Rheumatology International

, Volume 33, Issue 5, pp 1149–1157 | Cite as

EBV reactivation serological profile in primary Sjögren’s syndrome: an underlying trigger of active articular involvement?

  • Sandra Gofinet PasotoEmail author
  • Renato Romera Natalino
  • Henrique Pires Chakkour
  • Vilma dos Santos Trindade Viana
  • Cleonice Bueno
  • Elaine Pires Leon
  • Margarete Borges Gualhardo Vendramini
  • Mauricio Levy Neto
  • Eloisa Bonfa
Original Article


Antibody to Epstein–Barr virus (EBV) early antigen diffuse (anti-EA-D) is associated with viral replication. However, their possible associations with clinical/therapeutic features in primary Sjögren’s syndrome (pSS) were not established. We evaluated 100 pSS patients (American–European Criteria) and 89 age/gender/ethnicity-matched healthy controls. Disease activity was measured by EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI). Antibodies to EBV (anti-VCA IgG/IgM, anti-EBNA-1 IgG, anti-EA-D IgG) were determined by ELISA. Patients and controls had comparable frequencies and mean levels of anti-VCA IgG (90 vs. 86.5 %, p = 0.501; 2.6 ± 1.1 vs. 2.5 ± 1.1 AU/mL, p = 0.737) and anti-EBNA-1 IgG (92 vs. 94.4 %, p = 0.576; 141.3 ± 69.8 vs. 135.6 ± 67.5 RU/mL, p = 0.464). Anti-VCA IgM was negative in all cases. Noteworthy, higher frequency and increased mean levels of anti-EA-D were observed in patients than controls (36 vs. 4.5 %, p < 0.0001; 38.6 ± 57.4 vs. 7.9 ± 26.3 RU/mL, p < 0.0001). Further analysis of patients with (n = 36) and without (n = 64) anti-EA-D revealed comparable age/gender/ethnicity (p ≥ 0.551), current prednisone dose (4.8 ± 6.9 vs. 5.1 ± 10.4 mg/day, p = 0.319), and current uses of prednisone (52.8 vs. 37.5 %, p = 0.148) and immunosuppressants (44.4 vs. 31.3 %, p = 0.201). ESSDAI values were comparable (p = 0.102), but joint activity was more frequent (25 vs. 9.4 %, p = 0.045) in anti-EA-D positive patients. Anti-EA-D antibodies were not associated with anti-Ro/SSA (p = 1.000), anti-La/SSB (p = 0.652), rheumatoid factor (p = 1.000), anti-α-fodrin (p = 0.390) or antiphospholipid antibodies (p = 0.573), not suggesting cross-reactivity. The higher anti-EA-D frequency associated with joint activity raises the possibility that a subclinical EBV reactivation may trigger or perpetuate the articular involvement in pSS.


Primary Sjögren’s syndrome Epstein–Barr virus EBV early antigen diffuse Anti-EBV early antigen diffuse Human T leukemia virus 1 



This work was supported by Agency for Promotion of Research, Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) # 2010/10013-4, 2010/10017-0 to RRN, 2010/13463-0 to HPC, and Conselho Nacional de Pesquisa (CNPQ) # 301411/2009-3 to EB. We thank the biomedicals Angela Maria Egydio Barreto e Maria Aparecida de Oliveira Bellesa of the Blood Bank (Fundação Pró-Sangue-Hemocentro) for their help in confirmation of positive sera for HTLV and the staff of the Laboratory of the Hospital das Clínicas da Faculdade de Medicina da USP for carrying out the research of anti-VCA, HTLV serology (ELISA), lupus anticoagulant and determination of serum levels of IgG.

Conflict of interest

None of the authors has any conflicts of interest to declare.


  1. 1.
    Tzioufas AG, Voulgarelis M (2007) Update on Sjögren’s syndrome autoimmune epithelitis: from classification to increased neoplasias. Best Pract Res Clin Rheumatol 21:989–1010PubMedCrossRefGoogle Scholar
  2. 2.
    Amarasena R, Bowman S (2007) Sjögren’s syndrome. Clin Med 7:53–56PubMedGoogle Scholar
  3. 3.
    García-Carrasco M, Ramos-Casals M, Rosas J et al (2002) Primary Sjögren syndrome: clinical and immunologic disease patterns in a cohort of 400 patients. Medicine 81:270–280PubMedCrossRefGoogle Scholar
  4. 4.
    Nardi N, Brito-Zerón P, Ramos-Casals M et al (2006) Circulating auto-antibodies against nuclear and non-nuclear antigens in primary Sjögren’s syndrome. Prevalence and clinical significance in 335 patients. Clin Rheumatol 25:341–346PubMedCrossRefGoogle Scholar
  5. 5.
    Routsias JG, Tzioufas AG (2007) Sjögren’s syndrome- study of autoantigens and autoantibodies. Clinic Rev Allerg Immunol 32:238–251CrossRefGoogle Scholar
  6. 6.
    Vitali C, Bombardieri S, Jonsson R et al (2002) Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 61:554–558PubMedCrossRefGoogle Scholar
  7. 7.
    James JA, Harley JB, Scofield RH (2001) Role of viruses in systemic lupus erythematosus and Sjögren syndrome. Curr Opin Rheumatol 13:370–376PubMedCrossRefGoogle Scholar
  8. 8.
    Toussirot E, Roudier J (2008) Epstein–Barr virus in autoimmune diseases. Best Pract Res Clin Rheumatol 22:883–896PubMedCrossRefGoogle Scholar
  9. 9.
    Poole BD, Scofield RH, Harley JB, James JA (2006) Epstein–Barr virus and molecular mimicry in systemic lupus erythematosus. Autoimmunity 39:63–70PubMedCrossRefGoogle Scholar
  10. 10.
    Origgi L, Hu C, Bertetti E et al (1988) Antibodies to Epstein–Barr virus and cytomegalovirus in primary Sjogren’s syndrome. Boll Ist Sieroter Milan 67:265–274PubMedGoogle Scholar
  11. 11.
    Yamaoka K, Miyasaka N, Yamamoto K (1988) Possible involvement of Epstein–Barr virus in polyclonal B cell activation in Sjögren’s syndrome. Arthritis Rheum 31:1014–1021PubMedCrossRefGoogle Scholar
  12. 12.
    Miyasaka N, Yamaoka K, Tateishi M, Nishioka K, Yamamoto K (1989) Possible involvement of Epstein–Barr virus (EBV) in polyclonal B-cell activation in Sjögren’s syndrome. J Autoimmun 2:427–432PubMedCrossRefGoogle Scholar
  13. 13.
    Mariette X, Gozlan J, Clerc D, Bisson M, Morinet F (1991) Detection of Epstein–Barr virus DNA by in situ hybridization and polymerase chain reaction in salivary gland biopsy specimens from patients with Sjögren’s syndrome. Am J Med 90:286–294PubMedGoogle Scholar
  14. 14.
    Perrot S, Calvez V, Escande JP, Dupin N, Marcelin AG (2003) Prevalences of herpesviruses DNA sequences in salivary gland biopsies from primary and secondary Sjögren’s syndrome using degenerated consensus PCR primers. J Clin Virol 28:165–168PubMedCrossRefGoogle Scholar
  15. 15.
    Pflugfelder SC, Crouse C, Pereira I, Atherton S (1990) Amplification of Epstein–Barr virus genomic sequences in blood cells, lacrimal glands, and tears from primary Sjögren’s syndrome patients. Ophthalmology 97:976–984PubMedGoogle Scholar
  16. 16.
    Newkirk MM, Shiroky JB, Johnson N et al (1996) Rheumatic disease patients, prone to Sjögren’s syndrome and/or lymphoma, mount an antibody response to BHRF1, the Epstein-Barr viral homologue of BCL-2. Br J Rheumatol 35:1075–1081PubMedCrossRefGoogle Scholar
  17. 17.
    Yang EV, Webster Marketon JI, Chen M, Lo KW, Kim SJ, Glaser R (2010) Glucocorticoids activate Epstein Barr virus lytic replication through the upregulation of immediate early BZLF1 gene expression. Brain Behav Immun 24:1089–1096PubMedCrossRefGoogle Scholar
  18. 18.
    Feng WH, Cohen JI, Fischer S et al (2004) Reactivation of latent Epstein–Barr virus by methotrexate: a potential contributor to methotrexate-associated lymphomas. J Natl Cancer Inst 96:1691–1702PubMedCrossRefGoogle Scholar
  19. 19.
    Seror R, Ravaud P, Bowman SJ et al (2010) EULAR Sjogren’s syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjogren’s syndrome. Ann Rheum Dis 69:1103–1109PubMedCrossRefGoogle Scholar
  20. 20.
    Mitchell JL, Doyle CM, Land MV, Devine PL (1998) Comparison of commercial ELISA for detection of antibodies to the viral capsid antigen (VCA) of Epstein–Barr virus (EBV). Dis Markers 13:245–249PubMedGoogle Scholar
  21. 21.
    De Paschale M, Cagnin D, Cerulli T et al (2010) Search for anti-EA(D) antibodies in subjects with an “isolated VCA IgG” pattern. Int J Microbiol 2010:1–4Google Scholar
  22. 22.
    Berini CA, Susana Pascuccio M, Bautista CT et al (2008) Comparison of four commercial screening assays for the diagnosis of human T-cell lymphotropic virus types 1 and 2. J Virol Methods 147:322–327PubMedCrossRefGoogle Scholar
  23. 23.
    Esparza RH, Swaak T, Aarden L, Smeenk R (1985) Complement-fixing antibodies to dsDNA detected by the immunofluorescence technique on Crithidia luciliae. A critical appraisal. J Rheumatol 12:1109–1117PubMedGoogle Scholar
  24. 24.
    Mahler M, Stinton LM, Fritzler MJ (2005) Improved serological differentiation between systemic lupus erythematosus and mixed connective tissue disease by use of a SmD3 peptide-based immunoassay. Clin Diagn Lab Immunol 12:107–113PubMedGoogle Scholar
  25. 25.
    Ruiz-Tíscar JL, López-Longo FJ, Sánchez-Ramón S et al (2005) Prevalence of IgG anti-{alpha}-fodrin antibodies in Sjogren’s syndrome. Ann N Y Acad Sci 1050:210–216PubMedCrossRefGoogle Scholar
  26. 26.
    Goeldner I, Skare TL, de Messias Reason IT, Nisihara RM, Silva MB, Utiyama SR (2010) Anti-cyclic citrullinated peptide antibodies and rheumatoid factor in rheumatoid arthritis patients and relatives from Brazil. Rheumatology (Oxford) 49:1590–1593CrossRefGoogle Scholar
  27. 27.
    Bakker AJ, Slomp J, de Vries T et al (2003) Adequate sampling in cryoglobulinaemia: recommended warmly. Clin Chem Lab Med 41:85–89PubMedCrossRefGoogle Scholar
  28. 28.
    Harris EN, Pierangeli S (1991) The anticardiolipin ELISA test. Clin Immunol Newsletter 11:33–44CrossRefGoogle Scholar
  29. 29.
    Miyakis S, Lockshin MD, Atsumi T et al (2006) International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4:295–306PubMedCrossRefGoogle Scholar
  30. 30.
    Haeri S, Baker AM, Boggess KA (2010) Prevalence of Epstein–Barr virus reactivation in pregnancy. Am J Perinatol 27:715–719PubMedCrossRefGoogle Scholar
  31. 31.
    Macsween KF, Crawford DH (2003) Epstein–Barr virus-recent advances. Lancet Infect Dis 3:131–140PubMedCrossRefGoogle Scholar
  32. 32.
    Quinlivan EB, Holley-Guthrie EA, Norris M, Gutsch D, Bachenheimer SL, Kenney SC (1993) Direct BRLF1 binding is required for cooperative BZLF1/BRLF1 activation of the Epstein–Barr virus early promoter, BMRF1. Nucleic Acids Res 21:1999–2007PubMedCrossRefGoogle Scholar
  33. 33.
    National Center for Infectious Diseases, Centers for Disease Control and Prevention (2006) Epstein–Barr virus and infectious mononucleosis. Updated: 05/16/2006. The web page has been accessed in October/2011
  34. 34.
    Glaser R, Strain EC, Tarr KL, Holliday JE, Donnerberg RL, Kiecolt-Glaser JK (1985) Changes in Epstein–Barr virus antibody titers associated with aging. Proc Soc Exp Biol Med 179:352–355PubMedGoogle Scholar
  35. 35.
    Wagner HJ, Hornef M, Teichert HM, Kirchner H (1994) Sex difference in the serostatus of adults to the Epstein–Barr virus. Immunobiology 190:424–429PubMedCrossRefGoogle Scholar
  36. 36.
    Parks CG, Cooper GS, Hudson LL et al (2005) Association of Epstein–Barr virus with systemic lupus erythematosus: effect modification by race, age, and cytotoxic T lymphocyte-associated antigen 4 genotype. Arthritis Rheum 52:1148–1159PubMedCrossRefGoogle Scholar
  37. 37.
    de-Thé G (1976) Epstein–Barr virus behavior in different populations and implications for control of Epstein–Barr virus-associated tumors. Cancer Res 36:692–695PubMedGoogle Scholar
  38. 38.
    McClain MT, Heinlen LD, Dennis GJ, Roebuck J, Harley JB, James JA (2005) Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry. Nat Med 11:85–89PubMedCrossRefGoogle Scholar
  39. 39.
    Zandman-Goddard G, Berkun Y, Barzilai O et al (2009) Exposure to Epstein–Barr virus infection is associated with mild systemic lupus erythematosus disease. Ann N Y Acad Sci 1173:658–663PubMedCrossRefGoogle Scholar
  40. 40.
    Esen BA, Yilmaz G, Uzun S et al (2012) Serologic response to Epstein–Barr virus antigen in patients with systemic lupus erythematosus: a controlled study. Rheumatol Int 32:79–83PubMedCrossRefGoogle Scholar
  41. 41.
    Harley JB, Harley IT, Guthridge JM, James JA (2006) The curiously suspicious: a role for Epstein–Barr virus in lupus. Lupus 15:768–777PubMedCrossRefGoogle Scholar
  42. 42.
    Kuwana Y, Takei M, Yajima M et al (2011) Epstein–Barr virus induces erosive arthritis in humanized mice. PLoS One 6: e26630 (Epub 2011 Oct 19)Google Scholar
  43. 43.
    Terada K, Katamine S, Eguchi K et al (1994) Prevalence of serum and salivary antibodies to HTLV-1 in Sjögren’s syndrome. Lancet 344:1116–1119PubMedCrossRefGoogle Scholar
  44. 44.
    Mariette X, Agbalika F, Zucker-Franklin D et al (2000) Detection of the tax gene of HTLV-I in labial salivary glands from patients with Sjögren’s syndrome and other diseases of the oral cavity. Clin Exp Rheumatol 18:341–347PubMedGoogle Scholar
  45. 45.
    Segurado AA, Malaque CM, Sumita LM, Pannuti CS, Lal RB (1997) Laboratory characterization of human T cell lymphotropic virus types 1 (HTLV-1) and 2 (HTLV-2) infections in blood donors from Sao Paulo, Brazil. Am J Trop Med Hyg 57:142–148PubMedGoogle Scholar
  46. 46.
    Morofuji-Hirata M, Kajiyama W, Nakashima K, Noguchi A, Hayashi J, Kashiwagi S (1993) Prevalence of antibody to human T-cell lymphotropic virus type I in Okinawa, Japan, after an interval of 9 years. Am J Epidemiol 137:43–48PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Sandra Gofinet Pasoto
    • 1
    • 2
    Email author
  • Renato Romera Natalino
    • 1
  • Henrique Pires Chakkour
    • 1
  • Vilma dos Santos Trindade Viana
    • 1
  • Cleonice Bueno
    • 1
  • Elaine Pires Leon
    • 1
  • Margarete Borges Gualhardo Vendramini
    • 1
  • Mauricio Levy Neto
    • 1
  • Eloisa Bonfa
    • 1
  1. 1.Rheumatology DivisionHospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (USP)São PauloBrazil
  2. 2.Disciplina de ReumatologiaFaculdade de Medicina da Universidade de São PauloSão PauloBrazil

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