Satoshi Motoya

Adsorptive granulocyte and monocyte apheresis for refractory Crohn's disease : an open multicenter prospective study

BackgroundActive Crohn’s disease (CD) is often associated with elevated levels of platelets, granulocytes, and monocytes that are activated and resistant to apoptosis. The level of neutrophils in the intestinal mucosa has been quantitatively related to the severity of intestinal inflammation in CD. We postulated that patients with CD that is refractory to conventional medications might respond to a reduction of granulocytes and monocytes by adsorptive apheresis.MethodsTwenty-one patients with a CD activity index (CDAI) of 200–399 and unresponsive to standard medication, which included nutritional intervention, received granulocyte and monocyte adsorptive apheresis (GCAP) as an adjunct to their ongoing medication. GCAP was performed with an Adacolumn, which adsorbs granulocytes, monocytes, and a small fraction of lymphocytes (FcγR and complement receptor-bearing leucocytes). Patients received one GCAP session/week for 5 consecutive weeks. CDAI, International Organization for the Study of Inflammatory Bowel Disease (IOIBD), and IBD questionnaire (IBDQ) scores were evaluated.ResultsDuring the initial conventional/nutritional therapy, no significant improvement was seen in any patient. However, at week 7 of GCAP therapy, significant improvements in CDAI, IOIBD, and IBDQ scores were observed. The CDAI, IOIBD, and IBDQ scores before GCAP were 275.6 ± 54.2, 3.4 ± 1.4, and 152 ± 22, respectively. The corresponding values after GCAP were 214.8 ± 89.2 (P = 0.0005), 2.54 ± 1.5 (P = 0.0224), and 165 ± 29 (P = 0.0327), respectively.ConclusionsGCAP could be effective for inducing remission and improving quality of life in patients with active CD that is refractory to conventional therapy.

A genome-wide association study identifies 2 susceptibility Loci for Crohn's disease in a Japanese population.

BACKGROUND & AIMS Crohns disease is an inflammatory bowel disease induced by multiple genetic and environmental factors. Genome-wide association studies have identified genetic factors that affect the risk for Crohns disease in European populations, but information from other ethnic groups is scarce. We therefore investigated genetic factors associated with Crohns disease in the Japanese population. METHODS We performed a genome-wide association study with 372 individuals with Crohns disease (cases) and 3389 controls, all from the Japanese population. To confirm identified associations, we performed a replication study with an independent panel of 1151 Crohns disease cases and 15,800 controls. We also performed an association analysis using genome-wide genotype imputation in the discovery cohort. RESULTS We confirmed associations of Crohns disease with variants in MHC (rs7765379, P = 2.11 × 10(-59)), TNFSF15 (rs6478106, P = 3.87 × 10(-45)), and STAT3 (rs9891119, P = 2.24 × 10(-14)). We identified 2 new susceptibility loci: on chromosome 4p14 (rs1487630, P = 2.40 × 10(-11); odds ratio, 1.33), and in the SLC25A15-ELF1-WBP4 region on 13q14 (rs7329174 in ELF1, P = 5.12 × 10(-9); odds ratio, 1.27). CONCLUSIONS In a genome-wide association study, we identified 2 new susceptibility loci for Crohns disease in a Japanese population. These findings could increase our understanding of the pathogenesis of Crohns disease.

Prevalence of Barrett's esophagus and expression of mucin antigens detected by a panel of monoclonal antibodies in Barrett's esophagus and esophageal adenocarcinoma in Japan.

Abstract: Barretts esophagus (BE) is an acquired disorder associated with a high incidence of adenocarcinoma of the lower esophagus. Moreover, it has been reported that short-segment BE may be associated with adenocarcinoma of the esophagogastric junction. The objective of this study was to define the prevalence of BE and the mucin profile in BE, including the short-segment type, and to compare the mucin profile in BE with the profiles of Barretts adenocarcinoma and distal esophageal adenocarcinoma among Japanese. In total, 650 adult subjects underwent endoscopic examination for evaluation of BE. Although the prevalence of traditional (long segment) BE was 0.62%, the overall prevalence of BE including short-segment type was 15.7%. In Barretts epithelium, the short-segment type predominantly had gastric type mucin, while the middle- and long-segment types possessed intestinal mucin, especially colonic type mucin (sulfo-Lewisa), with high frequency. In Barretts epithelium with adenocarcinoma, all Barretts epithelium adjacent to carcinomas showed a predominance of immunoreactivity to sulfo-Lewisa. In Barretts adenocarcinomas, colonic type mucin was detected in 100% by monoclonal antibody (MoAb) 91.9H. Small-intestinal mucin and gastric mucin were stained in 50% and 12.5% of the subjects, respectively. Colonic type mucin was also detected with high frequency (80%) in distal esophageal adenocarcinomas without Barretts epithelium. These data suggest that the epitope, not of small-intestinal type or gastric type mucin, but of colonic type mucin (sulfo-Lewisa), may be associated with, at least in part, the malignant phenotype of BE.

Inflammatory gene signature in ulcerative colitis with cDNA macroarray analysis

Background : Most array analyses of ulcerative colitis have focused on identifying susceptibility genes for ulcerative colitis.

MUC1 Mucin Core Protein Binds to the Domain 1 of ICAM-1

Background: MUC1 is aberrantly expressed on a variety of epithelial tumors. We have reported that MUC1 plays important roles in separation from primary site, invasion into the stromal tissue, and protection from immune responses. The aim of this study is to determine the precise binding of MUC1 to intercellular adhesion molecule 1 (ICAM-1) that accelerates the cancer metastasis. Methods: A cell aggregation assay between MUC1 cDNA transfectants and ICAM-1 expressing cells was employed. An anti-MUC1 antibody, anti-ICAM-1 antibody or synthetic peptide of MUC1 core protein was added to the assay to inhibit the cell aggregation. Results: MUC1 transfectants showed a significantly higher aggregation rate compared to the control cells. This aggregation was further enhanced by the inhibition of O-glycan biosynthesis. It was inhibited by either an anti-MUC1 antibody recognizing the tandem repeat domain of MUC1 core protein or an anti-ICAM-1 antibody identifying domain 1. It was also inhibited by a synthetic MUC1 peptide of 40 amino acids corresponding to two tandem repeats. Conclusions: The results revealed that a tandem repeat domain of MUC1 mucin core protein binds to domain 1 of ICAM-1, suggesting a potential role of MUC1- ICAM-1 interaction in the metastasis of epithelial tumors.

Retrieval of serum infliximab level by shortening the maintenance infusion interval is correlated with clinical efficacy in Crohn's disease.

Background: Infliximab has shown beneficial effects in the treatment of Crohns disease (CD). The aim of this study was to assess 1) the clinical efficacy of shortening the infusion interval from 8 to 4 weeks when patients had shown loss of response during maintenance therapy, and 2) the association between the serum trough level and clinical efficacy. Methods: This was an open‐label prospective multicenter study. Infliximab was administered at 5 mg/kg to patients with active CD at weeks 0, 2, and 6. Week 10 responders received infliximab every 8 weeks thereafter. In those with loss of response after week 14 the interval was switched to every 4 weeks. Co‐primary endpoints were the rate of patients achieving clinical response and remission at week 54. Serum level of infliximab was measured at each visit. Results: Fifty‐seven patients who responded to induction treatment received maintenance therapy after week 14. Thirty‐seven patients continued at the 8‐week interval and 20 patients were switched to a 4‐week interval. The overall clinical response and remission rates at week 54 were 82.5% and 61.4%, respectively. For those with loss of response, treatment at the 4‐week interval resulted in clinical response and remission rates of 83.3% (15/18) and 55.6% (10/18), respectively, at week 54. A correlation between clinical efficacy and serum trough level was found (P < 0.01, overall). Conclusions: A treatment strategy with an option of shortening the dosing interval of infliximab retrieves its trough level and may be useful for maintaining its efficacy. (Inflamm Bowel Dis 2012)

Association study of 71 European Crohn's disease susceptibility loci in a Japanese population.

Background:A large-scale meta-analysis of a series of European genome-wide association studies revealed 71 susceptibility loci for Crohns disease (CD). However, it is not clear whether these susceptibility loci are also shared with Japanese populations. Methods:We genotyped 71 single-nucleotide polymorphisms (SNPs) comprising 1311 CD cases and 6585 controls of Japanese descent, and their associations with CD were evaluated using the Cochran–Armitage trend test. In addition, genotype–phenotype analyses were conducted on the SNPs showing associations with Japanese CD based on the Montreal classification. Results:Twenty-seven SNPs showed at least nominal association (P < 0.05) and 11 of them remained significant even after Bonferroni correction (P < 0.0007). Despite high statistical power, we could not find any association in 17 loci. Moreover, SNPs in 9 loci were rare or absent in the Japanese population. Genetic variations involved in the innate immune system (NOD2, ATG16L1, and IRGM) showed no association with CD susceptibility in the Japanese population. Genotype–phenotype analyses showed that rs3810936, a marker of TNFSF15, correlated with severe CD phenotypes. Conclusions:Our study suggests that there is a differential genetic background of CD susceptibility between Japanese and European populations.

Adalimumab for the Treatment of Japanese Patients With Intestinal Behçet’s Disease

BACKGROUND & AIMS Behçets disease is a chronic, relapsing inflammatory disease that can involve the mouth, skin, eyes, genitals, and intestines. Active intestinal Behçets disease can be complicated by gastrointestinal (GI) bleeding and perforation. We performed a multicenter, open-label, uncontrolled study to evaluate the efficacy and safety of adalimumab, a fully human monoclonal antibody against tumor necrosis factor α, in patients with intestinal Behçets disease who were refractory to corticosteroid and/or immunomodulator therapies. METHODS The study was conducted at 12 sites in Japan, from November 2010 through October 2012. Twenty patients were given 160 mg adalimumab at the start of the study and 80 mg 2 weeks later, followed by 40 mg every other week for 52 weeks; for some patients, the dose was increased to 80 mg every other week. A composite efficacy index, combining GI symptom and endoscopic assessments, was used to evaluate efficacy. The primary efficacy end point was the percentage of patients with scores of 1 or lower for GI symptom and endoscopic assessments at week 24. Secondary end points included complete remission and resolution of non-GI Behçets-related symptoms. RESULTS Nine patients (45%) had GI symptom and endoscopic assessment scores of 1 or lower at week 24 of treatment, and 12 patients (60%) had these scores by week 52. Four patients (20%) achieved complete remission at weeks 24 and 52. Individual global GI symptom and endoscopic scores improved for most patients at weeks 24 and 52. Two thirds of patients with oral aphthous ulcers, skin symptoms, and genital ulcers, and 88% of patients with erythema nodosum had complete resolution of these conditions at week 52. A total of 9 of 13 patients (69%) taking steroids at baseline were able to taper (n = 1) or completely discontinue steroids (n = 8) during the study. No new safety signals were observed. CONCLUSIONS Adalimumab is a potentially effective treatment for intestinal Behçets disease in Japanese patients who are refractory to conventional treatments. ClinicalTrials.gov number: NCT01243671.

Mucins and Immune Reactions to Mucins in Ulcerative Colitis

Ulcerative colitis (UC) is an inflammatory bowel disease of undetermined etiology. Mucins, mainly produced by goblet cells, protect colon cells from various kinds of stress. Alteration in the quality or quantity of mucins may be the cause of the disease. Another possible cause is immune reactions to colonic cells. Anti-MUC1 antibodies were detected in the sera of patients with UC. Antibodies would destroy the colonic cells through antibody-dependent cell-mediated cytotoxicity. We reviewed the significance of mucins as well as humoral and cellular immunity in the pathogenesis of UC.

Use of capsule endoscopy in patients with Crohn's disease in Japan: A multicenter survey

Until the approval of patency capsule, capsule endoscopy (CE) has not been routinely applied for the diagnosis of Crohns disease (CD) in Japan. We aimed to survey current situation of CE use for patients with CD in Japan.