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

Abstract

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 Reumatoide 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.