Pharmacogenetic Testing for Prevention of Severe Cutaneous Adverse Drug Reactions

Abstract

Severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS), are idiosyncratic and unpredictable drug-hypersensitivity reactions with a high-mortality rate ranging from 10% to over 30%, thus causing a major burden on the healthcare system. Recent pharmacogenomic studies have revealed strong associations between SCAR and the genes encoding human-leukocyte antigens (HLAs) or drug-metabolizing enzymes. Some of pharmacogenetic markers have been successfully applied in clinical practice to protect patients from SCAR, such as HLA-B*15:02 and HLA-A*31:01 for new users of carbamazepine, HLA-B*58:01 for allopurinol, and HLA-B*57:01 for abacavir. This article aims to update the current knowledge in the field of pharmacogenomics of drug hypersensitivities or SCAR, and its implementation in the clinical practice.

Keywords: T cell receptor; drug hypersensitivity; human-leukocyte antigen; pharmacogenetics; severe cutaneous adverse reactions.

Figure 1

Four models of interaction between small molecule drugs and the HLA-peptide-TCR in drug hypersensitivity. (A) Hapten/pro-hapten concept: Drugs or reactive metabolites serve as haptens and bind to the endogenous peptides to form the haptenated peptides (neo-epitopes) that presented by HLA molecules at the cell surface where the novel peptide is recognized as foreign. The HLA/drug/peptide complex is recognized by TCR, which trigger the drug-specific T cell activation. (B) The “pharmacological interaction with immune receptors (p-i)” concept: T cells are proposed to recognize immunogenic complexes formed through a labile interaction of the causative drug, HLA and TCR at the cell surface or TCR and active drug-specific T cells without the intercellular processing in APC. (C) The altered repertoire model: The drug interacts with the antigen-binding cleft of the HLA molecule altering the space available to anchor residues of peptide ligands and results in selection of ligands with a novel HLA binding motif, which promotes polyclonal T-cell activation. (D) The “altered TCR repertoire” model. Drugs bind to TCR, resulting in conformational change of TCR, which then bind to the HLA/self-peptide complex to elicit immune reaction.