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Cytokines, autoantibodies and viral antibodies in premorbid and postdiagnostic sera from patients with rheumatoid arthritis: case–control study nested in a cohort of Norwegian blood donors
  1. K T Jørgensen1,
  2. A Wiik2,
  3. M Pedersen1,
  4. C J Hedegaard4,
  5. B F Vestergaard3,
  6. R E Gislefoss5,
  7. T K Kvien6,7,
  8. J Wohlfahrt1,
  9. K Bendtzen4,
  10. M Frisch1
  1. 1
    Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
  2. 2
    Department of Autoimmunity, Statens Serum Institut, Copenhagen, Denmark
  3. 3
    Department of Virology, Statens Serum Institut, Copenhagen, Denmark
  4. 4
    Institute for Inflammation Research, Rigshospitalet, Copenhagen, Denmark
  5. 5
    The Norwegian Cancer Registry, Oslo, Norway
  6. 6
    Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway
  7. 7
    Faculty of Medicine, University of Oslo, Oslo, Norway
  1. Kristian T Jørgensen, Department of Epidemiology Research, Statens Serum Institut, 5 Artillerivej, DK-2300 Copenhagen S, Denmark; ktj{at}


Objective: To assess the timing of changes in cytokines, cytokine-related markers, autoantibodies and viral antibodies in the pathogenesis of rheumatoid arthritis (RA).

Methods: Case–control study nested in a prospective cohort of 31 330 blood donors in Oslo, Norway. Forty-nine donors developed RA up to 23 years after their most recent blood donation. Stored sera from these donors (case sera) and a sex- and age-matched sample of 245 healthy donors (control sera), and postdiagnostic sera from 33 of the 49 RA cases, were analysed for a panel of cytokines and cytokine-related markers, autoantibodies and antibodies against Epstein–Barr virus and parvovirus B19.

Results: Cytokines and cytokine-related markers were generally negative in case sera from >5 years before the diagnosis of RA. In the 5-year interval immediately before the diagnosis of RA, more case than control sera were positive (odds ratios >2) for interleukin (IL)-1α, IL-1β, IL-1 receptor antagonist, IL-4, IL-10, tumour necrosis factor-α and soluble tumour necrosis factor receptor I. In postdiagnostic sera, however, 11 of 16 examined cytokines and cytokine-related markers were statistically significantly elevated compared with control sera. Seropositivity for IgG antibodies against cyclic citrullinated peptides and for IgM and IgA rheumatoid factors were seen in case sera from up to 18 years before the diagnosis of RA. IgG antibodies against Epstein–Barr virus and parvovirus B19 did not differ significantly between case and control sera.

Conclusions: Cytokines and cytokine-related markers appear to be upregulated rather late in RA pathogenesis. In contrast, IgM rheumatoid factor and IgG anti-cyclic citrullinated peptide autoantibodies may precede the diagnosis of RA by up to two decades.

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  • Funding: The study has been supported by unrestricted research grants from The Danish Rheumatism Association, The Danish Medical Research Council, Health Insurance Denmark Science Foundation, Aase and Ejnar Danielsen’s Foundation, The Gangsted Foundation, Dagmar Marshall’s Foundation, Krista and Viggo Petersen’s Foundation, Frederik Leth Christiansen’s Foundation, Lily Benthine Lund’s Foundation, Kurt Bønnelycke and Mrs Grethe Bønnelycke’s Foundation, Hede Nielsen’s Foundation, Poul Martin Christiansen’s Foundation, The Linex Foundation, Apotekerfonden and the Frimodt-Heineke Foundation, Director Ib Henriksen’s Foundation, Henny and Helge Holgersens Memorial Fund, Torben and Alice Frimodt’s Foundation, Max Fodgaard’s Foundation, Niels Hansen and Wife’s Foundation and Frode V. Nyegaard and Wife’s Foundation.

  • Competing interests: None.

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