title: Autoantibodies binding to citrullinated telopeptide of type II collagen and to cyclic citrullinated peptides predict synergistically the development of seropositive rheumatoid arthritis.
abstract: OBJECTIVE
  To find out whether autoantibodies to citrullinated telopeptides of type I and II collagens and to cyclic citrullinated peptides (CCPs) predict the development of rheumatoid arthritis (RA).
  
  
  METHODS
  A case-control study (matched for sex, age and municipality) was nested within a Finnish cohort of 19072 adults who had neither arthritis nor a history of it at the baseline examination during 1973-7. 124 subjects developed RA by late 1989, and of these, 89 were positive for rheumatoid factor (RF). Preillness serum specimens were analysed for autoantibodies against arginine (A)- or citrulline (C)-containing synthetic telopeptides using a chemiluminescence method and for anti-CCPs Mark2 with an enzyme-linked immunosorbent assay method.
  
  
  RESULTS
  The mean levels of autoantibodies to citrulline-containing telopeptides and the C/A ratios of type I and II collagens and to CCP were higher in subjects who later developed RF-positive RA. In the highest tertiles of C/A (I), C/A (II) ratios and anti-CCPs levels, the relative risk of RF-positive RA was significantly increased. In the multifactorial model, only anti-CCPs retained its statistical significance. However, the interaction term of C/A (II) ratio and anti-CCPs proved to be statistically significant (p = 0.02). The subjects ranked into the highest tertiles of both C/A (II) ratio and anti-CCPs had an odds ratio of 20.06 (95% confidence interval, 4.37 to 92.06) of developing RF-positive RA compared with those in the lowest tertiles of these antibodies. None of the autoantibodies predicted RF-negative RA.
  
  
  CONCLUSIONS
  Autoantibodies to citrullinated telopeptides of type I and II collagen and to CCPs exert a synergistic effect on the risk of seropositive RA.
authors.affiliation: Department of Clinical Chemistry, University of Oulu and University of Turku, Oulu and Turku, Finland.
authors.forename: Marja-Kaisa
authors.initials: MK
authors.lastname: Koivula
authors.forename: Markku
authors.initials: M
authors.lastname: Heliövaara
authors.forename: Jarmo
authors.initials: J
authors.lastname: Ramberg
authors.forename: Paul
authors.initials: P
authors.lastname: Knekt
authors.forename: Harri
authors.initials: H
authors.lastname: Rissanen
authors.forename: Timo
authors.initials: T
authors.lastname: Palosuo
authors.forename: Juha
authors.initials: J
authors.lastname: Risteli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D024042:Collagen Type I / Q000276:immunology; D024043:Collagen Type II / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000276:immunology; D010456:Peptides, Cyclic / Q000276:immunology*; D011379:Prognosis
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D015415:Biomarkers; D024042:Collagen Type I; D024043:Collagen Type II; D010455:Peptides; D010456:Peptides, Cyclic; C052929:collagen type I trimeric cross-linked peptide; C487763:cyclic citrullinated peptide