May 8, 2008 Juvenile rheumatoid arthritis (JRA) is a chronic autoimmune disease that strikes children between the ages of newborn to 16 years. All children with JRA have joint pain, stiffness, and swelling and some also have fever and skin rashes. JRA can impede growth, damage joints, and lead to disability in adulthood. Traditionally, children with JRA have been treated with the same drugs prescribed to adults with inflammatory diseases: corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and disease-modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX). Unfortunately, these medications fail to improve disease activity for many children with JRA.
Tumor necrosis factor (TNF) plays a key role in the inflammatory process. In the past decade, TNF-blockers have brought dramatic gains in treatment for rheumatoid arthritis patients. Etanercept, the only FDA-approved biologic for JRA patients until very recently, has also been proven highly effective and safe for children in short-term trials. Yet, since many children with JRA have active disease that lasts for many years, past adolescence and into adult life for many, assurance of the effectiveness and safety of long-term anti-TNF treatment is essential.
Toward that goal, the Pediatric Rheumatology Collaborative Study Group—comprised of over 70 pediatric rheumatology centers in the US and Canada has been conducting a trial of etanercept in JRA patients for more than 8 years. The group shares reassuring news for pediatricians, parents, and, above all, children afflicted with JRA.
To evaluate the long-term therapeutic value of etanercept, the study group began with a randomized controlled trial, focusing on 69 JRA patients between the ages of 4 and 17 years. Treatment with MTX and other DMARDs was discontinued a minimum of 2 weeks before enrollment, while maintaining a low-dose regimen of corticosteroids or NSAIDs was allowed. Patients received injections of etanercept based on the patient’s body weight with a maximum weekly dosage of 50 milligrams. As the trial was extended beyond 1 year, participants were permitted to add low-dose MTX if recommended by their physician.
At every 3 months during the first year of the extension phase, and then every 4 to 6 months during the following years, participants were assessed for improvement in overall disease status using the American College of Rheumatology Pediatric (ACR Pedi) criteria, as well as evaluated for changes in joint inflammation, mobility, pain, ability to perform routine daily tasks and C-reactive protein level. Patients were also monitored for frequency of serious adverse events (SAEs) such as those that required hospitalization, resulted in prolonged incapacity or death. Also medically important infections (MIIs) defined as those that required treatment with intravenous antibiotics were monitored.
58 JRA patients, 84 percent of the participants in the randomized controlled trial, enrolled in the long-term extension trial and received weekly treatment for a total of 318 patient years of etanercept exposure. Most patients were female (67 percent) and white (74 percent), and all had taken MTX prior to the study. At baseline, the mean age of the patients was 10 years and the mean duration of disease was 5.9 years. 42 of these patients (72 percent) entered the fourth year of continuous etanercept treatment, and 26 patients (45 percent) entered the eighth year. Here’s an overview of the results:
- 16 of the original 69 study participants reported 39 serious adverse events, for an overall exposure-adjusted rate of 0.12 SAEs per patient year. This rate did not increase with long-term exposure to etanercept.
- 8 patients reported 9 medically important infections over the course of the long-term trial, for an overall exposure-adjusted rate of 0.03 MIIs per patient year. This rate did not increase with long-term exposure to etanercept.
- The most common adverse event was a flare of JRA. There were no reported cases of tuberculosis, which has been linked to anti-TNF therapy, or lupus; no malignancies or lymphomas; no nervous system disorders; and no deaths.
- Among patients who received 8 years worth of weekly etanercept treatment, 100 percent achieved an ACR Pedi 70 response, indicating 70 percent improvement in joint symptoms from baseline. Over the course of the study, only 7 patients withdrew due to the therapy’s lack of effectiveness on disease activity.
“Continuous treatment with etanercept resulted in truly important, often profound, sustained improvement in all aspects of this disease including clinically important signs and symptoms of JRA, improvements in functional ability and decreased pain for up to 8 years,” notes study group spokesperson Dr. Daniel J. Lovell. Demonstrating long-term safety comparable to studies of patients across a variety of rheumatic disorders, this study supports the potential of etanercept therapy to give children with JRA the promise of a better quality of life as adults.
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- Safety and Efficacy of up to Eight Years of Continuous Etanercept Therapy in Patients with Juvenile Rheumatoid Arthritis. Daniel J. Lovell, Andreas Reiff, Norman T. Ilowite, Carol A. Wallace, Yun Chon, Shao-Lee Lin, Scott W. Baumgartner, and Edward H. Giannini, for the Pediatric Rheumatology Collaborative Study Group, Arthritis & Rheumatism, May 2008; 58:5 pp. 1496-1504.
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