- Email: [email protected]
An update on gout
Indian Journal of Rheumatology 2006 September Volume 1, Number 2; pp. 60–65
Review Article
An update on gout I Pande
ABSTRACT Gout is the most common cause of inflammatory arthritis in men aged more than 50, affecting approximately 1–2% of adult men in the Western world. The incidence and prevalence of gout is on the rise. Increasing longevity, dietary trends, obesity, metabolic syndrome, hypertension, increased use of low-dose aspirin, major organ transplantation and increased survival from coronary artery disease and end-stage renal disease have been implicated as the possible contributory factors. By far, the commonest cause of hyperuricaemia (that accounts for 90% of patients with gout) is decreased renal clearance. Patients with gout should avoid excess of alcohol (beer and spirits, particularly), red-meat and sea-food. Vegetarian food and dairy products reduce the risk of gouty arthritis. For the treatment of acute gout, options include non-steroidal antirheumatic drugs (NSAIDs), steroids (systemic or intra-articular) and colchicine. High dose of colchicine often results in diarrhoea and should be best avoided. Most patients respond within 18 hours to a dose of 0.5 mg twice daily. Colchicine is contraindicated if creatinine clearance is lower than 30 ml/min. Optimal treatment of chronic gout requires long-term reduction of serum urate to the lower half of the normal uric acid reference range. Prevention of attacks requires modification of lifestyle factors such as weight loss, moderation in the consumption of alcohol and meat and withdrawal of drugs known to cause elevated uric acid levels. Drugs used for chronic gout can be divided in three categories: (a) Uricostatic (xanthine oxidase inhibitor), e.g. allopurinol, oxipurinol, febuxostat, (b) Uricosuric, e.g. benzbromarone, sulfinpyrazone, probenecid, losartan, fenofibrate and (c) Uricolytic, e.g. uricozyme, rasburicase. Febuxostat is a new oral xanthine oxidase inhibitor, which has been shown to be more powerful in lowering uric acid levels compared to allopurinol. The drug is mainly metabolised by the liver and can be used in renal and hepatic insufficiency with no dose adjustment. Benzbromarone is an excellent uricosuric agent. Pegylated uricase is currently under development. Keywords: Gout, treatment, update.
INTRODUCTION Gout is derived from the Latin word gutta, meaning drop, as it was believed that poison falling in drops into the affected joints caused gout. Sir Alfred Garrod linked gout with hyperuricaemia in 1848. We now know that hyperuricaemia is a common serum abnormality, and not everybody with raised serum uric acid will develop gout; may be only 1 in 5 progress. In 1961 McCarty and Hollander1 identified monosodium urate (MSU) crystals in the synovial fluid of patients with acute gout. Year later (1962) calcium, pyrophosphate crystals were identified in patients with pseudogout.2 Gout
we now believe is a multifactorial disease characterized by hyperuricaemia and MSU crystal deposition in the joint.
EPIDEMIOLOGY The incidence and prevalence of gout is on the rise. A study by Arromdee3 in 2002 showed the annual incidence of gout in Rochester Minnesota to increase from 45/100,000 in 1977–1978 to 62/100,000 on repeat survey in 1995–1996. The male to female ratio remained unchanged (3.3 : 1). The later study also suggested that gout was increasingly being
Consultant Rheumatology, Nottingham University Hospital’s NHS Trust, Nottingham, UK. Correspondence: Dr. Ira Pande, email: [email protected]
An update on gout
diagnosed at a younger age. It also suggested that there was a greater than a 2-fold increase in the incidence of primary gout. A more recent study by Mikuls et al.4 in 2005 has also shown similar increases in incidence in gout in the UK. Prevalence of gout has doubled over the last two decades according to Wallace et al.5 and Mikuls et al.4 The rise is mainly in the older population, and the increase is similar in men and woman. Men are affected three times more frequently than women. These findings are echoed by a survey in England, which also found a three-fold increase between 1975 and 1993. The Rochester epidemiology project suggests following factors to play a role in the changing demographics: increasing longevity, dietary trends, obesity, metabolic syndrome, hypertension, increased use of low-dose aspirin, major organ transplantation and increased survival from coronary artery disease and end-stage renal disease. Gout is the most common cause of inflammatory arthritis in men aged more than 50, affecting approximately 1–2% of adult men in the Western world. It is rare in children and premenopausal women. Men have higher serum urate levels, which rise shortly after puberty. Oestrogens increase urate clearance and levels of urate in premenopausal women are generally well below solubility limit. After the menopause, reduced oestrogen will reduce excretion of uric acid thereby putting women at equal risk of gout as men. Of gout patients over 60 years of age, 50% are women. The declining use of HRT may further increase the frequency of gout in women and at an earlier age too.
WHY DO HUMANS GET GOUT? Purines derived either from the diet or by de novo synthesis convert nucleotides to hypoxanthine (a monoxide) which then converts to xanthine (a dioxypurine) with final conversion to uric acid, a trioxypurine. Uric acid has three oxygen groups attached to it and at normal body temperature has limited solubility in the serum. A concentration of > 416 μmol/l is taken to denote hyperuricaemia, the concentration above which urate saturation occurs with crystal precipitation and resulting gout. During the evolutionary process humans and the greater apes lost the enzyme uricase, which converts uric acid (insoluble) to allantoin (soluble) and carbon dioxide.
PATHOGENESIS AND RISK FACTORS FOR GOUT5 Purines are derived from two sources, diet and de novo synthesis. Dietary purines constitute one-third with the remaining
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two-thirds obtained from tissue nucleic acids and endogenous purines synthesis. Uric acid is the end product of purine biosynthesis whereby purine nucleotides are converted to hypoxanthine and then xanthine before converting to uric acid. At a concentration of around 6.8 mg per decilitre (around 400 μmol per litre) uric acid remains in a soluble state. Factors such as local trauma with resultant increase in tissue breakdown, infection or surgery with associated alteration in pH or dietary excess, fasting or binges of alcohol precipitate uric acid in tissues leading to gout. Two-thirds of the serum uric acid is excreted by the kidney with the remaining one-third by intestinal uricolysis. The process of elimination of uric acid by the kidney involves the glomerulus and proximal convoluted tubule (PCT). Glomerular filtration is 100% with 98% being reabsorbed in the first part of the PCT followed by 50% secretion in the second part with further reabsorption of approximately 40–48% resulting in a net reabsorption of approximately 90% leading to only 8–12% of the uric acid being excreted by the kidney. By far, the commonest cause of hyperuricaemia (that accounts for 90% of patients with gout) is decreased renal clearance. Dehydration, use of diuretics, insulin resistance and metabolic syndrome increase reabsorption of uric acid in the first part of the proximal convoluted tubule. Surgery, trauma, infection leading to keto or lactic acidosis reduce secretion in the second part. Low-dose aspirin not only increases mean serum uric acid by 6% but reduces uric acid clearance by approximately 23% leading to increased gout. Drugs such as cyclosporine compete with urate for renal excretion in addition to impairing renal tubular handling of uric acid. This accounts for cyclosporine-induced gout in patients with renal impairment and transplant subjects. Other factors such as hypertension, hyperparathyroidism and hypothyroidism lower glomerular filtration with further impairment of uric acid excretion causing hyperuricaemia and gout. Uric acid over production accounts for only 10% of gout. Increase in dietary purines associated with diet and lifestyle changes such as increased consumption of seafood, red meat and intake of beer, lager and spirits increases uric acid synthesis as a result of the end product of purine biosynthesis. Rare disorders such as HGPRT deficiency, myelo and lympho-proliferative diseases and psoriasis account for increased endogenous purine synthesis causing hyperuricaemia and gout. Decreased solubility of urate (low pH and low temperature), disturbance to joint and soft tissue (trauma/tissue injury), or reabsorption of water resulting in super saturation of uric acid in the serum (lack of joint activity during sleep) are some of the factors influencing crystal deposition leading to gout. Certain drugs also cause increased gout. Diuretics reduce uric acid reabsorption and low dose aspirin
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as mentioned earlier increases mean serum uric acid levels and reduce uric acid clearance leading to gout. There are differences in risk of gout in men and women. Men have higher serum urate levels at all ages compared to women. In men serum uric acid rises shortly after puberty accounting for an overwhelming proportion of younger patients with gout being men. Women have serum uric acid levels well below solubility limit. Furthermore, oestrogens in the premenopausal woman increase urate clearance. However, after the menopause decreased oestrogen may reduce renal excretion of uric acid accounting for an equal proportion of women and men having gout aged over 60. The declining use of HRT may increase the frequency of gout in younger women and result in gout at an earlier age. The Health Professionals Study6 has shown an increased risk of gout amongst those who consumed the highest quintile of meat, seafood and alcohol. A 41% increased risk of gout was associated with high intake of organ meats and a 51% increased risk with high intake of seafood. No association was seen with moderate intake of purine rich vegetables. High dairy intake reduced the risk by 44%. Amongst alcohol beverages, beer and spirits (not wine) were the main risk factors for gout.
GOUT IN TRANSPLANT PATIENTS Gout is common in transplant patients. Some of the factors are frequent use of diuretic and cyclosporine. Hyperuricaemia develops in 70–80% of cyclosporine treated patients. Gout develops in 8–13% usually within 2–3 years of starting cyclosporine. The presentation is atypical with rapid and extensive tophi, involvement of upper extremity and the axial skeleton, being polyarticular and refractory to treatment. In this group, a higher incidence of colchicine toxicity with rapid onset of myopathy is also noted. Mycophenolate mofetil may reduce the risk and should be considered in this group with gout.
MANAGEMENT There are two main reasons for treatment failure; poor compliance associated with lack of patient understanding of the disease/drugs and second misuse of allopurinol. Both patient and physician education is crucial for the long-term optimal management of this disease. In recent years, key prospective epidemiological studies have provided insights into the role of lifestyle modification in treating gout. Results from these studies can be used to inform patients and increase chances of success in lifestyle modification. Obesity (BMI > 30) is linked to the development of insulin resistance (metabolic syndrome) which is
Pande
complicated by hypertension, hyperlipidaemia, increased risk of gout and coronary artery disease. The Health Professionals Follow-up Study7 and the Nurses Health Study8 have shown a clear dose–response relationship between body mass index (BMI) and risk of gout. In addition to absolute BMI, increase in BMI over time is also associated with an increased risk for gout. However, a loss of more than 10 lbs since study entry was shown to be associated with a 30% reduction in risk of gout (RR 0.61). These observations support weight loss as an important factor in the long-term management of patients with chronic gout. Until recently, patients with gout were typically advised to avoid foods rich in purines. The recent study by Choi et al.6 provided evidence to advice patients with gout to consume meat and sea food in moderation, with special attention to food portion size and content of non-complex carbohydrates. Men with highest quintiles of meat and seafood intake were noted to have an increased risk of gout compared to those in the lowest quintile, with odds ratios (ORs) of 1.4 and 1.5, respectively. Total protein intake was not associated with increased risk. In fact, high protein diets have been associated with increased urinary excretion of uric acid. Vegetable protein and dairy intake inversely correlated with risk of gout, with ORs of 0.56. The Nurses Health Study8 further strengthens these associations. Therefore, patients should be cautioned against using the protein content of food as a surrogate marker of purine content. Alcohol increases uric acid production and decreases uric acid excretion. Beer, which has the highest content of malt of the readily absorbable purine guanosine further increases uric acid production. Chronic heavy alcohol intake also inhibits conversion of pro-drug allopurinol to its active metabolite oxypurinol. The Health Professionals Study9 found that alcohol intake was associated with an increased risk of developing gout. The risk increased with increasing intake of total alcohol, with greatest association with beer and spirits. The risk of gout increased by 1.17/10 g increase in daily alcohol intake. Wine did not show an association. Results of these two prospective studies showing the impact of diet on hyperuricaemia and gout encourages modification of reversible risk factors such as consumption of beer, lager, spirits, red meat and seafood in patents with gout. Addressing other risk factors like hypertension, hyperlipidaemia, use of diuretics, aspirin and considering use of mycophenolate mofetil (MMF) instead of cyclosporine where applicable is useful adjunct to therapy.
ACUTE GOUT Most patients know when an acute episode is imminent. Due to mast cell degranulation and histamine release a
An update on gout
number of patients, report local itching and burning. Most have experienced gout at night (around 2 AM). Low temperature and lack of joint activity during sleep leading to reabsorption of water with super saturation of serum uric acid precipitating as crystals accounts for it. The episode builds to a peak over several hours with intense pain and increased sensitivity of the overlying skin. In over 70% the first metatarsophalangeal joint (MTP) is involved. Other common joints involved are the tarsal joints, ankle, knee and wrist. The hip, shoulder and spine are usually spared probably due to the higher temperature whereby crystals don’t precipitate. Complete resolution of the attack is usually seen within a week even without treatment. A positive family history and a previous self-limiting episode are helpful/or deceptive (pointer). It can occasionally cause bursitis or tenosynovitis in isolation. In less than 50% acute gout is polyarticular. One needs to remember that gout in the elderly can be polyarticular and chronic. Serum uric acid levels can be normal, especially during an attack and diseases other than gout may respond to colchicine. Atypical joint involvements can occur for example, Heberden’s nodes in elderly women with nodal osteoarthritis. The diagnosis is based on classical history and examination findings. The gold standard test is synovial fluid analysis, which reveals negatively birefrengent crystals on polarised light microscopy. In the elderly, pseudogout forms an important differential. Septic arthritis, which is often indistinguishable, may coexist. A polyarticular presentation mimics rheumatoid arthritis. Sixty-two per cent of individuals experience a second episode within a year, 78% within 2 years. Seven per cent have no episodes of gout following the first attack for upto 10 years. Once a patient has had 2, 3 or more attacks, the chances of further attacks are quite high. These factors may help physician and the patient decide when to initiate treatment. Prophylaxis against recurrent episodes is indicated for patients with frequent episodes, chronic tophaceous or polyarticular gout, patients with comorbidities where attacks are difficult to treat and those at risk of urate nephropathy or those in whom radiology reveals established erosions.
TREATMENT OF ACUTE GOUT10 The affected joint/s should be rested and drug therapy started as soon as possible to ensure the most rapid and complete response. There is evidence that rest and cold application to the affected joint may shorten the attack and decrease the need for medication. Drug options for the acute attack include oral non-steroidal antirheumatic drugs (NSAIDs), oral colchicines and corticosteroids (oral, intramuscular,
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intraarticular). The most important determinant of success is how soon therapy is initiated rather than with which agent. If a single joint is involved many rheumatologists prefer joint aspiration followed by intra-articular steroids once sepsis is ruled out. Oral NSAIDs should be used with caution in patients with previous peptic ulcer disease, concurrent use of oral anticoagulant, hypertension, congestive cardiac failure and renal impairment. Urate lowering drugs should be continued throughout the acute episodes if they have been commenced previously but should not be commenced during an acute episode. For colchicine to be optimally effective, the drug should be started at the first sign of an acute attack. Colchicine acts by inhibiting phagocytosis, which is set up when urate crystals deposit into local tissues resulting in acute inflammation and arthritis. Most patients respond within 18 hours to a dose of 0.5 mg twice daily. Colchicine once commenced should be continued for upto 1 year after the serum urate has returned to normal. This will help in reducing frequency and duration of further attacks. High doses of colchicine (as recommended in most textbooks) often results in diarrhoea and should be best avoided. Colchicine is contraindicated if creatinine clearance is lower than 30 ml/min. In patients with chronic heart failure, renal or hepatic impairment when the use of NSAIDs is problematic corticosteroid either oral or intramuscular is very useful. Such high dose short course oral steroid (30 mg of Prednisolone tapered over 7–10 days) may also be used in patients intolerant to colchicine and when an attack is polyarticular.
TREATMENT OF CHRONIC GOUT Optimal treatment of chronic gout requires long-term reduction of serum urate to the lower half of the normal uric acid reference range. This is important in order to prevent ongoing uric acid crystal deposition in tissues, reduce the frequency of acute gouty attacks and size of tophi. It is, therefore, important to monitor uric acid levels once treatment with urate lowering drugs has been initiated. One also needs to remember that flares may be brought by sudden lowering of uric acid. Concomitant use of low dose oral colchicine or NSAIDs will reduce the probability of this occurrence. As a corollary, urate lowering therapy should not be commenced during an acute episode. Drugs used for chronic gout can be divided in three categories: 1. Uricostatic (xanthine oxidase inhibitor) e.g. allopurinol, oxipurinol, febuxostat 2. Uricosuric e.g. benzbromarone, sulfinpyrazone, probenecid, losartan, fenofibrate 3. Uricolytic e.g. uricozyme, rasburicase
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Allopurinol11 is the urate-lowering drug of choice. It is a xanthine oxidase inhibitor and accordingly inhibits the biosynthesis of uric acid. The drug can be used in both overproducers and underexcretors, has convenient once daily dosing, and is appropriate in patients with renal impairment and not contraindicated in patients with renal stones making it the drug of choice in over 95% of patients with gout. The risk of precipitating an acute episode of gout on initiation is reduced by starting allopurinol once the acute attack has completely resolved, i.e. approximately 4–8 weeks. Hypersensitivity is common. Allopurinol is therefore commenced at a low dose of 100 mg daily escalating by 100 mg every week to obtain an initial maintenance dose of 300 mg daily. Uric acid levels fall within 2–4 weeks. Ideally, one should monitor uric acid monthly and titrate the dose of allopurinol to achieve serum uric levels in the lower half of the normal reference range. This would help reliably dissolve the crystals, prevent future attacks and dissolve existing tophi. Most patients would need 300–500 mg daily, although occasionally one might have to use doses as high as 900 mg daily. Once target serum uric acid has been achieved, measurements can be spaced out to 6 months or even a year. A major problem is lack of proper use of allopurinol with most patients not achieving target urate levels. Hypersensitivity reactions are well known with allopurinol. Desensitisation with allopurinol may be necessary and appears to be affective. This is done by giving an initial oral dose of 25–50 μg of allopurinol, progressively increasing every third to seventh day to achieve a dose sufficient to normalise serum uric acid. For patients unable to tolerate allopurinol, oxipurinol can be used. However, as it is the active metabolite of allopurinol, similar adverse reactions have been noted in 40% of these patients. There are numerous potential drug interactions particularly with oral anticoagulants, azathioprine and theophylline. In renal transplant patients if used together with azathioprine, remember to reduce the dose of the latter as both drugs are metabolised by xanthine oxidase. Care needs to be taken in patients with renal impairment and adjustment according to creatinine clearance must be made. Febuxostat12, 13 is a new oral xanthine oxidase inhibitor, which has been shown to be more powerful in lowering uric acid levels compared to allopurinol. The drug is very similar to allopurinol except it is a non-purine raising the likelihood that it may not have the same kinds of allergic reactions as seen with the former drug. The drug is mainly metabolised by the liver and can be used in renal and hepatic insufficiency with no dose adjustment. It is safe, effective and well tolerated. Phase 2 study results of a trial show that with dosage of 80 and 120 mg, 59% patients achieved target serum uric acid levels within 2 days. With doses of 120 mg, well over 90% of patients achieved the target.
Pande
Uricosuric drugs increase the renal excretion of urate by inhibiting reabsorption in the PCT. They hence run the risk of nephrolithiasis. When used they should be initiated at a low dose, increased slowly and attention paid to adequate hydration. They should not be used in conditions where there is overproduction of uric acid or pre-exisiting renal stones. They are also risky if urinary urate excretion is already high (> 800 mg/24 hours). Probenecid is no longer available in the UK and sulfinpyrazone is ineffective in presence of significant renal impairment or concurrent diuretic use. Probenecid is used in a dose of 500 mg/day gradually increased to 2 g daily, while sulfinpyrazone is used in a dose of 100 mg/day gradually increased to 600 mg daily. Allergic rashes and gastrointestinal upset is common. Low doses of aspirin abolish the uricosuric action of these drugs. Benzbromarone11 available in the UK on a named patient basis and is a good alternative to allopurinol in patients with normal and impaired renal function (creatinine clearanace as low as 25 ml/min). Doses of 25–150 mg/day are given with monitoring of liver function, as it can be hepatotoxic. It is an option for patients where gout has been difficult to control with allopurinol alone, in renal transplant patients on cyclosporine and patients with significantly impaired renal function. Losartan,14 an angiotensin II converting enzyme inhibitor, inhibits renal tubular reabsorption of urate and acts as a uricosuric agent. It is particularly useful as adjunct therapy in patients with hypertension and effective in lowering urate caused by thiazides. Fenofibrate,14 increases renal urate clearance with 20–35% reductions in serum uric acid. This is useful to consider in patients with gout and hyperlipidaemia. Combinations of antihyperuricaemic drug (allopurinol/benzbromarone) with fenofibrate or losartan are potentially a good option for the treatment of this subset of gout patients. There is interest in using uriolytics in the treatment of gout.15 Urate oxidase catalyses the conversion of uric acid into allantoin in lower animals. Humans lack this enzyme. Urate oxidase prevents formation of urate and breaks down pre-existing uric acid, inlike allopurinol. Uricase therefore is faster acting and more potent than allopurinol. There are two main preparations: non-recombinant uricozyme and recombinant rasburicase. Rasburicase is licensed for hyperuricemia in tumour lysis syndrome.16 It is widely used in patients who are allergic to allopurinol17 and are going to undergo chemotherapy for a haematologic malignancy. This drug dramatically reduces serum uric acid and is given intravenously. Its use is limited to a single course18 at the time of the tumour therapy because there are associated black box warnings. These are largely due to the fact that it is a foreign protein and there is potential for immnogenicity,
An update on gout
development of neutralising antibodies and subsequent fatalities. In subjects with G6PD deficiency there is theoretical risk of haemolysis and methaemoglobinaemia. A PEGylated uricase is now under development.19, 20 Adding polyethylene glycol prolongs the half-life of the uricase and decreases the antigenicity. This is given intravenous and preliminary results are encouraging with dramatic reductions in serum uric acid over 4 weeks. It is currently being studied as a potential treatment for severe tophaceous gout in patients who are hypersensitive to allopurinol. This is still in early development, but it is theoretically likely to be a useful adjunct to our therapy.
CONCLUSION Gout remains an important cause of arthritis whose prevalence appears to be on the increase. Diagnosis rests on the recognition of characteristic clinical features in conjunction with hyperuricemia and the demonstration of monosodium urate crystals in joint fluid. Acute attacks are best managed with rest, non-steroidal anti inflammatory drugs, colchicine or intra-articular corticosteoids. Prevention of attacks requires modification of lifestyle factors such as weight loss, moderation in the consumption of alcohol and meat and withdrawal of drugs known to cause elevated uric acid levels. Allopurinol has been the time-tested prophylactic therapy. However, newer agents such as rasburicase and febuxostat promise equal efficacy with a possibility of fewer adverse effects. Drug development continues to be a fruitful research in this field.
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14. 15.
REFERENCES 1. 2.
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McCarty DJ, Hollander JL. Identification of urate crystals in gouty synovial fluid. Ann Intern Med 1961; 54: 452–60. Kohn NN, Hughes RE, McCarty DJ Jr, Faires JS. The significance of calcium phosphate crystals in the synovial fluid of arthritic patients: the “pseudogout syndrome”. II. Identification of crystals. Ann Intern Med 1962; 56: 738–45. Arromdee E, Michet CJ, Crowson CS, et al. Epidemiology of gout: is the incidence rising? J Rheumatol 2002; 29: 2403–6. Mikuls TR, Farrar JT, Bilker WB, Fernandes S, Schumacher HR Jr, Saag KG. Gout epidemiology: results from the UK General Practice Research Database, 1990–1999. Ann Rheum Dis 2005; 64: 267–72. Wallace KL, Riedel AA, Joseph-Ridge N, Wortmann R. Increasing prevalence of gout and hyperuricemia over 10 years among older adults in a managed care population. J Rheumatol 2004; 31: 1582–7.
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Choi HK, Atkinson K, Karlson EW, et al. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med 2004; 350: 1093–103. Choi HK, Atkinson K, Karlson EW, Curhan G. Obesity, weight change, hypertension, diuretic use, and risk of gout in men: the health professionals follow-up study. Arch Intern Med 2005; 165: 742–8. Choi H, Curhan G. Adiposity, hypertension, diuretic use and risk of incident gout in women—The Nurses Health Study. Abstract presented at the American College of Rheumatology. Annual Conference 2005. Choi HK, Atkinson K, Karlson EW, et al. Alcohol intake and risk of incident gout in men: a prospective study. Lancet 2004; 363: 1277–81. Kim KY, Schumacher R, Hunsche E, et al. A literature review of the epidemiology and treatment of acute gout. Clin Ther 2003; 25: 1593–617. Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, et al. Efficacy of allopurinol and benzbromarone for the control of hyperuricameia: a pathogenic approach to the treatment of primary gout. Ann Rheum Dis 1998; 57: 549–59. Schumacher HR Jr. Febuxostat: a non-purine, selective inhibitor of xanthine oxidase for the management of hyperuricaemia in patients with gout. Expert Opin Investig Drugs 2005; 14: 893–903. Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Eustace D, Palo WA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005; 353: 2450–61. Bardin T. Fenofibrate and losartan. Ann Rheum Dis 2003; 62: 497–8. Bieber J, Terkeltaub RA. Gout: on the brink of novel therapeutic options for an ancient disease. Arthritis Rheum 2004; 50: 2400–14. Oldfield V, Perry CM. Rasburicase: a review of its use in the management of anticancer therapy-induced hyperuricaemia. Drugs 2006; 66: 529–45. Fam AG. Alternate urate-lowering drugs and the management of hyperuricaemia in allopurinol intolerant patients. Int J Adv Rheumatol 2003; 1: 12–30. Liu CY, Sims-McCallum RP, Schiffer CA. A single dose of rasburicase is sufficient for the treatment of hyperuricemia in patients receiving chemotherapy. Leuk Res. 2005; 29: 463–5. Schumacher HR Jr, Chen LX. Newer therapeutic approaches: gout. Rheum Dis Clin North Am 2006; 32: 235–44. Ganson NJ, Kelly SJ, Scarlett E, Sundy JS, Hershfield MS. Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene) glycol (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase. Arthritis Res Ther 2005; 8: R12.
Review Article
An update on gout I Pande
ABSTRACT Gout is the most common cause of inflammatory arthritis in men aged more than 50, affecting approximately 1–2% of adult men in the Western world. The incidence and prevalence of gout is on the rise. Increasing longevity, dietary trends, obesity, metabolic syndrome, hypertension, increased use of low-dose aspirin, major organ transplantation and increased survival from coronary artery disease and end-stage renal disease have been implicated as the possible contributory factors. By far, the commonest cause of hyperuricaemia (that accounts for 90% of patients with gout) is decreased renal clearance. Patients with gout should avoid excess of alcohol (beer and spirits, particularly), red-meat and sea-food. Vegetarian food and dairy products reduce the risk of gouty arthritis. For the treatment of acute gout, options include non-steroidal antirheumatic drugs (NSAIDs), steroids (systemic or intra-articular) and colchicine. High dose of colchicine often results in diarrhoea and should be best avoided. Most patients respond within 18 hours to a dose of 0.5 mg twice daily. Colchicine is contraindicated if creatinine clearance is lower than 30 ml/min. Optimal treatment of chronic gout requires long-term reduction of serum urate to the lower half of the normal uric acid reference range. Prevention of attacks requires modification of lifestyle factors such as weight loss, moderation in the consumption of alcohol and meat and withdrawal of drugs known to cause elevated uric acid levels. Drugs used for chronic gout can be divided in three categories: (a) Uricostatic (xanthine oxidase inhibitor), e.g. allopurinol, oxipurinol, febuxostat, (b) Uricosuric, e.g. benzbromarone, sulfinpyrazone, probenecid, losartan, fenofibrate and (c) Uricolytic, e.g. uricozyme, rasburicase. Febuxostat is a new oral xanthine oxidase inhibitor, which has been shown to be more powerful in lowering uric acid levels compared to allopurinol. The drug is mainly metabolised by the liver and can be used in renal and hepatic insufficiency with no dose adjustment. Benzbromarone is an excellent uricosuric agent. Pegylated uricase is currently under development. Keywords: Gout, treatment, update.
INTRODUCTION Gout is derived from the Latin word gutta, meaning drop, as it was believed that poison falling in drops into the affected joints caused gout. Sir Alfred Garrod linked gout with hyperuricaemia in 1848. We now know that hyperuricaemia is a common serum abnormality, and not everybody with raised serum uric acid will develop gout; may be only 1 in 5 progress. In 1961 McCarty and Hollander1 identified monosodium urate (MSU) crystals in the synovial fluid of patients with acute gout. Year later (1962) calcium, pyrophosphate crystals were identified in patients with pseudogout.2 Gout
we now believe is a multifactorial disease characterized by hyperuricaemia and MSU crystal deposition in the joint.
EPIDEMIOLOGY The incidence and prevalence of gout is on the rise. A study by Arromdee3 in 2002 showed the annual incidence of gout in Rochester Minnesota to increase from 45/100,000 in 1977–1978 to 62/100,000 on repeat survey in 1995–1996. The male to female ratio remained unchanged (3.3 : 1). The later study also suggested that gout was increasingly being
Consultant Rheumatology, Nottingham University Hospital’s NHS Trust, Nottingham, UK. Correspondence: Dr. Ira Pande, email: [email protected]
An update on gout
diagnosed at a younger age. It also suggested that there was a greater than a 2-fold increase in the incidence of primary gout. A more recent study by Mikuls et al.4 in 2005 has also shown similar increases in incidence in gout in the UK. Prevalence of gout has doubled over the last two decades according to Wallace et al.5 and Mikuls et al.4 The rise is mainly in the older population, and the increase is similar in men and woman. Men are affected three times more frequently than women. These findings are echoed by a survey in England, which also found a three-fold increase between 1975 and 1993. The Rochester epidemiology project suggests following factors to play a role in the changing demographics: increasing longevity, dietary trends, obesity, metabolic syndrome, hypertension, increased use of low-dose aspirin, major organ transplantation and increased survival from coronary artery disease and end-stage renal disease. Gout is the most common cause of inflammatory arthritis in men aged more than 50, affecting approximately 1–2% of adult men in the Western world. It is rare in children and premenopausal women. Men have higher serum urate levels, which rise shortly after puberty. Oestrogens increase urate clearance and levels of urate in premenopausal women are generally well below solubility limit. After the menopause, reduced oestrogen will reduce excretion of uric acid thereby putting women at equal risk of gout as men. Of gout patients over 60 years of age, 50% are women. The declining use of HRT may further increase the frequency of gout in women and at an earlier age too.
WHY DO HUMANS GET GOUT? Purines derived either from the diet or by de novo synthesis convert nucleotides to hypoxanthine (a monoxide) which then converts to xanthine (a dioxypurine) with final conversion to uric acid, a trioxypurine. Uric acid has three oxygen groups attached to it and at normal body temperature has limited solubility in the serum. A concentration of > 416 μmol/l is taken to denote hyperuricaemia, the concentration above which urate saturation occurs with crystal precipitation and resulting gout. During the evolutionary process humans and the greater apes lost the enzyme uricase, which converts uric acid (insoluble) to allantoin (soluble) and carbon dioxide.
PATHOGENESIS AND RISK FACTORS FOR GOUT5 Purines are derived from two sources, diet and de novo synthesis. Dietary purines constitute one-third with the remaining
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two-thirds obtained from tissue nucleic acids and endogenous purines synthesis. Uric acid is the end product of purine biosynthesis whereby purine nucleotides are converted to hypoxanthine and then xanthine before converting to uric acid. At a concentration of around 6.8 mg per decilitre (around 400 μmol per litre) uric acid remains in a soluble state. Factors such as local trauma with resultant increase in tissue breakdown, infection or surgery with associated alteration in pH or dietary excess, fasting or binges of alcohol precipitate uric acid in tissues leading to gout. Two-thirds of the serum uric acid is excreted by the kidney with the remaining one-third by intestinal uricolysis. The process of elimination of uric acid by the kidney involves the glomerulus and proximal convoluted tubule (PCT). Glomerular filtration is 100% with 98% being reabsorbed in the first part of the PCT followed by 50% secretion in the second part with further reabsorption of approximately 40–48% resulting in a net reabsorption of approximately 90% leading to only 8–12% of the uric acid being excreted by the kidney. By far, the commonest cause of hyperuricaemia (that accounts for 90% of patients with gout) is decreased renal clearance. Dehydration, use of diuretics, insulin resistance and metabolic syndrome increase reabsorption of uric acid in the first part of the proximal convoluted tubule. Surgery, trauma, infection leading to keto or lactic acidosis reduce secretion in the second part. Low-dose aspirin not only increases mean serum uric acid by 6% but reduces uric acid clearance by approximately 23% leading to increased gout. Drugs such as cyclosporine compete with urate for renal excretion in addition to impairing renal tubular handling of uric acid. This accounts for cyclosporine-induced gout in patients with renal impairment and transplant subjects. Other factors such as hypertension, hyperparathyroidism and hypothyroidism lower glomerular filtration with further impairment of uric acid excretion causing hyperuricaemia and gout. Uric acid over production accounts for only 10% of gout. Increase in dietary purines associated with diet and lifestyle changes such as increased consumption of seafood, red meat and intake of beer, lager and spirits increases uric acid synthesis as a result of the end product of purine biosynthesis. Rare disorders such as HGPRT deficiency, myelo and lympho-proliferative diseases and psoriasis account for increased endogenous purine synthesis causing hyperuricaemia and gout. Decreased solubility of urate (low pH and low temperature), disturbance to joint and soft tissue (trauma/tissue injury), or reabsorption of water resulting in super saturation of uric acid in the serum (lack of joint activity during sleep) are some of the factors influencing crystal deposition leading to gout. Certain drugs also cause increased gout. Diuretics reduce uric acid reabsorption and low dose aspirin
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as mentioned earlier increases mean serum uric acid levels and reduce uric acid clearance leading to gout. There are differences in risk of gout in men and women. Men have higher serum urate levels at all ages compared to women. In men serum uric acid rises shortly after puberty accounting for an overwhelming proportion of younger patients with gout being men. Women have serum uric acid levels well below solubility limit. Furthermore, oestrogens in the premenopausal woman increase urate clearance. However, after the menopause decreased oestrogen may reduce renal excretion of uric acid accounting for an equal proportion of women and men having gout aged over 60. The declining use of HRT may increase the frequency of gout in younger women and result in gout at an earlier age. The Health Professionals Study6 has shown an increased risk of gout amongst those who consumed the highest quintile of meat, seafood and alcohol. A 41% increased risk of gout was associated with high intake of organ meats and a 51% increased risk with high intake of seafood. No association was seen with moderate intake of purine rich vegetables. High dairy intake reduced the risk by 44%. Amongst alcohol beverages, beer and spirits (not wine) were the main risk factors for gout.
GOUT IN TRANSPLANT PATIENTS Gout is common in transplant patients. Some of the factors are frequent use of diuretic and cyclosporine. Hyperuricaemia develops in 70–80% of cyclosporine treated patients. Gout develops in 8–13% usually within 2–3 years of starting cyclosporine. The presentation is atypical with rapid and extensive tophi, involvement of upper extremity and the axial skeleton, being polyarticular and refractory to treatment. In this group, a higher incidence of colchicine toxicity with rapid onset of myopathy is also noted. Mycophenolate mofetil may reduce the risk and should be considered in this group with gout.
MANAGEMENT There are two main reasons for treatment failure; poor compliance associated with lack of patient understanding of the disease/drugs and second misuse of allopurinol. Both patient and physician education is crucial for the long-term optimal management of this disease. In recent years, key prospective epidemiological studies have provided insights into the role of lifestyle modification in treating gout. Results from these studies can be used to inform patients and increase chances of success in lifestyle modification. Obesity (BMI > 30) is linked to the development of insulin resistance (metabolic syndrome) which is
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complicated by hypertension, hyperlipidaemia, increased risk of gout and coronary artery disease. The Health Professionals Follow-up Study7 and the Nurses Health Study8 have shown a clear dose–response relationship between body mass index (BMI) and risk of gout. In addition to absolute BMI, increase in BMI over time is also associated with an increased risk for gout. However, a loss of more than 10 lbs since study entry was shown to be associated with a 30% reduction in risk of gout (RR 0.61). These observations support weight loss as an important factor in the long-term management of patients with chronic gout. Until recently, patients with gout were typically advised to avoid foods rich in purines. The recent study by Choi et al.6 provided evidence to advice patients with gout to consume meat and sea food in moderation, with special attention to food portion size and content of non-complex carbohydrates. Men with highest quintiles of meat and seafood intake were noted to have an increased risk of gout compared to those in the lowest quintile, with odds ratios (ORs) of 1.4 and 1.5, respectively. Total protein intake was not associated with increased risk. In fact, high protein diets have been associated with increased urinary excretion of uric acid. Vegetable protein and dairy intake inversely correlated with risk of gout, with ORs of 0.56. The Nurses Health Study8 further strengthens these associations. Therefore, patients should be cautioned against using the protein content of food as a surrogate marker of purine content. Alcohol increases uric acid production and decreases uric acid excretion. Beer, which has the highest content of malt of the readily absorbable purine guanosine further increases uric acid production. Chronic heavy alcohol intake also inhibits conversion of pro-drug allopurinol to its active metabolite oxypurinol. The Health Professionals Study9 found that alcohol intake was associated with an increased risk of developing gout. The risk increased with increasing intake of total alcohol, with greatest association with beer and spirits. The risk of gout increased by 1.17/10 g increase in daily alcohol intake. Wine did not show an association. Results of these two prospective studies showing the impact of diet on hyperuricaemia and gout encourages modification of reversible risk factors such as consumption of beer, lager, spirits, red meat and seafood in patents with gout. Addressing other risk factors like hypertension, hyperlipidaemia, use of diuretics, aspirin and considering use of mycophenolate mofetil (MMF) instead of cyclosporine where applicable is useful adjunct to therapy.
ACUTE GOUT Most patients know when an acute episode is imminent. Due to mast cell degranulation and histamine release a
An update on gout
number of patients, report local itching and burning. Most have experienced gout at night (around 2 AM). Low temperature and lack of joint activity during sleep leading to reabsorption of water with super saturation of serum uric acid precipitating as crystals accounts for it. The episode builds to a peak over several hours with intense pain and increased sensitivity of the overlying skin. In over 70% the first metatarsophalangeal joint (MTP) is involved. Other common joints involved are the tarsal joints, ankle, knee and wrist. The hip, shoulder and spine are usually spared probably due to the higher temperature whereby crystals don’t precipitate. Complete resolution of the attack is usually seen within a week even without treatment. A positive family history and a previous self-limiting episode are helpful/or deceptive (pointer). It can occasionally cause bursitis or tenosynovitis in isolation. In less than 50% acute gout is polyarticular. One needs to remember that gout in the elderly can be polyarticular and chronic. Serum uric acid levels can be normal, especially during an attack and diseases other than gout may respond to colchicine. Atypical joint involvements can occur for example, Heberden’s nodes in elderly women with nodal osteoarthritis. The diagnosis is based on classical history and examination findings. The gold standard test is synovial fluid analysis, which reveals negatively birefrengent crystals on polarised light microscopy. In the elderly, pseudogout forms an important differential. Septic arthritis, which is often indistinguishable, may coexist. A polyarticular presentation mimics rheumatoid arthritis. Sixty-two per cent of individuals experience a second episode within a year, 78% within 2 years. Seven per cent have no episodes of gout following the first attack for upto 10 years. Once a patient has had 2, 3 or more attacks, the chances of further attacks are quite high. These factors may help physician and the patient decide when to initiate treatment. Prophylaxis against recurrent episodes is indicated for patients with frequent episodes, chronic tophaceous or polyarticular gout, patients with comorbidities where attacks are difficult to treat and those at risk of urate nephropathy or those in whom radiology reveals established erosions.
TREATMENT OF ACUTE GOUT10 The affected joint/s should be rested and drug therapy started as soon as possible to ensure the most rapid and complete response. There is evidence that rest and cold application to the affected joint may shorten the attack and decrease the need for medication. Drug options for the acute attack include oral non-steroidal antirheumatic drugs (NSAIDs), oral colchicines and corticosteroids (oral, intramuscular,
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intraarticular). The most important determinant of success is how soon therapy is initiated rather than with which agent. If a single joint is involved many rheumatologists prefer joint aspiration followed by intra-articular steroids once sepsis is ruled out. Oral NSAIDs should be used with caution in patients with previous peptic ulcer disease, concurrent use of oral anticoagulant, hypertension, congestive cardiac failure and renal impairment. Urate lowering drugs should be continued throughout the acute episodes if they have been commenced previously but should not be commenced during an acute episode. For colchicine to be optimally effective, the drug should be started at the first sign of an acute attack. Colchicine acts by inhibiting phagocytosis, which is set up when urate crystals deposit into local tissues resulting in acute inflammation and arthritis. Most patients respond within 18 hours to a dose of 0.5 mg twice daily. Colchicine once commenced should be continued for upto 1 year after the serum urate has returned to normal. This will help in reducing frequency and duration of further attacks. High doses of colchicine (as recommended in most textbooks) often results in diarrhoea and should be best avoided. Colchicine is contraindicated if creatinine clearance is lower than 30 ml/min. In patients with chronic heart failure, renal or hepatic impairment when the use of NSAIDs is problematic corticosteroid either oral or intramuscular is very useful. Such high dose short course oral steroid (30 mg of Prednisolone tapered over 7–10 days) may also be used in patients intolerant to colchicine and when an attack is polyarticular.
TREATMENT OF CHRONIC GOUT Optimal treatment of chronic gout requires long-term reduction of serum urate to the lower half of the normal uric acid reference range. This is important in order to prevent ongoing uric acid crystal deposition in tissues, reduce the frequency of acute gouty attacks and size of tophi. It is, therefore, important to monitor uric acid levels once treatment with urate lowering drugs has been initiated. One also needs to remember that flares may be brought by sudden lowering of uric acid. Concomitant use of low dose oral colchicine or NSAIDs will reduce the probability of this occurrence. As a corollary, urate lowering therapy should not be commenced during an acute episode. Drugs used for chronic gout can be divided in three categories: 1. Uricostatic (xanthine oxidase inhibitor) e.g. allopurinol, oxipurinol, febuxostat 2. Uricosuric e.g. benzbromarone, sulfinpyrazone, probenecid, losartan, fenofibrate 3. Uricolytic e.g. uricozyme, rasburicase
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Allopurinol11 is the urate-lowering drug of choice. It is a xanthine oxidase inhibitor and accordingly inhibits the biosynthesis of uric acid. The drug can be used in both overproducers and underexcretors, has convenient once daily dosing, and is appropriate in patients with renal impairment and not contraindicated in patients with renal stones making it the drug of choice in over 95% of patients with gout. The risk of precipitating an acute episode of gout on initiation is reduced by starting allopurinol once the acute attack has completely resolved, i.e. approximately 4–8 weeks. Hypersensitivity is common. Allopurinol is therefore commenced at a low dose of 100 mg daily escalating by 100 mg every week to obtain an initial maintenance dose of 300 mg daily. Uric acid levels fall within 2–4 weeks. Ideally, one should monitor uric acid monthly and titrate the dose of allopurinol to achieve serum uric levels in the lower half of the normal reference range. This would help reliably dissolve the crystals, prevent future attacks and dissolve existing tophi. Most patients would need 300–500 mg daily, although occasionally one might have to use doses as high as 900 mg daily. Once target serum uric acid has been achieved, measurements can be spaced out to 6 months or even a year. A major problem is lack of proper use of allopurinol with most patients not achieving target urate levels. Hypersensitivity reactions are well known with allopurinol. Desensitisation with allopurinol may be necessary and appears to be affective. This is done by giving an initial oral dose of 25–50 μg of allopurinol, progressively increasing every third to seventh day to achieve a dose sufficient to normalise serum uric acid. For patients unable to tolerate allopurinol, oxipurinol can be used. However, as it is the active metabolite of allopurinol, similar adverse reactions have been noted in 40% of these patients. There are numerous potential drug interactions particularly with oral anticoagulants, azathioprine and theophylline. In renal transplant patients if used together with azathioprine, remember to reduce the dose of the latter as both drugs are metabolised by xanthine oxidase. Care needs to be taken in patients with renal impairment and adjustment according to creatinine clearance must be made. Febuxostat12, 13 is a new oral xanthine oxidase inhibitor, which has been shown to be more powerful in lowering uric acid levels compared to allopurinol. The drug is very similar to allopurinol except it is a non-purine raising the likelihood that it may not have the same kinds of allergic reactions as seen with the former drug. The drug is mainly metabolised by the liver and can be used in renal and hepatic insufficiency with no dose adjustment. It is safe, effective and well tolerated. Phase 2 study results of a trial show that with dosage of 80 and 120 mg, 59% patients achieved target serum uric acid levels within 2 days. With doses of 120 mg, well over 90% of patients achieved the target.
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Uricosuric drugs increase the renal excretion of urate by inhibiting reabsorption in the PCT. They hence run the risk of nephrolithiasis. When used they should be initiated at a low dose, increased slowly and attention paid to adequate hydration. They should not be used in conditions where there is overproduction of uric acid or pre-exisiting renal stones. They are also risky if urinary urate excretion is already high (> 800 mg/24 hours). Probenecid is no longer available in the UK and sulfinpyrazone is ineffective in presence of significant renal impairment or concurrent diuretic use. Probenecid is used in a dose of 500 mg/day gradually increased to 2 g daily, while sulfinpyrazone is used in a dose of 100 mg/day gradually increased to 600 mg daily. Allergic rashes and gastrointestinal upset is common. Low doses of aspirin abolish the uricosuric action of these drugs. Benzbromarone11 available in the UK on a named patient basis and is a good alternative to allopurinol in patients with normal and impaired renal function (creatinine clearanace as low as 25 ml/min). Doses of 25–150 mg/day are given with monitoring of liver function, as it can be hepatotoxic. It is an option for patients where gout has been difficult to control with allopurinol alone, in renal transplant patients on cyclosporine and patients with significantly impaired renal function. Losartan,14 an angiotensin II converting enzyme inhibitor, inhibits renal tubular reabsorption of urate and acts as a uricosuric agent. It is particularly useful as adjunct therapy in patients with hypertension and effective in lowering urate caused by thiazides. Fenofibrate,14 increases renal urate clearance with 20–35% reductions in serum uric acid. This is useful to consider in patients with gout and hyperlipidaemia. Combinations of antihyperuricaemic drug (allopurinol/benzbromarone) with fenofibrate or losartan are potentially a good option for the treatment of this subset of gout patients. There is interest in using uriolytics in the treatment of gout.15 Urate oxidase catalyses the conversion of uric acid into allantoin in lower animals. Humans lack this enzyme. Urate oxidase prevents formation of urate and breaks down pre-existing uric acid, inlike allopurinol. Uricase therefore is faster acting and more potent than allopurinol. There are two main preparations: non-recombinant uricozyme and recombinant rasburicase. Rasburicase is licensed for hyperuricemia in tumour lysis syndrome.16 It is widely used in patients who are allergic to allopurinol17 and are going to undergo chemotherapy for a haematologic malignancy. This drug dramatically reduces serum uric acid and is given intravenously. Its use is limited to a single course18 at the time of the tumour therapy because there are associated black box warnings. These are largely due to the fact that it is a foreign protein and there is potential for immnogenicity,
An update on gout
development of neutralising antibodies and subsequent fatalities. In subjects with G6PD deficiency there is theoretical risk of haemolysis and methaemoglobinaemia. A PEGylated uricase is now under development.19, 20 Adding polyethylene glycol prolongs the half-life of the uricase and decreases the antigenicity. This is given intravenous and preliminary results are encouraging with dramatic reductions in serum uric acid over 4 weeks. It is currently being studied as a potential treatment for severe tophaceous gout in patients who are hypersensitive to allopurinol. This is still in early development, but it is theoretically likely to be a useful adjunct to our therapy.
CONCLUSION Gout remains an important cause of arthritis whose prevalence appears to be on the increase. Diagnosis rests on the recognition of characteristic clinical features in conjunction with hyperuricemia and the demonstration of monosodium urate crystals in joint fluid. Acute attacks are best managed with rest, non-steroidal anti inflammatory drugs, colchicine or intra-articular corticosteoids. Prevention of attacks requires modification of lifestyle factors such as weight loss, moderation in the consumption of alcohol and meat and withdrawal of drugs known to cause elevated uric acid levels. Allopurinol has been the time-tested prophylactic therapy. However, newer agents such as rasburicase and febuxostat promise equal efficacy with a possibility of fewer adverse effects. Drug development continues to be a fruitful research in this field.
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Choi HK, Atkinson K, Karlson EW, et al. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med 2004; 350: 1093–103. Choi HK, Atkinson K, Karlson EW, Curhan G. Obesity, weight change, hypertension, diuretic use, and risk of gout in men: the health professionals follow-up study. Arch Intern Med 2005; 165: 742–8. Choi H, Curhan G. Adiposity, hypertension, diuretic use and risk of incident gout in women—The Nurses Health Study. Abstract presented at the American College of Rheumatology. Annual Conference 2005. Choi HK, Atkinson K, Karlson EW, et al. Alcohol intake and risk of incident gout in men: a prospective study. Lancet 2004; 363: 1277–81. Kim KY, Schumacher R, Hunsche E, et al. A literature review of the epidemiology and treatment of acute gout. Clin Ther 2003; 25: 1593–617. Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, et al. Efficacy of allopurinol and benzbromarone for the control of hyperuricameia: a pathogenic approach to the treatment of primary gout. Ann Rheum Dis 1998; 57: 549–59. Schumacher HR Jr. Febuxostat: a non-purine, selective inhibitor of xanthine oxidase for the management of hyperuricaemia in patients with gout. Expert Opin Investig Drugs 2005; 14: 893–903. Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Eustace D, Palo WA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005; 353: 2450–61. Bardin T. Fenofibrate and losartan. Ann Rheum Dis 2003; 62: 497–8. Bieber J, Terkeltaub RA. Gout: on the brink of novel therapeutic options for an ancient disease. Arthritis Rheum 2004; 50: 2400–14. Oldfield V, Perry CM. Rasburicase: a review of its use in the management of anticancer therapy-induced hyperuricaemia. Drugs 2006; 66: 529–45. Fam AG. Alternate urate-lowering drugs and the management of hyperuricaemia in allopurinol intolerant patients. Int J Adv Rheumatol 2003; 1: 12–30. Liu CY, Sims-McCallum RP, Schiffer CA. A single dose of rasburicase is sufficient for the treatment of hyperuricemia in patients receiving chemotherapy. Leuk Res. 2005; 29: 463–5. Schumacher HR Jr, Chen LX. Newer therapeutic approaches: gout. Rheum Dis Clin North Am 2006; 32: 235–44. Ganson NJ, Kelly SJ, Scarlett E, Sundy JS, Hershfield MS. Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene) glycol (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase. Arthritis Res Ther 2005; 8: R12.