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|Newsletters: New Medical Treatment for Crohn’s Disease|
New Medical Treatment for Crohn’s Disease
Douglas L. Seidner, MD
Dr. Seidner led a breakout session at this year’s conference which focused on the treatments available for patients with Crohn’s disease, and highlighted a new type of anti TNF-alpha therapy. In this article he describes the benefits and drawbacks of this exciting new treatment which has improved the symptoms in patients with moderate to severely active Crohn’s disease when more traditional therapies have not worked.Crohn’s disease is a chronic inflammatory disease of the bowel which results from an inappropriate over activity of the immune cells of the bowel. The immune cells of the bowel, such as macrophages, lymphocytes and neutrophils, reside in the wall of the bowel just below the lining or mucosal surface. These cells help keep bacteria and other potentially injurious substances from entering the body while the digestive tract is absorbing nutrients from the diet. If the mucosa is breached by a disease-causing bacteria, such as E.coli or Salmonella, the immune cells begin a highly integrated process to isolate and kill the bacteria. The bowel may become acutely inflamed, but under normal circumstances, once the immune cells have killed the bacteria, the bowel returns to normal and the immune cells revert back to their former state of readiness.
In patients with Crohn’s disease the immune cells of the bowel are inappropriately active for a protracted length of time. This results in the signs and symptoms of Crohn’s disease which may include abdominal pain, diarrhea, gastrointestinal bleeding, nausea and vomiting. Although the body’s reaction to a bacteria is as an example of how the immune cells of the body work, it should be pointed out that the cause of Crohn’s disease remains unknown.
Fortunately, the symptoms of Crohn’s disease can be controlled in most people through the use of medication which diminishes the activity of the immune cells, and thus decreases the chronic inflammation seen with this condition. The decision to take medication is dependent on the degree of disease activity and the region of the bowel which is inflamed.
Medications can be divided into several categories which include sulfasalazine and other mesalamine containing compounds, antibiotics corticosteroids and other immunosuppressive agents. Several immunosuppressive agents have recently been developed which effect very specific steps in the interaction between the immune cells of the bowel and shift the activity of these cells from active inflammation to a normal resting state. Infliximab (Remicade®, Centocor Inc.) is the first of these immunosuppressive medications to be approved for use in the treatment of Crohn’s disease. To understand the role of this new medication in Crohn’s disease, it is helpful to review the use of some of the more conventional medications.
Sulfasalazine has been shown to benefit patients with mild to moderately active Crohn’s disease involving the colon and distal small bowel. Mesalamine, which is a 5 ASA derivative and the active component of sulfasalazine, is used instead of sulfasalazine in patients who develop side effects such as nausea and headache or who are allergic to the sulfa component of sulfasalazine. Preparations of mesalamine include Asacol® (Proctor & Gamble), Dipentum® (Pharmacia & Upjohn), Rowasa® (Solvay) and Pentasa® (Roberts). Some of these medications are available in enema or suppository form, or are formulated for a greater degree of release in the small bowel and thus can be used to target specific levels of the bowel. The newer preparations have been shown to maintain Crohn’s disease in remission for one to two years, if started soon after surgical resection of active disease.
Antibiotics, such as metronidazole and ciprofloxacin, have been shown to control symptoms of Crohn’s disease involving the colon, distal small bowel and perianal region. The exact mechanism of action for these antibiotics is not known. One theory is that antibiotics decrease the concentration of the normal bacteria that reside in the bowel and that their decreased number leads to a diminished concentration of the breakdown products which are released when they die. These breakdown products may contribute to the inflammation associated with Crohn’s disease. Another theory is that these antibiotics have a direct immunosuppressive effect on the white blood cells of the bowel. Metronidazole has been most widely used because studies have shown it to be effective and safe. Side effects include nausea, a metallic taste and peripheral neuropathy characterized as numbness in the hands and feet. These symptoms resolve when the medication is discontinued. Ciprofloxacin has also been shown to be useful but is more expensive than metronidazole.
Corticosteroids, such as prednisone or hydrocortisone, are potent immunosuppressive medications which are used to treat inflammation of the entire small and large bowel in moderate to severely active Crohn’s disease. Preparations are available for oral, rectal and intravenous administration. Corticosteroids work very quickly and are also fairly inexpensive. Unfortunately, they have many undesirable side effects when used long term, which include adrenal gland suppression, hypertension, diabetes, osteoporosis, cataracts and hip fracture. Because of these side effects, the duration of their use should be limited when possible.
Azathioprine (Imuran®, Faro) and 6-mercaptopurine are two closely related immunosuppressive medications which are used for Crohn’s disease when inflammation cannot be controlled with corticosteroids, or when corticosteroids cannot be discontinued without recurrence of active disease. These medications can maintain Crohn’s disease in remission and can be used to treat fistulas associated with Crohn’s disease. Methotrexate is another immunosuppressive medication used to treat patients dependent on steroids to control their Crohn’s disease. As with all immunosuppressive medications, these drugs have substantial side effects. However, under the right circumstances, it is generally felt that these side effects are less common, or are easier to monitor and treat than those experienced with corticosteroids — especially when they are used for an extended period of time.
New Anti TNF-alpha Therapy
Infliximab was released by the U.S. Food and Drug Administration in August 1998 to treat patients with moderate to severely active Crohn’s disease which is resistant to management with the immunosuppressors and medications described above. Infliximab specifically acts against tumor necrosis factor alpha (TNF-alpha), which is a proinflammatory protein believed to play a major role in the development of inflammation in Crohn’s disease. The initials m-a-b in infliximab stand for monoclonal antibody. The major portion of this antibody is derived from a human IgG antibody, while the biologically active portion of this molecule is derived from a mouse antibody. Using molecular biologic techniques, many identical copies of the molecule derived from the mouse antibody are produced, hence the term “monoclonal.”
Infliximab, also referred to as anti TNF-alpha therapy, has been studied in two randomized-controlled trials involving approximately 100 patients with Crohn’s disease. In the first study, patients with medically resistant, moderate to severe disease were treated with infliximab or a placebo. Four weeks after receiving the medication, 50 to 81 percent of the patients showed signs of improvement and 33 percent went into remission, while only 17 percent in the placebo group improved and 4 percent entered remission. In the second study, patients with active fistulas received infliximab or placebo on three occasions, two weeks apart. There was a 50 percent reduction in fistula drainage in nearly two-thirds of patients who received infliximab, and over half of the patients’ fistulas closed.
While the use of anti TNF-alpha therapy appears to be greatly beneficial, it also has several serious potential side effects. First, anti TNF-alpha therapy is contraindicated in patients with an active infection because it can impair the body’s defense against bacteria and can lead to an inability of the body to control the infection which may be life-threatening. Anti TNF-alpha therapy is also contraindicated in patients with a history of malignancy because of the role that TNF-alpha plays in combating the development and spread of cancer. Allergy to the medication and pregnancy are other contraindications to the use of this medication. Further, patients with marked narrowing of the bowel should not receive this medication, since rapid healing may lead to scar tissue formation with complete bowel obstruction and the need for emergency surgery. Finally, anti TNF-alpha therapy is expensive, and there is no data available on its long term use in patients.
Infliximab is currently approved for use in patients with Crohn’s disease which is medically resistant to maximal therapy of traditional medication and severely fistulizing disease. It can also be used for patients who cannot tolerate corticosteroids and other immunosuppressive medications. It is administered in the ambulatory setting as an intravenous infusion over approximately two hours. Some people will experience a headache, nausea, low blood pressure, rapid heart rate and occasional chest pain and facial swelling during administration of the medication. These symptoms are usually treated by discontinuing the infusion and administering acetominophen (Tylenol®, McNeil Laboratories) or diphenhydramine (Benadryl®, Parke-Davis). Since infliximab can increase a patient’s susceptibility to infection, especially pneumonia, symptoms such as a cough, sputum and fever must be reported to the doctor if they should occur. Finally, in rare instances, the body can develop antibodies against Infliximab which can lead to the development of a lupus-like illness. This illness, which is characterized as a rash and arthritis, has thus far resolved when the medication was discontinued.
Anti TNF-alpha therapy has greatly enhanced our ability to treat patients with Crohn’s disease. To date, well over 1500 patients have been treated with this therapy. Our experience at the Cleveland Clinic with infliximab is similar to those reported in the two clinical trials which I have discussed. As we treat more patients with this new medication we will gain a tremendous amount of information regarding the effectiveness and safety of this potent drug, and will be better able to define the group of patients who will benefit most.
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