Current Directions in IBD Therapy: What Goals Are Feasible With Biological Modifiers?

Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Gastroenterology (Impact Factor: 13.93). 11/2008; 135(5):1442-7. DOI: 10.1053/j.gastro.2008.09.053
Source: PubMed
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    ABSTRACT: Limited pools of resident adult stem cells are critical effectors of epithelial renewal in the intestine throughout life. Recently, significant progress has been made regarding the isolation and in vitro propagation of fetal and adult intestinal stem cells in mammals. It is now possible to generate ever-expanding, three-dimensional epithelial structures in culture that closely parallel the in vivo epithelium of the intestine. Growing such organotypic epithelium ex vivo facilitates a detailed description of endogenous niche factors or stem-cell characteristics, as they can be monitored in real time. Accordingly, this technology has already greatly contributed to our understanding of intestinal adult stem-cell renewal and differentiation. Transplanted organoids have also been proven to readily integrate into, and effect the long-term repair of, mouse colonic epithelia in vivo, establishing the organoid culture as a promising tool for adult stem cell/gene therapy. In another exciting development, novel genome-editing techniques have been successfully employed to functionally repair disease loci in cultured intestinal stem cells from human patients with a hereditary defect. It is anticipated that this technology will be instrumental in exploiting the regenerative medicine potential of human intestinal stem cells for treating human disorders in the intestinal tract and for creating near-physiological ex vivo models of human gastrointestinal disease.
    Gut 05/2014; 63(8). DOI:10.1136/gutjnl-2014-307204 · 13.32 Impact Factor
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    ABSTRACT: Background & Aims: There is an increasing need for new treatments for patients with Crohn’s disease (CD) in whom previous therapy with tumor necrosis factor (TNF) antagonists has failed. We performed a placebo-controlled, phase 3, double-blind trial to evaluate the efficacy and safety of vedolizumab, an antibody against the integrin α4β7, as induction therapy. Methods Patients with moderately to severely active CD (CD activity index [CDAI] scores of 220–400 points) were randomly assigned to groups given vedolizumab (300 mg) or placebo intravenously at weeks 0, 2, and 6. The primary analysis involved 315 patients with previous TNF antagonist failure (ie, an inadequate response to, loss of response to, or intolerance of ≥1 TNF antagonist); we determined the proportion in clinical remission (CDAI ≤150 points) at week 6. Secondary analyses evaluated outcomes at weeks 6 and 10 in this population and in the overall population (n=416), which included patients naïve to TNF antagonist therapy (n=101). Results Among patients who had experienced previous TNF antagonist failure, 15.2% of those given vedolizumab and 12.1% of those given placebo were in remission at week 6 (P=.433). At week 10, a higher proportion of this population given vedolizumab were in remission (26.6%) than those given placebo (12.1%) (nominal P=.001; relative risk, 2.2; 95% confidence interval [CI], 1.3–3.6). A higher proportion of patients with previous TNF antagonist failure given vedolizumab also had a CDAI-100 response (≥100 point decrease in CDAI score from baseline) at week 6 than those given placebo (39.2% vs 22.3%; nominal P=.001; relative risk, 1.8; 95% CI, 1.2–2.5). Adverse event results were similar among all groups. Conclusions Vedolizumab was not more effective than placebo in inducing clinical remission at week 6 among patients with CD in whom previous treatment with TNF antagonists had failed. Therapeutic benefits of vedolizumab in these patients were detectable at week 10. number: NCT01224171.
    Gastroenterology 09/2014; 147(3). DOI:10.1053/j.gastro.2014.05.008 · 13.93 Impact Factor
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    ABSTRACT: AIM: To assess "top-down" treatment for deep remission of early moderate to severe Crohn's disease (CD) by double balloon enteroscopy. METHODS: Patients with early active moderate to severe ileocolonic CD received either infusion of infliximab 5 mg/kg at weeks 0, 2, 6, 14, 22 and 30 with azathioprine from week 6 onwards (Group I), or prednisone from week 0 as induction therapy with azathioprine from week 6 onwards (Group II). Endoscopic evaluation was performed at weeks 0, 30, 54 and 102 by double balloon enteroscopy. The primary endpoints were deep remission rates at weeks 30, 54 and 102. Secondary endpoints included the time to achieve clinical remission, clinical remission rates at weeks 2, 6, 14, 22, 30, 54 and 102, and improvement of Crohn's Disease Endoscopic Index of Severity scores at weeks 30 and 54 relative to baseline. Intention-to-treat analyses of the endpoints were performed. RESULTS: Seventy-seven patients were enrolled, with 38 in Group I and 39 in Group II By week 30, deep remission rates were 44.7% and 17.9% in Groups I and II, respectively (P = 0.011). The median time to clinical remission was longer for patients in Group II (14.2 wk) than for patients in Group I (6.8 wk, P = 0.009). More patients in Group I were in clinical remission than in Group II at weeks 2, 6, 22 and 30 (2 wk: 26.3% vs 2.6%; 6 wk: 65.8% vs 28.2%; 22 wk: 71.1% vs 46.2%; 30 wk: 68.4% vs 43.6%, P < 0.05). The rates of clinical remission and deep remission were greater at weeks 54 and 102 in Group I, but the differences were insignificant. CONCLUSION: Top-down treatment with infliximab and azathioprine, as compared with corticosteroid and azathioprine, results in higher rates of earlier deep remission in early CD.
    World Journal of Gastroenterology 10/2014; 20(39):14479-87. DOI:10.3748/wjg.v20.i39.14479 · 2.43 Impact Factor