Received Date : 11-Feb-2016

Accepted Article
Revised Date : 06-May-2016

Accepted Date : 06-May-2016

Article type : Review of Therapeutics

Gouty Arthritis: A Review of Acute Management and Prevention

Authors: Liza Wilson1,2; Joseph J. Saseen1,2

Institution:

1- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences; Anschutz

Medical Campus, Department of Clinical Pharmacy

2- University of Colorado School of Medicine; Anschutz Medical Campus, Department of Family

Medicine

Corresponding Author:

Liza Wilson

Assistant Professor

University of Colorado Anschutz Medical Campus (C238)

12850 E. Montview Blvd., V20-2126

Aurora, CO 80045

Ph: 303-724-9548 liza.wilson@ucdenver.edu

Key words: gout, gouty, arthritis, treatment, review, management, assessment, prevention

Running Head: Review of Gouty Arthritis

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as an
'Accepted Article', doi: 10.1002/phar.1788
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 Abstract
Accepted Article
Gouty arthritis is one of the most common rheumatic diseases. The clinical burden of gouty arthritis has

historically been well recognized; however, gout is often misdiagnosed and mismanaged. The

prevalence of gout is rising and is likely attributed to several factors including increased incidence of

comorbidities, lifestyle factors, and increased use of causative medications. With the increasing

prevalence, there have been several innovations and evidence-based updates related to the diagnosis

and management of gout. Acute gouty arthritis should be treated with nonsteroidal antiinflammatory

drugs (NSAIDs), colchicine, or corticosteroids, or a combination of two agents. Xanthine oxidase inhibitor

therapy remains the consensus first-line treatment option for the prevention of recurrent gout. Add-on

therapies that reduce serum urate concentration include traditional uricosuric agents and a novel uric

acid reabsorption inhibitor. Prophylaxis of acute gout with NSAIDs, colchicine, or corticosteroids is

universally recommended when initiating any urate-lowering therapy in order to prevent acute gouty

arthritis for a period of at least 6 months. In this review, we discuss the epidemiology and risk factors for

gouty arthritis and evaluate diagnostic strategies and therapeutic regimens for the management of gout,

including a new drug approval.

Introduction

Gout, historically referred to as “the unwalkable disease” and the “disease of kings,” was first

recognized by the Egyptians in 2640 B.C. and later by Hippocrates in the 5th century B.C. Gout was

characterized by podagra, defined as pain occurring in the first metatarsophalangeal joint.1 This

debilitating disease was associated with a diet consisting of rich foods and excessive alcohol

consumption, a lifestyle that could only be afforded by the wealthiest social class at the time. In the

present day, gout is a well-defined rheumatologic disease known to be related to more than just lifestyle

factors and can manifest as a variety of clinical presentations in addition to the classic podagra.

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 Gout is a broad term for a spectrum of clinical conditions related to an excess of serum urate (uric acid).
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Gouty arthritis is commonly the first clinical manifestation of gout and typically presents as acute and

episodic, although it can manifest or progress to chronic arthritis.2,3 Tophi are monosodium urate

crystals that are deposited in tissues and may be present in both acute and chronic forms of gouty

arthritis. In progressive disease, interstitial nephropathy and uric acid nephrolithiasis can occur, but this

typically occurs only in patients with prolonged and more severe cases of hyperuricemia. These renal

manifestations of gout are considered rare; however, gout, in general, is widely recognized and is

becoming more common.

Gout is one of the most common rheumatology diseases and is the most common cause of

inflammatory arthritis among adults in the United States.2,3 An analysis of the National Health and

Nutrition Examination Survey estimates that approximately 8 million Americans are affected by gout,

with most of these patients suffering from gouty arthritis.4 Gout prevalence continues to rise,

particularly in the United States. The frequency of outpatient office visits for gout increased 3-fold from

1993 to 2009, with the most significant increase observed after 2003.5 In addition to poor dietary

patterns, likely contributing factors are an increase in comorbidities that are associated with

hyperuricemia such as obesity, hypertension, metabolic syndrome, type 2 diabetes mellitus, and chronic

kidney disease (CKD).6 Another factor that can increase the risk of gout is use of medications known to

increase serum urate concentrations.

As the prevalence of gout continues to rise, several innovations and evidence-based updates have been

addressing the diagnosis and management of gout. Historically, gout management has largely been

based on tradition and expert opinion, but recent clinical research is providing evidence-based insight

into this historical disease state. In this review, we discuss the epidemiology and risk factors for gouty

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 arthritis and evaluate diagnostic strategies and therapeutic regimens for the management of gout,
Accepted Article
including a new drug approval.

Pathophysiology of Gout and Hyperuricemia

The production of serum urate is the final step of purine metabolism. Humans lack the enzyme uricase

that converts uric acid into highly soluble allantoin in nonprimate mammals, amphibians, and fish. Thus,

the typical serum urate concentration in humans is near the limit of solubility, leaving humans as one of

the only species that can develop gout spontaneously.7 A delicate balance exists between the amount of

serum urate produced versus the amount excreted. Excess serum urate can accumulate from either

overproduction or underexcretion of uric acid. This accumulation is known as hyperuricemia and is

variably defined as a serum urate concentration greater than 6.8–7.0 mg/dL.2 Gout does not manifest in

all individuals with hyperuricemia. In fact, many individuals have asymptomatic hyperuricemia with

serum urate concentrations greater than 7.0 mg/dL and may never develop any signs or symptoms

related to gout. Alternatively, there are individuals who will experience gout symptoms at the desired

serum urate concentration of less than 6 mg/dL.

Overproduction of Uric Acid

Uric acid overproduction is rare and accounts for only about 10% of gout cases.7 Uric acid can be

produced by de novo synthesis of purine bases, conversion of tissue nucleic acid into purine nucleotides,

and dietary purines.7 Each of these purines is metabolized through the same pathway that leads to the

production of either uric acid or nucleic acid (Figure 1). This metabolic pathway is regulated by several

enzyme systems. Two recognized enzyme abnormalities can lead to the overproduction of uric acid:

increased activity of phosphoribosyl pyrophosphate (PRPP) synthetase and deficiency of hypoxanthine-

guanine phosphoribosyltransferase (HGPRTase). An increase in PRPP synthetase leads to the increased

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 conversion of ribose 5-phosphate to PRPP, a precursor to uric acid synthesis. HGPRTase coupled with
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PRPP is responsible for the conversion of hypoxanthine and guanine to inosinic acid and guanylic acid,

respectively, which in turn are converted to nucleic acids. In the presence of HGPRTase deficiency,

guanine and hypoxanthine are metabolized to uric acid, and more free PRPP is available to couple with

glutamine in the first step of the purine pathway.7

Breakdown of tissue nucleic acids is another mechanism of uric acid overproduction. Myeloproliferative

and lymphoproliferative disorders, psoriasis, some types of anemias, and the cytotoxic medications used

to treat these disorders can result in hyperuricemia secondary to enhanced turnover of nucleic acids and

breakdown of cellular matter. Contrary to popular thought, ingestion of dietary purines have the least

significant effect on uric acid overproduction. Although dietary consumption is a contributing factor to

consider in patients with clinical gout, it is not important in the absence of a purine metabolism or

elimination abnormality.7

Underexcretion of Uric Acid

Renal excretion is the primary mechanism by which uric acid is eliminated from the body. This pathway

accounts for approximately two thirds of daily uric acid elimination. The remaining one third is excreted

via the gastrointestinal tract. When urinary excretion of uric acid is not maintained at or above the rate

of uric acid production, hyperuricemia can ensue. There are multiple renal mechanisms responsible for

the elimination of uric acid including glomerular filtration, tubular secretion, and postsecretory

reabsorption. Ninety percent of the renally filtered uric acid is reabsorbed in the proximal tubule and is

mediated by specific transporters, primarily by URAT1. Uric acid reabsorption can be enhanced by

increased sodium reabsorption, and certain medications can raise serum urate by interfering with

transport mechanisms and decreasing uric acid clearance (Table 1).

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 Monosodium urate crystals can develop in the presence of hyperuricemia and result in clinical
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manifestations of gout (e.g., acute gouty arthritis). The most common area for urate crystals to form is

in peripheral joints of the lower extremities likely due to the high local concentration of urate in joint

fluids and a reduced temperature.7,8 Deposition of urate crystals triggers an acute inflammatory

reaction. On the cellular level, synoviocytes and macrophages act as phagocytes that engulf the

developed urate crystals. In response, inflammatory cytokines, such as interleukin-1 (IL-1), and

prostaglandins are released. Prostaglandins cause direct pain and inflammation of the joint space. IL-1

recruits polymorphonuclear leukocytes, which in turn cross into the synovium and joint space to release

leukotrienes and additional prostaglandins. This inflammatory response results in intense joint pain,

erythema, redness, and swelling. Systemic symptoms, such as a fever, may occur.

Risk Factors and Comorbidities

Men are nearly 3 times as likely to develop gout compared with women, with black males most

commonly affected.4,9 Gout incidence increases with age in both men and women, with the most

significant age-related increase noticed in postmenopausal women. Medical conditions associated with

gout include metabolic syndrome, renal insufficiency, diabetes, hypertension, heart failure, and organ

transplantation.10 Rare genetic polymorphisms in genes (GLUT9, URAT1) involved in renal urate

transport have been identified and are thought to play a role in the development of gout.11,12

Prospective studies have suggested that increased intake of dietary purines, particularly meat and

seafood, beer, spirits, soft drinks, and fructose may be linked to incident gout.13-15 Lastly, several

medications are known to elevate serum urate concentrations (Table 1).2,7

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 Diagnosis and Imaging
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Several diagnostic criteria recommendations have been developed for gout, with the most widely used

dating back to 1977 from the American College of Rheumatology (ACR).16-19 Traditionally, a clinical

diagnosis could be made in a patient presenting with podagra or acute monoarticular arthritis with an

elevated serum urate concentration (> 7 mg/dL), but it is not considered definitive without crystal

identification. Aspiration of synovial fluid from an affected joint or tophus and recognition of

monosodium urate crystals enables a definitive diagnosis and is considered the gold standard.16,17 Each

of these diagnostic techniques possesses limitations. In some patients, select classic gout features such

as sudden onset of joint pain, swelling, and tenderness may be absent, or there is involvement of a joint

other than the metatarsophalangeal joint. Furthermore, uric acid is considered a surrogate marker for

acute gouty arthritis. Approximately one third of patients have a normal serum urate concentration

during an acute gout attack whereas others may have hyperuricemia with no evident gout symptoms.20

These factors can make a clinical diagnosis difficult, requiring investigation through joint or tophi

aspiration. However, the skills and equipment to perform and evaluate diagnostic joint aspiration in

primary care, where most patients are diagnosed and managed, are limited.21,22 Additionally, the

existing published criteria were developed prior to advanced imaging modalities, such as

ultrasonography or dual-energy computed tomography (DECT). These imaging methods, in addition to

conventional radiography, have gained popularity over recent years and have been more widely

studied.23

The ACR and the European League Against Rheumatism (EULAR) funded the Study for Updated Gout

Classification Criteria (SUGAR) to update outdated recommendations.23 As a result of this international

collaboration, new ACR/EULAR gout classification criteria were made available in 2015 (Table 2). This is a

multifaceted scoring system that is available online (http://goutclassificationcalculator.auckland.ac.nz);

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 a score of 8 or higher (of a maximum possible score of 23) indicates a positive gout diagnosis. The
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ACR/EULAR gout classification criteria have superior performance characteristics, with high sensitivity

and improved specificity compared with previously published criteria. Of importance, the new criteria

incorporate novel imaging modalities. These criteria should be incorporated as inclusion criteria for

future gout clinical trials.23

Other crystal-induced arthropathies can closely resemble the clinical presentation of gouty arthritis and

should be considered for differential diagnosis. Calcium pyrophosphate dehydrate crystal deposition

(CPPD) can cause a rapid onset of severely painful, self-limiting attacks of synovitis with erythema.

Traditionally, this phenomenon was referred to as “pseudogout” because of the symptom similarities

caused by monosodium urate crystals in gout.23 Compared to gout, CPPD may take longer to reach peak

intensity, persists for months despite therapy, and more commonly affects large joints. Differentiation

of CPPD from true gouty arthritis requires arthrocentesis to confirm either the presence of calcium

pyrophosphate dehydrate crystals (in CPPD) or monosodium urate crystals (in gout) in the synovial fluid.

CPPD should be ruled out in patients with presumed gouty arthritis who are treated with

pharmacotherapy but do not respond within an anticipated time frame.

Acute Gouty Arthritis

A classic gouty arthritis attack is characterized by a rapid escalation and localized onset of intense pain,

swelling and inflammation. A typical attack, or flare, is monoarticular affecting the metatarsophalangeal

joint (great toe). Less common areas are the insteps, ankles, heels, knees, wrists, fingers, and elbows.

Most patients will have at least one episode involving the metatarsophalangeal joint.7 Atypical acute

gouty arthritis presentations may by polyarticular. Episodes of acute gouty arthritis may first occur

infrequently and may be recurrent, with the interval between attacks shortening over time.

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 The goals of treatment of acute gouty arthritis are to terminate acute attacks, prevent recurrent attacks,
Accepted Article
and prevent complications.7 These goals can be accomplished through a combination of an accurate

assessment of acute gouty arthritis, pharmacologic and nonpharmacologic treatment, and patient

education as recommended by the ACR 2012 Guidelines for Management of Gout.2,3

Assessment

An ACR expert panel developed case scenarios to aid in the assessment of acute gouty arthritis attacks

based on severity, duration of symptoms, and extent of involvement.3 Severity refers to the self-

reported intensity of the gout attack using a 0–10 visual analog scale. A score of 7–10 is considered

severe, 5 or 6 is considered moderate, and 4 or less is considered mild. Duration in terms of time from

onset of acute symptoms was also considered and divided into early (within 12 hours), well established

(13–36 hours), and late (> 36 hours). Lastly, extent of involvement describes the number of active joints

affected and distinguishes between small joints, large joints, and joint regions. These factors determine

whether monotherapy or combination therapy should be used for the initial management of acute

gouty arthritis. For example, if the patient-reported pain is severe and the acute gout attack affects

three separate large joints, the expert panel recommends initial combination pharmacologic therapy

over monotherapy.3

Nonpharmacologic Therapy

Nonpharmacologic options for the management of acute gouty arthritis are limited and are intended

only to supplement pharmacologic therapy. Local application of topical ice is supported by limited

evidence and is the only nonpharmacologic therapy recommended in the 2012 ACR guidelines.3 In a

small study, a group receiving topical ice therapy in addition to standard care experienced a greater

reduction in pain compared to the control group.23 The ACR specifically recommends against the use of

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 complementary agents for acute gout attacks due to lack of proven efficacy (e.g., cherry juice or extract,
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salicylate-rich willow bark extract, ginger, flaxseed, charcoal, strawberries, black currant, burdock, sour

cream, olive oil, horsetail, pears, or celery root).3

Pharmacologic Therapy

Pharmacologic therapy should be initiated for acute gouty arthritis episodes, preferentially within 24

hours of symptom onset. Choice of initial pharmacologic treatment is based on symptom severity and

number of joints involved (Figure 2).3 The recommended treatment options include nonsteroidal

antiinflammatory drugs (NSAIDs), systemic corticosteroids, and colchicine (Table 3). No individual agent

is routinely recommended over another; rather, selection is based on patient-specific factors such as

drug-drug interactions, comorbidities, contraindications or intolerances to a certain treatment option,

and patient and/or provider preference.

Some patients are candidates for initial combination therapy due to severe pain, polyarticular attacks, or

an attack affecting multiple large joints. Recommended combinations include colchicine with an NSAID,

colchicine with an oral corticosteroid, or an intraarticular steroid with an NSAID, colchicine, or an oral

corticosteroid. Of note, the combination of an NSAID and oral corticosteroid is not recommended by

ACR secondary to the concern for synergistic toxicity (e.g., gastrointestinal bleed).3

NSAIDs

Naproxen, naproxen sodium, indomethacin, and sulindac are the only U.S. Food and Drug

Administration (FDA)-approved NSAIDs for acute gouty arthritis. However, all NSAIDs are likely equally

effective when used at antiinflammatory doses. Regardless of which agent is used, when an NSAID is

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 used to treat acute gouty arthritis, the full antiinflammatory dose should be continued until resolution
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of acute gout symptoms. This is typically 5–8 days after initiation.3

NSAIDs possess numerous relative and absolute contraindications. These complicating situations must

be carefully considered by clinicians prior to treating a patient with NSAID therapy. Many times, relative

and/or absolute contraindications (e.g., history of gastrointestinal bleed, renal failure, elderly) will lead

clinicians to selecting an alternative agent. Celecoxib, a cyclooxygenase 2 (COX-2) inhibitor, may be used

in place of nonselective NSAIDs for some patients at risk of gastrointestinal toxicity, although the data

are not convincing. The recommended dosage of celecoxib is 800 mg once, followed by 400 mg on day

1, then 400 mg twice daily for a week. 3 In addition, clinicians may add a proton pump inhibitor to a

nonselective NSAID regimen to reduce the risk of gastrointestinal toxicity. All NSAIDs carry similar

adverse effect profiles. The most widely affected organ systems include cardiovascular (fluid retention,

hypertension, edema), gastrointestinal (abdominal pain, dysplasia, ulcers, or bleeding), and renal (renal

insufficiency or failure, proteinuria).

Colchicine

Colchicine was used to treat acute gouty arthritis for decades without FDA approval, clear prescribing

information, or dosage recommendations, as its availability predated these contemporary regulatory

requirements. Historical dosing of colchicine followed the “dose to diarrhea” mantra, with a dose

administered every 2 hours until any of the following occurred: relief of gouty arthritis, toxicity

(diarrhea, nausea, vomiting), or achieving a maximum dose of 4.8 mg.24 This arbitrary approach resulted

in patients receiving high doses of colchicine, and they often experienced excessive gastrointestinal

effects. In 2009, Colcrys (Takeda Pharmaceuticals, Deerfield, IL) was introduced to the market as the

exclusive, brand-name–only colchicine product.25 This new drug approval was granted by the FDA as a

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 result of a study providing dosing and safety information. The 184-person study demonstrated that the
Accepted Article
efficacy of low-dose colchicine (total dose of 1.8 mg over 1 hour) was comparable to that of high-dose

colchicine (4.8 mg over 6 hours), with a significantly lower occurrence of adverse effects.26

Colchicine is now approved for the treatment of gout flares at a dose of 1.2 mg orally at the first sign of

gout flare followed by 0.6 mg orally 1 hour later and is accompanied by dosage adjustments for renal

impairment, hepatic impairment, and coadministration with interacting drugs.27 Its use is recommended

in the 2012 ACR guidelines for gout attacks only when symptom onset is within 36 hours, as efficacy is

significantly reduced beyond 24-36 hours.3 In contrast to the FDA-approved dosing, the ACR also

suggests that colchicine 0.6 mg once or twice daily can be started 12 hours after the initial 1.2-mg dose

and continued until the acute attack resolves.3 This recommendation is not based on clinical outcomes.

Pharmacokinetic data suggest that exposure to colchicine in plasma becomes markedly reduced

approximately 12 hours after administration of the low-dose colchicine regimen.26 The ACR recommends

continued dosing based on these data.

The initial branding and market exclusivity of Colcrys in 2009, which was also influenced by the orphan

status use of colchicine for familial Mediterranean fever, resulted in expanded clinical data that have

provided additional evidence regarding safety and efficacy. However, this was joined by barriers to

patient access due to increased medication costs. The price of colchicine was raised by a factor of more

than 50, increasing from approximately $0.09 per to pill to $4.85 per pill.25 As of 2015, colchicine is once

again available as a generic medication and is available in both tablet and capsule forms.

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 Corticosteroids
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As is typical for many inflammatory and rheumatologic conditions, corticosteroids have a prominent role

in the treatment of acute gouty arthritis. The 2012 ACR guidelines recommend evaluating the number of

joints affected with active arthritis to select the route of administration when using a corticosteroid.

When more than two joints are involved or intraarticular corticosteroid injections are not feasible (e.g.,

due to patient preference, polyarticular joint involvement, injections not available), oral corticosteroids

may be considered.3 There are several systemic drug and dosing regimens (e.g., prednisone 0.5 mg/kg

for 5–10 days, prednisone 0.5 mg/kg for 2 days followed by a 7–10 day taper, a methylprednisolone

dose pack).

In the event that one or two large joints are affected, intraarticular corticosteroids (e.g., triamcinolone)

are recommended as an option and can be used in combination with an NSAID, colchicine, or an oral

corticosteroid for patients with severe pain. The intraarticular corticosteroid dose should be based on

the joint size and may be diluted with a local anesthetic (e.g., lidocaine) to reduce injection-site pain.3

Alternative regimens might include intramuscular triamcinolone acetonide 60 mg as a bolus followed by

oral prednisone when a more rapid effect is desired. Additionally, adrenocorticotropic hormone may be

considered in patients who are unable to take oral antiinflammatory medications, although it does not

offer a significant benefit over synthetic corticosteroids.3

Off-Label Therapies: IL-1 Blockers

IL-1 is released in the synovium of joint spaces as an element of the inflammatory response triggered by

urate crystals. This step in the pathophysiology of acute gouty arthritis has led to investigational use of

IL-1 inhibitors.28,29 The available IL-1 inhibitors, anakinra and canakinumab, are not FDA approved for the

treatment of acute gouty arthritis, and randomized study data demonstrating efficacy are lacking.

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 Moreover, these biologic medications are expensive and have potential adverse effects (e.g., infections).
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However, for patients presenting with a severe gout attack that is refractory to recommended

pharmacologic options, treatment with an IL-1 inhibitor may be considered. In these scenarios, the 2012

ACR guidelines recommend anakinra 100 mg subcutaneously daily for 3 consecutive days or

canakinumab 150 mg subcutaneously as a single dose.3

Prevention of Recurrent Gouty Arthritis

On identification of acute gouty arthritis, prophylactic gout therapy must be considered in order to

prevent or reduce the risk of future recurrent episodes. The foundation of preventing gout recurrence is

based on reduction of reducing serum urate concentrations below the saturation point for monosodium

urate. This is accomplished through implementation of nonpharmacologic and pharmacologic strategies.

Nonpharmacologic therapies are recommended for all patients with a history of gout whereas the

decision to start pharmacologic therapy should be based on a risk versus benefit assessment as outlined

in the ACR guidelines.

Assessment

Clinicians should complete a patient-centered assessment to evaluate gout disease symptom severity

and burden, including estimated number of acute attacks per year. A thorough physical examination

should be performed to assess for the presence of tophi. A complete medical history should be obtained

to identify the presence gout comorbidities such as obesity, excessive alcohol intake, metabolic

syndrome, diabetes, hypertension, hyperlipidemia, urolithiasis, and kidney disease. If present, additional

treatment modalities should be considered as a component of comprehensive appropriate patient care.

Specifically for the prevention of recurrent acute gouty arthritis, indications for urate-lowering

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 pharmacotherapy include any one of the following factors: presence of tophus or tophi; frequent gout
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attacks, defined as ≥ 2 attacks per year; chronic kidney disease (CKD) stages 2–5; or past urolithiasis.2

Nonpharmacologic Therapy

Diet and lifestyle recommendations are the mainstay of preventing gouty arthritis recurrence. The 2012

ACR guidelines provide recommendations that target lowering of serum urate concentrations. Food and

beverage items thought to increase serum urate are categorized as those to “avoid” or “limit,” and

those with potential urate-lowering effects are categorized as those to “encourage” (Table 4).2 Quality

evidence related to individual dietary items is lacking because prospective randomized trials would be

difficult to conduct and could pose ethical risks, particularly related to items known to pose health risks

in addition to gout (e.g., alcohol consumption, high-fructose corn syrup). Therefore, dietary

recommendations are based on single randomized trials, nonrandomized studies, case studies, or expert

opinion. Emphasis should be placed on diet and lifestyle choices that promote prevention and optimal

management of diabetes, obesity, and cardiovascular diseases. Weight loss for obese patients is

recommended, although it should be noted that very rapid weight loss or fasting, particularly after

bariatric surgery, may result in increased serum urate concentrations. Additional recommendations

include smoking cessation, hydration, routine exercise, and an overall healthy diet.2 These strategies

may reduce the frequency of recurrent acute gouty arthritis attacks but are not meant to replace

pharmacologic treatment in patients with an indication for urate-lowering pharmacotherapy.

Patients should be evaluated to identify the use of medications known to increase serum urate

concentrations. If use of medications known to increase serum urate is identified in a patient with a

history of gout, the risk of gout exacerbation should be carefully weighed against the therapeutic

benefits offered by continued treatment of the potentially offending agent. It has been documented

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 that patients with frequent recurrent gouty arthritis have a higher prevalence of using medications
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known to increase serum urate concentration, especially thiazides, than patients with infrequent gouty

arthritis.30 The 2012 ACR guidelines recognize the benefit of thiazide diuretics for blood pressure

control.2 This suggests that the use of thiazide diuretics in the presence of gout should be based on

patient-specific factors and comorbid disease state management. Interestingly, the risk of gout seemed

similar in patients treated with chlorthalidone when compared to hydrochlorothiazide, despite a known

difference in antihypertensive potency.31 Furthermore, the ACR guidelines do not recommend

discontinuation of low-dose (≤325 mg) aspirin, despite the known increase in serum urate because of

cardiovascular disease prevention benefits in patients with gout.2

Pharmacologic Therapy

Urate-lowering is best achieved through two primary pharmacologic mechanisms: decreased synthesis

of uric acid by inhibition of xanthine oxidase and increased renal excretion of uric acid (uricosurics).

When indicated, urate-lowering pharmacotherapy can be initiated during an acute gout attack if acute

gouty arthritis pharmacotherapy (NSAID, colchicine, or corticosteroids) is initiated concomitantly, or

once the acute gouty arthritis attack is resolved. The goal of urate-lowering therapy is to achieve and

maintain a serum urate concentration < 6 mg/dL.2 An alternate goal serum urate concentration of < 5

mg/dL can be used if gout symptoms persist after achieving a goal serum urate concentration of < 6

mg/dL.2 Urate-lowering therapy is intended for chronic use in order to maintain serum urate

concentrations at or below goal. However, less than half of patients with gout in real-world settings are

adherent to their maintenance regimen.32 Reasons for this phenomenon might be explained by the lack

of symptoms between acute gout attacks, patient unawareness of the need for chronic preventive

medications, and a high pill burden in patients with several gout-related comorbidities. Medication

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 nonadherence can be mitigated through the provision of patient education including information on the
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nature and characteristics of gout, treatment options, and diet and lifestyle recommendations.33

Xanthine Oxidase Inhibitors

In the purine synthesis pathway, xanthine oxidase is responsible for the conversion of hypoxanthine to

xanthine and xanthine to uric acid (Figure 1). Inhibition of xanthine oxidase results in decreased uric acid

production. Although overproduction of uric acid is rare, reducing its synthesis will, in turn, reduce the

risk of acute gouty arthritis related to underexcretion. Xanthine oxidase inhibitors are considered first-

line treatment options for the prevention of recurrent gouty arthritis. Two xanthine oxidase inhibitors,

allopurinol and febuxostat, are available and widely prescribed.

Allopurinol should be initiated at a dose not greater than 100 mg daily.36 For patients with stage 4 or 5

CKD, the starting dose should be reduced to 50 mg daily. 2 In all patients, the dose may be increased by

50–100 mg every 2–5 weeks until the desired serum urate goal is achieved. 2 Dose titration should be

anticipated, as daily doses < 300 mg regularly fail to achieve serum urate targets.34,35 The 2012 ACR

guidelines recommend that doses can be increased above 300 mg daily, noting that the FDA-approved

maximum dose is 800 mg daily.2,36 These ACR guidelines also recommend dose escalation to achieve

serum urate goal for patients with renal impairment despite FDA-approved product information that

suggests a lower daily dose in patients with reduced estimated glomerular filtration rates. These

patients should be provided with patient education and monitoring for allopurinol drug hypersensitivity

and other adverse effects such as pruritus, rash, and elevated hepatic enzyme levels.

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 Allopurinol hypersensitivity syndrome (AHS) is a rare but potentially life-threatening adverse effect. The
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underlying mechanism of AHS likely involves an immunologic mechanism and an accumulation of the

drug.37 The incidence of AHS is estimated to be 1:1000 individuals in the United States.2 Increased risk is

associated with poor kidney function; high allopurinol starting doses; concurrent thiazide diuretic,

captopril, amoxicillin, or ampicillin use; and genetic predisposition.37-40 The presence of a variant allele,

HLA-B*5801, is strongly associated with severe cutaneous adverse reactions during treatment with

allopurinol. 2 The allele is most commonly found in Asian subpopulations and is most predominant in

individuals of Korean, Han Chinese, and Thai descent. 2 Screening for HLA-B*5801 should be considered

in the following populations considered to be at higher risk of AHS: Koreans with stage 3 or worse CKD;

and Han Chinese and Thai individuals, irrespective of renal function.2

Febuxostat is primarily considered as an alternative to allopurinol. Similar to allopurinol, it decreases

serum urate concentrations in a dose-dependent manner. The recommended starting dose is 40 mg

daily and may be titrated to 80 mg daily after 2 weeks if serum urate concentration remains > 6 mg/dL.41

The maximum FDA-approved dose or febuxostat is 80 mg daily;41 however, a maximum dose of 120 mg

daily is approved in countries outside the United States and is recommended by the ACR.2,41 Of note,

the risk versus benefit of the 120-mg dose is unclear. Febuxostat does not require dosage adjustment

based on renal impairment when creatinine clearance is greater 30 mL/minute. 41 Due to a lack of

published safety data in the setting of stage 4 or worse CKD, dosage adjustment in patients with a

creatinine clearance less than 30 mL/minute is not defined.41

The 2012 ACR guidelines do not recommend one xanthine oxidase inhibitor over the other.2 In a head-

to-head comparison, 762 study participants were randomized to receive either allopurinol 300 mg daily

or febuxostat 80 or 120 mg daily for 52 weeks.42 This study demonstrated that febuxostat at both the

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 80-and 120-mg doses was more effective than allopurinol 300 mg at achieving the primary endpoint, a
Accepted Article
serum urate concentration of < 6 mg/dL (p < 0.001 for the comparisons of each febuxostat group with

the allopurinol group). No statistically significant differences were noted in reductions in gout flares and

tophus flares, however, between each febuxostat group and the allopurinol group. One limitation to the

study results is the fixed 300-mg dose of allopurinol used without titration to a serum urate target, as

recommended by ACR guidelines. Additionally, the study did not demonstrate a statistically significant

difference in the occurrence of recurrent acute gouty arthritis attacks. The primary finding was a greater

reduction in serum urate concentrations, a surrogate marker for gout management. The 2012 ACR

guidelines recommend that febuxostat can be substituted for allopurinol or vice versa in the event of

drug intolerance and adverse events.2

Uricosurics

Uricosuric drugs increase the renal clearance of uric acid by inhibiting postsecretory renal proximal

tubular reabsorption of uric acid. Uricosurics are considered alternatives to first-line agents in the event

that one or more xanthine oxidase inhibitors are contraindicated or not well tolerated. Probenecid is the

first choice among uricosuric agents.2 Probenecid should be initiated at a dose of 250 mg orally twice

daily for 1–2 weeks, followed by 500 mg orally twice daily.43 The dose can be titrated by 500 mg/day

each month as tolerated if symptoms persist, up to a maximum dose of 2000 mg daily.43 Probenecid

monotherapy is contraindicated in patients with a history of urolithiasis or a creatinine clearance < 50

mL/minute secondary to a lack of data on long-term safety and efficacy in patients with stage 3 CKD. 2

Adverse effects include gastrointestinal toxicity, rash and hypersensitivity, and urolithiasis. Risk of

urolithiasis is approximately 9% and can be reduced by maintaining adequate hydration and alkalization

of the urine with sodium bicarbonate or acetazolamide.2

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 Other agents that are not gout-specific medications may also have a role in the prevention of recurrent
Accepted Article
gouty arthritis through secondary uricosuric effects. Fenofibrate, a triglyceride-lowering medication,

increases the clearance of hypoxanthine and xanthine.44 Losartan, an antihypertensive, inhibits renal

tubular reabsorption of uric acid, increases urinary excretion, and alkalinizes the urine.45 These agents

are not FDA approved for the prevention of recurrent gouty arthritis but can be useful if indicated for

the treatment of other comorbidities (e.g., hypertension, hypertriglyceridemia) and potentially can

reduce serum urate by 20-30%. The 2012 ACR guidelines recommend probenecid, fenofibrate, or

losartan in refractory disease or in combination with a xanthine oxidase inhibitor when the serum urate

target has not been achieved with monotherapy.2

Pegloticase

Pegloticase is a pegylated uric acid–specific enzyme that lowers serum urate concentrations by

converting uric acid to allantoin. Allantoin is a water-soluble purine metabolite that is readily eliminated,

primarily by renal excretion.46 It is indicated for the treatment of severe gout in adult patients refractory

to or intolerant of conventional, appropriately dosed, urate-lowering therapy.2 Pegloticase is

administered as an 8-mg intravenous infusion over no less than 120 minutes every 2 weeks.

Premedication with antihistamines and corticosteroids is required to reduce the potential for infusion-

mediated reactions.46 Immunogenicity can also occur. In one study, anti-pegloticase (anti-PEG)

antibodies developed in 92% of patients treated with pegloticase every 2 weeks versus 28% of patients

treated with placebo.46 In another study, anti-PEG antibodies were detected in 42% of patients treated

with pegloticase.46 High anti-pegloticase antibody titer was associated with a failure to maintain

pegloticase-induced normalization of uric acid and an increased incidence of infusion reactions. 46

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

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 due to the risk of hemolysis and methemoglobinemia.46 Patients at higher risk for G6PD deficiency (e.g.,
Accepted Article
patients of African or Mediterranean ancestry) should be screened before initiating therapy.46

Randomized controlled trials demonstrated the efficacy of pegloticase at reducing serum urate

concentrations and resolving tophi.47 However, the route of administration (intravenous infusion

administered over at least 2 hours), the potential for serious infusion-related allergic reactions

(anaphylaxis), and the extremely high cost are important limiting factors for the use of pegloticase.

Lesinurad

Lenisurad is a new agent that was approved by the FDA in December 2015 for the prevention of acute

gouty arthritis in combination with a xanthine oxidase inhibitor. This medication decreases serum urate

by inhibiting the function of transporter proteins (URAT1, OAT4) that reabsorb uric acid in the kidney.

URAT1 is responsible for the majority of uric acid reabsorption from the renal tubular lumen, and OAT4

is the transporter involved in diuretic-induced hyperuricemia.48 Targeting these transporters is a novel

mechanism of action for treatment of gout.

Three multicenter, randomized, placebo-controlled studies compared the efficacy and safety of

lesinurad 200 mg or 400 mg when added to a xanthine oxidase inhibitor.49, 50 In two of these phase III

studies, lesinurad was added to allopurinol in patients with a serum urate concentration > 6.5 mg/dL

and a history of at least two gout flares in the 12 months prior to randomization.49 Compared to

allopurinol monotherapy, lesinurad in combination with allopurinol was superior at lowering serum

urate concentrations to < 6 mg/dL after 6 months of therapy. No significant differences were observed

for important secondary outcomes including gout flare rates and tophus resolution. In the third trial,

lesinurad 200 mg or 400 mg daily was added to febuxostat 80 mg daily in patients with at least one

This article is protected by copyright. All rights reserved.

 measurable tophus.50 Compared to febuxostat monotherapy, a statistically significant difference was
Accepted Article
noted in the proportion of patients treated with lesinurad 400 mg in combination with febuxostat who

achieved the primary endpoint of a target serum urate concentration < 5 mg/dL after 6 months.

Although the proportion of patients who achieved the primary endpoint in the lesinurad 200 mg plus

febuxostat group was not statistically significant at 6 months, a significant difference was noted at 12

months. There was no significant difference in resolution of target tophus, but there was a significant

difference in percent reduction of tophus area at 12 months.

Lesinurad is currently FDA approved for use in combination with a xanthine oxidase inhibitor for the

treatment of hyperuricemia in patients with a history of acute gouty arthritis who have not achieved

target serum urate concentrations with xanthine oxidase monotherapy. Lesinurad is dosed at 200 mg

daily and is recommended to be taken in the morning with food and water at the same time as the

xanthine oxidase inhibitor.48 No dose adjustment is required in patients with mild or moderate renal

impairment, as clinical trials included patients with this degree of kidney impairment; however,

lesinurad should not be used in patients with an estimated creatinine clearance < 45 mL/minute.48 Renal

function should be assessed at baseline and periodically thereafter in patients treated with lesinurad.

More frequent monitoring is recommended in patients with an estimated creatinine clearance below 60

mL/minute. Lesinurad carries an FDA boxed warning advising that acute renal failure is more common

when used without a xanthine oxidase inhibitor, further reinforcing that this agent should always be

used in combination with either allopurinol or febuxostat.48

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 Acute Gout Prophylaxis
Accepted Article
The initiation of urate-lowering therapy is associated with an increased risk of acute gouty arthritis.

Historically, this has been referred to as mobilization gout. Although the exact mechanism of this

phenomenon is unknown, the reduction of serum urate is thought to cause temporary remodeling and

mobilization of uric acid crystals, prompting an acute gout attack. Patients who experience a gout attack

shortly after the initiation of a urate-lowering agent may be less likely to continue therapy. The risk of

mobilization gout has been a hindrance to the optimal use of urate-lowering pharmacotherapy and is a

reason why eligible patients are not treated in a timely manner after experiencing an acute gouty

arthritis attack. The historical strategy used to mitigate the risk of mobilization gout consisted of waiting

several weeks to months after an acute gout attack before initiating serum urate–lowering therapy and

impeded initiation of effective therapy. The 2012 ACR guidelines now recommends initiating

pharmacologic prophylaxis, acute gout prophylaxis, when starting urate-lowering therapy (Figure 3).3

Oral colchicine 0.6 mg once or twice daily (or 0.5 mg, as available outside the United States, once or

twice daily) or low-dose NSAIDs (e.g., naproxen 250 mg twice daily) are first-line options for acute gout

prophylaxis. In patients with an intolerance, contraindication, or refractoriness to both colchicine and

NSAIDs, low-dose corticosteroid therapy (e.g., prednisone ≤ 10 mg daily) may be used as an alternative.3

Acute gout prophylaxis should be continued for 3 months after achieving a serum urate target in

patients without tophi and for 6 months after achieving a serum urate target in patients with one or

more tophi present on physical examination.3 The minimum duration of prophylactic therapy is 6

months for patients in both scenarios.3 Due to the prolonged duration of acute gout prophylaxis

therapy, patients should be carefully monitored for adverse effects during this period. The addition of a

proton pump inhibitor may be necessary in patients treated with low-dose NSAID therapy who are at

high risk of NSAID-associated gastrointestinal bleeding. NSAIDs also have the potential to cause

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 nephrotoxicity, fluid retention, and increased cardiovascular risk. Prolonged corticosteroid therapy can
Accepted Article
cause an array of adverse effects including hyperglycemia, hypertension, mood disorders, osteoporosis,

and Cushing’s syndrome. Thus, both NSAIDs and corticosteroids should be used at their lowest effective

doses.

Three specific medications carry explicit acute gout prophylaxis recommendations in their prescribing

information: pegloticase, lesinurad, and febuxostat. Prophylaxis with an NSAID or colchicine should be

started 1 week prior to pegloticase initiation and continued for at least 6 months.46 All lesinurad studies

included prophylactic colchicine or NSAIDs during the first 5 months of treatment.48 Lastly, acute gout

prophylaxis with an NSAID or colchicine is recommended when initiating febuxostat therapy.41

Conclusion

The burden of gout is significant. Acute gouty arthritis is a very painful and bothersome condition that is

associated with a decreased quality of life. Patients with frequent gout have been associated with more

comorbidities and have significantly higher gout-related health care costs than those with infrequent

gout due to increased use of emergency department, inpatient, and outpatient resources.30

Important developments in the clinical management of gouty arthritis have occurred in recent years.

The ACR/EULAR gout classification criteria provide clinicians with the ability to more specifically identify

patients with acute gouty arthritis. The ACR guidelines provide evidence-based recommendations to

optimize the use of NSAIDS, colchicine, and corticosteroids for the management of acute gout and

prevention of recurrent gout. These guidelines recommend aggressive and target-directed serum urate

lowering as a primary strategy for the prevention of recurrent gouty arthritis, especially for patients with

renal dysfunction. A novel medication, lesinurad, has been introduced to the U.S. market as an add-on

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 therapy to allopurinol in patients who require further serum urate reduction. The need for acute gout
Accepted Article
prophylaxis with daily use of colchicine, low-dose NSAIDs, or prednisone is nearly always recommended

when starting urate-lowering therapy.

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Accepted Article
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Tables

Table 1. Substances That Increase Serum Urate Concentrations8

Diuretics (especially thiazides)

Calcineurin inhibitors (cyclosporine and tacrolimus)

Antituberculosis agents (pyrazinamide and ethambutol)

Cytotoxic chemotherapy agents

Ethanol

Low-dose salicylates (< 2 g/day)

Nicotinic acid

Levodopa

Ribavirin and interferon

Teriparatide

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Accepted Article
Table 2: American College of Rheumatology/European League Against Rheumatism Gout Classification
Criteria for Patients with the Entry Criterion of at Least One Episode of Swelling, Pain, or Tenderness in a
Peripheral Joint or Bursaa,16

Diagnostic Criteria Categories Scoreb

Clinical pattern of joint/bursa involvement Ankle or midfoot (as part of monoarticular or 1
during symptomatic episodes (during any polyarticular episode without involvement of
episode) the first metatarsophalangeal joint)
Involvement of the first metatarsophalangeal 2
joint (as part of monoarticular or polyarticular
episode)
Characteristics of symptomatic episodes (during 1 characteristic 1
any episode): 2 characteristics 2
• Erythema overlying affected joint 3 characteristics 3
• Cannot bear touch or pressure to affected
joint
• Great difficulty with walking or inability to
use affected joint
Time course of episodes (during any episode): 1 typical episode 1
Presence (during any episode) of ≥2, Recurrent typical episodes 2
irrespective of antiinflammatory treatment:
• Time to maximal pain <24 hours
• Resolution of symptoms in <14 days
• Complete resolution between symptomatic
episodes
Clinical evidence of tophus: Present 4
Draining or chalk-like subcutaneous nodule
under transparent skin, often with overlying
vascularity, located in typical locations: joints,
ears, olecranon bursae, finger pads, tendons
(e.g., Achilles)
Laboratory: <4 mg/dL -4
Serum urate level measured by uricase method 6–8 mg/dL 2
(ideally when not receiving urate-lowering 8 to <10 mg/dL 3
treatment and >4 weeks from the start of an ≥10 mg/dL 4
episode; if practical, retest under those
conditions); use highest value irrespective of
timing for scoringc
Synovial fluid analysis of a symptomatic (during Monosodium urate monohydrate negative -2
any episode) joint or bursac, d
Imagingc:
Imaging evidence of urate deposition in Present (either modality) 4
symptomatic (ever) joint or bursa: ultrasound

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 evidence of double-contour sign or dual-energy
Accepted Article
computed tomography demonstrating urate
deposition
Imaging evidence of gout-related joint damage: Present 4
Conventional radiography of the hands and/or
feet demonstrates at least 1 erosion

a
A Web-based calculator can be accessed at http://goutclassificationcalculator.auckland.ac.nz and
through the American College of Rheumatology and European League Against Rheumatism Web sites.
b
A total score of 8 or higher (of a maximum possible score of 23) indicates a positive gout diagnosis.
c
If the serum urate level is ≥ 4 to < 6 mg/dL, the score is 0
d
If not available or not performed, the score is 0.
e
Patients with the presence of monosodium urate monohydrate crystals in a symptomatic joint or bursa
(i.e., in synovial fluid) or tophus are considered to have a sufficient diagnostic criterion (if met, can
classify as gout without applying criteria above).

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ccepted Articl
Agent
Table 3: Summary of Select Pharmacotherapy for the Treatment and Prevention of Gout
Use in Gout Dosing Contraindications Comments
Management
NSAIDs Acute gouty Full antiinflammatory dose (e.g., naproxen 500 mg Hypersensitivity, aspirin- or Naproxen, indomethacin, and sulindac
arthritis orally twice daily; naproxen sodium 825 mg initially, NSAID-induced asthma or are FDA approved agents for gout; all
then 275 mg orally every 8 hours) urticaria, aspirin triad (nasal NSAIDs are effective at antiinflammatory
polyps, asthma, and aspirin doses
Acute gout Low dose intolerance), third trimester of
prophylaxis (e.g., naproxen 250 mg orally twice daily) pregnancy, perioperative use
during CABG surgery

Use with caution in patients with

cardiovascular disease, renal
impairment, hepatic impairment,
and history of gastrointestinal
bleeding
Colchicine Acute gouty 1.2 mg orally at the first sign of a flare, followed by 0.6 Patients with renal or hepatic Use only when onset of gout attack
arthritis mg 1 hour later; maximum dose = 1.8 mg over 1 hour impairment should not be given within 36 hours
colchicine in conjunction with P-
Dose adjustment: gp or strong CYP3A4 inhibitors Drug interactions:
• Renal impairment: CrCl < 30 mL/min, do not repeat (including all protease inhibitors Strong CYP3A4 inhibitors (see dose
course more than once every 2 weeks except fosamprenavir) adjustment):
• Dialysis: Single dose of 0.6 mg orally; do not repeat • Atazanavir
course more than once every 2 weeks Use with caution in patients with • Clarithromycin
• Hepatic impairment: do not repeat course more blood dyscrasias or hepatic or • Darunavir/ritonavir
than once every 2 weeks renal impairment • Indinavir
• Concomitant strong CYP3A4 inhibitors: 0.6 mg • Itraconazole
orally for 1 dose, followed by 0.3mg orally 1 hour • Ketoconazole
later; do not repeat dose earlier than 3 days • Lopinavir/ritonavir
• Concomitant moderate CYP3A4 inhibitors: 1.2 mg • Nefazodone
orally for 1 dose; do not repeat dose earlier than 3 • Nelfinavir
days • Ritonavir
• Concomitant P-gp inhibitors: 0.6 mg orally for 1 • Saquinavir
dose; do not repeat dose earlier than 3 days • Telithromycin
Acute gout 0.6 mg orally once or twice daily; maximum dose = 1.2 • Tipranavir/rRitonavir
prophylaxis mg/day
a
The capsule formulation of colchicine (Mitigare ) is only

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ccepted Articl approved for acute gout prophylaxis

Dose adjustment:
Moderate CYP3A4 Inhibitors (see dose
adjustment):
• Amprenavir
• Renal impairment: if CrCl < 30 mL/min, 0.3 mg/day • Aprepitant
orally initially; increase dose with adequate • Diltiazem
monitoring • Erythromycin
• Dialysis: 0.3 mg 2 times a week; monitor closely • Fluconazole
• Hepatic Impairment: if severe, consider dose • Fosamprenavir
reduction • Grapefruit juice
• Concomitant strong CYP3A4 inhibitors: 0.3 mg • Verapamil
orally every other day to 0.3 mg orally once a day
• Concomitant moderate CYP3A4 inhibitors: 0.3 mg P-gp Inhibitors (see dose adjustment):
to 0.6 mg orally once a day • Cyclosporine
• Concomitant P-gp inhibitors: 0.3 mg orally every • Ranolazine
other day to 0.3 mg orally once a day
Statins, fibrates and digoxin: weigh
risk/benefit; monitor for muscle-related
complications
Corticosteroids Acute gouty Weight-based prednisone or prednisolone: Hypersensitivity, systemic fungal
arthritis • At least 0.5 mg/kg orally per day for 5–10 days, infection
then discontinue
Or Use with caution in patients with
• At least 0.5 mg/kg orally per day for 2–5 days, gastrointestinal disorders,
followed by tapering for 7–10 days, then cirrhosis, osteoporosis, ocular
discontinue herpes simplex, glaucoma,
psychiatric derangements, renal
Methylprednisolone dose pack: insufficiency, active tuberculosis,
• Start 24 mg orally daily, taper by 4 mg per day over recent myocardial infarction,
6 days per package instructions heart failure
Acute gout Low dose prednisone or prednisolone:
prophylaxis • ≤ 10 mg orally daily
Allopurinol Recurrent FDA-approved dosing: Hypersensitivity, concomitant use Consider HLA-B*5801 testing in Koreans
gout • Mild: 100-300 mg/day orally as a single or divided with didanosine with stage 3 or worse chronic kidney
prevention dose (2-3 times daily) disease and in Han Chinese and Thai
Use with caution in patients with populations due to increased risk of
• Moderate to severe: 400-600 mg/day orally as a hepatic or renal impairment allopurinol hypersensitivity syndrome; if
single or divided dose (2-3 times daily); maximum HLA-B*5801 is positive, avoid use of

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ccepted Articl dose = 800 mg/day allopurinol

Significant drug interactions:

ACR-recommended dosing:
• Didanosine: contraindicated
• Start at no greater than 100 mg orally daily; titrate
• Azathioprine
dose every 2–5 weeks to an appropriate maximum
• Cyclophosphamide
dose to achieve serum urate target
• Captopril
FDA dose adjustment: • Enalapril
• Mercaptopurine
• Renal impairment:
o CrCL 10–20 mL/min: 200 mg daily • Pegloticase
o CrCL 3–10 mL/min: 100 mg daily • Warfarin
o CrCL < 3 mL/min: 100 mg at extended intervals
> every 24 hours

ACR-recommended dose adjustment:

• Renal impairment: if CrCl < 30 ml/min, start at 50
mg daily; titrate dose every 2–5 weeks to an
appropriate maximum dose for gout to achieve
serum urate target; doses may be raised above 300
mg daily if accompanied by adequate patient
education and monitoring for drug toxicity
(pruritus, rash, elevated hepatic enzyme levels)
Febuxostat Recurrent 40 mg orally once daily; may be increased to 80 mg Concomitant use of azathioprine Febuxostat 120 mg is approved in many
gout orally once daily if serum uric acid level < 6 mg/dL is not or mercaptopurine countries outside the U.S.
prevention achieved after 2 weeks
Use with caution in patients with
cardiovascular disease, malignant
disease, Lesch-Nyhan syndrome,
hepatic impairment
Lesinurad Recurrent 200 mg orally once daily in the morning with food and Severe renal impairment, end- Coadministration of lesinurad and
gout water; maximum dose = 200 mg/day; give at the same stage renal disease, kidney hormonal contraceptives, including oral,
prevention time of the day with a xanthine oxidase inhibitor transplant recipients, dialysis, injectable, transdermal, and implantable
including allopurinol (at least 300 mg/day or 200 tumor lysis syndrome, Lesch- forms, may result in decreased
mg/day if CrCl < 60 mL/min) or febuxostat Nyhan syndrome effectiveness of the contraceptive;
additional methods of contraception are
Dose adjustment: Use with caution in patients with recommended
• Renal impairment: cardiovascular disease,

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ccepted Articl o Serum creatinine concentration > 2 times
pretreatment level: interrupt therapy, and do
not reinitiate unless another cause is identified
urolithiasis, or renal and hepatic
impairment, and in patients
taking concomitant valproic acid
o CrCl persistently < 45 mL/min: discontinue use
o CrCl < 30 mL/min: use is contraindicated
• Dialysis: use is contraindicated
• Severe hepatic impairment: use not recommended
NSAID = nonsteroidal antiinflammatory drug; CABG = coronary artery bypass graft; FDA = U.S. Food and Drug Administration; CrCl = creatinine
clearance; CYP = cytochrome P450; P-gp = P-glycoprotein; ACR = American College of Rheumatology.
a
West-Ward Pharmaceuticals, Eatontown, NJ

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 Table 4: American College of Rheumatology Dietary Recommendations for Preventing Recurrent Gouty
Accepted Article
Arthritis2

Avoid

• Organ meats high in purine content (e.g., sweetbreads, liver, kidney)

• High-fructose corn syrup–sweetened sodas, other beverages, foods

• Alcohol overuse (> 2 servings per day for men, > 1 for women) in all patients with

gout

• Alcohol during periods of frequent gout attacks or advanced gout under poor control

Limit

• Serving sizes of beef, lamb, pork, and seafood with high purine content (e.g., sardines,

shellfish)

• Servings of naturally sweet fruit juices

• Table sugar, sweetened beverages and desserts

• Alcohol (particularly beer, but also wine and spirits) in all patients with gout

Encourage

• Low-fat or nonfat dairy products

• Vegetables

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Accepted Article
Figure 1. Purine metabolism pathway. Increased activity of phosphoribosyl pyrophosphate
ate (PRPP)

synthetase promotes the conversion of ribose 5-phosphate to PRPP, potentially leadingg to

overproduction of uric acid. Decreased activity of hypoxanthine-guanine phosphoribosyltransferase

yltransferase

(HGPRTase) can lead to overproduction of uric acid by promoting the conversion of guanine
anine and

hypoxanthine to xanthine instead of coupling with PRPP to convert these purines into nucleic acid.

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 Figure 2: Management of an acute gout attack. NSAID = nonsteroidal antiinflammatory drug.
Accepted Article

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 Figure 3: American College of Rheumatology–recommended pharmacotherapy for acute
te gout
Accepted Article
prophylaxis. NSAID = nonsteroidal antiinflammatory drug.

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