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

被引：0

作者：

Makuuchi, Motoki ^{[1
]}

Kakuta, Yoichi ^{[1
]}

Umeno, Junji ^{[2
]}

Fujii, Toshimitsu ^{[3
]}

Takagawa, Tetsuya ^{[4
]}

Ibuka, Takashi ^{[5
]}

Miura, Miki ^{[6
]}

Sasaki, Yu ^{[7
]}

Takahashi, Sakuma ^{[8
]}

Nakase, Hiroshi ^{[9
]}

Kiyohara, Hiroki ^{[10
]}

Tominaga, Keiichi ^{[11
]}

Shimodaira, Yosuke ^{[12
]}

Hiraoka, Sakiko ^{[13
]}

Ueno, Nobuhiro ^{[14
]}

Yanai, Shunichi ^{[15
]}

Yoshihara, Takeo ^{[16
]}

Kakimoto, Kazuki ^{[17
]}

Matsuoka, Katsuyoshi ^{[18
]}

Hayashi, Ryohei ^{[19
]}

Nanjo, Sohachi ^{[20
]}

Iwama, Itaru ^{[21
]}

Ishiguro, Yoh ^{[22
]}

Chiba, Hirofumi ^{[23
]}

Endo, Katsuya ^{[24
]}

Kagaya, Takashi ^{[25
]}

Fukuda, Tomohiro ^{[26
]}

Sakata, Yasuhisa ^{[27
]}

Kudo, Takahiro ^{[28
]}

Takagi, Tomohisa ^{[29
]}

Takahashi, Kenichi ^{[30
]}

Naganuma, Makoto ^{[31
]}

Shinozaki, Masaru ^{[32
]}

Ogata, Noriyuki ^{[33
]}

Tanaka, Hiroki ^{[34
]}

Narimatsu, Kazuyuki ^{[35
]}

Miyazaki, Haruka ^{[36
]}

Ishige, Takashi ^{[37
]}

Onodera, Motoyuki ^{[38
]}

Hashimoto, Yu ^{[39
]}

Nagai, Hiroshi ^{[1
]}

Shimoyama, Yusuke ^{[1
]}

Naito, Takeo ^{[1
]}

Moroi, Rintaro ^{[1
]}

Shiga, Hisashi ^{[1
]}

Kinouchi, Yoshitaka ^{[40
]}

Andoh, Akira ^{[41
]}

Hisamatsu, Tadakazu ^{[6
]}

Masamune, Atsushi ^{[1
]}

机构：

[1] Tohoku Univ, Div Gastroenterol, Grad Sch Med, 1-1 Seiryo, Sendai 9808574, Japan

[2] Kyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Fukuoka, Japan

[3] Tokyo Med & Dent Univ, Dept Gastroenterol & Hepatol, Tokyo, Japan

[4] Hyogo Med Univ, Ctr Clin Res & Educ, Ctr Inflammatory Bowel Dis, Nishinomiya, Japan

[5] Gifu Univ, Grad Sch Med, Dept Gastroenterol, Gifu, Japan

[6] Kyorin Univ, Sch Med, Dept Gastroenterol & Hepatol, Tokyo, Japan

[7] Yamagata Univ, Fac Med, Dept Gastroenterol, Yamagata, Japan

[8] Kagawa Prefectural Cent Hosp, Dept Gastroenterol, Takamatsu, Japan

[9] Sapporo Med Univ, Dept Gastroenterol & Hepatol, Sch Med, Sapporo, Japan

[10] Keio Univ, Sch Med, Dept Internal Med, Div Gastroenterol & Hepatol, Tokyo, Japan

[11] Dokkyo Med Univ, Dept Gastroenterol, Tochigi, Japan

[12] Akita Univ, Dept Gastroenterol & Neurol, Akita 0108543, Japan

[13] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Gastroenterol & Hepatol, Okayama, Japan

[14] Asahikawa Med Univ Hosp, Div Gen Med, Asahikawa, Japan

[15] Iwate Med Univ, Dept Internal Med, Div Gastroenterol & Hepatol, Morioka, Japan

[16] Osaka Univ, Grad Sch Med, Dept Gastroenterol & Hepatol, Osaka, Japan

[17] Osaka Med & Pharmaceut Univ, Dept Internal Med 2, Osaka, Japan

[18] Toho Univ, Sakura Med Ctr, Dept Internal Med, Div Gastroenterol & Hepatol, Chiba, Japan

[19] Hiroshima Univ Hosp, Dept Gastroenterol, Hiroshima, Japan

[20] Univ Toyama, Grad Sch Med, Dept Internal Med 3, Toyama, Japan

[21] Saitama Childrens Med Ctr, Div Gastroenterol & Hepatol, Saitama, Japan

[22] Hirosaki Gen Med Ctr, Div Clin Res, NHO, Hirosaki, Japan

[23] Iwate Prefectural Isawa Hosp, Dept Gastroenterol, Oshu, Japan

[24] Tohoku Med & Pharmaceut Univ, Div Gastroenterol, Sch Med, Sendai, Japan

[25] NHO Kanazawa Med Ctr, Dept Gastroenterol, Kanazawa, Japan

[26] Kitasato Univ, Kitasato Inst Hosp, Ctr Adv IBD Res & Treatment, Tokyo, Japan

[27] Saga Univ, Fac Med, Dept Internal Med, Div Gastroenterol, Saga, Japan

[28] Juntendo Univ, Fac Med, Dept Pediat, Tokyo, Japan

[29] Kyoto Prefectural Univ Med, Dept Mol Gastroenterol & Hepatol, Kyoto, Japan

[30] Tohoku Rosai Hosp, Dept Colorectal Surg, Sendai, Japan

[31] Kansai Med Univ, Dept Internal Med 3, Hirakata, Japan

[32] Saitama Gastroenterol Clin, Saitama, Japan

[33] Showa Univ Northern Yokohama Hosp, Digest Dis Ctr, Yokohama, Japan

[34] Sapporo IBD Clin, Sapporo, Japan

[35] Natl Def Med Coll, Dept Internal Med, Tokorozawa, Japan

[36] Kobe Univ, Grad Sch Med, Dept Internal Med, Div Gastroenterol, Kobe, Japan

[37] Gunma Univ, Dept Pediat, Grad Sch Med, Maebashi, Japan

[38] Osaki Citizen Hosp, Osaki, Japan

[39] Gunma Univ, Grad Sch Med, Dept Gastroenterol & Hepatol, Maebashi, Japan

[40] Tohoku Univ, Inst Excellence Higher Educ, Student Healthcare Ctr, Sendai, Japan

[41] Shiga Univ Med Sci, Dept Med, Div Gastroenterol & Hematol, Otsu, Japan

来源：

JOURNAL OF GASTROENTEROLOGY | 2024年 / 59卷 / 06期

关键词：

NUDT15; Thiopurine; Azathioprine; 6-mercaptopurine; Adverse event; ULCERATIVE-COLITIS; INDUCED LEUKOPENIA; JAPANESE PATIENTS; VARIANTS; AZATHIOPRINE; 6-MERCAPTOPURINE; SUSCEPTIBILITY; PANCREATITIS; MECHANISM; THERAPY;

D O I：

10.1007/s00535-024-02099-7

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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.

引用

页码：468 / 482

页数：15

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