Prediction of 6-thioguanine nucleotides levels in Japanese patients with inflammatory bowel diseases during long-term thiopurine administration.

BACKGROUND: The monitoring of 6-thioguanine nucleotides (6-TGN) levels is warranted during thiopurine therapy for patients with inflammatory bowel diseases. AIMS: The aim of this study was to elucidate the parameters that can predict the 6-TGN levels among Japanese patients with inflammatory bowel diseases undergoing thiopurine therapy. MATERIAL AND METHODS: The 6-TGN levels were measured in 54 patients with inflammatory bowel diseases (32 with ulcerative colitis and 22 with Crohn's disease), who had been administered azathioprine or 6-mercaptopurine for more than 90 days. Possible correlations between the hematologic parameters and 6-TGN levels were investigated. The clinical and hematologic variables were evaluated to determine the 6-TGN levels of less than or over 235 pmol/8 x 10(8) RBCs. RESULTS: The 6-TGN levels correlated significantly with changes in the mean corpuscular volume (R = 0.423, p = 0.001) and the lymphocyte counts (R = -0.280, p = 0.04). A multivariate analysis revealed changes in the mean corpuscular volume (OR: 1.22, 95% CI: 1.07-1.40) and hemoglobin levels (OR: 0.59, 95% CI: 0.35-0.99) to be factors predictive of the 6-TGN levels. An increase in the mean corpuscular volume of 3.5 fl was determined to be the most preferable cut-off value to distinguish patients with 6-TGN >or= 235 pmol/8 x 10(8) RBCs from those with a lower concentration. CONCLUSIONS: Changes in the mean corpuscular volume are considered to be predictive of the 6-TGN levels in patients with inflammatory bowel diseases receiving thiopurine therapy.

Differential expression of leukocyte functions associated antigen-1 (LFA-1) on peripheral blood mononuclear cells in patients with Crohn's disease.

BACKGROUND: The leukocyte function associated antigen-1 (LFA-1) intracellular adhesion molecule-1 pathway is presumed to play a pivotal role in the perpetuation of inflammatory bowel disease. We aimed to elucidate the effect of 2 different therapies on LFA-1 expression in patients with Crohn's disease (CD) and correlate LFA-1 expression with disease activity. METHODS: In all, 30 patients with active CD were recruited for the present investigation. Eleven patients were treated with infliximab and 19 patients with total parenteral nutrition. The clinical activity and the expression of LFA-1 in peripheral blood mononuclear cells were assessed prior to and 4 weeks after treatment. Clinical activity was determined by measuring the Crohn's Disease Activity Index and LFA-1 expression was measured by mean fluorescence intensity (MFI) under fluorescence-activated cell sorter analysis. RESULTS: In each treatment group the clinical disease activity index decreased significantly 4 weeks after treatment. In patients treated with infliximab, LFA-1 expression decreased significantly (mean MFI decreased from 1983 to 1487, P < 0.05). However, LFA-1 expression remained unchanged in the total parenteral nutrition group (mean MFI elevated from 1684 to 1902, P > 0.05). CONCLUSIONS: The mechanism of therapeutic action on CD is different between infliximab and total parenteral nutrition.

Is small-bowel radiography necessary before double-balloon endoscopy?

OBJECTIVE: Small-bowel radiography may be replaced by enteroscopy in the diagnosis of small-intestine lesions. We retrospectively elucidated the diagnostic yield of small-bowel radiography performed before double-balloon endoscopy. MATERIALS AND METHODS: One hundred twenty-four patients who underwent double-balloon endoscopy during the period 2004-2006 were classified into those with abnormal radiographic findings (n = 45), normal radiographic findings (n = 31), and no small-bowl radiographs (n = 48). The classification was based on the use of small-bowel radiography and the diagnosis before double-balloon endoscopy. The indications for, approaches to, and diagnostic yields of double-balloon endoscopy were compared for the three groups. The diagnostic yield of small-bowel radiography was considered positive when any sign of pathologic change in the small bowel was identified. The diagnostic yield of double-balloon endoscopy was considered positive when endoscopic or biopsy findings explained the clinical manifestations. RESULTS: The group with abnormal findings on small-bowel radiography was younger (15-86 years) and less frequently had obscure bleeding (8.9%) than the group with normal findings on small-bowel radiography (age, 17-84 years; frequency of obscure bleeding, 45.2%) (p = 0.01) or the group without small-bowel radiographs (age, 15-91 years; frequency of obscure bleeding, 64.6%) (p < 0.0001). The positive diagnostic yield of double-balloon endoscopy was highest in the group with abnormal findings on small-bowel radiography (71.1%), followed by the group with no small-bowel radiographs (45.8%) and the group with normal findings on small-bowel radiography (35.5%) (p = 0.0002). Among patients who did undergo small-bowl radiography, the accuracy of the technique was 68.4%, the positive predictive value was 71.1%, and the negative predictive value was 64.5%. The positive diagnostic yields of small-bowel radiography and double-balloon endoscopy were not statistically different (59.2% for small-bowel radiography, 56.6% for double-balloon endoscopy; p > 0.1). CONCLUSION: The diagnostic accuracy of double-balloon endoscopy seems to improve if the procedure is preceded by small-bowel radiography.

Recombinant human granulocyte colony-stimulating factor reduces colonic epithelial cell apoptosis and ameliorates murine dextran sulfate sodium-induced colitis.

OBJECTIVE: Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is a potentially effective therapy for Crohn's disease. The purpose of this study was to test the rhG-CSF in murine dextran sulfate sodium-induced colitis (DSS colitis). MATERIAL AND METHODS: Murine colitis was induced by feeding with water containing 3% DSS for 9 days. Six to 7-week-old female BALB/c mice were given rhG-CSF (100 microg/kg) or phosphate-buffered saline (PBS) subcutaneously once a day from day 0 to day 8, and the mice were sacrificed at days 3, 5, 7 and 9. Tissue specimens from the transverse colon, descending colon and rectum were obtained and stained with hematoxylin and eosin. Inflammation was scored for severity, extent, epithelial damage and crypt loss. TUNEL staining was performed to assess epithelial cell apoptosis. RESULTS: Treatment with rhG-CSF significantly attenuated body-weight loss, stool score and shortening of the colon length in comparison with treatment with PBS (p<0.01,<0.05,<0.01, respectively). Histological scores for inflammation, epithelial cell damage and crypt loss of the rectum were less severe at day 9 in the rhG-CSF group than in the PBS group (p<0.01, 0.05, 0.01, respectively). The number of TUNEL-positive cells in the rectum was smaller in the rhG-CSF group than in the PBS group (p<0.001). CONCLUSIONS: Treatment with rhG-CSF ameliorates murine DSS colitis by suppressing mucosal inflammation and epithelial damage in the rectum. The prevention of epithelial cell apoptosis seems to precede the anti-inflammatory action of rhG-CSF.

Linear mucosal defect may be characteristic of lansoprazole-associated collagenous colitis.

BACKGROUND: Although some cases of collagenous colitis have been induced by lansoprazole (LPZ), the clinicopathologic features of LPZ-associated collagenous colitis have not been elucidated. OBJECTIVE: To elucidate the clinical, endoscopic, and histopathologic features of LPZ-associated collagenous colitis. DESIGN: Retrospective case study. PATIENTS: The subjects were 13 patients with collagenous colitis diagnosed during a period from 2002 to 2007. MAIN OUTCOME MEASUREMENTS: The colonoscopic and histopathologic findings were compared retrospectively between 9 cases of LPZ use (LPZ group) and 4 cases without the use of LPZ (non-LPZ group). RESULTS: A colonoscopy revealed a linear mucosal defect more frequently in the LPZ group (7 of 9 cases [78%]) than in the non-LPZ group (0 of 4 cases [0%], P = .02). Friable mucosa was also noted in 4 patients (44%) in the LPZ group but none in the non-LPZ group. The colonoscopic finding in the non-LPZ group was either normal mucosa or nonspecific minimal abnormalities, whereas patients in the LPZ group had either a linear mucosal defect, mucosal bleeding, or both (P = .001). On histologic examination, the subepithelial collagen band was thicker in patients in the LPZ group than in those in the non-LPZ group (median 45 vs 26.3 mum). All patients in the LPZ group recovered from diarrhea after discontinuance of LPZ. LIMITATION: A small number of patients. CONCLUSIONS: Linear mucosal defects and friable mucosa may be characteristic colonoscopic findings in cases of LPZ-associated collagenous colitis.

Magnifying colonoscopy with narrow band imaging system for the diagnosis of dysplasia in ulcerative colitis: a pilot study.

BACKGROUND: Narrow-band imaging (NBI) is a novel illumination technology for endoscopy that enhances vasculature of the GI tract. OBJECTIVE: The aim was to elucidate whether NBI colonoscopy can identify dysplasia in patients with ulcerative colitis (UC). DESIGN: Cross-sectional study of eligible patients. SETTING: Single center. PATIENTS: 46 patients with UC. INTERVENTIONS: Apparently flat mucosa at each segment and visible protruding lesions were observed by magnifying NBI colonoscopy. The surface structure was classified into honeycomb-like, villous, or tortuous pattern. The grade of dysplasia was determined in the specimens obtained from protrusions and from flat mucosa. MAIN OUTCOME MEASUREMENTS: The positive predictive value of conventional and NBI colonoscopy for the diagnosis of dysplasia. RESULTS: A total of 296 sites (20 protruding lesions and 276 flat areas) were examined by NBI colonoscopy. The surface pattern was determined to be honeycomb like in 161 sites, villous in 85 sites, and tortuous in 50 sites. Five dysplastic lesions were detected in 3 patients. A patient had 3 dysplastic lesions and the other 2 had a dysplastic lesion each. The positive rate of dysplasia was higher in protrusions (2/20 sites, 10%) than in flat mucosa (3/276 sites, 1.1%, P = .038; however, correction for the multiple testing of data removes this significance). When the surface pattern was taken into account, the rate of positive dysplasia was higher in the tortuous pattern (4/50 sites, 8%) than in the honeycomb-like or villous patterns (1/246 sites, 0.4%, P = .003). LIMITATIONS: Uncontrolled study. CONCLUSIONS: The tortuous pattern determined by NBI colonoscopy may be a clue for the identification of dysplasia during surveillance for UC.

Hypermethylation of p14 (ARF) may be predictive of colitic cancer in patients with ulcerative colitis.

PURPOSE: The microsatellite instability and CpG island hypermethylation of p14 ( ARF ) and p16 ( INK4a ) are related to the pathogenesis of neoplasia in ulcerative colitis. This study was designed to assess the significance of those genetic or epigenetic alterations for cancer surveillance in ulcerative colitis. METHODS: During surveillance colonoscopy in 39 patients with ulcerative colitis, biopsy specimens were obtained from the cecum and the rectum as well as from any other areas suspected of being neoplasia by chromoscopy. Using DNA extracts, the methylation status of p14 ( ARF ) and p16 ( INK4a ) and the microsatellite status were determined. RESULTS: Microsatellite instability was positive in one of five dysplasias, but it was negative in the cecum and the rectum. The incidence of hypermethylation of p14 ( ARF ) was 0 percent in the cecum, 26 percent in the rectum, and 100 percent in dysplasia, whereas that of p16 ( INK4a ) was 10, 10, and 0 percent, respectively. Patients who were positive for the hypermethylation of p14 ( ARF )in the rectum had a longer duration of ulcerative colitis than those who were negative for such hypermethylation. Two of 10 patients who were positive for p14 ( ARF ) hypermethylation in the rectum and 1 of 29 patients who were negative for the hypermethylation had dysplasia. During the subsequent surveillance of 36 patients, dysplasia was detected in 2 of 8 patients with p14 ( ARF ) hypermethylation and in none of 28 patients without hypermethylation (P = 0.044). CONCLUSIONS: In patients with ulcerative colitis, hypermethylation of p14 ( ARF ) seems to be associated with an early stage of dysplasia. The hypermethylation may be one of candidates for potential biomarker to identify patients at a high risk of dysplasia.

Factors affecting recurrence in patients with Crohn's disease under nutritional therapy.

PURPOSE: This retrospective study was designed to determine risk factors for recurrence of Crohn's disease under enteral nutrition. METHODS: The clinical course of 145 patients with Crohn's disease, who were primarily induced into remission by total parenteral nutrition, was reviewed. The patients were classified into two groups: enteral nutrition group (n = 98; >/=1,200 kcal/day of enteral nutrition), or nonenteral nutrition group (n = 47;<1,200 kcal/day of enteral nutrition) according to the amount of their daily elemental or polymeric diet. Contributions of enteral nutrition and other clinical variables to the recurrence were analyzed retrospectively. A Crohn's disease activity index of >150 plus an increase in Crohn's disease activity index of >70 from the baseline value was defined as recurrence. RESULTS: Forty-two patients in the enteral nutrition group and 29 patients in the nonenteral nutrition group recurred during periods ranging from 3 to 159 months. The cumulative rate of recurrence was significantly higher in the nonenteral nutrition group than in the enteral nutrition group (P = 0.047). Among the Crohn's disease patients in the enteral nutrition group, penetrating type (relative risk, 3.89; 95 percent confidence interval, 1.58-9.62), colonic involvement (relative risk, 3.10; 95 percent confidence interval, 1.39-6.9), and previous history of surgery (relative risk, 2.48; 95 percent confidence interval, 1.16-5.33) were factors that significantly affected recurrence. In contrast, penetrating type was the only possible factor associated with recurrence in the nonenteral nutrition group (relative risk, 2.75; 95 percent confidence interval, 0.96-7.81). CONCLUSIONS: Among patients with Crohn's disease under maintenance enteral nutrition, the risk of recurrence differs according to the disease type and the site of involvement. The maintenance treatment by enteral nutrition alone seems insufficient for patients with penetrating type or with colonic involvement.

Preventive effect of nutritional therapy against postoperative recurrence of Crohn disease, with reference to findings determined by intra-operative enteroscopy.

OBJECTIVE: The aim of this study was to elucidate the predictive value of intra-operative enteroscopy (IOE) and the effect of enteral nutrition (EN) with regard to the postoperative recurrence of Crohn disease (CD). MATERIAL AND METHODS: Forty patients requiring surgery for severe intestinal complications of CD were examined by IOE, and the severity of the remnant small intestine was determined. Patients were subclassified into either an EN group (>1,200 kcal/day) or a non-EN group (<1,200 kcal/day) according to the amount of daily EN intake after surgery. Contributions of IOE findings and EN to postoperative recurrence were analysed retrospectively. RESULTS: IOE identified intestinal lesions in 39 patients and active intestinal lesions in 24 patients. The cumulative rate of postoperative recurrence was significantly higher in patients with cobblestone appearance confirmed by IOE (p=0.006). However, other active intestinal lesions were not related to postoperative recurrence. EN reduced the cumulative rate of postoperative recurrence (p=0.017), especially in patients with penetrating type (p=0.005), in patients who did not have colitis (p=0.051) and in patients who did not have active intestinal lesions confirmed by IOE (p=0.02). CONCLUSIONS: EN is a prophylactic that prevents the postoperative recurrence of small intestinal CD. Patients with the penetrating type of CD, and those who do not have active lesions in the small intestine according to IOE, are candidates for EN after surgery.

[Drug therapy for ulcerative colitis: salazosulfapyridine and 5-ASA].

Aminosalicylates have a wide range of anti-inflammatory and immunomodulatory effects. Oral salazosulfapyridine (SASP) and 5-aminosalicylic acid (5-ASA) are the 'first-line' therapy for induction of remission in mild to moderate active ulcerative colitis (UC). SASP, which is consisted of 5-ASA and sulfapyridine, has greater incidence of side effects. 5-ASA is a therapeutically active compound, while sulfapyridine is related to adverse effects. For this reason, 5-ASA formulas exclusive of sulfapyridine were developed and they enabled higher dose of 5-ASA administration without adverse effects. Topical treatment by 5-ASA enema or SASP suppository should be considered for the treatment of proctitis or distal type of UC. Oral aminosalicylate therapy is also effective for the maintenance of remission in UC. Therefore, aminosalicylates are key drugs for the treatment of UC.

Addition of leukocytapheresis to steroid therapy: is it beneficial in recurrence of moderate-to-severe ulcerative colitis?

PURPOSE: In Japan, leukocytapheresis has become an accepted therapy for ulcerative colitis. The purpose of this retrospective study was to determine the efficacy of additional leukocytapheresis in patients with moderate-to-severe recurrence of ulcerative colitis. METHODS: From 1998 to 2002, 35 patients with moderate-to-severe recurrence of ulcerative colitis were treated by intravenous prednisolone only or prednisolone plus leukocytapheresis once per week. Previous clinical features of ulcerative colitis, activity index at four weeks, and subsequent course were compared between patients with leukocytapheresis and those without. RESULTS: Sixteen patients were treated with prednisolone only (prednisolone group), and 19 patients were treated with prednisolone plus leukocytapheresis (leukocytapheresis group). Previous prednisolone dose (13.6 +/- 10.4 g vs. 7.9 +/- 9.8 g; P < 0.05) was higher in the leukocytapheresis group than the prednisolone group. Clinical response rate at four weeks was not different between the two groups (leukocytapheresis group, 68.4 percent vs. prednisolone group, 75 percent). However, ulcerative colitis activity index at four weeks was significantly higher in the leukocytapheresis group than the prednisolone group (180.5 +/- 44.2 vs. 142.5 +/- 45.3; P < 0.05). During the subsequent clinical course, 15 of 35 patients required proctocolectomy (leukocytapheresis group, 11 patients vs. prednisolone group, 4 patients). Proctocolectomy rate was significantly different when patients were divided by previous prednisolone dose (P = 0.0029) and ulcerative colitis activity index at four weeks (P = 0.002), but it was not different according to the application of leukocytapheresis. Cox proportional hazards model revealed previous prednisolone dose to be the only independent risk factor for proctocolectomy. CONCLUSIONS: Addition of leukocytapheresis to prednisolone therapy does not seem beneficial in ulcerative colitis patients with moderate-to-severe recurrence.

Chromoscopy might improve diagnostic accuracy in cancer surveillance for ulcerative colitis.

OBJECTIVES: Multiple biopsy has been a recommended procedure for cancer surveillance in patients with ulcerative colitis (UC). The aim of this study was to investigate the accuracy of chromoscopic findings in surveillance for patients with UC. METHODS: During the period 1995-2002, we performed 117 surveillance colonoscopies in 57 patients with pancolitis for more than 5 yr. Multiple biopsy specimens were uniformly obtained from flat mucosa in each segment of the colorectum, and, when necessary, from areas specified by chromoscopy. The specified area was classified as polypoid lesion or visible flat lesion. In each specimen, histology was graded according to the classification of dysplasia. RESULTS: Among 818 specimens, 28 (3.4%) were positive for dysplasia. There were 20 low grade dysplasias and eight high grade dysplasias. Dysplasia was more frequently positive in visible flat lesions (37.1%, p < 0001) and in polypoid lesions (16.9%, p < 0.0001) than in flat mucosa (0.4%, p < 0.0001). Furthermore, it was more frequently positive in visible flat lesions than in polypoid lesions (p < 0.05). High-grade dysplasia was found in 4.4% of polypoid lesions and in 14.8% of visible flat lesions, but it was not detected in flat mucosa. Overall, dysplasia was detected in 12 patients. Positive dysplasia was confined to visible flat lesions in four patients and to flat mucosa in one patient. CONCLUSIONS: Our results suggest that biopsy from flat visible lesions under chromoscopy might improve the accuracy of cancer surveillance in UC.

Histological and immunological features of appendix in patients with ulcerative colitis.

Patients with ulcerative colitis (UC) have a less frequent prior history of appendectomy than the general population. The aim of the present investigation was to elucidate histological and immunological characteristics of the appendix in UC and to assess the effect of appendectomy on the disease. Nine subjects with mildly active UC were treated by surgical appendectomy. In four subjects, the histological findings of the appendix were compatible with ulcerative appendicitis. CD3+CD4+CD25+, CD3+CD4+CD45RO+, and CD3+CD8+CD45RO+ appendiceal mononuclear cells were significantly higher in UC than in acute appendicitis and in normal appendix. There was a trend towards higher mRNA transcripts of IFN-gamma in the appendix of UC than those in other two groups. Clinical activity index decreased significantly four weeks after the appendectomy, although the effect was transient. The appendix is a site of involvement in UC, where mononuclear cells are presumed to be at a state of basal activation.