management of gout: 2017 - ucsf cme · 2017-10-20 · management of gout: 2017 jonathan graf, m.d....
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ManagementofGout:2017
JonathanGraf,M.D.ProfessorofClinicalMedicineUCSFDivisionofRheumatology,SFGH
Gout and its place in world history
Henry VIIIKing of England 1509-1547
Benjamin Franklin co-draftedDeclaration of Independence
1776
David Wells 15th perfectgame in Major League history
1998
2000 1800 1600 1500
JamesGillray:18th Century
“Personsaffectedwiththegoutwhoareaged,havetophiintheirjoints,whohaveledahardlife,andwhosebowelsareconstipatedarebeyondthepowerofmedicinetocure”– Hippocratesc.400BCE
Gout and its place in ancient history
Pity a Tyrannosaur? Sue Had GoutBy MALCOLM W. BROWNE
For all the suffering she probably caused her Cretaceous prey, a tyrannosaur named Sue seems to have paid dearly. Scientists have determined that the big dinosaur probably was a victim of agonizing gout and other debilitating ailments.
May 22, 1997
Gout and its place in prehistory
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Whygiveaprimarycareupdateongout?1.Goutisprevalent:2007-2008NHANES3.9%(8.3million)1
– Men=5.9%(6.1million)1
– Women=2.0%(2.2million)1
– Prevalencehasincreasedby1.2percentagepoints(30%)inpasttwodecades1
– Crystallinearthritisaccountedfor2.3%(39million)admissions2
– Goutresponsiblefor5%(5million)outpatientvisits20102
2 The United States Bone and Joint Initiative: American Academy of OrthopaedicSurgeons; 2014. Chapter 4. Arthritis.
1Chandratre P, Roddy E, Clarson L, Richardson J, Hider SL, Mallen CD. Rheumatology (Oxford). 2013; 52(11): 2031–2040.
Whygiveaprimarycareupdateongout?
In2002,Whatpercentageofoutpatientvisitsspecificallyforgoutweretorheumatologists?
A. 1.3%B. 13%C. 33%D. 53%E. 73%
Whygiveaprimarycareupdateongout?
In2002,Whatpercentageofoutpatientvisitsspecificallyforgoutweretorheumatologists?
A. 1.3%B. 13%C. 33%D. 53%E. 73%
Whygiveaprimarycareupdateongout?
2.GoutistreatedprimarilybyPCP’sinU.S.
– Only1.3%ofalloutpatientvisitsforgouttreatedbyrheumatologists1
– 70%ofpatientswithgoutareunderthecareofprimarycarephysicians
– Only3%ofgoutpatientsarereferredbyPCP’storheumatologists
1Krishnan et al. J Rheumatol. 2008 Mar;35(3):498-501.
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Whygiveaprimarycareupdateongout?3.Goutisgenerallymismanaged
–Underuseofuricacidloweringtherapy(ULT)ineligiblepatientslikelytobenefit
–Under-dosingofallopurinolinpatientsonULT(40%withserumuricacid>6oncurrentdose)
– Initialoverdosingofallopurinolinsomepatientsatriskforhypersensitivity
Whygiveaprimarycareupdateongout?
4.Plethoraofurate loweringtherapiescurrentlyavailableorcomingtomarket
Goutinrecentgeneralmedicalliterature
NEJM
Lancet
ACPGuidelines2017:Extraordinarydisappointment
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Goutguidelinespublishedbyrheumatologysocieties
US: ACR 2012 Europe: EULAR 2016
AcuteGout• Acute,usuallyselflimitedmonoarticularinflammatoryarthropathy
• Inflammatoryresponsedirectedagainstmonosodiumurate crystalsinsynovium
• Usuallybutnotalwaysassociatedwithhyperuricemia
• Monosodiumurate crystalsprecipitatearoundataconcentrationof6.8mg/dL,withinreferencerangeinmostUSpopulations
DistributionofSerumUricAcidLevelsinJapan:34,000People
“Normal”= Mean + 2SD
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AcuteGoutDiagnosis■ Definitive:CrystalIdentification– theonlyway!
– Jointfluidexaminationunderpolarizedmicroscopywithredcompensator
– Stronglynegativelybirefringentneedleshapedcrystals
■ Suspected:Characteristicradiographic“gouty”corticatederosionsawayfromjointspace
■ Possible:Classicclinicalpicturewithelevatedserumurate
■ However– presenceofhyperuricemia aloneisnotdiagnosticofgout
TherapyforAcuteGoutyFlares
• Acutegoutattacksareoftenselflimited(3-5days)
• Goals:reducebothseverityanddurationofattack
• NSAIDs– Effectiveandrapidreliefofsymptoms– ContraindicatedinpatientswithGI,Renal,orhypersensitivityconcerns
• Corticosteroids(intra-articularand/orsystemicuse)
• Colchicine:– Lowdoseonly(0.6mgBID)!Noteveryhouruntilpatientgetssick– Mustbeusedwithin48hoursofattackonset(blocksleukocytemigration)– LikelynotaseffectiveaseitherNSAIDsorcorticosteroids
Colchicine:HowEffectiveforAcuteGout??
Fewer than 40% of patients achieve primary endpoint High dose no more efficacious and more toxic
ManagingChronicGout:2012ACRGuidelines
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QuestionI• 55yearoldmalewithahistoryofknowngoutawakenswith
rightkneepainandswellingonemorningthatworsensovernext48hoursuntilhehasdifficultywalkingonthatknee.OnarecentChem.20panel,uricacidlevelwaselevatedat10.7.Hedeniesanyotherjointpains,IVDU,orrecentsexualcontacts.
Afterundergoingarthrocentesis confirmingthediagnosisofgoutandrulingoutaninfectiousprocess,thepatientisstartedonindomethacin andallopurinol 300mg/dayandsenthome.Whichofthefollowingactionsinthiscasewasamistake?
• A.Allopurinol dose• B.Indomethacin therapy• C.Thepatientwasnotadmittedandtreatedwithantibiotics
untilsynovialfluidcultureswerenegativefor5days• D.Useofallopurinol duringacutephaseofgout
QuestionI• 55yearoldmalewithahistoryofknowngoutawakenswith
rightkneepainandswellingonemorningthatworsensovernext48hoursuntilhehasdifficultywalkingonthatknee.OnarecentChem.20panel,uricacidlevelwaselevatedat10.7.Hedeniesanyotherjointpains,IVDU,orrecentsexualcontacts.
Afterundergoingarthrocentesis confirmingthediagnosisofgoutandrulingoutaninfectiousprocess,thepatientisstartedonindomethacin andallopurinol 300mg/dayandsenthome.Whichofthefollowingactionsinthiscasewasamistake?
• A.Allopurinol dose• B.Indomethacin therapy• C.Thepatientwasnotadmittedandtreatedwithantibiotics
untilsynovialfluidcultureswerenegativefor5days• D.Useofallopurinol duringacutephaseofgout
ChronicGout- Progression
• Morefrequentinflammatoryarthriticattacks– Monoarticular attacks
• Samejoint• Spreadtootherjoints
– Polyarticular attacksofarthritisasdiseaseprogresses
• Attacksblendtogether/Nolongercompletelyself-limited
• Chronicsynovitisresemblingrheumatoidarthritis
• Destructivearthritis/Tophaceous gout:• Uricacidcontainingtophidepositinjoints/tendons/softtissues,canleadtoerosionsanddeformities
ChronicGout– 2012ACRguidelines• Goal:Treattotargeturicacidlevel
– Lowerserumuricacidlevelsareassociatedwithfewerattacks– Targetserumurate levelsbelowcrystallizationconcentration(<6.0
oreven5.0inseveregout)toreabsorbtophiandremoveUAstores– 1st lineUricacidloweringtherapies:allopurinol andFebuxostat– Othertherapiesnowavailabletogeturicacidlevelstotargetfor
patientswhofailorarecontraindicated/intolerantto1st linemeds
• Prophylaxis– Prophylax againstacutegoutflareswheninitiatingoradjustinguric
acidloweringtherapy(Europeansrecommendsixmonths)– Colchine doesworkwellforthis(0.6mg/dayusuallysuffices)– NSAIDsandprednisoneworkaswell
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Treatinghyperuricemia: ACR2012guidelines• Donottreatasymptomatichyperuricemia
– primaryhyperuricemiamaysomedaybelinkedtocardiovascularormetabolicsyndromes
• Generalgoalis:
– Toreducefrequencyandseverityofsubsequentattacksofgout
– Toresorbtophacousuricaciddepositsthatcancausejointdamage
• Alloprurinolandfebuxostatareconsideredfirst-linetherapiesforhyperuricemiaassociatedwithgout
• It’snowconsideredacceptabletoinitiateurate-loweringtherapyduringacuteflaresprovidedadequatetreatmentofflareisbegunandprophylaxisagainstfutureflaresismaintainedforatleastthreemonthsafterflare
ACPGuidelines:Keyfailure• TheACPexpertpanelcouldn’tbringitselftorecommendtreatingtoaserum
uricacidtarget
• Citedlackofevidencetorecommendation(formalrandomizedprospectivetrialscomparingtreatingtospecifictargetonoutcomesofgoutflares,tophusreduction,metabolicsyndrome,etc…)
• Citedclinicaltrialsofurateloweringtherapywithincreasedgoutflares(lackedadequateprophylaxis)
• Ignoreditsowncitedmountainsofotherliterature/evidence(2RCTspost-hocanalysisand8resposprectivecohortstudies) suportinglongtermreductioningoutflaresandcomplicationsofhyperuricemiawithtreatmenttoserumurate<6andbetterif<5.
• Ignoredcommonsense:“Theguideline…..imperilsgoodoutcomes,andcouldsetoptimaltreatmentofthediseasebackdecades.”– R.Turkeltaub MDUCSD
Addressingco-morbidconditionsingoutpatientswithhyperuricemia
Non-pharmacologictreatmentsforhyperuricemia
• Patienteducationabouthyperuricemia,diet,andlifestylemodifications
• Considerationgiventouricacid-elevatingmedications
– Keyculpritsarethiazideandloopdiuretics,niacin,andcyclosporine
– Obviouslyifdrugbenefitsoutweighsmallimprovementinuricacid,thendonotadjustordiscontinue
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Question2A62YOmalepatientofyourswithgoutcomestoyourofficeaskingwhatdietarychangesheshouldmakeinhelpingtotreathisgoutandhyperuricemia.AccordingtotheACRguidelines,yourecommendthatheavoidwhichofthefollowing?
A. ModestalcoholintakeB. FoodsandbeverageswithhighfructosecornsyrupC. ChickenandturkeyD. Lowfatdairyproducts
Question2A62YOmalepatientofyourswithgoutcomestoyourofficeaskingwhatdietarychangesheshouldmakeinhelpingtotreathisgoutandhyperuricemia.AccordingtotheACRguidelines,yourecommendthatheavoidwhichofthefollowing?
A. ModestalcoholintakeB. FoodsandbeverageswithhighfructosecornsyrupC. ChickenandturkeyD. Lowfatdairyproducts
Dietrecommendations:FairlyMeagerevidence
Khanna et al. Arth Care and Research 2012: 64;10 1431-1446
ChronicGout:UricAcidLoweringTherapies
• Allopurinol– Xanthine Oxidase Inhibitor(blocksmetabolismofpurines touricacid)
– Effectiveforbothunder-excreters andoverproducersofuricacid
– Nowacceptabletostartmanygoutpatientsonallopurinol duringaflareiftheyarerespondingappropriatelytoanti-inflammatoryagents
– Don’tstoptherapyduringanacuteattack
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Allopurinol ispurine derivative:adeadringerforhypoxanthine
AllopurinolcompeteswithHypoxanthineforxanthineoxidase
PurineMetabolism
Usingallopurinolproperly• Donotstartpatientsonmorethan100mg/day
• DosereduceALLpatientswithmoderatetosevererenalinsufficiency
• Graduallyup-titratethedose,whichinsomecases, canbemorethan300mg/dayifneeded
• TreattoTarget:serumurateconcentration<6iftreatingtophi,and<5ideally.
• Pushtheallopurinoldoseover300mg/dayifnecessary!!
EULAR2016TreattoTargetRecommendations
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AllopurinolToxicities
• Carefuluseinpatientswithrenalfailure– Metabolitesarerenally cleared– hypersensitivityreactionsaremorecommoninpatientswithrenalinsufficiency
• Purine-associatedhypersensitivitysyndromeisDIFFERENTfromallergicrash
• Systemicandsometimeslifethreateningillness• Fever,Steven’s-Johnson/TEN,hepatitis,marrowsuppression,nephritis,DRESS
(DrugRashwithEosinophila andSystemicSymptoms) TheRoleofHLA5801andAllopurinol Hypersensitivityisunquestioned
• AllpatientsfrompopulationswithahighallelefrequencyforHLA5801andhighhazardratiofordevelopinghypersensitivityshouldbescreened!!
HLAB5801andAllopurinol HypersensitivityHungetal.PNAS2005
1. B5801 confers nearly 600 fold increased risk of allopurinol hypersensitivity
2. Allele and association is particularly important in Han Chinese patients, Thai,And Korean patients
Allopurinol PharmacogeneticsBench Clinic
1. The Role of HLA 5801 and Allopurinol Hypersensitivity is unquestioned2. All patients from populations with a high allele frequency for HLA 5801 and high hazard ratio for developing hypersensitivity should be screened!!
ThePresentStateofGoutTherapy:WhattodowithaMoreChallengingCase?
Youareseeinga56yearoldmalewithlongstandingdiabetes,hypertension,chronicrenalinsufficiency,anddestructivetophaceousgout.Hisgoutoriginallybeganasepisodicpodagrathatbecamemorefrequentandinvolvedmorejointsovertime.Inthepastfewyears,histophihavegrownlargerandmorenumerous,andacuteepisodesofinflammatoryarthritishavebeguntoblendtogetherintoachronic,painful,polyarticularinflammatorysynovitisinhishands,elbows,knees,andfeetfromwhichhehascometoyourofficeseekingrelief.
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Gout:Findings• Hehaschronicswelling,
synovitis,anddeformitiesreminiscentofrheumatoidarthritis
• Numeroustophiscatteredonarms,legs,andears
• Serumcreatinineis1.8
• UricAcid10.2
ManagingtheChronicDisease
Whichofthefollowingoptionsisbestsuitedtotreathishyperuricemia totarget:
A. Startingallopurinol300/dayB. Colchicine0.6mg/dayC. Probenecid 250mgtwicedailyD. Startfebuxostat 40mg/day
ManagingtheChronicDisease
Whichofthefollowingoptionsisbestsuitedtotreathishyperuricemia totarget:
A. Startingallopurinol300/dayB. Colchicine0.6mg/dayC. Probenecid 250mgtwicedailyD. Startfebuxostat 40mg/day
Difficulttomanagechronicgout• Generallydonotstart300mg/dayofallopurinolonmostpatients,especiallywithchronickidneydisease
• Mechanismofcolchicinedoesn’ttreathyperuricemia
• Probenecid won’tworkwithoutadequateGFRandiscontraindicatedintophaceous goutanyway
• Startingverylowallopurinol(50mgor100mgQODandtitratingupisanoption,butfubuxostat iseffectiveandsafeinpatientswithmoderateCKD
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Febuxostat (FDAapproved2009)
• Firsttreatmentin40yearsforchronicgout
• NON-PURINE inhibitorofxanthineoxidase
• Theoreticallysafetouseinpatientswithallopurinolreactions
• Beenstudiedinpatientswithmildrenalinsufficiency
• Dosedat40-80mg/oncedaily
FubuxostatisNotaPurine
PurineMetabolismComparisonofFebuxostat toAllopurinol
Beckeretal.NEJM2005
• 80mgand120mgoffebuxostat superiortoallopurinol 300mg/day– Percentofpatientsachievinguricacid<6– Greaterreductioninserumuricacidlevels
• Safeinpatientswithmild-moderaterenalinsufficiency(SCr <1.5inthisstudy)andpatientswithprevious allopurinolreactions
• Note:Allopurinol 300/dayisprobablysuboptimaldoseformanypatients
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Febuxostat:Summary• Morepotentthan300mg/dayallopurinol(butmanypatientscantoleratehigherdosesofallopurinol)
• Asitisnotapurine:Appropriateforpatientswithallopurinolhypersensitivity
• Canbeusedsafelyinpatientswithmildrenalinsufficiency(unlikeallopurinol)
Treatingsevere,refractorytophaceous gout
Lifetime of standard uric acid lowering treatment won’t eliminate these tophi
Uricase• Enzymethatconvertsinsolubleuricacidtomoresolublemetaboliteallantoin
• Mostofanimalkingdom(&manymammals)possesuricase,butnothumanshavelostgenefunction
• Rasburicase:adrugderivedfromaspergillisusedtotreattumorlysissyndromeinpediatricleukemia
• Rasburicaseisextremelyimmunogenic,whichlimitsitshalflifeanduseinchronicdiseases
Pegloticase(FDAapprovalSept.2010)
• Mammalianuricase
• Pegylated– Increaseshalflife– Reducesimmunogenicity
• AdministeredbyIVinfusionevery2weeks
Uric Acid
Allantoin
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PurineMetabolism
Urinary Excretion
EfficacyofPegloticaseSundyetal.A&R2008
• Phase2randomizedopenlabeldoserangingstudy41patientswithserumurate>8
• Intoleranceorinadequateresponsetostandardurateloweringtherapy(UA>6)foratleast3months
• Plusoneofthefollowing:– Atleastonetophus– Atleastoneflareinlast6months– Chronicgoutyarthropathy
EfficacyofPegloticasePhase2(12week)openlabeldosingtrial41patients
VisibleResults
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Pegloticase:Notholygrail
• Adverseevets:– Infusionreactions(nothuman,evenwithPEG)– Manypatientsdevelopantibodiestodrugthatincreasesitsclearanceand?Effectsitsefficacy
– Anaphylaxis– 80%patientshadgoutflaresdespiteprophylaxis– ContraindicatedinG6PDdeficientpatients– MayexacerbateCHF
Pegloticase:Summary
• Effectiveagentforacuteloweringandchronicreductioninserumuricacidlevels
• Serumuricacidlevelsarelowenoughinsomepatientstopromotetophusresorption
• Medicationisexpensive,immunogenic,andassociatedwithadverseevents
• Referthesepatientswithseveretophaceousgouttorheumatologists!!
Renal excretion of uric acid
Bergamini C et al. Eur J Heart Fail 2009;11:444-452
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: [email protected].
Hyperuricemia
ChronicGout:Uricosuric agents
• Probenecid:Anoldfriend– Uricosuric agentblockstubularre-absorptionofuricacid
– Usefulinpatientswhounder-excreteuricacid(90%)
– Ifneedbe,confirmunder-excretionwith24hr.uricacid<800mg/24hrs.
– Donotuseif:• Tophi• Renalinsufficiency• Clearoverproductionsyndrome
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Target #1: URAT 1Enhancing Uric Acid Elimination
Adaped from Rees et al. Nature Reviews Rheumatology 10, 271–283 (2014)
Lesinurad
Lesinurad• FDAapproved2016uricosuric foruseincombinationwith
xanthineoxixdase inhibitor(allopurinolorfebuxostat)toloweruricacid
• Usefuladd-ontherapyintreattotargetscenario
• Similarcontraindicationsandlimitationstoprobenecid inkidneydisease(usewithallopurinolisrequired)
EffectivenessofLesinurad asadd- ontoAllopurinolintreattotarget
Saag etal.Vol.69,No.1,January2017,pp203–212
CLEAR 1 (N=603) and CLEAR 2 (N=610), 91% and 84% were receiving allopurinol 300 mg (range: 200-900 mg) daily
AdvancesinTherapiesforGout:Summary• Goutisanancientdiseaseforwhommoderntherapyisfinallyavailable– ShouldbemanagedeffectivelybyinternistsandPCPswhousetreattotargetapproach(notinACPguidelines)
• Newtherapiesareavailable• Febuxostat (allopurinolrefractory,intolerant,orcontraindicated)
• Pegylated uricase:severetophaceous disease• Noveluricosuric agentslikelesinurad
• Rheumatologyreferralappropriatefordifficulttomanagecases
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The future is bright for those with gout who do not go extinctGoutTherapy:TheFuture
BacktoourChallengingCase….• Hehaschronicswelling,
synovitis,anddeformitiesreminiscentofrheumatoidarthritis
• Numeroustophiscatteredonarms,legs,andears
• Serumcreatinineis1.8
• UricAcid10.2
• Diabetes
ManagingtheAcuteSymptoms
Intheacutesetting,thebestapproachtomanagingthispatient’ssymptomswouldbetostart?:
A. Indomethacin75mg-100mgPOTIDB. Colchicine0.6mgPOq2hruntilheimprovesC. Prednisone20mgPOQDD. Allopurinol300mgPOQD
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ManagingtheAcuteSymptoms
Intheacutesetting,thebestapproachtomanagingthispatient’ssymptomswouldbetostart?:
A. Indomethacin75mg-100mgPOTIDB. Colchicine0.6mgPOq2hruntilheimprovesC. Prednisone20mgPOQDD. Allopurinol300mgPOQD
ManagingtheAcuteSymptomsA. Indomethacin75mg-100mgPOTID
• Can’tusebecauseofrenaldiseaseB. Colchicine0.6mgPOq2hruntilheimproves
• NotstandardofcareforacutegoutC. Prednisone20mgPOQD
• Bestchoice,butnotidealgivendiabetesD. Allopurinol300mgPOQD
• Notusedtotreatacuteinflammation
Arethereanyanti-inflammatorytreatmentsonthehorizonforthoserefractorytoorintolerantofstandardtherapy??
TherapyforAcuteGout:A“Biologic”Future??Target#2:TheInflammasome
Goutpathogenesis:– Supersaturatedserumlevelsofuricacidleadtocrystalformationanddepositsinjoints
– Crystalsareengulfedbymacrophages– Macrophagesreleaseinflammatorycytokines– Recruitmoreinflammatorycellsandperpetuatejointinflammation
HowdoinertUAcrystalsleadtoinflammation?
Howdoesuricacidleadtoinflammation???
• InnateImmuneSystem:– Inflammatorycellscaninnatelyrecognizecommonmicrobialfeaturesasdangersignals
• Flagella,viralRNA,etc…– Leadstorapidinflammation(evensepticshock)thatactsas“speedbump”untiladaptiveimmuneresponsekicksin
– MicrobialpatternsbindtoToll-likereceptorsandleadtoproductionofproIL-1
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IL-1Production
• Pro-IL1isinactive,butcapableofbeingrapidlymetabolizedtoactiveIL-1
• MachinerythatcleavesproIL-1toactiveIL-1iscalledtheinflammasome andisinducedbyasecondrequireddangersignal
• UricAcidiscapableofactivatingtheinflammasome
DualactivationofpatternreceptorsPLUSahostdangersignal(UricAcid)
Inflammation
N Engl J Med 2011;364:443-52.Copyright © 2011 Massachusetts Medical Society.
IsIL-1BlockadeEffectiveforGout?
• IL-1blockadevia– IL-1Receptorantagonist(Anakinra,commerciallyavailableforRheumatoidArthritis)
– AntiIL-1antibody(Canakinumab,commerciallyavailabletotreatcertainperiodicfevers)
– IL-1decoyreceptorfusionprotein(Rilanocept,commerciallyavailabletotreatcertainperiodicfevers)
• Severalpilotstudiessuggesttheseallwork!
• SingledoseofCanakinumabsuperiortotriamcinoloneinjection(haslonghalflife)
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Canakinumab(CK)vs.TriamcinoloneSoetal.A&R2010
• CKadministeredasoneof5singledoses– Previousgoutflare– Acutegoutflare<5days– Inabilitytotakeotheracutegout
therapy
• Primaryendpoint:finddoseofCKequivalenttotriamcinoloneforreductionofpainat72hours
• Noequivalentdose!Allcanakinumabdosessuperiortotriamcinoloneat72hours
TimetoFirstGoutFlareSoetal.A&R2010
Secondaryendpoints:•8weekreductioningoutflares•Timeto50%reductioninpain•Reductioninseruminflammatorymarkers•Patientandphysicianglobalassessments•Useofothergouttherapies
NotQuiteReadyforPrimeTimeFDA rejects expanded use of Regeneron drug for goutPublished July 31, 2012ReutersRegeneron Pharmaceuticals Inc said U.S. regulators have denied approval for it to expand use of its Arcalyst drug to prevent gout flares, asking that the company provide more clinical data.The rejection follows a unanimous vote against the drug's approval in early May by advisors to the U.S. Food and Drug Administration, with panel members expressing concern that the company had only done a 16-week study.
FDA Panel Votes Against Gout Drug
By THOMAS M. BURTONWASHINGTON—The Food and Drug Administration is grappling with the novel question of whether a Novartis AG NVS +0.97%gout-pain drug should be marketed when patients receiving just one injection had a higher rate of serious infections in clinical studies. An FDA advisory committee Tuesday voted 11-1 against approving the drug, called Ilaris, because of the safety concerns.