Infliximab improves endothelial dysfunction in systemic vasculitis: a model of vascular inflammation.
BACKGROUND
Endothelial vasomotor dysfunction and markers of systemic inflammation are independent determinants of cardiovascular risk. However, the link between clinical inflammation and endothelial dysfunction is unclear. The aim of this study was to use anti-neutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) as a model of systemic inflammation in which to test the hypothesis that inflammation is associated with endothelial dysfunction and can be reversed with anti-tumor necrosis factor-alpha (TNF-alpha) therapy.


RESULTS
Fourteen patients with active AASV and 21 age-matched control subjects were studied. Endothelial function was assessed through the use of forearm plethysmography and related to clinical disease activity: Birmingham Vasculitis Activity Score (BVAS) and serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), and TNF-alpha. The effects of anti-TNF-alpha therapy (infliximab), either alone (n=6) or in combination with standard treatment (n=4), on endothelial function were subsequently determined. Patients had a mean BVAS of 11+/-1, and CRP and IL-6 were higher in the AASV group than in control subjects (34.8+/-10.5 versus 1.6+/-0.2 pg/mL, P<0.001; 9.0+/-0.7 versus 6.7+/-0.6 pg/mL, P=0.02). Forearm blood flow response to acetylcholine (ACh) was reduced in the patients compared with control subjects (P=0.002), but sodium nitroprusside (SNP) responses were not (P=0.3). The response to ACh improved with infliximab treatment (P=0.004) in particular, with infliximab alone (P=0.03).


CONCLUSIONS
AASV is associated with endothelial dysfunction. Anti-TNF-alpha therapy, alone or in combination with standard treatment, results in clinical remission, reduced inflammation, and improved endothelium-dependent vasomotor responses.
Booth
A D
AD
Clinical Pharmacology Unit, University of Cambridge, Box 110, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, UK. tonybooth1@yahoo.co.uk
Jayne
D R W
DR
Kharbanda
R K
RK
McEniery
C M
CM
Mackenzie
I S
IS
Brown
J
J
Wilkinson
I B
IB
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000032:analysis; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D002097:C-Reactive Protein / Q000032:analysis; D015267:Churg-Strauss Syndrome / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply; D014890:Granulomatosis with Polyangiitis / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D000069285:Infliximab; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D010865:Pilot Projects; D010991:Plethysmography; D011239:Prednisolone / Q000008:administration & dosage / Q000627:therapeutic use; D012039:Regional Blood Flow / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors*; D014657:Vasculitis / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D019268:Antibodies, Antineutrophil Cytoplasmic; D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D003520:Cyclophosphamide; D002097:C-Reactive Protein; D011239:Prednisolone; D000069285:Infliximab; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D009173:Mycophenolic Acid