Long-term efficacy and tolerability of dose-adjusted thiopurine treatment in maintaining remission in inflammatory bowel disease patients with NUDT15 heterozygosity

Maeda, Takato; Sakuraba, Hirotake; Hiraga, Hiroto; Yoshida, Shukuko; Kakuta, Yoichi; Kikuchi, Hidezumi; Kawaguchi, Shogo; Hasui, Keisuke; Tatsuta, Tetsuya; Chinda, Daisuke; Mikami, Taisei; Fukuda, Shinsaku

doi:10.5217/ir.2020.00133

Cited by 10 publications

(5 citation statements)

References 25 publications

(79 reference statements)

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“…While this study could not directly assess treatment efficacy, the continuation rate may reflect treatment effectiveness to some extent. Moreover, reports have been published suggesting that a small dose of 6-MP in Arg/Cys cases is as effective as the standard dose in Arg/Arg cases [ 20 ]. Considering these findings, it appears preferable to initiate treatment for Arg/Cys patients with less than 25 mg, specifically 6-MP at 10 mg/day or AZA at 12.5 mg/day, in terms of both safety and dosage efficacy.…”

Section: Discussionmentioning

confidence: 99%

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

Makuuchi,

Kakuta,

Umeno

et al. 2024

J Gastroenterol

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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.

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Section: Discussionmentioning

confidence: 99%

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

Makuuchi,

Kakuta,

Umeno

et al. 2024

J Gastroenterol

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“…Studies of SNPs in NUDT15 and thiopurine administration have mainly been concerned with short-term follow-up, especially in relation to side effects [8,19]. On the other hand, the association between NUDT15 SNPs and clinical features of IBD has not been reported.…”

Section: Factors Involved In Hospitalization and Surgerymentioning

confidence: 99%

Influence of NUDT15 Genotyping on Dose Intensity of Thiopurine Administration and Long-Term Clinical Outcomes (Hospitalization and Surgery)

Tsunoda,

Kojima,

Hirotsu

et al. 2024

Arch Clin Biomed Res

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BackgroundThiopurines are one of the major drugs for treatment of in ammatory bowel disease. It is well known that SNPs in TPMT are the main cause of leucopenia and hair loss in European descent. In Asian individuals, the SNP p.Arg139Cys in exon 3 of NUDT15 is associated with leucopenia and hair loss. Previously, we demonstrated that thiopurine-induced leucopenia is related not only to exon 3 but also exon 1 SNPs in a cohort followed for a short term. The aim of this study was to evaluate the long-term effects of NUDT15 on clinical outcomes. MethodsPatients (ulcerative colitis130 cases, Crohn's disease 55 cases) were divided into mutation and wild-type NUDT15 groups, and the daily dosage of thiopurines and the effect of mutation on hospitalization and surgery were retrospectively investigated over a long period of up to 10 years (median, 7.8 years). ResultsRegarding TPMT SNPs, p. Pro80Ala, p. Thy154Ala and p. Tyr240Cys were not detected, and all genes were wild-type. Compared to the NUDT15 mutation group (n = 48), the daily thiopurine dosage was increased in the wild-type group (n = 137) (p = 0.024). The time to dose reduction and discontinuation of thiopurines was signi cantly shorter in the NUDT15 mutation group (p < 0.001, p = 0.039). The NUDT15 mutation group tended to have more hospitalizations (p = 0.067), and surgeries were signi cantly more frequent (p = 0.028). In ulcerative colitis patients, thiopurine discontinuation was associated with hospitalization and surgery (p = 0.003, HR 2.87, 95% CI 1. p = 0.036, HR 5.45,).

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“…In East Asian countries, nudix hydrolase 15 ( NUDT15 ) gene variants (T/T genotype) are more frequent than TPMT gene variants and they more accurately predict severe thiopurine-related leukopenia [ 70 ]. Blood tests for full blood counts, renal, and liver biochemistry, TDM of thiopurines, and genotyping of NUDT15 and TPMT in routine practice could improve the efficacy and safety of IBD patients [ 71 , 72 ]. In particular, genotyping NUDT15 is essential, and if it is not available, close monitoring should be performed with a complete blood count test at intervals of 1 to 2 weeks for the first 4 weeks.…”

Section: Immunomodulatorsmentioning

confidence: 99%

Updates on conventional therapies for inflammatory bowel diseases: 5-aminosalicylates, corticosteroids, immunomodulators, and anti-TNF-α

Park

Cheon

2022

Korean J Intern Med

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The incidence and prevalence of inflammatory bowel diseases (IBDs) are rapidly increasing worldwide. IBDs are considered an emerging problem not only in Western countries but also in developing counties. The relapses and complications of active IBD mandate various medications. Nevertheless, hospitalization, emergency room visits, or surgery may be required, resulting in a socioeconomic burden. Great advances have been made in the development of new therapeutic options for IBD to achieve induction and maintenance remission. Nevertheless, conventional therapy is still the mainstay in the treatment of IBD. This review article provides an update on recent advances in conventional therapies, including 5-aminosalicylates, corticosteroids, immunomodulators, and anti-tumor necrosis factor-α agents to treat IBD.

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Long-term efficacy and tolerability of dose-adjusted thiopurine treatment in maintaining remission in inflammatory bowel disease patients with NUDT15 heterozygosity

Cited by 10 publications

References 25 publications

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

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

Influence of NUDT15 Genotyping on Dose Intensity of Thiopurine Administration and Long-Term Clinical Outcomes (Hospitalization and Surgery)

Updates on conventional therapies for inflammatory bowel diseases: 5-aminosalicylates, corticosteroids, immunomodulators, and anti-TNF-α

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