Crohn's Disease (cont.)
Immuno-modulator medications
Immuno-modulators are medications that affect the body's immune system. The
immune system is composed of immune cells and the proteins that they produce.
These cells and proteins serve to protect 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 used by the immune system to
defend the body.) Normally, the immune system is activated only when the body is
exposed to foreign 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.
Immuno-modulators decrease tissue inflammation by reducing the population of
immune cells and/or by interfering with their production of proteins. Decreasing
the activity of the immune system with immuno-modulators increases the risk of
infections; however, the benefits of controlling moderate to severe Crohn's
disease usually outweigh the risks of infection due to weakened immunity.
Examples of immuno-modulators are 6-mercaptopurine (6-MP),
azathioprine (Imuran),
methotrexate (Rheumatrex,
Trexall), infliximab
(Remicade), adalimumab
(Humira).
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:
- 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 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 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-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-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 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. 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 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.
- 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.
Next: Infliximab (Remicade) »
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