REPORTS

Understanding Treatments for Gout

Amy C. Cannella, MD; and Ted R. Mikuls, MD, MSPH

Abstract Purine Metabolism and Hyperuricemia

Gout is one of the most readily manageable of Purines are crucial for a range of normal
the rheumatic diseases. This article reviews basic physiologic functions. They are the essen-
pathways in purine metabolism, uric acid handling, tial building blocks for nucleic acids
and the pathogenic mechanism of clinical gout, as (deoxyribonucleic and ribonucleic acid),
well as the areas in those pathways amenable to
extra- and intracellular messengers (adeno-
intervention. Attention is also given to associated
sine triphosphate and G-protein coupled
comorbidities, such as hyperuricemia and obesity,
hypertension, hyperinsulinemia, and coronary reactions), metabolic regulators (cyclic
artery disease. The significance of lifestyle modifica- adenosine monophosphate), coenzymes,
tions, such as weight loss and alcohol reduction, is antioxidants, and neurotransmitters. In
discussed as an important adjunct to pharmacother- humans, uric acid is the end product of
apy in gout. Current and investigational agents used purine degradation. It exists as the urate
in gout management are also reviewed. Finally, ion at physiologic pH and has a very narrow
treatment recommendations for acute and chronic window of solubility. The enzyme xanthine
gout are suggested. oxidase is required for the conversion of
(Am J Manag Care. 2005;11:S451-S458) xanthine to urate. Humans lack the enzyme
urate oxidase (uricase), which converts
urate in other species to the highly soluble
he clinical description of gout dates compound allantoin. This may have con-

T back to antiquity, and evidence of the

disease has been found in early skele-
tal remains.1 Physicians since the time of
ferred a survival advantage because of the
function of uric acid as an antioxidant. Urate
oxidase is present in most fish, amphibians,
Hippocrates have sought to understand the and nonprimate mammals.4
origin of gout and alleviate its suffering. About one third of the daily urate load
Modern medicine has led to a clearer comes from dietary sources, with the
understanding of the biochemical pathway remainder generated endogenously. Once
of purine nucleotide metabolism, leading to urate has been formed, it can be eliminated
the formation of monosodium urate (MSU) by the gastrointestinal tract or kidneys, or
crystals and the pathogenesis of clinical deposited in tissue. Enteric excretion is
gout. 2,3 As a result, advances in therapy responsible for handling one third of the
have made gout one of the most readily daily urate load.5 The remainder is handled
manageable rheumatic diseases. primarily by the kidneys. Approximately
Although a complete review of purine 95% of urate is filtered by the glomerulus
metabolism, uric acid handling, and the and subsequently undergoes bidirectional
pathogenic mechanism of clinical gout is proximal convoluted tubule (PCT) move-
beyond the scope of this article, a brief ment with presecretory reabsorption (99%),
overview of each is warranted to better secretion (50%), and postsecretory reab-
comprehend current therapeutic strategies sorption (40%-50%). The movement of urate
for gout. Figure 1 illustrates a simplified is accomplished via several recently de-
schematic of urate handling and the factors scribed anion transmembrane channels.4,6,7
that can have both a negative and positive The balance between the PCT’s secretory
impact in the context of gout management. and reabsorptive activities exerts a major

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REPORTS
interaction with mononuclear cells, which
Figure 1. Simplified Schematic of Urate Handling results in a release of inflammatory
cytokines and chemokines, resulting in neu-
Purines
Increased by: trophil recruitment and activation. Once
Diet neutrophils migrate to the site of inflamma-
Alcohol
tion, there is aggressive phagocytosis of the
uric acid crystals, delayed phagocytic apop-
Xanthine tosis, and, ultimately, neutrophil death with
Xanthine oxidase massive enzyme and mediator release,
Inhibited by: which leads to the clinical acute gouty
Allopurinol
Oxypurinol attack.2,4
Febuxostat Although it is clear that hyperuricemia is
Urate the harbinger of gout, both genetic and
Urate oxidase
environmental factors are recognized con-
tributors to the development of hyper-
Renal elimination Uric acid uricemia.9 Hypertension, the use of thiazide
Decreased by: Allantoin crystals or loop diuretics, obesity, a high alcohol
Hyperinsulinemia
Hypertension intake, and certain dietary factors (ie, high
Diuretics Inflammation meat intake) all contribute in an additive
Low-dose aspirin Decreased by:
NSAIDs
manner to the risk of developing hyper-
Alcohol
Cyclosporine Colchicine uricemia and gout.10-13 These are modifiable
Increased by: Corticosteroids risk factors, and targeting lifestyle and
Probenecid ACTH
health behaviors is important not only for
Sulfinpyrazone
Losartan secondary prevention and treatment of
Estrogen gout, but also for the overall health of the
High-dose aspirin patient.
For example, a strong correlation exists
This simplified schematic illustrates several key steps in the pathogenesis of between obesity, hyperuricemia,8,14,15 and
gout, the sites of action of drugs used for acute and chronic gout, and
factors that can negatively impact gout as discussed in the text. Multiple
gout.16 Furthermore, hyperinsulinemia and
steps and other pathways have been omitted for simplification. insulin resistance syndrome (metabolic syn-
drome) have been estimated to occur in 95%
and 76% of gout sufferers, respectively.17
NSAIDs indicates nonsteroidal anti-inflammatory drugs; ACTH,
corticotropin.
Hyperinsulinemia stimulates the renal tubu-
lar sodium-hydrogen exchanger to reabsorb
sodium and uric acid, resulting in hyperten-
influence on renal excretion of uric acid. sion and hyperuricemia, respectively.18-20 In
Although the secretory capacity of the kid- addition to centripetal obesity, hyperten-
neys can increase with hyperuricemia, the sion, and hyperuricemia, insulin resistance
compensation is often not enough. syndrome is often associated with hyper-
Therefore, in the majority (90%) of patients triglyceridemia, type 2 diabetes, and coro-
with primary gout, hyperuricemia results nary artery disease. Indeed, numerous stud-
from relative renal underexcretion, whereas ies have shown an association of hyper-
in 10% of patients there is overproduction of uricemia with both cardiovascular morbidity
endogenous uric acid.8 and mortality.21 Thus, even in the absence of
clinical gout, hyperuricemia may serve as an
Gout Risk Factors and Disease Comorbidity important surrogate marker of insulin resis-
The transition from hyperuricemia to the tance and warrant screening and treatment
formation of uric acid crystals and subse- for its comorbidities.8
quent inflammation is dependent on several
factors in the local microenvironment, Gout Treatment: Lifestyle and Health
including both pH and temperature. Once Factors
crystals form, an intense inflammatory Dietary Factors. Consumption of high-
response is triggered. There is an initial purine meats and shellfish has been associ-

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 Understanding Treatments for Gout

ated with an increased risk of gout, but con- renal clearance of serum urate, leading to
sumption of purine-rich vegetables, such as both hyperuricemia and an increased risk of
spinach, has not.22 gout.32 Other commonly used medications
Traditional low-purine diets, once a main- that influence renal handling of uric acid
stay of gout management, are difficult for are aspirin and estrogen. Low-dose aspirin
patients to adhere to and less crucial now (up to 1-2 g/day) decreases renal urate
that potent and effective urate-lowering excretion, especially in the setting of low
therapy is available.8 Dietary intervention albumin. Paradoxically, high-dose aspirin
has received recent attention, however, actually has a uricosuric effect, leading to
because of the association of hyperuricemia an increase in urate excretion. Estrogen
with insulin resistance. In a pilot study of also exerts a uricosuric effect. It is possible
men with gout, serum levels of urate and that declining use of postmenopausal estro-
the rate of acute gouty attacks significantly gen replacement may lead to an increase in
decreased by 17.5% and 71%, respectively, postmenopausal gout and an earlier age of
with a diet moderately restricted in calories onset.2,33 As discussed below, 2 cardiovascu-
and carbohydrates and increased propor- lar drugs, losartan and fenofibrate, also have
tional intake of protein and unsaturated uricosuric effects.
fats. Additionally, weight and triglycerides
decreased significantly. The beneficial Gout Treatment: Pharmacotherapy
effects of this diet are likely mediated via Although nondrug therapy certainly plays
improved insulin sensitivity, reduction of an important role in gout management,
plasma insulin levels, and increased renal pharmacologic therapy remains the main-
excretion of urate with concomitant lower- stay. Most people with asymptomatic hyper-
ing of serum urate levels.17 uricemia do not develop clinical gout; there-
fore, in most cases, treatment is not neces-
Alcohol Intake. Alcohol consumption is sary.34,35 However, hyperuricemia should be
also closely associated with gout, and it is thought of as a marker for associated comor-
estimated that more than one half of gout bidities, as outlined above, and these comor-
sufferers drink excessively.23-25 Several factors bidities should be screened for and treated.
contribute to this relationship: transient lac- Although somewhat controversial, possi-
tic acidemia from acute alcohol excess ble treatment exceptions include uric acid
reduces renal urate excretion26; long-term levels >13 mg/dL (733 µmol/L) in men and
alcohol ingestion stimulates purine produc- >10 mg/dL (595 µmol/L) in women because
tion27; alcohol (especially beer28) contains of a possible nephrotoxic risk; urinary uric
purines26,27; and lead-contaminated beverages acid excretion of >1100 mg/day (6.5
(ie, moonshine) reduce renal urate excre- mmol/day), which increases the risk of
tion.29 In patients with hyperuricemia, an nephrolithiasis. Additionally, urate-lowering
alcohol history should be sought, with strong therapy is indicated in patients at risk for
recommendations to reduce or discontinue tumor lysis syndrome because of high cell
drinking.8 turnover, such as those undergoing treat-
ment for leukemia.36
Hypertension and Medications. Hyper-
tension reduces renal excretion of urate4,30 Treatment of Acute Gout. The goal of
leading to hyperuricemia. Thiazide and loop therapy is rapid resolution of pain and
diuretics, often used in the treatment of inflammation (Figure 2). Nonsteroidal anti-
hypertension, further increase serum urate inflammatory drugs (NSAIDs) are the treat-
levels by interfering with renal tubular ion ment of choice in most patients with acute
transport and lead to effective volume gout who are otherwise healthy. A number
depletion, which causes PCT urate reab- of head-to-head studies have shown most
sorption.31 Cyclosporine, an immunosup- NSAIDs to be equivalent; thus, the choice of
pressant commonly used to prevent graft NSAID is not as important as initiating ther-
rejection in patients undergoing solid organ apy early in an attack. More than 90% of
transplantation, substantially reduces the patients will experience complete resolution

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REPORTS

Figure 2. Acute Gout Treatment Algorithm

Acute gout

Single joint Normal renal and liver function Renal or hepatic impairment

Consider intra-articular Low risk for cardiac

steroid injection and GI toxicity Taking oral medications Unable to take oral medications

NSAIDs Colchicine Solumedrol IM/IV

Consider maximum dose PO: maximum of 3 tablets (0.6 mg/tablet) 100-150 mg/day for 1-2 days
on days 1-2 with a taper in 24 hours
as symptoms allow IV: routine use is not recommended
OR
Corticotropin
25-40 USP units SC/IM or IV once
Prednisone
30-60 mg po/day for 3 days then taper
by 10-15 mg/day every 3 days

GI indicates gastrointestinal; NSAIDs, nonsteroidal anti-inflammatory drugs; PO, by mouth; IV, intravenous;
IM, intramuscular; USP, United States Pharmacopeia; SC, subcutaneous.

of the attack within 5 to 8 days.37,38 Higher sporine or statins.9,42 Colchicine should not
doses may be needed in the first 24 to 48 be used in patients with leukopenia or sig-
hours and should be tapered as symptoms nificant renal or hepatic impairment. Intra-
allow. Unfortunately, the use of NSAIDs is venous (IV) colchicine should be used only
limited by adverse effects, and they should in a hospital setting by physicians experi-
be used cautiously or not at all in patients enced with its use, and patients should not
with any of the following: significant renal have received oral colchicine for at least 7
impairment, poorly controlled congestive days before the IV administration. The total
heart failure, history of or active peptic IV colchicine dose should not exceed 3 to 4
ulcer disease, anticoagulation therapy, or mg. Not available for use in many countries,
hepatic dysfunction.38,39 IV colchicine can cause tissue necrosis with
Colchicine is derived from the autumn venous extravasation and anaphylaxis.
crocus and has been in widespread use Death has been reported with the inappro-
since the early 1800s, 40 first as a plant priate use of IV colchicine,43 and its routine
extract and later in pill form. The mecha- use is not recommended.
Treatment algorithm for acute gout with proposed treatment outlined according to comorbidities.
nism of action is due to interference of Corticosteroids can be used for patients
tubulin dimers40 and subsequent leukocyte with a suboptimal response or contraindica-
functions, including diapedesis, lysosomal tions to either colchicine or NSAIDs, and can
degranulation, and chemotaxis. Colchicine be administered orally, intravenously, intra-
is most effective during the first 12 to 24 muscularly, or indirectly via corticotropin
hours of an attack. It can be given orally or (ACTH). Corticosteroids are effective thera-
intravenously; however, it has the smallest py because of their anti-inflammatory
benefit-to-toxicity ratio of all the drugs used effects.44,45 Intra-articular corticosteroids are
in the management of gout and should particularly beneficial if only 1 or 2 joints are
therefore be used with caution.41 involved. Oral prednisone can be given at a
Oral colchicine is limited by nausea, dose of 30 to 60 mg daily for 1 to 3 days then
vomiting, diarrhea, and abdominal pain. tapered over 1 to 2 weeks. Parenteral ste-
The major nongastrointestinal toxicity of roids are useful if the patient cannot take
colchicine is neuromyopathy, which is oral medications, but have no therapeutic
more common in patients with renal insuffi- advantage over oral dosing. Most patients will
ciency and those taking concomitant cyclo- note improvement within the first 12 to 24

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 Understanding Treatments for Gout

hours, with resolution of symptoms in the purinol and its active metabolite oxypurinol
next 7 to 10 days.45 (not yet commercially available in the
ACTH is secreted from the pituitary United States) reduce serum and urine uric
gland and stimulates the adrenal cortex to acid levels. Allopurinol is given in a once-
produce cortisol, corticosterone, and other daily dose but must be adjusted for renal
androgens. The exact mechanism of action function. Side effects include rash, pruritis,
for its efficacy in gout is unknown, but may cytopenias, diarrhea, and fever. Desensiti-
be due to release of anti-inflammatory hor- zation can be attempted if minor hypersen-
mones or leukocyte modulation via ACTH sitivity reactions, such as rash, occur but
receptors.46 ACTH has been shown to work symptoms may recur.51 A dose-dependent
faster than indomethacin47,48 but time to res- allopurinol hypersensitivity syndrome
olution is similar to that with systemic exists that includes fever, eosinophilia,
steroids.44 ACTH can be used in patients rash, hepatic and renal dysfunction, and
with multiple medical problems, including vasculitis, with a mortality rate of approxi-
congestive heart failure, chronic renal insuf- mately 20%.52 Patients with renal insuffi-
ficiency, and peptic ulcer disease; however, ciency on diuretic therapy are at the great-
its use is limited by patient comfort (admin- est risk. Allopurinol has 2 drug interactions
istered by intramuscular injections), cost, that merit attention: one is potentiation of
and availability. the immunosuppressive and cytolytic ef-
fects of azathioprine. Combined use should
Treatment of Chronic Gout. Although be avoided if possible, or the dose of aza-
there is little argument that acute gout thioprine should be markedly reduced.
should be treated to try to minimize patient Second, concomitant use with ampicillin
discomfort, there is debate about when to causes a maculopapular rash.
initiate urate-lowering therapy. Urate-lower- A second class of urate-lowering drugs is
ing therapy is cost effective for patients who the uricosuric agents, probenecid and sulfin-
have 2 or more attacks of gout per year.16 pyrazone, which act on the renal uric acid
Some physicians advocate treating gout in anion transport pathway to increase uric
patients who experience more than 4 at- acid excretion in urine. These agents should
tacks per year because of the varying nature be used only in patients whose hyper-
of the intercritical periods.49 The general uricemia results from underexcretion of uric
goal of antihyperuricemic therapy is to acid (≤800 mg/24 hours). When therapy is
lower serum urate concentration to at least initiated, intense uricosuria may result in
5 to 6 mg/dL (297-357 µmol/L), a level sub- deposition of uric acid crystals in the renal
stantially below that at which MSU is satu- tubules and urinary stones. To minimize this
rated in extracellular fluids.50 risk, these agents should be started at low
Regardless of the urate-lowering therapy doses and gradually increased. A high urine
chosen, it is important to consider the need volume should also be maintained and alka-
for anti-inflammatory prophylaxis (see linization of urine considered. Uricosuric
“Treatment Recommendations” below), be- agents should be avoided in patients with a
cause rebound gout flares are perhaps the history of nephrolithiasis and are ineffective
most common adverse effect complicating when given to patients with renal insufficien-
the management of chronic gout. Further- cy.53 The major side effects include rash, gas-
more, some patients will have an acute flare trointestinal intolerance, and uric acid stone
of gouty arthritis while receiving mainte- formation. One limitation of uricosuric med-
nance urate-lowering therapy (ie, during an ications is that low doses of aspirin can block
acute illness), and, in those cases, the urate- their uricosuric effects.9
lowering therapy should be continued and Losartan is an angiotensin II receptor
the acute gouty flare treated appropriately. antagonist with a uricosuric effect. Losartan
The most commonly used class of urate- also raises urinary pH, which prevents stone
lowering drug is the uricostatic agents, formation. Micronized fenofibrate is a fibric
which inhibit xanthine oxidase and lead to acid derivative used to lower serum lipids.
decreased production of uric acid. Allo- Fenofibrate also reduces renal tubular reab-

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REPORTS
sorption of uric acid and enhances its ex- Aspergillus flavus. Rasburicase has been
cretion. With both agents, the uricosuric effective in the prevention of acute tumor
effect is independent of the angiotensin lysis syndrome, but when given parenterally
antagonism and lipid-lowering effect, can be highly immunogenic, triggering ana-
respectively. These agents may be particu- phylaxis.56,57 Modification by covalent attach-
larly useful in patients with gout with con- ment of polyethylene glycol (PEG) appears
comitant hypertension or hyperlipidemia.2,37 to reduce immunogenicity and prolong the
Several investigational agents are being circulating half-life of the enzyme, making
studied for treatment of chronic gout. the use of PEG-uricase a potentially feasible
Febuxostat is a novel oral nonpurine selec- treatment for gout. Studies examining the
tive inhibitor of xanthine oxidase. Daily oral efficacy and tolerability of parenteral PEG-
dosing significantly reduces serum uric uricase in gout treatment are currently
acid, and it is well tolerated.54 Febuxostat is under way.58,59
metabolized by the liver and appears to be
relatively well tolerated in patients with Treatment Recommendations
renal insufficiency. To the extent that some Although gout is readily treated, medica-
of the untoward effects of allopurinol are tion errors are common.60 The goal of treat-
related to its purine analog compound and ment of acute gouty flares is to rapidly con-
not xanthine oxidase inhibition, febuxostat trol inflammation and reduce pain and suf-
may be a good option in patients intolerant fering. When initiating treatment, comorbid
to allopurinol. Additionally, febuxostat conditions dictate medication selection. In
appears to have a significantly more potent patients who are healthy, initial therapy
urate-lowering effect than allopurinol in with an NSAID or oral colchicine is accept-

(serum creatinine ≥2 mg/dL or creatinine

standard doses, suggesting that this agent able. In patients with renal insufficiency

clearance ≤50 mL/minute), prednisone 30

may be particularly helpful in difficult-to-
treat patients.55
A second investigational agent is urate to 60 mg/day may be appropriate. Intra-
oxidase (uricase), which mediates the con- articular corticosteroid therapy should be
version of uric acid into a more soluble mol- considered when a single joint is affected.
ecule allantoin. Preparations include recom- Treatment with oral agents is usually
binant and nonrecombinant urate oxidase tapered with symptomatic improvement
from fungi, including rasburicase from and can be discontinued within 2 weeks in
most cases. Urate-lowering drugs should not
be started until after the acute attack has
Table. Treatment of Chronic Gout: Clinical Pearls completely resolved.
Most rheumatologists would agree that
• Consider the initiation of urate-lowering therapy in patients with more urate-lowering therapy should be started in
than 2 attacks per year. patients with at least 2 flares of acute gouty
• Do not start urate-lowering drugs during an acute attack. If a patient on a arthritis per year and in those with topha-
urate-lowering drug has an acute flare, do not discontinue the urate- ceous deposits or gouty erosions on radiog-
lowering medication.
raphy. The Table outlines clinical pearls for
• Twenty-four-hour urinary uric acid excretion is not routinely measured,
although should be considered before initiating a uricosuric.
treatment of chronic gout. The choice of
• Allopurinol is usually the drug of choice for initial therapy, but uricosurics
long-term therapy should again be guided
may be used in allopurinol-allergic patients with normal renal function, by comorbid conditions. In most cases with-
uric acid underexcretion, and no history of nephrolithiasis. out contraindications, prophylactic therapy
• Use concomitant prophylaxis with oral colchicine or NSAIDs (if no con- with colchicine (0.6 mg daily to twice
tra-indications) when initiating urate-lowering therapy. daily), NSAIDs, or oral corticosteroids are
• Routinely measure serum uric acid levels (every 3-6 months) and adjust started concomitantly to avoid rebound
medications until a target uric acid of <6 mg/dL is achieved. flares during uric acid level fluctuation. At
• Consider and treat associated comorbidities such as obesity, hypertension, least 1 recent study suggested that prophy-
hyperlipidemia, and coronary artery disease.
lactic therapy should be extended for at
NSAIDs indicates nonsteroidal anti-inflammatory drugs. least 3 to 6 months during the initiation of
urate-lowering therapy.61 Although low-dose

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 Understanding Treatments for Gout
Rheum. 2004;50:2400-2414.
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3. Terkeltaub RA. Gout and mechanisms of crystal
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of urate-lowering therapy, it is important to 5:510-516.
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Behavioral modifications, such as weight Kinmen. J Rheumatol. 2000;27:1045-1050.
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22. Choi HK, Atkinson K, Karlson EW, Willett W,
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