Current Rheumatology Reviews - Volume 7, Issue 2, 2011

This Hot Topic issue focuses on gout, for the first time in Current Rheumatology Reviews. The pathogenesis of gout encompasses many pathways, all of relevance for prevention and treatment, all with genetic and environmental risk factors, including but not limited to, production of urate in the blood, renal urate transport, monosodium urate crystal formation, activity of the inflammasome, bone erosion and the relationship with the metabolic syndrome. Collectively, the nine review articles in this issue take a broad-brush approach to reviewing gout. Gout is not only a manifest form of arthritis, but it's etiology is inter-twined with the metabolic syndrome, a constellation of metabolic perturbations (dyslipidemia, hypertension, insulin resistance, central adiposity, renal disease) that increase the risk of cardiovascular disease and type 2 diabetes. Common risk factors, both environmental and genetic, are likely to be shared by this suite of metabolic disorders. The relationship of hyperuricaemia and gout with the metabolic syndrome is a thread linking many of the articles in this Hot Topic issue. A second commonality will be revealed at the end of this editorial. The issue begins with an article by Taylor [1] on current procedures for the diagnosis of gout, comparatively straightforward when based upon the identification of monosodium urate crystals in synovial fluid. However this is not always practical, meaning that classification criteria are required in clinical research, whereas in clinical practice additional factors can be considered. The article describes the potential of ultrasound as a diagnostic tool. Classification of gout is important as suboptimal classification does impact on the power of clinical research [2]. The next two articles paint a picture of the interaction of environmental and genetic risk factors in gout. Buckley [3] describes paleopathological evidence for a higher incidence of gout in ancient Pacific cultures than in past European cultures. Over the past century the incidence of gout in these populations has increased in response to a changing environment but with a parallel dichotomy, with Polynesian populations now exhibiting the highest prevalence worldwide. Historically, gout was associated with individuals of higher status whereas there is no such distinction now. Fructose is a very strong candidate environmental risk factor, raising serum urate levels as a consequence of it's catabolism and perhaps by interfering with renal uric acid excretion. Gene association studies, described by Merriman and Dalbeth [4], show that genetic variation in urate transporters (such as SLC2A9 and ABCG2) control serum urate levels and influence the risk of gout in diverse populations. The epidemiological and genetic data are consistent with fructose and other environmental factors (such as obesity and purinerich food) raising serum urate levels, which is exacerbated in people with genetic variants that reduce urate excretion, thus increasing the risk of gout. An intriguing association between serum urate levels and the glucokinase regulator gene suggests a possible genetic link between gout, dyslipidemia and diabetes. Two articles focus on key regulatory steps in gout, namely renal urate transport and the inflammasome [5,6]. As described by Anzai et al. [5], the previous ten years has seen the identification and characterisation of several renal urate transporters, including the kidney-specific URAT1 (SLC22A12) and several organic anion transporters, whereas genetic approaches have identified the urate transporters SLC2A9 and ABCG2 [4]. Collectively, these and other molecules, are referred to as the urate ‘transportasome’, a molecular machine central to gout and other disorders of urate metabolism. The development of unique mouse lines, with tissue-specific expression of urate transporters is allowing the dissection of the transportasome, in a fashion not possible in humans. The gout ‘NALP3’ inflammasome is the subject of the review by Guarda et al. [6]. This inflammasome is another molecular machine in the innate immune system that responds to signals initiated by urate crystals. The inflammasome produces mature interleukin-1β, triggering an inflammatory cascade that culminates in a painful but self limiting acute attack of gout. Intriguingly, the NALP3 inflammasome has very recently been shown to be activated by cholesterol crystals [7], suggesting a possible link between gout and dyslipidemia. The article by Stamp and Chapman [8] reviews current clinical practice in management of gout. Central to clinical practice is an accurate diagnosis and treatment of the acute attack, followed by a urate-lowering therapy (typically allopurinol, that inhibits the production of urate in the blood) alongside adequate prophylaxis against acute gout attacks during the introduction of the urate-lowering therapy. Promising for the management of acute attacks are biologics that inhibit the action of interleukin- 1β. The potent but not widely available drug benzbromarone, that stimulates renal urate excretion, will retain a role in patients with renal impairment. The interleukin-1β biologics and benzbromarone target the product of the inflammasome and renal urate transportasome, respectively, emphasizing the importance to gout of these molecular machines [6,7]. Chhana and Dalbeth [9] discuss mechanisms of bone erosion in chronic gout, a source of disability when gout is poorly managed. Owing to the paucity of research in this area, they draw on knowledge of the processes of bone erosion in other more heavily researched arthropathies (for example, rheumatoid arthritis and wear debris-induced osteolysis). Therapies targeting the osteoclast show promise, but research in this area is hindered by the absence of a suitable animal model of tophaceous gout. The penultimate article directly addresses the relationship of hyperuricemia with the metabolic syndrome. Lanaspa et al. [10] point out that elevated uric acid was considered a part of the metabolic syndrome in the early part of the twentieth century, when diabetes was rare. However, elevated uric acid is no longer considered part of the metabolic syndrome. In recent decades the relationship between uric acid, gout and the metabolic syndrome has again come under the spotlight, with the key question: ‘Is uric acid causal or a consequence of the metabolic syndrome?’ Lanaspa et al. [10] address this question, concluding that the answer is ‘both of the above’. Important in considering the relationship between hyperuricemia and metabolic syndrome is the context of action of uric acid - is it influencing oxidative stress within the cell? Is it acting as a proinflammatory molecule? Is it having vasoactive effects? The role of fructose in these processes is also evaluated by Lanaspa et al. [10]. Lanaspa et al. [10] sensibly focused on hyperuricemia and metabolic syndrome and did not address the relationship with gout per se, where associated localized and systemic inflammation may prove to add an extra dimension to the relationship with metabolic syndrome. As Stamp and Chapman [8] emphasise, we need to integrate gout management with treatment of metabolic comorbidities. This approach will require a sound evidence base, derived from multidisciplinary and longitudinal research, including molecular understanding of the role of the environment in the pathogenesis of gout and co-morbidities.....

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.

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.

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.

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.

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.

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.

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.

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.

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 whanau 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 Maori, 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 Maori. A response to a gout diagnosis arising from a sense of embarrassment (whakama), 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 whanau, 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.