title: Metastasin S100A4 is increased in proportion to radiographic damage in patients with RA.
abstract: OBJECTIVE
  To assess the potential of metastasin S100A4 as a biological marker in patients with RA.
  
  
  METHODS
  A total of 87 unselected patients with established RA (disease duration 2-44 years) and treated with MTX and infliximab at a single rheumatology centre were included in a cross-sectional study. Radiographs of hands and feet were taken prior to infliximab treatment and at inclusion (time interval 48 ± 27 months) and scored for the radiographic damage. S100A4 levels were analysed in relation to radiographic damage, clinical disease activity (DAS-28), inflammation (IL-6, CRP, ESR), bone and cartilage markers [MMP-3, COMP, C-telopeptide of type I collagen (CTX-I)] and proto-oncogenes [survivin, insulin-like growth factor 1 (IGF-1), Flt3 ligand].
  
  
  RESULTS
  High levels of S100A4 were associated with severe radiographic damage (OR = 3.40, P = 0.025), non-response to infliximab (OR = 4.63, P = 0.003), presence of antibodies to infliximab (OR = 6.24, P = 0.003) and high levels of Flt3 ligand (OR = 2.73, P = 0.04). Regression analysis showed that high S100A4 was predictive for radiographic progression during infliximab treatment [positive predictive value (PPV) 0.68, P = 0.05]. Low levels of S100A4 were associated with response to infliximab (OR = 2.67, P = 0.049), clinical remission (OR = 4.01, P = 0.0047) and negative RF (OR = 9.22, P = 0.0047). S100A4 correlated with survivin (r = 0.71, P > 0.0001).
  
  
  CONCLUSIONS
  S100A4 levels are increased in proportion to radiographic damage and its further progression in RA patients. High S100A4 levels were associated with a poor clinical response to infliximab and high rate of anti-infliximab antibodies. The finding of a correlation between S100A4 and survivin and Flt3 ligand suggests that these proteins may represent a new cluster of biomarkers predicting radiographic progression and poor treatment response in RA patients.
authors.affiliation: Department of Rheumatology and Inflammation Research, Guldhedsgatan 10, S-413 46 Göteborg, Sweden. maria.bokarewa@rheuma.gu.se
authors.forename: Malin C
authors.initials: MC
authors.lastname: Erlandsson
authors.forename: Kristina
authors.initials: K
authors.lastname: Forslind
authors.forename: Sofia E M
authors.initials: SE
authors.lastname: Andersson
authors.forename: Annelie
authors.initials: A
authors.lastname: Lund
authors.forename: Maria I
authors.initials: MI
authors.lastname: Bokarewa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000000981:diagnostic imaging* / Q000188:drug therapy; D015415:Biomarkers / Q000097:blood; D001842:Bone and Bones / Q000000981:diagnostic imaging; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D005528:Foot / Q000000981:diagnostic imaging*; D006225:Hand / Q000000981:diagnostic imaging*; D006801:Humans; D000069285:Infliximab; D051034:Inhibitor of Apoptosis Proteins / Q000097:blood; D008297:Male; D008565:Membrane Proteins / Q000097:blood; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D011237:Predictive Value of Tests; D011859:Radiography; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000097:blood*; D000077022:Survivin
chemical_list: D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; C107489:BIRC5 protein, human; D015415:Biomarkers; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D000077022:Survivin; C084881:flt3 ligand protein; C077591:S100A4 protein, human; D000069285:Infliximab; D008727:Methotrexate