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Sunday, May 18, 2008

Immuno-Modulator Medications Used To Treat Crohn's Disease

The bodys immune system is its defense against infection and disease. By suppressing the bodys immune system, doctors can reduce inflammation and other symptoms of Crohn's Disease. These types of medications are used to help continue remission. Your physician will know the best medications for you and will discuss with you the pros and cons of taking different medications. DO NOTDISCONTINUE taking medications that are prescribed to you until talking with your physician. Below is a list of different medications used to treat Crohn;s Disease as well as the side effects of them. To read more about different medications used to treat other symptoms of Crohn's Disease such as inflammation click on the link below.

Anti-Inflammation Medications

Herbal Supplements

Azathioprine (Imuran) and 6-mercaptopurine (6-MP, Purinethol)

Azathioprine (Imuran) and 6-mercaptopurine (6-MP, Purinethol) are medications that weaken the body's immune system by reducing the population of a class of immune cells called lymphocytes. Azathioprine and 6-MP are related chemically. (Actually, azathioprine is converted into 6-MP within the body.) In high doses, these two drugs have been useful in preventing rejection of transplanted organs and in treating leukemia. In low doses, they have been used for many years to treat patients with moderate to severe Crohn's Disease and ulcerative colitis. Azathioprine and 6-MP are increasingly recognized by doctors as valuable drugs in treating Crohn's Disease and ulcerative colitis. Some 70% of patients with moderate to severe disease will benefit from these drugs. Azathioprine and 6-MP are used primarily in the following situations:
  1. Severe Crohn's Disease and ulcerative colitis not responding to corticosteroids.
  2. The presence of undesirable corticosteroid-related side effects.
  3. Corticosteroid dependency, a condition in which patients are unable to discontinue corticosteroids without developing relapses of their disease.
  4. Maintenance of remission.
When azathioprine and 6-MP are added to corticosteroids in the treatment of Crohn's Disease not responding to corticosteroids alone, there may be an improved response. Also, smaller doses and shorter courses of corticosteroids may be able to be used. Some patients can discontinue corticosteroids altogether without experiencing relapses of their disease. This corticosteroid-lowering effect has earned azathioprine and 6-MP their reputation as "steroid-sparing" medications. In Crohn's Disease patients with severe disease who suffer frequent relapses, 5-ASA may not be sufficient, and the more potent azathioprine and 6-MP will be necessary to maintain remissions. In the lower doses used to treat Crohn's Disease, the long-term side effects of azathioprine or 6- MP are less serious than those of long-term corticosteroids or repeated courses of corticosteroids. Patients with Crohn's Disease may undergo surgery to remove a segment of the intestine that is obstructed or contains a fistula. After surgical removal of the diseased segments, the patients often will be free of disease and symptoms for a while, but many eventually will have their disease recur. During these recurrences, previously healthy intestine can become inflamed. Long-term 5-ASA (such as Pentasa) and 6-MP both are effective in reducing the chances of recurrence after surgery. Anal fistulae can develop in some patients with Crohn's Disease. Anal fistulae are abnormal tracts (tunnels) that form between the small intestine or colon and the skin around the anus. Drainage of fluid and mucous from the opening of the fistula is a troublesome problem. These fistulae are difficult to treat and do not heal readily. Metronidazole (Flagyl) has been used with some success in promoting healing of these fistulae. In difficult cases, azathioprine and 6-MP may be successful in promoting healing.

Side effects of azathioprine and 6-MP

Side effects of azathioprine and 6-MP include increased vulnerability to infections, inflammation of the liver (hepatitis) and the pancreas (pancreatitis), and bone marrow toxicity (interference with the formation of cells that circulate in the blood). The goal of treatment with azathioprine and 6-MP is to lower the body's production of certain types o fwhite blood cells (lymphocytes) in order to decrease the inflammation in the intestines; however, lowering the number of lymphocytes may increase vulnerability to infections. For example, in a group of patients with severe Crohn's Disease unresponsive to standard doses of azathioprine, raising the dose of azathioprine helped to control the disease, but two patients developed cytomegalovirus (CMV) infection. (CMV typically infects individuals with weakened immune systems such as patients with AIDS and cancer patients receiving chemotherapy). Azathioprine and 6-MP can induce inflammation of the liver (hepatitis) and pancreas (pancreatitis). Pancreatitis typically causes severe abdominal pain and sometimes vomiting. Pancreatitis due to azathioprine or 6-MP occurs in 3%-5% of patients, usually during the first several weeks of treatment. Patients who develop pancreatitis should not receive either of these two medications again. Azathioprine and 6-MP also suppress the bone marrow. The bone marrow is where the red blood cells, white blood cells, and platelets are made. Actually, a slight reduction in the white cell count during treatment is desirable since it suggests that the dose of azathioprine or 6-MP is high enough to have an effect; however, excessively low red or white blood cell counts indicates bone marrow toxicity. Therefore, patients on azathioprine or 6-MP should have periodic blood counts (usually every two weeks initially and then every 3 months during maintenance) to monitor the effect of the drugs on the bone marrow. Patients on long-term, high dose azathioprine to prevent rejection of the Kidney after kidney transplantation have an increased risk of developing lymphoma, a malignant disease of lymph cells. There is no evidence at present that long term use of azathioprine or 6-MP, in the lower doses used in Crohn's Disease, increases the risk of lymphoma, leukemia or other malignancies. The use of azathioprine and 6-MP in pregnant women must be carefully considered. There are reports suggesting that the use of azathioprine or 6-MP in pregnancy is safer than once thought. The risk of continuing azathioprine or 6-MP during conception and pregnancy must be weighed against the risk of worsening disease if they are stopped. On the other hand, worsening disease has been shown clearly to be a significant risk to the fetus.

Other issues with azathioprine and 6-MP

One problem with 6-MP and azathioprine is their slow onset of action. Typically, full benefit of these drugs is not realized for 3 months or longer. During this time, corticosteroids frequently have to be maintained at high levels to control inflammation. The reason for this slow onset of action is partly due to the way doctors prescribe these drugs. For example, 6-MP is typically started at a dose of 50 mg daily. The blood count is then checked two weeks later. If the lymphocytes are not reduced, the dose of 6-MP is increased. This cautious, stepwise approach helps reduce bone marrow and liver toxicity but also delays benefit from the drug. Studies have shown that giving higher doses of 6-MP early can hasten the benefit of 6-MP without increasing the toxicity in most patients, but some patients do develop severe bone marrow toxicity. Scientists now believe that an individual's vulnerability to 6-MP toxicity is genetically inherited. Blood tests can be performed to identify those individuals with increased vulnerability to 6-MP toxicity. Blood tests also can be performed to measure the levels of certain by-products of 6-MP. The levels of these by-products in the blood help doctors more quickly determine whether the dose of 6-MP is right for the patient. TPMT genetics and safety of azathioprine and 6-MP Azathioprine is converted into 6-MP in the body and 6-MP then is partially converted in the body into inactive and non-toxic chemicals by an enzyme called TPMT. These chemicals then are eliminated from the body. The activity of TPMT enzyme (i.e. the ability of the enzyme to convert 6-MP into inactive and non-toxic chemicals) is genetically determined, and approximately 10% of the population in the Untied States has a reduced or absent TPMT activity. In this 10% of patients, 6-MP accumulates and is converted into chemicals that are toxic to the bone marrow where blood cells are produced. Thus, when given normal doses of azathioprine or 6-MP, these patients with reduced or absent TPMT activities can develop seriously low white blood cell counts for prolonged periods of time, exposing them to serious life-threatening infections. Doctors now can perform genetic testing for TPMT before starting azathioprine or 6-MP. Patients found to have associated with reduced or absent TPMT activity are treated with alternative medications or are prescribed substantially lower than normal doses of 6-MP or Azathioprine. A word of caution is in order, however. Having normal TPMT genes is no guarantee against azathioprine or 6-MP toxicity. Rarely, a patient with normal TPMT genes can develop severe toxicity in the bone marrow and a low white blood cell count even with normal doses of 6-MP or azathioprine. Therefore, all patients taking 6-MP or azathioprine (regardless of TPMT genetics) have to be closely monitored by a doctor who will order periodic blood counts for as long as the medication is taken. Another cautionary note; allopurinol (Zyloprim), used in treating high blood uric acids levels, can induce bone marrow toxicity when used together with azathioprine or 6 MP. Zyloprim used together with azathiprine or 6-MP has similar effect as having reduced TPMT activity, causing increased accumulation of the 6-MP metabolite that is toxic to the bone marrow. 6-MP metabolite levels In addition to monitoring blood cell counts and liver tests, doctors also may measure blood levels of the chemicals that are formed from 6-MP (6-MP metabolites), which can be helpful in several situations such as:
  1. If a patient's disease is not responding to standard doses of 6-MP or azathioprine and his/her 6-MP blood metabolite levels are low, doctors may increase the 6-MP or azathioprine dose.
  2. If a patient's disease is not responding to treatment and his/her 6-MP blood metabolite levels are zero, he/she is not taking his/her medication. The lack of response in this case is due to patient non-compliance.
Duration of treatment with azathioprine and 6-MP

Patients have been maintained on 6-MP or azathioprine for years without important long-term side effects. Patients on long-term azathioprine or 6-MP, however, should be closely monitored by their doctors. There are data suggesting that patients on long-term maintenance fare better than those who stop these medications. Thus, those who stop azathioprine or 6-MP are more likely to experience recurrence of their disease and are more likely to need corticosteroids or undergo surgery.

Infliximab (Remicade)

Infliximab (Remicade) is an antibody that attaches to a protein called tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is one of the proteins produced by immune cells during activation of the immune system. TNF-alpha, in turn, stimulates other cells of the immune system to produce and release other proteins that promote inflammation. In Crohn's Disease, there is continued production of TNF-alpha as part of the immune activation. Infliximab, by attaching to TNF-alpha, blocks its activity and in so doing decreases the inflammation. Infliximab, an antibody to TNF-alpha, is produced by the immune system of mice after the mice are injected with human TNF-alpha. The mouse antibody then is modified to make it look more like a human antibody, and this modified antibody is infliximab. Such modifications are necessary to decrease the likelihood of allergic reactions when the antibody is administered to humans. Infliximab is given by intravenous infusion over two hours. Patients are monitored throughout the infusion for adverse reactions. In August, 1998 the United States Food and Drug Administration approved the use of infliximab for the short-term treatment of moderate to severe Crohn's Disease patients who respond inadequately to corticosteroids, azathioprine, or 6-MP.

Effectiveness of infliximab

Infliximab is an effective and fast-acting drug for the treatment of active Crohn's Disease. In a study involving patients with moderate to severe Crohn's Disease who were not responding to corticosteroids or immuno-modulators, 65% experienced improvement in their disease after one infusion of infliximab. Some patients noticed improvement in symptoms within days of the infusion. Most patients experienced improvement within 2 weeks. In patients who respond to infliximab, the improvements in symptoms can be dramatic. Moreover, there can be impressively rapid healing of the ulcers and the inflammation in the intestines after just one infusion. The anal fistulae of Crohn's Disease are troublesome and often difficult to treat. Infliximab has been found to be effective for treating fistulae.

Duration of benefits with infliximab

The majority of the patients who responded to a first infusion of infliximab developed recurrence of their disease within 3 months. However, studies have shown that repeated infusions of Infliximab every 8 weeks are safe and effective in maintaining remission in many patients over a 1-2 year period. Response to infliximab after repeated infusions sometimes is lost if the patient starts to develop antibodies to the infliximab (which attach to the infliximab and prevent it from working). Studies are now being done to determine the long-term safety and effectiveness of repeated infusions of infliximab. One potential use of infliximab is to quickly control active and severe disease. The use of infliximab then may be followed by maintenance treatment with azathioprine, 6-MP or 5-ASA compounds. Azathioprine or 6-MP also may be helpful in preventing the development of antibodies against infliximab.

Side effects of infliximab

Infliximab generally is well-tolerated. There have been rare reports of side effects during infusions, including chest pain, shortness of breath, and nausea. These effects usually resolve spontaneously within minutes if the infusion is stopped. Other commonly-reported side effects include headache and upper respiratory tract infection. TNF-alpha is an important protein for defending the body against infections. Infliximab, like immuno-modulators, increases the risk for infection. One case of salmonella colitis and several cases of pneumonia have been reported with the use of infliximab. Because infliximab is partly a mouse protein, it may induce an immune reaction when given to humans, especially with repeated infusions. In addition to the side effects that occur while the infusion is being given, patients also may develop a "delayed allergic reaction" that occurs 7-10 days after receiving the infliximab. This type of reaction may cause flu-like symptoms with fever, joint pain and swelling, and a worsening of Crohn's Disease symptoms. It can be serious, and if it occurs, a physician should be contacted. Paradoxically, those patients who have more frequent infusions of Remicade are less likely to develop this type of delayed reaction compared to those patients who receive infusions separated by long intervals (6-12 months). Although Remicade is only FDA approved at this time for a single infusion, patients should be aware that they are likely to require repeated infusions once Remicade therapy has been initiated.

Precautions with infliximab

Infliximab can aggravate and cause the spread of an existing infection. Therefore, it should not be given to patients with pneumonia, urinary tract infection or abscess (localized collection of pus). There also have been cases of tuberculosis (TB) reported after the use of infliximab. The majority of these cases occurred in Europe and in individuals who had tuberculosis in the past. It now is recommended that patients be tested for TB prior to receiving infliximab. Patients who previously had TB should inform their physician of this before they receive infliximab Infliximab can cause the spread of cancer cells. Therefore, it should not be given to patients with cancer or a history of cancer. Infliximab can promote intestinal scarring (part of the process of healing) and, therefore, can worsen strictures (narrowed areas of the intestine caused by inflammation and subsequent scaring) and lead to intestinal obstruction. It also can cause partial healing (partial closure) of anal fistulae. Partial closure of fistulae impedes drainage of fluid through the fistulae and may result in collections of fluid in which bacteria multiply. This can result in abscesses. Infliximab also should be avoided in pregnancy since its effects on the fetus are not known. Because infliximab is partly a mouse protein, some patients can develop antibodies against infliximab with repeated infusions. Such antibodies occur in approximately 13% of patients. There are some reports of worsening heart disease in patients who have received Remicade. The precise mechanism and role of infliximab in the development of this side effect is unclear. As a precaution, individuals with heart disease should inform their physician of this condition before receiving infliximab. While infliximab represents an exciting new class of medications in the fight against Crohn's Disease, caution is warranted in its use. The long-term safety and effectiveness is not yet known.

Identifying patients who will respond to infliximab

There is insufficient data regarding infliximab in ulcerative colitis. Infliximab most likely is not effective in treating ulcerative colitis. PANCA and ASCA are serologic tests performed on blood that frequently are abnormal in patients with ulcerative colitis and Crohn's Disease. These serologic tests can be helpful in establishing a diagnosis of ulcerative colitis and Crohn's Disease and in distinguishing Crohn's Disease from ulcerative colitis. Studies are now being done to see whether these antibodies are useful in predicting which patients will respond to infliximab.


Methotrexate is both an immuno-modulator and anti-inflammatory medication. Methotrexate has been used for many years in the treatment of severe rheumatoid arthritis and psoriasis. It has been helpful in treating patients with moderate to severe Crohn's Disease who are either not responding to azathioprine and 6- MP or are intolerant of them. Methotrexate also may be effective in patients with moderate to severe ulcerative colitis who are not responding to corticosteroids, azathioprine, or 6-MP. It can be given orally or by weekly injections under the skin or into the muscles, but it is more reliably absorbed with the injections. One major complication of methotrexate is the development of liver cirrhosis when the medication is given over a prolonged period of time (years). The risk of liver damage is higher in patients who also abuse alcohol or are severely obese. Although it has been recommended that a liver biopsy should be obtained in patients who have received a cumulative (total) methotrexate dose of 1.5 grams or higher, the need for such biopsies is controversial. Other side effects of methotrexate include low white blood cell counts and inflammation of the lungs. Methotrexate should not be used in pregnant women because of toxic effects on the fetus.

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