A Trial of Rosuvastatin in Systemic Lupus Erythematosus
Condition: Atherosclerosis; Systemic Lupus Erythematosus
MeSH terms: Atherosclerosis; Lupus Erythematosus, Systemic
Study type: Interventional
Phase: Phase 2

Summary: 
      Systemic Lupus Erythematosus (SLE) is a condition that affects the whole body. It can cause
      inflammation of the blood vessels resulting in an earlier thickening and hardening of the
      arteries resulting in strokes. It has been reported that SLE can worsen the function
      resulting in heart failure.

      The aim of the study is to examine what effects Rosuvastatin, a cholesterol lowering drug,
      given to patients has on the degree of thickening of the arteries over the course of two
      years. We also want to see how it affects the function of the blood vessels and also of the
      heart.

      Individuals who agree to participate will be randomly assigned into two groups. One group
      will be given the active drug whereas the other will have a placebo. Subjects in the study
      will all have a cardiac magnetic resonance (CMR) scan before treatment, at 1 year and then 2
      years at the end of the treatment. Each scan will involve imaging the carotid arteries in the
      neck, the arteries in the arm and also the heart. Individuals will continue to have regular
      out-patient reviews by their own team of doctors, regular blood tests will be taken to
      monitor the disease and also to ensure the safety and well being of the individual.

      At the end of the 2 year study we hope that we will be able to slow down the rate of arterial
      thickening and retard any plaque build up in the arteries. We also want to see what effect
      rosuvastatin has on heart function. Ultimately, we hope to prove that people with SLE should
      be treated with a cholesterol lowering drug as part of their routine treatment.
    

Detailed description: 
      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.
    

Intervention name(s): Rosuvastatin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): All patients will be uptitrated from an initial start dose of 5mg to 20mg rosuvastatin. This will be given once a day for 2 years.; Placebo
Other intervention name(s): Crestor
Intervention MeSH terms: Rosuvastatin Calcium
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment