rheumatoid arthritis john imboden md. disclosures: john imboden i am an investigator on a grant...
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Rheumatoid Arthritis
John Imboden MD
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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.
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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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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
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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
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Rheumatoid Arthritis: pathogenesis
• Etiology uncertain• Autoimmune disease
– Characteristic autoantibodies• Genetic predisposition• Mechanisms of joint damage
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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
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Posttranslational modification of proteins: PAD converts arginine to citrulline
Peptidylargininedeiminase (PAD)
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RA-associated autoantibodies recognize protein epitopes containing
citrulline
Peptide sequence Antibody recognition
ESSRDGSRHPRSHD No
PAD
ESSRDGScitHPRSHD Yes
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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
inflammation– NOT specific for RA
• Loss of tolerance to citrullinated proteins is specific for RA
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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
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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
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Manhattan plot from a genome-wide association study of RA
Criswell, LA Immunological Reviews 233: 55, 2010
HLA
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The shared epitope (DRB1*0401)
A74 Q70
A73 R72
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Gene-environment interaction in RA: Is smoking an environmental trigger?
Klareskog et al Ann Rev Immunol 26:651. 2008
Evidence for an interaction between smoking and the shared epitope in risk for anti-CCP-positive RA in a European cohort
Anti-CCP positive Anti-CCP negative
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Loss of tolerance to citrulline due to smoking-associated inflammation?
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Preclinical autoimmunity in RA:appearance of anti-CCP abs and
RF prior to onset of arthritis
Nielen et al Arth Rheum 50: 380, 2004
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Environmental event(s) Genetic predisposition
Loss of tolerance to self antigens
Preclinical autoimmunity
Clinically apparent joint inflammation (synovitis)
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Synovial inflammation in RA
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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
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Joint inflammation in RA Rheumatoid wrist Normal wrist
Inflammation within bone synovial inflammation
3 Tesla MRI provided by Xiaojuan Li PhD
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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 >
Th1)
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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 cytokinestumor necrosis factor ++ ++interleukin-1 + +interleukin-6 ++ ++
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Synovial inflammation in RA:a role for CD4 Th17 cells?
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Roles of TNF, IL-6, and IL-1 in cartilage degradation and erosion of bone
cartilagebone
Induce chondrocytes andfibroblasts to produce matrix metalloproteinases and otherproteases that degrade cartilage
Together with RANK-RANKL interactions, promote differentiation of precursorsinto osteoclasts, which are the destructive element where the pannus invades bone
TNF, IL-6, IL-1
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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
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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
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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
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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
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Early RA with fusiform swelling of the 3rd and 4th PIP joints
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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
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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
co
un
t
joint narrowing
joint erosions
jointdeformities
Arb
itrar
y sc
ale
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Characteristic joint deformities in RA
“Swan neck”deformities:hyperextensionof PIPs and flexion of DIPs
“Boutonniere” deformity:flexion of PIP and hyperextension of DIP
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Characteristic joint deformities in RA
Ulnar deviationof the fingers
Volar subluxationof MCPs
Rheumatoid nodules
Note the symmetry of the joint involvement
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Characteristic joint deformities in RA
Subluxation of the metatarsals as a consequence of MTP arthritis
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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)
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Rheumatoid nodule
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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
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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
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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
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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
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Goals of therapy for RA
• Reduce signs and symptoms of inflammation
• Prevent joint deformities
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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
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Raoul Dufy
“La Cortisone” 1951
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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
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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)• $$$
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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
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Treatment of RA: general principles
• Patients should be started on effective therapy (eg, a DMARD) within 3 months of diagnosis
• 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
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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
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Rheumatoid arthritis: 2012
• 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
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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