J Gastroenterol. 2024 Jun;59(6):468-482.doi: 10.1007/s00535-024-02099-7. Epub 2024 Apr 8.

Motoki Makuuchi ^# 1, Yoichi Kakuta ^# 2, Junji Umeno ³, Toshimitsu Fujii ⁴, Tetsuya Takagawa ⁵, Takashi Ibuka ⁶, Miki Miura ⁷, Yu Sasaki ⁸, Sakuma Takahashi ⁹, Hiroshi Nakase ¹⁰, Hiroki Kiyohara ¹¹, Keiichi Tominaga ¹², Yosuke Shimodaira ¹³, Sakiko Hiraoka ¹⁴, Nobuhiro Ueno ¹⁵, Shunichi Yanai ¹⁶, Takeo Yoshihara ¹⁷, Kazuki Kakimoto ¹⁸, Katsuyoshi Matsuoka ¹⁹, Ryohei Hayashi ²⁰, Sohachi Nanjo ²¹, Itaru Iwama ²², Yoh Ishiguro ²³, Hirofumi Chiba ²⁴, Katsuya Endo ²⁵, Takashi Kagaya ²⁶, Tomohiro Fukuda ²⁷, Yasuhisa Sakata ²⁸, Takahiro Kudo ²⁹, Tomohisa Takagi ³⁰, Kenichi Takahashi ³¹, Makoto Naganuma ³², Masaru Shinozaki ³³, Noriyuki Ogata ³⁴, Hiroki Tanaka ³⁵, Kazuyuki Narimatsu ³⁶, Haruka Miyazaki ³⁷, Takashi Ishige ³⁸, Motoyuki Onodera ³⁹, Yu Hashimoto ⁴⁰, Hiroshi Nagai ¹, Yusuke Shimoyama ¹, Takeo Naito ¹, Rintaro Moroi ¹, Hisashi Shiga ¹; Post-MENDEL study group; Yoshitaka Kinouchi ⁴¹, Akira Andoh ⁴², Tadakazu Hisamatsu ⁷, Atsushi Masamune ¹

Author information

¹Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan.

²Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan. ykakuta@med.tohoku.ac.jp.

³Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

⁴Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.

⁵Center for Clinical Research and Education/Center for Inflammatory Bowel Disease, Hyogo Medical University, Nishinomiya, Japan.

⁶Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan.

⁷Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Tokyo, Japan.

⁸Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Japan.

⁹Department of Gastroenterology, Kagawa Prefectural Central Hospital, Takamatsu, Japan.

¹⁰Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan.

¹¹Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.

¹²Department of Gastroenterology, Dokkyo Medical University, Tochigi, Japan.

¹³Department of Gastroenterology and Neurology, Akita University, Akita, Japan.

¹⁴Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

¹⁵Division of General Medicine, Asahikawa Medical University Hospital, Asahikawa, Japan.

¹⁶Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan.

¹⁷Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.

¹⁸Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Osaka, Japan.

¹⁹Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Sakura Medical Center, Chiba, Japan.

²⁰Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan.

²¹Third Department of Internal Medicine, Graduate School of Medicine, University of Toyama, Toyama, Japan.

²²Division of Gastroenterology and Hepatology, Saitama Children's Medical Center, Saitama, Japan.

²³Division of Clinical Research, Hirosaki General Medical Center, NHO, Hirosaki, Japan.

²⁴Department of Gastroenterology, Iwate Prefectural Isawa Hospital, Oshu, Japan.

²⁵Division of Gastroenterology, Tohoku Medical and Pharmaceutical University School of Medicine, Sendai, Japan.

²⁶Department of Gastroenterology, NHO Kanazawa Medical Center, Kanazawa, Japan.

²⁷Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.

²⁸Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.

²⁹Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan.

³⁰Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

³¹Department of Colorectal Surgery, Tohoku Rosai Hospital, Sendai, Japan.

³²Third Department of Internal Medicine, Kansai Medical University, Hirakata, Japan.

³³Saitama Gastroenterology Clinic, Saitama, Japan.

³⁴Digestive Disease Center, Showa University Northern Yokohama Hospital, Yokohama, Japan.

³⁵Sapporo IBD Clinic, Sapporo, Japan.

³⁶Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.

³⁷Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.

³⁸Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan.

³⁹Osaki Citizen Hospital, Osaki, Japan.

⁴⁰Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan.

⁴¹Student Healthcare Center, Institute for Excellence in Higher Education, Tohoku University, Sendai, Japan.

⁴²Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Otsu, Japan.

^#Contributed equally.

Abstract

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.