The 2010 Competency Standards addressed by this activity include (but may not be limited to): 4.2.2, 4.2.3, 6.1.2, 6.2.1, 7.1.2, 7.1.3,

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1 UPDATE ON GOUT Learning objectives: After completing this activity, pharmacists should be able to: 1. describe the mechanisms underlying hyperuricaemia 2. state the risk factors for development of gout 3. identify drug-related causes of gout 4. list the treatment options for acute gout and prevention of gout 5. counsel patients on lifestyle modifications The 2010 Competency Standards addressed by this activity include (but may not be limited to): 4.2.2, 4.2.3, 6.1.2, 6.2.1, 7.1.2, 7.1.3, Gout is a common inflammatory arthritis, occurring predominantly in 40 to 60 year old men. The prevalence increases with age, and the gender disparity decreases as women reach menopause, due to the fact that oestrogen is uricosuric. The ageing population, changing diets and increasing obesity will see a rising prevalence of gout in the community. In older people, gout may present with fever or delirium. There are many myths around the impact of diet and lifestyle for the risk of gout and its recurrence. However it is possible that moderate lifestyle interventions may reduce the incidence of recurrent gout. KEY POINTS Gout is mainly caused by reduced excretion of uric acid Primary treatment of an acute gout attack is high dose NSAID, but unsuitable for many older patients Colchicine should be only used as a second line therapy when NSAIDs or corticosteroids are contraindicated or ineffective, at the revised dosing of maximum of 1.5mg per treatment course Dietary and lifestyle changes are difficult to maintain but may be effective in reducing the incidence of recurrent gout Allopurinol may be used for prevention, but the dose needs to be reduced in renal impairment, and should not be initiated during an acute attack WHAT IS GOUT? Gout is defined as arthritis associated with the presence of monosodium urate monohydrate (MSU) crystals in and around joint tissues. Urate crystals cause an inflammatory response in joints. High serum uric acid is required for the formation of these crystals. Gout is often classified as primary or secondary and both forms are associated with hyperuricaemia. Gout associated with an inborn error in metabolism or decreased renal excretion without other renal disease is referred to as primary gout, whereas gout associated with an acquired disease or the use of a drug is called secondary gout. A number of different racial groups in Pacific area appear to have inherited a reduced ability to excrete urate. In both primary and secondary gout, chronic hyperuricaemia may be the result of overproduction of uric acid caused by increased purine intake, synthesis, or breakdown, or it may be the result of decreased renal excretion of urate. Renal clearance of serum urate is modified by renal disease, medications, effect of lactate, ketones or

2 angiotensin on kidney tubule, and hypertension. In 90 percent of patients, gout is caused by the decreased excretion of uric acid. Gout commonly occurs in the big toe but may affect other joints such as heels, ankles, knees, fingers, wrists and elbows. URIC ACID CONCENTRATION Hyperuricaemia is defined as a serum uric acid concentration above 0.42 mmol/l, although this may vary in different laboratories and is higher in men than women. Saturation occurs with serum urate levels greater than 0.42mmol/L and gout prevalence increases above this value. It is important to note that many persons with hyperuricaemia never experience an attack of gout; and, conversely, acute gout can occur in the presence of normal uric acid concentrations. Serum urate concentration may reduce during an acute attack; a normal urate concentration during an acute attack does not rule out a diagnosis of gout. 1,2 Only a minority of people with hyperuricaemia develop gout. Hyperuricaemia can also lead to renal impairment and renal failure and is an independent risk factor for cardiovascular disease. 3 Recommended laboratory testing for patients with gout include serum urate, full blood count, renal function, fasting lipids, glucose, and thyroid function tests. 1 RISK FACTORS Modifiable risk factors for gout attacks include alcohol consumption, obesity, and hypertension. Insulin resistance in metabolic syndrome can lead to reduced urinary excretion of uric acid. Factors found to be predictive for development of gout in people with hyperuricaemia include: - Increasing serum uric acid levels - Alcohol consumption - Use of diuretic drugs - Increased body mass index Older people with decreased creatinine clearance, low albumin levels, or requiring diuretic and/or aspirin therapy, are at higher risk of developing gout. Patients with renal impairment, regardless of cause, have diminished excretion of uric acid. Risk factors Decrease serum urate concentration Increase serum urate concentration Diet Low fat dairy products Meat, fish, alcohol (beer, spirits), obesity, weight gain Medications Xanthine oxidase inhibitors (allopurinol) Oestrogens Diuretics Low dose aspirin Diseases Inborn errors of metabolism Hypertension Hypothyroidism Hyperparathyroidism Chronic kidney disease SIGNS AND SYMPTOMS Gout typically has a sudden, abrupt onset with intense joint pain reaching its maximum over 6 to 12 hours. Swelling and erythema usually occurs commonly in the first metatarsophalangeal joint (big toe). Any joint can be affected including the instep, ankle or knee. In an older person, gout may present atypically, with more insidious and less abrupt onset of pain. 4

3 Chronic gout can lead to the development of solid urate deposits (tophi) in connective tissues such as the upper extremity on the fingers, nodes over the olecranon bursa (bony tip of elbow) or ear. These tophi may ulcerate or get infected. CAUSES Decreased uric acid excretion may occur with renal insufficiency, hypertension, hyperparathyroidism, and hypothyroidism or may be drug-induced. Drug-induced hyperuricaemia may be caused by: - diuretics - cyclopsorin - low-dose salicylates - nicotinic acid - levodopa Diuretic use has been reported in over 75 percent of patients with late-onset gout, and almost 100 percent in women. 5 Whilst it is generally accepted that diuretics increase the risk of gout, there is a general lack of evidence on this topic. Diuretics act on proximal tubule of kidney to enhance urate reabsorption and produce higher blood urate levels. However, heart failure and hypertension predispose patients to gout due to associated poor urate clearance. Hypertension has a 3 fold risk of gout, independent of diuretic use. So perhaps it is the underlying condition, rather than the diuretics prescribed to treat that condition, that increases the risk of gout. A small case controlled study suggested that diuretics do not actually increase the risk of gout. 6 The authors conclude that gout should not be considered as a compelling contraindication to prescription of a diuretic. Low dose aspirin may also precipitate gout and may necessitate alternative antiplatelet agents. TREATMENT Asymptomatic hyperuricaemia should not be treated. Management of gout should begin with reducing or eliminating factors contributing to high serum urate levels: - limit alcohol consumption - treat hyperlidipaemia - avoid diuretic therapy Losartan has mild uricosuric properties and has been proven to decrease serum uric acid levels. 7 Acute treatment The first goal is to treat the inflammation lowering serum urate concentrations (ie starting allopurinol) is not advised at the time of symptom onset, as any change will cause prolongation of the attack. Patients already taking allopurinol should not stop the drug during an acute attack of gout. Treatment of an acute attack of gout includes NSAIDs, corticosteroids or colchicine. Most patients will have complete resolution of symptoms within 5 days. NSAIDs For the acute attack of gout, the Therapeutic Guidelines recommends any NSAID orally in high dose, reducing to zero over a period of about one week. NSAIDs do not correct the hyperuricaemia but do control the inflammation and decrease pain.

4 All NSAIDs including COX-2 selective inhibitors such as celecoxib are equally effective. The most important issue is how soon the therapy is initiated rather than which NSAID is used. Treatment should be continued at least until the attack has settled and often for one further week. 8 All NSAIDs should be used cautiously in patients with renal dysfunction and cardiovascular disease, and those at high risk of GI bleeding (elderly patients, patients with peptic ulcer disease and those taking anticoagulants or corticosteroids). Naproxen carries the least cardiovascular risk, whereas diclofenac is associated with the greatest risk. 9 Even shortterm NSAID use can increase cardiovascular risk in patients with prior MI. 10 NSAIDs should also be used cautiously in patients with heart failure because of the risk of exacerbating fluid overload. NSAIDs with long plasma half-life and with a slow-release formulation were associated with a greater risk of upper GI bleeding or perforation than NSAIDs with a short half-life. 11 The GI risk overall is lower with ibuprofen and celecoxib and highest with ketorolac and piroxicam. 11 Indomethacin appears to be the most commonly prescribed NSAID for gout and whilst proven effective, it should be avoided in older persons due to high GI risk and CNS effects. Corticosteroids Corticosteroid drugs have been used with success in older people with multiple comorbidities. They may be administered intra-articularly, IM or orally. Therapeutic Guidelines recommends prednisone or prednisolone 15 to 25mg orally, daily until symptoms abate (usually 3 to 5 days) then cease. Prednisone and dexamethasone may be used in concomitantly. A Cochrane review concluded there is inconclusive evidence for the efficacy and effectiveness of systemic corticosteroids in the treatment of acute gout. 12 Colchicine Colchicine is an effective treatment for the reduction of pain and clinical symptoms in patients experiencing acute attacks of gout, although its low benefit to toxicity ratio limits its usefulness. It has anti-inflammatory activity but no analgesic activity. Colchicine does not reduce plasma urate concentration or prevent joint damage. Colchicine should be only used as a second line therapy when NSAIDs or corticosteroids are contraindicated or ineffective. 13 It can be used in conjunction with a NSAID. The number needed to treat (NNT) with colchicine versus placebo to reduce pain is 3 and the NNT to reduce clinical symptoms is Last year NPS RADAR issued a warning on the concerns for colchicine dosing and toxicity. The recommended dosing schedule is now 2 tablets followed by one tablet 1 hour later. No additional colchicine should be administered for at least 3 days, when a repeat course may be considered. Whilst the current Product Information still lists the dose as 2 tablets then one every 6 hrs until relief, this dosing schedule offers no additional clinical benefit with an increased the risk of gastrointestinal toxicity. 14 Colchicine is less effective once an attack has persisted for a few days. Colchicine is contraindicated if creatinine clearance is less than 30mL/min and in patients with heart disease or hepatic insufficiency. Colchicine does not cause fluid retention and is an option in patients with heart failure who may be at risk from fluid-retaining effects of NSAIDs. Colchicine is not well tolerated in the older person, with nausea, vomiting and diarrhoea common. These GI side effects may occur before symptomatic relief. Even in low dose, adverse effects such as myopathy are more likely especially in people with renal impairment. As colchicine is a substrate for cytochrome P450 3A4 (CYP3A4) or P-glycoprotein (P-gp) concurrent prescribing of inhibitors increases the potential for colchicine toxicity, including myopathy and GI upset. 15 Colchicine should be

5 avoided with graepfruit and grapefruit juice, erythromycin, cyclosporin, statins and calcium-channel blockers, including verapamil and diltiazem. 16 Concurrent administration of colchicine and statins increases the risk of rhabdomyolysis. 4 Prevention Long-term management of gout involves treating hyperuricaemia through risk modification and once the acute episode has been well controlled, drug therapy. For most people with occasional attacks of gout, the risks of preventive treatment probably outweigh the benefits. 1 Patient preferences should be considered when making a decision to commence life-long therapy. In clinical practice patients may be offered preventive treatment if they experience more than two acute attacks per year. Probenecid Probenecid is a uricosuric and renal tubular blocking agent. It inhibits the tubular reabsorption of urate, thus increasing the urinary excretion of uric acid and decreasing serum urate levels. Probenecid is completely ineffective when the patient's creatinine clearance is lower than 30 ml per minute. Patients should be well hydrated early in the course of probenecid treatment to reduce the risk of precipitation of uric acid in the renal tubules. The risk can be further lowered by alkalinising the patient s urine. Low doses of aspirin negate the uricosuric action of probenecid. Allopurinol Allopurinol, a xanthine oxidase inhibitor, is the drug of choice for prevention of gout in a dose of 300mg daily. Patients should be commenced on a low dose which can be increased every few weeks to avoid a sudden drop in serum urate concentration, which can precipitate a gout attack. Failure to adequately increase the dose of allopurinol for therapeutic benefit is common to 900mg may be necessary in some patients. Dose reduction is required when renal insufficiency is evident. In patients with a creatinine clearance (CrCl) of 60 ml/min the maximum dosage is 200mg per day. The maximum dose when CrCl is 30 ml/min is 100mg per day. Allopurinol prophylaxis is usually a life-long commitment and introduction is never urgent and should be delayed until the acute attack has settled. Treating acute attacks early and reducing risk factors may be sufficient if attacks are infrequent. Allopurinol is preferred to probenecid in older people as urate-lowering effect of probenecid is reduced by renal impairment. Allopurinol and probenecid have been used in conjunction by rheumatologists. Colchicine Low dose colchicine (0.5mg twice daily) is usually well-tolerated and effective in preventing recurrences. A dose of 0.5mg daily may be sufficient in the elderly or patients with renal impairment. It can be used with the introduction of allopurinol to reduce the frequency of attacks during this relatively high-risk period. DIETARY ADVICE Dietary changes will only result in limited decrease in uric acid levels and may be difficult to maintain. A focus on weight reduction and reduction in alcohol intake is likely to produce the most gains. However non-pharmacological interventions should be promoted as part of a healthy lifestyle. Dieting and exercise may reduce serum urate concentrations. Adequate fluid intake of 2 litres per day is recommended especially in persons with a history of renal stones. Various purine-rich foods and high protein intake have long been thought to be risk factors for gout. However, a prospective study of dietary factors in gout published in the New England Journal of Medicine showed an increased risk of gout with high intake of meat and seafood, and a reduced risk with low-fat dairy foods. 17 Moderate intake of

6 purine-rich vegetables (peas, beans, lentils, spinach, mushrooms, oatmeal, and cauliflower) or protein was not associated with an increased risk of gout. 17 Men are often advised to cut back on alcohol, but evidence suggests that soft drinks and fruit juices may also increase the risk of gout. Soft drinks contain low levels of purine but have large amounts of fructose, the only carbohydrate known to increase uric acid levels. Fructose is used in soft drinks in the USA as a sweetener, but largely is not used in Australia. In a large study of over 46,000 men over 40 years with no history of gout followed for 12 years, consumption of sugar sweetened soft drinks and fructose was strongly associated with an increased risk of gout in men. 18 One soft drink per day resulted in a 29 percent higher risk of gout, while two or more a day increased the risk by 85 percent. These associations were independent of dietary and other risk factors for gout such as body mass index, age, hypertension, diuretic use, alcohol intake and history of chronic renal failure. Diet soft drinks were not associated with the risk of gout. Men should reduce alcohol intake, particularly beer which is high in purine. Wine is not considered a major risk factor. Regular consumption of six or more cups of coffee (regular or decaf) a day is associated with lower serum uric acid levels compared with no coffee intake at all. 19 Coffee contains antioxidants (chlorogenic acid) that reduce serum uric acid levels, and other compounds that lower insulin levels and increase insulin sensitivity. Insulin resistance has been strongly linked in other studies to elevated uric acid levels. Tea intake is not associated with any decrease in risk. In another study, drinking 4 or more cups of coffee a day dramatically reduced the risk of gout for men. 20 The risk of gout was 40 percent lower for men who drank 4 to 5 cups a day and 59 percent lower for men who drank 6 or more cups a day than for men who never drank coffee. There was a modest inverse association with decaffeinated coffee consumption. These findings were independent of all other risk factors for gout. Tea drinking and total caffeine intake were both shown to have no effect on the incidence of gout among the subjects. PATIENT EDUCATION Patients should be informed about the disease, predisposing factors, and the rationale for using different drugs to target different processes. They should be encouraged and supported to lose weight, limit alcohol, fructosecontaining soft drink and fruit juice consumption, take medications to treat high lipids and diabetes and avoid diuretic therapy if possible. Author: Debbie Rigby BPharm, GradDipClinPharm, AdvDipNutrPharm, CGP, AACPA, FASCP, FPS Debbie is a consultant clinical pharmacist from Brisbane.

7 MCQs 1. An overweight 60 year old man tells you he has had four episodes of gout over the past year and wants to know how to reduce the chance of further attacks. He takes amlodipine for hypertension. Which of the following recommendations is LEAST appropriate: a. Advise him to lose weight b. Advise him to reduce his alcohol intake c. Advise him to restrict fluid intake d. Suggest allopurinol prophylaxis e. Consider switching amlodipine to losartan 2. Which of the following drugs and doses should be avoided in treating older patients for gout? a. Indomethacin 50mg three times daily b. Colchicine where creatinine clearance is lower than 30mL/min c. Allopurinol 300mg daily d. Probenecid where creatinine clearance is lower than 60mL/min e. All of the above 3. Which of the following doses of allopurinol is MOST appropriate in a 75 year old male weighing 75kg with a serum creatinine of 100µmol/L? a. 300mg daily b. 200mg daily c. 100mg daily d. 100mg alternate days e. contraindicated 4. Which of the following statements is INCORRECT? a. Low-dose aspirin increases serum urate by inhibiting renal elimination of uric acid b. Hypertension is an established independent risk factor for gout c. Acute flares of gout can be managed with NSAIDs and glucocorticoids d. Beer consumption significantly increases serum urate and gout risk e. Drinking 4 or more cups of coffee a day may increase the risk of gout 5. A 62 year old obese male presents to the pharmacy with a painful right big toe. His symptoms developed abruptly 2 days previously, after attending a retirement party for one of his coworkers. At the party, he consumed at least 5 beers and multiple helpings of a seafood appetizer. Currently, the toe hurts on the mildest contact, and he is not able to stand on his foot. His medical history includes a hypertension, osteoarthritis and hyperlipidemia. He was recently diagnosed with glucose intolerance. His prescription medications include hydrochlorothiazide, losartan, atenolol, atorvastatin, and a low-dose aspirin. He states he has recently begun a high-protein, low-carbohydrate diet. Which of the following is NOT a risk factor for gout in this patient? a. Losartan b. Obesity c. Alcohol d. High meat and seafood intake e. Insulin resistance

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