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

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.

Whygiveaprimarycareupdateongout?3.Goutisgenerallymismanaged

–Underuseofuricacidloweringtherapy(ULT)ineligiblepatientslikelytobenefit

–Under-dosingofallopurinolinpatientsonULT(40%withserumuricacid>6oncurrentdose)

– Initialoverdosingofallopurinolinsomepatientsatriskforhypersensitivity

Whygiveaprimarycareupdateongout?

4.Plethoraofurate loweringtherapiescurrentlyavailableorcomingtomarket

Goutinrecentgeneralmedicalliterature

NEJM

Lancet

ACPGuidelines2017:Extraordinarydisappointment

Goutguidelinespublishedbyrheumatologysocieties

US: ACR 2012 Europe: EULAR 2016

AcuteGout• Acute,usuallyselflimitedmonoarticularinflammatoryarthropathy

• Inflammatoryresponsedirectedagainstmonosodiumurate crystalsinsynovium

• Usuallybutnotalwaysassociatedwithhyperuricemia

• Monosodiumurate crystalsprecipitatearoundataconcentrationof6.8mg/dL,withinreferencerangeinmostUSpopulations

DistributionofSerumUricAcidLevelsinJapan:34,000People

“Normal”= Mean + 2SD

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

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

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

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

Allopurinol ispurine derivative:adeadringerforhypoxanthine

AllopurinolcompeteswithHypoxanthineforxanthineoxidase

PurineMetabolism

Usingallopurinolproperly• Donotstartpatientsonmorethan100mg/day

• DosereduceALLpatientswithmoderatetosevererenalinsufficiency

• Graduallyup-titratethedose,whichinsomecases, canbemorethan300mg/dayifneeded

• TreattoTarget:serumurateconcentration<6iftreatingtophi,and<5ideally.

• Pushtheallopurinoldoseover300mg/dayifnecessary!!

EULAR2016TreattoTargetRecommendations

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.

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

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

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

PurineMetabolism

Urinary Excretion

EfficacyofPegloticaseSundyetal.A&R2008

• Phase2randomizedopenlabeldoserangingstudy41patientswithserumurate>8

• Intoleranceorinadequateresponsetostandardurateloweringtherapy(UA>6)foratleast3months

• Plusoneofthefollowing:– Atleastonetophus– Atleastoneflareinlast6months– Chronicgoutyarthropathy

EfficacyofPegloticasePhase2(12week)openlabeldosingtrial41patients

VisibleResults

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: journals.permissions@oxfordjournals.org.

Hyperuricemia

ChronicGout:Uricosuric agents

• Probenecid:Anoldfriend– Uricosuric agentblockstubularre-absorptionofuricacid

– Usefulinpatientswhounder-excreteuricacid(90%)

– Ifneedbe,confirmunder-excretionwith24hr.uricacid<800mg/24hrs.

– Donotuseif:• Tophi• Renalinsufficiency• Clearoverproductionsyndrome

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

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

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

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)

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.