Current treatment approaches for children with Juvenile Idiopathic Arthritis (JIA) have resulted in dramatic improvements in disease control with Methotrexate (MTX) and anti-tumor necrosis factor (anti-TNF) biologic therapies as cornerstones of advanced therapy. At the present time, =70% of patients demonstrate 70% improvement in JIA manifestations, and up to 50% of patients will demonstrate clinically inactive disease while on treatment. Much of this profound improvement is due to anti-TNF biologic therapies that are often used early in the treatment of JIA, though MTX alone will eventually result in over 50% of JIA patients demonstrating at least 70% improvement. Conversely, in patients treated with anti-TNF biologies, =60% of children who demonstrate clinically inactive disease while on treatment will demonstrate an obvious and clinically important worsening of disease within 3 to 12 months of treatment withdrawal. We currently are unable to accurately predict which JIA patients will demonstrate an excellent clinical response to MTX, will demonstrate an excellent clinical response to anti-TNF therapy, or have achieved clinically inactive disease on anti-TNF therapy and can discontinue treatment without having disease flare. This project will use gene expression profiling to identify molecular markers that address each of the issues raised above. The primary goal will be to develop gene expression biomarkers to accurately identify patients in whom advanced therapy with either MTX or anti-TNF biologies will be highly successful, and in whom anti-TNF agents can be effectively stopped. For each specific aim there are two hypotheses - one testing the predictive ability of peripheral blood mononuclear cell (PBMC) gene expression signatures that we have previously identified in treatment-naive polyarticular JIA patients, and the other hypothesis is directed at improved understanding of the biologic effects of MTX and anti-TNF therapies in JIA.
Our Specific Aims will be: 1) determine relationship of MTX therapy to PBMC gene expression in JIA, 2) determine relationship of anti-TNF therapy to PBMC gene expression in JIA, and 3) determine relationship of stopping anti-TNF therapy to PBMC gene expression in JIA with S6 months of clinically inactive disease. If successful, this project will improve understanding of the clinical use of MTX and anti-TNF biologies in JIA allowing safer and more cost-effective utilization of these cornerstone therapies.

Public Health Relevance

This project will study the expression of thousands of genes in blood cells of children with juvenile arthritis, particularly looking at how these genes are affected by specific treatments or if their expression can predict how a patient will respond to certain medications. Identification of such biomarkers that can be measured in blood will offer clues to determine what disease processes are active in juvenile arthritis, and also help guide physicians to use the most optimal treatments for individual patients with juvenile arthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
5P01AR048929-08
Application #
8532633
Study Section
Special Emphasis Panel (ZAR1-HL)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
8
Fiscal Year
2013
Total Cost
$12,885
Indirect Cost
$10,748
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Schulert, Grant S; Grom, Alexei A (2015) Pathogenesis of macrophage activation syndrome and potential for cytokine- directed therapies. Annu Rev Med 66:145-59
Schulert, Grant S; Grom, Alexei A (2014) Macrophage activation syndrome and cytokine-directed therapies. Best Pract Res Clin Rheumatol 28:277-92
Moncrieffe, Halima; Prahalad, Sampath; Thompson, Susan D (2014) Genetics of juvenile idiopathic arthritis: new tools bring new approaches. Curr Opin Rheumatol 26:579-84

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