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Infliximab (Remicade) Approved for Use in Rheumatoid Arthritis

In November 1999, the Food & Drug Administration (FDA) approved infliximab for use in rheumatoid arthritis (RA). Infliximab is the second tumor necrosis factor (TNF) inhibitor to be approved for use in RA (etanercept was approved in November 1998). Infliximab was FDA-approved in 1998 for use in fistulizing and moderate to severe Crohn's disease. Based on Crohn's data and updated RA clinical studies, the FDA extended the indication to include RA patients who have not responded to an adequate trial of methotrexate (MTX). Infliximab is given as an intravenous infusion every eight weeks.

Biologic effects. Infliximab is a chimeric IgG1 monoclonal antibody that binds with great affinity to cell-bound and circulating TNFa, but does not bind to TNFb. TNFa is a pleiotropic proinflammatory cytokine that has local and systemic effects on a variety of cells and tissues. By binding to circulating and cell-bound TNF, infliximab abrogates the biologic effects of TNF.

Clinical Trials. More than 600 RA patients have received infliximab in clinical trials. The results of placebo-controlled trials showed significant ACR20 response rates for infliximab-treated patients when compared to placebo. Most of these studies were conducted in RA patients with longstanding, severe disease. Whereas early protocols tested the efficacy and safety of infliximab alone, recent trials have tested the combination of infliximab and MTX in MTX non- or partial-responders.

FDA approval for RA followed the completion of the large multicenter, multinational ATTRACT (Anti-TNF Therapy in Rheumatoid Arthritis patients on Concomitant Therapy) trial. The ATTRACT trial studied 428 MTX-treated patients randomized to five treatment groups: placebo, 3 mg/kg every 4 or 8 weeks, or 10 mg/kg every 4 or 8 weeks. All patients received the same induction regimen with infliximab or sham infusions at day 0, week 2, and week 6, then every 4 weeks according to treatment assignment. The clinical results of the first 30 weeks were presented at the 1998 ACR annual meeting and the one-year clinical and radiographic data were presented at the 1999 ACR annual meeting in Boston. The week 30 data demonstrated highly significant improvement in all infliximab-treated groups, such that the lowest dose and least frequent dosing (3 mg/kg every 8 weeks) demonstrated an ACR20 of 50% compared with a 20% placebo response. Analysis after one year of blinded therapy confirmed the statistical superiority of all methotrexate plus infliximab treatment groups compared to placebo, with the group receiving 10 mg/kg every 8 weeks demonstrating the best responses after a year. Radiographic results, based on 81% of the study population, demonstrated negligible or no change for the majority of infliximab-treated patients (a minority progressed despite therapy), while the patients treated with only MTX showed x-ray worsening. These results were unaffected by disease duration or responder status.

Indications. The FDA has approved infliximab for use in RA patients with an inadequate response to MTX alone. Patients should be maintained on weekly methotrexate at a clinically effective and tolerable dose. It appears that patients on methotrexate are less likely to have an immunogenic response to the drug. The standard starting dose is 3 mg/kg with a loading regimen at weeks 0, 2 and 6 and thereafter every eight weeks. Most patients will receive 200 mg (~3 mg/kg) IV per infusion. Nearly half of those responding will improve with their first infusion and in most, the efficacy of the drug can be determined by the week 6 infusion. Patients not responding to the induction protocol should consult their rheumatologist to consider a change in therapy or escalate the dose of infliximab. Although higher doses may be more effective in some, dose escalation should only be considered after discussing the risks, benefits and costs with the patient. As with etanercept, caution should be exercised when considering the initiation of TNF inhibition in patients with an increased risk of infection (IDDM, CHF, renal insufficiency, debility, etc.) and should be avoided in those with active serious infections (e.g., sepsis, tuberculosis) or chronic and recurrent infections. Patients who develop serious infections requiring hospitalization, acute or chronic antibiotic therapy should have their TNF-inhibitor suspended until resolution of the infection and careful reevaluation.

Side effects. Infliximab is generally well tolerated. A small number of patients may develop headache, rash, minor upper respiratory tract infections or infusion-related reactions. For the nearly 600 patients treated thus far, there has been no increased risk of serious infections, malignancies or death when compared to the control populations and historic controls (such as the NIH SEER cancer database). The impact of infliximab in patients with established neoplasia is unknown. Although some drug study patients have received infliximab for over two years, the long-term consequences of chronic TNF-inhibition with infliximab are not known.

"Infusion reactions" were more common in early trials (without MTX) when compared with more recent trials conducted in patients on background MTX therapy. Findings of pruritis, rash, urticaria, nausea, headache, flushing, sweating, tachycardia, and dyspnea have been reported, but serious bronchospasm, hypotension, hemodynamic instability and anaphylaxis have not been seen in RA patients on MTX and are rare in the Crohn's population where infusions are only given intermittently during active disease and often without background immunosuppression. Most infusion reactions can be managed by slowing the rate of infusion and employing symptomatic therapies with the initial reaction and as pretreatment for subsequent infusions. It is postulated that infusion reactions may be related to the development of human anti-chimeric antibodies (HACA) seen in fewer than 10% of patients. Infusion reactions are quite uncommon in patients receiving concomitant MTX (possibly by suppressing HACA formation), may occur at any time, do not increase in frequency over time and are not associated with reduced efficacy.

There is a 9% incidence of anti-dsDNA antibodies, and for most these do not appear to be pathogenic and other autoantibodies have not been reported. Three patients have developed a drug-induced lupus-like illness (migratory arthritis, pleuropericarditis, malar rash) while on drug.

Costs. The average wholesale price of infliximab is roughly $611 per 100 mg vial. The average purchase price is $482 per vial, or $964 per infusion for an average patient. Infusion costs vary widely and are at the discretion of the clinic or infusion site.

February 29, 2000
John J. Cush, MD*, and Robert Spiera, MD
Hotline editors

*Dr. Cush is on the speakers bureau for Centocor, Inc.

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