Rheumatoid Arthritis

Rheumatoid Arthritis
John Imboden MD
Disclosures: John Imboden
• I am an investigator on a grant funded by
the Research and Education Foundation
of the American College of Rheumatology.
• Abbott has agreed to provide adalimumab
and placebo for the study.
Rheumatoid arthritis:
typical presentation
• Prevalence 1%
• Female > male (3:1)
• Peak onset: age 30s to
• 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
Rheumatoid Arthritis
• 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
Rheumatoid Arthritis: pathogenesis
• Etiology uncertain
• Autoimmune disease
– Characteristic autoantibodies
• Genetic predisposition
• Mechanisms of joint damage
Rheumatoid Arthritis:
• 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
deiminase (PAD)
RA-associated autoantibodies
recognize protein epitopes containing
Peptide sequence
Antibody recognition
Protein Citrullination
• Constitutive citrullination of proteins in skin
and elsewhere
– Physiological roles of citrullination are diverse
and incompletely understood
• Citrullination of proteins occurs at sites of
– NOT specific for RA
• Loss of tolerance to citrullinated proteins is
specific for RA
Antibodies to Citrullinated Protein
• Detected using synthetic cyclic citrullinated
– “anti-CCP antibodies”
• Anti-CCP positive RA:
– Genetically distinct form of RA
– More aggressive arthritis
RA: genetic susceptibility
• Heritability 60%
• Multiple genes involved
• Most important: HLA-DRB1
– Encodes b chain of a MHC class II antigen
– Linked to “CCP-positive” RA
Manhattan plot from a genome-wide association study of RA
Criswell, LA Immunological Reviews 233: 55, 2010
The shared epitope (DRB1*0401)
Gene-environment interaction in RA:
Is smoking an environmental trigger?
Klareskog et al Ann Rev Immunol 26:651. 2008
Anti-CCP positive
Anti-CCP negative
Evidence for an interaction between smoking and the shared
epitope in risk for anti-CCP-positive RA in a European cohort
Loss of tolerance to citrulline due to
smoking-associated inflammation?
Preclinical autoimmunity in RA:
appearance of anti-CCP abs and
RF prior to onset of arthritis
Nielen et al Arth Rheum 50: 380, 2004
Environmental event(s)
Genetic predisposition
Loss of tolerance to self antigens
Preclinical autoimmunity
Clinically apparent joint
Synovial inflammation in RA
Synovial inflammation in RA
- proliferation of synovial
lining cells
- influx of mononuclear cells
- angiogenesis
- the component of the
inflamed synovium that
invades cartilage and bone
Joint effusion:
- influx of neutrophils into
synovial fluid
Joint inflammation in RA
Rheumatoid wrist
Inflammation within bone
Normal wrist
synovial inflammation
3 Tesla MRI provided by Xiaojuan Li PhD
Cytokine production in rheumatoid
• 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 > Th1)
Mechanisms of joint inflammation and
destruction in RA:
conclusions from trials with selective inhibitors
Joint damage
T cell co-stimulation
B cell
Proinflammatory cytokines
tumor necrosis factor
Synovial inflammation in RA:
a role for CD4 Th17 cells?
Roles of TNF, IL-6, and IL-1 in cartilage
degradation and erosion of bone
TNF, IL-6, IL-1
Induce chondrocytes and
fibroblasts to produce matrix
metalloproteinases and other
proteases that degrade
Together with RANK-RANKL
interactions, promote
differentiation of precursors
cartilage into osteoclasts, which are
the destructive element where
the pannus invades bone
RA: clinical presentation
• 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: articular symptoms
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
RA: joint involvement
• 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
RA: pattern of joint involvement
• 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
onset of RA
6 months after
onset of symptoms
3 years after onset
of symptoms
Radiographic changes in the same joint over time
Radiographic changes occur early and
precede joint deformities by years
(adapted from Wolfe & Sharp, Arth Rheum 41: 1571, 1998)
joint narrowing
joint erosions
Characteristic joint deformities in RA
“Swan neck”
of PIPs and
flexion of DIPs
“Boutonniere” deformity:
flexion of PIP and hyperextension of DIP
Characteristic joint deformities in RA
Ulnar deviation
of the fingers
of MCPs
Rheumatoid nodules
Note the symmetry of the joint involvement
Characteristic joint deformities in RA
Subluxation of the metatarsals as a
consequence of MTP arthritis
RA: extraarticular manifestations
• 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)
Rheumatoid nodule
RA: Laboratory findings
• 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
RA: Autoantibodies
• Anti-CCP Antibodies
– High specificity
– Identifies patients with more aggressive joint
• Rheumatoid factor
– Limited specificity
– Patients who develop extra-articular disease
are almost always “sero-positive” for RF
Diagnosis of RA
• Clinical diagnosis
• Key feature: inflammatory polyarthritis
affecting proximal joints of the hands
• Compatible laboratory data, serologies,
and radiographs
• Exclusion of other causes of inflammatory
Diagnosis: some mimics of RA
• 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
• Spondyloarthropathies
• Primary osteoarthritis of the hands
• Systemic vasculitis
Goals of therapy for RA
• Reduce signs and symptoms of
• Prevent joint deformities
Treatments for RA
• Nonsteroidal anti-inflammatory drugs
– Aspirin 1890s
• Low dose glucocorticoids
– Early 1950s
• Disease-modifying antirheumatic drugs
– Methotrexate mid-1980s
• Biological agents
– Anti-TNF agents late 1990s
Raoul Dufy
“La Cortisone” 1951
Methotrexate: most commonly
used DMARD
• Mainstay of treatment for RA
– reduces signs and symptoms in majority
– slows radiographic progression
• Works slowly (weeks)
• Uncertain mechanism of action in RA
Biological agents for RA
• Monoclonal antibodies, receptor/antibody
• Targets:
Tumor necrosis factor (TNF)
T cell-costimulation
IL-6 receptor
• Parenteral administration (SQ or IV)
• Toxicity (infection, ?malignancy)
• $$$
Anti-TNF therapy of RA
• 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
– prevents radiographic progression for most patients,
at least for 1-2 years
• Not all patients respond, and many responses
are incomplete
Treatment of RA: general principles
• Patients should be started on effective
therapy (eg, a DMARD) within 3 months of
• Combination therapy is more effective
than monotherapy
• Goal is remission or “mild” activity by
standardized assessments
• There are few head-to-head comparisons
to guide therapeutic decisions
A therapeutic approach to new
onset RA
• 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
Rheumatoid arthritis: 2012
• Treatable, but not curable
– Therapies can slow or even prevent joint
• 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
Rheumatoid arthritis: key points
• 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

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