Jay W. Marks, MD, is a board-certified internist and gastroenterologist. He graduated from Yale University School of Medicine and trained in internal medicine and gastroenterology at UCLA/Cedars-Sinai Medical Center in Los Angeles.
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:
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% to 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-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 and
liver 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.
Crohn's Disease - Symptoms at Onset of DiseaseQuestion: The symptoms of crohn's disease can vary greatly from patient to patient. What were your symptoms at the onset of your disease?
Abdominal pain is pain in the belly and can be acute or chronic. Causes include inflammation, distention of an organ, and loss of the blood supply to an organ. Abdominal pain can reflect a major problem with one of the organs in the abdomen such as the appendix, gallbladder, large and small intestine, pancreas, liver, colon, duodenum, and spleen.
Diarrhea is a change is the frequency and looseness of bowel movements. Cramping, abdominal pain, and the sensation of rectal urgency are all symptoms of diarrhea. Absorbents and anti-motility medications are used to treat diarrhea.
Gallstones are stones that form when substances in the bile harden. Gallstones (formed in the gallbladder) can be as small as a grain of sand or as large as a golf ball. There can be just one large stone, hundreds of tiny stones, or any combination. The majority of gallstones do not cause symptoms.
Pink eye, also called conjunctivitis, is redness or irritation of the conjunctivae, the membranes on the inner part of the eyelids and the membranes covering the whites of the eyes. These membranes react to a wide range of bacteria, viruses, allergy-provoking agents, irritants, and toxic agents.
Anemia is the condition of having less than the normal number of red blood cells or less than the normal quantity of hemoglobin in the blood. The oxygen-carrying capacity of the blood is, therefore, decreased.
Colon cancer is a malignancy that arises from the inner lining of the colon. Most, if not all, of these cancers develop from colonic polyps. Removal of these precancerous polyps can prevent colon cancer.
Anal itching is the irritation of the skin at the exit of the rectum, known as the anus, accompanied by the desire to scratch. Causes include everything from irritating foods we eat, to certain disease and infections. Treatment options include local anesthetics, vasoconstrictors, protectants, astringents, antiseptics, keratolytics, analgesics, and corticosteroids. If condition persists, a doctor examination may be needed to identify an underlying cause.
Clostridium difficile (C. difficile) is a bacterium, and is one of the most common causes of infection of the colon. C. difficile spores are found frequently in hospitals, nursing homes, extended care facilities, and nurseries for newborn infants. They can be found on bedpans, furniture, toilet seats, linens, telephones, stethoscopes, fingernails, rings, floors, infants' rooms, and diaper pails. They even can be carried by pets. Antibiotic-associated (C. difficile) colitis is an infection of the colon caused by C. difficile that occurs primarily among individuals who have been using antibiotics. Treatment for C. difficile colitis hydration, replenishment of electrolyte deficiencies, discontinuing the antibiotic that caused the colitis, and using antibiotics to eradicate the C. difficile bacterium.
Ulcerative colitis is a chronic inflammation of the colon. Symptoms include abdominal pain, diarrhea, and rectal bleeding. Ulcerative colitis is closely related to Crohn's disease, and together they are referred to as inflammatory bowel disease. Treatment depends upon the type of ulcerative colitis diagnosed.
Small intestinal bacterial overgrowth (SIBO) refers to a condition in which abnormally large numbers of bacteria (at least 100,000 bacteria per ml of fluid) are present in the small intestine and the types of bacteria in the small intestine resemble more the bacteria of the colon than the small intestine. There are many conditions associated with small intestinal bacterial overgrowth, to include: diabetes, scleroderma, Crohn's disease, and others. There is a striking similarity between the symptoms of irritable bowel syndrome and SIBO. It has been theorized that SIBO may be responsible for the symptoms of at least some patients with irritable bowel syndrome. Symptoms of SIBO include: excess gas, abdominal bloating, diarrhea, and abdominal pain.
Ankylosing spondylitis is a type of arthritis that causes chronic inflammation of the spine. The tendency to develop ankylosing spondylitis is genetically inherited.
Psoriatic arthritis is a disease that causes skin and joint inflammation. Symptoms include painful, stiff, and swollen joints, tendinitis, and organ inflammation. Treatment involves antiinflammatory medications and exercise.
Inflammation of the inner lining of the colon is referred to as colitis. Symptoms of the inflammation of the colon lining include diarrhea, pain, and blood in the stool. There are several causes of colitis including infection, ischemia of the colon, inflammatory bowel disease (Crohn's disease, Ulcerative colitis, or microscopic colitis). Treatment depends on the cause of the colitis.
Canker sore is a small ulcer crater in the lining of the mouth. Canker sores are one of the most
common problems that occur in the mouth. Canker sores typically last for
10-14 days and they heal without leaving a scar.
The inflammatory bowel diseases (IBD) are Crohn's disease (CD) and ulcerative colitis (UC). The intestinal complications of Crohn's disease and ulcerative colitis differ because of the characteristically dissimilar behaviors of the intestinal inflammation in these two diseases.
Gastritis is an inflammation of the stomach lining. Causes of gastritis include drinking too much alcohol, medications such as NSAIDs, ibuprofen, aspirin, H. pylori infection, severe infections, burns, anemia, and autoimmune disorders. Gastritis is diagnosed with endoscopy, blood tests, or stool tests. Treatment depends upon the cause of gastritis.
Erythema nodosum is a skin inflammation that results in reddish, painful, tender lumps most commonly located in the front of the legs below the knees. Erythema nodosum can resolve on its own in 3 to 6 weeks, leaving a bruised area. Treatments include anti-inflammatory medications and cortisone by mouth or injection.
Corticosteroid drugs such as prednisone and prednisolone are commonly used to treat asthma, allergic reactions, RA, and IBD. Steroids such as these do have serious drawbacks such as steroid withdrawal symptoms such as: fatigue, weakness, decreased appetite, weight loss, nausea, vomiting, abdominal pain, and diarrhea. Speak with your healthcare provider prior to tapering off steroid medications.
Chronic pain is pain (an unpleasant sense of discomfort) that persists or progresses over a long period of time. In contrast to acute pain that arises suddenly in response to a specific injury and is usually treatable, chronic pain persists over time and is often resistant to medical treatments.
Bronchiectasis is a condition in which the bronchial tubes of the lung become damaged. Inflammation from infection or other causes destroys the smooth muscles of the bronchial tubes. Bronchiectasis is a form of COPD (which includes emphysema and chronic bronchitis). There are three primary types of bronchiectasis: 1) cylindrical bronchiectasis; 2) saccular bronchiectasis; and 3) cystic bronchiectasis. Bronchiectasis may also be acquired or congenital. The most common symptoms of bronchiectasis are recurrent cough and sputum production. There is no cure for bronchiectasis. Treatment is often geared toward controlling the symptoms of bronchiectasis.
Primary sclerosing cholangitis (PSC) is a chronic, progressive disease of the bile ducts that channel bile from the liver into the intestines. There is an association between primary sclerosing cholangitis and ulcerative colitis and Crohn's disease. Symptoms of primary sclerosing cholangitis include abnormal liver blood tests, itching, fatigue, and jaundice. Primary sclerosing cholangitis is treated with medications and in some cases, liver transplant.
Digestion is the complex process of turning food you eat into the energy you need to survive. The digestive process also involves creating waste to be eliminated, and is made of a series of muscles that coordinate the movement of food.
Vitamin D deficiency has been linked with rickets, cancer, cardiovascular disease, severe asthma in children and cognitive impairment in older adults. Causes include not ingesting enough of the vitamin over time, having limited exposure to sunlight, having dark skin, and obesity. Symptoms include bone pain and muscle weakness. Treatment for vitamin D deficiency involves obtaining more vitamin D through supplements, diet, or exposure to sunlight.
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