IBD Watch^®

^{Timely Information for Practicing Physicians}

JANUARY 2005

Anti-interleukin-12 therapy for Crohn's Disease (CD). Antibodies directed against interleukin-12 (IL-12) have been shown to be effective treatment for the intestinal inflammation in animal models of CD.  These findings led Peter Mannon, Ivan Fuss, and others to conduct a multicenter, double-blind study in which 79 patients with active CD were randomized to receive seven weekly subcutaneous injections of 1 mg/kg or 3 mg/kg of an anti-IL-12 monoclonal antibody or placebo.  Two cohorts were treated: the dosing schedule for patients in the first cohort (Cohort 1) included a 4-week interval between the first and second injections and the dosing schedule for patients in the second cohort (Cohort 2) did not have an interruption between the first and second injections.  After the completion of 7 weeks of uninterrupted treatment, patients receiving 3 mg/kg of anti-IL-12 therapy had a higher response (reduction of CDAI by ≥ 100 points) rate than patients given placebo (75% vs. 25%).  Clinical improvement in patients receiving anti-IL-12 monoclonal antibody therapy was accompanied by decreases in secretion of IL-12, interferon-γ, and tumor necrosis factor α by mononuclear cells of the colonic lamina propria.  The difference in response rate lost significance at 18 weeks of follow-up.  No differences in response rate were observed between treatment groups in Cohort 1.  The safety profiles of patients treated with anti-IL-12 or placebo were similar.  Thus, anti-IL-12 monoclonal antibody therapy has activity against CD that is associated with decreases in Th1-mediated inflammatory cytokines at the site of disease.  In an accompanying brief review of the involvement of cytokines in the pathogenesis of CD, Fabio Cominelli states there is mounting evidence that the classic paradigm of an exclusive role for Th1 cytokines in the development of CD may be too simplistic.  New immunologic models include the involvement of Th2 cytokines, such as interleukin-4 and interleukin-13.  In addition, individual cytokines may have diverse functions in different clinical and immunologic scenarios.  Interleukin-12 has been strongly implicated in the pathogenesis of CD and the blockade of this cytokine may neutralize its inflammatory effects and induce apoptosis in activated lymphocytes that have infiltrated the intestinal mucosa.  An improved understanding of the complex pathogenesis of CD may lead to future therapeutic strategies involving the blockade of multiple cytokines to effect several different pathways.  (Mannon PJ, et al. N Engl J Med 2004;351:2069-2079 and Cominelli F. N Engl J Med 2004;351:2045-2048)

A systematic review of collagenous colitis. Nilesh Chande et al reviewed the literature to determine effective treatments for patients with clinically active collagenous colitis.  Five randomized trials assessing treatments for collagenous colitis were identified via MEDLINE, PUBMED, and Cochrane Collaboration databases.  Current therapies may induce clinical and histological improvements, but there is no clear evidence of remissions. The authors found strong evidence that budesonide is safe and effective therapy for patients with collagenous colitis.  The evidence that bismuth subsalicylate or prednisolone is of clinical benefit is much weaker.  (Chande N, et al. Am J Gastroenterol 2004;99:2459-2465)

Infliximab therapy and pregnancy outcomes.  Jeffrey Katz and colleagues, in collaboration with Centocor Inc., analyzed a large series of pregnancy outcomes in women with rheumatoid arthritis or Crohn's disease exposed to infliximab.  Pregnancy outcome data were available for 96 women directly exposed to infliximab.  Live births occurred in 64 women (67%), miscarriages in 14 women (15%), and pregnancy was therapeutically terminated in 18 women (19%).  These results are similar to those expected for the general US population of pregnant women.  These data indicate that exposure of pregnant women to infliximab does not increase the risk for adverse pregnancy outcomes.  Follow-up of larger numbers of pregnant women exposed to infliximab are needed to definitively exclude any risk to the fetus.  (Katz JA, et al. Am J Gastroenterol 2004;99:2385-2392)

Endoscopic cancer surveillance in ulcerative colitis. Matthew Rutter et al performed a case control study to determine colonoscopic markers for cancer risk in patients with ulcerative colitis (UC).  Each UC patient with neoplasia detected between 1988 and 2002 (n = 68) was matched with 2 non-dysplastic colitic controls (n = 136).  Multivariate analysis identified post-inflammatory polyps (odds ratio [OR] 2.29; 95% CI: 1.28-4.11) and strictures (OR 4.62; 95% CI: 1.03-20.8) to be colonoscopic features significantly associated with UC patients who developed neoplasia.  Furthermore, neoplastic cases were less likely to have had a macroscopically normal-looking colonoscopy (OR 0.38; 95% CI: 0.19-0.73).  These findings show that macroscopic colonoscopic features may help predict neoplasia risk in patients with UC.  (Rutter MD, et al. Gut 2004;53:1813-1816)

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