Preclinical Atherosclerosis in Rheumatoid Arthritis

429 Pages·2017·2.1 MB·English

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Title Preclinical atherosclerosis in rheumatoid arthritis
Author(s) O'Sullivan, Miriam Jane
Publication date 2014
Original citation O'Sullivan, M. J. 2014. Preclinical atherosclerosis in rheumatoid
arthritis. PhD Thesis, University College Cork.
Type of publication Doctoral thesis
Rights © 2014, Miriam J. O'Sullivan.
http://creativecommons.org/licenses/by-nc-nd/3.0/
Embargo information No embargo required
Item downloaded http://hdl.handle.net/10468/1908
from
Downloaded on 2023-02-20T00:32:42Z
Preclinical Atherosclerosis in
Rheumatoid Arthritis

A Thesis Presented To The National University Of Ireland,
Cork
For the Degree of Doctor of Philosophy
by
Dr Miriam Jane O’Sullivan MB BCh BAO MMedSc
Department of Medicine
January 2014
Head of Department: Prof Fergus Shanahan MD, BSc, FRCP(UK),
FRCPI, FACP, FRCP(C)
Professor of Medicine, National University of
Ireland, Cork
Supervisors: Dr Sinead Harney MB, Bch, MMedSc, D.Phil (Oxon)
Consultant Rheumatologist, CUH
Prof David Kerins MD, FRCPI, FACC, FAHA,
FASE
Professor of Therapeutics and Consultant Cardiologist
UCC and MUH
Acknowledgements

This work would not have been possible without the help and support of a number of
people. Firstly, I would like to thank all the patients who participated and
volunteered their time so willingly.
My rheumatology supervisor, Dr Sinead Harney, having completed her own PhD in
recent years, was very supportive and understanding of the trials and tribulations that
come with clinical research. Her positive attitude and ability to see the silver lining
in all situations throughout the course of the work was uplifting. My cardiology
supervisor, Professor David Kerins, provided invaluable expertise with respect to the
cardiovascular aspects of this study. He was also very supportive and patient in the
final writing up period of this thesis.
Professor Michael Molloy introduced me to rheumatology and encouraged me to
undertake this PhD. I am grateful for the years of support and wisdom he has
provided me in my career thus far.
I thank Mary Daly who helped me continuously throughout this research, both with
patient recruitment and follow-up and as a supportive friend over the last number of
years. Also, thanks to Lindsay Horgan was always so helpful with administration. I
am grateful to Rita Lynch in the department of medicine for her expertise and
guidance in the area of medical administration.
Professor Joseph Eustace was an excellent guide in my often turbulent journey
through medical statistics. Thank you also to Dr Cathy Dewhurst and Professor
Michael Maher for providing the radiology support for this project, and to Mary
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Stapleton and her colleagues in the biochemistry department for their support and
expertise. Orla Murray was a very patient teacher when it came to showing the ropes
of echocardiography to a rheumatologist. I also have to thank Dr Pat Barry for
persevering in his task of teaching me the skill set required for assessment of flow
mediated dilatation. He had a difficult job.
Drs Sinead Kinsella and Eanna Falvey, who were also writing their theses at the
same time as myself, provided moral support on numerous occasions. In particular,
thanks to Sinead who somehow seemed to have the answer to all my questions, no
matter how many or what time of the day or night I asked her.
I would like to thank my Dad, who died during the early stages of this research and
whose last conversation with me was of the importance of sticking to my goals and
believing in myself. I have called on this advice numerous times over the last few
years. Thanks to my wonderful mum, Mary, who has always been there to listen to
and support me. At this stage, she must wonder if my education will ever be
complete! Also thanks to my brothers, John and Andrew and my sister, Karoline, for
their support and good company.
Finally, I must express my gratitude to three very important men. My husband,
Shomik, whose ongoing support and advice kept me going. His belief in me and
unfaltering encouragement were what got me over the final hurdle. Without him,
this would not be complete. To my sons, Searlan and Jehan, who make me laugh out
loud every day and whose expert ability to sleep deeply, allowed me to burn the
midnight oil in the final months of writing. They make me realise what is really
important in life.

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Contents
Declaration of Original Work 12
Abstract 13
Chapter 1. Introduction 16
Rheumatoid Arthritis 16
Cardiovascular Disease 17
Heart Failure 23
Cardiovascular Disease in RA 27
Traditional and non-traditional risk factors for CVD in RA 27
Carotid IMT in RA 32
PVD in RA 32
Endothelial dysfunction in RA 33
Haemostasis in RA 33
Diastolic dysfunction in RA 34
Risk assessment in RA 36
Osteoarthritis 37
Reasons for undertaking this research 38
Hypothesis 39
Aims 39
References 41

Chapter 2. Materials and Methods 59
Patient Recruitment 59
Baseline Demographic Data 60
Phlebotomy 61
Brain Natriuretic Peptide 62
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Plasminogen Activator Inhibitor-1 62
Cytokine and Adhesion Molecule Analysis 63
Ankle Brachial Index 64
Transthoracic Echocardiography 65
Limitations of echocardiography in assessment of diastolic function 70
Limitations to echocardiographic measurements in this study 71
Carotid Artery Ultrasound 72
Flow Mediated Dilatation of Brachial Artery 74
Endothelium-Dependent Dilatation 75
Endothelium-Independent Vasodilatation with Nitroglycerin 76
Limitations of FMD technique 77
Edge Detection/FMD Analysis Software 78
Statistical Calculations 82
References 83

Chapter 3. Demographics, Disease Activity Scores and Baseline
Bloods 85
Introduction 85
Aims 88
Methods 88
Statistical Methods 89
Demographic Results 90
Gender 93
Age 94
Disease Duration 95
Education Level 97
Occupation 98
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Medications 100
DMARD use 100
Biologic use 101
NSAIDs 102
Prednisolone 107
Statins 108
Other Cardiac Medications 109
Non-cardiac Medications 109
Family History 110
Smoking status 111
Smoking Pack Years 112
Alcohol Consumption 113
Other medical conditions 114
Menopause 116
Clinical Examination 117
Weight 119
Height 120
Body Mass Index 121
Waist Hip Ratio 122
General Health Measures and Disease Activity Scores 123
Short Form 36 124
Physical component score 124
Mental Component Score 126
Health Assessment Questionnaire 127
Visual Analogue Scale 130
Disease Activity Scores for Rheumatoid Arthritis 131
Western Ontario and McMaster Universities Osteoarthritis Index 137
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Baseline Phlebotomy 139
Serum Concentrations of Antibodies in RA 143
Fasting Lipid and Glucose Profiles 144
Metabolic Syndrome 151
Electrocardiogram 151
Discussion 152
Demographics and Disease Activity 152
Baseline Phlebotomy 155
ECG 159
Conclusions 159
References 162

Chapter 4. Serum, Plasma and Urinary Markers of Inflammation,
Endothelial Dysfunction and Thrombosis 168
Introduction 168
Traditional Inflammatory markers in CVD 169
Adhesion molecules in RA and CVD 170
Cytokines in RA and CVD 171
Markers of thrombosis in RA and CVD 173
Urinary protein as a marker of vascular disease in general and RA 174
Aims 176
Methods 177
Cytokine and Adhesion Molecule Analysis 177
PAI-1 analysis 178
Urine for albuminuria measurement 179
Statistical Methods 179
Results for Routine Inflammatory Markers 180
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Comparison of ESR, CRP and Urate in RA and OA 180
ESR, CRP and Urate Levels and RA Serological Markers and Anti-Rheumatic
Medications 180
ESR, CRP and Urate levels and Markers of Cardiovascular Disease in RA 182
ESR, CRP and Urate in OA 187
Adhesion molecules Results 189
Comparison of Adhesion Molecule Concentrations in RA and OA 189
Adhesion Molecule Concentrations and RA Serological Markers and Anti-
Rheumatic Medications 190
Adhesion Molecule Concentrations and Cardiovascular Markers in RA 192
Osteoarthritis and Adhesion Molecule Concentrations 197
Cytokine Results 198
Comparison of Cytokine Concentrations in RA and OA 198
Cytokine Concentrations and RA Serological Markers and Anti-Rheumatic
Medications 200
Cytokine Concentrations and Cardiovascular Markers in RA 209
Osteoarthritis and Cytokine Concentrations 212
Results for Markers of Thrombosis 214
Comparison of Thrombotic Markers in RA and OA 214
Markers of Thrombosis and RA Serological Markers and Anti-Rheumatic
Medications 216
Markers of Thrombosis and Cardiovascular Markers in RA 218
Osteoarthritis and Markers of Thrombosis 222
Results for Urinary Protein-Creatinine Ratio and Microalbuminuria 222
Discussion 224
Comparison of ESR, CRP and Urate in RA and OA 224
Comparison of Adhesion Molecules in RA and OA 225
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Adhesion Molecule Concentrations and RA Serological Markers and Anti-
Rheumatic Medications 227
Adhesion Molecule Concentrations and Cardiovascular Markers in RA 228
Osteoarthritis and Adhesion Molecule Concentrations 230
Comparison of Cytokine Concentrations in RA and OA 232
Cytokine Concentrations and RA Serological Markers and Anti-Rheumatic
Medications 232
Cytokine Concentrations and Cardiovascular Markers in RA 235
OA and Cytokine Concentrations 235
Comparison of Thrombotic Markers in RA and OA 236
Markers of Thrombosis and RA Serological Markers and Anti-Rheumatic
Medications 238
Markers of Thrombosis and Cardiovascular Markers in RA 239
Osteoarthritis and Markers of Thrombosis 240
Urinary Protein Measures in RA and OA 241
Conclusions 242
References 246

Chapter 5. Macrovascular Endothelial Function in RA 264
Background 264
Aims 268
Methods 268
Statistical Methods 270
Results 271
Comparison of FMD and NMD in RA and OA patients 271
Comparison of FMD and NMD in Males and Females 274
RA Disease Activity and Macrovascular Endothelial Function 275
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