Yi-Hsin Hsiao1, Rosaline Chung-Yee Hui2, Tony Wu3, Wan-Chun Chang4, Mo-Song Hsih3, Chih-Hsun Yang2, Hsin-Chun Ho2, Ya-Ging Chang2, Ming-Jing Chen2, Jing-Yi Lin2, Ding-Ping Chen5, Pi-Yueh Chang5, Tsu-Lan Wu5, Shuen-Iu Hung6, Wen-Hung Chung7. 1. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, Taipei, Linkou and Keelung, Taiwan. 2. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, Taipei, Linkou and Keelung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan. 3. College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Neurology, Chang Gung Memorial Hospital, Taipei, Linkou, Taiwan. 4. Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan. 5. Department of Laboratory Medicine, Chang-Gung Memorial Hospital, Taoyuan County, Taiwan; Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan County, Taiwan. 6. Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address: sihung@ym.edu.tw. 7. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, Taipei, Linkou and Keelung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address: chung1@cgmh.org.tw.
Abstract
BACKGROUND: Increasing studies reported genetic susceptibility to drug hypersensitivity reactions, as exemplified by the HLA-A*31:01 and HLA-B*15:02 association with carbamazepine (CBZ)-induced hypersensitivity reactions, such as maculopapular exanthema (MPE), drug rash with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). OBJECTIVE: To carry out a comprehensive analysis on the clinical spectrum and HLA genotype-phenotype correlations in CBZ-induced hypersensitivity reactions. METHODS: We analyzed the clinical information of 194 patients with CBZ hypersensitivity (51 MPE, 23 DRESS, 112 SJS/TEN, and 8 cases with other phenotypes), and 152 CBZ-tolerant controls. All are Han Chinese. We examined the HLA-A/HLA-B genotypes, gene dosage, and drug dosage effects. RESULTS: CBZ-SJS/TEN showed the strongest association with the HLA-B*15:02 allele (Pc=5.8×10(-43); odds ratio (OR) (95% CI)=97.6(42.0-226.8)), in which HLA-B*15:02 was identified in all patients (25/25) with SJS/TEN with >5% body surface area (BSA) skin detachment, but lost its 100% association (85.1%, 74/87) in SJS with <5% BSA detachment. In contrast, HLA-B*40:01 showed negative association with CBZ-induced SJS/TEN ((Pc=8.3×10(-5); OR (95% CI)=0.22(0.1-0.4)). By comparison, CBZ-induced MPE/DRESS had no association with HLA-B*15:02, but linked to HLA-A*31:01 (Pc=2.7×10(-3); OR (95% CI)=6.86(2.4-19.9), and HLA-B*51:01 (Pc=0.01; OR (95% CI)=4.56(2.0-10.5)). No gene dosage or CBZ dosage effects was observed. CONCLUSION: This study reported the different strength of HLA association with CBZ hypersensitivity in Han Chinese. With the increasing application of pharmacogenetic markers, the HLA genotype-phenotype correlations and the results of the test need to be carefully interpreted for CBZ-induced hypersensitivity reactions.
BACKGROUND: Increasing studies reported genetic susceptibility to drug hypersensitivity reactions, as exemplified by the HLA-A*31:01 and HLA-B*15:02 association with carbamazepine (CBZ)-induced hypersensitivity reactions, such as maculopapular exanthema (MPE), drug rash with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). OBJECTIVE: To carry out a comprehensive analysis on the clinical spectrum and HLA genotype-phenotype correlations in CBZ-induced hypersensitivity reactions. METHODS: We analyzed the clinical information of 194 patients with CBZhypersensitivity (51 MPE, 23 DRESS, 112 SJS/TEN, and 8 cases with other phenotypes), and 152 CBZ-tolerant controls. All are Han Chinese. We examined the HLA-A/HLA-B genotypes, gene dosage, and drug dosage effects. RESULTS:CBZ-SJS/TEN showed the strongest association with the HLA-B*15:02 allele (Pc=5.8×10(-43); odds ratio (OR) (95% CI)=97.6(42.0-226.8)), in which HLA-B*15:02 was identified in all patients (25/25) with SJS/TEN with >5% body surface area (BSA) skin detachment, but lost its 100% association (85.1%, 74/87) in SJS with <5% BSA detachment. In contrast, HLA-B*40:01 showed negative association with CBZ-induced SJS/TEN ((Pc=8.3×10(-5); OR (95% CI)=0.22(0.1-0.4)). By comparison, CBZ-induced MPE/DRESS had no association with HLA-B*15:02, but linked to HLA-A*31:01 (Pc=2.7×10(-3); OR (95% CI)=6.86(2.4-19.9), and HLA-B*51:01 (Pc=0.01; OR (95% CI)=4.56(2.0-10.5)). No gene dosage or CBZ dosage effects was observed. CONCLUSION: This study reported the different strength of HLA association with CBZhypersensitivity in Han Chinese. With the increasing application of pharmacogenetic markers, the HLA genotype-phenotype correlations and the results of the test need to be carefully interpreted for CBZ-induced hypersensitivity reactions.
Authors: Daniel Morgado-Carrasco; Xavier Fustà-Novell; José M Mascaró; María Antonia Gonzalez-Enseñat; Asunción Vicente-Villa Journal: Indian J Dermatol Venereol Leprol Date: 2021 May-Jun Impact factor: 2.545