Use of mass spectrometry to identify protein biomarkers of disease severity in the synovial fluid and serum of patients with rheumatoid arthritis

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Abstract
Objective To identify a panel of candidate protein biomarkers of rheumatoid arthritis (RA) that can predict which patients will develop erosive, disabling disease. Methods A 2-step proteomic approach was used for biomarker discovery and verification. In the first step, 2-dimensional liquid chromatography–coupled tandem mass spectrometry was used to generate protein profiles of synovial fluid (SF) from patients with either erosive RA (n = 5) or nonerosive RA (n = 5). In the second step, the selected candidate markers were verified using quantitative multiple reaction monitoring mass spectrometry in sera of patients with erosive RA (n = 15) or nonerosive RA (n = 15) and of healthy controls (n = 15). Results Through differential profiling of proteins in the <40-kd portion of the SF proteome, we selected 33 prospective candidate biomarkers from a total of 418 identified proteins. Among the proteins that were elevated in the SF of patients with erosive RA were C-reactive protein (CRP) and 6 members of the S100 protein family of calcium-binding proteins. Significantly, levels of CRP, S100A8 (calgranulin A), S100A9 (calgranulin B), and S100A12 (calgranulin C) proteins were also elevated in the serum of patients with erosive disease compared with patients with nonerosive RA or healthy individuals. Conclusion Several potential protein marker candidates have been identified for prognosis of the erosive form of RA. This study demonstrates the facility of using protein mass spectrometry in SF and serum for global discovery and verification of clinically relevant sets of disease biomarkers.