title: 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.
abstract: 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)-1 alpha, IL-1 beta, IL-1 receptor antagonist, IL-4, IL-10, tumour necrosis factor-alpha 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.
authors.affiliation: Department of Epidemiology Research, Statens Serum Institut, 5 Artillerivej, DK-2300 Copenhagen, Denmark. ktj@ssi.dk
authors.forename: K T
authors.initials: KT
authors.lastname: Jørgensen
authors.forename: A
authors.initials: A
authors.lastname: Wiik
authors.forename: M
authors.initials: M
authors.lastname: Pedersen
authors.forename: C J
authors.initials: CJ
authors.lastname: Hedegaard
authors.forename: B F
authors.initials: BF
authors.lastname: Vestergaard
authors.forename: R E
authors.initials: RE
authors.lastname: Gislefoss
authors.forename: T K
authors.initials: TK
authors.lastname: Kvien
authors.forename: J
authors.initials: J
authors.lastname: Wohlfahrt
authors.forename: K
authors.initials: K
authors.lastname: Bendtzen
authors.forename: M
authors.initials: M
authors.lastname: Frisch
mesh_terms: D000328:Adult; D000914:Antibodies, Viral / Q000097:blood*; D001172:Arthritis, Rheumatoid / Q000097:blood*; D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D001782:Blood Donors; D016022:Case-Control Studies; D016207:Cytokines / Q000097:blood*; D005260:Female; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D008297:Male; D008875:Middle Aged; D016732:Parvovirus B19, Human / Q000276:immunology; D010456:Peptides, Cyclic / Q000276:immunology; D011446:Prospective Studies; D012217:Rheumatoid Factor / Q000097:blood; D013995:Time; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000914:Antibodies, Viral; D001323:Autoantibodies; D015415:Biomarkers; D016207:Cytokines; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D010456:Peptides, Cyclic; D014409:Tumor Necrosis Factor-alpha; C487763:cyclic citrullinated peptide; D012217:Rheumatoid Factor