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Expert Commentary -- Continuing Challenges in the Management of Crohn's Disease

Authors: William J. Sandborn, MDFaculty and Disclosures

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Introduction and Context -- Challenges Associated With the Currently Available Therapies

Historically, patients with Crohn's disease received induction of remission therapy with sulfasalazine or prednisone; neither drug was effective for maintaining remission.[1] In the 1990s, mesalamine came into widespread use, based on a single positive induction study.[2] More recently, previously unpublished data have demonstrated that mesalamine is not effective for either inducing or maintaining remission.[3] Eventually, 80% or more of patients come to surgical resection.[4] This cumulative requirement for surgery appears to parallel the progression of the Crohn's disease from luminal inflammatory disease to penetrating disease (fistulas or abscesses) or stricturing disease.[5] Thus, Crohn's disease is a chronic, progressive, destructive disease that can lead to disability. Drugs that maintain remission, are steroid-sparing, and induce and maintain mucosal healing (immunosuppressive agents and biologic agents) have the potential to alter the natural history of Crohn's disease (ie, disease-modifying anti-Crohn's disease drugs). The major challenges facing physicians who manage Crohn's disease today are to recognize the lack of efficacy of mesalamine for the treatment of Crohn's disease and to institute early in the disease course drugs that can potentially modify the natural history of this chronic illness.

The immunosuppressive agents azathioprine, 6-mercaptopurine, and methotrexate can maintain remission, are steroid-sparing, and in the case of azathioprine, may induce mucosal healing.[6-10] However, recent information has suggested that azathioprine introduced in the standard sequential therapy treatment paradigm may not alter surgery rates.[11] The chimeric IgG1 antibody to tumor necrosis factor (TNF), infliximab, induces and maintains remission, is steroid-sparing, induces and maintains mucosal healing, and closes fistulas and maintains fistula closure in patients with Crohn's disease.[12-17] This profile of efficacy may lead to lower rates of hospitalization and surgery.[15,18] Formation of antibodies to infliximab (immunogenicity) can lead to treatment-limiting acute and delayed infusion reactions and to loss of efficacy.[19,20] Given the efficacy profile of infliximab, and the fact that some patients who initially respond to infliximab later become intolerant or lose response due to immunogenicity, there is an unmet medical need for anti-TNF antibodies that are effective in Crohn's disease and that may be less immunogenic than infliximab.

Table of Contents

  1. Introduction and Context -- Challenges Associated With the Currently Available Therapies
  2. Fully Human IgG1 Monoclonal Antibody to TNF
  3. Concluding Remarks and Looking to the Future