Infliximab Improves Endothelial Dysfunction in Systemic Vasculitis

Booth, A. D.; Jayne, D.; Kharbanda, Rajesh K.; McEniery, CM; Mackenzie, Iain; Brown, John C.; Wilkinson, Ian B.

doi:10.1097/00004872-200402001-00177

Cited by 17 publications

(22 citation statements)

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“…12 Endothelial dysfunction, which may lead to atherosclerosis, has been demonstrated in systemic vasculitis. [19][20][21] The present study shows for the first time an increased prevalence of atherosclerosis in patients with systemic vasculitis.…”

Section: Discussionsupporting

confidence: 59%

Accelerated atherosclerosis in patients with Wegener's granulomatosis

Leeuw

2005

Annals of the Rheumatic Diseases

136

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Background: Several autoimmune disorders are complicated by excess cardiovascular disease. In addition to traditional risk factors, non-traditional risk factors such as endothelial activation and excessive vascular remodelling might be determinants of the progression of atherosclerosis in patients with an autoimmune disease. Objective: To evaluate whether patients with Wegener's granulomatosis (WG) have an increased prevalence of atherosclerosis and to determine predisposing factors. Methods: 29 WG patients (19 men; mean (SD) age, 53 (14) years) with inactive disease and 26 controls (16 men; age 53 (15) years) were studied. Common carotid intima-media thickness (IMT) was measured by ultrasound. In all individuals traditional risk factors for cardiovascular disease were determined. High sensitivity C reactive protein (hsCRP) was measured. Endothelial activation was assessed by measuring thrombomodulin, vascular cell adhesion molecule-1, and von Willebrand factor. As a marker of vascular remodelling matrix metalloproteinases (MMP-3 and MMP-9) and TIMP-1 were measured. Results: IMT was increased in WG patients compared with controls (p,0.05). No differences in traditional risk factors and endothelial activation markers between patients and controls were found. Levels of hsCRP, MMPs, and TIMP-1 were increased in WG patients (p,0.05). Conclusions: Increased IMT found in WG patients cannot be explained by an increased prevalence of traditional risk factors. Although endothelial activation markers in WG patients with inactive disease were not increased, the raised levels of hsCRP, MMPs, and TIMP-1 suggest that enhanced inflammation and excessive vascular remodelling are contributing factors in the development of accelerated atherosclerosis in WG.

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Section: Discussionsupporting

confidence: 59%

Accelerated atherosclerosis in patients with Wegener's granulomatosis

Leeuw

2005

Annals of the Rheumatic Diseases

136

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“…We have previously demonstrated that TNF-α mediates vascular inflammation with potentially beneficial pro-fibrinolytic effects; however, it is associated with adverse inhibitory effects on endothelium-dependent vasodilatation 11. Consistent with these deleterious effects, antagonism of the TNF-α receptor has been demonstrated to improve endothelium-dependent vasodilatation in a variety of clinical settings such as congestive cardiac failure,12 acute systemic vasculitis13 and rheumatoid arthritis 14. The positive vascular effects of TNF-α antagonism may therefore be beneficial in the management of acute coronary syndromes, which are strongly associated with endothelial dysfunction.…”

Section: Introductionmentioning

confidence: 93%

Cardiovascular effects of tumour necrosis factor α antagonism in patients with acute myocardial infarction: a first in human study

Padfield

Din

Koushiappi

et al. 2013

Heart

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ObjectiveThe inflammatory cytokine, tumour necrosis factor α (TNF-α), exerts deleterious cardiovascular effects. We wished to determine the effects of TNF-α antagonism on endothelial function and platelet activation in patients with acute myocardial infarction.Design and setting and patientsA double-blind, parallel group, randomised controlled trial performed in a tertiary referral cardiac centre. 26 patients presenting with acute myocardial infarction randomised to receive an intravenous infusion of etanercept (10 mg) or saline placebo.Main outcome measuresLeucocyte count, plasma cytokine concentrations, flow cytometric measures of platelet activation and peripheral vasomotor and fibrinolytic function were determined before and 24 h after study intervention.ResultsConsistent with effective conjugation of circulating TNF-α, plasma TNF-α concentrations increased in all patients following etanercept (254±15 vs 0.12±0.02 pg/ml; p<0.0001), but not saline infusion. Etanercept treatment reduced neutrophil (7.4±0.6 vs 8.8±0.6×109 cells/l; p=0.03) and plasma interleukin-6 concentrations (5.8±2.0 vs 10.6±4.0 pg/ml; p=0.012) at 24 h but increased platelet–monocyte aggregation (30±5 vs 20±3%; p=0.02). Vasodilatation in response to substance P, acetylcholine and sodium nitroprusside, and acute tissue plasminogen activator release were unaffected by either treatment (p>0.1 for all).ConclusionsFollowing acute myocardial infarction, etanercept reduces systemic inflammation but increases platelet activation without affecting peripheral vasomotor or fibrinolytic function. We conclude that TNF-α antagonism is unlikely to be a beneficial therapeutic strategy in patients with acute myocardial infarction.

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“…Endothelial cell (EC) dysfunction (ECD) occurs in antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV)1 2 but improves with anti-tumour necrosis factor α (anti-TNFα) treatment,1 suggesting a key role for this cytokine. TNFα and interleukin 1 can induce secretion of acid sphingomyelinase (ASM) from ECs,3 4 which are the major source of this enzyme.…”

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confidence: 99%