REWIEW : Role of the CXC12-CXCR4 Axis and CXCL16 in Inflammatory Bowel Disease

( Hiroshi Nakase ),( Minoru Matsuura ),( Sakae Mikami ),( Norimitsu Uza ),( Tsutomu Chiba ) 대한장연구학회 2012 Intestinal Research Vol.10 No.2

Numerous studies of colitis in IBD (inflammatory bowel diseases) patients and in animal models have demonstrated that both inflammatory cytokines and chemokines are up-regulated in settings of active inflammation. Blockade or absence of various cytokines and chemokines attenuates the disease in murine models of IBD. Therefore, identifying cytokines and chemokines involved in intestinal inflammation provide promising targets for the development of new drugs in the treatment of IBD. In general, chemokines have been implicated in many fundamental immune processes including lymphoid organogenesis, immune cell differentiation, development and positioning. Many chemokines are markedly increased in intestinal tissue from patients with IBD. In this study, we focused on the role of CXCL12-CXCR4 and CXCL16. CXCL12-CXCR4 axis plays a crucial role in the pathophysiology of IBD, especially UC, while SR-PSOX/CXCL16 plays a significant role in the pathophysiology of CD. Our present data suggest new insights into the etiology of IBD and we hope that the manipulation of these chemokines may have therapeutic value. (Intest Res 2012;10:125-133)

Efficacy of Thiopurines in Biologic-Naive Japanese Patients With Crohn`s Disease: A Single-Center Experience

( Takuya Yoshino ),( Minoru Matsuura ),( Naoki Minami ),( Satoshi Yamada ),( Yusuke Honzawa ),( Masamichi Kimura ),( Yorimitsu Koshikawa ),( Ali Madian ),( Takahiko Toyonaga ),( Hiroshi Nakase ) 대한장연구학회 2015 Intestinal Research Vol.13 No.3

Background/Aims: Early use of biologics in patients with Crohn`s disease (CD) improves quality of life. However, the effects of the early use of immunomodulators on long-term outcomes remain unclear. This study aimed to evaluate the effects of immunomodulatorsin patients with CD. Methods: Between January 2004 and December 2011, 47 biologic-naive CD patients treated with thiopurines alone for remission maintenance were analyzed. The patients were classified into 2 groups depending on the presence or absence of digestive complications. We evaluated the efficacy of and predictive factors for thiopurine use for remission maintenance. Results: The cumulative relapse rates at 24 and 60 months were 13.7% and 35.4%, respectively. Regarding patient characteristics, there was a significant difference in patient history of surgery between the non-relapse and relapse groups (P =0.021). The cumulative relapse rate was lower in patients without a history of surgery than in those with such a history (27.2% and 52.9% at 60.0 months, respectively). Multivariate analysis suggested that the prevalence of stricturing and penetrating complications is an independent factor for relapse. The cumulative relapse rate in patients without a history ofsurgery was significantly lower in the non-stricturing and non-penetrating group than in the stricturing and penetrating group (11.8% at 85.0 months vs. 58.5% at 69.0 months; P =0.036). Conclusions: Thiopurine use might be beneficial for the long-term maintenance of remission in biologic-naive Crohn`s disease patients without digestive complications and a history of surgery. (Intest Res 2015;13:266-273)

Maternal and fetal outcomes in pregnant Japanese women with inflammatory bowel disease: our experience with a series of 23 cases

( Naoki Minami ),( Minoru Matsuura ),( Yorimitsu Koshikawa ),( Satoshi Yamada ),( Yusuke Honzawa ),( Shuji Yamamoto ),( Hiroshi Nakase ) 대한장연구학회 2017 Intestinal Research Vol.15 No.1

Background/Aims: Our physicians work to expand the possibilities to treat female patients with inflammatory bowel disease (IBD) who wish to become pregnant. Although many drugs, including 5-aminosalicylate (5-ASA), corticosteroids, immunomodulators, and biologics, are used safely during pregnancy, few reports have described the therapeutic regimen throughout pregnancy and the management of patients who relapse during pregnancy precisely. The aim of this study was to assess the management of patients with IBD during pregnancy. Methods: We identified 19 patients (five with Crohn`s disease and 14 with ulcerative colitis [UC]) who became pregnant with a total of 23 pregnancies between May 2005 and May 2015 by reviewing the medical records of Kyoto University Hospital. The following data were collected: the maternal variables, the IBD treatment type, the disease activity, the pregnancy outcome, and the mode of delivery. Results: Among the 19 patients, 18 had become pregnant after being diagnosed with IBD, while one had developed UC newly after pregnancy. Throughout the gestation, all patients were treated with probiotics, 5-ASA, prednisolone, cytapheresis, or infliximab. The relapse rate during pregnancy was 21.7% (5/23 cases). The five patients who experienced a relapse were able to pursue their pregnancy after intensification of their treatments. There were no adverse fetal or neonatal problems, except in one case that required an emergency Caesarean section because of placental dysfunction and in which a very low-birth-weight infant was born preterm. Conclusions: Our present data confirmed that even if the disease flares up during pregnancy, good pregnancy outcomes can be achieved with an optimal intensification of the patient`s treatment. (Intest Res 2017;15:90-96)

Efficacy and Safety of Long-Term Thiopurine Maintenance Treatment in Japanese Patients With Ulcerative Colitis

( Satoshi Yamada ),( Takuya Yoshino ),( Minoru Matsuura ),( Masamichi Kimura ),( Yorimitsu Koshikawa ),( Naoki Minami ),( Takahiko Toyonaga ),( Yusuke Honzawa ),( Hiroshi Nakase ) 대한장연구학회 2015 Intestinal Research Vol.13 No.3

Background/Aims: The long-term clinical outcomes of patients with bio-naive ulcerative colitis (UC) who maintain remission with thiopurine are unclear. The aim of this study was to assess the long-term efficacy and safety of maintenance treatment with thiopurine in UC patients. Methods: This was a retrospective observational cohort analysis conducted at a single center. Between December 1998 and August 2013, 59 of 87 patients with bio-naive UC who achieved remission after induction with treatments other than biologics were enrolled. Remission maintenance with thiopurine was defined as no concomitant treatment needed other than 5-aminosalicylate without relapse. We assessed the remissionmaintenance rate, mucosal healing rate, colectomy-free rate, and treatment safety in UC patients who received thiopurineas maintenance treatment. Results: The 84-month cumulative remission-maintenance and colectomy-free survival rates in the UC patients who were receiving maintenance treatment with thiopurine and 5-aminosalicylate were 43.9% and 88.0%, respectively. Of the 38 patients who underwent colonoscopy during thiopurine maintenance treatment, 23 (60.5%) achieved mucosal healing. Of the 59 patients who achieved clinical remission with thiopurine, 6 patients (10.2%) discontinued the thiopurine therapy because of adverse events. Conclusions: Our study demonstrates the long-term efficacy and safety of thiopurine treatment in patients with bio-naive UC. (Intest Res 2015;13:250-258)

Ischemic enteritis with intestinal stenosis

( Yorimitsu Koshikawa ),( Hiroshi Nakase ),( Minoru Matsuura ),( Takuya Yoshino ),( Yusuke Honzawa ),( Naoki Minami ),( Satoshi Yamada ),( Yumiko Yasuhara ),( Shigehiko Fujii ),( Toshihiro Kusaka ),( 대한장연구학회 2016 Intestinal Research Vol.14 No.1

A 75-year-old man was admitted to our hospital with sudden onset of vomiting and abdominal distension. The patient was taking medication for arrhythmia. Computed tomography showed stenosis of the ileum and a small bowel dilatation on the oral side from the region of stenosis. A transnasal ileus tube was placed. Enteroclysis using contrast medium revealed an approximately 6-cm afferent tubular stenosis 10 cm from the terminal ileum and thumbprinting in the proximal bowel. Transanal double-balloon enteroscopy showed a circumferential shallow ulcer with a smooth margin and edema of the surrounding mucosa. The stenosis was so extensive that we could not perform endoscopic balloon dilation therapy. During hospitalization, the patient’s nutritional status deteriorated. In response, we surgically resected the region of stenosis. Histologic examination revealed disappearance of the mucosal layer and transmural ulceration with marked fibrosis, especially in the submucosal layer. Hemosiderin staining revealed sideroferous cells in the submucosal layers. Based on the pathologic findings, the patient was diagnosed with ischemic enteritis. The patient’s postoperative course was uneventful. (Intest Res 2016;14:89-95)

FOCUSED REVIEW: INFECTION AND IBD : Diagnosis and Treatment of Ulcerative Colitis with Cytomegalovirus Infection: Importance of Controlling Mucosal Inflammation to Prevent Cytomegalovirus Reactivation

( Hiroshi Nakase ),( Yusuke Honzawa ),( Takahiko Toyonaga ),( Satoshi Yamada ),( Naoki Minami ),( Takuya Yoshino ),( Minoru Matsuura ) 대한장연구학회 2014 Intestinal Research Vol.12 No.1

Human cytomegalovirus (HCMV) is a member of the herpesvirus family. HCMV infection persists throughout the host lifespan in a latent state following primary infection. The ability of HCMV to escape control by the host immune system and its resulting reactivation suggests the importance of ongoing immune surveillance in the prevention of HCMV reactivation. HCMV is a common cause of opportunistic infection that causes severe and fatal disease in immune-compromised individuals. In inflammatory bowel disease patients, particularly those with ulcerative colitis (UC), HCMV is often reactivated because these patients are frequently treated with immunosuppressive agents. This reactivation exacerbates colitis. Additionally, HCMV infection can induce severe colitis, even in patients with UC who have never been treated with immunosuppressive agents. However, the role of HCMV in colonic inflammation in patients with UC remains unclear. Here, we present previous and current clinical data on the diagnosis and treatment of HCMV infection in UC. Additionally, our experimental data from a newly established mouse model mimicking UC with concomitant CMV infection clearly demonstrate that inflammation could result in the exacerbation of UC disease activity with induction of HCMV reactivation. In summary, optimal control of colonic inflammation should be achieved in UC patients who are refractory to conventional immunosuppressive therapies and are positive for HCMV. (Intest Res 2014;12:5-11)

CASE REPORT : Usefulness of Adalimumab for Treating a Case of Intestinal Behcet`s Disease With Trisomy 8 Myelodysplastic Syndrome

( Masamichi Kimura ),( Yoshihisa Tsuji ),( Masako Iwai ),( Masahiro Inagaki ),( Ali Madian ),( Takuya Yoshino ),( Minoru Matsuura ),( Hiroshi Nakase ) 대한장연구학회 2015 Intestinal Research Vol.13 No.2

Behcet`s disease (BD) is a systemic vasculitis, while myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematologic disorders characterized by ineffective hematopoiesis. Some studies suggest a relationship between MDS and BD, especially intestinal BD, and trisomy 8 seems to play an important role in both diseases. There are several reports on patients with BD comorbid with MDS involving trisomy 8 that frequently have intestinal lesions refractory to conventional medical therapies. Tumor necrosis factor (TNF)-αis strongly involved in the pathophysiology of several autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and BD. In addition, TNF-α plays an important role in the pathophysiology of MDS by inhibiting normal hematopoiesis and inducing the programmed cell death of normal total bone marrow cells and normal CD34+ cells. Recent clinical reports demonstrate the favorable effect of TNF-α antagonists in patients with refractory intestinal BD and in those with MDS. We present the case of a patient with intestinal BD and MDS involving trisomy 8 who was successfully treated with adalimumab. (Intest Res 2015;13:166-169)

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 Nak 대한장연구학회 2018 Intestinal Research Vol.16 No.4

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 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 (r_s=0.676, P<0.0001) and Mayo endoscopic subscore (MES; r_s=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. (Intest Res 2018;16:554-562)