Hypourecemic therapy should be considered for most gouty patients, including those with end stage renal disease and nephrolithiasis. The main reason to use hypourecemic treatment is to prevent long-term complications of gout such as urate nephropathy, urate kidney stones, development of tophi and joint damage. Once the patient has suffered 1 attack of acute gout, the likelihood of recurrent attacks is extremely high. In patients not treated with urate-lowering drugs, 62% will experience a recurrence within 1 year of the initial attack, 78% by 2 years, and 89% by 5 years.200
For patient comfort, it is important to reduce or eliminate gouty flares. Thus, once urate-lowering medication is begun, the treatment is not intermittent; it is continuous and lifelong.
Uric acid level should be maintained below the solubility concentration of 6.8 mg/dL, preferably below 6.0 mg/dL. Still, some patients may continue to have clinically important deposits of MSU and/or attacks. Hypourecemic agents should not be started during the acute attack as that can exacerbate a flare. We recommend that patients who experience acute attacks while taking a hypourecemic agent do not discontinue the agent because the subsequent increase in serum uric acid level may worsen the attack.
On the other hand, hypourecemic therapy may not be necessary for patients with a frequency of gout attacks less then 2 or 3 times per year, who have no tophaceous deposits, and who have mildly elevated uric acid levels that may be amenable to lifestyle changes and nonpharmacological treatment (see above). Hypouricemic treatment may not be indicated in very elderly patients who may not require long-term prophylaxis against renal or joint damage. Such patients may do very well simply with colchicine prophylaxis against acute attacks.
Allopurinol and febuxostat (but not probenecid) both provide effective prophylaxis against nephrolithiasis in most gouty patients.
Allopurinol has been the cornerstone of urate-lowering treatment in the US since 1966, but despite potent xanthine oxidase inhibition and urate-lowering properties, allopurinol is commonly underdosed or poorly adhered to in long-term treatment.201
In patients with normal renal and liver function, allopurinol is generally started in a dose of 100 mg/day and increased by 100 mg/day weekly until 300 mg/day is being taken. The goal is to maintain a serum uric acid level <6.0 mg/dL. The dose may be gradually increased to 800 mg/day in patients with normal renal function, but the risk of serious idiosyncratic toxicity increases at higher doses, and with renal insufficiency (see below). Despite the wide dose range over which allopurinol is approved in the US, only a single randomized controlled trial has evaluated the efficacy and safety of allopurinol in doses exceeding 300 mg/day.204
The most common adverse effects are gastrointestinal upset and rash. The incidence of rash is estimated at ~2%.205
Unfortunately, serious toxicity is completely unpredictable and is considered to be allergic in nature. Allopurinol-induced rash usually resolves upon discontinuation of the drug, but rechallenge may lead to life-threatening toxic epidermal necrolysis. In the past, persons who required allopurinol could sometimes successfully undergo desensitization,207
but this is less commonly done since febuxostat has provided an alternative for allopurinol-allergic patients. The occurrence of xanthine urinary calculi is a theoretical possibility under low urinary flow conditions.
One rare but exceedingly important reaction to allopurinol is the allopurinol hypersensitivity syndrome (AHS), which consists of rash (sometimes severe as in toxic epidermal necrolysis or exfoliative dermatitis), eosinophilia, leukocytosis, fever, hepatitis and progressive renal failure (usually due to interstitial nephritis).206
One particularly alarming feature of the syndrome is that it often is relentlessly progressive (and fatal) despite discontinuation of allopurinol and institution of corticosteroid therapy.208
There are no published trials or case reports that examined immunosuppressive treatments. The incidence of AHS is estimated at ~0.1%.205
Allopurinol is one of the more commonly used drugs that can cause severe hypersensitivity reactions.210
Risk factors for AHS include higher dose, renal insufficiency, diuretic use and higher oxypurinol concentrations.211
There may also be a genetic predisposition. HLA-B*501 was found in 100% of 51 Taiwanese patients with severe cutaneous reactions to allopurinol, but in only 20% of the general population.212
According to the allopurinol prescribing information,213
the frequency of hypersensitivity reactions may be increased in patients with decreased renal function who are receiving thiazides concurrently. It is also stated in the package insert that patients with decreased renal function require lower doses. “Therefore, a dose of 100 mg/day or 300 mg twice a week or perhaps less may be sufficient ...” With a creatinine clearance of 10 to 20 mL/min, a dose of 200 mg “is suitable”, and for creatinine clearance between 3 and 10 mL/min, the dose “should not exceed 100 mg”.
Allopurinol dosing in the presence of renal insufficiency has recently been reviewed.205
The main concern has been accumulation of the major metabolite oxypurinol which has a half-life of 18 to 30 hours in the presence of normal renal function, increasing up to a week in those with severely impaired renal function.205
Unfortunately reductions in serum uric acid level do not correlate well with oxypurinol concentrations, hence some persons are resistant to the urate-lowering effects even at very high serum levels of oxypurinol.
Recommendations for lower doses of allopurinol in the presence of renal insufficiency stem mainly from reports that most patients with AHS had pre-existing renal insufficiency and were receiving full doses of allopurinol.209
Critics point out that the relationship between oxypurinol concentrations and AHS remains unproven,219
and that no study has systematically demonstrated that dosage reduction in renal insufficiency reduces the risk of severe AHS. Some studies have found no relationship of AHS with dose in renal insufficiency.212
In other words, it is suggested that the renal insufficiency itself confers the risk, not the dose of allopurinol.219
Lastly, the increased risk of AHS (if any) must be balanced against the risk of inadequate control of gout that often follows from using the lower recommended doses.
The frequency of gouty attacks seems to decline once CKD patients are placed on dialysis.221
Nevertheless, when allopurinol is required by patients undergoing dialysis, it may be started at 100 mg every other day, to be administered post-dialysis. If dialysis is performed daily, then an additional 50% may be required post-dialysis.205
Interestingly, the package insert makes no mention of dialysis.213
It is noteworthy that the phosphate binder sevelamer has been reported to have a modest urate-lowering effect and may be useful as an adjunct.205
Unfortunately gout becomes more frequent in transplant recipients. Minimizing diuretic use and calcineurin dose seems to be important in renal transplant recipients. The management of gout in transplant patients can be difficult and has been reviewed.224
Although allopurinol and uricosuric agents may be used together, it is worth noting that uricosuric agents also tend to increase the excretion of oxypurinol, resulting in either a reduction of efficacy or a need for additional allopurinol.
The prescribing information Dosage and Administration section notes that the average dose is 400 to 600 mg/day for patients with moderately severe tophaceous gout (and presumably with normal renal function). Doses above 400 mg/day should be administered in divided doses. It is best to begin with 100 mg/day to minimize the risk of acute gout attacks and increase by 100 mg/day per week. The effect of any given dose adjustment upon serum uric acid level will generally be apparent by 1 week, occasionally longer if many tophaceous deposits are present. The maximum recommended dose is 800 mg/day.
Allopurinol has life-threatening interactions with azathioprine and 6-mercaptopurine because metabolism of these immunosuppressive agents is inhibited by allopurinol, but they may be used together with proper dosage adjustment. Allopurinol may prolong anticoagulation times in those taking warfarin and may elevate theophylline levels by inhibiting metabolism of this purine derivative.
Neither allopurinol nor febuxostat is indicated for asymptomatic hyperuricemia, although this was fairly common practice in years past.226
Given the emerging risks of sustained hyperuricemia,16
debate on this question may be renewed, but the benefits of lowering uric acid must be balanced against the risk of serious reactions.
Febuxostat was approved in the US in 2008, the first FDA-approved hypouricemic agent in more than 40 years. It is a nonpurine inhibitor of xanthine oxidase. It has several potential advantages over allopurinol including tolerability in those who are allopurinol-hypersensitive, better retention of efficacy in renal insufficiency (without an increased incidence of hypersensitivity reactions, based on limited data), better efficacy than allopurinol in many persons and possibly more rapid dissolution of tophi. Potential problems include liver enzyme elevation, possibly more gastrointestinal symptomatology than with allopurinol and a small increase in the risk of vascular events compared with allopurinol. Questions that are still unanswered include dose and efficacy in patients with advanced renal failure or on dialysis, and whether there are special hazards in this population. Clinical trials are ongoing in this population.
Information on efficacy in persons with normal renal function comes from a short-term, randomized controlled trial.229
The primary endpoint for the trial was the proportion of patients with a serum uric acid level <6.0 mg/dL. This endpoint was achieved by 56%, 76% and 94% of those taking 40 mg, 80 mg and 120 mg/day of febuxostat, respectively, and by 0% in the placebo group. Perhaps surprisingly, the rate of gout flares in the 40 mg group (35%) was similar to that in the placebo group (37%). The rate of gout flares increased to 55% in those taking 120 mg. Concomitant colchicine provided effective prophylaxis against flares, reducing the rate to 8% to 13%. Doses of febuxostat approved in the US are 40 mg and 80 mg/day.
A subsequent 1-year trial compared doses of 80 mg and 120 mg with allopurinol 300 mg.230
Entry criteria included a serum uric acid >8.0 mg/dL and a serum creatinine <1.50 mg/dL. (This study has been criticized because the dose of allopurinol could not be increased, as it typically would in real life). By the final visit, a serum uric acid level <6.0 mg/dL was achieved by 81%, 82% and 39%, respectively. In subjects with a baseline serum uric acid level >10.0 mg/dL, the primary endpoint was achieved by 47%, 44% and 8% respectively. There was a trend toward more rapid dissolution of tophi in the febuxostat groups (83% reduction in tophus surface area in the 40 mg febuxostat group versus 50% reduction in the allopurinol group), although this difference did not achieve statistical significance, perhaps because a relatively small percentage of subjects had tophi at baseline. (Our observations in clinical practice suggest that febuxostat dissolves tophi significantly faster than allopurinol.) There were more rashes in the allopurinol group. The incidence of liver enzyme elevation was similar in all 3 groups. It is difficult to know if febuxostat is superior to allopurinol in dissolving tophi since the dose of allopurinol was not increased beyond 300 mg/day, as it would be in real life.
Doses above 120 mg/day did not significantly reduce uric acid further.231
According to the package insert, there are insufficient data to make a recommendation in patients with severe renal insufficiency (<30 mL/min), and “caution is advised,” but it is not considered a contraindication.179
and area under the plasma concentration time curve for febuxostat and for 3 active metabolites are increased in severe renal insufficiency. There are no published data in patients receiving dialysis.179
Febuxostat works fairly quickly; treatment begins with 40 mg/day. If serum uric acid is not less than 6.0 mg/dL by 2 weeks, the dose may be increased to 80 mg/day. Mean reduction in serum uric acid level is 40% and 56% at 40 mg/day and 80 mg/day respectively and is similar in those with and without renal insufficiency, in contrast to allopurinol. Half-life of the parent compound and of major metabolites is significantly prolonged in persons with renal insufficiency, but this does not appear to be clinically important. Elimination is partially hepatic, allowing greater dosage flexibility in those with renal impairment. Transaminase elevation greater than 3 times the upper limit of normal occurs in 2% to 3% of patients and is similar in this regard to allopurinol. It is recommended to follow liver enzymes periodically, certainly by 2 months after beginning treatment.
The association of cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) with allopurinol treatment remains unsettled. In Phase 3 studies, rates of events per 100 patient-years of exposure were: placebo 0, febuxostat 40 mg 0, febuxostat 80 mg 1.09 and allopurinol 0.60.179
In long-term extension studies, the rates were 0.97 for febuxostat 80 mg and 0.58 for allopurinol (there was no placebo group). In all these cases the confidence intervals overlapped, but there seems to be a trend. As noted in the package insert,179
a causal relationship has not been established. Cardiovascular disease is not a contraindication to the use of febuxostat or allopurinol, but the febuxostat package insert further recommends that the practitioner “monitor for signs and symptoms of MI and stroke”.179
Given the ability of both febuxostat and allopurinol to dissolve tophi, it is hypothesized that these agents may destabilize plaque (which may contain urate) in the walls of blood vessels.
Febuxostat is expected to be at least as effective as allopurinol for prophylaxis of nephrolithiasis, based on its mechanism of action.
Because febuxostat is a xanthine oxidase inhibitor, it prolongs the half-life of purine analogs such as azathioprine and 6-mercaptopurine and theophylline, similar to the case with allopurinol. This is a potentially life-threatening interaction, and according to the package insert, febuxostat is contraindicated with the above 3 drugs. Hypersensitivity to allopurinol is not a contraindication to use of febuxostat.
Febuxostat is more expensive than generic allopurinol, costing approximately US$166 for 30 tablets.
In clinical trials, adverse effects associated with febuxostat included rash (<2% incidence), but without reported severe cutaneous reactions. Incidence of rash with febuxostat 80 mg/day was similar to that with allopurinol 300 mg/day. Diarrhea and elevated hepatic transaminases occurred in small proportions of patients. In current clinical practice, to contain drug costs, the primary use of febuxostat is reserved for patients with allopurinol hypersensitivity, intolerance, or treatment failure, including those in whom uricosuric therapy is not indicated or has failed.
Hyperuricemia in the vast majority (85% to 90%) of gouty patients results from impaired renal uric acid excretion rather than from overproduction.232
In these individuals, renal uric acid clearance is subnormal (<6 mL/min), so that maintenance of the balance between urate production and disposal can be achieved only at a saturating serum urate level, a circumstance predisposing to urate crystal formation and deposition. Although uricosuric agents provide a rational and even preferable means to lower serum uric acid in these patients, this class of urate-lowering agents is prescribed infrequently in the US.201
In general, the ideal candidate for a uricosuric agent is the gouty patient who is younger than 60 years of age, has a creatinine clearance greater than 80 mL/min, a 24-hour urinary uric acid excretion of less than 800 mg on a general diet and no history of renal calculi.
Probenecid is the only potent uricosuric agent available in the US. It acts by interfering with renal urate or anion exchange, thus inhibiting proximal tubular uric acid reabsorption.88
The infrequent use of probenecid (<5% of treated gout patients) likely reflects several circumstances: the availability of allopurinol and febuxostat; the requirement for multiple daily dosing; diminished or complete loss of urate-lowering efficacy in gout patients with moderate or more advanced CKD; relative contraindication in patients with prior urolithiasis or uric acid overproduction; a perception that it is less effective than allopurinol; many drug–drug interactions. The maintenance dosage of probenecid ranges from 500 mg/day to 3.0 g/day and must be taken in divided doses. Rash, gastrointestinal complaints and hypersensitivity occur in approximately 5% of patients. Although serious toxicity is rarely reported (it is perceived as safer than allopurinol in that regard), approximately one-third of patients become intolerant and discontinue it.
Alkalinization of the urine has been recommended when using a uricosuric agent to decrease the risk of forming uric acid calculi. Some authors believe that adequate hydration may be sufficient to avoid this complication.
Benzbromarone, a uricosuric drug not commercially available in the US and many other countries, is a potent but potentially hepatotoxic agent. The drug is metabolized by the hepatic cytochrome P450 system and is effective in patients with moderate renal impairment. “Standard doses” of benzbromarone (100 mg/day) produce greater hypouricemic effects than ‘standard doses’ of allopurinol (300 mg/day) or probenecid (1000 mg/day).233
In a recently published study of “allopurinol-intolerant” patients, 92% of patients given benzbromarone were successfully treated to sUA <5 mg/dL compared with 65% of patients given probenecid.234
Sulfinpyrazone, another uricosuric agent, is no longer available in the US, mainly because of the potential for serious gastrointestinal toxicity.
Losartan and fenofibrate
Losartan and fenofibrate are drugs developed for indications other than urate-lowering but have modest uricosuric effects. They are thus useful urate-lowering adjuncts in selected patients. Urate-lowering effects of fenofibrate or losartan are generally in the range of 12% to 20%, respectively.235
Effect of aspirin
Aspirin has a urate-retaining effect on the kidney at low doses (<3 g/day), but a marked uricosuric effect at high doses (>3 g/day). Even mini-dose aspirin can affect serum uric acid. In one study of elderly patients, aspirin in a dose of 75 mg/day raised sUA by 0.27 mg/dL, 150 mg/day raised it less and 325 mg/day did not raise sUA.10
Creatinine clearance declined 12% to 13% regardless of dose, corresponding to a serum creatinine rise of ~0.04 mg/dL. Interestingly, significant effects on creatinine clearance were largely confined to subjects with lower serum albumin levels, presumably because of higher free salicylate levels in that group. Concomitant diuretic use seemed to increase the aspirin effect.
Uricase could enable accelerated dissolution of tophi over intervals of weeks or months instead of years. Uricase has the potential to dramatically improve the chronic crippling effects of tophaceous gout in those who are intolerant or unresponsive to current therapies.
Pegylation of uricase helps to suppress its immunogenicity and to increase its half-life. In one pivotal, Phase 3 study in patients with particularly severe gout, ~70% of whom had visible tophi, treatment with recombinant, pegylated intravenous uricase (pegloticase) 8 mg every 2 weeks achieved the target serum uric acid level of <6 mg/dL at 6 months in ~42%.12
This regimen also achieved complete resolution of tophi in 20% of patients by 13 weeks and ~40% by 25 weeks. The immunogenicity of uricases, including pegloticase, has limited their tolerability and efficacy. Antibodies to these drugs develop in most patients, despite the use of pegylation, and infusion reactions are common. Such reactions were observed in more than a quarter of patients. High titers of antipegloticase antibodies were linked with infusion reactions and were often associated with loss of efficacy. An important point to note is that in the first few months of pegloticase therapy, acute gout flares are frequent, up to 80% of patients in one study12
but taper off with continued therapy in responders.
Uricase treatment has the capability to induce oxidative stress mediated by generation of hydrogen peroxide.236
The presence of glucose-6-phosphate dehydrogenase deficiency is an exclusion criterion for uricase treatment, to prevent drug-induced methemoglobinemia and hemolysis. Short-term and long-term safety are not yet clearly defined for uricase therapy. It has been proposed that uricase therapy should be reserved for selected patients who could potentially benefit from accelerated tophus debulking, for example, to resolve incapacitating tophi linked with active synovitis, or under circumstances where patients have failed to respond to appropriate doses of oral urate-lowering therapies. At the time of writing (August, 2010) pegloticase (Krystexxa™
; Savient Pharmaceuticals, Inc.) has been resubmitted to the FDA for approval for selected gout indications.
The critical importance of URAT-1 to uric acid homeostasis has made it a prime target for therapeutic manipulation. RDEA594 is a novel inhibitor of URAT-1 that was recently found in a Phase 2a trial to perform about as well as the allopurinol comparator, and was well tolerated.237
Studies are ongoing. RDEA594 is a major metabolite of RDEA806, a non-nucleoside reverse transcriptase inhibitor currently in trials for treatment of HIV.238
Chronic kidney disease and renal transplant patients
Treatment of the acute gout attack in patients with renal insufficiency has been recently reviewed.215
NSAIDs are frequently not an option in such cases. Colchicine may be used, but the maintenance dose must be reduced. There is a real long-term risk of myopathy and/or neuropathy in renal insufficiency with maintenance doses as low as 1.2 mg/day, even with relatively short courses. Cyclosporine also interacts with colchicine to increase colchicine levels. Corticosteroids frequently become the agents of choice. While local joint injections result in the least systemic exposure, systemic steroids are frequently necessary. Systemic corticosteroids must be administered in divided doses 2 or even 3 times per day to achieve rapid control.
Whereas most gouty dialysis patients enjoy a marked reduction in the frequency of gout attacks, the opposite occurs post-kidney transplant. Patients receiving cyclosporine have been reported to have an incidence between 3.5% and 28%; without cyclosporine the incidence is between 0% and 8%. Several mechanisms of action have been proposed.215
Tacrolimus is slightly less offensive in its effect on uric acid handling.215
There are no published data on the use of febuxostat in transplant patients. Allopurinol remains the hypouricemic agent of choice as a rule, but there is a potentially life-threatening interaction with azathioprine, as noted above.