title: Intravascular tumor necrosis factor alpha blockade reverses endothelial dysfunction in rheumatoid arthritis.
abstract: BACKGROUND
  Patients with rheumatoid arthritis (RA) have endothelial dysfunction, which may predispose them to the risk of premature atherosclerosis. This study investigated the involvement of tumor necrosis factor (TNF) alpha in the pathophysiologic characteristics of this abnormality by use of the TNF-alpha-neutralizing antibody infliximab.
  
  
  METHODS
  Endothelium-dependent and -independent vasodilator responses to intra-arterial infusion of increasing doses of acetylcholine and sodium nitroprusside, respectively, were assessed by strain-gauge plethysmography in patients (n = 10) with early RA during saline solution infusion and after intra-arterial infusion of infliximab (200 microg/min).
  
  
  RESULTS
  Circulating markers of systemic inflammation (C-reactive protein and interleukin 6) were higher in patients than in control subjects (n = 10, both P < .05), whereas plasma levels of TNF-alpha and soluble TNF receptor types 1 and 2 were similar in both groups (all P > .05). During saline solution infusion, the vasodilator response to acetylcholine was blunted in patients with RA compared with control subjects (14.2 +/- 9.2 mL . min-(1). dL-(1) versus 23.7 +/- 9.2 mL . min-(1). dL-(1) at the highest dose, P = .004) whereas vasodilation to sodium nitroprusside was not different between groups (P = .10). In patients with RA infliximab did not modify circulating C-reactive protein levels (P = .29, versus saline solution) but did potentiate the vasodilator response to acetylcholine (21.0 +/- 11.1 mL . min-(1). dL-(1); P = .004, versus saline solution). The response to sodium nitroprusside, in contrast, was not modified by infliximab (P = .28 versus saline solution).
  
  
  CONCLUSIONS
  Intravascular administration of anti-TNF-alpha antibody ameliorates endothelial function in patients with RA but does not concurrently affect systemic inflammatory changes. Our findings suggest that enhanced TNF-alpha generation within the vessel wall, rather than systemic mechanisms, plays a role in the pathobiologic features of endothelial dysfunction in RA.
authors.affiliation: Department of Internal Medicine, Divisione di Terapia Medica, Università Cattolica del Sacro Cuore, Rome, Italy. carmine.cardillo@rm.unicatt.it <carmine.cardillo@rm.unicatt.it>
authors.forename: Carmine
authors.initials: C
authors.lastname: Cardillo
authors.forename: Francesca
authors.initials: F
authors.lastname: Schinzari
authors.forename: Nadia
authors.initials: N
authors.lastname: Mores
authors.forename: Marco
authors.initials: M
authors.lastname: Mettimano
authors.forename: Domenico
authors.initials: D
authors.lastname: Melina
authors.forename: Angelo
authors.initials: A
authors.lastname: Zoli
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Ferraccioli
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002097:C-Reactive Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006801:Humans; D000069285:Infliximab; D007261:Infusions, Intra-Arterial; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009599:Nitroprusside / Q000494:pharmacology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D009599:Nitroprusside; D002097:C-Reactive Protein; D000069285:Infliximab; D000109:Acetylcholine