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基于模型的荟萃分析以优化特应性皮炎的靶向治疗

Model-Based Meta-Analysis to Optimize ‒Targeted Therapies for Atopic Dermatitis.

作者信息

Miyano Takuya, Irvine Alan D, Tanaka Reiko J

机构信息

Department of Bioengineering, Imperial College London, London, United Kingdom.

Pediatric Dermatology, Children's Health Ireland at Crumlin, Dublin, Ireland.

出版信息

JID Innov. 2022 Feb 18;2(3):100110. doi: 10.1016/j.xjidi.2022.100110. eCollection 2022 May.

DOI:10.1016/j.xjidi.2022.100110
PMID:35757782
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9214323/
Abstract

Several clinical trials of ()‒targeted therapies for atopic dermatitis (AD) have shown conflicting results about whether they improve AD severity scores. This study performs a model-based meta-analysis to investigate the possible causes of these conflicting results and suggests how to improve the efficacies of ‒targeted therapies. We developed a mathematical model that describes systems-level AD pathogenesis involving dynamic interactions between and coagulase-negative (CoNS). Our model simulation reproduced the clinically observed detrimental effects of the application of A9 and flucloxacillin on AD severity and showed that these effects disappeared if the bactericidal activity against CoNS was removed. A hypothetical (modeled) eradication of by 3.0 log colony-forming unit per cm without killing CoNS achieved Eczema Area and Severity Index 75 comparable with that of dupilumab. This efficacy was potentiated if dupilumab was administered in conjunction with eradication (Eczema Area and Severity Index 75 at week 16) ( eradication: 66.7%, dupilumab 61.6% and combination 87.8%). The improved efficacy was also seen for virtual dupilumab poor responders. Our model simulation suggests that killing CoNS worsens AD severity and that ‒specific eradication without killing CoNS could be effective for patients with AD, including dupilumab poor responders. This study will contribute to designing promising ‒targeted therapy.

摘要

几项针对特应性皮炎（AD）的（）靶向治疗的临床试验，在这些治疗是否能改善AD严重程度评分方面给出了相互矛盾的结果。本研究进行了基于模型的荟萃分析，以探究这些相互矛盾结果的可能原因，并提出如何提高靶向治疗的疗效。我们开发了一个数学模型，该模型描述了涉及（）与凝固酶阴性菌（CoNS）之间动态相互作用的系统层面的AD发病机制。我们的模型模拟重现了临床上观察到的应用A9和氟氯西林对AD严重程度的有害影响，并表明如果去除针对CoNS的杀菌活性，这些影响就会消失。假设每平方厘米通过3.0对数菌落形成单位消灭（）而不杀死CoNS，所达到的湿疹面积和严重程度指数75与度普利尤单抗相当。如果度普利尤单抗与消灭（）联合使用（第16周时湿疹面积和严重程度指数75），这种疗效会增强（消灭（）：66.7%，度普利尤单抗61.6%，联合使用87.8%）。对于虚拟的度普利尤单抗疗效不佳者也观察到了疗效的提高。我们的模型模拟表明，杀死CoNS会加重AD严重程度，而不杀死CoNS的特异性消灭对AD患者可能有效，包括度普利尤单抗疗效不佳者。本研究将有助于设计有前景的靶向治疗。 （注：原文中括号部分缺失具体内容）

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