The purpose of lowering serum urate concentrations is to prevent acute gout attacks and the development of tophi. According to the ACR, pharmacologic treatment of hyperuricemia is indicated for any patient with an established diagnosis of active gouty arthritis (Table 1).[1,7] ULT may be initiated during a gouty attack provided that effective anti-inflammatory management has been instituted. Furthermore, prophylaxis is recommended to reduce the risk of gout attacks associated with the initiation of ULTs and should be continued for 6 months (Table 3). Proper dose titration of medications and monitoring (every 2–5 weeks) of urate concentrations, renal function, and adverse effects of treatment are necessary. A minimum serum urate target concentration of <6 mg/dL should be obtained with therapy. Three classes of drugs are approved for lowering urate concentrations: xanthine oxidase inhibitors (XOIs), uricosuric agents, and uricase agents.
XOIs (e.g., allopurinol, febuxostat) block the synthesis of uric acid. Allopurinol is recommended for monotherapy and should be titrated over 2 to 5 weeks to achieve the serum urate target or the maximum tolerated doses. Allopurinol should be initiated at low doses to reduce the risk of hypersensitivity reactions and acute gout attack.[1,10,20] Allopurinol-induced hypersensitivity reactions are rare but carry substantial morbidity and mortality rates of up to 25%.[21,22] Allopurinol hypersensitivity reactions may be mitigated by screening for the presence of the HLA-B*5801 allele prior to initiation of therapy in susceptible patients (i.e., Koreans with CKD stage 3 or worse, Han Chinese or Thai descendants).[23–25] Success in achieving target serum concentrations most often occurs when daily doses of allopurinol are titrated above an average dose of 300 mg/daily.[26,27]
Febuxostat, an XOI, is approved for the treatment of hyperuricemia in patients with gout and is also recommended for first-line treatment.[1,28] In two randomized, controlled trials, all doses of febuxostat were more effective than allopurinol at usual doses in lowering serum urate concentrations to <6 mg/dL in both patients with normal kidney function and renally impaired patients.[29,30] Patients frequently complained of acute gout attack with high-dose febuxostat. The major limitation of both trials is that allopurinol doses were not titrated higher than 300 mg, which is often necessary and more effective in obtaining target urate concentrations.[25,26] Febuxostat can be substituted for allopurinol or vice versa in the event of drug intolerance or adverse events and after initial failure of upward dose titration. The safety of febuxostat in patients with allopurinol hypersensitivity has not been studied rigorously; however, a recent retrospective study revealed that it may be safe to use.
Uricosuric agents (e.g., probenecid) reduce the serum urate concentration via blockade of renal tubular urate reabsorption. Probenecid is contraindicated in patients with a history of urolithiasis or presence of uric acid overproduction. To mitigate the risk of nephrolithiasis, it is recommended that patients be screened for urine uric acid. Patients should be encouraged to increase fluid intake and urine alkalinization with potassium citrate may be considered. Uricosuric agents may be added to XOIs to achieve target serum urate concentrations. Fenofibrate and losartan have shown to possess uricosuric effects. Although studies are limited to small trials and case reports,[33–36] fenofibrate or losartan may be considered as adjuvant therapy in gouty patients on allopurinol and hyperlipidemia or hypertension, respectively. Ingestion of vitamin C 500 mg has also been associated with minimal lowering of serum urate concentrations, which may have little clinical significance.
Uricase agents (e.g., pegloticase) convert uric acid into soluble allantoin. Pegloticase is approved for chronic gout that is refractory to conventional treatments.[1,39] Treatment with pegloticase resulted in successful reduction of serum urate to <6 mg/dL in a phase II randomized study, with gouty flares being the most common adverse effect in this trial. Other cited adverse effects include infusion site reactions and anaphylaxis.
US Pharmacist. 2013;38(3):22-26. © 2013 Jobson Publishing