RHEUMATOID ARTHRITIS. CASE PRESENTATION - 34 YEAR OLD FEMALE Presented to family physician c/oPresented to family physician c/o >Mild stiffness in fingers

RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS

CASE PRESENTATION - CASE PRESENTATION - 34 YEAR OLD FEMALE34 YEAR OLD FEMALE

• Presented to family physician c/o Presented to family physician c/o > Mild stiffness in fingers and wrists upon awakening for past monthMild stiffness in fingers and wrists upon awakening for past month> Stiffness lasted for approximately 1 hourStiffness lasted for approximately 1 hour

• Nine months later, family physician was seen when swelling Nine months later, family physician was seen when swelling appeared in fingers and wrists and fatigue appeared in fingers and wrists and fatigue

• Laboratory testsLaboratory tests

> Complete blood count (CBC)Complete blood count (CBC)> Rheumatoid factor (RF)Rheumatoid factor (RF)> C-reactive protein (CRP)C-reactive protein (CRP)> Anti-nuclear antibody (ANA)Anti-nuclear antibody (ANA)

CASE PRESENTATION -CASE PRESENTATION -34 YEAR OLD FEMALE34 YEAR OLD FEMALE

• Laboratory Test ResultsLaboratory Test Results Reference Ranges Reference Ranges

> CBC CBC

– Mild anemiaMild anemia

> Rheumatoid factor (RF)Rheumatoid factor (RF)– Positive at a titer of 1:80 (< 1:40)Positive at a titer of 1:80 (< 1:40)

> C-reactive protein (CRP)C-reactive protein (CRP)– 30 mg/L 30 mg/L ((<< 8.0 mg/L) 8.0 mg/L)

> Anti-nuclear antibody (ANA)Anti-nuclear antibody (ANA)– Negative Negative (Negative)(Negative)

CASE PRESNTATION - CASE PRESNTATION - 34 YEAR OLD FEMALE34 YEAR OLD FEMALE

• Diagnosis of rheumatoid arthritisDiagnosis of rheumatoid arthritis

• Family historyFamily history> Negative for rheumatoid diseaseNegative for rheumatoid disease

• TreatmentTreatment> Aspirin 325 mg TIDAspirin 325 mg TID

CASE PRESNTATION - CASE PRESNTATION - 34 YEAR OLD FEMALE34 YEAR OLD FEMALE

• One year later, referred to Rheumatologist as joints became more One year later, referred to Rheumatologist as joints became more stiff and painfulstiff and painful

• Physical exam revealed spongy swelling in joints (thickening of Physical exam revealed spongy swelling in joints (thickening of synovium)synovium)

• Prescribed non-steroidal anti-inflammatory drug (NSAID)Prescribed non-steroidal anti-inflammatory drug (NSAID)> Ibuprofen (Motrin) 600 mg QIDIbuprofen (Motrin) 600 mg QID

• 1 year later, continued thickening of synovium, prescribed1 year later, continued thickening of synovium, prescribed> Hydroxychloroquine (Plaquenil)Hydroxychloroquine (Plaquenil)


• At 42 years of ageAt 42 years of age> RF by LA was positive at titer of 1:2560RF by LA was positive at titer of 1:2560> X-rays showed erosion of a number of jointsX-rays showed erosion of a number of joints

• At 45 years of age, prescribed methotrexate for At 45 years of age, prescribed methotrexate for exacerbation of symptomsexacerbation of symptoms

• At age 51, symptoms continued to worsen, At age 51, symptoms continued to worsen, prescribed infliximab (Remicade)prescribed infliximab (Remicade)


• Presents with 3 month history of asymptomatic lesions on Presents with 3 month history of asymptomatic lesions on lower legslower legs

• HistoryHistory> Rheumatoid arthritis treated withRheumatoid arthritis treated with

– Prednizone and etanercept (Enbrel)Prednizone and etanercept (Enbrel)> No recent leg traumaNo recent leg trauma> Biweekly pedicuresBiweekly pedicures

• Biopsy of two lesions submitted forBiopsy of two lesions submitted for> HistopathologyHistopathology> Routine cultureRoutine culture


• HistopathologyHistopathology> H and EH and E

– Necrotizing, granulomatous inflammationNecrotizing, granulomatous inflammation> Acid-fast stainAcid-fast stain

– Positive for few acid-fast bacilli (AFB)Positive for few acid-fast bacilli (AFB)

• Routine cultureRoutine culture> No organisms seen on gram stainNo organisms seen on gram stain> Culture positive for Culture positive for

– Rapid growing acid-fast bacilliRapid growing acid-fast bacilli> Mycobacterium mucogenicum identifiedMycobacterium mucogenicum identified


• Chronic systemic inflammatory disease affecting synovial Chronic systemic inflammatory disease affecting synovial membranes and articular structures of multiple jointsmembranes and articular structures of multiple joints

• Etiology is unknownEtiology is unknown

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

• Age of onset usually between 25 and 50 yearsAge of onset usually between 25 and 50 years

• Prevalence of 1% in USPrevalence of 1% in US


• Risk factorsRisk factors> SmokingSmoking

• PathophysiologyPathophysiology> Infectious triggers, genetic predispostion and autoimmune responseInfectious triggers, genetic predispostion and autoimmune response

• Infectious triggersInfectious triggers> Mycoplasma, parvovirus B19, HHV-6 and Epstein-Barr virus Mycoplasma, parvovirus B19, HHV-6 and Epstein-Barr virus > ““Mistaken identity” (“molecular mimicry”) theoryMistaken identity” (“molecular mimicry”) theory

• Genetic predispositionGenetic predisposition> HLA-DR4HLA-DR4

– 65% of caucasians with RA65% of caucasians with RA


• Autoimmune responseAutoimmune response> Inflammation and hyperplasia of synoviumInflammation and hyperplasia of synovium

> CD4 TH1 cells activate macrophages and synovial CD4 TH1 cells activate macrophages and synovial fibroblasts to produce cytokinesfibroblasts to produce cytokines

– TNF-alpha, IL-1, IL-6, IL-15 and IL-17TNF-alpha, IL-1, IL-6, IL-15 and IL-17

> Osteoclasts and chondroclasts are activatedOsteoclasts and chondroclasts are activated

> CD4 TH2 cells activate B cellsCD4 TH2 cells activate B cells

DIAGNOSIS OF DIAGNOSIS OF RHEUMATOID ARTHRITIS – AMERICAN RHEUMATOID ARTHRITIS – AMERICAN

COLLEGE OF RHEUMATOLOGYCOLLEGE OF RHEUMATOLOGY

• Morning stiffness of > 1 hourMorning stiffness of > 1 hour• Arthritis involving 3 or more jointsArthritis involving 3 or more joints• Arthritis of hand jointsArthritis of hand joints• Symmetric arthritisSymmetric arthritis• Subcutaneous nodulesSubcutaneous nodules• Positive test for rheumatoid factor (RF)Positive test for rheumatoid factor (RF)• Radiographic evidence of RARadiographic evidence of RA

LABORATORY DIAGNOSIS OF LABORATORY DIAGNOSIS OF RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS

• Complete blood count (CBC)Complete blood count (CBC)• Rheumatoid factor (Latex agglutination)Rheumatoid factor (Latex agglutination)

> Screen and titerScreen and titer

• Rheumatoid factor (Nephelometry)Rheumatoid factor (Nephelometry)> IgM, IgG and IgAIgM, IgG and IgA

• Cyclic citrullinated peptide (CCP) antibodyCyclic citrullinated peptide (CCP) antibody• C-reactive protein (CRP)C-reactive protein (CRP)• Erythrocyte sedimentation rate (ESR)Erythrocyte sedimentation rate (ESR)• Anti-nuclear antibody (ANA)Anti-nuclear antibody (ANA)

RHEUMATOID FACTORSRHEUMATOID FACTORS

• Autoantibodies (IgM, IgG and IgA) to Fc region of Autoantibodies (IgM, IgG and IgA) to Fc region of IgGIgG

• 80% of patient80% of patient’’s with RA show RFs with RA show RF

• RF by Latex AgglutinationRF by Latex Agglutination> Latex particles coated with human IgGLatex particles coated with human IgG> Screen with reflex titerScreen with reflex titer> Reference range of < 1:40Reference range of < 1:40

RHEUMATOID FACTORSRHEUMATOID FACTORS

• RF by NephelometryRF by Nephelometry> Reported in IU/mLReported in IU/mL> Reference range (< 20 IL/mL)Reference range (< 20 IL/mL)

• Rheumatoid Factor IgMRheumatoid Factor IgM> Most consistent finding Most consistent finding

• Rheumatoid Factor IgGRheumatoid Factor IgG> High specificity for RA and strong correlation with vasculitisHigh specificity for RA and strong correlation with vasculitis

• Rheumatoid Factor IgARheumatoid Factor IgA> Prognostic for more severe diseasePrognostic for more severe disease

CYCLIC CITRULLINATED PEPTIDE CYCLIC CITRULLINATED PEPTIDE (CCP) ANTIBODY(CCP) ANTIBODY

• Circular peptide containing citrullineCircular peptide containing citrulline

• Citrulline is produced by citrullination (Deimidation)Citrulline is produced by citrullination (Deimidation)

• Citrullination (Deimidation)Citrullination (Deimidation)> Post-translational modification of arginine Post-translational modification of arginine

– Peptidylarginine deiminase (PAD) Peptidylarginine deiminase (PAD)

• Proteins containing citrullineProteins containing citrulline> Myelin basic protein, filaggren, fibrinogen, vimentin, EBV nuclear Myelin basic protein, filaggren, fibrinogen, vimentin, EBV nuclear

antigen 1 antigen 1

CYCLIC CITRULLINATED PEPTIDE CYCLIC CITRULLINATED PEPTIDE (CCP) ANTIBODY(CCP) ANTIBODY

• Autoantibodies in RA react with a number of citrullinated proteins / Autoantibodies in RA react with a number of citrullinated proteins / peptidespeptides> Fibrinogen, EBV nuclear antigen 1, vimentinFibrinogen, EBV nuclear antigen 1, vimentin

• VimentinVimentin> Secreted and citrullinated by macrophagesSecreted and citrullinated by macrophages

– Response to apoptosisResponse to apoptosis– Response to pro-inflammatory cytokine TNF-alphaResponse to pro-inflammatory cytokine TNF-alpha

• EIA for IgG to anti-citrullinated proteins/peptidesEIA for IgG to anti-citrullinated proteins/peptides> Sensitivity (80%) and specificity (97%)Sensitivity (80%) and specificity (97%)> Reference range Reference range << 5.0 U/L 5.0 U/L> Detected earlier than RFDetected earlier than RF> Indicator of more severe disease and disease in futureIndicator of more severe disease and disease in future

ERYTHROCYTE ERYTHROCYTE SEDIMENTATION RATE (ESR)SEDIMENTATION RATE (ESR)

• Sedimentation rate (Sed rate)Sedimentation rate (Sed rate)

• Non-specific measure of inflammationNon-specific measure of inflammation> Specific analyte not measuredSpecific analyte not measured> Physical phenomenon with many variablesPhysical phenomenon with many variables> Fibrinogen causes RBCFibrinogen causes RBC’’s to stick togethers to stick together

• Distance (mm) erythrocyte layer moves in 1 hourDistance (mm) erythrocyte layer moves in 1 hour

• Reference range (Westergren method)Reference range (Westergren method)> < 15 mm/hr (Males < 50)< 15 mm/hr (Males < 50)> < 20 mm/hr (Females < 50)< 20 mm/hr (Females < 50)

ERYTHROCYTE ERYTHROCYTE SEDIMENTATION RATE (ESR)SEDIMENTATION RATE (ESR)• Automated and semi-automated methodsAutomated and semi-automated methods

> More rapid resultsMore rapid results

• Less sensitive than CRPLess sensitive than CRP> Elevation within 5 to 7 daysElevation within 5 to 7 days> Simple and inexpensive Simple and inexpensive

C-REACTIVE PROTEIN (CRP)C-REACTIVE PROTEIN (CRP)

• Marker for (acute) inflammationMarker for (acute) inflammation> Infection, cancer, autoimmunity, trauma, hypersensitivityInfection, cancer, autoimmunity, trauma, hypersensitivity

• Origin of nameOrigin of name> Reacts with Reacts with ““C polysaccharideC polysaccharide”” of pneumococcus of pneumococcus

• Mechanism of actionMechanism of action> Binds to phosphocholine on dead/dying cells and pathogensBinds to phosphocholine on dead/dying cells and pathogens

– Activates classical complement pathwayActivates classical complement pathway


• Produced by liver in response to IL-6Produced by liver in response to IL-6

• More sensitive than ESRMore sensitive than ESR> Elevation within 6 hoursElevation within 6 hours> Peak within 48 hoursPeak within 48 hours

• Laboratory methodLaboratory method> NephelometryNephelometry


• Reference rangeReference range> << 8.0 mg/L 8.0 mg/L

• Acute inflammationAcute inflammation> Greater than 10 mg/LGreater than 10 mg/L> Viral infection (10 to 40 mg/L)Viral infection (10 to 40 mg/L)> Bacterial infection (40 to Bacterial infection (40 to >> 200 mg/L) 200 mg/L)

• Cardiac risk stratificationCardiac risk stratification> Low risk: < 1.0 mg/LLow risk: < 1.0 mg/L> Average risk: 1.0 to 3.0 mg/LAverage risk: 1.0 to 3.0 mg/L> High risk: > 3.0 mg/LHigh risk: > 3.0 mg/L

ANTINUCLEAR ANTIBODY ANTINUCLEAR ANTIBODY (ANA) TEST(ANA) TEST

• Detects autoantibodies against nuclear antigens Detects autoantibodies against nuclear antigens

• Nuclear antigensNuclear antigens> DS-DNA, SS-A, SS-B, histonesDS-DNA, SS-A, SS-B, histones

• Laboratory methodsLaboratory methods> Enzyme immunoassay (EIA)Enzyme immunoassay (EIA)> Indirect immunofluorescence assay (IFA)Indirect immunofluorescence assay (IFA)

• Positive resultsPositive results> Rheumatoid arthritis (25-90%)Rheumatoid arthritis (25-90%)

TREATMENT OF TREATMENT OF RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS

• Nonsteroidal anti-inflammatory drugs (NSAIDs)Nonsteroidal anti-inflammatory drugs (NSAIDs)> AspirinAspirin> Ibuprofen (Advil and Motrin)Ibuprofen (Advil and Motrin)> Naproxen (Aleve)Naproxen (Aleve)> Celecoxib (Celebrex)Celecoxib (Celebrex)

• CorticosteroidsCorticosteroids> PrednizonePrednizone

• Analgesic drugsAnalgesic drugs> AcetaminophenAcetaminophen


• Disease Modifying Anti-Rheumatic Drugs (DMARDs)Disease Modifying Anti-Rheumatic Drugs (DMARDs)> Methotrexate (Rheumatrex)Methotrexate (Rheumatrex)> Hydroxychloroquine (Plaquenil)Hydroxychloroquine (Plaquenil)> Azathioprine (Imuran)Azathioprine (Imuran)> Cyclophosphamide (Cytoxan)Cyclophosphamide (Cytoxan)> Cyclosporine (Sandimmune)Cyclosporine (Sandimmune)> Minocycline (Minocin)Minocycline (Minocin)

• Biological Response Modifiers (Biologic DMARDs)Biological Response Modifiers (Biologic DMARDs)> Tumor necrosis factor-alpha (TNF-alpha) inhibitorsTumor necrosis factor-alpha (TNF-alpha) inhibitors

– Etanercept (Enbrel)Etanercept (Enbrel)– Infliximab (Remicade)Infliximab (Remicade)– Adalimumab (Humira)Adalimumab (Humira)– Golimumab (Simponi)Golimumab (Simponi)


• Biological Response Modifiers (Biologic DMARDs)Biological Response Modifiers (Biologic DMARDs)> B cell depleting agentsB cell depleting agents

– Rituximab (Rituxan)Rituximab (Rituxan)

> T-cell co-stimulatory blocking agentsT-cell co-stimulatory blocking agents– Abatacept (Orencia)Abatacept (Orencia)

> Interleukin-1 (IL-1) receptor antagonistInterleukin-1 (IL-1) receptor antagonist– Anakinra (Kineret)Anakinra (Kineret)

> Interleukin-6 (IL-6) receptor antagonistInterleukin-6 (IL-6) receptor antagonist– Tocilizumab (Actemra)Tocilizumab (Actemra)

ETANERCEPT (ENBREL)ETANERCEPT (ENBREL)

• Dimeric fusion protein Dimeric fusion protein > Extracellular binding domain of p75 TNF receptor and Extracellular binding domain of p75 TNF receptor and

the Fc portion of human IgG1the Fc portion of human IgG1

• Prevents binding of TNF-alpha to cell surface Prevents binding of TNF-alpha to cell surface receptorreceptor

• Adverse reactionsAdverse reactions> Infections, Malignancies, AutoimmunityInfections, Malignancies, Autoimmunity

INFLIXIMAB (REMICADE)INFLIXIMAB (REMICADE)

• Chimeric IgG1 monoclonal antibody Chimeric IgG1 monoclonal antibody > Human (constant region)Human (constant region)> Mouse (variable region)Mouse (variable region)

• Prevents binding of TNF-alpha to receptorPrevents binding of TNF-alpha to receptor

• Administration is IV along with methotrexateAdministration is IV along with methotrexate> 10 to 30% anti-infliximab antibodies10 to 30% anti-infliximab antibodies

• Adverse effectsAdverse effects> Infections, Malignancies, AutoimmunityInfections, Malignancies, Autoimmunity

ADALIMUMAB (HUMIRA)ADALIMUMAB (HUMIRA)

• Human IgG1 monoclonal antibodyHuman IgG1 monoclonal antibody

• Binds to TNF-alpha and prevents binding of TNF to Binds to TNF-alpha and prevents binding of TNF to p55 and p75 cell surface receptorsp55 and p75 cell surface receptors

• Adverse reactionsAdverse reactions> InfectionsInfections> MalignanciesMalignancies> Autoimmunity Autoimmunity

ABATACEPT (ORENCIA)ABATACEPT (ORENCIA)

• Soluble fusion proteinSoluble fusion protein> Extracellular domain of human cytotoxic T-lymphocyte Extracellular domain of human cytotoxic T-lymphocyte

associated antigen 4 (CTLA-4) associated antigen 4 (CTLA-4) > Fc region of human IgG1Fc region of human IgG1

• Indication in RAIndication in RA> Adults with moderate to severe RA with inadequate response to Adults with moderate to severe RA with inadequate response to

one or more TNF-alpha antagonist therapiesone or more TNF-alpha antagonist therapies> Administered by 30 minute IV infusionAdministered by 30 minute IV infusion> Concurrent therapy with TNF-alpha inhibitors not Concurrent therapy with TNF-alpha inhibitors not

recommendedrecommended

ABATACEPT (ORENCIA)ABATACEPT (ORENCIA)

• CTLA-4CTLA-4> Expressed on surface of CD4 T cellsExpressed on surface of CD4 T cells> Binds to CD80 and CD86 and transmits inhibitory signalBinds to CD80 and CD86 and transmits inhibitory signal

• Mechanism of actionMechanism of action> Binds to CD80 (B7.1) and CD86 (B7.2) on APCBinds to CD80 (B7.1) and CD86 (B7.2) on APC> Blocks access to CD28 co-stimulatory receptor on T cellsBlocks access to CD28 co-stimulatory receptor on T cells

• Activation of T cells by APCActivation of T cells by APC> Stimulation by MHC class II molecule to TCRStimulation by MHC class II molecule to TCR> Co-stimulation by B7 to Co-stimulation by B7 to

– CD28 (stimulation)CD28 (stimulation)– CTLA4 (inhibition)CTLA4 (inhibition)

ANAKINRA (KINERET)ANAKINRA (KINERET)

• Recombinant, nonglycosylated proteinRecombinant, nonglycosylated protein> Synthetic version of human endogenous IL-1 Synthetic version of human endogenous IL-1

receptor antagonist (IL-1Ra)receptor antagonist (IL-1Ra)

• Indication in RAIndication in RA> Adults with moderate to severe RA with inadequate Adults with moderate to severe RA with inadequate

response to one or more DMARD agentsresponse to one or more DMARD agents> Administered by daily subcutaneous injectionAdministered by daily subcutaneous injection> Not compatible with TNF-alpha inhibitorsNot compatible with TNF-alpha inhibitors

ANAKINRA (KINERET)ANAKINRA (KINERET)

• Normal jointNormal joint> Endogenous IL-1Ra competes with IL-1 for IL-1 receptor Endogenous IL-1Ra competes with IL-1 for IL-1 receptor

type I (IL-1RI)type I (IL-1RI)> IL-1Ra most important regulator of synovial IL-1 activityIL-1Ra most important regulator of synovial IL-1 activity

• RA jointRA joint> Higher level of IL-1 compared to IL-1RaHigher level of IL-1 compared to IL-1Ra

• Mechanism of actionMechanism of action> Binding of IL-1Ra competitively inhibits binding of IL-1 to Binding of IL-1Ra competitively inhibits binding of IL-1 to

IL-1 receptor type 1 (IL-1RI) IL-1 receptor type 1 (IL-1RI)

RITUXIMAB (RITUXAN)RITUXIMAB (RITUXAN)

• Chimeric IgG1 monoclonal antibodyChimeric IgG1 monoclonal antibody> Variable domains are mouseVariable domains are mouse> Constant domains are humanConstant domains are human

• FDA approvalFDA approval> 1997 for non-Hodgkin1997 for non-Hodgkin’’s lymphoma (NHL)s lymphoma (NHL)> 2006 for rheumatoid arthritis (RA)2006 for rheumatoid arthritis (RA)

• Indication in RAIndication in RA> Adults with moderate to severe RA with inadequate response to one Adults with moderate to severe RA with inadequate response to one

or more TNF-alpha antagonist therapiesor more TNF-alpha antagonist therapies

RITUXIMAB (RITUXAN)RITUXIMAB (RITUXAN)

• Mechanism of actionMechanism of action> Binds to CD20 antigen on normal and malignant B lymphocytes and Binds to CD20 antigen on normal and malignant B lymphocytes and

mediates lysismediates lysis

• Mechanisms of B cell lysisMechanisms of B cell lysis> ComplementComplement> ADCCADCC> Induction of apoptosisInduction of apoptosis

• CD20 antigen not present onCD20 antigen not present on> Hematopoietic stem cells, proB cells and normal plasma cellsHematopoietic stem cells, proB cells and normal plasma cells

B LYMPHOCYTES ROLE IN B LYMPHOCYTES ROLE IN RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS

• Three potential important rolesThree potential important roles

> Antigen presentationAntigen presentation

> Autoantibody productionAutoantibody production

> Cytokine productionCytokine production

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RHEUMATOID ARTHRITIS. CASE PRESENTATION - 34 YEAR OLD FEMALE Presented to family physician c/oPresented to family physician c/o >Mild stiffness in fingers