(ACR Pediatrics 2014) Large research partnerships are proving key to conquering childhood rheumatic diseases like juvenile idiopathic arthritis. To continue the advance, however, larger mergers and newer kinds of data are required.
How can you advance against an enemy when your numbers are too small to win ? You join forces with your allies. So it has been in pediatric rheumatology.
“The last decade in pediatric rheumatology has been the decade of the registry,” said Harvard rheumatology professor Daniel Solomon MD at the ACR pediatric rheumatology symposium in Orlando. “And I think we have learned a lot.”
One of the best examples is CARRA, the Childhood Arthritis & Rheumatology Research Alliance, formed 13 years ago because “pediatric rheumatologists were unhappy with the pace of research,” says its vice chair Laura Schanberg MD, co-chief of pediatric rheumatology at Duke University. “The diseases are so rare that no one site could do meaningful work.”
CARRA’s membership now includes three of every four pediatric radiologists in North America, all of them submitting data about young patients with rare pediatric disorders. Its seed money came from the Arthritis Foundation, which continues its support, but CARRA now receives about $40 million in grants from foundations and the National Institutes of Health.
Another motive for founding CARRA, said Schanberg, is that much of the research agenda at the time was industry-driven. The Pediatric Rheumatology Collaborative Study Group (PRCSG) was founded more than 40 years ago partly at the initiative of the pharmaceutical industry to conduct high-quality clinical trials of therapeutic agents in children with rheumatic diseases. PRCSG is behind much of the recent revolution in treatment of juvenile idiopathic arthritis (JIA), having sponsored trials of at least 13 agents for the condition.
CARRA’s agenda for the future will be guided, increasingly, by parents and their families. The alliance has now partnered with the National Patient-Centered Clinical Research Network to create the PARTNERS Consortium, which will enroll almost 9,000 patients with pediatric rheumatic disease into registries at 62 medical centers. The goal is to conduct research projects based on “patient-centered” priorities, according to its website.
This hardly overshadows the priorities of clinicians, however. CARRA has published six consensus treatment plans for childhood rheumatic conditions, one on polyarticular JIA is in press, and another on uveitis is in the works.
This will be bolstered by new data reported at the Orlando meeting. In a CARRA cohort of 1,104 patients from 16 Canadian centers, the first solid evidence for the incidence of new-onset uveitis in JIA has emerged: It increases at a steady 2.9% per year (highlighting the urgency of long-term vigilance for the complication).
Another study reported in Orlando documents current practice patterns in teating uveitis, an important precursor to a consensus treatment plan. Among 92 children with idiopathic uveitis in its registry, 70 were taking methotrexate (MTX), about half of them orally, and more than half had taken a TNF inhibitor, usually concomitant with the MTX.
Another insight tracing to a CARRA registry was a distinction between two subsets of ANCA-associated vasculitis, microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), which earlier studies have often viewed as the same condition. Using a pediatric modification of adult classification criteria to analyze data from 227 children, it emerged that those classified as MPA had much more severe kidney involvement, often requiring dialysis, and were significantly younger at diagnosis (the mean difference was 2.7 years) than those with GPA, who were more likely to show airway involvement.
CARRA has also been central to the development of PR-COIN (Pediatric Rheumatology Care & Outcomes Improvement Network), an 11-site international registry devoted to sharing outcomes and best practices. There are currently more than 1,200 JIA patients in the registry, and a pilot study of lupus is also underway.
Other registries exist in pediatric rheumatology, including one coordinated by the NIH and another from the UK which both reported data on childhood myositis at the Orlando meeting. What would happen when their conclusions conflict? The next agenda includes a call for meta-collaboration, between different registries, to resolve discrepancies.
“I think linking datasets is going to be the future,” said Harvard’s Solomon, “as a way of reducing weaknesses in any one of them.”
It is also urgent, said Lucy Wedderburn, head of the rheumatology unit at the UK’s Institute of Child Health, to begin routinely collecting biological samples such as urine, blood, and DNA from all children in the registries. “Then we can ask questions about the phenotypes and link them to the biology.”
A member of the research team involved in the UK myositis registry, Wedderburn added that it should be seen as unethical not to enter every child with a rheumatic condition into a registry, and therefore into research. “Otherwise,” she said, “we will never learn anything.”