Medications

The primary goal of drug therapy is to reduce inflammation in the intestine. Drugs are effective in reducing the inflammation and accompanying symptoms in up to 80% of patients. Unfortunately, relapses are still frequent, and researchers continue to look for the optimal treatments that will both control symptoms and prevent relapse.

Drugs Used for Crohn's Disease. The drugs used depend on the severity of the condition:

• Mild-to-moderate Crohn's disease is generally treated with antibiotics and an oral mesalamine or sulfasalazine. (Some researchers suggest, however, that corticosteroids are more effective than these drugs in patients with disease in the small intestine and ascending colon. Furthermore, new forms of oral corticosteroids, such as budesonide capsules, pose a lower risk for adverse effects.)
• Moderate to severe Crohn's disease is treated with corticosteroids, infliximab, and drugs that modify or suppress the immune system. Such drugs may be used alone or in combinations. Some patients with severe Crohn's may be candidates for surgery.

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 (painful defecation), are normal or close to normal. It is more difficult to define remission in Crohn's disease because diagnostic test results do not always correlate with a patient's symptoms or complications outside the intestine.

Corticosteroids

General Guidelines. Corticosteroids (commonly called steroids) are powerful anti-inflammatory drugs that are the drugs most often used for Crohn's disease in adults. Because of their adverse effects, in treating children, steroids should be reserved for those with severe disease or who relapse after other therapies. Steroids appear to be safe for pregnant women and can be used if necessary during pregnancy.

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.

In general, they are recommended only for active Crohn's, because long-term treatments cause significant side effects and alternative drugs exist. Unfortunately, most doctors also use them for maintenance treatment, in spite of the fact that two major analyses of oral steroids reported no reduction in relapse rates with their use.

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. Some patients who have had Crohn's disease for a long time may have partial or complete resistance to corticosteroids.

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 conventional steroids. Recent studies suggest that budesonide can help prolong and maintain remission periods in patients with Crohn’s disease.

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 Crohn's disease. 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 Crohn's disease without causing systemic side effects.

If the patient requires hospitalization, intravenous steroid therapy is administered initially. (If these drugs are not effective after a week of intravenous therapy, they are not likely to work.)

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

• 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
• 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 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.

Mesalamine (5-Aminosalicylic Acid): Sulfasalazine and Other Preparations

Mesalamine is the common name of the compound 5-aminosalicylic acid or 5-ASA. This drug inhibits factors in the immune system, especially cytokines that cause inflammation. Mesalamine and its different preparations are very effective for IBD. Some evidence suggests that mesalamine reduces the risk for colon cancer. Mesalamine is not very effective in preventing recurrence in Crohn's disease, however.

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.

Mesalamine seems to benefit women more than men. All mesalamine preparations, including sulfasalazine, appear to be safe for children and for women who are pregnant or nursing.

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. 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.

For patients with mild-to-moderate Crohn's disease, sulfasalazine and other mesalamine preparations and formulations are generally most useful in combination with steroids and when the disease is limited to the colon. 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. 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. 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. 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 (Colazide) 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 side effects that are as severe as those of sulfasalazine.

Delayed Release Mesalamine. 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 ulcerative colitis patients with mild to moderate disease. It also appears to be useful in some patients with Crohn's, particularly in those with disease confined to the small intestine.
• Asacol and Salofalk are coated with an acrylic, and the active drug is released in an alkaline environment. It is effective from the colon through the last section of the ileum. Limited data has also suggested that it produces remission in up to 45% of patients with active Crohn's disease and prevents relapse in as many as two-thirds of patients for up to a year. Asacol may become a good choice for mild-to-moderate Crohn's disease.

Immunosuppressive Drugs

For very active inflammatory bowel disease that does not respond to standard treatments, immunosuppressant drugs are now used for long-term therapy. Such drugs suppress actions of the immune system and therefore its inflammatory response, which causes Crohn's disease. Immunosuppressants may help maintain remission in Crohn's disease and to heal fistulas and intestinal ulcers caused by this disease.

The standard drugs are purine analogues, especially azathioprine and mercaptopurine. Other immunosuppressants being investigated include methotrexate, cyclosporine, and mycophenolate. Methotrexate is the least expensive of these drugs, but it also has the greatest adverse effects on the liver and in pregnant women. Experts recommend that they be used very cautiously in children, generally only if they relapse after being treated with mesalamine drugs and corticosteroids.

Most of these drugs can take up to 10 - 12 weeks to achieve peak effectiveness. (They may work more rapidly for subsequent attacks). Administering an immunosuppressant intravenously (called a loading dose) may speed up the initial response.

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. For this reason, immunosuppressants are sometimes referred to as steroid-sparing drugs.

Purine Analogues. Purine analogues include mercaptopurine (Purinethol) and its prodrug azathioprine (Imuran). (A prodrug is a compound that breaks down into the active drug.) These drugs prevent cell proliferation in ways that are not yet clear. Both are useful for maintenance treatment in Crohn's disease to reduce dependency on steroids. However, purine analogues can take several weeks to 6 months to achieve peak effectiveness, so they are not useful for treating an acute attack.

Studies of the effects of purine analogues on fistulas report that about a third that occur around the anus close completely, and a quarter improve during treatment. In one study, intestinal and abdominal fistulas healed even better than anal fistulas with azathioprine. They may be helpful for children with moderate-to-severe Crohn's disease. Some evidence suggests that these drugs are safe during pregnancy. Mercaptopurine may have fewer adverse effects than its parent drug, azathioprine.

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. (However, 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 help predict patients genetically at risk for these effects and for determining adequate doses.

Methotrexate. Methotrexate (Rheumatrex) may be an effective alternative for patients with Crohn's disease who have failed other treatments and cannot tolerate the standard purine analogues. According to a 2000 study, 40 weeks of low dose weekly injections reduced the rates of Crohn's disease relapse by 26% and the use of prednisone by about half. These results suggest a role for methotrexate in long-term maintenance of remission. Methotrexate may also be useful in treating fistulas in patients with Crohn's. Methotrexate does not appear to help ulcerative colitis. Methotrexate can cause liver scarring and lung inflammation and should not be used by people with liver damage or who are at risk for it. Use of methotrexate in children is limited due to its toxicity.

Cyclosporine. Cyclosporine, particularly administered intravenously, may be useful for Crohn's disease accompanied by severe fistulas. (It is not generally used in treating Crohn's disease itself, however.) In one study, the rate of overall response to cyclosporine was 83% and improvement occurred within 2 weeks. Other studies show even stronger results. Relapses and adverse effects occur commonly with cyclosporine, however, when patients are switched to oral forms, so it does not seem to be beneficial for long-term maintenance. Several studies indicated that patients with fistula who received cyclosporine overlapping with a combination of azathioprine and mercaptopurine for more than 4 months were more likely to maintain their response when cyclosporine therapy was stopped.

Other Immunosuppressants. Tacrolimus is similar to cyclosporine, but its oral form is better absorbed than oral cyclosporine. It is showing promise in small studies of severe Crohn's disease. Less than half of patients, however, achieve long-term remission.

Mycophenolate mofetil (CellCept), also called MMF, is being studied as an alternative for patients with fistulas who cannot tolerate azathioprine or mercaptopurine. It appears to be roughly equivalent in effectiveness and safety to the other drugs, although not as effective in maintaining remission. Very small studies have shown a 75% closure rate with an average of 8 months treatment with MMF.

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, also have more serious effects:

• They inhibit certain rapidly growing immune system cells, including those that produce antibodies, causing an increased risk for infections.
• Oversuppression of the immune system can result in low blood cell counts and anemia.
• Between 3 - 15% of patients taking immunosuppressants develop pancreatitis, which is usually mild and resolves on withdrawal. In some cases patients may be able to resume the immunosuppressants. Symptoms of pancreatitis usually occur within the first few weeks and include nausea, vomiting, and upper abdominal pain that may radiate to the back.
• 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 prevent infertility in women.)

Antibiotics

Antibiotics are often used to induce remission in mild-to-moderate Crohn's disease. They are also important for treating fistulas, bacterial overgrowth, abdominal abscesses, and any infections around the anus and genital areas. Stopping antibiotics brings on relapse, so long-term therapy is required, carrying a risk for side effects.

The standard antibiotics used for inducing remission in Crohn's disease are ciprofloxacin (Cipro) and metronidazole (Flagyl). Ciprofloxacin is the antibiotic of choice. Evidence for the benefit of metronidazole (Flagyl) is weaker than for Cipro. Furthermore, over time Flagyl can cause peripheral neuropathy, which are nerve abnormalities that can cause numbness and tingling in the hands and feet. Other antibiotics used for Crohn's disease include trimethoprim/sulfamethoxazole (Bactrim, Cotrim, Septra) and tetracycline.

Small studies have reported that either ciprofloxacin or metronidazole has produced disease remission rates of about 70% that last a year. Comparison studies with corticosteroids, however, have not clearly identified any additional benefits from antibiotics for mild-to-moderate Crohn's disease. More research is needed to clarify this issue.

Infliximab and Other Tumor Necrosis Factors (TNF) Modifiers

Biologic response modifiers are drugs that interfere with the inflammatory response. Of special interest for patients with Crohn's disease are drugs that target the inflammatory immune factor known as tumor necrosis factor (TNF).

Infliximab. Infliximab (Remicade) acts against TNF and was the first genetically engineered drug approved for treating adults with Crohn's disease. It is made from a genetically designed antibody called a monoclonal antibody (MAb) that blocks the activity of tumor necrosis factor-alpha (TNF-a). In 2006, the FDA approved infliximab for children with active Crohn’s disease.

Infliximab cannot cure Crohn’s disease, but it can help control symptoms and, possibly, keep the disease in remission. Studies suggest that up to 80% of patients respond initially, and about a third of all patients remain in remission after a single infusion. Remissions last a few weeks to several months. A 6-week course of infliximab helps close and heal fistulas in half of patients and reduces drainage in 70%. The drug is also being studied for maintenance therapy, although given some significant side effects, it will most likely be reserved for active disease that does not respond to other treatments.

Infliximab’s severe side effects may include tuberculosis, pneumonia, and other infections; lymphoma (a type of cancer); liver failure; and aplastic anemia

Other Anti-TNF Drugs. Several other TNF modifiers are being investigated. To date, however, infliximab (Remicade) is the only TNF modifier that has been useful for Crohn's disease. Investigative anti-TNF monoclonal antibodies that are showing promise in clinical trials include adalimumab (Humira), which is currently approved for treating symptoms of rheumatoid arthritis, and certolizumab (Cimzia).

Investigational Therapies

Selective Adhesion Molecule Inhibitors. Selective adhesion molecule inhibitors block the genetic expression of cell adhesion molecules (CAMs). CAMs play an important role in the accumulation of immune factors that cause the inflammatory response. Natalizumab (Tysabri) is a monoclonal antibody that blocks alpha4 integrin, a protein that binds to CAMs. This drug is approved to treat multiple sclerosis and is also being studied for Crohn’s disease. Some studies suggest that natalizumab can help patients achieve and maintain remission. However, natalizumab is associated with severe side effects, including a rare neurological condition called progressive multifocal leukoencephalopathy (PML). A 2006 study found that patients who take natalizumab have a very low risk for PML. Still, the potential benefits of natalizumab need to be weighed against its risks for serious side effects.

Other Biologic Therapies. Biologic therapies are designed to block immune factors that play a role in the inflammatory response. Among them are interferons, anti-interferon antibodies, anti-interleukin antibodies, p65 anti-sense oligonucleotides, growth factors, and others. Several 2006 studies indicated that fontolizumab (HuZaf), an anti-interferon gamma monoclonal antibody, shows promise as a treatment for Crohn’s disease. Sargramostim (Leukine), a granulocyte-macrophage colony stimulating factor, is another biologic drug that may help improve symptoms and quality of life for patients with active Crohn’s disease.

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.

Growth Factors. Growth factor hormones increase immune factors, so one would think they might be harmful for patients with Crohn's disease. However, some research suggests that using growth factors might be helpful for certain patients. For example, small studies on granulocyte macrophage colony stimulating factors are reporting some promise.

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