Crohn's Disease (cont.)
Adam Schoenfeld, MD
George Y. Wu, MD, PhD
In this Article
Infliximab (Remicade) is an antibody that attaches to a protein called tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is one of the proteins produced by immune cells during activation of the immune system. TNF-alpha, in turn, stimulates other cells of the immune system to produce and release other proteins that promote inflammation. In Crohn's disease, there is continued production of TNF-alpha as part of the immune activation. Infliximab, by attaching to TNF-alpha, blocks its activity and in so doing decreases the inflammation.
Infliximab, an antibody to TNF-alpha, is produced by the immune system of mice after the mice are injected with human TNF-alpha. The mouse antibody then is modified to make it look more like a human antibody, and this modified antibody is infliximab. Such modifications are necessary to decrease the likelihood of allergic reactions when the antibody is administered to humans. Infliximab is given by intravenous infusion over two hours. Patients are monitored throughout the infusion for adverse reactions.
In August 1998 the United States Food and Drug Administration approved the use of infliximab for the short-term treatment of moderate to severe Crohn's disease patients who respond inadequately to corticosteroids, azathioprine, or 6-MP.
Effectiveness of infliximab (Remicade)
Infliximab (Remicade) is an effective and fast-acting drug for the treatment of active Crohn's disease. In a study involving patients with moderate to severe Crohn's disease who were not responding to corticosteroids or oral immuno-modulators, 65% experienced improvement in their disease after one infusion of infliximab. Some patients noticed improvement in symptoms within days of the infusion. Most patients experienced improvement within two weeks.
In patients who respond to infliximab, the improvements in symptoms can be dramatic. Moreover, there can be impressively rapid healing of the ulcers and the inflammation in the intestines after just one infusion.
The anal fistulae of Crohn's disease are troublesome and often difficult to treat. Infliximab has been found to be effective for treating fistulae.
Duration of benefits with infliximab (Remicade)
The majority of the patients who responded to a first infusion of infliximab developed recurrence of their disease within three months. However, studies have shown that repeated infusions of infliximab every 8 weeks are safe and effective in maintaining remission in many patients over a 1 to 2 year period. Response to infliximab after repeated infusions sometimes is lost if the patient starts to develop antibodies to the infliximab (which attach to the infliximab and prevent it from working). Studies are now being done to determine the long-term safety and effectiveness of repeated infusions of infliximab.
One potential use of infliximab is to quickly control active and severe disease. The use of infliximab then may be followed by maintenance treatment with azathioprine, 6-MP or 5-ASA compounds. Azathioprine or 6-MP also may be helpful in preventing the development of antibodies against infliximab.
Side effects of infliximab (Remicade)
Infliximab generally is well-tolerated. There have been rare reports of side effects during infusions, including chest pain, shortness of breath, and nausea. These effects usually resolve spontaneously within minutes if the infusion is stopped. Other commonly-reported side effects include headache and upper respiratory tract infection.
TNF-alpha is an important protein for defending the body against infections. Infliximab, like immuno-modulators, increases the risk for infection. One case of salmonella colitis and several cases of pneumonia have been reported with the use of infliximab. There also have been cases of tuberculosis (TB) reported after the use of infliximab.
More recently, a rare form lymphoma called hepatosplenic T-cell lymphoma has been described associated with azathioprine therapy for Crohn's disease either alone or in combination with infliximab. Although there is not much known about this disease, it appears to be aggressive and poorly responsive to treatment.
Because infliximab is partly a mouse protein, it may induce an immune reaction when given to humans, especially with repeated infusions. In addition to the side effects that occur while the infusion is being given, patients also may develop a "delayed allergic reaction" that occurs 7 to 10 days after receiving the infliximab. This type of reaction may cause flu-like symptoms with fever, joint pain and swelling, and a worsening of Crohn's disease symptoms. It can be serious, and if it occurs, a physician should be contacted. Paradoxically, those patients who have more frequent infusions of infliximab are less likely to develop this type of delayed reaction compared to those patients who receive infusions separated by long intervals (6-12 months).
Infliximab is typically given to induce remission in a three dose cycle at time zero, 2 weeks, then 4 weeks after that. After remission is attained, maintenance dosing can be given every other month.
Rare cases of nerve inflammation such as optic neuritis (inflammation of the nerve of the eye) and motor neuropathy also has reported with the use of infliximab.
Precautions with infliximab (Remicade)
Infliximab can aggravate and cause the spread of an existing infection. Therefore, it should not be given to patients with pneumonia, urinary tract infections, or abscess (localized collection of pus). It now is recommended that patients be tested for TB prior to receiving infliximab. Patients who previously had TB should inform their physician of this before they receive infliximab. Infliximab also can cause the spread of cancer cells; therefore, it should not be given to patients with cancer.
Infliximab can promote intestinal scarring (part of the process of healing) and, therefore, can worsen strictures (narrowed areas of the intestine caused by inflammation and subsequent scaring) and lead to intestinal obstruction. It also can cause partial healing (partial closure) of anal fistulae. Partial closure of fistulae impedes drainage of fluid through the fistulae, and may result in collections of fluid in which bacteria multiply, which can result in abscesses.
The effects infliximab on the fetus are not known, although the literature suggests that this medication is safe for women to continue until week 32 of pregnancy. At that time, the risk of exposure of the fetus to this medication via placental transfer is increased. Infliximab is listed as a pregnancy category B drug by the FDA (meaning that animal studies show no increased risk, but there are no human studies).
Because infliximab is partly a mouse protein, some patients can develop antibodies against infliximab with repeated infusions. Such antibodies can decrease the effectiveness of the drug. The chance of developing such antibodies can be decreased by the concomitant use of 6-MP and corticosteroids. There are ongoing studies in patients who have lost their initial response to infliximab to determine whether measurement of anti-infliximab antibodies will be helpful in guiding further treatment. Results of these studies are not yet available. There are some reports of worsening heart disease in patients who have received infliximab (Remicade). The precise mechanism and role of infliximab in the development of this side effect is unclear. As a precaution, individuals with heart disease should inform their physician of this condition before receiving infliximab.
While infliximab represents an exciting new class of medications in the fight against Crohn's disease, caution is warranted in its use. The long-term safety and effectiveness is not yet known although recent 10 year data from patients who received at least 1 dose of infliximab for CD showed the safety profile similar to what was previously known. In that data set, the treated patients seemed to have an increased risk of developing infections, infusion reactions, autoimmune reactions, and malignancy5.
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