Drug hypersensitivity: pharmacogenetics and clinical syndromes

Abstract

Severe cutaneous adverse reactions include syndromes such as drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS) and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). An important advance has been the discovery of associations between HLA alleles and many of these syndromes, including abacavir-associated hypersensitivity reaction, allopurinol-associated DRESS/DIHS and SJS/TEN, and SJS/TEN associated with aromatic amine anticonvulsants. These HLA associations have created the promise for prevention through screening and have additionally shed further light on the immunopathogenesis of severe cutaneous adverse reactions. The rollout of HLA-B∗5701 into routine clinical practice as a genetic screening test to prevent abacavir hypersensitivity provides a translational roadmap for other drugs. Numerous hurdles exist in the widespread translation of several other drugs, such as carbamazepine, in which the positive predictive value of HLA-B∗1502 is low and the negative predictive value of HLA-B∗1502 for SJS/TEN might not be 100% in all ethnic groups. International collaborative consortia have been formed with the goal of developing phenotypic standardization and undertaking HLA and genome-wide analyses in diverse populations with these syndromes.

Figure 1

Translational Roadmap from Discovery of HLA-B*5701 Association with Abacavir Hypersensitivity to Widespread Clinical Implementation

Figure 2

Number needed to test (NNT) to prevent one case of specific drug reaction Numbers shown are for abacavir hypersensitivity, allopurinol associated SJS/TEN/drug hypersensitivity, carbamazepine associated SJS/TEN and flucloxacillin associated drug induced liver disease. Adapted from Phillips E, Pharmacogenomics 2010 ref 24.