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Population-based epidemiologic studies of gout in British Columbia, Canada Rai, Sharan Kimberly 2016

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Population-Based Epidemiologic Studies of Gout in British Columbia, Canada by  Sharan Kimberly Rai  B.Sc., The University of British Columbia, 2013  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Experimental Medicine)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  August 2016  © Sharan Kimberly Rai, 2016 ii  Abstract  Introduction: This thesis contains original analyses aimed at better understanding the burden of gout, an excruciatingly painful form of inflammatory arthritis, in the Canadian context. While gout is increasingly recognized as the most common form of inflammatory arthritis worldwide (e.g., reported prevalence of 3.9% and 2.5% in the United States and United Kingdom, respectively), no Canadian trend data are available.    Objectives: 1) To evaluate the contemporary prevalence and incidence of gout over the past decade, as well as gout treatment patterns and comorbidity burden. 2) To evaluate the burden of hospitalized gout and corresponding inpatient costs as compared to rheumatoid arthritis (RA), another inflammatory joint disease known to incur substantial resource use.  Methods: To address both objectives, I used PopulationData BC, a large administrative database spanning the province of British Columbia (BC). For Objective 1, I used physician and hospital visits to identify gout cases and estimate the annual trends in prevalence and incidence among the general population. I additionally used data from PharmaNet, BC’s prescription drug database, to examine gout treatment patterns (i.e., urate-lowering therapy, colchicine, glucocorticoids, and non-steroidal anti-inflammatory drugs) over the same time period. For Objective 2, I used hospital diagnoses and procedure codes to assess annual trends in hospitalizations and joint surgeries as well as inpatient costs for both gout and RA.  Results: 1) Both the prevalence and incidence of gout have increased over the past decade (i.e., a 59% and 48% increase, respectively), while the prescription of gout treatment remains low. 2) The hospitalization rates for gout have doubled over the past decade, while those for RA have declined by 49%. The inpatient costs iii  also reflected the hospitalization trends, with a 40% decrease in RA hospital costs, while gout costs more than doubled over the study period.   Conclusion: Altogether, this thesis provides evidence that the burden of gout in Canada is substantial and increasing. These findings are further contrasted against the hospitalization burden of RA, which has decreased considerably over the same period. This thesis highlights the critical need to improve gout prevention and care to mitigate its rising disease burden in Canada and beyond.  iv  Preface  Sections of this thesis are multi-authored manuscripts intended for publication in peer-reviewed journals. Details of authors’ contributions are provided below.  Chapter 1: Sharan Rai was responsible for the design, literature search, review and synthesis of studies, and writing of Chapter 1. Dr. Hyon Choi and Dr. J. Antonio Aviña-Zubieta were responsible for critical review of Chapter 1.  Chapter 2: Sharan Rai was responsible for study concept/design, data management and statistical analysis, interpretation of results, manuscript preparation, and corresponding revisions. Dr. Hyon Choi was responsible for study concept/design, statistical analysis, interpretation of results, and preparation and critical review of the manuscript. Dr. J. Antonio Aviña-Zubieta, Dr. Mary De Vera, Dr. Kam Shojania, Dr. Eric Sayre, and Ms. Natalie McCormick were responsible for interpretation of results and preparation and critical review of the manuscript.   Chapter 3: Sharan Rai was responsible for study concept/design, data management and statistical analysis, interpretation of results, manuscript preparation, and corresponding revisions. Dr. Hyon Choi was responsible for study concept/design, statistical analysis, interpretation of results, and preparation and critical review of the manuscript. Dr. J. Antonio Aviña-Zubieta, Dr. Mary De Vera, Dr. Diane Lacaille, Dr. Eric Sayre, and Ms. Natalie McCormick were responsible for interpretation of results and preparation and critical review of the manuscript.  v  Chapter 4: Sharan Rai was responsible for the design, literature search, review and synthesis of studies, and writing of Chapter 4. Dr. Hyon Choi and Dr. J. Antonio Aviña-Zubieta were responsible for critical review of Chapter 4.  This research was reviewed and approved by the UBC Behavioural Research Ethics Board under ethics certificate number H15-00887.     vi  Table of Contents  Abstract ........................................................................................................................................................ ii Preface ......................................................................................................................................................... iv Table of Contents ....................................................................................................................................... vi List of Tables .............................................................................................................................................. ix List of Figures .............................................................................................................................................. x List of Abbreviations .................................................................................................................................. xi Acknowledgements ................................................................................................................................... xii Dedication ................................................................................................................................................. xiv Chapter 1: Introduction and Background .................................................................................................. 1 1.1 Thesis Overview ........................................................................................................................... 1 1.1.1 Research Statement ................................................................................................................ 1 1.1.2 Overview of Thesis Themes and Chapters .............................................................................. 2 1.2 Gout Epidemiology ....................................................................................................................... 3 1.2.1 Westernization and Impact on Gout Burden ............................................................................ 3 1.2.2 Overview of Gout Case Definitions .......................................................................................... 5 1.2.3 Prevalence of Gout .................................................................................................................. 5 1.2.4 Incidence of Gout ..................................................................................................................... 9 1.3 Overview of Thesis Studies ........................................................................................................ 12 1.3.1 Specific Objectives for Thesis Studies ................................................................................... 12 1.3.2 Epidemiologic Studies of Gout in British Columbia, Canada .................................................. 13 1.3.3 Use of Administrative Health Data ......................................................................................... 13 vii  Chapter 2: Trends in Gout Prevalence and Incidence in British Columbia, Canada ........................... 16 2.1 Introduction ................................................................................................................................ 16 2.2 Methods ..................................................................................................................................... 17 2.2.1 Data Sources and Study Population ...................................................................................... 17 2.2.2 Gout Case Definition .............................................................................................................. 17 2.2.3 Estimation of Prevalence and Incidence ................................................................................ 18 2.2.4 Patterns of Gout Treatment ................................................................................................... 19 2.2.5 Assessment of Comorbidities................................................................................................. 20 2.2.6 Statistical Analysis ................................................................................................................. 20 2.3 Results ....................................................................................................................................... 20 2.3.1 Prevalence and Incidence in 2012 ......................................................................................... 20 2.3.2 Annual Trends of Prevalence and Incidence.......................................................................... 28 2.3.3 Comorbidity Burden ............................................................................................................... 36 2.3.4 Prescription Patterns .............................................................................................................. 37 2.4 Discussion .................................................................................................................................. 39 Chapter 3: Trends in Gout Hospitalizations in British Columbia, Canada ............................................ 44 3.1 Background ................................................................................................................................ 44 3.2 Methods ..................................................................................................................................... 45 3.2.1 Study Design and Population ................................................................................................. 45 3.2.2 Statistical Analysis ................................................................................................................. 46 3.3 Results ....................................................................................................................................... 46 3.3.1 Characteristics of the Study Population ................................................................................. 46 3.3.2 Hospitalization Trends ........................................................................................................... 47 viii  3.3.3 Joint Replacement Surgery Trends ........................................................................................ 50 3.3.4 Inpatient Costs ....................................................................................................................... 50 3.4 Discussion .................................................................................................................................. 50 Chapter 4: Conclusion .............................................................................................................................. 55 4.1 Summary of Key Findings .......................................................................................................... 55 4.2 Integration and Implications of Research ................................................................................... 56 4.3 Strengths and Limitations ........................................................................................................... 57 4.4 Future Research Directions and Recommendations .................................................................. 58 4.5 Conclusion ................................................................................................................................. 60 References ................................................................................................................................................. 61  ix  List of Tables  Table 1.1 Summary of Selected Studies Assessing Gout Prevalence ........................................................... 8 Table 1.2 Summary of Selected Studies Assessing Gout Incidence ........................................................... 11 Table 2.1 Prevalence According to Age Category (Primary Case Definition) .............................................. 21 Table 2.2 Prevalence According to Age Category (Secondary Case Definition).......................................... 23 Table 2.3 Incidence According to Age Category (Primary Case Definition) ................................................. 25 Table 2.4 Incidence According to Age Category (Secondary Case Definition) ............................................ 27 Table 2.5 Annual Gout Prevalence (Primary Case Definition) ..................................................................... 29 Table 2.6 Annual Gout Prevalence (Secondary Case Definition) ................................................................ 31 Table 2.7 Annual Gout Incidence (Primary Case Definition) ........................................................................ 33 Table 2.8 Annual Gout Incidence (Secondary Case Definition) ................................................................... 35 Table 3.1 Annual Hospitalization Rate for Patients with Gout or RA ............................................................ 49  x  List of Figures  Figure 1.1 Overview of Thesis ....................................................................................................................... 2 Figure 2.1 Schematic of Run-In Time for Incident Cases ............................................................................ 19 Figure 2.2 Prevalence According to Age Category (Primary Case Definition) ............................................. 22 Figure 2.3 Prevalence According to Age Category (Secondary Case Definition) ........................................ 24 Figure 2.4 Incidence According to Age Category (Primary Case Definition) ................................................ 26 Figure 2.5 Incidence According to Age Category (Secondary Case Definition) ........................................... 28 Figure 2.6 Annual Gout Prevalence (Primary Case Definition) .................................................................... 30 Figure 2.7 Annual Gout Prevalence (Secondary Case Definition) ............................................................... 32 Figure 2.8 Annual Gout Incidence (Primary Case Definition) ...................................................................... 34 Figure 2.9 Annual Gout Incidence (Secondary Case Definition) .................................................................. 36 Figure 2.10 Gout Comorbidity Burden ......................................................................................................... 37 Figure 2.11 Annual Prescription Pattern ...................................................................................................... 38 Figure 3.1 Annual Hospitalization Rate for Patients with Gout or RA .......................................................... 48  xi  List of Abbreviations  ACR  American College of Rheumatology BC  British Columbia CCI  Canadian Classification of Health Interventions CCP  Canadian Classification of Diagnostic, Therapeutic, and Surgical Procedures DIN  Drug Identification Number EMR  Electronic Medical Record ICD  International Classification of Diseases MOH  Ministry of Health MSP  Medical Services Plan NHANES National Health and Nutrition Examination Survey NHS  National Health Service PopData PopulationData BC PY  Person-Years RA  Rheumatoid Arthritis RIW  Resource Intensity Weight SUA  Serum Uric Acid TNF  Tumor Necrosis Factor UK  United Kingdom ULT  Urate-Lowering Therapy USA  United States of America WHO  World Health Organization xii  Acknowledgements  This thesis would not have been possible without the support of a team of extraordinary researchers and healthcare professionals. First, I offer my sincerest gratitude Dr. Hyon Choi for his outstanding mentorship, guidance, expertise, and support over the years. I feel extremely fortunate to have a supervisor who cared so much about my work and trajectory as a young scientist. I thank Dr. J. Antonio Aviña-Zubieta for his mentorship and expertise, and for the wonderful professional development opportunities he provided me throughout my training. I thank Dr. Mary De Vera for her mentorship, wisdom, and collaboration. Finally, I offer my enduring gratitude to Dr. Kam Shojania, for without him I would not be here today.   I am grateful to the UCBeyond Scholarship Program, Lupus Canada, the BC Lupus Society, and the Arthritis Society for their generous funding support during my Master’s training.   I thank the research and administrative team members of Arthritis Research Canada for providing an unparalleled training environment, including Dr. John Esdaile, Dr. Linda Li, Shauneen Kellner, Patricia Webb, Lisa Singh, Dan Aveline, Garrett Hughes, Dylan Davidson, Lindsay Burns, Kathryn Reimer, Lynn Nowoselski, Brendan van As, Joanna Ye, and Jasmina Geldman. Special thanks are owed to Dr. Eric Sayre for teaching me everything I know about statistics and SAS programming. I would also like to thank my fellow graduate students, including Natalie McCormick, Tim Schmidt, Cam Clayton, Pavan Mehat, Jenny Leese, and Alex Klemm for providing methodological, statistical, and life advice.    To the Arthritis Patient Advisory Board, thank you for bringing me into your family. Your stories and experiences are inspiring.  xiii   Lastly, I wish to express my heartfelt gratitude to my family and friends. To Alex Hughes, one of my oldest friends, thank you for your constant words of encouragement. To my mom, dad, grandmother, uncle, and stepfather, thank you for your love and support. This would not have been possible without you.     xiv  Dedication  I dedicate this thesis to my family. To my parents, Nastasha Baron and Charanjit Rai, for supporting me throughout these many years of education, and for inspiring me to pursue my dreams. To my grandmother, Éva Kerti, for showing me that there is nothing that cannot be conquered. To my uncle, John Kerti, for introducing me to the world of science. To my stepfather, Andrew Nagy, for teaching me to never give up. This body of work would not have been possible without you all. 1  Chapter 1: Introduction and Background  1.1 Thesis Overview  1.1.1 Research Statement  The overarching aim of this thesis is to better understand the contemporary burden of gout, an excruciatingly painful form of inflammatory arthritis caused by hyperuricemia [1], in the Canadian context. Gout is associated with a large comorbidity burden [2, 3], as well as premature death [4, 5], reduced health-related quality of life [6], and a high cost of illness [7]. The disease is increasingly becoming recognized as the most common form of inflammatory arthritis worldwide. For example, gout has been estimated to affect as many as 3.9% of adults (8.3 million individuals) in the US according to the National Health and Nutrition Examination Survey (NHANES) 2007-2008, a significant increase since the NHANES III (i.e., prevalence of 2.7% in 1988–1994) [8]. Moreover, a recent study conducted using a United Kingdom (UK) primary care database reported a gout prevalence of 2.5% among the overall population in 2012, which had increased substantially from 1.5% in 1997 [9]. Although more limited, studies of gout incidence have also reported substantial and increasing trends. For instance, according to findings from the Rochester Epidemiology Project, the incidence of primary gout had doubled between the 1970’s and 1990’s [10], and a more recent UK-based study also found an increase in gout incidence over nearly two decades [9]. Despite these findings, no Canadian general population-based trend data on the disease burden of gout are available, calling for a comprehensive investigation of the topic.    2  1.1.2 Overview of Thesis Themes and Chapters  This thesis unifies two distinct themes of the contemporary burden of gout in Canada. Theme 1 is the “Population Burden of Gout” and addresses a question that is of current interest to the Canadian rheumatology community: what is the burden of gout in Canada at the population level, and has it changed over the past decade? Theme 2, “Hospital Burden of Gout” aims to clarify the burden of hospitalized gout, and compare it to that of rheumatoid arthritis (RA), another inflammatory joint disease known to incur substantial resource use [11]. Thus, Theme 2 addresses the following question: what is the in-hospital burden of gout as compared to RA, and has it changed over the past decade? Figure 1.1 provides an overview of the thesis.    Figure 1.1 Overview of Thesis 3  Addressing these research questions has given rise to two original epidemiologic studies using BC’s rich administrative data environment. Following Chapter 1, which provides a comprehensive introduction and covers background material and rationale, are two chapters of original analyses. Chapter 2 is a population-based epidemiologic study that describes the contemporary trends in the prevalence and incidence of gout over the past decade, as well as gout treatment patterns and comorbidity burden. Chapter 3 is an epidemiologic study that describes the contemporary burden of hospitalized gout and corresponding inpatient costs as compared to RA, another inflammatory joint disease known to incur substantial resource use. Following these two content chapters, Chapter 4 synthesizes findings from each independent thesis study and provides a thorough discussion of the strengths, limitations, and implications of this research.  1.2 Gout Epidemiology  Gout, the health problem of interest throughout this thesis, is an excruciatingly painful form of inflammatory arthritis that is caused by hyperuricemia. Traditionally regarded as a “disease of kings”, the disease has evolved to a “disease of commoners” in modern society. This section reviews the epidemiology of gout, including a comprehensive review of the incidence and prevalence of the disease as well as the impact of westernization on gout trends.   1.2.1 Westernization and Impact on Gout Burden  Gout is historically regarded as a disease of the affluent (i.e., “a disease of kings”), affecting middle-aged, wealthy, and upper-class men who were able to afford the comforts—and excesses—of life [1, 12, 13]. However, in today’s society, such a lifestyle has become more affordable and common (particularly in 4  Western societies) in the general population [1, 12, 13]. Together with our society’s growing tendency toward sedentary behaviours, gout has evolved from a “disease of kings” to a “disease of commoners” [1, 12, 13].  Gout is only known to develop spontaneously in humans, likely owing to the fact that humans are the only mammals in which hyperuricemia commonly develops [1, 12, 13]. Unlike humans, most mammals have a low SUA level (ranging from 0.5 to 1.0 mg/dL), resulting from the presence of the enzyme uricase which converts uric acid generated from purine metabolism to allantoin, a more soluble compound that is readily excreted through urine [1, 12, 13]. As in humans, the great apes also lack uricase, and their SUA level is slightly higher than other mammals (ranging from 1.5 to 3.0 mg/dL) [1, 12, 13]; however, these levels are substantially lower than the mean SUA of humans in modern society, which has been reported to be 6.1 mg/dL among men in the US general population [8, 13]. Unlike modern humans, the diet of the great apes consists of fruits and vegetables with a minimal intake of animal protein [1, 12, 13]. Similarly, early humans of hunter-gather societies who consumed traditional diets mainly comprised of fruits and vegetables with occasional consumption of fish and game likely had SUA levels comparable to the great apes [1, 12, 13].  Studies conducted in various geographic settings worldwide have suggested that the prevalence of gout has risen in recent decades [14, 15], which is likely explained by the adoption of lifestyle factors associated with Westernization [1, 12, 13]. For example, gout has become epidemic among certain indigenous populations, such as the Maori people of New Zealand [12, 13, 16, 17]. Prior to the introduction of the Western lifestyle, the Maori primarily consumed a diet of sweet potato, taro, fern root, birds, and fish, and gout was unknown [12, 13, 18]. In the early 1990s, consumption of a diet high in fatty meats and carbohydrates and low in dairy increased, leading to an epidemic of obesity and gout [12, 13, 16, 18]. Similarly, although previously 5  considered rare in blacks in the US, dietary changes have resulted in growing trends in obesity, diabetes, and hypertension, and now gout is more prevalent among blacks than whites [12, 13, 19].  1.2.2 Overview of Gout Case Definitions  As with any other disease, estimates of the prevalence and incidence of gout depend on the case definition selected by the investigative team. The gold standard of gout diagnosis has long been recognized as the confirmation of urate crystals through synovial fluid aspiration [1]. However, as this is not practical for large-scale population studies estimating the burden of disease, other gout case definitions have since been established, including self-reported gout (e.g., as was done in the National Health and Nutrition Examination Survey [NHANES]), the Rome criteria [20], the New York criteria [21], the 1977 American College of Rheumatology (ACR) preliminary criteria [22], and most recently the 2015 ACR/European League Against Rheumatism (EULAR) criteria [23]. Moreover, recent epidemiologic studies of gout and other conditions have utilized large-scale administrative (i.e., claims) health databases or electronic medical record (EMR) databases; in these settings, gout cases can be ascertained using the International Classification of Diseases (ICD) system of diagnostic codes [24-26], which is published and maintained by the World Health Organization (WHO), or the Read Clinical Classification (known more simply as Read codes), a hierarchical coded thesaurus of clinical terms used in the National Health Service (NHS) [9, 27, 28].   1.2.3 Prevalence of Gout  Gout prevalence estimates from various geographic settings and time periods are summarized in Table 1.1 along with their data sources and specific case definitions. Gout is increasingly recognized as the most common form of inflammatory arthritis worldwide [14, 15], and disproportionately affects males as compared 6  to females, particularly prior to menopause (likely owing to increased renal urate clearance by estrogen among females) [1, 13, 29-31]. For example, gout has been estimated to affect as many as 3.9% of adults (8.3 million individuals) in the US according to the NHANES 2007-2008 (prevalence of 5.9% and 2.0% among males and females, respectively), a significant increase since the NHANES III (i.e., prevalence of 2.7% in 1988–1994) [8]. Another US-based study found a similarly increasing trend among a managed care population, with a near-doubling of gout prevalence from 1990-1999 [24].   Similar findings have also been reported in Europe, including in the UK [9] and Italy [26]. Indeed, a recent study conducted using a UK primary care-based EMR database reported a gout prevalence of 2.5% among the overall population in 2012, which had increased substantially from 1.5% in 1997 [9]. An Italy-based study also found an increasing trend in gout prevalence between 2005-2009, although estimates were lower as compared to other studies (i.e., 0.9% in 2009), possibly owing to an increased consumption of the Mediterranean diet among this population which has been suggested to protect against gout risk [26]. Another study conducted in Germany and the UK reported a prevalence of 1.4% during the period 2000-2005, although the authors did not examine annual trends [32].   The highest prevalence estimates have been reported in Oceanian countries, particularly among certain racial and ethnic groups, such as Taiwanese aboriginals as well as Maori people and Pacific Islanders [14]. Indeed, a study conducted among a population of Taiwanese aboriginals (who are closely linked to Pacific Islanders) found a prevalence of nearly 12% [14, 33]. Another study found a prevalence of 15.2% and 4.8% among Taiwanese aboriginal men and women, respectively, compared to 0.3% among non-aboriginals [34]. In New Zealand, prevalence estimates have been reported to be as high as 6.4% and 7.6% among Maori and Pacific Islanders, respectively [16, 17]. Comparatively, estimates have been reported to be much lower 7  in other geographic settings, including Guatemala (0.01%) [35], Venezuela (0.3%) [36], Turkey (0.02%-0.31%) [37, 38], and Pakistan (0.23%) [39].     8  Table 1.1 Summary of Selected Studies Assessing Gout Prevalence First Author Country Study Period Data Source Gout Case Ascertainment Prevalence (%) Trend Wallace [24] USA 1990-1999 Administrative data Either 1 ICD code for gout or 1 prescription for gout Overall: 0.5 ↑ Klemp [16] New Zealand 1992 Physician interview Medical history and exam European: 2.9 Maori: 6.4 ↑ Barnabe [40] Canada 1993-2011 Administrative data Either 2 ICD codes or 1 hospitalization within two years Aboriginals: 0.8 Non-aboriginals: 1.2  NR Chou [33] Taiwan 1994 Physician interview Medical history and exam Aboriginals: 11.7 NR Kuo [9]     UK 1997-2012 EMR database 1 Read code for gout Overall: 2.5 Male: 4.0 Female: 1.1  ↑ Mikuls [41]  UK 1999 EMR database 1 Read code for gout Overall: 1.4 NR Annemans [32]  UK and Germany 2000-2005 EMR database Either 2 ICD codes for gout or 1 ICD code for gout + 1 prescription for gout UK: 1.4 Germany: 1.4 NR Dehlin [42] Sweden 2002-2012 Administrative data 1 ICD code for gout Overall: 1.8 NR Miao [43] China 2004 Physician interview Medical history and exam Overall: 1.1 Male: 1.9  Female: 0.4 ↑ Trifirò [26] Italy 2005–2009 EMR database 1 ICD code for gout Overall: 0.9 Male: 1.5 Female: 0.4 ↑ Kuo [25]  Taiwan 2005-2010 Administrative data 1 ICD code for gout Overall: 6.2 Male: 9.3 Female:  ↔ Zhu [8] USA 2007-2008 NHANES Self-reported gout Overall: 3.9 Male: 5.9 Female: 2.0 ↑ Winnard [17] New Zealand 2009 Administrative data 1 ICD code for gout from a hospital or 1 prescription for gout  European: 3.2 Maori: 6.1 Pacific: 7.6 NR Bardin [44] France  2013 Telephone interview Self-reported gout Overall: 0.9 NR NR, Not reported.   9  1.2.4 Incidence of Gout  As in gout prevalence, many estimates of gout incidence are available worldwide, and a summary of selected studies is available in Table 1.2. Beginning in 1948 as the Johns Hopkins Precursors Study, 1,216 male medical students were enrolled and followed for a median of 29 years, during which 60 cases of incident gout were self-reported for an incidence rate of 1.73 per 1,000 person-years [45]. In the Health Professionals Follow-Up Study (an ongoing longitudinal study of male dentists, optometrists, osteopaths, pharmacists, podiatrists, and veterinarians), 47,150 men were followed for 12 years, after which 730 cases of incident gout were identified that met the American College of Rheumatology (ACR) criteria  (incidence rate, 1.5 per 1,000 person-years) [22]. Similarly, using the Nurses’ Health Study, 89,433 female nurses were followed for 26 years which led to the identification of 896 cases of incident gout that met the ACR criteria (incidence rate, 0.42 per 1,000 person-years) [46]. In the Framingham Heart Study, participants were followed for a median of 28 years, during which 104 and 200 cases of incident gout were identified among women and men, respectively, for an incidence rate of 1.4 and 4.0 per 1,000 person-years [47]. Finally, using data from the Atherosclerosis Risk in Communities Study, Maynard et al. followed 11,963 study participants and found an increased incidence of self-reported physician-diagnosed gout among black and white individuals (i.e., 1.6 vs. 9.4 cases per 1,000 person-years among black and white males, respectively, and 1.2 and 0.5 cases per 1,000 person-years among black and white females, respectively) [48].  Trend data on the incidence of gout are more limited, although most existing studies have reported substantial and increasing trends in various settings. For instance, according to findings from the Rochester Epidemiology Project (an EMR system capturing both inpatient and outpatient records by all local health providers), the incidence of gout had doubled between the 1970’s and 1990’s [10]. A more recent study from 10  the UK using a primary care-based EMR database also found an increase in gout incidence over nearly two decades, reaching an incidence rate of 1.77 new cases per 1,000 person-years in 2012 (2.58 and 0.99 in males and females, respectively) [9]. A similar increase was observed in a study from Western Sweden [42]. Meanwhile, a Taiwan-based study conducted from 2005-2010 found a decrease in gout incidence over the study period (i.e., from 3.93 to 2.74 cases per 1,000 person-years) [25], while an Italy-based study found a stable incidence from 2005-2009 (i.e., 0.93 to 0.95 cases per 1,000 person-years) [26].     11  Table 1.2 Summary of Selected Studies Assessing Gout Incidence  First Author Country Study Period Data Source Gout Case Ascertainment Incidence rate  (per 1,000 PY) Trend Roubenoff [45] USA 1948-1989 Johns Hopkins Precursors Study Self-reported gout Male: 1.7 NR Bhole [47] USA 1950-2002 Framingham Heart Study Medical history and exam Male: 4.0 Female: 1.4 NR Campion [49] USA 1963–1978 Normative Ageing Study Self-reported gout Male: 2.8 NR Choi [46] USA 1980-2006 Nurses’ Health Study ACR criteria Female: 0.4 NR Choi [22] USA 1986-1998 Health Professionals Follow Up Study ACR criteria Male: 1.5 NR Maynard [48] USA 1987-2012 Atherosclerosis Risk in Communities Study Self-reported gout Black male: 1.6 Black female: 1.2 White male: 0.9 White female: 0.5 NR Mikuls [41] UK 1990-1999 EMR database 1 Read code for gout Overall: 1.4 Male: 1.9 Female: 0.7 ↔ Arromdee [10] USA 1995-1996 Rochester Epidemiology Project ACR criteria Overall: 0.5 ↑ Kuo [9] UK 1997-2012 EMR database 1 Read code for gout Overall: 1.8 Male: 2.6 Female: 1.0 ↑ Cea Soriano [50] UK 2000–2007 EMR database 1 Read code for gout Overall: 2.7 Male: 4.4 Female: 1.3 NR Dehlin [42] Sweden 2002-2012 Administrative data 1 ICD code for gout Overall: 1.9 Male: 2.7 Female: 1.2 ↑ Trifirò [26] Italy 2005-2009 EMR database 1 ICD code for gout Overall: 1.0 Male: 1.5 Female: 0.5 ↔ Kuo [25] Taiwan 2005-2010 Administrative data 1 ICD code for gout Overall: 2.7 Male: 4.1 Female: 1.5 ↓ PY, Person-years. NR, Not reported.   12  1.3 Overview of Thesis Studies  In this concluding section, specific objectives addressed in each of the ensuing thesis chapters are highlighted. These chapters represent two population-based epidemiologic studies that separately and collectively contribute to addressing the overall thesis goal of better understanding the disease burden of gout in Canada. Following the objectives, a brief overview of administrative health data is provided.  1.3.1 Specific Objectives for Thesis Studies  1. To describe the contemporary burden of gout in the Canadian context at the general population level.  Chapter 2 is a population-based epidemiologic study that describes the prevalence and incidence of gout over the past decade, as well as gout treatment patterns and comorbidity burden.  2. To describe contemporary trends in the burden of hospitalized gout in Canada, and compared these trends to RA, another form of inflammatory arthritis.   Chapter 3 is an epidemiologic study that describes the contemporary burden of hospitalized gout (including hospitalization and joint surgery rates as well as inpatient costs) as compared to RA.   13  1.3.2 Epidemiologic Studies of Gout in British Columbia, Canada  The two analytic chapters (Chapters 2 and 3) of this thesis are epidemiologic studies that address respective themes of the burden of gout in the Canadian context. Chapter 2’s study falls under Theme 1 by providing a comprehensive assessment of the prevalence, incidence, treatment patterns, and comorbidity burden of gout using a population-based administrative health dataset spanning the entire Canadian province of British Columbia (BC). Chapter 3 falls under Theme 2 and provides an analysis of the in-hospital burden (including hospitalization and surgery rates as well as inpatient costs) of gout as compared to RA, another form of inflammatory joint disease. While several studies have evaluated the burden of gout in other geographic settings worldwide [14, 51], there is a paucity of Canadian trend data, calling for rigorous analyses on the topic.   1.3.3 Use of Administrative Health Data   Administrative health data refers to data that are collected for non-research purposes, generally through routine processing of claims for accessed health services (e.g., physician and hospital visits, medication dispensations) [52]. The use of such data to answer pressing clinical and public health questions has grown remarkably over recent years, and numerous administrative data sources are available in various settings worldwide. For example, in the United States, researchers have access to datasets such as Medicare and Medicaid claims, Veterans Administration, the Healthcare Cost and Utilization Project (e.g., the Nationwide Inpatient Sample), and various private insurers [51-58]. In Canada, where the healthcare system is universal and publicly-funded, various provincial administrative databases are available to researchers including those in BC (i.e., PopulationData BC [PopData], which is used in this thesis), Alberta, Ontario, and Quebec. These 14  well-established databases are internationally recognized as some of the most comprehensive resources for conducting methodologically rigorous epidemiologic studies.  To that effect, PopData (the database used in both analyses comprising this thesis) captures all provincially funded health services since 1990, including health professional visits [59], hospital admissions and discharges [60], demographic data [61], cancer registry files [62], and vital statistics [63]. Furthermore, PopData encompasses a comprehensive prescription drug database, PharmaNet [64], which includes detailed medication dispensation information for all BC residents since 1996. Specific data files utilized in Chapters 2 and 3 include:    The Medical Services Plan (MSP), which encompasses outpatient visits, includes the service date, specialty type (e.g., general practitioner, rheumatologist, etc.), and up to 5 diagnostic codes associated with the visit. All outpatient diagnoses are coded using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM).   Discharge Abstract Database/Hospital Separations File, which encompasses hospitalizations (classified as either acute, day surgery, or rehabilitation), includes the date of admission, length of stay, up to 25 diagnostic codes associated with the hospitalization (coded as either ICD-9-CM or International Classification of Diseases, 10th Revision, Canadian Enhancement [ICD-10-CA] depending on calendar year), any interventions or procedures performed during the stay (coded as either Canadian Classification of Diagnostic, Therapeutic, and Surgical Procedures [CCP] or Canadian 15  Classification of Health Interventions [CCI] depending on calendar year), and resource intensity weights for costing purposes.   BC PharmaNet, which encompasses all prescriptions dispensed in BC community pharmacies, includes the date of dispensation, unique drug identification number (DIN), medication dosage, and days of medication supplied.   The Consolidation File, which is PopData’s central demographics file, contains basic demographic information such as age and sex.    Vital Statistics contains data on all births and deaths registered in BC, as well as the underlying cause of death (using either ICD-9-CM or ICD-10-CA codes depending on calendar year).    16  Chapter 2: Trends in Gout Prevalence and Incidence in British Columbia, Canada  A version of this chapter has been accepted for publication at Seminars in Arthritis & Rheumatism. Rai SK, Aviña-Zubieta JA, McCormick N, De Vera MA, Shojania K, Sayre EC, Choi HK. The Rising Prevalence and Incidence of Gout in British Columbia, Canada: Population-Based Trends from 2000-2012.  2.1  Introduction  Gout is an excruciatingly painful form of inflammatory arthritis caused by hyperuricemia [1]. The disease is associated with a substantial comorbidity burden [2, 3], as well as premature mortality [4, 5], reduced quality of life [6], and a high cost of illness [7]. Gout is increasingly becoming recognized as the most common form of inflammatory arthritis worldwide. For example, gout has been estimated to affect as many as 3.9% of adults (8.3 million individuals) in the US according to the National Health and Nutrition Examination Survey (NHANES) 2007-2008, a significant increase since the NHANES III (i.e., prevalence of 2.7% in 1988–1994) [8]. Moreover, a recent study conducted using a UK primary care database reported a gout prevalence of 2.5% among the overall population in 2012, which had increased substantially from 1.5% in 1997 [9]. Although more limited, studies of gout incidence have also reported substantial and increasing trends. For instance, according to findings from the Rochester Epidemiology Project, the incidence of gout had doubled between the 1970’s and 1990’s [10], and a more recent UK-based study also found an increase in gout incidence over nearly two decades [9].    17  Despite these findings, no Canadian general population-based data on the disease burden of gout are available. To address this, I estimated contemporary trends in the incidence and prevalence of gout in the Canadian province of British Columbia (BC) from 2000-2012 using a large administrative health database spanning the entire province. I also examined annual trends in prescription patterns of common gout medications and assessed the comorbidity burden among gout patients in 2012.  2.2 Methods  2.2.1 Data Sources and Study Population  Universal health coverage is a feature of Canada, including the province of BC (approximately 4.5 million individuals), and PopData is a population-based database from the provincial health care system that includes all patients who received care in BC. PopData captures all provincially funded health services since 1990, including health professional visits [59], hospital admissions and discharges [60], demographic data [61], cancer registry files [62], and vital statistics [63]. Furthermore, PopData encompasses a comprehensive prescription drug database, PharmaNet [64], which includes detailed medication dispensation information for all BC residents since 1996. A more detailed description of this data environment is available in Chapter 1.  2.2.2 Gout Case Definition  This study was comprised of all individuals who contributed data to PopData from 1 January 1990 until 31 December 2012.  To facilitate comparisons with prior studies of gout prevalence and incidence in other countries [9, 17, 24, 25, 41, 42], the primary case definition of gout required at least one recorded principal diagnosis of gout (ICD-9-CM 274 or ICD-10-CA M10) at either a physician or hospital visit (primary case 18  definition). I additionally applied a more restrictive case definition of gout comprised of individuals with at least two recorded principal diagnoses of gout from an outpatient visit on separate dates or at least one recorded principal diagnosis of gout from a hospital visit over the study period (secondary case definition).  2.2.3 Estimation of Prevalence and Incidence  I estimated trends of gout prevalence and incidence according to calendar year from 2000-2012 for the overall population as well as according to sex. To remove the effect of different age and sex structures over the study period, all annual estimates were age-sex-standardized using the population distribution of BC in 2012 as the reference. I additionally estimated the prevalence and incidence of gout by age category in 2012, both in the overall population as well as according to sex. To estimate the prevalence of gout, I defined prevalent cases as those who had received a diagnosis of gout by 1 July of each calendar year, with the number of individuals in BC at the same time point as the denominator. Population estimates were obtained from BC Stats.  To estimate the incidence of gout, I defined new cases as those who met the case definitions for the first time in each calendar year. To ensure incident gout cases, I required all newly diagnosed individuals to have at least ten years of prior registration (i.e., “run-in” period) without any record of a gout diagnosis (Figure 2.1), as has been done in previous epidemiologic investigations of gout [25] and other rheumatic conditions [65]. Individuals previously diagnosed with gout during this run-in period were not eligible to become incident cases. I estimated person-years of at-risk time using population data obtained from BC Stats.   19   Figure 2.1 Schematic of Run-In Time for Incident Cases   2.2.4 Patterns of Gout Treatment  I examined treatment patterns for the following medications commonly used in gout care: urate-lowering therapy (ULT; i.e., allopurinol, febuxostat, probenecid, and sulfinpyrazone), colchicine, oral glucocorticoids, and non-steroidal anti-inflammatory drugs (NSAIDs). All medications were identified using their unique Drug Identification Number provided by the Health Canada Drug Product Database [66]. I ascertained the proportion of prevalent gout cases where the patient received at least one prescription for these medications in each calendar year over the study period. 20  2.2.5 Assessment of Comorbidities  I assessed key comorbidities (i.e., hypertension, hyperlipidemia, diabetes mellitus, chronic kidney disease, heart failure, myocardial infarction, and ischemic stroke) among 2012 prevalent and incident gout cases. Patients were considered to have a given comorbidity of interest if they had received at least one recorded diagnosis for the condition at either an outpatient or hospital visit (a) anytime during the study period for prevalent cases and (b) within 10 years prior to the index date for incident cases.  2.2.6 Statistical Analysis  I analyzed annual trends in incidence, prevalence, and medication use using Poisson regression models that included a variable representing the linear trend from the baseline year of 2000. All p-values were 2-sided with a significance threshold of p<0.05. All statistical analyses were performed using SAS Version 9.4 (SAS Institute, Cary, North Carolina).   2.3 Results  2.3.1 Prevalence and Incidence in 2012  Of 4,542,508 individuals living in BC in 2012, I identified 171,165 prevalent gout cases (68% male, mean age 63 years [standard deviation 15.4]) according to the primary case definition, corresponding to an overall prevalence of 3.8%. Males had a higher overall prevalence of gout as compared to females (5.2% and 2.4%, respectively), and this sex difference persisted across all age categories (Table 2.1 and Figure 2.2). Gout prevalence was low among individuals younger than 30 years of age (less than 1%), and the prevalence 21  increased according to age category thereafter. Among individuals aged 50-59 years, 5.1% of individuals had received a diagnosis of gout, and by 70-79 years, 11.8% had received a diagnosis of gout.   Table 2.1 Prevalence According to Age Category (Primary Case Definition) Age Category  (years) Overall  (%) Males  (%) Females  (%) 0-19 0.07 0.08 0.07 20-29 0.45 0.57 0.32 30-39 1.40 2.03 0.77 40-49 2.99 4.55 1.47 50-59 5.14 7.49 2.82 60-69 8.19 11.61 4.79 70-79 11.80 16.31 7.62 80+ 13.88 19.16 10.32  22   Figure 2.2 Prevalence According to Age Category (Primary Case Definition)   After applying the secondary case definition, I identified 91,028 prevalent gout cases (77% male, mean age 65 years [standard deviation 14.5]), corresponding to an overall prevalence of 2.0%. As in the primary case definition, males had a higher overall prevalence as compared to females (i.e., 3.1% vs. 0.9%), and this sex difference again persisted across all age categories (Table 2.2 and Figure 2.3). Among those 50-59 years old, 2.6% had received a diagnosis of gout, and by 70-79 years, nearly 7% had received a diagnosis of gout.   23  Table 2.2 Prevalence According to Age Category (Secondary Case Definition) Age Category  (years) Overall  (%) Males  (%) Females  (%) 0-19 0.01 0.01 0.01 20-29 0.13 0.21 0.06 30-39 0.58 1.00 0.16 40-49 1.41 2.49 0.35 50-59 2.57 4.39 0.77 60-69 4.51 7.27 1.75 70-79 6.87 10.51 3.49 80+ 8.32 12.70 5.36   24   Figure 2.3 Prevalence According to Age Category (Secondary Case Definition)    With regard to gout incidence, there were a total of 4,384,315 person-years of follow-up in 2012, during which I identified 12,672 incident gout cases according to my primary case definition, corresponding to an overall incidence rate of 2.9 new cases per 1,000 person-years. As in gout prevalence, males had a higher incidence 25  of gout as compared to females (3.8 and 2.0 cases per 1,000 person-years, respectively), and this sex difference persisted across all age categories (Table 2.3 and Figure 2.4). The incidence rate also increased according to age category, reaching nearly 10 new cases per 1,000 person-years among individuals at least 80 years old.  Table 2.3 Incidence According to Age Category (Primary Case Definition) Age Category (years) Overall (per 1,000 PY) Males (per 1,000 PY) Females (per 1,000 PY) 0-19 0.06 0.06 0.07 20-29 0.62 0.86 0.38 30-39 1.61 2.53 0.72 40-49 2.70 4.17 1.31 50-59 4.40 5.97 2.93 60-69 5.87 7.92 3.97 70-79 8.51 10.96 6.43 80+ 9.53 12.00 8.02    26   Figure 2.4 Incidence According to Age Category (Primary Case Definition)       27  After applying the secondary case definition, I found an incidence rate of 1.7 new cases per 1,000 person-years (2.5 and 0.9 new cases per 1,000 person-years among males and females, respectively). As in the primary case definition, the incidence rate increased according to age category (Table 2.4 and Figure 2.5), reaching over 5 new cases per 1,000 person-years among individuals 70-79 years old.  Table 2.4 Incidence According to Age Category (Secondary Case Definition) Age Category (years) Overall (per 1,000 PY) Males (per 1,000 PY) Females (per 1,000 PY) 0-19 0.01 0.01 0.02 20-29 0.25 0.43 0.06 30-39 0.81 1.46 0.17 40-49 1.42 2.57 0.33 50-59 2.34 3.81 0.95 60-69 3.47 5.03 2.00 70-79 5.45 7.69 3.52 80+ 6.32 8.72 4.81     28   Figure 2.5 Incidence According to Age Category (Secondary Case Definition)   2.3.2 Annual Trends of Prevalence and Incidence  Both the crude and age-sex-standardized trends in gout prevalence from 2000-2012 (according to my primary case definition) are shown in Table 2.5 and Figure 2.6. The standardized prevalence among the overall population increased by 59% from 2.4% in 2000 to 3.8% in 2012 (p for trend <0.001). Increasing prevalence trends were also seen among both males and females (p for both trends <0.001).  29   Table 2.5 Annual Gout Prevalence (Primary Case Definition)  Overall (%)  Males (%)  Females (%) Year Crude Prevalence Standardized Prevalence  Crude Prevalence Standardized Prevalence  Crude Prevalence Standardized Prevalence 2000 2.01 2.37  2.85 3.40  1.17 1.35 2001 2.14 2.49  3.04 3.56  1.25 1.43 2002 2.28 2.61  3.23 3.72  1.35 1.52 2003 2.44 2.74  3.44 3.89  1.45 1.61 2004 2.59 2.86  3.63 4.03  1.56 1.70 2005 2.74 2.99  3.82 4.19  1.67 1.80 2006 2.89 3.11  4.03 4.35  1.77 1.88 2007 3.03 3.22  4.21 4.49  1.87 1.97 2008 3.18 3.34  4.40 4.64  1.97 2.06 2009 3.31 3.45  4.57 4.77  2.06 2.14 2010 3.46 3.56  4.77 4.91  2.17 2.23 2011 3.61 3.66  4.97 5.04  2.28 2.31 2012 3.77 3.77  5.17 5.17  2.38 2.38   30   Figure 2.6 Annual Gout Prevalence (Primary Case Definition)   I observed similar rising trends after applying my secondary case definition (p for all trends <0.001) (Table 2.6 and Figure 2.7).  Specifically, the standardized prevalence increased by 64% over the study period among the overall population.     31   Table 2.6 Annual Gout Prevalence (Secondary Case Definition)  Overall (%)  Males (%)  Females (%) Year Crude Prevalence Standardized Prevalence  Crude Prevalence Standardized Prevalence  Crude Prevalence Standardized Prevalence 2000 1.02 1.22  1.60 1.93  0.44 0.51 2001 1.09 1.28  1.71 2.03  0.47 0.55 2002 1.16 1.35  1.84 2.14  0.50 0.57 2003 1.25 1.42  1.97 2.25  0.54 0.60 2004 1.33 1.49  2.09 2.34  0.58 0.64 2005 1.41 1.55  2.22 2.45  0.61 0.67 2006 1.49 1.62  2.35 2.55  0.65 0.71 2007 1.58 1.69  2.47 2.65  0.69 0.74 2008 1.66 1.76  2.60 2.75  0.74 0.77 2009 1.74 1.82  2.71 2.84  0.77 0.81 2010 1.82 1.88  2.84 2.93  0.81 0.84 2011 1.91 1.94  2.97 3.02  0.86 0.87 2012 2.00 2.00  3.12 3.12  0.90 0.90   32   Figure 2.7 Annual Gout Prevalence (Secondary Case Definition)   I also observed similar increasing trends in gout incidence over the study period, with a standardized incidence rate of nearly 2 new cases per 1,000 PY in 2000 which rose to 2.9 new cases per 1,000 PY by 2012 (i.e., a 48% increase; p for trend <0.001) according to my primary case definition. Similar increasing trends were seen among males and females (p for both trends <0.001) (Table 2.7 and Figure 2.8).   33  Table 2.7 Annual Gout Incidence (Primary Case Definition)  Overall (1,000 PY)  Males (1,000 PY)  Females (1,000 PY) Year Crude Incidence Standardized Incidence  Crude Incidence Standardized Incidence  Crude Incidence Standardized Incidence 2000 1.71 1.95  2.25 2.59  1.18 1.34 2001 1.85 2.09  2.47 2.80  1.25 1.41 2002 1.97 2.19  2.63 2.92  1.34 1.49 2003 2.09 2.29  2.68 2.94  1.51 1.65 2004 2.22 2.39  2.90 3.13  1.56 1.68 2005 2.35 2.51  3.08 3.28  1.65 1.76 2006 2.38 2.52  3.18 3.35  1.62 1.71 2007 2.55 2.66  3.39 3.55  1.73 1.82 2008 2.53 2.63  3.32 3.44  1.78 1.84 2009 2.59 2.67  3.45 3.55  1.77 1.83 2010 2.60 2.66  3.46 3.53  1.78 1.82 2011 2.70 2.73  3.57 3.60  1.87 1.89 2012 2.89 2.89  3.79 3.79  2.03 2.03   34   Figure 2.8 Annual Gout Incidence (Primary Case Definition)   I observed reduced estimates in gout burden after applying my secondary case definition, although I again found similar increasing trends over the study period (p for all trends <0.001) (Table 2.8 and Figure 2.9). Specifically, the standardized annual prevalence of gout increased from 1.2% to 2.0% among the overall population from 2000 to 2012. The standardized annual incidence rate also increased from 1.1 to 1.7 new cases per 1,000 PY among the overall population from 2000 to 2012 (according to the secondary case definition).  35  Table 2.8 Annual Gout Incidence (Secondary Case Definition)  Overall (1,000 PY)  Males (1,000 PY)  Females (1,000 PY) Year Crude Incidence Standardized Incidence  Crude Incidence Standardized Incidence  Crude Incidence Standardized Incidence 2000 0.95 1.11  1.42 1.67  0.49 0.58 2001 0.99 1.13  1.49 1.71  0.50 0.58 2002 1.11 1.25  1.68 1.90  0.55 0.63 2003 1.17 1.30  1.75 1.95  0.60 0.67 2004 1.21 1.33  1.79 1.96  0.65 0.71 2005 1.30 1.41  1.93 2.08  0.70 0.76 2006 1.38 1.47  2.05 2.18  0.72 0.78 2007 1.46 1.54  2.19 2.31  0.75 0.80 2008 1.44 1.50  2.11 2.21  0.78 0.82 2009 1.47 1.52  2.18 2.26  0.78 0.81 2010 1.52 1.56  2.23 2.29  0.83 0.85 2011 1.57 1.59  2.34 2.36  0.83 0.84 2012 1.69 1.69  2.48 2.48  0.92 0.92    36   Figure 2.9 Annual Gout Incidence (Secondary Case Definition)   2.3.3 Comorbidity Burden  Of the 171,165 prevalent gout cases identified as of 2012 (according to the primary case definition), 71.9% had ever received a diagnosis of hypertension, compared to 62.9% of incident gout cases over the 10 years prior to gout onset. (Figure 2.10). Similar trends were seen for other key comorbid conditions (Figure 2.10), including hyperlipidemia (52.1% vs. 39.7% among prevalent and incident cases, respectively), diabetes 37  mellitus (18.4% vs. 13.3%), chronic kidney disease (17.1% vs. 13.6%), heart failure (15.3% vs. 11.4%), myocardial infarction (9.7% vs. 5.9%), and ischemic stroke (7.1% vs. 4.7%).    Figure 2.10 Gout Comorbidity Burden   2.3.4 Prescription Patterns  The temporal trend in anti-gout medication use among prevalent gout patients from 2000-2012 is shown in Figure 2.11. Approximately one in five patients received treatment with ULT over the study period (range 22.3% to 22.9%). Allopurinol use constituted the majority of ULT prescriptions, with less than 1% of prevalent 38  cases receiving a dispensation of febuxostat, probenecid, or sulfinpyrazone over the study period (i.e., prevalence of  use=0.6%, 0.04%, and 0.02%, respectively, in 2012). Both colchicine and glucocorticoid use showed increasing trends (p for both trends <0.001) over the study period (Figure 2.11). Specifically, colchicine use increased by 50%, reaching nearly 9% of prevalent gout cases in 2012, while glucocorticoid use increased by 43%, reaching 8.5% of cases in 2012. Conversely, the prescription of traditional NSAIDs declined by 31% over the study period from 35.4% in 2000 to 24.5% in 2012 (p for trend <0.001) (Figure 2.11).   Figure 2.11 Annual Prescription Pattern  39   2.4 Discussion  In this large general population-based study, I found that both the prevalence and incidence of gout have increased substantially over the past decade, constituting a modern gout epidemic. Specifically, the annual prevalence of gout increased by 59% such that 3.8% of individuals in BC had received a diagnosis of gout by 2012. Moreover, the annual incidence rate increased by 48% over the study period, reaching 2.9 new cases per 1,000 person-years in 2012. These increasing trends persisted when I applied a more restrictive definition of gout. My analysis of treatment patterns showed a stable trend of ULT prescription over the study period, with approximately one in five patients receiving treatment with ULT, whereas colchicine and glucocorticoid use increased modestly. Finally, I also found a substantial comorbidity burden among those with gout. These findings collectively provide the first contemporary trend data on the burden of gout and pattern of gout treatment in a Canadian general population context.  Gout prevalence had increased substantially over the study period, which is consistent with prior literature from other countries, and particularly with estimates from other western societies. Specifically, I observed a prevalence of 3.8% among the overall BC population in 2012 (5.2% and 2.4% among males and females, respectively), which coincides with the US general population prevalence estimate of 3.9% (5.9% and 2.0% among males and females, respectively) from the NHANES 2007-2008 (based on self-reported physician-diagnosed gout) [8]. These data based on the NHANES 2007-2008 were significantly higher than those in the NHANES III (which reported prevalence of 2.7% in 1988-1994) [8]. Moreover, another study conducted among a US managed care population also found an increasing prevalence over a ten-year period, from 2.9 to 5.2 cases per 1000 enrollees [24]. Such increasing trends in gout prevalence have also been reported in 40  other countries from other continents, including the UK [9, 67], Italy [26], China [43], New Zealand [16], and urban African communities [68]. My age-specific prevalence estimates also tended to agree with previously reported ranges. For example, I observed 2012 prevalence estimates of 5.1% and 13.9% among individuals 50-59 years of age and at least 80 years old, respectively; the NHANES 2007-2008 data found age-specific prevalence estimates of 3.7% and 12.6% among individuals 50-59 years and at least 80 years old, respectively, similar to my estimates [8] Further, a UK-based study reported a 2012 prevalence of approximately 5% and 10% among those 55-59 and 80-84 years old, respectively, also similar to my estimates [9].   My gout incidence trends were also consistent with data from other western countries, although prior incidence data are more limited. I found incidence rates of 2.9, 3.8, and 2.0 per 1,000 person-years among the overall population, males, and females, respectively, in 2012, which coincides with US-based estimates of 4.0 and 1.4 per 1,000 person-years among men and women, respectively (based on prospectively collected, community-based data from the Framingham Heart Study) [47]. Similarly, a UK-based study found an incidence rate of 2.7 new cases per 1,000 person-years (4.4 and 1.3 in men and women, respectively) among adults during 2000-2007 [50]. The increasing trend in gout incidence found in this study has also been previously reported in other settings. For example, the Rochester Epidemiology Project found that the incidence of those with gout had doubled between 1977-1978 and 1995-1996 [10], as in the increasing trends reported here. Similarly, in the UK, the incidence rate among the overall population reached 1.8 new cases per 1,000 person-years in 2012 [9], corresponding to a 30% increase since 1997.   This rising gout burden identified in this study may be explained by similar increasing Canadian trends of associated conditions, including those of obesity [69-71] and hypertension [72]. Thus, efforts to stop or reduce 41  this increasing disease burden could focus on modifiable risk factors for gout and its causal precursor (hyperuricemia), including the presence of other chronic conditions (e.g., obesity [73]), the use of certain medications (e.g., choice of antihypertensive agent [74]), and dietary and lifestyle factors (e.g., consumption of red meat [75, 76], alcohol [77, 78], and sugar-sweetened soft drinks [79, 80]).   My analysis of prescription patterns showed a stable trend of ULT use from 2000 to 2012 (ranging from 22.3% to 22.9%), which has also been observed in other countries worldwide. For instance, two recent studies from the UK and Taiwan also found unchanging trends in ULT treatment among prevalent gout patients, with approximately 25-35% of patients receiving ULT over the study period [9, 25]. In an earlier UK-based study (i.e., 1990-1999), Mikuls et al. also reported a stable proportion of allopurinol use, ranging from 25-30% [41]. I additionally found a substantial decreasing trend of NSAID use (i.e., from 35% to 25%) from 2000 to 2012. In the decade immediately prior (i.e., 1990-1999), Mikuls et al. reported a similar declining trend in the UK, with a decrease from 67% at the beginning of the study to 41% by 1999 [41]. The continuing decline in NSAID use observed in this study was contrasted by a modest increase in both colchicine and glucocorticoid use among gout patients over the study period. By comparison, a recent US-based study reported an increasing trend of colchicine initiation among those with newly diagnosed gout until the medication’s substantial price increase in the US, after which colchicine initiation declined [81, 82]. Meanwhile, such a decline was not observed in the current Canadian setting where colchicine remains at its original low cost.   My study also found a substantial comorbidity burden among gout patients, similar to many prior studies from other countries [2, 3, 26, 32, 41]. Specifically, approximately 72% of prevalent gout patients had been diagnosed with hypertension as of 2012, as well as 52% with hyperlipidemia, 18% with diabetes, 17% with 42  kidney disease, 15% with heart failure, 10% with myocardial infarction, and 7% with ischemic stroke. These findings are highly consistent with prior findings from other countries; for example, according to the 2007-2008 NHANES in the US, 74% of those with gout had hypertension, 26% had diabetes, 14% had a myocardial infarction, and 11% had heart failure [2]. I additionally identified a large level of prior comorbidity among those who were newly diagnosed with gout in 2012. In my analysis of incident gout cases, 63% had already been diagnosed with hypertension, 40% with hyperlipidemia, and 13% with diabetes, showing a substantial comorbidity burden even in the ten years prior to gout diagnosis.  The strengths and limitations of this study deserve comment. First, I used a population-based dataset covering the entire province of BC, thereby ensuring capture of all provincial residents covered by BC’s healthcare program who sought care for their gout during the study period. My study spanned over two decades, thereby providing a 23-year ascertainment period to maximize the capture of prevalent cases. My primary case definition allowed for comparisons with multiple prior studies using similar methodology [9, 17, 24, 25, 41, 42].  Nevertheless, a certain level of misclassification of diagnostic codes in a study using an administrative database such as mine is inevitable. However, I restricted my case definitions to include only those with a diagnosis of gout in the primary position, which has previously been shown to substantially improve the validity of the case definition and thus minimize misclassification bias [83-85]. Moreover, my estimates agreed very well with findings from other countries as discussed above. Furthermore, I additionally applied a more restrictive definition, which also showed increasing trends in both incidence and prevalence.  Finally, to reduce the potential misclassification of prevalent cases as incident cases, I applied a rigorous 10-year run-in period during which individuals could have no prior gout diagnosis.  43  In conclusion, these contemporary findings from an entire Canadian province demonstrate that both the prevalence and incidence of gout have increased substantially over the past decade, constituting a substantial disease burden. By 2012, nearly 4% of individuals in BC had received a diagnosis of gout, while only one in five patients have received treatment with ULT. These data support the need to improve gout prevention and care.      44  Chapter 3: Trends in Gout Hospitalizations in British Columbia, Canada  A version of this chapter has been accepted for publication at Arthritis Care & Research. Rai SK, Aviña-Zubieta JA, McCormick N, De Vera MA, Lacaille D, Sayre EC, Choi HK. Trends in Gout and Rheumatoid Arthritis Hospitalizations in Canada from 2000-2011.  3.1 Background  Gout and rheumatoid arthritis (RA) are the two most common forms of inflammatory arthritis worldwide. As hospitalizations for both conditions lead to substantial health resource use, contemporary inpatient trends and associated costs may provide important benchmarks of disease burden. For example, a previous study during the pre-biologic era found that hospital costs accounted for more than half of the total medical costs of RA [11]. Indeed, varying levels of perceived success in care and changing epidemiology may have substantially impacted the hospitalization trends of RA and gout over the past decade. For example, new potent drugs (e.g., biologics), effective combination therapy, and management strategies (e.g., treating to target, early RA intervention) have become increasingly adopted for RA care [86-88]; however, whether these perceived improvements have been translated into a reduction in hospitalization rates and costs among RA patients in recent years is largely unknown. In contrast, despite the availability of effective pharmacological options, gout management remains remarkably suboptimal with a high rate of recurrent attacks [89-91]. Further, the prevalence and incidence of gout have been increasing worldwide [9, 10, 14, 42]. Nevertheless, 45  as in RA, whether these factors have translated to rising hospitalization trends among gout patients also remains unclear.  Thus, to fill this important knowledge gap, I evaluated contemporary hospitalization trends for gout and RA in a Canadian general population context from 2000 to 2011. I examined both conditions concurrently as I hypothesized contrasting trends over the past decade, and as each condition could serve as the other’s internal comparison group.  3.2 Methods  3.2.1 Study Design and Population  I utilized PopData, a population-based dataset spanning the entire Canadian province of British Columbia (BC). PopData captures all provincially-funded health care services, including hospital admissions and discharges [60]. A more detailed description of this data environment is available in Chapter 1. I included patients at least 18 years of age who were hospitalized during the study period with a principal diagnosis of either gout (ICD-9-CM 274 or ICD-10-CA M10) or RA (ICD-9-CM 714 or ICD-10-CA M05 or M06). I studied the temporal hospitalization trends of RA and gout, both among the overall population as well as according to age and sex, using data from 2000-2011.  I also assessed the trend of hospitalizations for total hip and knee replacements among study patients, as I anticipated the main reason for hospitalization with a principal discharge diagnosis of RA would be for these joint-related surgeries. All joint surgeries were identified using the Canadian Classification of Diagnostic, Therapeutic, and Surgical Procedures (CCP) and Canadian Classification of Health Interventions (CCI). 46  Furthermore, I evaluated the inpatient economic burden for both conditions using Resource Intensity Weights determined by the Canadian Institute for Health Information.  3.2.2 Statistical Analysis  I calculated annual rates of hospitalizations (expressed per 100,000 Canadian adults) for gout and RA. I assessed annual trends in hospitalization and surgery rates using Poisson regression models that included a variable representing the linear trend from the baseline year of 2000; a similar analysis was conducted for hospitalization costs with linear regression. Costs were inflation-adjusted to 2011 Canadian dollars using the Consumer Price Index. All p-values were 2- sided with a significance threshold of p<0.05. Statistical analyses were performed using SAS Version 9.4 (SAS Institute, Cary, North Carolina).  3.3 Results  3.3.1 Characteristics of the Study Population  I identified 4604 and 2136 hospitalizations for RA and gout, respectively, between 2000 and 2011. Approximately 68% of hospitalizations with a principal diagnosis of gout were for males, and approximately 76% were 65 years or older. Conversely, 77% of hospitalizations with a principal diagnosis of RA were for females, and approximately 44% were 65 years or older. The demographics for both conditions were stable throughout the study period.   47  3.3.2 Hospitalization Trends  From 2000 to 2011, the annual hospitalization rate for those with a principal diagnosis of RA declined by 49% from 15.4 to 7.9 per 100,000 Canadian adults (p<0.001), whereas that for gout increased by 100% (i.e., doubled) from 3.8 to 7.6 per 100,000 Canadian adults (p<0.001) (Figure 3.1 and Table 3.1). Thus, at the beginning of the study period, hospitalizations for RA were approximately 4 times more frequent than those for gout; however, these opposing trends of the two conditions led to similar hospitalization rates by 2011 (i.e., 7.9 and 7.6 per 100,000 Canadian adults for RA and gout, respectively). These trends persisted in subgroups according to age and sex (Table 3.1).  48   Figure 3.1 Annual Hospitalization Rate for Patients with Gout or RA         49  Table 3.1 Annual Hospitalization Rate for Patients with Gout or RA   Year 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 P for trend Gout Overall 3.8 3.5 4.0 5.2 4.8 5.6 5.1 5.3 5.2 6.2 6.4 7.6 <0.001 Sex                Male 5.0 4.9 5.5 7.3 7.1 7.6 7.0 6.6 7.7 8.5 8.8 10.7 <0.001   Female 2.6 2.2 2.5 3.1 2.6 3.7 3.2 4.0 2.8 4.0 4.0 4.5 <0.001 Age Group                <65 years 1.1 1.1 1.2 1.5 1.6 1.6 1.3 1.6 1.6 1.8 1.8 2.2 0.001   65+ years 16.9 15.2 17.3 22.9 20.0 24.8 22.5 22.3 22.0 26.5 26.8 30.7 <0.001 Rheumatoid Arthritis Overall 15.4 13.9 12.4 13.5 12.0 12.6 12.3 10.4 9.3 9.0 8.7 7.9 <0.001 Sex                Male 6.9 6.2 5.3 6.3 5.5 6.2 6.2 5.0 4.1 3.9 3.8 3.7 <0.001   Female 23.5 21.3 19.3 20.4 18.2 18.8 18.1 15.7 14.4 14.0 13.5 12.0 <0.001 Age Group                <65 years 10.9 9.3 8.2 9.4 7.6 8.3 8.0 7.2 6.3 6.6 6.3 5.2 <0.001   65+ years 37.5 36.3 32.7 33.3 32.7 33.2 32.3 25.4 23.3 20.1 19.4 19.5 <0.001 50  3.3.3 Joint Replacement Surgery Trends  Approximately 31% of hospitalizations with a principal discharge diagnosis of RA were associated with total hip or knee replacement. From 2000 to 2011, the rate of these surgeries in patients with a principal discharge diagnosis of RA decreased from 3.8 to 2.9 per 100,000 Canadian adults (p=0.0097). In contrast, less than 1% of hospitalizations with a principal discharge diagnosis of gout were associated with total hip or knee replacement.  3.3.4 Inpatient Costs  The inflation-adjusted inpatient costs with a principal diagnosis of gout more than doubled over the study period from $19,426 to $43,783 (2011 CAD) per 100,000 Canadian adults (p<0.001), whereas those for RA decreased by 40% from $103,314 to $62,348 per 100,000 Canadian adults (p=0.0023) over the same period.  3.4 Discussion  My findings indicate that hospitalization rates for those with a principal diagnosis of gout have doubled over the past decade, while those for RA have decreased substantially. These opposing trends were also reflected by the inpatient cost burden. My findings support perceived improvements in RA care over recent decades, including the use of effective therapies and management strategies [86-88]. These data are also consistent with the widely-reported suboptimal care of gout patients [89-91], in addition to the increasing incidence and prevalence of the disease worldwide [9, 10, 14, 42]. Thus, while these findings provide an encouraging benchmark for the improvement in RA care over the past decade, they also highlight the critical need to improve gout management and prevention to mitigate its rising disease burden in Canada and beyond. 51   From 2000 to 2011, I found that hospitalizations with a principal diagnosis of RA had progressively declined (i.e., nearly halved), and the corresponding costs showed a similar declining trend. These trends are meaningful as more than half of the total medical costs of RA during the pre-biologic era were for hospitalizations [11], and my data suggest that the contribution of hospitalizations to the costs of modern RA care (specifically during the biologic era) are substantially lower. As the incidence of RA among Canadians has previously been found to be stable during the study period [92], these trends should reflect the improvements in RA care over the past decade, including the use of effective therapies (e.g., methotrexate, combination therapy, and biologics) and management strategies (e.g., treating to target, early RA intervention) [86-88]. For example, a recent analysis of 57 UK hospitals found a 46% decline in RA inpatient days between 1996 and 2010, while also reporting a tripling in methotrexate prescriptions between 2001 and 2012 and a 156% annual increase in the use of TNF inhibitors [93]. These changes have likely contributed to the declining rates of severe systemic complications of RA (e.g., rheumatoid vasculitis, splenectomy for Felty’s syndrome, and cervical fusion) observed previously [94, 95], as well as reduced rates of major joint surgeries as observed in my study.  My finding of a declining rate in joint replacement surgery in RA patients is generally consistent with the results of previous analyses from other settings, including California state data (1983-2007) [96], 57 UK hospitals (1996-2010) [93], and 8 German practices [97]. Notably, these decreasing trends among RA patients contrast the overall dramatic increase of these surgeries among the Canadian general population [98]. For example, according to the Canadian Joint Replacement Registry, the number of hip and knee replacements increased by 101% between 1995-1996 and 2005-2006 (i.e., a 10-year period) and by 17% between 2004-2005 and 2005-2006 [98]. 52   In contrast, I found a doubling of the annual hospitalization rate (adjusted for population growth) for patients with a principal diagnosis of gout over the study period. A recent study found a similarly increasing number of primary gout hospitalizations in New Zealand and England between 1999 and 2009, although hospitalization rates were not reported [99]. Moreover, my inpatient trends are consistent with the increasing incidence of gout in Canada over the same study period (i.e., a 30% increase) (Chapter 2). However, this magnitude of increase appears substantially smaller than that of gout hospitalizations, as above.  Thus, these increasing inpatient trends are highly likely due to suboptimal gout care [89-91], which has been shown to contribute to many avoidable hospitalizations. For example, a recent abstract highlighted that up to 89% of hospitalizations with a primary diagnosis of gout were preventable, owing to inefficient or inadequate care [100]. For example, although the vast majority of gout patients are indicated for urate-lowering therapy (ULT) (e.g., 87% within 5 years of diagnosis), only a small proportion receive treatment [101]. Further, despite the well-established serum uric acid target (i.e., ≤ 5 or 6 mg/dL), the level is not even measured in the vast majority of patients in current practice, even after ULT prescription [23, 102]. Moreover, many patients are often prescribed ULT at a single insufficient fixed dose [90, 103]. Finally, few patients receive a clear explanation about their gout and treatment expectations (e.g., the ‘curable’ nature of the disease) or appropriate lifestyle advice to reduce risk factors [104, 105]. As a consequence, only a minority become free of gout, with the majority continuing to experience acute attacks, thereby contributing to an increased inpatient burden as observed in my study [90, 103].  My study also provides contemporary data on the cost burden associated with hospitalizations for gout and RA. Reflecting the increase in annual hospitalization rates, the annual costs related to primary gout 53  hospitalizations more than doubled over the study period. Similarly, a US-based study reported increasing charges of $38 million from 2006 to 2008 for emergency visits with gout as the principal diagnosis [106]. In contrast, I found that hospital costs related to primary RA admissions declined by 40% over the study period. These findings are consistent with a recent analysis of eight German clinics or practices that showed a 13% to 22% decrease in hospitalization costs per capita, which partially offset the increasing costs of biologic use in the same study population [97].  The strengths of my study deserve comment. First, I used a large population-based dataset spanning the entire province of BC, thereby ensuring capture of all residents covered by BC’s universal healthcare program who were hospitalized for RA or gout during the study period. Further, my study simultaneously addressed the two most common inflammatory arthritic conditions using one dataset, which allowed for an internal control group for each condition to help protect against the potential limitations discussed further below. For example, because PopData is an administrative database, certain levels of misclassification of diagnostic codes are inevitable. However, to improve the validity of my case definition and thus minimize misclassification bias, I limited my case definitions to principal diagnoses. Finally, changes in hospital billing practices over time may account for changes in hospitalization trends; however, the observed contrasting trends of these two arthritic conditions would not be explained by such unlikely secular changes in coding arthritic conditions.  In conclusion, my findings based on these population-based data indicate that hospitalization rates and the inpatient economic burden of gout have increased substantially over the past decade, while those for RA have decreased considerably. Thus, while these findings provide an encouraging benchmark for the 54  improvement in RA care over the past decade, they also highlight the critical need to improve gout management and prevention to mitigate its rising disease burden in Canada and beyond.     55  Chapter 4: Conclusion  The body of original work comprising this thesis (Chapters 2 and 3) is unified by the common and overarching goal of better understanding the contemporary burden of gout in the Canadian context. In this concluding chapter, key results arising from each independent study are highlighted, the implications, strengths, and limitations of the collective work are further discussed, and specific recommendations are made for future research.  4.1 Summary of Key Findings  Addressing the overarching goal of better understanding the contemporary burden of gout in the Canadian context first called for a comprehensive epidemiologic investigation of the prevalence and incidence of gout. Chapter 2’s original analysis using an administrative health database spanning the entire province of BC directly addressed this research gap by providing population-based estimates of gout’s prevalence and incidence from 2000-2012. This study found that both the prevalence and incidence of gout have increased substantially over the past decade, constituting a modern gout epidemic. Specifically, the annual prevalence of gout increased by 59% such that 3.8% of individuals in BC had received a diagnosis of gout by 2012. Moreover, the annual incidence rate increased by 48% over the study period, reaching 2.9 new cases per 1,000 person-years in 2012.   Building on Chapter 2’s original analysis, Chapter 3 reported the results of a subsequent epidemiologic investigation of the in-hospital burden of gout, including hospitalization and joint surgery rates as well as 56  inpatient costs. This subsequent chapter further employed rheumatoid arthritis (the second most common form of inflammatory arthritis) as an internal comparison group for relevant trends of interest.  Key findings from Chapter 3 indicate that hospitalization rates for those with a principal diagnosis of gout have doubled over the past decade, while those for RA have decreased substantially. These opposing trends were also reflected by the inpatient cost burden. These findings support perceived improvements in RA care over recent decades, including the use of effective therapies and management strategies. These data are also consistent with the widely-reported suboptimal care of gout patients, in addition to the increasing incidence and prevalence of the disease in Canada (shown in Chapter 2).   4.2 Integration and Implications of Research  This thesis integrates two distinct population-based epidemiologic investigations to comprehensively evaluate the contemporary burden of gout in the Canadian context. Altogether, this body of work has identified that the burden of gout is substantial and rising, with a 59% and 48%  increase in the prevalence and incidence of the disease, respectively, as well as a doubling of the primary hospitalization rate over the past decade. Conversely, RA (the second most common form of inflammatory arthritis for which new treatments and management strategies have become available) patients have experienced a decline in the primary hospitalization and joint surgery rate, supporting the perceived improvements in care for RA. This body of work has several important implications for the gout field. First, as the rising gout burden may be explained by similar increasing Canadian trends of associated conditions, including those of obesity [69-71] and hypertension [72], efforts to stop or reduce this increasing disease burden are urgently needed. Such efforts could focus on modifiable risk factors for gout and its causal precursor (hyperuricemia), including the presence of other chronic conditions (e.g., obesity [73]), the use of certain medications (e.g., choice of 57  antihypertensive agent [74]), and dietary and lifestyle factors (e.g., consumption of red meat [75, 76], alcohol [77, 78], and sugar-sweetened soft drinks [79, 80]). Next, the doubling of primary gout hospitalizations over the past decade, which are highly likely owing to the widely reported suboptimal care of this ‘curable’ condition (as well as the increasing prevalence and incidence of gout over the same period) [89-91, 105], highlight the critical need to improve gout management.   4.3 Strengths and Limitations  As Chapters 2 and 3 each provided their own comprehensive discussion of study-specific strengths and limitations, this section will focus on the collective body of work with a particular emphasis on study design and the use of administrative health data. Where possible, issues that are consistent across independent thesis studies will be highlighted.   Methodological strengths of Chapter 2 include the application of a rigorous 10-year run-in period during which individuals could have no prior gout diagnosis to minimize the misclassification of prevalent cases as incident cases, as has been done in other studies of gout [25] and other rheumatic disease conditions [65], as well as the selection of a primary case definition which allowed for comparisons with multiple prior studies using methodology [9, 17, 24, 25, 41, 42].  As detailed in Chapter 1, the use of large-scale administrative databases has grown remarkably over recent years, and such data have become extremely valuable resources for the conduct of epidemiologic studies. Accordingly, both thesis studies used PopData, a large-scale population-based administrative health dataset spanning the entire Canadian province of BC, thereby ensuring capture of all provincial residents covered by 58  BC’s healthcare program who sought care for their gout or RA during the study period. This comprehensive data source captured all outpatient visits and hospitalizations over the study period and additionally provided pertinent patient-level data including demographics and vital statistics information which enabled me to evaluate the burden of disease on a truly population level.   It is also important to recognize the limitations of administrative databases. Such administrative data are routinely collected for non-research purposes, generally through routine processing of claims for accessed health services (e.g., physician and hospital visits, medication dispensations). Thus, a certain level of misclassification of diagnostic codes is inevitable in studies using such data. However, across both thesis studies, I restricted the case definitions for gout (and RA, in the case of Chapter 3) to include only those with a diagnosis in the primary position, which has previously been shown to substantially improve the validity of the case definition and thus minimize misclassification bias [83-85]. Moreover, as discussed in Chapter 2, I additionally applied a secondary, more restrictive case definition of gout, which did not change the overall trends.  4.4 Future Research Directions and Recommendations  This thesis has provided a comprehensive evaluation of the burden of gout in the Canadian province of BC, including the first trend data of gout prevalence and incidence as well as an analysis of the in-hospital burden of gout as compared to RA, another form of inflammatory arthritis. As above, key findings include the substantial and rising burden of gout in BC, with a 59% and 48% increase in the prevalence and incidence of the disease (Chapter 2), respectively, as well as a doubling of the primary hospitalization rate over the past decade (Chapter 3). These findings are in contrast to RA, which saw a decline in the primary 59  hospitalization rate, inpatient cost burden, and joint surgery rate, supporting perceived improvements in RA care over recent decades, including the use of effective therapies and management strategies (Chapter 3). Collectively, these alarming findings give rise to the following key future research directions and recommendations:  1) Identification of preventive measures to halt or reduce the rising disease burden of gout.  As above, efforts could focus on modifiable risk factors for gout and its causal precursor (hyperuricemia), including the presence of other chronic conditions (e.g., obesity [73]), the use of certain medications (e.g., choice of antihypertensive agent [74]), and dietary and lifestyle factors (e.g., consumption of red meat [75, 76], alcohol [77, 78], and sugar-sweetened soft drinks [79, 80]). Moreover, emerging studies have suggested protective impacts of major dietary patterns (i.e., the DASH and Prudent diets) [107] which may offer an attractive non-pharmacological approach for gout prevention and management and is likely to be a fruitful area of research.   2) Improvement of gout care to avoid costly and preventable hospitalizations.  Despite our understanding of gout’s pathogenesis (e.g., the direct causal role of hyperuricemia and the ‘curable’ nature of the disease) and available ULT, gout care remains remarkably suboptimal [89-91, 105]. Indeed, one study found that up to 89% of hospitalizations were preventable, arising due to gaps in clinical care [100], further highlighting the critical need for future research to improve the quality of gout care. Indeed, 60  a recent UK-based proof-of-concept clinical study showed that remarkable success rates can be achieved by implementing a comprehensive nurse-led educational intervention to achieve and sustain SUA treatment targets (i.e., 92% reaching the target SUA goal of <6 mg/dL) [108], forming an excellent foundation for further research this area with the eventual goal of large-scale policy change to facilitate the uptake of multidisciplinary gout care involving allied health professionals.  4.5 Conclusion  In this comprehensive investigation of the burden of gout in the Canadian province of BC, several key points are emphasized. First, in a population-based epidemiologic study, I identified that the prevalence and incidence of gout have both increased substantially over the past decade, constituting a modern gout epidemic. Second, in a subsequent study of the in-hospital burden of gout as compared to RA (another form of inflammatory arthritis), I identified a doubling of the primary gout hospitalization rate over the past decade as well as a substantial increase in the inpatient economic burden. This finding was in sharp contrast to RA, which saw a decline in the in-hospital burden, supporting perceived improvements in RA care over recent decades. These findings collective demonstrate that the burden of gout is substantial in BC, and highlight the critical need to improve gout management and prevention to mitigate its rising disease burden in Canada and beyond. 61  References  1. Choi HK, Mount DB, Reginato AM. Pathogenesis of Gout. Annals of Internal Medicine 2005;143:499-516. 2. Zhu Y, Pandya BJ, Choi HK. 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