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. 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
Chronic, systemic inflammatory disease 1% of North American Caucasians Peak incidence 4th to 6th decades Females 2-3X > Males Pathogenesis unknown
Pathogenesis
Synovial Hyperplasia Hypercellularity Inflammatory cells Joint effusions Pannus
– Invasive synovium – Erodes cartilage and bone
Normal Joint Diagram
Normal PIP joint
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
Synovial lining
– Hyperplasia – 10 cell layers thick
Subsynovial
– – – – T cells: CD4>CD8 Dendritic cells MΦ B cells/Plasma cells
RF
– Vast blood supply
Rheumatoid Ankle -- Pannus
Unique to RA Synovial fibroblast cells migrate over cartilage surface Transformed phenotype RANKL-RANK
– Osteoclasts at interface
RA: Erosions
Pathogenesis of Rheumatoid Arthritis
Choy, E. H.S. et al. N Engl J Med 2001;344:907-916
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 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
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
Gender
– Nulliparity – 3 mo. after pregnancy
– HLA-DR4
Shared epitope HLA-DRB1
– *0401, 0404, 0101
Infections
– Proteus, Mycoplasma – EBV, Parvo, HTLV-1
– Homozygosity
Increased risk Increased severity
Cigarette smoking Age
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
Predominantly peripheral synovial joints
– Hand and Feet
Symmetric involvement Hands predominate
– Wrist – MCP’s – PIP’s – Not DIP’s
RA: Joint distribution
Synovitis
RA - hands
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
Swan neck and Boutonniere
Ulnar Deviation
RA- extensor tendon rupture
Carpal Tunnel Syndrome
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
Popliteal Cyst
Ruptured Baker’s Cyst
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
MTP subluxation
Cock-up deformity
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
Atlantoaxial Instability
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
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
Rheumatoid nodules
RA - Chronic changes
Extraarticular manifestations
Vasculitis
– Leukocytoclastic vasculitis
Palpable purpura
– Vasculitic lesions on fingers – Mononeuritis multiplex – Visceral involvement (PAN)
RA - Vasculitis
RA - Vasculitis
Extraarticular RA -- Ocular
Sicca symptoms Episcleritis Scleritis
Scleromalacia perforans
Extraarticular Manifestations
Pulmonary
– Pleural effusions – Interstitial lung disease – Nodules
Cardiac
– Pericarditis -- < 10% clinically – Myocarditis – Atherosclerosis – 3X increased risk of CAD
RA: Pulmonary nodules
RA: Pulmonary fibrosis
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)
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
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.
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-cyclic citrullinated peptide Specificity = 90% Sensitivity = 50-80%
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.
RA - Erosions
RA - imaging
RA - knees
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
Differential Diagnosis
Viral polyarthritis Connective tissue disease Fibromyalgia Spondyloarthropathy Psoriatic arthritis Crystalline arthritis Septic arthritis Osteoarthritis Paraneoplastic disease Multicentric reticulohistiocytosis
RA -- Treatment
Aggressive treatment early! DMARDs = disease modifying antirheumatic drugs
– Combinations
Biologics – TNF- inhibitors, IL-1 antagonists, Anti-CD20, CTLA4 Ig NSAIDs Steroids
– Osteoporosis prophylaxis