title: Epitope spreading of the anti-citrullinated protein antibody response occurs before disease onset and is associated with the disease course of early arthritis.
abstract: BACKGROUND
  Anti-citrullinated protein antibodies (ACPA) are the most predictive factor for the development of rheumatoid arthritis (RA).
  
  
  OBJECTIVE
  To investigate whether the recognition of citrullinated epitopes changes during disease onset or progression, by studying the fine specificity of ACPA in serum samples collected throughout the disease course, from before the onset of arthritis to longstanding RA.
  
  
  METHODS
  Antibodies recognising five distinct citrullinated antigens were determined by enzyme-linked immunosorbent assay. Serum samples from 36 individuals who had donated blood before and after disease manifestation were used to investigate the development of citrullinated antigen recognition before disease onset. The association of ACPA reactivities with disease outcome was studied using sera from anti-cyclic citrullinated peptide-2 (CCP2)-positive patients with undifferentiated arthritis (UA) who did or did not progress to RA (UA-RA n=81, or UA-UA n=35). To investigate the ACPA recognition profile in patients with RA over a prolonged period of time, baseline serum samples from 68 patients were compared with samples obtained 7 years later.
  
  
  RESULTS
  The number of recognised citrullinated peptides increased in the period preceding disease onset. At the time of disease manifestation, patients with UA who later developed RA recognised significantly more peptides than UA-UA patients. At later stages of the disease course, the ACPA fine specificity did not change.
  
  
  CONCLUSIONS
  Epitope spreading with an increase in the recognition of citrullinated antigens occurs before the onset of RA. Immunological differences in ACPA fine specificity between UA-UA patients and UA-RA patients are present at baseline and are associated with the future disease course.
authors.affiliation: Department of Rheumatology, Leiden University Medical Centre, PO Box 9600, Leiden RC 2300, The Netherlands. dvanderwoude@lumc.nl
authors.forename: Diane
authors.initials: D
authors.lastname: van der Woude
authors.forename: Solbritt
authors.initials: S
authors.lastname: Rantapää-Dahlqvist
authors.forename: Andreea
authors.initials: A
authors.lastname: Ioan-Facsinay
authors.forename: Carla
authors.initials: C
authors.lastname: Onnekink
authors.forename: Carla M
authors.initials: CM
authors.lastname: Schwarte
authors.forename: Kirsten N
authors.initials: KN
authors.lastname: Verpoort
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: Rene E M
authors.initials: RE
authors.lastname: Toes
authors.forename: Ger J M
authors.initials: GJ
authors.lastname: Pruijn
mesh_terms: D001168:Arthritis / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis*; D018450:Disease Progression; D000939:Epitopes / Q000097:blood*; D005500:Follow-Up Studies; D006801:Humans; D010456:Peptides, Cyclic / Q000276:immunology*; D011379:Prognosis
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide