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.
A majority of patients with moderate to severe disease will benefit from these drugs. Azathioprine and 6-MP are used primarily in the following situations:
- Severe Crohn's disease and ulcerative colitis not responding to corticosteroids.
- The presence of undesirable corticosteroid-related side effects.
- Corticosteroid dependency, a condition in which patients are unable to discontinue corticosteroids without developing relapses of their disease.
- 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 of white 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
a small percentage 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 three 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 three 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-marrow toxic chemicals by an enzyme called thiopurine methyltransferase (TPMT). These chemicals then are eliminated from the body. The activity of TPMT enzyme (the ability of the enzyme to convert 6-MP into inactive and non-marrow 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.
The U.S. Food and Drug Administration now recommends that doctors check TPMT levels prior to starting treatment with azathioprine or 6-MP. Patients found to have genes 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. Also, hepatotoxicity in the presence of normal TPMT levels been reported15. Therefore, all patients taking 6-MP or azathioprine (regardless of TPMT genetics) have to be closely monitored by periodic blood counts andliver enzyme tests 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. Allopurinol (Zyloprim) used together with azathioprine 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 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;
- 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.