A Dim View of the Brave New World for JIA

April 11, 2014

(ACR Pediatrics 2014) New biologics have revolutionized care for children with juvenile arthritis in recent years. But a pediatric rheumatologist says this progress isn't nearly good enough, urging a much tougher agenda.

Suddenly, as of the past few years, pediatric rheumatologists can offer parents of children with severe juvenile idiopathic arthritis (JIA) many good options, not just a few bad ones. But far from basking in this success, a speaker at the ACR pediatric rheumatology symposium in Orlando last week challenged them to raise the bar on their own expectations.

“The problem nowadays is not so much that we do not have drugs to achieve our goals,” said Dirk Foell MD of University Childrens Hospital in Muenster, Germany. Pediatric rheumatologists really don’t know how best to start these drugs or when to stop, he said, and their goals are either poorly defined or too modest.

Daniel J Lovell MD of Cincinnati Childrens Hospital, who has headed many clinical trials in the subspecialty and pioneered ethical trial designs for young patients who should not be consigned to placebo, spoke in an interview about the “luxury” of too many options, recalling “when we didn’t have any options, only crappy drugs with side effects.”

Polyarticular JIA is “wonderfully benefitted” by tumor necrosis factor inhibitors such as etanercept (Enbrel) and adalimumab (Humira), he said. The agents canakinumb (Ilaris) and tocilizumab (Actemra), both approved last year for JIA, are “tightly fitted to pathophysiology” of systemic JIA, he added. Each works for 80% of patients, within a few days, and if one drug fails, the other works.

Several studies reported at the symposium showed improved results after longer-term follow-ups with these new drugs (click on the boldface headers to see the abstracts):

Non-progression with tocilizumab (TCZ) in sJIA. Phase 3 results from the randomized placebo-controlled TENDER trial of sJIA showed no  “noticeable” radiographic progression over two years of treatment.
 

Tapering TCZ. Patients who maintained clinically inactive diseases (CID) status for 12 weeks in the TENDER trial were allowed to enter a five-stage withdrawal regimen. Nearly a fourth (23%) of those eligible for tapering were able to discontinue all treatments.
 

TCZ exonerated from neutropenia risk?  Increased neutrophil count in the TENDER trial was higher in those on concomitant methotrexate, not specifically in patients on TCZ. In any case, there was no concurrent increase in infections.
 

Sustained good results for TCZ in polyarticular JIA. After two years of followup in the three-phase, placebo-controlled CHERISH trial, the number of patients in CID grew to 63% from 40% at 40 weeks. For those on continuous TCZ through the placebo-controlled phase, 71% reached ACR90 status by 104 weeks, up from 50% at 40 weeks. No new adverse events emerged.
 

IV abatacept has a long-term impact on real-world quality-of-life issues. In the long-term extension phase of the AWAKEN trial, JIA patients treated for 7 years with the T-cell blocker abatacept (Orencia) scored above the normal range for physical and psychosocial quality of life. Children still on treatment missed between 2 and 6 fewer days of school per month than at baseline (depending on the treatment response group), and parents or caregivers missed about 4 fewer workdays.
 

Adalimumab is safe and effective in toddlers and smaller 4-year-olds.The drug is approved in the US only for children with polyarticular JIA over the age of 4. This small (32-patient) international multicenter trial established that it is equally effective and just as safe for children aged two or older and smaller 4-year-olds.

“We are really lucky that the high-quality trials are now available, but we are looking primarily at response to treatment,” observed Foell, who challenged his audience to consider whether they are “really happy” with aiming only at improvement.

The term “treat to target” is nearly meaningless in pediatric rheumatology today, judging from his remarks. Foell’s PubMed search the previous week had yielded 117 results for the term “treat to target,” he said. But adding the term “juvenile” produced only one.

“There are no studies with the primary endpoint ‘inactive disease’,” he went on. “We have not defined such an endpoint.”

Foell’s suggested priorities for future research:

Clearly define targets and timelines, rather than just watching for changes in ACR disease parameters.  Major recommendations don’t define targets, he said, because there is no “high-level” evidence from  randomized trials to support doing so. (Rheumatologic conditions of childhood are too rare to support large trials without collaboration, and much of the data from the growing number of disease registries in pediatric rheumatology is observational, not experimental and comparative.) 

Controlled studies on withdrawing or tapering treatment. Parents are eager to know when treatment can stop, he said. Their doctors don’t have any idea.

Test step-down rather than step-up regimens. Emulating the strategies of pediatric oncology, Foell urged pediatric rheumatologists to consider testing early aggressive treatment of more severe or threatening forms of JIA, reducing to maintenance therapy only after reaching a target, rather than starting with less potent drugs and progressing to DMARDs.

Some pediatric rheumatologists appear to be trying this approach independently, following reports of success from both Finland and the Netherlands with aggressive first-line use of biologics for early JIA. Lovell said in an interview that a trend is emerging to start very early with biologics, akin to accepted treatment for rheumatoid arthritis, and bypass steroids completely.

Find biomarkers that define subtypes of patients or predict outcomes. Mentioning a neutrophil activation marker called MRP8/14 that is high in patients before flares, and two classes of proteins (S100 and high-sensitivity C reactive protein) that appear to predict remission, Foell concluded that “stratification of patients for optimized individual therapeutics is the future, I’m pretty sure."

It's not here yet, he added, "but it is within reach.”