title: Multiplex analyses of antibodies against citrullinated peptides in individuals prior to development of rheumatoid arthritis.
abstract: OBJECTIVE
  The presence of antibodies against cyclic citrullinated peptides has been demonstrated to precede the onset of symptoms of rheumatoid arthritis (RA) by several years. The aim of this study was to analyze antibodies against 10 citrullinated autoantigen-derived peptides for reactivity before the onset of RA symptoms.
  
  
  METHODS
  A case-control study was conducted within the Medical Biobank of Northern Sweden. The study was performed in 409 individuals, 386 of whom donated 717 blood samples before the onset of symptoms of RA (pre-patients). The median period of time predating the onset of RA was 7.4 years. A total of 1,305 population-based control subjects were also studied. Antibodies to 10 citrullinated peptides, fibrinogen α573 (Fibα573), Fibα591, Fibβ36-52, Fibβ72, Fibβ74, α-enolase (citrullinated α-enolase peptide 1 [CEP-1]), triple-helical type II collagen peptide C1 (citC1III), filaggrin, vimentin 2-17 (Vim2-17), and Vim60-75, were analyzed using a microarray system.
  
  
  RESULTS
  The fluorescence intensity of antibodies against Fibβ36-52, Fibβ74, CEP-1, citC1III, and filaggrin was significantly increased in pre-patients compared with controls (P<0.001). The levels of the earliest-detectable antibodies (Fibα591 and Vim60-75) fluctuated over time, with only a slight increase after the onset of disease. The frequency of antibodies against Fibβ36-52, CEP-1, and filaggrin increased gradually, reaching the highest levels before symptom onset. The frequency of a cluster of antibodies, citC1III, Fibα573, and Fibβ74, increased only slightly before the onset of symptoms but increased prominently after disease onset. The odds ratio for the development of RA in individuals expressing both CEP-1 and Fibβ36-52 antibodies (using data from samples obtained <3.35 years predating symptom onset) was 40.4 (95% confidence interval 19.8-82.3) compared with having either antibody alone.
  
  
  CONCLUSIONS
  Development of an immune response toward citrullinated peptides is initially restricted but expands with time to induce a more specific response, with levels, particularly those of antibodies against CEP-1, Fibβ36-52, and filaggrin, increasing during the predating time period closer to the onset of symptoms.
authors: Umeå University, Umeå, Sweden.
authors: Mikael
authors: M
authors: Brink
authors: Monika
authors: M
authors: Hansson
authors: Linda
authors: L
authors: Mathsson
authors: Per-Johan
authors: PJ
authors: Jakobsson
authors: Rikard
authors: R
authors: Holmdahl
authors: Göran
authors: G
authors: Hallmans
authors: Hans
authors: H
authors: Stenlund
authors: Johan
authors: J
authors: Rönnelid
authors: Lars
authors: L
authors: Klareskog
authors: Solbritt
authors: S
authors: Rantapää-Dahlqvist
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000276:immunology*; D001323:Autoantibodies / Q000378:metabolism*; D018070:Biological Specimen Banks; D016022:Case-Control Studies; D002956:Citrulline; D024043:Collagen Type II / Q000276:immunology; D005260:Female; D005340:Fibrinogen / Q000276:immunology; D000091344:Filaggrin Proteins; D006801:Humans; D007381:Intermediate Filament Proteins / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*; D010751:Phosphopyruvate Hydratase / Q000276:immunology; D062706:Prodromal Symptoms; D040081:Protein Array Analysis; D011499:Protein Processing, Post-Translational; D013997:Time Factors; D014746:Vimentin / Q000276:immunology
chemical_list: D001323:Autoantibodies; D024043:Collagen Type II; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D010456:Peptides, Cyclic; D014746:Vimentin; C487763:cyclic citrullinated peptide; D002956:Citrulline; D005340:Fibrinogen; D010751:Phosphopyruvate Hydratase