Long-Term Safety and Efficacy of Etanercept
With the release of etanercept (Enbrel) eight years ago, the ability of physicians to treat juvenile idiopathic arthritis (JIA; a group of inflammatory diseases often called juvenile rheumatoid arthritis) not responsive to methotrexate therapy greatly improved. Etanercept binds to tumor necrosis factor (TNF) that is floating free in the circulation, preventing it from interacting with TNF receptors on cell surfaces. Therefore, some of the steps that lead to inflammation and joint damage are blocked.
Earlier this year, the Pediatric Rheumatology Collaborative Study Group, which includes past Arthritis Foundation grant recipients Daniel J. Lovell, MD, MPH, and Edward H. Giannini, MSc, DrPH, published results of a long-term safety and efficacy trial of etanercept in children with polyarticular JIA.
What Problem Was Studied?
Previous studies of etanercept in children with polyarticular JIA showed that the drug provided rapid clinical improvement that was sustained for as long as two years. This study sought to extend the assessment to a total of at least four years.
What Was Done in the Study?
Patients, ages four to 17 years with very active polyarticular-course disease and who had failed to receive relief from methotrexate were enrolled in the original efficacy study of etanercept. Of those participants, 58 remained in the extension study. They were assessed at months one, two and three, then every three months for the first year of the extension, and then every four to six months thereafter.
Reports of serious adverse events (for example, fatal or life-threatening events, significant disability, prolonged hospitalization) and serious infections (those requiring hospitalization or intravenous antibiotics) were collected. Efficacy was assessed using the American College of Rheumatology Pediatric 30, 50, and 70 criteria (definitions of improvement in juvenile arthritis); pain on a visual analog scale; the articular severity score (swelling, tenderness, limitation of motion and pain on motion); and duration of morning stiffness, among others.
What Were the Study Results?
More than 80 percent of participants who received corticosteroids at any time during the extension were able to discontinue or decrease their dosage to a minimal amount. Six patients withdrew from the study because of lack of efficacy. Most participants, however, showed sustained improvements in disease activity measures in the extension study. Although methotrexate was not permitted as adjunctive therapy in the first part of the trial, methotrexate was permitted in the extension, and may have contributed to the sustained improvements seen.
All told, this study provides data for 225 patient-years (number of patients times years of study). During the total length of the study, 29 serious adverse events occurred, yielding a rate of 0.13 events per patient-year. Included in that 29 were eight patients with serious infections, for a rate of 0.04 infections per patient-year. This infection rate is lower than that observed for adults with rheumatoid arthritis. These rates compare favorably to those seen with the use of low-to-moderate doses of methotrexate, and are lower than those seen with higher doses of corticosteroids.
What Do These Results Mean to People with JIA?
The Pediatric Rheumatology Collaborative Study Group was able to determine that children with very active JIA showed sustained improvements for four years or more while taking etanercept. Furthermore, they showed that the rates of serious adverse events and serious infections did not increase over time, indicating that sustained exposure to etanercept does not increase the patient’s risk of infection compared with short-term exposure. Dr. Lovell concludes, “Overall, etanercept offers significant clinical benefit with an acceptable safety profile in patients with polyarticular-course juvenile arthritis.”
Lovell DJ, Reiff A, Jones OY, et al. Long-term safety and efficacy of etanercept in children with polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum 2006;54:1987-94.
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