IBD Watch^®

^{Timely Information for Practicing Physicians}

MARCH 2008

Role of intestinal microflora. A dysregulated immunologic response to microbial flora residing in the intestinal lumen may play an important role in the pathogenesis of IBD. It is not known if the altered intestinal microflora are the cause or the result of the associated chronic inflammation. Swidsinski and others investigated sections of paraffin-imbedded punched fecal cylinders using fluorescent in situ hybridization (FISH) to study the impact of the spatial organization of intestinal microflora on IBD. Fluctuations in the spatial distribution of 11 bacterial groups were monitored in 32 healthy subjects, 204 patients with IBD, and 186 patients with other gastrointestinal diseases. The profiles of patients with Crohn’s disease (CD) and ulcerative colitis (UC) were distinctly opposite in six of 11 FISH probes used. The most prominent finding was a depletion of Faecalibacterium prausnitzii with a normal leukocyte count in patients who had CD compared with a high concentration of F prausnitzii and a large increase of leukocytes in the fecal-mucus transition zone in patients who had UC. These two features alone allowed for the recognition of active CD or UC with a high degree of sensitivity and specificity. When patients with IBD were pooled, the sensitivity of microbial structure profile results was 100% for severe disease, 84% for moderate activity, 72% for IBD with remission of ≤12 months, and 24% for IBD with remission of >12 months. These data demonstrate that fecal flora are highly structured and spatially organized. (Hecht GA. N Engl J Med 2008;358:528–530; Swidsinski A, et al. Inflamm Bowel Dis 2008;14:147–161.) Editor’s Comment: It is more likely that poorly classified and non-culturable species lining the epithelium and mucus, rather than the populations that could be cultured from the feces, will be identified as contributors to the pathogenesis.—SH

New and upcoming. Prednisolone metasulfobenzoate (PM) is a sparingly absorbed formulation not available in the US . Rhodes and associates conducted a double-blind study in which patients with active UC were randomized to receive PM 40 mg/day for 6 months (n = 59), PM 60 mg/day for 6 months (n = 61), or prednisolone 40 mg/day for 2 weeks (n = 61), tapered to week 8, followed by placebo until 6 months. There were fewer steroid-related side effects, as assessed by a 10-cm visual analog scale, at 2 months in both PM treatment groups than in the prednisolone group (P = 0.01). Mood changes were reported in 43% of patients treated with prednisolone at 4 weeks while only 8% of patients treated with PM 40 mg/day reported mood changes (P = 0.001). Remission rates at 6 months were 51%, 38%, and 32% in the PM 40-mg, PM 60-mg, and prednisolone groups, respectively (P = 0.08). These results indicate that PM has similar efficacy but markedly fewer side effects than a conventional tapering prednisolone regimen. (Rhodes JM, et al. Aliment Pharmacol Ther 2008;27:228–240.)  In a separate study by Cassinotti and co-workers, four patients with refractory moderate-to-severe CD were treated with autologous hematopoietic stem cell transplantation. Unselected peripheral blood stem cells were collected after mobilization with high-dose cyclophosphamide and granulocyte colony–stimulating factor. The conditioning regimen included cyclophosphamide 50 mg/kg on days –5 to –2 and rabbit anti-thymocyte globulin 2.5 mg/kg on days –4 to –2. Clinical remission was achieved in all four patients by the third month, and complete endoscopic remission occurred in two of three evaluable patients. After a median follow-up of 16.5 months, three of four patients maintained clinical remission. No deaths or life-threatening infections occurred. These early results indicate that autologous stem cell transplantation is safe and effective in patients with previously refractory CD. (Cassinotti A, et al. Gut 2008;57:211–217.) Editor’s Comment: It remains to be determined whether the “conditioning” immune suppression or the repopulation by stem cells is the effective component of this regimen. Controlled studies are under way in the United States and United Kingdom.—SH

Mercaptopurine following intolerance to azathioprine. Azathioprine intolerance occurs in up to 30% of treated patients. Lees and colleagues described the tolerability of mercaptopurine in 61 patients with IBD previously intolerant of azathioprine. The cohort consisted of 31 patients with CD and 30 patients with UC. Among these patients, mercaptopurine was tolerated in 36 (59%; median dose, 1.0 mg/kg), including 11 of 18 patients who discontinued azathioprine because of nausea, vomiting, or flu-like symptoms, and three of three patients who stopped azathioprine due to rash. Those patients intolerant of mercaptopurine were younger (P = 0.014) and more frequently female (P = 0.027). These findings show that mercaptopurine may be tolerated in up to 60% of azathioprine-intolerant patients. Mercaptopurine should be considered especially in patients in whom azathioprine intolerance is the result of nausea, vomiting, flu-like illness, or rash. (Lees CW, et al. Aliment Pharmacol Ther 2008;27:220–227.)

Chromoscopic endomicroscopy vs chromoscopy alone. The diagnosis of intraepithelial neoplasia is important for the clinical management of UC. Hurlstone and associates conducted a prospective study in which patients with UC were randomized in a 1:1 ratio to undergo screening colonoscopy using chromoscopy-assisted endomicroscopy or pan-colonic chromoscopy alone. Circumscribed lesions were characterized using endomicroscopy and chromoscopy with pit pattern analysis. Targeted biopsy samples and conventional 10-cm quadrantic biopsy samples were obtained. Endomicroscopy-targeted biopsies increased the yields of intraepithelial neoplasia and high-grade dysplastic lesions compared with pan chromoscopy and biopsy alone (P <0.001). Endomicroscopy-targeted biopsies increased the diagnostic yield of intraepithelial neoplasia compared with chromoscopy-guided biopsies by 2.5 fold. The authors suggest that endomicroscopy with targeted biopsy may become the gold standard for the detection of intraepithelial neoplasia in patients with UC. In the February issue of Inflammatory Bowel Disease, Matsumoto and colleagues provide a review demonstrating the typical endoscopic findings by conventional endoscopy and chromoscopy in patients with UC. (Hurlstone DP, et al. Gut 2008;57:196–204; Matsumoto T, et al. Inflamm Bowel Dis 2008;14:259–264.)

Primary sclerosing cholangitis (PSC) in patients undergoing proctocolectomy. Lepistö and associates reviewed clinical data from 441 consecutive patients with UC who underwent proctocolectomy with ileal pouch–anal anastomosis between 1993 and 2004 at the Helsinki University Central Hospital . Liver biopsy samples were taken at the time of surgery. PSC was found to be present in 52 patients (11.8%). The sensitivity of perioperative liver biopsy to diagnose PSC was 83.3%. Pouchitis occurred more often in patients with PSC (P = 0.001) although the failure rate of ileal pouch–anal anastomosis did not differ between patients with and without PSC. These findings indicate that liver biopsy can be predictive of PSC and the risk of pouchitis after proctocolectomy and ileoanal anastomoses. (Lepisto A, et al. Inflamm Bowel Dis 2008 Feb 5 [Epub ahead of print]).

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