Nobuyuki Hida

Treatment of ulcerative colitis by feeding with germinated barley foodstuff: first report of a multicenter open control trial

Background. Germinated barley foodstuff (GBF) is a prebiotic foodstuff that effectively increases luminal butyrate production by stimulating the growth of protective bacteria. In the first pilot study, GBF has been shown to reduce both clinical activity and mucosal inflammation in ulcerative colitis (UC). The aim of this study was to investigate the efficacy of GBF in the treatment of UC in a multicenter open control trial. Methods. Eighteen patients with mildly to moderately active UC were divided into two groups using a random allocation protocol. The control group (n = 7) were given a baseline anti-inflammatory therapy for 4 weeks. In the GBF-treated group (n = 11), patients received 20–30 g GBF daily, together with the baseline treatment, for 4 weeks. The response to the treatments was evaluated clinically and endoscopically. Fecal micro-flora were also analyzed. Results. After 4 weeks of observation, the GBF-treated group showed a significant decrease in clinical activity index scores compared with the control group (P < 0.05). No side effects related to GBF were observed. GBF therapy increased fecal concentrations of Bifidobacterium and Eubacterium limosum. Conclusions. Oral GBF therapy may have the potency to reduce clinical activity of UC. We believe that these results support the use of GBF administration as a new adjunct therapy for UC.

Double‐blind, placebo‐controlled trial of oral tacrolimus (FK506) in the management of hospitalized patients with steroid‐refractory ulcerative colitis

Background: We report a multicenter study of oral tacrolimus (FK506) therapy in steroid‐refractory ulcerative colitis (UC). Methods: In a placebo‐controlled, double‐blind study, 62 patients with steroid‐refractory, moderate‐to‐severe UC were randomized into either a tacrolimus group or a placebo for 2 weeks. Patients were evaluated using the Disease Activity Index (DAI). As an entry criterion, patients had to have a total DAI score of 6 or more as well as a mucosal appearance subscore of 2 or 3. Clinical response was defined as improvement in all DAI subscores. Mucosal healing was defined as mucosal appearance subscore of 0 or 1. Clinical remission was defined as a total DAI score ≤2 with an individual subscore of 0 or 1. Results: The mean total DAI score at study entry was 9.8 ± 1.61 in the tacrolimus group and 9.1 ± 1.05 in the placebo group. At week 2 the clinical response rate was 50.0% (16/32) in the tacrolimus group and 13.3% (4/30) in the placebo group (P = 0.003). The rate of mucosal healing observed was 43.8% (14/32) in the tacrolimus group and 13.3% (4/30) in the placebo group (P = 0.012) and the rate of clinical remission observed was 9.4% (3/32) in the tacrolimus group and 0.0% (0/30) in the placebo group (P = 0.238). The therapies in this study were well tolerated, with only minor side effects. Conclusions: Oral tacrolimus therapy in patients with steroid‐refractory UC shortened the acute phase and induced rapid mucosal healing. These results suggest that tacrolimus therapy is useful as an alternative therapy for steroid‐refractory UC. (Inflamm Bowel Dis 2011;)

Scheduled infliximab monotherapy to prevent recurrence of Crohn's disease following ileocolic or ileal resection: A 3-year prospective randomized open trial

Background: Infliximab (IFX) is effective for remission induction and maintenance of Crohns disease (CD). This trial assessed the efficacy of scheduled maintenance IFX monotherapy to prevent postoperative CD recurrence. Methods: Thirty‐one CD patients who had ileocolic resection within the past 4 weeks were randomly assigned to scheduled IFX at 5 mg/kg intravenously every 8 weeks for 36 months (n = 15) or without IFX (control, n = 16). All patients were treated without immunomodulator or corticosteroid following surgery. The primary and secondary endpoints were remission rates at 12 and 36 months, defined as CD Activity Index (CDAI) ≤150, an International Organization for the Study of Inflammatory Bowel Disease (IOIBD) score <2, and C‐reactive protein (CRP) <0.3 mg/dL. Additionally, endoscopic recurrences at 12 and 36 months were evaluated. Results: At 12 and 36 months, 100%, and 93.3% of patients in the IFX group were in remission (IOIBD <2), respectively vs. 68.8% and 56.3% in the control arm (P < 0.03). Similarly, 86.7% and 86.7% of patients in the IFX group maintained serological remission (CRP <0.3 mg/dL) vs. 37.5% and 37.5% in the control arm (P < 0.02). Further, the IFX group achieved higher endoscopic remission at 12 months, 78.6% vs. 18.8% (P = 0.004). However, in the Kaplan–Meier survival analysis the CDAI scores between the two arms were not significantly different either at 12 or at 36 months. No adverse event (AE) was observed. Conclusions: An early intervention with IFX monotherapy should prevent clinical, serological, and endoscopic CD recurrence following ileocolic resection. Thiopurine naivety and eliminating the initial loading dose of IFX might minimize serious AEs. (Inflamm Bowel Dis 2012)

Demonstration of Low-Regulatory CD25High+CD4+ and High-Pro-inflammatory CD28−CD4+ T-Cell Subsets in Patients with Ulcerative Colitis: Modified by Selective Granulocyte and Monocyte Adsorption Apheresis

Low-CD25High+CD4+, a subset of regulatory CD25+CD4+ T cells and high-inflammatory CD28−CD4+ T cells can exacerbate ulcerative colitis (UC). This study sought to investigate the frequency of CD25High+CD4+ and CD28−CD4+ T cells in patients with UC and the changes in these cells during Adacolumn granulocyte and monocyte adsorption apheresis (GMA). Subjects were 12 patients with active UC, 11 with quiescent UC, and 14 healthy volunteers (HVs). The mean clinical activity index was 15.7xa0±xa02.2 in active UC and 4.5xa0±xa01.1 in quiescent UC. Peripheral blood samples were stained with CD4, CD25, and CD28 antibodies for flow cytometry. Patients with active UC received GMA and blood samples were examined before and after the first GMA session. Patients with active UC (Pxa0<xa00.04) or quiescent UC (Pxa0<xa00.02) had a higher percentage of CD28−D4+T cells compared with HVs, while the percentage of CD28+CD4+ T cells was lower in both UC groups compared with HVs (Pxa0=xa00.03 and Pxa0<xa00.02). Patients with active UC had a lower percentage of CD25High+CD4+T cells compared with quiescent UC patients (Pxa0<xa00.001). A significant increase in CD25High+CD4+ T cells was associated with GMA (Pxa0<xa00.03). Low CD25High+CD4+ and high CD28−CD4+ are prominent features in UC. The increase in CD25High+CD4+ T cells induced by GMA should contribute to improved immune function. Additional studies are warranted, since a low frequency of CD25High+CD4+− and a high frequency of CD28−CD4+− expressing T cells might be a predictor of clinical response to GMA.

Comparison of Targeted vs Random Biopsies for Surveillance of Ulcerative Colitis-Associated Colorectal Cancer.

BACKGROUND & AIMSnA random biopsy is recommended for surveillance of ulcerative colitis (UC)-associated colorectal cancer. However, a targeted biopsy might be more effective. We conducted a randomized controlled trial to compare rates of neoplasia detection by targeted vs random biopsies in patients with UC.nnnMETHODSnWe performed a study of 246 patients with UC for 7 years or more, seen at 52 institutions in Japan from October 1, 2008 through December 31, 2010. Patients were randomly assigned to the random group (4 random biopsies collected every 10 cm in addition to targeted biopsies, nxa0= 122) or the target group (biopsies collected from locations of suspected neoplasia, nxa0= 124). The primary end point was the number of neoplastic lesions detected in a single surveillance colonoscopy. We estimated the ratio and difference in the mean number of neoplastic lesions between the groups. We also evaluated the non-inferiority between the groups as an exploratory study. A non-inferiority margin of 0.65 (0.13 of 0.20) was considered for the ratio of the mean number of neoplastic lesions between groups.nnnRESULTSnThe mean number of biopsies found to contain neoplastic tissue per colonoscopy was 0.211 (24 of 114) in the target group and 0.168 (18 of 107) in the random group (ratio of 1.251; 95% confidence interval, 0.679-2.306). The lower limit was above the non-inferiority margin of 0.65. Neoplasias were detected in 11.4% of patients in the target group and 9.3% of patients in the random group (Pxa0= .617). Larger numbers of biopsy samples per colonoscopy were collected in the random group (34.8 vs 3.1 in the target group; P < .001), and the total examination time was longer (41.7 vs 26.6 minutes in the target group; Pxa0<xa0.001). In the random group, all neoplastic tissues found in random biopsies were collected from areas of the mucosa with a history or presence of inflammation.nnnCONCLUSIONSnIn a randomized controlled trial, we found that targeted and random biopsies detect similar proportions of neoplasias. However, a targeted biopsy appears to be a more cost-effective method. Random biopsies from areas without any signs of present or past inflammation were not found to contain neoplastic tissues. Clinical Trial Registry: UMIN000001608.

Association between IL-18 gene promoter polymorphisms and inflammatory bowel disease in a Japanese population

Background: Interleukin‐18 (IL‐18) is a pleiotropic cytokine that induces the production of interferon (IFN)‐&ggr; and also to regulate Th2 cytokines. Recently, association studies between IL‐18 gene promoter polymorphisms and several Th1‐ or Th2‐mediated inflammatory diseases were reported. In inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohns disease (CD), recent evidence suggests that IL‐18 is involved in the pathogenesis. Methods: Using DNA direct sequencing, we investigated IL‐18 gene promoter polymorphisms at −607C/A and −137G/C. Allele, genotype, and haplotype frequencies were determined in 210 Japanese patients with UC, 205 patients with CD, and 212 controls. Results: In UC, the −137C allele frequency was significantly higher in the proctitis‐type patients than in controls (Pc = 0.0068). The −137 genotype frequency was also significantly different in the proctitis‐type patients than in controls (Pc = 0.032). No other allele and genotype frequencies were significantly associated with UC after Bonferroni correction. Furthermore, the frequency of haplotype 2 (−607A, −137C), which had a lower promoter activity and IFN‐&ggr; mRNA level than the other haplotypes as previously reported, was significantly higher in the proctitis‐type patients than in controls (Pc = 0.01). In CD, we could not find any significant differences. Conclusions: IL‐18 gene promoter polymorphisms may not be associated with disease susceptibility but related to the extent of disease in UC.

Gastroduodenitis associated with ulcerative colitis

BackgroundUlcerative colitis (UC) is regarded as confined to the colorectum; however, there are several case reports showing upper gastrointestinal involvement. The aim of this study was to examine the prevalence and characteristics of gastroduodenitis associated with UC (GDUC).MethodsEsophagogastroduodenoscopy with biopsies was prospectively performed on 250 UC patients (134 men, 116 women; mean age, 42 years; 162 with colectomy, 163 with pancolitis). Criteria for GDUC were created on the basis of endoscopic and histological comparisons with non-UC controls, and the prevalence and characteristics were statistically analyzed.ResultsGDUC was defined endoscopically as friable mucosa (erosive or ulcerative mucosa with contact or spontaneous bleeding), granular mucosa (multiple white spots almost without a red halo), or, conditionally, multiple aphthae (multiple white spots surrounded by a red halo, clinically excluding other disorders such as Crohn’s disease). The prevalence of GDUC was 19/250 (7.6%). The clinical characteristics included more extensive colitis, lower dose of prednisolone, higher prevalence of pouchitis, and longer postoperative period. In our population, the presence of pancolitis and a lower dose of prednisolone were significant risk factors for developing GDUC in multivariate analysis.ConclusionsThe high prevalence of GDUC suggests that the gut inflammatory reaction in UC may not be restricted to the large intestine. Administered steroids might conceal GDUC, and more aggressive UC such as active pancolitis may be related to the development of GDUC.

Effects of Hepatocyte Growth Factor on Rat Inflammatory Bowel Disease Models

Hepatocyte growth factor (HGF) is a hepatotrophic factor and, also, functions as an epithelial growth factor. We examined the therapeutic effects of HGF on rat inflammatory bowel disease models induced by trinitrobenzensulfonic acid or dextran sulfate sodium. Recombinant human HGF was continuously administered at 50 μg/body/day using an intraperitoneally implanted pump for 7 days. Treatment of HGF reduced the ulcerated area, histological damage score, mucosal myeloperoxidase activity, and epithelial apoptotic rate but did not increase epithelial mitotic rate and immunohistochemical labeling indexes of proliferating cell nuclear antigen, Ki-67, and bromodeoxyuridine as indexes of epithelial cell proliferation in either model. We then examined the epithelial localization of the HGF receptor c-met and identified it on the surface epithelia, where apoptosis was observed, but did not find it in the proliferative zone. These results suggest that HGF exhibits therapeutic effects via anti-inflammation including antiapoptosis rather than epithelial cell proliferation in these inflammatory bowel disease models.

Placebo controlled evaluation of Xilei San, a herbal preparation in patients with intractable ulcerative proctitis

Background and Aim:u2002 Topical mesalamine or corticosteroid has shown efficacy in patients with ulcerative proctitis, but patients often become refractory to these interventions. Xilei San is a herbal preparation with evidence of anti‐inflammatory effects. We evaluated the efficacy of topical Xilei San in ulcerative proctitis patients.

Activated platelets as a possible early marker to predict clinical efficacy of leukocytapheresis in severe ulcerative colitis patients

BackgroundLeukocytapheresis (LCAP) is an effective adjunct for patients with active ulcerative colitis (UC). Because LCAP may have the potential to remove and modulate not only leukocytes but also platelets, we evaluated the correlation between activated platelets and the therapeutic response to LCAP.MethodsFourteen patients with severe UC received weekly LCAP for 5 consecutive weeks. Their average clinical activity index (CAI) and endoscopic index (EI) were 9.6 ± 3.4 and 10.9 ± 1.0, respectively. Their peripheral blood was sampled before and after every LCAP and stained with fluorescent antibodies to the activation-dependent surface antigens of platelets (CD63, CD62-P) prior to flow cytometry. Endoscopic evaluations were performed after the last LCAP.ResultsClinical remission (CAI < 4) was induced in 50% of the patients (7/14) after 5 weeks, and there were no significant differences observed in clinical background between the responder group (RG) and the nonresponder group (NG). In the RG, the populations of CD63+ (P < 0.03) and CD62-P+ (P < 0.05) platelets were significantly decreased after the first LCAP, and their reduction ratio decreased gradually with repeated LCAP. A significant improvement of the EI score, especially mucosal damage, was achieved in RG (P < 0.04) but not in NG.ConclusionsThese results indicate that the therapeutic responses to LCAP were reflected in modulations of population and/or platelet functions, especially after the first session. The decrease of such activated platelets immediately after the first LCAP may be an early marker for predicting the response in patients with severe UC.