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Rheumatoid Arthritis 11/05. Stephanie Boade Silas, M.D. Division of Rheumatology, UUMC. Objectives. Know the epidemiology and risk factors of rheumatoid arthritis. Have a basic understanding of the pathology and pathogenesis of RA.

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rheumatoid arthritis 11 05

Rheumatoid Arthritis11/05

Stephanie Boade Silas, M.D.

Division of Rheumatology, UUMC

objectives
Objectives
  • Know the epidemiology and risk factors of rheumatoid arthritis.
  • Have a basic understanding of the pathology and pathogenesis of RA.
  • Know the distinctive musculoskeletal and extraarticular clinical features of RA.
  • Understand how labs and imaging studies are used to make a diagnosis of RA.
rheumatoid arthritis
Rheumatoid Arthritis
  • Chronic, systemic inflammatory disease
  • 1% of North American Caucasians
  • Peak incidence 4th to 6th decades
  • Females 2-3X > Males
  • Pathogenesis unknown
pathogenesis
Pathogenesis
  • Synovial Hyperplasia
  • Hypercellularity
  • Inflammatory cells
  • Joint effusions
  • Pannus
    • Invasive synovium
    • Erodes cartilage and bone
normal synovium
Normal Synovium
  • Synovial lining
    • Loosely organized
    • 1-3 cell layers
    • Type A = MΦ
    • Type B = fibroblast
  • Subsynovium
    • Few cells
    • Scattered vessels, nerves, lymphatics
rheumatoid synovium
Rheumatoid Synovium
  • Synovial lining
    • Hyperplasia
    • 10 cell layers thick
  • Subsynovial
    • T cells: CD4>CD8
    • Dendritic cells
    • B cells/Plasma cells
      • RF
    • Vast blood supply
rheumatoid ankle pannus
Rheumatoid Ankle -- Pannus
  • Unique to RA
  • Synovial fibroblast cells migrate over cartilage surface
  • Transformed phenotype
  • RANKL-RANK
    • Osteoclasts at interface
slide14

Pathogenesis of Rheumatoid Arthritis

Choy, E. H.S. et al. N Engl J Med 2001;344:907-916

inflammatory mediators
Inflammatory Mediators
  • Cytokines
    • Products of activated macrophages and fibroblasts
      • IL-1, TNF-α, IL-6
    • Th-1 cell-driven disease
      • TNF-α, IL-2, IFNγ, IL-12
    • Recruit/activate inflammatory cells
    • Angiogenesis
    • Adhesion molecule expression
inflammatory mediators16
Inflammatory Mediators
  • Chemokines
  • Cell surface proteins
    • Adhesion molecules, membrane bound TNF, RANKL
    • Costimulatory molecules
      • CD80 or CD86 on APC bind CD28 T cell
        • CTLA-4 on T cell also binds CD80/86 – inhibits costim.
  • Enzymes
    • Matrix metalloproteinases (MMPs)
  • Transcription factors
    • NF-κB, AP-1
  • Complement/Immune complexes
slide17

Cytokine Signaling Pathways Involved in Inflammatory Arthritis

Choy, E. H.S. et al. N Engl J Med 2001;344:907-916

ra etiology risk factors
Genetic

Monozygotic twins

15-30% concordance

HLA-DR4

Shared epitope

HLA-DRB1

*0401, 0404, 0101

Homozygosity

Increased risk

Increased severity

Gender

Nulliparity

3 mo. after pregnancy

Infections

Proteus, Mycoplasma

EBV, Parvo, HTLV-1

Cigarette smoking

Age

RA – Etiology/Risk Factors
ra clinical features
RA -- Clinical Features
  • Morning stiffness = hallmark of inflammatory joint disease
  • Joint inflammation – Synovitis/Effusions
    • Warmth, swelling, (erythema)
  • Structural changes
    • Cartilage loss, bony erosions, periarticular damage
joint distribution
Joint Distribution
  • Predominantly peripheral synovial joints
    • Hand and Feet
  • Symmetric involvement
  • Hands predominate
    • Wrist
    • MCP’s
    • PIP’s
    • Not DIP’s
ra hand deformity
Ulnar deviation at MCP’s

Radial deviation at wrists

Swan-neck deformities

Boutonniere deformities

Tendon nodules

Tendon rupture

3rd, 4th, and 5th extensor tendons

Carpal tunnel syndrome

Ulnar neuropathy

RA Hand Deformity
ra knees
RA - Knees
  • Symmetric lateral and medial joint space loss
  • Effusions
  • Synovial proliferation
  • Baker’s cyst
    • Posterior herniation of joint capsule
    • May rupture
      • Hx and U/S can distinguish
      • Crescent-sign on exam
ra feet
RA - feet
  • MTP synovitis
    • Direct palpation
    • Global lateral/medial squeezing
  • MTP subluxation
    • Cock-up deformities of toes
    • Callous formation on soles
  • Ankles - synovitis/effusions
    • Tarsal tunnel syndrome -- medial foot and sole paresthesias
ra cervical spine
RA - Cervical Spine
  • Apophyseal joint destruction
    • C4-5 and C5-6 most common
  • Atlantoaxial Instability
    • C1-C2
    • Tenosynovitis of transverse ligament of C1
    • Erosion of odontoid process of C2
      • Cranial settling
    • Neck/Occiput pain, Paresthesias, Pathologic reflexes
ra extraarticular features
Constitutional sx’s

Fever/fatigue/wt loss

Osteopenia

Muscle weakness

Skin

Eye

Lung

Kidney

Cardiac

Vascular

Sjogren’s

Neurologic

Hematologic

Felty’s

RA—Extraarticular Features
extraarticular features
Extraarticular Features
  • Rheumatoid nodules (15%)
    • Central necrosis surrounded by palisading fibroblasts and lymphocytes
    • Subcutaneous, bursal, tendon sheaths
    • Extensor surfaces / Pressure points
      • Forearms
      • Achilles
      • Ischial area
      • MTP’s
      • Flexor surface of fingers
extraarticular manifestations
Extraarticular manifestations
  • Vasculitis
    • Leukocytoclastic vasculitis
      • Palpable purpura
    • Vasculitic lesions on fingers
    • Mononeuritis multiplex
    • Visceral involvement (PAN)
extraarticular ra ocular
Extraarticular RA -- Ocular
  • Sicca symptoms
  • Episcleritis
  • Scleritis
extraarticular manifestations47
Extraarticular Manifestations
  • Pulmonary
    • Pleural effusions
    • Interstitial lung disease
    • Nodules
  • Cardiac
    • Pericarditis -- < 10% clinically
    • Myocarditis
    • Atherosclerosis – 3X increased risk of CAD
hematologic
Hematologic
  • Anemia of chronic disease
    • Low Fe, Low TIBC, Ferritin > 40 - 100
  • Felty’s syndrome
    • Triad
      • RA
      • Splenomegaly
      • Neutropenia
    • Frequent infections/Leg ulcers
  • Iron deficiency anemia (NSAIDs)
slide51

Lab – Evidence of Inflammation

  • Synovial Fluid – WBC > 2000/mm3
  • Serum – Acute phase response
    • Acute phase proteins
      • CRP, ceruloplasmin, complement, serum amyloid A, fibrinogen, alpha-1-antitrypsin, haptoglobin, and ferritin
      • Negative APP’s = albumin, transferrin
  • Erythrocyte sedimentation rate
laboratory rf
Laboratory – RF
  • Rheumatoid Factor
    • Antibody against the Fc fragment of Ig
    • Not sensitive
      • 80% of RA patients
    • RF+ patients more likely to have
      • More severe disease
      • Extraarticular manifestations
rf is not specific for ra
RF is not specific for RA.
  • Other autoimmune disease
    • Sjogren’s syndrome , Systemic Lupus
  • Chronic infection
    • Hep B/C, SBE, Viral, Parasites, TB
  • Pulmonary inflammation
    • Sarcoid, IPF, Silicosis, Asbestosis
  • Malignancy
  • Healthy – 4% young; 5-25% > age 60
anti ccp
Anti-CCP
  • Anti-cyclic citrullinated peptide
  • Specificity = 90%
  • Sensitivity = 50-80%
radiography
Radiography
  • Periarticular osteopenia
  • Symmetric joint space loss
  • Marginal erosions
  • Absence of productive changes
  • Best films for diagnosis:
    • Bilateral Hand Arthritis Series
    • Bilateral Foot Series
  • Larger joints may not show erosions early due to thicker cartilage.
classification criteria for ra 4 criteria present 6 wks
Morning stiffness > 1 hour

Arthritis of ≥ 3 joints areas (PIP, MCP, wrist, elbow, knee, ankle, and MTP)

Arthritis of hand joints (wrist, MCP, PIP)

Symmetric arthritis

Rheumatoid nodules

RF+

Radiographic changes

Erosions

Unequivocal periarticular osteopenia

Classification Criteria for RA≥ 4 criteria present > 6 wks
differential diagnosis
Viral polyarthritis

Connective tissue disease

Fibromyalgia

Spondyloarthropathy

Psoriatic arthritis

Crystalline arthritis

Septic arthritis

Osteoarthritis

Paraneoplastic disease

Multicentric reticulohistiocytosis

Differential Diagnosis
ra treatment
RA -- Treatment
  • Aggressive treatment early!
  • DMARDs = disease modifying anti-rheumatic drugs
    • Combinations
  • Biologics – TNF- inhibitors, IL-1 antagonists, Anti-CD20, CTLA4 Ig
  • NSAIDs
  • Steroids
    • Osteoporosis prophylaxis