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Previous Volume 351:2069-2079 November 11, 2004 Number 20 Next

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ABSTRACT

Background Crohn's disease is associated with excess cytokine activity mediated by type 1 helper T (Th1) cells. Interleukin-12 is a key cytokine that initiates Th1-mediated inflammatory responses.

Methods This double-blind trial evaluated the safety and efficacy of a human monoclonal antibody against interleukin-12 (anti–interleukin-12) in 79 patients with active Crohn's disease. Patients were randomly assigned to receive seven weekly subcutaneous injections of 1 mg or 3 mg of anti–interleukin-12 per kilogram of body weight or placebo, with either a four-week interval between the first and second injection (Cohort 1) or no interruption between the two injections (Cohort 2). Safety was the primary end point, and the rates of clinical response (defined by a reduction in the score for the Crohn's Disease Activity Index [CDAI] of at least 100 points) and remission (defined by a CDAI score of 150 or less) were secondary end points.

Results Seven weeks of uninterrupted treatment with 3 mg of anti–interleukin-12 per kilogram resulted in higher response rates than did placebo administration (75 percent vs. 25 percent, P=0.03). At 18 weeks of follow-up, the difference in response rates was no longer significant (69 percent vs. 25 percent, P=0.08). Differences in remission rates between the group given 3 mg of anti–interleukin-12 per kilogram and the placebo group in Cohort 2 were not significant at either the end of treatment or the end of follow-up (38 percent and 0 percent, respectively, at both times; P=0.07). There were no significant differences in response rates among the groups in Cohort 1. The rates of adverse events among patients receiving anti–interleukin-12 were similar to those among patients given placebo, except for a higher rate of local reactions at injection sites in the former group. Decreases in the secretion of interleukin-12, interferon-, and tumor necrosis factor by mononuclear cells of the colonic lamina propria accompanied clinical improvement in patients receiving anti–interleukin-12.

Conclusions Treatment with a monoclonal antibody against interleukin-12 may induce clinical responses and remissions in patients with active Crohn's disease. This treatment is associated with decreases in Th1-mediated inflammatory cytokines at the site of disease.

Source Information

From the Mucosal Immunity Section, National Institute of Allergy and Infectious Diseases (P.J.M., I.J.F., C.G., W.S.), and the Surgical Pathology Section, National Cancer Institute (M.Q.), National Institutes of Health, Bethesda, Md.; the Immunobiology Center and Division of Gastroenterology, Mount Sinai School of Medicine, New York (L.M., D.P.); the Division of Gastroenterology, University of Alabama School of Medicine, Birmingham (C.O.E.); the Mayo Clinic, Rochester, Minn. (W.J.S.); the Health Advance Institute, Peoria, Ill. (B.D.); Wyeth, Cambridge, Mass. (N.G., U.S.); Clinical Services Program, Scientific Applications International, Frederick, Md. (R.L.H.); the First Medizinische Klinik der Universität Mainz, Mainz, Germany (M.F.N.); and Abbott Bioresearch Center, Worcester, Mass. (J.S., G.M.V.).

Drs. Mannon and Fuss contributed equally to this article.

Address reprint requests to Dr. Mannon at the Mucosal Immunity Section, Laboratory of Host Defense, National Institute of Allergy and Infectious Diseases, NIH, 10 Center Dr., Rm. 11/N238, Bethesda, MD 20892, or at pmannon{at}niaid.nih.gov.

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Anti–Interleukin-12 Antibody for Active Crohn's Disease
Orenstein R., Kolls J. K., Zhang Z., Mannon P. J., Fuss I. J., Strober W.
Extract | Full Text | PDF  
N Engl J Med 2005; 352:627-628, Feb 10, 2005. Correspondence

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