From the Rheumatology Department, Kettering General Hospital, Kettering, UK

Transcription

1 Q J Med 2012; 105: doi: /qjmed/hcr242 Advance Access Publication 23 December 2011 Review Recent advances in management of gout E. SURESH and P. DAS From the Rheumatology Department, Kettering General Hospital, Kettering, UK Address correspondence to E. Suresh, Rheumatology Department, Kettering General Hospital, Rothwell Road, Kettering, NN16 8UZ, UK. dr_esuresh@hotmail.com Summary Incidence and prevalence of gout have markedly increased over the last few decades in keeping with the rise in prevalence of obesity and metabolic syndrome. Until recently, management of gout in patients with associated metabolic syndrome and comorbid illnesses such as renal impairment was difficult because of limited treatment options. However, significant progress has been made in the last few years, with introduction of new treatments such as interleukin-1 antagonists for management of acute gout, and febuxostat and pegloticase for chronic gout. The association of gout with alcohol, dietary purines and fructose ingestion has been Gout is the most common form of inflammatory arthritis in men over the age of 40, with estimated prevalence in the UK of 1.4%. 1,2 It is characterized by recurrent episodes of extremely painful and debilitating joint and/or soft tissue inflammation induced by monosodium urate (MSU) crystals (acute gout). Patients with chronic uncontrolled hyperuricaemia develop macroscopic aggregates of MSU in soft tissues that can lead to disabling and deforming arthropathy (chronic tophaceous gout). Some patients with persistent hyperuricaemia develop urate nephropathy and renal calculi. Additionally, >60% of patients with gout are diagnosed with metabolic syndrome that includes central obesity, hypertension, insulin resistance and hyperlipidaemia. 3 Patients with gout also have a higher risk of death, mainly because of coronary confirmed in large prospective studies, thus enabling the clinician to now provide evidencebased advice to patients. Recent efficacy and safety data favour lower over higher doses of colchicine, and oral corticosteroids over non-steroidal anti-inflammatory drugs for patients with acute gout. Local ice therapy might help to differentiate gout from other forms of inflammatory arthritis, and supplementation with vitamin C help to reduce risk of gout. Several other drugs with rational mechanisms of action are in the pipeline, and likely to be introduced over the next few years. A new era has thus begun in the field of gout. heart disease. 4 Thus, gout is associated with significant morbidity, higher mortality, functional impairment and reduced quality of life. 5 7 Several recent studies have indicated that incidence and prevalence of gout have markedly increased over the last three decades, in keeping with the rise in prevalence of obesity and metabolic syndrome. 8,9 Management of gout in patients with associated metabolic syndrome and comorbid illnesses such as chronic kidney disease was, however, difficult because of limited treatment options. For example, it was challenging to select an appropriate drug to control acute polyarticular gout in an elderly patient with history of chronic kidney disease, hypertension, diabetes and previous intolerance to colchicine because of increased likelihood of drug toxicity and potential to worsen associated! The Author Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please journals.permissions@oup.com

2 408 E. Suresh and P. Das illnesses with both non-steroidal anti-inflammatory drugs (NSAIDs) as well as corticosteroids. 10 Likewise, if gout patients with chronic kidney disease developed hypersensitivity reactions with allopurinol, it was challenging to choose an appropriate prophylactic agent because alternative therapeutic options were limited. These drawbacks called for more pharmacological options, both for controlling acute attacks of gout as well as for long-term prophylaxis. Although no major advances happened in the field of gout for over 40 years since allopurinol was introduced in 1965, 11 several exciting new therapies have been studied in the last few years, marking the onset of a new era in the field of gout. Some of these drugs have already been introduced into practice. Several more drugs with rational mechanisms of action are in the pipeline, and likely to be introduced in the next few years. The remainder of this article aims to provide an update for the general physician on some of these recent advances focussing on progress in (i) management of acute gout and (ii) long-term management options. The article concludes with discussion of future directives. Information presented in this review was collected by searching Medline (from 2004 to October 2011) using several search terms in combination with gout including colchicine, NSAIDs, corticosteroid, prednisolone, biological therapies, anakinra, canakinumab, rilonacept, topical ice, allopurinol, febuxostat, rasburicase, pegloticase, vitamin C, diet, alcohol, fructose, CT scan and ultrasound. The search returned several hundreds of papers, but only key studies that led to advancement in the field of gout, and those that were published in English were included. Citations of these papers were used to get additional relevant studies. Expert reviews, some recent guidelines as well as abstracts presented at recent International conferences (American College of Rheumatology, European League against Rheumatism and British Society of Rheumatology) were also studied. Progress in management of acute gout Acute gout is a self-limiting condition that lasts for 7 10 days, but treatment ensures pain relief and speeds recovery. Drugs used to treat an acute episode of gout aim to control the inflammatory reaction induced by MSU crystals. None of the available options including NSAIDs, corticosteroids or colchicine are universally effective or completely safe. NSAIDs are the drugs of choice in patients without comorbid illnesses, but are inappropriate for patients with renal impairment, congestive cardiac failure and peptic ulcer disease, in the very elderly, and in those receiving anti-coagulant treatment. It is also worth noting that NSAIDs have to be used in a higher than usual dose for patients with acute gout, especially in the first 24 h to get adequate control of inflammation. 12 Such higher doses can potentially cause gastric toxicity, and reduce creatinine clearance by 25% in most patients (relevant in patients with pre-existing renal impairment). There have also been concerns about cardiovascular safety, especially with the use of selective COX-II (cyclooxygenase) NSAIDs, 13 and it may be prudent to avoid these drugs in patients with pre-existing ischaemic heart or cerebrovascular disease. Corticosteroids are also effective but even short courses may affect blood pressure or glucose control, and their use might be problematic among post-operative patients because of increased risk of infection and impaired wound healing. Colchicine is another useful option, particularly in patients in whom a NSAID or corticosteroids cannot be used, but it has a narrow therapeutic index. Patients can develop gastrointestinal side effects such as diarrhoea, nausea and vomiting, especially when high doses are used. 14 The good news is that some new therapies have been studied in the last few years, thus widening the choice, especially for those patients with comorbid illnesses. These newer therapies along with other recent key advances in management of acute gout are discussed further in this section. Newer treatments for gout Biological therapies, which target specific elements of the immune system that play a key role in pathogenesis, are widely used for management of various rheumatic diseases such as rheumatoid arthritis (RA), psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, systemic lupus erythematosus and systemic vasculitis. These therapies have recently been explored for patients with gout as well. There are several cytokines such as interleukin-1 (IL-1), IL-8 and TNF-a that play a role in pathogenesis of gout, but IL-1b seems to be the key mediator. 15 Based on animal experiments, it was well known that monocytes and macrophages produced IL-1b in response to MSU crystals, and that inhibition of IL-1 resulted in suppression of gout inflammation. 16 These observations led to the conduct of the first human trial with IL-1 antagonists among patients with gout a few years ago. It was an open-labelled study that tested efficacy and safety

3 Gout advances 409 of anakinra (IL-1 receptor antagonist) among 10 patients who failed conventional treatments such as NSAIDs, colchicine or corticosteroids. Anakinra, administered subcutaneously for 3 days resulted in rapid and complete pain relief in 9 out of 10 patients within 48 h and importantly, without causing any side-effects. 17 This was in contrast to the incomplete response often seen with currently available therapies. Other drugs that inhibit IL-1 have been developed since in the last few years, including rilonacept (soluble IL-1 receptor that binds with IL-1 to prevent it from binding with its original receptor) and canakinumab (monoclonal antibody against IL-1b). Some early trials have shown that much better and more rapid pain relief could be achieved with these drugs compared to placebo and corticosteroids. 18,19 They have also been shown to be effective in reducing gouty flares among patients commencing long-term prophylactic treatment with allopurinol. 20 Results of some larger trials are awaited but going by the results of these early studies, it could be predicted that IL-1 antagonists are likely to emerge as promising new addition to the therapeutic armamentarium for patients with gout. They would certainly expand treatment options for those patients in whom cardiovascular, renal and gastrointestinal comorbidity would preclude use of NSAIDs, corticosteroids and colchicine. It is also worth mentioning here that anakinra was initially tested and used for patients with RA, but it is not used for that indication at present in the UK because of disapproval by National Institute for health and Clinical Excellence (NICE). Anakinra is very expensive (a single pre-filled syringe of anakinra costs 26.23) when used for treating patients with RA, as it needs to be administered daily, but drug costs of treating gout are a lot lower because of the short treatment courses. Although not formally tested, anakinra, because of its rapid onset of action, is likely to reduce hospital stay and bed costs for in-patients who develop gout, and therefore prove cost-effective. 12 This is particularly important because studies have shown that an acute flare of gout can extend hospital stay for in-patients by at least 3 days. 21 Efficacy and safety of low-dose colchicine Another notable recent advance has been the demonstration of efficacy and safety of low-dose colchicine. Colchicine has been used for gout since ancient times but higher doses were recommended previously ( 1 mg initially followed by 500 mg every 2 3 h until relief of pain is obtained or vomiting or diarrhoea occurs or until a total dose of 6 mg has been reached according to previous editions of the British National Formulary [BNF]). Gastrointestinal toxicity is common with such high doses. Hence, this was challenged by an article in the British Medical Journal that recommended the use of lower doses of colchicine (500 mg three times daily or less frequently in patients with renal impairment) based on personal experiences of many rheumatologists and some empirical studies. 22 The EULAR (European League against Rheumatism) guidelines for management of gout also supported the use of lower doses of colchicine, 23 and the BNF then changed its recommendation to 500 mg 2 4 times daily until symptoms relieved, maximum 6 mg per course. However, only one controlled trial had ever been conducted before with colchicine among patients with gout, 24 and there was no trial evidence to support the use of lower doses of colchicine. More recently, a double-blind, randomized controlled trial among patients with acute gout flare has demonstrated that lower doses of colchicine (1.2 mg followed by 0.6 mg after an hour, total dose of 1.8 mg) were as effective as higher doses (1.2 mg followed by 0.6 mg every hour for up to 6 h, total dose of 4.8 mg) in relieving pain. 25 This was achieved at the cost of no increased risk of toxicity for the lower dose of colchicine compared to placebo. The other important key to successful control of an acute episode is timing of therapy. All patients in this trial were commenced on treatment within 12 h of onset of an attack of gout, and it has indeed been suggested before that colchicine is most effective when commenced at the onset of an attack of gout before phagocytosis establishes itself. 26 The results of this trial have important implications for promoting safer use of colchicine in practice. Efficacy of corticosteroids versus NSAIDs Several head to head trials comparing different NSAIDs have been performed among patients with acute gout before, but none comparing the three groups of drugs (colchicine, NSAID and corticosteroids) against each other. Since NSAIDs are associated with gastrointestinal, renal and cardiovascular adverse effects, one recent double-blind randomized controlled trial compared efficacy and safety of prednisolone versus naproxen for patients with acute gout. 27 Both drugs were found to be equally effective in achieving pain reduction over the first 4 days, and adverse effects were noted to be mild and similar. Another double-blind randomized controlled trial 28 showed that oral

4 410 E. Suresh and P. Das prednisolone was as effective as indomethacin in achieving pain relief, and caused fewer side effects. The results of these trials have implications for managing gout in patients with renal impairment (creatinine clearance <60 ml/min), in whom it may be preferable to choose corticosteroids. Prednisolone was used in a dose of mg/day for 5 days in these two trials. A dose of mg/ day, gradually tapering over 10 days (to prevent rebound flare) has also been suggested before. 29 Such larger doses of prednisolone are required because gout episodes are known to occur in renal transplant patients receiving 7.5 mg of prednisolone/day. 30 As discussed earlier, corticosteroids should be used with caution among diabetic and post-operative patients. Usefulness of topical ice for acute attacks of gout Local ice therapy is another useful therapeutic modality for patients with acute gout. A randomized trial with a small sample size of 19 patients had previously shown that pain reduction among patients with acute gout was greater when local ice therapy was added to their usual therapy including prednisolone and colchicines. 31 More recently, it has been suggested on the basis of a prospective study that response to topical ice is more specific for gout, and that this may help to differentiate gout from other forms of inflammatory arthritis. 32 Interestingly, patients with RA who reported improvement with topical ice subsequently had their joint effusions aspirated and were found to have MSU or calcium pyrophosphate crystals in their synovial fluid, suggesting co-existence of the two conditions or previous misdiagnosis. It is therefore worth recommending topical ice application as an adjunctive treatment for patients with acute gout. Progress in long-term management of gout There are three prerequisites for development of gout: (i) development of hyperuricaemia leading to serum urate saturation (ii) formation of MSU crystals from saturated serum and (ii) interaction between MSU crystals and inflammatory system. Drugs given for long-term prophylaxis act at step (i), aiming to reduce serum urate levels. 33 If serum urate is reduced to below saturation point, then MSU crystals will dissolve and no new crystals can form, thereby offering the potential to cure gout. 34 EULAR guidelines recommend reducing serum urate to <360 mmol/l, 23 whereas the British Society of Rheumatology recommends a stricter target of 300 mmol/l. 35 Urate lowering therapy is generally offered for patients with recurrent acute episodes, chronic tophaceous gout, structural joint damage and renal calculi. For many years, only two classes of drugs were used for lowering serum urate in patients who needed prophylactic treatment: uricostatic drugs (allopurinol), which reduced uric acid production through competitive inhibition of xanthine oxidase (the enzyme that converts xanthine and hypoxanthine to uric acid) and uricosuric drugs (sulphinpyrazone, probeneceid and benzbromarone), which increased urinary uric acid excretion by blocking renal tubular re-absorption of urate. Allopurinol is the drug of choice in almost all patients who require prophylactic treatment. It is generally a safe drug, but 2% of patients develop hypersensitivity reactions, which can sometimes be severe and fatal with mortality rate of 20%. 36 Such reactions are more likely among patients with renal impairment, in whom the dose of allopurinol has not been appropriately reduced. 37 Allopurinol desensitization can be tried for patients with milder reactions, but this is not easy to achieve in practice, and often unsuccessful. Also, lower doses of allopurinol that are used in patients with renal impairment do not adequately control gout. 38 Uricosuric drugs are an option in patients who are intolerant of allopurinol, but they are contraindicated in those with renal calculi, and ineffective in patients with renal impairment (although benzbromarone can be used in patients with creatinine clearance as low as 25 ml/min). Moreover, probeneceid is not available in the UK, 39 and benzbromarone is not licensed because of its association with fulminant hepatic failure. 40 Patients with renal impairment and those who were intolerant of allopurinol, therefore, posed therapeutic challenges because of limited alternative options. In the last few years, two new treatments have become available: febuxostat, a novel xanthine oxidase inhibitor, and pegloticase, a recombinant uricase. 41,42 These new treatments have widened therapeutic options for challenging patients, and are discussed further in this section along with some new evidence on usefulness of vitamin C in reducing risk of developing gout. Results of recent large prospective studies that confirmed association of gout with alcohol intake, dietary purines and fructose ingestion are also discussed.

5 Gout advances 411 Febuxostat: a novel xanthine oxidase inhibitor Febuxostat is a non-purine, xanthine oxidase inhibitor with a chemical structure different from allopurinol. 43 It was recently approved by NICE for use in patients intolerant of allopurinol. No hypersensitivity reactions have been reported with febuxostat so far, and it might be associated with less toxicity compared to allopurinol. This is probably because it does not inhibit any other enzyme, apart from xanthine oxidase in the purine or pyrimidine metabolic pathway. The other advantage with febuxostat is that dose adjustments are not needed in patients with mild to moderate renal impairment, as it is mainly metabolized in the liver. 44 Febuxostat has been shown to be more effective in reducing serum urate levels compared to allopurinol and placebo It should, however, be noted that allopurinol was used in a fixed dose of 300 mg/ day in trials, and it is not known if febuxostat would have been as effective as higher doses of allopurinol (in practice, allopurinol can be increased up to 900 mg/day, assuming compliance and normal renal function). There is of course an increasing risk of intolerance with higher doses of allopurinol, and hence, the recommendation to use allopurinol as first line therapy with gradual titration of the dose to achieve target urate levels, and febuxostat only in those patients who are intolerant to allopurinol. Febuxostat is initiated in a dose of 80 mg once daily, but if urate levels remain high, the dose could be increased up to 120 mg/day after 4 weeks (in the USA, approval has been granted for use of 40 and 80 mg). Like allopurinol, febuxostat should not be commenced during or soon after an acute episode of gout. Gout flares are common in the first few months after commencing treatment with febuxostat, and hence, prophylaxis with colchicine or NSAID is recommended for up to 6 months. Liver function test abnormalities are known to occur in patients taking febuxostat, and the recommendation is to check and confirm satisfactory liver function before commencing treatment. It would also be prudent to check liver function periodically after commencing treatment. Since some trials have shown numerically higher cardiovascular events among patients receiving febuxostat compared to other treatments, 45,46,50 the European Medicines Agency does not recommend its use in patients with pre-existing ischaemic heart disease or congestive cardiac failure. Febuxostat is generally well tolerated, but some patients (1 2%) may experience side effects like nausea, diarrhoea and headache. Because azathioprine is metabolized by xanthine oxidase, it is best to avoid febuxostat in patients receiving this drug (relevant in posttransplant patients on azathioprine who develop gout). In summary, treatment with febuxostat would be appropriate for (i) patients intolerant of allopurinol, (ii) patients with mild or moderate renal impairment (creatinine clearance of >30 ml/min) and (iii) patients in whom gout cannot be controlled with allopurinol or other treatments. Uricolytic drugs for treatment of refractory gout Unlike lower mammals, humans do not possess the enzyme uricase (uric acid oxidase) that catalyses conversion of uric acid to allantoin. Allantoin is highly water soluble, and hence more readily excreted by kidneys. The use of uricase is therefore an attractive option for management of gout. 51 Rasburicase, a recombinant uricase, has long been used by oncologists for management of hyperuricaemia among patients with tumour lysis syndrome, but rasburicase itself is not suitable for use in patients with gout because of its very short halflife of <18 h. 52 This would necessitate frequent administration of rasburicase, but that would be impractical because of its very high antigenicity. Hence, a pegylated form of uricase (pegloticase) has recently been developed and tested among patients with refractory gout (pegylated simply means that the drug is conjugated with polyethylene glycol to prolong its half life and reduce antigenicity). 53 Pegloticase has been shown to rapidly reduce serum urate levels and debulk tophi. In early studies, target serum urate levels were achieved in 42% of patients, and resolution of tophi noted in 40%. 54,55 Due to the rapid reduction of serum urate levels, >80% of patients experience acute gout flares, and hence, pegloticase is co-prescribed with colchicine, NSAID or corticosteroids. It was recently approved by FDA (Federation of Drugs Administration) in the USA for treatment of chronic gout in adult patients refractory to conventional therapy, and an application has been submitted for approval in the European Union as well. Pegloticase has to be given by intravenous infusion every 2 4 weeks, but it can only be used over a finite period of time (3 6 months) because many patients eventually develop anti-pegloticase antibodies that could reduce efficacy and cause infusion reactions. Infusion reactions can be predicted by serum urate rising to over the target level of 357 mmol/l (indicating presence of anti-pegloticase antibodies and loss of drug efficacy). It has been suggested that if serum urate is monitored regularly and pegloticase discontinued when urate rises to

6 412 E. Suresh and P. Das >357 mmol/l, then infusion reactions can be avoided in >90% of patients. In summary, pegloticase would be appropriate for short-term use, mainly for rapid debulking of tophi in patients with treatment-refractory, chronic tophaceous gout, prior to using other drugs such as allopurinol or febuxostat to maintain control over the longer term. Usefulness of vitamin C for patients with gout Another interesting recent development is the realization that vitamin C supplementation is useful for patients with gout. It has long been known that vitamin C lowers serum urate via a uricosuric effect but it was thought that mega doses were required to achieve this effect. 56 A recent double-blind, randomized controlled trial found that vitamin C in a dose as low as 500 mg/day was better than placebo in reducing serum urate levels. The reduction in serum urate was as much as 10% at the end of 2 months in the vitamin C group compared to no reduction in the placebo group. Another large prospective follow-up study of health professionals in the USA reported up to 45% lower risk of gout for vitamin C intake of >1500 mg/day, and 34% lower risk for vitamin C intake between 1000 and 1499 mg/day compared to no intake of vitamin C, and independent of dietary and other risk factors. 57,58 Supplemental vitamin C in doses of mg/ day could therefore be recommended for patients with gout but this should not replace standard advice on diet and alcohol. Association of gout with alcohol intake, dietary purines and fructose ingestion The association of gout with alcohol intake and increased dietary purine consumption had been known since ancient times, but there were no prospective trial data to back up this notion. The recently reported results of the large Health Professionals Follow-up study involving male participants have now confirmed these associations These subjects had been followed up since Those with gout were excluded at baseline, and 730 subjects developed gout during 12 years of follow-up. Increased risk of gout was found with higher levels of meat (particularly beef, pork or lamb) and seafood consumption but not with consumption of animal or vegetable protein and purine-rich vegetables. 63 Eating purine-rich vegetables such as beans, peas and lentils is, therefore, not associated with increased risk of gout. A lower incidence of gout was also found among those with higher intake of low-fat dairy products (explained by uricosuric effects of milk proteins such as casein and lactalbumin). Conversely, a significant increase in serum urate levels following 4 weeks of dairy-free diet was demonstrated in another randomized trial. 65 Association between gout and alcohol intake was also confirmed in the same cohort. 64 Risk of gout was proportional to the amount of alcohol consumed, with risk varying according to the type of beverage consumed. Beer conferred a larger risk than spirits (perhaps because of its purine content), while moderate drinking of wine (two 4-oz glasses per day) did not increase risk of gout. The increased risk of gout with alcohol and dietary factors was independent of other standard risk factors such as age, body mass index, hypertension, chronic renal impairment and diuretic therapy. Conventional dietary recommendations have focused on restricting purine intake but recent studies have highlighted the importance of fructose containing sugar sweetened soft drinks in increasing risk of gout. 66,67 There has been substantial increase in consumption of fructose rich beverages in parallel with the rise in prevalence of obesity, metabolic syndrome, hyperuricaemia and gout over the last few decades. Consumption of naturally occurring fructose such as fruit or fruit juices may also increase risk. Eating an apple or orange a day, for example, can increase risk of gout by 64%. Current data, however, do not support a change in current advice on fruit intake because of their benefits in reducing cardiovascular risk. Diet soft drinks, on the other hand, do not increase risk of gout, while long-term consumption of coffee may actually reduce risk. 68 These recent findings have important practical implications for prevention and management of gout. Patients should be informed that their risk of gout could be reduced even without the use of drug treatments through modification of diet, and reduction of alcohol and fructose consumption. An earlier study had, in fact, demonstrated that weight loss achieved through reducing dietary saturated fat and carbohydrate intake with proportional increase in protein and unsaturated far consumption could not only reduce serum urate levels but also frequency of gout attacks. 69 Such a diet would also, of course, have cardiovascular benefits by improving insulin sensitivity and reducing triglyceride levels. Crash dieting and fasting should, however, be discouraged because of their potential to cause ketoacidosis and precipitate acute attacks of gout.

7 Gout advances 413 Table 1 Learning points on progress in management of acute gout IL-1 antagonists can rapidly control inflammation among patients with acute gout, and without causing any side effects. IL-1 antagonists are particularly likely to be useful in patients in whom cardiovascular, renal and gastrointestinal morbidity would preclude the use of NSAIDs, corticosteroids and colchicine. Lower doses of colchicine are as effective as higher doses in controlling inflammation among patients with acute gout, and at the cost of no increased risk of toxicity compared to placebo. Corticosteroids are comparable in efficacy to NSAIDs, and cause fewer side effects; they are, therefore, a useful option for patients with renal impairment. Local ice is a useful adjunctive therapeutic modality for patients with acute gout; response to ice may help to distinguish gout from other forms of inflammatory arthritis. Table 2 Learning points on progress in long-term management of gout Therapeutic options for allopurinol-intolerant patients were limited until recently. Two new drugs have become available recently: febuxostat, a novel xanthine oxidase inhibitor, and pegloticase, a recombinant uricase. Febuxostat is recommended for patients intolerant of allopurinol. Febuxostat can safely be used in patients with mild to moderate renal impairment (creatinine clearance >30 ml/min). Pegloticase (recombinant uricase) could be used in the short-term for rapid debulking of tophi in patients with treatment-refractory chronic gout prior to using other drugs such as allopurinol or febuxostat to maintain control over the longer term. Infusion reactions are common with pegloticase, but could be predicted by rising serum urate levels (>357 mmol/l) Supplemental vitamin C ( mg/day) may be beneficial in prevention of gout. Risk of gout is increased with alcohol intake (especially beer), higher consumption of meat and seafood, and ingestion of fructose. The way forward In conclusion, several exciting developments have taken place in the field of gout in the last few years, with improved understanding of pathogenesis, introduction of new treatments, better use of existing therapies and publication of treatment guidelines. The future too appears promising, with several other drugs in the pipeline (Table 3). These experimental drugs, when they become available, would no doubt widen therapeutic options for challenging patients. Some molecular targets that are currently being studied include URAT-1(urate anion exchange transporter), which transports urate from renal tubular lumen into epithelial cells, purine nucleoside phosphorylase (PNP), an enzyme that functions in the purine salvage pathway and phosphodiesterase-4 (PDE4) that mediates inflammation Diagnostic methods for gout have also significantly improved in recent years with introduction of advanced imaging techniques such as ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI). 73 They are useful to make an early and non-invasive diagnosis of gout as well as monitor response to urate lowering therapy in the long term. Ultrasound, for example, is more sensitive than plain radiographs in detecting gouty erosions, and for diagnosing tophi and guiding synovial fluid aspiration. 74,75 More recently, dual energy CT has been shown to be an extremely useful non-invasive tool for early diagnosis of gout and uric acid urolithiasis because of its ability to differentiate MSU from calcium. 76 Tophaceous deposits can be diagnosed even during pre-clinical stage using this modality. If and when dual energy CT is introduced into practice, it would allow for early commencement of treatment in patients with crystal deposition and inflammation. This would not only offer the potential to prevent articular damage, but also improve cardiovascular outcomes because of the association of gout with myocardial infarction. Despite introduction of new drugs and diagnostic modalities, practical management of gout remains sub-optimal Many patients with gout, especially those with renal impairment receive inadequate therapy in practice, and therefore do not achieve target serum urate levels. Serum urate levels are not monitored satisfactorily following commencement of urate lowering therapy, or even when they are measured, the dose of allopurinol is not titrated accordingly to achieve target urate

8 414 E. Suresh and P. Das Table 3 Some gout drugs in development Lesinurad (RDEA594) Blocks URAT-1 more selectively than currently available uricosuric drugs levels. 80 Compliance with urate lowering therapy remains poor, with only 50% of patients still receiving allopurinol after the first year of therapy Studies have also shown that about a third of patients with acute gout are treated inappropriately with a hypouricemic agent. 83 There is therefore an urgent need to educate patients as well as physicians to improve outcome. 84 There are also several other gaps that need to be addressed in future studies (Table 4). For instance, it is recommended that urate lowering therapy be continued indefinitely, but it is not known with certainty if this is essential. Results of a recent prospective observational study suggest that following a period of good control with intensive treatment (aiming for target serum urate <303 mmol/l), it might be feasible to withdraw treatment for a period, or at least that control may be less rigid during the long term. 85 Patients in whom urate lowering therapy was withdrawn after 55 years remained free from gout for as long as a mean period of 49 months. It is also not known what the lower safe limit of urate is. Since urate is an anti-oxidant and neuroprotective, there Could be safely combined with febuxostat; >90% of patients given the combination of febuxostat and lesinurad achieved target serum urate levels in phase Ib studies. BCX-4208 Inhibits PNP activity Early phase I and II studies have shown significant reduction in serum urate in patients who were given this drug. Apremilast Inhibits PDE4 Being compared with indomethacin in a single-blind trial for patients with acute gout flares. Tranilast Possesses uricosuric as well as anti-inflammatory properties Currently being studied as part of combination therapy with allopurinol. URAT-1, urate anion exchange transporter; PNP, purine nucleoside phosphorylase; PDE4, phosphodiesterase 4. Table 4 Some key research questions What is the cost-effectiveness of biological therapies for gout? Does febuxostat increase the risk of cardiac adverse events? How could we improve safety of uricase based therapies? What will be the place for newer therapies in the therapeutic armamentarium of gout? What is the role of combination drug therapy for patients with acute and chronic gout? Once commenced, should urate lowering therapy be continued indefinitely? Could target levels of serum urate be relaxed after the initial crystal depletion phase? What is the safe lower limit of serum urate? Should subjects with asymptomatic hyperuricaemia receive hypouricaemic therapy to reduce cardiovascular risk? What is the usefulness of dual energy CT scan in the pre-clinical phase? Would early treatment of patients with crystal induced inflammation improve cardiovascular outcome? is a concern that very low urate levels might increase risk of neurodegenerative diseases such as Parkinson s disease, Alzheimer s dementia and multiple sclerosis. 86,87 Further studies are required to clarify these issues. Combination drug therapy for management of gout needs to be explored further as well. Few small trials have demonstrated that allopurinol in combination with benzbromarone or sulphinpyrazone results in better control of serum urate and resolution of tophi compared to monotherapy, 88,89 but controlled trials and long-term data are needed. Trial data for usefulness of combining corticosteroids or NSAIDs with colchicine for patients with acute gout are also lacking. And lastly, the debate on whether or not asymptomatic hyperuricaemia constitutes an independent risk factor for cardiovascular disease continues Elevated uric acid levels are associated with metabolic syndrome and established cardiovascular risk factors, especially hypertension, and it is therefore difficult to deduce if hyperuricaemia increases the risk of cardiovascular disease independent of

9 Gout advances 415 other risk factors. Some studies that controlled for other risk factors have indeed suggested that hyperuricaemia may be an independent risk factor for not only cardiovascular but also renal disease, but they were generally small trials that examined well defined populations. Some recent reports have also indicated that treatment of hyperuricaemia lowers blood pressure and improves renal function among patients with chronic kidney disease stage III. 94,95 At present, there are insufficient data to recommend treatment of asymptomatic hyperuricaemia to reduce cardiovascular risk, but should more definite data become available in future, it would significantly change the way we manage gout. Conflict of interest: None declared. References 1. Mikuls TR, Farrar JT, Bilker WB, Fernandes S, Schumacher HR Jr, Saag KG. 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