Drug hypersensitivity: Pharmacogenetics and clinical syndromes - 10/08/11

Doi : 10.1016/j.jaci.2010.11.046

Elizabeth J. Phillips, MD ^a,^b,^c,^d,^⁎ , Wen-Hung Chung, MD, PhD ^e, Maja Mockenhaupt, MD, PhD ^f, Jean-Claude Roujeau, MD ^g, Simon A. Mallal, MBBS ^a,^b
^a Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Australia
^b Department of Clinical Immunology and Immunogenetics, Royal Perth Hospital, Perth, Australia
^c Department of Clinical Immunology, Infectious Diseases and Clinical Pharmacology/Toxicology, Sir Charles Gairdner Hospital, Nedlands, Australia
^d School of Pathology & Laboratory Medicine and Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Crawley, Australia
^e Department of Dermatology, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taipei, Taiwan
^f Dokumentationszentrum schewerer Hautreaktionen (dZh), Department of Dermatology, University Medical Center, Freiburg, Germany
^g Department of Dermatology, Paris XII University, Créteil, France

Reprint requests: Elizabeth J. Phillips, MD, Institute for Immunology & Infectious Diseases Discovery Way, Murdoch, Western Australia 6150 Australia.

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-B5701 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-B1502 is low and the negative predictive value of HLA-B1502 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.

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Key words : Drug hypersensitivity, drug reaction with eosinophilia and systemic symptoms, drug-induced hypersensitivity syndrome, Stevens-Johnson syndrome/toxic epidermal necrolysis, pharmacogenetics, severe cutaneous adverse reaction, abacavir, nevirapine, carbamazepine, allopurinol

Abbreviations used : CBZ, CTL, DIHS, DRESS, SCAR, SJS, TEN

Plan

Pharmacogenetics of drug hypersensitivity

Abacavir

Nevirapine

Pharmacogenetics of other SCARs

Progress in pharmacogenetics of SCARs in Han Chinese

Progress of pharmacogenetics of SCARs in other countries

RegiSCAR studies on pharmacogenetics and pharmacogenetics of SCARs in Europe

Functional studies and pathogenesis of SCARs in relation the pharmacogenetics

Other findings and future directions

Publication of this article was supported by iDea Congress. The RegiSCAR-study was funded by grants from the European Commission (QLRT-2002-01738), GIS-Institut des Maladies Rares and INSERM (4CH09G) in France, and by a consortium of pharmaceutical companies (Bayer Vital, Boehringer-Ingelheim, Cephalon, GlaxoSmithKline, MSD Sharp and Dohme, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Servier). M.M. received the Else Kröner Memorial Stipendium for support of clinical research through Else Kröner-Fresenius-Foundation, Germany. The GWAS was performed in collaboration with Centre National de Genotypage (CNG), France.

Disclosure of potential conflict of interest: E. J. Phillips has received honoraria from Merck, ViiV Healthcare, and Tibotec Johnson & Johnson and has received research support from the National Health and Medical Research Council, Australia. W.-H. Chung has received research support from the National Science Council Taiwan and Chang Gung Memorial Hospital. M. Mockenhaupt has received research support from CNG and EC. J.-C. Roujeau has received research support from GlaxoSmithKline, Boehringer Ingelheim France, Novartis Pharma, Astellas Pharma SAS, Science et Technologie, and OM Pharma. S. A. Mallal has received honoraria from ViiV Healthcare, MSD, and Tibotec Johnson & Johnson and has received research support from the National Health and Medical Research Council and the National Institutes of Health.