Intestinal Research

Original Articles

IBD

Real-world data for golimumab treatment in patients with ulcerative colitis in Japan: interim analysis in post-marketing surveillance: Shiro Nakamura, Teita Asano, Hiroaki Tsuchiya, Kanami Sugimoto, Yuya Imai, Seiji Yokoyama, Yasuo Suzuki; Intest Res 2022;20(3):329-341. Published online August 4, 2021; DOI: https://doi.org/10.5217/ir.2021.00032

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Background/Aims
Golimumab (GLM) is an anti-tumor necrosis factor-α drug approved for treating moderate-to-severe active ulcerative colitis (UC). A 52-week post-marketing surveillance (PMS) was initiated to evaluate its safety and effectiveness in patients with UC in Japan. We present an interim report of the ongoing PMS.
Methods
Patients received 200 mg of subcutaneous GLM at week 0, 100 mg at week 2, and 100 mg 4 weekly thereafter. The safety analysis set included 392 patients with UC, and the effectiveness analysis set 387 patients. Safety and effectiveness were assessed at week 6.
Results
Adverse drug reactions (ADRs) were reported in 8.2% (32/392) and serious ADRs in 4.6% (18/392). The most frequent ADRs were infection and infestation (3.3%), with herpes zoster being the most common. ADRs were significantly higher in patients with concomitant corticosteroid use (odds ratio [OR], 3.45; 95% confidence interval [CI], 1.40–9.68). No significant difference in ADR incidence was observed between patients aged ≥65 and <65 years (OR, 1.23; 95% CI, 0.35–3.47). Six-week effectiveness of GLM was confirmed by a decrease in the partial Mayo score (–2.3; 95% CI, –2.6 to –2.1) and C-reactive protein levels (–0.64; 95% CI, –0.92 to –0.36), including in the biologics-experienced population.
Conclusions
The safety and effectiveness of GLM at week 6 in a real-world setting were demonstrated in patients with UC in Japan. ADR patterns were consistent with previous reports with no new safety signals. Concomitant corticosteroid use may be associated with increased ADR incidence. The final results of the ongoing PMS are necessary for further evaluation.

Citations

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Real-world effectiveness and safety of advanced therapies for the treatment of moderate-to-severe ulcerative colitis: Evidence from a systematic literature review
Peter M. Irving, Peter Hur, Raju Gautam, Xiang Guo, Severine Vermeire
Journal of Managed Care & Specialty Pharmacy.2024; 30(9): 1026. CrossRef
Reviewing not Homer’s Iliad, but “Kai Bao Ben Cao”: indigo dye—the past, present, and future
Yusuke Yoshimatsu, Tomohisa Sujino, Takanori Kanai
Intestinal Research.2023; 21(2): 174. CrossRef
Golimumab for Ulcerative Colitis: One More Option to SAVE the Colon
Sang Hyoung Park
Crohn's & Colitis 360.2023;[Epub] CrossRef
Advancements in the Management of Moderate-to-Severe Ulcerative Colitis: A Revised 2023 Korean Treatment Guidelines
Soo-Young Na
The Korean Journal of Medicine.2023; 98(5): 223. 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

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Inflammatory bowel diseases

Efficacy and safety of abrilumab, an α4β7 integrin inhibitor, in Japanese patients with moderate-to-severe ulcerative colitis: a phase II study: Toshifumi Hibi, Satoshi Motoya, Toshifumi Ashida, Souken Sai, Yukinori Sameshima, Shiro Nakamura, Atsuo Maemoto, Masahiro Nii, Barbara A Sullivan, Robert A. Gasser Jr, Yasuo Suzuki; Intest Res 2019;17(3):375-386. Published online February 12, 2019; DOI: https://doi.org/10.5217/ir.2018.00141

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Background/Aims
Inhibition of α4β7 integrin has been shown to be effective for induction and maintenance therapy in patients with ulcerative colitis (UC). We investigated the effects of varying doses of the α4β7 inhibitor abrilumab in Japanese patients with moderate-to-severe UC despite conventional treatments.
Methods
In this randomized, double-blind, placebocontrolled study, 45 UC patients were randomized to abrilumab 21 mg (n=11), 70 mg (n=12), 210 mg (n=9), or placebo (n=13) via subcutaneous (SC) injection for 12 weeks. The double-blind period was followed by a 36-week open-label period, in which all patients received abrilumab 210 mg SC every 12 weeks, and a 28-week safety follow-up period. The primary efficacy variable was clinical remission at week 8 (total Mayo score ≤2 points with no individual subscore >1 point).
Results
Clinical remission at week 8 was 4 out of 31 (12.9%) overall in the abrilumab groups versus 0 out of 13 in the placebo group (abrilumab 21 mg, 1/10 [10.0%]; 70 mg, 2/12 [16.7%]; 210 mg, 1/9 [11.1%]). In both the double-blind and open-label periods, fewer patients in the abrilumab groups experienced ≥1 adverse event compared with those in the placebo group. There were no cases of progressive multifocal leukoencephalopathy and no deaths.
Conclusions
Abrilumab 70 mg and 210 mg yielded numerically better results in terms of clinical remission rate at Week 8 than placebo, with the 210 mg dose showing more consistent treatment effects. Abrilumab was well tolerated in Japanese patients with UC.

Citations

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Paradigm Shift in Inflammatory Bowel Disease Management: Precision Medicine, Artificial Intelligence, and Emerging Therapies
Antonio M. Caballero Mateos, Guillermo A. Cañadas de la Fuente, Beatriz Gros
Journal of Clinical Medicine.2025; 14(5): 1536. CrossRef
Biosimilars versus biological therapy in inflammatory bowel disease: challenges and targeting strategies using drug delivery systems
Ahmed Aljabri, Ghareb M. Soliman, Yasmin N. Ramadan, Mohammed A. Medhat, Helal F. Hetta
Clinical and Experimental Medicine.2025;[Epub] CrossRef
Development of New Molecularly Targeted Agents in Inflammatory Bowel Disease
Hiroshi Nakase
Internal Medicine.2025;[Epub] CrossRef
Drug-Induced Progressive Multifocal Leukoencephalopathy (PML): A Systematic Review and Meta-Analysis
Lorenzo Vittorio Rindi, Drieda Zaçe, Neva Braccialarghe, Barbara Massa, Virginia Barchi, Roberta Iannazzo, Ilenia Fato, Francesco De Maria, Dimitra Kontogiannis, Vincenzo Malagnino, Loredana Sarmati, Marco Iannetta
Drug Safety.2024; 47(4): 333. CrossRef
Targeting integrin pathways: mechanisms and advances in therapy
Xiaocong Pang, Xu He, Zhiwei Qiu, Hanxu Zhang, Ran Xie, Zhiyan Liu, Yanlun Gu, Nan Zhao, Qian Xiang, Yimin Cui
Signal Transduction and Targeted Therapy.2023;[Epub] CrossRef
Emerging drugs for the treatment of moderately to severely active ulcerative colitis: review of phase II and III clinical trials
Laura Neurath, Ferdinando D’Amico, Silvio Danese
Expert Opinion on Emerging Drugs.2023; 28(1): 27. CrossRef
Inflammatory Bowel Disease: Emerging Therapies and Future Treatment Strategies
Elisabetta Bretto, Davide Giuseppe Ribaldone, Gian Paolo Caviglia, Giorgio Maria Saracco, Elisabetta Bugianesi, Simone Frara
Biomedicines.2023; 11(8): 2249. CrossRef
Integrin signaling in cancer: bidirectional mechanisms and therapeutic opportunities
Siyi Li, Chibuzo Sampson, Changhao Liu, Hai-long Piao, Hong-Xu Liu
Cell Communication and Signaling.2023;[Epub] CrossRef
Immunology of Inflammatory Bowel Disease: Molecular Mechanisms and Therapeutics
Quan Lu, Mei-feng Yang, Yu-jie Liang, Jing Xu, Hao-ming Xu, Yu-qiang Nie, Li-sheng Wang, Jun Yao, De-feng Li
Journal of Inflammation Research.2022; Volume 15: 1825. CrossRef
Factors predicting clinical and endoscopic remission with placebo therapy in East Asian patients with ulcerative colitis: a systematic review and meta-analysis
Jian Zeng, Zhong Wang, Xiao-Jun Yang
European Journal of Clinical Pharmacology.2022; 78(7): 1069. CrossRef
Tackling Inflammatory Bowel Diseases: Targeting Proinflammatory Cytokines and Lymphocyte Homing
Yijie Song, Man Yuan, Yu Xu, Hongxi Xu
Pharmaceuticals.2022; 15(9): 1080. CrossRef
Targeting Immune Cell Trafficking – Insights From Research Models and Implications for Future IBD Therapy
Maximilian Wiendl, Emily Becker, Tanja M. Müller, Caroline J. Voskens, Markus F. Neurath, Sebastian Zundler
Frontiers in Immunology.2021;[Epub] CrossRef
Anti-Integrins for the Treatment of Inflammatory Bowel Disease: Current Evidence and Perspectives
John Gubatan, Kian Keyashian, Samuel JS Rubin, Jenny Wang, Cyrus Buckman, Sidhartha Sinha
Clinical and Experimental Gastroenterology.2021; Volume 14: 333. CrossRef
Anti-integrin drugs in clinical trials for inflammatory bowel disease (IBD): insights into promising agents
Virginia Solitano, Tommaso Lorenzo Parigi, Elisa Ragaini, Silvio Danese
Expert Opinion on Investigational Drugs.2021; 30(10): 1037. CrossRef
Efficacy and safety of a new vedolizumab subcutaneous formulation in Japanese patients with moderately to severely active ulcerative colitis
Taku Kobayashi, Hiroaki Ito, Toshifumi Ashida, Tadashi Yokoyama, Masakazu Nagahori, Tomoki Inaba, Mitsuhiro Shikamura, Takayoshi Yamaguchi, Tetsuharu Hori, Philippe Pinton, Mamoru Watanabe, Toshifumi Hibi
Intestinal Research.2021; 19(4): 448. CrossRef
Emerging therapeutic options in inflammatory bowel disease
Jesus K Yamamoto-Furusho, Norma N Parra-Holguín
World Journal of Gastroenterology.2021; 27(48): 8242. CrossRef
Subcutaneous integrin inhibitors may provide more treatment options for patients with moderate-to-severe ulcerative colitis
Hyuk Yoon
Intestinal Research.2019; 17(3): 283. CrossRef

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IBD

Usefulness of fecal calprotectin by monoclonal antibody testing in adult Japanese with inflammatory bowel diseases: a prospective multicenter study: Shiro Nakamura, Hirotsugu Imaeda, Hiroki Nishikawa, Masaki Iimuro, Minoru Matsuura, Hideo Oka, Junsuke Oku, Takako Miyazaki, Hirohito Honda, Kenji Watanabe, Hiroshi Nakase, Akira Andoh; Intest Res 2018;16(4):554-562. Published online October 10, 2018; DOI: https://doi.org/10.5217/ir.2018.00027

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Background/Aims
Noninvasive objective monitoring is advantageous for optimizing treatment strategies in patients inflammatory bowel disease (IBD). Fecal calprotectin (FCP) is superior to traditional biomarkers in terms of assessing the activity in patients with IBD. However, there are the differences among several FCP assays in the dynamics of FCP. In this prospective multicenter trial, we investigated the usefulness of fecal FCP measurements in adult Japanese patients with IBD by reliable enzyme immunoassay using a monoclonal antibody.
Methods
We assessed the relationship between FCP levels and disease or endoscopic activity in patients with ulcerative colitis (UC, n=64) or Crohn’s disease (CD, n=46) compared with healthy controls (HCs, n=64).
Results
FCP levels in UC patients strongly correlated with the Disease Activity Index (rs=0.676, P<0.0001) and Mayo endoscopic subscore (MES; rs=0.677, P<0.0001). FCP levels were significantly higher even in patients with inactive UC or CD compared with HCs (P=0.0068, P<0.0001). The optimal cutoff value between MES 1 and 2 exhibited higher sensitivity (94.1%). FCP levels were significantly higher in active UC patients than in inactive patients (P<0.001), except those with proctitis. The Crohn’s Disease Activity Index tended to correlate with the FCP level (rs=0.283, P=0.0565).
Conclusions
Our testing method using a monoclonal antibody for FCP was well-validated and differentiated IBD patients from HCs. FCP may be a useful biomarker for objective assessment of disease activity in adult Japanese IBD patients, especially those with UC.

Citations

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Journal of Gastroenterology.2023; 58(4): 313. CrossRef
Mucosal concentrations of N‐acetyl‐5‐aminosalicylic acid related to endoscopic activity in ulcerative colitis patients with mesalamine
Tomohiro Fukuda, Makoto Naganuma, Kaoru Takabayashi, Yuya Hagihara, Shun Tanemoto, Ena Nomura, Yusuke Yoshimatsu, Shinya Sugimoto, Kosaku Nanki, Shinta Mizuno, Yohei Mikami, Kayoko Fukuhara, Tomohisa Sujino, Makoto Mutaguchi, Nagamu Inoue, Haruhiko Ogata,
Journal of Gastroenterology and Hepatology.2020; 35(11): 1878. CrossRef
Clinical management for small bowel of Crohn’s disease in the treat-to-target era: now is the time to optimize treatment based on the dominant lesion
Kenji Watanabe
Intestinal Research.2020; 18(4): 347. CrossRef

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Brief Communication

IBD

Effect of elemental diet combined with infliximab dose escalation in patients with Crohn's disease with loss of response to infliximab: CERISIER trial: Tadakazu Hisamatsu, Reiko Kunisaki, Shiro Nakamura, Tomoyuki Tsujikawa, Fumihito Hirai, Hiroshi Nakase, Kenji Watanabe, Kaoru Yokoyama, Masakazu Nagahori, Takanori Kanai, Makoto Naganuma, Hirofumi Michimae, Akira Andoh, Akihiro Yamada, Tadashi Yokoyama, Noriko Kamata, Shinji Tanaka, Yasuo Suzuki, Toshifumi Hibi, Mamoru Watanabe; Intest Res 2018;16(3):494-498. Published online July 27, 2018; DOI: https://doi.org/10.5217/ir.2018.16.3.494

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Statement

IBD

Predicting outcomes to optimize disease management in inflammatory bowel disease in Japan: their differences and similarities to Western countries: Taku Kobayashi, Tadakazu Hisamatsu, Yasuo Suzuki, Haruhiko Ogata, Akira Andoh, Toshimitsu Araki, Ryota Hokari, Hideki Iijima, Hiroki Ikeuchi, Yoh Ishiguro, Shingo Kato, Reiko Kunisaki, Takayuki Matsumoto, Satoshi Motoya, Masakazu Nagahori, Shiro Nakamura, Hiroshi Nakase, Tomoyuki Tsujikawa, Makoto Sasaki, Kaoru Yokoyama, Naoki Yoshimura, Kenji Watanabe, Miiko Katafuchi, Mamoru Watanabe, Toshifumi Hibi; Intest Res 2018;16(2):168-177. Published online April 30, 2018; DOI: https://doi.org/10.5217/ir.2018.16.2.168

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Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease of the gastrointestinal tract, with increasing prevalence worldwide. IBD Ahead is an international educational program that aims to explore questions commonly raised by clinicians about various areas of IBD care and to consolidate available published evidence and expert opinion into a consensus for the optimization of IBD management. Given differences in the epidemiology, clinical and genetic characteristics, management, and prognosis of IBD between patients in Japan and the rest of the world, this statement was formulated as the result of literature reviews and discussions among Japanese experts as part of the IBD Ahead program to consolidate statements of factors for disease prognosis in IBD. Evidence levels were assigned to summary statements in the following categories: disease progression in CD and UC; surgery, hospitalization, intestinal failure, and permanent stoma in CD; acute severe UC; colectomy in UC; and colorectal carcinoma and dysplasia in IBD. The goal is that this statement can aid in the optimization of the treatment strategy for Japanese patients with IBD and help identify high-risk patients that require early intervention, to provide a better long-term prognosis in these patients.

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Ashwin N. Ananthakrishnan
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Inflammatory Intestinal Diseases.2024; 9(1): 260. CrossRef
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Yanfang Liu, Choo Hua Goh, Hong Qiu, Kuan-Chih Huang, Hsingwen Chung, Carine Saadoun
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MR-enterography in Crohn’s disease: what MRE mural parameters are associated to one-year therapeutic management outcome?
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Passion fruit (Passiflora edulis) leaf aqueous extract ameliorates intestinal epithelial barrier dysfunction and reverts inflammatory parameters in Caco-2 cells monolayer
Mônica Cristina Lopes do Carmo, Isabela Mateus Martins, Ana Elisa Ramos Magalhães, Mário Roberto Maróstica Júnior, Juliana Alves Macedo
Food Research International.2020; 133: 109162. CrossRef
Efficacy and safety of abrilumab, an α4β7 integrin inhibitor, in Japanese patients with moderate-to-severe ulcerative colitis: a phase II study
Toshifumi Hibi, Satoshi Motoya, Toshifumi Ashida, Souken Sai, Yukinori Sameshima, Shiro Nakamura, Atsuo Maemoto, Masahiro Nii, Barbara A Sullivan, Robert A. Gasser Jr, Yasuo Suzuki
Intestinal Research.2019; 17(3): 375. CrossRef

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Original Article

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

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<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
Comparative study on the pathogenesis of Crohn’s disease and ulcerative colitis
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