Bret S. Stetka, MD; Sarah Ringold, MD


July 29, 2014

Editor's Note: While on site at the 2014 European League Against Rheumatism annual congress, held in Paris, France, June 11-14, 2014, Medscape spoke with Sarah Ringold, MD, Assistant Professor, University of Washington School of Medicine, and Attending Physician, Seattle Children's Hospital (SCH), Seattle, Washington, about her new study of a biomarker blood test to help assess disease activity in juvenile idiopathic arthritis (JIA).[1]

Medscape: What was the objective of your study?

Dr. Ringold: The primary objective was to evaluate the multi-biomarker disease activity (MBDA) blood test in children with polyarticular or extended oligoarticular JIA, as a tool to assist in determination of disease activity.

A secondary objective was to evaluate the potential of the MBDA to assist in identification of children with inactive disease -- both clinical and inflammatory aspects.

Medscape: What biomarkers does the test include?

Dr. Ringold: The MBDA is a commercially available test, Vectra® DA (Crescendo Bioscience; South San Francisco, California), that has been validated to measure disease activity in adults diagnosed with rheumatoid arthritis (RA). The concentrations of 12 serum proteins involved in the pathobiology of RA are measured, and an algorithm is applied to calculate a single Vectra DA score that categorizes RA as low, moderate, or high disease activity. The test includes the following biomarkers:

  • Vascular cell adhesion molecule 1 (VCAM-1) plays a role in the interaction among cells, blood vessels, and connective tissue in the joint. These interactions contribute to the build-up of cells within joints affected by RA.

  • Epidermal growth factor (EGF) is a growth factor produced by cells in RA joint tissue that can cause cell growth and inflammation.

  • Vascular endothelial growth factor A (VEGF-A) is a growth factor produced in inflamed joints that contributes to blood vessel formation, fluid build-up, and bone erosion.

  • Interleukin 6 (IL-6) is a major driver of RA inflammation, cartilage deterioration, and bone erosion.

  • Tumor necrosis factor receptor, type 1 (TNF-R1), is a receptor for TNF alpha, which is another molecule that drives joint inflammation and destruction. TNF-R1 is expressed on the surface of many different types of cells, where it joins with TNF alpha to drive inflammation. It can also be released from the cells, in which case it neutralizes TNF alpha.

  • Matrix metalloproteinase 1 (MMP-1), or pro-collagenase 1, is an enzyme that contributes to cartilage destruction in RA.

  • MMP-3, or stromelysin-1, is an enzyme that destroys components of cartilage.

  • YKL-40 is protein that helps regulate tissue remodeling and destruction.

  • Leptin is a hormone secreted by fat tissue, cells in the joint tissue, and bone cells. Leptin can contribute to inflammation and regulates bone remodeling.

  • Resistin is another hormone secreted by cells in the joint tissue and bone that contributes to inflammation and helps to control bone remodeling.

  • Serum amyloid A is a protein produced by the liver in response to inflammation. SAA may also be produced by the joint tissue, where it can activate tissue and bone cells.

  • C-reactive protein (CRP) is also produced by the liver in response to inflammation. Elevated CRP levels are associated with an increased risk for cardiovascular disease.

Medscape: Briefly describe the methods of your study.

Dr. Ringold: This study of 90 patients with JIA analyzed 60 treated patients from the SHC Cohort, a cross-sectional, observational study, and 30 untreated patients from the Trial of Early Aggressive Therapy in Polyarticular Juvenile Idiopathic Arthritis (TREAT).[1] A cohort of 58 disease-free 18-year-olds obtained from the ProMeDx (Norton, Massachusetts) specimen bank served as controls.

The Juvenile Arthritis Disease Activity Score (JADAS) is a composite tool that includes 4 core variables of the American College of Rheumatology pediatric measure: physician global assessment of disease activity, parent/patient global assessment of well-being, active joint count, and erythrocyte sedimentation rate.

Serum samples were analyzed for the 12 biomarkers that form the Vectra DA test for disease activity in RA. The biomarker concentrations were measured with sandwich immunoassays, run in a multiplex format in the research and development laboratory of Crescendo Bioscience using the same reagents, platform, and validated algorithm as the Vectra DA test for adults with RA (which is run in a CLIA-certified clinical laboratory).

Clinically inactive disease was defined as: (1) no joints with active arthritis; (2) no fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributable to JIA; (3) no active uveitis; (4) erythrocyte sedimentation rate in the normal range of the laboratory where tested; and (5) a physician's global assessment of disease activity score of 0.


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