It's not often said but it must be admitted: current therapy for polyarticular juvenile idiopathic arthritis (JIA) is little more than an exercise in """"""""chasing failure."""""""" That is, medications are added or doses adjusted only after a child has failed to respond to the initial therapy. The result, of course, is weeks or months of unnecessary pain and limitation of function for the affected children. What we urgently need in pediatric rheumatology is a method to determine at the outset of treatment which children will respond to relatively conservative therapies (e.g., methotrexate plus non-steroidal anti-inflammatory drugs), and which children will respond better to methotrexate plus biological therapies. Our laboratory has shown the feasibility of developing gene-array based biomarkers that will both model and predict responses to therapy in polyarticular JIA. However, we have been hampered by the empiric nature of therapy as it is given in the typical clinical setting. In the Trial of Early Aggressive Therapy (TREAT) for Juvenile Idiopathic Arthritis (R01 AR04962, Carol Wallace, M.D., P.I), we have a once-in-a-generation opportunity to address vexing questions about treatment and response to therapy that have hindered both the clinical and scientific progress of our field. The trial will match two treatment arms, methotrexate vs. methotrexate + etanercept (a genetically-engineered inhibitor of TNF alpha), in children newly diagnosed with the polyarticular form of JIA. Furthermore, NIH has required the TREAT study investigators to collect whole blood samples (PAXgene) for adjunct, translational studies. We will use those samples to: (1) take the first steps in developing array-base prognostic biomarkers for treatment response and (2) model the molecular dynamics of response/non-response. In accomplishing these aims, we also expect to shed new light on disease pathogenesis, generating testable models that have eluded reductionist approaches to understanding this disease. In this application, we discuss the limits of whole blood RNA profiling and the need for further studies. However, both the TREAT study and the translational research proposed here will provide a critically-needed platform from which to set pediatric rheumatology firmly in the post-genomic era and begin to realize the promise of individualized therapy.
Juvenile idiopathic arthritis is one of the most common chronic disease conditions in children. Clinical care of children with this disease is largely trial-and-error, since we have very little understanding of why certain children respond to certain medications and others don't respond at all. In the context of a large clinical trial comparing 2 different ways of treating juvenile arthritis, we propose to use state-of-the-art genomics technologies to gain a better understanding of how drugs for arthritis work. In addition, we will begin the process of the long-promised individualized therapy in childhood arthritis by asking whether children's responses to specific drugs can be predicted when they first seek medical attention. This project will provide a model of the future for identifying targets of therapy in chronic inflammatory diseases. Data that is emerging from the plethora of genomics sciences all support the concept of identifying the hubs of disease processes, as we will be doing here, as the most effective way of altering those processes. Only the systems biology approach proposed here is likely to do that in an efficient manner.
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