In this article the clinical presentation and management of gout are described, together with the modifiable risk factors which provide opportunities for primary prevention
Credit for Learning: 2This article will form the basis of questions under the PJ/College of Pharmacy Practice Credit for Learning scheme |
Gout is an abnormality of urate metabolism resulting in the deposition of urate (uric acid) crystals in the joints, soft tissue and urinary tract. The condition is manifested by acute or chronic recurrent arthritis. Gout is five to eight times more common in men than women and seldom occurs in boys before puberty or women before the menopause.1 It is most often associated with hyperuricaemia (a serum urate concentration of >0.42mmol/L in men and >0.36mmol/L in women).
The risk of developing gout increases with the duration of hyperuricaemia and as the serum urate concentration increases. For example, in men with a serum urate of 0.42mmol/L the risk is approximately 0.5 per cent per annum and this rises to about 5 per cent per annum for a serum urate of 0.54mmol/L.1,2 However, gout may occur in the presence of normal serum urate levels and individuals who are hyperuricaemic may never experience an attack. Therefore, gout should be considered as a clinical diagnosis and hyperuricaemia as a biochemical one. To establish a clinical diagnosis the presence of urate crystals in the joint needs to be confirmed (by studying fresh synovial fluid or tissue under polarised light) and the possibility of infection must be excluded.1
Increased serum urate concentrations can result from an increase in the production of urate, a decrease in renal excretion of urate or a combination of both.1 Under-excretion is found in about 90 per cent of patients with gout. The underlying reasons for under-
excretion of urate are unknown but factors such as obesity, hypertension, hyperlipidaemia, renal insufficiency, alcohol intake and medications may play a role. Gout is common in men with an alcohol intake in excess of 40 units per week, especially in those who drink beer or lager, as these contain purines, such as guanine, which are degraded to urate. Alcohol consumption also leads to decreased uric acid excretion.2
Overproduction of urate is most commonly associated with diseases that are characterised by high cell turnover (eg, myeloproliferative disorders, haemolytic anaemia, psoriasis and Paget's disease) and, more rarely, with hereditary enzyme defects of purine metabolism or impaired ATP regeneration (eg, glycogen storage diseases).1
Certain drugs can also cause hyperuricaemia and precipitate gout. Loop and thiazide diuretics, which inhibit distal tubular excretion of uric acid, are the most common drugs that cause hyperuricaemia. They rarely cause acute gout, but may encourage the formation of tophi around previously damaged joints, particularly in the fingers. (Tophi are massive accumulations of microcrystals of sodium urate and amorphous urates, surrounded by histiocytes, giant cells and fibrosis.) Low-dose salicylates have a similar effect on urate excretion. Cytotoxic drugs cause overproduction of uric acid from cellular purines during the treatment of leukaemias and lymphomas because they increase the rate of cell death.
The symptoms of gout include intense pain in the affected joint and reddening of the surrounding skin, which feels hot and may look shiny. An attack of gout most commonly starts during the night or early hours of the morning and reaches a peak within a few hours. Acute attacks of gout may also be accompanied by a fever, leucocytosis (raised number of leucocytes), raised erythrocyte sedimentation rate (ESR) and an increased C-reactive protein (CRP) concentration.3
First attacks occur most commonly in men aged between 30 and 60 years and most frequently affect the first metatarsophalangeal joint (at the base of the toe). Other commonly affected joints include the knees, elbows, wrists and the small joints of the hands. Gout seldom occurs in the axial skeleton or in large joints such as the hip or shoulder.1 Untreated attacks last a few days or weeks before subsiding spontaneously.
Following the first attack of gout, patients enter an asymptomatic period of variable duration. Some patients have a single attack, some suffer another attack only after many months or years, but many experience recurrent episodes, with progressive shortening of the symptom-free period between attacks.2 Subsequent attacks tend to be more severe, longer in duration and often involve additional joints. In patients who have recurrent episodes, gout becomes tophaceous, with visible and/or palpable deposits of monosodium urate crystals occurring in and around the joints or subcutaneous tissues, most commonly on the extensor surfaces of the elbows or at sites of minor trauma.
Intra-articular and peri-articular tophi may result in gradual joint erosion and crippling end-stage degenerative arthritis. Left untreated, 60 per cent of patients with recurrent gout will develop tophi after a period of 10 years.1
Treatment of gout comprises three phases:
The aim of treatment of an acute attack of gout is to provide symptomatic relief. It is important to avoid sudden fluctuations in the serum urate concentration as this may prolong the attack or trigger further episodes. Therefore, hypouricaemic agents, such as allopurinol, should not be started until at least three weeks after the acute attack has subsided and also should be continued in patients who experience an attack while taking allopurinol.
Three treatments options are available for acute gout: non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and corticosteroids. Each of these treatments has advantages and disadvantages. The choice for a particular patient depends on a number of factors, including the time of onset of the attack in relation to starting treatment, contraindications to treatment as a result of concurrent medical conditions, and the likely efficacy of a particular treatment versus the potential risk of side effects.
Non steroidal anti-inflammatory drugs (NSAIDs)NSAIDs are effective first-line therapy for an otherwise healthy patient who presents with acute gout. Their mechanism of action in gout is complex and involves more than inhibition of prostaglandin synthesis.4 NSAIDs do not affect serum urate levels.
Seven NSAIDs are licensed for gout: azapropazone, diclofenac, indomethacin, ketoprofen, naproxen, piroxicam and sulindac. Indomethacin tends to be the most commonly used and has traditionally been linked to successful treatment although no significant difference between this and the other licensed agents has been demonstrated.2 Azapropazone probably still has a role in the treatment of gout but the Committee on Safety of Medicines has restricted its use to patients in whom other NSAIDs have been tried and have failed. Use of aspirin should be avoided because it causes uric acid retention unless given in very high doses.
Depending on the severity of the attack and the time between onset and initiation of treatment, a dose of 50mg to 100mg indomethacin orally will often provide pain relief within two to four hours. This may be followed by 150mg to 200mg daily, with the dosage gradually reduced to 25mg three times daily over a period of five to seven days as the attack subsides. This approach minimises the risk of gastrointestinal toxicity.2
NSAIDs are normally required for between seven and 14 days depending on the patient's response, although patients with chronic or tophaceous gout may require long-term NSAID therapy to control their symptoms. The usefulness of NSAIDs is limited by their side effects, which can be a particular problem in the elderly and in patients with poor renal function. In elderly patients, or in those with a history of peptic ulcer disease, concurrent administration of an H2 antagonist, misoprostol or a proton pump inhibitor should always be considered.
In patients with renal insufficiency, NSAIDs should be avoided whenever possible or very low doses used if the benefits are expected to outweigh the risks. In such cases, serum creatinine, urea and electrolytes must be monitored regularly.
ColchicineOral colchicine is an effective and specific treatment for acute gout. However, it is less favoured than NSAIDs because of its slow onset of action and high incidence of side effects. Colchicine is an antimitotic agent which does not affect serum urate levels. It is concentrated by leucocytes, within which it binds to microtubular protein and interferes with the function of mitotic spindles, leading to a decrease in leucocyte migration, chemotaxis, adhesion and phagocytosis in the areas in which monosodium urate crystals are deposited in the acute gouty attack. In this way, colchicine reduces the inflammatory response.5
Colchicine therapy should be started as early as possible after symptoms appear since it becomes less effective over time. For example, if given within the first few hours of the start of an attack over 90 per cent of patients will respond, but if given after 24 hours only 75 per cent of patients will respond. Colchicine is of little benefit in longstanding or polyarticular gouty attacks. For these reasons it is considered as a second-line agent.
It is not easy to use colchicine optimally as the effective dose is close to that which causes toxicity (gastrointestinal side effects occur in up to 80 per cent of patients). The recommended dose is usually 1mg initially followed by 500µg every two to three hours until vomiting/diarrhoea or relief of symptoms occurs. A total dose of 10mg is recommended as a single course and a course should not be repeated within three days. Frail, elderly patients may respond better to 500µg every four to six hours for 24 to 48 hours, as this minimises side effects which may be more pronounced in this population. The dose of colchicine must also be reduced in renal insufficiency and the maximum dose should not be used for an acute attack in any patient who has been receiving colchicine maintenance therapy.
As indicated above, the most common side effects of colchicine are diarrhoea, nausea, vomiting and abdominal pain; excessive doses may also cause bone marrow failure and renal damage. Most patients will obtain some pain relief about 18 hours after starting colchicine therapy and will experience diarrhoea after 24 hours; joint inflammation usually subsides gradually within a period of 48 hours.2
CorticosteroidsIntra-articular corticosteroids are useful treatments for gout if only one or a few joints are affected although it is essential to exclude joint infection before their administration. This treatment is becoming more widespread as experience with its use increases. In practice, the appropriate dose varies with the joint involved and the corticosteroid used. For example, the intra-articular dose of methylprednisolone acetate ranges from 4 to 10mg for a small joint to 20 to 80mg for a large joint such as the knee, depending on the volume of the effusion. In the past, oral corticosteroids were not recommended for treating acute gout because they were thought to give inconsistent results or to cause a rebound phenomenon. However, recent findings suggest that in certain circumstances (for example, in patients with severe or polyarticular attacks, or in those with renal disease or heart failure which may preclude use of NSAIDs or colchicine) doses equivalent to 20 to 40mg of oral prednisolone per day initially may be useful. The dosage is then reduced gradually over a period of seven to 10 days as gout may flare if steroids are stopped abruptly. Alternatively, intramuscular injection of triamcinolone 40mg to 100mg daily or intravenous methylprednisolone 50 to 150mg daily may be administered. The dosage is then tapered over a period of five days.6
Causes of hyperuricaemiaEndogenous
Exogenous
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Allopurinol Allopurinol inhibits the formation of uric acid from precursor xanthines by inhibiting the enzyme xanthine oxidase. It therefore decreases serum and urinary uric acid levels. It also prevents deposition of urate crystals in the kidney and other tissues. It is especially appropriate for patients who are overproducers of urate, those with renal insufficiency or those with a history of renal calculi, which complicate gout in 10 to 25 per cent of patients.
Renal function should always be checked before allopurinol is started. Textbooks recommend an initial dose of 300mg allopurinol daily for patients with normal renal function. However, in practice most patients are started on 100mg daily and the dose is titrated according to the serum urate level. The usual maintenance dose of allopurinol is 100mg to 600mg daily (depending on renal function). A dose of 300mg daily reduces serum urate to normal in approximately 85 per cent of patients.2 Only rarely are doses greater than 300mg daily needed to bring the serum urate within the normal range.1
Dosage should be reduced in renal failure because oxypurinol (the active metabolite of allopurinol) has a prolonged half-life in such patients and its accumulation is dependent on the dose of allopurinol. In patients with decreased renal function, a dose of 200mg daily is usually recommended for those with a creatinine clearance of 60ml/minute and 100mg daily for those with a creatinine clearance of 30ml/minute.1,2
A response to allopurinol, which is reflected by a decrease in the serum urate concentration, is seen about two days after starting therapy and is maximal after about seven to 10 days.
When starting therapy, acute attacks of gout may occur. The mechanism for this is poorly understood but is usually attributed to changes in the serum urate concentration. For this reason an NSAID or colchicine (500µg twice daily) should be given concurrently for at least three months. This is an arbitrary period and there is still a risk of recurrent gout for up to 12 months after starting allopurinol.3 In patients with visible tophi it is wise to continue prophylaxis until these have disappeared.
Adverse reactions to allopurinol are more common in patients with renal insufficiency or hypertension and in those receiving diuretics. The most common reaction is a rash, which occurs in approximately 2 per cent of patients. This usually subsides after allopurinol has been discontinued and may not recur if therapy is resumed at a lower dose. The most serious side effect, which occurs in fewer than 1 in 1,000 patients, is exfoliative dermatitis. In cases where patients have minor hypersensitivity rashes, a desensitisation regimen, in which the dosage of allopurinol is gradually increased over a period of three to four weeks, is often successful in enabling the patient to tolerate long-term allopurinol therapy. However, desensitisation should not be attempted in patients who have had toxic epidermal necrolysis or drug-induced vasculitis.2
Uricosurics If a patient is intolerant of allopurinol, uricosurics such as probenecid or sulphinpyrazone may be used, although they are relatively ineffective in patients with poor renal function. Uricosurics increase uric acid excretion, primarily by blocking tubular reabsorption of urate.5 They are contraindicated in patients with renal failure and in those who have, or have had, uric acid stones in the kidney. They should also be avoided in patients who have a high rate of uric acid secretion before drug treatment (>3.6mmol/day on a purine restricted diet) and should not be given within three weeks of recovery from an acute attack. As with allopurinol, their initial use should be accompanied by prophylactic therapy against an acute attack using an NSAID or colchicine for about three months.
The greatest potential risk of therapy with uricosurics is the formation of urate crystals in urine and the deposition of crystals in the renal tubules, pelvis or ureter, causing renal colic or deterioration of renal function. Therefore, during the first few weeks of therapy it is necessary to ensure adequate clearance of the extra urinary load of urate by ensuring that fluid intake is at least 2L per day. It may also be necessary to alkalinise the urine by giving potassium citrate mixture, sodium bicarbonate (1g three or four times daily) or acetazolamide (250mg at night), if not contraindicated. In addition, uricosuric therapy should be started at a low dose and gradually increased. Low dose aspirin blocks active secretion and causes retention of uric acid, and must be avoided.
Probenecid is started at a low dose (eg, 250mg twice daily) and increased gradually to 500mg twice daily after a week and then to 2g daily in two to four divided doses. Doses are then adjusted according to the serum urate concentration. Satisfactory control of hyperuricaemia can be achieved in 60 per cent of patients with a dose of 1g daily and in 85 per cent of patients with 2g daily. In practice, control of hyperuricaemia is inadequate in up to 25 per cent of patients.2 The most common side effects of probenecid include gastrointestinal disturbances, hypersensitivity reactions and skin rashes. Its major limiting factor is a lack of efficacy due to poor compliance, concurrent low dose salicylates or renal insufficiency.
Sulphinpyrazone is an alternative to probenecid as it shares the same mechanism of action. It is still used occasionally to prevent recurrent attacks of gout in patients who are unable to tolerate allopurinol. It is started at an initial dose of 50 to 100mg twice daily increasing to 600mg (or rarely 800mg) daily. The maintenance dose is decided according to the serum urate concentration but may be as low as 200mg daily. Like probenecid, sulphinpyrazone is less effective in patients with poor renal function.
The side effects of sulphinpyrazone include rashes, nausea and vomiting. A high incidence of uric acid crystalluria has been reported with sulphinpyrazone and has led to a significant decrease in its use over the past 15 years.
Goals of hypouricaemic therapy
The aim of hypouricaemic therapy is to reduce the serum urate levels to <0.36mmol/L, although if there is clinical or radiological evidence of tophi a serum urate of less than or equal to 0.3mmol/L is required to aid dissolution.2 This may take between six and 12 months.
Once the serum urate has been reduced to target levels the patient should be evaluated periodically. The frequency of monitoring is dependent upon the serum urate and whether the patient has any cardiovascular risk factors such as hypertension, hyperlipidaemia or renal failure. Hyperuricaemia may persist in some patients despite apparently adequate compliance with drug treatment. This may be related to factors such as regular/excessive alcohol consumption, the need to continue diuretic therapy and/or obesity.
Before treatment for gout is started it is important to confirm the diagnosis and to exclude joint infection. Removal of factors contributing to hyperuricaemia, such as obesity, a high purine diet, excessive alcohol consumption and diuretic therapy, can be successful in primary prevention. However, in patients with persistent hyperuricaemia despite lifestyle modifications, medication can be successfully employed to normalise serum urate levels. The continuing challenge is to educate patients about lifestyle modifications, and to stress the importance of compliance with drug therapy to ensure that attacks of gout do not recur and that long term morbidity from tophaceous deposits is avoided.
Mrs Wood is deputy chief pharmacist at University Hospital, Liverpool
References
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