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Volume 4, Supplement 3, 2004

Volume 4, Supplement 3, 2004

Table of Contents

An Historical Overview of the Treatment of Crohn's Disease: Why Do We Need Biological Therapies?
Crohn’s disease is a disabling inflammatory bowel disease that may involve any part of the gastrointestinal tract. The disease decreases quality of life and leads to complications including stenoses, abscesses, and fistulae necessitating repeated surgeries and bowel resections. Until the late 1990s, standard therapies included mainly glucocorticosteroids, 5-aminosalicylic acid (5-ASA), antibiotics, and to a lesser extent, immunosuppression with azathioprine (AZA)/6-mercaptopurine (6-MP) or methotrexate. These therapies, especially glucocorticosteroids, mainly controlled symptoms without modifying the long-term disease course. Glucocorticosteroids also do not induce sustained mucosal healing. The lack of healing capacity mirrors the absent long-term efficacy of these drugs. Moreover, long-term use of glucocorticosteroids is associated with serious and sometimes irreversible side effects. AZA/6-MP are effective disease-modifying therapies that have been used in patients who are refractory to or relapse after steroids. Unfortunately, these agents have yet to have an established optimal benefit due to variations in genetically determined metabolism. With the advent of biologicals, new treatment aims have been advanced, including induction of remission with bowel healing both short term and long term, as well as reduction in the rate of complications, surgeries, and mortality. [Rev Gastroenterol Disord. 2004;4(suppl 3):S3-S9]
Why Do Anti-Tumor Necrosis Factor Antibodies Work in Crohn's Disease?
Anti-tumor necrosis factor (TNF) antibodies are powerful therapeutic agents for the treatment of Crohn’s disease. TNF has diverse proinflammatory effects within the intestinal mucosa and is a pivotal cytokine in the inflammatory cascade. Although anti-TNF antibodies exert a variety of anti-inflammatory effects by neutralizing the cytokine, these agents vary in their efficacy. Recent data suggest that the ability to bind transmembrane TNF is a key property necessary for efficacy. Transmembrane binding of TNF effects apoptosis of T cells, thereby alleviating a fundamental defect in Crohn’s disease in the regulation of T cell populations. [Rev Gastroenterol Disord. 2004;4(suppl 3):S10-S17]
Efficacy and Safety of Tumor Necrosis Factor Antagonists in Crohn's Disease: Overview of Randomized Clinical Trials
The past decade has brought forth a series of novel biologic agents targeting tumor necrosis factor (TNF) for the treatment of Crohn’s disease. The introduction of infliximab has paved the way for additional anti-TNF strategies that have the potential to build on that drug’s efficacy and safety profile. However, the anti-TNF strategies might not have identical efficacy and safety profiles and might differ in dosing compared with therapy for rheumatoid arthritis. Most recently, adalimumab has been approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis and is undergoing evaluation in Crohn’s disease, with promising initial results. This review discusses the results of controlled clinical trials of anti-TNF agents for Crohn’s disease. [Rev Gastroenterol Disord. 2004;4(suppl 3):S18-S24]
How Future Tumor Necrosis Factor Antagonists and Other Compounds Will Meet the Remaining Challenges in Crohn's Disease
The chimeric monoclonal antibody to tumor necrosis factor (TNF), infliximab, is an effective therapy for Crohn’s disease. However, the formation of human anti-chimeric antibodies to infliximab (immunogenicity) can lead to loss of efficacy as well as acute infusion reactions and delayed hypersensitivity reactions. The fully human monoclonal antibody adalimumab and the pegylated humanized monoclonal antibody fragment CDP870 are biologic therapies against TNF that might be effective for Crohn’s disease and less immunogenic than infliximab. Other potential alternatives to infliximab for Crohn’s disease include the humanized anti–adhesion molecule antibodies natalizumab and MLN-02, the humanized anti–interleukin 12 antibody ABT-874, the humanized anti–interferon  antibody fontolizumab, the humanized anti–interleukin 6 receptor antibody MRA, and human recombinant granulocyte macrophage colony stimulating factor (sargramostim). Some, or all, of these therapies will likely represent important treatments for Crohn’s disease in the future. [Rev Gastroenterol Disord. 2004;4(suppl 3):S25-S33]