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Therapeutic Uses of Infliximab

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Infliximab is an antibody that binds to tumor necrosis factor alpha (TNF-α), which is believed to be a central causative factor in the inflammatory process in humans.

On August 24, 1998, the FDA approved infliximab for the treatment of moderately to severely active Crohn's disease. Approved use is for the reduction of signs and symptoms, in patients who have had an inadequate response to conventional therapy, and for the treatment of patients with fistulizing Crohn's disease (to aid in reducing the number of draining enterocutaneous fistulas). It was the first and only FDA-approved product indicated for Crohn's disease.

On November 10, 1999, FDA approval was granted for the use of infliximab in combination with methotrexate for reducing the signs and symptoms of rheumatoid arthritis (RA) in patients who have not responded well to methotrexate alone. It was the first monoclonal antibody to reduce the signs and symptoms of RA.

On December 29, 2000, the FDA granted Centocor (the pharmaceutical manufacturer of infliximab) approval to market infliximab (Remicade) in combination with methotrexate, for inhibiting the progression of structural joint damage in patients with moderately to severely active rheumatoid arthritis for those who have not responded well to methotrexate alone.

On April 3, 2003, the FDA approved the use of infliximab for long-term use in the treatment of fistulizing Crohn’s disease patients using an eight-week maintenance dosing schedule.³

The approval of the most recent indication - inhibiting the progression of structural damage - was based on 54-week data from the two-year ATTRACT trial (Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy) involving 428 patients at 34 centers in North America and Europe. Patients treated with infliximab, in combination with methotrexate, were compared to those patients treated with methotrexate plus a placebo.

In the ATTRACT trial, progression of joint damage was measured radiographically using the van der Heijde-modified Sharp scoring system, which evaluates changes in joint-space narrowing and bone erosions. Among all infliximab treatment groups, the overall median change from baseline (decrease) for total radiographic scores (erosions and joint-space narrowing) was 0.0 among patients treated with the combination of infliximab plus methotrexate (n=285) compared to a median change of 4.0 for patients treated with methotrexate alone (n=64). Placebo-only participants saw a 7 to 8 percent decrease in their scores over the came time period. A total of 53 percent of infliximab patients demonstrated no deterioration in their total van der Heijde-modified Sharp score at 54 weeks. The patients treated with methotrexate plus placebo demonstrated progression comparable to that previously reported for patients with established rheumatoid arthritis treated with methotrexate.⁴

There are reports of serious infections, including tuberculosis (TB) and sepsis associated with the use of infliximab. TB is the most serious potential problem associated with the use of infliximab, and some of these infections have been fatal. Patients should tell their doctor if they have had recent or past exposure to people with TB. Their doctor will evaluate them for TB and perform a skin test. If a patient has latent (inactive) TB, his or her doctor should begin TB treatment before starting infliximab therapy. The rapidity of development of TB after initiation of infliximab therapy suggests that this is a re-activation of latent disease, rather than development of new disease.  If a patient is prone to or has a history of infections, currently has one, or develops one while taking infliximab, he or she should tell his or her doctor right away. Patients should also tell their doctor if they have lived in a region where histoplasmosis is common or if they have or have had a disease that affects the nervous system, or if they experience any numbness, tingling, or visual disturbances. Chronic depletion of TNF by infliximab presumably removes the protective responses of Tumor necrosis factor resulting in increases risk of serious infections.

There are also reports of serious infusion reactions with hives, difficulty breathing, and low blood pressure. New dosing schedules have been implemented that allow for the drug to be given every eight weeks after the initial three doses.

References:

1. National Digestive Diseases Information Clearinghouse (NDDIC), accessed July 29, 2003. http://digestive.niddk.nih.gov/ddiseases/pubs/crohns/index.htm#symp.

2. National Association of Colitis and Crohn's Disease (NACC), accessed July 23, 2003. "Fact Sheet on Inflammatory Bowel Disease", http://www.nacc.org.uk/.

3. Biospace CCIS, accessed August 3, 2003. "Background", http://www.biospace.com/ccis/detail.cfm?ClinicalID=105.

4. Lipsky PE, van der Heyde DM, St. Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group.
N Engl J Med
2000 Nov 30;343(22):1594-602