Study Paves Way for Personalized Juvenile Arthritis Treatment

Their study, led by James N. Jarvis, MD, clinical professor of pediatrics, offers a possible explanation for common disease flares.

The research team also identified a transcription factor involved in remission.

With standard treatment, 35 to 50 percent of children with JIA achieve remission.

Yet many still experience flares even when their condition has been stable for weeks or months. Half of children who try to go off medication experience disease flares within two to six months.

“Our study provides some insight into why,” Jarvis says. “Although children in remission appear to be symptom-free, their immune systems are still perturbed.”

Researchers found that more than 200 genes in white blood cells were expressed differently in children taking methotrexate and the biological drug etanercept compared with healthy controls.

Some of those differentially expressed genes have been shown to bind to HNF4a, a transcription factor that acts as an on-off switch for gene expression.

The researchers compared gene expression profiles from two cohorts of 14 patients each, all in remission from JIA—formerly known as juvenile rheumatoid arthritis—with those of 15 healthy controls.

The patients, who were followed every two to three months for at least a year, had been treated with two different standard medication regimens.

A key finding from the research is that remission is tied to HNF4a.

Researchers now suspect that this transcription factor is one of a group of master switches that regulates responses to therapeutic agents.

Until now, HNF4a was seen only as a regulator of metabolism in liver and pancreatic cells, Jarvis explains.

The study confirms preliminary research by Jarvis’ team suggesting that remission is not a return to normal, but a distinct biologic state.

The researchers have learned that this new state occurs as pro-inflammatory responses are counterbalanced by anti-inflammatory responses caused by medication-induced changes in gene expression.

The team’s findings lay the groundwork for studies to identify biomarkers involved in individual responses to specific therapies, Jarvis says.

“This is a first step toward identifying biomarkers that will ultimately allow clinicians to personalize treatment by predicting which patients will respond best to which therapies.”

Longitudinal research that monitors gene expression before, during and after treatment is needed, Jarvis notes, but he’s already engaged in the quest. With a $1.2 million grant from the National Institutes of Health, he’s leading a study of microarray-based biomarkers in JIA.

He’s also using several foundation grants to study the role of epigenetics—altered gene expression via environmental factors—in JIA.

The researchers’ long-term goal is to build the first genomic roadmap to define and achieve remission, says Jarvis, whose lab is located in UB's Clinical and Translational Science Institute.

This would allow doctors to help patients reach remission more quickly and for longer periods.

The study, “Genomic Characterization of Remission in Juvenile Idiopathic Arthritis,” was published in Arthritis Research & Therapy.

Most of the research was conducted at the University of Oklahoma Health Sciences Center with two co-authors who have since joined Jarvis in UB’s Department of Pediatrics: Kaiyu Jiang, research scientist, and Yanmin Chen, research technician.

Colleagues at the Oklahoma Medical Research Foundation also contributed.

Funding was provided by the NIH, the Oklahoma Center for the Advancement of Science and Technology and the Arthritis Foundation.