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Lipid Associated Biomarkers in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis

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Lipid Associated Biomarkers in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis Lipid Associated Biomarkers in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis A thesis submitted to the university of manchester for the degree of Doctor of Philosophy in the Faculty of Medical and Human Sciences By Awal Zaki Almohmedhusain The University of Manchester School of Medicine Institute of Inflammation and Repair 2012 Contents Abstract 26 Declaration 28 Copyright 29 Dedication 31 Acknowledgements 32 Preface 34 Publication arising from this thesis 35 List of abbreviation 38 1 Background 40 1.1 Introduction . 40 1.2 Systemic lupus erythematosus . 40 1.2.1 Incidence and prevalence . 41 2 3 1.2.2 Clinical features . 41 1.2.3 Clinical manifestations . 42 1.2.4 Diagnosis . 43 1.2.5 Assessment of disease activity . 45 1.2.6 Management of SLE . 45 1.3 Rheumatoid arthritis . 46 1.3.1 Incidence and prevalence . 46 1.3.2 The aetiology of RA . 48 1.3.3 Clinical features . 49 1.3.4 Diagnosis of RA . 50 1.3.5 Disease activity . 52 1.3.6 Management of RA . 52 1.4 Cardiovascular disease in SLE . 53 1.5 Subclinical atherosclerosis in SLE . 54 1.6 Mortality in rheumatoid arthritis . 56 1.7 Do patients with RA have increased CVD risk prior to diagnosis? 58 1.8 Risk factors for CVD . 61 1.8.1 Traditional risk factors for cardiovascular disease . 61 1.8.2 Traditional risk factors in SLE and RA . 62 1.8.3 Do SLE patients have more risk factors? . 62 1.8.4 Do traditional risk factors influence cardiovascular risk in SLE? . 64 4 1.8.5 Do traditional risk factors fully explain excess risk in SLE? 64 1.8.6 Do patients with RA have more traditional risk factors? . 65 1.8.7 Do traditional risk factors influence CV risk in RA? . 68 1.8.8 Do traditional risk factors fully explain excess risk in RA? 69 1.8.9 Overview of SLE, RA traditional risk factors . 70 1.9 Disease related factors . 72 1.10 Chronic inflammation in the general population . 72 1.10.1 Chronic inflammation in SLE . 73 1.10.2 Chronic inflammation in RA . 74 1.10.3 Mechanisms by which chronic inflammation, in the general population and in SLE/RA, lead to atherosclerosis and CVD 76 1.11 Dyslipidemia . 78 1.11.1 Dyslipidemia in SLE and RA . 78 1.11.2 Possible mechanisms for dyslipidemia in inflammatory dis- eases . 79 1.12 Lipoproteins and apolipoproteins . 81 1.12.1 The attribution of lipids to CVD risks . 82 1.12.2 Apolipoprotein B . 82 1.12.3 Is ApoB better than other lipids in predicting risk? . 83 1.12.4 Apolipoprotein A-1 . 84 1.12.5 The ApoB/ApoA-1 ratio vs lipids ratio . 85 1.12.6 ApoB/ApoA-1 ratio and events . 86 5 1.13 Oxidative stress . 87 1.14 Endothelial dysfunction . 89 1.14.1 Markers of endothelial function . 90 1.14.2 Circulating biomarkers of endothelial function . 90 1.14.3 Non-invasive techniques to measure endothelial function . 91 1.15 Treatment . 94 1.16 Effects of traditional DMARDs on cardiovascular risk in RA/SLE 95 1.16.1 Steroid therapy . 95 1.16.2 Anti-malarial drugs . 96 1.16.3 Methotrexate . 97 1.16.4 Cyclophosphamide . 100 1.16.5 Azathioprine . 100 1.16.6 Mycophenolate mofetil (MMF) . 101 1.17 Conclusions of usual treatment . 102 1.18 Effects of the usual preventative agents for traditional cardiovascu- lar risk factors on cardiovascular risk and disease activity in RA/SLE103 1.18.1 Statins . 103 1.18.2 Angiotensin converting enzyme inhibitor . 105 1.18.3 Aspirin . 106 1.18.4 Fish oils in SLE . 107 1.18.5 Do novel interventions affect the CHD risk in RA/SLE? . 107 1.18.6 Anti TNF (RA) . 108 6 1.18.7 B-Cell depletion . 111 1.19 Overall hypothesis . 112 1.20 Aims . 113 2 Methods 114 2.1 Introduction . 114 2.1.1 Contribution of the candidate . 115 2.1.2 Sample collection . 116 2.2 Assays used in this project . 117 2.3 Principles of ELISA technique . 117 2.4 Oxidised LDL . 118 2.4.1 Principles of the assay . 118 2.4.2 Materials and reagents . 118 2.4.3 Assay procedure . 119 2.4.4 Calculation of the results . 120 2.4.5 Assay characteristics . 120 2.5 Urinary 8-Isoprostane . 122 2.5.1 Reagents and materials . 122 2.5.2 Assay procedure . 122 2.6 Glycated LDL . 124 2.6.1 Reagents and materials . 124 2.6.2 Principles of the assay . 125 2.6.3 Dilution of glycated-LDL standards . 125 7 2.6.4 Dilution of plasma samples . 126 2.6.5 Test procedure . 126 2.6.6 Calculation of results . 128 2.7 Assay for Human RAGE (receptor for advanced glycation end products) . 129 2.7.1 Principles of the assay . 129 2.7.2 Assay reagents and buffers . 129 2.7.3 Reagents preparation . 130 2.7.4 Assay procedure . 131 2.7.5 Calculation of results . 131 2.8 Measurements of lipids and apolipoproteins . 132 2.8.1 Lipoprotein and apolipoproteins measures . 132 2.9 Methods . 132 2.9.1 Serum Cholesterol . 132 2.9.2 Serum triglycerides . 133 2.9.3 Serum direct HDL . 134 2.9.4 The agreement between measurement in Manchester and Norwich laboratories . 135 2.9.5 LDL cholesterol determination by the Friedewald equation 137 2.9.6 Determination of Apo A-I and Apo B . 137 2.10 Assay for lipoprotein (a) . 139 2.10.1 Assay procedure . 139 8 2.10.2 Calculation of results . 140 2.11 Study of endothelial function . 140 2.11.1 Hypothesis: . 140 2.11.2 Assessment of endothelial function . 140 2.12 The settings . 141 2.12.1 EndoPat . 141 2.12.2 Flow mediated dilatation . 144 2.13 Validation of the FMD on healthy volunteers . 147 2.13.1 The reliability of measurements . 147 2.13.2 Reliability of baseline resting/post-deflation diameter mea- surement . 148 2.13.3 The reliability of %FMD/RHI measurements . 148 2.13.4 The association between resting diameter and %FMD . 148 2.13.5 The correlation between FMD and RHI . 150 2.13.6 The reproducibility of measurements . 151 2.14 Discussion . 153 3 Oxidant Stress in SLE Patients and Subclinical Atherosclerosis 156 3.1 Introduction . 156 3.1.1 Hypothesis . 157 3.1.2 Aims . 158 3.2 Study design and setting . 158 3.2.1 Study setting . 158 9 3.2.2 Study population . 159 3.3 Methods . 160 3.3.1 Estimation of subclinical atherosclerosis . 160 3.3.2 Measurement of oxidant stress and modified lipids . 160 3.4 Statistical analysis . 161 3.5 Results . 161 3.6 Description of the study cohort . 161 3.6.1 Demographic data . 161 3.6.2 SLE related factors . 162 3.6.3 Treatment . 163 3.6.4 Traditional risk factors in SLE vs healthy control . 163 3.6.5 Modified lipids and markers of oxidation . 165 3.7 Predictors of oxidant stress in SLE patients and healthy controls . 166 3.7.1 Oxidised-LDL . 166 3.7.2.
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