Biomarkers predict radiographic progression in early rheumatoid arthritis and perform well compared with traditional markers

Arthritis Rheum. 2007 Oct;56(10):3236-47. doi: 10.1002/art.22923.


Objective: To evaluate the performance of biochemical and traditional markers in predicting radiographic progression in rheumatoid arthritis (RA).

Methods: One hundred thirty-two patients with early RA were treated with nonbiologic therapies for 2 years and studied longitudinally. Genomic DNA was analyzed for presence of the shared epitope. Levels of matrix metalloproteinases (matrix metalloproteinase 1 [MMP-1], MMP-13, and MMP-3), tissue inhibitor of metalloproteinases 1 (TIMP-1), and cartilage oligomeric matrix protein (COMP) were assessed in serially obtained serum samples. The presence of pyridinoline (Pyr), deoxypyridinoline, glycosylated Pyr (Glc-Gal-Pyr), and C-telopeptide of type II collagen (CTX-II) was assessed in urine samples. Radiographs obtained at entry and at 2 years were evaluated using the modified Larsen score.

Results: Baseline and 2-year radiographs were available from 118 patients. Larsen scores worsened during the 2 years in 50 patients, while 68 patients had no radiographic progression. Levels of a variety of biochemical markers, i.e., MMP-3, CTX-II, COMP, TIMP-1, Pyr, and Glc-Gal-Pyr, correlated significantly with radiographic progression at entry and longitudinally as assessed by area under the curve (AUC). By multivariate analysis, a model including MMP-3 and CTX-II was identified as providing the best prediction of radiographic progression at entry (predictive accuracy by receiver operating characteristic [ROC] AUC = 0.76 [95% confidence interval 0.66-0.85]), while a combination of MMP-3, CTX-II, and swollen joint count formed the best longitudinal AUC model (predictive accuracy by ROC AUC = 0.81 [95% confidence interval 0.73-0.89]). Patient-reported measures (Health Assessment Questionnaire, pain scores) were of limited use. In a subset of 50 patients who were treated with methotrexate (MTX) during the followup period, median serum MMP-3 levels decreased after the initiation of MTX therapy (P = 0.0003).

Conclusion: These results indicate that biochemical markers are useful predictors of radiographic progression in RA and that serum MMP-3 levels decrease significantly with MTX therapy. Multivariate models that include MMP-3 and CTX-II perform better than existing traditional markers in predicting radiographic outcome in RA.

Publication types

  • Clinical Trial
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amino Acids / urine
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / diagnosis*
  • Arthritis, Rheumatoid / diagnostic imaging
  • Arthritis, Rheumatoid / urine
  • Biomarkers / blood
  • Biomarkers / urine
  • Cartilage Oligomeric Matrix Protein
  • Collagen Type II / urine*
  • Disease Progression
  • Extracellular Matrix Proteins / blood*
  • Female
  • Glycoproteins / blood*
  • Humans
  • Male
  • Matrilin Proteins
  • Matrix Metalloproteinase 1 / blood
  • Matrix Metalloproteinase 13 / blood
  • Matrix Metalloproteinase 3 / blood*
  • Matrix Metalloproteinases / blood
  • Middle Aged
  • Predictive Value of Tests
  • Radiography
  • Time Factors
  • Tissue Inhibitor of Metalloproteinase-1 / blood


  • Amino Acids
  • Biomarkers
  • Cartilage Oligomeric Matrix Protein
  • Collagen Type II
  • Extracellular Matrix Proteins
  • Glycoproteins
  • Matrilin Proteins
  • TSP5 protein, human
  • Tissue Inhibitor of Metalloproteinase-1
  • pyridinoline
  • deoxypyridinoline
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinases
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 1