Intestinal Research

Original Articles

Endoscopic radial incision and cutting using balloonassisted enteroscopy for small intestinal stenosis related to Crohn’s disease: a pilot study: Rintaro Moroi, Kotaro Nochioka, Satoshi Miyata, Hideya Iwaki, Hirofumi Chiba, Hiroshi Nagai, Yusuke Shimoyama, Takeo Naito, Hisashi Shiga, Masaki Tosa, Yoichi Kakuta, Shoichi Kayaba, Seiichi Takahashi, Yoshitaka Kinouchi, Atsushi Masamune; Received September 11, 2024 Accepted October 24, 2024 Published online January 21, 2025; DOI: https://doi.org/10.5217/ir.2024.00143 [Epub ahead of print]

Abstract PDF Supplementary Material PubReader ePub: Background/Aims
Radial incision and cutting (RIC) is an alternative dilation method for stenosis of the lower gastrointestinal tract. However, its safety and efficacy for the small intestine requiring balloon-assisted enteroscopy (BAE) remain limited. Therefore, this pilot study aimed to evaluate the safety and efficacy of RIC using BAE.
Methods
We included 10 patients with Crohn’s disease and performed 12 sessions of RIC for 10 lesions. The rate of adverse events 1 month after RIC was the primary outcome, whereas short- and long-term prognoses and improvements in subjective symptoms that were evaluated using a visual analog scale were the secondary outcomes.
Results
The technical success rate for RIC, defined as scope passage immediately following the procedure, was 100% (12/12). The rates of delayed bleeding and perforation were 0% (0/12). One patient developed restenosis because of the worsening of Crohn’s disease and underwent surgery 2 months after RIC. The cumulative restenosis-, reintervention-, and surgery-free rates at 1 year after RIC were 67.5%, 78.7%, and 90.0%, respectively. Abdominal pain, abdominal bloating, nausea, and difficulties in defecation significantly improved 4 weeks after RIC.
Conclusions
RIC for small intestine using BAE has the potential to be safe and effective for relieving symptoms (jRCT identifier jRCTs022200040).

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IBD

Live-attenuated vaccination in patients with inflammatory bowel disease while continuing or after elective switch to vedolizumab: Hisashi Shiga, Hiroshi Nagai, Yusuke Shimoyama, Takeo Naito, Rintaro Moroi, Yoichi Kakuta, Yoshitaka Kinouchi, Atsushi Masamune; Intest Res 2024;22(3):378-386. Published online March 26, 2024; DOI: https://doi.org/10.5217/ir.2023.00203

Abstract PDF PubReader ePub

Background/Aims
Vedolizumab (VDZ) is a gut-selective agent with a favorable safety profile. We aimed to assess the feasibility of elective switch from other advanced therapies to VDZ and subsequent live-attenuated vaccination while continuing VDZ in patients with inflammatory bowel diseases (IBD).
Methods
We measured antibody titers specific for measles, rubella, mumps, and varicella viruses in IBD patients under immunosuppressive therapy. Those with negative titers and without vaccination history were judged unimmunized. Patients were administered vaccines while continuing VDZ or switched to VDZ if receiving other advanced therapies and then administered vaccines. Co-primary outcomes were the rate of maintaining disease severity after vaccination and the rate without vaccine-induced infection.
Results
Among 107 unimmunized patients, 37 agreed to receive live-attenuated vaccines while continuing VDZ (17 patients) or after switching to VDZ (20 patients). In the 20 patients who electively switched to VDZ, disease severity was maintained except for 1 patient who developed intestinal infection. After 54 weeks, 18 patients (90%) continued to receive VDZ, excluding 2 patients who reverted to their originally administered biologics. In all 37 patients administered live-attenuated vaccines under VDZ treatment, disease severity was maintained after vaccination. Antibody titers became positive or equivocal in 34 patients (91.9%). There were no cases of vaccine-induced infection during a median observation period of 121 weeks.
Conclusions
While live-attenuated vaccines are contraindicated under immunosuppressive therapy, they may be safely administered while receiving VDZ immunotherapy. Switching from other advanced therapies to VDZ and subsequently receiving live-attenuated vaccines may be a safe alternative in unimmunized patients.

Citations

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Live Typhoid and Yellow Fever Vaccines Administered to a Patient With Ulcerative Colitis on Vedolizumab
Yash Hegde, Mary S. Hayney, Freddy Caldera
ACG Case Reports Journal.2024; 11(10): e01507. CrossRef

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IBD

Long-term efficacy and tolerability of dose-adjusted thiopurine treatment in maintaining remission in inflammatory bowel disease patients with NUDT15 heterozygosity: Takato Maeda, Hirotake Sakuraba, Hiroto Hiraga, Shukuko Yoshida, Yoichi Kakuta, Hidezumi Kikuchi, Shogo Kawaguchi, Keisuke Hasui, Tetsuya Tatsuta, Daisuke Chinda, Tatsuya Mikami, Shinsaku Fukuda; Intest Res 2022;20(1):90-100. Published online January 22, 2021; DOI: https://doi.org/10.5217/ir.2020.00133

Abstract PDF Supplementary Material PubReader ePub

Background/Aims
Thiopurines are key drugs for inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD). Recently, NUDT15 polymorphism (R139C, c.415C > T) has been shown to be associated with thiopurineinduced adverse events in Asian populations. In patients with the C/T genotype, low-dose thiopurine treatment is recommended, but its long-term efficacy and tolerability remain unclear. This study aimed to uncover the long-term efficacy and appropriate dosage of thiopurine for IBD patients with the C/T genotype.
Methods
A total of 210 patients with IBD (103 UC and 107 CD) determined to have NUDT15 R139C variants were enrolled. Clinical data were retrospectively reviewed from medical records.
Results
Of 46 patients (21.9%) with the C/T genotype, 30 patients (65.2%) were treated with thiopurines. Three of whom (10.0%) discontinued thiopurine treatment due to adverse events and 27 of whom continued. The median maintenance dosage of 6-mercaptopurine was 0.25 mg/kg/day (range, 0.19–0.36 mg/kg/day), and 6-thioguanine nucleotides level was 230 (104–298) pmol/8 × 10⁸ red blood cells. Cumulative thiopurine continuation rates for 120 months for patients with the C/C and C/T genotypes were not significantly different (P= 0.895). Cumulative non-relapse rates in the patients with UC treated with thiopurine monotherapy and surgery-free rates in CD patients treated with combination therapy (thiopurines and anti-tumor necrosis factor-α agents) for maintenance remission were not significantly different at 60 months (C/C vs. C/T, P= 0.339 and P= 0.422, respectively).
Conclusions
Low-dose thiopurine treatment is an effective and acceptable treatment for patients with C/T genotype.

Citations

Citations to this article as recorded by

Effectiveness and Tolerability of Methotrexate Combined with Biologics in Patients with Crohn’s Disease: A Multicenter Observational Study
Jihye Park, Jaeyoung Chun, Soo Jung Park, Jae Jun Park, Tae Il Kim, Hyuk Yoon, Jae Hee Cheon
Digestive Diseases and Sciences.2024; 69(3): 901. CrossRef
New genetic biomarkers predicting 5-aminosalicylate-induced adverse events in patients with inflammatory bowel diseases
Jihye Park, I. Seul Park, Ji Hyung Kim, Jung Hyun Ji, Soo Jung Park, Jae Jun Park, Tae Il Kim, Seung Won Kim, Jae Hee Cheon
Therapeutic Advances in Gastroenterology.2024;[Epub] CrossRef
Efficacy of optimised thiopurine therapy in patients with moderate-to-severe ulcerative colitis: retrospective long-term follow-up from two randomised trials
Anette Mertz Nielsen, Klaus Theede, Lise Lotte Gluud, Marianne Kiszka-Kanowitz
Scandinavian Journal of Gastroenterology.2024; 59(6): 669. CrossRef
Real-world NUDT15 genotyping and thiopurine treatment optimization in inflammatory bowel disease: a multicenter study
Motoki Makuuchi, Yoichi Kakuta, Junji Umeno, Toshimitsu Fujii, Tetsuya Takagawa, Takashi Ibuka, Miki Miura, Yu Sasaki, Sakuma Takahashi, Hiroshi Nakase, Hiroki Kiyohara, Keiichi Tominaga, Yosuke Shimodaira, Sakiko Hiraoka, Nobuhiro Ueno, Shunichi Yanai, T
Journal of Gastroenterology.2024; 59(6): 468. CrossRef
A systematic review of aspects of NUDT15 pharmacogenomic variants and thiopurine-induced myelosuppression
Rachel Palmer, Jaime Peters
RPS Pharmacy and Pharmacology Reports.2024;[Epub] CrossRef
Updates on conventional therapies for inflammatory bowel diseases: 5-aminosalicylates, corticosteroids, immunomodulators, and anti-TNF-α
Jihye Park, Jae Hee Cheon
The Korean Journal of Internal Medicine.2022; 37(5): 895. CrossRef
Risk factors and prognostic value of acute severe lower gastrointestinal bleeding in Crohn’s disease
Jiyoung Yoon, Dae Sung Kim, Ye-Jee Kim, Jin Wook Lee, Seung Wook Hong, Ha Won Hwang, Sung Wook Hwang, Sang Hyoung Park, Dong-Hoon Yang, Byong Duk Ye, Jeong-Sik Byeon, Seung-Jae Myung, Suk-Kyun Yang
World Journal of Gastroenterology.2021; 27(19): 2353. CrossRef
Importance of NUDT15 Polymorphisms in Thiopurine Treatments
Yoichi Tanaka, Yoshiro Saito
Journal of Personalized Medicine.2021; 11(8): 778. CrossRef

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IBD

Long-term prognosis of Japanese patients with biologic-naïve Crohn’s disease treated with anti-tumor necrosis factor-α antibodies: Rintaro Moroi, Katsuya Endo, Katsutoshi Yamamoto, Takeo Naito, Motoyuki Onodera, Masatake Kuroha, Yoshitake Kanazawa, Tomoya Kimura, Yoichi Kakuta, Atsushi Masamune, Yoshitaka Kinouchi, Tooru Shimosegawa; Intest Res 2019;17(1):94-106. Published online December 3, 2018; DOI: https://doi.org/10.5217/ir.2018.00048

Abstract PDF Supplementary Material PubReader ePub

Background/Aims
Few reports have described the long-term treatment outcomes of the anti-tumor necrosis factor-α antibody for Japanese Crohn’s disease (CD) patients. The aim of this study was to evaluate them and clarify the clinical factors that affect the long-term prognosis of the anti-tumor necrosis factor-α treatments.
Methods
This was a retrospective, observational, single-center cohort study. Japanese CD patients treated with either infliximab or adalimumab as a first-line therapy were analyzed. The cumulative retention rates of the biologics, relapse-free survival, and surgery-free survival were analyzed using Kaplan-Meier methods. The clinical factors associated with the long-term outcomes were estimated by both the log-rank test and Cox proportional hazard model.
Results
The cumulative retention rate was significantly higher in the group with a concomitant elemental diet of ≥900 kcal/day, baseline C-reactive protein (CRP) levels <2.6 mg/dL, and baseline serum albumin levels ≥3.5 g/dL, respectively. The baseline serum albumin levels were also associated with both relapse-free and surgery-free survival. The lack of concomitant use of an elemental diet ≥900 kcal/day was identified as the only independent risk factor for the withdrawal of the biologics.
Conclusions
Baseline CRP levels and serum albumin levels could affect the long-term outcomes in CD patients. Concomitant elemental diet of ≥900 kcal/day could have a positive influence on clinical treatment course.

Citations

Citations to this article as recorded by

Nutrition, Nutritional Status, Micronutrients Deficiency, and Disease Course of Inflammatory Bowel Disease
Marco Valvano, Annalisa Capannolo, Nicola Cesaro, Gianpiero Stefanelli, Stefano Fabiani, Sara Frassino, Sabrina Monaco, Marco Magistroni, Angelo Viscido, Giovanni Latella
Nutrients.2023; 15(17): 3824. CrossRef
Long-term clinical and real-world experience with Crohn’s disease treated with anti-tumor necrosis factor-α antibodies
Haruka Otake, Satohiro Matsumoto, Hirosato Mashima
Intestinal Research.2022; 20(4): 464. CrossRef
Natural history of inflammatory bowel disease: a comparison between the East and the West
Eun Mi Song, Suk-Kyun Yang
Intestinal Research.2022; 20(4): 418. CrossRef
Treatment of inflammatory bowel diseases: focusing on biologic agents and new therapies
Hyo Yeop Song, Geom Seog Seo
Journal of the Korean Medical Association.2021; 64(9): 605. CrossRef
C-reactive protein is associated with postoperative outcomes in patients with intestinal Behçet’s disease
Eun Ae Kang, Jung Won Park, Yehyun Park, Soo Jung Park, Tae Il Kim, Won Ho Kim, Min Soo Cho, Jae Hee Cheon
BMC Gastroenterology.2021;[Epub] CrossRef
Pharmacogenetics-based personalized treatment in patients with inflammatory bowel disease: A review
Ji Young Chang, Jae Hee Cheon
Precision and Future Medicine.2021; 5(4): 151. CrossRef
Efficacy of enteral nutrition in patients with Crohn’s disease on maintenance anti-TNF-alpha antibody therapy: a meta-analysis
Fumihito Hirai, Teruyuki Takeda, Yasumichi Takada, Masahiro Kishi, Tsuyoshi Beppu, Noritaka Takatsu, Masaki Miyaoka, Takashi Hisabe, Kenshi Yao, Tosiharu Ueki
Journal of Gastroenterology.2020; 55(2): 133. CrossRef
TL1A (TNFSF15) genotype affects the long‐term therapeutic outcomes of anti‐TNFα antibodies for Crohn's disease patients
Katsuya Endo, Yoichi Kakuta, Rintaro Moroi, Katsutoshi Yamamoto, Hisashi Shiga, Masatake Kuroha, Takeo Naito, Yoshitaka Kinouchi, Atsushi Masamune
JGH Open.2020; 4(6): 1108. CrossRef

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NUDT15, FTO, and RUNX1 genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases: Toshiyuki Sato, Tetsuya Takagawa, Yoichi Kakuta, Akihiro Nishio, Mikio Kawai, Koji Kamikozuru, Yoko Yokoyama, Yuko Kita, Takako Miyazaki, Masaki Iimuro, Nobuyuki Hida, Kazutoshi Hori, Hiroki Ikeuchi, Shiro Nakamura; Intest Res 2017;15(3):328-337. Published online June 12, 2017; DOI: https://doi.org/10.5217/ir.2017.15.3.328

Abstract PDF PubReader ePub

<b>Background/Aims</b><br/>

Recent genome-wide analyses have provided strong evidence concerning adverse events caused by thiopurine drugs such as azathioprine (AZA) and 6-mercaptopurine. The strong associations identified between NUDT15 p.Arg139Cys and thiopurine-induced leukopenia and severe hair loss have been studied and confirmed over the last 2 years. However, other coding variants, including NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, and FTO p.Ala134Thr, and a noncoding variation in RUNX1 (rs2834826) remain to be examined in detail in this respect. Therefore, we investigated the correlation between these adverse events and the 5 recently identified variants mentioned above among Japanese patients with inflammatory bowel diseases (IBD).

Methods

One hundred sixty thiopurine-treated patients with IBD were enrolled. Genotyping was performed using TaqMan SNP Genotyping Assays or Sanger sequencing.

Results

None of the 5 variants were associated with gastrointestinal intolerance to AZA. However, NUDT15 p.Arg139Cys was significantly associated with the interval between initiation and discontinuation of AZA among patients with gastrointestinal intolerance. This variant was strongly associated with early (<8 weeks) and late (≥8 weeks) leukopenia and severe hair loss. Moreover, it correlated with the interval between initiation of thiopurine therapy and leukopenia occurrence, and average thiopurine dose. NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, FTO p.Ala134Thr, and RUNX1 rs2834826 exhibited no significant relationship with the adverse events examined.

Conclusions

Of the 5 variants investigated, NUDT15 p.Arg139Cys had the strongest impact on thiopurine-induced leukopenia and severe hair loss; therefore, its genotyping should be prioritized over that of other variants in efforts to predict these adverse events in Japanese patients with IBD.

Citations

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A case of rapidly progressive hair loss due to azathioprine, and the prevalence of NUDT15 variants among Japanese patients with autoimmune blistering diseases: A single‐center retrospective observational study
Sho Katayama, Kentaro Izumi, Inkin Ujiie, Hideyuki Ujiie
The Journal of Dermatology.2025; 52(2): 363. CrossRef
Real-world NUDT15 genotyping and thiopurine treatment optimization in inflammatory bowel disease: a multicenter study
Motoki Makuuchi, Yoichi Kakuta, Junji Umeno, Toshimitsu Fujii, Tetsuya Takagawa, Takashi Ibuka, Miki Miura, Yu Sasaki, Sakuma Takahashi, Hiroshi Nakase, Hiroki Kiyohara, Keiichi Tominaga, Yosuke Shimodaira, Sakiko Hiraoka, Nobuhiro Ueno, Shunichi Yanai, T
Journal of Gastroenterology.2024; 59(6): 468. CrossRef
Differences in the risk of clinical failure between thiopurine and methotrexate in bio-naïve patients with Crohn’s disease: a Korean nationwide population-based study
Yu Kyung Jun, Eunjeong Ji, Hye Ran Yang, Yonghoon Choi, Cheol Min Shin, Young Soo Park, Nayoung Kim, Dong Ho Lee, Hyuk Yoon
Therapeutic Advances in Gastroenterology.2024;[Epub] CrossRef
A systematic review of aspects of NUDT15 pharmacogenomic variants and thiopurine-induced myelosuppression
Rachel Palmer, Jaime Peters
RPS Pharmacy and Pharmacology Reports.2024;[Epub] CrossRef
m6A modification in inflammatory bowel disease provides new insights into clinical applications
Jiamin Zhang, Bimei Song, Yue Zeng, Chao Xu, Liang Gao, Yan Guo, Jingbo Liu
Biomedicine & Pharmacotherapy.2023; 159: 114298. CrossRef
Targeting FTO by Dac51 contributes to attenuating DSS-induced colitis
Chunyan Peng, Chang Zheng, Fan Zhou, Ying Xie, Lei Wang, Deyan Chen, Xiaoqi Zhang
International Immunopharmacology.2023; 116: 109789. CrossRef
Single-Nucleotide Polymorphisms, c.415C > T (Arg139Cys) and c.416G > A (Arg139His), in the NUDT15 Gene Are Associated with Thiopurine-Induced Leukopenia
Tetsuichiro Isono, Daiki Hira, Yoshito Ikeda, Masahiro Kawahara, Satoshi Noda, Atsushi Nishida, Osamu Inatomi, Noriki Fujimoto, Akira Andoh, Tomohiro Terada, Shin-ya Morita
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Evaluation of FTO polymorphism in 6-mercaptopurine related intolerance in children with acute lymphoblastic leukemia
Minu Singh, Divya Bhaskar, Prateek Bhatia, Rozy Thakur, Pankaj Sharma, Deepak Bansal, Richa Jain, Amita Trehan
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Time to incorporate preemptive NUDT15 testing before starting thiopurines in inflammatory bowel disease in Asia and beyond: a review
Devendra Desai, Anuraag Jena, Vishal Sharma, Toshifumi Hibi
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Anuraag Jena, Chhagan L Birda, Arup Choudhury, Vishal Sharma
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V. Janakiraman, M. Sudhan, Khalaf F. Alsharif, Ibrahim F. Halawani, Shiek S.S.J. Ahmed, Shankargouda Patil
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Importance of NUDT15 Polymorphisms in Thiopurine Treatments
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Randomised clinical trial: dose optimising strategy by NUDT15 genotyping reduces leucopenia during thiopurine treatment of Crohn's disease
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Yoichi Kakuta, Yoshitaka Kinouchi, Tooru Shimosegawa
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NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study
Yoichi Kakuta, Yosuke Kawai, Daisuke Okamoto, Tetsuya Takagawa, Kentaro Ikeya, Hirotake Sakuraba, Atsushi Nishida, Shoko Nakagawa, Miki Miura, Takahiko Toyonaga, Kei Onodera, Masaru Shinozaki, Yoh Ishiguro, Shinta Mizuno, Masahiro Takahara, Shunichi Yanai
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Mari Kishibe, Hiroyoshi Nozaki, Mizue Fujii, Shin Iinuma, Sawa Ohtsubo, Satomi Igawa, Kyoko Kanno, Masaru Honma, Kan Kishibe, Kensaku Okamoto, Akemi Ishida‐Yamamoto
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Diagnostic accuracy of NUDT15 gene variants for thiopurine-induced leukopenia: a systematic review and meta-analysis
Sarah Cargnin, Armando A. Genazzani, Pier Luigi Canonico, Salvatore Terrazzino
Pharmacological Research.2018; 135: 102. CrossRef
A single‐center experience with methotrexate in the treatment of Chinese Crohn’s disease patients
Tian Rong Wang, Yu Qi Qiao, Duo Wu Zou, Zhi Hua Ran
Journal of Digestive Diseases.2018; 19(12): 753. CrossRef

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