Real-world NUDT15 genotyping and thiopurine treatment optimization in inflammatory bowel disease: a multicenter study.
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Makuuchi Motoki, Kakuta Yoichi, Umeno Junji, Fujii Toshimitsu, Takagawa Tetsuya, Ibuka Takashi, Miura Miki, Sasaki Yu, Takahashi Sakuma, Nakase Hiroshi, Kiyohara Hiroki, Tominaga Keiichi, Shimodaira Yosuke, Hiraoka Sakiko, Ueno Nobuhiro, Yanai Shunichi, Yoshihara Takeo, Kakimoto Kazuki, Matsuoka Katsuyoshi, Hayashi Ryohei, Nanjo Sohachi, Iwama Itaru, Ishiguro Yoh, Chiba Hirofumi, Endo Katsuya, Kagaya Takashi, Fukuda Tomohiro, Sakata Yasuhisa, Kudo Takahiro, Takagi Tomohisa, Takahashi Kenichi, Naganuma Makoto, Shinozaki Masaru, Ogata Noriyuki, Tanaka Hiroki, Narimatsu Kazuyuki, Miyazaki Haruka, Ishige Takashi, Onodera Motoyuki, Hashimoto Yu, Nagai Hiroshi, Shimoyama Yusuke, Naito Takeo, Moroi Rintaro, Shiga Hisashi, Post-MENDEL study group, Kinouchi Yoshitaka, Andoh Akira, Hisamatsu Tadakazu, Masamune Atsushi
Аннотация
METHODS: A retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status.
RESULTS: Genotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with < 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users.
CONCLUSIONS: NUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.