Clinical Therapeutics/Volume 39, Number 2, 2017

Commentary

Limitations of the Current Standards of Care forTreating Gout and Crystal Deposition in thePrimary Care Setting: A Review

Robert T. Keenan, MD, MPH

Department of Medicine, Division of Rheumatology and Immunology, Duke University School of Medicine,Durham, North Carolina

Accepted for publication December 13, 2016.http://dx.doi.org/10.1016/j.clinthera.2016.12.0110149-2918/$ - see front matter

& 2017 The Authors. Published by Elsevier HS Journals, Inc. This is anopen access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

ABSTRACT

Purpose: This article outlines several importantissues regarding the management of patients withgout. The topics discussed include best practices forgout based on the most current guidelines, opportu-nities for improving gout management, and currentand emerging therapies for gout.

Methods: [PubMed and Google Scholar databases]were search for all articles and trials published before2016, using the key terms [hyperuricemia, gout, tophi,joint erosion, joint damage, treatment guidelines, Amer-ican College of Rheumatology (ACR), European LeagueAgainst Rheumatism (EULAR), flare, comorbidity,epidemiology, adherence, serum uric acid (sUA), mono-sodium urate (MSU), o6 mg/dL, MSU crystal forma-tion, as well as individual drug names and classes oftreatments of interest (allopurinol, febuxostat, colchicine,non-steroidal anti-inflammatories (NSAIDs)]. Studieswere selected that presented data on gout treatment,including drugs under development, and on the manage-ment of gout from both the physician and patientperspectives. The reference lists of identified articles weresearched manually for additional publications.

Findings: Gout, a progressive debilitating form ofinflammatory arthritis, is caused by factors thatelevate serum uric acid (sUA) levels, leading to hyper-uricemia. Continued elevated sUA can result in mono-sodium urate crystal deposition in joints and softtissues, causing acute and chronic inflammation.Crystal deposition can lead to chronic gout, with anincreased number of flares, tophi development, andstructural joint damage. The aims of gout treatmentare to reduce the sUA level to o6 mg/dL, to inhibitthe formation of new crystals, and to promote thedissolution of existing crystals. Gout is often poorly

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managed for several reasons, including a lack ofadherence to treatment guidelines by health careproviders, patients’ poor adherence to therapy, anddifferences between a provider’s and patient’s per-spectives regarding treatment.

Implications: Patients need to be educated abouttheir diagnosis and management of the disease, suchas the importance of compliance with long-termtreatment. Gout treatment may also confounded bycontraindications to current standards of therapy andthe limitations of current treatment paradigms. Re-cently approved medications, as well as drugs underdevelopment, may provide new ways for reaching thesUA target and also “curing” the disease. (Clin Ther.2017;39:430–441) & 2017 The Authors. Published byElsevier HS Journals, Inc.

Key words: gout, hyperuricemia, serum uric acid,treatment, uricosuric drugs, xanthine oxidase inhibitors.

INTRODUCTIONThis article outlines several important issues regardingthe management of patients with gout. The topicsdiscussed include best practices for gout based on themost current guidelines, opportunities for improvinggout management, and current and emerging therapiesfor gout.

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0<6.0 6.0-6.9 7.0-7.9 8.0-8.9 9.0-9.9 ≥10

Serum uric acid (mg/dL)

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Figure 1. Five-year cumulative incidence of goutaccording to serum uric acid level inmen in the Normative Aging Study.9

Reproduced with permission.10

Figure 2. Arthroscopy of the knee of a patientwho was thought to have had his goutunder control given the absence of

R.T. Keenan

MATERIALS AND METHODSFor this review, PubMed and Google Scholar data-bases were search for all articles and trials publishedbetween 1999 and 2016, using the key terms hyper-uricemia, gout, tophi, joint erosion, joint damage,treatment guidelines, American College of Rheuma-tology (ACR), European League Against Rheumatism(EULAR), flare, comorbidity, epidemiology, adher-ence, serum uric acid (sUA), monosodium urate(MSU), o6 mg/dL, MSU crystal formation, as wellas individual drug names and classes of treatments ofinterest (allopurinol, febuxostat, colchicine, non-ster-oidal anti-inflammatories (NSAIDs). Studies wereselected that presented data on gout treatment, in-cluding drugs under development, and on the manage-ment of gout from both the physician and patientperspectives. The reference lists of identified articleswere searched manually for additional publications.

flares despite his serum uric acid(sUA) concentration being above therecommended target of o6 mg/dL.The patient presented with redness,warmth, swelling, pain, and drainingat the arthroscopy surgical incisionsite 8 weeks after surgery. Note thesignificant intra-articular crystal de-position (tophus formation) and thebackground synovial inflammation(lower right and left). & Robert T.Keenan, MD, MPH.

RESULTSBackground and Epidemiology

Gout is the most common inflammatory arthritis inthe United States, affecting 8.3 million adults (�4%),while hyperuricemia, the root cause of gout, affects43.3 million (�21%).1,2 The prevalence of gout in theUnited States increased 2-fold between the 1960s andthe 1990s, with further increases anticipated over thenext several decades.1 Considering this increase, andthe multiple comorbid conditions associated with gout,

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it may be of no surprise that there has been a rise in thecosts of care of patients with gouty arthritis. During2005 to 2011, the estimated costs of all-cause gout,which include the costs of emergency departmentvisits, ambulatory care visits, inpatient stays, prescrip-tion medications, and other costs (eg, home healthcare), was $31.8 billion.3 In 2008, gout was the reasonfor �175,000 emergency department visits,accounting for �0.2% of all visits that year, and in2002 gout was associated with 3.9 million ambulatorycare visits, �40% of cases of which were treated byprimary care providers (PCPs).4 Gout can have asignificant impact on a person’s life, and refractorygout, in which signs and symptoms are poorlycontrolled, is associated with a significant loss of theability to perform daily activities, a loss of workproductivity, and a low health-related quality of life.5,6

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Dietary purineload

Endogenouspurinesynthesis

Urate level

Renalexcretion

Gut

Urate supersaturationand crystallization

Gout

Figure 3. Gout is mediated by the supersatura-tion and crystallization of uric acidwithin the joints. The amount of uratein the body depends on the balancebetween dietary intake, synthesis, andexcretion. Hyperuricemia results fromthe overproduction of urate (10%),from underexcretion of urate (90%),and often from a combination of thetwo. Approximately one third of urateelimination occurs in the gastrointest-inal tract, with the remainder excretedin the urine. Reproduced withpermission.17.

Clinical Therapeutics

Gout is characterized by the deposition of mono-sodium urate (MSU) crystals resulting from hyper-uricemia, defined as a serum uric acid (sUA)concentration that exceeds the point of physiologicsaturation of sUA (�6.8 mg/dL in vitro, at 371C andpH 7.4).7,8 Hyperuricemia is the greatest risk factorfor the development and prevalence of gout, whichresults from the crystallization, deposition, and aggre-gation of MSU crystals in the joints and soft tissue,such as the kidneys (Figure 1).7,10 Once crystaldeposition occurs, an inflammatory response ensues,causing low-level or subclinical inflammation resultingin bone erosion and soft tissue destruction.11,12 Beforethe development of clinically evident tophi, this on-going crystal deposition may be apparent only with

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advanced imaging techniques, such as dual-energycomputed tomography, computed tomography, orultrasonography (Figure 2).7,13–15 The episodic natureof acute flares can be misleading because continuingdamage, due to persistent MSU crystal deposition andinflammation, can occur during intercritical (asymp-tomatic) periods.15 Chronic gout typically developsafter years of acute episodic gout, and is indicated by aloss of intermittent pain-free periods.2,3

Only �22% of patients with asymptomatic hyper-uricemia develop gout, depending on age, dietarytendencies, and the presence of comorbid conditions,such as renal insufficiency, congestive heart failure,hyperinsulinemia, and obesity.16 In boys,hyperuricemia can begin just after puberty, and inhealthy women, it usually does not develop untilmenopause, indicating the role that the sexhormones play in urate regulation.2 Additionally,certain medications and even osteoarthritis and jointdamage may play active roles in the promotion ofhyperuricemia and the development of gout.2

Urate levels are in part, determined by how muchthe body produces and how much it is able toeliminate, with decreased renal excretion being theprimary cause of increased sUA levels in �90% ofpeople (Figure 3).17,18 In a healthy person, �10% ofuric acid filtered by the glomerulus is excreted in theurine.2 The rest is reabsorbed via organic aniontransporters, such as urate transporter (URAT)-1,organic anion transporters 4 and 10, and glucosetransporter 9. The most important of the transporterswith respect to urate levels is URAT1.2

Current Clinical Targets as per Clinical PracticeGuidelines on Gout Management

Crystal formation is reversible, which means thatgout can be “cured.” The crystals will dissolve whensUA levels drop to below the limit of solubility (ie, 6.8mg/dL).19,20 The lower the sUA level, the faster thecrystal deposition (and tophi) will resolve.21 Therefore,the goal of therapy is to lower the sUA level to belowthe limit of solubility (sometimes well below). TheAmerican College of Rheumatology (ACR) and theEuropean League Against Rheumatism recommend aminimum sUA target of o6 mg/dL22,23 and a lowertarget (o5 mg/dL) to improve gout signs and symp-toms in patients with more severe disease.23,24 TheBritish Society of Rheumatology recommends a targetof o5 mg/dL in all patients with gout.25

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Establish diagnosis of gout

Baseline recommendations for patients diagnosed with goutPatient education, with initiation of diet, lifestyle recommendationsConsider secondary causes of hyperuricemia (eg, comorbidities)Consider elimination of non-essential prescription medications that inducehyperuricemiaClinically evaluate gout disease burden (palpable tophi, frequency and severity of acute and chronic gout symptoms

Assess whether pharmacologic urate-lowering therapy is necessary

Presence of tophus or tophiFrequent flaresStage 2 or greater kidney diseasePast urolithiasis

If pharmacologic urate-lowering therapy is necessary TREAT TO SERUM URATE TARGET(<6 mg/dL)

Select first-line therapy: xanthine oxidase inhibitors (allopurinol or febuxostat) ifxanthine oxidase inhibitors contraindicated or not tolerated, alternative first line:probenecidAcute gout prophylaxis: initiate concurrent pharmacologic anti-inflammatory goutattack prophylaxis

Once achieved TARGET (6 mg/dL) - long-term management of gout

Continue gout attack prophylaxisContinue to regularly monitor serum urate even after palpable tophi and all acute and chronic gout symptoms have resolvedIf necessary, refer patient to a specialist (unclear hyperuricemia etilology, refractory signsand symptoms, difficulty in reaching target serum urate levels, multiple or servere adverseevents for pharmacologic treatment

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Interventions targeting adherencePatient education & self-management trainingMedication titration

Patient factorsBarriers

Younger ageFewer comorbiditiesEthnic populationsConcerns about ULT effectiveness, side effects, polypharmacy

FacilitatorsPain and prevention of flaresMedication as part of daily routine

Healthy System factorsBarriers

Prescription costs

Physician factorsBarriers

Low rates of ULT prescription Failure to co-prescribeprophylactic when initiating ULTMinimal referral to specialistsfor gout management

Medication adherence

Recent estimates:40% to 88%

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•

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A

B

Figure 4. Gout treatment and treatment barriers. A, American College of Rheumatology treatment algorithmfor gout. Adapted with permission.23 B, Barriers to long-term gout treatment adherence. ULT ¼urate-lowering therapy. Adapted with permission.33.

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Table. Reasons for hyperuricemia.

Impaired uric acid excretionPrimary gout with decreased uric acid clearanceSecondary gout

Clinical conditionsReduced GFRHypertensionObesitySystemic acidosisFamilial juvenile hyperuricemicnephropathyMedullary cystic kidney diseaseLead nephropathy

DrugsDiureticsEthanolLow-dose salicylates (0.3–3.0 g/d)CyclosporineTacrolimusLevodopa

Excessive urate productionPrimary metabolic disorders

HPRT deficiencyPRPP synthetase overactivityGlucose-6-phosphatase deficiencyFructose-1-phosphate aldolase deficiency

Secondary causesClinical conditionsMyelo- and lymphoproliferative disordersObesityPsoriasisGlycogenoses III, V, VII

Drugs and dietary componentsNicotinic acidPancreatic extractCytotoxic drugsRed meat, organ meat, shellfishAlcoholic beverages (especially beer)Fructose

GFR ¼ glomerular filtration rate; HPRT ¼hypoxanthine-guanine phosphoribosyltransferase; PRPP¼ phosphoribosyl pyrophosphate.Adapted with permission.18

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Gout treatment should improve disease outcomes byeliminating gout flares, by inducing long-term resolutionof tophi, and by effectively managing comorbidities,many of which promote hyperuricemia.23,26 The ACRrecommends both nonpharmacologic and pharmaco-logic approaches to treating the disease (Figure 4A).27

Nonpharmacologic approaches include educatingpatients about lifestyle changes that reduce the risk forflares, such as losing weight and avoiding "trigger"foods that are rich in purines (eg, beer, shrimp, redmeat).23,28 Patients need education about treatmentobjectives and about the management of comorbid-ities,23 and should discontinue nonessential prescriptiondrugs that elevate sUA (Table).18,23

Following nonpharmacologic approaches, theACR recommends an evaluation for the use ofurate-lowering therapy (ULT),23 which may beappropriate in patients with the following: tophus ortophi (verified by clinical examination or imagingstudy), Z2 gout flares per year, stage Z2 chronickidney disease, and/or previous urolithiasis.23 Anindividual’s risk for further gouty attacks, existingdamage from tophi and/or associated disability,medication/treatment preference, and relative risks ofavailable treatments should also be considered.25

First-line therapy involves xanthine oxidase inhib-itors (XOIs; eg, allopurinol or febuxostat), or, ifnecessary due to poor tolerability or contraindica-tions, alternative therapy (eg, probenecid).23 If an sUAlevel of o6 mg/dL is not achieved with an XOI, theULT dose can be increased, or a uricosuric, such asprobenecid, may be added.23 Pegloticase can beconsidered for severe or refractory disease or inpatients who are intolerant to appropriately dosedoral therapy.23,27 When ULT is started, prophylaxistreatment, which may include NSAIDs and low-dosecolchicine, should also be initiated to reduce theincreased risk for acute gouty attacks during the earlyphase of treatment.23,27 If a patient cannot take one ofthese drugs (eg, due to a contraindication), or if apatient is not responding to flare prevention, then alow-dose glucocorticoid can be used instead.27 Oncethe target of o6 mg/dL is achieved, long-term main-tenance ULT is prescribed to keep the sUA level o6mg/dL, and flare prophylaxis treatment should con-tinue for at least 6 months, or 6 months after the last

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flare, whichever is longer.23,27 sUA levels should bemonitored every 2 to 5 weeks (in addition to liverfunction testing, creatinine measurement, and com-plete blood counts) while the ULT dose is titrated.After the target sUA has been reached and no ULTdose adjustments are needed, laboratory monitoringcan be performed every 6 months.

Health care providers may also consider treatmentin patients who might not meet all of the criteria forULT as defined in the guidelines. For example, apatient who experiences flares only once per year,but who has an sUA level of 49.0 mg/dL, maybenefit from ULT because increased flares and dis-ability are more likely over time. In addition, somepatients with chronic or recurrent gout plus otherconditions will require tailored management requir-ing a specialist, such as elderly patients (475 yearsof age, multiple comorbid conditions, on CYP3A4inhibitors) and those with renal insufficiency, under-lying myeloproliferative disease, or rare inheriteddisorders.25

Maintaining a level of sUA o6 mg/dL can helpreduce the occurrence of flares, inhibit furtherMSU crystal deposition, prevent tophi formation,and accelerate dissolution of tophi.8 It also can alterprogression of radiographic changes and possiblyimprove bone erosions, but not structural changes tocartilage.29

Barriers to Treatment Success and Unmet Needsfor Better Treatment Options

Although effective treatment options for gout areavailable and the disease is well understood, gout isoften poorly managed.10 For example, in a study in400 patients treated with allopurinol for symptomaticgout, 36% had a urate level of Z6 mg/dL at screeningand required a dose increase.30 A recent 12-monthretrospective study of data from the clinics of 124PCPs and 125 rheumatologists managing 41200patients over the course of 12 months found thatdisease control, defined as an sUA of o6 mg/dL, noflares, and no tophi, was achieved in only 11% ofpatients.31 In a 6-month, multicenter, open-label,uncontrolled observational study in patients withgout that allowed for a titration of allopurinol fromo300 to 4300 mg/d, a target sUA of o6.0 mg/dLwas achieved in 35.9% of patients.32 The studyrevealed that an obstacle to treating to target wasunderdosing of allopurinol.32

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Patients’ Treatment AdherenceThere are several challenges with regard to treating

and managing gout (Figure 4B).15,33 Studies haveshown that patients and providers are both involvedin suboptimal outcomes. Two retrospective studiesfound that �14% to 56% of patients who werestarted on ULT were nonadherent, particularly thosewho were younger (o45 years of age), had fewercomorbidities, and/or had not visited a health careprovider before the gout developed.34,35 A systematicreview of data from electronic prescription recordsacross 10 studies found that adherence rates rangedfrom 10% to 46%, which is below the World HealthOrganization’s estimate that 50% of adults adhere tolong-term therapy across the chronic disease spec-trum.36,37 However, increased adherence rates wereassociated with older age and comorbid hyperten-sion.36 Further reasons for poor adherence included alack of education and understanding about how totake the medication, and about how the medicationfits into disease management. Additional reasons forpoor adherence included the lack of financialresources and the lack of self-motivation for takingmedication regularly.33,38 Other barriers to patients’gout management are the feeling/belief that a drug isineffective, confusion about whether ULT is for acuteflares versus chronic prophylaxis of flares, copaymentcosts, adverse events with medication use, and con-cerns regarding taking multiple medications on thesame day.33 One US study found that patients had alack of awareness about the duration of therapy,about the role of allopurinol in treatment(prevention vs pain relief), and/or about whattriggers a gout flare, and that they were unhappywith the information provided by their health careprofessionals.39 Another US study found that patientsalso had a poor understanding about dietary triggersand about the need for long-term use of medica-tions.38 These studies illustrate the need for betterpatient education about gout management and itsshort- and long-term implications.

Health Care Providers’ Adherence to ClinicalPractice Guidelines

Rheumatologists and PCPs have less-than-optimaloverall adherence to treatment guidelines, particularlywith regard to first-line ULT and duration of prophy-lactic treatment.40,41 For example, a comprehensivequantitative US survey that assessed PCPs’ (n = 120)

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and rheumatologists’ (n = 71) adherence to the ACRguidelines found that 53.7% of PCPs and 35.3% ofrheumatologists had low adherence, defined as follow-ing r4 of the 8 ACR treatment recommendations,and only 36.4% and 35.2%, respectively, prescribedthe recommended initial ULT dose.40 Another studyshowed that only �50% of patients with acute goutflares received treatment that was consistent with theguideline recommendations, and o20% of patientswith intercritical (the time between acute flares) andtophaceous gout were managed according toguidelines.41 Prophylaxis to prevent acute attacks inpatients with tophaceous gout before or at the time ofULT initiation was implemented in only �17% ofcases. The lack of compliance with guidelines waslargely accounted for by inappropriate dosing ofmedications in the setting of renal disease and by alack of prophylaxis when initiating ULT.41 There wasalso poor compliance with the recommendations ofpatient education and lifestyle counseling.41 The samestudy reported that only a quarter to a third of PCPsmonitored sUA levels as recommended by theguidelines, raising questions about whether providersare treating to the sUA target of o6 mg/dL.41 Theappropriate medication was not being prescribed inpatients who were candidates for ULT, resulting inpreventable gouty flares with associated morbidityand hospitalizations.41 The suboptimal treatment ofgout may in part reflect a poor understanding ofhyperuricemia and gout on the part of health careproviders, due to infrequent medical education,insufficient evidence-based medicine, and, for thosein busy practices, a lack of motivation to relearnthe disease.42 Additional challenges occur withthe presence of comorbidities and drug–druginteractions. One study found that, in a cohort ofpatients meeting the ACR’s criteria for gout (N ¼575), 490% had at least 1 contraindication toNSAIDs; 43%, to allopurinol; �50%, to colchicine;and 94.4%, to glucorcorticoids.43

Patient–Provider Discordance Regarding Perceptionsabout the Disease and Its Treatment

Differences between health care providers andpatients with regard to perceptions about gout andits treatment can also influence care. One study fromthe United States examined patients’ and providers’views on the treatment of gout to provide insightinto why gout management is suboptimal.39

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The investigators found that health care providersthought that the majority of patients had excellentrelief with NSAIDs, colchicine, and/or glucocorticoids,although some patients believed that the medicationswere ineffective.39 In addition, most providers thoughtthat patients had a good understanding of therationale for ULT and that patients responded wellto treatment, whereas patients believed that ULTworsened, triggered, or had no impact on theirdisease.39 Most providers also believed that therapyadherence was good; however, a number of patientsdiscontinued their medication due to financial and/orclinical concerns, such as the belief that treatmentworsened the disease or that medications wereineffective.39 Providers believed that they adequatelyeducated their patients about disease management,whereas most patients indicated that they hadrequested additional information. Finally, mostproviders were not aware of the difficulties thatpatients have with gout treatment, such as financialconcerns, adverse events with medication use,inadequate symptom relief, and a lack ofinformation from their health care providers.39

Current Treatment OptionsCurrently, ULT options are limited and may be

contraindicated in many patients with gout. It iscommon for gout flares to occur on initiation ofULT or when a dose is increased, thus the ACR’sguidelines recommend concurrent anti-inflammatoryprophylaxis for a minimum of 6 months.23,44 Colchi-cine and NSAIDs are first-line prophylactic anti-inflammatory treatment, and low-dose prednisoloneis second line.45 An interleukin-1 blocker may be usedin patients with frequent flares and contraindicationsto colchicine, NSAIDs, and/or corticosteroids. Theanti–interleukin-1β monoclonal antibody canakinu-mab has been approved for this indication inEurope46; however, it has not been approved by theUS Food and Drug Administration.

Although 490% of hyperuricemia is due to renalunderexcretion,18 the first-line ULTs, allopurinol andfebuxostat, address uric acid production. The ACRrecommends a 100-mg/d starting dose of allopurinol,with gradual up-titration every 2 to 4 weeks until thetarget serum urate level is achieved.23 In patients withchronic kidney disease, treatment should be started ata low dosage (50 mg/d) and increased more slowlythan in patients without renal function impairment.23

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Historically, patients with chronic kidney disease wereconsidered to be at greater risk for toxicity withallopurinol use because oxypurinol, a metabolicproduct of allopurinol, is cleared by the kidney.47

However, a recent study found that allopurinol wasnot associated with an increased risk for renalfunction deterioration in patients with gout.48

A study by Stamp et al49 found that a high startingdose of allopurinol rather than the maximum dose,regardless of renal function, was a risk factor forallopurinol hypersensitivity syndrome, which is rarebut has been associated with a mortality rate of27%.50 Patients of Han Chinese and other Asiandescent and having the HLA-B*5801 genotype havean increased risk for allopurinol hypersensitivitysyndrome and should be screened for the allele prior toinitiating allopurinol treatment.23,24 A number of otheradverse events, such as nausea or vomiting, rash, andStevens-Johnson syndrome, have also been associatedwith allopurinol use.50

Febuxostat, in contrast to allopurinol, is not apurine analogue. The recommended starting dosageis 40 mg once daily.51 In patients who do not achievean sUA of o6 mg/dL after 2 weeks at 40 mg, 80 mg/dis recommended.52 Febuxostat is eliminated by boththe hepatic and renal pathways, and no doseadjustments are needed in patients with mild tomoderate hepatic or renal impairment. It has beenassociated with limited drug interactions, but with astatistically nonsignificant increase in cardiovascularevents.44,50

Uricosuric agents such as probenecid, sulfinpyra-zone, and benzbromarone were introduced for thetreatment of gout before the availability of allopur-inol. Benzbromarone was withdrawn from the USmarket by the original manufacturer due to potentialhepatotoxicity, and the availability of sulfinpyrazoneworldwide is limited. As a result, probenecid is theonly uricosuric readily available in the United States;however, probenecid has been associated with drug–drug interactions, some of which are related to itsability to block the renal tubular transport of acidicdrugs.53 Despite its declining use in the United Statesand abroad, probenecid is still used by some patientswith gout. Caution is required when prescribinguricosurics in patients with a history of kidney stones,as uricosurics can precipitate uric acid stones.44

In 2010, the US Food and Drug Administrationapproved the use of pegloticase. Unlike other ULTs

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that either block the production or increase theexcretion of uric acid, pegloticase is unique in that itprovides the absent enzyme, uricase, that catalyzes theoxidation of uric acid into allantoin, which is moresoluble than uric acid and allows for easier excretionby the kidney. The oxidative products of hydrogenperoxide and carbon dioxide are the byproducts ofthis lost conversion process in humans and primates.53

Due to the rapid urate reduction with pegloticase, itsuse has been associated with a significant prevalenceof acute flares even in the presence of prophylactictreatment.54 In studies, infusion reaction–relatedadverse events occurred in about 26% to 41% ofpatients and included flushing, chest discomfort, anddyspnea.55,56 Infusion reactions were particularlymore common in patients in whom a high level ofantipegloticase antibodies developed.55

Treatment guidelines recommend combinationtherapy (uricosuric plus an XOI) when treatmentgoals are not achieved with single-agent XOI, orpegloticase for severe, refractory chronic gout.23

Using drug combinations that reduce uric acidproduction and increase renal excretion target the 2etiologies of the disease, which may more effectivelyreduce the concentration of sUA to o6 mg/dL.57

Pegloticase may be a viable option in cases in whichthe target sUA is not reached or gouty arthritis anddisability persist.23

New Treatment OptionsA number of new uricosuric agents that may be

more efficacious in reducing sUA levels are beingdeveloped for treating gout.58 Lesinurad wasrecently approved by the US Food and DrugAdministration for use as an adjunct therapy withan XOI. Lesinurad works by inhibiting URAT1 in thekidney, thereby increasing uric acid secretion.58,59 Theprevalence of renal related adverse events, includingthose resolved, occurred in 5.9% of lesinurad 200 mgþ allopurinol and 4.9% of allopurinol-alone groups.In the lesinurad 400 mg þ allopurinol group, 15.0%had either a permanent or temporary increase inserum creatinine.60 Lesinurad 200 mg with axanthine oxidase inhibitor was approved by theFDA, while the 400 mg dose was not. Lesinurad hasbeen associated with adverse events related to renalfunction, including transient elevations in creatinineand kidney stones. In clinical studies, an elevation ofserum creatinine to 2-fold above baseline level was

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observed in some patients, but most cases resolvedwithout treatment adjustment.50,61 Lesinurad use iscontraindicated in patients with severe renal impair-ment (estimated creatinine clearance o30mL/min), tumor lysis syndrome, or Lesch-Nyhansyndrome.61 Other common adverse events includedheadache, influenza, and gastroesophageal refluxdisease.62 Arhalofenate is in Phase III clinicaldevelopment for use in fixed-dose combination withfebuxostat as a once-daily, oral gout treatment.Arhalofenate has dual mechanisms of action that lowersUA levels by inhibiting URAT1 and decrease inflam-mation by limiting interleukin-1β production.58

RDEA3170 is a URAT1 inhibitor in Phase II clinicaldevelopment for use as monotherapy or in combinationwith febuxostat.58 URC102 is another URAT1inhibitor in Phase II clinical development in Korea.63,64

CONCLUSIONSGout is the most common inflammatory arthritis inthe United States, causing significant disability andmorbidity, and is characterized by underlying hyper-uricemia, MSU crystal deposition, and recurrentflares. Even when patients are asymptomatic and freeof flares, in the setting of crystal deposition, ongoinginflammation and subsequent damage occur in thejoints and soft tissues. The ACR and the EuropeanLeague Against Rheumatism guidelines recommend atarget sUA level of o6 mg/dL to prevent the for-mation of MSU crystals and to eliminate crystaldeposition, thereby dissolving tophi.23,24 In addition,they recommend pharmacologic and nonpharmaco-logic (ie, education, lifestyle counseling) interventionsto treat and manage the disease.23,24

Despite the increased dialogue regarding gout overthe past several years, many patients continue toreceive suboptimal care due to a number of factors,including patients’ treatment nonadherence, healthcare providers’ lack of adherence to treatment guide-lines, and differences in patients’ and providers’perspectives on the treatment of gout. To improvecare, there is a need for ensuring proper dosing ofprescribed medications and treatment compliance, andfor increasing education of both patients and healthcare providers regarding the disease, its treatment, andthe importance of achieving the goal of an sUA levelo6 mg/dL. Treatment may also be improved byincluding the topic of gout in provider–patient

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discussions about chronic disease and comorbidities,by providing patient education, by regularly monitor-ing adherence, and by attaining patients’ participationin their treatment plans to facilitate adherence.

The treatment of gout is confounded in patientswith multiple comorbidities and/or contraindicationsto current therapies, and by current treatment para-digms that fail to address the etiology of hyper-uricemia in the vast majority of patients. The use oflesinurad has recently been approved, and additionalnew uricosuric drugs are being developed, for use incombination with an XOI for the long-term manage-ment of gout. These treatments are expected toprovide additional options for reaching not only thesUA target but also the clinical target of "curing"these patients of the disease.

ACKNOWLEDGMENTSEditorial assistance was provided by Charlotte Singh,MD, CMPP, and Elizabeth Goodwin, PhD, The Lock-wood Group (Stamford, Connecticut).

The author was involved in the content anddevelopment of the manuscript and approved the finalversion.

CONFLICTS OF INTERESTThis research, its publication, and editorial assistancewere funded by AstraZeneca Pharmaceuticals, thedevelopers of lesinurad.

The author has been a member of the scientificadvisory boards of AstraZeneca, Crealta Pharmaceut-icals, and Horizon Pharmaceuticals. The author hasindicated that he has no other conflicts of interest withregard to the content of this article.

REFERENCES1. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and

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February 2017

Address correspondence to: Robert T. Keenan, MD, MPH, Division ofRheumatology and Immunology, Duke University Hospital, 4022 HospitalSouth, Box 3544, Durham, NC 27710. E-mail: robert.keenan@duke.edu

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