updated review of gout...

ìUpdatedReviewofGoutManagementDrGarethSTarr-28thMay2016

MBBcHFCP(SA)Mmed(IntMed)Cert(Rheum)PhdCandidate(STB)

ReproducEonmadefromacopyheldbytheHarvardMedicalLibraryintheFrancisA.CountwayLibraryofMedicine.

‘TheGout’byJamesGillray(1799)

Epidemiology

ì  CommonestinflammatoryarthriEsinmen;ì  Increasingfrequencyinfemales.

ì  7%ofmenovertheageof65;

ì  3%ofwomenagedover85years;

ì  Stronglyrelatedto:ì  Metabolicsyndrome,ì  Chronicrenalimpairment,ì  Certaindrugtreatments,includingdiureEcs.

MikulsTr,elal.CurOpinRheumatol2006;18:199-203.LawrenceRC,etal.ArthriEsRheum2008;58:26-32.

Epidemiology(cont.)

Severalepidemiologicalstudieshavedemonstratedanincreaseintheseverityandprevalenceofgout.

ì  ArromdeeE,etal.JRheumatol2002;29:2403–6.

ì  FelsE,etal.CurrOpinRheumatol2008;20:198–202.

ì  WallaceKL,etal.JRheumatol2004;31:1582–7.

ì  Perez-RuizF.AnnRheumDis2006;65(Suppl2):436.

Conundrum

Why,then,

despitethepossibilityofearlyandaccuratediagnosis,

theavailabilityofeffecEvetreatmentandourinsightintotheseverityandconsequencesofthedisease,

isgoutmanagedsoineffecEvely?

DohertyM,etal.AnnRheumDis2012;71:1765–1770

ProgressionofJointDamage

RheumatoidArthriEs ChronicTophaceousGout

CommonMisconceptions

ì  Self-limiteddisease

ì  CrystaldeposiEonconEnuesdespitelong‘symptom’freeperiodèDestrucEveArthriEs.

ì  Benign,ratherthanserious

ì  Humorous.

ì  Historically–“Diseaseofkings”.

ì  AssociaEonofCardio-renaldiseaseandshortenedlifeexpectancy.

FeigDl,etal.NEnglJMed2008;359:1811–21

Zandman-GoddardG,etal.Rheumatology2013;52:11261131

‘PunchCurestheGout,theColicandthe“tisick”’byJamesGillray

(1799)

ThesedistortedpercepEonsofthenatureofgouthaveamarkednegaEveeffecton

paEents’adtudestotheirgoutand

itstreatment.

WhatabouttheDoctor’sapproach?

ì  GoutislargelymanagedbygeneralpracEEoners.

ì  MajorityofpaEentsareneverreferredforaspecialistopinion.

ì  ApproachtogoutmanagementisbesetwithmisconcepEonsandmyths.

LeslieR,etal.Rheumatology2013;52:16231629

ManagementQuestions

ì  WhendoIstartUrateloweringtherapy(ULT)?

ì  DoIconEnueULTduringanacuteahack?

ì  Whatistheroleofcolchicine?

ì  HowlongdoIconEnuecolchicinefor?

ì  WhatlevelofserumuricacidamIaimingfor?

ManagementofAcuteGoutyAttack

KhannaD,elAl.ArthriEsCare&Research.2012;64(10):1447–1461.

AssesstheSeverity

Monotherapy

NSAID(e.g.Arcoxia)

SystemicSteroids Colchicine

OpEon:IniEalCombinaEonTherapy

Mild-moderatepain,parEcularlyforanaSackaffecEngonly1orafewsmalljoints,or1-2largejoints.

SeverePain,PolyarEcularaSack,mulEplelargejoints.

Etoricoxibcon

centraEo

n(ng/ml)

Time(hours)0 12 24 36 48

0

500

1500

200060mg120mg(n=12)

t1/2=half-life*SingleoraldosestohealthysubjectsAdaptedfromAgrawalNGBetalJClinPharmacol2003;43:268–276.

1000

EtoricoxibPharmacokineEcs:AbsorpEonandt1/2*

Tmax(hour) t1/2(hour)

Etoricoxib 1 22

Celecoxib 2–3 8–12

Diclofenac 1–5.25 2

Ibuprofen 0.75–1.5 2

Meloxicam 4–5 20

Naproxen 2–4 12–17

Indomethacin 2 4.5

Nimesulide 2–3 2–5

Tmax=EmetomaximumplasmaconcentraEon

Etoricoxib:Tmaxandt1/2

12-W

eekcumulaE

ve

incide

ncerate(%

)a

aCumulaEveincidencerateofgastroduodenalulcers≥3mmatweek12.CumulaEveincidenceratefromlife-tableanalysismaynotequalnumberofevents/n×100;bp<0.001foretoricoxibandplacebovs.naproxen;cp<0.001forplacebovs.ibuprofen;dp=0.007foretoricoxibvs.ibuprofen;e500mgtwicedaily;f800mgthreeEmesdailyHuntRHetalAlimentPharmacolTher2003;17:201–210;HuntRHetalAmJGastroenterol2003;98:1725–1733.

Etoricoxib120mg(n=207)

Naproxen1000mge(n=164)

Etoricoxib120mg(n=186)

Ibuprofen2400mgf(n=181)

Placebo(n=207)

0

RAorOA

510152025

3530

7.42b

25.27

1.35b

OA

0

5

10

15

20

25

8.12d

17.02

1.86c

Placebo(n=203)

Study1 Study2

Althoughthestudieswerenotdesignedtocompareulcerratesofplacebowithetoricoxib,subsequentanalysisrevealedsignificantdifferencesinStudy1(p=0.002)andStudy2(p=0.003).2,3

Etoricoxibvs.NaproxenorIbuprofenEndoscopyStudies:Gastro-duodenalUlcers

NSAIDs=nonsteroidalanE-inflammatorydrugs;PUBs=perforaEons,ulcers,bleeds*Combinedanalysisof10clinicaltrialsinOA,RA,andchroniclowbackpain;**Naproxen1000mg/day,ibuprofen2400mg/day,ordiclofenac150mg/dayAdaptedfromHuntRHetalAmJGastroenterol2003;98:1725–1733;CurEsSetal.PosterpresentedatEULAR,2002.

CumulaE

veincide

nce

Days(acEvetreatmentperiod)

0 90 180 270 360 540

0.02

0.04

0.06

0.00

Etoricoxib≥60mg(n=3142)NonselecEveNSAIDscombined**(n=1828)

p<0.001

~55%Risk

reducEon

450

Etoricoxibvs.NonselecEveNSAIDs:GIPUBsEtoricoxibhadlowerincidenceofconfirmedPUBsintheclinicaldevelopmentprogram*

AcuteGoutyArthritisTrialsDrug No.ofpaEents Year

Indomethacinvs.phenylbutazone 28 1973Proquazonevs.indomethacin 18 1978Sulindacvs.phenylbutazone 47 1979Fenoprofenvs.phenylbutazone 30 1979Feprazonevs.phenylbutazone 24 1980Meclofenamatevs.indomethacin 20 1983Flurbiprofenvs.phenylbutazone 33 1985Flurbiprofenvs.indomethacin 29 1986Indomethacin+allopurinolvs.azapropazone 93 1987Tenoxicam 10 1987Colchicinevs.placebo 43 1987Ketoprofenvs.indomethacin 59 1988Etodolacvs.naproxen 60 1990Etodolacvs.naproxen 61 1991Etoricoxibvs.indomethacin 150 2002Etoricoxibvs.indomethacin 189 2004*Listincludesonlydouble-blindclinicalstudiesoforalagentsbasedonextensiveEnglish-languageMedlineliteraturesearch(drugnamesand*gout assearchterms;nolimitonyearofpublicaEon;accessedJanuary2004).Allpublisheddouble-blindclinicalstudiesmaynotbeincluded.

ìCardiovascularrisk??

Coxib,tradiEonalNTC,etal.Lancet.2013;382(9894):769-79..


•  Meta-analysis•  280trials•  124513pateints•  68342paEentyears•  ibuprofen=diclofenac=coxibs•  Naproxenassociatedlessvascularevents.


BavryAA,etall.Circu

laEonCardiovascular

qualityandoutcomes.2014;7

(4):603-10.

ChronicNSAIDuseininflammatoryconditions.

ì  ConEnuousNSAIDsfor30years

ì  Overallmortalityrisk14.2%(Cardiovasculardisease=40%).

ì  BUT

ì  ConEnuousNSAIDsreducedCVSmortality.AnnRheumDis2011;70(11):1921

CelestoneIASvs.IMI

ì  Highlyfatsoluble

ì  Crossallcellmembranesrapidly.

ì  SystemicallyavailablewithinafewminutesauerinjecEon.

ì  Youdon’thavetoinjectlocally.

ì  Intra-muscular(IM)injecEonsarealsoveryeffecEve.

ì  BenefitofalocalinjecEonismainly‘duraEonofsymptomrelief’.

KhannaD,elAl.ArthriEsCare&Research.2012;64(10):1447–1461.

TreatmentOutcome

SwitchtoalternaEve

Monotherapy

TreatmentOutcome?

OpEon:AddoncombinaEontherapy.

TreatmentOutcome?

InadequateResponseConsideranalternaEvediagnosis

•  ≤20%improvementinpainscorewithin24hours

•  <50%at>24hours

ExperimentalDrugsforanAcuteAttack

ì  TherapiestargeEngIL-1bblockagearecurrentlybeinginvesEgated.

ì  Theseinclude:ì  Anakinra(anIL-1receptorantagonist),ì  Rilonacept(asolublereceptor-Fcfusionproteinthat

engagesandinhibitsbothIL-1aandIL-1bì  Canakinumab(afullyhumanmonoclonalanE-IL-1b

anEbody).

HarroldL.,CurOpinRheumatol20133;25(3).304-309.

KhannaD,etal.ArthriEsCare&Research.2012;64(10):1431–1446


EstablishtheDiagnosis

• PaEenteducaEon,withtheiniEaEonofdiet,lifestylechanges.• Secondarycausesofhyperuricaemia• PrescripEonmedicaEonsthatcanexacerbatehyperuricaemia• Evaluatediseaseburden.

BaselinerecommendaEonsforPaEentswith

Gout

• Tophusortophi• >2aSacksperyear• CKDstage2orworse• Pasturolithiasis

IndicaEonsforUrateLowering

Therapy


TREATTOTARGETURICACIDLEVEL

1stLineXanthineOxidaseInhibitor

Allopurinol

Febuxostat

AlternaEve1stLinetherapy Probenecid

AcuteGoutprophylaxis

Colchicine0.5mgBD

NSAID(egArcoxia)

Uricacid≤0.35mmol/L

Allopurinol

ì  Doseadjustedforserumuricacid

ì  Begina100mgdaily,andEtrateupwards

ì  Maxdose900mgdaily(individeddoses)

ì  Renalimpairment:beginwith50mgdaily

ElZawawyH,etal.ClevelandClinicaljouralofmedicine.2010;77(12):919-928.

MatsuoH,etal.AnnRheumDis2016;75:652–659


TREATTOTARGETachieved

YES

ConEnueacutegoutprophylaxis

Ongoinggoutsymptoms

>1TophuspresentRegularly

monitoruricacidlevel

DuraEonofgoutprophylaxis

NotophiiniEally–3months

TophiiniEally–6months

NO BigProblem?

GoutProphylaxis

ì  Long-termtreatmentwitheithercolchicineorNSAIDs.

TherapeuticoptionsforChronicGout

BigProblem?

PegloEcase UricosuricAgents

Lesinurad Arhalofenate

Ulodesine Levotofitospam

Reversalofchronicrefractorytophaceousgoutwitherosionswithpegloticase

InternaEonalJournalofRheumaEcDiseases2013;16:369–370

ProgressionofGout

InabaS,etal.Rheumatology2013;52:963-965.

AsymptomaEcHyper-

uricaemiaAcuteAhack

Recurrentahacks

ChronicGout

Uricacidnephro-lithiasis

ChronicNephro-pathy

Study No.ofPaEents RelaEveRiskofHypertension

Hawaii–LosAngeles–Hiroshima,2001

140men 2.0Emesgreaterat15yr(highvs.lowquarEle)

OsakaFactory,2003 433men 1.0mg/dl,increased27mmHgSBPat5yr

OsakaHealthSurvey,2003 2310men 1.13EmesgreaterperSDincrementat6yr

Okinawa,2004 4489men 1.46Emesgreaterformen(uricacid≥7mg/dl)and1.94forwomen(uricacid≥6mg/dl)at13yr

FraminghamHeart,2005 3329adults 1.17EmesgreaterperSDincrementat4yr

NormaEveAging,2006 2062men 125Emesgreaterat21yr(uricacid>6.5mg/dl)

ARIC,2006 9104adults 1.1EmesgreaterperSDincrementat9yr

BeaverDamHealthSurvey,2006

2520adults 1.65Emesgreaterat10yr(highvs.lowquinEle)

MRFIT,2007 3073men 1.1EmesgreaterperSDincrementat6yr

SinghJA.AnnRheumDisApril2015Vol74No4

WeiL,etal.BrJClinPharmacol.2011;71:4600–607.

Grimaldi-BensoudaL,etal.AnnRheumDis2014;0:1–7.

ì  Useofallopurinolmaybeassociatedwithanapproximately20%decreasedriskoffirst-evernon-lethalMI.

ì  OurstudydidnotconfirmthatMIriskwasreducedincolchicine.

ì  Gout,althoughcorrelatedwithuricacidandcardiovasculardisease,wasindependentlyassociatedwithtotalandcardiovascularmortality.

ì  MortalityimpactofgoutincreasedwithrisinguricacidConcentraEons.

StackA,etal.QJMeddoi:10.1093/qjmed/hct083

OlenaO,etal.Rheumatology2013;52:22512259

KumralE,etal.ActaNeurolScand2013:130:11–17

AmJCardiol2011;108:1362–1370

•  18%reducedriskofMyocardialInfarcEon•  21%reducedriskfortotalCardio-vasculardisease

Howlowistoolow?

LuN,etal.AnnRheumDis2015;0:1–5.

ìTheEnd–Thankyou

updated review of gout...

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