title: Uncoupling of collagen II metabolism in newly diagnosed, untreated rheumatoid arthritis is linked to inflammation and antibodies against cyclic citrullinated peptides.
abstract: OBJECTIVE
  To investigate the relationship between markers of collagen II synthesis and degradation with disease activity measures, autoantibodies, and radiographic outcomes in a 4-year protocol on patients with early rheumatoid arthritis (RA) who are naïve to disease-modifying antirheumatic drugs.
  
  
  METHODS
  One hundred sixty patients with newly diagnosed, untreated RA entered the Cyclosporine, Methotrexate, Steroid in RA (CIMESTRA) trial. Disease activity and radiograph status were measured at baseline and 4 years. The N-terminal propeptide of collagen IIA (PIIANP) and the cross-linked C-telopeptide of collagen II (CTX-II) were quantified at baseline by ELISA. PIIANP was also assayed at 2 and 4 years. Anticyclic citrullinated peptide (anti-CCP) was recorded at baseline. An uncoupling index for cartilage collagen metabolism was calculated from PIIANP and CTX-II measurements.
  
  
  RESULTS
  PIIANP was low at diagnosis and 4 years on (p < 0.001), irrespective of treatment and disease activity. PIIANP was lowest in anti-CCP positive patients (p = 0.006), and there was a negative correlation between PIIANP and anti-CCP titers (rho = -0.25, p 0.002). CTX-II was increased (p < 0.001) and correlated positively with disease activity and radiographic progression, but not with anti-CCP (p = 0.93). The uncoupling index was not superior to CTX-II in predicting radiographic changes.
  
  
  CONCLUSIONS
  These results suggest that cartilage collagen formation and degradation are unbalanced when RA is diagnosed. The different associations of collagen II anabolism (PIIANP) and collagen II degradation (CTX-II) with anti-CCP, synovitis, and radiographic progression indicate that at this early stage of RA, cartilage collagen degradation is mainly driven by synovitis, while anti-CCP antibodies may interfere with cartilage regeneration by inhibiting collagen IIA formation. Trial registration j.nr NCT00209859.
authors.affiliation: Department of Rheumatology at Odense University Hospital and Institute of Clinical Research, Medical Biotechnology Centre, University of Southern Denmark, Odense, Denmark. a.friesgaard@gmail.com
authors.forename: Anne Friesgaard
authors.initials: AF
authors.lastname: Christensen
authors.forename: Kim
authors.initials: K
authors.lastname: Hørslev-Petersen
authors.forename: Stephan
authors.initials: S
authors.lastname: Christgau
authors.forename: Hanne Merete
authors.initials: HM
authors.lastname: Lindegaard
authors.forename: Tine
authors.initials: T
authors.lastname: Lottenburger
authors.forename: Kirsten
authors.initials: K
authors.lastname: Junker
authors.forename: Merete Lund
authors.initials: ML
authors.lastname: Hetland
authors.forename: Kristian
authors.initials: K
authors.lastname: Stengaard-Pedersen
authors.forename: Søren
authors.initials: S
authors.lastname: Jacobsen
authors.forename: Torkell
authors.initials: T
authors.lastname: Ellingsen
authors.forename: Lis Smedegaard
authors.initials: LS
authors.lastname: Andersen
authors.forename: Ib
authors.initials: I
authors.lastname: Hansen
authors.forename: Henrik
authors.initials: H
authors.lastname: Skjødt
authors.forename: Jens Kristian
authors.initials: JK
authors.lastname: Pedersen
authors.forename: Ulrik Birk
authors.initials: UB
authors.lastname: Lauridsen
authors.forename: Anders Jørgen
authors.initials: AJ
authors.lastname: Svendsen
authors.forename: Ulrik
authors.initials: U
authors.lastname: Tarp
authors.forename: Jan
authors.initials: J
authors.lastname: Pødenphant
authors.forename: Niels H H
authors.initials: NH
authors.lastname: Heegaard
authors.forename: Aage
authors.initials: A
authors.lastname: Vestergaard
authors.forename: Anne Grethe
authors.initials: AG
authors.lastname: Jurik
authors.forename: Mikkel
authors.initials: M
authors.lastname: Ostergaard
authors.forename: Peter
authors.initials: P
authors.lastname: Junker
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D002358:Cartilage, Articular / Q000378:metabolism; D024043:Collagen Type II / Q000096:biosynthesis* / Q000097:blood / Q000276:immunology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000097:blood / Q000276:immunology; D010456:Peptides, Cyclic / Q000097:blood / Q000276:immunology*; D011347:Procollagen / Q000096:biosynthesis* / Q000097:blood / Q000276:immunology; D012720:Severity of Illness Index; D013585:Synovitis / Q000378:metabolism; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D024043:Collagen Type II; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D011347:Procollagen; C543437:collagen II C-telopeptide; C487763:cyclic citrullinated peptide; C109195:procollagen type IIA amino-terminal peptide