Treatment of Systemic Juvenile Idiopathic Arthritis Is Changing Gradually Toward Biologics

VBCR - December 2012, Volume 1, No 6 - Juvenile Idiopathic Arthritis

By Mark Knight

Washington, DC—Medication use in patients with systemic juvenile idiopathic arthritis (JIA) is highly variable but is gradually shifting toward the increased use of biologic agents, according to presenters who participated at a symposium on the topic at the 2012 meeting of the American College of Rheumatology (ACR).

Data from recent phase 3 clinical trials involving biologic agents may prompt further changes in treatment choices based on positive responses with these agents.

A Gradual Shift
Yukiko Kimura, MD, a pediatric rheumatologist at Hackensack University Medical Center, NJ, presented an overview of current practices in systemic JIA. Dr Kimura’s data show that the use of biologics, especially interleukin (IL)-1 and IL-6 inhibitors, has increased over time, accompanied by a decrease in the use of disease-modifying antirheumatic drugs. However, the use of methotrexate and glucocorticoids is still very common.

The Childhood Arthritis & Rheumatology Research Alliance (CARRA), a consortium of pediatric rheumatologists in the United States and Canada, revealed that steroid-containing regimens were the most common choice of treatment in 2010, followed by methotrexate and an IL-1 inhibitor. The least popular choices in 2010 were an IL-6 inhibitor, a tumor necrosis factor (TNF) inhibitor, and a calcineurin inhibitor.

As initial therapy, respondents were most likely to choose prednisone and intravenous pulse steroids. For patients with refractory JIA (defined as disease that does not respond to treatment after 3 months), an IL-1 inhibitor and an IL-6 inhibitor gained popularity.

The prospective CARRA registry that has enrolled more than 8000 patients as of November 2012 shows that steroids are the most frequent choice of treatment for patients with systemic JIA, and they are chosen by >80% of the 418 pediatric rheumatologists in the registry.

Methotrexate was chosen by >70% of the rheumatologists, a TNF inhibitor by approximately 60% of the rheumatologists, and an IL-1 inhibitor by approximately 50% of the rheumatologists. Methotrexate topped the list of current medications used, selected by approximately 50% of the rheumatologists.

Corticosteroids and an IL-1 inhibitor were each selected by approximately 25% of the rheumatologists, and a TNF inhibitor by approximately 20% of the rheumatologists.

IL-1 and IL-6 Inhibitors
Anakinra  
Recent data with IL-1– and IL-6–inhibiting agents were discussed by Ronald M. Laxer, MD, FRCP, Professor of Pediatrics and Medicine at the University of Toronto and a staff rheumatologist at The Hospital for Sick Children, Toronto, Ontario, Canada. Anakinra (Kineret) is a recombinant molecule that links into the IL-1 receptor site to prevent signal transduction. Early response to anakinra is good, but that response is lost over time, Dr Laxer said.

“Anakinra may be more effective for systemic symptoms than for polyarthritis, [and] it likely can reduce the need for corticosteroids,” he noted. “Perhaps the earlier that anakinra is started, the better the response is going to be.”

Canakinumab and Tocilizumab
Canakinumab (Ilaris), a humanized monoclonal antibody, binds IL-1 beta in the circulation to prevent it from binding with the receptor. Tocilizumab (Actemra) is a humanized monoclonal antibody against the IL-6 receptor. Each drug has been studied in short-term randomized clinical trials, and both demonstrate rapid response with good relative safety in the short-term. Results show good responses, as measured by ACR50 or ACR30 improvement criteria.

With tocilizumab, “there is an early mild response, with about a 30% ACR50 response at 2 weeks, and it continues to climb over the 12-week period,” Dr Laxer said. A JIA-adapted ACR30 response combined with the absence of a fever at week 12 occurred in 85.3% of the tocilizumab recipients compared with 24.3% of the placebo recipients. The JIA-adapted ACR 50%, 70%, and 90% improvement criteria (ACR50/70/90) responses were also significantly greater in the tociliz­­umab group.

In a 4-week randomized study, the response to canakinumab as a single subcutaneous dose was superior to placebo for the primary and secondary end points at day 15: an adapted ACR Pediatric 30 criteria response (aACRPed30), 83.7% versus 9.8%; an aACRPed50, 67.4% versus 4.9%; and an aACRPed100, 32.6% versus 0%, respectively (all P <.001). “Given the response at day 15, there might be an earlier response to canakinumab,” Dr Laxer suggested. Overall, there was a 63% relative risk reduction in the flare rate with canakinumab versus placebo.

A 2-year, open-label, follow-up study showed continuing increases in the aACRPed30/50/70/90 responses to tocilizumab over time. At 2 years, the aACRPed90 approached 80%, and 60% of the patients in the tocilizumab group were able to stop taking steroids.

Four serious adverse events (AEs) occurred in 3 patients randomized to tocilizumab (ie, varicella, septic arthritis, and urticarial/angioedema), and 2 serious AEs occurred in patients randomized to canakinumab (ie, varicella and macrophage activation syndrome).

Timothy Buekelman, MD, a pediatric rheumatologist at the University of Alabama, Birmingham, called for the use of biologics at the time of diagnosis in patients with systemic JIA, adding that steroid-sparing therapy should be a treatment goal because of the side effects associated with systemic glucocorticoids. Methotrexate is often used as a steroid-sparing therapy; however, patients with JIA can rarely reduce their dosage of prednisone when using methotrexate.

The ACR guidelines for the treatment of systemic JIA say that methotrexate is “inappropriate for initial management of patients with active fever and active arthritis,” Dr Buekelman noted.

Very early use of biologics in pa­tients with systemic JIA is supported by data from clinical trials, he said. The ACR70 response at 3 months in the blinded phase of a clinical trial of toci­lizumab for the treatment of patients with systemic JIA was 71% and, in an open-label extension of this study, the ACR70 response improved to 87% at 12 months. A similar excellent ACR70 response of 63% was achieved with canakinumab at 8 months (during glucocorticoid taper) for the treatment of patients with systemic JIA. “This is a highly effective target for this condition,” Dr Buekelman said.

Targeting IL-1 also appears to be successful for treating synovitis in patients with systemic JIA, according to Dr Buekelman. Anakinra has been shown to improve the number of active joints versus placebo at 1 month, and, in a clinical trial of canakin­u­mab, the median number of active joints decreased from 10 to 1 during the first 2 months of open-label use in 177 patients.

Adalimumab for Pediatric
Patients with JIA
Children and adolescents with JIA often experience growth impairment. In another phase 3 clinical trial presented at the meeting, researchers explored the impact of adalimumab (Humira) therapy on pediatric patients with JIA in terms of growth parameters.

This randomized, double-blind, parallel-group study included 171 pa­tients aged 4 to 17 years. Overall, 144 patients met the ACRPed30 response criteria at week 16, and 133 entered the double-blind phase. All patients who received ≥1 dose of adalimumab, with or without methotrexate, were included in the final analysis.

At baseline, 55 patients were in the ≤33 percentile group for weight and 77 patients were in the >33 percentile group. Response rates for ACRPed30/50/70/90 improved over time in both groups.

Long-term (32 week) treatment with adalimumab, with or without metho­trexate, was associated with mainte­nance of growth in patients with impaired growth at baseline; it also improved JIA symptoms in all patients, regardless of baseline growth status.

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