Rheumatoid ArthritisRheumatoid Arthritis

ByBy

Dr. Nate JosephsonDr. Nate Josephson

Case PresentationCase Presentation

32 year old WF presents to PCP with a 3 month 32 year old WF presents to PCP with a 3 month history of progressive pain and stiffness of history of progressive pain and stiffness of several joints, notably the wrists, hands, feet, several joints, notably the wrists, hands, feet, and ankles. She feels worse in the morning and and ankles. She feels worse in the morning and takes several hours to loosen up. takes several hours to loosen up.

On your exam you think there may be some mild On your exam you think there may be some mild swelling in her MCP joints and wrists, but you swelling in her MCP joints and wrists, but you are not absolutely sure. You are concerned that are not absolutely sure. You are concerned that she may early rheumatoid arthritis.she may early rheumatoid arthritis.

QuestionsQuestions

1.1. How do you confirm the diagnosis of How do you confirm the diagnosis of rheumatoid arthritis?rheumatoid arthritis?

2.2. If she does have rheumatoid arthritis, is it If she does have rheumatoid arthritis, is it okay to see how she does for a while on okay to see how she does for a while on NSAIDS +/- corticosteroids?NSAIDS +/- corticosteroids?

3.3. Is it important to refer to rheumatology Is it important to refer to rheumatology early?early?

Rheumatoid ArthritisRheumatoid Arthritis

A symmetric, peripheral polyarthritis of A symmetric, peripheral polyarthritis of unknown etiology that, untreated or if unknown etiology that, untreated or if unresponsive to therapy, typically, leads to unresponsive to therapy, typically, leads to deformity and destruction of joints through deformity and destruction of joints through the erosion of cartilage and bone. the erosion of cartilage and bone.

Epidemiology of RAEpidemiology of RA

Prevalence ranges from 0.5 to 1.0%, Prevalence ranges from 0.5 to 1.0%, affecting more than 2 million Americansaffecting more than 2 million Americans

Age of onset typically between 20 and 45 Age of onset typically between 20 and 45 years but over 25% cases start over 60 years but over 25% cases start over 60 years oldyears old

Female to male ratio is nearly 3:1Female to male ratio is nearly 3:1

Annual incidence: 36 cases per 100,000 Annual incidence: 36 cases per 100,000 womenwomen

Initial Clinical Presentation - ClassicInitial Clinical Presentation - Classic

Insidious onset of symmetric polyarthritis, Insidious onset of symmetric polyarthritis, particularly MCPs, MTPs, PIPs, wristsparticularly MCPs, MTPs, PIPs, wrists

Morning stiffness lasting more than one Morning stiffness lasting more than one hourhour

Constitutional symptoms such as fatigue Constitutional symptoms such as fatigue commoncommon

Initial Clinical Presentations – Less CommonInitial Clinical Presentations – Less Common

Acute polyarthritis with prominent myalgias Acute polyarthritis with prominent myalgias and constitutional symptomsand constitutional symptoms

Palindromic rheumatism – one or several Palindromic rheumatism – one or several joints acutely involved for hours to few joints acutely involved for hours to few days with symptom free intervals lasting days with symptom free intervals lasting days to monthsdays to months

Persistent monoarthritis as herald of Persistent monoarthritis as herald of diseasedisease

Key Physical FindingsKey Physical Findings

Symmetrical soft tissue swelling / Symmetrical soft tissue swelling / tenderness in peripheral jointstenderness in peripheral joints

>20 joints in severe disease>20 joints in severe disease

Most common are MCP and MTP jointsMost common are MCP and MTP joints

MCP and MTP squeeze testMCP and MTP squeeze test

Confirmation of SynovitisConfirmation of Synovitis

Synovitis needs to be confirmed by Synovitis needs to be confirmed by reliable examiner since it is essential reliable examiner since it is essential requirement for diagnosisrequirement for diagnosis

If synovitis is equivocal on examIf synovitis is equivocal on exam

*May need to follow patient*May need to follow patient

*Occasionally imaging techniques *Occasionally imaging techniques such such

as MRI helpfulas MRI helpful

Clinically Useful Biologic MarkersClinically Useful Biologic Markers

Rheumatoid factorRheumatoid factor

Anti-CCP antibodyAnti-CCP antibody

ESR / CRPESR / CRP

Rheumatoid Factor(s)Rheumatoid Factor(s)

Found in 75-80% of RA patientsFound in 75-80% of RA patients

Positivity lower at onset but peaks by 6-12 Positivity lower at onset but peaks by 6-12 monthsmonths

High levels associated with more High levels associated with more aggressive diseaseaggressive disease

Nonspecific – can occur in chronic Nonspecific – can occur in chronic infections (such as HCV) and other infections (such as HCV) and other autoimmune diseaseautoimmune disease

Anti-Cyclic Citrullinated Peptide Anti-Cyclic Citrullinated Peptide (CCP) Antibodies(CCP) Antibodies

Found in 50-75% of RA patientsFound in 50-75% of RA patients

May precede clinical symptomsMay precede clinical symptoms

Confers increased risk of progressive Confers increased risk of progressive diseasedisease

More specific than RFMore specific than RF

Testing for both RF and anti-CCP antibodiesTesting for both RF and anti-CCP antibodies

SensitivitySensitivity SpecificitySpecificity

RFRF 73% 73% 82% 82%

Anti-CCPAnti-CCP 56% 56% 90% 90%

Both positiveBoth positive 48% 96% 48% 96%

Remember:Remember: higher the specificity, higher the positive predictive higher the specificity, higher the positive predictive value (more likely to have disease)value (more likely to have disease)

Acute Phase Reactants – ESR/CRPAcute Phase Reactants – ESR/CRP

Not specific, but fairly sensitiveNot specific, but fairly sensitive

Elevation of both: stronger indication of Elevation of both: stronger indication of radiographic progressionradiographic progression

Correlate with disease activity and used in Correlate with disease activity and used in various metrics to follow disease activityvarious metrics to follow disease activity

ImagingImaging

Plain film radiography: unlikely to reveal Plain film radiography: unlikely to reveal erosive disease in very early disease but erosive disease in very early disease but may serve as baselinemay serve as baseline

MRI: much more sensitive for erosive MRI: much more sensitive for erosive diseasedisease

How often is MRI needed for diagnosis How often is MRI needed for diagnosis and as a guide to therapy – remains and as a guide to therapy – remains controversial given costcontroversial given cost

Rheumatoid Arthritis - DiagnosisRheumatoid Arthritis - Diagnosis

Based on a constellation of compatible Based on a constellation of compatible features and exclusion of other causes of features and exclusion of other causes of chronic (>6 weeks) inflammatory arthritischronic (>6 weeks) inflammatory arthritis

Other Causes of Chronic Other Causes of Chronic Inflammatory ArthritisInflammatory Arthritis

SLE and other connective tissue diseasesSLE and other connective tissue diseases

Psoriatic arthritisPsoriatic arthritis

Reactive arthritis and undifferentiated Reactive arthritis and undifferentiated spondyloarthropathyspondyloarthropathy

Polyarticular gout / pseudogoutPolyarticular gout / pseudogout

Inflammatory (erosive) interphalangeal OAInflammatory (erosive) interphalangeal OA

Polymyalgia rheumatica/RS3PE syndrome Polymyalgia rheumatica/RS3PE syndrome in elderlyin elderly

Natural History & Prognosis of RA Natural History & Prognosis of RA (Prior to DMARDS)(Prior to DMARDS)

At 20 years 70% of RA patients severely At 20 years 70% of RA patients severely disableddisabledAlthough disease activity (inflammation) varies, Although disease activity (inflammation) varies, structural damage is cumulative and irreversiblestructural damage is cumulative and irreversibleUp to 90% of patients < 2 years disease show Up to 90% of patients < 2 years disease show radiographic damageradiographic damagePoor outcomes, including life expectancy, Poor outcomes, including life expectancy, associated with early adverse prognostic factors associated with early adverse prognostic factors – functional limitation, extraarticular disease, – functional limitation, extraarticular disease, positive RF or anti-CCP, bony erosionspositive RF or anti-CCP, bony erosions

Aims of TherapyAims of Therapy

1.1. Relief of signs and symptoms.Relief of signs and symptoms.2.2. Improvement in patient reported Improvement in patient reported

outcomesoutcomes3.3. Inhibition of structural damageInhibition of structural damage

These 3 interrelated aims best achieved by These 3 interrelated aims best achieved by rapid and sustained suppression of rapid and sustained suppression of disease to remission or low disease disease to remission or low disease activity with DMARDs.activity with DMARDs.

Disease Modifying Antirheumatic Disease Modifying Antirheumatic Drugs (DMARDS)Drugs (DMARDS)

Traditional DMARDSTraditional DMARDSHydroxychlroquineHydroxychlroquineSulfasalazineSulfasalazineDoxycyclineDoxycyclineMethotrexateMethotrexateLeflunomideLeflunomide

Biologic agents – targeting the immune Biologic agents – targeting the immune systemsystem

Biologic Agents for RABiologic Agents for RA

TargetTarget DrugDrug

TNFTNF etanerceptetanerceptinfliximabinfliximab

adalimumabadalimumabgolimumabgolimumabcertolizumabcertolizumab

B cellsB cells rituximabrituximab

T cellT cell abataceptabatacept

1L-6 receptor1L-6 receptor tocilizumabtocilizumab

What Emerges from Randomized What Emerges from Randomized Clinical Therapeutic Trials in Early RAClinical Therapeutic Trials in Early RA

Clearly the earlier the therapy the better Clearly the earlier the therapy the better the outcomethe outcome

The tighter the control the better the The tighter the control the better the outcomeoutcome

Combinations employing biologic agents Combinations employing biologic agents are more effective in controlling symptoms are more effective in controlling symptoms and and radiographic progressionradiographic progression than than traditional DMARDstraditional DMARDs

Measures of Disease ActivityMeasures of Disease Activity

A metric utilizing several parameters to A metric utilizing several parameters to assess activityassess activity

Used to initially stage diseaseUsed to initially stage disease

Can evaluate response to therapy – Can evaluate response to therapy – adequate (tight) or notadequate (tight) or not

Can be used to define remissonCan be used to define remisson

Assessment of Disease Activity in Assessment of Disease Activity in Early RAEarly RA

Semi QuantitativeSemi Quantitative

MildMild ModerateModerate SevereSevere

# joints# joints < 6< 6 6-206-20 > 20> 20

ExtraarticularExtraarticular NoNo NoNo CommonCommon

ErosionsErosions NoNo +/-+/- ++++

RF/CCP+RF/CCP+ +/-+/- ++ ++++

ESR/CRPESR/CRP +/-+/- ++ ++++

QuantitativeQuantitative

DAS 28DAS 28 2.4-3.62.4-3.6 3.7-5.53.7-5.5 > 5.5> 5.5

Treatment of Mild Disease in Early RATreatment of Mild Disease in Early RA

NSAIDS and traditional DMARDs may suffice – NSAIDS and traditional DMARDs may suffice – *hydroxychloroquine*hydroxychloroquine (HCQ)(HCQ)*sulfasalazine*sulfasalazine (SSA)(SSA)*methotrexate*methotrexate (MTX)(MTX)*leflunomide*leflunomide (LEF)(LEF)*doxycycline*doxycycline

Combination of traditional DMARDS sometimes Combination of traditional DMARDS sometimes usedusedCorticosteroids – not at all or sparinglyCorticosteroids – not at all or sparingly

Treatment of Moderate/Severe Early RATreatment of Moderate/Severe Early RA

Goal: Remission of low disease activityGoal: Remission of low disease activity

A. MTX (or LEF) monotherapy for 8-12 week trialA. MTX (or LEF) monotherapy for 8-12 week trial

B. Inadequate responders to A: MTX + anti-TNFB. Inadequate responders to A: MTX + anti-TNF

C. Inadequate responders to B: TNF switching orC. Inadequate responders to B: TNF switching or

MTX + other traditional DMARDs orMTX + other traditional DMARDs or

MTX + newer biologic agentMTX + newer biologic agent

tocilizumab (Actemra)tocilizumab (Actemra)

rituximab (Rituxin)rituximab (Rituxin)

abatacept (Orencia)abatacept (Orencia)

NSAIDS and Corticosteroids adjunctiveNSAIDS and Corticosteroids adjunctive

Role of Corticosteroids in Early RARole of Corticosteroids in Early RA

If patient systemically ill or experiencing rapid If patient systemically ill or experiencing rapid decline in function, prednisone 10 mgm/dailydecline in function, prednisone 10 mgm/daily

Once patient responds sufficiently, dose should Once patient responds sufficiently, dose should be tapered to 5 mgm/day or lessbe tapered to 5 mgm/day or less

Intraarticular route very effective and may Intraarticular route very effective and may bypass systemic usebypass systemic use

Also consider protection for osteoporosis if Also consider protection for osteoporosis if prednisone used at >5 mgm/day for greater than prednisone used at >5 mgm/day for greater than 3 months3 months

Safety Issues - NSAIDSSafety Issues - NSAIDS

Toxicity increases with dose escalation Toxicity increases with dose escalation regardless of agentregardless of agent

Gastroprotection in patients with risk Gastroprotection in patients with risk factors for gastropathy – age > 65, past factors for gastropathy – age > 65, past history of ulcerhistory of ulcer

Safety Issues - MethotrexateSafety Issues - Methotrexate

HepatotoxicityHepatotoxicity

Pulmonary toxicityPulmonary toxicity

Bone marrow suppressionBone marrow suppression

TeratogenecityTeratogenecity

Although not nephrotoxic lower doses with Although not nephrotoxic lower doses with reduced renal functionreduced renal function

Potential Safety Issues with TNF Potential Safety Issues with TNF InhibitorsInhibitors

Target Related (general immunomodulatory / TNF Target Related (general immunomodulatory / TNF Specific)Specific)Infectious / serious infectionsInfectious / serious infectionsOpportunistic infections (eg, TB)Opportunistic infections (eg, TB)Malignancies (lymphoma, skin, etc)Malignancies (lymphoma, skin, etc)Demyelinating conditionsDemyelinating conditionsHematologic abnormalitiesHematologic abnormalitiesCongestive heart failureCongestive heart failureAutoantibodies (>40% het ANA+, 10% anti-DNA; ACL also seen: however, few Autoantibodies (>40% het ANA+, 10% anti-DNA; ACL also seen: however, few other autoantibodies, and lupus-like syndromes rare)other autoantibodies, and lupus-like syndromes rare)HepatotoxicityHepatotoxicitySkin reactions / psoriasisSkin reactions / psoriasis

Agent relatedAgent relatedAdministration reactionAdministration reactionImmunogenicityImmunogenicity

Tuberculosis & TNF AntagonistsTuberculosis & TNF Antagonists

Latent TB (LTBI): +PPD/-Sxs/-CXRLatent TB (LTBI): +PPD/-Sxs/-CXRAll TNF inhibitor Rx patients should be evaluated for All TNF inhibitor Rx patients should be evaluated for LTBI with a tuberculin skin test prior to initiationLTBI with a tuberculin skin test prior to initiationObtain CXR? Not routinely advocated in USA. Do:Obtain CXR? Not routinely advocated in USA. Do:

*If PPD positive*If PPD positive*If signs/Sxs present*If signs/Sxs present*Recent known TB contact*Recent known TB contact

If latent TB (no signs/Sxs): initiate INH prior to or with If latent TB (no signs/Sxs): initiate INH prior to or with TNF inhibitor therapyTNF inhibitor therapyIf active TB infection, treat 4 drugs, delay initiation of If active TB infection, treat 4 drugs, delay initiation of TNF inhibitor therapyTNF inhibitor therapy

Prevention While on TNFiPrevention While on TNFi

General precautionsGeneral precautions*General infection control*General infection control*Manage comorbidities (alcohol and *Manage comorbidities (alcohol and smoking cessationsmoking cessation, DM , DM

control, minimize steroid dose)control, minimize steroid dose)

2006 ACIP Guidelines on Immunizations2006 ACIP Guidelines on Immunizations*Influenza vaccine every year*Influenza vaccine every year*Pneumococcal vaccine*Pneumococcal vaccine*Meningococcal, Hepatitis B where exposure is likely*Meningococcal, Hepatitis B where exposure is likely*Avoid live-attenuated vaccines (oral polio*, MMR, varicella, *Avoid live-attenuated vaccines (oral polio*, MMR, varicella,

shingles)shingles)

ConclusionsConclusions

Early diagnosis important, which leads to –Early diagnosis important, which leads to –

Early treatment, aggressive if necessary, Early treatment, aggressive if necessary, which leads to – which leads to –

Better outcomesBetter outcomes

Communication important between PCP Communication important between PCP and rheumatologistand rheumatologist