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

被引：147

作者：

Centola, Michael ^{[1
]}

Cavet, Guy ^{[2
]}

Shen, Yijing ^{[3
]}

Ramanujan, Saroja ^{[2
]}

Knowlton, Nicholas ^{[4
]}

Swan, Kathryn A. ^{[2
]}

Turner, Mary ^{[1
]}

Sutton, Chris ^{[1
]}

Smith, Dustin R. ^{[1
]}

Haney, Douglas J. ^{[2
]}

Chernoff, David ^{[5
]}

Hesterberg, Lyndal K. ^{[6
]}

Carulli, John P. ^{[7
]}

Taylor, Peter C. ^{[8
]}

Shadick, Nancy A. ^{[9
]}

Weinblatt, Michael E. ^{[9
]}

Curtis, Jeffrey R. ^{[10
]}

机构：

[1] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA

[2] Crescendo Biosci Inc, Dept Informat, San Francisco, CA USA

[3] Crescendo Biosci Inc, Dept Biostat & Bioinformat, San Francisco, CA USA

[4] Oklahoma Med Res Fdn, Biomarker & Prote Core Facil, Oklahoma City, OK 73104 USA

[5] Crescendo Biosci Inc, Dept Med, San Francisco, CA USA

[6] Crescendo Biosci Inc, Dept Dev, San Francisco, CA USA

[7] Biogen Idec Inc, Genet & Genom Grp, Cambridge, MA USA

[8] Univ Oxford, Kennedy Inst Rheumatol, Oxford, England

[9] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA

[10] Univ Alabama Birmingham, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA

来源：

PLOS ONE | 2013年 / 8卷 / 04期

关键词：

C-REACTIVE PROTEIN; ERYTHROCYTE SEDIMENTATION-RATE; ACTIVITY SCORE; THERAPY; RECOMMENDATIONS; METHOTREXATE; FIBROMYALGIA; CALPROTECTIN; ASSOCIATION; INFLIXIMAB;

D O I：

10.1371/journal.pone.0060635

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Background: Disease 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. Objectives: To develop a multi-biomarker disease activity (MBDA) test for rheumatoid arthritis. Methods: Candidate 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. Results: 130 candidate biomarkers were tested in feasibility studies and 25 were selected for algorithm training. Multibiomarker 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. Conclusion: We 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.

引用

页数：13

共 48 条

[1]

THE AMERICAN-RHEUMATISM-ASSOCIATION 1987 REVISED CRITERIA FOR THE CLASSIFICATION OF RHEUMATOID-ARTHRITIS [J].