REVIEW : Tacrolimus for the Treatment of Ulcerative Colitis

( Katsuyoshi Matsuoka ),( Eiko Saito ),( Toshimitsu Fujii ),( Kento Takenaka ),( Maiko Kimura ),( Masakazu Nagahori ),( Kazuo Ohtsuka ),( Mamoru Watanabe ) 대한장연구학회 2015 Intestinal Research Vol.13 No.3

Tacrolimus is a calcineurin inhibitor used for the treatment of corticosteroid-refractory ulcerative colitis (UC). Two randomized controlled trials and a number of retrospective studies have assessed the therapeutic effect of tacrolimus in UC patients. These studies showed that tacrolimus has excellent short-term efficacy in corticosteroid-refractory patients, with the rates of clinical response ranging from 61% to 96%. However, the long-term prognosis of patients treated with tacrolimus is disappointing, and almost 50% of patients eventually underwent colectomy in long-term follow-up. Tacrolimus can achieve mucosal healing in40-50% of patients, and this is associated with a favorable long-term prognosis. Anti-tumor necrosis factor (TNF)-α antibodies are another therapeutic option in corticosteroid-refractory patients. A prospective head-to-head comparative study of tacrolimus and infliximab is currently being performed to determine which treatment is more effective in corticosteroid-refractory patients. Several retrospective studies have demonstrated that switching between tacrolimus and anti-TNF-α antibody therapy was effective in patients who were refractory to one of the treatments. Most adverse events of tacrolimus are mild; however,opportunistic infections, especially pneumocystis pneumonia, are the most important adverse events, and these should be carefully considered during treatment. Several issues on tacrolimus treatment in UC patients remain unsolved (e.g., use of tacrolimus as remission maintenance therapy). Further controlled studies are needed to optimize the use of tacrolimus for the treatment of UC. (Intest Res 2015;13:219-226)

NUDT15 gene variants and thiopurine-induced leukopenia in patients with inflammatory bowel disease

( Katsuyoshi Matsuoka ) 대한장연구학회 2020 Intestinal Research Vol.18 No.3

Thiopurine has been used to maintain remission and to reduce antidrug antibody formation in monoclonal antibody therapy in patients with inflammatory bowel disease (IBD). The use of thiopurine is limited by side effects such as leukopenia. Thiopurine S-methyltransferase (TPMT) variants are associated with thiopurine-induced leukopenia in Westerners, but the frequency of the risk alleles is low in Asians. Recently, a variant in the nudix hydrolase 15 (NUDT15) gene (R139C, c.415C>T) was reported to be associated with early severe leukopenia in Asians. NUDT15 is an enzyme that converts 6-thio-(deoxy)guanosine triphosphate (6-T(d)GTP) to 6-thio-(deoxy)guanosine monophosphate (6-T(d)GMTP). The R139C variant impairs the stability of the protein and increases incorporation of 6-TGTP and 6-TdGTP into RNA and DNA, respectively, resulting in leukopenia. The frequency of C/C, C/T, and T/T are approximately 80%, 20%, and 1%, respectively in East Asians. Early leukopenia occurred in less than 3% of patients with C/C and in around 20% of those with C/T, whereas it occurred in almost all patients with T/T. Patients homozygous for this variant also develop severe hair loss. The measurement of NUDT15 R139C can increase the safety of thiopurine dramatically and is a successful example of personalized medicine in the field of IBD. (Intest Res 2020;18:275-281)

Incidence rates for hospitalized infections, herpes zoster, and malignancies in patients with ulcerative colitis in Japan: an administrative health claims database analysis

Katsuyoshi Matsuoka,Kanae Togo,Noritoshi Yoshii,Masato Hoshi,Shoko Arai 대한장연구학회 2023 Intestinal Research Vol.21 No.1

Background/Aims: Patients with ulcerative colitis (UC) are at an increased risk of certain infections and malignancies compared with the general population. Incidence rates (IRs) of hospitalized infections, herpes zoster (HZ), and malignancies in patients with UC, stratified by treatment, in Japan were estimated. Methods: This retrospective study identified patients with UC treated with corticosteroids, immunosuppressants, or tumor necrosis factor inhibitors (TNFi) from 2 administrative databases (Japan Medical Data Center [JMDC] and Medical Data Vision [MDV]). IRs (unique patients with events per 100 patient‐years) were estimated for hospitalized infections, HZ, and malignancies, between June 2010 and May 2018. Results: Among 6,033 MDV patients with UC receiving corticosteroids, immunosuppressants, or TNFi, IRs (95% confidence intervals) were: hospitalized infections, 1.73 (1.52–1.93); HZ, 1.00 (0.85–1.16), and malignancies, 1.48 (1.29–1.66). Among 958 JMDC patients with UC receiving corticosteroids, immunosuppressants, or TNFi, IRs (95% confidence intervals) were: HZ, 1.82 (1.27–2.37) and malignancies, 1.35 (0.87–1.82). In both cohorts, IRs of malignancies were generally similar among patients receiving immunosuppressants, TNFi, or combination therapy (immunosuppressants and TNFi); this was also true for IRs of hospitalized infections and HZ in the MDV cohort. IRs of hospitalized infections, HZ, and malignancies were higher in patients receiving calcineurin inhibitors compared with immunosuppressants or TNFi, in both cohorts. Conclusions: IRs of hospitalized infections, HZ, and malignancies among patients with UC were generally similar regardless of UC treatment, except for calcineurin inhibitors.

REVIEW : Diet, microbiota, and inflammatory bowel disease: Lessons from Japanese foods

( Takanori Kanai ),( Katsuyoshi Matsuoka ),( Makoto Naganuma ),( Atsushi Hayashi ),( Tadakazu Hisamatsu ) 대한내과학회 2014 The Korean Journal of Internal Medicine Vol.29 No.4

The incidence and prevalence of inflammatory bowel diseases (IBDs) including ulcerative colitis and Crohn disease are rapidly increasing in Western countries and in developed Asian countries. Although biologic agents targeting the immune system have been effective in patients with IBD, cessation of treatment leads to relapse in the majority of patients, suggesting that intrinsic immune dysregulation is an effect, not a cause, of IBD. Dramatic changes in the environment, resulting in the dysregulated composition of intestinal microbiota or dysbiosis, may be associated with the fundamental causes of IBD. Japan now has upgraded water supply and sewerage systems, as well as dietary habits and antibiotic overuse that are similar to such features found in developed Western countries. The purpose of this review article was to describe the association of diet, particularly Japanese food and microbiota, with IBD.

5-Aminosalicylic acid aggravates colitis mimicking exacerbation of ulcerative colitis

( Jun Miyoshi ),( Katsuyoshi Matsuoka ),( Atsushi Yoshida ),( Makoto Naganuma ),( Tadakazu Hisamatsu ),( Tomoharu Yajima ),( Nagamu Inoue ),( Susumu Okamoto ),( Yasushi Iwao ),( Haruhiko Ogata ),( Fum 대한장연구학회 2018 Intestinal Research Vol.16 No.4

Ulcerative colitis (UC) is one of the major clinical phenotypes of inflammatory bowel diseases. Although 5-aminosalicylic acid (5-ASA) is widely used for UC and its efficacy and safety have been demonstrated, a few patients paradoxically develop a severe exacerbation of colitis by 5-ASA administration. It is crucial to know clinical features including endoscopic findings in this condition for making a correct diagnosis and a prompt decision to withdraw the medication. Here, we report case series with UC exacerbated by 5-ASA. Medical records of 8 UC patients experiencing an exacerbation of colitis after induction of 5-ASA that was improved by the withdrawal of 5-ASA but also re-aggravated by dose increase or re-administration of 5-ASA were reviewed. The patients were newly diagnosed with UC, started 5-ASA and developed an exacerbation in approximately 2 to 3 weeks. They did not appear to have systemic allergic reactions. Seven of the 8 patients had a high fever. Three of 5 patients who undertook total colonoscopy showed right-side-dominant colitis. These findings suggest clinical characteristics in this condition. Further assessment of clinical and endoscopic features in more cases is necessary for establishing diagnostic criteria and understanding underlying mechanisms in those cases where 5-ASA aggravates the colitis. (Intest Res 2018;16:635-640)

Fecal microbiota transplantation for recurrent Clostridium difficile infection in a patient with ulcerative colitis

Kosaku Nanki,Shinta Mizuno,Katsuyoshi Matsuoka,Keiko Ono,Shinya Sugimoto,Hiroki Kiyohara,Mari Arai,Moeko Nakashima,Kozue Takeshita,Keiichiro Saigusa,Mitsutoshi Senoh,Tadashi Fukuda,Makoto Naganuma,Har 대한장연구학회 2018 Intestinal Research Vol.16 No.1

Fecal microbiota transplantation (FMT) has been reported as a safe and effective therapy in patients with refractory and recurrentClostridium difficile infection (CDI). FMT has also been reported as a promising therapy in patients with ulcerative colitis(UC). Both, CDI and UC, are believed to be caused by dysbiosis, such as altered compositions or decreased diversity of the intestinal microbiota. This report describes a patient with UC in remission with a second recurrent episode of CDI, who was treated with FMT. A single FMT performed via colonoscopy completely resolved the patient’s diarrhea and eradicated C. difficilebacteriologically without any severe complications. Molecular biological analysis of the patient’s fecal microbiota showedthat FMT could dramatically change the altered composition of intestinal microbiota and restore its diversity. Despite the restoration of the intestinal microbiota, FMT could not prevent a relapse of UC in this patient. However, it improved the intestinalsymptoms of CDI and could prevent further recurrences of CDI.

Single fecal microbiota transplantation failed to change intestinal microbiota and had limited effectiveness against ulcerative colitis in Japanese patients

( Shinta Mizuno ),( Kosaku Nanki ),( Katsuyoshi Matsuoka ),( Keiichiro Saigusa ),( Keiko Ono ),( Mari Arai ),( Shinya Sugimoto ),( Hiroki Kiyohara ),( Moeko Nakashima ),( Kozue Takeshita ),( Makoto Na 대한장연구학회 2017 Intestinal Research Vol.15 No.1

Background/Aims: Recent developments in analytical techniques including next-generation sequencing have clarified the correlation between intestinal microbiota and inflammatory bowel disease. Fecal microbiota transplantation (FMT) for patients with ulcerative colitis (UC) is proposed as a potential approach to resolving their dysbiosis; however, its safety and efficacy have not been confirmed. This single-arm, open-label, non-randomized study aimed to evaluate the safety and efficacy of FMT for Japanese patients with UC as the first registered clinical trial in Japan. Methods: We enrolled 10 patients with active UC despite medical therapy. The donors were the patients` relatives and were carefully screened for infectious diseases. Fecal material was administered via colonoscopy, and the primary endpoint was the presence or absence of serious adverse events related to FMT. The secondary endpoint was a change in partial Mayo score at 12 weeks post-FMT. Scores ≤2 were considered a clinical response. Fecal samples were collected to follow changes in gut microbiota, while extracted complementary DNA were analyzed by a next-generation sequencer. We obtained written informed consent from all patients and donors. This study was approved by our Institutional Review Board and is registered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN 000012814). Results: Five patients with moderate disease and five with severe disease were enrolled. No severe adverse effects were observed. One patient achieved clinical response; however, none of the patients` microbiota diversity recovered to the donor levels. Conclusions: The use of single FMT for UC was safe; however, we failed to show its clinical efficacy and potential to change the intestinal microbiota. (Intest Res 2017;15:68-74)

REVIEW : Immunological Abnormalities in the Pathogenesis of Inflammatory Bowel Disease

( Tadakazu Hisamatsu ),( Yohei Mikami ),( Katsuyoshi Matsuoka ),( Takanori Kanai ),( Toshifumi Hibi ) 대한장연구학회 2012 Intestinal Research Vol.10 No.4

Crohn`s disease and ulcerative colitis represent two distinct forms of inflammatory bowel diseases (IBD). In this paper, we discuss how immunological mechanisms contribute to the pathogenesis of IBD. Intestinal homeostasis is sustained by various kinds of cells, such as epithelial cells, lymphocytes, antigen presenting cells, and other innate immune cells. We pay special attention to intestinal CD14+ macrophages. Intestinal macrophages play a central role in the regulation of immune responses against commensal bacteria. In the physiological condition, intestinal macrophages lack the expression of innate-immune receptor CD14 and do not produce proinfl ammatory cytokines. We identified a unique macrophage subset of IBD in the human intestine, which expressed both macrophage (CD14, CD33, CD68) and dendritic cell (DC) markers (CD205, CD209) and produced larger amounts of proinflammatory cytokines, such as interleukin (IL)-23 and tumor necrosis factor (TNF)-α. In addition, the CD14+ macrophages contributed to interferon (IFN)-γ production rather than IL-17 production by lamina propria mononuclear cells dependent on IL-23. We discuss herein this IL-23/IFN-γ-positive feedback loop in IBD patients. We also discuss IFN-γ and IL-17 production from mucosal T cells and natural killer (NK) cells. Here, we show our recent findings about the plasticity of T helper cells in colitis. Th 17 cells express T-bet, and finally lose the expression of retinoic acid-related orphan receptor (ROR)γt, the master regulator of Th 17 cells, and are differentiated ‘alternative Th 1 cells.’ In addition to Th 1 cells, mucosal NK cells are also important sources of IFN-γ. Some of our ideas may be provocative, but we hope this review paper will provide new and firm understanding of the pathogenesis of IBD. (Intest Res 2012;10:317-323)

Efficacy and safety of filgotinib as induction and maintenance therapy for Japanese patients with moderately to severely active ulcerative colitis: a post-hoc analysis of the phase 2b/3 SELECTION trial

Toshifumi Hibi,Satoshi Motoya,Tadakazu Hisamatsu,Fumihito Hirai,Kenji Watanabe,Katsuyoshi Matsuoka,Masayuki Saruta,Taku Kobayashi,Brian G Feagan,Chantal Tasset,Robin Besuyen,Chohee Yun,Gerald Crans,Ji 대한장연구학회 2023 Intestinal Research Vol.21 No.1

Background/Aims: The safety and efficacy of filgotinib, a once-daily oral Janus kinase 1 preferential inhibitor, were evaluated in Japanese patients with ulcerative colitis (UC) in the phase 2b/3 SELECTION trial. Methods: SELECTION (NCT02914522) was a randomized, placebo-controlled trial comprising 2 induction studies and a maintenance study. Adults with moderately to severely active UC were randomized in induction study A (biologic-naïve) or B (biologic-experienced) to receive filgotinib 200 mg, 100 mg, or placebo once daily for 11 weeks. Patients in clinical remission or Mayo Clinic score response at week 10 entered the 47-week maintenance study. Efficacy and safety outcomes were assessed in Japanese patients enrolled in Japan. Results: Overall, 37 and 72 Japanese patients were enrolled in Japan in induction studies A and B, respectively, and 54 entered the maintenance study. Numerically higher proportions of filgotinib 200 mg-treated than placebo-treated patients achieved clinical remission in induction study A (4/15 [26.7%] vs. 0/6 [0%]) and the maintenance study (5/20 [25.0%] vs. 0/9 [0%]), but not induction study B (1/29 [3.4%] vs. 1/14 [7.1%]). Both doses were well tolerated, and no new safety signals were noted. Herpes zoster was reported in 1 filgotinib 200 mg-treated patient in each of induction study A (2.3%, 1/44) and the maintenance study (5.0%, 1/20). Conclusions: These data, alongside those of the overall SELECTION population, suggest the potential of filgotinib 200 mg as a viable treatment option for Japanese patients with UC. Owing to small patient numbers, data should be interpreted cautiously.

Pregnancy outcome in women with inflammatory bowel disease treated with anti-tumor necrosis factor and/or thiopurine therapy: a multicenter study from Japan

( Shunsuke Komoto ),( Satoshi Motoya ),( Yuji Nishiwaki ),( Toshiyuki Matsui ),( Reiko Kunisaki ),( Katsuyoshi Matsuoka ),( Naoki Yoshimura ),( Takashi Kagaya ),( Makoto Naganuma ),( Nobuyuki Hida ),( 대한장연구학회 2016 Intestinal Research Vol.14 No.2

Background/Aims: Anti-tumor necrosis factor drugs (anti-TNF) and thiopurines are important treatment options in patients with inflammatory bowel disease (IBD), including during pregnancy. However, there are limited data on the benefit/risk profile of anti-TNF and thiopurines during pregnancy in Asia. The aim of this study was to analyze pregnancy outcomes of female Japanese IBD patients treated with anti-TNF and/or thiopurines. Methods: This cross-sectional study assessed pregnancy outcomes in 72 women with IBD. Pregnancy outcomes were compared among 31 pregnancies without exposure to infliximab (IFX), adalimumab (ADA), or thiopurines; 24 pregnancies with exposure to anti-TNF treatment (23 IFX, 1 ADA); 7 pregnancies with exposure to thiopurines alone; and 10 pregnancies with exposure to both IFX and thiopurines. Results: Thirty-five of the 41 pregnancies (85.3%) that were exposed to anti-TNF treatment and/or thiopurines resulted in live births after a median gestational period of 38 weeks. Of the 35 live births, 3 involved premature deliveries; 7, low birth weight; and 1, a congenital abnormality. There were 6 spontaneous abortions in pregnancies that were exposed to anti-TNF treatment (17.7%). Pregnancy outcomes among the 4 groups were similar, except for the rate of spontaneous abortions (P =0.037). Conclusions: Exposure to anti-TNF treatment or thiopurines during pregnancy was not related to a higher incidence of adverse pregnancy outcomes in Japanese IBD patients except for spontaneous abortion. (Intest Res 2016;14:139-145)