title: 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 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]).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine/Rheumatology, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Rlan@sint.azm.nl
authors.forename: Robert
authors.initials: R
authors.lastname: Landewé
authors.forename: Piet
authors.initials: P
authors.lastname: Geusens
authors.forename: Maarten
authors.initials: M
authors.lastname: Boers
authors.forename: Désirée
authors.initials: D
authors.lastname: van der Heijde
authors.forename: Willem
authors.initials: W
authors.lastname: Lems
authors.forename: Johan
authors.initials: J
authors.lastname: te Koppele
authors.forename: Sjef
authors.initials: S
authors.lastname: van der Linden
authors.forename: Patrick
authors.initials: P
authors.lastname: Garnero
mesh_terms: D000328:Adult; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D018501:Antirheumatic Agents / Q000008:administration & dosage; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000652:urine*; D015415:Biomarkers; D003094:Collagen / Q000652:urine*; D024042:Collagen Type I; D024043:Collagen Type II / Q000652:urine*; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D010455:Peptides / Q000652:urine*; D011239:Prednisolone / Q000008:administration & dosage; D011859:Radiography; D012460:Sulfasalazine / Q000008:administration & dosage
chemical_list: D000893:Anti-Inflammatory Agents; D018501:Antirheumatic Agents; D015415:Biomarkers; D024042:Collagen Type I; D024043:Collagen Type II; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide; D012460:Sulfasalazine; D003094:Collagen; D011239:Prednisolone; D008727:Methotrexate