Arthritis MedicationsArthritis MedicationsPart IIPart II

Dr. Sherry RohekarDr. Sherry Rohekar

June 24, 2010June 24, 2010

OverviewOverview

Acknowledgement: Dr. Andrew Thompson for his kind use Acknowledgement: Dr. Andrew Thompson for his kind use of his slides! Wealth of information on his website of his slides! Wealth of information on his website (mentioned later in presentation)(mentioned later in presentation)

DMARDSDMARDS TraditionalTraditional

MethotrexateMethotrexate SulfasalazineSulfasalazine PlaquenilPlaquenil LeflunomideLeflunomide

TNF Inhibitors (infliximab, adalimumab, etancercept)TNF Inhibitors (infliximab, adalimumab, etancercept) Newer biologics (abatacept, rituximab)Newer biologics (abatacept, rituximab)

Approach to Inflammatory Approach to Inflammatory ArthritisArthritis

Paradigm shift in the treatment of Paradigm shift in the treatment of inflammatory arthritisinflammatory arthritis

Rationale for TreatmentRationale for Treatment Large body of evidence which shows joint Large body of evidence which shows joint

damage is an early phenomenon of rheumatoid damage is an early phenomenon of rheumatoid arthritisarthritis

Joint erosions occur in up to 93% of patients Joint erosions occur in up to 93% of patients with less than 2 years of disease activitywith less than 2 years of disease activity

The rate of radiographic progression is greatest The rate of radiographic progression is greatest in the first two yearsin the first two years

Disability occurs early – 50% of patients with RA Disability occurs early – 50% of patients with RA will be work disabled at 10 yearswill be work disabled at 10 years

Severe disease is associated with increased Severe disease is associated with increased mortality!mortality!

It’s like an IcebergIt’s like an Iceberg

It’s what you don’t see!It’s what you don’t see!

Approach to Inflammatory Approach to Inflammatory ArthritisArthritis

““Window of Opportunity”Window of Opportunity” Early and aggressive treatment may Early and aggressive treatment may

have long-term benefitshave long-term benefits Principles of TreatmentPrinciples of Treatment

Treat EarlyTreat Early Treat Appropriately Treat Appropriately

A Fire in the JointsA Fire in the JointsIf there’s a fire in the kitchen do you wait until it spreads to the living room or do you try and put it out?

Therapeutic StrategiesTherapeutic Strategies

Use of early DMARDsUse of early DMARDs Combinations of Conventional DMARDsCombinations of Conventional DMARDs

Three studies have confirmed the use of Three studies have confirmed the use of “triple therapy” in early RA is more “triple therapy” in early RA is more effective than a single agent. effective than a single agent. (Clin Exp (Clin Exp Rheumatol 17:699-704, 1999, Arthritis Rheum 50:2072-81, 2004, Rheumatol 17:699-704, 1999, Arthritis Rheum 50:2072-81, 2004, Arthritis Rheum 46:1164-70, 2002).Arthritis Rheum 46:1164-70, 2002).

Combinations of Methotrexate plus Combinations of Methotrexate plus Biologic agentsBiologic agents

What are DMARDs?What are DMARDs? Disease Modifying Anti-Rheumatic Disease Modifying Anti-Rheumatic

Drugs (DMARDs).Drugs (DMARDs). Symptom ControlSymptom Control

Control current inflammatory featuresControl current inflammatory features Modify the course of diseaseModify the course of disease

Reduce joint damage and deformityReduce joint damage and deformity Reduce radiographic progressionReduce radiographic progression Reduce long-term disabilityReduce long-term disability

Available DMARDsAvailable DMARDs MethotrexateMethotrexate Sulfasalazine (Salazopyrin®)Sulfasalazine (Salazopyrin®) Hydroxychloroquine (Plaquenil®)Hydroxychloroquine (Plaquenil®) Leflunomide (Arava®)Leflunomide (Arava®) Gold (Myochrisine®)Gold (Myochrisine®) OthersOthers

CyclosporineCyclosporine AzathioprineAzathioprine CyclophosphamideCyclophosphamide

Common DMARD Common DMARD CombinationsCombinations

Triple TherapyTriple Therapy Methotrexate, Sulfasalazine, HydroxychloroquineMethotrexate, Sulfasalazine, Hydroxychloroquine

Double TherapyDouble Therapy Methotrexate & LeflunomideMethotrexate & Leflunomide Methotrexate & SulfasalazineMethotrexate & Sulfasalazine Methotrexate & HydroxychloroquineMethotrexate & Hydroxychloroquine Methotrexate & GoldMethotrexate & Gold Sulfasalazine & PlaquenilSulfasalazine & Plaquenil

MonotherapyMonotherapy

MethotrexateMethotrexate

Tetrahydrofolate is an important cofactor in the production of purines transferring a carbon atom.

MethotrexateMethotrexate

MethotrexateMethotrexate

Substitutes as Folic Acid Substitutes as Folic Acid Interferes with the production of Interferes with the production of

TetrahydrofolateTetrahydrofolate Interferes with the de novo synthesis of Interferes with the de novo synthesis of

purinespurines Affects cells that rapidly turn overAffects cells that rapidly turn over

Immune cellsImmune cells Mucosal cellsMucosal cells Hair folliclesHair follicles

Methotrexate – What to tell Methotrexate – What to tell PatientsPatients

Dose and AdministrationDose and Administration Dose ranges from 7.5 to 25 mg Dose ranges from 7.5 to 25 mg ONLY GIVEN ONCE A WEEKONLY GIVEN ONCE A WEEK 2.5 mg Tablets or Subcutaneous Injection 25 2.5 mg Tablets or Subcutaneous Injection 25

mg/mLmg/mL Onset of ActionOnset of Action

6-8 weeks6-8 weeks AvoidAvoid

Pregnancy – TeratogenicPregnancy – Teratogenic AlcoholAlcohol Sulfa Antibiotics (Sulfasalazine is ok)Sulfa Antibiotics (Sulfasalazine is ok)

Methotrexate – What to Tell Methotrexate – What to Tell PatientsPatients

Common S/ECommon S/E Malaise, NauseaMalaise, Nausea Rise in Liver EnzymesRise in Liver Enzymes

Dose/SensitivityDose/Sensitivity Oral ulcers, alopecia, liver and bone Oral ulcers, alopecia, liver and bone

marrow toxicitymarrow toxicity Rare S/ERare S/E

Pulmonary: Fever, cough, SOB (early, old, lung disease)Pulmonary: Fever, cough, SOB (early, old, lung disease) Bone Marrow: Follow bloodwork – dose/sensitivity relatedBone Marrow: Follow bloodwork – dose/sensitivity related InfectionInfection PregnancyPregnancy MalignancyMalignancy

Methotrexate – What to Methotrexate – What to give Patientsgive Patients

Information Sheet – Information Sheet – www.RheumInfo.com Folic Acid supplementation may help with Folic Acid supplementation may help with

nuisance side effects (nausea, mouth nuisance side effects (nausea, mouth sores) sores)

Lab Monitoring (monthly initially)Lab Monitoring (monthly initially) CBC, ESR, CRPCBC, ESR, CRP AST, ALT, ALP, AlbuminAST, ALT, ALP, Albumin CrCr

MTX Dose Response in RAMTX Dose Response in RA

0

20

40

60

TJC SJC MD Global ADL

39

5347

23

41

15

8

29

Furst et al, J Rheum 11:313,1989

Perc

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10 mg/ m2

MTX

5 mg/m2 MTX

Hydroxychloroquine Hydroxychloroquine (Plaquenil(Plaquenil®)®)

Anti-malarial medication found useful Anti-malarial medication found useful for the treatment of inflammatory for the treatment of inflammatory arthritisarthritis

Highly concentrated within cellsHighly concentrated within cells Increases intracellular pHIncreases intracellular pH Interferes with cell’s ability to Interferes with cell’s ability to

degrade and process proteinsdegrade and process proteins

Hydroxychloroquine Hydroxychloroquine (Plaquenil(Plaquenil®)®)

Dose & AdministrationDose & Administration 200 mg tablets200 mg tablets Dose ranges from 200 – 400 mg per dayDose ranges from 200 – 400 mg per day

OnsetOnset 6-12 weeks6-12 weeks

AvoidAvoid May increase sensitivity to the sunMay increase sensitivity to the sun

Common S/ECommon S/E Rash, nausea, diarrheaRash, nausea, diarrhea Difficult with reading (affects Difficult with reading (affects

accomodation)accomodation) Rare S/ERare S/E

Ocular, Skeletal muscle, heartOcular, Skeletal muscle, heart

Hydroxychloroquine Hydroxychloroquine (Plaquenil®)(Plaquenil®)

Hydroxychloroquine – Hydroxychloroquine – What to give PatientsWhat to give Patients

Information Sheet – Information Sheet – www.RheumInfo.com

Dose is based on lean body weight (6.5 Dose is based on lean body weight (6.5 mg/kg/day)mg/kg/day)

Average Dose 300 (2 alt with 1 per Average Dose 300 (2 alt with 1 per day)– 400 (2 per day) mg per dayday)– 400 (2 per day) mg per day

No laboratory monitoringNo laboratory monitoring Ophthalmologic screen for visual acuity, Ophthalmologic screen for visual acuity,

colour vision, and visual fields qyearlycolour vision, and visual fields qyearly

SulfasalazineSulfasalazine Developed in the late 1930s by Dr. Nana Developed in the late 1930s by Dr. Nana

Svartz (Swedish Rheumatologist) for the Svartz (Swedish Rheumatologist) for the treatment of “infective polyarthritis”treatment of “infective polyarthritis”

Anti-inflammatory: Salicylic AcidAnti-inflammatory: Salicylic Acid Antibiotic: SulfapyridineAntibiotic: Sulfapyridine Sulfasalazine consists of salicylic acid Sulfasalazine consists of salicylic acid

and sulfapyridine joined by an azo bond.and sulfapyridine joined by an azo bond. Sulfinpyradone is thought to be the Sulfinpyradone is thought to be the

active ingredient although, in RA, the active ingredient although, in RA, the mechanism of action is not understood mechanism of action is not understood

SulfasalazineSulfasalazine

Salicylate Sulfinpyradone

SulfasalazineSulfasalazine Pills taken twice daily (CPS and some pharmacists – Pills taken twice daily (CPS and some pharmacists –

QID!)QID!) Start at a low dose 1 per day and gradually work up Start at a low dose 1 per day and gradually work up

to 4 per dayto 4 per day Takes 6-8 weeks to workTakes 6-8 weeks to work Common S/E: Malaise, Nausea, Abd pain, Rash, Common S/E: Malaise, Nausea, Abd pain, Rash,

headaches, dizzinessheadaches, dizziness Rare S/E: Rare S/E:

Hypersensitivity reactionHypersensitivity reaction Liver: Follow enzymes – not usually a problemLiver: Follow enzymes – not usually a problem Bone Marrow: Follow bloodwork – dose/sensitivity relatedBone Marrow: Follow bloodwork – dose/sensitivity related Renal: Very RareRenal: Very Rare

Sulfasalazine – What to give Sulfasalazine – What to give PatientsPatients

Information Sheet – Information Sheet – www.RheumInfo.com Sulfasalazine 500 mg tabletsSulfasalazine 500 mg tablets

Week 1: Take 1 tab PO qamWeek 1: Take 1 tab PO qam Week 2: Take 1 tab PO BIDWeek 2: Take 1 tab PO BID Week 3: Take 2 tabs PO qam and 1 tab PO qpmWeek 3: Take 2 tabs PO qam and 1 tab PO qpm Week 4 & therafter: Take 2 tabs PO BIDWeek 4 & therafter: Take 2 tabs PO BID

Lab Monitoring (week 2, 4 and then monthly)Lab Monitoring (week 2, 4 and then monthly) CBC, ESR, CRPCBC, ESR, CRP AST, ALT, ALP, AlbuminAST, ALT, ALP, Albumin CrCr

Leflunomide (AravaLeflunomide (Arava®)®)

Newer DMARDNewer DMARD Inactive and Inactive and

converted to A177-converted to A177-1726 in the GI tract 1726 in the GI tract and liverand liver

Leflunomide (AravaLeflunomide (Arava®)®)

A77-1726 A77-1726 inhibits the inhibits the activity of activity of dihydro-orotate dihydro-orotate dehydrogenasedehydrogenase, an important , an important enzyme in the enzyme in the de novo de novo synthesis of synthesis of pyrimidines.pyrimidines.

Leflunomide (AravaLeflunomide (Arava®)®) Dose and AdministrationDose and Administration

10 & 20 mg Tablets10 & 20 mg Tablets Given daily – ranges from 10-20 mg per Given daily – ranges from 10-20 mg per

dayday Onset of ActionOnset of Action

6-8 weeks6-8 weeks AvoidAvoid

Pregnancy – TeratogenicPregnancy – Teratogenic AlcoholAlcohol

Leflunomide (AravaLeflunomide (Arava®)®)

Common S/ECommon S/E Diarrhea, nausea, malaise, Diarrhea, nausea, malaise,

hypertension, alopecia, rashhypertension, alopecia, rash Rare S/ERare S/E

Liver: Follow enzymes – not usually a problemLiver: Follow enzymes – not usually a problem Bone Marrow: Follow bloodwork – dose/sensitivity relatedBone Marrow: Follow bloodwork – dose/sensitivity related InfectionInfection PregnancyPregnancy MalignancyMalignancy

Leflunomide (AravaLeflunomide (Arava®)®) Information Sheet – Information Sheet – www.RheumInfo.com Leflunomide 20 mg tablet PO OD – If side Leflunomide 20 mg tablet PO OD – If side

effects can:effects can: Reduce to 10 mg PO OD orReduce to 10 mg PO OD or Reduce to 20 mg every other day (Cheaper)Reduce to 20 mg every other day (Cheaper)

Lab Monitoring (monthly initially)Lab Monitoring (monthly initially) CBC, ESR, CRPCBC, ESR, CRP AST, ALT, ALP, AlbuminAST, ALT, ALP, Albumin CrCr

Common StrategiesCommon Strategies

Triple therapy for 3-6 monthsTriple therapy for 3-6 months Optimize dose and route of medicationsOptimize dose and route of medications

Incomplete Response Incomplete Response Changing to sc methotrexateChanging to sc methotrexate Adding LeflunomideAdding Leflunomide Adding a Biologic AgentAdding a Biologic Agent

BiologicsBiologics

Specially designed to treat Specially designed to treat inflammatory types of arthritis such as inflammatory types of arthritis such as rheumatoid and psoriatic arthritis. rheumatoid and psoriatic arthritis.

Six biologics currently available (and Six biologics currently available (and more coming) more coming)

Work by different mechanisms. Work by different mechanisms. Like DMARDs, biologics are used to Like DMARDs, biologics are used to

suppress inflammation and help suppress inflammation and help prevent damage to the joint.prevent damage to the joint.

Current Available BiologicsCurrent Available Biologics

TNF InhibitorsTNF Inhibitors AdalimumabAdalimumab EtanerceptEtanercept Infliximab (Remicade)Infliximab (Remicade)

IL-1 InhibitorsIL-1 Inhibitors Anakinra (Kineret)Anakinra (Kineret)

T-Cell Co-Stimulatory BlockadeT-Cell Co-Stimulatory Blockade Abatacept (Orencia)Abatacept (Orencia)

B-Cell DepletionB-Cell Depletion Rituximab (Rituxan)Rituximab (Rituxan)

Available BiologicsAvailable Biologics

COMMONLY PRESCRIBED BIOLOGICS Brand Names Product Common Dose

50 mg injection once weekly or Enbrel Etanercept

25 mg injection twice weekly

Humira Adalimumab 40 mg injection every other week

Kineret Anakinra 100 mg injection every other week

Orencia Abatacept 500 to 1000 mg intravenous infusion every 4 weeks

Remicade Infliximab 200 – 1000 mg intravenous infusion every 6 to 8 weeks

Rituxan Rituximab 1000 mg intravenous infusion given twice two weeks apart

TNF InhibitorsTNF Inhibitors

In some people with arthritis, a In some people with arthritis, a protein called Tumour Necrosis protein called Tumour Necrosis Factor (TNF) is present in the blood Factor (TNF) is present in the blood and joints in excessive amounts and joints in excessive amounts where it increases inflammation where it increases inflammation (pain & swelling). (pain & swelling).

TNF

SIGNAL

Monoclonal Antibody directed against TNF-alpha: Infliximab (Remicade ®), Adalimumab (Humira®)

Soluble TNF-Receptors serve as a balance to TNF

Engineered Soluble TNF Receptor Etanercept (Enbrel®)

TNF-InhibitorsTNF-Inhibitors

Mechanism of ActionMechanism of Action Infliximab and Adalimumab are Infliximab and Adalimumab are

antibodies directed against TNFantibodies directed against TNF Etanercept is a soluble receptor decoyEtanercept is a soluble receptor decoy

AdministrationAdministration Infliximab is given intravenouslyInfliximab is given intravenously Etanercept and Adalimumab are given Etanercept and Adalimumab are given

by subcutaneous injectionby subcutaneous injection

Side Effects of TNF Side Effects of TNF InhibitionInhibition

Infusion Reactions with Infliximab, Injection Site Infusion Reactions with Infliximab, Injection Site Reactions with Adalimumab and EtanerceptReactions with Adalimumab and Etanercept

Infection Infection TuberculosisTuberculosis Serious resulting in deathSerious resulting in death

MalignancyMalignancy Increased risk of lymphoma – early dataIncreased risk of lymphoma – early data Solid tumors?Solid tumors?

NeurologicNeurologic Multiple Sclerosis, seizures, inflammation of the Multiple Sclerosis, seizures, inflammation of the

ocular nerveocular nerve AutoimmuneAutoimmune

Antibody formation – SLE like illnessAntibody formation – SLE like illness Worsening of Congestive Heart FailureWorsening of Congestive Heart Failure

When to Stop TNF-When to Stop TNF-Inhibitors Inhibitors

STOP if develop a fever, have an STOP if develop a fever, have an infection, or have been prescribed infection, or have been prescribed antibioticsantibiotics

Tell your doctor about any Tell your doctor about any upcoming surgeriesupcoming surgeries

T-Cell Co-T-Cell Co-Stimulatory Stimulatory Blockade Blockade

(Abatacept)(Abatacept)

Practical AspectsPractical Aspects

Given on week 0, 2, and 4 then every Given on week 0, 2, and 4 then every 4 weeks4 weeks

Quick infusions over 30 minutesQuick infusions over 30 minutes Well toleratedWell tolerated Home infusion programHome infusion program

Practical AspectsPractical Aspects

Side EffectsSide Effects INFECTIONINFECTION COPD ExacerbationCOPD Exacerbation MALIGNANCY – Lung CancerMALIGNANCY – Lung Cancer Infusion Reactions – RareInfusion Reactions – Rare

B-Cell DepletionB-Cell Depletion(Rituximab)(Rituximab)

Rheumatoid Arthritis (RA)Rheumatoid Arthritis (RA)

RA was thought to be RA was thought to be T-CellT-Cell mediated mediated Most widely accepted hypothesis:Most widely accepted hypothesis:

Professional Antigen Presenting Cell Professional Antigen Presenting Cell encounters some “unknown” antigenencounters some “unknown” antigen

It presents this “unknown” antigen to a CD4 It presents this “unknown” antigen to a CD4 T-helper CellT-helper Cell

In a genetically predisposed individual, this In a genetically predisposed individual, this starts an immune chain reactionstarts an immune chain reaction

Immune system is confused and targets Immune system is confused and targets healthy tissuehealthy tissue

B-Cell can serve role as Antigen B-Cell can serve role as Antigen Presenting Cell and Antibody Presenting Cell and Antibody

Producing CellProducing Cell

Immune Reaction

AutoantibodyCytokines

Antigen Presenting

CellCD4 T-Cell

Antigen

B-Cell

Rheumatoid ArthritisRheumatoid Arthritis

Autoantibody

B-Cell CD4 T-Cell

Auto-Antigen

B-Cell

B-Cell Depletion Therapy B-Cell Depletion Therapy in RAin RA

How does B-Cell Depletion work? How does B-Cell Depletion work? B-Cells cannot act as antigen presenting B-Cells cannot act as antigen presenting

cells to activate T-Cellscells to activate T-Cells B-Cells cannot produce Rheumatoid B-Cells cannot produce Rheumatoid

FactorFactor B-Cells cannot release cytokinesB-Cells cannot release cytokines

B-Cell

Plasma Cell

Antibodies

Rheumatoid Factor

RituximabRituximab

Rituximab in RARituximab in RA

B-Cell

CD-20

Rituximab: anti-CD-20

Initial StudiesInitial Studies

Professor J.C. Edwards at University Professor J.C. Edwards at University College in London EnglandCollege in London England

Treated 5 patients with RituximabTreated 5 patients with Rituximab Based on the premise of reducing Based on the premise of reducing

auto-antibodiesauto-antibodies All 5 respondedAll 5 responded Since then multiple large trials have Since then multiple large trials have

confirmed these resultsconfirmed these results

Practical AspectsPractical Aspects

Given as two (2) infusions of 1000mg Given as two (2) infusions of 1000mg spaced two weeks apartspaced two weeks apart

All patients given 100 mg of All patients given 100 mg of solumedrol with each infusionsolumedrol with each infusion

Takes about 3-4 months to kick inTakes about 3-4 months to kick in Time to re-treatment – 6 to 9 monthsTime to re-treatment – 6 to 9 months

Practical AspectsPractical Aspects

Side EffectsSide Effects INFECTIONINFECTION INFUSION REACTIONSINFUSION REACTIONS Other rare things – severe skin Other rare things – severe skin

reactions, arrhythmia, drop in blood reactions, arrhythmia, drop in blood countscounts

Any questions?Any questions?