Nobuo Hiwatashi

Crohn's disease in Japan: Diagnostic criteria and epidemiology

New diagnostic criteria for Crohns disease and a review of Japanese epidemiologic studies are presented. New diagnostic criteria for Crohns disease were established by the Research Committee of Inflammatory Bowel Disease, set up by the Japanese Ministry of Health and Welfare. For a definite diagnosis one of the following three conditions is required: 1) longitudinal ulcer or luminal deformity induced by longitudinal ulcer or cobblestone pattern, 2) intestinal small aphthous ulcerations arranged in a longitudinal fashion for at least three months plus noncaseating granulomas, and 3) multiple small aphthous ulcerations in both the upper and lower digestive tract not necessarily with longitudinal arrangement, for at least three months, plus noncaseating granulomas. Moreover, ulcerative colitis, ischemic enterocolitis, and acute infectious enterocolitis should be excluded. Data from the Japanese Ministry of Health and Welfare, in addition to data collected from two study groups, these being the two largest studies in Japan, are reviewed with regard to epidemiology. The number of patients with Crohns disease has increased remarkably. The prevalence and the annual incidence of patients with Crohns disease in Japan were estimated to be approximately 2.9 and 0.6 per 105 population in 1986, respectively, and 13.5 and 1.2 per 105 population in 1998. Characteristic features of Crohns disease in Japan are that the male-female ratio exceeds 2, and that there is no second peak of incidence in the age group of 55 to 65 years. Clinically, Crohns disease with only multiple small aphthous ulcerations, which is the earliest stage of the disease that is diagnosable, was found in 5 percent of patients.

Multicenter Randomized Controlled Trial for the Treatment of Ulcerative Colitis with a Leukocytapheresis Column

The administration of steroids is not always effective for the treatment of ulcerative colitis (UC). Their long-term use often causes adverse effects which sometimes result in their stoppage and acute exacerbation. Therefore, an alternative treatment is necessary in order to decrease steroid dosage and avoid the clinical problems associated with steroids. Methods The effectiveness and adverse effects of a leukocytapheresis (LCAP) were investigated in a controlled multicenter trial with randomized assignment of 76 active-stage UC patients in two groups. In the LCAP group (39 patients), LCAP weekly for 5 weeks as an intensive therapy was added to the on-going drug therapy, while steroids were maintained but not increased, and then LCAP was gradually reduced to once every 4 weeks as a maintenance therapy. In the high dose prednisolone (h-PSL) group (37 patients), PSL was added or increased 30 approximately 40 mg/day for moderately severe and 60 approximately 80 mg/day for severe patients and then gradually tapered. Findings The LCAP group showed a significantly higher effectiveness (74% vs. 38%; p=0.005) and lower incidence of adverse effects (24% vs. 68%; p<0.001). The patients were able to continue the trial for a longer period in the LCAP group than the h-PSL group (p=0.012). Clinical activity and endoscopic indexes showed the LCAP group had better improvements than the h-PSL group. Interpretation The results of the trial show that LCAP permits a reduction in total PSL dosage and is more effective and safer than high-dose PSL administration for intensive therapy, and LCAP may maintain remission longer than PSL.

Effectiveness of an ‘half elemental diet’ as maintenance therapy for Crohn's disease: a randomized-controlled trial

Although thiopurines have a proven role in maintenance therapy for Crohns disease, an alternative therapy is needed for patients intolerant or resistant to thiopurines.

Development of consensus statements for the diagnosis and management of intestinal Behçet's disease using a modified Delphi approach

BackgroundAlthough intestinal Behçets disease has been treated anecdotally with various therapeutic modalities, clinical evidence regarding management of intestinal Behçets disease is lacking. The objective of this study was to develop consensus-based practice guidelines for diagnosis and treatment of intestinal Behçets disease by using a modified Delphi approach.MethodsThree groups of Japanese gastroenterology specialists were involved in the study: moderators, an expert panel, and a professional group. Clinical statements for ratings were extracted from relevant literature, a survey of the professional group, and by discussion among the expert panel. The expert panel rated the clinical statements according to a nine point scale. After the first round of ratings, a panelist meeting was held to discuss areas of disagreement and to clarify areas of uncertainty. The list of clinical statements was revised after the panelist meeting, and a second round of rating was conducted.ResultsThirty-two relevant articles were selected in a literature search, and 35 clinical statements were extracted. An additional 209 clinical statements were developed from the survey and discussion among gastroenterology specialists. In the first and second rounds, 56% and 60% of statements, respectively, received median scores ≥7. The range of scores decreased considerably from the first to the second round.Conclusions5-Aminosalycylic acid, corticosteroids, immunosuppressants, enteral nutrition, total parenteral nutrition, and surgical therapy were considered standard therapy for intestinal Behçets disease. Infliximab, colchicines, thalidomide, other pharmacological therapy, endoscopic therapy, and leukocytapheresis were deemed experimental therapy. Based on a two-round modified Delphi approach, practice guidelines for diagnosis and treatment of intestinal Behçets disease were developed.

A randomized, double-blind, placebo-controlled clinical trial of the effectiveness of the novel serotonin type 3 receptor antagonist ramosetron in both male and female Japanese patients with diarrhea-predominant irritable bowel syndrome

Objective. Irritable bowel syndrome is characterized by abdominal discomfort and/or pain associated with altered bowel habits. The neurotransmitter serotonin and serotonin type 3 receptors that are extensively distributed on enteric neurons in the human gastrointestinal tract play a role in increasing the sensation of pain and affecting bowel habits in patients with irritable bowel syndrome. The aim of this study was to evaluate the efficacy and safety of the serotonin type 3 receptor antagonist ramosetron hydrochloride in Japanese patients with diarrhea-predominant irritable bowel syndrome. Material and methods. In a double-blind, placebo-controlled, parallel group-comparative study with a 1-week run-in period, 539 patients with diarrhea-predominant irritable bowel syndrome meeting the Rome II diagnostic criteria received either 5 µg ramosetron hydrochloride (n=270) or placebo (n=269) once daily for 12 weeks. Results. Forty-seven percent of ramosetron hydrochloride-treated patients were monthly responders in the primary end-point, “Patient-reported global assessment of relief of irritable bowel syndrome symptoms”, compared with 27% for placebos (p<0.001). The most frequently reported adverse event in the ramosetron hydrochloride-treated group compared with the placebo group was hard stool. Conclusions. Ramosetron hydrochloride 5 µg once daily is effective and well tolerated in the treatment of abdominal pain, discomfort and bowel habits in patients with diarrhea-predominant irritable bowel syndrome.

Dietary fat attenuates the benefits of an elemental diet in active Crohn's disease: a randomized, controlled trial.

Objectives Although an elemental diet has been established as the primary treatment for patients with Crohns disease, the influence of dietary fat on the elemental diet remains unclear. We have designed the first randomized, controlled trial for elemental diets containing different fat percentages in patients with active Crohns disease. Methods Each patient was randomized to receive one of three dose levels of fat in an elemental diet (Elental) for 4 weeks: 10 patients received low fat (3.06 g/day), 10 patients received medium fat (16.56 g/day) and eight patients received high fat (30.06 g/day). The additional fat was composed of long-chain fatty acids. All patients were evaluated using the International Organization of Inflammatory Bowel Disease rating, plus C-reactive protein level and erythrocyte sedimentation rate, which were measured at weekly intervals. Results Although the International Organization of Inflammatory Bowel Disease rating, C-reactive protein level and erythrocyte sedimentation rate in the low-fat group decreased, the values in the medium- and high-fat groups fluctuated during the study. The remission rate after 4 weeks in each group was 80%, 40% and 25% for patients in the low-, medium- and high-fat groups, respectively. Conclusions When the fat consisted of long-chain triglycerides, a high amount of this fat in the elemental diet formula decreased its therapeutic effect against active Crohns disease.

Changes in neuropeptide-containing nerves in human colonic mucosa with inflammatory bowel disease

The distribution abnormality of vasoactive intestinal polypeptide‐containing nerves (VIP‐nerves) and substance P‐containing nerves (SP‐nerves) was immunohistochemically investigated in the colonic mucosa with inflammatory bowel disease (IBD) in relation to colonic glands and blood vessels In the lamina propria. In active ulcerative colitis (UC), VIP‐ and SP‐nerves decreased in severe inflammatory lesions. VIP‐nerves were almost absent particularly around crypt abscesses. Even In resolving and quiescent UC, VIP‐nerves still decreased, depending on the decrease of glands and blood vessels. On the other hand, both nerves Increased in some hypervascular lesions. In the uninvolved mucosa of UC, they did not change their distribution. In Crohns disease, the distribution abnormality of both nerves resembled that of UC. These results suggest that the changes in VIP‐and SP‐nerve distributions in the mucosa with IBD are subsequent to mucosal inflammation and damage. However, these peptides are known to be immunoregulators, and their distribution abnormalities may induce the disorder of immunoregulation in the IBD mucosa and cause the mucosal damage and/or chronicity.

A Phase II Trial of the Novel Serotonin Type 3 Receptor Antagonist Ramosetron in Japanese Male and Female Patients with Diarrhea-Predominant Irritable Bowel Syndrome

Background: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder. Serotonin type 3 (5-HT3) receptor antagonist alosetron hydrochloride is indicated for women with chronic, severe diarrhea-predominant IBS who have not responded adequately to conventional therapy. However, whether or not the therapeutic efficacy of 5-HT3 receptor antagonists has gender difference is uncertain. Methods: A double-blind, placebo-controlled, parallel-group, comparative study was conducted to evaluate the effect of novel 5-HT3 receptor antagonist, ramosetron hydrochloride, in male and female patients with diarrhea-predominant IBS. 418 subjects were randomized (109 subjects: placebo, 105 subjects: 1 µg, 103 subjects: 5 µg, and 101 subjects: 10 µg) and administered the study drug once daily. Results: The monthly responder rates of ‘Patient-reported global assessment of relief of irritable bowel syndrome symptoms’ in the 5- and 10-µg ramosetron hydrochloride-administered groups were higher than the placebo group (26.92, 42.57, and 43.01% for placebo, 5 and 10 µg). Moreover, the difference of the responder rate in comparison with the placebo group was similar in males and females. As for safety, there was tolerability at doses up to 10 µg. Conclusion: Ramosetron is an effective and well-tolerated treatment not only for female IBS patients but also for male patients.

Telomere shortening in the colonic mucosa of patients with ulcerative colitis.

Abstract: Telomere length in human somatic cells gradually decreases with the number of cell divisions and is regarded as a marker of somatic cell turnover. Mucosal cells of the affected colon show rapid turnover in individuals with active ulcerative colitis (UC). Telomere length was determined by Southern blot analysis of terminal restriction fragments (TRFs) from the colonic mucosa of 17 patients with UC in remission, two of whom showed dysplasia, and 17 control subjects without colitis. For each individual, mean TRF length was compared between rectal mucosa and unaffected cecal mucosa. The mean TRF length of the rectal mucosa was significantly less than that of cecal mucosa in UC patients (7.87 ± 0.36 kb versus 8.77 ± 0.21 kb; P = 0.0015, Wilcoxon signed rank test), whereas no significant difference was detected in the control subjects. The extent of telomere shortening was 10.6 ± 3.35% in UC patients, compared with 0.8 ± 0.64% in noncolitis controls (P = 0.0024, Mann-Whitney U-test). Four UC patients, two of whom had dysplasia, showed telomere shortening of more than 20% in the rectal mucosa. These observations suggest that telomere shortening in the colonic mucosa of individuals with UC may represent the history of mucosal inflammation during disease of long duration, and that it may contribute to aneuploidy in UC.

Clinical course and longterm prognosis of Japanese patients with Crohn's disease: predictive factors, rates of operation, and mortality.

BackgroundThe purpose of this study was to clarify the long-term course of Crohn’s disease (CD) and predictors of its prognosis in Japan.MethodsThis was a historical cohort study of 276 patients with CD who had been diagnosed between 1965 and 1998. The clinical course was evaluated by the course of the CD score (CCDS) according to the required treatments. The predictive factors were examined by stepwise regression test. The cumulative rates of operation and survival were calculated by the Kaplan-Meier method.ResultsPatients with colitis-type CD had significantly lower annual and cumulative operation rates than those with other types, and showed significantly better progress, estimated by the CCDS, than patients with ileocolitis type. Reliable predictors for the 2- to 5-year clinical course after starting treatment were the CCDS, the presence of laparotomy during the initial year, and onset at age 30 years or more. The predictors for the 6- to 10-year clinical course were the duration of symptoms at diagnosis and onset at age 16 years or less. The predictors for the 11- to 15-year clinical course were the CCDS, the maximum International Organization of the Study of Inflammatory Bowel Disease (IOIBD) assessment score during the first year after starting treatment, and the effectiveness of the initial treatment. Relative survival rates at 5, 10, 15, and 20 years after the onset were 98.9%, 98.1%, 97.7%, and 94.9%, respectively.ConclusionsCD patients with colitis type showed a better clinical course and had significantly different clinical features compared with the patients with ileitis and ileocolitis type. Prediction of the longterm course of CD is possible by using clinical factors during the first year after starting treatment. The relative survival rates in Japanese patients with CD are not different from those seen in Western countries.