4.Introduction (literature review citing key references)
Rheumatoid Arthritis (RA) is a common inflammatory disease affecting 0.5-1% of the population andis associated with increased mortality (Chung et al 2005). Cardiovascular (CV) disease is theleading cause of death in this group with a 50% increased risk of death (Pieringer and Pichler 2011). Although less publicised in RA, research indicates that atherosclerosis, a precursor to CV disease,occurs to the same frequency and severity in both RA and Diabetes Mellitus of similar diseaseduration (Stamatelopouos et al 2009).Chronic inflammation in RA is thought to play a significant role in the development of atherosclerosisand CV risk. Accumulated inflammatory cells, released cytokines and collagen-breaking enzymes,an increased expression of adhesion molecules and activated T-cells are all found in delicateatherosclerotic plaques. Joint synovitis in RA has been linked with the release of a number of proinflammatory mediators cytokines. These cytokines can gain access to the vascular systemaffecting organs and the endothelium resulting in a ‘proatherogenic’ state. Another contributor tothe accelerated atherothrombotic disease is the elevated levels of pro-thrombotic factors includingfibrinogen, von Willebrand factor, tissue plasminogen activator of D-dimer (Pieringer and Pichler 2011).C-Reactive Proteins (CRP) has been shown to inversely correlate to endothelial dysfunction in RApatients (De Groot et al 2010). Erythrocyte Sedimentation Rate (ESR) is also linked with theamount of endothelial dysfunction. A peak in ESR levels may be seen immediately prior to new-onset heart failure in RA patients confirming the involvement of inflammatory stimuli in CV disease(Gerli et al 2007).It is important to consider that common drugs used to treat RA may negatively or positively impactthe progression of atherosclerosis by favouring traditional CV risk factors or by reducing diseaseactivity (Gerli et al 2007). Research highlights that methotrexate and Tumor Necrosing Factor-α(TNFα) blocking agents may reduce the amount of cardiovascular events however diseasemodifying drugs such as leflunomide, cyclosporine, cyclo-oxygenase-2 inhibitors and non-steroidalanti-inflammatory drugs may worsen cardiovascular prognosis (Pieringer and Pichler 2011). Additonally, vascular complications play an important role in development of atherosclerosis and CVdisease. Compared to controls, RA patients exhibit a higher level of arterial stiffness against pulsewave velocity which explains the need for higher levels of pulse pressure. RA patients also showhigher levels of coronary artery calcifications and intima-media thickness which independentlyassociated with higher levels of CV morbidity (Pieringer and Pichler 2011).