Ulcerative Colitis: Inflammatory Bowel Disease

Description

Alternative Names

Medications

Drugs cannot cure inflammatory bowel disease, but they are effective in reducing 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. 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. Some patients may require oral forms.
• 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 patient's disease is limited to the lowest parts of the intestine. Oral forms may be taken for moderate to severe cases. In patients who do not respond to less aggressive treatments, intravenous steroids may be warranted.
• 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.

Determining Success. The success of therapy is determined by its ability to induce and maintain remissions without incurring 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 agent. 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. In fact, in such patients a combination of oral and topical mesalamine 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 agent 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 patients with ulcerative colitis. 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 all oral forms of mesalamine are skin disorders, nausea, cramps, itchiness, anxiety attacks, and inflammation of other organs, although one study reported that mesalamine caused no more side effects than placebos (inactive substances used for comparisons in drug studies). 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 taking this drug. Some 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. (It should be noted that 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 patients 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 literature review published in 2000, mesalamine enemas were 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 small intestine and colon. Twelve-month remission rates of up to 64% have been reported in ulcerative colitis patients with mild to moderate disease.
• Asacol and Salofalk are coated with an acrylic and the active agent 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 agents 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) are 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 the following:

• Susceptibility to infection.
• Weight gain (particularly increased fatty tissue on the face and upper trunk and back).
• Acne.
• Excess hair growth.
• 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 two 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 mercaptopurine (Purinethol) and its prodrug azathioprine (Imuran). (A prodrug is a compound that breaks down into the active agent.) They are used for maintenance treatment in chronic active ulcerative colitis to reduce dependency on steroids. These agents can take several weeks to six months to achieve peak effectiveness, so they are not useful for treating an acute attack. In a small 2003 study, azathioprine was comparable to sulfasalazine, but patients tended to relapse earlier with azathioprine. Some evidence suggests that these agents 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 effects 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 the following:

• 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 Agents

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

Infliximab.Infliximab (Remicade) is made from a specially developed antibody (termed a monoclonal antibody) called cA2, which acts against tumor necrosis factor (TNF), a major player in the inflammatory process that causes IBD. The drug is currently approved only for IBD patients with Crohns disease, and is being investigated for ulcerative colitis. Studies to date suggest that it can achieve a rapid response in some patients but the effects wane over time in most patients. So far, evidence does not support its use in UC patients who have become resistant to steroids. More research is needed to determine if adding other agents or using higher doses or repeated infusions will improve results without causing severe side effects.

RCP-58. RDP-58 is a novel drug that interferes with the production of a number of inflammatory factors, including tumor necrosis factors, which 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.

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 agents 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 it for four 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 agent 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 agent interferon (IFN) beta-1a (Avonex, Rebif) may help patients with ulcerative colitis. Side effects include flu-like symptoms and reactions at the injections.

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. In a 2003 study, enemas were used to administer EGF into the intestine. The EGF achieved remission rates of 83%, with 67% of the patients remaining in remission at 12 weeks. The study was small, however, and had limitations. In addition, experts are concerned about the theoretical possibility of cancerous changes caused by high amounts of EGF. Still, it warrants more investigation.

Prosorba Column and Plasmapheresis. Plasmapheresis 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 and filtering it through a device called the Prosorba column. 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.

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 disease went into remission for several weeks in five of the six patients. 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 over-activity of cytokines that trigger Crohn's.

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