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Comparative Study
. 2019 Aug;75(8):1135-1141.
doi: 10.1007/s00228-019-02670-9. Epub 2019 Mar 27.

Adverse drug reaction causality assessment tools for drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: room for improvement

Jennifer L Goldman  1 , Wen-Hung Chung  2 , Brian R Lee  3 , Chun-Bing Chen  2 , Chun-Wei Lu  2 , Wolfram Hoetzenecker  4 , Robert Micheletti  5 , Sally Usdin Yasuda  6 , David J Margolis  5   7 , Neil H Shear  8 , Jeffery P Struewing  9 , Munir Pirmohamed  10
Affiliations
Comparative Study

Adverse drug reaction causality assessment tools for drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: room for improvement

Jennifer L Goldman et al. Eur J Clin Pharmacol. 2019 Aug.

Erratum in

Abstract

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.

Keywords: Adverse drug reactions; Causality assessment tool; Stevens-Johnson syndrome; Toxic epidermal necrolysis.

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Conflict of interest statement

Conflict of interest

The authors declare they have no conflict of interest.

Figures

Fig. 1
Fig. 1. Variability of Causality Assessment Tool (CAT) Results for 10 SJS/TEN Cases
Results of three CAT involving 10 cases of severe cutaneous drug reactions performed by 7 reviewers is displayed. Causality classification of unlikely, possible, probable, or definite is depicted by color/shading. The figure demonstrates the observed inter and intra-rater reviewer variability by case and CAT.
See this image and copyright information in PMC

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