Rheumatoid Arthritis

John Imboden MD
Rheumatoid arthritis:
typical presentation
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
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:
autoantibodies
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)
RA-associated autoantibodies
recognize protein epitopes containing
citrulline

Peptide sequence Antibody recognition

ESSRDGSRHPRSHD No

PAD

ESSRDGScitHPRSHD Yes

Protein Citrullination
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

Antibodies to Citrullinated Protein
Epitopes
Detected using synthetic cyclic citrullinated
peptides
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


Environmental event(s) Genetic predisposition

Loss of tolerance to self antigens

Preclinical autoimmunity



Clinically apparent joint
inflammation
(synovitis)
Synovial inflammation in RA
Synovial inflammation in RA
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
Joint inflammation in RA
Rheumatoid wrist Normal wrist
Inflammation within bone synovial inflammation
3 Tesla MRI provided by Xiaojuan Li PhD
Cytokine production in rheumatoid
synovium
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)
Mechanisms of joint inflammation and
destruction in RA:
conclusions from trials with selective inhibitors
Response
Target Clinical Joint damage

T cell co-stimulation ++ ++
B cell ++ ++

Proinflammatory cytokines
tumor necrosis factor ++ ++
interleukin-1 + +
interleukin-6 ++ ++



Roles of TNF and IL-1 in cartilage
degradation and erosion of bone
cartilage
bone
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
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 (<38C)
Uncommon: extensive weight loss,
fever > 38C
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 3
rd
and 4
th
PIP joints
1 year prior to 6 months after 3 years after onset
onset of RA onset of symptoms of symptoms
Rheumatoid arthritis: irreversible damage
can occur early in disease course
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)
0
5
10
15
20
0 10 20
years
c
o
u
n
t
joint narrowing
joint erosions
joint
deformities
A
r
b
i
t
r
a
r
y

s
c
a
l
e

Characteristic joint deformities in RA

Swan neck
deformities:
hyperextension
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
Volar
subluxation
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 (Sjgren) 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
disease
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
polyarthritis
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
diseases
Spondyloarthropathies
Primary osteoarthritis of the hands
Systemic vasculitis


Goals of therapy for RA
Reduce signs and symptoms of
inflammation
Prevent joint deformities

Treatments for RA
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
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
chimeras
Targets:
Tumor necrosis factor (TNF)
T cell-costimulation
B-cells
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
activity
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
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

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: 2010
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
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