Serum biomarker panel for the diagnosis of rheumatoid arthritis

Arthritis Res Ther. 2021 Jan 18;23(1):31. doi: 10.1186/s13075-020-02405-7.


Background: Rheumatoid arthritis (RA) is an autoimmune disease of inflammatory joint damage, wherein C-reactive protein and autoantibodies including rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) are rapidly elevated. These serological factors are diagnostic markers of RA; however, their sensitivity and specificity for prediction warrant improvement for an early and accurate diagnosis.

Methods: We aimed to identify alternative biomarkers by serum protein profiling using LC-MS/MS. We performed statistical and functional analysis of differentially expressed proteins to identify biomarker candidates complementing conventional serological tests.

Results: Seven biomarker candidates were verified through multiple reaction monitoring-based quantitative analysis, of which angiotensinogen (AGT), serum amyloid A-4 protein (SAA4), vitamin D-binding protein (VDBP), and retinol-binding protein-4 (RBP4) had an area under the curve over 0.8, thus distinguishing RA patients, including seronegative (RF- and anti-CCP-negative) RA patients, from healthy controls.

Conclusions: Therefore, among seronegative RA patients, a four-biomarker panel (AGT, SAA4, VDBP, and RBP4) can prevent false negatives and help diagnose RA accurately.

Keywords: Angiotensinogen; Biomarkers; Retinol-binding protein-4; Rheumatoid arthritis; Serum amyloid A-4 protein; Vitamin D-binding protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthritis, Rheumatoid* / diagnosis
  • Autoantibodies
  • Biomarkers
  • Chromatography, Liquid
  • Humans
  • Peptides, Cyclic*
  • Retinol-Binding Proteins, Plasma
  • Rheumatoid Factor
  • Sensitivity and Specificity
  • Tandem Mass Spectrometry


  • Autoantibodies
  • Biomarkers
  • Peptides, Cyclic
  • RBP4 protein, human
  • Retinol-Binding Proteins, Plasma
  • Rheumatoid Factor