Real-world NUDT15 genotyping and thiopurine treatment optimization in inflammatory bowel disease: a multicenter study

• Published in: Journal of gastroenterology Vol. 59; no. 6; pp. 468 - 482
• Main Authors: 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, Kinouchi, Yoshitaka, Andoh, Akira, Hisamatsu, Tadakazu, Masamune, Atsushi
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01.06.2024; Springer Nature B.V
• Subjects: Abdominal Surgery; Adolescent; Adult; Aged; Azathioprine - adverse effects; Azathioprine - therapeutic use; Codon; Colorectal Surgery; Female; Gastroenterology; Genotype; Genotype & phenotype; Genotypes; Genotyping; Hepatology; Humans; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - therapeutic use; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory Bowel Diseases - drug therapy; Inflammatory Bowel Diseases - genetics; Intestine; Japan; Leukopenia; Male; Medicine; Medicine & Public Health; Mercaptopurine - adverse effects; Mercaptopurine - therapeutic use; Middle Aged; Nudix Hydrolases; Original Article—Alimentary Tract; Original —Alimentary Tract; Patients; pH effects; Pyrophosphatases - genetics; Retrospective Studies; Risk Factors; Surgical Oncology; Young Adult; Japan; Adverse event; 6-mercaptopurine; NUDT15; Azathioprine; Thiopurine
• ISSN: 0944-1174; 1435-5922
• DOI: 10.1007/s00535-024-02099-7

Background This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies. 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.