Systematic review and meta-analysis of the sero-epidemiological association between Epstein-Barr virus and rheumatoid arthritis

Robert J Ball, Alison Avenell, Lorna Aucott, Peter Hanlon, Mark A Vickers

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Abstract

Introduction
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.
Original languageEnglish
Pages (from-to)274
JournalArthritis Research & Therapy
Volume17
DOIs
Publication statusPublished - 29 Sep 2015

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Human Herpesvirus 4
Meta-Analysis
Rheumatoid Arthritis
Odds Ratio
Confidence Intervals
Epstein-Barr Virus Infections
Seroepidemiologic Studies
Systemic Lupus Erythematosus
Antibodies
Virus Diseases
Patient Selection
Autoimmune Diseases
Multiple Sclerosis
Language
Cross-Sectional Studies
Databases
Control Groups
Infection
Serum

Cite this

@article{41537fd9aeda445e961996664cfff10c,
title = "Systematic review and meta-analysis of the sero-epidemiological association between Epstein-Barr virus and rheumatoid arthritis",
abstract = "IntroductionInfection 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.MethodsWe 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.ResultsTwenty-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).ConclusionsOverall, 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.",
author = "Ball, {Robert J} and Alison Avenell and Lorna Aucott and Peter Hanlon and Vickers, {Mark A}",
note = "Acknowledgements The authors would like to thank Cynthia Fraser for helping run the literature search, Dr Neil Basu for providing advice on search terms for rheumatoid arthritis and to Xueli Jia, Katie Bannister and Kubra Boza for their help with foreign language papers. The authors would also like to thank the University of Aberdeen librarians at the Foresterhill medical library for their help in locating articles used for this systematic review and meta-analysis.",
year = "2015",
month = "9",
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language = "English",
volume = "17",
pages = "274",
journal = "Arthritis Research & Therapy",
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T1 - Systematic review and meta-analysis of the sero-epidemiological association between Epstein-Barr virus and rheumatoid arthritis

AU - Ball, Robert J

AU - Avenell, Alison

AU - Aucott, Lorna

AU - Hanlon, Peter

AU - Vickers, Mark A

N1 - Acknowledgements The authors would like to thank Cynthia Fraser for helping run the literature search, Dr Neil Basu for providing advice on search terms for rheumatoid arthritis and to Xueli Jia, Katie Bannister and Kubra Boza for their help with foreign language papers. The authors would also like to thank the University of Aberdeen librarians at the Foresterhill medical library for their help in locating articles used for this systematic review and meta-analysis.

PY - 2015/9/29

Y1 - 2015/9/29

N2 - IntroductionInfection 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.MethodsWe 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.ResultsTwenty-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).ConclusionsOverall, 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.

AB - IntroductionInfection 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.MethodsWe 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.ResultsTwenty-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).ConclusionsOverall, 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.

U2 - 10.1186/s13075-015-0755-6

DO - 10.1186/s13075-015-0755-6

M3 - Article

VL - 17

SP - 274

JO - Arthritis Research & Therapy

JF - Arthritis Research & Therapy

SN - 1478-6354

ER -