Rheumatoid Arthritis - PowerPoint PPT Presentation

Rheumatoid Arthritis

John Imboden MD

• Prevalence 1%
• Female > male (3:1)
• Peak onset: age 30s to 40s
• Insidious onset of joint pain & AM stiffness lasting hours
• Swelling of wrists and small joints of the hands

The natural history of rheumatoid arthritis

at presentation after 5 years after 15 years

• - Chronic disease
• - Progressive damage leading to joint deformity & disability
• Extra-articular disease: nodules, lung, eye, vasculitis, etc
• Diminished life expectancy

• Polyarthritis of synovial lined joints
• Characteristic pattern of joint involvement
• Inflammatory arthritis
• autoimmune
• Destructive arthritis
• Cartilage degradation
• Erosion of bone adjacent to joints
• Joint deformities
• Systemic disease

• Etiology uncertain
• Autoimmune disease
• Characteristic autoantibodies
• Genetic predisposition
• Mechanisms of joint damage

• Rheumatoid factor
• Autoantibody to Fc region of IgG
• Occur in c. 70% of RA patients
• Despite the name, not specific for RA
• Antibodies to citrullinated protein epitopes
• Occur in c. 70% of RA patients
• Highly specific for RA
• May be pathogenic

Posttranslational modification of proteins:

PAD converts arginine to citrulline

Peptidylarginine

deiminase (PAD)

Peptide sequenceAntibody recognition

ESSRDGSRHPRSHD No

PAD

ESSRDGScitHPRSHD Yes

• Constitutive citrullination of proteins in skin and elsewhere
• Physiological roles of citrullination are diverse and incompletely understood
• Citrullination of proteins occurs in inflamed joints in many forms of arthritis
• NOT specific for RA
• Loss of tolerance to citrullinated proteins is specific for RA

• Detected using synthetic cyclic citrullinated peptides
• “anti-CCP antibodies”
• Anti-CCP positive RA:
• Genetically distinct form of RA
• More aggressive arthritis

• Heritability 60%
• Multiple genes involved
• Most important: HLA-DRB1
• Encodes b chain of a MHC class II antigen
• Linked to “CCP-positive” RA

Environmental event(s) Genetic predisposition

Loss of tolerance to self antigens

Preclinical autoimmunity

Clinically apparent joint inflammation (synovitis)

Synovitis:

- proliferation of synovial

lining cells

- influx of mononuclear cells

- angiogenesis

Pannus:

- the component of the

inflamed synovium that

invades cartilage and bone

Joint effusion:

- influx of neutrophils into

synovial fluid

normal rheumatoid

joint joint

Rheumatoid wrist Normal wrist

Inflammation within bone synovial inflammation

3 Tesla MRI provided by Xiaojuan Li PhD

• Large number of cytokines produced
• Macrophage-derived cytokines:
• Proinflammatory cytokines: TNF-a, IL-1, IL-6
• Dominant cytokines in quantitative terms
• T cell cytokines:
• Interleukin-17 > interferon-g (Th17 cells may be more important than Th1)

Response

TargetClinicalJoint damage

T cell co-stimulation ++ ++

B cell ++ ++

Proinflammatory cytokines

tumor necrosis factor ++ ++

interleukin-1 + +

interleukin-6 ++ ++

Induce chondrocytes and

fibroblasts to produce matrix

metalloproteinases and other

proteases that degrade

cartilage

Together with RANK-RANKL

interactions, promote

differentiation of precursors

into osteoclasts, which are

the destructive element where

the pannus invades bone

cartilage

bone

• Onset: usually insidious
• Patients typically present after weeks to months of symptoms
• Articular symptoms dominate
• Constitutional symptoms
• Common: fatigue, low grade fever (<38°C)
• Uncommon: extensive weight loss,

fever > 38°C

RA is an inflammatory arthritis:

• Morning stiffness
• Often lasts hours
• Can be the dominant symptom
• Joint pain and stiffness improve with activity
• “gel phenomenon”
• Stiffness recurs after prolonged inactivity

• Symmetric
• e.g., both wrists, both knees
• Additive
• Polyarthritis (>5 joints involved)
• Arthritis, not just arthralgias
• Involved joints: tender and swollen
• Larger joints: warm, effusions
• Not erythematous

• Hands (involved in >90%)
• Wrists, metacarpophalangeal (MCP) & proximal interphalangeal (PIP) joints
• Spares distal interphalangeal (DIP) joints
• Axial skeleton
• Cervical spine can be involved
• Spares thoracic, lumbosacral spine, SI joints
• Large joints
• Feet

Early RA with fusiform swelling of the 3rd and 4th PIP joints

Rheumatoid arthritis: irreversible damage

can occur early in disease course

1 year prior to 6 months after 3 years after onset

onset of RA onset of symptoms of symptoms

Radiographic changes in the same joint over time

Arbitrary scale

“Swan neck”

deformities:

hyperextension

of PIPs and

flexion of DIPs

“Boutonniere” deformity:

flexion of PIP and hyperextension of DIP

Ulnar deviation

of the fingers

Volar

subluxation

of MCPs

Rheumatoid nodules

Note the symmetry of the joint involvement

Subluxation of the metatarsals as a

consequence of MTP arthritis

• Common:
• Rheumatoid nodules
• Sicca (Sjögren) syndrome
• Interstitial lung disease
• Ocular inflammation: Scleritis and episcleritis
• Uncommon:
• Vasculitis
• Clinically apparent pleuritis or pericarditis
• Felty syndrome (RA, splenomegaly, neutropenia)

• Routine laboratory:
• Mild to moderate anemia
• Mild to moderate thrombocytosis
• High erythrocyte sedimentation rate or elevated C-reactive protein
• Synovial fluid analysis
• Inflammatory
• WBC counts usually in 5,000 – 50,000 range
• Neutrophil predominance

• Anti-CCP Antibodies
• High specificity
• Identifies patients with more aggressive joint disease
• Rheumatoid factor
• Limited specificity
• Patients who develop extra-articular disease are almost always “sero-positive” for RF

• Clinical diagnosis
• Key feature: inflammatory polyarthritis affecting proximal joints of the hands
• Compatible laboratory data, serologies, and radiographs
• Exclusion of other causes of inflammatory polyarthritis

• Acute viral infections: self-limited polyarthritis
• Acute parvovirus B19 infection in adults
• Chronic hepatitis C infection
• RF-positive non-erosive chronic polyarthrtis
• Systemic lupus and other systemic rheumatic diseases
• Spondyloarthropathies
• Primary osteoarthritis of the hands
• Systemic vasculitis

• Reduce signs and symptoms of inflammation
• Prevent joint deformities

• Nonsteroidal anti-inflammatory drugs
• Aspirin 1890s
• Low dose glucocorticoids
• Early 1950s
• Disease-modifying antirheumatic drugs (DMARDs)
• Methotrexate mid-1980s
• Biological agents
• Anti-TNF agents late 1990s

Raoul Dufy “La Cortisone” 1951

• Mainstay of treatment for RA
• reduces signs and symptoms in majority
• slows radiographic progression
• Works slowly (weeks)
• Uncertain mechanism of action in RA

• Monoclonal antibodies, receptor/antibody chimeras
• Targets:
• Tumor necrosis factor (TNF)
• T cell-costimulation
• B-cells
• IL-6 receptor
• Parenteral administration (SQ or IV)
• Toxicity (infection, ?malignancy)
• $$$

• Reduces signs and symptoms for patients with active disease despite methotrexate
• Combination of anti-TNF and methotrexate:
• superior to either agent alone for reducing disease activity
• prevents radiographic progression for most patients, at least for 1-2 years
• Not all patients respond, and many responses are incomplete

• Patients should be started on effective therapy (eg, a DMARD) within 3 months of diagnosis
• Combination therapy appears more effective than monotherapy
• Goal is remission or “mild” activity by standardized assessments
• There are few head-to-head comparisons to guide therapeutic decisions

• Start prednisone 5 mg/day
• Acts quickly, joint-protective
• Start methotrexate
• Initiate long term therapy with an agent shown to retard radiographic progression
• If disease still active despite optimal methotrexate, add an anti-TNF agent
• Alternative: start with methotrexate plus anti-TNF
• If disease refractory to anti-TNF, switch to another biological agent

• Treatable, but not curable
• Therapies can slow or even prevent joint damage
• Early RA is a therapeutic opportunity
• Clinical remission achieved in 50%
• Most treated RA patients have residual mild to moderate activity
• 10-20% have refractory disease

• Pathogenesis
• Genetic predisposition
• Anti-CCP antibodies
• Connection between proinflammatory cytokines and joint destruction
• Clinical course of RA: descriptors of common joint deformities, extraarticular manifestations
• Distinguish RA from osteoarthritis, spondyloarthropathies, and lupus
• Major classes of therapies