objectives gout: what’s out Ø - university blog...
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Gout:What’sOutMikaelaDeBarba, Pharm.D.
PGY1Community PharmacyResidentH-E-BPharmacy/Univers ity of Texasat Aust in
January13, 2017mikaelafarrel [email protected]
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