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FormularyJournalClinicalPharmacologyLogintosavetomylocker

Treatmentofrheumatoidarthritis:Areviewofrecommendationsand
emergingtherapy
December01,2011
ByJenniferN.Clements,PharmD,BCPS,CDE
Abstract
Rheumatoidarthritis(RA)isacomplexdisease,resultinginlocalizederosiontothejointanditsaccessorystructures.
Duetotheprogressivenatureofthedisease,extraarticularcomplicationswilloccurinmultipleorgansystems.Over
thepastdecade,themanagementofRAhasevolvedwithdiseasemodifyingantirheumaticagentswithbiologic
activitytargetingspecificcomponentsoftheimmunesystem.Withadvancedtherapy,managementincludeshalting
furtherprogressionofthediseaseandmaintainingqualityoflife.TheAmericanCollegeofRheumatologyhas
providedupdatedguidelinesregardingtheuseofbiologictherapiesasmonotherapyorincombinationwith
nonbiologictherapysuchasmethotrexate.Unmetneedsremain,however,forthemanagementofRAduetothe
complexityofthedisease.Innovativeagentsareneededtocreateadditionalstrategiesandachievedesiredgoalsforits
management.(Formulary.201146:532545.)
Rheumatoidarthritis(RA)ischaracterizedasachronic,inflammatorydiseaseinwhichtheimmunesystemdestroyssynovial
jointsandaccessorystructures.1,2Duetotheprogressivenature,thisautoimmuneconditioncancauseextraarticular
complicationswithinseveralorgansystems.3RAisthemostcommonautoimmunedisease,andthesecondmostcommon
formofarthritiscomparedtoosteoarthritis(OA).1,2
RAaffectsapproximately1%ofadultsallovertheworld.1,2Individualsareusuallydiagnosedbetweenthethirdandfifth
decadeoflifeandwomenare2to3timesmorelikelytobediagnosedthanmen.1,2Therefore,individualswithRAmay
experiencealowerqualityoflifeandamassalargeamountofdirectandindirectcostsduetothemanagementofthedisease,
hospitalizations,andphysicianvisits.
TheetiologyofRAisnotfullyunderstood,butenvironmentalandgeneticfactorshavebeenproposedaspotentialtheories.
Geneticpredispositionresultsinthedestructivenatureofthisautoimmunedisease.2Theinheritanceofcertaingenesinthe
majorhistocompatibilitycomplexcanincreasethesusceptibilityofdevelopingRA.Forexample,anindividualwith
expressionofahumanleukocyteantigen(HLA)DR4antigenwillbe3.5timesmorelikelytodevelopRAcomparedto
someonewithotherHLADRantigens.2Otherpotentialriskfactorsincludefemalegender,useoforalcontraceptives,
tobaccouse,andinfectiousagents.2
PATHOPHYSIOLOGY
Synovialjoints,suchastheknee,havethemostflexibilityduetounityofbonesbyconnectivetissueofanarticularcapsule
andaccessoryligaments.InRA,theimmuneresponsewillbeactivatedinanearlystageoflife.Thisimmuneresponsecould
betriggeredbygeneticandenvironmentalfactors.Oncetheimmunesystemisunbalanced,subclinicalinflammationwill
occurduetoactivationofTcellsfromanantigenpresentingcell.OnceTcellsareproliferated,acascadeofeventsoccursin
theimmunesystem:activationofBcellsandmacrophages,aswellasotherproinflammatorymediatorssuchastumor
necrosisfactor(TNF)andinterleukin(IL).Astheimmunesystemremainsunchecked,symptomsassociatedwithRAwill
occurandthecriteriaforthediseasewillbefulfilled.Oncethediagnosisisconfirmed,thepathologicinflammatoryresponse
cancontinue,resultinginjointdestructionandextraarticularcomplications.Withinasynovialjoint,boneandcartilage
erosionwilloccur,causingaswollenjointcapsuleandinflamedjointsynovium.Theextraarticularcomplicationscanoccur
overtimeandincludeinfections,lymphomas,cardiovasculardisease,andosteoporosis.13
CLINICALPRESENTATION
RAcanoccuratanyage,butinmenonsetbeforeage45yearsisuncommon.1Thediseasecandevelop
rapidlywithinweekstomonths.3Commonlyaffectedareasincludethehands,wrists,elbows,knee,
metatarsophalangealjoint,shoulder,andcervicalspine.Theareaofjointinvolvementissymmetricand
resultsinpain,morningstiffnesslastingmorethan1hour,gelling(orlockingwithinactivity),tenderness,
warmth,redness,andinflammation.Duetotheautoimmunenatureofthedisease,constitutionalsymptoms
willoccursuchaslowgradefeverandmalaise.AsRAprogresses,therecanbeextraarticularinvolvement
leadingtocomplications,suchasvasculitisandpulmonaryandcardiacissues.3
DIAGNOSIS
In1987,theAmericanCollegeofRheumatology(ACR)developedcriteriaforthe
classificationofthisdisease.4Developmentofnewer,moreaggressiveoptions,
however,hasmadetheACRclassificationoutdatedbecausethecriteriaarenot
sensitiveenoughtoidentifyearlyRA.ThereforeACRandtheEuropeanLeague

ILLUSTRATION
BYCHRISTY
KRAMES,MA,
CMI

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AgainstRheumatism(EULAR)collaboratedtodevelopnewclassificationcriteriafor
RAin2010.5Table1comparestheobsoleteandnewclassificationcriteriaforthe
disease.4,5Thenewclassificationcriteriaaresimpletofollowforpractitionerssuchas
primarycareproviderstodetermineanappropriatereferraltoarheumatologist.For
rheumatologists,thecriteriawillallowearlierinitiationofmoreaggressivetreatment
topreventprogressionanddisabilityofthedisease.Beforethenewclassification
criteriacanbeimplemented,2requirementsmustbemettoconfirmthediagnosisof
RA:evidenceofclinicalsynovitisinatleast1joint(excludingcommonjointsseenin
OA),andrulingoutsystemiclupuserythematosus,gout,andpsoriatricarthritis.5It
Table1:
willtakesometime,however,forthenewcriteriatobeusedbypractitionersand
Comparison
implementedinclinicaltrials.
between1987
criteriaand2010
MANAGEMENT
criteriafor
rheumatoidarthritis

ACRandEULARhavespecifictreatmentguidelinesforRA.68Onceadiagnosisis
made,thecombinationofnonpharmacologicandpharmacologictherapyshouldbeinitiated.Initially,educationisalways
warrantedregardingthediseaseanditsprogressivenature.Dependingonthepatient'slevelofdisability,physicaland/or
occupationaltherapyshouldbeconsideredtoimprovequalityoflife.Overall,pharmacologictherapyisthemainstayof
treatmentforRAandcanbedividedintosymptomatictherapyanddiseasemodifyingantirheumaticdrugs(DMARDs).Even
thoughthetreatmenthasemergedwithinnovative,morespecificagents,thereisnocureforRA.Aggressivetreatmentis
usedtopreventfurtherprogressionofthediseaseandhelpmaintainthepatient'squalityoflife.
TREATMENTOFRA
In2008,ACRdevelopednewrecommendationsfromthe2002guidelinesonthetreatmentofRA.6,7Inaddition,EULAR
publishedupdatedguidelinesin2010,whicharesimilartotheupdatesbyACR.8Thepurposeofthenewrecommendations
wastoprovideadditionalguidancefromclinicalevidenceandinputofanexpertpanel.Overall,theguidelinesaresimilarin
theirrecommendations.TreatmentwithaDMARDshouldbeginassoonasthediagnosisofRAisconfirmed.Therapycan
beintensifiedevery3to6monthswithnonbiologicand/orbiologicDMARDs,withmethotrexateaspartofthetreatment
regimenunlesscontraindicatedornottolerated.
Severalkeyrecommendationsareincludedintheupdatedtreatmentguidelines.First,
methotrexateorleflunomideisrecommendedformostpatientswithRA.Bothagentshave
documentedimprovementinobjectiveassessmentofthediseaseandreductionin
radiographicprogression.Table2summarizestherecommendationsforDMARDswithout
biologicactivityfromtheACR.7CombinationtherapyofaTNFantagonistandmethotrexate
canbeusedforpatientswithnewlydiagnosedorearlyRA.IfapatientfailsaparticularTNF
antagonistwithorwithoutmethotrexate,anotherDMARDwithbiologicactivitycanbe
Table2:Summaryof
initiatedaslongasthepatientdoesnothaveanycontraindications.Failureincludes
continuationornoimprovementinsymptomswithin3to6monthsofpharmacologictherapy recommendationsfromthe
ordevelopmentofpoorprognosis.ThealternativeDMARDswithbiologicactivityinclude ACRforDMARDswithout
anotherTNFantagonist,abatacept,orrituximabwithcost,comorbidities,anddrugrelated biologicactivity*
risksasthedecidingfactors.7PriortoinitiationofanyDMARDwithbiologicactivity,allpatientsshouldbeevaluatedfor
activeinfections(includingbacterial),herpeszosterinfection,hepatitisBandC,andactiveorlatenttuberculosis.Thelast
recommendationwasaddingacontraindicationofTNFantagonistsamongpatientswithheartfailure,lymphoma,ormultiple
sclerosisduetoongoingevidenceofacausalrelationship.ThechoiceofanyDMARDwithbiologicactivitywillbebasedon
theseverityofthedisease,previousresponsewithanagent,andcost.68ForthetreatmentofRA,questionsremainregarding
thebesttreatmentchoiceforamajorityofpatients.ComparativeefficacystudiesamongDMARDswithbiologicactivityare
lacking,asitisdifficulttoobtainthesamepatientpopulationandpredictthesamepatientresponsewithinaclinicaltrial.For
RA,clinicaltrialsaretypicallyshortinstudydurationtherefore,longtermevidenceislimitedregardingsafetyuntil
postmarketinginformationbecomesavailable.
Duetotheprogressivenatureofthedisease,therecanbeextraarticularcomplicationsforpatientswithRA.Oneofthe
majorcomplicationscanbecardiovascularmortalityormorbidity.9,10In2010,EULARpublished10keyrecommendations
regardingcardiovascularriskscreeningandmanagementforpatientswithRA,aswellasotherinflammatoryconditions(ie,
ankylosingspondylitisandpsoriaticarthritis).9Ingeneral,therecommendationsrecognizeearlyidentificationof
cardiovascularriskfactorsduetotheincreasedprevalenceinthegeneralpopulationandinflammatorypropertiesofthe
disease.Adequateriskmanagementandongoingmonitoringisrecommendedtolowerthecardiovascularriskofapatient
withRA.Forexample,itisrecommendedthatallpatientswithRAshouldundergoanannualcardiovascularriskassessment
usingariskscoremodel.EULARrecommendstheuseofnationalguidelinesfordeterminingtheappropriatemanagementof
apatient'shypertensionoryperlipidemia,suchasstatins,angiotensinconvertingenzymeinhibitors,andangiotensinreceptor
blockers.ForthetreatmentofRA,cyclooxygenase(COX2)inhibitorsandnonsteroidalantiinflammatorydrugs(NSAIDs)
shouldbeprescribedcautiouslyforapatientwithorwithoutdocumentedcardiovasculardisease,weighingtherisksand
benefits.Thelowestpossibledoseofanoralcorticosteroidshouldbeprescribedduetothelongtermsafetyprofile(ie,
hypertension,yperlipidemia,atherosclerosis).Lastly,smokingcessationshouldbeencouragedamongallpatientswithRA
whoactivelysmoke.9

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NSAIDs.NSAIDshavebeenusedinthemanagementofRAforseveraldecades.NSAIDsinhibitCOXtopreventfurther
formationofprostaglandinsandotherrelatedinflammatorymediators.Basedonitsmechanismofaction,NSAIDsareuseful
adjuvanttherapyforthesymptomaticmanagementofRA,asthisclassofmedicationscanreducejointswelling,tenderness,
andpain.6,11,12AllNSAIDsposeantiinflammatorypropertiesand,whenprescribedathighdoses,areequallyeffective.As
aclass,themaindisadvantageofNSAIDsincludesthesafetyprofile(ie,gastrointestinal[GI],nephrotoxicity,and
cardiovascular).Inaddition,itisdifficulttopredictanindividual'sresponsewithaparticularNSAID.Comparedtomore
specificagents(ie,COX2inhibitor),thereisnosuperiorevidencebetweenthesetherapeuticclassificationsof
medications.6,11Therefore,celecoxibistheonlyCOX2inhibitorthatcanbeanalternativeagentforanindividualproneto
GIbleedingorulcers.
Corticosteroids.Corticosteroidspossessantiinflammatoryandimmunosuppressivepropertiesthroughanunknownspecific
mechanism.However,itissuspectedthattheseagentshaveinhibitorypropertiesonthegenerationandmigrationofimmune
systemmediators.SimilartoNSAIDs,corticosteroidsarecommonlyusedforsymptomaticmanagement.6,11Theadvantage
ofcorticosteroidsistheavailableoralandintraarticularformulationsforthetreatmentofRA.Therefore,apatientcan
receivesystemicorlocalizedcorticosteroidtreatmentbasedonclinicalpresentation,particularlywithjointinvolvement.
Intraarticularinjectionsareusefulwhen1largejointisinvolvedintheclinicalpresentation.Specificinstructions,however,
shouldbeprovidedtothepatientregardingintraarticularinjections.Corticosteroidsmaybeusedasbridgetherapywith
DMARDstoavoidlongtermadverseevents.Somepatientsalsowillrequirecontinuoustherapytomaintainremissionofthe
disease.Withcontinuoustherapy,ACRrecommendsthelowestdoseofcorticosteroid(eg,prednisone<10mgdaily/d)to
controlsymptomsandreducetheriskofadverseevents.6Highdosesofcorticosteroidsalsomayneedtobeprescribedas
"burst"therapyduringexacerbations.
Diseasemodifyingantirheumaticdrugs.DMARDsarethemainstayofpharmacologictreatmentfor
RA.68Theseagentsconsistofagentswithnonbiologicorbiologicactivity.BasedonACRguidelines,
DMARDsshouldbeinitiatedwithin3monthsofRAdiagnosis,allowingforaggressivetreatmentofthe
disease.68Basedonseverityofthedisease,particularDMARDsmayberecommendedandprescribed
foranindividualorspecificpatient.DMARDswithoutbiologicactivityincludemethotrexate,
hydroxychloroquine,sulfasalazine,andleflunomide.Theseagentsdonottargetaspecificcomponentof
theimmunesysteminvolvedinthepathophysiologyofRAbutthesenonbiologicagentshavebeen
showntoimproveclinicaloutcomes.DuetoanenhancedunderstandinginthepathophysiologyofRA,
therapieswithbiologicactivityhavebeendevelopedtotargetaspecificcomponentoftheimmune
Table3:Summary
system.DMARDswithbiologicactivityincludeTNFantagonists,ILantagonists,Tcellmodulator,and ofDMARDs
Bcellmodulator.Table3summarizesDMARDswithoutandwithbiologicactivitybasedontherapeutic withoutandwith
classification,dosage,andcommonadverseeventswithmonitoringparameters.68,11,12
biologicactivity
PIPELINEAGENTS
SeveraltherapiesforRAarecurrentlybeinginvestigatedtoachievetheunmetneedsofitsmanagement,suchasoralandless
expensivemedicationsthemostpromisingtherapiesincludetofacitinib,fostamatinib,veltuzumab,ofatumumab,apremilast,
andsecukinumab.1333
TofacitinibisanoralJanuskinase(JAK)inhibitor,whichwillblockthesignalingforcytokineproliferation.13This
investigationalagentisnotaspecificinhibitorforaproinflammatoryimmunesystemmediator.Tofacitinib,however,targets
multiplecytokinestopreventinflammationandfurthererosionanddamagetojointsandaccessorystructures.13Inclinical
trials,thisJAKinhibitorhasbeeneffectivetoreduceACRclinicalparameters,buteachtrialhasdifferedinthestudydesign,
dosageoftofacitinib,andpatientpopulation.1416Thesafetyconcernwithtofacitinibincludeslongterm
immunosuppressionduetoitsmechanismofactionontheimmunesystemandchronicdosingcharacteristics.Inaddition,
cardiaceventsmaybeaconcernduetothedosedependentchangesinthecholesterolpanel.13Itispredictedthatthe
manufacturerwillbesubmittinganewdrugapplicationoftofacitinibforFDAapprovalattheendoftheyear.Ifapproved,
tofacitinibmaybeacompetitorforotherDMARDswithbiologicactivity,butlongtermsafetywillcontinuetobeaconcern
amongpractitioners.
Fostamatinibisatyrosinekinaseinhibitor,whichblockssignalingtoimmunecells.Thiscellsignalinhibitionwillprevent
theproliferationofimmunecellmediatorstocausefurtherdestructiononthejointsynovium.17Inaphase2multicenter,
randomized,doubleblindtrial,fostamatinibwasstudiedfor6monthsamongpatientswhofailedmethotrexateorother
biologictherapies.Nosignificantdifferencewasfoundinefficacyendpointsbetweenthedosesoffostamatinib(100mg
dailyorallytwicedailyvs150mgdailyorallyoncedaily),buteachdosewassuperiortoplacebo.Thistrialmaygenerate
interesttoinvestigatefostamatinibamongasubpopulationofpatientswithanelevatedCreactiveproteinduetoan
improvementinclinicaloutcomesfrombaseline.Themostcommonadverseeventsinthistrialwerenauseaanddiarrheaat
bothdosesoffostamatinib.18Phase3trialsareneededtoinvestigatetheuseoffostamatinibamongcertainsubpopulationsto
determineitsroleasapotentialalternateDMARD.
Veltuzumabandofatumumabaresimilaragentstorituximabtheseagentsaremonoclonalantibodies,blockingtheCD20
signaltopreventtheproliferationofimmatureandmatureBlymphocytes.Forveltuzumab,aphase2trialhascurrentlybeen
suspendedtoclarifyissuesaboutdrugproductionandfillingprocessitwillbeseveralyearsbeforeanyclinicalresultsare
available.19Ofatumumabiscurrentlyapprovedforchroniclymphocyticleukemia20duetoitsmechanismofaction,itwill
beanalternativeagentamongpatientswithRAwhohavehadaninadequateresponsetomethotrexateorotherbiologic
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therapies,particularlyTNFantagonists.2123Thedisadvantageforofatumumabwouldbeinfusiondelivery,whichmaynot
beconvenientforpatients.20OcrelizumabisanotheragentwithinhibitorypropertiesofCD20signalforBlymphocyte
proliferationhowever,clinicaltrialsforRAweresuspendedbecauseocrelizumabincreasedtheriskofopportunistic
infections.24
Apremilastisatype4phosphodiesterase(PDE4)inhibitor,whichisinvolvedwiththeinhibitionofTNFproduction.This
particulartypeofPDEisexpressedonmacrophages,lymphocytes,andneutrophils.25Currently,phase2clinicaltrialsare
underwaytodeterminetheroleofthisagentinRA.2628
Secukinumabisahumanizedmonoclonalantibody,targetingIL17Athisspecifictargetinhibitsthemigrationofmonocytes
andneutrophilsaroundthesiteofinflammation.29Thisparticularagenthasbeeninvestigatedas150mgdailysubcutaneous
psoriasistreatment.29Basedonitsmechanismofaction,secukinumabmaybeanoptionforRAduetoapotentialroleon
autoimmunediseases.3033
UPDATES
Overrecentmonths,severalupdateshavebeenreported.IntheJuneissueoftheJournaloftheAmericanMedical
Association,aretrospectivecohortstudywaspublishedregardingtheriskofdiabetesmellituswithDMARDsamong
patientswithRA.34ThepurposeofthestudywastoevaluatenewlydiagnoseddiabetesamongpatientswithRAorpsoriasis
onaparticulardrugregimen.ThesedrugregimensincludedaTNFantagonistwithorwithoutanotherDMARD,
methotrexatewithoutaTNFantagonistorhydroxychloroquine,hydroxychloroquinewithoutaTNFantagonistor
methotrexate,orotherDMARDswithoutbiologicactivity.Afteranevaluationof13,905subjects,anincreasedincidence
rateofnewonsetofdiabeteswasfoundamongthevariousdrugregimens:50.2forDMARDswithoutbiologicactivity,19.7
forTNFantagonists,23.8formethotrexate,and22.2hydroxychloroquineper1,000personyears.Whencomparedto
DMARDswithnonbiologicactivity,TNFantagonistsandhydroxychloroquinehadaloweradjustedriskfordiabetes(hazard
ratio[HR],0.62and0.54,respectively),whereasmethotrexatehadanHRof0.77.Thisstudyhasseveralweaknesses,
includingthelackofrandomizationwiththestudydesign.34Inaddition,itisdifficulttodetermineorassesstheclassification
diabetesamongparticipantsbecausetheAmericanDiabetesAssociation(ADA)haschangedthediagnosticcriteriaof
diabetesinrecentyears.Inthestudy,the2010ADAguidelinesorphysicianestablishedcriteriadefinedadiagnosisof
diabetes.Finally,nodifferentiationwasmadebetweendiabetesclassifications(type1ortype2).Arandomizedcontrolled
trialwouldneedtobeconsideredtodeterminethepreventionofdiabetesamongDMARDs.
InJuly2011,golimumabdidnotreceiveanexpansiononitsproductlabel.35FDAdeniedtheexpansionofthelabelto
inhibitionofprogressivestructuraldamage,inductionofclinicalresponse,andmaintenanceofclinicalpresentation,aswell
asphysicalfunctionamongpatientswithRA.Thedenialofitslabelexpansionwasduetothelackofclinicaltrialstosupport
thedrug'sclaims,aswellaspotentialrisksregardinggolimumab'ssafetyfrompostmarketingdata.Hypersensitivityand
anaphylacticreactionshavebeenreportedthroughadverseeventsreportingtotheFDA.35
InAugust2011,FDAapprovedasubcutaneousformulationofabatacept.36Inadditiontoaninfusion,itwillbeavailableasa
selfinjectablesubcutaneousformulationatafixeddoseof125mgdailyweekly.Forpatientsfailingabataceptinfusion,an
intravenousloadingdosewillnotberequiredpriortotheinitiationofweeklyinjectionswithabatacept.Patientswhohave
neverreceivedabatacept,however,willberequiredtoreceiveanintravenousloadingdoseof10mgdaily/kgpriorto
initiationofweeklyinjections.36AbataceptisnowtheonlyDMARDwithbiologicactivityavailableinbothsubcutaneous
andintravenousformulations.
ForTNFantagonists,acoupleofrecentupdatesmayimpactprescribingbypractitioners.First,arecentstudypublishedin
RheumatologyconcludedthatthereisahigherriskofnonmelanomaskincanceramongpatientsreceivingTNF
antagonists.37Theincidenceofthisparticularcancerwas18.9per100patientyearswhencomparedtoaDMARDwithout
biologicactivity,theHRwas1.42forTNFantagonistsintheriskofnonmelanomaskincancer.Thegreatestriskwasamong
patientsofadvancedage,malegender,useofNSAIDsorcorticosteroids,andpriorhistoryofmalignancies.37Althoughthis
studydemonstratedacausalrelationshipbetweenTNFantagonistsandnonmelanomaskincancer,itisdifficulttomake
directconclusionsduetotheobservationalstudydesign.However,itmayleadtoadditionalpatienteducationinregardtoa
completeskinexaminationforpatientswithRAwhoarereceivingTNFantagonists.TNFantagonistsalsowillgetan
updatedblackboxwarningregardingtheriskofbacterialinfections.38Duetopostmarketingdata,ListeriaandLegionella
infectionswillbeincludedinthewarninggiventheconsistentinformationoftheseinfectionsfromadverseevent
reporting.38ThisparticularupdatefurtheremphasizestheimportanceofpatienteducationpriortotheinitiationofTNF
antagonists,inwhichallpatientsshouldbeinformedandevaluatedforactiveinfections(includingbacterial),herpeszoster
infection,hepatitisBandC,andactiveorlatenttuberculosis.
Inregardtosymptomatictherapy,arecentarticleinCirculationfocusedonthedeterminationofthedurationofNSAID
treatmentandrelationshipwithcardiovascularriskamongpatientswithpreviousmyocardialinfarction(MI).39Using
nationwideregistries,thelengthoftimeoffirstMIandNSAIDusewasdeterminedbyincidencerates.Among
approximately84,000patients,therewasanHRof1.45associatedwithNSAIDuseandtheriskofdeathand/orrecurrent
MI.AmongtheNSAIDclass,diclofenacwasassociatedwiththehighestrisk(HR,3.26).Amongpatientswithahistoryof
recurrentorpriorMI,NSAIDsshouldbeavoidedasbothshortandlongtermuse.39
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CONCLUSION
ForthemanagementofRA,thegoalistoslowdiseaseprogressionandpreventdisability,suchaslossofphysicalfunction.
Ifapproved,theemergingtherapiesforRAmaynotchangethealgorithmforRAandapprovalbyFDAmaybeseveralyears
fromthepresenttime.Treatmentguidelines,however,havebeenupdatedtosupporttheuseofearly,aggressivetreatmentfor
apatientwithRA.Onthedownside,economicconsiderationsmaybeadrawbacktoexisting,advancedtherapiesand
emergingtherapies.AdditionalevidencewillbeneededgiventhatclinicaltrialswithRAhaveexhibitedwidevariabilityin
thepatientpopulation,clinicaloutcomes,andinterventions.Longtermbenefitsremaintobeseen,andmorecomparative
studieswithstandardofcareareneeded.
DrClementsisassistantprofessorofpharmacypractice,BernardJ.DunnSchoolofPharmacy,ShenandoahUniversity,
Winchester,Va.
DisclosureInformation:Theauthorreportsnofinancialdisclosuresasrelatedtoproductsdiscussedinthisarticle.
REFERENCES
1.O'DellJR.Rheumatoidarthritis.In:GoldmanL,SchaferAI,eds.Goldman'sCecilMedicine,24thed.Philadelphia,PA:
SaundersElsevier2011:16811689.
2.FiresteinGS.Etiologyandpathogenesisofrheumatoidarthritis.In:FiresteinGS,BuddRC,HarrisEDJr,etal,eds.
Kelley'sTextbookofRheumatology,8thed.Philadelphia,PA:SaundersElsevier2008:10351086.
3.HarrisEDJr,FiresteinGS.Clinicalfeaturesofrheumatoidarthritis.In:FiresteinGS,BuddRC,HarrisEDJr,etal,eds.
Kelley'sTextbookofRheumatology,8thed.Philadelphia,PA:SaundersElsevier2008:10871118.
4.ArnettFC,EdworthySM,BlochDA,etal.TheAmericanRheumatismAssociation1987revisedcriteriaforthe
classificationofrheumatoidarthritis.ArthritisRheum.198831(3):315324.
5.AletahaD,NeogiT,SilmanAJ,etal.2010rheumatoidarthritisclassificationcriteria:AnAmericanCollegeof
RheumatologyandEuropeanLeagueAgainstRheumatismcollaborativeinitiative.ArthritisRheum.201069(9):25692581.
6.AmericanCollegeofRheumatologySubcommitteeonRheumatoidArthritisGuidelines.ArthritisRheum.
200246(2):328346.
7.SaagKG,TengGG,PatkarNM,etal.AmericanCollegeofRheumatology2008recommendationsfortheuseof
nonbiologicandbiologicdiseasemodifyingantirheumaticdrugsinrheumatoidarthritis.ArthritisRheum.200859(6):762
784.
8.SmolenJS,LandeweR,BreedveldFC,etal.EULARrecommendationsforthemanagementofrheumatoidarthritiswith
syntheticandbiologicaldiseasemodifyingantirheumaticdrugs.AnnRheumDis.201069:964975.
9.PetersMJL,SymmonsDP,McCareyD,etal.EULARevidencebasedrecommendationsforcardiovascularrisk
managementinpatientswithrheumatoidarthritisandotherformsofinflammatoryarthritis.AnnRheumDis.
201069(2):325331.
10.KaplanMJ.CardiovascularcomplicationsofrheumatoidarthritisAssessment,preventionandtreatment.RheumDis
ClinNorthAm.201036(2):405426.
11.BirchJTJr,BhattacharyaS.Emergingtrendsindiagnosisandtreatmentofrheumatoidarthritis.PrimCare.
201037(4):779792.
12.ScottDL,WolfeF,HuizingaTW.Rheumatoidarthritis.Lancet.2010376(9746):10941108.
13.YamaokaK,KuboS,SonomotoK,etal.JAKinhibitor:Tofacitinib,anewdiseasemodifyingantirheumaticdrug.
InflammationRegeneration.201131(4):349353.
14.CoombsJH,BloomBJ,BreedveldFC,etal.Improvedpain,physicalfunctioningandhealthstatusinpatientswith
rheumatoidarthritistreatedwithCP690,550,anorallyactiveJanuskinase(JAK)inhibitor:Resultsfromarandomised,
doubleblind,placebocontrolledtrial.AnnRheumDis.201069(2):413416.
15.RieseRJ,KrishnaswamiS,KremerJ.InhibitionofJAKkinasesinpatientswithrheumatoidarthritis:Scientificrationale
andclinicaloutcomes.BestPractResClinRheum.201024:513526.
16.BonillaHernnMG,MirandaCarsME,MartinMolaE.Newdrugsbeyondbiologicsinrheumatoidarthritis:The
kinaseinhibitors.Rheumatology.201150(9):15421550.
17.OkamotoH,KobayashiA.Tyrosinekinasesinrheumatoidarthritis.JInflammation.20118:21.
18.WeinblattME,KavanaughA,GenoveseMC,etal.Anoralspleentyrosinekinase(Syk)inhibitorforrheumatoidarthritis.
NEnglJMed.2010363:13031312.
5/7

6/1/2016

19.VELVET,adoserangefindingtrialofveltuzumabinsubjectswithmoderatetosevererheumatoidarthritis.
http://clinicaltrials.gov/|~http://clinicaltrials.gov/identifier:NCT01390545.AccessedDecember1,2011.
20.Arzerra(ofatumumab)[prescribinginformation].ResearchTrianglePark,NC:GlaxoSmithKlinerevised,September
2011.
21.Investigatingclinicalefficacyofofatumumabinadultrheumatoidarthritis(RA)patientswhohadaninadequateresponse
toMTXtherapy.Availableat:http://clinicaltrials.gov/|~http://clinicaltrials.gov/identifier:NCT00611455.Accessed
December1,2011.
22.Investigatingclinicalefficacyofofatumumabinadultrheumatoidarthritis(RA)patientswhohadaninadequateresponse
toTNFantagonisttherapy.Availableat:http://clinicaltrials.gov/|~http://clinicaltrials.gov/identifier:NCT00603525.
AccessedDecember1,2011.
23.LongtermefficacyandsafetyofrepeatedofatumumabtreatmentcoursesinRApatientswhopreviouslyreceived
ofatumumaborplacebointrialHxCD20403.Availableat:http://clinicaltrials.gov/|~http://clinicaltrials.gov/identifier:NCT
00655824.AccessedDecember1,2011.
24.Rochenewsbrief.Mediarelease.March8,2010.RocheandBiogenIdecdecidetosuspendocrelizumabtreatment
rheumatoidarthritisdevelopmentprogrammeonhold.Availableat:http://www.roche.com/media/media_releases/medcor
20100308.htm|~http://www.roche.com/media/media_releases/medcor20100308.htm.AccessedDecember1,2011.
25.McCannFE,PalfreemanAC,AndrewsM,etal.Apremilast,anovelPDE4inhibitor,inhibitsspontaneousproductionof
tumournecrosisfactoralphafromhumanrheumatoidsynovialcellsandamelioratesexperimentalarthritis.ArthritisRes
Ther.201012(3):R107.
26.Thecontrolledtrialofapremilastforrheumatoidarthritistreatment(CARAT).Availableat:
http://clinicaltrials.gov/|~http://clinicaltrials.gov/identifier:NCT01250548.AccessedDecember1,2011.
27.Studyofapremilasttoevaluatethesafetyandeffectivenessforpatientswithrheumatoidarthritis.Availableat:
http://clinicaltrials.gov/|~http://clinicaltrials.gov/identifier:NCT01285310.AccessedDecember1,2011.
28.ConcomitantuseofapremilastforthetreatmentofactiveRAdespiteTNFinhibitionandmethotrexateCATARA.
Availableat:http://clinicaltrials.gov/|~http://clinicaltrials.gov/identifier:NCT01204138.AccessedDecember1,2011.
29.KurzejaM,RudnickaL,OlszewskaM.Newinterleukin23pathwayinhibitorsindermatology:ustekinumab,
briakinumab,andsecukinumab.AmJClinDermatol.201112(2):113125.
30.Efficacy,safety,andtolerabilityofsecukinumabinpatientswithrheumatoidarthritistakingmethotrexate.Availableat:
http://clinicaltrials.gov/|~http://clinicaltrials.gov/identifier:NCT01359943.AccessedDecember1,2011.
31.Efficacyat24weeksandsafety,tolerabilityandlongtermefficacyupto2yearsofsecukinumab(AIN457)inpatients
withactiverheumatoidarthritisandaninadequateresponsetoantiTNFagents.Availableat:
http://clinicaltrials.gov/|~http://clinicaltrials.gov/identifier:NCT01377012.AccessedDecember1,2011.
32.Efficacyat24weeksandsafety,tolerabilityandlongtermefficacyupto1yearofsecukinumab(AIN457)inpatients
withactiverheumatoidarthritis(RA)andaninadequateresponsetoantitumornecrosisfactor(antiTNF)agents.
Availableat:http://clinicaltrials.gov/|~http://clinicaltrials.gov/identifier:NCT01350804.AccessedDecember1,2011.
33.Abiomarkerstudyofsecukinumabinrheumatoidarthritispatients.Availableat:
http://clinicaltrials.gov/|~http://clinicaltrials.gov/identifier:NCT01426789.AccessedDecember1,2011.
34.SolomonDH,MassarottiE,GargR,etal.Associationbetweendiseasemodifyingantirheumaticdrugsanddiabetesrisk
inpatientswithrheumatoidarthritisandpsoriasis.JAMA.2011305(24):25252531.
35.JanssenBiotech.Pressrelease.FDAissuescompleteresponselettertoJanssenBiotech,Inc.forSimponisupplemental
biologiclicenseapplication.Availableat:
http://www.janssenbiotech.com/assets/PressRelease07222011.pdf|~http://www.janssenbiotech.com/assets/PressRelease07222011.pdf
.AccessedDecember1,2011.
36.Orencia(abatacept)[prescribinginformation].Princeton,NJBristolMyersSquibbrevised,2011.
37.AmariW,ZeringueAL,McDonaldJR,etal.Riskofnonmelanomaskincancerinanationalcohortofveteranswith
rheumatoidarthritis.Rheumatology.201150(8):14311439.
38.FDAU.S.FoodandDrugAdministration.FDADrugSafetyCommunication:Druglabelsforthetumornecrosisfactor
alpha(TNF)blockersnowincludewarningsaboutinfectionwithLegionellaandListeriabacteria.Availableat:
http://www.fda.gov/Drugs/DrugSafety/ucm270849.htm|~http://www.fda.gov/Drugs/DrugSafety/ucm270849.htm.Accessed
December1,2011.
39.SchjerningOlsenAM,FosbolEL,LindhardsenJ,etal.Durationoftreatmentwithnonsteroidalantiinflammatorydrugs
andimpactonriskofdeathandrecurrentmyocardialinfarctioninpatientswithpriormyocardialinfarction:Anationwide
6/7

6/1/2016

cohortstudy.Circulation.2011:123:22262235.

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