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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 l.jpg

Rheumatoid Arthritis11/05

Stephanie Boade Silas, M.D.

Division of Rheumatology, UUMC


Objectives l.jpg
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 l.jpg
Rheumatoid Arthritis

  • Chronic, systemic inflammatory disease

  • 1% of North American Caucasians

  • Peak incidence 4th to 6th decades

  • Females 2-3X > Males

  • Pathogenesis unknown


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Pathogenesis

  • Synovial Hyperplasia

  • Hypercellularity

  • Inflammatory cells

  • Joint effusions

  • Pannus

    • Invasive synovium

    • Erodes cartilage and bone




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Normal Synovium

  • Synovial lining

    • Loosely organized

    • 1-3 cell layers

    • Type A = MΦ

    • Type B = fibroblast

  • Subsynovium

    • Few cells

    • Scattered vessels, nerves, lymphatics


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Rheumatoid Synovium

  • Synovial lining

    • Hyperplasia

    • 10 cell layers thick

  • Subsynovial

    • T cells: CD4>CD8

    • Dendritic cells

    • B cells/Plasma cells

      • RF

    • Vast blood supply


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Rheumatoid Ankle -- Pannus

  • Unique to RA

  • Synovial fibroblast cells migrate over cartilage surface

  • Transformed phenotype

  • RANKL-RANK

    • Osteoclasts at interface



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Pathogenesis of Rheumatoid Arthritis

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


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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


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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


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Cytokine Signaling Pathways Involved in Inflammatory Arthritis

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


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Genetic Arthritis

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


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RA -- Clinical Features Arthritis

  • Morning stiffness = hallmark of inflammatory joint disease

  • Joint inflammation – Synovitis/Effusions

    • Warmth, swelling, (erythema)

  • Structural changes

    • Cartilage loss, bony erosions, periarticular damage


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Joint Distribution Arthritis

  • Predominantly peripheral synovial joints

    • Hand and Feet

  • Symmetric involvement

  • Hands predominate

    • Wrist

    • MCP’s

    • PIP’s

    • Not DIP’s



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Synovitis Arthritis


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RA - hands Arthritis


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Ulnar deviation at MCP’s Arthritis

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



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Ulnar Deviation Arthritis




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RA - Knees Arthritis

  • 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


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Popliteal Cyst Arthritis



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RA - feet Arthritis

  • 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


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MTP subluxation Arthritis



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RA - Cervical Spine Arthritis

  • 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



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Constitutional sx’s Arthritis

Fever/fatigue/wt loss

Osteopenia

Muscle weakness

Skin

Eye

Lung

Kidney

Cardiac

Vascular

Sjogren’s

Neurologic

Hematologic

Felty’s

RA—Extraarticular Features


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Extraarticular Features Arthritis

  • 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




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Extraarticular manifestations Arthritis

  • Vasculitis

    • Leukocytoclastic vasculitis

      • Palpable purpura

    • Vasculitic lesions on fingers

    • Mononeuritis multiplex

    • Visceral involvement (PAN)


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RA - Vasculitis Arthritis


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RA - Vasculitis Arthritis


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Extraarticular RA -- Ocular Arthritis

  • Sicca symptoms

  • Episcleritis

  • Scleritis



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Extraarticular Manifestations Arthritis

  • Pulmonary

    • Pleural effusions

    • Interstitial lung disease

    • Nodules

  • Cardiac

    • Pericarditis -- < 10% clinically

    • Myocarditis

    • Atherosclerosis – 3X increased risk of CAD




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Hematologic Arthritis

  • 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)


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Lab – Evidence of Inflammation Arthritis

  • 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


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Laboratory – RF Arthritis

  • 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


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RF is not Arthritisspecific 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


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Anti-CCP Arthritis

  • Anti-cyclic citrullinated peptide

  • Specificity = 90%

  • Sensitivity = 50-80%


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Radiography Arthritis

  • 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.


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RA - Erosions Arthritis


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RA - imaging Arthritis


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RA - knees Arthritis


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Morning stiffness > 1 hour Arthritis

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


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Viral polyarthritis Arthritis

Connective tissue disease

Fibromyalgia

Spondyloarthropathy

Psoriatic arthritis

Crystalline arthritis

Septic arthritis

Osteoarthritis

Paraneoplastic disease

Multicentric reticulohistiocytosis

Differential Diagnosis


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RA -- Treatment Arthritis

  • Aggressive treatment early!

  • DMARDs = disease modifying anti-rheumatic drugs

    • Combinations

  • Biologics – TNF- inhibitors, IL-1 antagonists, Anti-CD20, CTLA4 Ig

  • NSAIDs

  • Steroids

    • Osteoporosis prophylaxis


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