Development of a Multi-Biomarker Disease Activity Test for Rheumatoid Arthritis

Abstract

BackgroundDisease activity measurement is a key component of rheumatoid arthritis (RA) management. Biomarkers that capture the complex and heterogeneous biology of RA have the potential to complement clinical disease activity assessment.ObjectivesTo develop a multi-biomarker disease activity (MBDA) test for rheumatoid arthritis.MethodsCandidate serum protein biomarkers were selected from extensive literature screens, bioinformatics databases, mRNA expression and protein microarray data. Quantitative assays were identified and optimized for measuring candidate biomarkers in RA patient sera. Biomarkers with qualifying assays were prioritized in a series of studies based on their correlations to RA clinical disease activity (e.g. the Disease Activity Score 28-C-Reactive Protein [DAS28-CRP], a validated metric commonly used in clinical trials) and their contributions to multivariate models. Prioritized biomarkers were used to train an algorithm to measure disease activity, assessed by correlation to DAS and area under the receiver operating characteristic curve for classification of low vs. moderate/high disease activity. The effect of comorbidities on the MBDA score was evaluated using linear models with adjustment for multiple hypothesis testing.Results130 candidate biomarkers were tested in feasibility studies and 25 were selected for algorithm training. Multi-biomarker statistical models outperformed individual biomarkers at estimating disease activity. Biomarker-based scores were significantly correlated with DAS28-CRP and could discriminate patients with low vs. moderate/high clinical disease activity. Such scores were also able to track changes in DAS28-CRP and were significantly associated with both joint inflammation measured by ultrasound and damage progression measured by radiography. The final MBDA algorithm uses 12 biomarkers to generate an MBDA score between 1 and 100. No significant effects on the MBDA score were found for common comorbidities.ConclusionWe followed a stepwise approach to develop a quantitative serum-based measure of RA disease activity, based on 12-biomarkers, which was consistently associated with clinical disease activity levels.

A Multibiomarker Disease Activity Score for Rheumatoid Arthritis Predicts Radiographic Joint Damage in the BeSt Study

“…Serum samples were stored at -80°C. Twelve biomarkers were measured: epidermal growth factor (EGF), vascular endothelial growth factor A (VEGF-A), leptin, interleukin 6 (IL-6), serum amyloid A, CRP, vascular cell adhesion molecule 1 (VCAM-1), matrix metalloproteinase 1 (MMP-1), matrix metalloproteinase 3 (MMP-3), tumor necrosis factor receptor superfamily member 1A (TNF-RI), human cartilage glycoprotein 39 (YKL-40), and resistin 4 . The biomarkers were measured with immunoassays using 3 custom multiplex panels on the Meso Scale Discovery Sector Imager 6000: panels A (for EGF, IL-6, leptin, and VEGF-A), B (for CRP, SSA, and VCAM-1), and C (for MMP-1, MMP-3, resistin, TNF-RI, and YKL-40).…”

“…The biomarkers were measured with immunoassays using 3 custom multiplex panels on the Meso Scale Discovery Sector Imager 6000: panels A (for EGF, IL-6, leptin, and VEGF-A), B (for CRP, SSA, and VCAM-1), and C (for MMP-1, MMP-3, resistin, TNF-RI, and YKL-40). Concentrations were calculated using standard curves with 4 parameter logistic regression curve fits 4 .…”

“…The Journal of on May 10, 2018 -Published by www.jrheum.org Downloaded from score was developed 4 , derived from 12 different serum proteins. This MBDA score shows a high correlation with conventional 28-joint Disease Activity Score (DAS28) 5 .…”

Reliable and cost-effective serodiagnosis of rheumatoid arthritis

“…Multiple biomarkers of disease activity in RA have been evaluated in studies originating from both Africa [6][7][8][9][10][11] and elsewhere [12][13][14][15][16]. In addition, commercial ventures have also focused on developing multi-array test profiles that may improve cost-effective management of RA [15,17].…”

“…In addition, commercial ventures have also focused on developing multi-array test profiles that may improve cost-effective management of RA [15,17]. However, estimating the cost of RA disease burden in the South African and continental African setting in general is lacking, with the majority of articles relating to this topic having been published prior to 1990 [18].…”