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Optimizing current treatment of gout nrrheum.2014.32
Optimizing current treatment of gout nrrheum.2014.32
Optimizing current treatment of gout nrrheum.2014.32
Optimizing current treatment of gout nrrheum.2014.32
Optimizing current treatment of gout nrrheum.2014.32
Optimizing current treatment of gout nrrheum.2014.32
Optimizing current treatment of gout nrrheum.2014.32
Optimizing current treatment of gout nrrheum.2014.32
Optimizing current treatment of gout nrrheum.2014.32
Optimizing current treatment of gout nrrheum.2014.32
Optimizing current treatment of gout nrrheum.2014.32
Optimizing current treatment of gout nrrheum.2014.32
Optimizing current treatment of gout nrrheum.2014.32
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  • 1. NATURE REVIEWS | RHEUMATOLOGY VOLUME 10  |  MAY 2014  |  271 Division of Academic Rheumatology, University of Nottingham, Clinical Sciences Building, City Hospital Nottingham, Hucknall Road, Nottingham NG5 1PB, UK (F.R., M.H., M.D.). Correspondence to: M.D. michael.doherty@ nottingham.ac.uk Optimizing current treatment of gout Frances Rees, Michelle Hui and Michael Doherty Abstract | Gout is the most common inflammatory arthritis worldwide. Although effective treatments exist to eliminate sodium urate crystals and to ‘cure’ the disease, the management of gout is often suboptimal. This article reviews available treatments, recommended best practice and barriers to effective care, and how these barriers might be overcome. To optimize the management of gout, health professionals need to know not only how to treat acute attacks but also how to up-titrate urate-lowering therapy against a specific target level of serum uric acid that is below the saturation point for crystal formation. Current perspectives are changing towards much earlier use of urate-lowering therapy, even at the time of first diagnosis of gout. Holistic assessment and patient education are essential to address patient-specific risk factors and ensuring adherence to individualized therapy. Shared decision-making between a fully informed patient and practitioner greatly increases the likelihood of curing gout. Rees, F. et al. Nat. Rev. Rheumatol. 10, 271–283 (2014); published online 11 March 2014; doi:10.1038/nrrheum.2014.32 Introduction Gout is the most common form of inflammatory arthri- tis, with crude estimates of adult prevalence of 2.5% in the UK,1 3.9% in the USA,2 and 3.8% in Taiwan.3 The prevalence and incidence of gout increase with age, and it is more common in men than women (approxi- mately 3:1).2 Fortunately, the pathogenesis of gout is relatively well understood. We know the causative agent—­monosodium urate crystals—and the multi- ple risk factors that lead to their formation, primar- ily through chronic elevation of uric acid levels above the saturation point at which urate crystals can form (Figure 1). Urate crystals are deposited preferentially in and around peripheral joints in the feet, knees, hands and elbows, especially those affected by osteoarthritis.4 The urate crystals predominantly form in the super­ficial layers of articular cartilage, in subchondral bone and in fibrous peri-articular tissues, but might also be evident clinically as subcutaneous tophi. During a prolonged asymptomatic phase (the duration of which is unknown but presumed to be measured in years), the concentra- tion of crystals gradually builds up and eventu­ally, once deposition is extensive, it is hypothesized that urate crystals ‘shed’ from the articular cartilage into the joint space and trigger an acute ‘attack’ of extremely painful joint inflammation. This acute attack is usually the reason patients first seek medical attention. However, if left untreated, continuing urate crystal deposition not only causes further acute attacks and involvement of additional joint sites, but also, and importantly, could cause eventual irreversible joint damage with chronic symptoms and disability. Apart from causing acute gout and chronic joint damage, there is increasing evidence, though still controversial,5 that a high serum uric acid (SUA) level is an independent risk factor for cardio­ vascular disease, stroke and chronic kidney disease (CKD).6–8 Therefore, there are several reasons to con- sider definitive treatment of elevated SUA levels once a patient is known to have gout. Fortunately, several treatment strategies exist to effectively reduce and maintain SUA levels below the saturation point, thus preventing further crystal for- mation and encouraging the dissolution of exist­ing crystals. Once the pathogenic urate crystals are elimi- nated, further acute attacks are impossible and the risk of further crystal-induced joint damage is removed. How­ever, although gout is the only form of chro­nic arthritis for which such a ‘cure’ exists, audits pub- lished in the past 4 years confirm that the treatment of gout both in primary care and hospital practice is far from optimal.1,9,10 This article reviews recommended available treat- ments, and highlights new perspectives relating to current standards of care and barriers that need to be addressed if gout is to be managed successfully. The Review largely reflects the latest EULAR11 and British Society for Rheumatology (BSR)12 guidelines, published in 2006 and 2007 respectively (both are currently being updated), as well as the more recent 2012 ACR guide- lines.13,14 In addition, we systematically searched the literature for individual treatments. Some drug options (including biologic agents and uricases) are not dis- cussed in detail because they are largely unlicenced for gout, are very expensive and have limited application. We first review the available options for managing acute attacks and for reducing SUA levels, and then focus on important barriers to care and how to successfully implement ‘curative’ management strategies. Competing interests M.D. has received honoraria for being a member of ad hoc advisory boards for Ardea Biosciences, Menarini, Novartis and Savient. F.R. and M.H. declare no competing interests. REVIEWS © 2014 Macmillan Publishers Limited. All rights reserved
  • 2. 272  |  MAY 2014  |  VOLUME 10 www.nature.com/nrrheum Management of acute attacks Acute gout is recognized as one of the most painful experi­ences known, on the same level as childbirth or visceral colic. Therefore, treatment of an attack should be initiated as soon as possible following initial diagno- sis or, in a patient with known gout, as soon as the first warning symptoms are perceived. Only a few recom­ mended options are available, and formal research evi- dence for most of these options is limited. This reflects not only the logistical challenges of undertaking ran- domized controlled trials (RCTs) in an unpredict- able and episodic condition that reaches its maximum intensity within just 24 h of onset, but also the fact that current treatments have been available for decades and are accepted as normal clinical practice without a per- ceived need for further research evidence to confirm their efficacy. NSAIDs An oral NSAID is by far the most commonly used treat- ment for acute gout in general practice.15 However, just one placebo-controlled RCT has confirmed that an Key points ■■ Many established treatments are already available for managing gout effectively ■■ Lowering serum uric acid to a target level below the saturation point for urate can effectively ‘cure’ gout ■■ Health professionals need to be aware of current best practice for the management of gout ■■ Patient education and discussion of illness perceptions is key to addressing patient-specific risk factors and ensuring adherence to an individualized management plan ■■ Shared decision-making between a fully informed patient and a health practitioner, whether a doctor, nurse or pharmacist, can greatly increase the likelihood of a ‘cure’ and lead to improvements in patient outcomes NSAID (tenoxicam 40 mg daily) is better than placebo at reducing pain at 24 h.16 Because of the severity of pain experienced in acute gout, the NSAID should be commenced at its maximum dose, rather than titrat- ing upwards from the lower end of the dose range.11,12,14 Although some doctors still hold the traditional belief that indomethacin is more effective than other NSAIDs, studies comparing different quick-acting NSAIDs dem­ on­strate their equal efficacy in acute gout.17–21 The main issue with oral NSAIDs is, of course, their safety. To reduce the risk of upper gastrointestinal ulcera­ tion, bleeding and perforation, co-administration of a ­proton-pump inhibitor (PPI) is recommended,22 although the addition of a PPI does not alter the risk of small and large bowel involvement. In addition, NSAIDs can cause acute renal failure and are contra­indicated in patients with CKD.23 Selective cyclo­oxygenase (COX)‑2 inhibitors compare favourably with non­selective NSAIDs24,25 for the treatment of acute gout in terms of similar efficacy but lower incidence of serious gastro­ intestinal events; however, concerns remain over the cardio­vascular and renal toxicity of COX‑2 inhibitors with frequent or chronic use.26 In the UK, co-­prescription of a PPI is recommended with these drugs.22 Colchicine Along with oral NSAIDs, oral colchicine is recom­mended as a first-line treatment for acute gout attacks.11,12,14 Interest in IL‑1 inhibition with bio­logic agents for acute gout has arisen due to the action of these drugs on the NLRP3 inflammasome; however, colchi­cine is also known to exert one of its many actions here27 and is a much less expensive option. Figure 2 demonstrates the metabolism and various mechanisms of action of colchicine. Oral colchicine has been used in clinical practice for centuries, but only two placebo-controlled RCTs have been published, both of which confirm its efficacy in acute attacks.28,29 These studies both demonstrated that colchicine significantly reduced pain compared with placebo, but high-dose regimens (4.8 mg total over 6 h) were associated with substantial gastrointestinal dis- turbance (nausea, vomiting or diarrhoea). Low-dose regimens (1.8 mg total over 1 h) were equally effective at reducing pain but adverse effects were minimized. Hence, current EULAR guidelines recommend a maxi­ mum dose of 0.5 mg colchicine three times a day,11 and the ACR guidelines14 recommend a regimen involving a loading dose of 1.2 mg then 0.6 mg 1 h later, followed after a further 12 h by 0.6 mg once or twice daily. Such low doses seem to be effective and well-tolerated in clinical practice. Even lower doses (0.5 mg once or twice daily) can be tried in patients with persistent adverse effects and in those with moderate to severe CKD.30 Following the publication of the ACR guidelines, an equivalent dosing is likely to become more widely adopted in Europe—with a modified dosage of a 1.0 mg loading dose followed 1 h later by 0.5 mg on the first day, then 0.5 mg two to four times a day on subsequent days. Colchicine is considered to work best when commenced Dietary purines Uric acid pool (serum, tissues) 30% 70% 70% renal excretion 30% gut elimination MSU crystals Purine nucleotides and bases Tissue nucleotide synthesis and metabolism Osteoarthritis Ageing ObesityHigh-purine diet ■ Genetic factors ■ Metabolic syndrome (hypertension, insulin resistance, hyperlipidaemia) ■ Renal impairment ■ Drugs that reduce renal function Figure 1 | Metabolism of uric acid and risk factors for gout. Crystallization of MSU occurs when uric acid levels exceed the saturation point, through inefficient elimination or excessive production of uric acid. The multiple risk factors for the formation of urate crystals are shown in yellow boxes at their sites of action. Abbreviation: MSU, monosodium urate. REVIEWS © 2014 Macmillan Publishers Limited. All rights reserved
  • 3. NATURE REVIEWS | RHEUMATOLOGY VOLUME 10  |  MAY 2014  |  273 within 24 h of first symptoms of an acute attack, and the ACR guidelines recommend that colchicine is not initi- ated more than 36 h after symptom onset. Treatment is usually continued until the acute attack has subsided. Colchicine should be used at low doses and with cau­ tion in patients taking a cytochrome P450 3A4 inhibitor (ciclosporin, ketoconazole, ritonavir, clari­thromycin, erythromycin, extended-release verapamil, extended- release diltiazem)27,30,31 owing to drug–drug inter­ actions,31,32 particularly in people with renal impairment, and those taking a statin should stop this medication temporarily while on colchicine.27 Intravenous colchicine is highly toxic and not recommended.11,12,14 Corticosteroids Intra-articular corticosteroids Aspiration of an affected joint followed by injection of corticosteroids (Figure 3) is ideal for treatment of acute gout attacks,11 particularly in a hospital setting where first-line use of this intervention can provide prompt relief with minimal adverse effects. This treatment is a particularly useful option where colchicine, NSAIDs or oral corticosteroids are contraindicated. Aspiration itself very quickly reduces the extreme pain of gout, pre­sumably by lowering the marked intra-articular hyper­tension caused by acute crystal-induced synovitis. Prac­tical difficulties with intra-articular aspiration and injection arise if the gout attack is polyarticular or affects the midfoot, or if no physician with sufficient expertise is available (the usual situation in general practice). One uncontrolled trial has been published, which supports the use of intra-articular corticosteroid injection.33 Although no evidence exists to guide optimal dosage, as for other arthropathies most physicians use a long-acting corticosteroid and adjust the dose according to the size of joint affected.34 Oral corticosteroids Oral prednisolone can be used where colchicine or NSAIDs are contraindicated or have failed to provide sufficient relief,11 and this method of delivery of cortico­ steroids is the one most commonly used in general practice. As with intra-articular corticosteroids, no evidence is available to guide optimal dosage. One key trial demonstrated that, in patients with acute gout, oral prednisolone 35 mg daily was equivalent in efficacy to oral naproxen 500 mg twice a day.35 Another trial demon­strated that 30 mg prednisolone daily for 6 days was equivalent in efficacy to intramuscular diclofenac 75 mg plus 50 mg indomethacin orally on day 1 followed by oral indomethacin 50 mg three times a day for 2 days then 25 mg three times a day for 3 days.36 Such doses of oral corticosteroids administered in short courses are commonly used in general practice for other conditions (for example, asthma) and considered overall to be a safe option, especially in patients with comorbidities. Intramuscular corticosteroids Intramuscular delivery of corticosteroids is another alternative treatment that is mainly limited to hospi- tal settings. Intramuscular corticosteroids are usually admini­stered as a single injection but, again, there is no con­sensus on dose. In one trial, 60 mg intra­mus­ cular triamcinolone acetonide was equivalent in effi- cacy to oral indomethacin 50 mg three times daily for the treatment of acute gout.37 However, higher intra­ muscular doses—120 mg of triamcinolone acetonide or m­ethylprednisolone—are often used to control an acute flare of rheumatoid arthritis or other painful inflamma- tory arthropathies38 and many physicians use such doses for acute gout. Biologic agents Considerable interest exists among rheumatologists in the use of biologic agents for the rare situation where all of the above treatments are considered to be contra-­ indicated or impractical. However, available biologic agents that inhibit IL‑1 and which have been assessed in treatment of acute attacks of gout—specifically ana­ kinra,39,40 canakinumab41–43 and rilonacept44–46 —have either had no comparator or have been compared to a possibly suboptimal dose of triamcinolone (40 mg intra- muscularly) rather than a more commonly used short course of oral prednisolone (for example, 30–35 mg prednisolone daily). Although some modest advan- tages of biologic agents have been reported, these treat- ments remain comparatively very expensive, and as yet are largely unlicenced for acute gout in most countries (canakinumab is now licenced for use in Europe, but not in the UK or USA). Main effects of colchicine ■ Binds to tubulin in cells (affecting cell division) ■ Inhibits function of leukocytes ■ Inhibits chemotactic factors ■ Inhibits inflammasome and IL-1 production ■ Inhibits release of histamine from mast cells Oral administration 80–90% faecal excretion Liver Kidney 10–20% renal excretion Enterohepatic recycling Figure 2 | Metabolism and mechanisms of action of colchicine. After oral administration and gastrointestinal absorption, colchicine is primarily metabolized by the liver but undergoes substantial enterohepatic circulation. Its pharmacological effects are multiple and varied. Colchicine is excreted primarily in faeces but also in urine. REVIEWS © 2014 Macmillan Publishers Limited. All rights reserved
  • 4. 274  |  MAY 2014  |  VOLUME 10 www.nature.com/nrrheum Physical treatment In support of widespread clinical experience, one small trial (n = 19) examining the effect of adding localized ice therapy to a standardized treatment for acute attacks47 found greater improvements at 1 week in those who received ice. Locally applied ice packs are therefore recom­mended as a simple and safe adjunct to pharmaco­ logical therapy. No RCTs are available to support resting of the affected joint,12 but such common-sense advice obviously accords with the patient’s natural inclination. Issues related to treatment of acute attacks NSAIDs are readily available but unfortunately are contra­indicated in many patients with gout owing to age, comorbidity, concomitant drug therapy or renal impair­ment.48,49 Pharmacoeconomic analysis has also shown oral NSAIDs to be less cost-effective than oral corticosteroids or colchicine, largely because of their adverse effects.50,51 NSAIDs and colchicine have not been directly compared with respect to their effi- cacy, but colchicine might be more applicable to most patients, with the caveats of severe renal impairment and certain drug interactions listed above. Where expertise is available, joint aspiration and injection with cortico­ steroids is often the safest option and this treatment should be regarded as recommended best practice in a hospital setting. The key to successful management of acute attacks of gout is to assess and treat each patient individually, discussing with them which option is most acceptable. Any treatment should be started as early as possible and drugs can be used in combination if needed (for example, intra-articular corticosteroids with oral colchicine).14 Long-term management The aim of long-term therapy is to ‘cure’ gout by lowering SUA levels to below the saturation point for urate—that is, to at least below 360 μmol/l (6 mg/dl)11 —thus promot- ing crystal dissolution and preventing formation of new crystals. The most effective method of achieving this SUA level is the use of urate-lowering therapy (ULT). Before commencement of ULT, each patient should be given a clear verbal explanation of the causes of gout, backed up by written information (for example, Arthritis Research UK’s patient information booklet52 ), along with an individualized explanation of the relevant risk factors that could elevate their SUA levels. The content listed in Box 1 was used in a study to explain to patients the causes and risk factors for the development of gout, and the patients subsequently demon­strated excellent ad­herence to individualized management plans.53 One of the many barriers to care is a stereotyped view of gout and the feeling that gout is self-induced through poor lifestyle, gluttony and excessive alcohol intake.54 Many patients have seen old cartoons that empha­ size such lifestyle factors (Figure 4). Patients can be embarrassed to have gout—particularly women, who often think it is a man’s disease—which can lead to a dis­inclination to seek help. Negative views about gout are associated with poorly controlled disease and lower adher­ence to ULT.55–57 Therefore, it is important that the explana­tion should be non-accusatory, emphasizing that having gout is not necessarily the patient’s fault, and that the condition is curable with treatment. Exploration and full discussion of the patient’s perception of their illness is crucial if they are to be sufficiently motivated to adhere to an appropriately developed management plan. Individualized, constructive advice on lifestyle modi- fications that might reduce predisposition to hyper­ uricaemia should be given if appropriate. This advice might include, for example: reduce weight by use of recom­mended strategies if overweight or obese;58 reduce excessive intake of beer and spirits;59 reduce exces- sive intake of purine-rich foods (such as red meat and seafood) and consume proportionately more dairy pro­ ducts;60 reduce intake of fructose-rich drinks and fruit (apples, oranges);61 and cease any retinol supplementa- tion (retinol increases SUA compared with β-carotene, which reduces SUA).62 Although these recommendations are based on observational studies rather than RCTs, clearly many health reasons exist for tackling being over- weight or drinking more than the recommended levels of alcohol, and receiving indivi­dualized lifestyle advice might enable the person with gout to take control of their condition and improve their self-efficacy. However, the benefit to gout of lifestyle modification should not be overemphasized since, firstly, this emphasis reinforces the negative perceptions of gout as a self-inflicted condi- tion and, secondly, ULT will still be required to achieve SUA levels low enough to treat the condition within a reasonable timescale. With respect to predisposition to hyperuricaemia and development of gout, being overweight or obese increases endogenous production of uric acid63 and is probably a a b Figure 3 | Management of acute gout attack. a | Example of an acute attack at the first metatarsophalangeal joint, known as ‘podagra’. b | Aspiration of an acutely inflamed joint; note the turbidity of the synovial fluid. Aspiration followed by injection of corticosteroids is safe, rapidly reduces the extreme pain of acute gout and enables confirmation of the diagnosis. In a hospital setting such treatment, especially in an ill patient with multiple comorbidities, should be considered best practice. REVIEWS © 2014 Macmillan Publishers Limited. All rights reserved
  • 5. NATURE REVIEWS | RHEUMATOLOGY VOLUME 10  |  MAY 2014  |  275 more important factor than individual dietary compo- nents. However, interest is growing in diet­ary altera­tions that might reduce the frequency of acute attacks in people with established gout, rather than influence hyper­ uricaemia and crystal deposition. A long-­recognized paradox is that many patients link the trig­gering of an acute attack to excessive consumption of dietary purine food and alcohol, which might be expected to increase SUA levels, whereas the accepted triggers for an acute attack (for example, intercurrent illness, surgery, initia- tion of ULT) are associated with a rapid decrease in uric acid levels that is hypothesized to encourage partial dis- solution and subsequent ‘shedding’ of preformed crys- tals into the joint space. A possible explanation for this paradox is that an increase in free fatty acids following a large meal might act as a ‘second signal’ and syner- gize with urate crystals to trigger the inflam­masome via ASC/caspase 1‑driven (but not NALP3-driven) release of IL‑1β.64 Conversely, the dairy fractions glyco­ macropeptide and G600 milk fat extract might inhibit triggering of the inflammasome by urate crystals.65 An RCT published in 2012 showed that daily intake of a skimmed milk powder enriched with glycomacropeptide and G600 reduces the frequency of acute gout attacks over a 3‑month period.66 Similarly, evidence from a 1-year case–crossover study showed that regular intake of cherry reduces the frequency of acute attacks, possibly owing to high levels of anthocyanins, which possess anti- inflammatory and antioxidant properties.67 There­fore, if patients are interested in dietary alterations, it might be very reasonable to advise avoidance of large, rich meals and to consider appropriate dairy supplements and cherry or cherry extract as safe self-­management st­rategies for reducing attack frequency. Other modifiable risk factors for hyperuricaemia can also sometimes be addressed. For example, chronic diuretic therapy for hypertension (rather than for heart failure) could be switched, where feasible, to an alterna- tive antihypertensive regimen, bearing in mind that in an observational cohort β-adrenergic blocking agents, angiotensin-converting enzyme inhibitors and non- losartan angiotensin II receptor blockers increased SUA whereas losartan and calcium-channel blockers lowered SUA68 (via reduced or enhanced renal excretion of uric acid, respectively). In some patients with end- stage renal disease, renal transplantation might nor- malize their SUA. Importantly, comorbidities that are associated with hyperuricaemia, such as hyper­tension, hyperlipidaemia and hyperglycaemia,7,69–71 need to be considered and optimally managed. These conditions are important in their own right, but tight control of each can indepen­dently reduce SUA levels through improved renal ex­cretion of uric acid.72,73 Urate-lowering therapy ULT is a key component of curative gout therapy and needs to be fully explained to each patient and upwardly titrated against a specific target SUA level. Patient edu- cation is crucial and, as shown in a proof-of-principle study,53 ensures excellent adherence to ULT. Upwards titration of ULT to achieve a level of SUA well below the saturation threshold of 360 μmol/l is important to enable the dissolution of existing crystals and prevent joint damage—in effect ‘curing’ gout. The lower the level of SUA obtained, the faster the dissolution of crystals and reduction in size of any tophi.74,75 It is important to explain to patients that they will remain at risk of acute Box 1 | Key messages when explaining the nature of gout Explanation of the causes of gout, including the following key points: ■■ We know its cause: deposition of urate crystals in and around peripheral joints ■■ Crystals form when SUA levels rise above the critical ‘saturation point’ for crystal formation ■■ In people with persistently raised SUA levels, crystals slowly but continuously accumulate without causing symptoms ■■ When sufficient crystals have formed in cartilage, some occasionally ‘spill out’ into the joint cavity, triggering severe inflammation of the joint lining and presenting as an acute attack ■■ Over many years, acute attacks can increase in frequency and spread to involve other joints ■■ In addition to acute attacks, continuing crystal deposition might eventually result in hard, slowly expanding lumps of crystals (tophi) that can cause pressure damage to joint cartilage and bone and can even appear as palpable lumps under the skin ■■ In some people, tophi could result in irreversible joint damage and cause regular chronic pain on using the joints ■■ Reduction and maintenance of SUA levels below the saturation point stops production of new crystals and encourages existing crystals to dissolve, so eventually there are no crystals and therefore no gout Explanation of relevant risk factors that elevate SUA levels above the saturation point, including: ■■ Hereditary factors that result in some people having relatively inefficient renal excretion of uric acid ■■ High body mass—the majority (around two-thirds) of uric acid is made by the body’s cells and this production increases with obesity ■■ A purine-rich diet—around one-third of uric acid comes from the diet ■■ Drugs (e.g. diuretics) that reduce the kidney’s ability to excrete uric acid ■■ Chronic renal impairment associated with ageing or kidney disease Abbreviation: SUA, serum uric acid. Figure 4 | “Punch cures the gout, the colic, and the ‘tisick” (anonymous). Historical sterotypes of gout persist and can act as barriers to adequate care. REVIEWS © 2014 Macmillan Publishers Limited. All rights reserved
  • 6. 276  |  MAY 2014  |  VOLUME 10 www.nature.com/nrrheum attacks until all existing crystals are dissolved, that if they do develop an attack it is not a sign that their ULT is ineffec­tive or making things worse, and that they should continue the ULT while they manage an acute attack. Gradual upward titration is probably important for reduc- ing the risk of acute flare, and in one study this strategy for initiating ULT seemed not to increase the frequency of attacks more than would have been expected (based on the frequency of self-reported attacks the previous year).53 Limited evidence is available to guide the commence- ment of ULT. Currently, indications for ULT include recurrent attacks of gout, clinically detectable tophi, joint damage or nephrolithiasis11 —in other words, well- established and relatively severe gout. However, urate crystal deposition is increasingly realized to be far more extensive than would be thought by clinical assessment alone. For example, ultrasonography studies published in 2011 and 2012 demonstrate obvious crystal deposition in a substantial proportion of people with asympto­matic hyperuricaemia,76,77 and dual-energy CT has shown extensive urate deposition in people with established gout, including at unsuspected sites such as the distal patellar tendon.78 In patients with gout, synovial fluid aspirated from knees that have not been the site of an acute attack will often show urate crystals.79 Therefore, it seems that crystal deposition is likely to be exten- sive in many peripheral joints even at the time of first presentation and that every person with gout is techni- cally ‘tophaceous’ in terms of having microtophi in and around their joints. Such a perspective is causing a trend towards earlier commencement of ULT, closer to the time of first diagnosis, particularly if a patient is young (for example, in their twenties, thirties or forties) or has a low estimated glomerular filtration rate.12 Certainly the patient should at least be informed at this time about the availability and expected benefits of ULT and be involved in the decision as to whether to start ULT. Most clinicians advocate delaying initiation of ULT until an acute attack has settled, owing to concern that commencing ULT will prolong the attack or precipitate a polyarticular flare. However, one placebo-controlled RCT found no difference in pain or flare rate when ULT with allopurinol (plus colchicine prophylaxis) was started during an acute attack compared with a delay of 10 days.80 Many general practitioners perceive logistical advantages to initiating ULT at the time a patient presents with an acute attack and argue that many patients will not re­attend 4 weeks later when everything is back to normal. Nevertheless, it seems sensible to provide enough infor- mation at the time of the acute attack to encourage sub- sequent reattendance and to wait until the second visit, when the patient is not in severe pain, to fully explain the disease and discuss its long-term management. Xanthine oxidase inhibitors Xanthine oxidase inhibitors (XOIs) are the usual first- choice ULT, with allopurinol favoured over febuxostat due to cost considerations and long-term safety data. XOIs reduce endogenous production of uric acid by inhibiting the conversion of hypoxanthine to xanthine and of xanthine to uric acid. Table 1 compares the key features of the two currently available XOIs. Allopurinol Allopurinol is a purine analogue and a nonspecific com- petitive inhibitor of xanthine oxidase. Its active metabo- lite, oxypurinol, is predominantly excreted via the kidney. Although no placebo-controlled RCTs have confirmed the efficacy of allopurinol, decades of clinical experience and several head-to-head studies81–83 have shown it to be an effective, well-established, cheap and relatively safe ULT, and it is therefore recommended as first-line ULT.11 The dose range of allopurinol is large, meaning it can be titrated in small increments for maximum effective- ness. In a 2013 observational study in the UK,53 the median dose of allopurinol required to reach the thera- peutic target of SUA ≤360 μmol/l (achieved in 90% of participants) was 400 mg once daily. This dose is higher than the commonly prescribed daily dose of 300 mg, demonstrating the importance of adjusting therapy for maximum effectiveness in individual patients. It might be that 300 mg was adequate for most people when the first dose-ranging studies for allopurinol were published around the 1960s, but that population-level increases in height and BMI mean 300 mg is now suboptimal; when used in RCTs in the USA in 2005, this dose achieved the therapeutic target in only around 20% of patients.84,85 An initial dose of 100 mg daily is recom­mended, with sub- sequent incremental increases of 100 mg approximately every month (up to a maximum of 900 mg), stopping these increases at the dose at which SUA is lowered to 360 μmol/l (6 mg/dl)13 or preferably 300 μmol/l (5 mg/dl). The evidence for dose-­adjustment of allo­ purinol in patients with renal impairment, using 50 mg increments, is inconclusive.86–89 Stamp et al.89 suggest that dose-adjustment algorithms based on creatinine clear- ance of allopurinol were overly cautious and that with gradual upward titration the target SUA level can often be reached safely, even in the setting of renal impairment, and at doses that are above those recommended. Table 1 | Comparison of XOIs Characteristic Allopurinol Febuxostat Action Nonspecific XOI Specific XOI Elimination Renal Hepatic Daily dose* (50 mg), 100–900 mg (40 mg), 80 mg, 120 mg DRESS Rare Rare Cautions Severe renal impairment Heart failure (NYHA class III or IV), hepatic failure, eGFR 30 ml/min/1.73 m2 Interactions Cytotoxic drugs metabolized by XO (for example, azathioprine, mercaptopurine) Warfarin Cytotoxic drugs metabolized by XO (for example, azathioprine, mercaptopurine) Cost of 28 tablets‡ £1.06 (300 mg tablets) £24.36 (80 mg or 120 mg tablets) *The doses in parentheses can be used in patients with renal impairment but are not routinely used. ‡ According to information from the British National Formulary.135 Abbreviations: DRESS, drug reaction with eosinophilia and systemic symptoms; eGFR, estimated glomerular filtration rate; NYHA, New York Heart Association; XO, xanthine oxidase; XOI, XO inhibitor. REVIEWS © 2014 Macmillan Publishers Limited. All rights reserved
  • 7. NATURE REVIEWS | RHEUMATOLOGY VOLUME 10  |  MAY 2014  |  277 Allopurinol is usually well-tolerated, by approximately 8–9 out of 10 patients,53,82 the usual cause of intolerance being nausea, gastrointestinal disturbance, headache or rash. However, allopurinol can rarely cause a serious syn- drome of drug reaction or rash with eosinophilia and sys- temic symptoms (DRESS; previously termed allopurinol hypersensitivity syndrome), which can cause fever, severe cutaneous adverse reactions (SCAR; including toxic epidermal necrolysis and Stevens–Johnson syndrome), hepatitis, vasculitis, renal impairment and sometimes death.90 Allopurinol-induced DRESS usually occurs within the first few months of treatment and reported risk factors include renal impairment, concomitant use of diuretics, initiation of treatment with a fixed dose of 300mg and, particularly in Korean, Chinese and Thai populations, presence of the HLA‑B*5801 allele.12,91 It might be reasonable to consider screening for this polymorphism in populations with a high prevalence of HLA‑B*5801.91 The precise incidence of DRESS from allopurinol use is unclear but allopurinol is reportedly the most frequent cause of SCAR.90 Although rare, the occur- rence of severe DRESS and SCAR is another reason to start low and gradually increase the dose of allopurinol.92 Allopurinol has also been shown to be beneficial in cardiovascular disease93,94 and renal disease,95,96 both of which commonly coexist with or occur as a complication of gout. Although still controversial and not currently licenced for these indications in most countries, this is another potential benefit of ULT which, if explained to patients at risk of cardiovascular or renal disease, might further encourage adherence to treatment. Whether the cardio-renal benefits result from lowering of SUA or from xanthine oxidase inhibition remains uncertain.97 Febuxostat Licenced in 2008 in Europe, febuxostat is a non-purine, highly specific XOI that undergoes predominantly hepatic metabolism. Two placebo-controlled double- blind RCTs have demonstrated its efficacy in reducing SUA.84,98 Two further double-blind RCTs compared doses of 40–240 mg febuxostat against a fixed daily dose of 300 mg allopurinol85,99 and showed that febuxo­stat was superior at doses of 80 mg and 120 mg daily. How­ever, the trials that included allopurinol did not allow for upward titration of the allopurinol dose against SUA level, which is the established best clinical practice. Furthermore, in these RCTs84,85 approximately 30% of participants on febuxostat do not reach the therapeutic target (SUA 360 umol/l) at the highest recommended dose (120 mg daily), whereas in clinical practice upward titra­tion of allopurinol in those who tolerate it would usually achieve this target at doses well under the maximum dose (900 mg daily).53 The most common adverse event deemed attributable to febuxostat in the early clinical trials was liver-­function test abnormalities, but the possibility of an adverse cardio­vascular signal (more myocardial infarction, stroke and cardiovascular death in febuxostat than allopurinol participants, though nonsignificant) led to febuxo­stat not being recommended in people with heart failure.100 Long-term safety studies to address these con­cerns are in progress. Also, although febuxostat was initially thought to be free of the serious SCAR and DRESS reac- tions associated with allopurinol, some cases of severe hypersensitivity cutaneous reactions have subsequently been reported.101,102 Undoubtedly, the main advantage of febuxostat over allopurinol is that it can be used without dose-adjustment or concern over toxicity in people with renal impairment (although it is not recommended for use in those with an estimated glomerular filtration rate 30 ml/min/1.73 m2 ). Disadvantages include the inability to slowly increase the dose (only 80 mg and 120 mg tablets are available in most countries, and provocation of acute gout attacks at the starting dose of 80 mg is likely),84,85,98,99 cardiovascular safety concerns, and high cost. Although the ACR guidelines (which did not consider cost) do not favour one XOI over the other,13 the UK National Institute for Health and Clinical Excellence (which does consider cost utility) recommends allo­purinol as the first-line XOI, with febuxostat recommended as a second option in those who cannot tolerate allopurinol or in whom it is contraindicated or ineffective.103 Uricosuric drugs Available uricosuric drugs act predominantly on urate anion exchanger 1 (URAT1)—an organic anion t­ransporter—to prevent reuptake of uric acid at the proxi­ mal renal tubule and thus increase renal excretion of uric acid (Figure 5). The resulting higher con­centration of uric acid in the collecting tubules can predispose to uric acid stone formation, so the patient should be advised to drink plenty of fluids and remain well-hydrated. Three uricosuric drugs are licenced and well-established as ULT: benzbromarone (50–200 mg daily), probenecid (250– 500 mg twice daily) and sulfin­pyrazone (200–800 mg daily). Although inexpensive, their use is limited by lack of availability in most countries. These medications are all effective at reducing SUA82,104–107 and have dose ranges that readily enable stepwise dosage increases. Probenecid and sulfin­pyrazone are contraindicated in patients with severe renal impairment or nephrolithiasis, which further Basolateral membrane Renal proximal tubule epithelial cell Apical (brush border) membrane Probenecid Benzbromarone Sulfinpyrazone Sulfinpyrazone OAT1 OAT3 GLUT9 URAT1 OAT4 Uric acid Uric acid Probenecid Benzbromarone Proximal tubule lumenCirculation Figure 5 | Mechanism of action of uricosuric drugs at the proximal renal tubule. Uricosuric drugs licenced for gout (shown in blue boxes) act on URAT1 to prevent re-uptake of uric acid and thus increase its renal excretion. As this is a simplified schema, not all transporters are shown. Abbreviations: OAT, organic anion transporter; GLUT9, glucose transporter type 9; URAT1, urate anion exchanger 1. REVIEWS © 2014 Macmillan Publishers Limited. All rights reserved
  • 8. 278  |  MAY 2014  |  VOLUME 10 www.nature.com/nrrheum limits their use. Benzbromarone is not contraindicated in those with mild or moderate renal impairment and can still be very effective in this situation. The avail- ability of benz­bromarone became limited mainly due to concerns over reports of hepatotoxicity, particularly in Asia, although the reported risk in European popula- tions is estimated to be at most 1 in 17,000 patients.108 Nevertheless, liver function should be checked whenever SUA level is meas­ured, especially in the first few months of initiation and dose-adjustment of uricosuric therapy. Other available ULTs Losartan,109 oral vitamin C supplements,110,111 and feno­ fibrate112 all have direct uricosuric effects and have been shown to reduce SUA levels in people with hyper­ uricaemia. For losartan and fenofibrate, this uricos­ uric action is in addition to their beneficial effects on hypertension and hyperlipidaemia, respectively. How­ ever, the urate-lowering effects of all three approaches are fairly modest and, on their own, are unlikely to achieve the therapeutic target level of SUA.113 These agents remain unlicenced for use in gout, but losartan and feno­fibrate can be considered as useful adjunctive ther­apy for patients who require treatment for coexistent hy­pertension or hyperlipidaemia. Unlike some other animals and bacteria, humans lack uricase—an enzyme that converts uric acid to highly soluble allantoin. Pegloticase is a pegylated uricase that was recently licenced (2010 in the USA, 2013 in Europe) for use in ‘treatment-refractory’ gout. This drug is administered by repeated intravenous infusion (8 mg every 2 weeks seems optimal), a regimen that limits its use to the hospital setting. Pegloticase is extremely effective at rapidly reducing SUA to very low levels for several weeks.114 However, it is also antigenic,115 with a risk of anaphylaxis and infusion reaction, so premedi- cation with antihistamine and corticosteroids in an appropriately staffed facility is recommended.116 Con­ cerns also remain over cardiovascular risk, and this drug should be used with caution in people with heart failure. A large proportion of patients undergoing repeat infusions develop blocking antibodies against the PEG component,115 which not only reduces ULT efficacy but also increases the risk of adverse reactions. Therefore, following successful initiation of treatment, a subse- quent preinfusion SUA 360 μmol/l is an indication to withdraw treatment (recom­mended by the manu­fac­ turers). Although pegloticase is seemingly very efficient at induc­ing rapid regression of tophi, the number of patients who are truly refractory to other standard ULTs is likely to be extremely small, and because of safety and tolerability concerns, and the cost and logistics of deliv- ery of this drug, its use is likely to be very restricted. Rasburicase, a uricase that has been licenced for many years for tumour lysis prophylaxis, has also been used to treat ‘refractory’ gout where intolerance or renal impair- ment precludes the use of other ULTs.117,118 However, although some patients seem to tolerate repeated doses, rasburicase is unlicenced for gout and is more antigenic than pegloticase.119,120 ULTs in development Other drugs that are undergoing clinical investigation as potential ULTs include RDEA594 (lesinurad), which is a uricosuric,121 and BCX4208 (ulodesine), which is a purine nucleoside phosphorylase inhibitor.122 How­ever, these agents are not yet available or licenced for use in gout, either as monotherapy or in combination with an XOI. What is the optimum SUA level? Current guidelines agree that SUA should be reduced and maintained to a level below 360 μmol/l (6 mg/dl)11,13 to prevent further crystal formation and to encourage dis- solution of exisiting crystals.123 However, the lower the SUA, the faster the dissolution of crystals and tophi75 and the sooner the patient reaches the state of being ‘cured’. Therefore, particularly in patients with a long history of gout79 or the presence of tophi, an initial target of 300 μmol/l (5 mg/dl) might be more successful; this is the target recommended by the BSR.12 Concern is increasing, however, that lifelong maintenance (that is, after acute attacks have stopped and any tophi have resolved) of SUA at very low levels might increase the risk of neuro­degenerative diseases such as Parkinson, dementia and multiple sclerosis, which appear to be negatively associated with gout.124 This is because uric acid is a strong antioxidant97 and although this benefit is countered by its other detrimental effects on vascular endothelium, its antioxidant benefits may predominate within the central nervous system. Although there is no absolute agreement on the optimal SUA level that asso- ciates with no disease risk in humans, the concept of an initial crystal-clearing ‘induction phase’ followed by a later ‘maintenance phase’ of ULT is one that is increas- ingly discussed.125 We suggest that the initial SUA target to effect a ‘cure’ should be well under 300 μmol/l for the first 3–5 years of treatment but that subsequently, when no further attacks have occurred and any tophi have regressed, the dose of ULT should be reduced to allow the SUA to rise somewhat but remain below the saturation point to prevent crystal formation (that is, in the range 300–360 μmol/l) (Figure 6). The length of time the patient should continue ULT is guided by SUA level. For most patients, use of this target could mean lifelong therapy, but at a low dose. However, in patients with an attributable risk factor that can be success­fully modified (for example, by stopping long-term thia­ zide therapy, successful renal transplantation, marked reduction in BMI) cessation of ULT might be consid- ered after the induction phase or some time into the maintenance phase. Flare prophylaxis Initiation of ULT can provoke acute attacks, some- times involving several joints and even joints pre­viously un­affected by gout. This flare of disease is particularly likely if SUA is rapidly and substantially lowered by a high or very efficient dose of ULT (for example, allo­ purinol 300 mg daily, febuxostat 80 mg daily, uricase). It is thought to result from the rapid partial dissolution REVIEWS © 2014 Macmillan Publishers Limited. All rights reserved
  • 9. NATURE REVIEWS | RHEUMATOLOGY VOLUME 10  |  MAY 2014  |  279 of and thus easier ‘shedding’ of crystals. If the patient is not fully informed about the possibility of this flare in advance, such an event might cause a patient, quite reason­ably, to give up on their ULT and even to be unwilling to consider further advice for their gout. To reduce the risk of ULT-induced flares, the EULAR guidelines recom­mend co-prescription of either low- dose colchicine (usually 0.5 mg once or twice daily) or an oral NSAID (plus PPI) as prophylaxis for the first few months of ULT.11 Certainly one RCT has confirmed that colchicine is more effective than placebo in reducing the number of acute attacks during the first 6 months of allopurinol treatment.126 Additionally, a post hoc analysis of three RCTs of febuxostat, in which patients received either 8 weeks or 6 months of prophylaxis with naproxen 250 mg twice daily or colchicine 0.6 mg daily, found an increase in flare rate (up to 40%) at the end of 8 weeks of prophylaxis, whereas flare rates remained low (3–5%) at the end of 6 months of prophylaxis.127 However, low-dose colchicine, and possibly NSAIDs, might reduce the flare rate in people who are not on ULT, and a key question is whether initiation of ULT using the recommended slow up-titration regimen (as is possible with allo­purinol in particular) actually causes more attacks than may have been expected otherwise. Furthermore, in a study (n = 96) where patients were given a full explanation of the possible risk of flare from ULT and of the avail­ability of prophylaxis, the vast majority (96%) preferred to take just the one drug (ULT) without prophylaxis and to just manage acute flares as they arose.53 Most patients in this study (65%) experienced fewer attacks in the year fol- lowing ULT initiation than in the preceding year and only one in five reported more attacks (mean 2.7 more). Further studies of whether or not slow up-titration increases the risk of flare are warranted to better inform shared decision-making. Rilonacept and canakinumab have shown efficacy in gout prophylaxis, but as already noted these agents are very expensive and currently not licenced for this use.45,46 Improving the standard of care Despite the availability of effective treatments for gout and of published recommendations to guide best prac- tice, it is apparent that the current standard of care for patients with gout is more than just “suboptimal”.128–132 This criticism applies to both primary and secondary care physicians, including rheumatologists. Few patients are given an adequate explanation of the cause of gout and its possible outcomes, or educated as to the avail­ability and possible benefits of treatment. Most doctors concentrate solely on the management of acute attacks rather than long-term therapy, and only one-third to one-half of gout patients ever receive ULT.1,10,15 Very few general practi- tioners who offer ULT aim for a speci­fic SUA level or serially check SUA133 and most use allopurinol at a fixed dose of 300 mg (which is insufficient for most patients).53 This ‘standard of care’ leads to many people with gout continuing to experience acute attacks and being at unnecessary risk of developing joint damage. Because appropriate information is not provided, patients with gout show poor adherence to any ULT offered and, if they stop ULT because ‘the tr­eatment’s not working’, they are often misclassified as ‘treatment failures’.130 Barriers to effective care can develop both from the patient and the physician (Box 2).54 Full clinical assessment followed by clear informa- tion from the practitioner and subsequent involvement Time SUAlevel Dissolution of MSU crystals 360μmol/l Introduction of ULT Figure 6 | Graph representing clearance induction and maintenance phases of therapy for gout. In the induction phase, ULT reduces the SUA level to well below the saturation threshold (indicated by the dashed line), to enable dissolution of existing crystals and ’cure’ of gout. In the maintenance phase, ULT is reduced following this ‘cure’, and the SUA level is allowed to rise to just below the threshold for maintenance. Abbreviations: MSU, monosodium urate; SUA, serum uric acid; ULT, urate-lowering therapy. Box 2 | Barriers to effective management of gout54,130 Patient barriers ■■ Patients lack knowledge and understanding about the causes and consequences of gout ■■ Gout is often not considered as ‘arthritis’ or as something serious, and is often associated with humour ■■ Gout is considered a man’s disease; women might be unwilling or embarrassed to receive the diagnosis, men might be reluctant to seek medical attention ■■ Gout is considered as a normal part of ageing, self- inflicted by overindulgence and poor lifestyle, stigma and negative stereotypical view ■■ Patients do not adhere to pharmacological treatment Physician barriers ■■ Many primary care staff lack knowledge and understanding about the causes and consequences of gout ■■ Gout is not always managed as a long-term chronic disease but as an acute condition ■■ Patients are not educated or given information to encourage lifestyle modification and adherence to long-term urate-lowering therapy ■■ Clinical guidelines for gout are not known or utilized, particularly in primary care ■■ Training and education in best practice for the treatment and management of gout is lacking at the undergraduate and postgraduate level ■■ Care providers lack incentives to improve treatment and long-term management of gout in general practice Adapted by permission from BMJ Publishing Group Limited. Spencer, K. et al. Ann. Rheum. Dis. 71, 1490–1495 (2012).54 REVIEWS © 2014 Macmillan Publishers Limited. All rights reserved
  • 10. 280  |  MAY 2014  |  VOLUME 10 www.nature.com/nrrheum of the informed patient in decision-making is impor- tant in any medical condition. This process is central to the principles of health care and is considered a key professional responsibility by the UK General Medical Council.134 Fortunately, gout is a very easy disease to explain—certainly easier than many other less-well- understood musculoskeletal conditions—and in the vast majority of cases the practitioner can be very posi- tive when discussing management options and progno- sis (Figure 7). Poor adherence is predominantly due to lack of patient education by the doctor. As demonstrated in a proof-of-­principle study,53 a package of care that includes full patient education on gout and its treatment, discussion of illness perceptions, and development of an individual­ized management plan (that is, recommended best practice) can result in excellent patient outcomes. When given appropriate information (Box 1), 100% of patients in this study opted for ULT and during 1 year of follow-up adherence was excellent, with more than 90% achieving and maintaining the therapeutic target of SUA level 360 μmol/l and beginning to show improve- ments in quality of life.53 Although participants in this study were first seen by a rheumatologist in a hospi­tal set­ting (for approximately 1 h), subsequent follow-up was carried out by a specially trained nurse, often in the patient’s home. As is the case with other prevalent chronic conditions (for example, diabetes, asthma), it is likely that nurse led-care of gout could be successful and cost-effective in a community setting; an RCT is currently comparing nurse-led care to ongoing general practitioner care over a 2‑year period in UK general practice. Given the high prevalence of gout and its potentially serious consequences, it is clearly important that health professionals have appropriate training in the ‘best prac- tice’ management of gout, to enable them to educate and treat their patients appropriately. General practitioners in the UK admit in general that incentives, especially finan- cial incentives, are required for them to alter their inter- est and practice,54 and this change could be facilitated if gout became a designated condition within the Quality and Outcomes Framework for general practice in the UK—a scheme in the UK that offers financial incentives to general practices for achieving specified medical targets for common conditions. Should the growing evidence that high SUA level is an independent risk factor for cardio- vascular disease, stroke and CKD become accepted, and should ULT become licenced for the treatment of hyper­ uricaemia per se, these developments would have a major impact on the prevalence and incidence of gout. How­ever, given the currently high prevalence of gout, the impact it has on patient health and quality of life, andthe availability of effective ‘curative’ treatment, it seems justified to argue for appropriate education of practitioners to improve standards of care on the basis of gout itself. Conclusions A number of established and effective treatments exist for managing gout, with new options on the horizon. Despite this, gout care is often suboptimal and it is apparent that just having effective drugs is not sufficient to effect a ‘cure’.131 Education of patients can empower them to make lifestyle changes and ensure they under- stand the importance of adherence to long-term ULT. In conjunction with this, health-care professionals need to be aware of current best practice and how to up-titrate ULT against a specific target level of SUA, but more importantly they need to know how to address illness perceptions and educate their patients appropriately, so that individualized management plans can be developed on the basis of shared decision-making. Current trends are towards much earlier consideration of ULT, increas- ingly towards the time of first diagnosis, and although still controversial the arguments to treat elevated SUA for cardiovascular and renal disease rather than just gout are becoming stronger and have been accepted in some countries including Japan. Although gout is relatively well-understood, further research is required into various aspects including the optimum level of SUA for long-term manage­ment and, most importantly, how current stand- ards of care can be improved using existing knowledge and effective treatments. Figure 7 | A full and holistic assessment followed by individualized patient education is core to the management of people with gout. In this instance, a specialist nurse practitioner is assessing a patient and her explanation of his chronic tophaceous gout, its treatment options, and the likely benefits he can expect from ULT will be backed up by focused patient literature. Written consent for publication was obtained from the patient and nurse. Image provided courtesy of M. Doherty. Review criteria Articles for this Review were found by systematic review of the following databases: MEDLINE (1946–present), Embase (1974–present), PubMed (from inception to present), Cochrane Controlled Trials Register (from inception to present), ISI Web of Science and AMED (1985–present). The search strategy used terms for gout, including “gouty arthritis”, “podagra”, “tophi”, “monosodium urate crystals” and “hyperuricaemia”, in combination with terms for studies or trials, including “RCTs”, “cohort studies”, “case–control studies” and “systematic reviews”. Preliminary searches were undertaken in March 2012, and were updated July 2012. Subsequent relevant articles were added as published. REVIEWS © 2014 Macmillan Publishers Limited. All rights reserved
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