Major progress has been made in the past decade in understanding the pathogenesis and treatment of gout. These advances include identification of the genetic and environmental risk factors for gout, recognition that gout is an important risk factor for cardiovascular disease, elucidation of the pathways regulating the acute gout attack and the development of novel therapeutic agents to treat both the acute and chronic phases of the disease. This review summarises these advances and highlights the research agenda for the next decade.
Statistics from Altmetric.com
Major advances in understanding the pathogenesis and treatment of gout have been made in the past decade. Key highlights include identification of the genetic and environmental risk factors for gout, recognition that gout is an important risk factor for cardiovascular disease (CVD), elucidation of the pathways regulating the acute gout attack and the development of novel therapeutic agents to treat both the acute and chronic phases of the disease. Here, we discuss these advances and future implications for research and clinical practice.
The genetic basis of hyperuricaemia and identification of novel urate transporters
It has been recognised for decades that rare, monogenic disorders typically of urate production are associated with severe hyperuricaemia, juvenile-onset gout, renal disease and neurodevelopmental disorders. In the past 5 years, major advances have been made in understanding the molecular and complex genetic basis of adult-onset hyperuricaemia and gout. Genome-wide association studies of hyperuricaemia have consistently reported a strong association between common variants of the SLC2A9 gene and serum urate concentrations.1,–,4 Genetic variants within this gene explain up to 5% of the variance in serum urate concentrations.5 Case–control studies have reported odds ratios for hyperuricaemia for SLC2A9 variants ranging from 1.7 to 1.9 and 1.3 to 5.0 for gout (summarised in Dalbeth and Merriman).6 The SLC2A9 gene encodes a known glucose and fructose transporter solute carrier family 2, member 9 protein (SLC2A9, also known as GLUT9), which is also a high capacity urate transporter.7 Two isoforms of this transporter exist on the proximal renal tubular cells; the short isoform on the apical membrane and the long isoform on the basolateral membrane.8 The presence of glucose or fructose promotes urate transport by this receptor, which ultimately facilitates the reabsorption of urate from the proximal renal tubule.7 Although benzbromarone inhibits this transporter at high concentrations, other currently available uricosuric agents do not alter its function.7 SLC2A9 is also expressed in other tissues including the human liver and in chondrocytes; the role of this transporter in other organs is currently unclear.
In addition to SLC2A9, other potential genetic regulators of serum urate concentrations have been confirmed or identified in a meta-analysis of genome-wide association studies comprising 28 141 participants of European ancestry3 (table 1). These include genes for recently identified urate transporters present on the apical membrane of the proximal renal tubular cells including human ATP-binding cassette, subfamily G, 2 (ABCG2), which encodes for ABCG2, SLC22A12, which encodes for urate anion exchanger 1 (URAT1), SLC22A11, which encodes for organic anion transporter 4 (OAT4) and SLC17A1, which encodes renal sodium phosphate transport protein 1 (NPT1). It should be noted that except for SLC2A9, the genetic variants identified to date each explain less than 1% of the variance in serum urate concentrations. Furthermore, for many of the newly identified genetic variants, the risks related to gout have not yet been demonstrated9 (table 1).
CVD, hypertension and hyperuricaemia/gout
The past decade has also seen increased awareness and recognition of the interactions between CVD and hyperuricaemia/gout. Numerous prospective cohort studies of people with high cardiovascular risk have reported that serum urate is an independent risk factor for CVD (including all-cause mortality, cardiovascular events, cardiovascular mortality and stroke mortality) (reviewed in Baker et al).10 Analysis of the Multiple Risk Factor Interventional Trial demonstrated that a diagnosis of gout is associated with cardiovascular events such as myocardial infarction and death related to CVD, particularly in those patients with persistent hyperuricaemia.11 12 Similar findings were reported in the Health Professionals Follow-Up Study; in men without previous coronary heart disease at enrolment, the multivariate relative risk for those with gout compared with those without gout was 1.28 for total mortality, 1.38 for cardiovascular death and 1.55 for fatal coronary heart disease.13
The underlying reasons for these observations are unclear at present. One potential mechanism relates to the relationship between hypertension and hyperuricaemia. Animal models have shown that modest hyperuricaemia leads to renal microvascular and tubulointerstitial disease, activation of the renin–angiotensin system and elevated blood pressure, which is reversed by urate-lowering therapy (ULT).14 These experimental observations have been validated in a recent short-term clinical trial of adolescents with newly diagnosed hypertension and hyperuricaemia, which demonstrated that allopurinol reduces blood pressure.15 Other potential explanations for the relationship between hyperuricaemia/gout and CVD include adverse effects of serum urate or circulating inflammatory mediators on endothelial function. Low grade inflammation, even in the absence of an acute gout flare, has been demonstrated in the joints of patients with chronic gout,16 and it is possible that this inflammation contributes to accelerated atherosclerosis in patients with gout. It is unlikely that this association is related to a shared genetic risk related to both hyperuricaemia and CVD, as genes associated with gout, such as SLC2A9, ABCG2 and the other genes identified in the genome-wide associations studies of serum urate concentrations, do not show association with coronary artery disease.9 17
Environmental factors associated with the development of gout
A series of papers clarifying the role of dietary factors in the past decade have provided new insights into the environmental factors contributing to the development of gout. Intensive analysis of the Health Professionals Follow-Up Study, led by Hyon Choi, has addressed a number of risk factors previously suspected to be involved in the pathogenesis of this disease (table 2). Many of these observations were confirmed by analysis of serum urate concentrations in the NHANESIII nutritional survey and other cross-sectional studies (table 2). This work has confirmed that weight gain, obesity and the ingestion of beer, spirits, meat and seafood, fructose and sugar-containing drinks are risk factors for the development of gout.18,–,21 Protective dietary factors have also been identified, including weight loss and the ingestion of low-fat dairy products, vitamin C and coffee.18 20 22 23 Other dietary factors have been shown to be neutral as risk factors for the development of gout, including the intake of wine, tea, diet soft drinks, high-fat dairy products and purine-rich vegetables.19,–,21 23
The reported relationship between fructose ingestion and hyperuricaemia/gout is of particular interest, given recent experimental data indicating that some features of the fructose-induced metabolic syndrome can be prevented by reducing serum urate concentrations. In a short-term clinical trial, high doses of fructose induced many features of the metabolic syndrome (elevated blood pressure, urate, triglycerides, fasting insulin and homeostasis model assessment and reduced high-density lipoprotein cholesterol) within 2 weeks, and ULT with allopurinol prevented increases in blood pressure, reduced low-density lipoprotein cholesterol and prevented the increase in newly diagnosed metabolic syndrome associated with fructose ingestion.24
Mechanisms of inflammation and the inflammasome in acute gout
A major question in the gout field is how monosodium urate (MSU) crystals trigger inflammation and how is this inflammatory process regulated. There is evidence that multiple cell types participate in the acute inflammatory reaction to MSU crystals, and the roles of monocytes/macrophages, neutrophils and mast cells have been the best studied.25,–,27 Contact between cells and MSU crystals leads to a release of inflammatory mediators such as nitric oxide and prostaglandins, pro-inflammatory cytokines such as interleukin 1beta (IL-1β) and tumour necrosis factor alpha (TNFα), as well as cell death. This process is rapid and peaks at approximately 1–2 days. There follows afterwards a phase of spontaneous resolution. The downregulatory mechanisms involved are only partly understood, and include the production of the anti-inflammatory cytokine transforming growth factor beta.28 Recent advances in our understanding of the regulation of IL-1β production by the ‘inflammasome’ have provided additional insights into what may be a key step in the initiation of the inflammatory process.
The term ‘inflammasome’ was coined in 2002 to describe an intracellular proteolytic complex that processes pro-IL-1β (35 kd) to active IL-1β (17 kd form). This complex can have different forms, but the prototypic inflammasome is composed of caspase-1, apoptotic speck protein and a protein of the nucleotide-binding oligomerisation domain, leucine rich repeat and pyrin domain (NLRP) family. Its substrates, apart from IL-1β, include IL-18 and possibly IL-33, cytokines that belong to the IL-1 family (reviewed in Martinon et al).29 The NLRP component is thought to act as a sensor, either of exogenous or endogenous danger signals generated during infection and/or cell stress, to initiate assembly of the complex, eventually leading to dimerisation and activation of the caspases. To date, three inflammasomes have been identified: the NLRP1, the NLRP3 and the interleukin converting enzyme protease activating factor inflammasome, and in the context of gout and crystal-induced inflammation, the NLRP3 inflammasome is the most relevant.
Medical interest in the inflammasomes was ignited by the identification of mutations in the NLRP3 gene as the molecular basis of the hereditary autoinflammatory condition now known as cryopyrin-associated periodic syndromes. The mutation results in dysregulated IL-1β production due to constitutive activity of the NLRP3 inflammasome, and accounts for clinical features such as fever, arthritis, rash and central nervous system disease.30 This was confirmed by the results of treatment with IL-1 inhibitors, which effectively controlled the signs and symptoms of the disease.31 32 The next major discovery was that MSU and calcium pyrophosphate dehydrate crystals activate macrophages to secrete IL-1β by the NLPR3 inflammasome.33 In the absence of the components of this complex, secretion of active IL-1β is blocked, suggesting that it may be a regulator of gouty inflammation. A proof-of-concept study using IL-1Ra as an inhibitor showed remarkable effects in acute gout,34 and controlled clinical trials with different inhibitors are ongoing (see below). Current studies implicate inflammasome activation in a remarkable number of different pathologies, ranging from infectious disease to asbestosis and diabetes. These findings will require confirmatory studies in the human disease setting, but suggest that the inflammasome could be involved in myriad disease-associated inflammatory processes.
The discovery of the inflammasome leads to further questions: how is the inflammasome regulated and does this have clinical relevance? A number of intracellular mediators appear to be involved in controlling activation of the inflammasome, but the molecular pathways that link them together have not been entirely resolved. Extracellular ATP has been shown to activate the inflammasome by binding to the P2X7 receptor, which in turn regulates the ion channel pannexin-1.35 Potassium efflux from the cell, as well as changes in intracellular calcium, are also capable of activating the NLRP3 inflammasome.36 One hypothesis is that the generation of reactive oxygen species (ROS) following cell contact with danger signals may be an intermediate step, as inhibitors of ROS attenuated caspase-1 activation and IL-1β release. Recent data showed that the thioredoxin signalling pathway regulator TXNIP can play such a role. TXNIP binds to NLRP3 when cells are exposed to MSU crystals in a ROS-dependent way, and deficiency of TXNIP blocks efficient activation of the NLRP3 inflammasome.37 The balance between these multiple regulatory mechanisms could explain why inflammation is episodic in gout, as patients are known to have ‘intercritical’ periods, in which despite the continual presence of MSU crystals (in the joint), symptoms and signs of inflammation could be minimal.
Among the plethora of inflammatory mediators released by cells on contact with MSU crystals is there a hierarchy of inflammation? So far the evidence suggests that IL-1β may be situated somewhere near the apex of this hierarchy, and that other mediators are released secondarily. In support of this hypothesis, it was found that when MSU crystals were injected into mice deficient for IL-1R1, there was an absence of neutrophil infiltration.38 The other mediators include products of neutrophils and macrophages, such as TNFα, IL-6, nitric oxide, prostaglandins and chemokines. A small number of clinical studies have concluded that TNFα inhibition may be beneficial in chronic gout,39 although no studies have investigated IL-6 or chemokine inhibition in vivo. We propose that the initial trigger is contact between MSU crystals and cells of the monocyte/macrophage lineage (including resident macrophage-derived cells in the joint lining),25 leading to the secretion of IL-1 (mainly β but a role for α is not excluded), which then acts to recruit other inflammatory cells as well as amplifying the local tissue response. This results in a rapid burst of inflammatory mediator release and clinical inflammation (figure 1). In the resolution phase of inflammation, macrophage release of transforming growth factor beta plays a role. Further research will probably provide more insights into the downregulation mechanisms.
Novel therapeutic agents
One of the major challenges in the treatment of gout and hyperuricaemia is the appropriate use of urate-lowering drugs in conjunction with effective patient education (in particular lifestyle and dietary recommendations). The European League Against Rheumatism guidelines for the management of this condition recommend that ULT should target a serum urate level of 360 mmol/l (6 mg/l),40 a level that is achieved in less than 50% of patients taking standard doses of allopurinol.41 42 A further concern is how to manage the patient who has an acute attack of gout, and has comorbid conditions such as renal and cardiac insufficiency. Recent advances in treatment of hyperuricaemia and acute gout give some hope for the future.
For over 40 years, the mainstay of treatment of hyperuricaemia has been allopurinol. Although moderately effective, it is not universally tolerated and a pharmacological alternative is potentially of great clinical importance. Recent trials have confirmed that febuxostat, a non-purine selective inhibitor of xanthine oxidase, is effective in lowering hyperuricaemia. In these clinical trials, 80 mg and 120 mg a day of febuxostat reduced urate levels more effectively that a fixed dose of allopurinol (300 mg a day).43 The allopurinol dose in that trial was not adjusted to achieve target urate levels, a point that has been emphasised by other experts.42 Patients with mild renal impairment responded well and demonstrated no signs of increased toxicity.44 The safety profile was judged to be comparable to that of allopurinol, although it was noted that some patients on febuxostat developed liver function abnormalities. These results are encouraging and suggest that febuxostat could be an alternative hypouricaemic drug in patients who cannot tolerate or are allergic to allopurinol.
Another approach to reduce a patient's urate levels is by the administration of recombinant uricase, an enzyme that breaks uric acid down to allantoin. The enzyme, normally absent in humans and high primates, reduces serum urate levels rapidly and dramatically after intravenous administration. However, because of its short half-life, administration needs to be repeated to have a sustained effect. As it is a ‘foreign’ protein, its administration can also provoke allergic side-effects, particularly on repeated administration. In order to overcome some of these drawbacks, a pegylated form of uricase has been developed (pegloticase) that has a longer half-life (10–12 days instead of 10 h). Its efficacy in lowering urate levels and reducing tophus size was demonstrated in clinical studies.45
Rapid lowering of the urate concentration is associated with gout flares. In the febuxostat study, over 60% of patients had flares of gout during the treatment period of 1 year (frequencies were similar between febuxostat and allopurinol), and in the pegloticase study, 88% of patients. In the febuxostat study, patients were given either naproxen or colchicine as prophylaxis for flare during the first 8 weeks, and the flare rate was approximately 10%. Indeed, the duration of prophylaxis when initiating ULT has not been ascertained in controlled trials, but is likely to be significantly longer than 8 weeks. As flares was one of the main reasons that patients discontinued the study, it is clear that effective prophylaxis for acute gout flare is essential to obtain the maximum benefit from the new urate-lowering agents.
The discovery of the inflammasome has provided impetus to investigate the efficacy of IL-1 inhibition in acute gout. Three inhibitors have been studied to date, canakinumab (anti-IL-1 monoclonal antibody), kineret (IL-1Ra) and rilonacept (IL-1 Trap). Both kineret and rilonacept inhibit IL-1 signalling by binding to bioactive IL-1 (both α and β forms), thereby inhibiting its binding to the IL-1 receptor. Canakinumab is highly specific for IL-1β, thereby blocking its interaction with the IL-1 receptor. In terms of clinical studies in humans, no controlled studies have been performed with kineret. In a small case series of 10 patients with acute gout and who presented either intolerance or contraindications to non-steroidal anti-inflammatory drugs and colchicine, the investigators observed a rapid clinical response in all 10 patients. No adverse effects were observed.34 Since then, other case reports have confirmed this favourable effect. Rilonacept was compared with placebo in a small study of 10 patients with chronic gout, and again showed significant benefit in terms of pain relief and reduction of signs of inflammation.46 Finally, the results of a controlled study comparing different doses of canakinumab with triamcinalone in the treatment of acute gout reported significantly better relief of pain with canakinumab have been reported47 Interestingly, in patients treated with canakinumab, a striking reduction of gout flares was seen, superior to that seen with triamcinalone. These studies indicate that IL-1 inhibition is likely to be effective in acute gout, although we await the results of controlled trials to be able to assess the overall effects of this mode of treatment, and to decide which patients would most benefit from targeted therapy.
Research agenda for the next decade
Genetic risk factors for gout
Given the advances in the molecular genetics of hyperuricaemia and gout to date, it is likely that the research agenda in the next decade will focus on the development of novel urate-lowering agents that specifically target SLC2A9 and other recently identified urate transporters; the development of treatment algorithms based on analysis of urate transporter genes to identify those most likely to respond to uricosuric agents; clarification of the role of these genes in gout prognosis; and identification of genes associated with the risk of gout in those with hyperuricaemia, noting that many individuals with hyperuricaemia do not develop gout. For many of these studies, large, well-characterised cohorts of patients with gout will be needed.
CVD and gout
At present ULT is primarily indicated for patients with frequent gout attacks (typically more than one attack per year) or other complications of gout such as tophi, chronic gouty arthropathy or radiographic damage.40 Given the work of the past decade implicating hyperuricaemia and gout in the development of CVD, large-scale intervention studies are now needed to determine the effect of treating hyperuricaemia on cardiovascular end points, including blood pressure, cardiovascular events and cardiovascular mortality, in patients with gout and also those with asymptomatic hyperuricaemia. It is likely that this will be a major area of progress in the next 10 years, particularly given the recent development of new, highly effective ULT.
Environmental risk factors for gout
To date, most of the data available on environmental factors associated with gout have been observational, with very few well-designed intervention studies. The research agenda for the next decade should include adequately powered clinical trials that address the mechanisms and impact of specific dietary changes on the development of gout and measures of disease activity in patients with established gout. This will provide crucial information to allow those with gout and those at risk of gout to make appropriate lifestyle changes to alter their risk of the disease and its complications. In addition, recent advances in understanding both the genetic and environmental risk factors provide an opportunity to understand gene–environment interactions that contribute to the development of hyperuricaemia/gout; the interaction between fructose ingestion and SLC2A9 variants may be of particular relevance.
Mechanisms of inflammation and the inflammasome in acute gout
The identification of factors that modulate the inflammatory response to MSU crystals will be an important subject of research. Understanding the intracellular processes that lead to the activation as well as the inactivation of the inflammasome is a subject of intense research. Although current interest has focused on the effects of IL-1β in acute gout, the contribution of other cytokines has not been extensively studied. A better definition of the roles either in inciting or downregulating the inflammatory response may be of clinical importance.
Development and testing of novel therapeutic agents
Our current armamentarium for the treatment of hyperuricaemia is actually very limited, when one compares it with the treatment of hypertension. The identification of new hypouricaemic drugs, either acting by inhibiting urate synthesis (such as xanthine oxidase inhibitors) or by promoting uricosuria is definitely needed. The ideal clinical indications and uses of these new therapies will also require clarification. Studies of these novel agents will also provide insights into the most reliable and valid methods for measuring outcomes in gout clinical trials.48 Our increasing knowledge of the mechanisms of urate transport and the inflammatory response that it induces should provide new targets for drug development in the near future.
Funding AS receives support from the Fonds National Suisse de Recherche.
Competing interests AS has received consulting fees from Novartis. ND has no competing interests to declare.
Provenance and peer review Not commissioned; externally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.