SAN ANTONIO, Texas – In an effort to provide rheumatologists with a better understanding of the risks and benefits of tumor necrosis factor-alpha-blocking agents for the treatment of rheumatoid arthritis (RA), an international post-marketing surveillance study has found that when patients are treated with the approved dose of infliximab (Remicade), they have no more risk of serious infection than do patients taking methotrexate.

"Although caution is still appropriate, these findings should be reassuring to clinicians," said principal investigator David E. Yocum, MD, Professor of Medicine at the University of Arizona, and Director of the Arizona Arthritis Center, Tucson. "This study involved the type of patients that rheumatologists see in their practice, with comorbidities and other infection risks, and we still found that infliximab could be used safely at the approved dose in these patients."

The investigators randomly assigned 1082 active RA patients who were getting an inadequate response from methotrexate to receive placebo, infliximab at the approved dose of 3 mg/kg, or a high-dose infliximab of 10 mg/kg. The patients were treated at the initial week, and then at weeks 2, 6, and 14.

The 361 patients who were initially in the placebo arm then crossed over to receive infliximab 3 mg/kg at weeks 22, 26, 30, 38, and 46, according to the protocol. At the 22nd week, the 360 patients who were initially on the 3 mg/kg dose of infliximab had their dose increased in increments of 1.5 mg/kg every 8 weeks, up to 10 mg/kg.

Dr. Yocum noted that the third arm, the 361 patients in the high-dose group, continued to receive 10 mg/kg through the 46th week of the study. All patients also received concomitant methotrexate, at a dose of 25 mg per week or less.

During the first 22 weeks, 1.7% of patients in the placebo group and 1.7% of those in the 3 mg/kg group had serious infections, as did 5.3% of patients in the high-dose group, Dr. Yocum reported. Compared to the placebo group, he said the relative risk of serious infection was 1.00 for the 3 mg/kg group (p = 0.008) and 2.13 for the high-dose group (p = 0.09).

Through the 54th week, 3.6% of the original placebo patients and 3.6% patients first treated at 3 mg/kg had serious infections, as did 8.3% of those in the high-dose group.

The types of serious infections the investigators documented through the 54th week included 12 cases of pneumonia – 5 patients each in the first two groups and in 7 patients in the high-dose group; 1, 2, and 4 cases of active tuberculosis in these groups, respectively; abscess in 2 of the original placebo patients and 5 of the high-dose patients; 3 cases of pyelonephritis in the original placebo patients and in one of the high-dose patients; and two cases of sepsis in the high-dose group.

"The group receiving treatment at the approved dose, even when they underwent dose escalation, did not have an increased risk of infection," Dr. Yocum said in an interview following a press briefing .

Among the patients overall, 45 had a positive tuberculosis test, and 15 had active tuberculosis at the study's onset. Encouragingly, Dr. Yocum said that these 60 patients were treated with standard tuberculosis therapy before undergoing infliximab treatment, and all cleared.

In other research, Joan M. Bathon, MD, of Johns Hopkins University School of Medicine, in Baltimore, Maryland, reported that patients with RA who undergo orthopedic surgery are more likely to develop postoperative infections if they are receiving TNF-alpha-blocking therapy.

In keeping with requirements that the Food and Drug Administration has mandated for biologic therapies, the current postmarketing surveillance research, unlike the controlled setting of many clinical trials, included patients with various comorbidities. For example, 8% had diabetes and 60% were being treated with corticosteroids, another risk factor for infection. The investigators wanted to determine the proportion of patients who developed serious infections, or serious adverse events that the investigator reported as infections, through 22 weeks of treatment.

Reference

Yocum D, Wolfe F, Mahboob U, et al. The safety and efficacy of infliximab in RA: 1-year results of a large, randomized, placebo-controlled trial in patients with various comorbidities and background treatments as encountered in clinical practice. Presented at: Annual Meeting of the American College of Rheumatology; October 18, 2004; San Antonio, Tex. Abstract 1761.