Update on Gout and Hyperuricemia

J. F. Baker; H. Ralph Schumacher


Int J Clin Pract. 2010;64(3):371-377. 

In This Article

Pharmacotherapy for Chronic Hyperuricemia in Gout

Treatment with agents to lower SUA is recommended for patients with recurrent attacks, polyarticular attacks, tophaceous gout, radiographical joint damage and/or severe hyperuricemia (Table 2). It is not recommended to treat asymptomatic hyperuricemia without one of these features of gout as the risks and benefits of such an intervention have not been clarified. Although the possible need for lowering of uric acid levels should be mentioned at the time of diagnosis, urate-lowering therapy should, in most cases, be initiated after resolution of an acute gouty attack. However, there is no specific evidence to support the widely accepted belief that acute flares of gout may worsen with immediate initiation of treatment, and this can be considered along with anti-inflammatory therapy in some patients.

The current guidelines suggest treating to a SUA goal below the saturation point for MSU of approximately 6.8 mg/dl, to achieve a level < 6 mg/dl (< 360 umol/l). Patients will over time note a reduction in clinical flares when maintained at this concentration, as urate stores are depleted. Achieving this goal requires frequent adjustment of doses of allopurinol or other urate-lowering agents with close attention to SUA levels. Allopurinol should be started at low dose (100 mg) and increased every 2–4 weeks to as much as 800 mg/day as required to reach the above goal. Prophylactic daily use of 0.5 mg once or twice a day colchicine or low dose NSAIDs is appropriate during the first 6 months of urate-lowering therapy or until resolution of tophi. Acute flares can occur during urate lowering and may interfere with patient adherence. Patients with tophi should be aware that resolution is slow and may take several years in some cases after SUA levels have met their treatment goal. Tophi that are complicated by infection or deformity and are difficult to treat with medication may require surgical excision or debridement.

Allopurinol is the first-line therapy for most patients. The side effects of allopurinol are largely limited to rash and fever, however, the allopurinol hypersensitivity syndrome (AHS) can be life threatening, occurring in an estimated 0.1% of those exposed.[23,24] Chronic kidney disease has been proposed as a risk factor for the development of AHS, and there have been guidelines for dosing of allopurinol in renal insufficiency. These were suggested by Hande et al.[25] in 1984, who reported that most patients who developed AHS at their institution had pre-existing renal impairment and were on full treatment doses of allopurinol (> 300 daily). Unfortunately, these recommendations for dose adjustment of allopurinol may limit the number of patients who attain an optimal SUA level. A study by Dalbeth et al.[23] found that target SUA concentrations were reached in only 28% of their patients on such recommended doses of allopurinol, whereas 60% reached that goal safely when on higher doses. More recent data would also challenge the current dosing recommendations.[26] Two recent large case-control studies found no difference in the dosing of allopurinol between patients who had developed AHS and those who were tolerant to allopurinol.[27,28] In addition, there are no prospective data to suggest that dose-adjustment results in a decreased risk of AHS. Understanding these uncertainties, the gradual escalation to more aggressive dosing regimens for many patients may be appropriate to avoid under-treatment.

Probenecid and other uricosuric agents may also be used in patients who are under-excreters of uric acid with otherwise normal renal function and are likely to comply with increased oral fluid intake needed to decrease the risk of stone formation. Benzbromarone is another, probably more potent uricosuric that is available in only a few countries but seems more effective, even in patients with mild renal disease.[29] Both medications act on the recently defined URAT1 transporter to decrease urate reabsorption from the renal proximal tubule.[30] Medications that may increase SUA such as thiazide diuretics should be discontinued if possible.

Under-treating hyperuricemia may have significant consequences to patients including increased number and frequency of gout flares, resultant decreased QOL and productivity, and increased use of NSAIDs and systemic steroids. Other possible risks of under-treated hyperuricemia include worsening of endothelial dysfunction, hypertension, renal disease, systemic inflammation and increased cardiovascular risk. These considerations will be discussed in greater detail. Further study is needed to determine if intervention with allopurinol or other methods to lower SUA ameliorates these risks.