BOSTON, Massachusetts—The costimulation blocker abatacept (Orencia®, Bristol-Myers Squibb Co) may be a safe and effective option for juvenile idiopathic arthritis (JIA) patients who have exhausted all other therapies, according to research presented at the American College of Rheumatology annual scientific meeting in Boston.¹

"These patients are desperate for a new treatment because they had exhausted all available treatments and still have active arthritis," said lead study author Daniel J. Lovell, MD, MPH, professor of pediatrics at Cincinnati Children's Hospital Medical Center in Ohio. "It is certainly important that this is a treatment that can work when all other treatments have failed."

Treatment cut flares in half, produced sustained responses

In the phase III trial of 190 patients, 170 completed the open-label, lead-in period, of whom 123 achieved an ACR PEDI 30 response at the end of 4 months. In those patients who had previously failed prior anti-TNF therapy, 39% met ACR PEDI 30. One hundred twenty-two responders entered the double-blind withdrawal phase of the study and were randomized to either continue abatacept or receive placebo for up to 6 months, or until they flared.

In this arm, 53% of patients randomized to the placebo group flared quickly, compared with 20% of those given abatacept. Fully 40% of patients in the abatacept arm achieved ACR PEDI 90 response during the 10-month study. "Abatacept works more upstream and closer to the source of the disease than other agents that bind up the cytokines that are produced [by the inflammatory response]," Dr. Lovell explained.

Safety profile in open-label arm

During the open-label lead-in, six patients reported serious adverse events, of which three cases were related to underlying disease and one case each involved varicella, acute lymphocytic leukemia, and ovarian cyst.

The leukemia was diagnosed at day 89 in a patient who was anemic at enrollment with progressive decreasing hemoglobin from day 1, thus relationship to study medication was unlikely.

Overall, 70% of patients reported adverse events most commonly headache (13.2%), nausea (10%), cough (8.9%), diarrhea (8.9%), upper respiratory tract infection (7.4%), and pyrexia (6.3%). There were few infectious adverse events except for upper respiratory tract infections, and there were no opportunistic infections. Eight (4.2%) patients experienced acute infusion adverse events, all but one of which were mild.

Safety profile of double-blind withdrawal arm

In the double-blind withdrawal period, there were no serious adverse events reported in the patients taking abatacept, but three serious adverse events were reported in two placebo-treated patients. All resolved, and none resulted in discontinuation.

Overall, 61.7% of patients taking abatacept and 54.8 % taking placebo experienced an adverse event. The most common events were influenza, bacteriuria, nasopharyngitis, upper respiratory tract infection, and pyrexia. Acute infusion adverse events were reported in 1.7% of the abatacept-treated patients and 3.2% of those who received placebo. All of these reactions were mild/moderate. Importantly, there were no serious infections, autoimmune disorders, or anaphylaxis episodes in any period, nor was there evidence of consistent patterns of abnormal liver/kidney function tests or hematological parameters in this study.

When asked how the advent of biologics has changed treatment for juvenile rheumatoid arthritis, Dr. Lovell said that it is really a whole new world. "We used to have very longstanding, intimate relations with our patients and their families, but now they come in with new onset disease, we put them on these [biologic] treatments, and within 3 or 4 months, they feel so much better [that] there is almost nothing to talk about."
 
Translating research into practice

"I was …pleased to see that abatacept was efficacious," said Kathleen A. Haines, MD, section chief of pediatric immunology in the department of pediatric rheumatology and immunology at Hackensack University Medical Center in New Jersey. "In my practice, I will turn to it after failing the more standard therapies which are methotrexate, with the addition of (if necessary) etanercept, adalimumab, or infliximab."

Bristol-Myers has filed for approval of abatacept to treat pediatric patients with JIA who have had an inadequate response to one or more disease-modifying antirheumatic drugs, such as methotrexate or tumor necrosis factor antagonists. The FDA is expected to make a decision in the first quarter of 2008.

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