This chapter deals with the treatment of gout and hyperuricemia and the drugs used mainly for these disorders.
Gout and Hyperuricaemia
Uric acid is the final product of man’s metabolism of endogenous and exogenous purine. An excess of uric acid, measured in the plasma as sodium urate, constitutes hyperuricemia. An overproduction or underexcretion of urate may cause this excess. It is influenced by genetic and environmental factors and may be classified as primary (mainly idiopathic) or secondary. Increased urate production may be caused by excessive dietary purine intake, certain cancers or their treatment, or, more rarely, enzyme defects of purine metabolism. Reduced urate excretion may be caused by renal disease, hypertension, or the intake of certain drugs such as thiazide diuretics. Other factors contributing to hyperuricemia include hyperlipidemia, obesity, alcohol consumption, and lead exposure.
A patient is usually considered to be hyperuricaemic when plasma-urate concentrations exceed 0.42 mmol/liter (7 mg per 100 mL) in men and postmenopausal women or 0.36 mmol/liter (6 mg per 100 mL) in premenopausal women. At high concentrations, there is a risk of crystals of monosodium urate monohydrate being formed and deposited in synovial fluid and various tissues. However, some subjects may have supersaturated plasma-urate concentrations without any crystal deposits, while others may suffer from deposits in the absence of apparent hyperuricemia.
The presence of urate crystals in the synovial fluid leads to an inflammatory response in the affected joint, commonly at the base of the big toe (podagra). The ensuing exquisite pain, tenderness, erythema, and swelling constitute the clinical manifestations of acute inflammatory gouty arthritis. Repeated acute attacks may be associated with a visible or palpable build-up of crystal deposits (tophi) at various sites, including in and around the affected joint. Tophi release urate crystals into the synovial fluid after various stimuli and so cause further acute attacks, leading to chronic tophaceous gout. Intra-articular and peri-articular tophi may cause gradual joint erosion, which, without treatment, results in disabling chronic gouty arthritis. Rarely the kidney can be affected by urate deposits producing gouty nephropathy or by uric acid calculi or stones (uric acid nephrolithiasis or urolithiasis).
Treatment aims to alleviate the acute attack, prevent future attacks, and lower plasma-urate concentration.
Plasma-urate concentrations may be reduced by control of obesity and modification of diet and alcohol intake. Drug treatment can relieve the pain of acute attacks. Still, more prolonged therapy for hyperuricemia is generally only considered if there are recurrent gout attacks or renal involvement (see Chronic Gout below).
Acute Gout. An attack of acute inflammatory gouty arthritis is best treated as soon as possible with an NSAID. Aspirin or other salicylates are not suitable since they may increase plasma-urate concentrations. Treatment is started with high doses of an NSAID, the doses being reduced as the patient responds. Usually, treatment can be withdrawn within 1 to 2 weeks. Colchicine is an effective alternative; it may be used alone or with an NSAID. Patients who do not respond to NSAIDs or colchicine or for whom these drugs are contra-indicated may be treated with a systemic corticosteroid. Intra-articular corticosteroids are effective in acute monoarticular gout or when used adjunctively in patients with polyarticular gout; infection of joints should be excluded before injection. Intravenous, intramuscular, or subcutaneous corticotropin has been reported to alleviate pain and inflammation in acute gout. It may be used alone or adjunctively and may be a helpful alternative in patients with renal and gastrointestinal contra-indications to other therapies. Other therapies for acute gout include adjunctive analgesics and ice. Drugs used for chronic gout (allopurinol or uricosurics) should not be started during an acute attack since they can exacerbate and prolong it (see below).
Chronic Gout. If the patient suffers frequent acute attacks, develops tophaceous gout or has renal complications due to urate overproduction, long-term treatment of hyperuricemia may be needed. Such urate-lowering therapy should not be started during an acute attack or within 2-3 weeks after that, as fluctuations in urate concentration may prolong the existing attack or initiate a new one. Treatment involves inhibiting the production of uric acid or enhancing its urinary excretion to maintain a serum urate concentration at or below 0.3 or 0.36 mmol/liter. Hyperuricaemia due to overproduction of urate is treated with allopurinol which inhibits the enzyme oxidase, involved in purine metabolism. Hyperuricaemia associated with underexcretion of uric acid can be treated with either allopurinol or a uricosuric such as benzbromarone, probenecid, or sulfinpyrazone. Allopurinol is most commonly given as first-line therapy but may be combined with or replaced by uricosurics if treatment fails. Allopurinol should also be used for patients with renal urate deposits or with uric acid renal calculi, as it reduces urolithiasis. Febuxostat is an alternative xanthine oxidase inhibitor under investigation.
With any treatment, mere mobilization of urate crystals from established tophi may occur as the plasma-urate concentration falls, which can trigger further acute attacks of gout. Therefore, patients are also given prophylaxis with an NSAID or colchicine from the start of urate-lowering treatment for a month after the plasma-urate has been reduced to an acceptable concentration. Up to 6 months of prophylactic is recommended.
Once the hyperuricemia is corrected, the patient continues to receive therapy with allopurinol or uricosurics indefinitely. However, suppose an acute attack occurs during such maintenance therapy. In that case, this therapy should be continued to avoid fluctuations in urate concentration, and the acute attack should be treated in its own right.
Surgery may have to be considered for patients severely affected by chronic tophaceous gout.