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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.

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rheumatoid arthritis

Rheumatoid Arthritis

John Imboden MD

rheumatoid arthritis typical presentation
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 arthritis4
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
Rheumatoid Arthritis: pathogenesis
  • Etiology uncertain
  • Autoimmune disease
    • Characteristic autoantibodies
  • Genetic predisposition
  • Mechanisms of joint damage
rheumatoid arthritis autoantibodies
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


deiminase (PAD)

ra associated autoantibodies recognize protein epitopes containing citrulline
RA-associated autoantibodies recognize protein epitopes containing citrulline

Peptide sequenceAntibody recognition




protein citrullination
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
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
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 ra14
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

normal rheumatoid

joint joint

joint inflammation in ra
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
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


TargetClinicalJoint 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
Roles of TNF and IL-1 in cartilage degradation and erosion of bone

Induce chondrocytes and

fibroblasts to produce matrix

metalloproteinases and other

proteases that degrade


Together with RANK-RANKL

interactions, promote

differentiation of precursors

into osteoclasts, which are

the destructive element where

the pannus invades bone



ra clinical presentation
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: 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
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
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

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

Radiographic changes occur early and precede joint deformities by years (adapted from Wolfe & Sharp, Arth Rheum 41: 1571, 1998)

Arbitrary scale

characteristic joint deformities in ra
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 ra27
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 ra28
Characteristic joint deformities in RA

Subluxation of the metatarsals as a

consequence of MTP arthritis

ra extraarticular manifestations
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)
ra laboratory findings
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
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
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
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
Goals of therapy for RA
  • Reduce signs and symptoms of inflammation
  • Prevent joint deformities
treatments for ra
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
methotrexate most commonly used dmard
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
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
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
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
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
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
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