Synovial Epstein-Barr virus infection increases the risk of rheumatoid arthritis in individuals with the shared HLA-DR4 epitope

Arthritis Rheum. 1999 Jul;42(7):1485-96. doi: 10.1002/1529-0131(199907)42:7<1485::AID-ANR24>3.0.CO;2-7.


Objective: To investigate the presence of the Epstein-Barr virus (EBV) in rheumatoid arthritis (RA) synovium and its correlation with the HLA genotype in an attempt to elucidate the role of EBV in the pathogenesis of RA.

Methods: EBV DNA/RNA was investigated by polymerase chain reaction (PCR) analysis of synovial tissue from 84 patients with RA and from 81 patients with non-RA arthritis (controls) and was correlated with the patients' HLA genotype.

Results: EBV DNA and EBV-encoded RNA 1 transcripts were significantly more frequently present in synovial tissue from the RA patients (29 of 84) than in that from the non-RA patient controls (8 of 81). EBV DNA-positive individuals had a 5.47 times higher risk of presenting with RA than did EBV DNA-negative individuals. In HLA-DRB1*0401,0404,0405,0408-positive or shared epitope-positive patients, the risk was further increased (odds ratio for EBV and HLA-DR4 approximately 41, for EBV and the shared epitope approximately 15) compared with those who lacked both EBV DNA and RA-linked HLA genotypes.

Conclusion: EBV seems to function as an environmental risk factor for RA, particularly in patients with the RA-linked HLA-DRB1 alleles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / virology*
  • Burkitt Lymphoma / epidemiology
  • DNA, Viral / analysis
  • Epitopes / analysis
  • Female
  • Genotype
  • HLA-DR Antigens / genetics
  • HLA-DR4 Antigen / immunology
  • HLA-DRB1 Chains
  • Herpesvirus 4, Human / genetics
  • Herpesvirus 4, Human / isolation & purification*
  • Humans
  • Male
  • Middle Aged
  • Polymerase Chain Reaction
  • RNA, Viral / analysis
  • Risk Factors
  • Sensitivity and Specificity
  • Synovial Membrane / virology


  • DNA, Viral
  • Epitopes
  • HLA-DR Antigens
  • HLA-DR4 Antigen
  • HLA-DRB1 Chains
  • HLA-DRB1*04:01 antigen
  • RNA, Viral