title: Identification of progressors in osteoarthritis by combining biochemical and MRI-based markers.
abstract: BACKGROUND
  At present, no disease-modifying osteoarthritis drugs (DMOADS) are approved by the FDA (US Food and Drug Administration); possibly partly due to inadequate trial design since efficacy demonstration requires disease progression in the placebo group. We investigated whether combinations of biochemical and magnetic resonance imaging (MRI)-based markers provided effective diagnostic and prognostic tools for identifying subjects with high risk of progression. Specifically, we investigated aggregate cartilage longevity markers combining markers of breakdown, quantity, and quality.
  
  
  METHODS
  The study included healthy individuals and subjects with radiographic osteoarthritis. In total, 159 subjects (48% female, age 56.0 +/- 15.9 years, body mass index 26.1 +/- 4.2 kg/m2) were recruited. At baseline and after 21 months, biochemical (urinary collagen type II C-telopeptide fragment, CTX-II) and MRI-based markers were quantified. MRI markers included cartilage volume, thickness, area, roughness, homogeneity, and curvature in the medial tibio-femoral compartment. Joint space width was measured from radiographs and at 21 months to assess progression of joint damage.
  
  
  RESULTS
  Cartilage roughness had the highest diagnostic accuracy quantified as the area under the receiver-operator characteristics curve (AUC) of 0.80 (95% confidence interval: 0.69 to 0.91) among the individual markers (higher than all others, P < 0.05) to distinguish subjects with radiographic osteoarthritis from healthy controls. Diagnostically, cartilage longevity scored AUC 0.84 (0.77 to 0.92, higher than roughness: P = 0.03). For prediction of longitudinal radiographic progression based on baseline marker values, the individual prognostic marker with highest AUC was homogeneity at 0.71 (0.56 to 0.81). Prognostically, cartilage longevity scored AUC 0.77 (0.62 to 0.90, borderline higher than homogeneity: P = 0.12). When comparing patients in the highest quartile for the longevity score to lowest quartile, the odds ratio of progression was 20.0 (95% confidence interval: 6.4 to 62.1).
  
  
  CONCLUSIONS
  Combination of biochemical and MRI-based biomarkers improved diagnosis and prognosis of knee osteoarthritis and may be useful to select high-risk patients for inclusion in DMOAD clinical trials.
authors.affiliation: Nordic Bioscience, Herlev Hovedgade 207, Herlev, Denmark. erikdam@nordicbioscience.com
authors.forename: Erik B
authors.initials: EB
authors.lastname: Dam
authors.forename: Marco
authors.initials: M
authors.lastname: Loog
authors.forename: Claus
authors.initials: C
authors.lastname: Christiansen
authors.forename: Inger
authors.initials: I
authors.lastname: Byrjalsen
authors.forename: Jenny
authors.initials: J
authors.lastname: Folkesson
authors.forename: Mads
authors.initials: M
authors.lastname: Nielsen
authors.forename: Arish A
authors.initials: AA
authors.lastname: Qazi
authors.forename: Paola C
authors.initials: PC
authors.lastname: Pettersen
authors.forename: Patrick
authors.initials: P
authors.lastname: Garnero
authors.forename: Morten A
authors.initials: MA
authors.lastname: Karsdal
mesh_terms: D019540:Area Under Curve; D015415:Biomarkers / Q000032:analysis*; D002356:Cartilage / Q000473:pathology*; D024042:Collagen Type I / Q000652:urine; D024043:Collagen Type II / Q000652:urine*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000473:pathology* / Q000652:urine*; D010446:Peptide Fragments; D010455:Peptides / Q000652:urine; D011379:Prognosis; D012372:ROC Curve
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; D024043:Collagen Type II; D010446:Peptide Fragments; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide