Juvenile rheumatoid arthritis

BOSTON -- Children with severe, longstanding polyarticular juvenile rheumatoid arthritis resistant to methotrexate experience significant, "sometimes even profound improvements with the biologic agent etanercept, Dr. Daniel J. Lovell said at the annual meeting of the American College of Rheumatology.

Approved for adults with rheumatoid arthritis in November 1998 and for children with juvenile rheumatoid arthritis (JRA) in May 1999, etanercept (Enbrel) is part of a new class of biologic agents that bind to tumor necrosis factor preventing it from activating inflammatory cells, said Dr. Lovell of Children's Hospital Medical Center in Cincinnati.

Results from an ongoing study at the medical center involving 69 children aged 4-17 years indicated that as many as 70% of the children who completed the 1-year study achieved a 50% improvement according to standardized criteria for assessing JRA improvement.

At baseline these children had a median of 29 affected joints and severe morning stiffness that often interfered with school and other activities. All had been on methotrexate. "In short, this was the most severe JRA population we've ever studied in over 20 years of doing trials," he said.

During the first phase of the three-part study, all 69 patients were given etanercept subcutaneously twice a week in an open-label trial. At 3 months, 51 of the children (74%) had clinically important improvements on etanercept.

Those 51 responders continued on to a double-blind, controlled trial in which patients were randomly assigned to receive placebo or etanercept at the same dose. Four months later -- or after the completion of 7 months of treatment for patients in the active treatment group -- 20 of the 25 patients taking etanercept achieved a 30% improvement on a standardized scale measuring function, joint pain, swelling, and loss of motion.

By comparison, only 9 of the 26 patients on placebo achieved a 30% improvement on the scale, Dr. Lovell reported.

Likewise, 18 of the 25 children on etanercept and 6 of the 26 children on placebo had a 50% reduction in disease severity.

Twenty-one on placebo experienced a disease flare, compared with seven patients in the etanercept group. The median length of time to a flare was 28 days for the placebo group versus 116 days for the etanercept group.

During the study's final phase, 58 patients--including initial responders and nonresponders -- participated in a 14-month open-label extension trial. Patients who had been taking placebo quickly caught up in terms of symptom relief, compared with patients who had been randomized to the etanercept group, Dr. Lovell said.

The open-label phases at the beginning and end of the trial were designed to minimize the number of children subjected to placebo. During the controlled phase, children were free to enter the extension phase upon their first flare, he said.

Five of seven of the nonresponders during the first open-label trial responded during the open-label extension trial, suggesting that 3 months is not adequate to determine who will respond, he said.

At the completion of the final open-label extension study 18 of the 58 patients had no active joints; 12 patients had physicians indicate that there was "no disease activity," and 17 patients had parents who said there was no impact of the arthritis on the child's daily activities. The sedimentation rate normalized in 4l patients.

"This degree of response is especially gratifying, given the fact that these patients had failed all standard therapy for over 6 years on average," Dr. Lovell said.

Of the 58 patients who enrolled in the final open-label phase, 50 still remain on therapy.

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