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
Adalimumab. The Food and Drug administration approved adalimumab (Humira) early in 2007 for treating adult patients with moderate-to-severe Crohn's disease. Like infliximab, adalimumab blocks TNF, an immune system chemical that promotes inflammation. Also approved for treating symptoms of rheumatoid arthritis, adalimumab requires injections to initiate treatment, followed by a maintenance shot every other week.
Adalimumab's label includes a boxed warning. The medicine has been associated with serious, sometimes fatal, infections, including tuberculosis and sepsis. Other sever side effecst may include lymphoma, upper respiratory infections, sinusitis, and nausea.
Other Anti-TNF Drugs. Several other TNF modifiers are being investigated. To date, however, infliximab (Remicade) and adalimumab (Humira) are the only TNF modifiers that have been useful for Crohn's disease. An investigative anti-TNF monoclonal antibodies that is showing promise in clinical trials is called 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.
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