Azathioprine for Ulcerative Colitis

Azathioprine for Ulcerative Colitis

What are Immunomodulator medications?
Mild and moderate ulcerative colitis can often be treated with 5-ASA medications: mesalazine (Asacol, Pentasa), balsalazide (Colazide), sulphasalazine (salazopyrin). These drugs also help maintain remission (reduce flare ups). Moderate/severe disease usually requires corticosteroids (prednisolone). Patients needing recurrent steroid courses (despite being on a 5-ASA drug like Asacol) or who become dependant on steroids may need to start azathioprine (or 6-mercaptopurine) which is an immunomodulator.

Immunomodulators are medications that weaken the body's immune system. The immune system is composed of immune cells and the proteins that these cells produce. These cells and proteins serve to defend the body against harmful bacteria, viruses, fungi, and other foreign invaders. Activation of the immune system causes inflammation within the tissues where the activation occurs. (Inflammation is, in fact, an important mechanism to defend the body used by the immune system.) Normally, the immune system is activated only when the body is exposed to harmful invaders. In patients with Crohn's disease and ulcerative colitis, however, the immune system is abnormally and chronically activated in the absence of any known invader. Immunomodulators decrease tissue inflammation by reducing the population of immune cells and/or by interfering with their production of proteins that promote immune activation and inflammation. Generally, the benefits of controlling moderate to severe ulcerative colitis outweigh the risks of infection due to weakened immunity. Examples of immunomodulators include azathioprine (Imuran), 6-mercaptopurine (6-MP, Purinethol), cyclosporine (Sandimmune), and methotrexate.

Azathioprine (Imuran) and 6-MP (Purinethol)
Azathioprine and 6-mercaptopurine (6-MP) are medications that weaken the body's immunity by reducing the population of a class of immune cells called lymphocytes. Azathioprine and 6-MP are related chemically. Specifically, azathioprine is converted into 6-MP inside 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. Because of the slow onset of action and the potential for side effects, however, 6-MP and azathioprine are used mainly in the following situations:

• Ulcerative colitis patients with severe disease not responding to corticosteroids.
• Patients who are experiencing undesirable corticosteroid-related side effects.
• Patients who are dependent on corticosteroids and are unable to discontinue them without developing relapses.

When azathioprine and 6-MP are added to corticosteroids in the treatment of ulcerative colitis patients who do not respond to corticosteroids alone, there may be an improved response or smaller doses and shorter courses of corticosteroids may be able to be used. Some patients can discontinue corticosteroids altogether without experiencing relapses. The ability to reduce corticosteroid requirements has earned 6-MP and azathioprine their reputation as "steroid-sparing" medications.
In ulcerative colitis patients with severe disease who suffer frequent relapses, 5-ASA may not be sufficient, and more potent azathioprine and 6-MP will be necessary to maintain remissions. In the doses used for treating ulcerative colitis and Crohn's disease, the long-term side effects of azathioprine and 6-MP are less serious than long-term oral corticosteroids or repeated courses of oral corticosteroids.

What Are the Side Effects of 6-MP and Azathioprine?
Side effects of 6-MP and azathioprine include increased vulnerability to infections, inflammation of the liver (hepatitis) and pancreas, (pancreatitis), and bone marrow toxicity (interfering with the formation of cells that circulate in the blood).
The goal of treatment with 6-MP and azathioprine is to weaken the body's immune system in order to decrease the intensity of inflammation in the intestines; however, weakening the immune system increases the 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 usually infects individuals with weakened immune systems such as patients with AIDS or cancer, especially if they are receiving chemotherapy, which further weakens the immune system.
Azathioprine and 6-MP-induced inflammation of the liver (hepatitis) and pancreas (pancreatitis) are rare. Pancreatitis typically causes severe abdominal pain and sometimes vomiting. Pancreatitis due to 6-MP or azathioprine 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 red blood cells, white blood cells, and platelets are made. Actually, a slight reduction in the white blood cell count during treatment is desirable since it indicates that the dose of 6-MP or azathioprine is high enough to have an effect; however, excessively low red or white blood cell counts indicates bone marrow toxicity. Therefore, patients on 6-MP and azathioprine 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 their bone marrow.
Pregnancy: the risk to the foetus of a disease flare up during pregnancy usually outweighs the risk of the mother taking 6-MP or azathioprine. A study of 341 pregnancies to mothers on azathioprine or 6-MP showed no increase n prematurity, spontaneous abortion, congenital abnormalities, prematurity, low birth weight or chromosomal abnormalities. The European guidelines for Crohn’s management (ECCO consensus 2006) state that these drugs should be considered safe during pregnancy (although the manufacturers and the BNF advise avoiding use in pregnancy where possible as there is insufficient data to be sure there is not a very small increased risk). If the disease has been extremely well controlled for a long period many mothers opt to slowly come off these medications prior to conception to be cautious. This should be discussed with their doctor first to weigh up the risks. 6-MP can reduce the sperm count in men. One small study suggested a slightly higher incidence of pregnancy complications when fathers were on 6-MP. Therefore, it is recommended that whenever feasible, male patients should stop 6-MP and azathioprine for three months before conception. Again this needs to be weighed against the risk of disease flare up.
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 lymphatic cells. There is no evidence at present that long term use of azathioprine and 6-MP in the low doses used in IBD increases the risk for lymphoma, leukemia or other malignancies. There is recent evidence that combining azathioprine or 6 MP with regular infliximab for long periods in young people carries a slightly increased risk of lymphoma.

Other Issues in the Use of 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. To reduce risk of bone marrow toxicity your doctor will measure the TPMT levels (a blood test) prior to treatment to identify those rare people who, for genetic reasons, require a smaller dose. To reduce the chance of nausea and other unpleasant side effects, it is common to start at a low dose and gradually build up to the target dose. Blood tests are needed regularly to monitor the white blood count, and occasionally to check liver function. These are done approximately every 2 weeks initially, but once established on the drug can be every 3 months.
Patients have been maintained on 6-MP or azathioprine for years without any important long-term side effects. Their doctors, however, should closely monitor their patients on long-term 6-MP. There is data suggesting that patients on long-term maintenance with 6-MP or azathioprine fare better than those who stop these medications. Those who stop 6-MP or azathioprine are more likely to experience relapses, more likely to need corticosteroids or undergo surgery.