“Magic Bullet” Approaching for Systemic JIA: But Which One?

Pediatric rheumatologists are dramatically changing their treatment strategies for systemic juvenile arthritis (JIA), choosing new interleukin inhibitors such as tocilizumab over steroids or methotrexate. But there’s still great uncertainty about the best treatment, to judge from a recent report from the 92-site US-Canadian Childhood Arthritis & Rheumatology Research Alliance (CARRA) registry, with the “vast proportion of respondents” still including steroids in treatment regimens, according to Yukiko Kimura MD, associate professor of pediatrics at Hackensack University Medical Center in New Jersey.

CARRA has launched a study to compare four alternative treatment options for juvenile arthritis. More than 8000 patients have been enrolled to date, Kimura said at the American College of Rheumatology meeting in Washington. About 70% of them have juvenile arthritis. But only 418 to date have systemic JIA, so help in this treatment dilemma may be long in coming.

Lacking head-to-head trials of the three most promising drugs-anakinra, tocilizumab, and canakinumab-this is no surprise. A systematic review reported at the meeting by a team from Rotterdam (Abstract #1142) found no identifiable differences between the three drugs, though the team concluded that canakinumab is superior to tocilizumab. For now, they added, pediatric rheumatooglists have to rely on indirect comparisons and observational data. At a session devoted to the topic, Kimura and other speakers tried to help specialists sort out the details, polling them meanwhile on their own opinions by an automated response system. 

Since initial optimism about anakinra faded when response rates in the recent ANAJIS trial dropped dramatically after one year, Ronald Laxer MD, professor of pediatrics at the University of Toronto, focused on the best recent evidence about the IL-1 blocker canakinumab and the anti-IL-6 agent tocilizumab. Although their age ranges are similar, the trials are otherwise so different as to make comparisons a challenge.

In a poster presented at the meeting (Abstract #759), researchers from pediatric rheumatology groups in the US and Europe reported on 84 patients in a 4-week double-blind single-dose study of subcutaneous canakinumab followed by a larger 177-patient phase that included steroid tapering. After a mere 15 days, 84% of patients receiving the drug in the first phase achieved ACR30 responses compared with fewer than 10% in the placebo group. During the second part of the trial, nearly a third of patients taking canakinumab stopped steroids completely, and at the end of the trial 62% of patients were clinically inactive.

Laxer compared this to data from the 5-year study of tocilizumab that supported its approval in the US last year, in which some 84% of patients achieved ACR30.  These results weren’t achieved in the 15 days claimed for canakinumab, but tocilizumab’s effectiveness has continued to increase over time, Laxer noted. Adding to the challenge of comparing the trials: Patients tested with tocilizumab had symptoms in more joints over far longer (about five years compared to about two) than those in the canakinumab trial.

In either case, pointed out Timothy Beukelman MD, a pharmacologist with the University of Alabama at Birmingham, there's good news. Tocilizumab achieves ACR70 in 71% of systemic JIA patients within 3 months, as does canakinumab in 63%. The typical rate for this kind of response in randomized trials of biologicals in rheumatology trials overall is about 20%.

“I don’t think this is a cure,” he added. “It’s not a magic bullet. But I think we’re getting very close.”

As to their safety, “people conclude that these drugs are relatively safe in the short term,” Laxer said. Serious adverse events including infections, septic arthritis, and macrophage activation syndrome (MAS) are about equally prevalent in treatment and placebo groups in both trials.
 
In summary, Laxer offered answers to the questions pediatric rheumatologists are likely to hear from their patients’ parents about these drugs:

•    How quickly will the drug work? (Perhaps canakinumab is faster.)
•    How well will it work in the long term? (For canakinumab, we have no data yet. For tocilizumab, the response is excellent.)
•    How safe is it? (We don’t know the answer. In the short term, it seems that MAS is no more prevalent than with placebo.)
•    Can it prevent or reduce the need for steroids? (Yes.)
•    How inconvenient is the treatment? (Canakinumab, every 2 weeks subcutanously. Tocilizumab, every 4 weeks IV.)

As to the “elephant in the room,” the price of treatment, Laxer said that tocilizumab costs about $150 a vial, compared to roughly $16,000 for a vial of canakinumab. “That’s a huge issue we have to face,” he said.

After summarizing data about the drugs in great detail, Laxer presented a question to the audience: Given what you now know about the three drugs in terms of safety and efficacy, which do you prefer?

Several hundred rheumatologists in the room were able to respond via an automated response system, their answers displayed on the screen. The results echoed Kimura’s initial statements about uncertaintly:

Tocilizumab > anakinra:  60%
Anakinra > tocilizumab: 22%
Equal overall:  28%

Canakinumab over anakinra:  60%
Anakinra > canakinumab:  27%
Equal overall:  23%

Canakinumab > tocilizumab: 31%
Tocilizumab > canakinumab:  32%
Equal overall:  37%

More from ACR2012:

Missed Lung Disease in Community-Treated Systemic JIA Often FatalACR2012 Highlights: Rheumatoid Arthritis Comorbidities and Adverse Events ACR2012 Highlights: Rheumatoid Arthritis Diagnosis and Prognosis ACR2012 Highlights: Rheumatoid Arthritis Treatment