Ulcerative Colitis (cont.)
What are Immunomodulator medications?
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 (Rheumatrex,
Trexall).
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 and Crohn's disease 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.
6-MP can reduce the
sperm count in men. When the partners of male patients on 6-MP conceive, there
is a higher incidence of miscarriages and vaginal bleeding. There also are
respiratory difficulties in the newborn. Therefore, it is recommended that
whenever feasible, male patients should stop 6-MP and
azathioprine for three months before conception.
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.
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 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 6-MP. Typically, 6-MP is started at a dose of 50 mg daily. The blood
count is then checked two weeks later. If the white blood cell count (specifically the lymphocyte count) is not
reduced, the dose is increased. This cautious, stepwise approach helps prevent
severe bone marrow and liver toxicity, but also delays benefit from the drug.
Studies have shown that giving higher doses of 6-MP early
can speed up the benefit of 6-MP without increased toxicity in most patients, but some patients do develop severe bone marrow toxicity. Therefore, the dose of
6-MP has to be individualized. 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. In these individuals, lower initial doses can be used. Blood tests
can also 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.
How Long Can Patients Continue on 6-MP?
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.
Methotrexate
Methotrexate (Rheumatrex,
Trexall) is an immunomodulator 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 6-MP and azathioprine
or are intolerant of these two medications. Methotrexate also may be effective
in patients with moderate to severe ulcerative colitis who are not responding to
corticosteroids or 6-MP and azathioprine. It can be given orally or by weekly
injections under the skin or into the muscles. 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 have morbid (severe)
obesity. Generally, periodic liver biopsies are recommended for a patient who
has received a cumulative (total) methotrexate dose of 1.5 grams and higher.
Other side effects of
methotrexate include low white blood cell counts and inflammation of the
lungs.
Methotrexate should not be used in pregnancy.
Cyclosporine
Cyclosporine (Sandimmune) is a potent immunosuppressant used in preventing
organ rejection after transplantation, for example, of the liver. It
also has been used to treat patients with severe ulcerative colitis and
Crohn's disease. Because of the approval of
infliximab (Remicade) for treating severe Crohn's
disease, cyclosporine probably will be used primarily in severe ulcerative
colitis. Cyclosporine is useful in fulminant ulcerative colitis and in severely ill
patients who are not responding to systemic corticosteroids. Administered
intravenously, cyclosporine can be very effective in rapidly controlling severe
colitis and avoiding or delaying surgery.
Cyclosporine also is available as an oral medication, but the relapse rate with oral
cyclosporine is high. Therefore, cyclosporine seems most useful when
administered intravenously in acute situations.
Side effects of cyclosporine include high blood pressure, impairment of kidney function, and tingling sensations in the extremities. More serous side effects
include anaphylactic shock and
seizures.
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 and in ulcerative
colitis, 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.
Infliximab has been used effectively for many years for the treatment of
moderate to severe Crohn's disease that was not responding to corticosteroids or
immuno-modulators. In Crohn's disease patients, 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 two 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.
For many years doctors were uncertain whether infliximab could be used to
treat ulcerative colitis. Only recently, have doctors begun to use
infliximab as treatment for ulcerative colitis. In one randomized placebo controlled study
involving more than 700 patients with moderate to severe ulcerative colitis,
infliximab (5mg or 10 mg per kilogram body weight) given intravenously was more
effective than placebo in inducing and maintaining remission.
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.
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. There also have been cases of
tuberculosis (TB)
reported after 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 for a single infusion at this time, patients should be aware that they
are likely to require repeated infusions once Remicade therapy has been
initiated.
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.
There have been rare reports of nerve damage such as optic neuritis
(inflammation of the nerve of the eye) and motor neuropathy.
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).
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.
Infliximab's effects on the fetus are not known.
Because infliximab is partly a mouse protein, some patients can develop
antibodies against infliximab with repeated infusions. The development of these
antibodies can decrease the effectiveness of the drug. The chances of developing
these antibodies can be decreased by concomitant use of 6-MP and
corticosteroids.
While infliximab represents an exciting new class of medications in the fight
against Crohn's disease and ulcerative colitis, caution is warranted because of
potentially serious side effects. Doctors are using infliximab in moderate to
severe ulcerative colitis not responding to other medications.
Next: Summary of medication treatment »
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