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Background: Activation of the NLRP3 inflammasome is critical in the inflammatory response to gout. Potassium ion (K + ) efflux mediated by the TWIK2 channel is an important upstream mechanism for NLRP3 inflammasome activation. Therefore, the TWIK2 channel may be a promising therapeutic target for MSU crystal-induced inflammation. In the present study, we investigated the effect of ML335, a known K2P channel modulator, on MSU crystal-induced inflammatory responses and its underlying molecular mechanisms., Methods: By molecular docking, we calculated the binding energies and inhibition constants of five K2P channel modulators (Hydroxychloroquine, Fluoxetine, DCPIB, ML365 and ML335) with TWIK2. Intracellular potassium ion concentration and mitochondrial function were assessed by flow cytometry. The interaction between MARCH5 and SIRT3 was demonstrated by immunoprecipitation and Western blotting assay. MSU suspensions were injected into mouse paw and peritoneal cavity to induce acute gout model., Results: ML335 has the highest binding energy and the lowest inhibition constant with TWIK2 in the five calculated K2P channel modulators. In comparison, among these five compounds, ML335 efficiently inhibited the release of IL-1β from MSU crystal-treated BMDMs. ML335 decreased MSU crystal-induced K + efflux mainly dependent on TWIK2 channel. More importantly, ML335 can effectively inhibit the expression of the mitochondrial E3 ubiquitin ligase MARCH5 induced by MSU crystals, and MARCH5 can interact with the SIRT3 protein. ML335 blocked MSU crystal-induced ubiquitination of SIRT3 protein by MARCH5. In addition, ML335 improved mitochondrial dynamics homeostasis and mitochondrial function by inhibiting MARCH5 protein expression. ML335 attenuated the inflammatory response induced by MSU crystals in vivo and in vitro., Conclusion: Inhibition of TWIK2-mediated K + efflux by ML335 alleviated mitochondrial injury via suppressing March5 expression, suggesting that ML335 may be an effective candidate for the future treatment of gout., (© 2024. The Author(s).)

Background: Uncontrolled gout can cause articular impairment but is also associated with a global and cardiovascular excess mortality, especially in dialysis population. Data documented within existing research is not conclusive regarding gout flares evolution during hemodialysis and their control by urate lowering therapy (ULT). Without clear guidelines concerning hemodialysis patients management with chronic gout, this study proposes to investigate whether gout flare incidence reduction could be observed on this population treated by urate lowering therapy versus patients without treatment., Methods: We performed a retrospective cohort study in two hemodialysis centers in France. Were selected patients over 18 years old with a gout history who started hemodialysis between January 2005 and September 2015. Demographics and clinicals data were recorded at hemodialysis start and throughout 5 years of follow up. Gout flare was defined as presence of uric acid crystal in joint punction or clinically diagnosed as such with a colchicine prescription. All statistical analysis were performed in SAS® version 9.4 (SAS Institute Inc., Cary, NC)., Results: One hundred eighty-one patients have been included, mean age at dialysis initiation was 68.6 years (± 12.4) with 72% of men, 54% were treated by ULT: 89.7% by allopurinol and 9.3% by febuxostat. One patient received both treatments successively. After hemodialysis initiation, 35.36% patients had experienced at least one gout flare. The appearance of at least one gout flare concerned 50% of patients in no ULT group and 22.68% patients in ULT group (p = 0.0002). Dialysis efficiency was measured at regular interval during follow-up and was similar in both groups. To study the association strength between clinical factors and gout flares occurrences, a Cox model was performed; ULT is a protector factor of gout flare (HR:0,42, CI 95: 0,25-0,71). The proportion of serum urate values within the target (median 53% vs 29.3%, p < 0.0001) was significantly higher in ULT group versus no ULT group (median 53% vs 29.3%, p < 0.0001)., Conclusion: Urate lowering therapy limit new gout flares occurrence in hemodialysis patients with gout historyCollaboration between rheumatologists and nephrologists may help to update guidelines for urate-lowering therapies in patients on dialysis., (© 2024. The Author(s).)

Background: Acute gouty is caused by the excessive accumulation of Monosodium Urate (MSU) crystals within various parts of the body, which leads to a deterioration of the local microenvironment. This degradation is marked by elevated levels of uric acid (UA), increased reactive oxygen species (ROS) production, hypoxic conditions, an upsurge in pro-inflammatory mediators, and mitochondrial dysfunction., Results: In this study, we developed a multifunctional nanoparticle of polydopamine-platinum (PDA@Pt) to combat acute gout by leveraging mild hyperthermia to synergistically enhance UA degradation and anti-inflammatory effect. Herein, PDA acts as a foundational template that facilitates the growth of a Pt shell on the surface of its nanospheres, leading to the formation of the PDA@Pt nanomedicine. Within this therapeutic agent, the Pt nanoparticle catalyzes the decomposition of UA and actively breaks down endogenous hydrogen peroxide (H 2 O 2 ) to produce O 2 , which helps to alleviate hypoxic conditions. Concurrently, the PDA component possesses exceptional capacity for ROS scavenging. Most significantly, Both PDA and Pt shell exhibit absorption in the Near-Infrared-II (NIR-II) region, which not only endow PDA@Pt with superior photothermal conversion efficiency for effective photothermal therapy (PTT) but also substantially enhances the nanomedicine's capacity for UA degradation, O 2 production and ROS scavenging enzymatic activities. This photothermally-enhanced approach effectively facilitates the repair of mitochondrial damage and downregulates the NF-κB signaling pathway to inhibit the expression of pro-inflammatory cytokines., Conclusions: The multifunctional nanomedicine PDA@Pt exhibits exceptional efficacy in UA reduction and anti-inflammatory effects, presenting a promising potential therapeutic strategy for the management of acute gout., (© 2024. The Author(s).)

Objective: It is well-established that patients with a history of gout are more susceptible to experiencing gastrointestinal bleeding. Gout flare during active gastrointestinal bleeding poses a significant challenge due to the gastrointestinal side effects of anti-inflammatory therapy. This study sought to investigate the risk factors associated with gout flares during episodes of gastrointestinal bleeding., Methods: We conducted a retrospective observational study involving 94 patients who experienced active gastrointestinal bleeding and had a history of gout. This study was conducted at Jinhua Municipal Central Hospital from January 2019 to October 2022. We collected and recorded demographic information and clinical characteristics., Results: Among the gout flare patients, hyperuricemia and intravenous fat emulsion therapy were more prevalent compared to those who remained stable (81.6% vs. 57.8% and 46.9% vs. 24.4%, p < 0.05). Multivariate logistic regression analysis revealed that both hyperuricemia (odds ratio 2.741, 95% CI 1.014-7.413, p = 0.047) and intravenous fat emulsion therapy (odds ratio 2.645, 95% CI 1.046-6.686, p = 0.040) were independent predictors of gout flares. Furthermore, gout attacks occurred sooner in patients receiving intravenous fat emulsion therapy compared to those not receiving it (median: 4 days (interquartile range: 2) vs. median: 5 days (interquartile range: 2.25), p = 0.049)., Conclusion: Our study revealed a high incidence of gout flares during episodes of active gastrointestinal bleeding, with patients undergoing intravenous fat emulsion therapy and those with hyperuricemia being at increased risk., (© 2024. The Author(s).)

Background/purpose: Little is known about long-term clinical outcomes or urate-lowering (ULT) therapy use following pegloticase discontinuation. We examined ULT use, serum urate (SU), inflammatory biomarkers, and renal function following pegloticase discontinuation., Methods: We conducted a retrospective analysis of gout patients who discontinued pegloticase using the Rheumatology Informatics System for Effectiveness (RISE) registry from 1/2016 to 6/2022. We defined discontinuation as a gap ≥ 12 weeks after last infusion. We examined outcomes beginning two weeks after last dose and identified ULT therapy following pegloticase discontinuation. We evaluated changes in lab values (SU, eGFR, CRP and ESR), comparing on- treatment (≤ 15 days of the second pegloticase dose) to post-treatment., Results: Of the 375 gout patients discontinuing pegloticase, median (IQR) laboratory changes following discontinuation were: SU: +2.4 mg/dL (0.0,6.3); eGFR: -1.9 mL/min (- 8.7,3.7); CRP: -0.8 mg/L (-12.8,0.0); and ESR: -4.0 mm/hr (-13.0,0.0). Therapy post-discontinuation included oral ULTs (86.0%), restarting pegloticase (4.5%), and no documentation of ULT (9.5%), excluding patients with multiple same-day prescriptions (n = 17). Oral ULTs following pegloticase were: 62.7% allopurinol, 34.1% febuxostat. The median (IQR) time to starting/restarting ULT was 92.0 days (55.0,173.0). Following ULT prescribing (≥ 30 days), only 51.0% of patients had SU < 6 mg/dL. Patients restarting pegloticase achieved a median SU of 0.9 mg/dL (IQR:0.2,9.7) and 58.3% had an SU < 6 mg/dL., Conclusion: Pegloticase treats uncontrolled gout in patients with failed response to xanthine oxidase inhibitors, but among patients who discontinue, optimal treatment is unclear. Based on this analysis, only half of those starting another ULT achieved target SU. Close follow-up is needed to optimize outcomes after pegloticase discontinuation., (© 2024. The Author(s).)

Background: To date, colchicine and prednisolone are two effective therapies for the treatment of acute gout but have never been compared directly in a randomized clinical trial. In addition, in previous trials of treating acute gout patients with concomitant comorbidities were often excluded due to contraindications to naproxen., Study Design: This pragmatic, prospective, double-blind, double-dummy, parallel-group, randomized, non-inferiority trial compares prednisolone with colchicine in terms of non-inferiority in patients with acute gout. Patients presenting to their general practitioner with acute gout can be included if the gout attack has occurred within the last 2 days. A total of 60 practices in the vicinity of three university medical centers (Greifswald, Göttingen, and Würzburg) participate in the study. The intervention group receives 30 mg prednisolone for 5 days, while the group of standard care receives low-dose colchicine (day 1: 1.5 mg; days 2-5: 1 mg). The first dose of treatment is provided at day 0 when patients present to the general practitioner due to an acute gout attack. From day 0 to day 6, patients will be asked to complete a study diary on daily basis regarding pain quantification. For safety reasons, potential side effects and the course of systolic blood pressure are also assessed., Statistical Analysis Plan: N = 314 patients have to be recruited to compensate for 10% of dropout and to allow for showing non-inferiority of prednisolone compared to colchicine with a power of 90%. We use permuted block randomization with block sizes of 2, 4, and 6 to avoid imbalanced treatment arms in this multi-center study; patients are randomized in a 1:1 ratio. The absolute level of pain on day 3 (in the last 24 h) is the primary outcome and measured on a numerical rating scale (NRS: 0-10). Using a multiple linear regression model adjusted for age, sex, and pain at baseline, prednisolone is considered non-inferior if the effect estimate including the confidence intervals is lower than a margin of 1 unit on the NRS. Average response to treatment, joint swelling and tenderness, physical function of the joint, and patients' global assessment of treatment success are secondary outcomes., Discussion: The trial will provide evidence from a direct comparison of colchicine and prednisolone regarding their efficacy of pain reduction in acute gout patients of primary care and to indicate possible safety signals., Trial Registration: ClinicalTrials.gov Identifier: NCT05698680 first posted on January 26, 2023 (retrospectively registered)., (© 2024. The Author(s).)

Background: Obesity is associated with elevated serum uric acid (SUA) levels and frequent gout flares. Losing weight can reduce the SUA level and gout flares. The effect of orlistat on SUA levels and gout flares in patients with overweight/obesity and hyperuricemia (HUA) has not been extensively studied. This study investigated the effects of orlistat on SUA levels and gout flares compared to placebo in overweight and obese patients with HUA., Methods: A total of 72 Chinese patients with overweight/obesity and HUA were randomly divided into a placebo group (35, 48.6%) and an orlistat group (37, 51.4%); the trial lasted 12 weeks. The primary endpoints were the relative changes in body weight, the SUA level, and gout flares in the per-protocol population., Results: Orlistat reduced the proportion of patients with gout flares (log-rank P = 0.023, hazard ratio = 0.31, 95% confidence interval 0.11-0.85). There was no significant difference in SUA level between the two groups. The average weight loss of the orlistat group was 2.85 kg, and the average weight loss of the placebo group was 0.76 kg. The weight loss in the orlistat group was significantly greater than that in the control group (P < 0.05)., Conclusions: This study is the first to demonstrate that orlistat has no significant effect on SUA levels in patients with overweight/obesity and HUA. The utility of orlistat as an adjunct therapy to prevent gout flares during weight loss in patients with HUA was emphasized., Trial Registration: Clinicaltrials.gov NCT05496075., (© 2024. The Author(s).)

Background: Exogenously providing engineered Uox with enhanced half-life is one of the important urate-lowering treatments for gout. The potential of PAT101, a recombinant human albumin (rHA)-conjugated variant, was evaluated and compared as a novel gout treatment through various in vivo studies with PAT101 and competing drugs., Methods: PAT101 was produced by site-specific conjugation of rHA and Aspergillus flavus Uox (AfUox-rHA) through clickable non-natural amino acid (frTet) and Inverse electron demand Diels-Alder (IEDDA) reaction. In vivo pharmacokinetics, efficacy tests and in vitro immunogenetic assay were performed after single or multiple doses of PAT101 and its competitors in BALB/c mice, transgenic (TG) mice, Sprague-Dawley (SD) rats, and non-human primate (NHP)., Results: The half-life of PAT101 in single-dose treated TG mice was more than doubled compared to pegloticase. In SD rats with 4 weeks of repeated administration of rasburicase, only 24% of Uox activity remained, whereas in PAT101, it was maintained by 86%. In the Uox KO model, the survival rate of PAT101 was comparable to that of pegloticase. In addition, human PBMC-based CD4 + /CD8 + T-cell activation analysis demonstrated that PAT101 has a lower immune response compared to the original drug, rasburicase., Conclusion: All results suggest that this rHA-conjugated AfUox, PAT101, can be provided as a reliable source of Uox for gout treatment., (© 2023. The Author(s).)

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., (© 2023. The Author(s).)

Background: Currently, it is not possible to predict whether patients with hyperuricemia (HUA) will develop gout and how this progression may be affected by urate-lowering treatment (ULT). Our study aimed to evaluate differences in plasma lipidome between patients with asymptomatic HUA detected ≤ 40 years (HUA ≤ 40) and > 40 years, gout patients with disease onset ≤ 40 years (Gout ≤ 40) and > 40 years, and normouricemic healthy controls (HC)., Methods: Plasma samples were collected from 94 asymptomatic HUA (77% HUA ≤ 40) subjects, 196 gout patients (59% Gout ≤ 40), and 53 HC. A comprehensive targeted lipidomic analysis was performed to semi-quantify 608 lipids in plasma. Univariate and multivariate statistics and advanced visualizations were applied., Results: Both HUA and gout patients showed alterations in lipid profiles with the most significant upregulation of phosphatidylethanolamines and downregulation of lysophosphatidylcholine plasmalogens/plasmanyls. More profound changes were observed in HUA ≤ 40 and Gout ≤ 40 without ULT. Multivariate statistics differentiated HUA ≤ 40 and Gout ≤ 40 groups from HC with an overall accuracy of > 95%., Conclusion: Alterations in the lipidome of HUA and Gout patients show a significant impact on lipid metabolism. The most significant glycerophospholipid dysregulation was found in HUA ≤ 40 and Gout ≤ 40 patients, together with a correction of this imbalance with ULT., (© 2023. The Author(s).)

Background and Aims: Bempedoic Acid (BA) is a novel Lipid-Lowering Therapy (LLT). We performed a systematic review and meta-analysis to assess the efficacy and safety of BA in patients with hypercholesterolemia., Methods: PubMed, Scopus, and Cochrane library databases were searched for randomised controlled trials evaluating the efficacy and/or safety of BA compared with placebo. Trials investigating dosages other than 180 mg/die were excluded. Major adverse cardiovascular events (MACE) were the primary efficacy endpoint. LDL-cholesterol reduction was the primary laboratory endpoint. Pre-specified safety endpoints included muscle-related adverse events, new-onset diabetes, and gout. The protocol was registered on PROSPERO (temporary ID:399,867)., Results: Study search identified 275 deduplicated results. 11 studies, encompassing 18,315 patients (9854 on BA vs 8461 on placebo/no treatment) were included. BA was associated with a reduced risk of MACE (OR 0.86, 95% CI 0.79-0.95), myocardial infarction (OR 0.76, 95% CI 0.64-0.88) and unstable angina (OR 0.69, 95% CI 0.54-0.88) compared to control, over a median follow up of 87 (15-162) weeks. BA was associated with a reduction of LDL-Cholesterol (mean difference [MD]-22.42,95% CI - 24.02% to - 20.82%), total cholesterol (- 16.50%,95% - 19.21% to - 13.79%), Apo-B lipoprotein (- 19.55%, - 22.68% to - 16.42%) and high-sensitivity CRP (- 27.83%, - 31.71% to - 23.96%) at 12 weeks. BA was associated with a higher risk of gout (OR 1.55, 95% CI 1.27-1.90) as compared with placebo. Efficacy on laboratory endpoints was confirmed, with a variable extent, across patients on statin or ezetimibe background therapy., Conclusions: The improved cholesterol control achieved with BA translates into a reduced risk of MACE, including myocardial infarction and coronary revascularisation. The drug has a satisfactory safety profile except for an increased risk of gout., (© 2023. The Author(s).)

Background: Gout is the most common form of rheumatic disease in which monosodium urate crystals are deposited in the joints followed by acute inflammatory reactions. There are various approved drugs that can be prescribed for pain relief during an acute gout attack. However, to date, no direct comparison of efficacy of colchicine and prednisolone for the treatment of acute gout attacks has been investigated. Furthermore, the majority of previous research studies were not only conducted in tertiary centres but also excluded patients with common comorbidities due to contraindications to naproxen., Methods: This pragmatic, prospective, double-blind, double-dummy, parallel-group, randomized, non-inferiority trial investigates whether prednisolone (intervention) is non-inferior to treatment with colchicine (active control) in patients with acute gout. Adult patients presenting with acute gout to their general practitioners in 60 practices across 3 university sites (Greifswald, Göttingen, and Würzburg) are eligible to participate in the study. Participants in the intervention group receive 30 mg prednisolone for 5 days. Those in the control group receive low-dose colchicine (day 1: 1.5 mg; days 2-5: 1 mg). The primary outcome is the absolute level of the most severe pain on day 3 (in the last 24 h) measured with an 11-item numerical rating scale. Day 0 is the day patients take their study medication for the first time. They are then asked to fill out a study diary the same time each day for pain quantification. Pain scores are used for comparison between the two medications. Secondary outcomes are average response to treatment, swelling, tenderness and physical function of the joint, patients' global assessment of treatment success, use of additional pain medication and non-pharmacological pain therapies. For safety reasons, potential side effects and course of systolic blood pressure are assessed., Discussion: This trial will provide evidence on the effectiveness of pain reduction and side effects of colchicine and prednisolone in acute gout in primary care., Trial Registration: ClinicalTrials.gov Identifier: NCT05698680 first posted on January 26, 2023 (retrospectively registered). URL of trial registry record: https://clinicaltrials.gov/study/NCT05698680., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Low urine pH, which may be mediated by metabolic syndrome (MetS), is common in gout. Tart cherries are shown to improve MetS symptoms and possess anti-inflammatory properties. However, the efficacy of tart cherry supplements on urine pH has yet to be studied., Objectives: This study aimed to investigate the efficacy and safety of tart cherry supplementary citrate (TaCCi) mixture on urine pH, serum urate (sUA), C-reactive protein (CRP), and gout flares in gout patients initiating urate-lowering therapy (ULT), in comparison to citrate mixture and sodium bicarbonate., Methods: A prospective, randomized (1:1:1), open-label, parallel-controlled trial was conducted among 282 men with gout and fasting urine pH ≤ 6, who were initiating ULT with febuxostat (initially 20 mg daily, escalating to 40 mg daily if serum urate ≥ 360 μmol/L). Participants were randomized to groups taking either sodium bicarbonate, citrate mixture, or TaCCi mixture. All participants were followed every 4 weeks until week 12. Urine pH and sUA were co-primary outcomes, with various biochemical and clinical secondary endpoints., Results: Urine pH increased to a similar extent in all three groups. SUA levels declined in all three groups as well, with no significant differences observed between the groups. At week 12, the TaCCi mixture group exhibited a greater reduction in the urine albumin/creatinine ratio (UACR) compared to the other two groups (p < 0.05). Participants taking TaCCi mixture or citrate mixture experienced fewer gout flares than those in the sodium bicarbonate group over the study period (p < 0.05). Additionally, the TaCCi mixture group had a lower CRP level at week 12 relative to the other two groups (p < 0.01). Adverse events were similar across all three groups., Conclusion: The TaCCi mixture had similar efficacy and safety on urine alkalization and sUA-lowering as the citrate mixture and sodium bicarbonate in patients with gout. However, the TaCCi mixture resulted in greater improvements in UACR and CRP, which suggests that tart cherry supplements may provide additional benefits for renal protection and reduce inflammation in gout, particularly when starting ULT., Trial Registration: This project was registered in ChiCTR ( www.chictr.org.cn ), with the registration number: ChiCTR2100050749., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objectives: The objective of this systematic review was to assess the effects of interleukin-1β (IL-1β) inhibitors on gout flares., Methods: Studies published between 2011 and 2022 that evaluated the effects of IL-1β inhibitors in adult patients experiencing gout flares were eligible for inclusion. Outcomes including pain, frequency and intensity of gout flares, inflammation, and safety were assessed. Five electronic databases (Pubmed/Medline, Embase, Biosis/Ovid, Web of Science and Cochrane Library) were searched. Two independent reviewers performed study screening, data extraction and risk of bias assessments (Cochrane Risk of Bias Tool 2 for randomised controlled trials [RCTs] and Downs and Black for non-RCTs). Data are reported as a narrative synthesis., Results: Fourteen studies (10 RCTs) met the inclusion criteria, with canakinumab, anakinra, and rilonacept being the three included IL-1β inhibitors. A total of 4367 patients with a history of gout were included from the 14 studies (N = 3446, RCTs; N = 159, retrospective studies [with a history of gout]; N = 762, post hoc analysis [with a history of gout]). In the RCTs, canakinumab and rilonacept were reported to have a better response compared to an active comparator for resolving pain, while anakinra appeared to be not inferior to an active comparator for resolving pain. Furthermore, canakinumab and rilonacept reduced the frequency of gout flares compared to the comparators. All three medications were mostly well-tolerated compared to their comparators., Conclusion: IL-1β inhibitors may be a beneficial and safe medication for patients experiencing gout flares for whom current standard therapies are unsuitable., Review Protocol Registration: PROSPERO ID: CRD42021267670., (© 2023. The Author(s).)

Background: Previous studies have revealed that Sirt3 deficiency is associated with several inflammatory responses. The purpose of this study is to investigate the role and potential molecular mechanisms of Sirt3 in the inflammation induced by monosodium urate (MSU) crystals., Methods: The Sirt3 expression level in the peripheral blood mononuclear cells (PBMCs) of patients with gout was measured. Function and molecular mechanism of Sirt3 in MSU crystal-induced inflammation were investigated in bone marrow-derived macrophages (BMDMs), C57BL/6 mouse, and Sirt3 -/- mouse., Results: Sirt3 expression was decreased in the PBMCs of patients with gout. Sirt3 agonist (Viniferin) inhibited the acetylation levels of mitochondrial proteins including the SOD2 protein. RNA sequencing, bio-informatics analysis, RT-PCR, and Western blot demonstrated that Sirt3 could suppress the expression of Acod1 (Irg1), which plays an important role in gout. In BMDMs treated with palmitic acid (C16:0) plus MSU crystals, Acod1 knockdown repressed mitochondrial reactive oxygen species (mtROS) over-production, macrophage migration, and mitochondrial fragmentation, and Acod1 improved AMPK activity. The over-expression of Acod1 did not significantly affect the level of itaconic acid, but greatly decreased the levels of some important intermediate metabolites of the tricarboxylic acid (TCA) cycle. These data indicate that Acod1 exerts a pro-inflammatory role in MSU crystal-induced inflammation and is independent of the metabolic level of itaconic acid. Sirt3 deficiency exacerbates inflammatory response induced by MSU crystals in vitro and in vivo., Conclusion: The current study has shown that Sirt3 can alleviate the MSU crystal-induced inflammation by inhibiting the expression of Acod1., (© 2023. The Author(s).)

Background: Gout is a common inflammatory arthritis caused by increased serum uric acid levels. Untreated or insufficiently treated gout can lead to deposition of monosodium urate crystals in joints, cartilage, and kidneys. Although Tongfengding capsules, a Chinese patent medicine, have long been used to treat gout, their effects and safety have not been reviewed systematically. This study evaluated its efficacy and safety for gout in adults., Methods: Randomized controlled trials involving Tongfengding capsule for gout in adults were searched from PubMed, EMBASE, Cochrane Central Register of Controlled Trials, CBM, CNKI, and VIP databases, and analyzed using the Cochrane Handbook criteria. The primary outcome measures were the total effective rate. The secondary outcome measures including the blood uric acid (BUA), 24-h urinary total protein (24-h UTP), blood urea nitrogen (BUN), interleukin (IL)-6, IL-8, tumor necrosis factor-alpha (TNF-α) and adverse effects. The risk of bias was evaluated in all included studies. RevMan ver. 5.3.5 and GRADE profiler was used for data analysis and assessing the quality of evidence, respectively., Results: Six studies (n = 607 Chinese participants) were included. Tongfengding capsules plus conventional treatment significantly increased the total effective rate (RR 1.21, 95% CI 1.11-1.33), while reducing the BUA (MD - 66.05 µmol/L, 95% CI - 81.26 to - 50.84), 24-h UTP (MD - 0.83 g/24 h, 95% CI - 0.96 to - 0.70), BUN (MD - 0.90 mmol/L, 95% CI - 1.60 to - 0.20), IL-6 (MD - 6.99 ng/L, 95% CI - 13.22 to - 0.75), IL-8 (MD - 12.17 ng/L, 95% CI - 18.07 to - 6.27), TNF-α (MD - 8.50 ng/L, 95% CI - 15.50 to - 1.51), and adverse effects (RR 0.21, 95% CI 0.04-0.95)., Conclusion: Tongfengding capsules plus conventional treatment is safe and beneficial for adults with gout compared with conventional treatment., (© 2023. The Author(s).)

Background: Long-term gout treatment is based on reducing serum urate levels using urate-lowering therapy (ULT). Most guidelines recommend using a lifelong continuation treat-to-target (T2T) strategy, in which ULT is dosed or combined until a serum urate target has been reached and maintained. However, a frequently used alternative strategy in clinical practice is a treat-to-avoid-symptoms (T2S) ULT discontinuation strategy, with the possibility of restarting the medication. This latter strategy aims at an acceptable symptom state, regardless of serum urate levels. High-quality evidence to support either strategy for patients in prolonged remission while using ULT is lacking., Methods: We developed an investigator-driven pragmatic, open-label, multicentre, randomized, superiority treatment strategy trial (GO TEST Finale). At least 278 gout patients using ULT who are in remission (>12 months, preliminary gout remission criteria) will be randomized 1:1 to a continued T2T strategy (treatment target serum urate < 0.36 mmol/l) or switched to a T2S discontinuation strategy in which ULT is tapered to stop and restarted in case of (persistent or recurrent) flaring. The primary outcome is the between-group difference in the proportion of patients not in remission during the last 6 months of 24 months follow-up and will be analyzed using a two proportion z test. Secondary outcomes are group differences in gout flare incidence, reintroduction or adaptation of ULT, use of anti-inflammatory drugs, serum urate changes, occurrence of adverse events (with a special interest in cardiovascular and renal events), and cost-effectiveness., Discussion: This study will be the first clinical trial comparing two ULT treatment strategies in patients with gout in remission. It will contribute to more specific and unambiguous guideline recommendations and improved cost-effectiveness of long-term gout treatment. It also paves the way (exploratory) to individualized long-term ULT treatment. In this article, we elaborate on some of our trial design choices and their clinical and methodological consequences., Trial Registration: International Clinical Trial Registry Platform (ICTRP) NL9245. Registered on 2 February 2021 (METC Oost-Nederland NL74350.091.20); EudraCT EUCTR2020-005730-15-NL. Registered on 11 January 2021., (© 2023. The Author(s).)

Background: Uncontrolled/refractory gout patients are recalcitrant/intolerant to oral urate-lowering therapies (ULTs), experiencing frequent gout flares, functionally limiting tophi, and low quality of life. Pegloticase lowers urate, but anti-pegloticase antibodies limit urate-lowering efficacy and increase infusion reaction (IR) risk. Immunomodulator + pegloticase co-administration may improve treatment response rates, with 79% of MIRROR open-label trial (MIRROR-OL, pegloticase + oral methotrexate) participants meeting 6-month response criteria. Exploratory outcomes from MIRROR-OL are described here., Methods: Adults with uncontrolled gout (serum urate [SU] ≥ 6 mg/dL and ULT-intolerance/recalcitrance or functionally limiting tophi) were included. Oral methotrexate (15 mg/week) was administered 4 weeks before and during pegloticase treatment (biweekly 8 mg infusion, ≤ 52 weeks). Exploratory outcomes included change from baseline (CFB) in number of affected joints, Health Assessment Questionnaires (HAQs), and Gout Global Assessments., Results: Fourteen patients received ≥ 1 pegloticase infusion, with 13 included in 52-week analyses (1 enrolled before treatment-extension amendment, exited at 24 weeks). Three patients prematurely exited due to SU rise; 10 completed 52-week evaluations (8 completed 52 weeks of co-therapy, 2 completed 24 weeks [met treatment goals]). At 52 weeks, SU averaged 1.1 ± 2.5 mg/dL, with improvements in HAQ pain and health (CFB: - 33.6 and - 0.7, respectively), Patient and Physician Global Assessments (CFB: - 4.6 and - 5.7, respectively), and joint involvement (CFB: - 5.6, - 8.4, - 6.0 tender, swollen, tophi-affected joints, respectively). Two patients underwent dual-energy computed tomography, showing concomitant monosodium urate volume reductions. All patients had ≥ 1 AE, with 92.9% experiencing acute flare. One mild IR ("cough") occurred and no new safety signals were identified., Conclusion: Pegloticase + methotrexate co-therapy resulted in sustained SU-lowering with meaningful improvements in clinical measures, urate burden, and patient-reported outcomes., Trial Registration: ClinicalTrials.gov (NCT03635957)., (© 2022. The Author(s).)

Objectives: The association between habitual glucosamine use and incident gout has not been examined in previous studies. We aimed to evaluate the association of habitual use of glucosamine with the risk of gout in general population., Methods: A total of 436,594 participants (55.4% female) without prior gout at baseline who completed a questionnaire on supplementation use, which included glucosamine, in the UK Biobank were enrolled. Incident gout was recorded from self-report, death register, primary care, and hospital admission data., Results: At baseline, 53,433 (22.1%) females and 30,685 (15.8%) males reported habitual glucosamine use. During a median follow-up period of 12.1 years, 1718 (0.7%) females and 5685 (2.9%) males developed gout. After multivariable adjustment for major risk factors, glucosamine use was associated with a significantly lower risk of incident gout in females (hazard ratio [HR], 0.81, 95% confidence interval [CI], 0.71-0.92), but not in males (HR, 1.05, 95% CI, 0.97-1.13), compared with non-use (P-interaction &lt; 0.001). Among females, the inverse association between glucosamine use and gout was stronger in participants with diuretics use (HR, 0.64, 95% CI, 0.50-0.81) than those without diuretics use (HR, 0.89, 95% CI, 0.77-1.03) (P-interaction = 0.015). Moreover, gout genetic risk scores did not significantly modify the association between glucosamine use and the risk of incident gout in males (P-interaction = 0.548) or females (P-interaction = 0.183)., Conclusions: Habitual glucosamine use to relieve osteoarthritis pain was related to lower risk of gout in females, but not in males., (© 2022. The Author(s).)

Background: Publications suggest immunomodulation co-therapy improves responder rates in uncontrolled/refractory gout patients undergoing pegloticase treatment. The MIRROR open-label trial showed a 6-month pegloticase + methotrexate co-therapy responder rate of 79%, compared to an established 42% pegloticase monotherapy responder rate. Longer-term efficacy/safety data are presented here., Methods: Uncontrolled gout patients (serum urate [SU] ≥ 6 mg/dL and SU ≥ 6 mg/dL despite urate-lowering therapy [ULT], ULT intolerance, or functionally-limiting tophi) were included. Patients with immunocompromised status, G6PD deficiency, severe kidney disease, or methotrexate contraindication were excluded. Oral methotrexate (15 mg/week) and folic acid (1 mg/day) were administered 4 weeks before and during pegloticase therapy. Twelve-month responder rate (SU < 6 mg/dL for ≥ 80% during month 12), 52-week change from baseline in SU, and extended safety were examined. Efficacy analyses were performed for patients receiving ≥ 1 pegloticase infusion. Pharmacokinetics (PK)/anti-drug antibodies (ADAs) were examined and related to efficacy/safety findings., Results: Fourteen patients were included (all male, 49.3 ± 8.7 years, 13.8 ± 7.4-year gout history, pre-therapy SU 9.2 ± 2.5 mg/dL). Three patients were non-responders and discontinued study treatment before 24 weeks, one patient exited the study per protocol at 24 weeks (enrolled prior to treatment extension amendment), and 10 remained in the study through week 52. Of the 10, 8 completed 52 weeks of pegloticase + methotrexate and were 12-month responders. The remaining two discontinued pegloticase + methotrexate at week 24 (met treatment goals) and stayed in the study under observation (allopurinol prescribed at physicians' discretion); one remained a responder at 12 months. At 52 weeks, change from baseline in SU was - 8.2 ± 4.1 mg/dL (SU 1.1 ± 2.4 mg/dL, n = 10). Gout flares were common early in treatment but progressively decreased while on therapy (weeks 1-12, 13/14 [92.9%]; weeks 36-52, 2/8 [25.0%]). One patient recovered from sepsis (serious AE). Two non-responders developed high ADA titers; fewer patients had trough concentrations (C min ) below the quantitation limit (BQL), and the median C min was higher (1.03 µg/mL vs. BQL) than pegloticase monotherapy trials., Conclusions: Pegloticase + methotrexate co-therapy was well-tolerated over 12 months, with sustained SU lowering, progressive gout flare reduction, and no new safety concerns. Antibody/PK findings suggest methotrexate attenuates ADA formation, coincident with higher treatment response rates., Trial Registration: ClinicalTrials.gov, NCT03635957 . Registered on 17 August 2018., (© 2022. The Author(s).)

Background: Asymptomatic hyperuricemia was found to be associated with increased cardiovascular disease risk but the potential benefits of urate-lowering therapy (ULT) remain controversial. We conducted a systematic review and network meta-analysis (NMA) with frequentist model to estimate the efficacy and safety of ULT in asymptomatic hyperuricemia., Methods: MEDLINE, Embase, and Scopus were searched without language restrictions. Randomized controlled trials (RCT) of adults with asymptomatic hyperuricemia were eligible if they compared any pair of ULTs (i.e., allopurinol, febuxostat, probenecid, benzbromarone, sulfinpyrazone, rasburicase, lesinurad, and topiroxostat) and placebo or no ULT, and had outcomes of interest, including composite renal events, major adverse cardiovascular events, serum urate levels, estimated glomerular filtration rate (eGFR), systolic blood pressure, and adverse events., Results: NMA with frequentist approach was applied to estimate relative treatment effects, i.e., risk ratio (RR) and mean difference (MD). A total of 23 RCTs were eligible. NMA identified beneficial effects of ULT on composite renal events and eGFR but not for other outcomes. Allopurinol and febuxostat had significantly lower composite renal events than placebo (RR 0.39, 95% confidence interval [CI] 0.23 to 0.66, and RR 0.68, 95% CI 0.46 to 0.99, respectively). Both treatments also resulted in significantly higher eGFR than placebo (MD 3.69 ml/min/1.73 m 2 , 95% CI 1.31 to 6.08, and MD 2.89 ml/min/1.73 m 2 , 95% CI 0.69 to 5.09, respectively). No evidence of inconsistency was identified., Conclusions: Evidence suggests that allopurinol and febuxostat are the ULTs of choice in reducing composite renal events and improving renal function., Trial Registration: This study was registered with PROSPERO: CRD42019145908. The date of the first registration was 12 th November 2019., (© 2022. The Author(s).)

Background: Gout is a common disease with high incidence due to unhealthy diet and living habits. Simiao Powder, as a classic formula consisted of four common herbs, has been widely used in clinical practice since ancient times to prevent and treat gout. However, the pharmacological mechanism of Simiao Powder is still unclear., Methods: Based on network pharmacology, Simiao Powder active compounds were identified in TCMSP, ETCM and BATMAN database, used to establish a network of interaction between potential targets of Simiao Powder and known therapeutic targets of gout. Subsequently, the key potential targets are being used for protein-protein interaction, GO enrichment analysis and KEGG pathway enrichment analysis through several authoritative open databases. Molecular docking through AutoDockTools software can verify interaction between molecules. Finally, to validate the predicted results, in vivo experiments based on hyperuricemic-gout mice model were designed and treated with Simiao powder and allopurinol. Serum levels of uric acid (UA), creatinine (Cr), blood urea nitrogen (BUN) and xanthine oxidase (XOD) were determined using a customized assay kit while the expression of PPAR-γ, PTGS1, IL-6 and Bcl2 mRNA were analyzed through qRT-PCR., Results: Disease-target-compound network was visualized basing on the 20 bioactive compounds and the 19 potential targets using Cytoscape software. The results of PPI analysis, GO enrichment and KEGG pathway enrichment analysis indicate that the potential mechanism of Simiao Powder in treating gout may be achieved by regulating immune and inflammatory reactions, improving metabolism and endocrine. The results of molecular docking show that most of the targets and components have good binding activity. In vivo experiments revealed that Simiao powder can decreased serum UA and XOD levels in hyperuricemic-gout mice, and improved renal function. Furthermore, Simiao powder certainly regulates the expression of PPAR-γ, PTGS1, IL-6 and Bcl2 mRNA in ankle tissue in hyperuricemic-gout mice., Conclusion: Collectively, this research predicted a multiple compounds, targets, and pathways model mechanism of Simiao Powder in the prevention and treatment of gout, providing new ideas and methods for in-depth research, via vivo experiments., (© 2022. The Author(s).)

Objectives: To explore the frequency and predictors of flares over 2 years during a treat-to-target strategy with urate-lowering therapy (ULT) in patients with gout., Methods: In the treat-to-target, tight control NOR-Gout study patients started ULT with escalating doses of allopurinol. Flares were recorded over 2 years. Baseline predictors of flares during months 9-12 in year 1 and during year 2 were analyzed by multivariable logistic regression., Results: Of 211 patients included (mean age 56.4 years, disease duration 7.8 years, 95% males), 81% (150/186) of patients experienced at least one gout flare during the first year and 26% (45/173) during the second year. The highest frequency of flares in the first year was seen during months 3-6 (46.8% of patients). Baseline crystal depositions detected by ultrasound and by dual-energy computed tomography (DECT) were the only variables which predicted flares both during the first period of interest at months 9-12 (OR 1.033; 95% CI 1.010-1.057, and OR 1.056; 95% CI 1.007-1.108) and also in year 2. Baseline subcutaneous tophi (OR 2.42, 95% CI 1.50-5.59) and prior use of colchicine at baseline (OR 2.48, 95% CI 1.28-4.79) were independent predictors of flares during months 9-12, whereas self-efficacy for pain was a protective predictor (OR 0.98 per unit, 95% CI 0.964-0.996)., Conclusions: In patients with gout, flares remain frequent during the first year of a treat-to-target ULT strategy, especially during months 3-6, but are much less frequent during year 2. Baseline crystal depositions predict flares over 2 years, supporting ULT early during disease course., Trial Registration: ACTRN12618001372279., (© 2022. The Author(s).)

Background: The aim of this study is to develop and assess usability of a web-based patient-tailored tool to support adherence to urate-lowering therapy (ULT) among gout patients in a clinical setting., Methods: The content of the tool was based on the Integrated Change (I-Change) model. This model combines various socio-cognitive theories and assumes behavioral change is a result of becoming aware of the necessity of change by integrating pre-motivational, motivational, and post-motivational factors. An expert group (five gout experts, three health services researchers, and one health behavior expert) was assembled that decided in three meetings on the tool's specific content (assessments and personalized feedback) using information from preparatory qualitative studies and literature reviews. Usability was tested by a think aloud approach and validated usability questionnaires., Results: The I-Change Gout tool contains three consecutive sessions comprising 80 questions, 66 tailored textual feedback messages, and 40 tailored animated videos. Navigation through the sessions was determined by the patients' intention to adapt suboptimal ULT adherence. After the sessions, patients receive an overview of the personalized advices and plans to support ULT adherence. Usability testing among 20 gout patients that (ever) used ULT and seven healthcare professionals revealed an overall score for the tool of 8.4 ± 0.9 and 7.7 ± 1.0 (scale 1-10). Furthermore, participants reported a high intention to use and/or recommend the tool to others. Participants identified some issues for further improvement (e.g. redundant questions, technical issues, and text readability). If relevant, these were subsequently implemented in the I-Change Gout tool, to allow further testing among the following participants., Conclusion: This study provides initial support for the usability by patients and healthcare professionals of the I-Change Gout tool to support ULT adherence behavior., (© 2022. The Author(s).)

Objective: The objective was to evaluate whether initiation of urate-lowering treatment (ULT) during an acute gout flare prolonged the current episode., Methods: A comprehensive search of MEDLINE and Web of Science databases was conducted from their inception to 15 March 2021. Five randomized controlled trials (RCTs) with 381 patients met the inclusion criteria. Standardized mean difference (SMD), odds ratio (OR), and 95% confidence interval (CI) were used for estimating the clinical efficacy of ULT in acute gout., Results: There was no statistical difference in days to resolution (intent-to-treat analysis) (SMD, 0.68; 95% CI - 0.42 to 1.78; I 2 , 49%; p = 0.22), the pain visual analogue score (VAS) by day 10 (SMD, - 0.07; 95% CI - 0.30 to 0.16; I 2 , 0%; p = 0.53), C-reactive protein (CRP) from day 7 to 10 (SMD, - 1.14; 95% CI - 5.63 to 3.36; I 2 , 55%; p = 0.62), erythrocyte sedimentation rate (ESR) from day 7 to 10 (SMD, - 2.51; 95% CI - 5.46 to 0.45; I 2 , 0%; p = 0.10) and the recurrence of gout flares within 28-30 days (OR 0.78; 95% CI 0.29 to 2.09; I 2 , 0%; p = 0.62)., Conclusion: Initiation of ULT during an acute gout flare did not prolong the duration of the flare. However, larger sample size studies are needed to confirm this finding. Trial registration number PROSPERO (CRD42021234581)., (© 2022. The Author(s).)

Background: Gout is a painful chronic disease which disrupts work and family life and can lead to chronic joint damage. Pacific people in Aotearoa/New Zealand experience significant inequities, with over three times the gout prevalence of the non-Pacific non-Māori populations. Pacific people receive less regular urate-lowering drugs to prevent gout flare-ups, and have nine times the hospitalisation from gout compared with non-Pacific non-Māori people. Rates for Indigenous Māori lie between Pacific and non-Pacific non-Māori. A long-established Collective comprising community members from the Pacific People's Health Advisory Group, clinical staff from the Pacific Practice-Based Research Network, and University of Auckland researchers have identified that improving Pacific urate-lowering therapy use as the research question of prime importance for improved health outcomes of Pacific people in South Auckland. Building on the existing knowledge, this study aims to develop, implement and evaluate a novel innovative intervention to improve the uptake of urate-lowering therapy by Pacific patients with gout., Methods: Three-phase mixed methods co-design study using the Fa'afaletui research framework following the STROBE statement. Phase1 is observational times series of prevalence of patients with gout, proportion with urate blood-level monitoring and use of urate-lowering medication over past 5 years. In Phase 2 the Collective will workshop new interventions to address previous uptake barriers, using culturally-appropriate Talanga communications with results synthesised in line with Kakala principles. The designed intervention will be implemented and process and outcome evaluations conducted. Finally, an implementation framework will be produced to facilitate further roll-out., Discussion: The study aims to enhance health and reduce inequities for Pacific people, contribute to creation of Pacific health knowledge and translation of research findings into Pacific health gains. Potential longer-term impact is a gout-management pathway for use throughout Aotearoa/New Zealand. Māori have similar issues with high gout prevalence and low urate-lowering therapy use hence the intervention is likely to translate to Māori healthcare. The project will contribute to Pacific research capacity and capability-building as well as general upskilling of community and practice members involved in the co-design processes., Trial Registration: The Australian New Zealand Clinical Trial Registry is in process, request number 38206, 1-09-2021., (© 2021. The Author(s).)

Background: Our previous research showed that uric acid lowering therapy (ULT) for gout and hyperuricemia is being prescribed for pediatric patients even though these drugs have not been approved for use in children. However, the actual clinical situation has not been clearly elucidated. In this paper, we provide an in-depth look at the details of actual clinical practice., Methods: This retrospective cross-sectional study accessed health insurance data for 696,277 children from April 2016 through March 2017 to identify pediatric patients with gout or asymptomatic hyperuricemia, calculate the proportion of patients prescribed ULTs, and analyze population characteristics. Adherence and mean dose for febuxostat and allopurinol, the most commonly prescribed drugs, were also analyzed., Results: Among children with gout or asymptomatic hyperuricemia, we found that 35.1% (97/276) were prescribed ULT. This proportion increased with age, especially among males. By comorbidity, ULT was prescribed to 47.9% (46/96) of patients with kidney disease, 41.3% (26/63) for cardiovascular disease, 40.0% (6/15) for Down syndrome, and 27.1% (32/118) for metabolic syndrome. In patients with kidney disease, febuxostat was prescribed more than twice as frequently as allopurinol (28 vs. 12). Median values for the medication possession ratio (MPR) of febuxostat and allopurinol were 70.1 and 76.7%, respectively, and prescriptions were continued for a relatively long period for both drugs. Both drugs were prescribed at about half the adult dose for patients 6-11 years old and about the same as the adult dose for patients 12-18 years old., Conclusions: This study showed that the continuous management of serum uric acid is being explored using off-label use of ULT in pediatric patients with gout or asymptomatic hyperuricemia in Japan. Drug selection is based on patient characteristics such as sex, age, and comorbidities, and pediatric dosage is based on usage experience in adults. To develop appropriate pediatric ULT, clinical trials are needed on the efficacy and safety of ULT in the pediatric population., Trial Registration: UMIN000036029 ., (© 2021. The Author(s).)

Objective: Medication adherence in gout is suboptimal, and the lack of effective interventions to address it presents a huge challenge. Medication adherence and gout outcomes are worse in racial/ethnic minorities. The objective of this paper was to provide the details of the study protocol for randomized, controlled trial (RCT) in African Americans (AAs) with gout that will test the effectiveness of a culturally appropriate gout storytelling intervention., Methods: The SToRytelliing to Improve Disease outcomes in Gout (STRIDE-GO) study will be a 12-month, multicenter, open-label RCT that will assess the effect of a culturally appropriate gout storytelling in at least 300 AA veterans with gout. Participants will be randomized to gout-storytelling intervention vs. a stress reduction video in a 1:1 ratio. The primary outcome is urate-lowering therapy (ULT) adherence measured with MEMSCap™, an electronic monitoring system (efficacy, 6 months; sustenance of efficacy, 12 months). Secondary outcomes include gout flares, serum urate (SU), gout-specific health-related quality of life [HRQOL], self-reported ULT adherence, patient satisfaction with treatment, and patient understanding of the intervention. AA veterans with gout who met the 1977 Preliminary American College of Rheumatology (ACR) classification criteria for gout, currently prescribed an oral ULT medication (allopurinol or febuxostat) for at least 6 months, and not using a pillbox to redistribute their medications, will be invited to an in-person study visit. After the study coordinators obtain informed consent, and ensure that participants meet the inclusion criteria, the eligible participants will be provided with their current ULT in a MEMSCap™ bottle for the 1-month run-in period and asked to return to the clinic in 1 month. ULT adherence with MEMSCap™ will be recorded at a 1-month return visit. Interested participants will complete the baseline assessments, randomized using the computerized system to either gout-storytelling intervention or a stress reduction intervention video arm and watch the respective video in-clinic. Patients will be interviewed on the phone at 2 and 4 months regarding the viewing of the videos at home at each time. Participants will be assessed in-clinic at 3, 6, 9, and 12 months; MEMSCap™ data and patient surveys will be captured at each visit. For any missed visit, assessments will be completed on the phone and MEMSCap™ data captured at the next in-clinic visit., Discussion: The study will assess the efficacy of a behavioral intervention to improve ULT adherence in minority populations with gout., Trial Registration: ClinicalTrials.gov NCT02741700. Registered on 14 September 2018., (© 2021. The Author(s).)

Background: Urate-lowering therapy (ULT) adherence is low in gout, and few, if any, effective, low-cost, interventions are available. Our objective was to assess if a culturally appropriate gout-storytelling intervention is superior to an attention control for improving gout outcomes in African-Americans (AAs)., Methods: In a 1-year, multicenter, randomized controlled trial, AA veterans with gout were randomized to gout-storytelling intervention vs. a stress reduction video (attention control group; 1:1 ratio). The primary outcome was ULT adherence measured with MEMSCap™, an electronic monitoring system that objectively measured ULT medication adherence., Results: The 306 male AA veterans with gout who met the eligibility criteria were randomized to the gout-storytelling intervention (n = 152) or stress reduction video (n = 154); 261/306 (85%) completed the 1-year study. The mean age was 64 years, body mass index was 33 kg/m 2 , and gout disease duration was 3 years. ULT adherence was similar in the intervention vs. control groups: 3 months, 73% versus 70%; 6 months, 69% versus 69%; 9 months, 66% versus 67%; and 12 months, 61% versus 64% (p > 0.05 each). Secondary outcomes (gout flares, serum urate and gout-specific health-related quality of life [HRQOL]) in the intervention versus control groups were similar at all time points except intervention group outcomes were better for the following: (1) number of gout flares at 9 months were fewer, 0.7 versus 1.3 in the previous month (p = 0.03); (2) lower/better scores on two gout specific HRQOL subscales: gout medication side effects at 3 months, 32.8 vs. 39.6 (p = 0.02); and unmet gout treatment need at 3 months, 30.9 vs. 38.2 (p = 0.003), and 6 months, 29.5 vs. 34.5 (p = 0.03), respectively., Conclusions: A culturally appropriate gout-storytelling intervention was not superior to attention control for improving gout outcomes in AAs with gout., Trial Registration: Registered at ClinicalTrials.gov NCT02741700., (© 2021. The Author(s).)

Background: The prevalence of renal calculi in patients with gout is high. Alkalized urine has been recommended by the 2020 European Association of Urology (EAU) guidelines to promote calculus dissolution. However, randomized controlled trials are lacking., Methods: In the protocol of this randomized, placebo-controlled, double-blinded trial, patients with gout combined with renal calculi are randomized (1:1) to the placebo and sodium bicarbonate groups. The intervention would be performed for 24 weeks, the 1-12 weeks are double-blinded, and the 13-24 weeks are open-labeled. Sodium bicarbonate (1 g tid) will be performed for 24 weeks in the sodium bicarbonate group. The placebo will be performed for 12 weeks and not be performed from 13 weeks to 24 weeks in the placebo group. All subjects will be administered febuxostat (40 mg/day) for 24 weeks and receive concomitant anti-inflammatory prophylaxis therapy for 12 weeks. The primary outcome is the proportion of patients whose renal calculus volume will be reduced after 12 weeks of treatment. The secondary outcomes include the volume changes of renal calculi, uric acid changes, the proportion of patients with serum uric acid (sUA) levels < 360 μmol/L, the changes in estimated glomerular filtration rate (eGFR), the pH value of urine, and the incidence of adverse events after treatment for 12 and 24 weeks., Discussion: This study will evaluate the efficacy and safety of sodium bicarbonate-alkalized urine on renal calculi in patients with gout., Trial Registration: ClinicalTrials.gov ChiCTR2100045183. Registered on April 7, 2021, with ChiCTR., (© 2021. The Author(s).)

Objective: To investigate whether baseline monosodium urate (MSU) burden estimated by ultrasound (US) predicts the achievement of the 2016 remission criteria for gout after 12 months., Methods: In this 12-month prospective, observational and single-center study, patients with gout fulfilling all the domains of the 2016 preliminary remission criteria for gout at baseline and on urate-lowering therapy (ULT) for at least the preceding 6 months were consecutively enrolled. The US findings indicative of MSU deposits [aggregates, double contour (DC) sign, and/or tophi] were identified according to the Outcome Measure in Rheumatology US Working Group definitions. The US MSU burden was estimated by evaluating elbows, wrists, 2nd metacarpophalangeal joints, knees, ankles, and 1st metatarsophalangeal joints., Results: Remission criteria were fulfilled in 21 (42.0%) out of 50 patients at 12 months. The baseline US MSU burden was significantly lower in patients who achieved remission than in those who did not fulfill the remission criteria at 12 months (1.9±1.8 vs 5.1±3.1, p<0.01). US scores and ongoing flare prophylaxis were the only significant predictors of remission with an odds ratio of 10.83 [(95%CI=1.14-102.59), p=0.04] for the absence of MSU deposits, 5.53 [(95%CI=1.34-22.76), p<0.01] for the absence of aggregates, 7.33 [(95%CI=1.71-31.44), p<0.01] for the absence of DC sign, 3.88 [(95%CI=1.08-13.92), p=0.04] for the absence of tophi, and 0.23 [(95%CI=0.07-0.75), p=0.02] for ongoing flare prophylaxis., Conclusion: In gout, baseline US estimation of MSU burden is an independent predictor of the achievement of the remission criteria at 12 months., (© 2021. The Author(s).)

Gout flare prophylaxis and therapy use in people with underlying chronic kidney disease (CKD) is challenging, given limited treatment options and risk of worsening renal function with inappropriate treatment dosing. This literature review aimed to describe the current literature on the efficacy and safety of gout flare prophylaxis and therapy use in people with CKD stages 3-5. A literature search via PubMed, the Cochrane Library, and EMBASE was performed from 1 January 1959 to 31 January 2018. Inclusion criteria were studies with people with gout and renal impairment (i.e. estimated glomerular filtration rate (eGFR) or creatinine clearance (CrCl) < 60 ml/min/1.73 m 2 ), and with exposure to colchicine, interleukin-1 inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), and glucocorticoids. All study designs were included. A total of 33 studies with efficacy and/or safety analysis stratified by renal function were reviewed-colchicine (n = 20), anakinra (n = 7), canakinumab (n = 1), NSAIDs (n = 3), and glucocorticoids (n = 2). A total of 58 studies reported these primary outcomes without renal function stratification-colchicine (n = 29), anakinra (n = 10), canakinumab (n = 6), rilonacept (n = 2), NSAIDs (n = 1), and glucocorticoids (n = 10). Most clinical trials excluded study participants with severe CKD (i.e. eGFR or CrCl of < 30 mL/min/1.73 m 2 ). Information on the efficacy and safety outcomes of gout flare prophylaxis and therapy use stratified by renal function is lacking. Clinical trial results cannot be extrapolated for those with advanced CKD. Where possible, current and future gout flare studies should include patients with CKD and with study outcomes reported based on renal function and using standardised gout flare definition.

Background: Although gout is rare in children, chronic sustained hyperuricemia can lead to monosodium urate deposits progressing to gout, just as in adults. This study assessed prevalence and characteristics of gout and asymptomatic hyperuricemia, and incidence of gouty arthritis in the pediatric population, using data from Japanese health insurance claims. The diagnosis and treatment of pediatric gout and hyperuricemia were analyzed, and specific characteristics of those patients were assessed. Since Japanese guidelines recommend treatment with uric acid lowering drugs for asymptomatic hyperuricemia as well as for gout, these data were also used to investigate the real-world use of uric acid lowering drugs in a pediatric population., Methods: This cross-sectional study was based on a 2016-2017 Japanese health insurance claims database, one of the largest epidemiology claims databases available in Japan, which included 356,790 males and 339,487 females 0-18 years of age. Outcomes were measured for prevalence, patient characteristics, treatment with uric acid lowering drugs for gout and asymptomatic hyperuricemia, and prevalence and incidence of gouty arthritis. Because uric acid can be elevated by some forms of chemotherapy, data from patients under treatment for malignancies were excluded from consideration., Results: Total prevalence of gout and asymptomatic hyperuricemia in 0-18 year-olds was 0.040% (276/696,277 patients), with gout prevalence at 0.007% (48/696,277) and asymptomatic hyperuricemia at 0.033% (228/696,277). Prevalence of gout and asymptomatic hyperuricemia was highest in adolescent males, at 0.135% (176/130,823). The most common comorbidities for gout and asymptomatic hyperuricemia were metabolic syndrome at 42.8% (118/276) and kidney disease at 34.8% (96/276). Of the patients diagnosed with gout or asymptomatic hyperuricemia, 35.1% (97/276) were treated with uric acid lowering drugs. Gouty arthritis developed in 43.8% (21/48) of gout patients during the study, at an incidence of 0.65 flares/person-year., Conclusions: Even the pediatric population could be affected by asymptomatic hyperuricemia, gout, and gouty arthritis, and uric acid lowering drugs are being used in this population even though those drugs have not been approved for pediatric indications. Such off-label use may indicate a potential need for therapeutic agents in this population., Trial Registration: UMIN000036029 .

Objective: To determine the incidence and prevalence of gout in the general population and the utilisation of urate-lowering therapy (ULT) among patients with gout in Hong Kong., Methods: A total of 2,741,862 subjects who attended any outpatient clinics or accident and emergency department (with or without hospitalisation) in 2005 and did not die before 2006 were identified from the Clinical Data Analysis and Reporting System (CDARS) of the Hospital Authority in Hong Kong. All subjects were followed until the end of 2016 or death. Demographics, diagnosis of gout, serum urate levels, and ULT prescriptions were retrieved from CDARS. Gout was defined by the diagnosis codes in CDARS. The serum urate levels achieved after prescribing ULT were the means of all serum urate levels measured 6 months after prescriptions. Results were analysed by R version 3.3.3 with package 'prevalence' version 0.4.0., Results: The crude incidence of gout increased from 113.05/100,000 person-years (PY) in 2006 to 211.62/100,000 PY in 2016. The crude prevalence of gout increased from 1.56% in 2006 to 2.92% in 2016. Only 25.55% of patients with gout were prescribed ULT in 2016. 35.8% of patients treated with ULT were able to achieve the target serum urate level of < 6 mg/dL., Conclusions: Population ageing as well as other risk factors contributed to an increase in the incidence and prevalence of gout in Hong Kong. In 2016, the crude prevalence of gout in Hong Kong was comparable to that in many western countries. However, only one in four patients with gout in Hong Kong was prescribed ULT.

Objective: To determine the feasibility and validity of using wearable activity trackers to test associations between gout flares with physical activity and sleep., Methods: Participants with physician-diagnosed gout, hyperuricemia (≥ 6.8 mg/dl), current smartphone use, and ≥ 2 self-reported flares in the previous 6 months were enrolled. Physical activity, heart rate, and sleep data were obtained from wearable activity trackers (Fitbit Charge HR2). Daily compliance was defined by the availability of sufficiently complete activity data at least 80% of the day. Associations of weekly gout flares with sleep and activity were measured by comparing flare-related values to average sleep and steps per day. We used mixed linear models to account for repeated observations., Results: Forty-four participants enrolled; 33 met the criteria for minimal wear time and flare reporting, with activity tracker data available for 60.5% of all total study days. Mean ± SD age was 48.8 ± 14.9 years; 85% were men; 15% were black; 88% were on allopurinol or febuxostat, and 30% reported ≥ 6 flares in the prior 6 months. Activity trackers captured 204 (38%) person-weeks with flares and 340 (62%) person-weeks without flares. Mean ± SD daily step count was significantly lower (p < 0.0001) during weeks with gout flares (5900 ± 4071) than during non-flare periods (6972 ± 5214); sleep however did not differ., Conclusion: The pattern of wear in this study illustrates reasonable feasibility of using such devices in future arthritis research. The use of these devices to passively measure changes in physical activity patterns may provide an estimate of gout flare occurrence and duration., Trial Registration: NCT, NCT02855437 . Registered 4 August 2016.

Background: Patients with gout have arterial dysfunction and systemic inflammation, even during intercritical episodes, which may be markers of future adverse cardiovascular outcomes. We conducted a prospective observational study to assess whether initiating guideline-concordant gout therapy with colchicine and a urate-lowering xanthine oxidase inhibitor (XOI) improves arterial function and reduces inflammation., Methods: Thirty-eight untreated gout patients meeting American College of Rheumatology (ACR)/European League Against Rheumatism classification criteria for gout and ACR guidelines for initiating urate-lowering therapy (ULT) received colchicine (0.6 mg twice daily, or once daily for tolerance) and an XOI (allopurinol or febuxostat) titrated to ACR guideline-defined serum urate (sU) target. Treatment was begun during intercritical periods. The initiation of colchicine and XOI was staggered to permit assessment of a potential independent effect of colchicine. Brachial artery flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD) assessed endothelium-dependent and endothelium-independent (smooth muscle) arterial responsiveness, respectively. High-sensitivity C-reactive protein (hsCRP), IL-1β, IL-6, myeloperoxidase (MPO) concentrations, and erythrocyte sedimentation rate (ESR) assessed systemic inflammation., Results: Four weeks after achieving target sU concentration on colchicine plus an XOI, FMD was significantly improved (58% increase, p = 0.03). hsCRP, ESR, IL-1β, and IL-6 also all significantly improved (30%, 27%, 19.5%, and 18.8% decrease respectively; all p ≤ 0.03). Prior to addition of XOI, treatment with colchicine alone resulted in smaller numerical improvements in FMD, hsCRP, and ESR (20.7%, 8.9%, 13% reductions, respectively; all non-significant), but not IL-1β or IL-6. MPO and NMD did not change with therapy. We observed a moderate inverse correlation between hsCRP concentration and FMD responsiveness (R = - 0.41, p = 0.01). Subgroup analyses demonstrated improvement in FMD after achieving target sU concentration in patients without but not with established cardiovascular risk factors and comorbidities, particularly hypertension and hyperlipidemia., Conclusions: Initiating guideline-concordant gout treatment reduces intercritical systemic inflammation and improves endothelial-dependent arterial function, particularly in patients without established cardiovascular comorbidities.

Background: Gout is a heterogeneous inflammatory disease with numerous clinical manifestations. A composite means to assess the impact of therapy on numerous aspects of gout could be useful., Methods: Results from patients treated with pegloticase or placebo in two randomized clinical trials and their open-label extension were assessed using a novel evidence-based Gout Multivariable Improvement Measure (GMIM) derived from previously reported criteria for remission and complete response. Improvement was defined as serum urate (sU) < 6 mg/dL and absence of flares during the preceding 3 months plus 20, 50, and 70% improvement in tophus size, patient global assessment, pain, and swollen and tender joints., Results: Patients treated with pegloticase manifested a significantly greater GMIM20, 50, and 70 response vs those treated with placebo (GMIM20 at 6 months 37.1% vs 0%, respectively). Higher response rates were significantly more frequent in subjects with persistent urate lowering (GMIM 58.1% at 6 months) in response to pegloticase versus those with only transient urate lowering (GMIM 7.1% at 6 months). However, when the requirement for a decrease in sU to < 6 mg/dL was omitted, a substantial percentage of subjects with transient urate lowering met the GMIM clinical criteria. A sensitivity analysis indicated that gout flares contributed minimally to the model. The response measured by GMIM persisted into the open-level extension for as long as 2 years. Finally, subjects who received placebo in the randomized control trials, but pegloticase in the open-label extension, manifested GMIM responses comparable to that noted with pegloticase-treated subjects in the randomized controlled trials., Conclusions: GMIM captures changes in disease activity in response to treatment with pegloticase and may serve as an evidence-based tool for assessment of responses to other urate-lowering therapies in gout patients.

Background: The aims of this article were to assess the prevalence of nephrolithiasis and the factors associated with nephrolithiasis in Brazilian patients with primary gout., Methods: One hundred twenty-three patients with primary gout were recruited from a tertiary referral hospital in São Paulo, Brazil. All patients underwent ultrasonography and had their clinical and laboratory characteristics assessed., Results: One hundred fifteen (93.5%) patients were male, with a mean age of 62.9 ± 9.4 years. Twenty-three (18.7%) patients had asymptomatic nephrolithiasis (detected only by ultrasonography), 7 (6.0%) had symptomatic nephrolithiasis (detected by ultrasonography and a positive clinical history), and 13 (10.0%) had a history of kidney stones, but ultrasonography at evaluation did not show nephrolithiasis. Therefore, 35.0% of the patients had nephrolithiasis (detected either by ultrasonography and/or a positive clinical history). Nephrolithiasis was associated with male gender (43 [100%] vs 72 [90%], p = 0.049), the use of potassium citrate (13 [30.2%] vs 0, p <  0.001) and the use of medications for diabetes (10 [23.3%] vs 8 [10%], p = 0.047) and dyslipidemia (15 [34.9%] vs 10 [12.5%], p = 0.003); benzbromarone had an inverse association with nephrolithiasis (21 [48.8%] vs 55 [68.8%], p = 0.030). In patients with and without nephrolithiasis, no differences were found in the laboratory and ultrasonography characteristics, including serum uric acid levels, urinary uric acid excretion and urine pH., Conclusions: The prevalence of nephrolithiasis in primary gout was 35.0%, and 18.7% of the patients were asymptomatic. Nephrolithiasis was associated with male gender, diabetes and dyslipidemia. A positive history of nephrolithiasis probably biased the prescription of potassium citrate and benzbromarone.

Background: For patients with recurrent flares of gout, tophi, urate crystal arthropathy, and renal stones, urate-lowering therapies (ULTs, including allopurinol and febuxostat) are the first-line treatment. Due to the widespread use of these ULTs (especially in patients with impaired renal function), assessment of the associated renal risk is essential. Accordingly, we performed a disproportionality analysis of reported cases of acute renal failure (ARF) associated with allopurinol and febuxostat., Methods: We carried out a case/non-case study of the World Health Organization's VigiBase® pharmacovigilance database between January 1, 2008, and December 31, 2018. The frequency of reports of ARF as a standardized Medical Dictionary for Regulatory Activities query for allopurinol and febuxostat was compared with that of all other reports for the two drugs and quoted as the reporting odds ratio (ROR) [95% confidence interval (CI)]. The results' stability was assessed in a series of sensitivity analyses (notably after the exclusion of putative competing drugs)., Results: Among 3509 "suspected drug" notifications for febuxostat and 18,730 for allopurinol, we identified respectively 317 and 1008 cases of ARF. Acute renal failure was reported significantly more frequently for febuxostat and allopurinol than for other drugs (ROR [95%CI] 5.67 [5.05-6.36] and 3.25 [3.05-3.47], respectively). For both drugs, the ROR was higher in women than in men, respectively 11.60 [9.74-13.82] vs. 3.14 [2.69-3.67] for febuxostat and 4.45 [4.04-4.91] vs. 2.29 [2.11-2.50] for allopurinol. The sensitivity analyses confirmed the disproportionality for these two ULTs., Conclusions: Acute renal failure was reported respectively 5.7 and 3.3 times more frequently for febuxostat and for allopurinol than for other drugs. Due to the potential consequences of ARF, physicians should take account of this disproportionality signal when prescribing the ULTs febuxostat and allopurinol.

Background: This study investigates the association between exposure to urate-lowering drugs (ULDs) and progression and recovery from chronic kidney disease (CKD)., Methods: We identified 5860 incident gout patients at Chang Gung Memorial Hospital from 2012 to 2015. Propensity score (PS)-weighted Cox proportional hazards model was used to estimate hazard ratios (HRs) for CKD progression and improvement. A separate analysis was conducted to assess the HR for CKD progression and CKD recovery among those with worsening CKD., Results: The incidence of CKD progression among allopurinol, febuxostat and uricosuric agent users were 1.98, 1.88 and 1.64 per 1000 person-days. Compared with allopurinol users, the PS-weighted HR (95% confidence intervals [CIs]) was 1.77 (0.85-1.76) for febuxostat users and 1.37 (0.71-1.37) for uricosuric agent users for CKD progression and 1.43 (1.26-1.62) for febuxostat users and 1.00 (0.88-1.14) for uricosuric agent users for CKD improvement. Compared to allopurinol users, the HRs for CKD progression were 1.14 (0.80-1.66) for febuxostat users and 0.92 (0.67-1.31) for uricosuric agent users. Among 741 patients who had CKD progression, the incidence of CKD recovery was 1.33, 6.21 and 3.53 per 1000 person-days for allopurinol, febuxostat and uricosuric agent users. The HRs (95% CIs) for recovery in febuxostat and uricosuric agent users were 2.17 (1.40-3.47) and 1.80 (1.20-2.83) compared to allopurinol users., Conclusions: CKD progression and recovery are common in gout patients using ULDs. Febuxostat and benzbromarone were associated with a similar risk of CKD progression with allopurinol, which has a poorer recovery compared with other ULDs.

Background: Low doses of febuxostat or benzbromarone are widely used in Asian countries, but lacking studies to compare the efficacy and safety of the two urate-lowering drugs., Methods: To compare the efficacy and safety of low-dose febuxostat with low-dose benzbromarone in patients with primary gout, a randomized controlled, open-label trial was performed among male patients with primary gout for urate-lowering therapy (ULT) in a dedicated gout clinic in China. Randomization was carried out by a third-party institution according to random number table. Patients were randomly assigned 1:1 to febuxostat group (Feb group) (20 mg daily) or benzbromarone group (Ben group) (25 mg daily) and treated for 12 weeks. General information and biochemical data were collected at baseline and at every visit monthly. Clinical characteristics before and after the ULT were analyzed in the two groups by SPSS and EmpowerStats software., Results: Two hundred forty patients were enrolled and randomized in the two groups, with 214 patients completing 12 weeks' ULT (105 in the Feb group and 109 in the Ben group). After 12 weeks, substantial percentages of patients in both Feb and Ben group achieved the target serum uric acid (sUA) (< 360 μmol/L) and serum urate levels were reduced significantly for both groups (Feb 39.5% and 156.83 μmol/L vs. Ben 35.7% and 163.99 μmol/L). Multivariate analysis suggests baseline sUA level and renal function were associated with the outcome of the rate of achieving target sUA (RAT). Sub-group analysis suggests low doses of febuxostat and benzbromarone rendered better RAT for patients with sUA < 540 μmol/L and creatinine clearance rate (Ccr) ≤ 110 mL min -1  1.73 m -2 at baseline. The drugs were well tolerated, and the incidence of gout flares in Feb group was similar with that in Ben group (22.85% vs. 33.94%)., Conclusion: Overall, febuxostat 20 mg daily and benzbromarone 25 mg daily reduced sUA, and gout patients with sUA level < 540 μmol/L or Ccr ≤ 110 mL min -1  1.73 m -2 at baseline had better chance to achieve target uric acid levels. The current study suggests sUA level and renal function are key factors to consider when recommending low doses of febuxostat and benzbromarone to gout patients., Trial Registration: Registered with ChiCTR, No. ChiCTR1800019352 (retrospectively registered).

Background: Numerous quantitatively based studies measuring the association between gout and the risk of fractures remain inconclusive. In order to determine whether gout could increase the risk of fractures, a meta-analysis was performed systematically., Methods: Electronic databases, MEDLINE/PubMed, Embase, and Cochrane Library were systematically searched to identify studies evaluating the association of gout and the risk of fractures. No restrictions on language, publication date, or journal of publication were imposed. Meta-analysis was performed to pool the outcome estimates of interest such as fracture incidence, fracture risk, and fracture risk in different sites and at different time points in the follow-up period., Results: Screening determined that seven studies involving a total of 684,964 participants (151,002 in the gout group and 533,962 in the control group) were deemed viable for inclusion in the meta-analysis. The results of the analysis showed that gout would not significantly have a relatively higher risk of any fracture (RR = 1.11, 95% CI 0.98-1.26). Subgroup analysis showed consistent results for sexuality (female: RR = 1.13, 95% CI 0.93-1.37; male: RR = 0.99, 95% CI 0.91-1.07) and several occurring sites (humerus, wrist, vertebra, hip, upper limbs, and lower limbs). Additionally, the results demonstrated that urate-lowering drugs prescribed early during disease had neither adverse nor beneficial effect on the long-term risk of fractures (RR = 0.89, 95% CI 0.76-1.05)., Conclusions: This meta-analysis confirmed that gout was not associated with an increased risk of fractures. Urate-lowering drugs prescribed early during the course of disease had neither adverse nor beneficial effect on the long-term risk of fractures.

Background: Gouty arthritis is characterized by the deposition of monosodium urate (MSU) within synovial joints and tissues due to increased urate concentrations. In this study, we explored the effect of the natural compound curcumin on the MSU crystal-stimulated inflammatory response., Methods: THP-1-derived macrophages and murine RAW264.7 macrophages were pretreated with curcumin for 1 h and then stimulated with MSU suspensions for 24 h. The protein level of TLR4, MyD88, and IκBα, the activation of the NF-κB signaling pathway, the expression of the NF-κB downstream inflammatory cytokines, and the activity of NLRP3 inflammasome were measured by western blotting and ELISA. THP-1 and RAW264.7 cells were loaded with MitoTracker Green to measure mitochondrial content, and MitoTracker Red to detect mitochondrial membrane potential. To measure mitochondrial reactive oxygen species (ROS) levels, cells were loaded with MitoSOX Red, which is a mitochondrial superoxide indicator. The effects of curcumin on mouse models of acute gout induced by the injection of MSU crystals into the footpad and synovial space of the ankle, paw and ankle joint swelling, lymphocyte infiltration, and MPO activity were evaluated., Results: Curcumin treatment markedly inhibited the degradation of IκBα, the activation of NF-κB signaling pathway, and the expression levels of the NF-κB downstream inflammatory genes such as IL-1β, IL-6, TNF-α, COX-2, and PGE2 in the MSU-stimulated THP-1-derived macrophages. Curcumin administration protected THP-1 and RAW264.7 cells from MSU induced mitochondrial damage through preventing mitochondrial membrane potential reduction, decreasing mitochondria ROS, and then inhibited the activity of NLRP3 inflammasome. Intraperitoneal administration of curcumin alleviated MSU crystal-induced paw and ankle joint swelling, inflammatory cell infiltration, and MPO activity in mouse models of acute gout. These results correlated with the inhibition of the degradation of IκBα, the phosphorylation levels of NF-κB subunits (p65 and p50), and the activity of NLRP3 inflammasome., Conclusion: Curcumin administration effectively alleviated MSU-induced inflammation by suppressing the degradation of IκBα, the activation NF-κB signaling pathway, the damage of mitochondria, and the activity of NLRP3 inflammasome. Our results provide a new strategy in which curcumin therapy may be helpful in the prevention of acute episodes of gout.

Background: Benzbromarone is a uricosuric drug that has been used in the treatment of gout over the last 30 years. Due to its potent inhibition of the dominant apical (luminal) urate exchanger in the human proximal tubule URAT1, it reduces the urate reabsorption, diminishing serum urate levels and therefore preventing gout flares. Through several clinical trials, Benzbromarone has been proved effective and safe, inclusive in patients with chronic kidney disease and as combination therapy with allopurinol. Due to hepatotoxicity reports, it was withdrawn from the European market by the manufacturer, however many authors have questioned the product's withdrawal due to a lack of clinical evidence in order to support its hepatotoxicity. Benzbromarone is still available in several European countries, New Zealand, Brazil and several other countries. Despite the product's marketing over more than 20 years after the first hepatotoxicity reports, we have found only five reports in our literature search, and no prospective or retrospective study correlating hepatotoxicity with benzbromarone use., Short Conclusion: Benzbromarone is a safe and effective molecule for the treatment of gout. However, due to in vitro and in vivo data related to hepatotoxicity, it is prudent to prescribe it with some caution, especially for patients with an already known liver condition.

Background: Provisional gout remission criteria including five domains (serum urate, tophus, flares, pain due to gout, and patient global assessment) have been proposed. The aim of this study was to test the concurrent validity of the provisional gout remission criteria by comparing the criteria with dual-energy CT (DECT) findings., Methods: Patients with gout on allopurinol ≥ 300 mg daily were prospectively recruited into a multicenter DECT study. Participants attended a standardized study visit which recorded gout flare frequency in the preceding 12 months, physical examination for tophus, serum urate, and patient questionnaires. DECT scans of both hands/wrists, feet/ankles/Achilles, and knees were analyzed by two DECT radiologists. The relationship between the DECT urate crystal volume and deposition with individual domains as well as the provisional remission criteria set was analyzed., Results: The provisional remission criteria were fulfilled in 23 (15.1%) participants. DECT urate crystal deposition was observed less frequently in those fulfilling the provisional remission criteria (44%), compared with those not fulfilling the criteria (73.6%, odds ratio 0.28, P = 0.004). The median (range) DECT urate crystal volume was 0.00 (0.00-0.46) cm 3 for those fulfilling the remission criteria, compared with 0.08 (0.00-19.53) cm 3 for those not fulfilling the criteria (P = 0.002). In multivariate regression analysis, the serum urate and tophus domains were most strongly associated with DECT urate crystal deposition., Conclusions: In people with gout established on allopurinol, a state of remission as defined by the provisional remission criteria is associated with less DECT urate crystal deposition. While this study provides support for the validity of the provisional gout remission criteria, it also demonstrates that some crystal deposition may be present in people achieving these criteria.

Background: There is a paucity of community-based data regarding the prevalence and impact of gout flares as these may often be self-managed. The aim of this study was to determine the prevalence of self-reported gout and gout flares, the use of urate-lowering therapy (ULT), and the association of gout flares with health-related quality of life (HRQoL) in a large community sample. Covariate associations with flare frequency and allopurinol use were also examined., Methods: The South Australian Health Omnibus Survey is an annual, face-to-face population-based survey. Data collected in the 2017 survey included self-reported medically diagnosed gout, allopurinol use (first-line ULT in Australia), and gout attacks (flares) in the last 12 months, in addition to sociodemographic variables and health-related quality of life (HRQoL, SF-12). Data were weighted to the Australian Bureau of Statistics 2016 census data to reflect the South Australian population. Participants 25 years and over (n = 2778) were included in the analysis., Results: The prevalence of gout was 6.5% (95%CI 5.5, 7.5). Amongst participants with gout, 37.1% (95%CI 29.6, 45.3) reported currently using allopurinol, while 23.2% (95%CI 16.9, 21.0) reported prior use (38% discontinuation rate). Frequent flares (≥ 2 in the last year) were reported by 25% of participants with gout and were more likely with younger age, higher body mass index, and current allopurinol use (p < 0.05). The frequency of gout flares was associated with a lower physical HRQoL (p = 0.012). Current allopurinol use was reported by 51% of participants with frequent gout flares., Conclusion: Flares were frequently reported by people with gout in the community. Gout flares were associated with reduced physical HRQoL. Almost one half of people with frequent gout flares were not receiving allopurinol, and current allopurinol use was associated with frequent gout flares, suggesting undertreated disease and suboptimal use of ULT. Determining covariate associations with flares and ineffective allopurinol use may identify means of improving treatment and reducing flares.

Background: ABCG2 is a high-capacity urate transporter that plays a crucial role in renal urate overload and extra-renal urate underexcretion. Previous studies have suggested an association between hyperuricemia and gout susceptibility relative to dysfunctional ABCG2 variants, with rs2231142 (Q141K) being the most common. In this study, we analyzed the ABCG2 gene in a hyperuricemia and gout cohort focusing on patients with pediatric-onset, i.e., before 18 years of age., Method: The cohort was recruited from the Czech Republic (n = 234) and consisted of 58 primary hyperuricemia and 176 gout patients, with a focus on pediatric-onset patients (n = 31, 17 hyperuricemia/14 gouts); 115 normouricemic controls were used for comparison. We amplified, sequenced, and analyzed 15 ABCG2 exons. The chi-square goodness-of-fit test was used to compare minor allele frequencies (MAF), and the log-rank test was used to compare empirical distribution functions., Results: In the pediatric-onset cohort, two common (p.V12M, p.Q141K) and three very rare (p.K360del, p.T421A, p.T434M) allelic ABCG2 variants were detected. The MAF of p.Q141K was 38.7% compared to adult-onset MAF 21.2% (OR = 2.4, P = 0.005), to the normouricemic controls cohort MAF 8.5% (OR = 6.8, P <  0.0001), and to the European population MAF 9.4% (OR = 5.7, P <  0.0001). The MAF was greatly elevated not only among pediatric-onset gout patients (42.9%) but also among patients with hyperuricemia (35.3%). Most (74%) of the pediatric-onset patients had affected family members (61% were first-degree relatives)., Conclusion: Our results show that genetic factors affecting ABCG2 function should be routinely considered in a hyperuricemia/gout diagnosis, especially in pediatric-onset patients. Genotyping of ABCG2 is essential for risk estimation of gout/hyperuricemia in patients with very early-onset and/or a family history.

Background: Recruitment to clinical trials can be challenging. Methods that improve the efficiency of trial recruitment are needed to increase successful study completions. The aim of this study was to ascertain whether sending an audio-visual presentation on a digital versatile disc (DVD), along with usual study invitation materials, would improve recruitment to the Febuxostat versus Allopurinol Streamlined Trial (FAST), a clinical trial in patients with established gout., Methods: Potential participants for the FAST study who were identified by searches of GP records in Scottish primary care practices between August 2013 and July 2014 were included in this study. Individuals were randomly allocated to receive either a standard invitation (letter and information leaflet) or a standard invitation and a DVD containing an audio-visual presentation explaining the background and operation of FAST. Data on invitation response rates, screening attendances and randomisations were collected by research nurses., Results: One thousand fifty potential participants were invited to take part in FAST during this period. 509 individuals were randomised to receive the DVD presentation and the standard invitation and 541 received a standard invitation only. DVD recipients were less likely to respond to the initial invitation (adjusted OR 0.76, CI 0.58-0.99) and marginally less likely to return a positive response (OR 0.75, CI 0.59-0.96). There was no statistically significant difference between the groups in attendance for screening or randomisation. The DVD did not influence the age, gender, or socioeconomic deprivation scores of those responding positively to a letter of invitation., Conclusions: The inclusion of a DVD presentation with FAST study invitations did not make any practical difference to the rate of positive response to invitation. Further innovation and evaluation will be required to improve recruitment to clinical trials., Trial Registration: EU Clinical Trials Register. EudraCT Number: 2011-001883-23 . ISRCTN registry.  ISRCTN72443278 .