Contributed by: AnneMarie Brescia, MD

Prognostic Synovial Biomarkers in Juvenile Idiopathic Arthritis

Juvenile Idiopathic Arthritis (JIA) is the most common pediatric rheumatic disease. There are 7 subsets, one of which, oligoarticular form (oligo-JIA), represents 50% of the cases. Outcome in oligo-JIA is usually benign, but 30% of affected children evolve from persistent oligo-JIA into another form known as extended oligo-JIA, with more joints involved. Since this evolution may entail disability, early prediction of this course is desirable. The aims of this study are to investigate biomarkers to predict disease extension and understanding underlying mechanisms of inflammatory arthritis.

Our previous work has revealed that the RNA being made in fibroblast-like synoviocytes (FLS), cells that reside in the joint, from JIA patients who remained persistent versus those who were destined to extend, is different early in disease, which may be useful for prediction of which patients will extend. Our comparison of RNA of FLS from children with a persistent oligo-JIA course versus those who evolve into extended oligo-JIA revealed many genes with different degrees of activation between these two groups. When activated, these genes tell the cell to make important proteins involved in cell growth, connective tissue development, and inflammation. Using 6 of these genes, we were able to predict prognosis correctly 100% of the time on a small set of blinded samples.

Using these 6 genes as a starting point, we have continued to develop a biomarker panel to distinguish between the persistent and extended oligo-JIA using aspirated synovial fluid, the fluid from inflamed joints. Using the proteins expressed by these six genes, we have measured the levels of these proteins in synovial fluid from persistent and extended oligo-JIA to see which correlate with disease course. We are currently working on blinded validation of these candidate biomarkers on new synovial fluid samples. Our next steps are to make prediction on newly obtained samples.

We are also investigating the role of the TGFbeta signaling pathway in the pathogenesis of JIA. TGFbeta is known to have an important role in the pathogenesis of adult rheumatoid arthritis. We have demonstrated that the FLS are actually secreting markers that chondrocytes, or cartilage cells, secrete. This is very important because it may be indicating that the FLS themselves are actually behaving like chondrocytes, thereby directly contributing to the bony overgrowth seen in JIA. The bony overgrowth is a significant cause of morbidity in JIA, leading to knee deformity and leg length discrepancies.

Much of parental concern surrounding this disease is fear of the unknown: Development of biomarkers allows us to provide families and patients with more complete information regarding prognosis and to make more informed decisions regarding treatment strategies. We are moving forward with validation of biomarker panel to predict prognosis. Addressing juvenile idiopathic arthritis as early as possible to prevent joint damage will in turn significantly improve the long-term functional outcome and life enjoyment of children with arthritis. Demonstrating the role of the TGFbeta signaling pathway in the pathogenesis of JIA has implications for future treatment options. This work has resulted in several scientific publications and has been presented locally in Delaware, regionally and on a national level.

Thank you so much for the support of the Open Net Foundation over the years—you have truly contributed to this project moving forward!