Infliximab Improves Endothelial Dysfunction in Systemic Vasculitis

Abstract

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 (nϭ6) or in combination with standard treatment (nϭ4), on endothelial function were subsequently determined. Patients had a mean BVAS of 11Ϯ1, and CRP and IL-6 were higher in the AASV group than in control subjects (34.8Ϯ10.5 versus 1.6Ϯ0.2 pg/mL, PϽ0.001; 9.0Ϯ0.7 versus 6.7Ϯ0.6 pg/mL, Pϭ0.02). Forearm blood flow response to acetylcholine (ACh) was reduced in the patients compared with control subjects (Pϭ0.002), but sodium nitroprusside (SNP) responses were not (Pϭ0.3). The response to ACh improved with infliximab treatment (Pϭ0.004) in particular, with infliximab alone (Pϭ0.03). 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.

Translational Mini-Review Series on Immunology of Vascular Disease: Accelerated atherosclerosis in vasculitis

“…Raza et al assessed endothelial function by measuring flow-mediated brachial artery vasodilatation after reactive hyperaemia [53] and found significantly impaired vasodilatation in patients with active vasculitis that normalized during therapy. Endothelial function as assessed by plethysmography after infusion of acetylcholine demonstrated impaired responses [54]. However, contradictory results were found in two other studies [55,56] where increased vasodilator responses after acetylcholine infusion were observed.…”

Effects of tumor necrosis factor blockade on cardiovascular risk factors in psoriatic arthritis: A double‐blind, placebo‐controlled study

“…By implication, long-term suppression of the systemic inflammatory response should reduce the risk of CHD. Results of early epidemiologic studies of methotrexate therapy are commensurate with this hypothesis (4), as is evidence suggesting that suppression of inflammation improves endothelial-dependent function (5,6).…”

“…Thus far, no adequately placebocontrolled study examining the effect of TNF modulation on a range of established and novel vascular risk factors has been reported. Currently available information from small, often uncontrolled studies suggests that TNF blockade either increases (7) or decreases (8) the level of high-density lipoprotein (HDL) cholesterol, with more consistent effects on endothelial-dependent vascular function (5,6).…”

Ceramide: A common pathway for atherosclerosis?

“…Additionally, TNF-α deficient mice were not affected by the galactosyl ceramide [40]. Recent studies have shown that anti-TNF-α therapy could significantly improve endothelial functions in human subjects with vascular inflammation [41,42]. However, it is not know whether this therapy could be correlated with ceramide production in these individuals.…”