Uncoupling of collagen II metabolism in newly diagnosed, untreated rheumatoid arthritis is linked to inflammation and antibodies against cyclic citrullinated peptides.
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.
Christensen
Anne Friesgaard
AF
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
Hørslev-Petersen
Kim
K
Christgau
Stephan
S
Lindegaard
Hanne Merete
HM
Lottenburger
Tine
T
Junker
Kirsten
K
Hetland
Merete Lund
ML
Stengaard-Pedersen
Kristian
K
Jacobsen
Søren
S
Ellingsen
Torkell
T
Andersen
Lis Smedegaard
LS
Hansen
Ib
I
Skjødt
Henrik
H
Pedersen
Jens Kristian
JK
Lauridsen
Ulrik Birk
UB
Svendsen
Anders Jørgen
AJ
Tarp
Ulrik
U
Pødenphant
Jan
J
Heegaard
Niels H H
NH
Vestergaard
Aage
A
Jurik
Anne Grethe
AG
Ostergaard
Mikkel
M
Junker
Peter
P
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
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