药物性 Stevens-Johnson 综合征和中毒性表皮坏死松解症的药物不良反应因果关系评估工具：仍有改进空间。
Adverse drug reaction causality assessment tools for drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: room for improvement.
机构信息
Department of Pediatrics, Divisions of Pediatric Infectious Diseases & Clinical Pharmacology, Children's Mercy Hospitals & Clinic, 2401 Gillham Rd., Kansas City, MO, 64108, USA.
Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Keelung and Linkou Branches, College of Medicine, Chang Gung University, Taipei, Taiwan.
出版信息
Eur J Clin Pharmacol. 2019 Aug;75(8):1135-1141. doi: 10.1007/s00228-019-02670-9. Epub 2019 Mar 27.
PURPOSE
Establishment of causality between drug exposure and adverse drug reactions (ADR) is challenging even for serious ADRs such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Several causality assessment tools (CAT) exist, but the reliability and validity of such tools is variable. The objective of this study was to compare the reliability and validity of existing ADR CATs on SJS/TEN cases.
METHODS
Seven investigators completed three CAT (ALDEN, Naranjo, Liverpool) for 10 SJS/TEN cases. Each CAT categorized the causality of 30 potential drugs as definite/very probable, probable, possible, or doubtful/unlikely. An additional reviewer provided expert opinion by designating the implicated drug(s) for each case. A Kappa score was generated to compare CAT responses both by method (reliability of all 7 reviewers, by CATs) and by reviewer (reliability of the 3 CAT, by reviewer). A c statistic was calculated to assess validity.
RESULTS
Inter-rater reliability by CAT was poor to fair: ALDEN 0.22, Naranjo 0.11, and Liverpool 0.12. Reliability was highest when causality classification was definite/very probable (0.16-0.41). Similarly, intra-rater reliability by reviewer was poor. When comparing the validity of the overall CAT to expert reviewer, area under the curve was highest for ALDEN (c statistic 0.65) as compared to Liverpool (0.55) or Naranjo (0.54).
CONCLUSION
Available CAT have poor reliability and validity for drug-induced SJS/TEN. Due to the importance of determining ADR causality for research, industry, and regulatory purposes, development of an enhanced tool that can incorporate data from immunological testing and pharmacogenetic results may strengthen CAT usefulness and applicability for drug-induced SJS/TEN.
目的
即使对于严重的不良反应（ADR），如史蒂文斯-约翰逊综合征/中毒性表皮坏死松解症（SJS/TEN），药物暴露与不良反应之间的因果关系的建立也具有挑战性。目前存在几种因果关系评估工具（CAT），但这些工具的可靠性和有效性是可变的。本研究的目的是比较现有的 SJS/TEN 病例的 ADR CAT 的可靠性和有效性。
方法
7 名调查员对 10 例 SJS/TEN 病例完成了 3 种 CAT（ALDEN、Naranjo、Liverpool）的评估。每个 CAT 将 30 种潜在药物的因果关系分为确定/极可能、可能、可能或不确定/不太可能。另一位评审员通过为每个病例指定相关药物，提供了专家意见。生成 Kappa 评分以比较 CAT 对方法（所有 7 位评审员的可靠性，通过 CAT）和评审员（3 种 CAT 的可靠性，通过评审员）的反应。计算 c 统计量以评估有效性。
结果
CAT 的组内可靠性为差至尚可：ALDEN 为 0.22，Naranjo 为 0.11，Liverpool 为 0.12。当因果关系分类为确定/极可能时，可靠性最高（0.16-0.41）。同样，评审员的组内可靠性也很差。当将整体 CAT 的有效性与专家评审员进行比较时，ALDEN 的曲线下面积最高（c 统计量为 0.65），而 Liverpool（0.55）或 Naranjo（0.54）则较低。
结论
现有的 CAT 对于药物引起的 SJS/TEN 的可靠性和有效性较差。由于确定 ADR 因果关系对于研究、行业和监管目的非常重要，因此开发一种能够整合免疫测试和药物遗传学结果数据的增强型工具可能会增强 CAT 在药物引起的 SJS/TEN 中的实用性和适用性。
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