Association of baseline levels of urinary glucosyl-galactosyl-pyridinoline and type II collagen C-telopeptide with progression of joint destruction in patients with early rheumatoid arthritis.
OBJECTIVE
To evaluate whether measurements of urinary glucosyl-galactosyl-pyridinoline (Glc-Gal-PYD) and urinary C-terminal crosslinking telopeptide of type II collagen (CTX-II), 2 new markers of destruction of the synovium and cartilage collagen breakdown, respectively, are associated with the progression of joint damage in patients with early rheumatoid arthritis (RA), and to compare this association with that with serum matrix metalloproteinase 3 (MMP-3), a proteinase expressed by synovial tissue and chondrocytes, and that with serum C-reactive protein (CRP), an index of systemic inflammation.


METHODS
The prospective study cohort comprised 116 patients with early RA who were part of a large, double-blind, randomized study comparing the efficacy of etanercept and methotrexate. The relationship between baseline levels of urinary Glc-Gal-PYD, urinary CTX-II, and serum MMP-3 and the progression of joint destruction, as measured by changes in the modified Sharp score (average findings of 2 independent readers) over 1 year, was investigated.


RESULTS
Levels of urinary Glc-Gal-PYD (+70%), urinary CTX-II (+104%), and serum MMP-3 (+219%) were elevated compared with the levels in 76 healthy controls. The baseline levels of Glc-Gal-PYD (r = 0.30), CTX-II (r = 0.25), and MMP-3 (r = 0.29) correlated with the changes over 1 year in the total Sharp score (joint space narrowing and bone erosion). Patients with baseline levels of Glc-Gal-PYD, CTX-II, and MMP-3 that were higher than the mean + 2 SD in healthy controls had a significantly greater progression of joint damage, with an increase in the total Sharp score over 1 year that was from 3- to 8-fold higher than that in patients with low baseline levels of these markers. Moreover, patients with these higher levels of Glc-Gal-PYD, CTX-II, and MMP-3 had a higher risk of progression of the disease (increase in total Sharp score > or =0.5 units) than did the other patients (relative risks and 95% confidence intervals [95% CI] 3.3 [95% CI 1.5-7.4], 2.5 [95% CI 1.1-5.7], and 2.5 [95% CI 1.1-5.6], respectively). The baseline serum level of CRP was not significantly associated with the progression of joint damage. Adjustment of the levels of Glc-Gal-PYD, CTX-II, and MMP-3 according to radiologic damage at baseline did not alter their association with progression. After adjustment for serum CRP, the relative risk slightly decreased, but remained significant, for Glc-Gal-PYD (2.6 [95% CI 1.1-6.3]). Patients with both increased levels of the molecular markers and radiologic damage at baseline had a higher risk of progression of joint damage than did those with either high molecular marker levels or radiologic damage.


CONCLUSIONS
High baseline levels of Glc-Gal-PYD, CTX-II, and MMP-3 are associated with increased risk of progression of joint destruction over 1 year in early RA. The association between baseline levels of urinary Glc-Gal-PYD and progression of joint erosion was independent of the severity of radiologic damage and inflammation at baseline. Combining the measurements of these molecular markers with radiologic assessment of joint damage may be useful for identifying patients with RA who are at high risk of rapid progression and for whom early aggressive treatment would be beneficial.
Garnero
Patrick
P
Synarc and Inserm Research Unit, Lyon, France. patrick.garnero@synarc.com
Gineyts
Evelyne
E
Christgau
Stephan
S
Finck
Barbara
B
Delmas
Pierre D
PD
D000328:Adult; D000596:Amino Acids / Q000652:urine*; D018501:Antirheumatic Agents / Q000008:administration & dosage; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000473:pathology* / Q000652:urine*; D015415:Biomarkers; D002097:C-Reactive Protein / Q000378:metabolism; D024043:Collagen Type II / Q000652:urine*; D003432:Cross-Linking Reagents / Q000378:metabolism; D000068800:Etanercept; D005260:Female; D005697:Galactosides / Q000652:urine*; D005947:Glucose / Q000378:metabolism*; D006029:Glycosuria; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage; D007596:Joints / Q000378:metabolism / Q000473:pathology*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000097:blood; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D010446:Peptide Fragments / Q000652:urine; D011446:Prospective Studies; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage
D000596:Amino Acids; D018501:Antirheumatic Agents; D015415:Biomarkers; D024043:Collagen Type II; D003432:Cross-Linking Reagents; D005697:Galactosides; D007074:Immunoglobulin G; D010446:Peptide Fragments; D018124:Receptors, Tumor Necrosis Factor; C039434:galactosylpyridinoline; D002097:C-Reactive Protein; D019278:Matrix Metalloproteinase 3; D005947:Glucose; D000068800:Etanercept; D008727:Methotrexate