title: Local synovial engagement of angiogenic TIE-2 is associated with the development of persistent erosive rheumatoid arthritis in patients with early arthritis.
abstract: OBJECTIVE
  To examine the role of vascular endothelial growth factor (VEGF) and angiopoietin signaling in the diagnosis and disease outcome of patients with early arthritis.
  
  
  METHODS
  Fifty patients with early arthritis (disease duration <1 year) who had not been treated with disease-modifying antirheumatic drugs (DMARDs) were monitored prospectively and were classified at baseline and after 2 years as having undifferentiated arthritis (UA), rheumatoid arthritis (RA), or spondyloarthritis (SpA). All patients underwent arthroscopic synovial biopsy at baseline. Synovial expression of VEGF, VEGF receptor, angiopoietin 1 (Ang-1), Ang-2, TIE-2, and activated p-TIE-2 was evaluated by immunohistochemistry. Serum levels of VEGF, Ang-1, and Ang-2 were measured by enzyme-linked immunosorbent assay. Secreted products of macrophages stimulated with Ang-1 and Ang-2 were measured using a multiplex system.
  
  
  RESULTS
  Expression of Ang-1 was comparable between the patients with RA at baseline and patients with UA who fulfilled the criteria for RA over time (UA/RA), and it was significantly higher in patients with RA (P < 0.05) or UA/RA (P < 0.005) than in patients with SpA. TIE-2 and p-TIE-2 were more highly expressed in patients with RA (P < 0.005) or UA/RA (P < 0.05) than in patients with SpA. Ang-1 significantly enhanced the tumor necrosis factor-dependent macrophage production of cytokines and chemokines that are known to be elevated in the synovial fluid of patients with early RA. In RA, relative TIE-2 activation predicted the development of erosive disease (R(2) = 0.35, P < 0.05).
  
  
  CONCLUSIONS
  Local engagement of synovial TIE-2 is observed during the earliest phases of RA, suggesting that TIE-2 signaling may contribute to disease development and progression or may indicate an attempt to protect against these processes. Early therapeutic targeting of TIE-2 signaling may be useful in improving outcome in arthritis.
authors: Academic Medical Center and University of Amsterdam, Amsterdam, The Netherlands.
authors: Marleen G H
authors: MG
authors: van de Sande
authors: Daphne
authors: D
authors: de Launay
authors: Maria J H
authors: MJ
authors: de Hair
authors: Samuel
authors: S
authors: García
authors: Gijs P M
authors: GP
authors: van de Sande
authors: Carla A
authors: CA
authors: Wijbrandts
authors: Danielle M
authors: DM
authors: Gerlag
authors: Kris A
authors: KA
authors: Reedquist
authors: Paul P
authors: PP
authors: Tak
mesh_terms: D000328:Adult; D042683:Angiopoietin-1 / Q000378:metabolism; D042702:Angiopoietin-2 / Q000378:metabolism; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D042787:Receptor, TIE-2 / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D025241:Spondylarthritis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D018501:Antirheumatic Agents; D042787:Receptor, TIE-2; D040262:Receptors, Vascular Endothelial Growth Factor