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Crohn's Disease- Pathophysiology and Conventional and Alternative Treatment Options
Conventional Treatment of Crohn’s Disease
Conventional therapies utilized for the treatment of Crohn’s disease include NSAIDS, corticosteroids, aminosalicylates and their derivatives, antibiotics, immunomodulatory drugs, and numerous cutting edge therapies including monoclonal antibody preparations, anti-sense nucleic acid drugs, mitogen-activated protein kinase inhibitors, integrin antibody therapy, recombinant growth factors and hormones, and macrolide combination antibiotic therapy. Many of these drugs show promise but are fraught with complications and side effects.
NSAIDS and COX-2 Inhibitors
NSAIDS, such as aspirin, ibuprofen, and naproxen sodium, act by inhibiting cyclooxygenase and blocking prostaglandin synthesis. Historically, they were used to treat the pain and intestinal inflammation of IBD, until studies demonstrated they caused gastrointestinal erosion and bleeding, protein loss enteropathy, bile acid malabsorption, perforation, and strictures, worsening the course of IBD.130-132
Although still currently contraindicated in IBD, cyclooxygenase-2 (COX-2) selective inhibitors have been investigated as therapeutic agents because they appear to cause less gastrointestinal injury than regular NSAIDS. There is some evidence COX-2 inhibitors actually may be involved in preserving intestinal mucosa and promoting healing of gastrointestinal ulcers.133,134 One COX- 2 inhibitor, rofecoxib (Vioxx®) has recently been removed from the market due to safety concerns. A three-year clinical study revealed an increased relative risk for serious cardiovascular effects (including strokes and heart attacks) in patients taking Vioxx longer than 18 months — about twice that observed in the placebo group. The trial investigating the effect of rofecoxib in preventing the recurrence of colorectal polyps was halted two months early. An increased risk of cardiovascular events was not observed in patients taking rofecoxib for less than 18 months.135
Other anti-inflammatory agents widely utilized for decades in treating IBD are the aminosalicylates, particularly sulfasalazine (comprised of sulfapyridine, an antibacterial agent, and 5-aminosalicylic acid, also known as mesalamine) or mesalamine alone. Research has shown sulfasalazine to be effective only in mild-to-moderate disease of the colon, but not for isolated small bowel disease,136 and its use often results in folate deficiency.137 A recent meta-analysis of slow-release mesalamine (Pentasa®) demonstrated it to be superior to placebo for reducing the CDAI in mild-to- moderate Crohn's Disease.138 The slow-release forms of mesalamine, Asacol® and Pentasa, are released into the small bowel as far as the distal ileum and tend to have fewer side effects than sulfasalazine.
Oral corticosteroids reduce inflammation and suppress the immune system. They comprise the standard conventional treatment of moderate-to- severe Crohn's Disease or disease that is refractory to other treatment. While useful for achieving remission, long-term use of steroids can have numerous side effects, ranging from edema, weight gain, insomnia, night sweats, increased facial hair, acne, and mood disturbances, progressing to more serious complications such as hypertension, osteoporosis, diabetes, increased risk of infection, depression, cataracts, and glaucoma.139 For many years the steroid most frequently used to treat Crohn's Disease was prednisone; however, because of the extensive side effects, other options were explored. Budesonide is a topically active corticosteroid with low systemic bioavailability. When given orally it decreases mucosal inflammation and then undergoes extensive first-pass metabolism in the liver, resulting in far fewer side effects than other oral corticosteroids, providing a safer option for children with Crohn's Disease.140 Budesonide has also been shown to be more effective than mesalamine in maintaining remission in adults with steroid-dependent Crohn's Disease.141
Other Immunosuppressive Agents
Azathioprine, 6-mercaptopurine (6-MP), and methotrexate are widely used immunosuppressive drugs for IBD. The latter two are antimetabolite antineoplastic agents normally used to treat cancer, but have also demonstrated effectiveness in treating refractive Crohn's Disease. Azathioprine has been shown to be effective for inducing remission in steroid-dependent Crohn's Disease, but has also been shown to cause side effects in significant numbers of patients. 142 According to the International Agency for Research on Cancer, this substance is listed as a known carcinogen.143 The immunosuppressive agent 6-MP has demonstrated effectiveness in maintaining remission in Crohn's Disease patients when administered without concomitant steroids.144 Low dose methotrexate is sometimes used in Crohn’s patients who have not responded to other drug treatments and is reasonably effective in place of steroids.145 Side effects can range from nausea, diarrhea, and skin reactions,146 to more serious problems such as bone marrow suppression, lung lesions, kidney dysfunction, and hepatotoxicity (including liver fibrosis).146 Methotrexate has also been shown to cause folic acid deficiency.147 All of these medications can take up to several months to begin working, although methotrexate seems to work more rapidly than the others. They can be useful therapies for fistular disease and maintaining remission, but have little value in treating acute flare-ups of Crohn's Disease.148
When a bacterial etiology was suggested for Crohn's Disease, numerous studies investigated the effectiveness of antibiotic therapies, mostly with negative results.71,74 Recent research has suggested MAP as a potential pathogenic agent for Crohn's Disease and research utilizing combination anti-mycobacterial antibiotic therapy has been conducted for up to 46 months. A long duration of therapy is indicated because Mycobacterium species are very slow growing, making long-term therapy necessary. Two studies published in 2002 demonstrate the effectiveness of a combination of rifabutin, a broad spectrum anti-tubercular agent and clarithromycin, a macrolide anti-mycobacterial antibiotic.77,78
Numerous promising biologic therapies are emerging, such as anti-TNF-alpha monoclonal antibodies, antibodies to integrins alpha4 and alpha4- beta 7, interleukin antibodies, mitogen-activated protein kinase inhibitors, anti-sense nucleic acids, recombinant growth factors, and colony stimulating factors.
Perhaps the most promising are the anti- TNF-alpha monoclonal antibodies, including infliximab, etanercept, adalimumab, CDP870, CDP571, and onercept. Exploring the mechanisms and efficacy of these drugs is beyond the scope of this article; for a brief description see Table 5. Infliximab has received the most attention in clinical trials and appears to be the most effective. Infliximab is a mouse-human IgG1 chimeric monoclonal antibody to TNF-alpha administered intravenously. Infliximab is used to achieve clinical improvement and induce remission in patients with moderate-to-severe luminal and fistular Crohn's Disease refractory to other treatments. Infliximab exerts its beneficial effects by TNF-alpha neutralization in mononuclear inflammatory cells, thereby inducing apoptosis.149 A single infusion of 5 mg/kg has been shown to induce short-term (four-week) remission in 48 percent of patients150 and infliximab appears to have the greatest degree of efficacy in maintaining remission for at least one year when dosed at 10 mg/kg body weight every eight weeks.151 Infliximab is fairly well-tolerated in most patients, although serious side effects include acute infusion reactions,152 serum sickness-like disease, drug-induced lupus, infectious events attributed to infliximab therapy, pneumonia, reactivation of latent tuberculosis,153 and even death.154
Other anti-TNF-alpha monoclonal agents under investigation are CDP571, CDP870, and onercept, but all have failed phase 2 and 3 clinical trials despite showing a short-term clinical benefit. 155-157 Future research on these drugs is uncertain. Adalimumab is a human monoclonal antibody administered subcutaneously and appears to be well-tolerated in most Crohn's Disease patients, particularly those with reactions to infliximab. Phase 2 and 3 trials with Crohn's Disease patients are currently underway.158
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