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Gout:What’sOutMikaelaDeBarba, Pharm.D.

PGY1Community PharmacyResidentH-E-BPharmacy/Univers ity of Texasat Aust in

January13, 2017mikaelafarrel l@utexas.edu

ObjectivesØDefinegoutandreviewepidemiologyØReviewguidelinesforgoutØReviewliteratureonmonitoringserumuratelevelwhileonuricloweringtherapyØFormulatearecommendationformonitoringserumuricacidlevels

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CaseYouareworkingonanMTMcase.Thepatientisa45yearoldmalewhosuffersfromchronicgout.Hehasbeenonallopurinol100mgdailyfor6weeks.Hehasnothadanyflaresandhisserumuratelevelhasnotbeenchecked.

§Doyourecommendlabtestingtothedoctorandpatient?

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Gout§Gout:mostcommonformofinflammatoryarthritiscausedbyaccumulationofexcessuratecrystals(monosodiumurate,MSU)injointfluid,cartilage,bones,tendons,buras,andothersites§Tophus:hard,MSUdepositsundertheskin

4http://www.homeopathyhealing.net/disease/gout/Qaseem A, Harris RP, Forciea MA. Management of Acute and Recurrent Gout: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016

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5http://tmedweb.tulane.edu/pharmwiki/doku.php/gout_its_treatment

Epidemiology

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§ $1billionannuallyonambulatorycareforgout

§ 60%ofpeoplewithinitialflareexperienceasecondflarewithin1yearand78%dosowithin2years

1. http://acrabstracts.org/wp-content/uploads/2015/09/Paper_49298_abstract_70881_0.gif2. Qaseem A, Harris RP, Forciea MA. Management of Acute and Recurrent Gout: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016

3. Halpern R, Fuldeore MJ, Mody RR, Patel PA, Mikuls TR. The effect of serum urate on gout flares and their associated costs: an administrative claims analysis. J Clin Rheumatol. 2009;15(1):3-7.

SerumUrateLevel(SUA)§Hyperuricemiaiswhenurateconcentrationexceedsthelimitofuratesolubilityinserum(approximately6.8mg/dl)§Hyperuricemiaisthemaincauseofflares,tophi,andjointdamage

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Question1TrueorFalse:

A45yearoldmalewithaSUAof8mg/dlismorelikelytohaveagoutattackthana50yearoldfemalewiththesameSUAlevel.

TRUEMenare3-4timesmorelikelytoexperienceagoutattackthan

women.

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MedicationsforgoutattacksAnti-inflammatoryØNSAIDs§MOA:Non-selectiveinhibitorsofCOX1&2whichreducesthesynthesisofprostaglandinsthatareinvolvedinmediatinginflammatoryresponses

ØColchicine§MOA:Bindstomicrotubular proteininneutrophils,inhibitingboththeirchemotacticandchemokinetic responses.InhibitsleukotrieneB4formationandinhibitsreleaseofhistaminefrommastcells

ØCorticosteroids§MOA:ThoughttoinvolvephospholipaseA2 inhibitoryproteinswhichcontrolthebiosynthesisofpotentmediatorsofinflammationsuchasprostaglandinsandleukotrienesbyinhibitingthereleaseoftheprecursormoleculearachidonicacid.

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MedicationsforchronicgoutUrateLoweringTherapy(ULT)ØXanathine oxidaseinhibitors(XO)

üMOA- decreasethesynthesisofuricacidfrompurines

§Allopurinol

§Purineanalog

§Drughypersensitivityreactions(eg.Stevens-Johnson&DRESSsyndromes)

§Febuxostat (Uloric ®)

§Non-purineselectivenon-competitiveinhibitorofxanthineoxidase

10http://tmedweb.tulane.edu/pharmwiki/doku.php/gout_its_treatment

MedicationsforchronicgoutUrateLoweringTherapy(ULT)ØUricosuric

üMOA:organicacidsthatinhibitthereabsorptionofuricacidbyinhibitinganionictransportsitesoftherenalproximaltubule

§Probenecid

§Forpatientswhocan'ttolerateallopurinol,orrequireadditionaluratelowering

ØUricoslytic

üMOA:convertsuricacidtoawatersolublemetabolite

§Pegloticase (Krystexxa ®)

§Reservedforthetreatmentofsevere,treatment-refractorychronicgout

11http://tmedweb.tulane.edu/pharmwiki/doku.php/gout_its_treatment 12https://www.hss.edu/conditions_gout-risk-factors-diagnosis-treatment.asp

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Question2A67yearoldmalepatientwithahistoryofkidneystoneswhoisonafixedincomeisnotrespondingtohisallopurinoltreatment.Whattreatmentshouldyouputthepatienton?

a) AllopurinolNotresponding

b)Febuxostat

c)ProbenecidContraindicatedinpatientswithkidneystones

d)PegloticaseVeryexpensive

B.Febuxostat13

Guidelines

• AmericanCollegeofRheumatology• 2012ACR

• Evidence,Expertise,Exchange• 20133e

• EuropeanLeagueAgainstRheumatism• 2016EULAR

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Newguidelines

ACP•AmericanCollegeofPhysicians•2016

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RecommendationsfortargetSUAlevelwhileonaULT

• Maximumof6mg/dlACR• <6mg/dl• 5mg/dliftophiarepresent3e• <6mg/dl• <5mg/dlforseveregoutEULAR• EvidenceisinsufficientformonitoringofserumuratelevelsinpatientswithgoutACP

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ControversyGoutexpertRobertTerkeltaub,MD,presidentoftheGout,HyperuricemiaandCrystal-AssociatedDiseaseNetwork(G-CAN)

“Theguidelinecompromisesgout-specificpatienteducation,imperilsgoodoutcomes,andcouldsetoptimaltreatmentofthediseasebackdecades”

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ControversyGoutexpertRobertTerkeltaub,MD,presidentoftheGout,HyperuricemiaandCrystal-AssociatedDiseaseNetwork(G-CAN)

“Itwouldbeunfortunateifsomethingassimpleasgettinguricacidlevelsdonetoroutinelymonitorserumuricacidweretobeimpactedatthethird- partypayerlevel”

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ControversyACPVicePresidentforClinicalPolicyAmirQaseem,MD,PhD,MHA

“Thisthreshold(6.8mg/dl)isnotabsolutebecausepatientswithhigherserumuratelevelsmaystillbeasymptomatic,andsomemayhaveacuteflaresbelowthisthreshold.Thereisanassociationbetweenloweruratelevelsandfewergoutflares,theextenttowhichuseofurate-loweringtherapytoachievevarioustargetscanreducegoutflaresisuncertain.”

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ControversyACPVicePresidentforClinicalPolicyAmirQaseem,MD,PhD,MHA

"Thereisnoevidencefromanexperimentalstudythatexaminedthehealthoutcomesoftreatingtooneserumuricacidlevelversusanother,noristhereatrialcomparingastrategyofbasingtreatmentonattainingaspecificuratelevelversusbasingtreatmentonreductioninsymptoms(suchasgoutflares)."

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Question3AllbutACPguidelinesrecommendsthetreat-to-targetrecommendation.Whichdrugdoesthispertainto?a) Naproxenb) Colchicinec) Allopurinold) Prednisone

C– AllopurinolTreattotargetrecommendationisinregardstohowurateloweringtherapyismonitoredforchronicgout

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Andrésetal.2014Title TreatmentTargetandFollow-upMeasuresforPatientswithGout:ASystematicLiterature

Review

Objective Systematicallyreviewthevalidityofserumuricacid(SUA)asatreatmenttargetforpatientswithgout

Design § Systemicliterature review§ SearchperformedinMedline,Embase andtheCochraneLibrary§ StudiesevaluatingdifferentSUAlevelsorSUAreductionwiththeachievementof

outcomeswere selectedPatients 54articlesusedStatistics Validity– correlationcoefficientsandregressionanalyses

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Andrésetal.2014Results

6studies

• FoundthatlowerSUAlevelwassignificantlyassociatedwithfewergoutyattacks

2studies

• AddressedtheassociationofSUAlevelwithchangesintophisize

5studies

• EvaluatedifloweringSUAisassociatedwithclearanceofMSUcrystalsfromjoints

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Andrésetal.2014Limitations§Nostatisticalanalysisdiscussed§Mostcurrentstudywas2010

Conclusions§EvidencesupportingreducingSUAlevelasatreatmenttargetforpatientswithgoutasasurrogatemarker§CutoffpointforSUAlevelremainsunclear

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Krishnanetal.2013Title Serumurateandincidenceofkidneydiseaseamongveteranswithgout

Objective Studytheassociationbetweenserumuratelevel(SUA)andtheriskofincidentkidneydiseaseamongUSveteranswithgoutyarthritis.

Design § Retrospectivecohortstudy§ SouthCentralVeterans’AffairsHealthCareNetwork§ January 1,2002toJanuary1,2011

Patients § 2116patients≥18yearsofage§ Atleast2recordedSUAlevelandenrolledinthedatabaseforaminimumof6months

beforeand12monthsafterthefirstmeasurement§ Groupedin2groups:overalllowSUAandhighSUAlevels

Statistics § Accumulatedhazardcurvesfortimeto eventwereestimatedforbothSUAgroupsandstatisticalcomparisonwasconductedusingalog-rankedtest

§ Multivariant adjustedanalysisusedaCoxproportionalhazardmodeltoestimatetherelativeriskofkidneydiseaseassociatedwithhighvslowSUA

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Krishnanetal.2013Results

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Krishnanetal.2013Results

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Krishnanetal.2013Limitations§Excludedwomen§Used>7mg/dlasthecutoff

Conclusions§GoutpatientswithSUA>7mg/dldevelopedmorekidneydiseasethangoutpatientswithSUA<7mg/dl

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Sarawate etal.2006Title SerumUrateLevelsandGoutFlares

AnalysisFromManagedCareData

Objective Determinetherelationshipamonggout-specificprescriptiondrugtherapy,serumuratelevel(SUA),andgoutflaresamongadultgoutpatients

Design § 2-year,nonrandomized,retrospective,databaseanalysisofpatientsidentifiedashavinggoutfromamanagedcareperspective

§ Databaseincludedmedicalclaims,pharmacyclaims,electroniclaboratoryresults,andhealthplaneligibility

§ January1,1999toMarch31,2004

Patients § 5942gout patients≥18yearsofage§ Differentiatedasnewlyorpreviouslydiagnosed

Statistics MultivariablelogisticregressionandnegativebinomialregressionanalyseswereconductedtoevaluatetheassociationbetweenSUAlevel6mg/dlandriskandrateofgoutflares,respectively

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Sarawate etal.2006Results

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Sarawate etal.2006Limitations§Nonrandomizedretrospectivestudy§SUAresultswerenotavailableforallpatientspre- andpostindex

Conclusion§PatientswithaSUAlevel≥6mg/dlwhileonurateloweringmedicationhaveagreaterlikelihoodofgoutflares§FailuretoattaintargetSUAlevelandtheoccurrenceofgoutflaresmayhavemultifactorialorigins

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Shojietal,2004Title Aretrospectivestudyoftherelationshipbetweenserumuratelevelandrecurrentattacksof

goutyarthritis:evidenceforreductionofrecurrentgoutyarthritiswithantihyperuricemictherapy

Objective Evaluatetheproposedrelationshipbetweenpersistentreductionofserumurateintothesubsaturating rangeandreductioninthefrequencyofacutegoutyattacks

Design • Retrospective analysis• InstituteofRheumatology,TokyoWomen’sMedicalUniversity• January1,1997toJune30,1998

Patients • 267patients; 35receivednoULT;232receivedULT• Experiencedatleast1attackofgoutyarthritisandnonewerethenreceivingULT

Statistics • Evaluatedtherelationshipbetweenaverageserumurateconcentrationduringthewholeinvestigationperiodandrecurrenceofgoutyattacksbyalogisticregressionmodel

• RelationshipbetweenULT andtherecurrenceofgoutyattackswasanalyzedusingalogisticregressionmode

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Shojietal,2004Results

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Shojietal,2004Results

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Shojietal,2004Limitations§Populationisnotgeneralizable§Attacksinfirstyearwerenotincluded

Conclusion§Demonstratedthatthelowertheserumuratelevel,thelessthelikelihoodofrecurrentacutegoutyattacks§Meanaverageserumurateconcentrationinthepatientsinthemedicationgroupwhoexperiencedrecurrentgoutyattackswasonly7.01mg/dlwhichsuggeststhat7mg/dlisnotasuitabletargetlevel

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Perez-Ruizetal,2002Title EffectofUrate-LoweringTherapyontheVelocityofSizeReductionofTophiinChronicGout

Objective Evaluatetherelationshipbetweenserumuratelevelduringtherapyandthevelocityofreductionoftophiinpatientswithchronictophaceous gout

Design • Prospective, observationalstudy• Goutclinicataregionalreferencehospital• 1995to2000

Patients • 63patients• Patientshadtophaceous goutandwerewillingtotakeULTwithlong- termfollow-up

Statistics Noanalysis

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Perez-Ruizetal,2002Results

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Perez-Ruizetal,2002Limitations§Smallsamplesize§SerumuratelevelduringULTwasconsideredtheaverageofallserumuratemeasurementsduringentirefollow-upperiod

Conclusion§LowertheserumuratelevelachievedduringULT,thefasterthereductionintophaceous deposits§AllserumuratelevelsbeforeULTwere≥8.78± 1.34duringfollow-upwerelessthan5.37± 0.79

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Question4TrueorFalse:

IfSUAlevelis<6mg/dlapatientwillnothaveagoutflare.

FalseStudieshaveshownpatientswithanySUAlevelcanhaveflares

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Conclusion§ThereisacorrelationbetweentheSUAlevelandgoutflares§Thevelocityofgoutytophussizereductionwasinverselyrelatedtoserumuratelevelachievedduringurate-loweringtherapy§Therearenostudiesthatprove<6mg/dlisthebesttargettoreduceflares§CheckingSUAlevelwhiletitratingULTsareinallguidelinesexceptACP

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CaseYouareworkingonanMTMcase.Thepatientisa45yearoldmalewhosuffersfromchronicgout.Hehasbeenonallopurinol100mgdailyfor6weeks.Hehasnothadanyflaresandhisserumuratelevelhasnotbeenchecked.§Doyourecommendlabtestingtothedoctorandpatient?

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ThankYou§NathanPope,Pharm.D.,BCACP§H-E-B/UTResidencyProgramPreceptors§Co-residentsatH-E-B/UT§LucasHill,Pharm.D.

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Questions

43http://zendegienab.com/category/articles/

Resources1. Qaseem A,HarrisRP,Forciea MA.ManagementofAcuteandRecurrentGout:AClinicalPracticeGuidelineFromtheAmericanCollegeofPhysicians.

AnnInternMed.2016.2. HalpernR,Fuldeore MJ,Mody RR,PatelPA,Mikuls TR.Theeffectofserumurateongoutflaresandtheirassociatedcosts:anadministrativeclaims

analysis.JClin Rheumatol.2009;15(1):3-7.3. KrishnanE,Akhras KS,SharmaH,etal.Serumurateandincidenceofkidneydiseaseamongveteranswithgout.JRheumatol.2013;40(7):1166-72.4. AndrésM,Sivera F,Falzon L,Vanderheijde DM,CarmonaL.Treatmenttargetandfollowup measuresforpatientswithgout:asystematicliterature

review.JRheumatol Suppl.2014;92:55-62.5. BeckerMA,MacdonaldPA,HuntBJ,Lademacher C,Joseph-ridgeN.Determinantsoftheclinicaloutcomesofgoutduringthefirstyearofurate-

loweringtherapy.NucleosidesNucleotidesNucleicAcids.2008;27(6):585-91.6. http://www.medscape.com/viewarticle/871265_print7. KhannaD,FitzgeraldJD,KhannaPP,etal.2012AmericanCollegeofRheumatologyguidelinesformanagementofgout.Part1:systematic

nonpharmacologic andpharmacologictherapeuticapproachestohyperuricemia.ArthritisCareRes(Hoboken).2012;64(10):1431-46.8. Richette P,DohertyM,Pascual E,etal.2016updatedEULARevidence-basedrecommendationsforthemanagementofgout.AnnRheumDis.2016.9. TamuraT,Cazander G,Rooijakkers SH,Trouw LA,Nibbering PH.Excretions/secretionsfrommedicinallarvae(Lucilia sericata)inhibitcomplement

activationbytwomechanisms.WoundRepairRegen.2016.10. Sivera F,AndrésM,CarmonaL,etal.Multinationalevidence-basedrecommendationsforthediagnosisandmanagementofgout:integrating

systematicliteraturereviewandexpertopinionofabroadpanelofrheumatologistsinthe3einitiative.AnnRheumDis.2014;73(2):328-35.11. https://www.hss.edu/conditions_gout-risk-factors-diagnosis-treatment.asp12. http://www.medscape.com/viewarticle/871265_print13. Sarawate CA,PatelPA,SchumacherHR,YangW,BrewerKK,BakstAW.Serumuratelevelsandgoutflares:analysisfrommanagedcaredata.JClin

Rheumatol.2006;12(2):61-5.14. ShojiA,YamanakaH,Kamatani N.Aretrospectivestudyoftherelationshipbetweenserumuratelevelandrecurrentattacksofgoutyarthritis:

evidenceforreductionofrecurrentgoutyarthritiswithantihyperuricemic therapy.ArthritisRheum.2004;51(3):321-5.15. Perez-ruiz F,Calabozo M,Pijoan JI,Herrero-beites AM,Ruibal A.Effectofurate-loweringtherapyonthevelocityofsizereductionoftophiinchronic

gout.ArthritisRheum.2002;47(4):356-60.

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MikaelaDeBarba,Pharm.D.PTRounds,Gout:What’sOutJanuary13,2017

MikaelaDeBarba,Pharm.D.PTRounds,Gout:What’sOutJanuary13,2017

MikaelaDeBarba,Pharm.D.PTRounds,Gout:What’sOutJanuary13,2017Krishnanetal.2013Results

Sarawateetal.2006Results

MikaelaDeBarba,Pharm.D.PTRounds,Gout:What’sOutJanuary13,2017Shojietal,2004Results

Perez-Ruizetal,2002Results