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Epidemiology of Gout in the United Kingdom and Taiwan

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Epidemiology of Gout in the United Kingdom and Taiwan Epidemiology of gout in the United Kingdom and Taiwan Kuo, Chang‐Fu Thesis submitted to the University of Nottingham for the degree of Doctor of Philosophy December 2014 Abstract Background: Gout is the most common inflammatory arthritis worldwide. The hallmarks of initial gout presentation are acute pain, swelling, erythema and tenderness in peripheral joints but eventually unremitting arthritis, joint deformity and tophus deposition may develop with long‐standing hyperuricaemia. Patients with gout suffer not only arthritis but also cardiovascular, renal, metabolic and other comorbidities. Since gout is the consequence of chronic hyperuricaemia, urate‐lowering treatments (ULT) helps prevent the formation of urate crystals and promote dissolution of existing crystals. Methods: This thesis contained results from a series of observational studies relating to gout. The data sources included the Clinical Practice Research Data‐link in the UK and the National Health Insurance Database in Taiwan, both of which are representative of the general population in these two countries. Six different analyses were carried out: (1) epidemiology of gout in the UK (chapter 3); (2) epidemiology of gout in Taiwan (chapter 4); (3) Nature history of gout following diagnosis in the UK (chapter 5); (4) familial aggregation and heritability of gout in Taiwan (chapter 6); (5) risk of comorbidities occurring before gout diagnosis (chapter 7) and (6) Effects of allopurinol on all‐cause mortality (chapter 8). i Results: This study estimated that the prevalence of gout was 2.49% in the UK in 2012 and 6.24% in Taiwan. Incidence of gout was also higher in Taiwan (3.47 per 1,000 person years in 2010) than in the UK (1.77 per 1,000 person years in 2012). The prevalence and incidence were increasing in the UK in the past decade, however, both of which remained stable in the period 2005‐2010 in Taiwan. Compared with the general population, individuals with a family history of gout had a two‐fold increased risk of the disease. The relative contributions of heritability, shared and non‐shared environmental factors to explain phenotypic variance of gout were 35.1%, 28.1% and 36.8% in men and 17.0%, 18.5% and 64.5% in women, respectively. Patients with gout were already at higher risk of multiple comorbidities at diagnosis, furthermore, gout was associated with higher all‐cause mortality. In both countries, the management of gout remains poor. Most gout patients were eligible for ULT at diagnosis or shortly after. Allopurinol, the most commonly prescribed ULT in primary care in the UK, exerted a neutral effect on all‐cause mortality, which reassures the safety of the drug in terms of all‐cause mortality. Conclusions: Gout is the most common inflammatory arthritis affecting one in 40 people in the UK and one in 16 people in Taiwan. It is influenced by both environmental and genetic factors. Both incidence and prevalence keep rising in the UK whilst they remain comparatively ii stable in Taiwan. The management in the UK remains poor. Primary care physicians should be encouraged to screen for possible existing comorbidities at diagnosis. Most patients are eligible for ULT at diagnosis or shortly after diagnosis, and given the many benefits of ULT for gout patients, early discussion of ULT with patients seems reasonable practice. Allopurinol is not associated with heightened mortality which should reassure practitioners who avoid ULT for fear of serious adverse events. iii Acknowledgements I would like to express my greatest gratitude to my supervisors, Professor Michael Doherty, Dr Weiya Zhang and Dr Matthew Grainge. They have assisted me on research question generation, study design, statistical analysis, critical appraisal, identification of clinical relevance, manuscript writing up and preparation of publishable papers. Their supervision has upgraded my research profile substantially. I am grateful to my mentors in Taiwan, Professor Shue‐Fen Luo, Dr Kuang‐Hui Yu and Professor Lai‐Chu See in their scientific and administrative support. Their support reduced my burden in data acquisition. In addition, their experiences in patient care in gout patients helped me align my study with practical and clinical relevance. I also would like to thank Professor Christian Mallen and Dr Ana Valdes who have worked with our team and contributed to the published papers based on this thesis. Finally I would like to thank my dearest wife, I‐Jun and my children, Chueh‐An, Chieh‐Chen and Chieh‐Jung. Their support and love kept me going through a lengthy study period. This research was funded by Chang Gung Memorial Hospital and University of Nottingham. iv Published papers from this thesis 1. Familial aggregation of gout and relative genetic and environmental contributions: a nationwide population study in Taiwan. Kuo CF, Grainge MJ, See LC, Yu KH, Luo SF, Valdes AM, Zhang W, Doherty M. Ann Rheum Dis. 2013 Nov 21. doi: 10.1136/annrheumdis‐2013‐204067. 2. Rising burden of gout in the UK but continuing suboptimal management: a nationwide population study. Kuo CF, Grainge MJ, Mallen C, Zhang W, Doherty M. Ann Rheum Dis. 2014 Jan 15. doi: 10.1136/annrheumdis‐2013‐204463. v Table of Contents ABSTRACT I ACKNOWLEDGEMENTS IV PUBLISHED PAPERS FROM THIS THESIS V TABLE OF CONTENTS VI LIST OF TABLES XIX LIST OF FIGURES XXIII INTRODUCTION 1 Historical aspect of gout 3 Prior to discovery of uric acid 3 Historical aspects of gout in ancient China 5 Monosodium urate crystal (MSU) deposition as the cause of gout 6 vi The definition of gout 8 "Gold" standard 10 Clinical diagnosis 11 Classification criteria 15 Case definition used in epidemiology 15 Clinical manifestations of gout 17 Epidemiology of gout 24 Prevalence 24 Limitations of current studies on gout epidemiology 28 Incidence 31 Risk factors for gout 33 Hyperuricaemia 33 vii Genetics 34 Age and gender 35 Other socioeconomic factors 36 Diet and alcohol consumption 36 Lead exposure 37 Comorbidities and health outcomes of gout 39 Metabolic syndrome 40 Diabetes mellitus (DM) 41 Hypertension 41 Kidney diseases 42 Urolithiasis 45 Cardiovascular diseases 47 viii Cancer 48 Osteoarthritis (OA) 49 Neurodegenerative disorders 50 Death 51 Treatment of gout 52 Epidemiological research based on administrative databases 55 Summary 57 Structure of this thesis 57 METHODS 60 Ethical approval 60 Funding 61 Data sources 62 Clinical Practice Research Data‐link 62 ix National Health Insurance (NHI) Research Database (NHIRD) 67 Comparison between CPRD and NHIRD 74 Case definition of gout 77 Case definition of comorbidities 80 Medication identification in the CPRD and NHIRD 85 Identification of kinships and ascertainment of family 85 Population structures in the UK and Taiwan 87 RISING BURDEN OF GOUT IN THE UK BUT CONTINUING SUBOPTIMAL MANAGEMENT: A NATIONWIDE POPULATION STUDY 93 Introduction 93 Methods 95 Source of data 95 Study population 95 x Case definition of gout 96 Estimation of prevalence and incidence 96 Pattern of treatment 97 Adherence to ULT 97 Trends of prevalence, incidence and management of gout 98 Statistical analysis 101 Results 102 Prevalence and incidence in 2012 102 Prevalence and incidence of gout between 1997 and 2012 104 Geographic variation in 2012 107 Management of gout between 1997 and 2012 110 Adherence to urate‐lowering treatment 112 xi Discussion 118 EPIDEMIOLOGY OF GOUT IN TAIWAN: A NATIONWIDE POPULATION STUDY 125 Introduction 125 Methods 126 Source of data and study population 126 Case definition of gout 126 Estimation of prevalence and incidence 126 Pattern of medication use 128 Trends of prevalence, incidence and management of gout 128 Statistical analysis 128 Results 130 Prevalence and incidence of gout in 2010 130 xii Prevalence and incidence of gout between 2005 and 2010 133 Geographic variation in 2010 136 Management of gout between 2005 and 2010 139 Comparison of gout epidemiology between the UK and Taiwan 141 Discussion 147 NATURE HISTORY OF GOUT AND ELIGIBILITY FOR URATE‐LOWERING TREATMENT FOLLOWING DIAGNOSIS IN THE UK 155 Introduction 155 Methods 157 Source of data 157 Study population 157 Study outcomes 157 xiii Statistical analysis 158 Results 160 Demographic characteristics 160 Timing of recurrence of acute attacks and the occurrence of complications 162 Percentages of patients fulfilling ULT at diagnosis and the end of the study 163 Cumulative probability of fulfilling ULT indications 166 Age and cumulative probability of fulfilling ULT indications 167 Discussion 170 FAMILIAL AGGREGATION OF GOUT AND RELATIVE GENETIC AND ENVIRONMENTAL CONTRIBUTIONS: A NATIONWIDE POPULATION STUDY IN TAIWAN 175 Introduction 175 Methods 177 Source of data 177 xiv Study population and classification 178 Identification of cases with gout 178 Identification of first‐ and second‐degree relatives and family ascertainment 178 Demographics and socioeconomic information 179 Threshold liability model 180 Statistical analysis 181 Results 184 Gout prevalence in individuals with affected family members versus the general population 184 Family exposure and risk of gout 187 Relative contributions of genetic, common and non‐shared environmental factors 193 Sensitivity analysis 194 Discussion 198 xv BURDEN OF COMORBIDITIES AND ALL‐CAUSE MORTALITY IN PATIENTS WITH INCIDENT GOUT: A NATIONWIDE POPULATION STUDY IN THE UK 203 Introduction 203 Methods 205 Data source 205 Definition of incident gout 205 Selection of controls 206 Study period 206 Comorbidity of interest and mortality 207 Statistical analysis 209 Results 211 Retrospective observation 212 xvi All‐cause mortality of gout after diagnosis 215 Discussion 217 EFFECT OF ALLOPURINOL ON ALL‐CAUSE MORTALITY IN ADULTS WITH INCIDENT GOUT: POPULATION BASED RETROSPECTIVE COHORT STUDY IN THE UK 223 Introduction 223 Methods 225 Data source 225 Definition of incident gout 225 Treatment group assignments 226 Covariates 230 Outcomes 231 Statistical analysis 231 Results 233 xvii Study population 233 Matching 235 Outcomes after matching 238 Propensity score adjustment analysis 241 Discussion 242 OVERALL DISCUSSION 249 REFERENCES 261 xviii List of Tables Table 1‐1 Prevalence of gout in the UK and Taiwan ............................................................................................
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