID 19303745
Felix M Arellano, Charles E Wentworth, Alejandro Arana, Carlos Fernández, Carle F Paul
Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis.
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
Hidemi Nakagawa, Osamu Nemoto, Atsuyuki Igarashi, Hidehisa Saeki, Hironobu Kaino, Takeshi Nagata
Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study.
J Am Acad Dermatol. 2020 Apr;82(4):823-831. doi: 10.1016/j.jaad.2019.12.015. Epub 2020 Feb 3.
Abstract/Text BACKGROUND: Previous studies showed the potential effectiveness of delgocitinib ointment, a novel topical Janus kinase inhibitor, in atopic dermatitis (AD).
OBJECTIVE: This study aimed to evaluate the efficacy and safety of delgocitinib 0.5% ointment.
METHODS: In part 1, a 4-week double-blind period, Japanese patients aged 16 years or older with moderate or severe AD were randomly assigned in a 2:1 ratio to delgocitinib 0.5% ointment or vehicle ointment. Eligible patients entered part 2, a 24-week extension period, to receive delgocitinib 0.5% ointment.
RESULTS: At the end of treatment in part 1, the least-squares mean percent changes from baseline in the modified Eczema Area and Severity Index score, the primary efficacy endpoint, were significantly greater in the delgocitinib group than in the vehicle group (-44.3% vs 1.7%, P < .001). The improvement in modified Eczema Area and Severity Index score was maintained in part 2. Most adverse events were mild and unrelated to delgocitinib across the study periods.
LIMITATIONS: Only Japanese patients were included. The vehicle-controlled period lasted only 4 weeks. In part 2, topical corticosteroids were allowed for the treatment of worsening of AD.
CONCLUSION: Delgocitinib ointment was effective and well tolerated in Japanese adult patients with moderate to severe AD for up to 28 weeks.

Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
PMID 32029304
Hidemi Nakagawa, Osamu Nemoto, Atsuyuki Igarashi, Hidehisa Saeki, Kenji Kabashima, Manabu Oda, Takeshi Nagata
Delgocitinib ointment in pediatric patients with atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and a subsequent open-label, long-term study.
J Am Acad Dermatol. 2021 Oct;85(4):854-862. doi: 10.1016/j.jaad.2021.06.014. Epub 2021 Jun 10.
Abstract/Text BACKGROUND: Delgocitinib 0.5% ointment, a topical Janus kinase inhibitor, has been approved in Japan for adult patients with atopic dermatitis (AD).
OBJECTIVE: To evaluate the efficacy and safety of delgocitinib ointment in pediatric patients with AD.
METHODS: Part 1 of this study was a 4-week double-blind period in which Japanese patients aged 2 through 15 years were randomized in a 1:1 ratio to delgocitinib 0.25% ointment or vehicle ointment. Part 2 was a 52-week extension period. Eligible patients entered part 2 to receive 0.25% or 0.5% delgocitinib ointment.
RESULTS: At the initiation of the study, approximately half of the patients had moderate AD. At the end of treatment in part 1, the least-squares mean percent change from baseline in modified Eczema Area and Severity Index score, the primary efficacy endpoint, was significantly greater for delgocitinib ointment than for vehicle (-39.3% vs +10.9%, P < .001). In part 2, improvements in AD were also seen through week 56. Most adverse events were mild and unrelated to delgocitinib across the study periods.
LIMITATIONS: Only Japanese patients were included. In part 2, no control group was included and rescue therapy was allowed.
CONCLUSION: Delgocitinib ointment was effective and well tolerated when applied to Japanese pediatric patients with AD for up to 56 weeks.

Copyright © 2021 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
PMID 34118298
J Schmitt, L von Kobyletzki, A Svensson, C Apfelbacher
Efficacy and tolerability of proactive treatment with topical corticosteroids and calcineurin inhibitors for atopic eczema: systematic review and meta-analysis of randomized controlled trials.
Br J Dermatol. 2011 Feb;164(2):415-28. doi: 10.1111/j.1365-2133.2010.10030.x. Epub 2010 Nov 23.
Abstract/Text BACKGROUND: Long-term low-level topical anti-inflammatory therapy has been suggested as a new paradigm in the treatment of atopic eczema (AE).
OBJECTIVES: To determine the efficacy and tolerability of topical corticosteroids and calcineurin inhibitors for flare prevention in AE.
METHODS: Systematic review of randomized controlled trials reporting efficacy of topical corticosteroids and/or topical calcineurin inhibitors for flare prevention in AE. Identification of relevant articles by systematic electronic searches (Cochrane Library, Medline) supplemented by hand search. Primary efficacy endpoint: proportion of participants experiencing at least one flare during proactive anti-inflammatory treatment. Relative risks (RRs) and corresponding 95% confidence intervals (CIs) were calculated and pooled by pharmaceutical agent using random-effects meta-analysis. Sensitivity analysis included meta-regression to explore the influence of study-specific covariates.
RESULTS: Nine articles reporting on eight vehicle-controlled trials were included. Three, four and one trial(s) evaluated proactive therapy with topical tacrolimus, fluticasone propionate and methylprednisolone aceponate, respectively. Each agent under study was more efficacious to prevent flares than vehicle. Meta-analysis suggested that topical fluticasone propionate (RR 0·46, 95% CI 0·38-0·55) may be more efficacious to prevent disease flares than topical tacrolimus (RR 0·78, 95% CI 0·60-1·00). Meta-regression indicated robustness of these findings. Proactive anti-inflammatory therapy was generally well tolerated. The trials identified, however, do not allow firm conclusions about long-term safety.
CONCLUSIONS: Vehicle-controlled trials indicate efficacy of proactive treatment with tacrolimus, fluticasone propionate and methylprednisolone aceponate to prevent AE flares. Indirect evidence from vehicle-controlled trials suggests that twice weekly application of the potent topical corticosteroid fluticasone propionate may be more efficacious to prevent AE flares than tacrolimus ointment. Head to head trials should be conducted to confirm these results. Future studies are also needed to evaluate the long-term safety of proactive treatment of AE.

© 2010 The Authors. BJD © 2010 British Association of Dermatologists.
PMID 20819086
Yoshikazu Kameyoshi, Toshihiko Tanaka, Mitsuru Mochizuki, Osamu Koro, Shoji Mihara, Takaaki Hiragun, Maiko Tanaka, Michihiro Hide
[Taking showers at school is beneficial for children with severer atopic dermatitis].
Arerugi. 2008 Feb;57(2):130-7.
Abstract/Text BACKGROUND: Sweat(ing) is a common aggravating factor of atopic dermatitis (AD), and many school children with AD experience the exacerbation of their disease in summer.
OBJECTIVE: We evaluated the usefulness of taking shower at the school for the management of AD in summer.
METHODS: Fifty-eight school children with moderate or severer atopic dermatitis were enrolled in the study. Subjects were allocated to one of following groups, group A: no shower (n=15), group B: 4-weeks shower (n=22), group C1: 2-weeks shower in the first half (n=11), or group C2: 2-weeks shower in the latter half (n=10), and took (or did not take) shower at the school from the beginning of September. Disease severity was evaluated on day 0, 2 weeks later and 4 weeks later using SCORAD scoring system.
RESULTS: Significant improvements in SCORAD scores after 4 weeks were observed only in groups B and C1. When the subjects were sub-divided by the severity of the disease, the significant effect of shower was limited to the patients with severe and most severe disease. Similar results were obtained with a modified SCORAD score in which subjective symptoms were excluded.
CONCLUSION: It is useful to take showers at the school for the management of AD for the children with severer disease.

PMID 18349587
Hiroyuki Mochizuki, Reiko Muramatsu, Hiromi Tadaki, Takahisa Mizuno, Hirokazu Arakawa, Akihiro Morikawa
Effects of skin care with shower therapy on children with atopic dermatitis in elementary schools.
Pediatr Dermatol. 2009 Mar-Apr;26(2):223-5. doi: 10.1111/j.1525-1470.2009.00887.x.
Abstract/Text For elementary school children with atopic dermatitis, a skin care program using shower therapy was performed during the school lunch break for 6 weeks from June to July in 2004 and 2005. All 53 participants showed an improvement in their atopic dermatitis during the 6-week periods studied. Skin care with daily showering at an elementary school was thus found to be effective for the treatment of atopic dermatitis.

PMID 19419481
C C Long, A Y Finlay
The finger-tip unit--a new practical measure.
Clin Exp Dermatol. 1991 Nov;16(6):444-7.
Abstract/Text A finger-tip unit (FTU) is the amount of ointment expressed from a tube with a 5 mm diameter nozzle, applied from the distal skin-crease to the tip of the index finger. Thirty adult-patients treated various anatomical regions using FTU's of ointment. The number of FTU's required was: face and neck 2.5 (s.d. +/- 0.8); front of trunk 6.7 (s.d. +/- 1.7); back of trunk 6.8 (s.d. +/- 1.2); arm and forearm 3.3 (s.d. +/- 1.0); hand 1.2 (s.d. +/- 0.4); leg and thigh 5.8 (s.d. +/- 1.7); foot 1.8 (s.d. +/- 0.6). One FTU covers 286 cm2 (s.d. +/- 80, n = 30). In males one FTU covers 312 cm2 (s.d. +/- 90, n = 16) and in females 257 cm2 (s.d. +/- 55, n = 14). The use of the FTU in dermatological prescribing provides a readily understandable measure for both patients and doctor.

PMID 1806320
F Bath-Hextall, F M Delamere, H C Williams
Dietary exclusions for improving established atopic eczema in adults and children: systematic review.
Allergy. 2009 Feb;64(2):258-64. doi: 10.1111/j.1398-9995.2008.01917.x.
Abstract/Text Atopic eczema is the most common inflammatory skin disease of childhood in developed countries. We performed a systematic review of randomized controlled trials to assess the effects of dietary exclusions for the treatment of established atopic eczema. Nine trials (421 participants) were included, most of which were poorly reported. Six were studies of egg and milk exclusion (n = 288), one was a study of few foods (n = 85) and two were studies of an elemental diet (n = 48). There appears to be no benefit of an egg- and milk-free diet in unselected participants with atopic eczema. There is also no evidence of benefit in the use of an elemental or few-foods diet in unselected cases of atopic eczema. There may be some benefit in using an egg-free diet in infants with suspected egg allergy who have positive specific IgE to eggs - one study found 51% of the children had a significant improvement in body surface area with the exclusion diet as compared with normal diet (95% CI 1.07-2.11) and change in surface area and severity score was significantly improved in the exclusion diet as compared with the normal diet at the end of 6 weeks (MD 5.50, 95% CI 0.19-10.81) and end of treatment (MD 6.10, 95% CI 0.06-12.14). Despite their frequent use, we find little good quality evidence to support the use of exclusion diets in atopic eczema.

PMID 19178405
Gideon Lack, Deborah Fox, Kate Northstone, Jean Golding, Avon Longitudinal Study of Parents and Children Study Team
Factors associated with the development of peanut allergy in childhood.
N Engl J Med. 2003 Mar 13;348(11):977-85. doi: 10.1056/NEJMoa013536. Epub 2003 Mar 10.
Abstract/Text BACKGROUND: The prevalence of peanut allergy appears to have increased in recent decades. Other than a family history of peanut allergy and the presence of atopy, there are no known risk factors.
METHODS: We used data from the Avon Longitudinal Study of Parents and Children, a geographically defined cohort study of 13,971 preschool children, to identify those with a convincing history of peanut allergy and the subgroup that reacted to a double-blind peanut challenge. We first prospectively collected data on the whole cohort and then collected detailed information retrospectively by interview from the parents of children with peanut reactions and of children from two groups of controls (a random sample from the cohort and a group of children whose mothers had a history of eczema and who had had eczema themselves in the first six months of life).
RESULTS: Forty-nine children had a history of peanut allergy; peanut allergy was confirmed by peanut challenge in 23 of 36 children tested. There was no evidence of prenatal sensitization from the maternal diet, and peanut-specific IgE was not detectable in the cord blood. Peanut allergy was independently associated with intake of soy milk or soy formula (odds ratio, 2.6; 95 percent confidence interval, 1.3 to 5.2), rash over joints and skin creases (odds ratio, 2.6; 95 percent confidence interval, 1.4 to 5.0), and oozing, crusted rash (odds ratio, 5.2; 95 percent confidence interval, 2.7 to 10.2). Analysis of interview data showed a significant independent relation of peanut allergy with the use of skin preparations containing peanut oil (odds ratio, 6.8; 95 percent confidence interval, 1.4 to 32.9).
CONCLUSIONS: Sensitization to peanut protein may occur in children through the application of peanut oil to inflamed skin. The association with soy protein could arise from cross-sensitization through common epitopes. Confirmation of these risk factors in future studies could lead to new strategies to prevent sensitization in infants who are at risk for subsequent peanut allergy.

Copyright 2003 Massachusetts Medical Society
PMID 12637607
Helen A Brough, Angela Simpson, Kerry Makinson, Jenny Hankinson, Sara Brown, Abdel Douiri, Danielle C M Belgrave, Martin Penagos, Alick C Stephens, W H Irwin McLean, Victor Turcanu, Nicolaos Nicolaou, Adnan Custovic, Gideon Lack
Peanut allergy: effect of environmental peanut exposure in children with filaggrin loss-of-function mutations.
J Allergy Clin Immunol. 2014 Oct;134(4):867-875.e1. doi: 10.1016/j.jaci.2014.08.011.
Abstract/Text BACKGROUND: Filaggrin (FLG) loss-of-function mutations lead to an impaired skin barrier associated with peanut allergy. Household peanut consumption is associated with peanut allergy, and peanut allergen in household dust correlates with household peanut consumption.
OBJECTIVE: We sought to determine whether environmental peanut exposure increases the odds of peanut allergy and whether FLG mutations modulate these odds.
METHODS: Exposure to peanut antigen in dust within the first year of life was measured in a population-based birth cohort. Peanut sensitization and peanut allergy (defined by using oral food challenges or component-resolved diagnostics [CRD]) were assessed at 8 and 11 years. Genotyping was performed for 6 FLG mutations.
RESULTS: After adjustment for infantile atopic dermatitis and preceding egg skin prick test (SPT) sensitization, we found a strong and significant interaction between natural log (ln [loge]) peanut dust levels and FLG mutations on peanut sensitization and peanut allergy. Among children with FLG mutations, for each ln unit increase in the house dust peanut protein level, there was a more than 6-fold increased odds of peanut SPT sensitization, CRD sensitization, or both in children at ages 8 years, 11 years, or both and a greater than 3-fold increased odds of peanut allergy compared with odds seen in children with wild-type FLG. There was no significant effect of exposure in children without FLG mutations. In children carrying an FLG mutation, the threshold level for peanut SPT sensitization was 0.92 μg of peanut protein per gram (95% CI, 0.70-1.22 μg/g), that for CRD sensitization was 1.03 μg/g (95% CI, 0.90-1.82 μg/g), and that for peanut allergy was 1.17 μg/g (95% CI, 0.01-163.83 μg/g).
CONCLUSION: Early-life environmental peanut exposure is associated with an increased risk of peanut sensitization and allergy in children who carry an FLG mutation. These data support the hypothesis that peanut allergy develops through transcutaneous sensitization in children with an impaired skin barrier.

Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
PMID 25282568
Helen A Brough, Andrew H Liu, Scott Sicherer, Kerry Makinson, Abdel Douiri, Sara J Brown, Alick C Stephens, W H Irwin McLean, Victor Turcanu, Robert A Wood, Stacie M Jones, Wesley Burks, Peter Dawson, Donald Stablein, Hugh Sampson, Gideon Lack
Atopic dermatitis increases the effect of exposure to peanut antigen in dust on peanut sensitization and likely peanut allergy.
J Allergy Clin Immunol. 2015 Jan;135(1):164-70. doi: 10.1016/j.jaci.2014.10.007. Epub 2014 Nov 18.
Abstract/Text BACKGROUND: History and severity of atopic dermatitis (AD) are risk factors for peanut allergy. Recent evidence suggests that children can become sensitized to food allergens through an impaired skin barrier. Household peanut consumption, which correlates strongly with peanut protein levels in household dust, is a risk factor for peanut allergy.
OBJECTIVE: We sought to assess whether environmental peanut exposure (EPE) is a risk for peanut sensitization and allergy and whether markers of an impaired skin barrier modify this risk.
METHODS: Peanut protein in household dust (in micrograms per gram) was assessed in highly atopic children (age, 3-15 months) recruited to the Consortium of Food Allergy Research Observational Study. History and severity of AD, peanut sensitization, and likely allergy (peanut-specific IgE, ≥5 kUA/mL) were assessed at recruitment into the Consortium of Food Allergy Research study.
RESULTS: There was an exposure-response relationship between peanut protein levels in household dust and peanut skin prick test (SPT) sensitization and likely allergy. In the final multivariate model an increase in 4 log2 EPE units increased the odds of peanut SPT sensitization (1.71-fold; 95% CI, 1.13- to 2.59-fold; P = .01) and likely peanut allergy (PA; 2.10-fold; 95% CI, 1.20- to 3.67-fold; P < .01). The effect of EPE on peanut SPT sensitization was augmented in children with a history of AD (OR, 1.97; 95% CI, 1.26-3.09; P < .01) and augmented even further in children with a history of severe AD (OR, 2.41; 95% CI, 1.30-4.47; P < .01); the effect of EPE on PA was also augmented in children with a history of AD (OR, 2.34; 95% CI, 1.31-4.18; P < .01).
CONCLUSION: Exposure to peanut antigen in dust through an impaired skin barrier in atopically inflamed skin is a plausible route for peanut SPT sensitization and PA.

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
PMID 25457149
G Ricci, A Patrizi, F Specchia, L Menna, P Bottau, V D'Angelo, M Masi
Effect of house dust mite avoidance measures in children with atopic dermatitis.
Br J Dermatol. 2000 Aug;143(2):379-84.
Abstract/Text BACKGROUND: House dust mite allergens are associated with atopic dermatitis (AD).
OBJECTIVES: The aim of our study was to verify if house dust mite allergen avoidance measures can improve the clinical manifestations of AD in children.
METHODS: Forty-one children (mean age 3.9 years) affected by AD associated with high total and/or specific IgE serum levels ('extrinsic' AD) were recruited. Clinical evaluation was performed utilizing the Severity Scoring of AD (SCORAD) index; dust was sampled from the children's beds and tested using an enzyme-linked immunosorbent assay. The study was planned in two parts. In the first part, a placebo-controlled trial of 2 months duration, mite allergen avoidance measures (encasing mattresses and pillows; a weekly hot wash of bedding; frequent vacuum cleaning of living room and bedroom; soft toys and carpets regularly cleaned or removed; no pets allowed) were recommended to group A patients, but not to group B. In the second part of the study, environmental avoidance measures were recommended to initial control group B patients also. One year after the start of the study the amounts of mite allergen in the home and clinical score of AD were measured in both groups.
RESULTS: At the end of the first part of the study, significant decreases in major allergens of Dermatophagoides pteronyssinus (Der p1) and D. farinae (Der f1) load (from 393 to 94 ng m-2) and concentration (from 1.84 to 0.73 microg g-1 of dust) in children's beds were observed in treatment group A. At the same time, in this group the mean SCORAD index improved significantly (from 33 to 26; P = 0.022). After 12 months, when all patients had used allergen avoidance measures, Der p1 + Der f1 load, concentration and clinical score had improved, reaching similar values in both groups.
CONCLUSIONS: Simple mite allergen avoidance measures should be recommended to families with children affected by extrinsic AD in order to control the clinical manifestations and prevent mite sensitization.

PMID 10951149
C Gutgesell, S Heise, S Seubert, A Seubert, S Domhof, E Brunner, C Neumann
Double-blind placebo-controlled house dust mite control measures in adult patients with atopic dermatitis.
Br J Dermatol. 2001 Jul;145(1):70-4.
Abstract/Text BACKGROUND: Avoidance of allergens has been shown to be of benefit in patients with atopic asthma sensitized to indoor allergens. In atopic dermatitis, there is so far little information about the effect of house dust mite elimination strategies.
OBJECTIVES: We therefore performed a randomized controlled study of house dust mite control in patients with this disease.
METHODS: Twenty adult patients with moderate to severe atopic dermatitis were included. Inclusion criteria were a positive RAST to house dust mite antigen (CAP class > 3) and a concentration of > 2 microg g(-1) of the house dust mite antigen Der p1 in the patient's mattress dust. Patients were randomized to either the active treatment group (allergen-impermeable mattress encasing, acaricide spray containing tannic acid and benzylbenzoate) or a control group (allergen-permeable encasing, spray containing water and traces of ethanol). Severity of disease was estimated every 2 months by an established score (SCORAD), and eosinophil cationic protein (ECP) in the serum was determined by enzyme-linked immunosorbent assay. Furthermore, the use of topical steroids was quantified. Patients assessed daytime pruritus and pruritus-induced sleeplessness weekly on a visual analogue scale. The study lasted 1 year.
RESULTS: At the end of the study, the active treatment group showed a statistically significant reduction in Der p1 exposure as compared with the control group. However, when comparing the change from the start to the end of the study, there was no statistically significant difference between active treatment and control groups as measured by the SCORAD score and by ECP levels in the serum. Some patients in the active treatment group reported less pruritus-induced sleeplessness, but there was no statistically significant difference between the two treatment groups.
CONCLUSIONS: For adult patients with atopic dermatitis it was shown that 1 year of house dust mite avoidance reduced the allergen exposure, but an improvement of overall disease activity was not demonstrated.

PMID 11453909
Eric L Simpson, Thomas Bieber, Emma Guttman-Yassky, Lisa A Beck, Andrew Blauvelt, Michael J Cork, Jonathan I Silverberg, Mette Deleuran, Yoko Kataoka, Jean-Philippe Lacour, Külli Kingo, Margitta Worm, Yves Poulin, Andreas Wollenberg, Yuhwen Soo, Neil M H Graham, Gianluca Pirozzi, Bolanle Akinlade, Heribert Staudinger, Vera Mastey, Laurent Eckert, Abhijit Gadkari, Neil Stahl, George D Yancopoulos, Marius Ardeleanu, SOLO 1 and SOLO 2 Investigators
Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis.
N Engl J Med. 2016 Dec 15;375(24):2335-2348. doi: 10.1056/NEJMoa1610020. Epub 2016 Sep 30.
Abstract/Text BACKGROUND: Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis.
METHODS: In two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose disease was inadequately controlled by topical treatment. Patients were randomly assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo. The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator's Global Assessment and a reduction of 2 points or more in that score from baseline at week 16.
RESULTS: We enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who received dupilumab every other week and in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received placebo (P<0.001 for both comparisons with placebo). The results were similar in SOLO 2, with the primary outcome occurring in 84 patients (36%) who received dupilumab every other week and in 87 (36%) who received dupilumab weekly, as compared with 20 (8%) who received placebo (P<0.001 for both comparisons). In addition, in the two trials, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index was reported in significantly more patients who received each regimen of dupilumab than in patients who received placebo (P<0.001 for all comparisons). Dupilumab was also associated with improvement in other clinical end points, including reduction in pruritus and symptoms of anxiety or depression and improvement in quality of life. Injection-site reactions and conjunctivitis were more frequent in the dupilumab groups than in the placebo groups.
CONCLUSIONS: In two phase 3 trials of identical design involving patients with atopic dermatitis, dupilumab improved the signs and symptoms of atopic dermatitis, including pruritus, symptoms of anxiety and depression, and quality of life, as compared with placebo. Trials of longer duration are needed to assess the long-term effectiveness and safety of dupilumab. (Funded by Sanofi and Regeneron Pharmaceuticals; SOLO 1 ClinicalTrials.gov number, NCT02277743 ; SOLO 2 ClinicalTrials.gov number, NCT02277769 .).

PMID 27690741
Hiromi Kobayashi, Masamitsu Ishii, Satoshi Takeuchi, Yoichi Tanaka, Takahiro Shintani, Atsushi Yamatodani, Tadashi Kusunoki, Masutaka Furue
Efficacy and Safety of a Traditional Herbal Medicine, Hochu-ekki-to in the Long-term Management of Kikyo (Delicate Constitution) Patients with Atopic Dermatitis: A 6-month, Multicenter, Double-blind, Randomized, Placebo-controlled Study.
Evid Based Complement Alternat Med. 2010 Sep;7(3):367-73. doi: 10.1093/ecam/nen003. Epub 2008 Jan 31.
Abstract/Text Hochu-ekki-to is a traditional herbal (Kampo) medicine that has been shown to be effective for patients with Kikyo (delicate, easily fatigable, or hypersensitive) constitution. Previous case reports have suggested that this herbal drug was effective for a certain subgroup of patients with atopic dermatitis (AD). We aimed to evaluate the efficacy and safety of Hochu-ekki-to in the long-term management of Kikyo patients with AD. In this multicenter, double blind, randomized, placebo-controlled study, 91 Kikyo patients with AD were enrolled. Kikyo condition was evaluated by a questionnaire scoring system. All patients continued their ordinary treatments (topical steroids, topical tacrolimus, emollients or oral antihistamines) before and after their protocol entry. Hochu-ekki-to or placebo was orally administered twice daily for 24 weeks. The skin severity scores, total equivalent amount (TEA) of topical agents used for AD treatment, prominent efficacy (cases with skin severity score = 0 at the end of the study) rate and aggravated rate (more than 50% increase of TEA of topical agents from the beginning of the study) were monitored and evaluated. Seventy-seven out of 91 enrolled patients completed the 24-week treatment course (Hochu-ekki-to: n = 37, placebo: n = 40). The TEA of topical agents (steroids and/or tacrolimus) was significantly (P < 0.05) lower in the Hochu-ekki-to group than in the placebo group, although the overall skin severity scores were not statistically different. The prominent efficacy rate was 19% (7 of 37) in the Hochu-ekki-to group and 5% (2 of 40) in the placebo group (P = 0.06). The aggravated rate was significantly (P < 0.05) lower in the Hochu-ekki-to group (3%; 1 of 37) than in the placebo group (18%; 7 of 39). Only mild adverse events such as nausea and diarrhea were noted in both groups without statistical difference. This placebo-controlled study demonstrates that Hochu-ekki-to is a useful adjunct to conventional treatments for AD patients with Kikyo constitution. Use of Hochu-ekki-to significantly reduces the dose of topical steroids and/or tacrolimus used for AD treatment without aggravating AD.

PMID 18955318
M P Sheehan, M H Rustin, D J Atherton, C Buckley, D W Harris, J Brostoff, L Ostlere, A Dawson, D J Harris
Efficacy of traditional Chinese herbal therapy in adult atopic dermatitis.
Lancet. 1992 Jul 4;340(8810):13-7.
Abstract/Text There has been considerable interest in traditional Chinese herbal therapy (TCHT) as a new treatment for atopic dermatitis. To establish the efficacy and safety of this treatment, a daily decoction of a formula containing ten herbs that has been found to be beneficial in open studies was tested in a double-blind placebo-controlled study. 40 adult patients with longstanding, refractory, widespread, atopic dermatitis were randomised into two groups to receive 2 months' treatment of either the active formulation of herbs (TCHT) or placebo herbs, followed by a crossover to the other treatment after a 4-week washout period. The main outcome measures were extent and severity of erythema and surface damage as judged by standardised body scores. The patients' own assessments of the overall response to treatment were also sought. The geometric mean score for erythema at the end of active treatment was 12.6 (95% confidence interval [CI] 5.9 to 22.0) and at the end of the placebo phase was 113 (65 to 180). The geometric mean score for surface damage was 11.3 (5.8 to 21.8) and 111.0 (68 to 182), respectively. The 95% CI for the mean geometric ratio for the two values with active treatment was 0.04 to 0.22 for erythema (p less than 0.0005) and 0.04 to 0.27 for surface damage (p less than 0.0005). Of the 31 patients who completed the study and expressed a preference, 20 preferred that phase of the trial in which they received TCHT whereas 4 patients preferred placebo (p less than 0.02). There was a subjective improvement in itching (p less than 0.001) and sleep (p less than 0.078) during the TCHT treatment phase. No side-effects were reported by the patients although many commented on the unpalatability of the decoction. TCHT seems to benefit patients with atopic dermatitis. Palatability of the treatment needs to be improved and its safety assured.

PMID 1351600
A Y Fung, P C Look, L Y Chong, P P But, E Wong
A controlled trial of traditional Chinese herbal medicine in Chinese patients with recalcitrant atopic dermatitis.
Int J Dermatol. 1999 May;38(5):387-92.
Abstract/Text BACKGROUND: There have been published reports from the United Kingdom of good responses to the use of traditional Chinese herbal medicine (Zemaphyte, Phytopharm Plc, Cambridge, UK) in treating recalcitrant atopic dermatitis. We conducted a double-blind, placebo-controlled, cross-over study among Chinese patients with recalcitrant atopic dermatitis using this same herbal preparation.
METHODS: Forty patients were recruited. They were given Zemaphyte and placebo in random order, each for 8 consecutive weeks with a 4-week wash-out period in between. Scores based on the severity and extent of four clinical parameters (erythema, surface damage, lichenification and scaling) were recorded at baseline and at 4-weekly intervals throughout the 20-week trial period.
RESULTS: Thirty-seven patients completed the trial. There was a general trend of clinical improvement with time throughout the trial period in both patient groups, irrespective of whether they received Zemaphyte or placebo first. Zemaphyte, however, offered no statistically significant treatment effect over placebo for all four clinical parameters, except for lichenification at week 4. There were no significant carry-over effects. Blood tests for hematologic, renal and liver functions were all normal throughout the trial.
CONCLUSIONS: Zemaphyte did not seem to benefit Chinese patients with recalcitrant atopic dermatitis in our study. Further research is required to evaluate its efficacy.

PMID 10369553
E L Simpson, J-P Lacour, L Spelman, R Galimberti, L F Eichenfield, R Bissonnette, B A King, J P Thyssen, J I Silverberg, T Bieber, K Kabashima, Y Tsunemi, A Costanzo, E Guttman-Yassky, L A Beck, J M Janes, A M DeLozier, M Gamalo, D R Brinker, T Cardillo, F P Nunes, A S Paller, A Wollenberg, K Reich
Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials.
Br J Dermatol. 2020 Aug;183(2):242-255. doi: 10.1111/bjd.18898. Epub 2020 Mar 5.
Abstract/Text BACKGROUND: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced atopic dermatitis (AD) severity in a phase II study with concomitant topical corticosteroids.
OBJECTIVES: To evaluate the efficacy and safety of baricitinib in patients with moderate-to-severe AD who had an inadequate response to topical therapies.
METHODS: In two independent, multicentre, double-blind, phase III monotherapy trials, BREEZE-AD1 and BREEZE-AD2, adults with moderate-to-severe AD were randomized 2 : 1 : 1 : 1 to once-daily placebo, baricitinib 1 mg, 2 mg, or 4 mg for 16 weeks.
RESULTS: At week 16, more patients achieved the primary end point of Validated Investigator's Global Assessment of AD (0, 1) on baricitinib 4 mg and 2 mg compared with placebo in BREEZE-AD1 [N = 624; baricitinib 4 mg 16·8% (P < 0·001), 2 mg 11·4% (P < 0·05), 1 mg 11·8% (P < 0·05), placebo 4·8%], and BREEZE-AD2 [N = 615; baricitinib 4 mg 13·8% (P = 0·001), 2 mg 10·6% (P < 0·05), 1 mg 8·8% (P = 0·085), placebo 4·5%]. Improvement in itch was achieved as early as week 1 for 4 mg and week 2 for 2 mg. Improvements in night-time awakenings, skin pain and quality-of-life measures were observed by week 1 for both 4 mg and 2 mg (P ≤ 0·05, all comparisons). The most common adverse events in patients treated with baricitinib were nasopharyngitis and headache. No cardiovascular events, venous thromboembolism, gastrointestinal perforation, significant haematological changes, or death were observed with any baricitinib dosage.
CONCLUSIONS: Baricitinib improved clinical signs and symptoms in patients with moderate-to-severe AD within 16 weeks of treatment and induced rapid reduction of itch. The safety profile remained consistent with prior findings from baricitinib clinical development in AD, with no new safety concerns.

© 2020 British Association of Dermatologists.
PMID 31995838
Emma Guttman-Yassky, Henrique D Teixeira, Eric L Simpson, Kim A Papp, Aileen L Pangan, Andrew Blauvelt, Diamant Thaçi, Chia-Yu Chu, H Chih-Ho Hong, Norito Katoh, Amy S Paller, Brian Calimlim, Yihua Gu, Xiaofei Hu, Meng Liu, Yang Yang, John Liu, Allan R Tenorio, Alvina D Chu, Alan D Irvine
Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials.
Lancet. 2021 Jun 5;397(10290):2151-2168. doi: 10.1016/S0140-6736(21)00588-2. Epub 2021 May 21.
Abstract/Text BACKGROUND: Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, and tyrosine kinase 2. We aimed to assess the efficacy and safety of upadacitinib compared with placebo for the treatment of moderate-to-severe atopic dermatitis.
METHODS: Measure Up 1 and Measure Up 2 were replicate multicentre, randomised, double-blind, placebo-controlled, phase 3 trials; Measure Up 1 was done at 151 clinical centres in 24 countries across Europe, North and South America, Oceania, and the Asia-Pacific region; and Measure Up 2 was done at 154 clinical centres in 23 countries across Europe, North America, Oceania, and the Asia-Pacific region. Eligible patients were adolescents (aged 12-17 years) and adults (aged 18-75 years) with moderate-to-severe atopic dermatitis (≥10% of body surface area affected by atopic dermatitis, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for Atopic Dermatitis [vIGA-AD] score of ≥3, and Worst Pruritus Numerical Rating Scale score of ≥4). Patients were randomly assigned (1:1:1) using an interactive response technology system to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily for 16 weeks, stratified by baseline disease severity, geographical region, and age. Coprimary endpoints were the proportion of patients who had achieved at least a 75% improvement in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of reduction from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all randomly assigned patients who received at least one dose of study drug. These trials are registered with ClinicalTrials.gov, NCT03569293 (Measure Up 1) and NCT03607422 (Measure Up 2), and are both active but not recruiting.
FINDINGS: Between Aug 13, 2018, and Dec 23, 2019, 847 patients were randomly assigned to upadacitinib 15 mg (n=281), upadacitinib 30 mg (n=285), or placebo (n=281) in the Measure Up 1 study. Between July 27, 2018, and Jan 17, 2020, 836 patients were randomly assigned to upadacitinib 15 mg (n=276), upadacitinib 30 mg (n=282), or placebo (n=278) in the Measure Up 2 study. At week 16, the coprimary endpoints were met in both studies (all p<0·0001). The proportion of patients who had achieved EASI-75 at week 16 was significantly higher in the upadacitinib 15 mg (196 [70%] of 281 patients) and upadacitinib 30 mg (227 [80%] of 285 patients) groups than the placebo group (46 [16%] of 281 patients) in Measure Up 1 (adjusted difference in EASI-75 response rate vs placebo, 53·3% [95% CI 46·4-60·2] for the upadacitinib 15 mg group; 63·4% [57·1-69·8] for the upadacitinib 30 mg group) and Measure Up 2 (166 [60%] of 276 patients in the upadacitinib 15 mg group and 206 [73%] of 282 patients in the upadacitinib 30 mg group vs 37 [13%] of 278 patients in the placebo group; adjusted difference in EASI-75 response rate vs placebo, 46·9% [39·9-53·9] for the upadacitinib 15 mg group; 59·6% [53·1-66·2] for the upadacitinib 30 mg group). The proportion of patients who achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg (135 [48%] patients) and upadacitinib 30 mg (177 [62%] patients) groups than the placebo group (24 [8%] patients) in Measure Up 1 (adjusted difference in vIGA-AD response rate vs placebo, 39·8% [33·2-46·4] for the upadacitinib 15 mg group; 53·6% [47·2-60·0] for the upadacitinib 30 mg group) and Measure Up 2 (107 [39%] patients in the upadacitinib 15 mg group and 147 [52%] patients in the upadacitinib 30 mg group vs 13 [5%] patients in the placebo group; adjusted difference in vIGA-AD response rate vs placebo, 34·0% [27·8-40·2] for the upadacitinib 15 mg group; 47·4% [41·0-53·7] for the upadacitinib 30 mg group). Both upadacitinib doses were well tolerated. The incidence of serious adverse events and adverse events leading to study drug discontinuation were similar among groups. The most frequently reported treatment-emergent adverse events were acne (19 [7%] of 281 patients in the upadacitinib 15 mg group, 49 [17%] of 285 patients in the upadacitinib 30 mg group, and six [2%] of 281 patients in the placebo group in Measure Up 1; 35 [13%] of 276 patients in the upadacitinib 15 mg group, 41 [15%] of 282 patients in the upadacitinib 30 mg group, and six [2%] of 278 patients in the placebo group in Measure Up 2), upper respiratory tract infection (25 [9%] patients, 38 [13%] patients, and 20 [7%] patients; 19 [7%] patients, 17 [16%] patients, and 12 [4%] patients), nasopharyngitis (22 [8%] patients, 33 [12%] patients, and 16 [6%] patients; 16 [6%] patients, 18 [6%] patients, and 13 [5%] patients), headache (14 [5%] patients, 19 [7%] patients, and 12 [4%] patients; 18 [7%] patients, 20 [7%] patients, and 11 [4%] patients), elevation in creatine phosphokinase levels (16 [6%] patients, 16 [6%] patients, and seven [3%] patients; nine [3%] patients, 12 [4%] patients, and five [2%] patients), and atopic dermatitis (nine [3%] patients, four [1%] patients, and 26 [9%] patients; eight [3%] patients, four [1%] patients, and 26 [9%] patients).
INTERPRETATION: Monotherapy with upadacitinib might be an effective treatment option and had a positive benefit-risk profile in adolescents and adults with moderate-to-severe atopic dermatitis.
FUNDING: AbbVie.

Copyright © 2021 Elsevier Ltd. All rights reserved.
PMID 34023008
Kristian Reich, Henrique D Teixeira, Marjolein de Bruin-Weller, Thomas Bieber, Weily Soong, Kenji Kabashima, Thomas Werfel, Jiewei Zeng, Xiaohong Huang, Xiaofei Hu, Barbara A Hendrickson, Barry Ladizinski, Alvina D Chu, Jonathan I Silverberg
Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet. 2021 Jun 5;397(10290):2169-2181. doi: 10.1016/S0140-6736(21)00589-4. Epub 2021 May 21.
Abstract/Text BACKGROUND: Systemic therapies are typically combined with topical corticosteroids for the management of moderate-to-severe atopic dermatitis. Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 that is being tested for atopic dermatitis. We aimed to assess the efficacy and safety of upadacitinib plus topical corticosteroids compared with placebo for the treatment of moderate-to-severe atopic dermatitis.
METHODS: In this randomised, double-blind, placebo-controlled, phase 3 trial (AD Up) adults (aged 18-75 years) and adolescents (aged 12-17 years) with chronic atopic dermatitis that was moderate to severe (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for atopic dermatitis [vIGA-AD] score of ≥3, and weekly average Worst Pruritus Numerical Rating Scale score of ≥4 at baseline) were enrolled at 171 clinical centres across 22 countries in the Asia-Pacific region, Europe, the Middle East, North America, and Oceania. Patients were randomly assigned (1:1:1) to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily, all in combination with topical corticosteroids for 16 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity, geographical region, and age. Study investigators, study site personnel, and patients were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved at least a 75% reduction in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of improvement from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03568318, and is active, but not recruiting.
FINDINGS: Between Aug 9, 2018, and Dec 20, 2019, 901 patients were randomly assigned to receive upadacitinib 15 mg plus topical corticosteroids (n=300), upadacitinib 30 mg plus topical corticosteroids (n=297), or placebo plus topical corticosteroids (n=304). At week 16, the proportion of patients who had achieved EASI-75 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (194 [65%] of 300 patients) and the upadacitinib 30 mg plus topical corticosteroids group (229 [77%] of 297 patients) than the placebo group (80 [26%] of 304 patients; adjusted difference in EASI-75 response rate vs placebo, 38·1% [95% CI 30·8-45·4] for the upadacitinib 15 mg group and 50·6% [43·8-57·4] for the upadacitinib 30 mg group; p<0·0001 for both doses). The proportion of patients who had achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (119 [40%] patients) and upadacitinib 30 mg plus topical corticosteroid group (174 [59%] patients) than the placebo group (33 [11%] patients; adjusted difference in vIGA-AD response vs placebo, 28·5% [22·1-34·9] for the upadacitinib 15 mg group and 47·6% [41·1-54·0] for the upadacitinib 30 mg group; p<0·0001 for both doses). During the double-blind period, upadacitinib 15 and 30 mg were well tolerated in combination with topical corticosteroids. The most frequently reported treatment-emergent adverse events (≥5% in any treatment group) were acne, nasopharyngitis, upper respiratory tract infection, oral herpes, elevation of blood creatine phosphokinase levels, headache, and atopic dermatitis. The incidence of acne was higher in the upadacitinib 15 mg (30 [10%] of 300 patients) and upadacitinib 30 mg (41 [14%] of 297 patients) groups than the placebo group (six [2%] of 304 patients). The incidence of adverse events leading to discontinuation of study drug (four [1%] patients in the upadacitinib 15 mg plus topical corticosteroids group, four [1%] patients in the upadacitinib 30 mg plus topical corticosteroids group, and seven [2%] patients in the placebo plus topical corticosteroids group) and serious adverse events (seven [2%] patients, four [1%] patients, and nine [3%] patients) were similar among treatment groups. No deaths were reported in any treatment group.
INTERPRETATION: Upadacitinib plus topical corticosteroids was well tolerated and superior to placebo plus topical corticosteroids. Upadacitinib as combination therapy had a positive benefit-risk profile in adults and adolescents with moderate-to-severe atopic dermatitis.
FUNDING: AbbVie.

Copyright © 2021 Elsevier Ltd. All rights reserved.
PMID 34023009
Thomas Bieber, Eric L Simpson, Jonathan I Silverberg, Diamant Thaçi, Carle Paul, Andrew E Pink, Yoko Kataoka, Chia-Yu Chu, Marco DiBonaventura, Ricardo Rojo, Jeremias Antinew, Ileana Ionita, Rodney Sinclair, Seth Forman, Jacek Zdybski, Pinaki Biswas, Bimal Malhotra, Fan Zhang, Hernan Valdez, JADE COMPARE Investigators
Abrocitinib versus Placebo or Dupilumab for Atopic Dermatitis.
N Engl J Med. 2021 Mar 25;384(12):1101-1112. doi: 10.1056/NEJMoa2019380.
Abstract/Text BACKGROUND: The oral Janus kinase 1 (JAK1) inhibitor abrocitinib, which reduces interleukin-4 and interleukin-13 signaling, is being investigated for the treatment of atopic dermatitis. Data from trials comparing JAK1 inhibitors with monoclonal antibodies, such as dupilumab, that block interleukin-4 receptors are limited.
METHODS: In a phase 3, double-blind trial, we randomly assigned patients with atopic dermatitis that was unresponsive to topical agents or that warranted systemic therapy (in a 2:2:2:1 ratio) to receive 200 mg or 100 mg of abrocitinib orally once daily, 300 mg of dupilumab subcutaneously every other week (after a loading dose of 600 mg), or placebo; all the patients received topical therapy. The primary end points were an Investigator's Global Assessment (IGA) response (defined as a score of 0 [clear] or 1 [almost clear] on the IGA [scores range from 0 to 4], with an improvement of ≥2 points from baseline) and an Eczema Area and Severity Index-75 (EASI-75) response (defined as ≥75% improvement from baseline in the score on the EASI [scores range from 0 to 72]) at week 12. The key secondary end points were itch response (defined as an improvement of ≥4 points in the score on the Peak Pruritus Numerical Rating Scale [scores range from 0 to 10]) at week 2 and IGA and EASI-75 responses at week 16.
RESULTS: A total of 838 patients underwent randomization; 226 patients were assigned to the 200-mg abrocitinib group, 238 to the 100-mg abrocitinib group, 243 to the dupilumab group, and 131 to the placebo group. An IGA response at week 12 was observed in 48.4% of patients in the 200-mg abrocitinib group, 36.6% in the 100-mg abrocitinib group, 36.5% in the dupilumab group, and 14.0% in the placebo group (P<0.001 for both abrocitinib doses vs. placebo); an EASI-75 response at week 12 was observed in 70.3%, 58.7%, 58.1%, and 27.1%, respectively (P<0.001 for both abrocitinib doses vs. placebo). The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. Nausea occurred in 11.1% of the patients in the 200-mg abrocitinib group and 4.2% of those in the 100-mg abrocitinib group, and acne occurred in 6.6% and 2.9%, respectively.
CONCLUSIONS: In this trial, abrocitinib at a dose of either 200 mg or 100 mg once daily resulted in significantly greater reductions in signs and symptoms of moderate-to-severe atopic dermatitis than placebo at weeks 12 and 16. The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. (Funded by Pfizer; JADE COMPARE ClinicalTrials.gov number, NCT03720470.).

Copyright © 2021 Massachusetts Medical Society.
PMID 33761207
Lawrence F Eichenfield, Carsten Flohr, Robert Sidbury, Elaine Siegfried, Zsuzsanna Szalai, Ryszard Galus, Zhirong Yao, Hidetoshi Takahashi, Sébastien Barbarot, Claire Feeney, Fan Zhang, Marco DiBonaventura, Ricardo Rojo, Hernan Valdez, Gary Chan
Efficacy and Safety of Abrocitinib in Combination With Topical Therapy in Adolescents With Moderate-to-Severe Atopic Dermatitis: The JADE TEEN Randomized Clinical Trial.
JAMA Dermatol. 2021 Oct 1;157(10):1165-1173. doi: 10.1001/jamadermatol.2021.2830.
Abstract/Text Importance: Dupilumab subcutaneous injection is approved for treating moderate-to-severe atopic dermatitis (AD) in adolescents, but there has been too little research on an efficacious systemic oral treatment with a favorable benefit-risk profile for adolescents with moderate-to-severe AD.
Objective: To investigate the efficacy and safety of oral abrocitinib plus topical therapy in adolescents with moderate-to-severe AD.
Design, Setting, and Participants: The phase 3, randomized, double-blind, placebo-controlled study JADE TEEN was conducted in countries of the Asia-Pacific region, Europe, and North America in patients aged 12 to 17 years with moderate-to-severe AD and an inadequate response to 4 consecutive weeks or longer of topical medication or a need for systemic therapy for AD. The study was conducted between February 18, 2019, and April 8, 2020. The data were analyzed after study completion.
Interventions: Patients were randomly assigned 1:1:1 to receive once-daily oral abrocitinib, 200 mg or 100 mg, or placebo for 12 weeks in combination with topical therapy.
Main Outcomes and Measures: Coprimary end points were achievement of an Investigator's Global Assessment (IGA) response of clear (0) or almost clear (1) with improvement of 2 or more grades from baseline (IGA 0/1) and 75% or greater improvement from baseline in Eczema Area and Severity Index (EASI-75) response at week 12. Key secondary end points included 4-point or greater improvement in Peak Pruritus Numerical Rating Scale (PP-NRS4) at week 12. Adverse events (AEs) were monitored.
Results: This study included 285 adolescents with moderate-to-severe AD (145 boys [50.9%] and 140 girls [49.1%]), of whom 160 (56.1%) were White and 94 (33.0%) were Asian; the median age was 15 years (interquartile range 13-17 years). Substantially more patients treated with abrocitinib (200 mg or 100 mg) vs placebo achieved an IGA response of 0/1 (46.2%; 41.6% vs 24.5%; P < .05 for both), EASI-75 (72.0%; 68.5% vs 41.5%; P < .05 for both), and PP-NRS4 (55.4%; 52.6% vs 29.8%; P < .01 for 200 mg vs placebo) at week 12. Adverse events were reported for 59 (62.8%), 54 (56.8%), and 50 (52.1%) patients in the 200 mg, 100 mg, and placebo groups, respectively; nausea was more common with abrocitinib, 200 mg (17 [18.1%]) and 100 mg (7 [7.4%]). Herpes-related AEs were infrequent; 1 (1.1%), 0, and 2 (2.1%) patients had serious AEs.
Conclusions and Relevance: This randomized clinical trial found that oral abrocitinib combined with topical therapy was significantly more effective than placebo with topical therapy in adolescents with moderate-to-severe AD, with an acceptable safety profile.
Trial Registration: ClinicalTrials.gov identifier: NCT03796676.

PMID 34406366
Eric L Simpson, Rodney Sinclair, Seth Forman, Andreas Wollenberg, Roland Aschoff, Michael Cork, Thomas Bieber, Jacob P Thyssen, Gil Yosipovitch, Carsten Flohr, Nina Magnolo, Catherine Maari, Claire Feeney, Pinaki Biswas, Svitlana Tatulych, Hernan Valdez, Ricardo Rojo
Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.
Lancet. 2020 Jul 25;396(10246):255-266. doi: 10.1016/S0140-6736(20)30732-7.
Abstract/Text BACKGROUND: Abrocitinib, an oral selective Janus kinase 1 inhibitor, was effective and well tolerated in adults with moderate-to-severe atopic dermatitis in a phase 2b trial. We aimed to assess the efficacy and safety of abrocitinib monotherapy in adolescents and adults with moderate-to-severe atopic dermatitis.
METHODS: In this multicentre, double-blind, randomised phase 3 trial (JADE MONO-1), patients (aged ≥12 years) with moderate-to-severe atopic dermatitis (Investigator Global Assessment score ≥3, Eczema Area and Severity Index [EASI] score ≥16, percentage of body surface area affected ≥10%, and Peak Pruritus Numerical Rating Scale score ≥4) with a bodyweight of 40 kg or more, were enrolled at 69 sites in Australia, Canada, Europe, and the USA. Patients were randomly assigned (2:2:1) to oral abrocitinib 100 mg, abrocitinib 200 mg, or placebo once daily for 12 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity and age. Patients, investigators, and the funder of the study were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved an Investigator Global Assessment response (score of 0 [clear] or 1 [almost clear] with a ≥2-grade improvement from baseline), and the proportion of patients who achieved at least a 75% improvement in EASI score from baseline (EASI-75) score, both assessed at week 12. Efficacy was assessed in the full analysis set, which included all randomised patients who received at least one dose of study medication. Safety was assessed in all randomised patients. This study is registered with ClinicalTrials.gov, NCT03349060.
FINDINGS: Between Dec 7, 2017, and March 26, 2019, 387 patients were enrolled: 156 were assigned to abrocitinib 100 mg, 154 to abrocitinib 200 mg, and 77 to placebo. All enrolled patients received at least one dose of study treatment and thus were evaluable for 12-week efficacy. Of the patients with available data for the coprimary endpoints at week 12, the proportion of patients who had achieved an Investigator Global Assessment response was significantly higher in the abrocitinib 100 mg group than in the placebo group (37 [24%] of 156 patients vs six [8%] of 76 patients; p=0·0037) and in the abrocitinib 200 mg group compared with the placebo group (67 [44%] of 153 patients vs six [8%] of 76 patients; p<0·0001). Of the patients with available data for the coprimary endpoints at week 12, compared with the placebo group, the proportion of patients who had achieved an EASI-75 response was significantly higher in the abrocitinib 100 mg group (62 [40%] of 156 patients vs nine [12%] of 76 patients; p<0·0001) and abrocitinib 200 mg group (96 [63%] of 153 patients vs nine [12%] of 76 patients; p<0·0001). Adverse events were reported in 108 (69%) of 156 patients in the abrocitinib 100 mg group, 120 (78%) of 154 patients in the abrocitinib 200 mg group, and 44 (57%) of 77 patients in the placebo group. Serious adverse events were reported in five (3%) of 156 patients in the abrocitinib 100 mg group, five (3%) of 154 patients in the abrocitinib 200 mg group, and three (4%) of 77 patients in the placebo group. No treatment-related deaths were reported.
INTERPRETATION: Monotherapy with oral abrocitinib once daily was effective and well tolerated in adolescents and adults with moderate-to-severe atopic dermatitis.
FUNDING: Pfizer.

Copyright © 2020 Elsevier Ltd. All rights reserved.
PMID 32711801
J Schmitt, N Schmitt, M Meurer
Cyclosporin in the treatment of patients with atopic eczema - a systematic review and meta-analysis.
J Eur Acad Dermatol Venereol. 2007 May;21(5):606-19. doi: 10.1111/j.1468-3083.2006.02023.x.
Abstract/Text OBJECTIVE: To systematically assess the effectiveness of systemic cyclosporin in patients with severe atopic eczema.
STUDY DESIGN: Systematic review and meta-analysis of controlled and uncontrolled trials. Electronic (MEDLINE, Cochrane databases) and hand search of published work. Independent standardized assessment of eligibility and data abstraction by two reviewers.
METHODS: For the qualitative review data on study design, study population, methodology, results, tolerability and methodological quality was independently extracted by two reviewers. Qualitatively homogeneous studies were pooled using a random-effects model. The mean relative change in objective disease severity was chosen as the main outcome measure for the quantitative analysis. Publication bias was explored by regressing treatment effect on sample size. Sensitivity analysis included meta-regression of study-specific covariates (inclusion of children, study type, concomitant topical therapy, study quality).
RESULTS: Fifteen studies including 602 patients met the eligibility criteria. In all studies analysed, cyclosporin consistently decreased the severity of atopic eczema. Twelve studies appeared homogeneous enough to be pooled. After 2 weeks of treatment we found a dose-related response with a pooled mean decrease in disease severity of 22% (95%-CI 8-36%) under low-dose cyclosporin ( 3 mg/kg) and 40% (95%-CI 29-51%) at dosages >or=4 mg/kg. After 6-8 weeks the relative effectiveness was 55% (95%-CI 48-62%).
CONCLUSIONS: Due to evidence of publication bias the quantitative results need to be interpreted with caution. Effectiveness of cyclosporin is similar in adults and children, but tolerability might be better in children. As data to adequately evaluate the long-term effectiveness and safety of cyclosporin in patients with atopic eczema are unavailable, long-term registries are encouraged.

PMID 17447974
Yoichi Chida, Andrew Steptoe, Noriaki Hirakawa, Nobuyuki Sudo, Chiharu Kubo
The effects of psychological intervention on atopic dermatitis. A systematic review and meta-analysis.
Int Arch Allergy Immunol. 2007;144(1):1-9. doi: 10.1159/000101940. Epub 2007 Apr 20.
Abstract/Text BACKGROUND: Psychological interventions may be valuable in atopic dermatitis. We systematically reviewed and carried out a meta-analysis of randomized controlled trials of psychological interventions.
METHODS: Electronic searches and manual journal searches were carried out. Two coders independently coded study designs, participants, treatments and outcome characteristics of the studies meeting the selection criteria.
RESULTS: Eight journal articles published between 1986 and 2006 were included. Eight types of intervention were tested: aromatherapy, autogenic training, brief dynamic psychotherapy, cognitive-behavioral therapy, dermatological education and cognitive-behavioral therapy, habit reversal behavioral therapy, a stress management program, and structured educational programs. Effect sizes were computed as correlation coefficient (r), and random effects models were used in the analysis. For eczema severity, the average effect size for the 8 trials including 8 interventions was -0.367 [chi(2)(1) = 7.452, p = 0.006; 95% CI -0.579 to -0.108]. The average effect sizes on itching intensity (5 trials with 5 interventions) and scratching (5 trials with 4 interventions) were -0.805 [chi(2)(1) = 4.719, p = 0.030; 95% CI -0.971 to -0.108] and -0.620 [chi(2)(1) = 24.24, p < 0.0001; 95% CI -0.767 to -0.410], respectively.
CONCLUSIONS: Although the present meta-analysis revealed that psychological interventions had a significant ameliorating effect on eczema severity, itching intensity and scratching in atopic dermatitis patients, a definite conclusion about their effectiveness seems premature. Accordingly, future studies should involve more sophisticated methodologies, use established measures of outcome variables, adjust for possible confounders between the intervention and control groups, and provide sufficient data to calculate the effect sizes for future meta-analyses.

PMID 17449959
N J Reynolds, V Franklin, J C Gray, B L Diffey, P M Farr
Narrow-band ultraviolet B and broad-band ultraviolet A phototherapy in adult atopic eczema: a randomised controlled trial.
Lancet. 2001 Jun 23;357(9273):2012-6. doi: 10.1016/S0140-6736(00)05114-X.
Abstract/Text BACKGROUND: Narrow-band ultraviolet B (UVB) is an effective treatment for psoriasis, and open studies suggest that this phototherapy might improve atopic eczema. We did a randomised controlled trial to compare narrow-band UVB, UVA, and visible light phototherapy as second-line, adjunctive treatments in adult patients with moderate to severe atopic eczema.
METHODS: Phototherapy was administered twice a week for 12 weeks. 26 patients were randomly assigned narrow-band UVB, 24 were assigned UVA, and 23 visible fluorescent light. The primary endpoints were change in total disease activity (sum of scores at six body sites) and change in extent of disease after 24 treatments compared with baseline. Data were analysed by the method of summary measures.
FINDINGS: 13 patients withdrew or were excluded from analysis. Mean reductions in total disease activity over 24 treatments in patients who received narrow-band UVB and UVA, respectively, were 9.4 points (95% CI 3.6 to 15.2) and 4.4 points (-1.0 to 9.8) more than in patients who received visible light. Mean reductions in extent of disease after 24 treatments with narrow-band UVB and UVA were 6.7% (1.5 to 11.9) and -1.0% (-5.3 to 3.3) compared with visible light. A small proportion of patients developed erythema after phototherapy or had a flare in their eczema sufficient to withdraw from treatment.
INTERPRETATION: Narrow-band UVB is an effective adjunctive treatment for moderate to severe atopic eczema, and the treatment is well tolerated by most patients.

PMID 11438134
I Man, I K Crombie, R S Dawe, S H Ibbotson, J Ferguson
The photocarcinogenic risk of narrowband UVB (TL-01) phototherapy: early follow-up data.
Br J Dermatol. 2005 Apr;152(4):755-7. doi: 10.1111/j.1365-2133.2005.06537.x.
Abstract/Text BACKGROUND: Limited information is available on the carcinogenic risk associated with narrowband TL-01 UVB phototherapy in humans.
OBJECTIVES: To determine the skin cancer incidence in a population treated with TL-01 phototherapy.
PATIENTS AND METHODS: All TL-01-treated patients were identified from the departmental computerized database. Patients with malignant melanoma (MM), squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) were identified by record linkage with the Scottish Cancer Registry. The incidence of each was compared with the normal Scottish population matched for age and sex.
RESULTS: Data were obtained from 1908 patients. The median follow-up duration was 4 years (range 0.04-13). The median cumulative number of TL-01 treatments and dose were 23 (1-199) and 13 337 (30-284 415) mJ cm(-2), respectively. No increased incidence of SCC or MM was observed. Ten patients developed BCC compared with an expected 4.7 in the Scottish population [standardized rate ratio 213 (95% confidence interval 102-391); P < 0.05].
CONCLUSIONS: A small but significant increase of BCC was detected in the TL-01 group. This could be explained by a number of factors, including ascertainment bias. To determine the true carcinogenic risk of TL-01 phototherapy, longer follow-up is essential.

PMID 15840109

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