title: Antiangiogenic effects of anti-tumor necrosis factor alpha therapy with infliximab in psoriatic arthritis.
abstract: OBJECTIVE
  Neovascularization, with an increased number of synovial vessels with a characteristic morphology, seems to contribute to the progression of psoriatic arthritis (PsA). Accordingly, angiogenesis may be an important therapeutic target in PsA. The aim of this study was to analyze the effects of infliximab on angiogenesis in the synovial membrane of patients with PsA who responded to this therapy.
  
  
  METHODS
  The study group comprised 9 patients with PsA who were selected for the presence of active polyarthritis (including knee synovitis) despite methotrexate therapy. Clinical and biologic evaluations were performed at each visit. Arthroscopy and synovial biopsies were performed at week 0, before infliximab therapy was initiated, and at week 8, after administration of 3 intravenous infusions of infliximab (5 mg/kg). We used immunohistochemistry to identify changes in infiltrating cells and in the angiogenesis modulators alphavbeta3 integrin, vascular endothelial growth factor (VEGF), angiopoietin 2 (Ang-2), flt-1 (VEGF receptor 1 [VEGFR-1]), kinase insert domain receptor [KDR]/flk-1 (VEGFR-2), and stromal cell-derived factor 1 (SDF-1). Neovascularization was assessed by automated histomorphometry of CD31+ vessels and by measuring alphavbeta3 expression.
  
  
  RESULTS
  Rapid and significant clinical and biological improvement were observed after treatment in all patients. In the synovium, infliximab therapy induced a significant reduction in macrophages, the CD31+ vascular area, alphavbeta3+ neovessels/Ulex europaeus agglutinin+ vessels, VEGF and its receptor KDR/flk-1 (VEGFR-2), and SDF-1+ vessels. Expression of flt-1 (VEGFR-1), and SDF-1 in lining cells showed a nonsignificant reduction, whereas expression of Ang-2 increased. In 3 patients, reverse transcription-polymerase chain reaction confirmed the changes in some of these markers at the messenger RNA level.
  
  
  CONCLUSIONS
  These results show consistent changes in several factors involved in angiogenesis regulation, in parallel with the clinical response to infliximab in patients with PsA. The pattern of reduced VEGF with increased Ang-2 suggests vascular regression as a potential mechanism underlying the antiangiogenic effect of infliximab.
authors.affiliation: Institut Clínic de l'Aparell Locomotor, and Unitat d'Artritis, Servei de Reumatologia, Hospital Clínic de Barcelona, Villaroel 170, 08036 Barcelona, Spain. jcanete@clinic.ub.es
authors.forename: Juan D
authors.initials: JD
authors.lastname: Cañete
authors.forename: José L
authors.initials: JL
authors.lastname: Pablos
authors.forename: Raimon
authors.initials: R
authors.lastname: Sanmartí
authors.forename: Carmen
authors.initials: C
authors.lastname: Mallofré
authors.forename: Sara
authors.initials: S
authors.lastname: Marsal
authors.forename: Joan
authors.initials: J
authors.lastname: Maymó
authors.forename: Jordi
authors.initials: J
authors.lastname: Gratacós
authors.forename: Jovita
authors.initials: J
authors.lastname: Mezquita
authors.forename: Cristobal
authors.initials: C
authors.lastname: Mezquita
authors.forename: Maria C
authors.initials: MC
authors.lastname: Cid
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D018501:Antirheumatic Agents / Q000008:administration & dosage*; D015535:Arthritis, Psoriatic / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D015415:Biomarkers; D006801:Humans; D000069285:Infliximab; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D042787:Receptor, TIE-2 / Q000235:genetics; D013583:Synovial Membrane / Q000098:blood supply; D013585:Synovitis / Q000188:drug therapy / Q000209:etiology / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D015415:Biomarkers; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000069285:Infliximab; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2