Antiangiogenic effects of anti-tumor necrosis factor alpha therapy with infliximab in psoriatic arthritis.
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.
Cañete
Juan D
JD
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
Pablos
José L
JL
Sanmartí
Raimon
R
Mallofré
Carmen
C
Marsal
Sara
S
Maymó
Joan
J
Gratacós
Jordi
J
Mezquita
Jovita
J
Mezquita
Cristobal
C
Cid
Maria C
MC
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
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