Markers for type II collagen breakdown predict the effect of disease-modifying treatment on long-term radiographic progression in patients with rheumatoid arthritis

Arthritis Rheum. 2004 May;50(5):1390-9. doi: 10.1002/art.20222.


Objective: To investigate in a randomized clinical trial setting with an aggressive combination-therapy arm and a mild-monotherapy arm, whether therapy-induced changes in urinary C-terminal crosslinking telopeptide of type I collagen (CTX-I) and type II collagen (CTX-II) predict 5-year radiographic progression in patients with rheumatoid arthritis (RA).

Methods: Patients had participated in the COBRA (Combinatietherapie Bij Reumatoïde Artritis) trial comparing aggressive step-down combination therapy (the COBRA regimen, including temporary high-dose prednisolone, temporary low-dose methotrexate, and sulfasalazine [SSZ]) and mild monotherapy (SSZ). Urinary CTX-I and CTX-II levels were measured at baseline and 3, 6, 9, and 12 months after initiation of treatment. Radiographs were scored according to the modified Sharp/van der Heijde method (mean of 2 independent readers who were aware of the sequence). Individual long-term radiographic progression was estimated, using baseline radiographs and all radiographs obtained during the followup period, by simple linear regression analysis (curve fitting).

Results: Both COBRA therapy and SSZ monotherapy produced a significant decrease in urinary CTX-I and CTX-II levels at 3 months, and this decrease was amplified at 6 months. COBRA therapy suppressed CTX-II (change from baseline levels -36% and -43% at 3 and 6 months, respectively), but not CTX-I, significantly better than did SSZ (-17% and -21% at 3 and 6 months, respectively) at 3 and 6 months. The magnitude of the decrease in urinary CTX-II levels at 3 months significantly predicted long-term (5-year) radiographic progression (beta = 0.48 [95% confidence interval (95% CI) 0.13, 0.83]). This effect was independent of the change in disease activity and inflammation indices at 3 months. Patients whose CTX-II levels were normalized (<150 ng/mmoles of urinary creatinine) at 3 months had a significantly higher chance of radiographic stability (no progression over 5 years) than did patients whose CTX-II levels were increased both at baseline and at 3 months (odds ratio 4.5 [95% CI 1.5, 13]).

Conclusion: The individual CTX-II response measured after 3 months of therapy in patients with active RA who had increased CTX-II levels at baseline independently predicts long-term radiographic progression. Urinary CTX-II levels may be used as early markers of treatment efficacy in patients with RA.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Anti-Inflammatory Agents / administration & dosage
  • Antirheumatic Agents / administration & dosage
  • Arthritis, Rheumatoid / diagnostic imaging*
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / urine*
  • Biomarkers
  • Collagen / urine*
  • Collagen Type I
  • Collagen Type II / urine*
  • Disease Progression
  • Drug Therapy, Combination
  • Female
  • Humans
  • Male
  • Methotrexate / administration & dosage
  • Middle Aged
  • Peptides / urine*
  • Prednisolone / administration & dosage
  • Radiography
  • Sulfasalazine / administration & dosage


  • Anti-Inflammatory Agents
  • Antirheumatic Agents
  • Biomarkers
  • Collagen Type I
  • Collagen Type II
  • Peptides
  • collagen type I trimeric cross-linked peptide
  • Sulfasalazine
  • Collagen
  • Prednisolone
  • Methotrexate