title: Systematic review and meta-analysis of the sero-epidemiological association between Epstein-Barr virus and rheumatoid arthritis.
abstract: BACKGROUND
  Infection with Epstein-Barr virus (EBV) has been suggested to contribute to the pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). We sought to determine whether prior infection with the virus occurs more frequently in patients with RA compared to controls.
  
  
  METHODS
  We performed a systematic review and meta-analyses of studies that reported the prevalence of anti-EBV antibodies in the sera of cases with RA and controls by searching Medline and Embase databases from 1946 to 2014, with no language restriction. Mantel-Haenszel odds ratios for the detection of anti-EBV antibodies were calculated, and meta-analyses conducted. Quality assessments were performed using a modified version of the Newcastle-Ottawa scale.
  
  
  RESULTS
  Twenty-three studies were included. Quality assessment found most studies reported acceptable selection criteria but poor descriptions of how cases and controls were recruited. When all studies were included, there was a statistically significant higher seroprevalence of anti-VCA IgG in patients with RA compared to controls with an odds ratio (OR) of 1.61 (95 % confidence interval (CI) 1.05-2.46, p = 0.03), which is a similar-sized summary OR to that reported for systemic lupus erythematosus (SLE). However, when studies were restricted to those reporting more plausible levels of exposure to EBV in the control groups, no significant association was apparent, OR 1.47 (95 % CI 0.88-2.46, p = 0.14). Using anti-EBNA 1 or anti-EA IgG as markers of previous infection also did not yield significant associations (OR 1.05, 95 % CI 0.68-1.61, p = 0.82; OR 2.2, 95 % CI 0.86-5.65, p = 0.10 respectively).
  
  
  CONCLUSIONS
  Overall, these findings do not demonstrate an association between EBV seroprevalence and RA and therefore do not support the hypothesis that prior infection with EBV predisposes to the development of RA. This contrasts with meta-analyses that indicate EBV infection is associated with multiple sclerosis and SLE.
authors.affiliation: Health Services Research Unit, Division of Applied Health Sciences, University of Aberdeen, Foresterhill, AB25 2ZD, Aberdeen, UK. robert.ball@nhs.net.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ball
authors.affiliation: Research Health Services Research Unit, Division of Applied Health Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK. a.avenell@abdn.ac.uk.
authors.forename: Alison
authors.initials: A
authors.lastname: Avenell
authors.affiliation: School of Medicine and Dentistry, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK. l.aucott@abdn.ac.uk.
authors.forename: Lorna
authors.initials: L
authors.lastname: Aucott
authors.affiliation: Health Services Research Unit, Division of Applied Health Sciences, University of Aberdeen, Foresterhill, AB25 2ZD, Aberdeen, UK. peter.hanlon@nhs.net.
authors.forename: Peter
authors.initials: P
authors.lastname: Hanlon
authors.affiliation: Division of Applied Medicine, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK. m.a.vickers@abdn.ac.uk.|Blood Transfusion Centre, Foresterhill Road, Aberdeen, AB25 2ZW, UK. m.a.vickers@abdn.ac.uk.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Vickers
mesh_terms: D000914:Antibodies, Viral / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000821:virology; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000821:virology; D004854:Herpesvirus 4, Human / Q000276:immunology* / Q000502:physiology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000821:virology; D009103:Multiple Sclerosis / Q000276:immunology / Q000821:virology; D016017:Odds Ratio; D016036:Seroepidemiologic Studies
chemical_list: D000914:Antibodies, Viral; D007074:Immunoglobulin G