Page not found

PhD/MPhil projects: completed

Vitamin D deficiency, disease activity and cardiovascular health in systemic lupus erythematosus

Abstract

Background

 

Systemic lupus erythematosus (SLE) is a systemic inflammatory disease associated with a significantly increased risk of cardiovascular disease (CVD).  The risk is up to 50-times increased and is not explained by traditional cardiovascular risk factors.  Vitamin D deficiency is more common in SLE than the general population (with a prevalence of 52% in our Manchester lupus cohort) and is a plausible mediator for cardiovascular risk either by a direct effect on endothelial cells or indirectly via increased inflammation.

 

Vitamin D deficiency is an independent risk factor for cardiovascular CVD in the general population.  Endothelial dysfunction precedes the development of CVD and in diabetic patients can be rapidly reversed with vitamin D treatment.  Endothelial cells (ECs) express both the vitamin D receptor (VDR) and 1-alpha-hydroxylase, suggesting a direct effect within the vasculature.  In addition B lymphocyte function is regulated by vitamin D, which may affect B cell hyperactivity and response to lupus treatment.

 

Hypothesis

 

Vitamin D modifies endothelial cell function and drug response in patients with SLE.

 

Aims/Objectives

 

1a. Establish the influence of vitamin D on endothelial function in a SLE cohort.

 

1b. Investigate the action of vitamin D on isolated endothelial cells (ECs) in an in vitro model of SLE.

 

2. Determine whether vitamin D status modifies response to therapy in patients with active SLE.

 

Methods

 

Changes in endothelial function by vitamin D will be assessed using flow-mediated dilatation (FMD) and by studying the function of endothelial progenitor cells (EPCs) ex vivo in a cohort of lupus patients.

 

Type-1 interferon (IFNα) is the dominant cytokine in SLE and has direct effects on endothelial cell function, offering a tractable model to study the lupus effect on endothelium and how vitamin D acts on damaged endothelial cells.

 

The importance of vitamin D in modifying response to therapy will be investigated in lupus patients enrolled in a national biologics register.

 

Scientific/Medical Opportunities

 

Epidemiological evidence suggests a novel role for vitamin D in the development of CVD.  This is of interest in the context of inflammatory disease, where the prevalence of both CVD and vitamin D deficiency are exaggerated.  Although an association is clear, studies need to focus on a causal relationship.  Demonstrating improvement in endothelial function both in vivo and in vitro will contribute to the understanding of premature CVD in SLE patients and identify novel therapeutic targets.  Vitamin D may be a novel modifiable predictor of clinical response to treatment.

Duration of the project

4 years

Funding body

North West England MRC Clinical Pharmacology and Therapuetics Clinical Research Fellowship

BRC Manchester Clinical Research Fellowship

Members of the project

Professor Ian BruceSupervisor
Professor Terence O'NeillSupervisor
Professor David RaySupervisor
Dr Yvonne AlexanderSupervisor
Dr John ReynoldsPhD student