Initiation of febuxostat for acute gout flare does not prolong the current episode: a randomized clinical trial.
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ABSTRACT: Objective
Our objective was to determine whether initiation of febuxostat during an acute gout flare prolongs the current episode.Methods
In this randomized, placebo-controlled, single-blinded, multicentre trial, patients with acute gout flares within 72 h were randomized (1:1) to the placebo and febuxostat (40 mg/day) groups. All patients were administered Diclofenac (150 mg/day) for 7 days and then open-labelled on the 8th day. Febuxostat 40 mg daily and Diclofenac 75 mg daily were administered from day 8 through 28 for the remission period. The dose of diclofenac was 150 mg/day before remission in both arms, and the original protocol was maintained until remission. The primary outcome was "days to resolution".Results
We randomized 140 patients, 70 into each arm. The mean days to resolution was 5.98 days (median 7.00, IQR 2.45 days) for the placebo and 6.50 days (median 7.00, IQR 3.67 days) for the febuxostat group (p= 0.578). The rate of resolution within 7 days was 84.38% for the placebo group and 76.92% for the febuxostat group (p= 0.284).There were no statistically significant differences in joint pain, swelling, tenderness, and erythema scores at days 1, 3, 5, and 7. The mean serum uric acid levels were 507.54 and 362.62 μmol/l for the placebo and febuxostat group respectively on day 7 (p= 0.000). The rate of recurrent gout flares was 10.00% for the placebo group and 6.56% for the febuxostat group from day 8 through 28 (p= 0.492).Conclusion
Initiation of febuxostat administration during an acute gout flare did not prolong the duration of acute flares.Clinical trial registration
Chinese Clinical Trial Registry, http://www.chictr.org.cn/, ChiCTR1800015962.
SUBMITTER: Jia E
PROVIDER: S-EPMC8409997 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The aim of this study was to systematically review the literature on effect of initiating urate-lowering treatment (ULT) during an acute attack of gout on duration of index attack and persistence on ULT. OVID (Medline), EMBASE and AMED were searched to identify randomized controlled trials (RCTs) of ULT initiation during acute gout attack published in English language. Two reviewers appraised the study quality and extracted data independently. Standardized mean difference (SMD) and relative risk (RR) were used to pool continuous and categorical data. Meta-analysis was carried out using STATA version 14. A total of 537 studies were selected. A total of 487 titles and abstracts were reviewed after removing duplicates. Three RCTs were identified. There was evidence from two high-quality studies that early initiation of allopurinol did not increase pain severity at days 10-15 [SMDpooled (95 % CI) 0.18 (-0.58, 0.93)]. Data from three studies suggested that initiation of ULT during an acute attack of gout did not associate with dropouts [RRpooled (95 % CI) 1.16 (0.58, 2.31)]. There is moderate-quality evidence that the initiation of ULT during an acute attack of gout does not increase pain severity and risk of ULT discontinuation. Larger studies are required to confirm these findings so that patients with acute gout can be initiated on ULT with confidence.
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Project description:BackgroundMethods of gout flare reporting in research settings are inconsistent and poorly defined. The aim of this study was to describe patterns of gout flare and assess the concurrent validity of different methods of flare reporting in a gout clinical trial.MethodsDaily flare diary entries including self-report of flare and pain scale from a randomised controlled trial of 120 patients with gout were analysed. Detailed pain-by-time plots for each participant were inspected and analysed for different methods of flare reporting for both self-report and the classification tree (CART)-defined flare developed by Gaffo in 2012. Concurrent validity for different methods of flare reporting were analysed.ResultsAlthough the single gout flare had a 'typical' average pattern (peak on day 1 and resolution over 14 days), individual pain-by-time plots showed wide variation in pain intensity, duration and frequency of flares. Over the four-month study period, there were 84/120 (70%) participants who experienced at least one self-reported flare that was not a 'typical' flare. The time to first self-reported flare correlated poorly with other measures of gout activity and other methods of flare reporting. The number of days with flare (either self-reported or Gaffo-defined) and the area under the pain-by-time curve correlated most strongly with other measures of disease severity.ConclusionThere is wide variation in the patterns of flare over time in individuals with gout, leading to challenges for flare reporting in clinical trials. Time-dependent reporting strategies such as number of days with flare or area under the pain-by-time curve correlate well with other measures of gout disease severity and may provide a more accurate measure of flare burden.Trial registrationClinical trial number: ACTRN12609000479202, registered 17/06/2009.
| S-EPMC6615178 | biostudies-literature
Project description:ObjectiveTo assess the effect of treatment with febuxostat versus placebo on joint damage in hyperuricemic subjects with early gout (1 or 2 gout flares).MethodsIn this double-blind, placebo-controlled study, 314 subjects with hyperuricemia (serum uric acid [UA] level of ≥7.0 mg/dl) and early gout were randomized 1:1 to receive once-daily febuxostat 40 mg (increased to 80 mg if the serum UA level was ≥6.0 mg/dl on day 14) or placebo. The primary efficacy end point was the mean change from baseline to month 24 in the modified Sharp/van der Heijde erosion score for the single affected joint. Additional efficacy end points included change from baseline to month 24 in the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) scores for synovitis, erosion, and edema in the single affected joint, the incidence of gout flares, and serum UA levels. Safety was assessed throughout the study.ResultsTreatment with febuxostat did not lead to any notable changes in joint erosion over 2 years. In both treatment groups, the mean change from baseline to month 24 in the modified Sharp/van der Heijde erosion score for the single affected joint was minimal, with no between-group differences. However, treatment with febuxostat significantly improved the RAMRIS synovitis score at month 24 compared with placebo treatment (change from baseline -0.43 versus -0.07; P <0.001), decreased the overall incidence of gout flares (29.3% versus 41.4%; P < 0.05), and improved serum UA control (62.8% versus 5.7%; P < 0.001). No major safety concerns were reported.ConclusionUrate-lowering therapy with febuxostat improved magnetic resonance imaging-determined synovitis and reduced the incidence of gout flares in subjects with early gout.
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Project description:ImportanceGout is associated with cardiovascular diseases. The temporal association between gout flares and cardiovascular events has not been investigated.ObjectiveTo investigate whether there is a transient increase in risk of cardiovascular events after a recent gout flare.Design, setting, and participantsA retrospective observational study was conducted using electronic health records from the Clinical Practice Research Datalink in England between January 1, 1997, and December 31, 2020. A multivariable nested case-control study was performed among 62 574 patients with gout, and a self-controlled case series, adjusted for season and age, was performed among 1421 patients with gout flare and cardiovascular event.ExposuresGout flares were ascertained using hospitalization, primary care outpatient, and prescription records.Main outcomes and measuresThe primary outcome was a cardiovascular event, defined as an acute myocardial infarction or stroke. Association with recent prior gout flares was measured using adjusted odds ratios (ORs) with 95% CIs in a nested case-control study and adjusted incidence rate ratios (IRRs) with 95% CIs in a self-controlled case series.ResultsAmong patients with a new diagnosis of gout (mean age, 76.5 years; 69.3% men, 30.7% women), 10 475 patients with subsequent cardiovascular events were matched with 52 099 patients without cardiovascular events. Patients with cardiovascular events, compared with those who did not have cardiovascular events, had significantly higher odds of gout flare within the prior 0 to 60 days (204/10 475 [2.0%] vs 743/52 099 [1.4%]; adjusted OR, 1.93 [95% CI, 1.57-2.38]) and within the prior 61 to 120 days (170/10 475 [1.6%] vs 628/52 099 [1.2%]; adjusted OR, 1.57 [95% CI, 1.26-1.96]). There was no significant difference in the odds of gout flare within the prior 121 to 180 days (148/10 475 [1.4%] vs 662/52 099 [1.3%]; adjusted OR, 1.06 [95% CI, 0.84-1.34]). In the self-controlled case series (N = 1421), cardiovascular event rates per 1000 person-days were 2.49 (95% CI, 2.16-2.82) within days 0 to 60; 2.16 (95% CI, 1.85-2.47) within days 61 to 120; and 1.70 (95% CI, 1.42-1.98) within days 121 to 180 after a gout flare, compared with cardiovascular event rates of 1.32 (95% CI, 1.23-1.41) per 1000 person-days within the 150 days before or the 181 to 540 days after the gout flare. Compared with 150 days before or the 181 to 540 days after a gout flare, incidence rate differences for cardiovascular events were 1.17 (95% CI, 0.83-1.52) per 1000 person-days, and adjusted IRRs were 1.89 (95% CI, 1.54-2.30) within days 0 to 60; 0.84 (95% CI, 0.52-1.17) per 1000 person-days and 1.64 (95% CI, 1.45-1.86) within days 61 to 120; and 0.38 (95% CI, 0.09-0.67) per 1000 person-days and 1.29 (95% CI, 1.02-1.64) within days 121 to 180 after a gout flare.Conclusions and relevanceAmong individuals with gout, those who experienced a cardiovascular event, compared with those who did not experience such an event, had significantly higher odds of a recent gout flare in the preceding days. These findings suggest gout flares are associated with a transient increase in cardiovascular events following the flare.
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Project description:BackgroundThe relative efficacy and safety of allopurinol and febuxostat when used according to current guidelines for the treatment of hyperuricemia are unknown. This double-blind noninferiority trial examined these issues.MethodsParticipants with gout and hyperuricemia (with at least 33% having stage 3 chronic kidney disease) were randomly assigned to allopurinol or febuxostat in this 72-week trial, with doses titrated to target serum urate. The trial had three phases: titration (weeks 0 to 24), maintenance (weeks 25 to 48), and observation (weeks 49 to 72). Allopurinol and febuxostat were initiated at daily doses of 100 and 40 mg, with maximum titration to 800 and 120 mg, respectively. Antiinflammatory prophylaxis was given during phases 1 and 2. The primary end point was the proportion of patients experiencing one or more flares during phase 3, with a prespecified noninferiority margin of less than 8 percentage points between allopurinol and febuxostat. Secondary end points included efficacy in patients with chronic kidney disease, proportion achieving target serum urate levels, and serious adverse events.ResultsThis study included 940 participants; 20.1% withdrew, with similar proportions in treatment arms. During phase 3, 36.5% of allopurinol-treated participants had one flare or more compared with 43.5% of febuxostat-treated participants (P<0.001 for noninferiority). Overall, 80% of participants achieved mean target urates during phase 2 with no differences by treatment. There were no treatment differences (including cardiovascular events) in serious adverse events.ConclusionsAllopurinol and febuxostat achieved serum urate goals in patients with gout; allopurinol was noninferior to febuxostat in controlling flares. Similar outcomes were noted in participants with stage 3 chronic kidney disease. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; ClinicalTrials.gov identifier, NCT02579096.).
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Project description:Assess influences of demographics and co-morbidities of gout patients with or without diabetes on safety and efficacy of urate-lowering agents.Post-hoc analysis of 312 diabetic and 1957 non-diabetic gout patients [baseline serum urate levels (sUA) ?8.0?mg/dl] enrolled in a 6-month randomized controlled trial comparing urate-lowering efficacy (ULE) and safety of daily xanthine oxidase inhibitors (XOIs) febuxostat (40?mg or 80?mg) and allopurinol (200?mg or 300?mg). We compared baseline demographic, gout and co-morbid characteristics, ULE, and safety of XOI treatment in diabetic and non-diabetic gout patients. ULE was measured by the proportion of diabetic and non-diabetic patients in each treatment group achieving final visit sUA?<?6.0?mg/dl. Safety was monitored throughout the trial.Diabetic gout patients were older, more frequently female, and had longer gout duration. Co-morbidities were more frequent among diabetic patients: cardiovascular disease; impaired renal function; hyperlipidemia; and obesity (body mass index >30?kg/m²) (p?<?0.001 for all comparisons). Febuxostat 80?mg ULE exceeded that of febuxostat 40?mg or allopurinol (p?<?0.050) at all levels of renal function, achieving sUA goal range in the majority of diabetic and non-diabetic patients. Diabetics and non-diabetics reported self-limiting diarrhoea and URIs as the most common adverse events.Despite higher co-morbidity rates in diabetic patients, febuxostat and allopurinol were safe in both groups at the doses tested. Febuxostat 80?mg achieved sUA <6.0?mg/dl more often than febuxostat 40?mg or allopurinol at commonly prescribed doses.
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Project description:ObjectiveThe predominant mechanism driving hyperuricemia in gout is renal uric acid underexcretion; however, the standard urate-lowering therapy (ULT) recommendation is first-line xanthine oxidase inhibitor (XOI), irrespective of the cause of hyperuricemia. This comparative effectiveness clinical trial was undertaken to compare first-line nontitrated low-dose benzbromarone (LDBen) uricosuric therapy to XOI ULT with low-dose febuxostat (LDFeb) in gout patients with renal uric acid underexcretion.MethodsWe conducted a prospective, randomized, single-center, open-label trial in men with gout and renal uric acid underexcretion (defined as fractional excretion of urate <5.5% and uric acid excretion ≤600 mg/day/1.73 m2 ). A total of 196 participants were randomly assigned to receive LDBen 25 mg daily or LDFeb 20 mg daily for 12 weeks. All participants received daily urine alkalization with oral sodium bicarbonate. The primary end point was the rate of achieving the serum urate target of <6 mg/dl.ResultsMore participants in the LDBen group achieved the serum urate target than those in the LDFeb group (61% compared to 32%, P < 0.001). Rates of adverse events, including gout flares and urolithiasis, did not differ between groups, with the exception of greater transaminase elevation in the LDFeb group (4% for LDBen compared to 15% for LDFeb, P = 0.008).ConclusionCompared to LDFeb, LDBen has superior urate-lowering efficacy and similar safety in treating relatively young and healthy patients with renal uric acid underexcretion-type gout.
| S-EPMC9771863 | biostudies-literature
Project description:BackgroundGout is an inflammatory arthritis and is characterized by the accumulation of deposited monosodium urate (MSU) crystals in the joints. miRNAs may act as key regulators of gout pathogenesis. The aim of our study was to explore the underlying role and molecular mechanism of miR-3146 in the formation of neutrophil extracellular traps (NETs) during the pathogenesis of gout.MethodsThe expression of miR-3146 and sirtuin 1 (SIRT1) was determined by real-time reverse transcription-polymerase chain reaction and Western blot, respectively. The luciferase reporter assay was performed to identify the targeting relationship between miR-3146 and SIRT1. Reactive oxygen species (ROS) production was detected by fluorescent staining. NETs formation was demonstrated via immunofluorescence staining and ELISA method. Gout model was induced in rats to verify the effects of miR-3146 inhibition on histopathological changes and NETs.ResultsHere, we found miR-3146 expression was dramatically increased in neutrophils of patients with gout, which was accompanied with the higher levels of NETs. MSU crystals significantly increased miR-3146 expression and ROS production in neutrophils. The NETs process was also triggered by MSU crystals. Furthermore, we verified the interaction between miR-3146 and SIRT1. Additionally, antagomir-3146-based therapy effectively inhibited the formation of NETs in rats with gout.ConclusionOur findings indicated that miR-3146-mediated NETs formation may play a potential role in the pathogenesis of gout. These results suggested that miR-3146 could be used as a potential therapeutic target for the treatment of gout.
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Project description:Gout flares require monosodium urate (MSU) to activate the NLRP3 inflammasome and secrete sufficient IL-1β. However, MSU alone is not sufficient to cause a flare. This is supported by the evidence that most patients with hyperuricemia do not develop gout throughout their lives. Recent studies have shown that, besides MSU, various purine metabolites, including adenosine triphosphate, adenosine diphosphate, and adenosine bind to different purine receptors for regulating IL-1β secretion implicated in the pathogenesis of gout flares. Purine metabolites such as adenosine triphosphate mainly activate the NLRP3 inflammasome through P2X ion channel receptors, which stimulates IL-1β secretion and induces gout flares, while some purine metabolites such as adenosine diphosphate and adenosine mainly act on the G protein-coupled receptors exerting pro-inflammatory or anti-inflammatory effects to regulate the onset and resolution of a gout flare. Given that the purine signaling pathway exerts different regulatory effects on inflammation and that, during the inflammatory process of a gout flare, an altered expression of purine metabolites and their receptors was observed in response to the changes in the internal environment. Thus, the purine signaling pathway is involved in regulating gout flare and resolution. This study was conducted to review and elucidate the role of various purine metabolites and purinergic receptors during the process.
| S-EPMC8671294 | biostudies-literature
Project description:IntroductionThis 24-week randomized, double-blind, non-inferiority study compared the efficacy and safety of febuxostat, a xanthine oxidase inhibitor, with allopurinol using an up-titration method in hyperuricemic Chinese subjects with or without gout.MethodsEligible adults (serum uric acid [SUA] > 7.0 mg/dl with a history of gout, SUA ≥ 8.0 mg/dl with complications or SUA ≥ 9.0 mg/dl without complications) were randomized (1:1:1) to febuxostat 40 mg/day, 80 mg/day, or allopurinol 300 mg/day. Starting doses of febuxostat 20 mg/day and allopurinol 100 mg/day were up-titrated, up to 16 weeks, to the randomized doses and maintained to week 24. Primary endpoint was non-inferiority of febuxostat 40 mg/day versus allopurinol 300 mg/day based on the percentage of subjects with SUA ≤ 6.0 mg/dl at week 24. The same comparison was made between febuxostat 60 mg/day or 80 mg/day versus allopurinol 300 mg/day. Safety assessments included measurement of treatment-emergent adverse events (TEAEs).ResultsThe per-protocol population comprised 472 subjects. Non-inferiority of febuxostat 40 mg/day versus allopurinol 300 mg/day was not demonstrated based on the protocol-defined margin of - 10% (44.7 vs. 50.0%; - 5.3% difference; 95% confidence interval [CI]: - 16.4%, 5.8%); however, superiority over allopurinol 300 mg/day was demonstrated for febuxostat 60 mg/day at week 16 (66.3 vs. 51.2%; a 15.0% difference; 95% CI: 4.2%, 25.9%) and febuxostat 80 mg/day at week 24 (70.0 vs. 50.0%; a 20.0% difference; 95% CI: 9.3%, 30.7%). The frequency of TEAEs was similar across groups, with gout flares occurring frequently.ConclusionsUsing a novel dose-titration method, although the primary endpoint of non-inferiority of febuxostat 40 mg/day versus allopurinol 300 mg/day was not reached, non-inferiority and superiority of febuxostat 60 mg/day and 80 mg/day versus allopurinol 300 mg/day was demonstrated at weeks 16 and 24, respectively. Febuxostat demonstrated an acceptable tolerability profile in the treatment of hyperuricemia in Chinese subjects with or without gout.Trial registrationJapicCTI-132106.FundingAstellas Pharma Global Development, Inc.
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