Background/Purpose: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease characterized by autoantibody production and periods of elevated and suppressed disease activity. Various genetic and environmental factors likely contribute to disease pathogenesis. Epstein Barr Virus (EBV) is an environmental factor consistently associated with SLE. EBV maintains latency in B cells and shows frequent reactivation, which can be measured indirectly in terms of antibodies to EBV antigens. In this study we determined whether antibody measures of viral reactivation and single nucleotide polymorphisms (SNPs) in EBV associated genes were associated with transitioning to SLE in at risk individuals.

Methods: Blood relatives (n=436) of SLE patients who did not meet ACR SLE classification criteria at baseline were evaluated an average of 6.3 (± 3.9) years later. At both baseline and follow-up, detailed demographic, environmental, clinical information, and blood samples were obtained. 56 individuals (13%) transitioned to SLE (> 4 cumulative ACR criteria) as verified by protocoled medical record review. Healthy, matched, unrelated individuals (n=122) were recruited at local health fairs. To assess evidence of viral exposure/reactivation, antibody responses against the EBV antigens Viral Capsid Antigen (VCA) and early antigen (EA) and Cytomegalovirus (CMV) were measured by ELISA. 5 SNPs in IL10, 1 in complement receptor 2 (CR2) and 3 in CD40 gene were typed by Immunochip. Generalized estimating equations (GEE), accounting for correlation within families, were used to test associations between the viral antibody variables and the categorical outcome of transitioning to SLE. Associations between SNPs, seroconversion and disease transition were examined in an additive model. Interactions between SNPs and antibody titers were examined.

Results: Higher proportion of individuals who transitioned to SLE were positive for anti EA IgG at baseline compared to healthy controls (37.5% vs 12.7%, p=0.0005). Mean baseline anti VCA and EA IgG levels were significantly different between those family members who transitioned to SLE and those who did not (4.88±1.80 vs 4.18±2.83; p=0.007; 1.19±1.11 vs 0.88±0.76; p=0.008 respectively). Increased levels of VCA IgG and EA IgG were associated with transitioning to SLE when compared to healthy controls (OR 1.05, 95%CI 1.01-1.10; OR 1.18, 95%CI 1.09-1.26 respectively). VCA IgG, EA IgG and CMV IgG positively correlated with number of autoantibody specificities and ACR scores at both baseline and follow-up visits. Significant interaction was observed between SNPs in CD40 and VCA IgG and between SNPs in IL10 and VCA IgA in transitioning to SLE.

Conclusion: Elevated EA IgG and VCA IgG were associated with transitioning to SLE in unaffected SLE relatives, suggesting that viral reactivation may contribute to development or worsening of SLE autoimmune responses. To our knowledge, this is the first prospective study examining the pre-clinical association between serologic measures of EBV reactivation and SLE disease transition.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/role-of-epstein-barr-virus-serologic-reactivation-in-transitioning-to-systemic-lupus-erythematosus-in-at-risk-individuals/