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Systemic lupus erythematosus
Association of Epstein-Barr virus serological reactivation with transitioning to systemic lupus erythematosus in at-risk individuals
  1. Neelakshi R Jog1,
  2. Kendra A Young2,
  3. Melissa E Munroe1,
  4. Michael T Harmon1,
  5. Joel M Guthridge1,
  6. Jennifer A Kelly1,
  7. Diane L Kamen3,
  8. Gary S Gilkeson3,
  9. Michael H Weisman4,
  10. David R Karp5,
  11. Patrick M Gaffney1,
  12. John B Harley6,7,8,
  13. Daniel J Wallace4,
  14. Jill M Norris2,
  15. Judith A James1,9
  1. 1Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  2. 2Department of Epidemiology, University of Colorado Anschutz Medical Campus, Colorado School of Public Health, Aurora, Colorado, USA
  3. 3Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
  4. 4Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, California, USA
  5. 5Division of Rheumatic Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  6. 6Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  7. 7Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
  8. 8US Department of Veterans Affairs Medical Center, Cincinnati, OH, United States
  9. 9Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
  1. Correspondence to Dr Judith A James, Arthritis & Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; judith-james{at}omrf.org

Abstract

Objective Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with unknown aetiology. Epstein-Barr virus (EBV) is an environmental factor associated with SLE. EBV maintains latency in B cells with frequent reactivation measured by antibodies against viral capsid antigen (VCA) and early antigen (EA). In this study, we determined whether EBV reactivation and single nucleotide polymorphisms (SNPs) in EBV-associated host genes are associated with SLE transition.

Methods SLE patient relatives (n=436) who did not have SLE at baseline were recontacted after 6.3 (±3.9) years and evaluated for interim transitioning to SLE (≥4 cumulative American College of Rheumatology criteria); 56 (13%) transitioned to SLE prior to the follow-up visit. At both visits, detailed demographic, environmental, clinical information and blood samples were obtained. Antibodies against viral antigens were measured by ELISA. SNPs in IL10, CR2, TNFAIP3 and CD40 genes were typed by ImmunoChip. Generalised estimating equations were used to test associations between viral antibody levels and transitioning to SLE.

Results Mean baseline VCA IgG (4.879±1.797 vs 3.866±1.795, p=0.0003) and EA IgG (1.192±1.113 vs 0.7774±0.8484, p=0.0236) levels were higher in transitioned compared with autoantibody negative non-transitioned relatives. Increased VCA IgG and EA IgG were associated with transitioning to SLE (OR 1.28 95% CI 1.07 to 1.53, p=0.007, OR 1.43 95% CI 1.06 to 1.93, p=0.02, respectively). Significant interactions were observed between CD40 variant rs48100485 and VCA IgG levels and IL10 variant rs3024493 and VCA IgA levels in transitioning to SLE.

Conclusion Heightened serologic reactivation of EBV increases the probability of transitioning to SLE in unaffected SLE relatives.

  • systemic lupus erythematosus
  • autoimmunity
  • epstein-barr virus

https://doi.org/10.1136/annrheumdis-2019-215361

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    Footnotes

    • Handling editor Josef S Smolen

    • Contributors All authors contributed to drafting or critically revising the article for intellectual content and approved the final version of the article. JAJ had access to all data and analyses.Study conception and design: NRJ, KAY, MEM, JMG, DLK, MW, DJW, GG, DRK, JBH, JMN and JJ. Acquisition of data. NRJ, MTH, JMG, DLK, MHW, DW, GG, DRK, PMG, JBH and JAJ. Analysis and interpretation of data. NRJ, KAY, MEM, MTH, JMG, DLK, MHW, DW, GG, DRK, JAK, JBH, JMN and JJ.

    • Funding This study was supported by the National Institute of General Medical Sciences (U54GM104938 [JAJ]), the National Institute of Arthritis, Musculoskeletal and Skin Diseases (P30AR053482 [JAJ], P30AR072582 [GG], P60AR062755 [GG and DLK], K24AR068406 [DLK], P50AR055503 [DRK]), the National Institute of Allergy and Infectious Diseases (U19AI082714 [JAJ], U01AI101934 [JAJ], R01AI024717 [JBH], U01AI130830 [JBH]), the National Human Genome Research Institute (U01HG008666 [JBH]) and the Department of Veterans Affairs (JBH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the US Government.

    • Competing interests Authors report funding from the National Institutes of Health. JBH has pending patents on broadly related work.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement All data relevant to the study are included in the article or uploaded as supplementary information.