Treatment of Rheumatoid Arthritis

Treatment of Rheumatic Arthritis

1. TREATMENT
OF
RHEUMATOID ARTHRITIS (RA)

2. RheumatoidArthritis(RA)
Autoimmunediseaseinwhichthereisjoint
inflammation,synovialproliferation&
destructionofarticularcartilage.

3. ▶ImmunecomplexescomposedofIgMactivate
complement&releasecytokines(mainlyTNF
alphaandIL-1)whicharechemotacticfor
Neutrophills.
▶Theseinflammatorycellssecretelysosomal
enzymeswhichdamagecartilage&erodebone,
whilePGsproducedintheprocesscause
vasodilatation&pain.
RheumatoidArthritis(RA)

4. ▶RAisachronicprogressive,cripplingdisorder.
▶NSAIDsarethefirstlinedrugs&afford
symptomaticreliefinpain,swelling,morning
stiffness,immobilitybutdonotarrestthe
diseaseprocess.
RheumatoidArthritis(RA)

5. Goalsofdrugtherapy:
▶Amelioratepain,swelling&jointstiffness
▶Preventarticularcartilagedamage&boneerosion.
▶Preventdeformity&preservejointfunction
RheumatoidArthritis(RA)

6. Inflammatory
Arthritis
Inflammatory
Mediators&Cells
Pain
Joint
Destruction
NSAIDS
DMARDS
Biologics
Cytotoxicdrugs
Surgery&
Rhabilitation
Immune
response
Immunomodulater

7. NSAIDs
Glucocorticoids
DMARDs(DiseaseModifyingAnti-RheumaticDrugs)
Immunosuppressive& cytotoxicdrugs
Biologics
Medicalmanagement

8. ▶Doesnotaffectdisease
progression
▶GItoxicitycommon
▶Renalcomplications
(eg,irreversiblerenalinsufficiency,
papillarynecrosis)
▶Hepaticdysfunction
▶CNStoxicity
Advantages Disadvantages
▶Effectivecontrolof
inflammationandpain
▶Effectivereductioninswelling
▶Improves mobility, flexibility,
rangeofmotion
▶Improvequalityoflife
▶Relativelylow-cost
ProsandConsofNSAID Therapy

9. Cons
▶Does not conclusively affect
diseaseprogression
▶Tapering &discontinuation of
useoftenunsuccessful
▶Low doses result in skin
thinning,ecchymoses&
Cushingoidappearance
▶Significantcause ofsteroid-
inducedosteopenia
Pros&Consof
Corticosteroid Therapy
▶Anti-inflammatory &
immunosuppressiveeffects
▶Canbeusedto bridgegap
betweeninitiationofDMARD
therapy&onset of action.
▶Intra-articular injections can
beusedforindividualjoint
flares
Pros

10. DiseaseModifyingAnti-RheumaticDrugs
▶Methotrexate(first choice)
▶Cyclosporine
▶Gold-oral /parenteral
▶Hydroxychloroquine
▶Leflunomide(Prodrug)
▶Azathioprine
▶D-Penicillamine
▶Sulfasalazine(Prodrug)
Minocycline
Tofacitinib

11. AdvantagesofDMARDs
▶Slowdiseaseprogression
▶Improvefunctionaldisability
▶Decreasepain
▶Interferewithinflammatoryprocesses
▶Retard developmentof jointerosions

12. BiologicDrugs
TumorNecrosis Factorα(TNFα)Inhibitors: IAEC G
Infliximab
Etanercept
Adalimumab
Certolizumabpegol
Golimumab
Interleukin-1 Receptorantagonist (IL-1R)
Anakinra
Interleukin-6Receptorantagonist (IL-6R)
Toclizumab, Sarilumab
FusionproteinblocksTcellactivation/ co-stimulation inhibitor
Abatacept, Belatacept

13. •DMARDoffirstchoicetotreatRA
Mechanism ofAction:
•Methotrexateactsondihydrofolate reductase
(DHFR)Increasethelocalreleaseofadenosine
•Whichactsasanti-inflammatoryagent
METHOTREXATE

14. (Anti-inflammation)
SAM-S –adenosylmethionine
METHOTREXATE

15. Inhibitionofamino-imidazolecarboxamide
ribonucleotide(AICAR)reductaseenzyme.
AICARwhichaccumulatesintracellularly,competitively
inhibitsAMPdeaminaseleadingtoanaccumulation
ofAMP.
TheAMPisreleased& convertedextracellularly to
adenosine,whichisapotentinhibitorof inflammation.
Inflammatoryfunctionsofneutrophils,macrophages,
dendriticcells&lymphocytesaresuppressed.
METHOTREXATE

17. Pharmacokinetics
•Itappr.70%absorbedafteroraladministration
•Metabolizedtoalessactivehydroxylated
metaboliteboththeparentcompound&the
metabolitearepolyglutamatedwithincellswhere
theystayforprolongedperiods.
•Methotrexate'sserumhalf-lifeisusuallyonly6–9hrs
•Excretedprincipallyintheurinebutupto30%may
beexcretedinbile.
METHOTREXATE

18. AdverseEffects
•Nausea& mucosalulcersarethemostcommon
•Pancytopenia
•Hepatotoxicitywith fibrosis & cirrhosis (Chronic hepatitis;
Heavy alcohol consumption; DM; Obesity; Kidney diseas)
•Interstitial pneumonits(hypersensitivity reaction)
•Teratogenicity
•Increased risk of B-cell lymphomas
Antidote: Reducedbytheuseofleucovorin24hoursafter
each weeklydose
Contraindicatedinpregnancy
DI: Amoxycillin& Probenecid increase risk of methotrexate
toxicity
METHOTREXATE

19. SelectionofanInitial DMARD:
Methotrexate
Pros
Favorablerateof
continuationof
therapy
Provenefficacyin
moderatetosevere
RA
Cons
Laboratorymonitoring
every4-8wks.
Toxicities:hepatotoxicity,
myelosuppression,
pulmonarytoxicity

20. Responseratesof DMARDs
▶Methotrexate,sulfasalazine,intramusculargold,
penicillamine,cyclosporin&leflunomideseem
tohavesimilarclinicalefficacy.
▶Hydroxychloroquin&oralgoldareless
effective.
▶HCQispreferredoverchloroquineduetolesschances
ofretinaldamage.

21. Sulfasalzine
Sulfasalazine,asyntheticNon-biologicDMARD
metabolizedtosulfapyridine&5-aminosalicylicacid.
PreviouslyactivemoietyisRA&Latterisusefulfor
ulcertivecolitis.
SuppressionofT-cellresponses
Inhibitthereleaseofinflammatorycytokines
producedbymonocytesormacrophages,
Eg:IL-1,-6,and-12,andTNF-α

22. ▶10–20%oforally administered sulfasalazineis
absorbed
▶Intestinalbacteria toliberate sulfapyridine&
5-aminosalicylic acid
▶Sulfasalazine’shalf-lifeis6–17hrs.
▶2–3g/d
Sulfasalzine

23. ▶30%ofpatientsdiscontinuethedrugNausea, vomiting,
headache& rash.
▶Hemolyticanemiaand methemoglobinemia
▶Neutropeniaoccursin1–5%ofpatients
▶Thrombocytopenia
▶Reversibleinfertilityoccursinmen
Side effects

24. Whichdrugfirst?
▶Basedonefficacy,rapidityofonsetofaction,safetyand
cost,manycliniciansprefermethotrexateor
sulfasalazine
▶Leflunomideisusuallydrugofsecondchoiceduetocost
(orcanbeusedinpatientsintoleranttoMTX)
▶CSA,D-PENandintramusculargoldareusedless
frequentlybecauseoftheirlessfavourablebenefit/risk
ratio

25. CombinationDMARDTherapy
▶CombinationDMARDregimen
▶Doesnot increasetoxicitylevels
▶Long-termoutcomemore favorable
▶Superiorefficacytosingle-DMARDregimen
▶Possiblecombinations
▶Methotrexate/sulfasalazine/hydroxychloroquine
▶Cyclosporine/methotrexate
▶Leflunomide/methotrexate

26. Whoshouldbeputon
combinationofDMARDs?
▶Failureto respondto > oneDMARD/ partialresponse
▶If responseisnotadequate/toxicity develops

27. Chloroquine&Hydroxychloroquine
Nonbiologicdrugsmainlyusedformalaria
1.SuppressionofT-lymphocyte
2.Inhibitionofleukocytechemotaxis
3.Stabilizationof lysosomalenzymes
4.Inhibitionof DNAandRNAsynthesis
5.Trappingoffreeradicals.

28. Chloroquine&Hydroxychloroquine
Chloroquine200mg/day
3-6months(response)
Dyspepsia,nausea,vomiting,abdominal pain,
rashes&nightmares
Cornealopacity,retinaldamage

29. Azathioprine
AzathioprineisasyntheticnonbiologicDMARDthat
actsthroughitsmajormetabolite6-thioguanine.
6-Thioguaninesuppressesinosinicacidsynthesis,B-cell
andT-cellfunction&immunoglobulinproduction
Azathioprinecanbegivenorallyorparenterally.Its
metabolismisbimodalinhumans,withrapid
metabolizersclearingthedrug4timesfasterthanslow
metabolizers.

30. Productionof6-thioguanineisdependenton
thiopurinemethyltransferase(TPMT)
LoworabsentTPMTactivity(0.3%ofthepopulation)
are atparticularlyhigh riskof myelosuppression
AzathioprineisapprovedforuseinRAatadosage
of2mg/kg/d.
Azathioprine

31. ▶Bonemarrowsuppression
▶GI disturbances
▶Infection risk
▶Lymphomas
▶Rarelyfever,rash,andhepatotoxicity
Azathioprine

32. Leflunomide/A771726
Dihydroorotate
DHODH
Glutamine
+
HCO
3
+
Aspartate
Orotate
UMP
Pyrimidine
nucleotides
DNA/RNAsynthesis;
glycosylation
Leflunomide
PrimaryMechanismofAction
DHODHDihydroorotatedehydrogenase enzyme

33. Completelyabsorbedfromthe gut,
Meanplasmahalf-lifeof19days.
ItsactivemetaboliteA77-1726has
approximatelythesamehalf-life&issubjectto
enterohepaticrecirculation.
Leflunomide/A771726

34. Leflunomide/A771726
Diarrhea(25%ofpatients)
10%discontinuedrugbecauseofthissideeffect
Elevationinliverenzymescanoccur
Mildalopecia,weightgain,&increasedBP
Leukopenia&thrombocytopeniaoccurrarely

35. Cons
Lackofclinical
experience
Toxicities
hepatotoxicity,
gastrointestinal
toxicity
SelectionofanInitial DMARD:
Leflunomide
Pros
▶Earlyonsetof
action(~4weeks)
▶Stabilizedbenefit
forlong-termuse
▶Selectivelytargets
autoimmune
lymphocytes

36. Biologicalagents
(anticytokine therapy)
▶Patientswithevidenceofhighlyactivedisease
whohavefailedatleasttwoDMARDsincluding
MTXareeligibleforanti-TNFalphatherapy.
GuidelinesoftheBritishSocietyforRheumatology

37. Whatisthebasisforanti-TNFalpha
therapies?
▶Tumornecrosisfactor-alpha(TNF-α)isan
importantmediatorinthepathophysiologyof
RA.
▶TNF-αaffectstheliningofthesynovium,aswell
asbone&cartilageleadingtopain,swelling&
evenjointdestruction.

38. Etanercept
▶Etanerceptisafusionprotein(nota
monoclonalantibody)
▶Consistsoftheligand-bindingportionofa
humanTNF-αreceptorlinkedtotheFcportion
ofhumanIgG1.
▶EtanerceptbindstoTNF–α&preventsitfrom
combiningwithitsreceptors.
▶25mgweeklytwicebys.c.

39. Etanercept
Thedrugisslowlyabsorbed
Peakconcentration72hrsafterdrug
administration
Meanserumeliminationhalf-lifeof4.5days
Reductionofradiographicprogressionwith
theuseof50mgofetanerceptweekly

40. Infliximab
▶Infliximabisachimeric
antiTNF-alphamonoclonal
antibodycomposed of
humanconstant&murine
variableregions.
▶Itbindstothecytokine&
preventsitfromcombining
withitsreceptors
▶3mg/kgi.v.
Human75%
Murine25%

41. Infliximabisgivenasanintravenousinfusion
with“induction”at0,2&6weeksand
maintenanceevery8weeksthereafter.
Dosingis3–10mg/kgtheusualdoseis3–
5mg/kgevery8weeks.
Afterintermittenttherapy,infliximabelicits
humanantichimericantibodiesinupto62%
ofpatients.
Concurrent therapywithmethotrexate
markedlydecreasestheprevalenceofhuman
antichimericantibodies.
Infliximab

42. Whataretheproblems?
▶Doseofinfliximabmustcontinuetobe
increasedtomaintainefficacyincrease
incost.
▶Antibodiesagainstinfliximabhavebeen
associatedwithdrug-inducedlupus

43. ▶Headache,fever,chills,urticaria,chestpain
havebeenseenin17%ofpatientsreceiving
infliximabversus7%receivingplacebo.
▶longtermuseinfections
▶25%willnotrespond
▶RouteofadministrationIVinfusion
Whataretheproblems?

44. Risk-benefitofTNF blockade
▶Clinical&radiographicamelioration
inducedbyTNFblockadeisparalleled
byanoticeableimprovementinthe
qualityoflife,includingfunctional
status&generalwell-being.
▶ADRsinfections
▶Costhigh

45. Abatacept
Co-stimulationmodulatorbiologicthatinhibitsthe
activationofTcells
AfteraTcellhasengagedanantigen-presentingcell
(APC)asecondsignalisproducedbyCD28onthe
TcellthatinteractswithCD80orCD86ontheAPC
leadingtoT-cellactivation
Abatacept(whichcontainstheendogenousligand
CTLA-4)bindstoCD80&86therebyinhibiting
thebindingtoCD28&preventingtheactivationof
Tcells

46. Abatacept
Threeintravenousinfusion“induction”doses(day0,
week2&week4)followedbymonthlyinfusions.
Lessthan60kgreceiving500mg
&60–100kgreceiving750mg
morethan100kgreceiving1000mg.
Subcutaneousformulation125mgonceweekly.

47. Abatacept
Upperrespiratorytract
ConcomitantusewithTNF-αantagonistsorother
biologicsLatenttuberculosis&viralhepatitis
Livevaccinesshouldbeavoidedinpatientswhile
taking abatacept&upto3monthsafter
discontinuation.
Infusionrelatedreactions&hypersensitivity
reactions,includinganaphylaxis,havebeenreported
butarerare.
Thereisapossibleincreaseinlymphomasbutnot
othermalignancieswhenusingabatacept.

48. Tosumup…
▶RAmaycauseseveredisability,butprompttreatment
withDMARDssignificantlyimprovesthelong-term
outcome.
▶PatientswithDMARD-refractoryRAcanrespondto
biologicalagentssuchascytokineinhibitors.
▶Noneofthecurrenttherapiesiscurative,butsignificant
clinicalameliorationcanbeachievedinthevast
majorityofpatients.
▶Properassessmentofdiseaseactivityiscrucialto
identifypatientswithsevere,progressivedisease&to
monitorresponsetoDMARDs&biologicagents.