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Current
Rheumatology Reviews
ISSN: 1573-3971
Current Rheumatology Reviews
Volume 7, Number 2, May 2011
Contents
Hot Topic
Gout
Guest Editor: Tony R. Merriman
Editorial: Pp. 94-96
Diagnosis of Gout: Considering Clinical and Research Settings Pp. 97-105
William J. Taylor
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Epidemiology of Gout: Perspectives from the Past Pp. 106-113
Hallie R. Buckley
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Genetic and Environmental Risk Factors in Hyperuricaemia and Common Gout Pp. 114-122
Tony R. Merriman and Nicola Dalbeth
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Urate Transport: Regulators of Serum Urate Levels in Humans Pp. 123-131
Naohiko Anzai, Promsuk Jutabha, Toru Kimura and Toshiyuki Fukutomi
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Acute Gout: The Inflammasome Pp. 132-140
Greta Guarda, Amir S. Yazdi, Marthe C. D’Ombrain and Stefan K. Drexler
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Existing and Emerging Therapies for Acute Gout and Long-Term Urate Lowering Pp. 141-151
Lisa K. Stamp and Peter T. Chapman
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Mechanisms of Bone Erosion in Chronic Gout: Lessons Learned from Other Erosive Arthropathies Pp. 152-161
Ashika Chhana and Nicola Dalbeth
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Uric acid and Metabolic Syndrome: What is the Relationship? Pp. 162-169
Miguel A. Lanaspa, Yuri Y. Sautin, A. Ahsan Ejaz, Magdalena Madero, MyPhuong Le, Jacek Manitius, Laura Gabriela Sanchez-Lozada, Takahiko Nakagawa and Richard J. Johnson
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Societal and Cultural Attitudes to Gout: An Important Consideration in the Successful Management of Gout among Māori in Aotearoa New Zealand Pp. 170-180
Peter J. Gow, Virginia F. Gow and John Waldon
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Abstracts
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Diagnosis of Gout: Considering Clinical and Research Settings
William J. Taylor
The diagnosis of gout is usually straightforward and should normally rely upon the identification of monosodium urate crystals in synovial fluid. EULAR have recently developed consensus recommendations regarding the diagnosis of gout. Where examination of synovial fluid is not possible or impractical, the best approach differs depending upon the context: in clinical research, classification criteria are necessary whereas in clinical practice, all available information should be carefully weighed and considered by the physician. A number of clinical features are useful pointers towards the diagnosis of gout and ultrasound is emerging as a useful diagnostic tool. The finding of hyperechoic enhancement of the superficial margin of the hyaline cartilage is a sensitive and specific feature of gout, although the performance of ultrasound in early disease is unclear. Serum uric acid is not a useful test for the diagnosis of gout but is very important in the long-term management. The 1977 American Rheumatism Association classification criteria have many shortcomings and improved criteria are urgently required for epidemiology and clinical research. The complete diagnostic evaluation may involve assessment of 24-hour urinary excretion of uric acid in a few selected patients and all patients should be evaluated for common comorbidities especially the metabolic syndrome and risk factors for cardiovascular disease.
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Epidemiology of Gout: Perspectives from the Past
Hallie R. Buckley
Gout is an ancient disease with a prevalence that has increased dramatically worldwide over recent years. This paper briefly reviews the recent literature on the frequency of gout and geographic variation in contemporary populations and attempts to provide a synthesis of reported cases of gout in the past. The palaeopathological evidence of gout in the Asia Pacific region is focussed on and the biocultural context of food and ritual influencing the selection of hyperuricaemia is discussed. It is proposed that the prehistoric selection pressures leading to the high prevalence of diabetes and other ‘diseases of modernisation’ may also, at least in part, explain the high frequencies of hyperuricaemia and gout in modern Pacific Islanders.
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Genetic and Environmental Risk Factors in Hyperuricaemia and Common Gout
Tony R. Merriman and Nicola Dalbeth
Gout results from hyperuricaemia. The most important cause of hyperuricaemia is reduced excretion of uric acid in the urine. Genome-wide association scans for genes regulating serum urate concentrations have identified two major regulators – the renal urate transporters SLC2A9 and ABCG2. The risk variants at each gene approximately double the risk for gout in people of Caucasian ancestry, with the urate and fructose transporter SLC2A9 also resulting in higher risk for gout in people of Polynesian ancestry, a diverse population characterized by a high prevalence of gout. Ongoing genetic association studies are identifying and confirming other genes (URAT1, OAT4, NPT1, PDZK1, GCKR) controlling serum urate concentrations; although genome-wide association studies in gout per se await recruitment of suitable case sample sets. The recent increase in gout incidence can only be explained by a change in the environment. One factor that fulfills most of the requirements for confirmation of an etiological role in gout is fructose. Fructose raises serum urate levels, which is exacerbated in people with genetic variants that reduce renal urate excretion, thus increasing the risk of gout. Use of GWAS approaches and application of new genomics technologies such as next-generation sequencing to very large well-phenotyped gout sample sets will enable identification of further genetic risk factors in gout. Intervention studies in cohorts characterized for genetic risk factors are needed to prove a direct link for environmental agents such as fructose in gout etiology.
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Urate Transport: Regulators of Serum Urate Levels in Humans
Naohiko Anzai, Promsuk Jutabha, Toru Kimura and Toshiyuki Fukutomi
Urate (uric acid) is the final product of purine metabolism, and its antioxidant capacity has drawn attention recently for its protective role against oxidative stress. However, hyperuricemia has a known association with onset of illnesses such as gout and cardiovascular diseases. Renal urate transport mechanisms are known to be major determinants of serum urate levels, but the molecular mechanisms involved have not yet been fully elucidated. Molecular identification of a kidney-specific urate transporter SLC22A12 (URAT1) by our research group in 2002 marked the start of a subsequent compilation of information on several different molecules contributing to urate transport by the kidneys. In addition, recent genome-wide association (GWA) studies have contributed to the detection of novel candidate genes related to uric acid metabolism such as SLC2A9 (GLUT9/URATv1), ABCG2 (BCRP), SLC17A1 (NPT1), SLC17A3 (NPT4) and PDZK1. Furthermore, use of urate transporter gene-modified mice for Slc22a12 and Slc2a9 may provide clues for understanding the physiological role of each transporter. Results of recent studies on urate transport with emphasis on the relation to serum urate disorders are described in this report.
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Acute Gout: The Inflammasome
Greta Guarda, Amir S. Yazdi, Marthe C. D’Ombrain and Stefan K. Drexler
Gout is one of the most common and painful forms of arthritis in humans with a growing incidence and prevalence over the last decades. Recent studies into the pathophysiology of acute gout have revealed that MSU (monosodium urate), the crystalline form of uric acid, is recognized by immune cells as a danger signal and can initiate an inflammatory response. This response is orchestrated by the intracellular pattern-recognition receptor NLRP3, which upon exposure to MSU, forms a cytosolic multiprotein-complex called the inflammasome, leading to the activation of caspase-1. Caspase-1 then cleaves the highly pro-inflammatory cytokines interleukin (IL)-1β and IL-18, leading to the secretion of their biologically active forms and culminating in an acute gout attack. This newfound molecular understanding of the pathology of gout has seen the introduction of IL-1 inhibitors as an improved treatment for acute gout with reduced side effects compared to conventional gout therapies.
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Existing and Emerging Therapies for Acute Gout and Long-Term Urate Lowering
Lisa K. Stamp and Peter T. Chapman
Untreated or inadequately treated gout results in recurrent acute gouty attacks (one of the most painful forms of acute arthritis), progressive joint damage, formation of tophi, loss of function and disability. The management of gout comprises several key areas. Firstly an accurate diagnosis is required, secondly, long-term urate lowering is required to dissolve monosodium urate crystals and prevent recurrent attacks and subsequent joint damage and disability, thirdly adequate prophylaxis against acute attacks during the introduction of urate lowering therapy is required and finally acute attacks need to be rapidly and effectively controlled. Therapies for acute attacks include non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids or colchicine. The choice of agent depends on the presence of co-existing medical conditions and therapies. Early institution of therapy is critical to prompt resolution of acute gout. The goal of prophylactic therapy is sustained reduction of serum urate <6mg/dL the minimum concentration required to dissolve monosodium urate crystals and to reliably prevent crystal precipitation. This “treat-to-target” approach is being increasingly practised. Allopurinol, which prevents the production of uric acid, is the most widely used agent. Alternatives include the uricosuric drugs, probenecid and benzbromarone. Each has its limitations and novel therapies have recently been developed. These include anti-interleukin-1 (acute gout), and febuxostat and the recombinant uricases (chronic tophaceous gout). This review will examine existing and emerging therapies in the management of gout.
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Mechanisms of Bone Erosion in Chronic Gout: Lessons Learned from Other Erosive Arthropathies
Ashika Chhana and Nicola Dalbeth
Gout is an inflammatory arthritis caused by deposition of monosodium urate (MSU) monohydrate crystals within the joint. Bone erosion is a frequent manifestation of chronic tophaceous gout, and leads to joint damage and deformity, with subsequent disability. This review summarises current understanding of bone remodelling, bone erosion in other erosive arthropathies and related conditions, and bone erosion in chronic gout. In particular, recent research implicating tophus invasion into bone and disordered osteoclastogenesis in the pathogenesis of bone erosion in gout is emphasised.
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Uric acid and Metabolic Syndrome: What is the Relationship?
Miguel A. Lanaspa, Yuri Y. Sautin, A. Ahsan Ejaz, Magdalena Madero, MyPhuong Le, Jacek Manitius, Laura Gabriela Sanchez-Lozada, Takahiko Nakagawa and Richard J. Johnson
An elevated uric acid is common in subjects with insulin resistance and obesity, and is in effect part of the metabolic syndrome complex. In this paper we review evidence for a potential causal role of uric acid in the metabolic syndrome. While some studies suggest that uric acid may simply be a consequence of the presence of oxidative stress or hyperinsulinemia present in subjects with metabolic syndrome, there is increasing evidence that uric acid could have a contributory causal role. First, an elevated serum uric acid often precedes the development of obesity and metabolic syndrome. Second, experimental and clinical studies provide increasing evidence that excessive intake of fructose, primarily in the form of added sugars, may have a key role in the development of metabolic syndrome. Fructose increases uric acid levels, and lowering uric acid in fructose fed rats can improve insulin resistance and features of metabolic syndrome. The mechanism may be via the improvement in endothelial function and due to direct actions of uric acid on adipocytes. However, the lowering of uric acid in human subjects ingesting high doses of fructose was associated with improvement in blood pressure but not in other features of metabolic syndrome. Clearly more studies are needed to better understand the role of uric acid in metabolic syndrome, but it seems likely that uric acid may have a role as both a marker and potential modifier of the metabolic syndrome.
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Societal and Cultural Attitudes to Gout: An Important Consideration in the Successful Management of Gout among Māori in Aotearoa New Zealand
Peter J. Gow, Virginia F. Gow and John Waldon
Although there has been a steady increase in the number of literature reviews on the epidemiology, pathophysiology, diagnosis and treatment of gout there has not been a similar output on the societal and cultural aspects, following the pivotal work of Porter and Rousseau, Gout: The Patrician Malady, which chronicled the socio-political aspects of gout from antiquity to the 1930s. Several excellent reviews which do discuss these issues include the history of gout from 2640BC up to the present, and a historical perspective on gout in women, but a survey of magazine articles and newspapers provides a useful additional perspective on social and cultural attitudes surrounding gout over the past century.
Despite advances in management, there are notable similarities between the impact of gout in society today, and in the past, including family and whānau life, employment, sport and recreation, and political activities. One notable difference is that the over-nourished nineteenth century sufferers of gout from the opulent aristocracy, have been replaced in the twenty first century by patients who are frequently from deprived communities. This article will review these aspects, including a discussion on societal and cultural impacts of gout on Māori, the indigenous population of New Zealand. Political and economic influences, such as the adverse effects of colonisation, compound an emerging genetic predisposition to hyperuricemia and gout in Māori. A response to a gout diagnosis arising from a sense of embarrassment (whakamā), contrasting with the social elevation once accorded to gout, may also delay effective treatment.
Other cultural factors influencing gout management include the perceptions of health and illness by both providers and recipients of health services, and the congruence of these perceptions, as demonstrated in our preliminary studies, though further research is required. The prioritisation of healthcare costs versus other priorities by the patients, as well as the appeal of alternatives to conventional medication may also have an impact. Unless such sociocultural factors are recognised and negotiated with the patient, family and whānau, in an atmosphere of mutual trust, the success of secondary prevention of chronic disease by either self management or the use of prescribed medications may well be thwarted, no matter how effective these might have been in randomised controlled clinical trials. |
