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RHEUMATOID ARTHRITIS. CASE PRESENTATION - 34 YEAR OLD FEMALE. Presented to family physician c/o Mild stiffness in fingers and wrists upon awakening for past month Stiffness lasted for approximately 1 hour

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case presentation 34 year old female
CASE PRESENTATION - 34 YEAR OLD FEMALE
  • Presented to family physician c/o
    • Mild stiffness in fingers and wrists upon awakening for past month
    • Stiffness lasted for approximately 1 hour
  • Nine months later, family physician was seen when swelling appeared in fingers and wrists and fatigue
  • Laboratory tests
    • Complete blood count (CBC)
    • Rheumatoid factor (RF)
    • C-reactive protein (CRP)
    • Anti-nuclear antibody (ANA)
case presentation 34 year old female3
CASE PRESENTATION -34 YEAR OLD FEMALE
  • Laboratory Test Results Reference Ranges
    • CBC
      • Mild anemia
    • Rheumatoid factor (RF)
      • Positive at a titer of 1:80 (< 1:40)
    • C-reactive protein (CRP)
      • 30 mg/L (< 8.0 mg/L)
    • Anti-nuclear antibody (ANA)
      • Negative (Negative)
case presntation 34 year old female
CASE PRESNTATION - 34 YEAR OLD FEMALE
  • Diagnosis of rheumatoid arthritis
  • Family history
    • Negative for rheumatoid disease
  • Treatment
    • Aspirin 325 mg TID
case presntation 34 year old female5
CASE PRESNTATION - 34 YEAR OLD FEMALE
  • One year later, referred to Rheumatologist as joints became more stiff and painful
  • Physical exam revealed spongy swelling in joints (thickening of synovium)
  • Prescribed non-steroidal anti-inflammatory drug (NSAID)
    • Ibuprofen (Motrin) 600 mg QID
  • 1 year later, continued thickening of synovium, prescribed
    • Hydroxychloroquine (Plaquenil)
case presentation 34 year old female6
CASE PRESENTATION -34 YEAR OLD FEMALE
  • At 42 years of age
    • RF by LA was positive at titer of 1:2560
    • X-rays showed erosion of a number of joints
  • At 45 years of age, prescribed methotrexate for exacerbation of symptoms
  • At age 51, symptoms continued to worsen, prescribed infliximab (Remicade)
case presentation 61 year old female
CASE PRESENTATION -61 YEAR OLD FEMALE
  • Presents with 3 month history of asymptomatic lesions on lower legs
  • History
    • Rheumatoid arthritis treated with
      • Prednizone and etanercept (Enbrel)
    • No recent leg trauma
    • Biweekly pedicures
  • Biopsy of two lesions submitted for
    • Histopathology
    • Routine culture
case presentation 61 year old female9
CASE PRESENTATION -61 YEAR OLD FEMALE
  • Histopathology
    • H and E
      • Necrotizing, granulomatous inflammation
    • Acid-fast stain
      • Positive for few acid-fast bacilli (AFB)
  • Routine culture
    • No organisms seen on gram stain
    • Culture positive for
      • Rapid growing acid-fast bacilli
    • Mycobacterium mucogenicum identified
rheumatoid arthritis10
RHEUMATOID ARTHRITIS
  • Chronic systemic inflammatory disease affecting synovial membranes and articular structures of multiple joints
  • Etiology is unknown
  • Female:Male ratio is 3:1
  • Age of onset usually between 25 and 50 years
  • Prevalence of 1% in US
rheumatoid arthritis11
RHEUMATOID ARTHRITIS
  • Risk factors
    • Smoking
  • Pathophysiology
    • Infectious triggers, genetic predispostion and autoimmune response
  • Infectious triggers
    • Mycoplasma, parvovirus B19, HHV-6 and Epstein-Barr virus
    • “Mistaken identity” (“molecular mimicry”) theory
  • Genetic predisposition
    • HLA-DR4
      • 65% of caucasians with RA
rheumatoid arthritis12
RHEUMATOID ARTHRITIS
  • Autoimmune response
    • Inflammation and hyperplasia of synovium
    • CD4 TH1 cells activate macrophages and synovial fibroblasts to produce cytokines
      • TNF-alpha, IL-1, IL-6, IL-15 and IL-17
    • Osteoclasts and chondroclasts are activated
    • CD4 TH2 cells activate B cells
diagnosis of rheumatoid arthritis american college of rheumatology
DIAGNOSIS OF RHEUMATOID ARTHRITIS – AMERICAN COLLEGE OF RHEUMATOLOGY
  • Morning stiffness of > 1 hour
  • Arthritis involving 3 or more joints
  • Arthritis of hand joints
  • Symmetric arthritis
  • Subcutaneous nodules
  • Positive test for rheumatoid factor (RF)
  • Radiographic evidence of RA
laboratory diagnosis of rheumatoid arthritis
LABORATORY DIAGNOSIS OF RHEUMATOID ARTHRITIS
  • Complete blood count (CBC)
  • Rheumatoid factor (Latex agglutination)
    • Screen and titer
  • Rheumatoid factor (Nephelometry)
    • IgM, IgG and IgA
  • Cyclic citrullinated peptide (CCP) antibody
  • C-reactive protein (CRP)
  • Erythrocyte sedimentation rate (ESR)
  • Anti-nuclear antibody (ANA)
rheumatoid factors
RHEUMATOID FACTORS
  • Autoantibodies (IgM, IgG and IgA) to Fc region of IgG
  • 80% of patient’s with RA show RF
  • RF by Latex Agglutination
    • Latex particles coated with human IgG
    • Screen with reflex titer
    • Reference range of < 1:40
rheumatoid factors19
RHEUMATOID FACTORS
  • RF by Nephelometry
    • Reported in IU/mL
    • Reference range (< 20 IL/mL)
  • Rheumatoid Factor IgM
    • Most consistent finding
  • Rheumatoid Factor IgG
    • High specificity for RA and strong correlation with vasculitis
  • Rheumatoid Factor IgA
    • Prognostic for more severe disease
cyclic citrullinated peptide ccp antibody
CYCLIC CITRULLINATED PEPTIDE (CCP) ANTIBODY
  • Circular peptide containing citrulline
  • Citrulline is produced by citrullination (Deimidation)
  • Citrullination (Deimidation)
    • Post-translational modification of arginine
      • Peptidylarginine deiminase (PAD)
  • Proteins containing citrulline
    • Myelin basic protein, filaggren, fibrinogen, vimentin, EBV nuclear antigen 1
cyclic citrullinated peptide ccp antibody21
CYCLIC CITRULLINATED PEPTIDE (CCP) ANTIBODY
  • Autoantibodies in RA react with a number of citrullinated proteins / peptides
    • Fibrinogen, EBV nuclear antigen 1, vimentin
  • Vimentin
    • Secreted and citrullinated by macrophages
      • Response to apoptosis
      • Response to pro-inflammatory cytokine TNF-alpha
  • EIA for IgG to anti-citrullinated proteins/peptides
    • Sensitivity (80%) and specificity (97%)
    • Reference range < 5.0 U/L
    • Detected earlier than RF
    • Indicator of more severe disease and disease in future
erythrocyte sedimentation rate esr
ERYTHROCYTE SEDIMENTATION RATE (ESR)
  • Sedimentation rate (Sed rate)
  • Non-specific measure of inflammation
    • Specific analyte not measured
    • Physical phenomenon with many variables
    • Fibrinogen causes RBC’s to stick together
  • Distance (mm) erythrocyte layer moves in 1 hour
  • Reference range (Westergren method)
    • < 15 mm/hr (Males < 50)
    • < 20 mm/hr (Females < 50)
erythrocyte sedimentation rate esr23
ERYTHROCYTE SEDIMENTATION RATE (ESR)
  • Automated and semi-automated methods
    • More rapid results
  • Less sensitive than CRP
    • Elevation within 5 to 7 days
    • Simple and inexpensive
c reactive protein crp
C-REACTIVE PROTEIN (CRP)
  • Marker for (acute) inflammation
    • Infection, cancer, autoimmunity, trauma, hypersensitivity
  • Origin of name
    • Reacts with “C polysaccharide” of pneumococcus
  • Mechanism of action
    • Binds to phosphocholine on dead/dying cells and pathogens
      • Activates classical complement pathway
c reactive protein crp28
C-REACTIVE PROTEIN (CRP)
  • Produced by liver in response to IL-6
  • More sensitive than ESR
    • Elevation within 6 hours
    • Peak within 48 hours
  • Laboratory method
    • Nephelometry
c reactive protein crp29
C-REACTIVE PROTEIN (CRP)
  • Reference range
    • < 8.0 mg/L
  • Acute inflammation
    • Greater than 10 mg/L
    • Viral infection (10 to 40 mg/L)
    • Bacterial infection (40 to > 200 mg/L)
  • Cardiac risk stratification
    • Low risk: < 1.0 mg/L
    • Average risk: 1.0 to 3.0 mg/L
    • High risk: > 3.0 mg/L
antinuclear antibody ana test
ANTINUCLEAR ANTIBODY (ANA) TEST
  • Detects autoantibodies against nuclear antigens
  • Nuclear antigens
    • DS-DNA, SS-A, SS-B, histones
  • Laboratory methods
    • Enzyme immunoassay (EIA)
    • Indirect immunofluorescence assay (IFA)
  • Positive results
    • Rheumatoid arthritis (25-90%)
treatment of rheumatoid arthritis
TREATMENT OF RHEUMATOID ARTHRITIS
  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
    • Aspirin
    • Ibuprofen (Advil and Motrin)
    • Naproxen (Aleve)
    • Celecoxib (Celebrex)
  • Corticosteroids
    • Prednizone
  • Analgesic drugs
    • Acetaminophen
treatment of rheumatoid arthritis32
TREATMENT OF RHEUMATOID ARTHRITIS
  • Disease Modifying Anti-Rheumatic Drugs (DMARDs)
    • Methotrexate (Rheumatrex)
    • Hydroxychloroquine (Plaquenil)
    • Azathioprine (Imuran)
    • Cyclophosphamide (Cytoxan)
    • Cyclosporine (Sandimmune)
    • Minocycline (Minocin)
  • Biological Response Modifiers (Biologic DMARDs)
    • Tumor necrosis factor-alpha (TNF-alpha) inhibitors
      • Etanercept (Enbrel)
      • Infliximab (Remicade)
      • Adalimumab (Humira)
      • Golimumab (Simponi)
treatment of rheumatoid arthritis33
TREATMENT OF RHEUMATOID ARTHRITIS
  • Biological Response Modifiers (Biologic DMARDs)
    • B cell depleting agents
      • Rituximab (Rituxan)
    • T-cell co-stimulatory blocking agents
      • Abatacept (Orencia)
    • Interleukin-1 (IL-1) receptor antagonist
      • Anakinra (Kineret)
    • Interleukin-6 (IL-6) receptor antagonist
      • Tocilizumab (Actemra)
etanercept enbrel
ETANERCEPT (ENBREL)
  • Dimeric fusion protein
    • Extracellular binding domain of p75 TNF receptor and the Fc portion of human IgG1
  • Prevents binding of TNF-alpha to cell surface receptor
  • Adverse reactions
    • Infections, Malignancies, Autoimmunity
infliximab remicade
INFLIXIMAB (REMICADE)
  • Chimeric IgG1 monoclonal antibody
    • Human (constant region)
    • Mouse (variable region)
  • Prevents binding of TNF-alpha to receptor
  • Administration is IV along with methotrexate
    • 10 to 30% anti-infliximab antibodies
  • Adverse effects
    • Infections, Malignancies, Autoimmunity
adalimumab humira
ADALIMUMAB (HUMIRA)
  • Human IgG1 monoclonal antibody
  • Binds to TNF-alpha and prevents binding of TNF to p55 and p75 cell surface receptors
  • Adverse reactions
    • Infections
    • Malignancies
    • Autoimmunity
abatacept orencia
ABATACEPT (ORENCIA)
  • Soluble fusion protein
    • Extracellular domain of human cytotoxic T-lymphocyte associated antigen 4 (CTLA-4)
    • Fc region of human IgG1
  • Indication in RA
    • Adults with moderate to severe RA with inadequate response to one or more TNF-alpha antagonist therapies
    • Administered by 30 minute IV infusion
    • Concurrent therapy with TNF-alpha inhibitors not recommended
abatacept orencia44
ABATACEPT (ORENCIA)
  • CTLA-4
    • Expressed on surface of CD4 T cells
    • Binds to CD80 and CD86 and transmits inhibitory signal
  • Mechanism of action
    • Binds to CD80 (B7.1) and CD86 (B7.2) on APC
    • Blocks access to CD28 co-stimulatory receptor on T cells
  • Activation of T cells by APC
    • Stimulation by MHC class II molecule to TCR
    • Co-stimulation by B7 to
      • CD28 (stimulation)
      • CTLA4 (inhibition)
anakinra kineret
ANAKINRA (KINERET)
  • Recombinant, nonglycosylated protein
    • Synthetic version of human endogenous IL-1 receptor antagonist (IL-1Ra)
  • Indication in RA
    • Adults with moderate to severe RA with inadequate response to one or more DMARD agents
    • Administered by daily subcutaneous injection
    • Not compatible with TNF-alpha inhibitors
anakinra kineret47
ANAKINRA (KINERET)
  • Normal joint
    • Endogenous IL-1Ra competes with IL-1 for IL-1 receptor type I (IL-1RI)
    • IL-1Ra most important regulator of synovial IL-1 activity
  • RA joint
    • Higher level of IL-1 compared to IL-1Ra
  • Mechanism of action
    • Binding of IL-1Ra competitively inhibits binding of IL-1 to IL-1 receptor type 1 (IL-1RI)
rituximab rituxan
RITUXIMAB (RITUXAN)
  • Chimeric IgG1 monoclonal antibody
    • Variable domains are mouse
    • Constant domains are human
  • FDA approval
    • 1997 for non-Hodgkin’s lymphoma (NHL)
    • 2006 for rheumatoid arthritis (RA)
  • Indication in RA
    • Adults with moderate to severe RA with inadequate response to one or more TNF-alpha antagonist therapies
rituximab rituxan50
RITUXIMAB (RITUXAN)
  • Mechanism of action
    • Binds to CD20 antigen on normal and malignant B lymphocytes and mediates lysis
  • Mechanisms of B cell lysis
    • Complement
    • ADCC
    • Induction of apoptosis
  • CD20 antigen not present on
    • Hematopoietic stem cells, proB cells and normal plasma cells
b lymphocytes role in rheumatoid arthritis
B LYMPHOCYTES ROLE IN RHEUMATOID ARTHRITIS
  • Three potential important roles
    • Antigen presentation
    • Autoantibody production
    • Cytokine production