When to start ULT to prevent and reverse urate deposition remains debatable. The first gout attack generally occurs after many years of hyperuricemia and so some would argue that ULT should be started immediately. However, only a minority of first attack sufferers go on to develop tophi and chronic gouty arthritis, and, rarely, some patients never experience another attack, particularly those with just mild serum urate elevations. Therefore, some clinicians believe it is best to take a wait and see approach, as once started, patients tend to stay on ULT for life. Beginning ULT after a second gout attack is easier to defend and we believe that all patients who have had three gout attacks should be started on ULT. All gout patients with tophi or nephrolithiasis should receive ULT.
ULT provides an effective means of controlling hyperuricemia and modifying the long-term ramifications of the gouty diathesis. Treatment is lifelong with a dose sufficient to maintain the serum urate below 6.8 mg/dl (404 μmol/l), preferably below 6.0 mg/dl (357 μmol/l). Anything short of this does not reverse the process, but merely slows the rate at which crystal deposition continues. The lower the serum urate achieved, the faster tophaceous deposits will resolve [Perez-Ruiz et al. 2002
]. Targeting a serum urate below 6.0 mg/dl is low enough to allow for normal fluctuations yet remain below the saturation level of 6.8 mg/dl, and high enough to minimize dosing and potential toxicity. That stated, an even lower target may be appropriate in patients with visible tophi.
The choices for ULT are xanthine oxidase inhibitors, uricosuric agents, or uricases. Xanthine oxidase catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid, and is inhibited by allopurinol, oxypurinol, and febuxostat. Uricosuric agents reduce serum urate by increasing the renal excretion of uric acid, and include probenecid, sulfinpyrazone, and benzbromarone. The uricases rasburicase and pegloticase enzymatically convert urate to allantoin, which is more soluble and readily excreted in the urine. Urate-lowering drugs are not anti-inflammatory and have no role in the treatment of acute gout.
Xanthine oxidase inhibitors or uricosuric drugs are equally effective in gouty patients who excrete <800 mg of uric acid per day and have normal renal function. Both can prevent deterioration of renal function in patients with primary gout [Perez-Ruiz et al. 2000
]. However, a xanthine oxidase inhibitor is usually the drug of choice due to fewer restrictions in use compared with uricosuric agents. The ideal candidate for a uricosuric agent is a gouty patient who is less than 60 years old, has a creatinine clearance >80 ml/min, a uric acid excretion <800 mg/24 hours on a general diet, no history of nephrolithiasis, and is not taking more than 81 mg of aspirin a day. Uricosurics should not be used in urinary uric acid overexcreters or those with a history of renal calculi of any type. Gouty patients who excrete more than 700 mg/day of uric acid have a 35% incidence of nephrolithiasis, and the risk increases with initiation of uricosurics [Yu and Gutman, 1967
]. A xanthine oxidase inhibitor is preferred in patients with tophaceous gout to avoid delivery of a high urate load to the kidney. Probenecid and sulfinpyrazone are ineffective in patients with glomerular filtration rates <50 ml/min. Patients who do not achieve a serum urate concentration <6 mg/dl on uricosurics or are intolerant should move on to a xanthine oxidase inhibitor. Xanthine oxidase inhibitors and uricosuric drugs may be used in combination, but this is rarely necessary when the drugs are dosed properly.
Xanthine oxidase inhibitors
Allopurinol is a substrate for xanthine oxidase, which converts it to oxypurinol, which in turn also inhibits xanthine oxidase. Allopurinol is metabolized in the liver and has a 1–3 hour half-life, while oxypurinol is excreted in the urine and has a 12–17 hour half-life. Therefore, allopurinol can be dosed once daily, with lower dosage requirements in patients with renal insufficiency, as the half-life of oxypurinol increases as the creatinine clearance decreases. The lowest dose that lowers the patient’s serum urate to <6 mg/dl should be used. The usual prescribed dose is 300 mg/day, but this fails to achieve a serum urate of <6 mg/dl in 21–55% of individuals [Perez-Ruiz et al. 1998
; Li-Yu et al. 2001
; Becker et al. 2005
]. Up to 800 mg/day may be required. Lower doses may be effective in patients with renal insufficiency, and slowly increasing the dose of allopurinol to achieve a serum urate <6.0 mg/dl is not associated with an increased risk of side effects or toxicity [Dalbeth and Stamp, 2007
The sudden lowering of serum urate after starting allopurinol or other ULT often triggers acute gout. Prophylactic colchicine or NSAID is recommended, starting 2 weeks before allopurinol whenever possible, and continuing for 3–6 months to prevent such attacks. An alternative is to start allopurinol at 50–100 mg/day and increase by similar increments weekly until the target serum urate is reached.
About 20% of patients on allopurinol report side effects and 5% discontinue, the commonest being gastrointestinal intolerance and skin rash. If the rash is mild, allopurinol can be held and the patient rechallenged after the rash has cleared. Desensitization protocols for allopurinol are effective in some patients, but cumbersome [Fam et al. 2001
]. Other adverse reactions include fever, toxic epidermal necrolysis, alopecia, bone marrow suppression, granulomatous hepatitis, jaundice, sarcoid-like reaction, and vasculitis. Allopurinol hypersensitivity syndrome is a dreaded severe reaction that includes fever, skin rash, eosinophilia, hepatitis, progressive renal failure, and death due to multi-organ vasculitis [Hande et al. 1984
]. Individuals with pre-existing renal insufficiency or on diuretics are at greatest risk. The risk of allopurinol hypersensitivity may correlate best with the starting dose, and that dose should be lowered based on creatinine clearance [Stamp et al. 2011
There are relatively few drug–drug interactions with allopurinol, but several drugs are inactivated by xanthine oxidase, including azathioprine and 6-mercaptopurine, and their levels may become toxic in the presence of allopurinol. Allopurinol may diminish hepatic microsomal drug-metabolizing enzyme activity resulting in longer half-lives of warfarin and theophylline. Concomitant ampicillin may increase the risk of rash and cyclophosphamide the risk of bone marrow suppression with allopurinol.
, Takeda Pharmaceuticals, Deerfield, IL, USA; Adenuric©
, Menarini and Ipsen, EU) is a potent xanthine oxidase inhibitor that was approved in the US and Europe in 2008-9 for the treatment of gout on the basis of extensive clinical trials [Becker et al. 2005
; Schumacher et al. 2008
]. It is of a different chemical class than allopurinol and a more selective inhibitor of enzyme activity. It appears to be an excellent alternative for allopurinol-intolerant patients. Febuxostat was more effective than allopurinol in lowering serum urate levels in trials, but importantly, allopurinol doses used were fixed and too low. The true comparative efficacy of these agents remains unknown. Gout flares were more frequent with febuxostat, and patients should be prophylaxed for up to 6 months after initiation. Dosing in the US is 40 or 80 mg daily, and in Europe 80 and 120 mg daily. Mild to moderate renal insufficiency (creatinine clearance >30 ml/min) does not require dose adjustment. As with allopurinol, febuxostat should not be used with drugs metabolized by xanthine oxidase, including azathioprine and 6-mercaptopurine.
Febuxostat and allopurinol have similar safety profiles. Common febuxostat side effects in the clinical trials included diarrhea, dizziness, headache, liver function test abnormalities, and altered thyroid function tests. Cardiovascular events were more frequent with febuxostat, but accounting for total drug exposure, the incidence was the same as in comparator arms. The European Medicines Agency (EMEA) recommendation is not to use febuxostat in patients with ischemic heart disease or congestive heart failure. Although a final phase III trial did not detect increased cardiovascular risk [Becker et al. 2010
], the FDA has required cardiovascular postmarketing surveillance by the manufacturer.
The ideal candidate for febuxostat is a gouty patient with intolerance of allopurinol, hyperuricemia not controlled with other urate-lowering therapy, or mild renal insufficiency (). Febuxostat should be tried before allopurinol desensitization. One study has shown that patients with previous allopurinol hypersensitivity were able to tolerate febuxostat [Becker et al. 2006
]. Febuxostat is preferred over uricosuric agents in patients with nephrolithiasis.
Clinically relevant data for febuxostat and pegloticase.
Uricosuric agents increase the renal excretion of uric acid. Separate transport systems for the secretion and reabsorption of organic ions, including uric acid, exist in the kidney. Reabsorption of urate by renal tubular brush border anion transporters can be inhibited by uricosuric agents which compete with urate for those transporters in the tubule lumen. This inhibition requires high doses of uricosuric agents.
Probenecid is now the only uricosuric agent available in the US. Benzbromarone is used in some other countries. Many other medications also reduce serum urate levels by enhancing the renal excretion of uric acid. Probenecid is well-absorbed orally with a dose-dependent half-life in plasma of 6–12 hours, which is prolonged by concomitant use of allopurinol. Probenecid is metabolized in the liver with <5% of the administered dose recovered in urine. A total daily dose of 500–3000 mg is administered in two or three divided doses. Initiation may precipitate gout flares, and, as with all uricosuric agents, probenecid increases the risk of renal calculi. Up to 18% of patients develop gastrointestinal side effects, and 5% develop hypersensitivity and rash. Serious toxicity is rare, yet still about one third of patients will eventually become intolerant and discontinue probenecid. Probenecid alters the metabolism and increases the potency of many drugs, such as penicillin, methotrexate, and NSAIDs, by decreasing their renal excretion, metabolism, or hepatic uptake. Potential drug interactions should always be considered when starting a patient on probenecid.
Benzbromarone is more potent than probenecid and sulfinpyrazone [Perez-Ruiz et al. 1998
]. It is well-tolerated and effective in cyclosporine-treated renal transplant patients. It can be used in patients with a creatinine clearance as low as 25 ml/min. Hepatotoxicity has led to its removal from some markets worldwide, but the true risk remains controversial [Perez-Ruiz et al. 1998
; Lee et al. 2008
Humans lost uricase during evolution due to a missense mutation in the gene encoding the enzyme [Wu et al. 1989
]. In many other species, uricase converts urate to allantoin, which is readily excreted in the urine. Rasburicase is a recombinant uricase cloned from Aspergillus flavus
approved for use in tumor lysis syndrome. Despite reports of its efficacy [Richette et al. 2007
], approval for use in gout has not been pursued due to its short half-life and immunogenicity.
, Savient Pharmaceuticals, East Brunswick, NJ, USA) is a pegylated mammalian (porcine-like) recombinant uricase. Recently approved in the US for the treatment of severe tophaceous gout. It is given at a dose of 8 mg every 2 weeks by IV infusion [Sherman et al. 2008
; Burns and Wortmann, 2011
]. The enzyme activity half-life is 6.4–13.8 days. Serum urate falls dramatically in 24–72 h, often to 1.0 mg/dl, and stays low for 21 days [Sundy et al. 2007
]. Pegloticase was studied in just over 250 patients in phase II and III trials prior to its approval in the US in late 2010 [Sundy et al. 2008
; Baraf et al. 2008a
]. In phase III trials of 212 subjects with treatment failure gout, pegloticase at 8 mg every 2 or 4 weeks was significantly more effective than placebo at achieving the primary endpoint of a plasma urate concentration < 6 mg/dl (357 μmol/l) [Sundy et al. 2011
]. Pegloticase was also capable of reducing tophi rapidly [Baraf et al. 2008a
]. However, despite specific prophylaxis, gout flares, infusion reactions, and serious adverse events were significantly more frequent in patients receiving pegloticase. The most common reason for withdrawal was infusion reaction.
The development of high-titer antibodies to pegloticase in treated patients is associated with loss of response and infusion reactions [Becker et al. 2008
]. In fact, 96% of patients with antibodies to the poly(ethylene glycol) portion of the drug became nonresponders, and 50–76% had infusion reactions. These antibodies do not inhibit uricase activity in vitro
. Development of these antibodies heralded a rise in serum urate levels and stopping pegloticase when serum urate levels rose above 6 mg/dl would have avoided 91% of infusion reactions [Wright et al. 2009
]. Accordingly, the FDA recommends clinicians stop pegloticase if the serum urate rises above 6.0 mg/dl during ongoing treatment. In open-label extension trials, gout attacks continued to decline, most patients maintained target serum urates, and more patients had tophus resolution [Sundy et al. 2009
]. Unfortunately, infusion reactions continue to occur, often resulting in discontinuation.
Pegloticase is appropriate for patients with tophaceous gout with persistent gout attacks or damaging arthropathy who have failed or are intolerant of conventional therapy (). Presumably, many such patients will now be eligible for and respond to febuxostat, but others will not and may receive pegloticase. A good way to conceptualize pegloticase is as a urate debulking agent, emphasizing it as adjunctive therapy that should be followed by other ULT whenever possible. Pegloticase could conceivably be used to reduce tophi more quickly than conventional treatment when that is felt to be necessary. Continuous use will be restricted by its immunogenicity. Over 25% of patients develop antibodies, infusion reactions, restricted efficacy, and/or drug withdrawal. There is a 5% anaphylaxis rate. Gout flares are almost certain, can be severe, and occur despite prophylaxis. Concomitant infusions of corticosteroids are required to ameliorate infusion reactions with pegloticase and may further restrict its use. Finally, pegloticase cannot be given to patients with glucose-6-phosphate-dehydrogenase deficiency as it may induce hemolysis. As for a potential cardiovascular signal in the clinical trials, the FDA’s own independent analysis could not verify an increased risk.
Despite these downsides, the target patient for this drug is often miserably symptomatic and often has no other options. Monitoring for a rising serum urate level as a sign of antibody development and impending infusion reaction will allow for safer administration [Wright et al. 2009
]. A recent report described a group of patients who were safely maintained on pegloticase alone for a median follow up of 2.5 years [Hamburger et al. 2010
]. The frequency of infusion reactions was low in this group, even in subjects with up to 6-month breaks between infusions. Nevertheless, this drug has significant potential toxicity and should only be administered at experienced infusion centers capable of dealing with serious reactions, including anaphylaxis.