NEW YORK — Early studies evaluating biologic therapies for juvenile idiopathic arthritis are showing benefits that in many cases are profound and persistent, even among patients with the most severe disease.
These trials also have taught some important lessons about study design, placebo responses, and the importance of correct dosing, according to Dr. Daniel J. Lovell.
In an initial trial investigating etanercept (Enbrel) in 58 patients (mean age 10.5 years) treatment-resistant polyarticular juvenile idiopathic arthritis (JIA) a unique study design was used, Dr. Lovell said at a rheumatology meeting sponsored by New York University.
All patients received a 0.4-mg/kg dose of the drug twice weekly on an open-label basis for 3 months, and those who achieved an American College of Rheumatology pediatric 30 response, which is equivalent to the adult ACR 20 response, were entered into the 4-month double-blind, placebo- controlled phase. As soon as a patient flared he or she could leave the blinded phase and go back on the drug. Flare was defined as a 30% worsening in disease activity.
On average these patients had 25 active joints at baseline; this fell to 4 after 3 months of etanercept, said Dr. Lovell, professor of pediatrics, Cincinnati Children's Hospital Medical Center.
Moreover, only those patients who initially demonstrated a response to etanercept—74% of the cohort—were enrolled in the blinded phase, he said.
Flares typically occurred quickly among patients randomized to placebo, but clinical benefits were regained once the patients restarted etanercept. Some patients have now been followed for 4 years, with persistent benefits in many disease domains. (See chart.) “It's also important to note that on each of these parameters 20%–40% of the population actually normalized, meaning they could have a pain assessment score of zero or no active joints,” he said.
Another double-blind study that enrolled 171 patients (mean age 11.4 years) with polyarticular JIA to adalimumab (Humira) at a dose of 24 mg/m
Among patients receiving adalimumab without background methotrexate, 67% achieved an ACR pediatric 30 response, while 63% and 45% achieved ACR 50 and 70 responses, respectively. Among those with background methotrexate, 88%, 85%, and 69% reached ACR 30, 50, and 70 levels of response, respectively.
“The lesson we can take home as clinicians is that if you're going to use [adalimumab] in patients with juvenile [idiopathic] arthritis it makes sense to combine it with methotrexate,” he said. The combination was as safe as adalimumab alone.
Responses were rapid: By week 8 all the patients who were going to respond to the drug had done so.
Another trial that was recently completed evaluated infliximab (Remicade) in doses of 3 mg/kg or 6 mg/kg. This was a more traditional study design, with patients receiving either placebo infusions or infliximab 3 mg/kg at prespecified intervals for 14 weeks. At that time, patients who had been on placebo received infusions of 6 mg/kg of infliximab, while those on the 3 mg/kg regimen continued at that dose.
At week 14, 65% of 122 patients on infliximab had achieved an ACR 30 response, which was the primary end point, as had 48% of those on placebo.
The difference in response rate from placebo for the 3 mg/kg dose, with a P value of .051, did not reach statistical significance, so this dose will not be approved by the FDA, Dr. Lovell said.
In the second phase of the trial, however, when patients were receiving infusions of either 3 mg/kg or 6 mg/kg every 8 weeks, approximately 70% of patients in both groups had an ACR 30 response. Among patients receiving the lower dose, 38% developed anti-infliximab antibodies, compared with 12% of those receiving the higher dose. Patients with these antibodies, which develop in response to the mouse component of this chimeric drug, have a three- to fourfold increased risk of having an infusion reaction and also have lower serum concentrations of the drug.
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