Non-steroidal anti-inflammatory drugs for acute gout.
van Durme Caroline M P G,Wechalekar Mihir D,Buchbinder Rachelle,Schlesinger Naomi,van der Heijde Désirée,Landewé Robert B M
The Cochrane database of systematic reviews
BACKGROUND:Gout is an inflammatory arthritis that is characterised by the deposition of monosodium urate crystals in synovial fluid and other tissues. The natural history of articular gout is generally characterised by three periods: asymptomatic hyperuricaemia, episodes of acute gout and chronic gouty arthritis. Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclo-oxygenase-2 (COX-2) inhibitors (COXIBs) are commonly used to treat acute gout. Published guidelines recommend their use to treat acute attacks, using maximum recommended doses for a short time. OBJECTIVES:To assess the benefit and safety of NSAIDs (including COXIBs) for acute gout. SEARCH METHODS:We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE for studies to 7 October 2013, the 2010 and 2011 ACR and EULAR abstracts and performed a handsearch of reference lists of articles. We searched the World Health Organization (WHO) trial register and ClinicalTrials.gov. We applied no date or language restrictions. SELECTION CRITERIA:We considered all published randomised controlled trials (RCTs) and quasi-randomised controlled clinical trials that compared NSAIDs with placebo or another therapy (including non-pharmacological therapies) for acute gout. Major outcomes were pain (proportion with 50% or more reduction in pain or mean pain when the dichotomous outcome was unavailable), inflammation (e.g. measured by joint swelling/erythema/tenderness), function of target joint, participant's global assessment of treatment success, health-related quality of life, withdrawals due to adverse events and total adverse events. DATA COLLECTION AND ANALYSIS:Two review authors independently selected the studies for inclusion, extracted the data, performed a risk of bias assessment and assessed the quality of the evidence using the GRADE approach. MAIN RESULTS:We included 23 trials (2200 participants).One trial (30 participants) of low-quality evidence compared an NSAID (tenoxicam) with placebo. It found that significantly more participants had more than 50% reduction in pain after 24 hours (11/15 participants) compared with those taking placebo (4/15 participants) (risk ratio (RR) 2.75, 95% confidence interval (CI) 1.13 to 6.72). A similar outcome was seen for more than 50% improvement in joint swelling after 24 hours (5/15 participants taking NSAIDs versus 2/15 participants taking placebo; RR 2.50, 95% CI 0.57 to 10.93). The trial did not measure function, participant global assessment of treatment success and health-related quality of life. There were no adverse events reported with the use of tenoxicam; two adverse events (nausea and polypuria) were reported in the placebo group. No between-group differences in outcome were observed after four days.Moderate-quality evidence based upon four trials (974 participants) indicated that NSAIDs and COXIBs produced similar benefits in terms of pain, swelling and global improvement, but COXIBs were associated with fewer adverse events. Pain reduction was 1.9 points on a 0- to 10-point scale with COXIBs (0 was no pain) while pain reduction with NSAIDs was 0.03 points lower or better (mean difference (MD) -0.03, 95% CI -0.19 to 0.13). Joint swelling in the COXIB group was 1.64 points on a 0- to 3-point scale (0 is no swelling) and 0.13 points higher with NSAIDs (MD 0.13, 95% CI -0.08 to 0.34). Function was not reported. Participant-reported global assessment was 1.56 points on a 0- to 4-point scale with COXIBs (0 was the best score) and was 0.04 points higher with NSAIDs (MD 0.04, 95% CI -0.12 to 0.20). Health-related quality of life assessed using the 36-item Short Form showed no evidence of a statistically significant between-group difference (MD 0.49, 95% CI -1.61 to 2.60 for the physical component). There were significantly fewer withdrawals due to adverse events in participants treated with COXIBs (3%) compared with NSAIDs (8%) (RR 2.39, 95% CI 1.34 to 4.28). There was a significantly lower number of total adverse events in participants treated with COXIBs (38%) compared with NSAIDs (60%) (RR 1.56, 95% CI 1.30 to 1.86).There was moderate-quality evidence based on two trials (210 participants) that oral glucocorticoids did not differ in pain reduction, function or adverse events when compared with NSAIDs. Pain reduction was 9.5 on a 0- to 100-point scale with glucocorticoids, pain reduction with NSAIDs was 1.74 higher or worse (MD 1.74, 95% CI -1.44 to 4.92). The trials did not assess inflammation. Function measured as walking disability was 17.4 points on a 0- to 100-point scale with glucocorticoids, function with NSAIDs was 0.1 lower or better (MD -0.10, 95% CI -4.72 to 4.52). The trials did not measure participant-reported global assessment and health-related quality of life. There were no withdrawals due to adverse events. There was no evidence of a difference in total number of adverse events with glucocorticoids (31%) versus NSAIDs (49%) (RR 1.58, 95% CI 0.76 to 3.28). AUTHORS' CONCLUSIONS:Limited evidence supported the use of NSAIDs in the treatment of acute gout. One placebo-controlled trial provided evidence of benefit at 24 hours and little or no harm. We downgraded the evidence due to potential selection and reporting biases, and imprecision. While these data were insufficient to draw firm conclusions, they did not conflict with clinical guideline recommendations based upon evidence from observational studies, other inflammatory arthritis and expert consensus, which support the use of NSAIDs in acute gout.Moderate-quality evidence suggested that selective COX-2 inhibitors and non-selective NSAIDs are probably equally beneficial although COX-2 inhibitors are likely to be associated with significantly fewer total and gastrointestinal adverse events. We downgraded the evidence due to an unclear risk of selection and reporting biases. Moderate-quality evidence indicated that systemic glucocorticoids and NSAIDs were also equally beneficial in terms of pain relief. There were no withdrawals due to adverse events and total adverse events were similar between groups. We downgraded the evidence due to unclear risk of selection and reporting bias. There was low-quality evidence that there was no difference in function. We downgraded the quality due to unclear risk of selection bias and imprecision.
Idiopathic renal hypouricemia: A case report and literature review.
Wang Cuiyu,Wang Jin,Liu Song,Liang Xinhua,Song Yifan,Feng Ling,Zhong Lanxin,Guo Xiaohua
Molecular medicine reports
Idiopathic renal hypouricemia is a rare hereditary condition. Type 2 renal hyperuricemia (RHUC2) is caused by a mutation in the SLC2A9 gene, which encodes a high‑capacity glucose and urate transporter, glucose transporter (GLUT)9. RHUC2 predisposes to exercise‑induced acute renal failure (EIARF) and nephrolithiasis, which is caused by a defect in renal tubular urate transport and is characterized by increased clearance of renal uric acid. In the present study a case of a 35‑year‑old Chinese man with EIARF is reported. The patient had isolated renal hypouricemia, with a serum uric acid level of 21 µmol/l and a fractional excretion of uric acid of 200%. The mutational analysis revealed a homozygous mutation (c.857G>A in exon 8) in the SLC2A9 gene. The patient's family members carried the same mutation, but were heterozygous and clinically asymptomatic. In conclusion, to the best of our knowledge, this is the first report of a RHUC2 patient with a GLUT9 mutation, p.W286X, which may be a pathogenic mutation of RHUC2. Further investigation into the functional role of GLUT9 in this novel SLC2A9 mutation is required.
Musculoskeletal ultrasonography in gout.
Scirocco Chiara,Rutigliano Iolanda Maria,Finucci Annacarla,Iagnocco Annamaria
Gout is a frequent inflammatory disease induced by the deposition of monosodium urate crystals in joints and extra-articular tissues. The natural history of the disease includes four different phases: asymptomatic hyperuricemia, acute attacks, intercritical phase, and chronic tophaceous gout. Imaging techniques have several applications in the diagnosis, clinical monitoring and management of the disease but particularly, musculoskeletal ultrasound is able to detect a wide set of abnormalities in gout. This review reports the most relevant findings detectable by ultrasound and the current available data in the literature regarding the role of musculoskeletal ultrasound in gout..
Lipoprotein (a) and Cardiovascular Risk: The Show Must go on.
Katsiki Niki,Al-Rasadi Khalid,Mikhailidis Dimitri P
Current medicinal chemistry
Lipoprotein (a) [Lp(a)] is an independent but moderate, predictor for coronary heart disease (CHD) prevalence and severity. Several established and emerging cardiovascular (CV) risk factors including age, gender, ethnicity, smoking, dyslipidemia, hypertension, obesity, type 2 diabetes mellitus, alcohol consumption, arterial stiffness and hyperuricemia have been linked to Lp(a) metabolism. Apart from CHD, Lp(a) has been also associated with non-cardiac vascular diseases and diseases associated with increased CV risk such as chronic kidney disease, metabolic syndrome, non-alcoholic fatty liver disease, erectile dysfunction, obstructive sleep apnea syndrome, inflammatory bowel diseases and human immunodeficiency virus infection. The above data are discussed in the present narrative review. Several guidelines suggest the clinical use of Lp(a) in (re)defining vascular risk, especially in asymptomatic individuals at intermediate or high CV risk and those with a family history of premature CHD. By improving individuals risk stratification, Lp(a) may contribute to a better secondary prevention strategy. However, there is still a need to establish a standardized method to measure Lp(a) as well as selective potent therapies for lowering Lp(a). This will support conducting large randomized trials in order to establish whether lowering circulating Lp(a) levels will result in a significant reduction in CV events.
Dual-Energy Computed Tomography of the Knee, Ankle, and Foot: Noninvasive Diagnosis of Gout and Quantification of Monosodium Urate in Tendons and Ligaments.
Fritz Jan,Henes Joerg C,Fuld Matthew K,Fishman Elliot K,Horger Marius S
Seminars in musculoskeletal radiology
Gout is a true crystal deposition arthropathy caused by the precipitation of monosodium urate into joints and periarticular soft tissues. It is the most common inflammatory arthropathy in men and women of older age with a male-to-female ratio of 3 to 8:1. The disease may progress from asymptomatic hyperuricemia through symptomatic acute gout attacks with asymptomatic periods into chronic symptomatic tophaceous gout. Although invasive arthrocentesis and demonstration of monosodium urate crystals on polarized light microscopy is definitive for the diagnosis of gout, dual-energy computed tomography (CT) allows for noninvasive visualization and reproducible volume quantification of monosodium urate crystals. Based on the high diagnostic performance, dual-energy CT has been included in the 2015 American College of Rheumatology/European League Against Rheumatism Collaborative Initiative Classification Criteria for Gout. Increasing evidence indicates the usefulness of dual-energy CT to guide the management of patients with suspected gout and monitor the effectiveness of urate-lowering medical therapy.
A Systematic Review of the Economic and Humanistic Burden of Gout.
Shields Gemma E,Beard Stephen M
BACKGROUND:Gout is a chronic and inflammatory form of arthritis that is often overlooked despite the associated pain caused by acute flares and associated joint damage caused by the development of debilitating tophi. The increasing burden of gout, due to an aging population and the increased prevalence of known risk factors for hyperuricaemia, means that there is a continued need for new and effective urate-lowering treatments. The evaluation of these treatments will require a comprehensive and comparative evidence base describing the economic and humanistic burden of gout, taken from the perspective of patients, the healthcare system, and wider society. OBJECTIVE:The objective of this study is to review and summarise the current evidence of the disease burden related to chronic gout, assessed in terms of both cost and health-related quality of life (HRQL), and to identify key factors correlated with an increased burden. The overall aim is to support the economic evaluation of new treatments for gout, and to highlight key data gaps that may need further study and exploration. METHODS:Relevant literature dating from January 2000 to July 2014 was sourced through searches of the MEDLINE database via PubMed and The Cochrane Library. Articles published in English and reporting either the economic burden (cost) or the humanistic burden (HRQL/utility) of gout were identified, and key data were extracted and summarised, with key themes and data gaps identified and discussed. RESULTS:Of the 323 studies identified, 39 met the inclusion criteria, of which 17 and 26 were relevant to the economic and humanistic burden, respectively. The economic burden of gout varied according to numerous factors, most notably serum urate acid levels and number of flares and tophi, resulting in higher healthcare resource use most often attributed to hospitalisation and inpatient stay. The incremental direct cost of gout has been suggested in the range of US$3165 to US$5515 (2004 and 2005 values, respectively) climbing to US$10,222 to US$21,467 (2008 values) per annum where patients are experiencing regular acute flares and have tophi present. The humanistic burden of gout was largely due to physical disability and pain resulting from chronic clinical manifestations. Short Form 6 dimensions (SF-6D) assessed utility weights are estimated at 0.53 for a patient with severe gout (≥3 flares/year and tophi) compared with 0.73 for an asymptomatic gout patient with serum acid levels <6 mg/dl. CONCLUSIONS:The evidence confirms that gout has a growing overall prevalence and represents a significant burden in terms of both direct healthcare cost and HRQL outcomes. In light of this, effective urate-lowering treatments are likely to be valued if they can be clearly demonstrated to be both clinically effective and cost effective. Published data to support healthcare decision making in non-US countries with regards to treatments for gout are currently limited, which is a key limitation of the current evidence base. More research is also required to extend our understanding of the impact of gout on indirect costs, and a need also exists to develop a more comprehensive set of comparative HRQL utility assessments.
Gout. New opportunities of diagnosis and treatment.
Yakupova S P
In recent yearsincidences of gout has increased. Despite the current diagnostic possibilities, doctors face the difficultiesin establishing the diagnosis. In 2015new criteria of diagnosis of goutwere developed by European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR). In 2016 the EULARexpert group offered the treatment strategy of patients with gout. Main features of the strategy and new researches, revealing the most effective and safest possibilities for gout treatment were laid down in article.
Clinical manifestations and diagnosis of gout.
Perez-Ruiz Fernando,Castillo Edwin,Chinchilla Sandra P,Herrero-Beites Ana M
Rheumatic diseases clinics of North America
Gout has been academically considered to be a step-up disease consisting of different stages: acute gout, intercritical gout, and chronic gout. This simple approach may lead to misinterpretation and misdiagnosis. In clinical practice, we should consider gout as a single disease with either or both acute (most commonly, episodes of acute inflammation) and persistent clinical manifestations, but not restricted to chronic synovitis. In this article, an innovative, practical, and rational approach to the clinical manifestations and diagnosis of gout is presented, which may be supportive for clinicians involved in everyday care and management of patients with gout.
Treatment Options for Gout.
Engel Bettina,Just Johannes,Bleckwenn Markus,Weckbecker Klaus
Deutsches Arzteblatt international
BACKGROUND:1-2% of adults in Germany suffer from gout. Gout is one of the few rheumatological diseases that can be cured. It arises through the deposition of uric acid crystals in joints as a result of hyperuricemia. Painful redness and swelling of the affected joints are typical findings. Multiple pertinent guidelines and treatment recommendations have been published, but there is reason to believe that patients with gout are not always treated accordingly. METHODS:This review is based on relevant publications from the years 2000-2016 that were retrieved by a selective search in the Cochrane and PubMed databases. RESULTS:In a person with normal renal function, asymptomatic hyperuricemia is not an indication for treatment to lower the serum uric acid level. The drugs of first choice for acute gouty arthritis are nonsteroidal antiinflammatory drugs (NSAID), corticosteroids, and colchicine. Treatment with xanthine oxidase inhibitors (XOI) or uricosuric drugs is indicated for patients with a recurrent or severe course; the target uric acid value is <6 mg/dL. Long-term treatment should be initiated only after resolution of the acute attack. For patients with refractory gout, lesinurad (approved in February 2016) in combination with XOI is a new treatment option that can be considered. Comprehensive patient education and counseling is an important component of the treatment of patients with gout. Regular laboratory follow-up is necessary as well. CONCLUSION:The prevalence of gout is rising around the world. Patients with gout could benefit greatly from consistent implementation of the existing treatment guidelines and recommendations. In the future, controlled trials should be conducted to determine the best time to start treatment and the optimal target level for the serum uric acid concentration in terms of a risk/benefit analysis.
Australian and New Zealand recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion in the 3e Initiative.
Graf Scott W,Whittle Samuel L,Wechalekar Mihir D,Moi John H Y,Barrett Claire,Hill Catherine L,Littlejohn Geoff,Lynch Nora,Major Gabor,Taylor Andrew L,Buchbinder Rachelle,Zochling Jane
International journal of rheumatic diseases
AIM:To develop evidence-based recommendations for the diagnosis and management of gout in Australia and New Zealand as part of the multi-national 3e Initiative. METHOD:Using a formal voting process, a panel of 78 international rheumatologists selected 10 key clinical questions pertinent to the diagnosis and management of gout. An additional question was also developed by participating Australian and New Zealand rheumatologists. Each question was investigated with a systematic literature review. MEDLINE, EMBASE, Cochrane CENTRAL and abstracts from 2010 to 2011 European League Against Rheumatism and American College of Rheumatology meetings were searched in each review. Relevant studies were independently reviewed by two individuals for data extraction and synthesis and risk of bias assessment. Using this evidence, 47 Australian and New Zealand rheumatologists developed national recommendations. For each recommendation the level of agreement was assessed and the level of evidence graded. RESULT:Eleven recommendations were produced relating to the diagnosis of gout, different aspects of the management of gout, cardiovascular and renal comorbidities and the management of asymptomatic hyperuricemia. The mean level of agreement with the recommendations was 9.1 on a 1-10 scale, with 10 representing full agreement. CONCLUSION:Eleven Australian and New Zealand recommendations on the diagnosis and management of gout were developed combining systematically reviewed evidence with local expertise, enhancing their utility in clinical practice.
Controversies in the treatment of gout.
Alušík Štefan,Paluch Zoltán
The authors discuss current options on the treatment of gout (acute gout attack, prophylaxis, management of hypouricemia) and asymptomatic hyperuricemia. They highlight the differences in individual guidelines in terms of the spectrum of drugs used, their preferences, dosing, dose titration, and goals of treatment as well as different positions over asymptomatic hyperuricemia. Further, the authors provide an overview of latest concepts related to uric acid and its association with some neurologic and cardiovascular diseases. Another issues discussed in the article are the completely different guidelines for general practitioners and their principles. In conclusion, the authors note that answers to some controversies in the treatment of gout can only be provided by data obtained from properly designed and conducted clinical trials. Key words: allopurinol - colchicine - glucocorticoids - gout - non-steroidal anti-inflammatory drugs - uric acid.
Overview of Serum Uric Acid Treatment Targets in Gout: Why Less Than 6 mg/dL?
Ruoff Gary,Edwards N Lawrence
Gout is a progressive, painful, debilitating form of inflammatory arthritis. It is caused by factors that elevate the concentration of serum uric acid (sUA), leading to hyperuricemia (sUA >6.8 mg/dL). Continued elevated sUA can result in monosodium urate (MSU) crystal deposition in joints and soft tissues, and can cause acute and chronic inflammation. The prevalence of hyperuricemia and gout has increased over the last few decades, likely due to an aging population, changes in lifestyles and diet, and an increase in gout-associated comorbidities. Untreated or improperly treated gout can lead to chronic manifestation of the disease, including persistent inflammation, increased number of flares, development of tophi, and structural joint damage. Data show that even when patients are asymptomatic, ongoing inflammation and subsequent damage occurs locally at the joint and systemically. The aim of long-term treatment of gout is to reduce sUA levels to <6 mg/dL, which is below the saturation point of MSU (6.8 mg/dL), to inhibit formation of new crystals and to promote dissolution of existing crystals. Gout treatment should improve disease outcomes by eliminating gout flares, inducing long-term resolution of tophi, and more effectively managing comorbidities, many of which are associated with hyperuricemia. A number of studies have demonstrated that treating to the target of <6 mg/dL, by using effective therapies to lower sUA, results in reduction in the incidence of gout flares as well as shrinkage and eventual disappearance of tophi. Gout is often poorly managed due to a number of factors including lack of physician and patient adherence to treatment guidelines. Patients need to be educated about their diagnosis and management of the disease, such as the influence of diet and the importance of compliance with long-term treatment. With treatment, regular sUA monitoring, and patient adherence, gout is a curable disease.
Improving cardiovascular and renal outcomes in gout: what should we target?
Richette Pascal,Perez-Ruiz Fernando,Doherty Michael,Jansen Tim L,Nuki George,Pascual Eliseo,Punzi Leonardo,So Alexander K,Bardin Thomas
Nature reviews. Rheumatology
Epidemiological and experimental studies have shown that hyperuricaemia and gout are intricately linked with hypertension, metabolic syndrome, chronic kidney disease and cardiovascular disease. A number of studies suggest that hyperuricaemia and gout are independent risk factors for the development of these conditions and that these conditions account, in part, for the increased mortality rate of patients with gout. In this Review, we first discuss the links between hyperuricaemia, gout and these comorbidities, and present the mechanisms by which uric acid production and gout might favour the development of cardiovascular and renal diseases. We then emphasize the potential benefit of urate-lowering therapies on cardiovascular and renal outcomes in patients with hyperuricaemia. The mechanisms that link elevated serum uric acid levels and gout with these comorbidities seem to be multifactorial, implicating low-grade systemic inflammation and xanthine oxidase (XO) activity, as well as the deleterious effects of hyperuricaemia itself. Patients with asymptomatic hyperuricaemia should be treated by nonpharmacological means to lower their SUA levels. In patients with gout, long-term pharmacological inhibition of XO is a treatment strategy that might also reduce cardiovascular and renal comorbidities, because of its dual effect of lowering SUA levels as well as reducing free-radical production during uric acid formation.
Hyperuricemia and renal risk.
Viazzi Francesca,Leoncini Giovanna,Ratto Elena,Pontremoli Roberto
High blood pressure & cardiovascular prevention : the official journal of the Italian Society of Hypertension
Asymptomatic mild hyperuricemia has been reported in association with a number of conditions associated with chronic kidney disease, including hypertension, insulin resistance, cerebrovascular and cardiac disease. Experimental studies indicate that serum uric acid may directly and indirectly promote renal damage by several pathogenetic mechanisms both at cellular and tissue level. While there is currently no consensus on the usefulness of urate lowering therapy with the aim of preventing chronic renal disease, growing evidence indicates a relationship between changes of serum uric acid over time and renal morbidity. The present manuscript will briefly review the evidence in favor and against an independent role for SUA in the pathogenesis of renal disease.
Review of the ophthalmic manifestations of gout and uric acid crystal deposition.
Ao Jack,Goldblatt Fiona,Casson Robert J
Clinical & experimental ophthalmology
Gout is a clinical disorder that is characterized by the deposition of monosodium urate crystals (MSU) in joints and tendons, usually in the presence of prolonged hyperuricaemia. Following an asymptomatic phase of hyperuricaemia, gout usually presents as acute monoarthritis followed by periods of remission and exacerbation. Conjunctival hyperaemia and subconjunctival haemorrhage exacerbated by purine intake are two of the more common manifestations that may go unrecognized. Other ocular and adnexal structures can be affected by urate crystal deposition and associated inflammation, with potentially vision-threatening consequences; however, ocular manifestations of gout are rare and may have been over-reported in the older literature, but our understanding of the clinic-pathological features of ocular urate deposits remains limited.
[URATE AS A POTENTIAL RISK FACTOR OF CARDIOVASCULAR AND RENAL DISEASES].
Acta medica Croatica : casopis Hravatske akademije medicinskih znanosti
Although asymptomatic hyperuricemia is rather often in laboratory reports, it cannot be considered a disease. Despite thehigh prevalence of hyperuricemia in patients with arterial hypertension (AH), chronic kidney disease (CKD), cardiovasculardisease (CVD) or metabolic syndrome, hyperuricemia is not confirmed as a causative factor of these disorders. The aim isto point to the latest studies of the importance of urate as a possible cardiorenal risk factor. The literature published in 2015and 2016 was searched for the possible impact of urate level on the development of cardiorenal diseases. The PubMed,Cochrane, Medline, and UpToDate databases were searched for the literature published between November 2009 andOctober 2016 using the following key words: urate, hyperuricemia, cardiovascular disease, and chronic kidney disease.Causative correlation of hyperuricemia is confirmed only in disorders where deposits of monosodium urate crystals arepresent. Results of recent studies do not justify routine use of xanthine oxidase inhibitors in asymptomatic hyperuricemia.Some studies with small numbers of patients and short follow up report on endothelial function improvement on therapywith xanthine oxidase inhibitors. Nonpharmacological intervention by changing unhealthy lifestyle is preferred. Treatmentof asymptomatic hyperuricemia in CKD is still debated, and additional studies are necessary to demonstrate the benefitof lowering urate level in CKD. Family doctors (general practitioners) should be familiar with the recommended approachto patients with asymptomatic hyperuricemia. Evidence based medicine still does not recommend target determinationof serum urate level for identifying CVD and CKD risk factors. Recent studies suggest the possible effect of uric acid incardiorenal diseases and that treatment of asymptomatic hyperuricemia with xanthine oxidase inhibitors may also beuseful in CVD prevention. Additional studies are needed to prove this statement.
Comorbidities in patients with crystal diseases and hyperuricemia.
Sattui Sebastian E,Singh Jasvinder A,Gaffo Angelo L
Rheumatic diseases clinics of North America
Crystal arthropathies are among the most common causes of painful inflammatory arthritis. Gout, the most common example, has been associated with cardiovascular and renal disease. In recent years, evidence for these associations and those involving other comorbidities, such as the metabolic syndrome, have emerged, and the importance of asymptomatic hyperuricemia has been established. In this review, an update on evidence, both experimental and clinical, is presented, and associations between hyperuricemia, gout, and several comorbidities are described. Causality regarding calcium pyrophosphate arthropathy and associated comorbidities is also reviewed.
Hyperuricaemia with deposition: latest evidence and therapeutic approach.
Perez-Ruiz Fernando,Marimon Estibaliz,Chinchilla Sandra P
Therapeutic advances in musculoskeletal disease
This article reviews recent evidence on urate deposition and the opportunity for a therapeutic approach. We reviewed Pubmed 2013-2015 literature using the search terms 'deposition' with 'hyperuricaemia', 'gout', 'ultrasonography', 'DECT' (dual-energy computed tomography), 'radiography', 'CT'(computed tomography), 'MRI' (magnetic resonance imaging), or 'cardiovascular', in addition to a digital bibliographic library compiled by the authors with 2072 papers on hyperuricaemia and gout. Relevant papers on the topic were selected. Recent evidence, mostly based on imaging studies, showed a continuum from hyperuricaemia to deposition and clinical manifestations. Chronic inflammation and structural damage may be present even in asymptomatic patients with crystal-proved deposition. The impact of early intervention in patients with asymptomatic deposition either on vascular outcomes or further structural joint damage has not been demonstrated yet. In conclusion, a worldwide definition of gout is still lacking, stages from hyperuricaemia to clinical gout not being definitively defined. Although there is increasing interest on the impact of early deposits on joint damage and cardiovascular outcomes, robust evidence is still lacking to fully support interventions.
Treatment of asymptomatic hyperuricemia in chronic kidney disease: A new target in an old enemy - A review.
Ramirez Maria Erika G,Bargman Joanne M
Journal of advanced research
Asymptomatic hyperuricemia is increasing in prevalence. There is a growing body of literature suggesting that uric acid has deleterious effects on vascular health and renal histological integrity. Several trials, reviewed herein, suggest that lowering the serum uric acid level is associated with a slowing in the rate of renal deterioration in those with chronic kidney disease. Given that there is little available in the general armamentarium to slow the rate of kidney deterioration, strong consideration could be given to the administration of agents or lifestyle changes that decrease uric acid production in hyperuricemic patients with deteriorating kidney function.
Asymptomatic hyperuricemia and chronic kidney disease: Narrative review of a treatment controversial.
Eleftheriadis Theodoros,Golphinopoulos Spyridon,Pissas Georgios,Stefanidis Ioannis
Journal of advanced research
Today there is plausible evidence both on experimental and epidemiological basis, that hyperuricemia represents a risk factor for the development and progression of chronic kidney disease (CKD). Nevertheless, the role of serum uric acid lowering treatment in CKD is still a matter of serious controversy. Review of randomised controlled trials, suggests that there may be an improvement of renal function with allopurinol treatment in CKD stage 3-5. However, these studies have included a relatively limited number of participants and provide insufficient information on adverse events and on the incidence of the end stage renal disease. Therefore, before adequately powered randomised, placebo-controlled trials are completed we cannot recommend treating asymptomatic hyperuricemia in patients with CKD.
Cardiovascular risk factors and comorbidities in patients with hyperuricemia and/or gout: a systematic review of the literature.
van Durme Caroline,van Echteld Irene A A M,Falzon Louise,Aletaha Daniel,van der Heijde Désirée M F M,Landewé Robert B
The Journal of rheumatology. Supplement
OBJECTIVE:To review the available literature on the likelihood of having cardiovascular (CV) risk factors and on developing CV comorbidities in patients with gout and/or asymptomatic hyperuricemia as an evidence base for generating multinational clinical practice recommendations in the 3e (Evidence, Expertise, Exchange) Initiative in Rheumatology. METHODS:A systematic literature search was carried out using MEDLINE, EMBASE, and The Cochrane Library, and abstracts presented at the 2010/2011 meetings of the American College of Rheumatology (ACR) and the European League Against Rheumatism, searching for CV risk factors and new CV comorbidities in patients with asymptomatic hyperuricemia and/or a diagnosis of gout. Trials that fulfilled predefined inclusion criteria were systematically reviewed. RESULTS:A total of 66 out of 8918 identified publications were included in this review. After assessment of the risk of bias, 32 articles with a high risk of bias were excluded. Data could not be pooled because of clinical and statistical heterogeneity. In general, both for asymptomatic hyperuricemia and for gout the hazard ratios for CV comorbidities were only modestly increased (1.5 to 2.0) as were the hazard ratios for CV risk factors, ranging from 1.4 to 2.0 for hypertension and from 1.0 to 2.4 for diabetes. CONCLUSION:Unlike the common opinion that patients with gout or hyperuricemia are at higher risk of developing CV disease, the actual risk to develop CV disease is either rather weak (for hyperuricemia) or poorly investigated (for gout).
Beyond Joints: a Review of Ocular Abnormalities in Gout and Hyperuricemia.
Sharon Yael,Schlesinger Naomi
Current rheumatology reports
Gout is a common inflammatory arthritis among middle-aged men and postmenopausal women and can be a debilitating disease. Gout results from an elevated body uric acid pool, which leads to deposition of monosodium urate (MSU) crystals, mainly in and around the joints. The MSU crystals trigger release of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. Ocular manifestations have been uncommonly reported in patients with gout. These include descriptions of tophaceous deposits in different locations of the eye including the eyelids, conjunctiva, cornea, iris, sclera, and orbit. Some depositions were coincidentally diagnosed in asymptomatic patients, while the majority were symptomatic. Other ocular abnormalities include dry eye syndrome, red eye, uveitis, intraocular hypertension, glaucoma, and cataracts. Herein, we review the medical literature pertaining to ocular manifestations in gout and hyperuricemia and propose a possible association between ocular abnormalities, hyperuricemia, and gout, including their common risk factors and comorbidities.
An update on the genetic architecture of hyperuricemia and gout.
Merriman Tony R
Arthritis research & therapy
Genome-wide association studies that scan the genome for common genetic variants associated with phenotype have greatly advanced medical knowledge. Hyperuricemia is no exception, with 28 loci identified. However, genetic control of pathways determining gout in the presence of hyperuricemia is still poorly understood. Two important pathways determining hyperuricemia have been confirmed (renal and gut excretion of uric acid with glycolysis now firmly implicated). Major urate loci are SLC2A9 and ABCG2. Recent studies show that SLC2A9 is involved in renal and gut excretion of uric acid and is implicated in antioxidant defense. Although etiological variants at SLC2A9 are yet to be identified, it is clear that considerable genetic complexity exists at the SLC2A9 locus, with multiple statistically independent genetic variants and local epistatic interactions. The positions of implicated genetic variants within or near chromatin regions involved in transcriptional control suggest that this mechanism (rather than structural changes in SLC2A9) is important in regulating the activity of SLC2A9. ABCG2 is involved primarily in extra-renal uric acid under-excretion with the etiological variant influencing expression. At the other 26 loci, probable causal genes can be identified at three (PDZK1, SLC22A11, and INHBB) with strong candidates at a further 10 loci. Confirmation of the causal gene will require a combination of re-sequencing, trans-ancestral mapping, and correlation of genetic association data with expression data. As expected, the urate loci associate with gout, although inconsistent effect sizes for gout require investigation. Finally, there has been no genome-wide association study using clinically ascertained cases to investigate the causes of gout in the presence of hyperuricemia. In such a study, use of asymptomatic hyperurcemic controls would be expected to increase the ability to detect genetic associations with gout.
Definition of hyperuricemia and gouty conditions.
Bardin Thomas,Richette Pascal
Current opinion in rheumatology
PURPOSE OF THE REVIEW:To define gout conditions and hyperuricemia. RECENT FINDINGS:Gout is defined as an arthritic condition resulting from the deposition of monosodium urate (MSU) crystals in and/or around joints, following long-standing hyperuricemia. Several recent ultrasound studies disclosed MSU deposits in a large proportion of asymptomatic hyperuricemic patients. A gout condition defined by asymptomatic MSU deposits can therefore be individualized. Such asymptomatic deposits appear to precede the occurrence of flares, which seem to be triggered by mobilization of preformed crystals. Hyperuricemia appears to be the main, if not the only, risk factor for gout. Recent studies also support the view that hyperuricemia is an independent risk factor for renal and cardiovascular diseases. The level at which uricemia becomes abnormal is still disputed. This lack of consensus precludes comparison of studies using different definitions and impairs the understanding of gout by doctors and patients. We propose to define hyperuricemia as greater than 6 mg/dl, as the life-long risk of gout seems to start at this level. This definition is identical to the minimum uricemia target of urate-lowering drugs (ULDs). SUMMARY:Asymptomatic MSU crystals deposits can now be identified and precede the onset of gout flares. Defining hyperuricemia as greater than 6 mg/dl would have the advantage to give the same value for normal and ULD-targeted uricemia, which would facilitate patients' adherence to this target.
[HYPERURICEMIA AND POTENTIAL RISK OF CARDIOVASCULAR AND RENAL DISEASES].
Schils R,Krzesinski J M
Revue medicale de Liege
Besides the well accepted need to treat hyperuricemia associated with gout, some large observational studies and small prospective therapeutic trials have suggested that treating asymptomatic hyperuricemia, especially by xanthine oxidase inhibition, the enzyme producing uric acid, could be beneficial for cardiovascular and renal risk prevention. This article discusses the literature about this promising approach, which, however, requests prospective validation.
Screening for hyperuricaemia and gout: a perspective and research agenda.
Stamp Lisa,Dalbeth Nicola
Nature reviews. Rheumatology
The goal of a screening programme is to reduce an adverse health outcome in a defined population. Screening can be undertaken at several stages throughout the disease course: before the onset of disease, early in the course of the disease, or in established disease (for complications). In the setting of asymptomatic hyperuricaemia and gout, the aim of screening would be to identify those individuals with hyperuricaemia and therefore at risk of gout, with the aim of introducing interventions to prevent the onset of gout. Herein we consider the concepts of screening for hyperuricaemia and gout, potential screening methods, and target populations that might benefit from such an approach.
Hyperuricemia, gout, and cardiovascular disease: an update.
Abeles Aryeh M
Current rheumatology reports
Across the globe, both gout and hyperuricemia have become increasingly common over the last few decades. The burden of gouty disease is made heavier by its association with several comorbid conditions, including hypertension, cardiovascular disease, and chronic kidney disease. Accruing evidence from prospective studies suggests that gout is an independent risk factor for developing cardiovascular disease and for higher cardiovascular mortality. While asymptomatic hyperuricemia does not seem to be an independent risk factor for cardiovascular disease, increasing data implicates hyperuricemia as a risk factor for developing incidental hypertension. Important questions that remain unanswered include whether addressing asymptomatic hyperuricemia forestalls the onset of hypertension, and whether treating gout with urate-lowering agents improves cardiovascular outcomes. This article reviews the most recent data regarding the relationship between hyperuricemia, gout, hypertension, and cardiovascular disease, as well as emerging evidence as to whether treatment of hyperuricemia and gout improves cardiovascular outcomes.
[Hyperuricemia, gout and cardiovascular diseases].
Murray Karsten,Burkard Thilo
Therapeutische Umschau. Revue therapeutique
Hyperuricemia, gout as well as arterial hypertension and metabolic syndrom are highly prevalent and clinicians are frequently confronted with both conditions in the same patient. Hyperuricemia and gout are associated with cardiovascular comorbidities and a high cardiovascular risk. Despite coherent pathophysiological concepts, it remains to be determined, if this association is independent and causal. In daily clinical practice, cardiovascular risk factors should be thoroughly identified and consequently treated in all patients with hyperuricemia and gout. If preventive treatment of asymptomatic hyperuricemia with urate-lowering agents may improve cardiovascular risk and outcomes remains to be determined and is recommended only in special situations like young patients with severe hyperuricemia.
[Hyperuricemia. When and how to treat?].
Reuss-Borst M A
The prevalence of (asymptomatic) hyperuricemia and gout has substantially increased in recent decades. This development is due to fundamental lifestyle changes, dramatically rising prevalence of obesity and metabolic syndrome, as well as the increasing age of patients. Therefore, medical treatment of hyperuricemia has regained interest in recent years, in particular since after decades of therapeutic stagnation, new treatments of hyperuricemia have been approved or are currently being investigated in clinical trials. European and American guidelines/recommendations for treatment of hyperuricemia and gout have been updated and revised. Furthermore, the role of asymptomatic hyperuricemia as an (independent) cardiovascular risk factor is again under debate. This article provides assistance in integrating our present knowledge in a therapeutic context and summarizes currently recommended treatment strategies.
Treatment of asymptomatic hyperuricemia for the prevention of gouty arthritis, renal disease, and cardiovascular events: a systematic literature review.
Vinik Ophir,Wechalekar Mihir D,Falzon Louise,Buchbinder Rachelle,van der Heijde Désirée M,Bombardier Claire
The Journal of rheumatology. Supplement
OBJECTIVE:To systematically review available literature on treatment of hyperuricemia (HU) as a measure of preventing gouty arthritis, renal disease, or cardiovascular events in asymptomatic patients. METHODS:A systematic literature search was conducted in the Cochrane Library, Medline, Embase, clinical trials registries of the World Health Organization and the US National Institutes of Health, and abstracts from American College of Rheumatology/European League Against Rheumatism meetings, for interventional studies involving adults with no history of gouty arthritis, who were treated for HU. Outcomes of interest included gouty arthritis, renal disease (i.e., renal insufficiency, urate nephropathy, nephrolithiasis), and cardiovascular events (i.e., myocardial infarction, heart failure, ischemic stroke). RESULTS:A total of 3 studies met the inclusion criteria, 2 studies assessing the prevention of renal disease and 1 study evaluating the potential for delaying progression of preexisting renal disease. In hyperuricemic patients without renal disease, treatment resulted in increased estimated glomerular filtration rate. In hyperuricemic patients with preexisting renal disease, treatment resulted in no significant elevation of serum creatinine over a 1-year followup. However, differences in renal function between the treatment and no-treatment groups were not statistically significant in any of the identified studies. CONCLUSION:Very limited data are available on the treatment of HU in asymptomatic patients. There is currently insufficient empiric evidence to suggest that lowering serum uric acid level in asymptomatic patients with HU can prevent gouty arthritis, renal disease, or cardiovascular events.
Impact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment options.
Bardin Thomas,Richette Pascal
Gout, the most prevalent inflammatory arthritis worldwide, is associated with cardiovascular and renal diseases, and is an independent predictor of premature death. The frequencies of obesity, chronic kidney disease (CKD), hypertension, type 2 diabetes, dyslipidaemias, cardiac diseases (including coronary heart disease, heart failure and atrial fibrillation), stroke and peripheral arterial disease have been repeatedly shown to be increased in gout. Therefore, the screening and care of these comorbidities as well as of cardiovascular risk factors are of outmost importance in patients with gout. Comorbidities, especially CKD, and drugs prescribed for their treatment, also impact gout management. Numerous epidemiological studies have shown the association of asymptomatic hyperuricaemia with the above-mentioned diseases and cardiovascular risk factors. Animal studies have also produced a mechanistic approach to the vascular toxicity of soluble urate. However, causality remains uncertain because confounders, reverse causality or common etiological factors might explain the epidemiological results. Additionally, these uncertainties remain unsolved despite recent studies using Mendelian randomisation or therapeutic approaches. Thus, large randomised placebo-controlled trials are still needed to assess the benefits of treating asymptomatic hyperuricaemia.
An update on the genetics of hyperuricaemia and gout.
Major Tanya J,Dalbeth Nicola,Stahl Eli A,Merriman Tony R
Nature reviews. Rheumatology
A central aspect of the pathogenesis of gout is elevated urate concentrations, which lead to the formation of monosodium urate crystals. The clinical features of gout result from an individual's immune response to these deposited crystals. Genome-wide association studies (GWAS) have confirmed the importance of urate excretion in the control of serum urate levels and the risk of gout and have identified the kidneys, the gut and the liver as sites of urate regulation. The genetic contribution to the progression from hyperuricaemia to gout remains relatively poorly understood, although genes encoding proteins that are involved in the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome pathway play a part. Genome-wide and targeted sequencing is beginning to identify uncommon population-specific variants that are associated with urate levels and gout. Mendelian randomization studies using urate-associated genetic variants as unconfounded surrogates for lifelong urate exposure have not supported claims that urate is causal for metabolic conditions that are comorbidities of hyperuricaemia and gout. Genetic studies have also identified genetic variants that predict responsiveness to therapies (for example, urate-lowering drugs) for treatment of hyperuricaemia. Future research should focus on large GWAS (that include asymptomatic hyperuricaemic individuals) and on increasing the use of whole-genome sequencing data to identify uncommon genetic variants with increased penetrance that might provide opportunities for clinical translation.
Asymptomatic hyperuricemia: is it time to intervene?
Paul Binoy J,Anoopkumar K,Krishnan Vinod
Whether to treat hyperuricemia uncomplicated by articular gout, urolithiasis, or uric acid nephropathy is an exercise in clinical judgment and universal agreement is lacking. Patients with coronary artery disease, chronic kidney disease, and early onset hypertension with persistent hyperuricemia are likely to be benefited with urate-lowering therapy. The paradigm of the causative association of hyperuricemia with cardiovascular and chronic kidney diseases seems to have progressed from skepticism to increasing evidence of a true relationship. Although such evidences are mounting, they are not enough to support pharmacotherapy for all patients with asymptomatic hyperuricemia. Further studies are needed to determine which patients are likely to get beneficial effects from pharmacotherapy and the minimum threshold of uric acid level required to experience clinical benefits.
Treatment of asymptomatic hyperuricemia complicated by renal damage: a controversial issue.
Hu Chun,Wu Xiaoyan
International urology and nephrology
The prevalence of asymptomatic HUA is increasing year after year. HUA is a risk factor for the occurrence and development of renal diseases. However, the role of urate-lowering therapy in asymptomatic HUA complicated by renal damage is still controversial. In some experiments, the treatment of asymptomatic HUA complicated by renal damage may delay the progression of kidney damage. In addition, there is increasing evidence, suggesting that elevated serum uric acid is an independent risk factor for kidney disease. However, in other studies, uric acid-lowering therapy did not improve renal function, and uric acid levels could not be used as an independent predictor for CKD development. Further experimental studies are needed to determine the starting threshold and target value of asymptomatic HUA complicated by renal damage. At the same time, confirmation of the benefits of urate-lowering therapy for kidneys requires studies with larger samples and high-quality RCTs.
How should we manage asymptomatic hyperuricemia?
Joint bone spine
The definition of asymptomatic hyperuricemia remains unclear, as no consensus exists about the serum urate cutoff or the relevance of ultrasound findings. Comorbidities associated with hyperuricemia have increased in frequency over the past two decades. Hyperuricemia (and/or gout) may be a cause or a consequence of a comorbidity. Whereas epidemiological studies suggest that hyperuricemia may be linked to cardiovascular, metabolic, and renal comorbidities, Mendelian randomization studies have not provided proof that these links are causal. Discrepancies between findings from observational studies and clinical trials preclude the development of recommendations about the potential benefits of urate-lowering therapy (ULT) in individual patients with asymptomatic hyperuricemia. The risk/benefit ratio of ULT is unclear. The risk of developing gout, estimated at 50%, must be weighed against the risk of cutaneous and cardiovascular side effects of xanthine oxidase inhibitors. The need for optimal comorbidity management, in contrast, is universally accepted. Medications for comorbidities that elevate urate levels should be discontinued and replaced with medications that have the opposite effect. Therapeutic lifestyle changes, weight loss as appropriate, and sufficient physical activity are useful for improving general health. Whether ULT has beneficial effects on comorbidities will be known only when well-powered interventional trials with relevant primary endpoints are available.
Urate-Lowering Agents in Asymptomatic Hyperuricemia: Role of Urine Sediment Analysis and Musculoskeletal Ultrasound.
Viggiano Davide,Gigliotti Giuseppe,Vallone Gianfranco,Giammarino Anna,Nigro Michelangelo,Capasso Giovambattista
Kidney & blood pressure research
Current urate-lowering therapy (ULT) includes three direct acting drugs (allopurinol, febuxostat, Rasburicase) and at least four 'indirect' drugs with other important targets (canagliflozin, losartan, fenofibrate and sevelamer). Moreover, the alcalinization of urines using bicarbonate can be used to dissolve urate crystals and the clinician may discontinue several drugs are known to increase serum levels of uric acid, such as diuretics, aspirin, cyclosporine, theophylline, mycophenolate and ACE inhibitors. While there is a consensus to start ULT in cases of symptomatic hyperuricemia (gout, urate-nephrolithiasis), the very frequent conditions of asymptomatic hyperuricemia remains a major conundrum. The effect of asymptomatic hyperuricemia on kidney function has had fluctuating positions over decades. The conflicting results might indicate: (i) the presence of counterbalancing positive and negative effects on kidney function of both serum uric acid and urate-lowering agents, (ii) the presence of a subpopulation of patients, as yet unidentified, which could truly benefit from a urate-lowering therapy. Therefore, today the treatment of asymptomatic hyperuricemia is not recommended nor excluded by current guidelines. Here we suggest that a possible guide for the treatment of asymptomatic hyperuricemia might be the presence of urate crystals in the urine sediment and/or signs of asymptomatic articular damage by urates, identified by musculo-skeletal ultrasound. Moreover, a watchful analysis of the trend in creatinine/eGFR, proteinuria or urate levels might also guide the clinician. Initiation of ULT and follow-up in cases of asymptomatic hyperuricemia should consider urine sediment analysis, musculoskeletal ultrasound and trends in creatinine, proteinuria and serum urate levels.
Urate-lowering therapy for asymptomatic hyperuricaemia: A need for caution.
Stamp Lisa,Dalbeth Nicola
Seminars in arthritis and rheumatism
OBJECTIVE:The observed associations of hyperuricaemia with hypertension, cardiovascular disease and kidney disease are receiving increasing interest. The potential role of urate-lowering therapy in the management of these "non-gout diseases" has been raised, and in some countries it is already recommended. However, there is no consistent definition of hyperuricaemia or asymptomatic hyperuricaemia, much remains unknown about the causal role of urate in these "non-gout diseases" and there is currently a lack of evidence about the effects of urate lowering on disease progression. In addition, there is potential for serious adverse effects associated with urate-lowering therapies with recent evidence suggesting that asymptomatic hyperuricaemia may be an independent risk factor for the potentially fatal allopurinol hypersensitivity syndrome. METHODS:Pubmed was searched in January 2016 using the search term "asymptomatic hyperuricaemia". RESULTS AND CONCLUSIONS:Herein, we discuss the issues related to treating asymptomatic hyperuricaemia, which at present seems premature.
Asymptomatic hyperuricaemia: a silent activator of the innate immune system.
Joosten Leo A B,Crişan Tania O,Bjornstad Petter,Johnson Richard J
Nature reviews. Rheumatology
Asymptomatic hyperuricaemia affects ~20% of the general population in the USA, with variable rates in other countries. Historically, asymptomatic hyperuricaemia was considered a benign laboratory finding with little clinical importance in the absence of gout or kidney stones. Yet, increasing evidence suggests that asymptomatic hyperuricaemia can predict the development of hypertension, obesity, diabetes mellitus and chronic kidney disease and might contribute to disease by stimulating inflammation. Although urate has been classically viewed as an antioxidant with beneficial effects, new data suggest that both crystalline and soluble urate activate various pro-inflammatory pathways. This Review summarizes what is known about the role of urate in the inflammatory response. Further research is needed to define the role of asymptomatic hyperuricaemia in these pro-inflammatory pathways.