Active surveillance of severe cutaneous adverse reactions: A case-population approach using a registry and a health care database

Pharmacoepidemiol Drug Saf. 2018 Sep;27(9):1042-1050. doi: 10.1002/pds.4622. Epub 2018 Jul 27.


Purpose: The "case-population" design has been proposed for the surveillance of rare events like Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), wherein a registry of cases is combined with sales data from the source population in order to estimate crude odds ratios (ORs). A major drawback of this method is the inability to distinguish between new and non-new users of drugs, which for the study of hypersensitivity reactions is of utmost importance.

Methods: We have explored an approach in which the exposure to the drugs of interest in the source population is inferred from a primary health care database (BIFAP), which helped us to identify drug initiators among all users and additionally adjust for potential confounders. A total of 44 SJS/TEN cases from the Registry and 44 000 controls randomly sampled from BIFAP and matched with cases for index date were included. We estimated the adjusted ORs (AORs) and 95% confidence intervals (CI) of SJS/TEN associated with the new use of 13 drugs (for which we had at least two exposed cases) through a conditional logistic regression model.

Results: AORs (95% CI) were estimated for phenytoin, 4618 (434-49112); cotrimoxazole, 1142 (163-8015); allopurinol, 160 (36-709); dexamethasone, 38 (1.33-1077); ibuprofen, 33 (8.6-124); lorazepam, 27 (5.8-124); paracetamol, 13 (2.8-62); levofloxacine, 12 (1.24-120); amoxicillin, 6.9 (1.39-35); pantoprazole, 6.5 (0.10-420); metamizole, 6.3 (0.69-57); amoxicillin clavulanic acid, 4.2 (0.53-34); and omeprazole, 1.34 (0.06-31). The inclusion of non-new users dramatically decreased the AORs for all drugs.

Conclusions: The case-population approach using a registry of cases and a primary health care database proved feasible and efficient for the active surveillance of SJS/TEN.

Keywords: SCARs; Stevens-Johnson syndrome; case-population study; drug surveillance; pharmacoepidemiology; registry of cases; severe cutaneous adverse reactions; toxic epidermal necrolysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Databases, Factual / statistics & numerical data*
  • Feasibility Studies
  • Humans
  • Primary Health Care / statistics & numerical data*
  • Product Surveillance, Postmarketing / methods*
  • Product Surveillance, Postmarketing / statistics & numerical data
  • Registries / statistics & numerical data*
  • Stevens-Johnson Syndrome / epidemiology*
  • Stevens-Johnson Syndrome / etiology