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Ulcerative colitis

Description

An in-depth report on the causes, diagnosis, treatment, and prevention of ulcerative colitis.

Alternative Names

Inflammatory bowel disease; Colitis - ulcerative

Medications

Drugs cannot cure inflammatory bowel disease, but they can help reduce the inflammation and accompanying symptoms in up to 80% of patients. The primary goal of drug therapy is to reduce inflammation in the intestine.

Drugs Used. Many drugs are available in different forms and may be used at various stages of the disease.

• Aminosalicylates. The best treatments of ulcerative colitis are preparations of aspirin-like medications called aminosalicylates or 5-ASAs. They are used in all phases of the disease, including maintenance during remission. They may be administered rectally in patients who have mild-to-moderate disease that occurs only in the lower intestine. They may also be taken by mouth.
• Corticosteroids. Corticosteroids (steroids) may be added or used alone to reduce acute inflammation. (They are not recommended for maintenance therapy). Steroids may be administered rectally as an alternative to an aminosalicylate if the disease is limited to the lowest parts of the intestine. Oral forms may treat moderate to severe cases. People who do not respond to less aggressive treatments may need intravenous steroids.
• Immunosuppressants. Drugs that suppress the immune system (immunosuppressants) are useful, either alone or in combinations, for disease that does not respond to other treatments or for maintenance of remissions.
• Biologic Response Modifiers. Unlike drugs that are made from chemicals, biologic response modifiers, (also called biologics), are produced from living organisms. Biologics are designed to stimulate the immune system and interfere with specific proteins (cytokines) involved with the inflammatory response. Infliximab (Remicade) is the first biologic drug approved for ulcerative colitis. It blocks a cytokine called tumor necrosis factor (TNF).

Determining Success. The success of therapy is determined by its ability to induce and maintain remissions without causing significant side effects. The patient's condition is generally considered in remission when the intestinal lining has healed and symptoms such as diarrhea, abdominal cramps, and tenesmus (straining painfully or ineffectively to defecate or urinate) are normal or close to normal.

Aminosalicylates (Mesalamine and its Derivatives)

Mesalamine is an aminosalicylate (the common name of the compound 5-aminosalicylic acid or 5-ASA). This compound inhibits factors in the immune system, importantly, the cytokines that cause inflammation. Mesalamine preparations and formulations are very useful for treating active mild-to-moderate ulcerative colitis. Although not as effective as corticosteroids in active disease, they can be used for maintenance therapy and for preventing relapse. (Corticosteroids cannot be used for this phase.) There is also some evidence that mesalamine reduces the risk for colon cancer. Mesalamine seems to benefit women more than men. All mesalamine preparations appear to be safe for children and for women who are pregnant or nursing.

Mesalamine has few side effects, but it is absorbed so quickly in the upper gastrointestinal tract that it usually fails to reach the colon if used orally and as a single drug. Other substances, therefore, are added to mesalamine or it is formulated so that it can reach the lower intestine before it is absorbed. Sulfasalazine (Azulfidine), which contains mesalamine and sulfapyridine (a sulfa antibiotic), is the standard preparation.

Administering mesalamine topically using enemas or suppositories is also an effective method for reaching disease in the lower left intestine, which occurs in about two-thirds of patients with ulcerative colitis. A combination of oral and topical mesalamine in such people is more effective than an oral form alone.

Sulfasalazine. Sulfasalazine (Azulfidine) is the standard mesalamine preparation. Sulfasalazine is known as a prodrug because it becomes an active drug when it breaks down by intestinal bacteria. In this event, it is broken down into two components: mesalamine and sulfapyridine.

• Mesalamine, the active component, blocks the inflammatory process
• Sulfapyridine (a sulfa antibiotic) plays no role in treating the disease, but it does prevent mesalamine from being absorbed until it reaches the colon

It is useful for treating mild-to-moderate UC attacks and for maintaining remission. Long-term therapy may even help protect against colon and rectal cancers in people with UC. A syrup form of sulfasalazine is available for children.

Side effects of sulfasalazine differ depending on the specific component.

• Mesalamine Component. Mesalamine has a chemical structure similar to aspirin. Therefore, people allergic to aspirin should not take any of the 5-ASA drugs or preparations. Mesalamine itself has few side effects and is considered safe to take during pregnancy. One of the most common side effects is diarrhea, which varies depending on the preparation. For example, olsalazine poses a risk for diarrhea, which may be minimized by starting out with lower doses and taking the medication with meals. Other side effects of oral forms of mesalamine are skin disorders, nausea, cramps, itchiness, anxiety attacks, and inflammation of other organs. Oral mesalamine, particularly Asacol, may slightly increase the risk for kidney damage. (Olsalazine has a lesser effect on the kidneys.)
• Sulfapyridine, the Sulfa Component. The sulfa component is responsible for most of sulfasalazine's adverse side effects, which are experienced by up to 30% of patients. Common side effects include allergic reactions, heartburn, headache, loss of appetite, abdominal discomfort, dizziness, anemia, fever, and rashes. The sulfa component may temporarily lower sperm count in men and can turn urine a bright orange-yellow color. Rare but serious side effects include a lupus-like disorder, pancreatitis, liver damage, and blood disorders, such as hemolytic anemia. (Hemolytic anemia occurs in some cases of ulcerative colitis even without this treatment.) Blood counts should be performed regularly, particularly during the first few weeks of treatment. Sulfasalazine completely inhibits the absorption of folic acid, and people with UC should take supplements of this important B vitamin. This is critical during pregnancy. As with most major drugs for IBD, withdrawal of sulfasalazine when the disease is still active can trigger a severe relapse.

Other Mesalamine Prodrugs. Olsalazine (Dipentum) and balsalazide (Colazal) are similar to sulfasalazine, in that they are broken down by intestinal bacteria into two components, one of which is mesalamine. Unlike sulfasalazine, however, the other component in each drug is a harmless molecule that does not produce the adverse side effects of the sulfa component. (Mesalamine side effects in all three drugs are the same.) Studies suggest that these newer preparations are effective both for first-line treatment and for maintenance in mild-to-moderate UC. Major 2002 analyses suggest that although they may be more effective in inducing remission than sulfasalazine, they are not as effective for maintenance. They are also considerably more expensive. They may have greater adverse effects on the kidney than sulfasalazine, so kidney function should be monitored periodically.

Mesalamine Enemas and Suppositories. Mesalamine enemas (Rowasa) and suppositories (Canasa) are available. Rowasa is effective for ulcerative colitis in the rectum and lower colon. Canasa is useful only in the rectum. Rowasa relieves mild-to-moderately active UC and prevents relapse. According to a 2000 review, mesalamine enemas are more effective than steroid enemas and oral therapies for left-sided ulcerative colitis.

Delayed or Sustained Release Mesalamines. Formulations have been developed that allow mesalamine alone to reach the lower intestine without the need for the sulfa component. A number of oral forms of mesalamine use coatings or time-released formulations to prevent absorption in the upper intestine. Different brands affect different regions in the intestine:

• Pentasa is an oral sustained-release mesalamine that is coated in a substance called ethyl cellulose. It is slowly released from the stomach through the intestine and is the only aminosalicylate that works in both the small intestine and colon. Twelve-month remission rates of up to 64% have been reported in patients with mild-to-moderate ulcerative colitis.
• Asacol and Salofalk are coated with an acrylic, and the active drug is released in an alkaline environment. It is therefore effective from the colon through the last section of the ileum. Studies have indicated that it has resulted in symptomatic improvement, including remission, in nearly three-quarters of patients with mild-to-moderate ulcerative colitis. In low doses, Asacol does not appear to be as effective as olsalazine for maintaining remission, although higher doses or combinations may improve its effectiveness.

Corticosteroids

General Guidelines. Corticosteroids (commonly called steroids ) are powerful anti-inflammatory drugs. They are used only for active ulcerative colitis. Steroids are frequently combined with other drugs to produce more rapid symptom relief and to allow quicker withdrawal, although such combinations do not improve remission time. Because they have serious long-term effects, steroids are not useful for maintenance therapy. Patients who are malnourished are less likely to respond to steroids, and those who had an initial inadequate response to steroids are also less likely to do well with repeat therapy.

Corticosteroid Types. Prednisone, prednisolone, hydrocortisone, and methylprednisolone are the most common corticosteroids. Newer steroids, such as budesonide, fluticasone, beclomethasone, dipropionate, prednisolone-21-methasulphobenzoate, and tixocortol, affect only local areas in the intestine and do not circulate throughout the body. Such drugs may avoid the widespread side effects that are a serious problem with long-term treatment using the older steroids.

Administering Corticosteroids. Steroids can be taken orally, intravenously, by injection, or rectally as a suppository, enema, or foam. The severity or location of the condition often determines the form.

• In general, oral preparations are used for moderate-to-severe ulcerative colitis. Oral steroids can have serious long-term widespread effects in the body. Delayed-release forms of corticosteroids, such as beclomethasone or budesonide, affect only local areas of the intestine and may be useful for mild-to-moderate UC without causing systemic side effects.
• Enemas, suppositories, and, in limited cases, foam preparations may be used for mild-to-moderate ulcerative colitis located in the left section of the colon, the rectum, and anus. Most of the newer drugs can be administered rectally. They affect only local areas in the intestine and do not circulate throughout the body. Such drugs may avoid the widespread side effects that are a serious problem with long-term treatment using the older steroids, but they are not without risks.
• If the patient requires hospitalization, intravenous steroid therapy (with or without rectal steroids) is administered initially. (If these drugs are not effective after a week of intravenous therapy, they are not likely to work.)
• Once bowel movements are normal and the patient can eat, oral doses replace intravenous and rectal forms, and then they are tapered gradually.

Side Effects of Corticosteroids. Standard steroids can have distressing and sometimes serious long-term side effects. Adverse effects include:

• Susceptibility to infection
• Weight gain (particularly increased fatty tissue on the face and upper trunk and back)
• Acne
• Excess hair growth
• High blood pressure (hypertension)
• Accelerated osteoporosis
• Cataracts and glaucoma
• Diabetes, wasting of the muscles
• Menstrual irregularities
• Upper gastrointestinal ulcers, especially when patients also take NSAIDs
• Personality change, including irritability, insomnia, psychosis, and depression. Such emotional changes are sometimes severe enough to produce suicidal thoughts
• Growth may be retarded in children

Treatments are available for steroid-induced diabetes, swelling, and hypertension. Vaccines are available to help prevent influenza and pneumonia. Any infection should be treated promptly. Supplemental calcium and vitamin D are important to help to preserve bone mass against osteoporosis. The newer oral steroids, such as budesonide, have far fewer and less severe side effects.

Withdrawing from Corticosteroids. Once the intestinal inflammation has subsided, steroids must be withdrawn very gradually in order to give the body time to recover its own ability to produce natural steroids. Withdrawal symptoms, including fever, malaise, and joint pain, may occur if the dosage is lowered too rapidly. If this happens, the dosage is increased slightly and maintained until symptoms are gone. More gradual withdrawal is then resumed.

Immunosuppressive Drugs

For very active inflammatory bowel disease that does not respond to standard treatments, immunosuppressant drugs are now being used for long-term therapy. Such drugs suppress actions of the immune system and therefore its inflammatory response, which causes ulcerative colitis. Immunosuppressants can prevent relapse, even when used alone, and in some studies have proved to be effective for maintaining remissions in ulcerative colitis that have lasted at least 2 years.

An immunosuppressant is often combined with a corticosteroid to speed up response during active attacks. Lower doses of the steroid are then needed, resulting in fewer side effects. Corticosteroids may also be withdrawn more quickly. Immunosuppressants, then, are sometimes referred to as steroid-sparing drugs.

Purine Analogues. Purine analogues prevent cell proliferation in ways that are not yet clear. They include 6-mercaptopurine (Purinethol) and its prodrug azathioprine (Imuran). (A prodrug is a compound that breaks down into the active drug.) They are used for maintenance treatment in chronic active ulcerative colitis to reduce dependency on steroids. These drugs can take several weeks to 6 months to achieve peak effectiveness, so they are not useful for treating an acute attack. Some evidence suggests that these drugs are safe during pregnancy.

Complications include a higher risk for infections, such as pneumonia and herpes zoster, a risk for diabetes, and liver toxicity. Other serious side effects include pancreatitis, which occurs in about 1.2% of patients taking these drugs. Symptoms of pancreatitis usually occur within the first few weeks and include nausea, vomiting, and upper abdominal pain that may radiate to the back. Both of these effects are reversible when the drugs are stopped. A small percentage of patients carry a genetic factor that poses a risk for a life-threatening side effect of the drug, which is bone-marrow suppression, causing a dangerous drop in white blood cell production. (Of note, a mild drop in white blood cells is an indicator that the drug is working.) Monitoring specific enzymes that are metabolized by these drugs may be very helpful in predicting patients genetically at risk for these effects and for determining adequate doses.

Cyclosporine. Intravenous cyclosporine in combination with corticosteroids is often used for patients with acute severe ulcerative colitis and can help many patients avoid surgery. Serious complications, some life threatening, can occur, however. They include kidney failure, hypertension, infections, seizures, and allergic reactions. An alternative approach uses low-dose intravenous cyclosporine alone without the steroids followed by azathioprine (Imuran). Some researchers report that this is as effective as the standard approach and should pose a lower risk for serious side effects.

Tacrolimus. Tacrolimus is similar to cyclosporine, but its oral form is better absorbed than oral cyclosporine. Studies have been mixed on its effects.

General Side Effects of Immunosuppressants. Although experts have been concerned about dangerous side effects based on experience with immunosuppressants used in transplant operations, the lower doses of the drugs required for IBD and other inflammatory disorders may make them safer for long-term treatments than steroids. Specific side effects occur with individual drugs.

The most common side effects of immunosuppressants include:

• Stomach and intestinal distress
• Rash
• Numbness or tingling in the hands and feet, mouth sores
• Hair loss (or excessive hair growth with cyclosporine)

The actions of immunosuppressants, however, have more serious effects:

• They inhibit certain rapidly growing immune system cells, including those that produce antibodies, causing an increased risk for infections.
• In pregnancy, the use of immunosuppressants by the mother is associated with birth defects such as cleft palate, limb deformities, and eye problems. Their use is generally not recommended for women during pregnancy or breastfeeding. Pregnant women should absolutely avoid methotrexate.
• Other serious adverse effects include hepatitis, bladder problems, and menstrual irregularity with possible sterility. (Administering pulsed doses at the time of menstruation may avert infertility in women.)

Infliximab and Anti-Tumor Necrosis Factor Drugs

Biologic response modifiers are drugs that interfere with the inflammatory response. Of special interest are drugs that are designed to target inflammatory immune factors known as cytokines, particularly a cytokine called tumor necrosis factor (TNF).

Infliximab. Infliximab (Remicade) is made from a specially developed antibody (a monoclonal antibody) called cA2, which blocks the activity of tumor necrosis factor-alpha (TNF-a), a major player in the inflammatory process that causes IBD. In 2005, infliximab was approved for treatment of moderate-to-severe ulcerative colitis in patients who have not responded well to other treatments. It is the first biologic drug approved for UC. Infliximab is also approved for Crohn’s disease.

Studies indicate that infliximab may reduce UC symptoms and help patients achieve remission. Infliximab may also help heal ulcers and inflammation of the colon’s inner lining (mucosa). Some patients who take infliximab may be able to stop taking corticosteroids or avoid surgical removal of the colon.

Infliximab is given as a 2-hour intravenous infusion in a doctor’s office. After the first dose, the patient receives a second dose 2 weeks later, and a third dose 6 weeks after that. After these three doses, the drug is given every 8 weeks.

Common side effects may include a skin reaction at the injection site, stomach pain, and coughing. Potential serious side effects include tuberculosis, pneumonia, and other respiratory infections; lymphoma (a type of cancer); liver failure; and aplastic anemia. Infliximab is not appropriate for most patients with heart failure.

Local Anesthetics

Small studies indicate that enemas or topical gels using the anesthetics lidocaine and ropivacaine may be helpful for patients with mild-to-moderate ulcerative colitis. These drugs not only block pain but may have properties that help block several steps in the inflammatory response.

Investigative Therapies

Nicotine. Studies show that nicotine patches help to induce remission and reduce symptoms in almost 40% of patients who use then for 4 weeks. A 2002 study further reported that nicotine patches improved the effectiveness of mesalamine enemas. Side effects, particularly in nonsmokers, include nausea, lightheadedness, and headache. Investigators are studying methods of applying nicotine directly into the colon. (No one should smoke for relief of ulcerative colitis symptoms. The risks from cigarettes far outweigh the potential benefits of their nicotine.)

Heparin . Intravenous heparin is an anti-blood clotting drug that also has anti-inflammatory properties. Some evidence is suggesting that specific forms of heparin, notably low-molecular weight heparin, may prove to be beneficial for patients with IBD.

Interferon . Interferons suppress important inflammatory factors in the immune system. They are now used in multiple sclerosis, and research suggests that the drug interferon (IFN) beta-1a (Avonex, Rebif) may help patients with ulcerative colitis. Side effects include flu-like symptoms and reactions at the site of injection.

Epidermal Growth Factor . Researchers are interested in specific peptide growth factors, especially epidermal growth factor (EGF), which is important in maintaining intestinal health and wound healing.

Adsorptive Granulocyte and Monocyte Apheresis (GMA) . Adsorptive apheresis is a process in which the fluid part of the blood, called plasma, is removed from blood cells. The procedure involves withdrawing blood from the patient, filtering it through a device, and then infusing the filtered blood back into the patient. The process removes inflammatory antibodies and other immunologically active substances. It is used for patients with rheumatoid arthritis and may be helpful for patients with UC. Recent clinical trials have reported promising results for treatment of refractory UC.

Parasites . Inflammatory bowel disease is rare in countries where intestinal infection with parasites called helminthes is common. Small studies are reporting significant remission rates in patients with Crohn's disease or ulcerative colitis who have swallowed the eggs of a specific parasitic worm. The parasite does not invade tissue or spread other diseases. The parasite induces production of specific T cells, called TH-2, which are immune factors that may be protective against overactivity of cytokines that trigger Crohn's.

DHEA . Some research is investigating the use of dehydroepiandrosterone (DHEA), a mild male hormone with anti-inflammatory effects that is reduced in inflammatory bowel disease. Very small studies suggest it may be helpful for patient with Crohn's disease or ulcerative colitis.

RDP58. RDP58 is a drug that interferes with the production of several inflammatory factors, including tumor necrosis factors, that are involved in UC and Crohn's disease. In one early study, it achieved remission rates of over 70% in patients with UC and caused few side effects.

Alicaforsen . Antisense drugs bind to target RNA and block the production of key proteins. Alicaforsen is an antisense drug that inhibits an intercellular adhesion molecule (ICAM-1) thought to play a pivotal role in the inflammatory process. Several clinical trials of alicaforsen enemas have reported encouraging results for improvement of ulcerative colitis symptoms.

• Review Date: 8/23/2006
• Reviewed By: Harvey Simon, M.D., Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital

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