Cytapheresis in Patients with Severe Ulcerative Colitis after Failure of Intravenous Corticosteroid: A Long-Term Retrospective Cohort Study

( Ken Fukunaga ),( Kazuko Nagase ),( Takeshi Kusaka ),( Nobuyuki Hida ),( Yoshio Ohda ),( Koji Yoshida ),( Katsuyuki Tozawa ),( Koji Kamikozuru ),( M Iimuro ),( Shiro Nakamura ),( Hiroto Miwa ),( Taka 대한소화기기능성질환·운동학회 2009 Gut and Liver Vol.3 No.1

Background/Aims: Cytapheresis (CAP) is a novel strategy for ulcerative colitis (UC). However, there is insufficient data on the long-term outcome of UC patients who achieve remission by CAP. This study involved patients with severe UC who refracted to intravenous (iv) corticosteroid. Methods: Forty-seven UC patients who had received CAP therapy for the first time within 1 year after UC diagnosis were followed for 36 months. One of the inclusion criteria was a clinical activity index (CAI) of ≥7 points at the end of a 2-week iv course of corticosteroid therapy. CAP therapy consisted of ten sessions over 10 weeks. Results: CAP induced clinical remission (CAI≤4) in 70.2% patients (33/47). The number of submissions for colectomy was higher for severe UC at entry (CAI≥12, n=25) than for moderately severe UC at entry (7≤CAI<12, p=15; p<0.02). The cumulative rates of avoiding surgery and relapse were 54.5% and 24.2%, respectively, at 36 months in patients who responded to CAP therapy. This was similar to that of iv cyclosporine reported recently. Conclusions: This study suggest that CAP is an effective therapy in patients who are refractory to conventional medications including iv corticosteroid. Increased remission rates should be expected in refractory patients with moderately severe UC. (Gut and Liver 2009;3:41-47)

Infl iximab Therapy Impacts the Peripheral Immune System of Immunomodulator and Corticosteroid Naive Patients with Crohn`s Disease

( Kyoichi Kato ),( Ken Fukunaga ),( Koji Kamikozuru ),( Shinichiro Kashiwamura ),( Nobuyuki Hida ),( Yoshio Ohda ),( Naohisa Takeda ),( Koji Yoshida ),( Masaki Iimuro ),( Yoko Yokoyama ),( Risa Kikuya 대한소화기기능성질환·운동학회 2011 Gut and Liver Vol.5 No.1

Background/Aims: Infliximab (IFX), an antibody to tumor necrosis factor, (TNF)-α has effi cacy in treating Crohn`s disease (CD). However, knowledge of the potential effects of IFX on patients` immune profi les is lacking. The purpose of this study was to reveal the immunological effects of IFX. Methods: Twenty-two patients with a CD activity index (CDAI) of 194.2±92.9 and an average duration of disease of 3.26 months and 21 healthy controls were included. Patients were to have their fi rst IFX remission induction therapy with 3 infusions (5 mg/kg) at weeks 0, 2, and 6. Oral 5-aminosalicylic acid was the only ongoing medication in the patient population. Blood samples at baseline, 12 hours after the first infusion and at week 14 were labeled with anti-CD4/ CD25 antibodies for immunohistochemical measurement of regulatory T-cells (Treg). Serum cytokines and chemokines were measured by suspension array and ELISA. Results: CDAI signifi cantly decreased prior to the second IFX infusion (p<0.001). Clinical remission rates were 77.3% and 91% by the second and third infusions, respectively. At baseline, interleukin (IL)-6 (p<0.03), IL-8 (p<0.03), IL-10 (p=0.050), IL-13 (p<0.01), transforming growth factor-β1 (p<0.01), and ``regulated on activation, normal T cell expressed and secreted`` (RANTES) (p<0.01) were elevated in patients. After the initial IFX infusion, TNF-α (p<0.04), IL-6 (p<0.03), interferon (IFN)-γ (p<0.04), IFN-γ-inducible protein-10 (p<0.01), monocyte chemoattractant protein-1 (p<0.01), macrophage infl ammatory protein-1β (p<0.01), and RANTES (p<0.01) were decreased. IFX infusion was associated with an increase in Treg (p<0.01) and a decrease in the Th1 (IFN-γ)/Th2 (IL-4) ratio (p<0.03). Conclusions: IFX use was associated with restoration of the Th1/Th2 balance after a single infusion and seemed to promote induction of naive Th0 lymphocytes to Treg. This knowledge should have clinical relevance. (Gut Liver 2011;5:37-45)

Infl iximab Therapy Impacts the Peripheral Immune System of Immunomodulator and Corticosteroid Naïve Patients with Crohn’s Disease

Kyoichi Kato,Ken Fukunaga,Koji Kamikozuru,Shinichiro Kashiwamura,Nobuyuki Hida,Yoshio Ohda,Naohisa Takeda,Koji Yoshida,Masaki Iimuro,Yoko Yokoyama,Risa Kikuyama,Hiroto Miwa,Takayuki Matsumoto 거트앤리버 소화기연관학회협의회 2011 Gut and Liver Vol.5 No.1

Background/Aims: Infliximab (IFX), an antibody to tumor necrosis factor, (TNF)-α has effi cacy in treating Crohn’s disease (CD). However, knowledge of the potential effects of IFX on patients’ immune profi les is lacking. The purpose of this study was to reveal the immunological effects of IFX. Methods: Twenty-two patients with a CD activity index (CDAI)of 194.2±92.9 and an average duration of disease of 3.26months and 21 healthy controls were included. Patients were to have their fi rst IFX remission induction therapy with 3 infusions (5 mg/kg) at weeks 0, 2, and 6. Oral 5-aminosalicylic acid was the only ongoing medication in the patient population. Blood samples at baseline, 12 hours after the first infusion and at week 14 were labeled with anti-CD4/CD25 antibodies for immunohistochemical measurement of regulatory T-cells (Treg). Serum cytokines and chemokines were measured by suspension array and ELISA. Results:CDAI signifi cantly decreased prior to the second IFX infusion (p<0.001). Clinical remission rates were 77.3% and 91% by the second and third infusions, respectively. At baseline, interleukin (IL)-6 (p<0.03), IL-8 (p<0.03), IL-10 (p=0.050), IL-13(p<0.01), transforming growth factor-β1 (p<0.01), and ‘regulated on activation, normal T cell expressed and secreted’(RANTES) (p<0.01) were elevated in patients. After the initial IFX infusion, TNF-α (p<0.04), IL-6 (p<0.03), interferon (IFN)-γ(p<0.04), IFN-γ-inducible protein-10 (p<0.01), monocyte chemoattractant protein-1 (p<0.01), macrophage infl ammatory protein-1β (p<0.01), and RANTES (p<0.01) were decreased. IFX infusion was associated with an increase in Treg (p<0.01)and a decrease in the Th1 (IFN-γ)/Th2 (IL-4) ratio (p<0.03). Conclusions: IFX use was associated with restoration of the Th1/Th2 balance after a single infusion and seemed to promote induction of naïve Th0 lymphocytes to Treg. This knowledge should have clinical relevance.

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)

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 ) 대한장연구학회 2017 Intestinal Research Vol.15 No.3

Background/Aims: 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 thiopurineinduced 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. (Intest Res 2017;15:328-337)