Genetic Variants Associated with T-Cell Mediated Cutaneous Adverse Drug Reactions: A Prisma-Compliant Systematic Review - an EAACI Position Paper.

Author information

1: INSERM, UMR_S 1256, NGERE - Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine, Nancy, F-54000, France.
2: Department of Molecular Medicine, Division of Biochemistry, Molecular Biology, and Nutrition, University Hospital of Nancy, Nancy, F-54000, France.
3: Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.
4: Royal Liverpool, Broadgreen University Hospital NHS Trust, Liverpool, L7 8XP, UK.
5: The Wolfson Centre for Personalized Medicine, Institute of Translational Medicine, University of Liverpool, Block A: Waterhouse Building, 1-5 Brownlow Street, Liverpool, L69 3GL, UK.
6: Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA-ARADyAL, Málaga, Spain.
7: Allergy Unit, Hospital Regional Universitario de Málaga-ARADyAL, Málaga, Spain.
8: Dermatology and Allergology Department, Tenon Hospital (AP-HP), Sorbonne Universities, UPMC University, Paris 06, Paris, France.
9: Allergy and Immunology Clinic Royal Liverpool and Broadgreen University Hospital, Thomas Drive, Liverpool, L14 3LB, UK.
10: Department of Allergy and Clinical Immunology, Centro Hospitalar Universitário de Sâo João, Allergy Clinic, Hospital Lusíadas, 4200-319, Porto, Portugal.
11: Center for Allergy and Immunology Research, Tbilisi, Georgia.
12: Klinik für Dermatologie und Allergologie am Biederstein, Technische Universität München, Biedersteiner Str. 29, 80802, München, Germany.
13: Division of Paediatrics, University Hospital of Geneva, Geneva, Switzerland.
14: Dermatologie/Allergologie, Universitätsspital Basel, Switzerland.
15: Medical Faculty, University of Belgrade, Department of Allergology and Pulmonology, University Children's Hospital, Belgrade, Serbia.
16: Department of Pulmonology - Division of Allergy, Hôpital Arnaud de Villeneuve, University Hospital of Montpellier, Montpellier, France.
17: Hospital Sírio-Libanês, São Paulo, Brazil.
18: Academisch Medisch Centrum University of Amsterdam, Amsterdam, Netherlands.
19: Allergy Unit, Hospital de la Cruz Roja, Madrid, Spain.
20: Fondazione Mediterranea G.B. Morgagni, Catania, Italy.

Abstract

Drug hypersensitivity reactions (DHRs) are associated with high global morbidity and mortality. Cutaneous T cell-mediated reactions classically occur more than 6 hours after drug administration and include life-threatening conditions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and hypersensitivity syndrome. Over the last 20 years, significant advances have been made in our understanding of the pathogenesis of DHRs with the identification of human leukocyte antigens as predisposing factors. This has led to the development of pharmacogenetic screening tests, such as HLA-B*57:01 in abacavir therapy, which has successfully reduced the incidence of abacavir hypersensitivity reactions. We have completed a PRISMA-compliant systematic review to identify genetic associations that have been reported in DHRs. In total, 105 studies (5554 cases and 123,548 controls) have been included in the review reporting genetic associations with carbamazepine (n=31), other aromatic antiepileptic drugs (n=24), abacavir (n=11), nevirapine (n=14), trimethoprim-sulfamethoxazole (n=11), dapsone (n=4), allopurinol (n=10), and other drugs (n=5). The most commonly reported genetic variants associated with DHRs are located in human leukocyte antigen genes and genes involved in drug metabolism pathways. Increasing our understanding of genetic variants that contribute to DHRs will allow us to improve diagnosis, develop new treatments, and predict and prevent DHRs in the future.

KEYWORDS:

Stevens-Johnson syndrome; T-cell mediated hypersensitivity; abacavir; allopurinol; aromatic antiepileptic-drugs; carbamazepine; cutaneous adverse drug reactions; dapsone; drug rash with eosinophilia and systemic symptoms; drug-induced hypersensitivity syndrome; hypersensitivity syndrome; maculopapular exanthema; nevirapine; severe cutaneous adverse drug reaction; toxic epidermal necrolysis; trimethoprim-sulfamethoxazole