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Pathological Investigation of Rosacea with Particular Regard Of A Clinico-Pathological Investigation of Rosacea with Particular Regard to Systemic Diseases Dr. Mustafa Hassan Marai Submitted in accordance with the requirements for the degree of Doctor of Medicine The University of Leeds School of Medicine May 2015 “I can confirm that the work submitted is my own and that appropriate credit has been given where reference has been made to the work of others” “This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement” May 2015 The University of Leeds Dr. Mustafa Hassan Marai “The right of Dr Mustafa Hassan Marai to be identified as Author of this work has been asserted by him in accordance with the Copyright, Designs and Patents Act 1988” Acknowledgement Firstly, I would like to thank all the patients who participate in my rosacea study, giving their time and providing me with all of the important information about their disease. This is helped me to collect all of my study data which resulted in my important outcome of my study. Secondly, I would like to thank my supervisor Dr Mark Goodfield, consultant Dermatologist, for his continuous support and help through out my research study. His flexibility, understanding and his quick response to my enquiries always helped me to relive my stress and give me more strength to solve the difficulties during my research. Also, I would like to thank Dr Elizabeth Hensor, Data Analyst at Leeds Institute of Molecular Medicine, Section of Musculoskeletal Medicine, University of Leeds for her understanding the purpose of my study and her help in analysing my study data. Thirdly, I would like to thank all my colleagues in the Dermatology Department at Doncaster and Bassetlaw Hospitals NHS Foundation Trust and Leeds Teaching Hospitals for their help and support as well as referring patients with rosacea symptoms to my clinic to participate in my study. Furthermore, I would like to extend my appreciation to my wife and children who support me and sacrificing their time during my research to help me to have all the time for my study. Lastly, I would like to thank the Galderma Pharmaceutical Company who provided me with great materials including educational CD's about rosacea and also gave me the permission to use the photos of the rosacea patients in these CD's in my thesis. 1 Abstract Background: Rosacea is a common skin disorder that predominantly affects fair skinned people, particularly of Celtic origin. It usually presents with erythema, telangiectasia, and papulo-pustular lesions on the face and chest and usually triggered by sun exposure. The finding of a positive anti-nuclear antibody (ANA) has been reported in rosacea, as a consequence, those rosacea patients may be mislabeled as lupus erythematosus, often with important consequences in terms of treatment, and presumed prognosis. There is a limited literature examining rosacea and its associations with the positivity of ANA and connective tissue diseases (CTD). Objectives: This study investigated the relationship of different sub-types of rosacea with positivity of ANA test, musculo-skeletal systemic symptoms including myalgia, arthralgia and Raynaud’s phenomenon and CTD particularly lupus. Method: This was principally an observational study, I investigated a large group of patients (169 patients) with different subtypes of rosacea, identified from the dermatology and rheumatology departments in Doncaster Hospitals (93 patients) and Leeds Hospitals (76 patients). All patients had ANA blood screening test and all required data about their rosacea, associated systemic symptoms and previous history of CTD were recorded in special proformas after patients read information leaflet sheet and signed participation consent form. Results: The results showed no significant increase in the ANA positivity test (overall 13%), however, in patients without a history of CTD, the level of ANA positivity of both centres combined was (5.3%) which is similar to that reported in the general population; (One-sample Binomial test compared to null hypothesis proportion [5%] p=0.500). Around 15 - 20% of patients had one or more systemic symptoms. Arthralgia and myalgia had the same percentage as reported by the control group and in normal populations; however, Raynaud's phenomenon was slightly greater than reported in the 2 control group and the general populations. There could be an inverse relationship between Raynaud's treatment with vasodilators and rosacea flushing symptom. Conclusion: This study confirmed that there is no evidence that any particular clinical sub-type of rosacea is associated with increased positivity of ANA or has specific relationship with CTD. The study also did not find any specific relationship between rosacea and systemic symptoms. 3 Table of Contents Title Pages • Acknowledgment …..................................................................... 1 • Abstract …..................................................................... 2,3 • Table of Contents …..................................................................... 4,5 • Abbreviation …..................................................................... 6 Chapter One - Introduction 1. Background ….................................................................. 8 - 10 2. History ….................................................................. 11, 12 3. Definition …………………………………....................... 13 4. Epidemiology …………………………………....................... 14, 15 5. Aetiopathogenesis .…................................................................. 16 - 34 6. Diagnosis …………………………………....................... 35 - 39 7. Classification …................................................................... 40 - 50 8. Other Rosacea Variant …................................................................... 51 - 54 9. Differential Diagnosis …………………………………........................ 55 - 62 10. Management …................................................................... 63 - 69 11. ANA Blood Test …................................................................... 70, 71 Chapter Two - The Study 1. Aim of the Study …………………………………......................... 73, 74 2. Method of the Study ……………………………………..................... 75 - 86 3. Statistical Analysis …..................................................................... 87 - 89 Chapter Three - Results 1. Analysis of Demographic Data …......................................................... 91 - 100 2. Analysis of Patients with Positive ANA ….......................................... 101 - 108 4 Table of Contents Title Pages Chapter Four - Discussion 1. Discussion of Demographic Data …................................................ 110 - 113 2. Discussion of Patients with Positive ANA ….................................... 114 - 119 3. Effect of Oral Antibiotics on ANA ….................................................. 120 - 123 4. Conclusion …................................................................................... 124, 125 5. Strength of the Study …................................................................... 126 6. Limitation of the Study …................................................................. 127 7. Weakness of the Study …................................................................ 128, 129 8. Recommendations …...................................................................... 130, 131 Chapter Five - References References ……………………………………......................................... 133 - 147 Chapter Six - Appendices 1. Leeds Central Committee Ethical Approval...……………….............. 149 - 152 2. Doncaster Hospitals R&D Approval ………………………….............. 153 - 155 3. Leeds Teaching Hospital R&D Approval …………………….............. 156, 157 4. List of Tables ….................................................................................... 158 - 160 5. List of Figures ….................................................................................. 161, 162 5 Table (1) - Abbreviations No Abbreviated ward Explanation 1 ANA Anti-nuclear antibody 2 CTD Connective tissue disease 3 NRS National Rosacea Society 4 UV Ultraviolet light 5 UVA Ultraviolet A 6 UVB Ultraviolet B 7 DIF Direct Immunofluorescence 8 IIF Indirect Immunofluorescence 9 TLR Toll-like receptor 10 ER Endoplasmic reticulum 11 VEGF Vascular endothelial growth factor 12 DF Demodex folliculorum 13 HP Helicobacter pylori 14 IL Interleukin 15 TNF-α Tumour necrosis factor alpha 16 ETR Erythematotelangiectatic rosacea 17 PPR Papulopustular rosacea 18 PR Phymatous rosacea 19 OR Ocular rosacea 20 GR Granulomatous rosacea 21 MMP Matrix metalloproteinase 22 ROS Reactive oxygen species 23 NO Nitric oxides 24 AMP Anti-microbial peptide 25 EGFR Epidermal growth factor receptor 26 LE Lupus erythematosus 27 CLE Cutaneous lupus erythematosus 28 ACLE Acute cutaneous lupus erythematosus 29 SCLE Subacute cutaneous lupus erythematosus 30 CCLE Chronic cutaneous lupus erythematosus 31 SLE Systemic lupus erythematosus 32 DLE Discoid lupus erythematosus 33 ENA Extractable nuclear antigen 6 Chapter One - Introduction 1. Background 2. History 3. Definition 4. Epidemiology 5. Aetiopathogenesis 6. Diagnosis 7. Classification 8. Other Rosacea Variants 9. Differential Diagnosis 10. Management 11. ANA Blood Test 7 1. Background This thesis has its origins in a clinic scenario well recognised by those Dermatologists working in the field of connective tissue disease. A female patient of 38 was seen with a prior diagnosis of lupus
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