GOUTYARTHRITIS:CURRENTTREATMENTS&NEWDEVELOPMENTS JenniferBettschen BSPCandidate2010 INTRODUCTION Goutyarthritis,morecommonlyreferredtoasgout,isoneofthebestunderstoodand mostmanageablerheumaticdiseases(9).Itisapainfulconditioncausedbydepositsofurate crystalsinajoint,mostcommonlythebig toe(1,2,5).Effectivetreatmentsareavailableforgout andothersarebeinginvestigatedallthetime. Uricacidisabyproductofpurinemetabolisminthebody(1).Purinescomefromfoods suchasredmeat,herring,asparagusandmushrooms.Uricacidhasnobiologicalfunctionin humans(2).Itisdissolvedintheblood,passesintothekidneys,andexcretedintheurine.An attackofgoutoccurswhentheuratecrystallizesintomonosodiumurate(MSU)crystals,and depositsinajoint,orjoints,somewhereinthebody.Thebuildupofthesharp,needlelike crystalscausespainandinflammation.

Hyperuricemiaiscausedbyincreasedproductionor decreasedexcretionofurateinthebody(1,2,5,6).Itisimportanttonotethatgoutand hyperuricemiaarenotthesamecondition.Aswell,apersoncanhaveanattackofgoutwithout thepresenceofhyperuricemia,andviceversa. Goutismoreprevalentinmenthaninwomen(1,6).Itisusuallyfirstseenbetweenthe agesof40and50inmen,andinpostmenopausalwomen.Premenopausalwomenareless likelytodevelopgoutbecauseestrogencausesincreasedurateclearance. Attacksofgoutdonottendtohaveprecipitatingevents(2).However,certainconditions cancontributetothedevelopmentofgout,suchas obesity,insulinresistance,hypertension, andhyperlipidemia(1,8).Crashdieting,adietofrichfoodsandtotalparenteralnutritionmay alsocontribute.Excessivealcoholconsumptioncanpredisposetogout(1,5,9).Excessivealcohol intakeisdefined asmorethan2drinksperdayformenandmorethanonedrinkperdayfor women.Itisimportanttonote,however,thatmoderatewineconsumptiondoesnotcontribute tothedevelopmentofgout.

Potentialsecondarycausesofgoutincludeinfection,traumaandsurgery,suchasa renalallograft(2,5).Drugsthatcompeteforrenalexcretionmayalsocontribute.Theseinclude drugssuchasloopandthiazidediuretics,lowdoseAspirin,andcyclosporine.Cyclosproineis particularlyproblematicinallograftpatients;upto80%ofallograftpatientsoncyclosporinewill develophyperuricemia(9). Somepatientswhoexperienceanattackofgoutwillneverhaveanotheroneintheirlife (2,5).However,manypatientsexperiencerecurrentattacks,soitisimportanttomonitor patientsandtoprovidebothacuteandpossiblyprophylactictreatment.

SIGNS&SYMPTOMS Anattackofgoutusuallyoccursatnight,suddenlyandwithoutwarning(1,2,5).Painis moderateatfirstandbuildsoverseveralhoursuntilitbecomes almostunbearable.Initial attacksofgoutaremonoarticular(affectingonlyonejoint)andareusuallysomewhereinthe lowerextremities.Themostcommonmanifestationofgoutiscalledpodagra(2).Thisiswhen thelargejointofthebigtoeisaffected.Theaffectedjointbecomesswollen,tenderandred (1,2,5).Thismayalsobeaccompaniedbyfeverandchills.Thepainisnotsharp,butratheran intensepressure,likebeingsqueezedinavice. Goutcanalsooccurinthefeet,ankles,knees,wristsandhands(1,2,5).Thehips, shouldersandspinearerarelyaffected,likelyduetotheseareasbeingofaslightlyhigher temperaturethatisnotconducivetocrystallization(8).Recurrentattacksofgoutbecome polyarticular(affectingmultiplejoints)andwillinvolvetheascendingextremities(2). Prophylactictreatmentofgoutcanbeusedinpatientsexperiencingrecurrentattacks.

DIAGNOSIS Goutissuspectedifapatientcallstheirphysiciancomplainingofjointpainandfever, thoughajointfluid testisneededtomaketheofficialdiagnosis(1,2).Synovialfluidisdrawn fromtheinflamedjointandlookedatunderamicroscopeforthepresenceofMSUcrystals.The crystalsarelongandneedleshaped.Serumuratelevelsarenotusuallyusedasan indicatorof goutbecause,ashasalreadybeenstated,hyperuricemiaisnotdiagnosticofgout(6).An

increasedserumuratelevelfavourscrystalformation,butevenduringanacuteattackofgout theserumlevelsmayappearnormal.

TREATMENT Acute Episodesofgoutareselflimitingandwillresolvewithin7to10dayswithouttreatment (6).However,treatmentcanprovidepainreliefandspeedtherecoveryprocess.Themain reasonfortreatmentfailureispatientnoncompliance,thoughthiscanbepreventedwith properpatientcounselling.Treatmentshouldbestartedassoonaspossibleafterthediagnosis; thesoonerthetreatmentisstarted,thequickertheresponse.

NSAIDs Nonsteroidalantiinflammatories(NSAIDs)areusedtorelievepainandinflammation, whichistheimmediategoalofantigouttherapy(1,2).NSAIDsincludeindomethacin, ibuprofen,naproxenanddicolfenac(4).NSAIDsarethedrugsofchoiceforthetreatmentof goutbecausetheyareoflongdurationandhaveabettersideeffectprofilethanotheranti goutdrugs,suchascolchicine.Thesedrugsaregenerallywelltoleratedandthesideeffectsare mildduetotheshortdurationoftherapy. ThechoiceofNSAIDuseddependsonthepatient(6).Whenimprovementinsymptoms begins tooccuritisrecommenedtotaperthedosetodecreasethepotentialfor gastrointestinal(GI)toxicity.NSAIDsarecontraindicatedforpatientswithheartfailure,GI disease,renalinsufficiencyandthosepatientsonanticoagulanttherapy(4,5,6).Luckilythere areothertherapeuticoptionsavailableforthesepatients.

Colchicine AlthoughNSAIDsarethepreferreddrugsforthetreatmentofacutegout,colchicine offerssomethingNSAIDsdonot:specificity.Colchicineisspecificforgout(4).Patientswhodo notwanttoundergoapainfuljointaspirationcanbegivencolchicine.Ifthesymptomsclearup, itisassumedthatthepatienthadanattackofgout.

ColchicineisanantimitoticthatpreventsMSUcrystalsfrombecomingdepositedin joints(7).ItalsopreventsphagocytosisofdepositedMSUcrystals,theprocessthatcontributes toinflammation.Colchicineismosteffectivewithin10to12hoursofanattack,andwillresolve anattackofgoutwithin2to3days(4).ThemajorflawofcolchicineisthatitcausesGIdistress, resultinginnauseaandvomitingordiarrhea(1,4).Theappearanceofthesesideeffects coincideswithimprovementinjointsymptoms.Patientsareadvisedtotakethedruguntilpain isrelievedoradverseGIeffectsoccur(2,3).OftenGIdistressoccursbeforepainrelief,and patientsareadvisedtostoptakingthedrugoncetheyoccur(6).Again,NSAIDsaregenerally preferredover colchicineitsbecauseofitsadverseGIeffects.

Corticosteroids Corticosteroidssuchasprednisonecanbeusedasalastresortforgouttherapy,when neitherNSAIDsnorcolchicinecanbeused(1,9).Aswell,intraarticularsteroidscanbeuseful whenmediumtolargejointsareaffected(9).Steroidsareusedtocontrolpainand inflammation.Normallypatientstakingcorticosteroidsaregiventapereddoseswhencoming offoftreatment(2,3).However,taperingisnotusuallynecessaryforgoutpatientsbecauseof theshortdurationoftherapy.

Prophylaxis Prophylactictreatmentofgoutinvolvesdecreasinguricacidproductionorincreasing uricacidsecretion(1,3,5).Atthetimeofanacuteattack,thesedrugscanactuallyworsenthe problem;byrapidlydecreasingserumurateconcentration,uratestoreswillmobilizeand prolongtheattack(2).Itisrecommendedtostartprophylaxis3to4weeksaftertheresolution ofanacuteepisode(2,6).Starttherapyatalowdoseandgraduallyincreaseover several weeks.Itisalsorecommendedtousecolchicineprophylacticallyforonemonth,atasmalldaily doseof0.5to0.6milligrams(5).

Uricosurics Uricosuricslikeprobenecidandsulfinpyrazoneincreaserenalexcretionofuricacidby inhibitingtubularreabsorptioninthekidneys(1,3).Itisimportanttostartatlowdosesbecause largeamountsofuricacidpassingthroughthekidneyswillincreasetheriskofforminguricacid stones(2).Theantihypertensivedruglosartanhasbeenshownto haveauricosuriceffect,but thiseffectdecreasesdrasticallyoncethedrughasreachsteadystate(9).Itcanalsoworsenpre existingrenalimpairment.Uricosuricdrugsarecontraindicatedforpatientswithkidneystones andrenalinsufficiency(7,9). Thosepatientsshoulduseadrugthatwillfunctionindependently ofkidneyfunction.

Allopurinol Allopurinolisaxanthineoxidaseinhibitorandworkstoblocktheproductionofuricacid (1,2).Allopurinolworksindependentlyofrenalfunction,soitisidealforpatientswithrenal insufficiency(5).Serumuratelevelsbegintofallwithin1to2daysofbeginningtherapy,and willreachmaximalsuppressionwithin7to10days. Allopurinolisgenerallywelltolerated,buthypersensitivityreactionscanbeaproblem (2,9).Rashisthemostcommonadverseeffectandpatientsareadvisedtodiscontinuetaking thedrugifarashappears(3).Thereisanincreasedriskofhypersensitivityreactionsinpatients concurrentlytakingangiotensinconverting enzymeinhibitorsandthiazidediuretics.

Diet&AlcoholIntake Dietaryintervention,weightmanagementanddecreasedalcoholconsumptioncan reducehyperuricemiaingoutpatients(9).Purinerestricteddietsarenotverypalatableand rarelymaintained,soresearchersarelookingintotailored,lowcarbohydrateandcalorie restricteddiets.Itisrecommendedtoincreaseproteinandunsaturatedfatintake,andtoavoid crashdietsandfasting(6,9).Aswasstatedearlier,excessivealcoholconsumptionisassociated withanincreasedriskofdevelopinggout.Goutpatientsshouldbediscouragedtoavoidalcohol intakeandtodrinklotsfluids(3,9).Dairyconsumptionhasbeenassociatedwithdecreasedrisk

ofgout,possiblyduetoauricosuriceffectofmilkproteins(12).Thisassociationhasnotbeen entirelyestablishedyetandisstillbeingresearched.

Fenofibrate Fenofibrateisemergingasanewpossibleprophylactictreatmentforgout.Thedrugis normallyusedtotreathyperlipidemiabydecreasing triglyceridelevelsandincreasingHDL cholesterollevels(8).Thedrughasalsobeenshowntolowerserumuratelevels.Longterm administrationoffenofibratehasbeenassociatedwithsubstantialandsustaineddecreasein serumurate.Ithasalsobeenassociatedwithadecreaseinacutegoutattacks. OnecasereportexplainshowaTypeIIdiabetesmellituspatient,withahistoryof severalgoutattacksperyear,hashadnoattackssincestartingfenofibratetherapy(8).The patienthasalsohadnoneedforprophylaxis.Anothercasereportshowsapatientwitha historyofgoutrespondingwelltofenofibratetherapywhenotherprophylactictreatments havefailed. Fenofibrateincreasesrenalclearanceofuricacid,aneffectnotseenwithotherfibrates (8).Althoughfenofibratesurateloweringeffectisnotasgoodastraditionaluricosuricssuchas probenecid,researchersaresuggestingitmaybeusedincombinationwithotherantigout drugs.Fenofibratelookstobeapromisingadjuncttoantigout therapy.

CONCLUSION Goutyarthritisisapainfulbutreadilytreatableconditionexperiencedbymanyadults. The prevalenceofgoutinWesterncountriesisontherise,mostlikelyduetolifestylechoices. Hypertension,highalcoholintake,diureticuse(specifically,thiazidesandloopdiuretics)and obesitycontributebothindependentlyandadditivelytothedevelopmentofgoutin hyperuricemicpatients(9).Prevalenceisalsorisinginelderlypatients,possiblyduetohigh ratesofdiureticuseandthedeclininguseofestrogenreplacementtherapy.Thisisproblematic becausetraditionaltreatmentsforgoutsuch ascolchicineandNSAIDshaveahigherriskof toxicityinelderlypatients.

Researchshowshyperuricemiatobeagoodpredictorofischemiccardiovascular diseasesandpooroutcomesrelatedtothesediseases(9).Althoughasymptomatic hyperuricemiaisnotanindicationfortherapy(3,9),researcherssuggestthattreating asymptomatichyperuricemiamayimprovemanagementofcardiovasculardisease(9). Thoughthetreatmentofgouthaslongbeenestablished,researchersarestillfinding potentialnewtreatments,suchasfenofibrate,andpotentialimplicationsfortreatment,suchas outcomesincardiovasculardisease.Goutresearchremainsanimportantendeavour.

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4)Hoskison,T.K.andWortmann,R.L.Advancesinthemanagementofgoutandhyperuricemia. ScandinavianJournalofRheumatology 2006;35(4):251260 5)Clive,D.M.Renaltransplantassociatedhyperuricemiaandgout. JournalofAmericanSociety ofNephrology 2000;11:974979 6)Suresh,E.Diagnosisandmanagementofgout:arationalapproach. PostgraduateMedical Journal 2005;81:572579 7)Nudo,C.G.andRuss,A. CanadianDrugPocketClinicalReferenceGuide. 8)Hepburn,A.L.,Kaye,S.A.andFeher,M.D.Longtermremissionfrom goutassociatedwith fenofibratetherapy. ClinicalRheumatology 2003;22:7376 9)Bieber,J.D.andTerkeltaub,R.A.Onthebrinkofnoveltherapeuticoptionsforanancient disease. Arthritis&Rheumatism 2004;50(8):24002414