Rheumatoid Arthritis John Imboden MD. Rheumatoid arthritis: typical presentation Prevalence 1%...
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![Page 1: Rheumatoid Arthritis John Imboden MD. Rheumatoid arthritis: typical presentation Prevalence 1% Female > male (3:1) Peak onset: age 30s to 40s Insidious.](https://reader035.fdocuments.in/reader035/viewer/2022062620/551a2456550346a4248b50b7/html5/thumbnails/1.jpg)
Rheumatoid Arthritis
John Imboden MD
![Page 2: Rheumatoid Arthritis John Imboden MD. Rheumatoid arthritis: typical presentation Prevalence 1% Female > male (3:1) Peak onset: age 30s to 40s Insidious.](https://reader035.fdocuments.in/reader035/viewer/2022062620/551a2456550346a4248b50b7/html5/thumbnails/2.jpg)
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
![Page 3: Rheumatoid Arthritis John Imboden MD. Rheumatoid arthritis: typical presentation Prevalence 1% Female > male (3:1) Peak onset: age 30s to 40s Insidious.](https://reader035.fdocuments.in/reader035/viewer/2022062620/551a2456550346a4248b50b7/html5/thumbnails/3.jpg)
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 in inflamed
joints in many forms of arthritis– 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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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 may
be more important than 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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Roles of TNF 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
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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 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
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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: 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
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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