Fumihito Hirai

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;)

White opaque substance within superficial elevated gastric neoplasia as visualized by magnification endoscopy with narrow-band imaging: a new optical sign for differentiating between adenoma and carcinoma

BACKGROUND The microvascular pattern (MVP) as visualized by magnification endoscopy (ME) is a reliable marker for differentiating between benign and malignant gastric flat lesions. However, in cases of gastric neoplasia of 0-IIa type, it is sometimes impossible to visualize the MVP because a white opaque substance (WOS) obscures the subepithelial MVP. OBJECTIVE To investigate whether the morphology of the WOS could be a useful optical sign for discriminating between adenoma and carcinoma. SETTING Single tertiary referral center. MATERIALS Forty-six gastric neoplasias of only 0-IIa type (18 adenomas and 28 early carcinomas) were evaluated. INTERVENTION The prevalence and the morphology of the WOS as visualized by ME with narrow-band imaging (NBI) according to histologic type (adenoma vs carcinoma). MAIN OUTCOME MEASUREMENTS The WOS is more frequently present in adenomas than in carcinomas. With regard to the morphology of the WOS, 100% of the examples of WOS within adenomas demonstrated a regular distribution; in contrast, 83% of the examples of WOS within carcinomas showed an irregular distribution. RESULTS In cases in which a neoplasia of 0-IIa type showed either WOS with a regular distribution or a regular MVP, the sensitivity and specificity for discriminating adenoma from carcinoma were 94% and 96%, respectively. LIMITATIONS The number of cases was limited. The WOS has not yet been characterized by chemical analysis. CONCLUSION In cases in which the WOS is observed, rather than assessing the MVP, morphologic analysis of the WOS could be an alternative new optical sign for discriminating adenoma from carcinoma when using ME with NBI.

Multicenter analysis of fecal microbiota profiles in Japanese patients with Crohn’s disease

BackgroundWe analyzed the fecal microbiota profiles of patients with Crohn’s disease (CD) at 4 inflammatory bowel disease (IBD) centers located in different districts in Japan.MethodsTerminal restriction fragment length polymorphism (T-RFLP) analysis was performed in 161 fecal samples from CD patients and 121 samples from healthy individuals. The bacterial diversity was evaluated by the Shannon diversity index (SDI).ResultsThere were no regional differences in the fecal microbiota profiles of the healthy individuals in Japan. A setting of similarity generated three major clusters of T-RFs: one included almost all the healthy individuals (118/121), and the other two clusters were mainly formed by CD patients at different stages of disease activity. The changes in simulated bacterial composition indicated that the class Clostridia, including the genus Faecalibacterium, was significantly decreased in CD patients with active disease and those in remission as compared with findings in the healthy individuals. In contrast, the genus Bacteroides was significantly increased in CD patients during the active phase as compared with findings in the healthy individuals. The genus Bifidobacterium was significantly decreased during the active phase of CD and increased to healthy levels during the remission phase. The bacterial diversity measured by the SDI was significantly reduced in CD patients during the active and remission phases as compared with findings in the healthy individuals. From the clinical data and T-RFLP analysis, we developed a logistic model to predict disease activity based on the fecal microbiota composition.ConclusionDysbiosis in CD patients was shown by a multi-IBD center study. The feasibility of using the fecal microbiota profile as a predictive marker for disease activity is proposed.

Short-term efficacy of enteral nutrition in the treatment of active Crohn's disease: a randomized, controlled trial comparing nutrient formulas

BACKGROUND The optimal dietary fat content to induce clinical remission in active Crohns disease has been the subject of controversy. We therefore performed a prospective, randomized, controlled study to compare the effects of nutrient formulas differing in the amount of medium-chain triglycerides (MCT). METHODS Thirty-six patients with active Crohns disease whose Crohns disease activity index (CDAI) was > or =150 were included in the study. A formula with 3.4 g of fat per 2000-kcal dose was used as the nutrient formula with a low-fat content (ED group), and a formula with 55.6 g of fat per 2000-kcal dose was used as the nutrient formula with a high amount of MCT (TL group). RESULTS The rate of short-term remission induction at 6 weeks was 67% in the ED group and 72% in the TL group (p = NS). Therapy markedly reduced the high CDAI and van Hees activity index in both groups, with no significant difference in the pattern of the time-course changes. C-reactive protein levels, erythrocyte sedimentation rate, and low serum albumin and plasma prealbumin levels normalized over the course of therapy, with no significant difference between the 2 groups. The assessment of fatty acid fractions revealed that the triene/tetraene ratio began to increase at 2 weeks in the ED group. The serum levels of linoleic acid, an omega-6 fatty acid, almost always varied within the normal range during the treatment period in the TL group, but in the ED group, levels began to decrease significantly at 2 weeks. The levels of linolenic acid, an omega-3 fatty acid, decreased in both groups. CONCLUSIONS Both nutrient formulas induced clinical remission in about two-thirds of patients. The results of the present study suggest that it is not necessary to restrict the amount of MCT when given in liquid form to patients with active Crohns disease.

Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase genotype in Japanese patients with inflammatory bowel disease

Background and Aims:  Azathioprine (AZA) is associated with a high frequency of adverse reactions. We examined polymorphism of the thiopurine S‐methyltransferase (TPMT) gene to determine whether the TPMT genotype would be a predictive marker for the development of adverse reactions to AZA.

ENDOSCOPIC BALLOON DILATATION USING DOUBLE‐BALLOON ENDOSCOPY IS A USEFUL AND SAFE TREATMENT FOR SMALL INTESTINAL STRICTURES IN CROHN'S DISEASE

Background:  Endoscopic balloon dilatation (EBD) is a therapeutic option for intestinal strictures of Crohns disease (CD). Double‐balloon endoscopy (DBE) enables EBD to be performed even for deep‐situated strictures of the small intestine. The aim of this study was to clarify the efficacy and safety of EBD using DBE for small bowel strictures in patients with CD.

The 2nd edition of consensus statements for the diagnosis and management of intestinal Behçet’s disease: indication of anti-TNFα monoclonal antibodies

BackgroundClinical evidence regarding intestinal Behçet’s disease (BD) management is lacking and intestinal lesions are a poor prognostic factor. In 2007, the Japan consensus statement for diagnosis and management of intestinal BD was developed. Recently, the efficacy of anti-tumor necrosis factor (TNF)α monoclonal antibodies (mAbs), and infliximab (IFX) was reported and adalimumab (ADA) was approved for intestinal BD in Japan. This study renewed consensus-based practice guidelines for diagnosis and treatment of intestinal BD focusing on the indication of anti-TNFα mAbs.MethodsAn expert panel of Japanese gastroenterology and rheumatology specialists was involved. Clinical statements for ratings were extracted from the literature, a professional group survey, and by an expert panel discussion, which rated clinical statements on a nine-point scale. After the first round of ratings, a panelist meeting discussed areas of disagreement and clarified areas of uncertainty. The list of clinical statements was revised after the panelist meeting and a second round of ratings was conducted.ResultsFifteen relevant articles were selected. Based on the first edition consensus statement, improved clinical statements regarding indications for anti-TNFα mAbs use were developed. After a two-round modified Delphi approach, the second edition of consensus statements was finalized.ConclusionsIn addition to standard therapies in the first edition, anti-TNFα mAbs (ADA and IFX) should be considered as a standard therapy for intestinal BD. Colchicines, thalidomide, other pharmacological therapy, endoscopic therapy, and leukocytapheresis were deemed experimental therapies.

Long-term outcome of endoscopic balloon dilation for small bowel strictures in patients with Crohn's disease.

Endoscopic balloon dilation (EBD) is an alternative to surgery for small bowel strictures of patients with Crohns disease (CD). However, little is known about the long‐term efficacy of EBD. The aim of the present study was to clarify the long‐term outcome of EBD for small bowel strictures in patients with CD.

Carbon dioxide insufflation compared with air insufflation in double-balloon enteroscopy: a prospective, randomized, double-blind trial

BACKGROUND Few studies have evaluated the degree of pain, the amount of retained gas, and the safety of carbon dioxide (CO(2)) insufflation in patients undergoing double-balloon enteroscopy (DBE). OBJECTIVE To clarify the usefulness and safety of CO(2) insufflation during DBE. DESIGN Single-center, prospective, randomized, double-blind, controlled trial. SETTING University hospital. PATIENTS Forty eligible patients with small-bowel disease for whom DBE was indicated were randomized to a CO(2) insufflation (CO(2)) group or an air insufflation (air) group by means of sealed envelopes. INTERVENTION DBE with insufflation of CO(2) or air. MAIN OUTCOME MEASUREMENTS Efficacy evaluation was based on the degree of pain as assessed by use of a visual analog scale (VAS) and the amount of residual gas retention within the small and large bowels on radiography. The safety of CO(2) insufflation was evaluated by arterial blood gas analysis. RESULTS Significantly fewer patients in the CO(2) group had severe pain of ≥ 50 mm on the VAS during DBE than in the air group (P = .02). Significantly less gas was retained in the small bowel just after and at 3 hours after DBE in the CO(2) group than in the air group (P = .003, P = .01, respectively). There was significantly less residual gas retention in the large bowel at 3 hours after DBE in the CO(2) group than in the air group (P = .02). There was no significant difference in pre-DBE and post-DBE partial pressure of oxygen in the blood (PaO(2)) and partial pressure of carbon dioxide in the blood (PaCO(2)) between groups. LIMITATIONS Small sample size. CONCLUSION CO(2) insufflation is a safe and useful procedure when performed during DBE.

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.