Research points to protein that triggers juvenile arthritis

Evidence suggests that juvenile idiopathic arthritis (JIA), the most common pediatric rheumatological condition, is an antigen-driven autoimmune disease. However, its autoantigens are still unknown. In a new study, researchers identified transthyretin (TTR) as the likely autoantigen involved in JIA’s pathogenesis, according results published online February 25, 2016 in JCI Insight.

In addition, “Our findings regarding TTR’s involvement in JIA point to a potential treatment—encouraging news for children with this debilitating disease,” said study leader Laura Santambrogio, MD, PhD, Professor of Pathology, Microbiology and Immunology, and Orthopedic Surgery at Albert Einstein College of Medicine in New York, NY.

That potential treatment is tafamidis, which targets TTR, Dr. Santambrogio said. Tafamidis is approved in Europe and Japan for treating hereditary amyloidosis, which is also related to TTR. The drug is now undergoing phase III clinical trials in the U.S.

In the current study, Dr. Santambrogio and her colleagues performed proteomic and biochemical profiling of the synovial fluid and blood of 50 pediatric patients with JIA to find any abnormal accumulations of proteins. After analyzing the samples, they found a significant increase in TTR in 70% to 75% of patients with JIA, but not in any of the 24 control children who did not have JIA.

Further analysis also showed that some JIA patients had unusually high levels of TTR autoantibodies. To confirm this finding, the researchers analyzed 43 other JIA patients and found a significant increase in TTR autoantibodies in all of them.

TTR is a molecular chaperone that carries several molecules, including thyroxine and retinol (vitamin A), in the blood and cerebrospinal fluid. “The TTR protein has a tendency to misfold and then aggregate, which for some reason seems to occur in children with JIA,” Dr. Santambrogio said. “And when proteins aggregate, they tend to become more immunogenic.”

The researchers suspect that JIA begins when TTR collects in the joints. “The synovial fluid is a highly viscous milieu, as compared to other biological fluids, and this high viscosity, which is associated with increased TTR production, could facilitate precipitation and aggregation,” the authors wrote.