A Trial of Rosuvastatin in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an auto-immune condition, multisystem, connective tissue disorder with a wide spectrum of disease (D'Cruz et al 2007), which includes cardiovascular manifestations. It is a condition which primarily affects females with a predominance of 10:1. The peak onset is between 18 and 40 years of age. The incidence is reported to be higher amongst Asian and African ethnic groups. In the UK, the incidence is 3.8 per 100 000 per year, with a prevalence of 26.2 per 100 000. The incidence among the white UK population is 3.0 per 100 000 per year, whereas it is 10.0 among Asians and 21.89 among the Afro-Caribbean population, the highest of any population studied so far (Danchenko 2006). No clear aetiology has been identified, and the genetics are complex.

The range of cardiovascular manifestations is varied; it includes accelerated atherosclerosis, vascular inflammation (El-Magadmi, 2002) and ventricular dysfunction (Pieretti J, 2007). The presence of carotid atherosclerosis is a strong predictor of future cardiovascular events (Belcaro G, 1996) and as such, identification of plaque within the carotid arteries has been studied using ultrasound. Studies have also been conducted to investigate endothelial dysfunction and the relationship with SLE.

• Case studies of patients with SLE have shown patients with SLE have increased carotid intima-media thickness (IMT) on ultrasound (US) studies (Svenungsson E, 2001).
• US studies in SLE have reported endothelial dysfunction as demonstrated bu US flow mediated dilatation (FMD) (Lima DS, 2002, Celermaier DS, 1994).
• Ultrasound studies in SLE have demonstrated a significant correlation between dysfunctional endothelium (reduced flow-mediated dilatation/brachial artery reactivity) and carotid IMT (Raza K, 2000).
• Myocardial dysfunction, in particular, an increased left ventricular ejection fraction and mass due to left ventricular hypertrophy has been identified in this population (Chow PC, 2007, Pieretti J, 2007).

The excess cardiovascular risk in patients with SLE has been attributed to corticosteroid usage in the treatment of the condition and as such was given as the explanation of the increased atherosclerosis (Petri M, 1992, 1996). Although, corticosteroid therapy can itself cause hypertension, diabetes and dyslipidaemia, the cumulative steroid dose is also a surrogate marker for disease severity. Studies have also shown that patients with the condition are more hypertensive and have an increased tendency to be smokers (Asanuma Y, 2003). However, a separate study showed that despite a higher incidence of hypertension, diabetes and an earlier menopause, the 10 year Framingham risk score was the same as matched healthy controls (Bruce IN, 2003). This would suggest that the risk factors present in SLE are not adequately explained by the conventional cardiovascular risk assessment model. In fact, SLE itself is a strong independent risk factor for atherosclerosis. Due to the inflammatory nature of SLE it is consistent with the recent paradigm shift towards the concept of atherosclerosis as a disease of vascular inflammation. Vascular inflammation leads to endothelial and vascular damage which can predispose to atherosclerosis (Ross R, 1999).

The association of dyslipidemia and SLE has been demonstrated (Svenungsson E, 2001). There is elevation of LDL-cholesterol, triglycerides and lipoprotein (a)(Asanuma Y, 2003) with a decrease in HDL-cholesterol (Borba EF, 1994). Together with the elevation of alpha-1 anti-trypsin and homocysteine levels lead to conditions with are conducive for the development of atherosclerosis.

The mainstay of treatment of atherosclerosis in SLE is predominantly directed at controlling inflammation with aggressive conventional cardiovascular disease risk factor management with corticosteroids, anti-inflammatories and disease modifying drugs (cyclosporin A and azathioprine). For lipid management, it has been suggested that even in the absence of atherosclerosis, the LDL-cholesterol level should be <2.6mmol/L. However, there has been limited clinical data to demonstrate the benefit of this approach (Wajed J,2004, Bruce IN, 2005).

There has been much published data on the effect of lipid lowering drugs or statins (HMG-Co A reductase inhibitors) and plaque regression (Corti,2001, 2005, Lima J, 2004). These trials demonstrated a significant reduction in the amount of plaque within the vessel wall as well as the reduction of LDL-cholesterol. A recently published randomised placebo-controlled trial (METEOR) (Crouse J, 2007)showed that rosuvastatin 40mg once daily over 2 years arrested carotid plaque progression which continued in the placebo group. This study was was highly significant (P<0.01). In this study, carotid plaque and carotid intima media thickness (CIMT) was assessed by B-mode ultrasound. Such studies prove that there is a benefit of using statins in those with low risk or who have established plaque disease.