Taisei Mushiroda1, Yukitoshi Takahashi2, Teiichi Onuma3, Yoshiaki Yamamoto2, Tetsumasa Kamei4, Tohru Hoshida5, Katsuya Takeuchi6,7, Kotaro Otsuka6, Mitsutoshi Okazaki8, Masako Watanabe8, Kosuke Kanemoto9, Tomohiro Oshima9, Atsushi Watanabe10, Shiro Minami11, Kayoko Saito12, Hisashi Tanii13, Yasushi Shimo14, Minoru Hara15, Shinji Saitoh16, Toshihiko Kinoshita17, Masaki Kato17, Naoto Yamada18, Naoki Akamatsu19, Toshihiko Fukuchi20, Shigenobu Ishida21, Shingo Yasumoto21, Atsushi Takahashi1, Takeshi Ozeki1, Takahisa Furuta22, Yoshiro Saito23, Nobuyuki Izumida24, Yoko Kano25, Tetsuo Shiohara25, Michiaki Kubo1. 1. RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 2. Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan. 3. Musashino-Kokubunji Clinic, Tokyo, Japan. 4. Tokushukai Hospital, Tokyo, Japan. 5. National Hospital Organization Nara Medical Center, Nara, Japan. 6. Department of Neuropsychiatry, Iwate Medical University, Iwate, Japan. 7. Kitariasu Hospital, Iwate, Japan. 8. Department of Psychiatry, National Center of Neurology and Psychiatry, Tokyo, Japan. 9. Neuropsychiatric Department, Aichi Medical University, Aichi, Japan. 10. Division of Personalized Genetic Medicine, Nippon Medical School, Tokyo, Japan. 11. Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, Japan. 12. Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan. 13. Department of Psychiatry, Mie University Graduate School of Medicine, Mie, Japan. 14. Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan. 15. Hara Clinic, Yokohama, Japan. 16. Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. 17. Department of Neuropsychiatry, Kansai Medical University, Osaka, Japan. 18. Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan. 19. Department of Neurology, University of Occupational and Environmental Health, Kitakyusyu, Japan. 20. Suzukake Clinic, Nagoya, Japan. 21. Department of Neuropsychiatry, Kurume University School of Medicine, Fukuoka, Japan. 22. Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan. 23. Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan. 24. Department of Empirical Social Security Research, National Institute of Population and Social Security Research, Tokyo, Japan. 25. Department of Dermatology, Kyorin University School of Medicine, Tokyo, Japan.
Abstract
Importance: Carbamazepine, a commonly used antiepileptic drug, is one of the most common causes of cutaneous adverse drug reactions (cADRs) worldwide. The allele HLA-A*31:01 is reportedly associated with carbamazepine-induced cADRs in Japanese and European populations; however, the clinical utility of HLA-A*31:01 has not been evaluated. Objective: To assess the use of HLA-A*31:01 genetic screening to identify Japanese individuals at risk of carbamazepine-induced cADRs. Design, Setting, and Participants: This cohort study was conducted across 36 hospitals in Japan from January 2012 to November 2014 among 1202 patients who had been deemed suitable to start treatment with carbamazepine. Preemptive HLA-A*31:01 genetic screening was performed for 1187 participants. Patients who did not start treatment with carbamazepine or alternative drugs were excluded. Participants were interviewed once weekly for 8 weeks to monitor the development of cADRs. Data analysis was performed from June 8, 2015, to December 27, 2016. Exposures: Neuropsychiatrists were asked to prescribe carbamazepine for patients who tested negative for HLA-A*31:01 and alternative drugs for those who tested positive for HLA-A*31:01. Main Outcomes and Measures: Incidence of carbamazepine-induced cADRs. Results: Of the 1130 included patients who were prescribed carbamazepine or alternative drugs, the mean (range) age was 37.4 (0-95) years, 614 (54.3%) were men, and 198 (17.5%) were positive for HLA-A*31:01. Expert dermatologists identified 23 patients (2.0%) who had carbamazepine-induced cADRs, of which 4 patients required hospitalization. Drug-induced hypersensitivity syndrome was observed for 3 patients, maculopapular eruption for 9 patients, erythema multiforme for 5 patients, and an undetermined type of cADR for 6 patients. No patient developed Stevens-Johnson syndrome or toxic epidermal necrolysis. Compared with historical controls, the incidence of carbamazepine-induced cADRs was significantly decreased (for BioBank Japan data: incidence, 3.4%; odds ratio, 0.60; 95% CI, 0.36-1.00; P = .048; for the Japan Medical Data Centre claims database: incidence, 5.1%; odds ratio, 0.39; 95% CI, 0.26-0.59; P < .001). Conclusions and Relevance: Preemptive HLA-A*31:01 genetic screening significantly decreased the incidence of carbamazepine-induced cADRs among Japanese patients, which suggests that it may be warranted in routine clinical practice.
Importance: Carbamazepine, a commonly used antiepileptic drug, is one of the most common causes of cutaneous adverse drug reactions (cADRs) worldwide. The allele HLA-A*31:01 is reportedly associated with carbamazepine-induced cADRs in Japanese and European populations; however, the clinical utility of HLA-A*31:01 has not been evaluated. Objective: To assess the use of HLA-A*31:01 genetic screening to identify Japanese individuals at risk of carbamazepine-induced cADRs. Design, Setting, and Participants: This cohort study was conducted across 36 hospitals in Japan from January 2012 to November 2014 among 1202 patients who had been deemed suitable to start treatment with carbamazepine. Preemptive HLA-A*31:01 genetic screening was performed for 1187 participants. Patients who did not start treatment with carbamazepine or alternative drugs were excluded. Participants were interviewed once weekly for 8 weeks to monitor the development of cADRs. Data analysis was performed from June 8, 2015, to December 27, 2016. Exposures: Neuropsychiatrists were asked to prescribe carbamazepine for patients who tested negative for HLA-A*31:01 and alternative drugs for those who tested positive for HLA-A*31:01. Main Outcomes and Measures: Incidence of carbamazepine-induced cADRs. Results: Of the 1130 included patients who were prescribed carbamazepine or alternative drugs, the mean (range) age was 37.4 (0-95) years, 614 (54.3%) were men, and 198 (17.5%) were positive for HLA-A*31:01. Expert dermatologists identified 23 patients (2.0%) who had carbamazepine-induced cADRs, of which 4 patients required hospitalization. Drug-induced hypersensitivity syndrome was observed for 3 patients, maculopapular eruption for 9 patients, erythema multiforme for 5 patients, and an undetermined type of cADR for 6 patients. No patient developed Stevens-Johnson syndrome or toxic epidermal necrolysis. Compared with historical controls, the incidence of carbamazepine-induced cADRs was significantly decreased (for BioBank Japan data: incidence, 3.4%; odds ratio, 0.60; 95% CI, 0.36-1.00; P = .048; for the Japan Medical Data Centre claims database: incidence, 5.1%; odds ratio, 0.39; 95% CI, 0.26-0.59; P < .001). Conclusions and Relevance: Preemptive HLA-A*31:01 genetic screening significantly decreased the incidence of carbamazepine-induced cADRs among Japanese patients, which suggests that it may be warranted in routine clinical practice.
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