Association between colchicine use and the risk of dementia among patients with gout: A nationwide retrospective cohort study.

BACKGROUND: Recent findings suggest a link between gout and the development of dementia. Early treatment with colchicine is recommended as a first-line therapy for gout flares. Animal studies demonstrate that colchicine could induce cognitive impairment. This cohort study aimed to investigate the association between colchicine use and the risk of developing dementia. METHODS: In this nationwide cohort study, we performed comparative analysis on 6147 patients ≥40 years, with gout and colchicine new users against 6147 controls to assess subsequent dementia risk. The colchicine group and the control group (urate lowering therapy group) were matched on the bases of age, sex, index year, and comorbidities. All participants were followed for up to 14 years for a diagnosis of dementia considering medical records were retrospectively checked over this period. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Sensitivity analyses were performed to validate our findings. RESULTS: The adjusted hazard ratio (aHR) of dementia for colchicine users was 1.45 (95% CI = 1.05, 1.99) relative to comparison group after adjusting for sex, age, and comorbidities. Sensitivity analysis aiming to minimize underdiagnosed occult dementia at the time of index year yielded consistent positive association. In higher accumulative dose colchicine group (cumulative defined daily dose [cDDD] >30), the aHR of dementia risk for colchicine users was 1.42 (95% CI = 1.03, 1.97) compared with nonusers. For those duration of colchicine use >30 days, the aHR was 1.53 (95% CI = 1.01-2.32) compared to the nonuser group. CONCLUSIONS: A significant risk of dementia was observed in this study in patients with gout using colchicine at higher cDDD and for a longer period. Further research is needed to elucidate the relationship between colchicine, gout, and dementia.

Comparison of the efficacy and safety of benzbromarone and febuxostat in gout and hyperuricemia: a systematic review and meta-analysis.

OBJECTIVE: Urate-lowering therapy (ULT) is widely recognized as the primary treatment for hyperuricemia and gout. Xanthine oxidase inhibitors (XOI), particularly febuxostat, have gained popularity as a frontline approach. However, the divergent efficacy and safety between febuxostat and the traditional ULT drug, benzbromarone, remain poorly understood. This knowledge gap necessitates a comprehensive analysis and evidence update to guide drug selection for physicians and patients. METHOD: We conducted a systematic analysis by extracting relevant clinical studies from four medical literature databases. Forest plots, funnel plots, sensitivity analysis, Egger's test, and subgroup analysis were utilized to compare relevant indicators. RESULTS: The advantages and disadvantages of the two drugs were evaluated based on various indicators such as serum uric acid (SUA), triglyceride (TG), urinary uric acid (UUA), white blood cell count (WBC), total cholesterol (TC), blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), estimated glomerular filtration rate (eGFR), and serum creatinine (SC). Benzbromarone demonstrated better efficacy in rapidly reducing SUA levels and inhibiting inflammation for hyperuricemia and gout patients. Febuxostat was slightly less effective in lowering SUA, but there was no significant difference in its impact on liver and kidney function after long-term use. CONCLUSION: This study highlights the superiority of benzbromarone in rapidly reducing SUA and inhibiting inflammation. Febuxostat shows comparable effects on liver and kidney function after long-term use. These findings provide valuable insights for clinicians and patients in drug selection. Key Points • Benzbromarone stands out as a highly effective treatment for hyperuricemia and gout, offering rapid reduction of serum uric acid levels and potent anti-inflammatory effects. • When it comes to long-term use, febuxostat demonstrates comparable effects on liver and kidney function. This provides reassurance for patients who require extended treatment duration. • Moreover, our study goes beyond previous research by presenting a more comprehensive and detailed analysis.

Cardiovascular safety of febuxostat versus allopurinol among the Asian patients with or without gout: A systematic review and meta-analysis.

The cardiovascular (CV) safety of febuxostat compared to allopurinol for the treatment of hyperuricemia among Asian patients is uncertain. In this study, we conducted a systematic review and meta-analysis to compare the CV safety profiles of febuxostat with allopurinol in Asian patients with hyperuricemia. A total of 13 studies were included. On the basis of the pooled results of cohort studies, febuxostat users were at a significantly higher risk for acute coronary syndrome (ACS; hazard ratio [HR]: 1.06, 95% confidence interval [CI]: 1.03-1.09, p < 0.01), atrial fibrillation (HR: 1.19, 95% CI: 1.05-1.35, p < 0.01) than allopurinol users, whereas no significant difference between febuxostat and allopurinol existed for urgent coronary revascularization (HR: 1.07, 95% CI: 0.98-1.16, p = 0.13), and stroke (HR: 0.96, 95% CI: 0.91-1.01, p = 0.13). Nevertheless, that difference in results of acute decompensated heart failure (ADHF; HR: 0.73, 95% CI: 0.35-1.53, p = 0.40) and all-cause death (HR = 0.86, 95% CI: 0.49-1.51, p = 0.60) was not significant based on randomized controlled trials. In the Chinese subgroup, febuxostat could increase the risk of ADHF (HR: 1.22, 95% CI: 1.01-1.48, p < 0.05), CV death (HR: 1.25, 95% CI: 1.03-1.50, p < 0.05), and all-cause mortality (HR: 1.07, 95% CI: 1.01-1.14, p < 0.05) compared to allopurinol. In conclusion, the use of febuxostat, compared with allopurinol among Asian patients, was associated with a significantly increased risk of adverse CV events.

Colchicine's Role in Cardiovascular Disease Management.

Colchicine-an anti-inflammatory alkaloid-has assumed an important role in the management of cardiovascular inflammation ≈3500 years after its first medicinal use in ancient Egypt. Primarily used in high doses for the treatment of acute gout flares during the 20th century, research in the early 21st century demonstrated that low-dose colchicine effectively treats acute gout attacks, lowers the risk of recurrent pericarditis, and can add to secondary prevention of major adverse cardiovascular events. As the first Food and Drug Administration-approved targeted anti-inflammatory cardiovascular therapy, colchicine currently has a unique role in the management of atherosclerotic cardiovascular disease. The safe use of colchicine requires careful monitoring for drug-drug interactions, changes in kidney and liver function, and counseling regarding gastrointestinal upset. Future research should elucidate the mechanisms of anti-inflammatory effects of colchicine relevant to atherosclerosis, the potential role of colchicine in primary prevention, in other cardiometabolic conditions, colchicine's safety in cardiovascular patients, and opportunities for individualizing colchicine therapy using clinical and molecular diagnostics.

How common are side effects of treatment to prevent gout flares when starting allopurinol?

The studyRoddy E, Bajpai R, Forrester H, et al. Safety of colchicine and NSAID prophylaxis when initiating urate-lowering therapy for gout: propensity score-matched cohort studies in the UK Clinical Practice Research Datalink. Ann Rheum Dis 2023;82:1618-25.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/how-common-are-side-effects-of-treatment-to-prevent-gout-flares-when-starting-allopurinol/.

Impacts of Febuxostat on Cerebral and Cardiovascular Events in Elderly Patients with Hyperuricemia: Post Hoc Analysis of a Randomized Controlled Trial.

A recent meta-analysis found no benefit of uric acid-lowering therapy including febuxostat on death, cardiovascular events, or renal impairment. However, there may be populations that benefit from febuxostat in reducing mortality and cerebral and cardiovascular events. The aim of the present study was to examine the clinical benefit of febuxostat in elderly patients stratified by age using Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy (FREED) data. FREED was a randomized study involving patients aged 65 years or older with hyperuricemia and risk factors for cerebral, cardiovascular, or renal diseases. A total of 1,070 patients were included in this post hoc analysis, divided into 2 age groups: 65-74 years and ≥ 75 years. Patients were randomized into febuxostat and non-febuxostat groups, with uric acid levels monitored for 36 months. The primary composite end point included cerebral, cardiovascular, and renal events. In patients aged between 65 and 74 years, febuxostat significantly reduced the risk of future cerebral and cardiorenovascular events. However, no effects of febuxostat were found in the older population aged ≥ 75 years. Heterogeneity in potential interactions between the age and febuxostat treatment was particularly observed in non-fatal cerebral and cardiovascular events and all-cause death. Patients aged ≥ 75 years exhibited more pre-existing factors associated with cerebral and cardiorenovascular events than those aged 65-74 years. The effectiveness of febuxostat varies by age group, with potential benefits for patients aged 65-74 years. The effects of febuxostat are complex and it is important to consider patient characteristics in its clinical use.

The COMPARE head-to-head, randomized controlled trial of SEL-212 (pegadricase plus rapamycin-containing nanoparticle, ImmTOR™) versus pegloticase for refractory gout.

OBJECTIVES: Serum urate (SU) lowering with PEGylated uricases in gout can reduce flares and tophi. However, treatment-emergent anti-drug antibodies adversely affect safety and efficacy and the currently approved PEGylated uricase pegloticase requires twice-monthly infusions. Investigational SEL-212 therapy aims to promote uricase-specific tolerance via monthly sequential infusions of a proprietary rapamycin-containing nanoparticle (ImmTOR) and pegadricase. METHODS: COMPARE was a randomized, phase 2, open-label trial of SEL-212 vs pegloticase in adults with refractory gout. SEL-212 [ImmTOR (0.15 mg/kg) and pegadricase (0.2 mg/kg)] was infused monthly or pegloticase (8 mg) twice monthly for 6 months. The primary endpoint was the proportion of participants with SU <6 mg/dl for ≥80% of the time during 3 and 6 months. Secondary outcomes were mean SU, gout flares, number of tender and/or swollen joints and safety. RESULTS: During months 3 and 6 combined, numerically more participants achieved and maintained a SU <6 mg/dl for ≥80% of the time with SEL-212 vs pegloticase (53.0% vs 46.0%, P = 0.181). The percentage reductions in SU levels were statistically greater during months 3 and 6 with SEL-212 vs pegloticase (-73.79% and -47.96%, P = 0.0161). Reductions in gout flare incidence and number of tender and/or swollen joints were comparable between treatments. There were numerical differences between the most common treatment-related adverse events of interest with SEL-212 and pegloticase: gout flares (60.2% vs 50.6%), infections (25.3% vs 18.4%) and infusion-related reactions (15.7% vs 11.5%), respectively. Stomatitis (and related terms) was experienced by eight participants (9.6%) with SEL-212 and none with pegloticase. Stomatitis, a known event for rapamycin, was associated with ImmTOR only. CONCLUSIONS: SEL-212 efficacy and tolerability were comparable to pegloticase in refractory gout. This was associated with a substantial reduction in treatment burden with SEL-212 due to decreased infusion frequency vs pegloticase. CLINICAL TRIAL REGISTRATION: NCT03905512.

Colchicine: the good, the bad, the ugly and how to minimize the risks.

Colchicine has an important role in managing various conditions, including gout, familial Mediterranean fever, amyloidosis, Behçet's syndrome, recurrent pericarditis and calcium pyrophosphate deposition disease. The adverse effect profile of colchicine is well understood. However, due to its narrow therapeutic index, colchicine has been associated with overdose and fatalities. When ingested in toxic amounts, the mainstay of management is supportive care. Strategies to minimize the risk of colchicine poisoning can focus on three broad causes: unauthorized access, intentional overdose and inappropriate dosing. Culturally safe and appropriate education about storage and appropriate use of colchicine is essential to minimize the risk of overdose.

Traditional Chinese medicine in the treatment of patients with hyperuricemia: A randomized placebo-controlled double-blinded clinical trial.

BACKGROUND: Studies have demonstrated the association of hyperuricemia with hypertension, metabolic syndrome, cardiovascular disease, and chronic renal disease. Although Western medicine presents promising effects for treating hyperuricemia and gout, identifying a safe and effective alternative to traditional Chinese medicine (TCM) for treating hyperuricemia is essential. OBJECTIVE: To evaluate the efficacy and safety of TCM formulas, "Wu-Ling San" and "Yin Chen Wu-Ling San," in patients with hyperuricemia. METHODS: A randomized, double-blinded, placebo-controlled clinical trial in adults with hyperuricemia was conducted. Sixty patients with serum urate level higher than 8 mg/dL were enrolled in the study. Patients were then randomized into three arms: "Wu-Ling San," "Yin Chen Wu-Ling San," and placebo for 4 weeks. Efficacy and safety were evaluated at weeks 2, 4, and 8. Primary and secondary endpoints were set to evaluate the serum urate concentration and related indicators at weeks 2, 4, and 8. RESULTS: No significant differences were observed among the three arms in terms of the serum urate level (<6 mg/dL) at week 4. The serum urate level was lower in the "Yin Chen Wi-Ling" arm at week 8 (8.1 mg/dL vs. 9.1 mg/dL, p = .034). The serum urate levels were significantly different in both the "Wu-Ling San" and "Yin Chen Wu-Ling San" arms from those at the baseline (p < .05). CONCLUSIONS: Two TCM formulas were found to be relatively safe for the short-term treatment of the patients with hyperuricemia. No statistically significant difference was observed in reaching the target-serum urate level <6 mg/dL.

Cardiovascular Safety of Febuxostat in Patients With Gout or Hyperuricemia: A Systematic Review of Randomized Controlled Trials.

INTRODUCTION: To this date, a causal relationship between febuxostat and cardiovascular disease remains controversial as comparison between trials can be challenging and may lead to misleading conclusions, especially when facing heterogeneous cardiovascular outcomes. We aimed to compare the cardiovascular outcomes in the most pertinent trials of febuxostat compared with controls. METHODS: We searched electronic databases using a PICOS-style approach search strategy of randomized controlled trials (RCTs) on cardiovascular outcomes of febuxostat in patients with gout or hyperuricemia. We conducted a quality and risk of bias assessment of the included clinical trials. The definition of major adverse cardiovascular event as well as all reported cardiovascular outcomes were retrieved from every involved trial. RESULTS: Of the 1173 records identified from all sources, 20 RCTs were included in the analysis. The mean duration of follow-up was 69.7 ± 81.5 weeks, and febuxostat dose ranged from 10 to 240 mg with 80 mg being the most commonly used dosage. Overall, the quality of evidence deriving from all RCTs showed concerns in most studies (65%). Major adverse cardiovascular event was defined in 7 of the 20 RCTs (35%), and cardiovascular outcome reporting was very heterogeneous. Overall, the data of cardiovascular safety of febuxostat were reassuring. CONCLUSIONS: Our systematic review showed high level of concerns in quality assessment domains as well heterogeneous cardiovascular outcomes across included studies. Cardiovascular outcomes in the majority of White males with gout treated with febuxostat were reassuring when compared with allopurinol. Further studies are needed to draw conclusions in patients with severe cardiovascular disease.

Effectiveness and safety of different doses of febuxostat compared with allopurinol in the treatment of hyperuricemia: a meta-analysis of randomized controlled trials.

BACKGROUND: The prevalence of hyperuricemia has increased steadily with the continuous improvement of living standards. Some studies have reported the clinical effectiveness and safety of different doses of febuxostat in comparison with allopurinol in hyperuricemia treatment, but the sample sizes of the studies have been small, and the results have been inconsistent. We designed this meta-analysis to evaluate the effectiveness and safety of different doses of febuxostat compared with allopurinol in the treatment of hyperuricemia. METHODS: The Cochrane Library, Embase, PubMed, Web of Science and ClinicalTrials.gov databases were searched to identify randomized controlled trials (RCTs) comparing the use of febuxostat and allopurinol for the treatment of hyperuricemia. The effectiveness and safety of different doses of febuxostat and allopurinol in treating hyperuricemia were assessed using meta-analysis. RESULTS: A total of 11 randomized controlled trials were included in the meta-analysis. The results of the meta-analysis showed that the percentage of patients achieving serum uric acid levels of 6.0 mg/dL or less was higher among patients taking febuxostat (80 mg/d) than among patients taking allopurinol (200-300 mg/d) [RR = 1.79, 95% CI (1.55, 2.08), P < 0.00001]. However, there was no statistically significant difference in the percentage of patients achieving serum uric acid levels of 6.0 mg/dL or less between febuxostat (40 mg/d) and allopurinol (200-300 mg/d) [RR = 1.10, 95% CI (0.93, 1.31), P = 0.25]. There was also no statistically significant difference in the incidence of gout between the febuxostat (40 mg/d) and allopurinol (200-300 mg/d) [RR = 0.97, 95% CI (0.64, 1.49), P = 0.91] or between the febuxostat (80 mg/d) and allopurinol (200-300 mg/d) [RR = 1.13, 95% CI (0.81, 1.58), P = 0.48].No significant difference in the incidence of major adverse reactions as observed between the febuxostat (40 mg/d) and allopurinol (200-300 mg/d) [RR = 1.16; 95% CI (0.43, 3.16), P = 0.77] or between the febuxostat (80 mg/d) and allopurinol (200-300 mg/d) [RR = 1.06; 95% CI (0.79, 1.42), P = 0.70]. The incidence of adverse cardiovascular events did not differ significantly between the febuxostat (40 mg/d) and allopurinol (200-300 mg/d) [RR = 1.30; 95% CI (0.57, 2.95), P = 0.53] or between the febuxostat (80 mg/d) and allopurinol (200-300 mg/d) [RR = 1.79; 95% CI (0.74, 4.32), P = 0.20]. CONCLUSIONS: Febuxostat (80 mg/d) was associated with a higher percentage of patients achieving serum uric acid levels of 6.0 mg/dL or less than allopurinol (200-300 mg/d), however, febuxostat (80 mg/d) did not exhibit better efficacy in reducing the incidence of gout. More attention should be devoted to the adverse reactions caused by an increase in febuxostat doses.

New animal model of chronic gout reproduces pathological features of the disease in humans.

OBJECTIVES: Gout, as the most prevalent form of inflammatory arthritis, necessitates the use of animal models to investigate the molecular mechanisms involved in its development. Therefore, our objective was to develop a novel chronic mouse model of gout that more closely mimics the progression of gout in humans. METHODS: A novel chronic mouse model of gout was established by a simple method, which does not require high technical proficiency, predominantly involves daily intraperitoneal injections of potassium oxonate for approximately 4 months, combined with a high fat-diet and injections of acetic acid into the hind paws to facilitate the formation of monosodium urate (MSU). Arthritis scores and paw oedema were assessed, behavioural tests were conducted, and histopathological and imaging evaluations of the arthritic paw joints were performed. RESULTS: After 4 months of induction, mice in the model group exhibited noticeable increases in arthritis severity, joint and cartilage damage, as well as bone erosion. Gomori's methenamine silver stain revealed the presence of MSU crystal deposition or tophi in the paw joints or ankle joints of up to 37.9% of the model mice (11 out of 29 mice). Moreover, treatment with benzbromarone effectively prevented the further development of gout or tophi formation in model mice. CONCLUSIONS: Our model more accurately replicates the pathological features of gouty arthritis compared with gout induced by MSU crystal injections. Therefore, it is particularly suitable for further investigations into the pathogenesis of gout and also serves as a valuable platform for screening potential antigout agents.

Safety of colchicine and NSAID prophylaxis when initiating urate-lowering therapy for gout: propensity score-matched cohort studies in the UK Clinical Practice Research Datalink.

OBJECTIVES: To determine the risk of adverse events associated with colchicine or non-steroidal anti-inflammatory drug (NSAID) prophylaxis when initiating allopurinol for gout. METHODS: We conducted two matched retrospective cohort studies in linked UK Clinical Practice Research Datalink and Hospital Episode Statistics datasets. Adults initiating allopurinol for gout with (1) colchicine or (2) NSAID prophylaxis were compared with those initiating without prophylaxis, individually matched by age, sex and propensity to receive the relevant prophylaxis. Weighted Cox proportional hazards models investigated associations between colchicine/NSAID and specified adverse events. RESULTS: 13 945 individuals prescribed colchicine were matched to 13 945 with no prophylaxis and 25 980 prescribed NSAID to 25 980 with no prophylaxis. Adverse event incidence rates were <200/10 000 patient-years except diarrhoea (784.4; 95% CI 694.0 to 886.5) and nausea (208.1; 95% CI 165.4 to 261.7) for colchicine and angina for NSAID (466.6; 95% CI 417.2 to 521.8). Diarrhoea (HR 2.22; 95% CI 1.83 to 2.69), myocardial infarction (MI) (1.55; 95% CI 1.10, 2.17), neuropathy (4.75; 95% CI 1.20 to 18.76), myalgia (2.64; 95% CI 1.45 to 4.81), bone marrow suppression (3.29; 95% CI 1.43 to 7.58) and any adverse event (1.91, 95% CI 1.65 to 2.20) were more common with colchicine than no prophylaxis, but not nausea/vomiting (1.34; 95% CI 0.97 to 1.85). Angina (1.60; 95% CI 1.37 to 1.86), acute kidney injury (1.56; 95% CI 1.20 to 2.03), MI (1.89; 95% CI 1.44 to 2.48), peptic ulcer disease (1.67; 95% CI 1.14 to 2.44) and any adverse event (1.63; 95% CI 1.44 to 1.85) were more common with NSAID than without. CONCLUSIONS: Adverse events were more common when allopurinol was initiated with prophylaxis, particularly diarrhoea with colchicine. Other events were uncommon, providing reassurance for patients and clinicians to enable shared decision-making.

Prediction of renal and cardiometabolic outcomes in gout during urate-lowering therapy by sonography.

OBJECTIVES: To assess whether the extent of monosodium urate (MSU) crystal deposition estimated by ultrasound could predict renal and cardiometabolic events during urate-lowering therapy (ULT). METHODS: A prospective study on gout patients from two referral centers initiating ULT who underwent baseline ultrasound and were followed for 1 year. Ultrasound scans assessed six joints for double-contour (DC) signs and tophi. A five-point change (mL/min/1.73 m2 ) in the glomerular filtration rate at month 12 (M12) was considered significant. Outcomes of interest were renal function degraded versus improved and a composite cardiometabolic outcome (new hypertension, diabetes, atherosclerotic disease, and cardiovascular death). Homogeneity analyses and Cox regression models were performed. RESULTS: One hundred sixty patients were recruited. At baseline, 81.1% of patients (n = 129) showed sonographic tophi with a mean number of 1.4 joints (±1.3) with a DC sign. At M12, 18 patients (11.3%) were lost to follow-up. The serum urate (SU) target (<6.0 mg/dL) was reached in 86 patients (69.9%). Regarding renal function, 15.9% of patients showed improvement, while in 31.0% it degraded. Fourteen new cardiometabolic events occurred in 12 patients. Neither the DC sign nor tophi showed any significant impact on the outcomes of interest. Baseline SU level was higher in those with renal improvement but not with renal decline, while achieving the SU target protected against new cardiometabolic events (HR = 0.2; 95% CI: 0.05-0.81). CONCLUSIONS: Sonographic MSU crystal burden was unhelpful in predicting renal and cardiometabolic events during the first year of ULT. Reaching the SU target prevented cardiometabolic events, while its benefit in preserving/improving renal function is unclear.

Mechanisms and rationale for uricase use in patients with gout.

Xanthine oxidase inhibitors such as allopurinol and febuxostat have been the mainstay urate-lowering therapy (ULT) for treating hyperuricaemia in patients with gout. However, not all patients receiving oral ULT achieve the target serum urate level, in part because some patients cannot tolerate, or have actual or misconceived contraindications to, their use, mainly due to comorbidities. ULT dosage is also limited by formularies and clinical inertia. This failure to sufficiently lower serum urate levels can lead to difficult-to-treat or uncontrolled gout, usually due to poorly managed and/or under-treated gout. In species other than humans, uricase (urate oxidase) converts urate to allantoin, which is more soluble in urine than uric acid. Exogenic uricases are an exciting therapeutic option for patients with gout. They can be viewed as enzyme replacement therapy. Uricases are being used to treat uncontrolled gout, and can achieve rapid reduction of hyperuricaemia, dramatic resolution of tophi, decreased chronic joint pain and improved quality of life. Availability, cost and uricase immunogenicity have limited their use. Uricases could become a leading choice in severe and difficult-to-treat gout as induction and/or debulking therapy (that is, for lowering of the urate pool) to be followed by chronic oral ULT. This Review summarizes the evidence regarding available uricases and those in the pipeline, their debulking effect and their outcomes related to gout and beyond.