Pharmacologic Urate-Lowering Therapy and Treatment of Tophi in Patients With Gout - UpToDate

2/19/2021 Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout - UpToDate
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Pharmacologic urate-lowering therapy and treatment of

tophi in patients with gout
Author: Fernando Perez-Ruiz, MD, PhD
Section Editor: Nicola Dalbeth, MBChB, MD, FRACP
Deputy Editor: Paul L Romain, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2021. | This topic last updated: Dec 16, 2020.
INTRODUCTION
Management for the prevention of recurrent gout flares and damage to joints and other tissues
from urate crystal deposition includes drug therapy, lifestyle modifications, and other strategies
for risk reduction. Gout is monosodium urate (MSU) crystal deposition disease; the symptoms
and signs of gout do not occur in the absence of urate saturation of extracellular fluids, which is
reflected by hyperuricemia (serum urate levels >6.8 mg/dL [405 micromol/L]), urate crystal
deposition, and inflammatory responses to crystal deposition. Long-term maintenance of
subsaturating urate levels results in cessation of gout flares, resolution of tophi, and
improvement in patient physical function and health-related quality of life.
The use of urate-lowering drugs for the prevention of recurrent gout flares and disease
progression and the treatment of tophi will be reviewed here, as will antiinflammatory
prophylaxis of gout flares during initiation of urate-lowering therapy. The prevention of
recurrent gout flares and disease progression by use of nonpharmacologic lifestyle
modifications for urate lowering and risk reduction involving drug choices for management of
comorbid diseases (eg, hypertension), the clinical manifestations and diagnosis of gout, the
treatment of gout flares, and issues related to asymptomatic hyperuricemia are discussed
separately. (See "Lifestyle modification and other strategies to reduce the risk of gout flares and
progression of gout" and "Clinical manifestations and diagnosis of gout" and "Treatment of
gout flares" and "Asymptomatic hyperuricemia".)
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MANAGEMENT PRINCIPLES AND INITIAL POSTDIAGNOSTIC ASSESSMENT
In most patients with gout, the disease can be successfully managed by achieving and
maintaining a subsaturating target serum urate level with a combination of lifestyle
modification/risk reduction strategies (in all patients) and pharmacologic therapy (in most
patients). In a few patients with complications due to tophaceous disease, surgical intervention
may be an adjunct to medical management.
The prevention of recurrent gout flares, tophi, and progressive structural joint damage
generally requires the long-term use of drugs that reduce the serum urate concentration either
by enhancing renal excretion of uric acid (uricosuric agents) or by decreasing urate synthesis
(xanthine oxidase inhibitors [XOIs]), a combination of both, or by uricolytic medications, such as
uricases. The choice of specific drug therapy depends upon several factors. (See 'Choosing the
urate-lowering drug' below.)
In the absence of evidence that serum urate reduction to levels that remain above the limit of
solubility carries with it clinical benefits equivalent to those achievable at subsaturating levels,
the importance of regarding gout as a "threshold" disease is underscored, as is the specific
therapeutic requirement for lowering and maintaining urate levels in the subsaturating range.
Upon resolution of a gout flare, the patient is said to have entered an intercritical (between
flares) period (see "Clinical manifestations and diagnosis of gout", section on 'Intercritical gout
and recurrent gout flares'). In newly diagnosed patients, the following preventive issues should
be addressed during this period:
● Risk reduction – Identification of reversible causes of hyperuricemia to facilitate lifestyle

modification and other changes that may be helpful in risk reduction, such as dietary
changes, weight loss, reduction in alcohol intake, and substitutions for medications that
can promote hyperuricemia and the risk of gout and may reduce the efficacy of urate-
lowering drug therapy [1-3]. (See "Lifestyle modification and other strategies to reduce the
risk of gout flares and progression of gout".)
● Comorbid disorders – Management of comorbid diseases common in patients with gout,

such as hypertension; obesity; diabetes; hyperlipidemia; atherosclerosis; unbalanced diets
rich in animal-based purines, sugar-sweetened drinks, and low in dairy protein; and high
ethanol use [4]. These issues and strategies to address them, such as changes in diet and
careful attention to the impact of medications used for the management of hypertension
on hyperuricemia and gout, are reviewed in detail separately. (See "Lifestyle modification
and other strategies to reduce the risk of gout flares and progression of gout".)
● Drug therapy for urate lowering – The need for pharmacologic urate-lowering therapy
should be determined. (See 'Indications' below.)
● Antiinflammatory gout flare prophylaxis – Prophylactic nonsteroidal antiinflammatory

drug (NSAID) or colchicine therapy may be required, primarily to reduce the risk of gout
flares during initiation of urate-lowering therapy. (See 'Prophylaxis during initiation of
urate-lowering therapy' below.)
While prolonged use of colchicine and NSAIDs may prevent recurrent gout flares (see
'Prophylaxis during initiation of urate-lowering therapy' below), they do not prevent the
development of silent bony erosions and tophaceous deposits, which may ultimately result
in impaired joint function and skeletal deformity. Similarly, the excessive use of
glucocorticoids in the absence of adequate, subsaturating urate-lowering therapy has been
associated with the development of extensive tophaceous deposits.
● Patient education – Patients should receive education regarding the nature of the disease,
the therapeutic interventions, the importance of adherence to drug regimens, the
treatment target for serum urate lowering to be therapeutically effective, and the duration
of therapy needed to effectively prevent flares and other disease-related injury.
During the intercritical period, classification of the patient with regard to the mechanism(s)
underlying hyperuricemia and gout (including hyperuricemia due to either increased purine
biosynthesis and/or urate overproduction ( table 1) or decreased uric acid clearance (
table 2)) may also be helpful in disease management. (See "Asymptomatic hyperuricemia",
section on 'Evaluation'.)
APPROACH TO DRUG THERAPY
Timely introduction, monitoring, and adjustment of urate-lowering therapy to achieve and

maintain subsaturating urate levels are important factors in successful accomplishment of
suppression and reversal of the signs and symptoms of gout.
Indications — The main indications for pharmacologic urate-lowering therapy in patients with

a diagnosis of gout are:
● Frequent or disabling gout flares – Precise definitions of frequent or disabling flares are
not strictly established. Two flares or more annually is often described as an indication for
urate-lowering treatment [5]. However, a lower threshold for treatment may be chosen
after discussion with the patient if even infrequent flares are especially prolonged, interfere
with vocational or avocational activities, and/or continue to recur over several years.
● Tophi and structural joint damage – Clinical or radiographic signs of severe gout,
including structural joint damage (eg, gouty bone erosion), polyarticular disease, and
tophaceous deposits in soft tissues or subchondral bone.
Urate-lowering therapies such as allopurinol, probenecid, or febuxostat can help reduce

tophaceous deposits that may be present [6,7]; in addition, pegloticase, a polyethylene-
glycolated, modified mammalian recombinant uricase (urate oxidase), which converts urate
to the more soluble purine end product allantoin, may be effective as a treatment for
refractory tophaceous gout due to the more intensive reduction of serum urate with this
agent. (See 'Uricase' below.)
● Gout with renal insufficiency – Patients with a creatinine clearance (CrCl) <60
mL/minute/1.73 m2 (stage 3 or higher chronic kidney disease [CKD]).
The role of urate-lowering pharmacotherapy in patients with uric acid nephrolithiasis or

recurrent calcium oxalate nephrolithiasis is discussed in detail separately. (See "Uric acid
nephrolithiasis", section on 'Treatment' and "Prevention of recurrent calcium stones in adults",
section on 'High urine uric acid'.)
Robust data confirm the view that sustained lowering of serum urate to subsaturating levels
prevents recurrent gout flares. By contrast, an effect of urate-lowering drugs in preventing or
slowing progression to functionally significant renal impairment in patients with gout has been
postulated but has not been established [8,9]. It remains uncertain as to whether
hyperuricemia alone or hyperuricemia in patients with gout produces functionally significant
renal disease. (See "Uric acid renal diseases".)
Serum urate goals and targeted therapy
● Target urate level – In practice, the most widely recommended goal range of urate-
lowering therapy is serum urate <6 mg/dL (<357 micromol/L) [10], which is substantially
below the urate solubility limit (serum urate of 6.8 mg/dL [405 micromol/L]) [11,12].
Although this specific goal was selected empirically, it has proven useful from an
operational point of view [13,14]. A goal serum urate of <5 mg/dL (<297 micromol/L) should
be used in patients with tophi, as lower serum urate levels appear to speed resolution of
tophi. The maintenance of subsaturating levels impedes the nucleation of new crystals in
tissues and dissolves those already formed. Most expert groups have supported this treat-
to-target approach. (See 'Recommendations of major groups' below.)
● Monitoring to maintain target – A key to successful long-term gout management is

monitoring of serum urate levels to assure maintenance of concentrations in the goal
range and to permit urate-lowering drug dose adjustment as needed. One approach is to
determine serum urate concentration after at least two to four weeks on a given dose
before considering a dose adjustment; testing should be repeated again three months
after the goal has been achieved to confirm that the target level has been maintained.
Once goal values are confirmed, measurement every six months for the next year and then
annually is usually acceptable unless drugs or lifestyle factors potentially altering urate
levels have been introduced in the interim.
● Efficacy of targeted approach – Evidence that strongly supports the "treat-to-target"

approach includes a randomized trial involving 517 patients from general practices in the
United Kingdom, which compared laboratory, clinical, and quality-of-life outcomes for
nurse-led care that involved a protocol of individualized education, regular serum urate
monitoring, and urate-lowering therapy titration according to the serum urate target with
usual care by the patients' general practitioners [6]. At two years, the patients receiving
nurse-led care were more likely to reach target urate levels of less than approximately 6
mg/dL (360 micromol/L; 95 versus 30 percent; risk ratio [RR] 3.18, 95% CI 2.42-4.18) and had
a reduced number of flares during the second year of the trial (eg, frequency of ≥2
flares/year of 8 versus 24 percent; RR 0.33, 95% CI 0.19-0.57). Patients in the nurse-led
group also had a greater reduction in tophi and improved quality-of-life measures.
The efficacy of lowering of serum urate to less than 6 mg/dL (<357 micromol/L) was also
illustrated by a retrospective study of Japanese patients with newly diagnosed gout [13].
Among patients with average serum urate levels in this range over three years of
observation/treatment, 71 of 81 patients (86 percent) had no flare recurrences in the
second and third years, a substantially lower proportion than in patients with higher
average urate levels. Another retrospective review found that the optimal range of
subsaturating serum urate concentrations to avoid gout flares that occur in treated
patients in the early months of urate-lowering therapy was 4.6 to 6.6 mg/dL (273 to 392
micromol/L) [15]. Lowering serum urate slowly (no more than 0.6 mg/dL [36 micromol/L]
per month during the first six months) was associated with the lowest rate of early gout
flares.
● Safety of low urate levels – For patients receiving urate-lowering therapy, no lower limit
for serum urate concentration has been established or is widely accepted. Population-
based "lower limits" of normal for urate levels in adults reported by clinical laboratories are
commonly in the range of approximately 3 mg/dL (180 micromol/L). Adverse neurologic or
cardiovascular consequences of very low urate levels have been postulated based upon
epidemiologic associations, but mechanistic and clinical evidence of such relationships
have not been established. Experience with pegloticase (pegylated recombinant modified
mammalian uricase) (see 'Uricase' below) has not identified adverse consequences in
patients maintaining profound reductions of urate, often to unmeasurable levels, over
many months to several years.
Similarly, patients with hereditary xanthinuria, who have very low urate levels as a
consequence of absent or nearly absent xanthine oxidase activity, along with patients with
renal hypouricemia type 1 (lack of expression of uric acid transporter 1 [URAT1]) and type 2
(lack of expression of glucose transporter 9 [Glut9]), are reported to have normal longevity
and no increase in the incidence of neurologic or cardiovascular disease. There is
considerable variation in individual responses to the available oral urate-lowering agents or
combinations of agents [16]; values less than 2 to 3 mg/dL (120 to 180 micromol/L) are
rarely encountered.
Initiation and duration of urate-lowering pharmacotherapy
● Timing for the initiation of urate-lowering drug therapy – We generally wait until at
least two weeks after a gout flare subsides to initiate urate-lowering medication. However,
in selected patients, a reasonable alternative is to initiate urate-lowering therapy during a
flare. This latter approach is most useful, in our view, in a cognitively intact patient with
documented gout in whom a baseline serum urate has been recorded during a flare-free
period, particularly in patients with very difficult-to-manage, almost perpetual flares. In
such patients, with rapidly recurring flares, successful initiation of urate-lowering therapy
during flare may be effective and tolerated in conjunction with prednisone or other
antiinflammatory cotreatment followed by very slow tapering (over weeks to months) of the
dose of the glucocorticoid or other agent (see 'Prophylaxis during initiation of urate-
lowering therapy' below). Some experts have suggested that urate-lowering medication can
more broadly be started together with antiinflammatory therapy during a gout flare [17].
In either case, once medications are started, urate-lowering therapy should not be
interrupted in patients who experience a subsequent acute flare.
The rationale supporting the well-established practice of delaying the start of urate-
lowering therapy until after a flare has resolved is based upon the following:
• Urate lowering in gout is a long-term treatment for which there is no evidence that
initiation during a gout flare promotes better outcomes or long-term adherence
• Serum urate levels are in a normal range in 25 to 40 percent of patients with gout
flares, and immediate addition of urate-lowering medication precludes obtaining an
accurate baseline (pretreatment) serum urate level, unless this has been established
earlier in the patient's course
• Introduction of urate-lowering therapy in the course of intensive antiinflammatory flare

treatment has the potential to cloud the interpretation of which agent may be
implicated in an adverse event accompanying antiinflammatory flare treatment, a
problem of some significance given the rather narrow range of available urate-
lowering agents of substantial efficacy
• There is no evidence that initiation of urate-lowering treatment during flare hastens

accomplishment of goal-range serum urate levels (<6 mg/dL [<357 micromol/L]), for
which periodic titration of the selected agent to effect is recommended
The practice of delaying the start of urate-lowering drug therapy until after flare resolution has
been based upon observations that acute urate-lowering can precipitate a gout flare and a
concern that initiation of urate-lowering therapy during a gout flare may worsen or prolong the
inflammatory arthritis. However, the absolute risks of these complications of early urate-
lowering therapy have not been established [18,19].
One rationale for initiating urate-lowering drugs during an ongoing flare is that this presents a
dramatic moment to instruct and initiate the patient in an overall gout pharmacotherapeutic
plan that would, in any event, initially involve urate-lowering and antiinflammatory flare
prophylaxis cotherapy. This approach is supported by a small trial in which 51 patients with
gout flares were randomly allocated to receive either allopurinol or placebo, along with a 10-
day course of antiinflammatory gout flare medication (indomethacin 50 mg every eight hours
and colchicine 0.6 mg twice daily) [20]. The investigators found no differences between the
groups in mean pain scores, the frequency of additional gout flares, or in levels of acute phase
reactants. Subsequently, another small trial has shown similar findings [21].
The initiation of urate-lowering therapy together with flare treatment is compulsory, per the
European Union label, when canakinumab, an interleukin (IL) 1beta inhibitor, is prescribed to
treat a gout flare.
● Prophylaxis during initial therapy – During the initial period of urate-lowering therapy,
patients should also receive prophylactic treatment to decrease or prevent recurrent
episodes of gout flare. Typically, colchicine, or alternatively, a nonsteroidal
antiinflammatory drug (NSAID; or less often, a glucocorticoid) are administered for this
purpose. (See 'Prophylaxis during initiation of urate-lowering therapy' below.)
● Duration of therapy – Once the decision is made to begin therapy to lower serum urate,
the treatment is usually indefinite and should be continuous if needed to maintain lifelong
subsaturating urate levels and to remain clinically effective. The rationale and importance
of ongoing therapy should be emphasized in initial patient education and subsequently
over the course of therapy in an effort to reduce nonadherence to treatment and to
optimize patient outcomes.
Selected patients may benefit from the withdrawal of urate-lowering medication but then
should be carefully observed to determine the safety of this approach, including:
• Patients who adhere to lifestyle changes and risk reduction only after urate lowering is
initiated, to assess the potential efficacy of nonpharmacologic management.
• The rare patient in whom the diagnosis of gout is unconfirmed by the demonstration of
urate crystals, and oral urate-lowering therapy achieves unusually low serum urate
levels (for example, <3 mg/dL [<180 micromol/L]) with minimal daily doses of an oral
urate-lowering agent. This is done to determine whether the diagnosis of gout was
correct or if so, whether any urate-lowering medication would be needed.
The majority of patients who achieve control of gout with long-term urate-lowering therapy
will have recurrent symptoms and/or tophi if treatment is stopped [22-25]. In addition,
lower serum urate concentrations during treatment correlate with a longer delay before
flares resume or tophi reappear. In one study, for example, patients with average serum
urate concentrations less than 5.05 mg/dL (<300 micromol/L) during continuous treatment
for at least five years had the longest time to recurrence (mean of three to four years) after
the cessation of urate-lowering therapy, probably due to a greater reduction in the total
body urate pool [26]. Another study found reduced benefit from intermittent allopurinol
(two months per year) compared with continuous therapy [27]; gout flares occurred with
similar frequency in both groups during the first year, but after one year, the continuous
allopurinol treatment group experienced fewer flares.
Nonadherence to recommended treatment is an important issue in patients with gout [28-

30]. Treatment is prolonged (perhaps lifelong), and the patient is asymptomatic for the vast
majority of the time. The extent of patient nonadherence was illustrated in a study that
tracked use of allopurinol over two years in a managed care setting [29]. Less than 20
percent of patients who initiated treatment complied well with therapy (defined as using
the drug on 80 percent or more of the days during the study). As noted, nurse-led follow-up
has been associated with high levels of adherence [6]. (See 'Serum urate goals and targeted
therapy' above.)
PROPHYLAXIS DURING INITIATION OF URATE-LOWERING THERAPY
In patients who are beginning urate-lowering therapy, we recommend low doses of oral
colchicine to decrease or prevent recurrent episodes of gout flare. In patients unable to use
colchicine, we suggest a nonsteroidal antiinflammatory drug (NSAID). (See 'Colchicine
prophylaxis' below and 'NSAID prophylaxis' below.)
In patients who experience frequent flares during initiation of urate-lowering therapy and
cannot tolerate low-dose colchicine or NSAIDs, low-dose glucocorticoids can be used (eg,
prednisone 5 to 7.5 mg daily) during the initiation phase in our experience; however, there are
no clinical trial data to demonstrate the efficacy or safety of this approach.
Resolution of the urate crystal burden may require many months to several years to attain, even
after subsaturating urate levels are achieved. During this period of crystal dissolution, a risk for
gout flare remains and is the primary basis for gout flare prophylaxis with antiinflammatory
agents.
Moreover, an acute fall in serum urate concentration often precipitates a gout flare [27,31],
although gradual titration of urate-lowering medication appears less likely to do so. As an
example, in a randomized trial comparing nurse- versus physician-led initiation of urate-
lowering therapy, slow up-titration from low doses of allopurinol needed to reach serum urate
goal of <6 mg/dL was not associated with increased numbers of flares during year 1 of
treatment, despite virtually no use of antiinflammatory drug flare prophylaxis [6].
In addition, the increase in uric acid excretion early in the course of treatment with uricosuric
agents can promote urinary stone or gravel formation, but the risk of precipitating urinary
stone formation and a gout flare can be minimized by starting with low doses of urate-lowering
therapy and by hydration (two or more liters of fluid daily). Alkalinization of the urine is
unnecessary in most patients. (See "Uric acid nephrolithiasis".)
A tenable explanation for the mechanism by which the acute fall in serum urate concentration
may precipitate a gout flare is that urate lowering disrupts the physical state and/or surface
chemical composition of preformed crystal deposits and thus makes the component crystals
interactive with local cells competent in initiating interleukin (IL) 1-mediated acute inflammatory
responses emanating from activation of toll-like receptors and the formation of NALP3
inflammasomes [32,33].
Identification of IL-1 as a major cytokine in the initiation of gout flares [33] has prompted
interest in potential roles for IL-1 inhibitory agents (eg, anakinra, canakinumab, or rilonacept)
both in treatment of ongoing flares [34-36] and as prophylaxis to prevent gout flares in patients
with or without a previous diagnosis of gout [37], and during the initiation of urate-lowering
therapy [38-40]. The role of these biologic agents in routine clinical practice remains to be
defined. (See "Pathophysiology of gout", section on 'Inflammation'.)
Colchicine prophylaxis — Oral colchicine can reduce the frequency of recurrent gout flares
early in the course of urate lowering with uricosuric agents or xanthine oxidase inhibitors (XOIs)
[41-44]. A typical colchicine regimen at the initiation of urate-lowering therapy is 0.5 to 0.6 mg
orally once or twice daily for patients with normal renal function [18]. Available colchicine
formulations may include tablets in doses of 0.5, 0.6, or 1 mg. Many patients, particularly older
individuals, develop loose or diarrheal stools that preclude use of the recommended colchicine
dose. Satisfactory prophylaxis in such patients is often attained with the lower colchicine doses
of 0.5 to 0.6 mg once daily or even every other day.
The dose of colchicine should also be reduced to 0.5 to 0.6 mg per day in patients with stage 3
chronic kidney disease (CKD; creatinine clearance [CrCl] 30 to 60 mL/minute) and to half of a 0.5
or 0.6 mg tablet daily (if tablets can be split) or one 0.5 or 0.6 mg tablet every two to three days
in patients with stage 4 CKD. Colchicine should not be used in patients with stage 5 CKD
undergoing dialysis for end-stage kidney disease. (See "Definition and staging of chronic kidney
disease in adults".)
In patients without tophi, colchicine is generally continued for at least three months and up to
six months after the initiation of urate-lowering therapy. Colchicine has a narrow therapeutic
index and does not prevent monosodium urate (MSU) crystal accumulation. It is thus
infrequently used for long-term prophylaxis, compared with the usual long-term use of
uricosuric drugs and XOIs. (See 'Duration of prophylactic therapy' below.)
Drug interactions of colchicine with other agents that may impact dosing are described in detail
separately, and further information is provided in the Lexicomp drug interactions program
included in UpToDate. (See "Treatment of gout flares", section on 'Dosing in renal or hepatic
impairment or with risk of drug interactions'.)
Colchicine-induced neuromyopathy is a potential complication of chronic therapy, particularly in

patients with a reduced CrCl. It should be suspected in patients who complain of paresthesias,
numbness, and/or weakness. Most cases occur in patients treated with daily low-dose
colchicine for months to years. Patients taking 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)
reductase inhibitors (statins) that interact with cytochrome enzyme CYP3A4 may be at increased
risk for colchicine-induced myopathy [45]. (See "Drug-induced myopathies", section on
'Colchicine'.)
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Organ transplant recipients who develop gout and are treated with colchicine while receiving
cyclosporine are at increased risk for colchicine myopathy [46]. Such patients should be treated,
if at all, with low doses of colchicine and for as brief a period of time as possible. (See "Kidney
transplantation in adults: Hyperuricemia and gout in kidney transplant recipients".)
The efficacy of prophylactic colchicine in patients beginning urate-lowering therapy was

demonstrated in a randomized trial in which 43 patients were assigned to treatment with
colchicine or placebo prior to initiation of urate-lowering therapy [43]. The patients were then
followed for at least three months beyond the time their serum urate levels were reduced to a
level of less than 6.5 mg/dL (<387 micromol/L). At six months, there were significantly fewer
gout flares in those who received colchicine (mean number of flares 0.1 versus 1.8 with
placebo).
The cost of prophylactic use of colchicine tablets is not a problem in many countries; however, it
may be for many patients and their clinicians in the United States. In the United States, one
manufacturer's brand is approved for use, and the cost of the US Food and Drug Administration
(FDA)-approved product was reportedly USD $4.30 per tablet [47]. A capsule form of colchicine
(0.6 mg) was subsequently made available as an alternative preparation. Both manufacturers
reportedly offer programs to defray the cost for eligible patients [48]. Resources for patients
who need assistance paying for colchicine or other medications are reviewed separately. (See
"Patient education: Coping with high drug prices (Beyond the Basics)", section on 'Help paying
for your medicine'.)
Oral colchicine is also effective for the treatment of gout flares, particularly when administered
early after the onset of symptoms. This agent does not affect serum urate levels and is thus not
a urate-lowering agent. (See "Treatment of gout flares", section on 'Efficacy of oral colchicine'.)
NSAID prophylaxis — Low-dose nonsteroidal antiinflammatory drugs (NSAIDs; eg, naproxen

250 mg twice daily) appear to be effective for prophylaxis in many of the patients who do not
tolerate low-dose colchicine, although the data are very limited [49,50]. Other NSAIDs
prescribed at a low dose may also be effective. Gastrointestinal toxicity is a potential
complication of all NSAIDs, often prompting coadministration with a proton pump inhibitor
once daily. NSAIDs should not be used in patients with moderate or more severe renal
impairment. (See "Nonselective NSAIDs: Overview of adverse effects" and "NSAIDs (including
aspirin): Primary prevention of gastroduodenal toxicity".)
Duration of prophylactic therapy — Because of potential toxicity, the continued use of

colchicine or NSAIDs is not recommended after persistent normouricemia has been achieved
with urate-lowering drugs. The recommended duration of prophylactic colchicine or NSAIDs

during the initiation of urate-lowering therapy varies with the clinical setting:
● Manufacturer's suggestions in some drug labels for prophylaxis when initiating urate-
lowering therapy suggest concurrent therapy for flare prophylaxis for up to six months.
However, we have found that in some patients without evident tophi, prophylaxis
medication can often be safely discontinued three to six months after normal serum urate
values have been attained.
The 2020 ACR guidelines support the use of colchicine prophylaxis for at least three to six
months, and note that the duration of therapy should be extended in the setting of
frequent ongoing flares [5].
● The optimal duration of prophylactic therapy for patients with tophi is uncertain. Our
practice for such patients is to continue colchicine for at least 6 months; treatment for
greater than 12 months is uncommonly needed [51].
CHOOSING THE URATE-LOWERING DRUG
Several uricosuric drugs and xanthine oxidase inhibitors (XOIs) are highly efficacious urate-
lowering medications; these agents can establish normouricemia, ultimately decrease or
abolish gout flares, and prevent or resolve tophi (see 'Uricosuric drugs' below and 'Xanthine
oxidase inhibitors' below). A number of factors can be determinants of which agent is chosen as
the initial agent. The most important of these are:
● Limitations on choice or dose of an agent due to comorbidities, which are frequent in gout
patients
● The range of agents approved and thus available to the clinician to prescribe
● The dose range recommended for each approved agent in the particular clinical
circumstance
For example, probenecid is the only potent uricosuric drug available in the United States as
urate-lowering monotherapy, but it is neither as efficacious as benzbromarone, which is
available in several other countries but not in the United States, nor as likely to achieve goal-
range serum urate levels in patients with moderate or severe chronic kidney disease (CKD).
Similarly, febuxostat is approved for treatment of gout in the United States in doses of 40 or 80
mg; by contrast, European approval of febuxostat is for doses of 80 or 120 mg. The 120 mg
dose has shown superior urate-lowering efficacy compared with lower doses.
We take the following approach to the selection of urate-lowering therapy ( algorithm 1),
given the considerations noted above:
● Role of allopurinol as usual first-line therapy – For most patients in whom a urate-
lowering medication is indicated, we use the XOI allopurinol as first-line urate-lowering
therapy. We initiate therapy with allopurinol at a low dose, typically 100 mg daily in a
patient with a weight-adjusted creatinine clearance (CrCl) >60 mL/minute, with dose
titration by 100 mg every two to four weeks to reach and maintain the urate-lowering goal
range <6 mg/dL (<357 micromol/L) or, in the case of patients with tophaceous gout, <5
mg/dL (<297 micromol/L). (See 'Allopurinol' below.)
We suggest screening patients who are Chinese, Thai, Korean, or another ethnicity with
similarly increased frequency of the human leukocyte antigen (HLA) B*5801 genetic variant
for this allele and do not administer allopurinol in patients who test positive. In patients
who are HLA-B*5801-positive, allopurinol should be avoided because of the substantially
increased risk of severe cutaneous adverse reactions (SCARs) in this group; Han Chinese
and Thai patients and patients with kidney disease who are of Korean descent are the
major high-risk populations who have been documented to have this association.
Additionally, evidence of a higher prevalence of the risk allele among African Americans
than Caucasians suggests that a similar precaution could be considered in these patients
[52], as well as in patients with a family history of SCARs to allopurinol. In patients in whom
testing is indicated but unavailable, we use allopurinol according to standard dosing
guidelines with appropriate precautions based upon the patient's renal function, potential
risk of adverse reactions, and other comorbidities; and counsel patients regarding the
importance of immediate drug discontinuation should a rash or other signs of a possible
adverse reaction occur. (See 'Allopurinol' below.)
• Dosing for reduced renal function – In patients with reduced renal function (stage 3
or more severe CKD), we initiate allopurinol at a dose not exceeding 1.5 mg per
mL/minute of estimated glomerular filtration rate (eGFR). As an example, for an eGFR
of 50 mL/minute, the initial daily dose of allopurinol should not exceed 75 mg daily. The
allopurinol dose should be titrated (by a similar amount but no more than 50 mg) every
four weeks to achieve and maintain the same target serum urate goal as in patients
with normal renal function. (See 'Allopurinol' below and 'Management of gout in
advanced chronic kidney disease' below.)
• Stop therapy for rash or signs of hypersensitivity – Patients on allopurinol should be

instructed to stop their medication immediately and seek medical advice if they
develop a rash or other evidence of hypersensitivity to the drug.
• Combination with uricosuric if optimal dosing is inadequate – In patients who do

not achieve the target serum urate range with maximal allopurinol doses (but tolerate
the drug), we prefer an alternative to febuxostat, for example, allopurinol in
combination with a uricosuric agent (such as probenecid or lesinurad [where the latter
is available]), particularly in patients at high risk of cardiovascular disease. (See
'Uricosuric drugs' below and 'Combination therapy' below and 'Agents and dosing'
below.)
Our preference for allopurinol over febuxostat is based upon the recommendations from
the US Food and Drug Administration (FDA) due to concerns about the cardiovascular
safety of febuxostat (in patients with elevated cardiovascular risk), as compared with
allopurinol, as well as cost considerations, given the findings of a 2014 cost-effectiveness
analysis of these medications [53] and until data from the Febuxostat versus Allopurinol
Streamlined Trial (FAST) are available from the European population [54]. (See 'Febuxostat'
below and 'Adverse effects' below.)
Our preference for allopurinol over uricosuric agents is based upon ease of use and the
reduced effectiveness of probenecid in patients with decreased renal function. Uricosuric
agents should be avoided in patients with urolithiasis and risk of uric acid nephropathy and
are less effective in patients who are overproducers of urate. (See 'Allopurinol' below and
'Uricosuric drugs' below.)
● Alternative of uricosuric if unable to take allopurinol – In most patients who are

intolerant of allopurinol or known to be at high risk of adverse reactions to allopurinol (eg,
are HLA-B*5801-positive), we suggest a uricosuric agent rather than febuxostat. In gout
patients who are willing to adhere to multiple daily dosing and who do not have limitations
to uricosuric treatment (such as moderate or more severe renal impairment or urate
overproduction), probenecid monotherapy provides a mechanistic alternative to treatment
with an XOI. (See 'Uricosuric drugs' below and 'Febuxostat' below.)
There is no evidence that tailoring urate-lowering therapy to the results of 24-hour urine
testing for uric acid excretion improves outcomes. Nevertheless, such an approach is
suggested if uricosuric monotherapy is being considered [55]. Patients with gout who
excrete less than 800 mg (4.76 mmol) of uric acid per day on a standard diet are potential
candidates for uricosuric monotherapy unless otherwise contraindicated.
● Role of febuxostat as alternative to allopurinol or uricosuric agent – Febuxostat, an XOI

with different structural and metabolic properties than allopurinol, is easier to use than
most uricosurics and remains a reasonable alternative to a uricosuric agent in patients
without elevated cardiovascular risk, provided patients are informed of the safety concerns
raised by the FDA and others regarding possible increased cardiovascular risk with this
agent compared with allopurinol. Febuxostat should be reserved for use in people in whom
allopurinol has failed due to intolerance or lack of efficacy. Febuxostat should be used with
particular caution in patients with high cardiovascular risk.
Febuxostat provides efficacious urate lowering in patients with estimated CrCl as low as 15
mL/minute; the FDA advises that febuxostat dosing should not exceed 40 mg daily in
patients with a CrCl <30 mL/minute but notes that patients with mild to moderate renal
impairment (30 to 89 mL/minute) do not require febuxostat dose adjustment. (See 'Urate-
lowering therapy in chronic kidney disease' below and 'Dosing, drug interactions, and
efficacy' below.)
● Other options in patients with hypertension or hyperlipidemia – For patients with gout
and hypertension or hyperlipidemia, an additional option is combining an XOI with one of
the following mildly uricosuric agents (see "Lifestyle modification and other strategies to
reduce the risk of gout flares and progression of gout", section on 'Hypertension and
diuretics' and 'Other drugs' below):
• Losartan – In patients with hypertension.
• Fenofibrate – In patients with hypertriglyceridemia.
• Atorvastatin – The only statin with a urate-lowering effect (if indicated for
hypercholesterolemia or as secondary prevention of cardiovascular events).
● Role of pegloticase in refractory gout or with severe tophaceous disease – For patients
with advanced gout refractory to conventional treatment or with tophaceous disease
significantly affecting physical function or health-related quality of life, use of pegloticase
(see 'Pegloticase' below) is a therapeutic consideration.
● Role of uricosurics as first-line agents – With regard to the choice of first-line urate-
lowering agents in countries other than the United States, and given the safety
considerations with allopurinol (see 'Allopurinol' below) and the demonstrated long-term
efficacy of certain uricosuric drugs (eg, benzbromarone), the use of a uricosuric agent (see
'Uricosuric drugs' below) as an alternative to an XOI as monotherapy merits strong
consideration in many patients with interval gout, but with the following exceptions:
• Lesinurad should only be prescribed in conjunction with XOI therapy.
• Patients who are overproducers of urate or who have a history of urolithiasis.

• In patients with moderate to severe CKD (CrCl <45 mL/minute), some uricosurics
(probenecid, sulfinpyrazone) show diminished urate-lowering efficacy. By contrast,
benzbromarone and lesinurad are reported to be efficacious in patients with mild to
moderate renal insufficiency [56]. However, benzbromarone and lesinurad are
unavailable in some countries, including the United States, and benzbromarone should
also be avoided in patients with liver disease [57].
● Use of combination therapy in patients refractory to oral monotherapies – In the

infrequent patient in whom the available oral urate-lowering monotherapies fail to achieve
the serum urate goal at the highest dose medically indicated, combination therapy using
both an XOI and a uricosuric agent may be of benefit. (See 'Uricosuric drugs' below and
'Combination therapy' below.)
Support for such a dual-mechanism approach to urate-lowering was suggested at the time
allopurinol was approved in the United States in 1966, and was included in the 2012
American College of Rheumatology (ACR) guidelines for the management of the
hyperuricemia of gout [17]. However, in our experience, this approach is not often
necessary, given the efficacy of optimally titrated xanthine oxidase inhibition.
URATE-LOWERING MEDICATIONS
Xanthine oxidase inhibitors — Allopurinol and febuxostat are the only commonly available
xanthine oxidase inhibitors (XOIs); topiroxostat, which is also an XOI, is available in Japan.
Oxypurinol, an active metabolite of allopurinol, was formerly available on a "compassionate
use" basis for patients intolerant of allopurinol, but some patients treated with this agent have
experienced adverse reactions similar to those when previously receiving allopurinol [58].
Indications — XOIs are likely to be effective in virtually all circumstances warranting urate-

lowering therapy for gout, in contrast to probenecid, although safety considerations limit XOI
use in some patients. (See 'Choosing the urate-lowering drug' above and 'Allopurinol' below and
'Febuxostat' below and 'Uricosuric drugs' below.)
Allopurinol — Allopurinol is our preferred urate-lowing agent for most patients. In clinical

trials, it has comparable efficacy to other agents, including febuxostat and benzbromarone, and
is generally well tolerated [59].
Dosing
● Usual dosing – We usually initiate allopurinol treatment at 100 mg daily in patients with
weight-adjusted creatinine clearances (CrCl) >60 mL/minute and titrate the dose every two
to four weeks to the minimum dose required to achieve and maintain the goal range of
serum urate. An initial dose of 100 mg or less of allopurinol is associated with reduced risks
for developing severe cutaneous adverse reactions (SCARs) and gout flares that are
otherwise common during initiation of urate-lowering therapy. (See 'Adverse effects'
below.)
Serum urate levels begin to fall within two days of allopurinol administration and reach
stable levels in one to two weeks. Thus, when titrating allopurinol dose, the urate-lowering
effect of the current dose can be assessed after two or three weeks of treatment.
Allopurinol may not induce goal serum urate levels early in the course of therapy of
patients with extensive tophaceous deposits. However, true refractoriness to the drug is
rare and most often reflects a failure of patient adherence or of clinician-patient
communication [11,60].
A majority of gout patients require doses of allopurinol exceeding 300 mg/day in order to
maintain serum urate <6 mg/dL (<357 micromol/L) (see 'Serum urate goals and targeted
therapy' above), although the most commonly used total daily dose of allopurinol is 300
mg, despite approval in the United States and Europe of daily doses up to 800 and 900 mg,
respectively. There is considerable variation among patients in the daily dose required to
achieve control of the serum urate concentration, ranging from 100 to 800 mg or even
more. Some studies suggest that baseline serum urate concentrations may have increased
among gout patients compared with values encountered several decades ago when
allopurinol was in clinical development [27,61].
We prefer to prescribe allopurinol in a single daily dose, regardless of the total dose
required, and this approach may enhance medication adherence. In an occasional patient
with gastrointestinal distress when starting or increasing the dose of the medication, we
administer the drug in a divided dose (two or three times daily), but this is usually only
necessary temporarily.
● Dose adjustment in renal disease – In patients with stage 3 or greater chronic kidney
disease (CKD; chronic renal insufficiency), the starting dose of allopurinol and the rate of
dose adjustment should be modified. A daily starting dose of allopurinol of <1.5 mg per
mL/minute of estimated glomerular filtration rate (eGFR) is advised in such patients, with
dose increments of no more than 50 mg daily every four weeks to the minimum daily dose
necessary to achieve the goal urate-lowering effect. As an example, for an eGFR of 50
mL/minute, the initial daily dose of allopurinol should not exceed 75 mg daily (see 'Urate-
lowering therapy in chronic kidney disease' below). In patients with acute kidney injury (AKI;
acute renal failure), it may not be not advisable to initiate allopurinol, as the serum
creatinine during the acute episode will not initially reflect the severity of the reduced renal
function.
The half-life of oxypurinol, the major active allopurinol metabolite, is prolonged in renal
functional impairment. This fact and the belief that metabolites of oxypurinol may play a
role in severe allopurinol toxic reactions, such as drug reaction with eosinophilia and
systemic symptoms (DRESS) and SCARs (including Stevens-Johnson syndrome and toxic
epidermal necrolysis [TEN]), led to the publication of recommendations for reducing
allopurinol doses for patients with renal functional impairment. However, a subsequent
analysis of 54 patients with allopurinol hypersensitivity syndrome (AHS) and 157 patients
receiving allopurinol for gout without evidence of hypersensitivity confirmed that
allopurinol hypersensitivity reactions are more likely to occur in patients with renal
insufficiency in whom the initial dose of allopurinol exceeds 1.5 mg per mL/minute of CrCl,
particularly in those with renal functional impairment also receiving a thiazide diuretic [62].
Thus, cautious titration of allopurinol to urate-lowering goal range is likely to be safe in the
great majority of patients with impaired renal function. (See 'Management of gout in
advanced chronic kidney disease' below.)
Adverse effects — Side effects and adverse reactions, sometimes severe, are infrequently
encountered with use of allopurinol [11]. As with all urate-lowering therapies, allopurinol
administration can precipitate gout flares early in therapy, especially if antiinflammatory flare
prophylaxis has been omitted (see 'Prophylaxis during initiation of urate-lowering therapy'
above). Among an array of largely mild adverse reactions occurring in approximately 3 to 5
percent of patients treated with allopurinol are rash, leukopenia or thrombocytopenia, and
diarrhea. Severe reactions, such as DRESS and SCARs, may occur but are very rare, with higher
incidence, but still occurring infrequently, in individuals with the human leukocyte antigen (HLA)
B*58:01 allele (discussed below), chronic renal impairment, and thiazide/loop diuretic use.
Additional adverse reactions to allopurinol include vasculitis, drug fever, and interstitial
nephritis.
Urolithiasis or crystalluria composed of xanthine or oxypurinol crystals are also rare and are
more likely to occur in patients with significant urate overproduction, resulting either from an
inherited defect in an enzyme of purine nucleotide synthesis or cytolytic cancer chemotherapy.
● Rash, hypersensitivity, and severe cutaneous reactions – Allopurinol should be avoided

in individuals who are HLA-B*5801-positive; this has been best shown in several
populations, including Chinese, Thai, and Korean patients [63,64]; and the risk allele is
more than five times more common among African Americans than among White and
Hispanic Americans, consistent with the threefold greater risk of SCARs among African
Americans compared with White Americans [52,65]. Accordingly, we suggest testing for this
HLA allele in Chinese, Thai, and Korean patients, as well as in African-American patients and
other ethnicities with similarly increased frequency of the risk allele. Screening has been
advised by several expert groups for high-risk patients (eg, Chinese and Thai populations,
Korean patients with renal impairment, and African Americans) because of its effectiveness
in reducing SCARs, as well as analyses suggesting cost effectiveness in these groups
[5,52,64]. However, the benefit of widespread application of testing in other populations is
less clear [52], and negative testing does not preclude the development of this adverse
effect, particularly in patients of European descent [17,63]. (See 'Choosing the urate-
lowering drug' above.)
Many types of allopurinol rashes have been described, but most rashes are mild and remit
with dose reduction or drug discontinuation. However, even a mild rash may be a harbinger
of allopurinol hypersensitivity, and it should be emphasized to all patients initiating
allopurinol therapy to discontinue treatment and contact the caregiver promptly upon
development of a rash. Severe cutaneous reactions have included TEN and Stevens-Johnson
syndrome. Allopurinol is the common drug cause of such reactions, as indicated by a
multinational study [66].
As examples of the data regarding HLA-B*5801 and risk of SCARs, in one report from
Taiwan, each of 51 patients with severe cutaneous reactions to allopurinol was found to
carry the HLA-B*5801 allele [67]. Subsequent studies have confirmed this association,
including: a study in Thailand, which described the association of this haplotype with severe
cutaneous reactions to allopurinol in each of 27 patients [68]; a study of 38 Han Chinese
patients with cutaneous adverse reactions to allopurinol, all of whom had the HLA-B*5801
allele [69]; and others, summarized in a 2013 systematic review [63]. An analysis using the
US Food and Drug Administration (FDA) adverse event databases also confirmed these
findings [70]. Based upon the pooled published data, this study estimated markedly
elevated risks of allopurinol-associated SCARs in HLA-B*5801 carriers, compared with
healthy controls and with allopurinol-tolerant controls (odds ratios [ORs] 73, 95% CI 32-164
and 165, 95% CI 23-1174, respectively), although the ORs were very imprecise.
● DRESS syndrome – Drug reaction with eosinophilia and systemic symptoms (DRESS)
syndrome consists of an erythematous rash, fever, hepatitis, eosinophilia, and acute renal
failure. DRESS syndrome is an unusual but potentially life-threatening reaction to several
medications, most commonly allopurinol, when it is referred to as AHS. AHS has a mortality
rate approaching 25 percent [71,72]. Although the incidence of AHS is unlikely to exceed 0.1
percent of allopurinol-treated patients, this dramatic side effect has, in our opinion,
influenced allopurinol prescribing patterns toward use of lower and often inadequate
doses of this agent. (See "Drug reaction with eosinophilia and systemic symptoms
(DRESS)".)
Desensitization protocols have been developed for the reintroduction of allopurinol to

patients with mild past cutaneous hypersensitivity reactions (generally maculopapular
exanthems). However, desensitization should be limited to patients with mild reactions
limited to the skin and without evidence of other organ involvement. There are several
published protocols, each involving oral solutions of gradually increasing concentration,
given over multiple days to weeks [73-75]. However, desensitization protocols are
cumbersome, and recurrence of hypersensitivity reactions has been reported [76].
Whenever feasible, consultation with an allergy specialist is helpful.
Drug interactions — There are several important drug interactions with allopurinol:
● Azathioprine and 6-MP – Allopurinol can potentiate the immunosuppressive and cytolytic
effects of 6-mercaptopurine (6-MP) and azathioprine, which are metabolized in part by
xanthine oxidase; thus allopurinol should generally be avoided in patients treated with
these agents [28,77]. In patients with severe gout who nonetheless require allopurinol, we
have reduced the azathioprine dose (by at least 50 percent) and carefully monitored the
white blood cell count. Azathioprine eventually has to be discontinued in many such
patients. A possible alternative in some disorders is switching from azathioprine to
mycophenolate, which does not interact with allopurinol. (See "Kidney transplantation in
adults: Hyperuricemia and gout in kidney transplant recipients".)
● Alkylating agents – Bone marrow suppression has been noted in patients receiving
alkylating agents, such as cyclophosphamide [78].
● Ampicillin – An increase in the likelihood of an ampicillin-induced rash has also been

reported; although patients should be monitored for its occurrence, in our experience, it is
very rare [79].
Mechanism of action — Allopurinol inhibition of urate production is in large part due to

inhibition of xanthine oxidase (xanthine dehydrogenase) by both the native drug and the active
metabolite oxypurinol. Allopurinol and oxypurinol are pyrazolopyrimidine analogs of the purine
bases hypoxanthine and xanthine, respectively [80,81].
Allopurinol has multiple effects on human purine and pyrimidine metabolism:

● It is a competitive inhibitor of xanthine oxidase and, along with oxypurinol, produces

pseudo-irreversible inactivation of the enzyme. As a result, urate production falls, but
hypoxanthine and xanthine accumulate in body fluids, producing a state of pharmacologic
xanthinuria.
● It substantially reduces total urinary purine (uric acid plus hypoxanthine plus xanthine)
excretion in most patients. This effect is due to inhibition of the pathway of purine
synthesis de novo by drug-derived and endogenous nucleotide products of enhanced
purine base reutilization. This effect requires activity of the enzyme hypoxanthine-guanine
phosphoribosyltransferase (HPRT) and potentiates the fall in serum urate levels.
● Through nucleotide derivatives of oxypurinol, it induces a state of oroticaciduria and

orotidinuria, due to inhibition of the enzyme orotidylate decarboxylase in the pathway of
pyrimidine nucleotide synthesis [82].
Febuxostat
Dosing, drug interactions, and efficacy
● Dosing – Febuxostat received approval from the FDA for treatment of hyperuricemia in
gout patients at daily doses of 40 and 80 mg [83]. The American manufacturers
recommended that the starting dose is 40 mg once daily. Titration to a daily dose of 80 mg
is suggested for patients whose serum urate level does not fall to <6 mg/dL (<357
micromol/L) after two weeks of treatment on the lower (40 mg daily) dose. In Europe,
higher doses have also received regulatory approval (up to 120 mg/day) [84].
Very gradual increases in the febuxostat dose when starting therapy can help reduce flare
frequency during this period. In a study in Japan, the gradual titration of the febuxostat
dose upon initiation of therapy (10 mg daily for four weeks, then 20 mg daily for four
weeks, then 40 mg daily), without colchicine prophylaxis, resulted in a comparable number
of gout flares in the first three months of therapy to patients started on febuxostat in a
fixed dose (40 mg daily) together with prophylactic colchicine (0.5 mg daily; 21 and 19
percent of patients) [85]. The combination of gradual titration of febuxostat with colchicine
prophylaxis was not examined in this study.
Febuxostat, initiated at 40 mg daily, is also an alternative XOI for use in patients with
reduced renal function; it is metabolized in a different manner than allopurinol. (See 'Urate-
lowering therapy in chronic kidney disease' below.)
● Major drug interactions and mechanism of action – Decreased metabolism of

azathioprine, mercaptopurine, and theophylline is an expected result of administration of
an XOI, and a need for continued use of any of these three drugs is considered by the
manufacturer to be a contraindication to the use of febuxostat [86]. As noted above, we
and others have used reduced doses of azathioprine or mercaptopurine with the XOI
allopurinol while carefully monitoring for bone marrow toxicity (ie, development of
cytopenias). It is uncertain whether such a strategy can safely be pursued with febuxostat,
but severe hematologic adverse events have also been reported with this agent [87,88].
Febuxostat is an XOI. It is a thiazolecarboxylic acid derivative that, unlike allopurinol, is not

a purine-base analog. It inhibits xanthine oxidase by occupying a channel in the xanthine
oxidase dimer and impairing access of purine-base substrates to the active site of xanthine
oxidase catalysis. The difference in the mechanism of inhibition may underlie the greater
specificity of febuxostat for inhibition of xanthine oxidase compared with allopurinol.
● Cost – The cost of treatment with brand name febuxostat is substantially higher than with
either generic allopurinol or its brand name equivalent, although generic febuxostat is
available at a lower cost in some countries, including the United States and those in the
European Union. (See 'Choosing the urate-lowering drug' above.)
● Efficacy – Febuxostat produces a dose-dependent decrease in serum urate levels [89]. A

daily dose of 40 mg produces a reduction that is roughly equivalent to that seen in patients
who are treated with allopurinol at a dose of 300 mg per day [27,59,90]. A major limitation
of the evidence comparing febuxostat with allopurinol is the use of a fixed allopurinol dose
without titration to achieve optimal benefit. (See 'Allopurinol' above.)
• A 52-week randomized trial assigned 760 patients with gout and serum urate ≥8 mg/dL
(≥476 micromol/L) to febuxostat at daily doses of 80 or 120 mg or to allopurinol at 300
mg daily (fixed dose) [27]. A sustained reduction of serum urate to a target level <6
mg/dL (<357 micromol/L) was more common in the 80 and 120 mg febuxostat groups
than the allopurinol 300 mg group (53 and 62 versus 21 percent, respectively).
Reductions in gout flare incidence and in tophus areas over time were similar in the
three groups. The incidence of adverse events did not differ across the groups, but
withdrawal from the study due to gout flares and abnormal liver function studies was
more common in both febuxostat groups than in the allopurinol group.
• In a six-month trial, febuxostat (80, 120, or 240 mg daily) was compared with
allopurinol (300 mg) and placebo [91]. The efficacy of febuxostat in reducing serum
urate at both doses was superior to the fixed dose of allopurinol and placebo, both in
subjects with normal renal function and in a small subgroup of subjects with mild to
moderate chronic renal impairment whose allopurinol dose was 100 mg daily.
However, allopurinol dosing was not escalated to achieve target serum urate levels. No
dose reduction in febuxostat appeared necessary in subjects with these levels of renal
function.
• The use of febuxostat in patients with mild or moderate renal functional impairment
(defined, respectively, as estimated CrCl of 60 to 89 mL/minute and 30 to 59
mL/minute) was assessed as part of a six-month trial that randomly assigned 2268
subjects with gout and baseline serum urate ≥8 mg/dL (≥476 micromol/L) to receive
febuxostat 40 or 80 mg daily or allopurinol (300 mg daily in subjects with normal or
mildly impaired renal function or 200 mg daily if baseline renal function was
moderately impaired) [90]. Approximately 65 percent of subjects had either mild or
moderate renal impairment. In this subset of patients, a single final urate level <6
mg/dL (<357 micromol/L) was achieved with febuxostat 40 and 80 mg daily in 50 and
72 percent of patients, and allopurinol (in the initially assigned doses) in 42 percent of
patients. Safety was comparable across all treatment groups.
• In patients with early gout (one or two gout flares), febuxostat can reduce the
frequency of subsequent gout flares and the degree of synovitis in the affected joint
[92]. In a randomized 24-month trial involving 314 patients, febuxostat (40 mg daily,
increased to 80 mg daily in patients with serum urate remaining greater than or equal
to 6 mg/dL) was more likely than placebo to decrease the incidence of gout flares (29
versus 41 percent) and the synovitis score on imaging compared with baseline
(rheumatoid arthritis magnetic resonance imaging scoring [RAMRIS], -0.43 versus
-0.07). After two years, the active treatment group included a greater proportion of
patients with serum urate <6 mg/dL (63 versus 6 percent). Joint erosions were minimal
in both groups.
Adverse effects — Several types of adverse effects have been associated with use of
febuxostat, some of which, including cardiovascular and hepatic abnormalities, may be more
common with use of febuxostat than with allopurinol [86,93-96]. A greater incidence of liver
function test abnormalities, nausea, arthralgia, and rash has been noted in febuxostat-treated
patients than in placebo controls, but not in allopurinol-treated subjects, during clinical trials.
Periodic monitoring of liver function, principally hepatic transaminase enzyme levels, is
suggested by the manufacturer of febuxostat [86]. Postmarketing studies have shown that
hypersensitivity reactions can also occur in people taking febuxostat, and those with a prior
drug reaction on allopurinol appear to be at higher risk for hypersensitivity to febuxostat [97].
As with any urate-lowering treatment, the risk of gout flares is increased when febuxostat is
initiated, and patients should receive prophylaxis for flares. (See 'Prophylaxis during initiation of
urate-lowering therapy' above.)
During clinical trials, patients treated with febuxostat had a higher incidence of
thromboembolic cardiovascular events than comparators who received allopurinol (0.74 [95%
CI 0.36-1.37] versus 0.60 [95% CI 0.16-1.53] events per 100 patient-years, respectively) [86].
However, such an imbalance was not confirmed in a subsequent randomized trial [90]. The
additional possibility of a febuxostat safety signal regarding heart failure has been raised in
Europe, in Canada, and by the World Health Organization (WHO), but remains uncertain [93,94].
As reported in a 2017 FDA drug safety communication [95], a greater frequency of adverse
cardiovascular events with febuxostat than allopurinol was described in a preliminary review of
a large postmarketing trial comparing the cardiovascular safety of febuxostat and allopurinol
therapy in gout patients at high risk for cardiovascular events [98,99]. Subsequent to this
communication, the full trial report has been published [96]; this safety trial was requested of
the manufacturer by the FDA at the time of febuxostat approval. The subsequent randomized
active comparator-controlled trial was conducted in 6190 patients with a diagnosis of gout and
a prior history of major cardiovascular disease; the median follow-up was for 32 months. Major
prior cardiovascular diseases defined for inclusion of patients in the trial included myocardial
infarction, hospitalization for unstable angina, stroke, hospitalized transient ischemic attack,
peripheral vascular disease, and diabetes mellitus with evidence for micro- or macrovascular
disease. The primary endpoint of the trial was the time to occurrence of any of a combination of
events including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and
unstable angina with urgent revascularization.
When the individual cardiovascular outcomes were evaluated separately, febuxostat showed an
increased risk of cardiovascular mortality and all-cause mortality, compared with allopurinol
(hazard ratios [HRs] 1.34, 95% CI 1.03-1.73 and 1.22, 95% CI 1.10-1.47, respectively); however,
febuxostat was not associated with an increased risk of the combination of events composing
the primary endpoint [95,96]. The absolute risks of cardiovascular mortality, all-cause mortality,
and the primary endpoints comparing febuxostat and allopurinol were 4.3 versus 3.2, 7.8
versus 6.4, and 10.8 versus 10.4 percent, respectively. The trial was not placebo-controlled; thus,
it remains unclear whether allopurinol had beneficial effects on mortality in this high-risk
population or whether febuxostat had deleterious effects.
In 2019, the FDA added a boxed warning for increased risk of death with febuxostat [100]. The
FDA has advised that febuxostat should be reserved for use only in patients who have failed or
do not tolerate allopurinol. Patients should be counseled about the cardiovascular risk with
febuxostat and advised to seek medical attention immediately if they experience symptoms of a
cardiovascular event.
Subsequently, another large post-marketing safety trial has failed to confirm greater
cardiovascular risk with febuxostat than allopurinol. In the open-label Febuxostat versus
Allopurinol Streamlined Trial (FAST), involving 6128 patients with gout in the European Union,
who were ≥ age 60 and being treated with allopurinol, patients were randomly assigned to
switch to febuxostat or continue allopurinol, with dose adjustment to maintain target serum
urate levels [101]. One-third of patients had a history of a previous cardiovascular event; the
others had at least one cardiovascular risk factor but no prior event. After a median follow-up of
approximately four years, there were no significant differences between the groups in overall
mortality; cardiovascular mortality; or in a composite outcome of cardiovascular events, which
included hospitalization for nonfatal myocardial infarction or biomarker-positive acute coronary
syndrome, nonfatal stroke, and cardiovascular death. At the time of the report's publication, the
European Medicines Agency (EMA) had not taken a new position regarding its warnings,
continuing to recommend not prescribing febuxostat in patients with a history of cardiovascular
events unless there is no other therapeutic option available.
Uricosuric drugs
Indications — Patients with relative renal underexcretion of uric acid (ie, low or normal
values for urinary uric acid excretion in the presence of hyperuricemia) are potentially
candidates for uricosuric drug therapy (see "Urate balance"). Decreased efficiency of renal uric
acid excretion is responsible for at least 85 to 90 percent of patients with primary or secondary
hyperuricemia ( table 2). Uricosuric drug monotherapy should be avoided in those with a
history of nephrolithiasis to avoid renal stone recurrence.
Uricosuric treatment has been used rather uncommonly in the United States and other
countries since the introduction of the XOI allopurinol in 1966, although a substantial
proportion of gout patients with indications for urate lowering could be candidates for a
uricosuric agent. Reasons for this discrepancy include the smaller range of gout patients for
whom uricosuric agents are appropriate in comparison with XOIs; the multiple drug
interactions with probenecid and sulfinpyrazone; and the requirement for multiple daily dosing
of probenecid, the only potent uricosuric agent available for monotherapy in the United States
[17]. The use of uricosuric therapy is less uncommon in countries where benzbromarone is
available, as this uricosuric agent is highly effective and can be administered in a single daily
dose [10,102]. Lesinurad, a uricosuric agent that should only be used in combination with an
XOI and not as monotherapy, became available in late 2015 in the United States and other
countries. In 2019, the manufacturer chose for business-related reasons to withdraw lesinurad
from the market in the United States, but it is available in some countries of the European
Union; no new safety concerns have been noted. (See 'Agents and dosing' below.)
One potential benefit of probenecid has been suggested by a large observational study of older
adults that described a modestly lower risk of adverse cardiovascular events in patients
receiving probenecid compared with those taking allopurinol (incidence ratio 2.36 versus 2.83
per 100 patient-years) [103]. However, the study had a number of limitations with respect to
potential confounding by indication (ie, due to nonrandomization) and misclassification of
outcomes (due to reliance upon billing and procedure codes used in the Medicare database).
There were also insufficient data to directly evaluate the cardiovascular risk factors and other
comorbidities in the populations in each cohort, and other potentially relevant clinical and
laboratory data were incomplete or lacking.
Probenecid and sulfinpyrazone are effective for most patients but are likely to be ineffective in
those with moderate to severe CKD [17]. Benzbromarone, where available, may be more
effective for patients with mild to moderate renal insufficiency (CrCl 30 to 59 mL per minute),
including some patients who have not responded to or tolerated allopurinol [55,104,105].
Dotinurad is a potent uric acid transporter 1 (URAT1) inhibitor that became available for use in
Japan in early 2020 [106,107].
Combination therapy — In the infrequent patient in whom the available oral urate-lowering
monotherapies fail to achieve the serum urate goal at the highest dose medically indicated,
combination therapy using both an XOI and a uricosuric agent may be of benefit. (See
'Choosing the urate-lowering drug' above and 'Uricosuric drugs' above.)
Support for such a dual-mechanism approach to urate lowering was suggested at the time
allopurinol was approved in the United States in 1966 and was included in the 2012 American
College of Rheumatology (ACR) guidelines for the management of the hyperuricemia of gout
[17]. In the experience of the authors, however, this approach has rarely been necessary
because we have had success in titrating doses of allopurinol or febuxostat to effect (ie, doses
necessary to reach subsaturating urate levels) in the great majority of patients.
It is clear, however, that in the broader practice setting, there is continued reluctance to titrate
allopurinol to doses higher than 300 mg per day [108-110], despite substantial evidence that
only a minority of current gout patients achieve goal serum urate levels on this dose [27,90,91].
Although we strongly prefer and have had success in treating to goal with one or another agent
as monotherapy, we acknowledge the potential for uricosuric therapy added to maximum
doses of XOIs to improve the overall outcome of urate-lowering efforts in gout. Limited
evidence of the efficacy and safety of combined XOI and uricosuric therapy has been published
[7,111-113], but we await the results of randomized trials directly comparing the urate-lowering
efficacy and safety of XOI dose titration with combined XOI and uricosuric therapy in a
substantial number of patients.
Agents and dosing — The uricosuric drugs are weak organic acids that promote renal
clearance of uric acid by inhibiting proximal tubule urate-anion exchangers that mediate urate
reabsorption [114,115]. Probenecid, although infrequently used, is the only agent of this class
specifically approved by the FDA for the purpose of promoting renal uric acid clearance that is
currently available in the United States, where sulfinpyrazone and lesinurad are no longer
marketed. Uricosuric agents in use elsewhere, in addition to probenecid, include
benzbromarone [10,102], sulfinpyrazone, and lesinurad.
● Probenecid – Probenecid is started at a dose of 250 mg twice daily; increments in dose are
titrated according to the serum urate concentration. The dose is typically raised every
several weeks to a usual maintenance dose of 500 to 1000 mg two or three times daily,
aiming for the usual target for urate lowering in gout of a serum urate <6 mg/dL (<357
micromol/L). The maximal effective dose is 3 g/day.
● Benzbromarone – Benzbromarone, where available, is increased from a starting dose of 50

mg/day to a maximum of 200 mg/day in 50 mg/day increments to achieve the desired level
of serum urate. The dose of 100 mg/day is commonly used [10,57].
● Sulfinpyrazone – Sulfinpyrazone, where available, is started at a dose of 50 mg twice daily,

with increments over several weeks to 100 to 200 mg three or four times daily as needed.
The maximum effective dose of sulfinpyrazone is 800 mg/day.
● Lesinurad – Lesinurad is taken in a single dose of 200 mg once daily always combined with
an XOI, either allopurinol or febuxostat. The drug is an inhibitor of the transporter proteins
URAT1 and organic anion transporter 4 (OAT4), which are involved in urate reabsorption in
the kidney. This agent was approved by the FDA for use in the United States in 2016 in
combination with an XOI in patients who have not achieved target serum urate levels with
an XOI alone [116,117]. Lesinurad became unavailable in the United States in early 2019 but
remains available in Europe. Several trials found that the addition of lesinurad further
reduced serum urate levels compared with allopurinol or febuxostat alone [7,112,113]. (See
'Combination therapy' above.)
As an example, in a trial involving 603 patients with mean serum urate levels of 6.9 mg/dL
(410 micromol/L), the addition of lesinurad (200 or 400 mg daily) to allopurinol (mean dose
of 307 mg daily, range 200 to 800 or 900 mg daily) increased the proportion of patients at
month 6 with a urate level <6 mg/dL (<357 micromol/L), compared with continuing
allopurinol alone (54 and 59 versus 28 percent) [113]. The 200 mg dose of lesinurad was
well tolerated, but adverse effects were seen more often with the 400 mg dose. However,
there was no evidence provided to demonstrate efficacy in patients who failed to respond
to optimal titration of the allopurinol dose, as such dose adjustments were neither required
nor reported.
Side effects and interactions — The major side effects of uricosuric drugs are precipitation
of a gout flare (see 'Prophylaxis during initiation of urate-lowering therapy' above), rash
(probenecid), gastrointestinal intolerance, and uric acid urolithiasis. A scheme for monitoring
the course of uricosuric therapy to reduce the risk of excessive uric acid crystal deposition and
stones or obstructive uropathy emphasizes adequate fluid intake and serial measurements of
urinary uric acid and pH as well as the serum urate concentration [55]. Probenecid also
increases urinary calcium excretion in patients with gout, reinforcing the contraindication for its
use in patients with prior nephrolithiasis [118].
Interference with the transport of other organic anions across cell membranes by uricosuric
drugs is the basis of numerous drug interactions. As an example, urinary excretion of penicillin
and ampicillin are decreased by probenecid, resulting in prolongation of the half-lives of these
antibiotics.
The uricosuric effect of probenecid may be reduced by relatively large doses of salicylates [119].
However, low-dose daily aspirin, as used to prevent cardiovascular disease, may not have such
an effect. In a crossover trial of 11 patients, the addition of low-dose aspirin (325 mg/day) to an
ongoing regimen of probenecid did not change the serum urate concentration or daily uric acid
excretion [120].
The availability and use of benzbromarone have been restricted in some countries because of
concerns regarding several reports of patients with severe hepatotoxicity [10,57].
The most common adverse effects in the lesinurad clinical trials were headache, influenza,
increased blood creatinine, and gastroesophageal reflux disease (GERD) [121]. There is also risk
of increased serum creatinine, which occurs more often when lesinurad is used without an XOI
(which is not recommended) and with doses higher than 200 mg daily, which are not approved
and should not be prescribed [122].
Other drugs
● Losartan – The angiotensin II receptor antagonist losartan is unique among this drug class
in having a modest uricosuric effect that appears to plateau at a dose of 50 mg/day [123].
Losartan may be an option for patients who need an antihypertensive agent and in whom
the use of probenecid is not feasible due, for example, to allergy or intolerance. (See
"Diuretic-induced hyperuricemia and gout", section on 'Benefits of angiotensin inhibition
and losartan'.)
● Atorvastatin – Atorvastatin, approved for the treatment of hyperlipidemia and for

secondary prevention of cardiovascular events, exerts a mild uricosuric effect that could be
of some clinical utility if indicated. This effect is not shared by other statins [124].
● Fenofibrate – Fenofibrate, a fibric acid derivative used for the treatment of hyperlipidemia,
also has uricosuric activity. In a short-term unblinded study of 10 patients with gout who
were already being treated with allopurinol, the addition of fenofibrate (200 mg/day)
resulted in a 19 percent reduction in serum urate and a mean increase in uric acid renal
clearance of 36 percent [125]. (See "Low density lipoprotein cholesterol lowering with drugs
other than statins and PCSK9 inhibitors", section on 'Fibrates'.)
Uricase — Recombinant forms of uricase, including pegloticase, are potent agents that can
rapidly reduce serum urate levels. Uricase (urate oxidase) is the enzyme that catalyzes
conversion of urate to a more soluble purine degradation product, allantoin. Uricase is present
in most mammals but is absent in humans and some primate species due to mutational
inactivation of the uricase gene. Urate-lowering therapy for gout with uricase is aimed at
supplying the absent enzyme activity safely and for a sufficient period of time to promote
depletion of body urate pools, thus resulting in clinical benefits such as gout flare reduction and
tophus resolution. Pursuit of these aims has resulted in the development of recombinant
uricases, modified by covalent linkage to polyethylene glycol, in order to prolong enzyme
activity and potentially reduce immunogenicity. (See 'Pegloticase' below and 'Rasburicase'
below.)
Pegloticase
● Indications and mechanism – Pegloticase is a porcine-like uricase [126] linked to methoxy

polyethylene glycol that is an alternative therapy for patients with severe gout in whom
treatment with other urate-lowering agents has failed to be effective. We use this biologic
agent as an option for patients whose gout is advanced and actively symptomatic or when
use of other urate-lowering therapies is either contraindicated or ineffective in achieving
and maintaining subsaturating serum urate levels. An important criterion in support of the
candidacy of such patients for pegloticase treatment is the need for rapid improvement in
clinical outcomes, such as flare and tophus reduction, restoration of function, and quality of
life, outcomes that take several years to achieve with oral agents and only months in some
pegloticase-treated patients. The maintenance of lower serum urate goal ranges (eg, <2 to
5 mg/dL [119 to 297 micromol/L]), which may be achieved with pegloticase, is associated
with more rapid reduction or reversal of gout signs and symptoms.
Although approved for use, pegloticase has been withdrawn in the European Union for
business-related reasons.
Use of pegloticase, with appropriate prophylaxis for gout flares and for infusion reactions,
can be expected to be effective in approximately 40 percent of the patients with gout who
had not responded to other available treatments (which was required for inclusion in the
randomized trials with this agent), and in those patients with contraindications to other
urate-lowering therapies [127,128].
● Dosing and administration – Pegloticase is administered intravenously every two weeks

as 8 mg of the agent diluted into 250 mL of 0.9 percent (or 0.45 percent) sodium chloride
(NaCl) infused over at least two hours. Serum urate should be monitored prior to each
infusion to confirm sustained urate-lowering efficacy (serum urate <6 mg/dL [<357
micromol/L]). All pegloticase-treated patients should be receiving gout flare prophylaxis for
at least the first six months of treatment. (See 'Prophylaxis during initiation of urate-
lowering therapy' above.)
Premedication for infusion reactions to pegloticase includes an oral antihistamine the

evening before and the morning of each infusion, and oral acetaminophen and intravenous
hydrocortisone (200 mg) during a period of hydration preceding infusion. Should an
adverse reaction occur during infusion, the infusion should be stopped and restarted at a
lower rate or discontinued at the discretion of the treating clinician. After infusion,
observation of the patient for up to one hour is recommended. Pegloticase should be
administered in a health care setting and by health care providers prepared to manage
anaphylaxis and infusion reactions [129].
Pegloticase treatment should be discontinued, as recommended by the manufacturer and

regulatory bodies, if there is loss of urate-lowering effectiveness as indicated (during
monitoring of each pre-infusion serum urate concentration) by serum urate values >6
mg/dL (>357 micromol/L) on one occasion, particularly if accompanied by an infusion
reaction, or on two successive occasions. These situations were reported to be associated
with an increased risk of infusion reactions due to the development of antidrug antibodies.
Other urate-lowering therapies should not be given to patients receiving pegloticase
because they may mask recognition of the increasing serum urate levels associated with an
increased risk for infusion-related reactions and loss of effectiveness resulting from the
effects of high titer pegloticase antibodies [128,130].
Use should also be discontinued, regardless of the level of serum urate, following a
moderate to severe infusion reaction with features suggestive of hypersensitivity (eg,
stridor, oral/lingual/pharyngeal edema, wheezing, or hemodynamic instability).
Pegloticase is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD)

deficiency.
● Efficacy and adverse effects – In the six-month randomized clinical trials of pegloticase,
involving a total of 225 patients with treatment-resistant gout and serum urate levels ≥8
mg/dL (≥475 micromol/L), efficacy (defined as lowering of plasma urate to less than 6
mg/dL [357 micromol/L] for 80 percent of the time during months 3 and 6 of the trial) was
observed much more often in patients receiving pegloticase (8 mg infusion every two
weeks and 8 mg every four weeks) compared with placebo (42 and 35 versus 0 percent)
[128]. Complete resolution of at least one tophus by the final visit was more frequent in
those receiving pegloticase every two weeks than placebo (40 versus 7 percent). There was
a similar but statistically nonsignificant trend for those receiving pegloticase every four
weeks (21 versus 7 percent).
Both efficacy and safety of pegloticase are influenced by the development of antidrug
antibodies, which, at high titers, are associated with both a rise in serum urate levels and
the appearance of infusion reactions [131,132]. In a pooled analysis of the randomized
trials and open-label extension studies, infusion reactions were reported in 45 percent of
the patients [131]; in most instances, this was associated with an absence or loss of the
urate-lowering response that had been observed. Serious infusion reactions occurred in 7
percent of the patients. Loss of urate-lowering efficacy among patients with infusion
reactions preceded the first infusion reaction in 91 percent of patients (20 of 22) receiving
pegloticase every two weeks.
Patients on immunosuppressive drugs may be less likely to develop antibodies and more
likely to tolerate the drug. In a small phase II trial with every-three-week dosing, the use of
medications in seven patients to prevent organ transplant rejection was associated with a
much lower frequency of antidrug antibodies and loss of response compared with use in 20
patients who were not transplant recipients (14 versus 45 percent) [133].
Gout flares and infusion reactions were the most common causes for patient withdrawal
from the trials, despite prophylaxis for both; withdrawals due to adverse events were more
frequent in the two- and four-week pegloticase groups than in the placebo group (18 and
19 versus 2 percent, respectively). As with the initiation of other urate-lowering therapies,
gout flares were more frequent in those receiving pegloticase than placebo during the first
three months of the trials, although they were less frequent with pegloticase during the
last three months of the trials.
Patients in the trials commonly had multiple comorbidities, including hypertension, obesity,
dyslipidemia, diabetes, and atherosclerotic vascular disease; and patients with unstable
angina, uncontrolled hypertension (>150/95 mmHg) or cardiac arrhythmia, uncompensated
heart failure, renal dialysis, or solid organ transplant were excluded from the trials.
However, although cardiovascular events were more frequent in patients on pegloticase, no
direct relationship could be ascertained, and a reduction in blood pressure has been
reported [134].
No new safety signals were observed in an open-label extension of the two randomized
trials during up to 2.5 years of pegloticase treatment [128,135,136]. As most of the
responders maintained serum urate responses during the extension studies, reductions in
flare rates and tophus resolution among patients maintaining urate-lowering efficacy
continued during the open-label extension, compared with treated patients in whom the
agent had lost its efficacy.
Rasburicase — The role of brief courses of nonpegylated recombinant uricase (rasburicase)

for the prevention of acute uric acid nephropathy due to tumor lysis syndrome in patients with
high-risk lymphoma and leukemia is discussed elsewhere. (See "Tumor lysis syndrome:
Prevention and treatment", section on 'Rasburicase'.)
Experience with this agent for the treatment of gout is limited [137], and rasburicase has not
been approved by the FDA for use in gout. It has a very short (less than 24-hour) half-life, and it
is thought that this unmodified foreign protein is likely to be more immunogenic than
pegylated uricases over the longer term of treatment needed for achieving the aims of gout
management (see 'Pegloticase' above). However, repeated infusions of modified or unmodified
uricase can reduce the size of tophi in patients with tophaceous disease, including those with
solid organ transplants [138-140].
MANAGEMENT OF GOUT IN ADVANCED CHRONIC KIDNEY DISEASE
Treatment to prevent gout flares and to reduce the size of tophi is challenging in patients with
advanced chronic kidney disease (CKD). The choice of agents and drug dosing for the
prophylaxis of gout flares and for urate-lowering therapy are influenced by significant
impairment of renal function, and nonsteroidal antiinflammatory drugs (NSAIDs) should be
avoided; treatment of hyperphosphatemia caused by kidney disease can also affect serum
urate levels. (See 'Prophylactic therapy' below and 'Urate-lowering therapy in chronic kidney
disease' below.)
Prophylactic therapy — Particular caution should be taken in patients with CKD treated

prophylactically with colchicine. The clearance of colchicine is reduced in patients with CKD,
increasing the risk of neuromyopathy [141]. If given for prophylaxis, the recommended
colchicine dose is 0.6 mg once daily at a creatinine clearance (CrCl) of 35 to 49 mL/minute and
0.6 mg every two to three days at a CrCl of 10 to 34 mL/minute. Colchicine is not dialyzable and
is contraindicated at a CrCl below 10 mL/minute.
Drug interactions involving colchicine are more problematic in patients with CKD. Among
patients with CKD, drugs that inhibit CYP3A4 or P-glycoprotein may further reduce clearance of
colchicine by interfering with colchicine metabolism. These agents include some commonly
used antibiotics such as clarithromycin, azithromycin, and ketoconazole; antiretroviral drugs;
and antihypertensive agents, including verapamil and diltiazem. Concurrent use of these
medications with colchicine may thus increase the risk of myelosuppression, and fatal
pancytopenia may ensue [141].
Low doses of glucocorticoids may reduce the frequency of gout flares, but a prophylactic
benefit for glucocorticoids is not supported by adequate evidence. Adverse effects of chronic
glucocorticoid use should be anticipated with long-term therapy. If used for prophylaxis, the
glucocorticoid dose should be the minimum necessary to prevent recurrent flares. (See "Major
side effects of systemic glucocorticoids".)
Urate-lowering therapy in chronic kidney disease — The half-lives of allopurinol and its

active metabolite, oxypurinol, are prolonged in renal failure [71]; we thus reduce the starting
dose of allopurinol in patients with CKD, depending upon the severity of the reduction in the
estimated glomerular filtration rate (eGFR) [17,62]. The initial daily dose of allopurinol should
not exceed 1.5 mg per mL/minute of eGFR. As an example, for an eGFR of 50 mL/minute, the
initial daily dose of allopurinol should not exceed 75 mg daily, and for such a patient, half of a
100 mg pill daily could be used as a starting dose. (See "Assessment of kidney function", section
on 'Drug dosing' and "Definition and staging of chronic kidney disease in adults".)
The desired serum urate concentration is often not achieved if treatment is limited to the dose
used to initiate therapy [142]. In such patients, cautious up-titration of the dose of allopurinol is
warranted (in 100 mg increments every two to five weeks in patients with eGFR ≥60 mL/minute
and in 50 mg increments in patients with CKD stage 3 or with more severe disease); this
approach to dose adjustment, with careful observation for adverse effects, has been successful
without increased toxicity [17,143-146]. We advise continued and careful dose titration and
monitoring of serum urate and eGFR in this clinical setting. (See 'Allopurinol' above.)
Febuxostat has also been effective in safely reducing the serum urate in patients with moderate
to severe renal impairment (eGFR 15 to 50 mL/minute/1.73 m2), as shown in a randomized 12-
month trial involving 96 such patients who were treated with febuxostat 30 mg twice daily,
febuxostat 40 mg once daily (increased after one month to 80 mg once daily if serum urate was
≥6 mg/dL after 14 days of therapy), or placebo [147]. The mean serum urate decreased from
baseline to month 12 in both groups receiving febuxostat (difference from placebo -4.8 mg/dL,
95% CI -5.7 to -3.9 mg/dL, and -4.0 mg/dL, 95% CI -4.9 to -3.1 mg/dL). There was no notable
imbalance in renal adverse events or renal function between the febuxostat and placebo
treatment groups.
Uricosuric drugs, such as probenecid, may be less effective in patients with moderately
impaired kidney function and are relatively ineffective, except for benzbromarone, when the
eGFR is more substantially reduced. Uricosurics should not be used in patients with severe CKD
(stages 4 to 5).
A modest lowering of serum urate is a potentially beneficial side effect of treatment of

hyperphosphatemic CKD patients with phosphate-binding agents (eg, calcium-containing
antacids or sevelamer). However, it is uncertain if serum urate lowering with these drugs results
in fewer gout flares or reduction in the size of tophi, and phosphate-lowering therapy should
not be used in patients with normal serum phosphate because hypophosphatemia may ensue.
The management of hyperphosphatemia in CKD is described in detail separately. (See
"Management of hyperphosphatemia in adults with chronic kidney disease".)
Organ transplant recipients — Patients with gout and impaired renal function due to organ
transplantation have additional issues including interactions between urate-lowering therapy
with xanthine oxidase inhibitors (XOIs; allopurinol, febuxostat) and immunosuppressive agents,
particularly azathioprine and mercaptopurine. Treatment of gout in patients following renal
transplantation is discussed separately. (See "Kidney transplantation in adults: Hyperuricemia
and gout in kidney transplant recipients".)
SURGERY
The role of surgery in the management of gout is generally limited to the complications of
tophaceous disease, which include infection, compression due to the mass effect of a tophus,
joint deformity, and intractable pain [148]. Although pharmacologic urate-lowering therapy can
slowly reduce the size of tophi, and pegloticase can reduce the size of tophi more rapidly [149],
some patients desire surgical excision for cosmetic reasons. Similarly, deformities due to joint
damage may require arthroplasty. Such surgery may be safely performed in the absence of skin
attenuation, ulceration, or soft tissue infection.
Whenever possible, institution of urate-lowering therapy should precede surgery in order to

increase the likelihood of prompt postoperative healing. Exceptions to this approach are nerve
compression and active infection, due to the greater urgency. Local surgery is not a substitute
for effective systemic control of serum urate levels.
Tophaceous deposits may compress peripheral nerves, the cauda equina, or the spinal cord
[150-152]. In these instances, prompt surgical decompression is essential to prevent permanent
neurologic impairment.
Tophi may erode through the skin, producing chronic ulcers. With the loss of skin integrity,
infection of the adjacent soft tissues, joint space, and bone is more likely.
In one report of 45 patients with tophaceous gout who required surgery, the most frequent
indications were infection (51 percent) and mechanical problems caused by foot, elbow, and
hand tophi (27 percent) [153]. Delayed wound healing was seen in 24 patients, 16 of whom had
infected or ulcerated tophi prior to surgery.
Less often, surgical excision of a soft tissue mass leads to the initial diagnosis of tophaceous
gout. In addition, permeative or erosive bone lesions have been mistaken for osteomyelitis and
have led to excisions or amputations prior to establishing a diagnosis of gout. In some cases, it
may be impossible to distinguish soft tissue or bone involvement due to gout from that due to
infection using noninvasive studies; in this setting, needle aspiration or a surgeon's assistance
in obtaining an excisional or needle biopsy may be invaluable. Biopsies should be examined for
crystals fresh, frozen, or fixed in alcohol, as formalin dissolves monosodium urate (MSU)
crystals. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis".)
PROGNOSIS
The capacity for effective urate-lowering treatment of gout has led to a dramatic reduction in
chronic gouty arthritis and tophaceous gout, particularly among gout patients who receive
long-term urate-lowering therapy [154]. A prevalence of these unsatisfactory outcomes of less
than 5 percent has been reported in some series. However, a number of factors appear to
contribute in patients with gout to suboptimal clinical outcomes, including both recurrent gout
flares and progression to tophaceous disease and chronic gouty arthritis [28,79,155]. When
progression does occur, it is most often in the context of nonadherence or nonpersistence of

urate-lowering therapy, those in whom the management scheme has not been adequately
communicated or properly prescribed, and those in whom the diagnosis of gout was incorrect.
(See 'Management principles and initial postdiagnostic assessment' above.)
Other patients liable to show progression of gout include those intolerant or treated with
inadequate doses of urate-lowering agents, those receiving medications (usually for
comorbidities) that interfere with urate-lowering agents, and organ transplant recipients.
Further impediments to successful management include inadequate monitoring of serum urate

levels to guide dose titration of urate-lowering agents, failure to titrate urate-lowering agents to
doses necessary to achieve and maintain subsaturating serum urate concentrations, few
management guidelines directed to primary care practitioners who manage the majority of
gout patients, and limited urate-lowering treatment alternatives [155].
These considerations differ from those associated with the manifestations of acute
hyperuricemia (primarily acute renal failure) seen in the tumor-lysis syndrome or with other
causes of massive tissue breakdown. (See "Uric acid renal diseases", section on 'Acute uric acid
nephropathy'.)
As examples:
● Residual prevalences of chronic polyarticular and tophaceous gout approaching 50 percent

have been reported in some series of men with gout whose major risk factors were
excessive alcohol consumption, diuretic use, and, most importantly, suboptimal
management or poor patient adherence [156,157].
● The triad of diuretic-induced hyperuricemia, renal insufficiency, and nodal osteoarthritis

plus overrepresentation of women represents a distinctly different presentation from the
classically described group of middle-aged men with tophaceous gout who have a higher
incidence of hypertension, obesity, and ethanol abuse. Patients in the former group are
typically older adults and prone to develop polyarticular and tophaceous gout in
osteoarthritic joints:
• In one report, 8 of 60 patients with gout were older women (mean age 82 years), all of
whom were receiving diuretic therapy; most had tophi in osteoarthritic interphalangeal
joints [158].
• In a second series, 17 percent of 149 patients with osteoarthritis had gout, often with
low-grade inflammation, in osteoarthritic finger joints [159]. These patients were older
(mean age 71 years) and were evenly distributed in gender. Over 70 percent were
receiving diuretics, 60 percent had impaired renal function, and the mean serum urate
concentration was 11 mg/dL (654 micromol/L).
● Organ transplant recipients treated with calcineurin inhibitors (and often diuretics as well)
are at increased risk for the accelerated development of chronic tophaceous gout [160,161].
Both renal and cardiac transplant recipients, particularly those with compromised renal
function, have developed severe and often difficult-to-manage complications of the
hyperuricemic effects of cyclosporine (and less commonly of tacrolimus), which result from
impaired renal urate excretion [160]. (See "Kidney transplantation in adults: Hyperuricemia
and gout in kidney transplant recipients".)
● Other patients at increased risk for chronic tophaceous gout are those who have chronic
kidney disease (CKD) that has been felt to preclude full-dose urate-lowering drug therapy,
those who are allergic to or intolerant of urate-lowering agents, and those receiving doses
of urate-lowering agents that are inadequate to achieve goal serum urate levels in a
subsaturating range (usually defined as <6 mg/dL [<357 micromol/L] in most gout patients
or <5 mg/dL [<297 micromol/L] in patients with tophaceous gout) [10,17].
RECOMMENDATIONS OF MAJOR GROUPS
Several professional organizations have published guidelines or recommendations for the

management of gout, including the European League Against Rheumatism (EULAR) [10,162];
the American College of Rheumatology (ACR) [5,17,49], which issued new guidelines in 2020;
the Japanese Society of Gout and Nucleic Acid Metabolism [163]; and the American College of
Physicians (ACP) [164]. Our recommendations are generally consistent with the approaches
recommended by the first three of these groups (EULAR, ACR, and the Japanese society) but
disagree strongly with the ACP guidelines, which in contrast with the other groups, reject
recommending the treat-to-target approach of monitoring or even measuring serum urate
levels and basing dosing and drug choice on such data. Instead, ACP guidelines suggest
monitoring the adequacy of urate-lowering drug dosing based upon the frequency and severity
of gout flares (treat-to-avoid-symptoms approach). The ACP guidelines further do not address
urate-lowering drug titration with monitoring of therapy and make rather limited mention of
either allopurinol initiation dose or a dose titration schedule. The treat-to-target approach has
also been supported by an international expert task force [165]. (See 'Approach to drug therapy'
above and 'Serum urate goals and targeted therapy' above.)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Gout and other crystal
disorders".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Gout (The Basics)")
● Beyond the Basics topics (see "Patient education: Gout (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
● Long-term success in achieving and maintaining subsaturating serum urate levels is

attended by clinical benefits that include cessation of gout flares, resolution of tophi, and
improvement in patient physical function and health-related quality of life. (See
'Management principles and initial postdiagnostic assessment' above.)
● Once the subsaturating serum urate target is achieved and maintained, complete clinical
remission may require many months to several years to achieve, due to the slow reduction
in body urate crystal burden that has accumulated in most patients over years of
hyperuricemia preceding the onset of gout. Even after sustained remission is achieved,
maintenance of lifestyle changes and medical management are required. (See
'Management principles and initial postdiagnostic assessment' above.)
● Indications for urate-lowering therapy in patients with a history of gout include frequent or
disabling gout flares, clinical or radiographic signs of chronic gouty arthritis, tophaceous
deposits in soft tissues or subchondral bone, and renal insufficiency (stage 3 or higher
chronic kidney disease). (See 'Indications' above.)
● For most patients who plan to initiate urate-lowering therapy, we suggest allopurinol as
first-line urate-lowering therapy rather than febuxostat or uricosuric agents (Grade 2C) (
algorithm 1). Our preference for allopurinol is based upon concerns with febuxostat
regarding cardiovascular adverse effects (in patients with elevated cardiovascular risk), the
ease of use of allopurinol compared with probenecid, and the reduced effectiveness of
probenecid in patients with decreased renal function. (See 'Choosing the urate-lowering
drug' above.)
In most patients who are unable to take or are intolerant of allopurinol, we prefer a
uricosuric agent rather than febuxostat. Febuxostat should be avoided or used with
particular caution in patients with high cardiovascular risk. However, it is easier to use than
most uricosurics and remains a reasonable choice in patients without elevated
cardiovascular risk, provided patients are informed of the safety concerns raised by the US
Food and Drug Administration (FDA) and others regarding possible increased
cardiovascular risk with this agent. (See 'Uricosuric drugs' above and 'Febuxostat' above.)
● We test patients who are Chinese, Thai, Korean, African American, or another ethnicity with
similarly increased frequency of the human leukocyte antigen (HLA) B*5801 genetic variant
for this allele and do not administer allopurinol in patients who test positive. Such patients
are at increased risk of a severe cutaneous adverse reaction (SCAR) to this drug. (See
'Adverse effects' above and 'Drug interactions' above.)
● Allopurinol and febuxostat should both be avoided in patients receiving azathioprine or 6-

mercaptopurine (6-MP). (See 'Adverse effects' above and 'Adverse effects' above.)
● Uricosuric agents should be avoided in patients with urolithiasis and risk of uric acid
nephropathy. (See 'Allopurinol' above and 'Febuxostat' above and 'Uricosuric drugs' above.)
● We initiate therapy with allopurinol at a low dose, typically 100 mg daily in a patient with a
weight-adjusted creatinine clearance (CrCl) >60 mL/minute, with dose titration by 100 mg
every two to four weeks to reach and maintain the urate-lowering goal range <6 mg/dL
(<357 micromol/L) or, in the case of patients with tophaceous gout, <5 mg/dL (<297
micromol/L). (See 'Allopurinol' above.)
• In patients with reduced renal function (stage 3 or more severe chronic kidney disease
[CKD]), we initiate allopurinol at a dose not exceeding 1.5 mg per mL/minute of
estimated glomerular filtration rate (eGFR). The allopurinol dose should be titrated (by
a similar amount but no more than 50 mg) every four weeks to achieve and maintain
the same target serum urate goal as in patients with normal renal function. (See
'Allopurinol' above and 'Management of gout in advanced chronic kidney disease'
above.)
• For patients not achieving serum urate target on allopurinol, combination therapy with
allopurinol and a uricosuric drug such as probenecid, or where available, lesinurad or
benzbromarone, are additional alternatives. Lesinurad, a uricosuric agent, should not
be used as monotherapy. (See 'Choosing the urate-lowering drug' above.)
● In patients with treatment-refractory gout who have advanced, tophaceous, and actively
symptomatic disease, pegloticase monotherapy (administered intravenously every two
weeks) is a treatment option. Patients most likely to benefit from pegloticase treatment
include those with frequent flares, large and numerous tophi, potentially reversible
functional limitations, and poor quality of life. In such patients, pegloticase provides more
rapid improvement compared with oral agents. (See 'Choosing the urate-lowering drug'
above and 'Pegloticase' above.)
● In patients receiving urate-lowering therapy, we suggest titration of the urate-lowering

medication to achieve a serum urate in the subsaturating range <6 mg/dL (<357
micromol/L) (Grade 2C). We lower the serum urate slowly (no more than 1 to 2
mg/dL/month) in an effort to minimize the occurrence of gout flares, which occur more
frequently in the early months of urate-lowering treatment and which consequently may
impair adherence to treatment. A goal serum urate <5 mg/dL (<297 micromol/L) may
hasten resolution of tophi. (See 'Serum urate goals and targeted therapy' above.)
Serum urate levels should be monitored to assure maintenance of concentrations in the

goal range and to permit urate-lowering drug dose adjustment as needed. One approach is
to determine serum urate concentration in two to four weeks of a dose adjustment, with
confirmation three months later. Once goal values are confirmed, measurement every six
months for the next year and then annually is usually adequate, unless drugs or lifestyle
factors potentially altering urate levels have been introduced in the interim. (See 'Serum
urate goals and targeted therapy' above.)
● For patients initiating urate-lowering drug therapy, we suggest colchicine for prophylactic
therapy to prevent flares during treatment initiation rather than no prophylactic therapy or
a nonsteroidal antiinflammatory drug (NSAID) (Grade 2C). We use low-dose colchicine (0.6
mg once or twice daily for patients with normal renal and hepatic function). An NSAID is a
reasonable alternative for patients who cannot tolerate colchicine; however, there is less
available evidence to support its use. Prophylactic therapy should be continued for three to
six months after initiating urate-lowering therapy. A longer duration of colchicine
prophylactic therapy may be needed for patients with ongoing gout flares and/or tophi.
(See 'Prophylaxis during initiation of urate-lowering therapy' above.)
● Surgery for gout is appropriate for patients with complications of tophaceous disease,
including infection, nerve compression, joint deformity, and intractable pain. Some patients
also desire surgery for cosmetic reasons. (See 'Surgery' above.)
ACKNOWLEDGMENT
The editorial staff at UpToDate would like to acknowledge Michael A Becker, MD, who
contributed to an earlier version of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
Topic 1672 Version 67.0
GRAPHICS
Causes of hyperuricemia due to increased purine biosynthesis and/or urate production
Inherited enzyme defects leading to purine overproduction (rare monogenic disorders)

Hypoxanthine-guanine phosphoribosyltransferase deficiency
Phosphoribosylpyrophosphate synthetase overactivity
Glucose-6-phosphatase deficiency (glycogen storage disease, type I)
Clinical disorders leading to purine and/or urate overproduction

Myeloproliferative disorders
Lymphoproliferative disorders
Malignancies
Hemolytic disorders
Psoriasis
Obesity
Tissue hypoxia
Down syndrome
Glycogen storage diseases (types III, V, VII)
Drug-, diet-, or toxin-induced purine and/or urate overproduction

Ethanol
Excessive dietary purine ingestion
Pancreatic extract
Fructose
Vitamin B12 deficiency
Ethylamino-1,3,4-thiadiazole
4-amino-5-imidazole carboxamide riboside
Cytotoxic drugs
Graphic 80891 Version 5.0
Causes of hyperuricemia due to decreased uric acid clearance
Clinical disorders
Chronic renal insufficiency of any form
Lead nephropathy (saturnine gout)
Effective volume depletion (eg, fluid losses, heart failure)
Diabetic or starvation ketoacidosis
Lactic acidosis
Preeclampsia
Obesity
Hyperparathyroidism
Hypothyroidism
Sarcoidosis
Chronic beryllium disease
Rare monogenic disorders causing decreased uric acid clearance

Autosomal dominant tubulointerstitial kidney disease caused by UMOD pathogenic variants
Glomerulocystic kidney disease
Common variants in genes encoding transporters that regulate renal or gut uric acid clearance
(numerous; genes with largest reported effect are shown)
SLC2A9
ABCG2
SLC17A1
SLC22A11
PDZK1
SLC16A9
SLC22A12
Drug- or diet-induced
Diuretics (thiazides and loop diuretics)
Cyclosporine and tacrolimus
Low-dose salicylates
Ethambutol
Pyrazinamide
Ethanol
Levodopa
Methoxyflurane
Laxative abuse (alkalosis)
Salt restriction
Nicotinic acid
Selection of urate-lowering pharmacotherapy for gout in adult

patients
Refer to the UpToDate topic review on pharmacologic urate-lowering therapy for gout
for additional details regarding the selection of urate-lowering pharmacotherapy and
the prophylaxis of gout flare during the initiation of urate-lowering therapy. Refer to
the UpToDate topic review on hyperuricemia and gout in kidney transplant recipients
for a discussion of management in this population, which is presented separately.
HLA: human leukocyte antigen.

* Increased risk of severe cutaneous adverse reactions with allopurinol use is associated
with HLA-B*5801, an allele increased in frequency in certain ethnicities, including Han
Chinese, Thai, and Korean populations. These and other adverse reactions can also occur in
the absence of this marker. Refer to the discussion of adverse effects of allopurinol in the
UpToDate topic review on pharmacologic urate-lowering therapy for gout.
¶ Dose adjustment is required in patients with impairment in renal function. In general,
allopurinol should be avoided in patients who are receiving azathioprine or 6-
mercaptopurine. Refer to the UpToDate topic review on pharmacologic urate-lowering
therapy for gout and to the drug interactions program for details.
Δ Goal for serum urate is <6 mg/dL (357 micromol/L) and in patients with tophi, <5 mg/dL
(297 micromol/L).
◊ In patients with creatinine clearance <50 mL/minute, uricosuric agents should be avoided
because of decreased efficacy with this level of renal impairment. Lesinurad should be used
only in combination with a xanthine oxidase inhibitor (allopurinol or febuxostat) and not as
monotherapy.
§ Refer to UpToDate topic reviews on risk factors and risk assessment for cardiovascular
diseases.
¥ Febuxostat is associated with greater cardiovascular risk compared with allopurinol in
patients at high cardiovascular risk. The safety of febuxostat without such risk factors is
unknown.
‡ Therapy should be individualized depending upon prior responses and drug tolerance.
Refer to UpToDate topic reviews on pharmacologic urate-lowering therapy for gout and on
lifestyle modification and other strategies to reduce the risk of gout flares and progression
of gout.

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Pharmacologic urate-lowering therapy and treatment of

MANAGEMENT PRINCIPLES AND INITIAL POSTDIAGNOSTIC ASSESSMENT

● Risk reduction – Identification of reversible causes of hyperuricemia to facilitate lifestyle

● Comorbid disorders – Management of comorbid diseases common in patients with gout,

● Antiinflammatory gout flare prophylaxis – Prophylactic nonsteroidal antiinflammatory

APPROACH TO DRUG THERAPY

Timely introduction, monitoring, and adjustment of urate-lowering therapy to achieve and

Indications — The main indications for pharmacologic urate-lowering therapy in patients with

Urate-lowering therapies such as allopurinol, probenecid, or febuxostat can help reduce

The role of urate-lowering pharmacotherapy in patients with uric acid nephrolithiasis or

Serum urate goals and targeted therapy

● Monitoring to maintain target – A key to successful long-term gout management is

● Efficacy of targeted approach – Evidence that strongly supports the "treat-to-target"

Initiation and duration of urate-lowering pharmacotherapy

• Introduction of urate-lowering therapy in the course of intensive antiinflammatory flare

• There is no evidence that initiation of urate-lowering treatment during flare hastens

Nonadherence to recommended treatment is an important issue in patients with gout [28-

PROPHYLAXIS DURING INITIATION OF URATE-LOWERING THERAPY

Colchicine-induced neuromyopathy is a potential complication of chronic therapy, particularly in

The efficacy of prophylactic colchicine in patients beginning urate-lowering therapy was

NSAID prophylaxis — Low-dose nonsteroidal antiinflammatory drugs (NSAIDs; eg, naproxen

Duration of prophylactic therapy — Because of potential toxicity, the continued use of

with urate-lowering drugs. The recommended duration of prophylactic colchicine or NSAIDs

CHOOSING THE URATE-LOWERING DRUG

• Stop therapy for rash or signs of hypersensitivity – Patients on allopurinol should be

• Combination with uricosuric if optimal dosing is inadequate – In patients who do

● Alternative of uricosuric if unable to take allopurinol – In most patients who are

● Role of febuxostat as alternative to allopurinol or uricosuric agent – Febuxostat, an XOI

• Losartan – In patients with hypertension.

• Fenofibrate – In patients with hypertriglyceridemia.

• Lesinurad should only be prescribed in conjunction with XOI therapy.

• Patients who are overproducers of urate or who have a history of urolithiasis.

● Use of combination therapy in patients refractory to oral monotherapies – In the

Indications — XOIs are likely to be effective in virtually all circumstances warranting urate-

Allopurinol — Allopurinol is our preferred urate-lowing agent for most patients. In clinical

● Rash, hypersensitivity, and severe cutaneous reactions – Allopurinol should be avoided

Desensitization protocols have been developed for the reintroduction of allopurinol to

Drug interactions — There are several important drug interactions with allopurinol:

● Ampicillin – An increase in the likelihood of an ampicillin-induced rash has also been

Mechanism of action — Allopurinol inhibition of urate production is in large part due to

Allopurinol has multiple effects on human purine and pyrimidine metabolism:

● It is a competitive inhibitor of xanthine oxidase and, along with oxypurinol, produces

● Through nucleotide derivatives of oxypurinol, it induces a state of oroticaciduria and

Dosing, drug interactions, and efficacy

● Major drug interactions and mechanism of action – Decreased metabolism of

Febuxostat is an XOI. It is a thiazolecarboxylic acid derivative that, unlike allopurinol, is not

● Efficacy – Febuxostat produces a dose-dependent decrease in serum urate levels [89]. A

● Benzbromarone – Benzbromarone, where available, is increased from a starting dose of 50

● Sulfinpyrazone – Sulfinpyrazone, where available, is started at a dose of 50 mg twice daily,

● Atorvastatin – Atorvastatin, approved for the treatment of hyperlipidemia and for

● Indications and mechanism – Pegloticase is a porcine-like uricase [126] linked to methoxy

● Dosing and administration – Pegloticase is administered intravenously every two weeks

Premedication for infusion reactions to pegloticase includes an oral antihistamine the

Pegloticase treatment should be discontinued, as recommended by the manufacturer and

Pegloticase is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD)

Rasburicase — The role of brief courses of nonpegylated recombinant uricase (rasburicase)

MANAGEMENT OF GOUT IN ADVANCED CHRONIC KIDNEY DISEASE

Prophylactic therapy — Particular caution should be taken in patients with CKD treated

Urate-lowering therapy in chronic kidney disease — The half-lives of allopurinol and its

A modest lowering of serum urate is a potentially beneficial side effect of treatment of

Whenever possible, institution of urate-lowering therapy should precede surgery in order to