title: Low-grade inflammation in symptomatic knee osteoarthritis: prognostic value of inflammatory plasma lipids and peripheral blood leukocyte biomarkers.
abstract: OBJECTIVE
  Inflammatory mediators, such as prostaglandin E2 (PGE2 ) and interleukin-1β (IL-1β), are produced by osteoarthritic (OA) joint tissue, where they may contribute to disease pathogenesis. We undertook the present study to examine whether inflammation, evidenced in plasma and peripheral blood leukocytes (PBLs), reflects the presence, progression, or specific symptoms of symptomatic knee OA.
  
  
  METHODS
  Patients with symptomatic knee OA were enrolled in a 24-month prospective study of radiographic progression. Standardized knee radiographs were obtained at baseline and 24 months. At baseline, levels of the plasma lipids PGE2 and 15-hydroxyeicosatetraenoic acid (15-HETE) were measured, and transcriptome analysis of PBLs was performed by microarray and quantitative polymerase chain reaction.
  
  
  RESULTS
  Baseline PGE2 synthase (PGES) levels determined by PBL microarray gene expression and plasma PGE2 levels distinguished patients with symptomatic knee OA from non-OA controls (area under the receiver operating characteristic curve [AUC] 0.87 and 0.89, respectively, P < 0.0001). Baseline plasma 15-HETE levels were significantly elevated in patients with symptomatic knee OA versus non-OA controls (P < 0.0195). In the 146 patients who completed the 24-month study, elevated baseline expression of IL-1β, tumor necrosis factor α, and cyclooxygenase 2 (COX-2) messenger RNA in PBLs predicted higher risk of radiographic progression as evidenced by joint space narrowing (JSN). In a multivariate model, AUC point estimates of models containing COX-2 in combination with demographic traits overlapped the confidence interval of the base model in 2 of the 3 JSN outcome measures (JSN >0.0 mm, JSN >0.2 mm, and JSN >0.5 mm; AUC 0.62-0.67).
  
  
  CONCLUSIONS
  The inflammatory plasma lipid biomarkers PGE2 and 15-HETE identify patients with symptomatic knee OA, and the PBL inflammatory transcriptome identifies a subset of patients with symptomatic knee OA who are at increased risk of radiographic progression. These findings may reflect low-grade inflammation in OA and may be useful as diagnostic and prognostic biomarkers in clinical development of disease-modifying OA drugs.
authors.affiliation: New York University School of Medicine and New York University Langone Medical Center, New York, New York.
authors.forename: Mukundan
authors.initials: M
authors.lastname: Attur
authors.affiliation: New York University School of Medicine and New York University Langone Medical Center, New York, New York.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Krasnokutsky
authors.affiliation: New York University School of Medicine and New York University Langone Medical Center, New York, New York.
authors.forename: Alexander
authors.initials: A
authors.lastname: Statnikov
authors.affiliation: New York University School of Medicine and New York University Langone Medical Center, New York, New York.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Samuels
authors.affiliation: New York University School of Medicine and New York University Langone Medical Center, New York, New York.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Li
authors.affiliation: Pfizer Worldwide Research and Development, St. Louis, Missouri.
authors.forename: Olga
authors.initials: O
authors.lastname: Friese
authors.affiliation: Pfizer Worldwide Research and Development, St. Louis, Missouri.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Hellio Le Graverand-Gastineau
authors.affiliation: New York University School of Medicine and New York University Langone Medical Center, New York, New York.
authors.forename: Leon
authors.initials: L
authors.lastname: Rybak
authors.affiliation: Duke University School of Medicine, Durham, North Carolina.
authors.forename: Virginia B
authors.initials: VB
authors.lastname: Kraus
authors.affiliation: University of North Carolina, Chapel Hill.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Jordan
authors.affiliation: New York University School of Medicine and New York University Langone Medical Center, New York, New York.
authors.forename: Constantin F
authors.initials: CF
authors.lastname: Aliferis
authors.affiliation: New York University School of Medicine and New York University Langone Medical Center, New York, New York.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Abramson
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D015232:Dinoprostone / Q000097:blood*; D018450:Disease Progression; D005260:Female; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood*; D007249:Inflammation / Q000097:blood / Q000473:pathology*; D007719:Knee Joint / Q000000981:diagnostic imaging / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000097:blood / Q000000981:diagnostic imaging / Q000473:pathology*; D011379:Prognosis; D011446:Prospective Studies; D011859:Radiography
chemical_list: D015415:Biomarkers; D006893:Hydroxyeicosatetraenoic Acids; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D015232:Dinoprostone