Rheumatoid Arthritis, Brief Rheumatoid Arthritis, Brief Review of Differential Review of Differential Diagnosis and Initial Diagnosis and Initial

TreatmentTreatment

Jonathan S. Coblyn, M.D.Jonathan S. Coblyn, M.D.

Brigham and WomenBrigham and Women’’s Hospitals Hospital

DisclosuresDisclosures

CVSCVS

ConclusionConclusionA new era in the treatment of rheumatoid A new era in the treatment of rheumatoid

arthritisarthritis

•• Proof of principle has been established that Proof of principle has been established that selective targeting of pathogenic elements is selective targeting of pathogenic elements is therapeutically effective. therapeutically effective.

•• Early therapyEarly therapy--especially combination therapy especially combination therapy tied to improved outcomes.tied to improved outcomes.

•• The future is now! Less joint replacements and The future is now! Less joint replacements and improved morbidity and mortality now improved morbidity and mortality now evident.evident.

•• A plea. Refer to confirm diagnosis and initiate A plea. Refer to confirm diagnosis and initiate treatmenttreatment

The Rapid Pace of Drug The Rapid Pace of Drug ““DiscoveryDiscovery”” in Rheumatologyin Rheumatology

1995 2000 2006-2010

CsA leflunomide

celecoxibrofecoxib

etanercept

infliximabadalimumab

Rituximab/abataceptTocilizumab (2010)

Year Marketed for RA

The Characteristics of RAThe Characteristics of RA

Systemic chronic inflammatory diseaseSystemic chronic inflammatory disease•• Mainly affects synovial jointsMainly affects synovial joints

•• Variable expressionVariable expression•• Risk increased by both genetic and Risk increased by both genetic and

environmental factorsenvironmental factors•• Strongest genetic risk conferred by shared Strongest genetic risk conferred by shared

epitope in close association with class II epitope in close association with class II MHC gene, (HLA) DR4MHC gene, (HLA) DR4

•• Cigarette smoking clearly an environmental Cigarette smoking clearly an environmental triggertrigger

The Characteristics of RA, contThe Characteristics of RA, cont’’dd

•• Prevalence about 1%Prevalence about 1%

•• Worldwide distributionWorldwide distribution

•• Female: Male ratio 3:1Female: Male ratio 3:1

•• Peak age of onset 25 Peak age of onset 25 –– 50 years50 years•• Synovitis, but tends to spare the LS spineSynovitis, but tends to spare the LS spine

Joint Involvement on Presentation of RAJoint Involvement on Presentation of RA

PolyarticularPolyarticular 75%75%

Small joints of Small joints of hands and feethands and feet 60%60%

Large jointsLarge joints 30%30%

Large and Large and small jointssmall joints

10%10%

MonoarticularMonoarticular 25%25%

KneeKnee 50%50%

ShoulderShoulderWristWristHipHip 50%50%AnkleAnkleElbowElbow

Characteristic Features of Rheumatoid Characteristic Features of Rheumatoid Arthritis, contArthritis, cont’’dd

ArticularArticular•• Characteristic distribution Characteristic distribution

patterns:patterns:•• SymmetricSymmetric•• Proximal interphalangeal, Proximal interphalangeal,

metacarpophalangeal, metacarpophalangeal, radiocarpal joint involvementradiocarpal joint involvement

•• Wrists, elbows, knees, Wrists, elbows, knees, ankles, shoulders, neck, ankles, shoulders, neck, intertarsals, intertarsals, metatarsophalangeals metatarsophalangeals affectedaffected

d

ExtraExtra--articulararticular•• VasculitisVasculitis•• Pulmonary Pulmonary

involvementinvolvement

Rheumatoid ArthritisRheumatoid Arthritis

Laboratory AbnormalitiesLaboratory AbnormalitiesFrequentFrequent OccasionalOccasionalAnemiaAnemia Leukocytosis; leukopenia Leukocytosis; leukopenia

(Felty(Felty’’s/LGL) s/LGL)

ESRESR PlateletsPlateletsRF (+)RF (+) ACPA (CCP+)ACPA (CCP+) ANA +ANA +

Hyper (Hyper () Globulinemia) GlobulinemiaInflammatory Synovial Fluid Inflammatory Synovial Fluid

The Pathology of RAThe Pathology of RA

SerositisSerositis1 1 –– SynovitisSynovitis

JointsJointsTendon sheathsTendon sheathsBursaeBursae

2 2 –– Serositis of pleura and pericardiumSerositis of pleura and pericardium

NodulesNodules

VasculitisVasculitis

Differential Diagnosis Differential Diagnosis of Polyarthritisof Polyarthritis

Rheumatoid ArthritisRheumatoid ArthritisPMR/GCAPMR/GCA

Psoriatic ArthritisPsoriatic ArthritisCrystal Crystal –– Gout, PseudogoutGout, Pseudogout

SLE/VasculitisSLE/VasculitisSjogrenSjogren’’s and variantss and variants

Any Any ““immune compleximmune complex”” illnessillnessSpondylitic variantsSpondylitic variants

ParaneoplasticParaneoplasticViral Viral –– Parvovirus, HepBSAg, HCV, RubellaParvovirus, HepBSAg, HCV, Rubella

LymeLyme

ACR Criteria for DiagnosisACR Criteria for Diagnosis

•• Four or more of the following criteria must Four or more of the following criteria must be present:be present:•• Morning stiffness > 1 hourMorning stiffness > 1 hour•• Arthritis of Arthritis of >> 3 joint areas3 joint areas•• Arthritis of hand joints (MCPs, PIPs, wrists)Arthritis of hand joints (MCPs, PIPs, wrists)•• Symmetric swellingSymmetric swelling•• Serum rheumatoid factorSerum rheumatoid factor•• Radiographic changesRadiographic changes

First 4 must be present for > 6 weeksFirst 4 must be present for > 6 weeks

Descriptor

Who should be tested? Patients with definite clinical synovitis of at least one joint not better explained by another disease process. Score-based algorithm: add scores of A-D; a score of ≥6/10 is needed for classification of a patient as having definite RA.

Score

New 2010 American College of Rheumatology/European League Against Rheumatism

Classification Criteria for Rheumatoid Arthritis

A. Joint involvement (use highest applicable category)

1 large joint2-10 large joints1-3 small joints (with or without large

joint involvement)4-10 small joints (with or without

large joint involvement)>10 joints (at least 1 small joint)

01235

B. Serology (high-positive: ≥ 3x upper limit normal for the test)Negative RF and negative ACPALow-positive RF or low-positive ACPAHigh-positive RF or high-positive ACPA

023

C. Acute phase reactantsNormal CRP and ESRAbnormally elevated CRP or ESR

01

D. Duration of symptoms<6 weeks≥6 weeks

01

ACPA: anti-citrullinated peptide antibodies; CRP: c-reactive protein; ESR: erythrocyte sedimentation rate; RA: rheumatoid arthritis

CAD in RACAD in RA

Risk of cardiovascular mortality in patients with Risk of cardiovascular mortality in patients with RA: a metaRA: a meta--analysis of observational studiesanalysis of observational studies

AvinaAvina--Zubieta et alZubieta et al

Arth Rheum 2008;59(12):1690Arth Rheum 2008;59(12):1690

24 studies/111,758 patients24 studies/111,758 patients——50% increased risk 50% increased risk of CVD deaths in RAof CVD deaths in RA

Systemic Disease AffectingSystemic Disease Affecting::

•• Heart and CADHeart and CAD

•• Lungs Lungs

•• Blood vesselsBlood vessels--vasculitisvasculitis

•• MusclesMuscles

•• EyesEyes

•• SkinSkin

•• Diarthrodial jointsDiarthrodial joints--““Unusual jointsUnusual joints””--cricoarytenoid and C cricoarytenoid and C --spinespine

•• Neurologic changesNeurologic changes

Pulmonary ManifestationsPulmonary Manifestations

Pleural EffusionsPleural Effusions•• Exudates > TransudatesExudates > Transudates•• Can have low PHCan have low PH•• Hallmark is low glucose Hallmark is low glucose –– Often < 30Often < 30

Rheumatoid nodulesRheumatoid nodules

Pulmonary ManifestationsPulmonary Manifestations

Interstitial FibrosisInterstitial Fibrosis

BrochiectasisBrochiectasis

Pulmonary HypertensionPulmonary Hypertension

VasculitisVasculitis

Bronchiolitis ObliteransBronchiolitis Obliterans

Cardiac ManifestationsCardiac Manifestations

Pericardial Effusions Pericardial Effusions –– Up to 1/3 in Sero + Up to 1/3 in Sero + GroupsGroups

••TamponadeTamponade••Constrictive pericarditisConstrictive pericarditis

Rheumatoid Nodules Rheumatoid Nodules –– CHB, Valvular LeisonsCHB, Valvular Leisons•• AortitisAortitis•• MyocarditisMyocarditis•• AmyloidosisAmyloidosis

Neurologic ManifestationsNeurologic Manifestations

Entrapment Neuropathies Entrapment Neuropathies ––Median N. > Ulna N.Median N. > Ulna N.

Peripheral Peripheral NeuropathyRheumatoid NeuropathyRheumatoid NodulesNodules

Myopathy and MyositisMyopathy and MyositisMononeuritis multiplexMononeuritis multiplexCervical spine and Cervical spine and ““brain stembrain stem””

entrapmentsentrapments

Cervical Spine DiseaseCervical Spine Disease

C1 C1 –– C2 Subluxation C2 Subluxation –– Myelopathy Myelopathy –– C2C2

Can damage sensory nucleus V nerveCan damage sensory nucleus V nerve

Vertebral Vertebral –– Basilar SyndromesBasilar Syndromes-- drop attacks, cerebellar signs, diplopiadrop attacks, cerebellar signs, diplopia

Lower cervical root involvement Lower cervical root involvement –– C5C5--66--77

The Importance of Early Diagnosis and The Importance of Early Diagnosis and TreatmentTreatment

•• RA is progressive, not benignRA is progressive, not benign•• Structural damage/disability occurs within Structural damage/disability occurs within

first 2 to 3 years of diseasefirst 2 to 3 years of disease•• Slower progression of disease linked to Slower progression of disease linked to

early and aggressive treatmentearly and aggressive treatment•• Less NSAIDS and steroidsLess NSAIDS and steroids•• Less Orthopedic surgeryLess Orthopedic surgery

Advantages of DMARDsAdvantages of DMARDs

•• Slow disease progressionSlow disease progression•• Improve functional disabilityImprove functional disability•• Decrease painDecrease pain•• Interfere with inflammatory processInterfere with inflammatory process•• Retard development of joint Retard development of joint

erosionserosions•• Remissions are now achievedRemissions are now achieved•• Most studies correlate favorable Most studies correlate favorable

outcomes with combination Rx or outcomes with combination Rx or early and aggressive therapyearly and aggressive therapy

Establish diagnosis of RA early

Initiate therapyPCP

Periodically assess disease activity

RHEUMATOLOGIST

Adequate response Inadequate response

Change/add DMARDs

MTX naïve Suboptimal MTX response

MTX Othermonotherapy

Combination Combination Othermonotherapy

Biologics

Monotherapy Combination

Multiple DMARD failure

Symptomatic and/or structural joint damage

ACR Treatment AlgorithmACR Treatment Algorithm

Adapted from ACR guidelines for the management of rheumatoid arthritis. Arthritis Rheum. 2002;46:328-346. 36

Are Steroids DMARDS?Are Steroids DMARDS?AIM 2002:136;1AIM 2002:136;1--1212

2 year randomized trials 2 year randomized trials

81 RA pts 81 RA pts –– no prior DMARDsno prior DMARDs

4141——10mg prednisone; 40 placebo10mg prednisone; 40 placebo

After 6 monthsAfter 6 months——SSZ added as SSZ added as ““rescuerescue”” if not adequate if not adequate responseresponse

11stst 6mo.6mo.--steroid group steroid group ––””more clinical improvementmore clinical improvement””

After 6 monthsAfter 6 months--better grip strength/28 jt scorebetter grip strength/28 jt score

BUT BUT ––increased compression fractures, skin fragility and increased compression fractures, skin fragility and weight gainweight gain

AntiAnti--Malarial DrugsMalarial Drugs

•• EfficacyEfficacyRA SLE, DLE, JRA, PsoriaticRA SLE, DLE, JRA, Psoriatic

•• ToxicityToxicityRashRashOcularOcularGastrointestinalGastrointestinalMyopathy, Conduction system and cardiac Myopathy, Conduction system and cardiac

changeschanges•• DosageDosage

Hydroxychloroquine Hydroxychloroquine –– 400 mg. 400 mg. –– Max. Max. 6.5mg/kg6.5mg/kg

Chloroquine Chloroquine –– 250 mg. 250 mg. –– Max.Max.•• Opthamology Exam Opthamology Exam –– 6 month intervals6 month intervals

SulfasalazineSulfasalazine

Efficacy in open, randomized studiesEfficacy in open, randomized studiesKey component of triple therapyKey component of triple therapy——with with

hydroxychloroquine and methotrexatehydroxychloroquine and methotrexate

Toxicity:Toxicity:GI most commonGI most commonHematologicHematologicHypersensitivity reactionHypersensitivity reaction

Potential Role:Potential Role:Early DMARDEarly DMARDReactive arthritisReactive arthritis

NEJM NEJM Volume 312:818Volume 312:818--822822 March 28, 1985March 28, 1985Number 13Number 13

Efficacy of lowEfficacy of low--dose methotrexate in dose methotrexate in rheumatoid arthritisrheumatoid arthritis

ME Weinblatt, JS Coblyn, DA Fox, PA Fraser, ME Weinblatt, JS Coblyn, DA Fox, PA Fraser, DE Holdsworth, DN Glass, and DE TrenthamDE Holdsworth, DN Glass, and DE Trentham

Methotrexate Methotrexate

Very effectiveVery effective

In use over 50 yearsIn use over 50 years

First double blind study published 1985 NEJMFirst double blind study published 1985 NEJM

Documented to change natural history, decrease Documented to change natural history, decrease extraextra--articular manifestations including possible articular manifestations including possible cardiac disease and increase QOL and probably cardiac disease and increase QOL and probably survivalsurvival

The standard of careThe standard of care

Dosing Dosing -- MTXMTXWeeklyWeekly

Oral Oral -- One DoseOne Dose-- Cycled Cycled

Initial DoseInitial Dose7.5 mg/wk 7.5 mg/wk

TherapeuticTherapeuticUnknown (7.5 Unknown (7.5 –– 25 mg/wk)25 mg/wk)--now now recognized effective dose=10mg/m2recognized effective dose=10mg/m2Always with folic acid or folinic acidAlways with folic acid or folinic acid

MaximumMaximum25 mg/wk/other ways to deliver and 25 mg/wk/other ways to deliver and make make ““more tolerablemore tolerable””(sc,folinic acid)(sc,folinic acid)

MaintenanceMaintenanceLowest dose possibleLowest dose possibleSteroid reductionSteroid reduction

““To doTo do”” list prior to MTX uselist prior to MTX use

LFTs, creatinine, albumin and CBCLFTs, creatinine, albumin and CBC

Up to date vaccinationsUp to date vaccinations-- flu and pneumovax and flu and pneumovax and discuss potential live vaccinesdiscuss potential live vaccines

HCV, HBsAg, HBcAgHCV, HBsAg, HBcAg

CXR CXR ––optional but would do in older patientoptional but would do in older patient

PPDPPD

Methotrexate: ToxicityMethotrexate: Toxicity•• GastrointestinalGastrointestinal•• StomatitisStomatitis•• HematologicHematologic--

comorbid comorbid conditionsconditions

•• PulmonaryPulmonary•• LiverLiver•• ReproductiveReproductive•• Opportunistic Opportunistic

infectionsinfections•• ? Neoplasia? Neoplasia•• NodulosisNodulosis

MTX: GastrointestinalMTX: Gastrointestinal

NauseaNauseaAnorexiaAnorexiaVomitingVomitingWeight lossWeight lossDiarrheaDiarrheaStomatitisStomatitis

•• Varying frequency and severityVarying frequency and severity•• Generally occurs at the time of administration and Generally occurs at the time of administration and

for next 2 for next 2 –– 3 days3 days•• Rx: Dose reduction, method of administrationRx: Dose reduction, method of administration

Folic acid, folinic acid therapyFolic acid, folinic acid therapy

MTX Toxicity: HematologicMTX Toxicity: HematologicLeukopeniaLeukopeniaThrombocytopeniaThrombocytopeniaAnemiaAnemiaPancytopeniaPancytopenia

Risk Factors:Risk Factors:Renal insufficiencyRenal insufficiencyFolate deficiency Folate deficiency –– elevated MCVelevated MCVInfectionInfectionConcomitant drugs: TMP/Sulfa, ProbenecidConcomitant drugs: TMP/Sulfa, Probenecid

Prevention:Prevention:Routine lab monitoringRoutine lab monitoringSupplemental folic acidSupplemental folic acid

Treatment:Treatment:LeucovorinLeucovorin

Methotrexate: PulmonaryMethotrexate: Pulmonary

Clinical Clinical –– Nonproductive cough, fever, Nonproductive cough, fever, dyspneadyspnea

Dose Dose –– VariableVariable

Lab Lab –– Eosinophilia, hypoxemiaEosinophilia, hypoxemia

Radiograph Radiograph –– InfiltratesInfiltrates

Methotrexate: Pulmonary, contMethotrexate: Pulmonary, cont’’dd

Pathology Pathology –– Interstitial pneumonitisInterstitial pneumonitisBronchiolitisBronchiolitisGranulomaGranuloma

Treatment Treatment –– SteroidsSteroidsSupportive careSupportive care

Outcome Outcome –– Variable Variable

MTX: Opportunistic InfectionsMTX: Opportunistic Infections

•• Case Reports in Rheumatoid ArthritisCase Reports in Rheumatoid Arthritis•• Varying duration and dose of MTXVarying duration and dose of MTX•• OrganismsOrganisms

Herpes zosterHerpes zosterlocalizedlocalizeddisseminateddisseminated

PCPPCPNocardiaNocardiaCryptococcusCryptococcusHistoplasmosisHistoplasmosisAspergillusAspergillus

MTX: Opportunistic Infections, contMTX: Opportunistic Infections, cont’’dd

•• No concomitant steroids in several patientsNo concomitant steroids in several patients

•• Normal CBC/differentials observedNormal CBC/differentials observed

MTX: LiverMTX: Liver

Survey of Members of ACRSurvey of Members of ACR

58% responded58% responded

Identified 24 cases of serious liver diseaseIdentified 24 cases of serious liver diseaseCriteria: Clinical Criteria: Clinical –– 1717

Biopsy Biopsy –– 77

Mean age: 65 yearsMean age: 65 years

MTX: NodulesMTX: Nodules

•• Risk factors: UnknownRisk factors: Unknown

•• Dose and duration: VariableDose and duration: Variable

•• Location: Diffuse Location: Diffuse –– CutaneousCutaneous--FeetFeet–– VisceralVisceral

Treatment: UnknownTreatment: UnknownDose reductionDose reductionDrug cessationDrug cessationSteroids Steroids –– Systemic and injectionSystemic and injectionCombination Rx:Combination Rx:

Plaquenil, Sulfasalazine, CsAPlaquenil, Sulfasalazine, CsA

MTX Toxicity: LymphomaMTX Toxicity: Lymphoma

•• NHL NHL –– 3 patients3 patients•• Diffuse large cell, B cellDiffuse large cell, B cell•• Treatment duration > 2 yearsTreatment duration > 2 years•• No SjogrenNo Sjogren’’s symptomss symptoms

J Rheumatol 18: 1741J Rheumatol 18: 1741--1743, 19911743, 199119: 146219: 1462--1468, 19921468, 1992

Methotrexate Methotrexate

EfficacyEfficacy——Now established DMARDNow established DMARD Lancet 2002;359:1173 1240 Lancet 2002;359:1173 1240

consecutive pts with RAconsecutive pts with RA——treated with treated with mtx decreased mortality and c/v riskmtx decreased mortality and c/v risk——Other studies confirmed these Other studies confirmed these observationsobservations

Still unclear how much Still unclear how much ““betterbetter”” newer newer therapies aretherapies are

Established Gold StandardEstablished Gold Standard

Selection of an Initial DMARD: LeflunomideSelection of an Initial DMARD: Leflunomide

•• Early onset of Early onset of action (~ 4 weeks)action (~ 4 weeks)

•• Stabilized benefit Stabilized benefit for longfor long--term useterm use

•• Selectively targets Selectively targets autoimmune autoimmune lymphocytes to lymphocytes to reduce untoward reduce untoward AEsAEs

•• Toxicities: Toxicities: hepatotoxicity, hepatotoxicity, gastrointestinal,gastrointestinal,

•• HypertensionHypertension•• ?pulmonary?pulmonary•• neuropathyneuropathy

PROS CONSLeflunomideLeflunomide

•• Pyrimidine synthesis inhibitorPyrimidine synthesis inhibitor•• Selective for dihydroorotate dehydrogenaseSelective for dihydroorotate dehydrogenase•• Metabolized in liver to active metaboliteMetabolized in liver to active metabolite•• Well absorbed orallyWell absorbed orally•• Requires loading doseRequires loading dose•• Prolonged halfProlonged half--life (14 d)life (14 d)•• TeratogenicTeratogenic

Leflunomide DosingLeflunomide Dosing

•• Loading dose Loading dose ––variablevariable-- 100 mg x 3 days or 100 mg x 3 days or qodx3 or even weekly x3, but most often qodx3 or even weekly x3, but most often start daily dosing atstart daily dosing at

20 mg QD20 mg QD

•• Dose may be decreased to 10 mg QD if Dose may be decreased to 10 mg QD if tolerability issues arisetolerability issues arise

Adverse Events of Potential Clinical Adverse Events of Potential Clinical SignificanceSignificance

•• Gastrointestinal EventsGastrointestinal Events•• Allergic ReactionsAllergic Reactions•• InfectionsInfections•• Reversible AlopeciaReversible Alopecia•• HypertensionHypertension•• LFTs/Cirrhosis/?death if LFTs/Cirrhosis/?death if

unmonitoredunmonitored•• Potential teratogenesisPotential teratogenesis--

consider avoiding in child consider avoiding in child bearing age unless document bearing age unless document counselingcounseling

•• Cholestyramine use to decrease Cholestyramine use to decrease half life as decreases half life as decreases enterohepatic circulationenterohepatic circulation

Next Therapy After Methotrexate:Next Therapy After Methotrexate:How to Decide When and WhatHow to Decide When and What

Disease activityDisease activity——Use objective Use objective measurementsmeasurements——DAS, CDAIDAS, CDAI

Radiographic progressionRadiographic progression PatientPatient’’s appetite for risks appetite for risk Prior medical issues which may make Prior medical issues which may make

some therapies contraindicatedsome therapies contraindicated Economic review of systems!Economic review of systems! And how to decide next drug?And how to decide next drug?

Biologics in the Treatment Biologics in the Treatment of Rheumatoid Arthritisof Rheumatoid Arthritis

Biologic TherapiesBiologic Therapies

Changed the face of RAChanged the face of RA Induce remissionInduce remission Change the natural history even Change the natural history even

without a clinical improvement!without a clinical improvement! Adverse events but no Adverse events but no ““new signalsnew signals”” Early use in methotrexate Early use in methotrexate ““inadequate inadequate

respondersresponders”” But methotrexate is great in 20But methotrexate is great in 20--30% if 30% if

used correctlyused correctly

Cost of CareCost of Care--Risk and ExpenseRisk and Expense

Biologic Therapies as of 2012Biologic Therapies as of 2012

Five antiFive anti--tnf agentstnf agents--etanercept, etanercept, adalimumab, infliximab, golimumab adalimumab, infliximab, golimumab and certolizumab pegoland certolizumab pegol

IL1IL1--receptor antagonistreceptor antagonist——anakinraanakinra CoCo--stimulatory blocker abataceptstimulatory blocker abatacept B cell depletion rituximabB cell depletion rituximab IL6 receptor antagonist tocilizumabIL6 receptor antagonist tocilizumab

AntiAnti--Tnf TherapyTnf Therapy

All have similar effectsAll have similar effects——with roughly a with roughly a response rate of 60response rate of 60--70%70%

Work in early disease and late Work in early disease and late diseasedisease——clinical outcomes better in clinical outcomes better in early diseaseearly disease

Stabilize Stabilize radiographicradiographic progressionprogression Decreased NSAIDS, steroids and mtx Decreased NSAIDS, steroids and mtx

dosesdoses Remission in some studies upon Remission in some studies upon

withdrawalwithdrawal

AntiAnti--TNF TherapiesTNF TherapiesAdverse EventsAdverse Events

Sepsis, Septic Joints,Pneumococci(Pneumovax)Sepsis, Septic Joints,Pneumococci(Pneumovax)Tuberculosis (PPD and treat prior)Tuberculosis (PPD and treat prior)

Injection site reactions/diffuse rashesInjection site reactions/diffuse rashesPulmonary symptomsPulmonary symptoms

? Increased risk lymphoma/solid tumors? Increased risk lymphoma/solid tumorsIncreased risk Class IIIIncreased risk Class III--IV CHFIV CHF

NeurologicNeurologic--demyelinationdemyelinationHematologicHematologic--pancytopeniapancytopeniaAutoimmune diseasesAutoimmune diseases--SLESLE

?LFT abnormalities?LFT abnormalities

Tb screeningTb screening

5mm positive, not 105mm positive, not 10 If pos, CXR to r/o active infectionIf pos, CXR to r/o active infection What if negative, but radiographic stigmata of What if negative, but radiographic stigmata of

prior Tb, including calcified granuloma?prior Tb, including calcified granuloma? INH 300mg qd 9 months or alternative INH 300mg qd 9 months or alternative

regimens if from country with drug resistant Tbregimens if from country with drug resistant Tb II’’ve had BCGve had BCG--what to do?what to do? What about quantiferonWhat about quantiferon––gold?gold? How long to wait before initiate antiHow long to wait before initiate anti--tnf?tnf?

TB in setting of antiTB in setting of anti--TNFTNF

Incidence increased fourfoldIncidence increased fourfold 57% developed extrapulmonary tb and increased 57% developed extrapulmonary tb and increased

mortality (15%) 17 miliary others including mortality (15%) 17 miliary others including bone,genital, bladder 25% developed disseminated bone,genital, bladder 25% developed disseminated diseasedisease

Often difficult to diagnose. Biopsies often needed Often difficult to diagnose. Biopsies often needed and granuloma often NOT foundand granuloma often NOT found

Less often associated with etanerceptLess often associated with etanercept Time to development shorter with infliximab vs Time to development shorter with infliximab vs

etanercept; 48/70 developed Tb after 3 or fewer etanercept; 48/70 developed Tb after 3 or fewer injectionsinjections

NEJM 345:1098; 2001.NEJM 345:1098; 2001.

Preventive MeasuresPreventive Measures

PneumovaxPneumovax How often?How often? High index of suspicion even if High index of suspicion even if

vaccinatedvaccinated ?Pcn prophylaxis in high risk patients?Pcn prophylaxis in high risk patients

AntiAnti--TNF and Demyelinating TNF and Demyelinating SyndromesSyndromes

19 patients developed demyelinating 19 patients developed demyelinating syndromes 17 on etanerceptsyndromes 17 on etanercept

Paresthesisas (13), optic neuritis (8), Paresthesisas (13), optic neuritis (8), confusion (5), gait disturbance,facial confusion (5), gait disturbance,facial palsy apraxiapalsy apraxia

Four/20 prior MS historyFour/20 prior MS history Most responded partially or Most responded partially or

completely to withdrawalcompletely to withdrawal A&R 44:2862,2001A&R 44:2862,2001

LymphomaLymphoma Med Watch dataMed Watch data 26 cases 26 cases ––18 w/ etanercept and 8 infliximab18 w/ etanercept and 8 infliximab 81% non Hodgkin81% non Hodgkin’’s lymphomass lymphomas Median interval from therapy to lymphoma Median interval from therapy to lymphoma

development= 8 weeksdevelopment= 8 weeks 2 individuals treated with anti2 individuals treated with anti--tnf while tnf while

lymphoma in remission relapsed and diedlymphoma in remission relapsed and died Spontaneous regression in 2 casesSpontaneous regression in 2 cases Arth Rheum 46:2002;3151Arth Rheum 46:2002;3151

? Increased Risk of Solid Tumors? Increased Risk of Solid Tumors

MetaMeta--analysis of multiple studies JAMA analysis of multiple studies JAMA 2006;295:22752006;295:2275--8585

Malignancy risk 0.8% compared to placebo Malignancy risk 0.8% compared to placebo +/+/-- Mtx of 0.2% (0.5% if exclude Mtx of 0.2% (0.5% if exclude nonmelanoma skin cancers)nonmelanoma skin cancers)

Etanercept not includedEtanercept not included——but other study but other study for Wegenerfor Wegener’’s showed increase risk of solid s showed increase risk of solid tumors in Cytoxan treated patientstumors in Cytoxan treated patients

InfliximabInfliximab--increased risk of Hepatosplenic T increased risk of Hepatosplenic T Cell Lymphoma in children with CrohnCell Lymphoma in children with Crohn’’s on s on azathioprine and 6MPazathioprine and 6MP——and rarely in adultsand rarely in adults

ACR hotline 6/1/2006ACR hotline 6/1/2006--and updatedand updated

AntiAnti--TNF and CHFTNF and CHF

Increased expression of tnf and response to Increased expression of tnf and response to treatment in animal modelstreatment in animal models

Human experience: Study using infliximab Human experience: Study using infliximab in 150 patients with Class IIIin 150 patients with Class III--IV CHF. IV CHF. Randomly Rx with placebo, 5, 10 mg/kg at Randomly Rx with placebo, 5, 10 mg/kg at 0,2, and 6 weeks0,2, and 6 weeks

No improvement despite modest increase in No improvement despite modest increase in ef at 5mg/kg dose, BUT increased hosp. ef at 5mg/kg dose, BUT increased hosp. and death in 10mg/kg group.and death in 10mg/kg group.

Role remains unclear as RA increases risk of Role remains unclear as RA increases risk of CHFCHF

Circulation 107: 3133,2003.Circulation 107: 3133,2003.

Case Report LevelCase Report Level

Pancytopenia and aplasiaPancytopenia and aplasia Granulomatous pulmonary diseaseGranulomatous pulmonary disease Vasculitis and common Injection site Vasculitis and common Injection site

reactionsreactions SLE type glomerulonephritisSLE type glomerulonephritis

Absolute Contraindications to Absolute Contraindications to TNFTNF--BlockersBlockers

CHF III/IVCHF III/IV Active/latent TbActive/latent Tb Active infectionActive infection Active or recent h/o malignancy (solid Active or recent h/o malignancy (solid

tumors)tumors) MS/optic neuritisMS/optic neuritis h/o lymphomah/o lymphoma Live vaccinesLive vaccines AnaphylaxisAnaphylaxis

Adapted Semin A&R 2005;34Adapted Semin A&R 2005;34

Newer Biologics in RANewer Biologics in RA

AbataceptAbatacept RituximabRituximab TocilizumabTocilizumab

How many antiHow many anti--TNFs should we try?TNFs should we try?Which one to select??? Use these first?Which one to select??? Use these first??Difference in side effects?Difference in side effects

ABATACEPTABATACEPT

Novel mechanism of actionNovel mechanism of actionBlocks cell coBlocks cell co--activation pathwayactivation pathwayApproved for use in RA and in evaluation in Approved for use in RA and in evaluation in

other rheumatic diseasesother rheumatic diseasesMonthly infusionsMonthly infusionsSimilar risks to anti tnf but less often TbSimilar risks to anti tnf but less often TbMay be used with or without mtxMay be used with or without mtxUsually after tnf Usually after tnf ““failurefailure””——response rate response rate

50%50%Onset 4Onset 4--16 weeks with improvement in 16 weeks with improvement in

fatigue and qol dramatic in some casesfatigue and qol dramatic in some cases

Interrupts Autoimmune Response Underlying RA

Abatacept (CTLA4Ig): Mechanism Abatacept (CTLA4Ig): Mechanism of Actionof Action

CTLA4Ig BlocksActivation

Normal Activation

Signal 1Signal 2

AbataceptAbataceptAIM: Significant ACR Responses AIM: Significant ACR Responses

at 6 Months and 12 Monthsat 6 Months and 12 Months11

AC

R r

esp

on

ses†

(%)

†Intent-to-treat population where all dropouts were considered as ACR non-responders subsequent to their dropout

0

10

20

30

40

50

60

70

80

ACR 20 ACR 50 ACR 70

67.9%

39.7%

*

39.9%

16.8%19.8%

6.5%

73.1%

39.7%

48.3%

18.2%

28.8%

6.1%

6 months 12 months6 months 6 months12 months12 months

*

**

**

Abatacept + MTX (n=424) Placebo + MTX (n=214)

*p<0.001

90

100

1Kremer JM, et al. Ann Intern Med. 2006;144:865-876.

ATTAIN: Significant ACR 20, 50 and 70 ATTAIN: Significant ACR 20, 50 and 70 Responses at 6 MonthsResponses at 6 Months11

1Genovese M. N Engl J Med 2005; 353(11):1114-23.‡Intent-to-treat population, where all dropouts were considered as ACR non-responders subsequent to their discontinuation

50.4%

AC

R r

esp

on

ses‡

(%)

ACR 50 ACR 70

10.2%3.8%

20.3%

1.5%0

10

20

Abatacept + DMARDs (n=256) Placebo + DMARDs (n=133)

*p<0.001 †p<0.01

30

40

50

19.5%

ACR 20

60

80

90

100

*

*†

RituximabRituximab

B cell depletionB cell depletion Works about 50% in tnf failuresWorks about 50% in tnf failures Onset 6Onset 6--12 weeks12 weeks--may have long may have long

term effectterm effect 2 infusions2 infusions——1000mg vs 500mg1000mg vs 500mg ToxicityToxicity

Rituximab: Mechanism of ActionRituximab: Mechanism of Action Rituximab selectively

depletes B cells bearing the CD20 surface marker via:

• Antibody-dependent cellular cytotoxicity (ADCC)

• Complement-dependent cytotoxicity (CDC)

• Apoptosis

Anderson et al. Biochem Soc Trans. 1997;25:705–708; Golay et al. Blood. 2000;95:3900–3908; Reff et al. Blood. 1994;83:435–445; Clynes et al. Nat Med. 2000;6:443–446; Shan et al. Cancer Immunol Immunother. 2000;48:673–683; Silverman GJ, Weisman A. Arthritis Rheum. 2003;48:1484–1492.

Phase III: REFLEX TrialPhase III: REFLEX TrialA&R Sept. 2006A&R Sept. 2006

RRandomized andomized EEvaluation ovaluation off LLongong--Term Term EEfficacy of fficacy of RituRituxximab in RA imab in RA

Study Description:Study Description: Phase III, randomized, placeboPhase III, randomized, placebo--controlled trialcontrolled trial

Objectives of the Study:Objectives of the Study: Determine efficacy and safety of rituximab when used in combinatDetermine efficacy and safety of rituximab when used in combination ion

with methotrexatewith methotrexate

Key Patient Eligibility Criteria:Key Patient Eligibility Criteria: Age 18Age 18––80 years80 years

Diagnosed with RA for at least 6 monthsDiagnosed with RA for at least 6 months

Inadequate response to etanercept, infliximab, or adalimumabInadequate response to etanercept, infliximab, or adalimumab

Concerns Regarding RituximabConcerns Regarding Rituximab

What studies should be done before?What studies should be done before? What order should we add these medicines?What order should we add these medicines? Can (should) we treat seronegative patients?Can (should) we treat seronegative patients? What dosing and intervals and how often?What dosing and intervals and how often? How much steroids to use?How much steroids to use? Can we use without methotrexate or with Can we use without methotrexate or with

other small molecules?other small molecules? When can we add another therapy?When can we add another therapy? Will there be more surprising side effects? Will there be more surprising side effects?

(PML)(PML)

Adverse eventsAdverse events

Infusion reactions and lengthInfusion reactions and length Infections including PML, HepB, othersInfections including PML, HepB, others Rashes including psoriasisRashes including psoriasis Low cell counts (wbc)Low cell counts (wbc) Low IgG for long durationsLow IgG for long durations----

?significance?significance ?increase infections?increase infections

TocilizumabTocilizumab

Humanized mAb IgG1 Humanized mAb IgG1 (MW ~150 kd)(MW ~150 kd)

Key Features:Key Features: Binds soluble and Binds soluble and

membrane bound ILmembrane bound IL--6R 6R

Weak/no CDC* or Weak/no CDC* or ADCC** effector ADCC** effector functions (functions (in vitroin vitro))

Heavy chain

Light chain

CDR region

*CDC: complement*CDC: complement--dependent cytotoxicitydependent cytotoxicity**ADCC: antibody**ADCC: antibody--dependent cellular cytotoxicitydependent cellular cytotoxicity

TocilizumabTocilizumab

Monoclonal antibody that blocks IL6Monoclonal antibody that blocks IL6

50% response rate in TNF failures50% response rate in TNF failures

Onset 2Onset 2--12 weeks12 weeks

Impressive improvements in CRP, QOL, fatigueImpressive improvements in CRP, QOL, fatigue

Toxicity: Infections, ? GI perforation, lipid, Toxicity: Infections, ? GI perforation, lipid, leukocyte and liver test abnormalities.leukocyte and liver test abnormalities.

ILIL--6 Has Numerous Articular Effects 6 Has Numerous Articular Effects in RAin RA1,21,2

Synoviocytes

Osteoclast activationbone resorption

Endothelial cells

VEGF

Pannus formationPannus formation

Joint destructionJoint destruction

Mediation of chronicMediation of chronicinflammationinflammation

ILIL--66Macrophage

T-cell

B-cell

Neutrophil

AntibodyAntibodyproductionproduction

Adapted from 1 Choy E. Adapted from 1 Choy E. Rheum Dis Clin North AmRheum Dis Clin North Am. 2004;30:405. 2004;30:405––415. 415. 2 Gabay C. 2 Gabay C. Arthritis Res Ther.Arthritis Res Ther. 2006;8(suppl 2):S3.2006;8(suppl 2):S3.

PlaceboPlacebo+ MTX+ MTX(N=158)(N=158)

4 mg/kg4 mg/kg+ MTX+ MTX(N=161)(N=161)

8 mg/kg8 mg/kg+ MTX+ MTX(N=170)(N=170)

****

PlaceboPlacebo+ MTX+ MTX(N=158)(N=158)

4 mg/kg4 mg/kg+ MTX+ MTX(N=161)(N=161)

8 mg/kg8 mg/kg+ MTX+ MTX(N=170)(N=170)

******

PlaceboPlacebo+ MTX+ MTX

(N=158)(N=158)

4 mg/kg4 mg/kg+ MTX+ MTX

(N=161)(N=161)

8 mg/kg8 mg/kg+ MTX+ MTX

(N=170)(N=170)

******

******

AntiAnti--TNF, ACR70 Response Rates at Week 24TNF, ACR70 Response Rates at Week 24Inadequate RespondersInadequate Responders: : ACR20, ACR50 ACR20, ACR50 ITT PopulationITT Population

** p<0.01 *** p<0.0001, TCZ vs. Placebo + MTX** p<0.01 *** p<0.0001, TCZ vs. Placebo + MTX

10%4%

1%

30%

17%

5%

50%

29%

12%

0%

10%

20%

30%

40%

50%

60%

WA18062WA18062

Percentage (%)Percentage (%)RespondersResponders ACR20ACR20 ACR50ACR50 ACR70ACR70

Newer Drugs in DevelopmentNewer Drugs in Development

Newer B cell and anti TNF agentsNewer B cell and anti TNF agents p38MAP kinase inhibitorsp38MAP kinase inhibitors Janus Kinase 3 inhibitorsJanus Kinase 3 inhibitors--tofacitinibtofacitinib--

FDA advisory board approvalFDA advisory board approval Spleen tyrosine kinase inhibitorsSpleen tyrosine kinase inhibitors CCR1 antagonistsCCR1 antagonists Gene therapyGene therapy

ConclusionConclusionA new era in the treatment of rheumatoid A new era in the treatment of rheumatoid

arthritisarthritis

•• Proof of principle has been established that Proof of principle has been established that selective targeting of pathogenic elements is selective targeting of pathogenic elements is therapeutically effective. therapeutically effective.

•• Early therapyEarly therapy--especially combination therapy especially combination therapy tied to improved outcomes.tied to improved outcomes.

•• The future is now! Less joint replacements and The future is now! Less joint replacements and improved morbidity and mortality now improved morbidity and mortality now evident.evident.

•• A plea. Refer to confirm diagnosis and initiate A plea. Refer to confirm diagnosis and initiate treatmenttreatment

Question 1Question 1

1. A 581. A 58--yearyear--old male patient presents with old male patient presents with polyarticular pain that has lasted for 6 weeks. He polyarticular pain that has lasted for 6 weeks. He has had fevers and weight loss, and has a history of has had fevers and weight loss, and has a history of traveling to the Cape and Vineyard. He has morning traveling to the Cape and Vineyard. He has morning stiffness, shoulder, hip and MCP pain on exam. stiffness, shoulder, hip and MCP pain on exam. After the usual complete history and physical After the usual complete history and physical performed that reveals a small knee effusion as performed that reveals a small knee effusion as well as above. The work need not include (not well as above. The work need not include (not maymay——we are cutting the CMS budget):we are cutting the CMS budget):

A. CXR and hand and feet filmsA. CXR and hand and feet films B. Lyme titer and ANA B. Lyme titer and ANA C. Rheumatoid factor and anti CCPC. Rheumatoid factor and anti CCP D. A diagnostic tap of the kneeD. A diagnostic tap of the knee E. ESR and CRPE. ESR and CRP

AnswerAnswer

A is correctA is correct The tap of the knee will establish whether this is The tap of the knee will establish whether this is

an inflammatory disease or not and is the single an inflammatory disease or not and is the single most important test outlined. Whether the patient most important test outlined. Whether the patient is seropositive or not, and/ or has elevated is seropositive or not, and/ or has elevated inflammatory markers is key to guiding future inflammatory markers is key to guiding future therapeutics. While it is not wrong to obtain a CXR therapeutics. While it is not wrong to obtain a CXR (and in fact may be done when deciding drug (and in fact may be done when deciding drug therapy) it is not essential at this time. Hand and therapy) it is not essential at this time. Hand and feet films are unlikely to reveal anything significant feet films are unlikely to reveal anything significant after only 6 weeks of symptoms. A lyme titer and is after only 6 weeks of symptoms. A lyme titer and is reasonable to obtain due to his travel in an reasonable to obtain due to his travel in an endemic area; the ANA is really gratuitous and endemic area; the ANA is really gratuitous and would not offer any diagnostic help, but I thought would not offer any diagnostic help, but I thought you should think about its role in the differential you should think about its role in the differential diagnosis of this patient.diagnosis of this patient.

Question 2Question 2

2. A 482. A 48--yearyear--old man presents with rheumatoid old man presents with rheumatoid arthritis. He is deciding what DMARDs to take. He arthritis. He is deciding what DMARDs to take. He has erosive disease, and has a history of travel to has erosive disease, and has a history of travel to Russia and Peru, and has a vague sulfa allergy. His Russia and Peru, and has a vague sulfa allergy. His labs are unremarkable, except for a creatinine of labs are unremarkable, except for a creatinine of 1.7 and an AST of 38. 1.7 and an AST of 38.

A. What further tests or interventions need not be A. What further tests or interventions need not be done?done?

Tests: Tests: a. CXRa. CXR b. PPDb. PPD c. Pneumovaxc. Pneumovax d. HCV and HBSAg and HBcAgd. HCV and HBSAg and HBcAg e. ACE level and SPEPe. ACE level and SPEP

AnswerAnswer

E is correctE is correct A, B, and C must be done prior to any A, B, and C must be done prior to any

immunosuppressive treatment in this patient. A immunosuppressive treatment in this patient. A CXR is not mandatory in many instances, but in this CXR is not mandatory in many instances, but in this man, with possible exposure to Tb, and with the man, with possible exposure to Tb, and with the additional consideration of adding methotrexate or additional consideration of adding methotrexate or an antian anti--TNF, it is imperative. Due to his travel TNF, it is imperative. Due to his travel history a PPD is imperative and hepatitis serologies history a PPD is imperative and hepatitis serologies are needed due to the abnormal liver blood tests, are needed due to the abnormal liver blood tests, as one may consider methotrexate or rituximab as one may consider methotrexate or rituximab (both associated with Hepatitis B reactivation (both associated with Hepatitis B reactivation syndromes). An ACE level is almost never helpful syndromes). An ACE level is almost never helpful for any reason and an SPEP, while always for any reason and an SPEP, while always interesting, is not needed at this juncture.interesting, is not needed at this juncture.

Question 3Question 3

A 44 y/o man who is doing well on A 44 y/o man who is doing well on methotrexate 25mg/week for 18 months methotrexate 25mg/week for 18 months develops a cough, fever and malaise. CXR develops a cough, fever and malaise. CXR reveals a diffuse infiltrate and small pleural reveals a diffuse infiltrate and small pleural effusions. The next interventions need not effusions. The next interventions need not include:include:

A. Cessation of methotrexateA. Cessation of methotrexate B. Chest CT scanB. Chest CT scan C. Emergency BronchoscopyC. Emergency Bronchoscopy D. Broad Spectrum antibiotics and steroidsD. Broad Spectrum antibiotics and steroids E. Sputum for C and S and methenamine E. Sputum for C and S and methenamine

silver and 1,3 beta glucansilver and 1,3 beta glucan

AnswerAnswer C. Emergency bronchoscopyC. Emergency bronchoscopyWhile this may be needed eventually, other While this may be needed eventually, other

interventions should be initiates. The interventions should be initiates. The differential diagnosis for this man includes differential diagnosis for this man includes a CAP, Legionella, methotrexate toxicity and a CAP, Legionella, methotrexate toxicity and opportunistic infections including PCP. A opportunistic infections including PCP. A chest CT will often show ground glass and a chest CT will often show ground glass and a more diffuse pattern in immunosuppressed more diffuse pattern in immunosuppressed patients and should be done, as well as A,B, patients and should be done, as well as A,B, D,and E, among other tests including D,and E, among other tests including legionella antigens, LDH, ABGs, etc. If a legionella antigens, LDH, ABGs, etc. If a bronchoscopy were done, one would prefer bronchoscopy were done, one would prefer a biopsy to help diagnose methotrexate a biopsy to help diagnose methotrexate lung toxicity which often is manifested as a lung toxicity which often is manifested as a granulomatous inflammatory processgranulomatous inflammatory process. .

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