Recent advances in the understanding of severe cutaneous adverse reactions

Summary Severe cutaneous adverse reactions (SCARs) encompass a heterogeneous group of delayed hypersensitivity reactions, which are most frequently caused by drugs. Our understanding of several aspects of SCAR syndromes has evolved considerably over the last decade. This review explores evolving knowledge of the immunopathogenic mechanisms, pharmacogenomic associations, in vivo and ex vivo diagnostics for causality assessment, and medication cross‐reactivity data related to SCAR syndromes. Given the rarity and severity of these diseases, multidisciplinary collaboration through large international, national and/or multicentre networks to collect prospective data on patients with SCAR syndromes should be prioritized. This will further enhance a systematized framework for translating epidemiological, clinical and immunopathogenetic advances into preventive efforts and improved outcomes for patients. What's already known about this topic? Severe cutaneous adverse reactions (SCARs) encompass a heterogeneous group of delayed hypersensitivity reactions, which are most frequently caused by drugs. The designation SCAR most commonly includes Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), SJS/TEN overlap, drug reaction with eosinophilia and systemic symptoms/drug‐induced hypersensitivity syndrome and acute generalized exanthematous pustulosis. The pathogenesis underlying T‐cell‐mediated delayed hypersensitivity reactions involves interactions between small‐molecule drugs, human leucocyte antigen (HLA) class I molecules and T‐cell receptors. What does this study add? Pharmacogenomic discoveries associating severe T‐cell‐mediated drug hypersensitivity syndromes have created the promise of prevention. This has led to universal HLA screening or HLA genotyping before drug prescription. Knowledge has evolved of the immunopathogenesis of SCARs and key novel and nonmutually exclusive mechanisms by which drugs activate T cells. In vivo and ex vivo diagnostics are being increasingly employed to aid causality assessment. Knowledge of cross‐reactivity between structurally related medications is still rudimentary, but may avoid precipitating subsequent severe episodes and minimize unwarranted restriction of therapeutic options. Plain language summary available online