Published Online
on March 22, 2004

A more recent version of this article appeared on April 13, 2004

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Submitted on August 28, 2003
Revised on November 18, 2003
Accepted on January 22, 2004

Infliximab Improves Endothelial Dysfunction in Systemic Vasculitis. A Model of Vascular Inflammation

A. D. Booth MRCP^*, D. R.W. Jayne FRCP, R. K. Kharbanda MRCP, C. M. McEniery PhD, I. S. Mackenzie MRCP, J. Brown FRCP, and I. B. Wilkinson MRCP

From the Clinical Pharmacology Unit, University of Cambridge, Addenbrooke’s Hospital (A.D.B., R.K.K., C.M.M., I.S.M., I.B.W.); the Department of Nephrology, Addenbrooke’s Hospital (D.R.W.J.); and GlaxoSmithKline Translational Medicine and Technology Group, GSK Clinical Research Unit, ACCI, Addenbrooke’s Hospital (J.B.), Cambridge, United Kingdom.

^* To whom correspondence should be addressed. E-mail: tonybooth1{at}yahoo.co.uk.

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- (TNF-) therapy.

Methods and 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-. The effects of anti-TNF- 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- therapy, alone or in combination with standard treatment, results in clinical remission, reduced inflammation, and improved endothelium-dependent vasomotor responses.

Key words: endothelium • inflammation • vasculature • antibodies

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