US Pharm. 2013;38(3):22-26.
ABSTRACT: Gout is a rheumatic disease that
results from an excess body burden of uric acid, or hyperuricemia, which
commonly manifests as recurrent episodes of acute joint pain and
inflammation secondary to the deposition of monosodium urate crystals,
or tophi, in the synovial fluid and lining. Hyperuricemia is caused by
an increased production or a decreased excretion of uric acid, or both.
Treatment of gout involves managing hyperuricemia with urate-lowering
therapy (i.e., diet, lifestyle, pharmacologic agents) and of acute gouty
arthritis with colchicine, nonsteroidal anti-inflammatory drugs, and/or
corticosteroids. Pharmacists play an integral role in patient education
and improving the care of patients with gout.
Gout is a rheumatic disease that results from an excess body burden of uric acid, or hyperuricemia, which is variably defined as a serum urate concentration >6.8 or 7 mg/dL.1
Gout commonly manifests as recurrent episodes of acute joint pain and
inflammation secondary to the deposition of monosodium urate (MSU)
crystals (tophi) in the synovial fluid and lining. Furthermore, renal
involvement of gout due to MSU deposition in the urinary tract can
result in urolithiasis and urinary obstruction.2,3
Hyperuricemia is caused by an increased production or a decreased
excretion of uric acid, or both. Underexcretion, the most common cause,
is thought to account for 80% to 90% of hyperuricemia.4
Although the risk of developing gout increases with the chronicity and
increased concentrations of uric acid (>9 mg/dL), not all patients
with hyperuricemia will develop gout.2,3
Gout is the most common rheumatic disease of adulthood,
with a self-reported prevalence of more than 8 million cases in the
United States, affecting 3.9% of adults, with a male-to-female ratio of
3:1.5 However, at an older age the incidence of gout in women approaches the incidence in men.6
New gout guidelines from the American College of
Rheumatology (ACR) have been recently published focusing on the use of
urate-lowering therapy (ULT), analgesic and anti-inflammatory
medications for the management of acute gouty arthritis, and drug
prophylaxis of acute attacks (TABLE 1).1,7
The prevalence of gout is increasing, mediated by an
increased prevalence of comorbidities that promote hyperuricemia such as
hypertension, obesity, metabolic syndrome, diabetes, and chronic kidney
disease (CKD). The consumption of certain foods and beverages has been
associated with increased incidence of gout, including purines found in
meat and seafood, ethanol, soft drinks, and fructose. Additionally,
certain drugs can also cause hyperuricemia (TABLE 2).1,2,8
There are a number of published criteria to diagnose gout.9,10
Several other conditions mimic the presentation of gout, including
other crystal-induced arthritis, trauma, and septic joint. A typical
presentation of gout includes severe pain, swelling, tenderness, fever,
flulike symptoms, and often erythema of the joint that reaches peak
intensity within 6 to 12 hours.11,12 The attack is most common at the first metatarsophalangeal joint or great toe (also known as podagra),
or at the knee. Several procedures and laboratory testing such as joint
aspiration, radiography, serum uric acid concentrations, and kidney
uric acid excretion may be considered if gout is suspected.2
Nonpharmacologic treatment includes diet, lifestyle
modifications, and general health promotion to control comorbid
conditions including obesity, metabolic syndrome, hypertension,
hyperlipidemia, diabetes, and CKD.1,10,13 There is a paucity
of rigorous data determining the true impact of diet and lifestyle
intervention in gout patients; however, smaller studies have been
published,14-18 and a systematic review is currently under way.19
Lifestyle recommendations include regular exercise to
achieve physical fitness, weight loss to achieve a body mass index (BMI)
that promotes general health, maintaining proper diet (i.e., low-fat or
nonfat dairy products, vegetables), hydration, and smoking cessation.
Foods that patients should avoid include organ meats high in purine
content (e.g., liver, kidney), high-fructose corn syrup–sweetened
beverages, alcohol overuse (i.e., >2 drinks/day in males and >1
drink/day in females), and alcohol consumption during gouty attacks.
Servings of red meats (e.g., beef, lamb, pork), seafood (e.g., canned
fish, shellfish), fruit juices, table sugar, and salt should be
Many drugs may elevate serum urate concentrations; thus,
it is recommended that if such a drug is determined nonessential, it be
discontinued once a diagnosis of gout is obtained. In some
circumstances, and if dictated by the presence of comorbid conditions,
some medications that could elevate serum urate concentrations may still
need to be continued.1
Urate-Lowering Therapies: The purpose of lowering
serum urate concentrations is to prevent acute gout attacks and the
development of tophi. According to the ACR, pharmacologic treatment of
hyperuricemia is indicated for any patient with an established diagnosis
of active gouty arthritis (TABLE 1).1,7 ULT may be
initiated during a gouty attack provided that effective
anti-inflammatory management has been instituted. Furthermore,
prophylaxis is recommended to reduce the risk of gout attacks associated
with the initiation of ULTs and should be continued for 6 months (TABLE 3).2
Proper dose titration of medications and monitoring (every 2-5 weeks)
of urate concentrations, renal function, and adverse effects of
treatment are necessary. A minimum serum urate target concentration of
<6 mg/dL should be obtained with therapy. Three classes of drugs are
approved for lowering urate concentrations: xanthine oxidase inhibitors
(XOIs), uricosuric agents, and uricase agents.
XOIs (e.g., allopurinol, febuxostat) block the synthesis
of uric acid. Allopurinol is recommended for monotherapy and should be
titrated over 2 to 5 weeks to achieve the serum urate target or the
maximum tolerated doses. Allopurinol should be initiated at low doses to
reduce the risk of hypersensitivity reactions and acute gout attack.1,10,20 Allopurinol-induced hypersensitivity reactions are rare but carry substantial morbidity and mortality rates of up to 25%.21,22
Allopurinol hypersensitivity reactions may be mitigated by screening
for the presence of the HLA-B*5801 allele prior to initiation of therapy
in susceptible patients (i.e., Koreans with CKD stage 3 or worse, Han
Chinese or Thai descendants).23-25 Success in achieving
target serum concentrations most often occurs when daily doses of
allopurinol are titrated above an average dose of 300 mg/daily.26,27
Febuxostat, an XOI, is approved for the treatment of
hyperuricemia in patients with gout and is also recommended for
first-line treatment.1,28 In two randomized, controlled
trials, all doses of febuxostat were more effective than allopurinol at
usual doses in lowering serum urate concentrations to <6 mg/dL in
both patients with normal kidney function and renally impaired patients.29,30 Patients frequently complained of acute gout attack with high-dose febuxostat.29 The
major limitation of both trials is that allopurinol doses were not
titrated higher than 300 mg, which is often necessary and more effective
in obtaining target urate concentrations.25,26 Febuxostat
can be substituted for allopurinol or vice versa in the event of drug
intolerance or adverse events and after initial failure of upward dose
titration.1 The safety of febuxostat in patients with
allopurinol hypersensitivity has not been studied rigorously; however, a
recent retrospective study revealed that it may be safe to use.31
Uricosuric agents (e.g., probenecid) reduce the serum
urate concentration via blockade of renal tubular urate reabsorption.
Probenecid is contraindicated in patients with a history of urolithiasis
or presence of uric acid overproduction. To mitigate the risk of
nephrolithiasis, it is recommended that patients be screened for urine
uric acid. Patients should be encouraged to increase fluid intake and
urine alkalinization with potassium citrate may be considered.32
Uricosuric agents may be added to XOIs to achieve target serum urate
concentrations. Fenofibrate and losartan have shown to possess
uricosuric effects. Although studies are limited to small trials and
case reports,33-36 fenofibrate or losartan may be considered
as adjuvant therapy in gouty patients on allopurinol and hyperlipidemia
or hypertension, respectively.37 Ingestion of vitamin C 500
mg has also been associated with minimal lowering of serum urate
concentrations, which may have little clinical significance.38
Uricase agents (e.g., pegloticase) convert uric acid into
soluble allantoin. Pegloticase is approved for chronic gout that is
refractory to conventional treatments.1,39 Treatment with
pegloticase resulted in successful reduction of serum urate to <6
mg/dL in a phase II randomized study, with gouty flares being the most
common adverse effect in this trial.40 Other cited adverse effects include infusion site reactions and anaphylaxis.39
Acute Gouty Arthritis
The diagnosis and treatment of gouty arthritis is
determined by the severity of pain, duration of attack, and extent of
joint involvement. Pain assessment is commonly based on a visual
analogue scale of 0 to 10 where ≤4 is mild, 5 to 6 is moderate, and ≥7
is severe. The duration of gouty arthritis is measured from the onset of
gouty pain where <12 hours is early, 12 to 36 hours is well
established, and >36 hours is late. The extent of an acute gouty
arthritis attack is determined by the number of active joints. Gouty
arthritis should be treated with pharmacologic therapy within 24 hours
of attack and for up 7 to 10 days.2,7 ULTs should be continued during an acute attack.7
Monotherapy with nonsteroidal anti-inflammatory drugs (NSAIDs),
systemic corticosteroids, or colchicine is recommended for
mild-to-moderate pain where only one or a few small joints are affected.
Combination therapy is recommended for polyarticular attacks or an
attack affecting multiple large joints that induce severe pain (TABLE 4).7
Colchicine exerts its effects by reducing lactic acid
production by leukocytes, which in turn decreases uric acid deposition
and reduces phagocytosis, with abatement of the inflammatory response.
Although an older drug, colchicine just recently obtained an FDA
indication for use in patients with acute gout.41 Colchicine
should be instituted only in early or well-established gouty attacks. In
a recent randomized trial, low-dose colchicine (1.8 mg over 1 h)
yielded both maximum plasma concentration and early gout-flare efficacy
comparable to high-dose colchicine (4.8 over 6 h), with a safety profile
indistinguishable from that of placebo.42
NSAIDs inhibit the cyclooxygenase (COX) enzymes, which are
involved in the inflammatory process and prostaglandin production. The
three NSAIDs that are FDA approved for the treatment of acute gout are
naproxen, indomethacin, and sulindac.7 Celecoxib, the only COX-2 inhibitor currently available in the U.S., does not have an indication for acute gout.43 However, celecoxib has been shown to effectively treat acute gout at high doses (800 mg/day) in a randomized study,44 although these doses exceed the recommended maximum daily doses.43
Corticosteroids are recommended by the ACR for
monotherapy, but these agents are generally reserved for patients who
cannot tolerate either colchicine or NSAIDs due to their systemic
adverse effects.7 Although the guidelines do not explicitly
recommend depo formulations, these agents have been used; however,
dosing is ambiguous.45 When selecting corticosteroids as the initial therapy, joint involvement needs to be considered (TABLE 4).7
Role of the Pharmacist
Pharmacists play an integral role in patient education and
improving the care of patients with gout. They can help patients
improve adherence to pharmacologic and nonpharmacologic therapies.
Pharmacists should emphasize lifestyle modifications and diet such as
managing weight, limiting meat and seafood intake, and minimizing
alcohol intake. Pharmacists should also educate patients about their
gout medications, including appropriate dosing, duration of therapy,
adverse effects, contraindications, and drug interactions.
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