(from "Abstract Band", ausgewählte Abstracts, American College of Rheumatology (ACR) 2002 Annual Meeting, 25.-29. Oktober 2002, New Orleans
Essex Pharma GmbH)
Robert J Stevens (1), David Carruthers (2), Stephen P Young (1), John Townend (1), Paul A Bacon (1)
(1)= Universitiy of Birmingham, UK, Birmingham, United Kingdom; (2) City Hospital, Birmingham, United Kingdom
Background
The vascular endothelium is the main target of local injury in vasculitis. We previously hypothesized that persistent endothelial cell dysfunction (ECD) due to the damage resulting from this injury was the initiating factor in the accelerated atherosclerosis of RA. We have since established that diffuse ECD, not restricted to the local inflammatory site, occurs in many subsets of primary systemic necrotizing vasculitis (1oSNV), involves more than one vascular bed, and has different mechanisms than the primary inflammation (1,2). The current work examines the reversibility of ECD to test whether it truly represents damage. Tumor necrosis factor alpha (TNFalpha) is a key player in the immune inflammation of RA, vasculitis, and atherosclerosis, which can also cause endothelial cell injury. Here we investigate its effects on ECD.
Methods
Endothelial function following therapy for 1oSNV was assessed using laser Doppler flowmetry. This measures the change from baseline flow to maximal flow in the skin microcirculation after locally applied acetylcholine (ACh), an endothelial dependent vasodilator, is driven across the dermis using a weak electric charge (iontophoresis). Serial measurements were taken pre-infusion and 1, 2, 5, and 14 days post-therapy. All other drugs were unchanged over the assessment period.
Results
A total of 10 infusions were studied in three cases of 1oSNV who received <4 infusions of Infliximab at 5mg/kg as part of their induction therapy for active flare of disease (table).
A single infusion induced rapid improvement in skin blood flow, maximal at 48 hours, which returned to baseline by 2 weeks. This pattern of results remained the same in the patients who received 3 subsequent Infliximab infusions. This is compared to the absence of significant responses from 5 pulses of Cyc (15 mg/kg) plus MePred (10 mg/kg) in 3 other patients.
Table. Changes in EC function after Therapy
| Tag | 1 | 2 | 5 | 14 |
| Infliximab | +3,0 (+ 0,9)* | +3,4 ( +1,1)** | +2,0 (+1,1) | +0,5 (+0,6) |
| Cyc/Mepred | -3,0 (+2,0) | -3,3(+0,8) | -5,4 (+3,8) | -2,6 (+3,8) |
Results expressed as the mean (+ SEM) Delta of EC function from pre-infusion values.
Significance was assessed against the pre-infusion result using the Wilcoxon signed rank test.
Conclusion
This is the first demonstration that Infliximab can directly affect EC function in vivo in 1oSNV, supporting the addition of TNF blockade to therapeutic regimes. The rapid positive effect of Infliximab indicates the relevance of TNFalpha in the mechanisms of the diffuse ECD seen in 1oSNV. The effects of TNF blockade on EC function in RA are currently under study.
(1) Raza K et al; Circulation 2000; (2) Filer et al; In press 2002