Features of the synovium of individuals at risk of developing rheumatoid arthritis: implications for understanding preclinical rheumatoid arthritis

Arthritis Rheumatol. 2014 Mar;66(3):513-22. doi: 10.1002/art.38273.


Objective: Findings from previous studies have suggested that subclinical inflammation of the synovium does not coincide with the appearance of rheumatoid arthritis (RA)-specific autoantibodies. This study was undertaken to examine the relationship between the presence of autoantibodies, changes in the synovium, and development of arthritis over time in a markedly larger, prospective study.

Methods: Fifty-five individuals who were IgM rheumatoid factor positive and/or anti-citrullinated protein antibody (ACPA) positive (detected by the anti-cyclic citrullinated peptide antibody test) and who were without any evidence of arthritis upon physical examination were included in the study. ACPAs were subsequently also detected using a multiplex chip-based assay. All individuals underwent magnetic resonance imaging and mini-arthroscopic synovial biopsy sampling of a knee joint at inclusion and were prospectively followed up. Proportional hazards regression analysis was performed to investigate whether changes in the synovium were associated with the onset of arthritis.

Results: Fifteen individuals (27%) developed arthritis after a median followup time of 13 months (interquartile range 6-27 months; range 1-47 months). No overt synovial inflammation was observed, but CD3+ T cell numbers in the biopsy tissue showed a borderline association with subsequent development of clinically manifest arthritis (hazard ratio 2.8, 95% confidence interval [95% CI] 0.9-9.1; P = 0.088). In addition, the presence of CD8+ T cells was associated with ACPA positivity (odds ratio [OR] 16.0, 95% CI 1.7-151.1) and with the total number of ACPAs present (OR 1.4, 95% CI 1.0-1.8).

Conclusion: These findings confirm and extend previous results showing the absence of clearcut synovial inflammation in individuals having systemic autoimmunity associated with RA. However, subtle infiltration by synovial T cells may precede the signs and symptoms of arthritis in preclinical RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Arthritis, Rheumatoid / etiology*
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / pathology
  • Autoantibodies / blood*
  • Autoantibodies / immunology
  • Disease Progression
  • Female
  • Humans
  • Inflammation / immunology
  • Inflammation / pathology
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Peptides, Cyclic / immunology*
  • Prodromal Symptoms
  • Rheumatoid Factor / blood
  • Synovial Membrane / immunology
  • Synovial Membrane / pathology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology


  • Autoantibodies
  • Peptides, Cyclic
  • cyclic citrullinated peptide
  • Rheumatoid Factor