multibiomarker disease activity blood test

Study Validates RA Disease Activity Biomarker Blood Test

Janis C. Kelly

July 10, 2012 — A blood test measuring 12 biomarkers for rheumatoid arthritis (RA), designed to complement standard clinical assessment, accurately discriminated both American College of Rheumatology criteria (ACR50) responses and Disease Activity Score 28–C-reactive protein (DAS28-CRP) improvement in patients with RA, according to data from a validation study. However, after reviewing the study, published online June 26 in Arthritis Care & Research, some experts think further validation of the test is necessary.

Lead author Jeffrey R. Curtis, MD, codirector of the University of Alabama at Birmingham Center for Education and Research on Therapeutics, told Medscape Medical News, "This study establishes validity of the multibiomarker disease activity (MBDA) blood test [Vectra DA, Crescendo Bioscience] with regard to DAS28-CRP in both seropositive and seronegative RA patients, and showed that changes in MBDA score at 6 to 12 weeks or even earlier could discriminate ACR50 response."

Dr. Curtis and colleagues emphasize that because the MBDA score reflects the activity of underlying biological pathways and does not include physical examination, it should be viewed as complementary to, not a replacement for, clinical assessment.

The 12 biomarkers used in the MBDA test were selected from a list of 396 candidates. The test algorithm combines the levels of interleukin 6, tumor necrosis factor receptor superfamily member 1A, vascular cell adhesion molecule 1, epidermal growth factor, vascular endothelial growth factor A, human cartilage glycoprotein 39, matrix metalloproteinases 1 and 3, CRP, serum amyloid A, leptin, and resistin to generate a MBDA score between 1 and 100. The researchers tested the MBDA score for criterion validity (the ability to measure disease activity), discriminant validity (sensitivity to changes in disease activity), face validity (credibility and relevance), content validity (comprehensiveness in measuring components of health status), and construct validity (relationship to outcomes such as damage and disability).

They used association with the DAS28-CRP to establish criterion validity and association with changes in DAS28-CRP and with clinical responses to establish discriminant validity.

The investigators selected patients (n = 512) and samples from 3 cohorts: the Index for Rheumatoid Arthritis Measurement (InFoRM) study, the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) Registry, and the Leiden Early Arthritis cohort.

They found that the MBDA score was associated with clinical disease activity in both seropositive and seronegative patients. MBDA thresholds were 29 for low/moderate disease activity and 44 for moderate/high disease activity. Furthermore, their analyses showed that changes in the MBDA score could differentiate clinical responders from nonresponders.

The authors conclude, "These results demonstrate a significant association between the MBDA score and the DAS28-CRP in heterogeneous groups of RA patients with diversity in autoantibody status, disease activity, and RA therapy receiving care in multiple clinical centers. The MBDA score was able to consistently distinguish patients in different categories of clinical disease activity. Our results provide evidence of criterion validity for the MBDA test by demonstrating significant association with D28-CRP and other validated disease activity measures."

Further Validation Needed

Some experts, however, are more cautious. After reviewing the study for Medscape Medical News, Karel Pavelka, MD, director of the Institute of Rheumatology at Charles University, Prague, Czech Republic, said "The whole concept [of the multibiomarker disease activity test] is very interesting. The study was very well performed. However, MBDA needs further validation." Dr. Pavelka's current work involves maximizing outcomes in patients with RA who have inadequate responses to disease-modifying antirheumatic drugs.

Dr. Curtis said that additional validation studies are ongoing, including tests of whether using the MBDA test as an adjunct to clinical assessment improves patient outcomes. He suggested that potential applications might include ability to predict flare, to know when to repeat intermittent drugs such as rituximab, to predict future radiographic joint damage to decide whether to change or add new treatments, to assess long-term longitudinal response, to make early prediction of longer response, or as a proxy for subclinical synovitis.

Crescendo Bioscience ran the InFoRM clinical study, is a contributor to the BRASS study, and carried out the biomarker analysis in this study. Dr. Curtis has served as a consultant for Crescendo Bioscience and receives research support from Amgen, UCB, CORRONA, Genentech, Centocor, Pfizer, and Crescendo Bioscience. Dr. Pavelka has disclosed no relevant financial relationships.

Arthritis Care Res. Published online June 26, 2012