Background Cardiovascular risk is increased in patients with gout. We compared cardiovascular outcomes associated with febuxostat, a nonpurine xanthine oxidase inhibitor, with those associated with allopurinol, a purine base analogue xanthine oxidase inhibitor, in patients with gout and cardiovascular disease. Methods We conducted a multicenter, double-blind, noninferiority trial involving patients with gout and cardiovascular disease; patients were randomly assigned to receive febuxostat or allopurinol and were stratified according to kidney function. The trial had a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization). Results In total, 6190 patients underwent randomization, received febuxostat or allopurinol, and were followed for a median of 32 months (maximum, 85 months). The trial regimen was discontinued in 56.6% of patients, and 45.0% discontinued follow-up. In the modified intention-to-treat analysis, a primary end-point event occurred in 335 patients (10.8%) in the febuxostat group and in 321 patients (10.4%) in the allopurinol group (hazard ratio, 1.03; upper limit of the one-sided 98.5% confidence interval [CI], 1.23; P=0.002 for noninferiority). All-cause and cardiovascular mortality were higher in the febuxostat group than in the allopurinol group (hazard ratio for death from any cause, 1.22 [95% CI, 1.01 to 1.47]; hazard ratio for cardiovascular death, 1.34 [95% CI, 1.03 to 1.73]). The results with regard to the primary end point and all-cause and cardiovascular mortality in the analysis of events that occurred while patients were being treated were similar to the results in the modified intention-to-treat analysis. Conclusions In patients with gout and major cardiovascular coexisting conditions, febuxostat was noninferior to allopurinol with respect to rates of adverse cardiovascular events. All-cause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol. (Funded by Takeda Development Center Americas; CARES ClinicalTrials.gov number, NCT01101035 .).
BACKGROUND: Research involving more representative samples is needed to extend our understanding of the broader impact of obesity in hip or knee joint disease (arthritis and OA) beyond clinical settings. Although population-based research has been conducted in the United States, how these findings translate to other countries is unclear. Using a national approach, this study explored associations between obesity and the burden of hip and knee joint disease in Australia (in terms of prevalence, pain, stiffness, function, Health-Related Quality of Life (HRQoL) and disease severity). METHODS: A random sample of 5000 Australians (>=39 years) from the federal electoral roll was invited to complete a mailed questionnaire to identify doctor-diagnosed hip arthritis, hip OA, knee arthritis and knee OA and evaluate the burden of these conditions. Validated questionnaires included the WOMAC Index, Assessment of Quality of Life instrument and Multi-Attribute Prioritisation Tool. Body Mass Index (BMI) was classified into underweight/normal weight (<=24.99 kg/m2), overweight (25--29.99) or obese (>=30). Multiple logistic regression was used to estimate odds of arthritis and OA, with demographic and socioeconomic variables included in the models. Associations between BMI and other variables were investigated using analysis of covariance, with adjustment for age and sex. RESULTS: Data were available from 1,157 participants (23%). Overweight participants had increased odds of knee arthritis (adjusted OR (AOR) 1.87, 95%CI 1.14-3.07) and knee OA (AOR 2.11, 95%CI 1.07-4.15). Obesity was associated with higher prevalence of hip arthritis (AOR 2.18, 95%CI 1.17-4.06), knee arthritis (AOR 5.47, 95%CI 3.35-8.95) and knee OA (AOR 7.35, 95%CI 3.85-14.02). Of those with arthritis or OA, obese individuals reported more pain (for hip arthritis, hip OA and knee OA), greater stiffness (for hip arthritis, knee arthritis and knee OA), worse function (all diagnoses), lower HRQoL (for hip arthritis and hip OA) and greater disease severity (all diagnoses). CONCLUSIONS: This national study has demonstrated that the odds of arthritis and OA was up to 7 times higher for obese individuals, compared with those classified as underweight/normal weight. Concurrent obesity and joint disease had a marked impact on several key aspects of wellbeing, highlighting the need for public health interventions.
Taking DMARDs as prescribed is an essential part of self-management for patients with Rheumatoid Arthritis. To date, the Compliance Questionnaire for Rheumatology (CQR) is the only self-report adherence measure created specifically for and validated in rheumatic diseases. However, the factor structure of the CQR has not been reported and it can be considered lengthy at 19 items. The aim of this study was to test the factor structure of the CQR and reduce the number of items whilst retaining robust explanation of non-adherence to DMARDs. Such a reduction would increase the clinical utility of the scale, to identify patients with sub-optimal adherence to DMARDs in the clinic as well as for research purposes.
Objective To prospectively examine the relation between the Dietary Approaches to Stop Hypertension (DASH) and Western diets and risk of gout (ie, the clinical endpoint of hyperuricemia) in men.Design Prospective cohort study.Setting The Health Professionals Follow-up Study.Participants 44 444 men with no history of gout at baseline. Using validated food frequency questionnaires, each participant was assigned a DASH dietary pattern score (based on high intake of fruits, vegetables, nuts and legumes, low fat dairy products, and whole grains, and low intake of sodium, sweetened beverages, and red and processed meats) and a Western dietary pattern score (based on high intake of red and processed meats, French fries, refined grains, sweets, and desserts).Main outcome measure Risk of incident gout meeting the preliminary American College of Rheumatology survey criteria for gout, adjusting for potential confounders, including age, body mass index, hypertension, diuretic use, and alcohol intake.Results During 26 years of follow-up, 1731 confirmed cases of incident gout were documented. A higher DASH dietary pattern score was associated with a lower risk for gout (adjusted relative risk for extreme fifths 0.68, 95% confidence interval 0.57 to 0.80, P value for trend <0.001). In contrast, a higher Western dietary pattern score was associated with an increased risk for gout (1.42, 1.16 to 1.74, P=0.005).Conclusion The DASH diet is associated with a lower risk of gout, suggesting that its effect of lowering uric acid levels in individuals with hyperuricemia translates to a lower risk of gout. Conversely, the Western diet is associated with a higher risk of gout. The DASH diet may provide an attractive preventive dietary approach for men at risk of gout.
Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of the NLRP3 inflammasome. Neutrophil-mediated production of interleukin-1β (IL-1β) drives gouty flares that cause joint destruction, intense pain, and fever. However, metabolites that impact neutrophil inflammasome remain unknown. Here, we identified that ketogenic diet (KD) increases β-hydroxybutyrate (BHB) and alleviates urate crystal-induced gout without impairing immune defense against bacterial infection. BHB inhibited NLRP3 inflammasome in S100A9 fibril-primed and urate crystal-activated macrophages, which serve to recruit inflammatory neutrophils in joints. Consistent with reduced gouty flares in rats fed a ketogenic diet, BHB blocked IL-1β in neutrophils in a NLRP3-dependent manner in mice and humans irrespective of age. Mechanistically, BHB inhibited the NLRP3 inflammasome in neutrophils by reducing priming and assembly steps. Collectively, our studies show that BHB, a known alternate metabolic fuel, is also an anti-inflammatory molecule that may serve as a treatment for gout.
Dietary fructose is implicated in metabolic syndrome, but intervention studies are confounded by positive caloric balance, changes in adiposity, or artifactually high amounts. This study determined whether isocaloric substitution of starch for sugar would improve metabolic parameters in Latino (n = 27) and African-American (n = 16) children with obesity and metabolic syndrome.
Maternal metabolic diseases increase offspring risk for low birth weight and cardiometabolic diseases in adulthood. Excess fructose consumption may confer metabolic risks for both women and their offspring. However, the direct consequences of fructose intake per se are unknown. We assessed the impact of a maternal high-fructose diet on the fetal-placental unit in mice in the absence of metabolic syndrome and determined the association between maternal serum fructose and placental uric acid levels in humans. In mice, maternal fructose consumption led to placental inefficiency, fetal growth restriction, elevated fetal serum glucose and triglyceride levels. In the placenta, fructose induced de novo uric acid synthesis by activating the activities of the enzymes AMP deaminase and xanthine oxidase. Moreover, the placentas had increased lipids and altered expression of genes that control oxidative stress. Treatment of mothers with the xanthine oxidase inhibitor allopurinol reduced placental uric acid levels, prevented placental inefficiency, and improved fetal weights and serum triglycerides. Finally, in 18 women delivering at term, maternal serum fructose levels significantly correlated with placental uric acid levels. These findings suggest that in mice, excess maternal fructose consumption impairs placental function via a xanthine oxidase/uric acid-dependent mechanism, and similar effects may occur in humans.
We aimed to develop evidence-based multinational recommendations for the diagnosis and management of gout. Using a formal voting process, a panel of 78 international rheumatologists developed 10 key clinical questions pertinent to the diagnosis and management of gout. Each question was investigated with a systematic literature review. Medline, Embase, Cochrane CENTRAL and abstracts from 2010-2011 European League Against Rheumatism and American College of Rheumatology meetings were searched in each review. Relevant studies were independently reviewed by two individuals for data extraction and synthesis and risk of bias assessment. Using this evidence, rheumatologists from 14 countries (Europe, South America and Australasia) developed national recommendations. After rounds of discussion and voting, multinational recommendations were formulated. Each recommendation was graded according to the level of evidence. Agreement and potential impact on clinical practice were assessed. Combining evidence and clinical expertise, 10 recommendations were produced. One recommendation referred to the diagnosis of gout, two referred to cardiovascular and renal comorbidities, six focused on different aspects of the management of gout (including drug treatment and monitoring), and the last recommendation referred to the management of asymptomatic hyperuricaemia. The level of agreement with the recommendations ranged from 8.1 to 9.2 (mean 8.7) on a 1-10 scale, with 10 representing full agreement. Ten recommendations on the diagnosis and management of gout were established. They are evidence-based and supported by a large panel of rheumatologists from 14 countries, enhancing their utility in clinical practice.
Juvenile idiopathic arthritis (JIA), as a chronic condition, is associated with significant disease- and treatment-related morbidity, thus impacting children’s quality of life. In order to optimize JIA management, the paediatric rheumatologist has begun to regularly use measurements of disease activity developed, validated and endorsed by international paediatric rheumatology professional societies in an effort to monitor the disease course over time and assess the efficacy of therapeutic interventions in JIA patients.A literature review was performed to describe the main outcome measures currently used in JIA patients to determine disease activity status.The Juvenile Disease Activity Score (JADAS), in its different versions (classic JADAS, JADAS-CRP and cJADAS) and the validated definitions of disease activity and response to treatment represent an important tool for the assessment of clinically relevant changes in disease activity, leading more and more to a treat-to-target strategy, based on a tight and thorough control of the patient condition. Moreover, in recent years, increasing attention on the incorporation of patient-reported or parent-reported outcomes (PRCOs), when measuring the health state of patients with paediatric rheumatic diseases has emerged.We think that the care of JIA patients cannot be possible without taking into account clinical outcome measures and, in this regard, further work is required.
Gout is a consequence of an innate immune reaction to monosodium urate crystals deposited in joints. Acute gout attacks can be triggered by dietary factors that are themselves associated with serum urate levels. Tomato consumption is an anecdotal trigger of gout flares. This study aimed to measure the frequency of tomato consumption as a self-reported trigger of gout attacks in a large New Zealand sample set, and to test the hypothesis that tomato consumption is associated with serum urate levels.