Medicine (St Vincent's) - Theses
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ItemRheumatoid arthritis, cardiovascular disease and inflammation.... and the effects of rheumatoid arthritis drug therapies on this musketeer trio( 2010)Rheumatoid arthritis (RA) is associated with a significantly higher rate of cardiovascular (CV) disease and mortality (1). The higher CV risk appears to be independent of traditional CV risk factors (2). Atherosclerosis is now recognised as an inflammatory disease, and the relationship between RA and CV disease may partly be explained by chronic systemic inflammation (3). Inflammation plays a role at all stages of the atherosclerotic process from the earliest stages of endothelial dysfunction to plaque development and eventually to plaque complications such as rupture and thrombosis which lead to clinical events such as heart attack and stroke (4). Medications commonly taken by RA patients may exacerbate or improve CV risk. Methotrexate improves RA disease activity, inflammation and CV mortality in RA (5). Non-steroidal anti-inflammatory medications (NSAIDs), cyclo-oxygenase inhibitors (COX-2 inhibitors) and TNFα-inhibitors are commonly used in RA with varying degrees of inflammation suppression. Their effect on CV risk in RA might therefore assist in our understanding of the complex relationship which we hypothesise exists between RA, CV disease and inflammation. The aim of this thesis was to investigate vascular dysfunction in RA and the relationship to markers of inflammation, and to assess whether intervention with NSAIDs, COX-2 inhibitors and TNFα-inhibitors has an effect on vascular function in RA. In a cross sectional study of 106 RA and control subjects pulse wave analysis (PWA) was performed. A subgroup of RA patients and controls had known coronary artery disease (CAD). Vascular measures were correlated with markers of inflammation (6).In a double blind placebo controlled trial, 37 RA patients were randomised to a two week course of COX-2 inhibitor, rofecoxib, NSAID, indomethacin or placebo. Flow mediated dilatation (FMD) and PWA were assessed before and after the two week treatment course (7). In a further intervention study 26 RA patients were randomised to TNFα-inhibitor Infliximab or placebo infusions. Vascular assessments included pulse wave velocity (PWV), PWA, carotid intima media-thickness (CIMT) and Carotid artery plaque (CAP). Follow up was to 56 weeks (8). Results from the cross sectional study confirmed that vascular function was impaired in RA and in the subgroup of patients with CAD when measured with PWA. Vascular function correlated with acute phase proteins when analysing the study group as a whole. In terms of short term intervention, COX inhibition with either rofecoxib or indomethacin did not significantly improve vascular function at two weeks as measured by FMD and PWA. Markers of inflammation also did not improve with these treatments. Post-hoc analysis of the infliximab intervention study using multivariate ANOVA modelling showed significant reduction in PWV over 56 weeks. RA disease activity and markers of inflammation also improved with this treatment. There was no change in PWA, CIMT or carotid plaques. In conclusion, patients with RA have impaired vascular function. This was independent of traditional CV risk factors but correlated with markers of inflammation. A short term intervention with a COX-2 inhibitor or NSAID did not improve vascular function at two weeks when measured with PWA in RA patients. Intervention with TNFα inhibitor improved PWV in RA patients at 56 weeks. These findings support the concept that chronic inflammation is associated with vascular dysfunction and this may relate at least in part to the increased CV risk in RA. Therapies effective in suppressing inflammation not only improve RA disease activity but also vascular function.