Hyon K. Choi

Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II.

OBJECTIVE To provide a single source for the best available estimates of the US prevalence of and number of individuals affected by osteoarthritis, polymyalgia rheumatica and giant cell arteritis, gout, fibromyalgia, and carpal tunnel syndrome, as well as the symptoms of neck and back pain. A companion article (part I) addresses additional conditions. METHODS The National Arthritis Data Workgroup reviewed published analyses from available national surveys, such as the National Health and Nutrition Examination Survey and the National Health Interview Survey. Because data based on national population samples are unavailable for most specific rheumatic conditions, we derived estimates from published studies of smaller, defined populations. For specific conditions, the best available prevalence estimates were applied to the corresponding 2005 US population estimates from the Census Bureau, to estimate the number affected with each condition. RESULTS We estimated that among US adults, nearly 27 million have clinical osteoarthritis (up from the estimate of 21 million for 1995), 711,000 have polymyalgia rheumatica, 228,000 have giant cell arteritis, up to 3.0 million have had self-reported gout in the past year (up from the estimate of 2.1 million for 1995), 5.0 million have fibromyalgia, 4-10 million have carpal tunnel syndrome, 59 million have had low back pain in the past 3 months, and 30.1 million have had neck pain in the past 3 months. CONCLUSION Estimates for many specific rheumatic conditions rely on a few, small studies of uncertain generalizability to the US population. This report provides the best available prevalence estimates for the US, but for most specific conditions more studies generalizable to the US or addressing understudied populations are needed.

Genetics of rheumatoid arthritis contributes to biology and drug discovery

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Prevalence of gout and hyperuricemia in the US general population: The National Health and Nutrition Examination Survey 2007–2008

OBJECTIVE To estimate the prevalence of gout and hyperuricemia based on the latest nationally representative sample of US men and women (National Health and Nutrition Examination Survey [NHANES] 2007-2008). METHODS Using data from 5,707 participants in NHANES 2007-2008, we estimated the prevalence of gout and hyperuricemia. During home interviews for NHANES 2007-2008, all participants were asked about a history of health professional- or physician-diagnosed gout. Our primary definition of hyperuricemia was a serum urate level of >7.0 mg/dl for men and >5.7 mg/dl for women. We explored potential secular trends in these estimates and their possible explanations by comparing them with estimates based on 18,825 participants in NHANES-III (1988-1994). RESULTS The prevalence of gout among US adults in 2007-2008 was 3.9% (8.3 million individuals). The prevalence among men was 5.9% (6.1 million), and the prevalence among women was 2.0% (2.2 million). The mean serum urate levels were 6.14 mg/dl among men and 4.87 mg/dl among women, corresponding to hyperuricemia prevalences of 21.2% and 21.6%, respectively. These estimates were higher than those in NHANES-III, with differences of 1.2% in the prevalence of gout (95% confidence interval [95% CI] 0.6, 1.9), 0.15 mg/dl in the serum urate level (95% CI 0.07, 0.24), and 3.2% in the prevalence of hyperuricemia (95% CI 1.2, 5.2). These differences were substantially attenuated after adjusting for body mass index and/or hypertension. CONCLUSION These findings from nationally representative samples of US adults suggest that the prevalence of both gout and hyperuricemia remains substantial and may have increased over the past 2 decades, which is likely related to increasing frequencies of adiposity and hypertension.

Risk of cardiovascular mortality in patients with rheumatoid arthritis: A meta-analysis of observational studies

OBJECTIVE To determine the magnitude of risk of cardiovascular mortality in patients with rheumatoid arthritis (RA) compared with the general population through a meta-analysis of observational studies. METHODS We searched Medline, EMBase, and Lilacs databases from their inception to July 2005. Observational studies that met the following criteria were assessed by 2 researchers: 1) prespecified RA definition, 2) clearly defined cardiovascular disease (CVD) outcome, including ischemic heart disease (IHD) and cerebrovascular accidents (CVAs), and 3) reported standardized mortality ratios (SMRs) and 95% confidence intervals (95% CIs). We calculated weighted-pooled summary estimates of SMRs (meta-SMRs) for CVD, IHD, and CVAs using the random-effects model, and tested for heterogeneity using the I(2) statistic. RESULTS Twenty-four studies met the inclusion criteria, comprising 111,758 patients with 22,927 cardiovascular events. Overall, there was a 50% increased risk of CVD death in patients with RA (meta-SMR 1.50, 95% CI 1.39-1.61). Mortality risks for IHD and CVA were increased by 59% and 52%, respectively (meta-SMR 1.59, 95% CI 1.46-1.73 and meta-SMR 1.52, 95% CI 1.40-1.67, respectively). We identified asymmetry in the funnel plot (Eggers test P = 0.002), as well as significant heterogeneity in all main analyses (P < 0.0001). Subgroup analyses showed that inception cohort studies (n = 4, comprising 2,175 RA cases) were the only group that did not show a significantly increased risk for CVD (meta-SMR 1.19, 95% CI 0.86-1.68). CONCLUSION Published data indicate that CVD mortality is increased by approximately 50% in RA patients compared with the general population. However, we found that study characteristics may influence the estimate.

2012 American College of Rheumatology Guidelines for Management of Gout. Part 1: Systematic Nonpharmacologic and Pharmacologic Therapeutic Approaches to Hyperuricemia

DINESH KHANNA, JOHN D. FITZGERALD, PUJA P. KHANNA, SANGMEE BAE, MANJIT K. SINGH, TUHINA NEOGI, MICHAEL H. PILLINGER, JOAN MERILL, SUSAN LEE, SHRADDHA PRAKASH, MARIAN KALDAS, MANEESH GOGIA, FERNANDO PEREZ-RUIZ, WILL TAYLOR, FREDERIC LIOTE, HYON CHOI, JASVINDER A. SINGH, NICOLA DALBETH, SANFORD KAPLAN, VANDANA NIYYAR, DANIELLE JONES, STEVEN A. YAROWS, BLAKE ROESSLER, GAIL KERR, CHARLES KING, GERALD LEVY, DANIEL E. FURST, N. LAWRENCE EDWARDS, BRIAN MANDELL, H. RALPH SCHUMACHER, MARK ROBBINS, NEIL WENGER, AND ROBERT TERKELTAUB

American College of Rheumatology/European League Against Rheumatism Provisional Definition of Remission in Rheumatoid Arthritis for Clinical Trials

OBJECTIVE Remission in rheumatoid arthritis (RA) is an increasingly attainable goal, but there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials. This work was undertaken to develop such a definition. METHODS A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism, and the Outcome Measures in Rheumatology Initiative met to guide the process and review prespecified analyses from RA clinical trials. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures including, as a minimum, joint counts and levels of an acute-phase reactant to define remission. Members were surveyed to select the level of each core set measure that would be consistent with remission. Candidate definitions of remission were tested, including those that constituted a number of individual measures of remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analyzed to examine the added contribution of patient-reported outcomes and the ability of candidate measures to predict later good radiographic and functional outcomes. RESULTS Survey results for the definition of remission suggested indexes at published thresholds and a count of core set measures, with each measure scored as 1 or less (e.g., tender and swollen joint counts, C-reactive protein [CRP] level, and global assessments on a 0-10 scale). Analyses suggested the need to include a patient-reported measure. Examination of 2-year followup data suggested that many candidate definitions performed comparably in terms of predicting later good radiographic and functional outcomes, although 28-joint Disease Activity Score-based measures of remission did not predict good radiographic outcomes as well as the other candidate definitions did. Given these and other considerations, we propose that a patients RA can be defined as being in remission based on one of two definitions: (a) when scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global assessment (0-10 scale) are all ≤ 1, or (b) when the score on the Simplified Disease Activity Index is ≤ 3.3. CONCLUSION We propose two new definitions of remission, both of which can be uniformly applied and widely used in RA clinical trials. We recommend that one of these be selected as an outcome measure in each trial and that the results on both be reported for each trial.

Pathogenesis of Gout

Clinical Principles The overall disease burden of gout is substantial and may be increasing. As more scientific data on the modifiable risk factors and comorbidities of gout become available, integration of these data into gout care strategies may become essential. Hyperuricemia and gout are associated with the insulin resistance syndrome and related comorbid conditions. Lifestyle modifications that are recommended for gout generally align with those for major chronic disorders (such as the insulin resistance syndrome, hypertension, and cardiovascular disorders); thus, these measures may be doubly beneficial for many patients with gout and particularly for individuals with these comorbid conditions. Effective management of risk factors for gout and careful selection of certain therapies for comorbid conditions (such as hypertension or the insulin resistance syndrome) may also aid gout care. The urateanion exchanger URAT1 (urate transporter-1) is a specific target of action for both antiuricosuric and uricosuric agents. The long-term health effect of hyperuricemia (beyond the increased risk for gout) needs to be clarified, including any potential consequences associated with the chronic hyperuricemia that anti-inflammatory treatment does not correct. Pathophysiologic Principles A direct causal relationship exists between serum urate levels and the risk for gout. Lifestyle factors, including adiposity and dietary habits, appear to contribute to serum uric acid levels and the risk for gout. Urate is extensively reabsorbed from the glomerular ultrafiltrate in the proximal tubule via the brush-border urateanion exchanger URAT1. Sodium-dependent reabsorption of anions increases their concentration in proximal tubule cells, resulting in increased urate exchange via URAT1, increased urate reabsorption by the kidney, and hyperuricemia. Genetic variation in renal urate transporters or upstream regulatory factors may explain the hereditary susceptibility to conditions associated with high urate levels and a patients particular response to medications; these transporters may also serve as targets for future drug development. Urate crystals are able to directly initiate, to amplify, and to sustain an intense inflammatory attack because of their ability to stimulate the synthesis and release of humoral and cellular inflammatory mediators. Cytokines, chemokines, proteases, and oxidants involved in acute urate crystalinduced inflammation also contribute to the chronic inflammation that leads to chronic gouty synovitis, cartilage loss, and bone erosion. For definition of terms used, see Glossary. Gout is a type of inflammatory arthritis that is triggered by the crystallization of uric acid within the joints and is often associated with hyperuricemia (Figure 1). Acute gout is typically intermittent, constituting one of the most painful conditions experienced by humans. Chronic tophaceous gout usually develops after years of acute intermittent gout, although tophi occasionally can be part of the initial presentation. In addition to the morbidity that is attributable to gout itself, the disease is associated with such conditions as the insulin resistance syndrome, hypertension, nephropathy, and disorders associated with increased cell turnover (1, 2). Figure 1. Overview of the pathogenesis of gout. The overall disease burden of gout remains substantial and may be increasing. The prevalence of self-reported, physician-diagnosed gout in the Third National Health and Nutrition Examination Survey was found to be greater than 2% in men older than 30 years of age and in women older than 50 years of age (3). The prevalence increased with increasing age and reached 9% in men and 6% in women older than 80 years of age (4). Furthermore, the incidence of primary gout (that is, patients without diuretic exposure) doubled over the past 20 years, according to the Rochester Epidemiology Project (4). Dietary and lifestyle trends and the increasing prevalence of obesity and the metabolic syndrome may explain the increasing incidence of gout. Researchers have recently made great advances in defining the pathogenesis of gout, including elucidating its risk factors and tracing the molecular mechanisms of renal urate transport and crystal-induced inflammation. This article reviews key aspects of the pathogenesis of gout with a focus on the recent advances. Absence of Uricase in Humans Humans are the only mammals in whom gout is known to develop spontaneously, probably because hyperuricemia only commonly develops in humans (5). In most fish, amphibians, and nonprimate mammals, uric acid that has been generated from purine (see Glossary) metabolism undergoes oxidative degradation through the uricase enzyme, producing the more soluble compound allantoin. In humans, the uricase gene is crippled by 2 mutations that introduce premature stop codons (see Glossary) (6). The absence of uricase, combined with extensive reabsorption of filtered urate, results in urate levels in human plasma that are approximately 10 times those of most other mammals (30 to 59 mol/L) (7). The evolutionary advantage of these findings is unclear, but urate may serve as a primary antioxidant in human blood because it can remove singlet oxygen and radicals as effectively as vitamin C (8). Of note, levels of plasma uric acid (about 300 M) are approximately 6 times those of vitamin C in humans (8, 9). Other potential advantages of the relative hyperuricemia in primate species have been speculated (8, 10, 11). However, hyperuricemia can be detrimental in humans, as demonstrated by its proven pathogenetic roles in gout and nephrolithiasis and by its putative roles in hypertension and other cardiovascular disorders (12). The Role of Urate Levels Uric acid is a weak acid (pKa, 5.8) that exists largely as urate, the ionized form, at physiologic pH. As urate concentration increases in physiologic fluids, the risk for supersaturation and crystal formation generally increases. Population studies indicate a direct positive association between serum urate levels and a future risk for gout (13, 14), as shown in Figure 2. Conversely, the use of antihyperuricemic medication is associated with an 80% reduced risk for recurrent gout, confirming the direct causal relationship between serum uric acid levels and risk for gouty arthritis (15). The solubility of urate in joint fluids, however, is influenced by other factors in the joint, as shown in Figure 3. Such factors include temperature, pH, concentration of cations, level of articular dehydration, and the presence of such nucleating agents as nonaggregated proteoglycans, insoluble collagens, and chondroitin sulfate (see Glossary) (16-18). Variation in these factors may account for some of the difference in the risk for gout associated with a given elevation in serum urate level (13, 14). Furthermore, these factors may explain the predilection of gout in the first metatarsal phalangeal joint (a peripheral joint with a lower temperature) and osteoarthritic joints (18) (degenerative joints with nucleating debris) and the nocturnal onset of pain (because of intra-articular dehydration) (19). Figure 2. The relationship between serum uric acid levels and the incidence of gout. Figure 3. Mechanisms of monosodium urate crystal formation and induction of crystal-induced inflammation. MSU Urate Balance The amount of urate in the body depends on the balance between dietary intake, synthesis, and the rate of excretion (20), as shown in Figure 1. Hyperuricemia results from urate overproduction (10%), underexcretion (90%), or often a combination of the two. The purine precursors come from exogenous (dietary) sources or endogenous metabolism (synthesis and cell turnover). The Relationship between Purine Intake and Urate Levels The dietary intake of purines contributes substantially to the blood uric acid. For example, the institution of an entirely purine-free diet over a period of days can reduce blood uric acid levels of healthy men from an average of 297 mol/L to 178 mol/L (21, 22). The bioavailable purine content of particular foods would depend on their relative cellularity and the transcriptional (see Glossary) and metabolic activity of the cellular content (20). Little is known, however, about the precise identity and quantity of individual purines in most foods, especially when cooked or processed (23). When a purine precursor is ingested, pancreatic nucleases break its nucleic acids into nucleotides (see Glossary), phosphodiesterases break oligonucleotides into simple nucleotides, and pancreatic and mucosal enzymes remove phosphates and sugars from nucleotides (20). The addition of dietary purines to purine-free dietary protocols has revealed a variable increase in blood uric acid levels, depending on the formulation and dose of purines administered (21). For example, RNA has a greater effect than an equivalent amount of DNA (24), ribomononucleotides have a greater effect than nucleic acid (21), and adenine has a greater effect than guanine (25, 26). A recent large prospective study showed that men in the highest quintile of meat intake had a 41% higher risk for gout compared with the lowest quintile, and men in the highest quintile of seafood intake had a 51% higher risk compared with the lowest quintile (27). Correspondingly, in a nationally representative sample of men and women in the United States, higher levels of meat and seafood consumption were associated with higher serum uric acid levels (28). However, consumption of oatmeal and purine-rich vegetables (for example, peas, beans, lentils, spinach, mushrooms, and cauliflower) was not associated with an increased risk for gout (27). The variation in the risk for gout associated with different purine-rich foods may be explained by varying amounts and type of purine content and their bioavailability for metabolizing purine to uric acid (28). At the practical level, these data suggest that dietary p

Alcohol intake and risk of incident gout in men: a prospective study.

BACKGROUND The association between alcohol consumption and risk of gout has been suspected since ancient times, but has not been prospectively confirmed. Additionally, potential differences in risk of gout posed by different alcoholic beverages have not been assessed. METHODS Over 12 years (1986-98) we used biennial questionnaires to investigate the relation between alcohol consumption and risk of incident gout in 47?150 male participants with no history of gout at baseline. We used a supplementary questionnaire to ascertain whether reported cases of gout met the American College of Rheumatology survey gout criteria. FINDINGS We documented 730 confirmed incident cases of gout. Compared with men who did not drink alcohol, the multivariate relative risk (RR) of gout was 1.32 (95% CI 0.99-1.75) for alcohol consumption 10.0-14.9 g/day, 1.49 (1.14-1.94) for 15.0-29.9 g/day, 1.96 (1.48-2.60) for 30.0-49.9 g/day, and 2.53 (1.73-3.70) for > or =50 g/day (p for trend <0.0001). Beer consumption showed the strongest independent association with the risk of gout (multivariate RR per 12-oz serving per day 1.49; 95% CI 1.32-1.70). Consumption of spirits was also significantly associated with gout (multivariate RR per drink or shot per day 1.15; 95% CI 1.04-1.28); however, wine consumption was not (multivariate RR per 4-oz serving per day 1.04; 95% CI 0.88-1.22). INTERPRETATION Alcohol intake is strongly associated with an increased risk of gout. This risk varies substantially according to type of alcoholic beverage: beer confers a larger risk than spirits, whereas moderate wine drinking does not increase the risk.

American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials

Objective Remission in rheumatoid arthritis (RA) is an increasingly attainable goal, but there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials. This work was undertaken to develop such a definition. Methods A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism, and the Outcome Measures in Rheumatology Initiative met to guide the process and review prespecified analyses from RA clinical trials. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures including, as a minimum, joint counts and levels of an acute-phase reactant to define remission. Members were surveyed to select the level of each core set measure that would be consistent with remission. Candidate definitions of remission were tested, including those that constituted a number of individual measures of remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analysed to examine the added contribution of patient-reported outcomes and the ability of candidate measures to predict later good radiographic and functional outcomes. Results Survey results for the definition of remission suggested indexes at published thresholds and a count of core set measures, with each measure scored as 1 or less (eg, tender and swollen joint counts, C reactive protein (CRP) level, and global assessments on a 0–10 scale). Analyses suggested the need to include a patient-reported measure. Examination of 2-year follow-up data suggested that many candidate definitions performed comparably in terms of predicting later good radiographic and functional outcomes, although 28-joint Disease Activity Score–based measures of remission did not predict good radiographic outcomes as well as the other candidate definitions did. Given these and other considerations, we propose that a patients RA can be defined as being in remission based on one of two definitions: (1) when scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global assessment (0–10 scale) are all ≤1, or (2) when the score on the Simplified Disease Activity Index is ≤3.3. Conclusion We propose two new definitions of remission, both of which can be uniformly applied and widely used in RA clinical trials. The authors recommend that one of these be selected as an outcome measure in each trial and that the results on both be reported for each trial.

Soft drinks, fructose consumption, and the risk of gout in men: prospective cohort study

Objective To examine the relation between intake of sugar sweetened soft drinks and fructose and the risk of incident gout in men. Design Prospective cohort over 12 years. Setting Health professionals follow-up study. Participants 46 393 men with no history of gout at baseline who provided information on intake of soft drinks and fructose through validated food frequency questionnaires. Main outcome measure Incident cases of gout meeting the American College of Rheumatology survey criteria for gout. Results During the 12 years of follow-up 755 confirmed incident cases of gout were reported. Increasing intake of sugar sweetened soft drinks was associated with an increasing risk of gout. Compared with consumption of less than one serving of sugar sweetened soft drinks a month the multivariate relative risk of gout for 5-6 servings a week was 1.29 (95% confidence interval 1.00 to 1.68), for one serving a day was 1.45 (1.02 to 2.08), and for two or more servings a day was 1.85 (1.08 to 3.16; P for trend=0.002). Diet soft drinks were not associated with risk of gout (P for trend=0.99). The multivariate relative risk of gout according to increasing fifths of fructose intake were 1.00, 1.29, 1.41, 1.84, and 2.02 (1.49 to 2.75; P for trend <0.001). Other major contributors to fructose intake such as total fruit juice or fructose rich fruits (apples and oranges) were also associated with a higher risk of gout (P values for trend <0.05). Conclusions Prospective data suggest that consumption of sugar sweetened soft drinks and fructose is strongly associated with an increased risk of gout in men. Furthermore, fructose rich fruits and fruit juices may also increase the risk. Diet soft drinks were not associated with the risk of gout.