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Arthritis Care & Research Jun 2020To provide guidance for the management of gout, including indications for and optimal use of urate-lowering therapy (ULT), treatment of gout flares, and lifestyle and...
OBJECTIVE
To provide guidance for the management of gout, including indications for and optimal use of urate-lowering therapy (ULT), treatment of gout flares, and lifestyle and other medication recommendations.
METHODS
Fifty-seven population, intervention, comparator, and outcomes questions were developed, followed by a systematic literature review, including network meta-analyses with ratings of the available evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and patient input. A group consensus process was used to compose the final recommendations and grade their strength as strong or conditional.
RESULTS
Forty-two recommendations (including 16 strong recommendations) were generated. Strong recommendations included initiation of ULT for all patients with tophaceous gout, radiographic damage due to gout, or frequent gout flares; allopurinol as the preferred first-line ULT, including for those with moderate-to-severe chronic kidney disease (CKD; stage >3); using a low starting dose of allopurinol (≤100 mg/day, and lower in CKD) or febuxostat (<40 mg/day); and a treat-to-target management strategy with ULT dose titration guided by serial serum urate (SU) measurements, with an SU target of <6 mg/dl. When initiating ULT, concomitant antiinflammatory prophylaxis therapy for a duration of at least 3-6 months was strongly recommended. For management of gout flares, colchicine, nonsteroidal antiinflammatory drugs, or glucocorticoids (oral, intraarticular, or intramuscular) were strongly recommended.
CONCLUSION
Using GRADE methodology and informed by a consensus process based on evidence from the current literature and patient preferences, this guideline provides direction for clinicians and patients making decisions on the management of gout.
Topics: Disease Management; Gout; Healthy Lifestyle; Humans; Symptom Flare Up; Uricosuric Agents
PubMed: 32391934
DOI: 10.1002/acr.24180 -
American Journal of Hypertension Jul 2020The association between increased serum urate and hypertension has been a subject of intense controversy. Extracellular uric acid drives uric acid deposition in gout,... (Review)
Review
The association between increased serum urate and hypertension has been a subject of intense controversy. Extracellular uric acid drives uric acid deposition in gout, kidney stones, and possibly vascular calcification. Mendelian randomization studies, however, indicate that serum urate is likely not the causal factor in hypertension although it does increase the risk for sudden cardiac death and diabetic vascular disease. Nevertheless, experimental evidence strongly suggests that an increase in intracellular urate is a key factor in the pathogenesis of primary hypertension. Pilot clinical trials show beneficial effect of lowering serum urate in hyperuricemic individuals who are young, hypertensive, and have preserved kidney function. Some evidence suggest that activation of the renin-angiotensin system (RAS) occurs in hyperuricemia and blocking the RAS may mimic the effects of xanthine oxidase inhibitors. A reduction in intracellular urate may be achieved by lowering serum urate concentration or by suppressing intracellular urate production with dietary measures that include reducing sugar, fructose, and salt intake. We suggest that these elements in the western diet may play a major role in the pathogenesis of primary hypertension. Studies are necessary to better define the interrelation between uric acid concentrations inside and outside the cell. In addition, large-scale clinical trials are needed to determine if extracellular and intracellular urate reduction can provide benefit hypertension and cardiometabolic disease.
Topics: Animals; Clinical Trials as Topic; Humans; Hypertension; Mendelian Randomization Analysis; Uric Acid; Uricosuric Agents
PubMed: 32179896
DOI: 10.1093/ajh/hpaa044 -
Arthritis & Rheumatology (Hoboken, N.J.) Jun 2019To estimate the current prevalence rates and decadal trends of gout and hyperuricemia in the US, as well as the prevalence of urate-lowering therapy (ULT) among gout...
OBJECTIVE
To estimate the current prevalence rates and decadal trends of gout and hyperuricemia in the US, as well as the prevalence of urate-lowering therapy (ULT) among gout patients, using 2007-2016 data from a nationally representative survey of American men and women (the National Health and Nutrition Examination Survey [NHANES]).
METHODS
Using data from 5,467 participants in the NHANES 2015-2016, we estimated the most recent prevalence rates of gout and hyperuricemia. When the NHANES was conducted, all participants were asked about their history of gout (as diagnosed by a health professional) and medication use. Hyperuricemia was defined as having a serum urate level of >7.0 mg/dl in men and >5.7 mg/dl in women. We examined decadal trends in these estimates using data from the NHANES 2007-2016 and investigated ULT usage trends using the NHANES 2007-14 (the most recent data available to date).
RESULTS
In 2015-2016, the prevalence of gout was 3.9% among adults in the US (9.2 million people), with 5.2% [5.9 million] in men and 2.7% [3.3 million] in women. Mean serum urate levels were 6.0 mg/dl in men and 4.8 mg/dl in women, and hyperuricemia prevalence rates were 20.2% and 20.0%, respectively. The prevalence rates of gout and hyperuricemia remained stable between 2007 and 2016 (P for trend > 0.05). The prevalence of ULT use among patients with gout was 33% in 2007-2014 and remained stable over time (P for trend > 0.05).
CONCLUSION
In this nationally representative survey sample of adults in the US, the prevalence rates of gout and hyperuricemia remained substantial, albeit unchanged, between 2007 and 2016. Despite these rates, only one-third of gout patients were receiving ULT.
Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Febuxostat; Female; Gout; Gout Suppressants; Humans; Hyperuricemia; Male; Middle Aged; Nutrition Surveys; Prevalence; Probenecid; United States; Uric Acid; Uricosuric Agents; Young Adult
PubMed: 30618180
DOI: 10.1002/art.40807 -
Blood Jul 2021Severe SARS-CoV-2 infection is complicated by dysregulation of the blood coagulation system and high rates of thrombosis, but virus-intrinsic mechanisms underlying this...
UNLABELLED
Severe SARS-CoV-2 infection is complicated by dysregulation of the blood coagulation system and high rates of thrombosis, but virus-intrinsic mechanisms underlying this phenomenon are poorly understood. Increased intracellular calcium concentrations promote externalization of phosphatidylserine (PS), the membrane anionic phospholipid required for assembly and activation of the tenase and prothrombinase complexes to drive blood coagulation. TMEM16F is a ubiquitous phospholipid scramblase that mediates externalization of PS in a calcium-dependent manner. As SARS-CoV-2 ORF3a encodes a presumed cation channel with the ability to transport calcium, we hypothesized that ORF3a expression by infected host cells perturbs the cellular calcium rheostat, driving TMEM16F-dependent externalization of PS and enhancing procoagulant activity. Using a doxycycline-inducible system, synchronized expression of ORF3a in A549 pulmonary epithelial cells resulted in a time-dependent augmentation of tissue factor (TF) procoagulant activity exceeding 9-fold by 48 hours (p < 0.0001), with no change in TF cell-surface expression. This enhancement was dependent upon PS as determined by inhibition with the PS-binding protein lactadherin. Over 2-fold enhancement of prothrombinase activity (p < 0.0001) was also observed by 48 hours. ORF3a increased intracellular calcium levels by 18-fold at 48 hours (p < 0.0001), as determined by the intracellular calcium indicator fluo-4. After 16 hours of ORF3a expression, more than 60% of cells had externalized PS (p < 0.001) without increased cell death, as quantified by flow cytometry following annexin V binding. Immunofluorescence microscopy staining for ORF3a, annexin V, and nuclei confirmed ORF3a expression within internal and cell surface membranes and increased PS externalization. PS externalization was insensitive to the pan-caspase inhibitor z-VAD-FMK, and there was no evidence of apoptotic activation as determined by caspase-3 cleavage. By contrast, ORF3a expression did not augment coagulation in cells deficient in the calcium-dependent phospholipid scramblase TMEM16F. Similarly, ORF3a-enhanced TF procoagulant activity (p < 0.01) and prothrombinase activity (p<0.05) was completely abrogated using TMEM16 inhibitors, including the uricosuric agent benzbromarone that has been registered for human use in over 20 countries. Live SARS-CoV-2 infection of A549-ACE2 cells increased cell surface factor Xa generation at MOI 0.1 (p < 0.01) but not MOI 0.01 or following heat inactivation of the virus, and RNA sequencing confirmed induction without increased expression. RNA sequencing of human SARS-CoV-2 infected lung autopsy and control tissue (n= 53) confirmed these findings Immunofluorescence staining for ORF3a and KRT8/18 and CD31 in SARS-CoV-2 infected human lung autopsy specimens demonstrated ORF3a expression in pulmonary epithelium and endothelial cells, highlighting the potential pathologic relevance of this mechanism. Here we demonstrate that expression of the SARS-CoV-2 accessory protein ORF3a increases the intracellular calcium concentration and TMEM16F-dependent PS scrambling to augment procoagulant activity of the tenase and prothrombinase complexes. Our studies of human cells and tissues infected with SARS-CoV-2 support the pathologic relevance of this mechanism. We highlight the therapeutic potential to target the ORF3a-TMEM16F axis as with benzbromarone to mitigate dysregulation of coagulation and thrombosis during severe SARS-CoV-2 infection.
DISCLOSURES
Membership on an entity's Board of Directors or advisory committees; Consultancy, Speakers Bureau. Consultancy, Research Funding.
Topics: Acetates; Cytomegalovirus; Cytomegalovirus Infections; Humans; Quinazolines
PubMed: 34236425
DOI: 10.1182/blood.2021011459 -
Frontiers in Pharmacology 2022We reviewed all currently available ULT, as well as any medications in development using following databases: United States Food and Drug Administration (FDA), European... (Review)
Review
We reviewed all currently available ULT, as well as any medications in development using following databases: United States Food and Drug Administration (FDA), European Medicines Agency (EMA), Japanese Pharmaceutical and Medical Devices Agency (PMDA), and ClinicalTrials.gov. We identified a total of 36 drugs, including 10 approved drugs, 17 in clinical testing phases, and 9 in preclinical developmental phases. The 26 drugs currently undergoing testing and development include 5 xanthine oxidase inhibitors, 14 uricosurics, 6 recombinant uricases, and one with multiple urate-lowering mechanisms of action. Herein, we reviewed the benefit and risk of each drug summarizing currently available drugs. New trials of uricosuric agents are underway to develop the new indication. New drugs are going on to improve the potency of recombinant uricase and to develop the new route administration of such as oral formulation. This review will provide valuable information on the properties, indications, and limitations of ULTs.
PubMed: 36081938
DOI: 10.3389/fphar.2022.925219 -
BMC Endocrine Disorders Feb 2021Hyperuricemia is associated with insulin resistance, pancreatic β-cell dysfunction and consequently with development of type 2 diabetes. Although a direct relationship... (Review)
Review
Hyperuricemia is associated with insulin resistance, pancreatic β-cell dysfunction and consequently with development of type 2 diabetes. Although a direct relationship between high levels of uric acid (UA) and the development of diabetes is still a controversial issue, there is some evidence that strongly points to pancreatic β-cells damage as a result of high serum UA levels. Here, the mechanisms underlying UA-induced β-cell damage are discussed. Available literature indicates that UA can decrease glucose-stimulated insulin secretion and cause β-cell death. The mechanisms underlying these effects are UA-induced oxidative stress and inflammation within the β-cells. UA also stimulates inducible nitric oxide (NO) synthase (iNOS) gene expression leading to NO-induced β-cell dysfunction. Thus hyperuricemia may potentially cause β-cell dysfunction, leading to diabetes. It may be hypothesized that in hyperuricemic subjects, UA-lowering drugs may be beneficial in preventing diabetes.
Topics: Animals; Cell Death; Diabetes Mellitus, Type 2; Humans; Hyperuricemia; Insulin Secretion; Insulin-Secreting Cells; Nitric Oxide; Uric Acid; Uricosuric Agents
PubMed: 33593356
DOI: 10.1186/s12902-021-00698-6 -
Physiological Reports Apr 2023Development of autosomal dominant polycystic kidney disease (ADPKD) involves renal epithelial cell abnormalities. Cystic fluid contains a high level of ATP that, among...
Development of autosomal dominant polycystic kidney disease (ADPKD) involves renal epithelial cell abnormalities. Cystic fluid contains a high level of ATP that, among other effects, leads to a reduced reabsorption of electrolytes in cyst-lining cells, and thus results in cystic fluid accumulation. Earlier, we demonstrated that Pkd1 mice, a hypomorphic model of ADPKD, exhibit increased expression of pannexin-1, a membrane channel capable of ATP release. In the current study, we found that human ADPKD cystic epithelia have higher pannexin-1 abundance than normal collecting ducts. We hypothesized that inhibition of pannexin-1 function with probenecid can be used to attenuate ADPKD development. Renal function in male and female Pkd1 and control mice was monitored between 9 and 20 months of age. To test the therapeutic effects of probenecid (a uricosuric agent and a pannexin-1 blocker), osmotic minipumps were implanted in male and female Pkd1 mice, and probenecid or vehicle was administered for 42 days until 1 year of age. Probenecid treatment improved glomerular filtration rates and slowed renal cyst formation in male mice (as shown in histopathology). The mechanistic effects of probenecid on sodium reabsorption and fluid transport were tested on polarized mpkCCD cells subjected to short-circuit current measurements, and in 3D cysts grown in Matrigel. In the mpkCCD epithelial cell line, probenecid elicited higher ENaC currents and attenuated in vitro cyst formation, indicating lower sodium and less fluid retention in the cysts. Our studies open new avenues of research into targeting pannexin-1 in ADPKD pathology.
Topics: Mice; Male; Female; Humans; Animals; Polycystic Kidney, Autosomal Dominant; Probenecid; Disease Models, Animal; Kidney; Disease Progression; Adenosine Triphosphate; Cysts; TRPP Cation Channels
PubMed: 37024297
DOI: 10.14814/phy2.15652 -
Srpski Arhiv Za Celokupno Lekarstvo 2013Chronic asymptomatic hyperuratemia (HUA), gout paroxysm in patients with chronic hyperuratemia (HU) and normouricemic attacks of gouty arthritis are well known, but... (Review)
Review
Chronic asymptomatic hyperuratemia (HUA), gout paroxysm in patients with chronic hyperuratemia (HU) and normouricemic attacks of gouty arthritis are well known, but poorly understood. A review of the current literature with attempt of its explanation is presented. The natural course of gout is associated with joint structure changes that may be evaluated by different imaging techniques; comparative advantages and shortcomings of each technique are presented. For almost over 50 years the market has not offered new drugs for the control of HU and gout, while management of such patients was a rather neglected field. Over the last five years an unpredictable number of prospective clinical studies have been conducted involving the investigation of the efficacy and safety of new drugs to control HU (febuxostat, pegloticase). The return of pharmaceutical industry into the world of gout has considerably changed the picture. New recommendations have been presented on appropriate colchicine dose regime for acute gouty flares. Emerging therapies, including pegloticase, uricosuric agent RDEA596 and the interleukin-1 inhibitors have shown promises in early and late phase clinical trials. Each of them deserves to be considered for implementation and feasibility in clinical practice as well as outcome measures for clinical trials. Another purpose of this review was to summarize new knowledge on approved drugs to treat hyperuricemia, or the clinical manifestations of gout. Results of several clinical trials provide new data on the efficacy and safety of the approved urate lowering drugs (allopurinol and febuxostat). Lifestyle and dietary recommendations for gout patients should take into consideration overall health benefits and risks, since gout is often associated with metabolic syndrome and an increased future risk of cardiovascular disease and mortality. This review also summarizes the recent data about lifestyle factors that influence serum uric acid levels and the gout risk, and attempts to provide holistic recommendations, considering both their impact on gout as well as on other health implications.
Topics: Gout; Humans; Hyperuricemia; Uric Acid
PubMed: 23539921
DOI: 10.2298/sarh1302109r -
The Cochrane Database of Systematic... Apr 2017High blood pressure represents a major public health problem. Worldwide, approximately one-fourth of the adult population has hypertension. Epidemiological and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
High blood pressure represents a major public health problem. Worldwide, approximately one-fourth of the adult population has hypertension. Epidemiological and experimental studies suggest a link between hyperuricemia and hypertension. Hyperuricemia affects 25% to 40 % of individuals with untreated hypertension; a much lower prevalence has been reported in normotensives or in the general population. However, whether lowering serum uric acid (UA) might lower blood pressure (BP) is an unanswered question.
OBJECTIVES
To determine whether UA-lowering agents reduce BP in patients with primary hypertension or prehypertension compared with placebo.
SEARCH METHODS
The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to February 2016: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 2), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also searched LILACS up to March 2016 and contacted authors of relevant papers regarding further published and unpublished work.
SELECTION CRITERIA
To be included in this review, the studies had to meet the following criteria: 1) randomized or quasi-randomized, with a group assigned to receive a UA-lowering agent and another group assigned to receive placebo; 2) double-blind, single-blind or open-label; 3) parallel or cross-over trial; 4) cross-over trials had to have a washout period of at least two weeks; 5) minimum treatment duration of four weeks; 6) participants had to have a diagnosis of essential hypertension or prehypertension, and hyperuricemia (serum UA greater than 6 mg/dL in women, 7 mg/dL in men and 5.5 mg/dL in children/adolescents); 7) outcome measures assessed included change in clinic systolic, diastolic or 24-hour ambulatory BP.
DATA COLLECTION AND ANALYSIS
The two review authors independently collected the data using a data extraction form, and resolved any disagreements via discussion. We assessed risk of bias using the Cochrane Collaboration' Risk of bias' tool.
MAIN RESULTS
In this review update, we examined the abstracts of 349 identified papers and selected 21 for evaluation. We also identified three ongoing studies, the results of which are not yet available. Three other randomized controlled trials (RCTs) (two new), enrolling individuals with hypertension or prehypertension, and hyperuricemia, met the inclusion criteria for the review and were included in the meta-analysis. Low quality of evidence from three RCTs indicate no reduction in systolic (MD -6.2 mmHg, 95% CI -12.8 to 0.5) or diastolic (-3.9 mmHg, 95% CI -9.2 to 1.4) 24-hour ambulatory BP with UA-lowering drugs compared with placebo. Low quality of evidence from two RCTs reveal a reduction of systolic clinic BP (-8.43 mmHg, 95% CI -15.24 to -1.62) but not diastolic clinic BP (-6.45 mmHg, 95% CI -13.60 to 0.70). High quality of evidence from three RCTs indicates that serum UA levels were reduced by 3.1 mg/dL (95% CI 2.4 to 3.8) in the participants that received UA-lowering drugs. Very low quality of evidence from three RCTs suggests that withdrawals due to adverse effects were not increased with UA-lowering therapy (RR 1.86, 95% CI 0.43 to 8.10).
AUTHORS' CONCLUSIONS
In this updated systematic review, the RCT data available at present are insufficient to know whether UA-lowering therapy also lowers BP. More studies are needed.
Topics: Adolescent; Adult; Allopurinol; Blood Pressure; Child; Humans; Hypertension; Hyperuricemia; Patient Dropouts; Prehypertension; Randomized Controlled Trials as Topic; Uricosuric Agents
PubMed: 28406263
DOI: 10.1002/14651858.CD008652.pub3