3 - Rheumatoid Arthritis Epidemiology, Features, Pathogenesis Flashcards
Rheumatoid Arthritis - Inflammation
Edema
Warmth
Erythema
Pain
Rheumatoid Arthritis - Joint Destruction
Bone Erosion
Cartilage Erosion
Ligamentous laxity/rupture
Rheumatoid Arthritis - Major Features
Genetic predisposition
Environment
Autoimmunity
Inflammation
Rheumatoid Arthritis - Epidemiology
Prevalence ~ 1%
Peak incidence 35 - 60 years
Women 2 - 4x greater risk than men
Rheumatoid Arthritis - Joint Involvement (Most common to least)
MCP/PIP Wrists Knees Shoulders Ankles Feet Elbows Hips
DIPs are spared
Rheumatoid Arthritis - Old Criteria
Need 4 out of 7
Morning stiffness ≥ 1 hour Simultaneous arthritis of ≥3 joints Arthritis of hand joints Symmetrical arthritis Rheumatoid nodules Serum rheumatoid factor Typical radiographic changes in hands and wrists
These old criteria are good for diagnosing established disease, but not catching early disease
Rheumatoid Arthritis - Definite Criteria
Need 6/10 points to qualify. Here are things that can give you points.
Joint involvement: 1 large joint - 0 points 2 - 10 large joints - 1 point 1 - 3 small joints - 2 points 4 - 10 small joints - 3 points > 10 joints (≥1 small) - 5 points
Serology:
Neg RF & neg anti-CCP - 0 points
Low pos RF OR low pos anti-CCP - 2 points
High pos RF OR high pos anti-CCP - 3 points
Acute phase reactants:
Normal CRP AND normal ESR - 0 points
Abnormal CRP OR abnormal ESR - 1 point
Duration of symptoms:
Pannus
Synovium that has hypertrophied in response to inflammation
Radiographic features of Rheumatoid Arthritis
Bone erosion
Loss of cartilage
Osteopenia
Why are fingers pulled in the ulnar direction when RA patients have hand deformities?
The extensor tendons are actually pulled around on the ulnar side. UGH
Why does bone erode in RA?
Synovium invades the contiguous bone
Macrophages and fibroblasts lining the synovium become activated
They release MMPs, prostaglandins, etc
This activates osteoclasts through TNF-α and RANK-L
Why does cartilage erode in RA?
In the fluid phase of RA, there are activated PMNs circulating in synovial fluid
They release free radicals and proteases
Separately, chondrocytes are activated due to the cytokines released.
They release MMPs and degrade the pericellular matrix
Rheumatoid Arthritis - Systemic Symptoms
Constitutional - Fever, Weight loss
Cachexia - Muscle atrophy, osteopenia
Extra-articular involvement
Rheumatoid Arthritis - Systemic Serological Indicators
Elevated ESR and CRP
Decreased albumin
Polyclonal gammopathy
Anemia (normochromic normocytic)
Thought mostly to be due to IL-6
RA - Other involvement
Rheumatoid scleritis
Rheumatoid vasculitis
Rheumatoid nodules (Subcutaneous, Pulmonary)
Higher mortality rate (one of the major causes is cardiovascular disease)
Rheumatoid Arthritis - Broad Pathogenesis
Genetic Background Environmental trigger CD4 T cell activation B Cell Activation Pre-Clinical (Autoimmunity) RF & APCA Clinical (Inflammation) Outcome (Disability, Joint surgery)
Rheumatoid Arthritis - Genetic Predisposition
Familial Clustering
Monozygotic > Dizygotic twins
Major histocompatibility Ag, DR4
MHC Association with Rheumatoid Arthritis
DR4 (Relative Risk 4)
MHC Association with Systemic Lupus Erythematosus
DR3 (Relative Risk 3)
MHC Association with Reactive Arthritis
B27 (Relative Risk 37)
MHC Association with Ankylosing Spondylitis
B27 (Relative Risk 69)
Shared Epitope of Rheumatoid Arthritis (HLA-DRB1)
Hypervariable region of the β1 chain of the MHC-II molecule
DR4 - Amino Acids 70 - 74:
QKRAA
QRRAA
DR1 - Amino Acids 70 - 74:
QRRAA
DR10 - Amino Acids 70 - 74:
RRRAA
T-Cell Antigens in RA that are now targets for biologic therapies
CD4 CD-28 CTLA-4 CD-W52 CD8 CD5 CD7 IL-2R
Rheumatoid Arthritis - Environmental Triggers
Smoking?
Periodontal Disease?
Gut Microbiome?
Rheumatoid Arthritis - Autoantibodies
Rheumatoid Factor (RF)
Anti-citrullinated protein antibodies (ACPA)
Antibodies against cartilage-derived proteins
Antibodies against G6P Isomerase
Rheumatoid Factor (RF)
IgM against the Fc portion of self IgG
Only 45% are positive in first 6 months of disease
85% are positive with established disease
Not specific for Rheumatoid Arthritis. Also positive in:
Chronic infection (eg endocarditis, osteomyelitis, hepatitis C)
Chronic lung/liver disease
Sarcoidosis
Anti-citrullinated protein antibodies (ACPA)
Vimentin
Fibrinogen
Enolase
High specificity for Rheumatoid Arthritis
Highly associated with HLA-DR SE+
High Positive Predictive Value for RA
Detectable earlier than RF
Found in 40% of patients who are RF(-) especially in early disease
Predictive of erosive disease and joint damage
Also not 100% specific for RA
Antibodies against cartilage derived proteins
Type II Collagen
Aggrecan
Glycoprotein 39
Citrullination of Arginine in Proteins
Peptidylarginine deiminase (PADI) is calcium-dependent enzymatic cleavage of an amine group from arginine, causing it to lose its positive charge, and turning it to citrulline. Causes loss of protein’s tertiary structure.
Why does smoking lead to more RA?
Tissue and cellular damage from smoking activates Peptidyl Arginine Deiminase (PADI), which leads to citrullination.
The citrullinated peptides are presented by APCs to T-Cells and you get Anti-CCP and RF antibodies.
Why does periodontal disease lead to more RA?
Bacterial pathogens that cause that disease also activate PADI enzymes, which leads to citrullination.
The citrullinated peptides are presented by APCs to T-Cells and you get Anti-CCP and RF antibodies.
Rheumatoid Arthritis - Other Pathogenic Factors
Other Genes:
PTNP22, STAT4, TRAF1-C5, PAD4, RUNX1, etc
Break tolerance to self-peptides????
Regulate tissue inflammation and destruction????
Other T-Cells:
More Th17, fewer Tregs
Cellular Sources of Synovial Cytokines in RA - T Cell Products
IL-2 IL-3 IL-4 IL-6 IFN-γ TNF-β GM-CSF
These are not expressed in RA Synovium
Cellular Sources of Synovial Cytokines in RA - Macrophage Products
IL-1 IL-6 TNF-α M-CSF IFN-α (+/-) GM-CSF
Cellular Sources of Synovial Cytokines in RA - Fibroblast Products
IL-6
GM-CSF
Which Cytokine is the boss?
TNF-α
Triggers IL-6 Triggers Prostaglandins Triggers Matrix Metalloproteinases Triggers Adhesion molecules Triggers IL-1, which triggers all of the above
Anti-Inflammatory Molecules we normally have
IL-1ra sIL-1R sTNFR IL-10 IL-4 IL-11
Cytokine Disequilibrium in Rheumatoid Arthritis
TNF-α and IL-1 just outweigh our anti-inflammatory mechanisms. There is too much to overcome!
Rheumatoid Arthritis - Amplification of the Inflammatory Response
One mediator has multiple effects:
There are TNF receptors on most cells, coupled to different types of signals
One mediator induces production of another:
TNF induces IL-1 and itself, same for IL-1
One mediator activates or inactivates another:
TNF/IL-1 induce collagenase
TNF/IL-1 inhibit collagen synthesis
Two mediators synergize with each other
Rheumatoid Arthritis - What leads to good outcomes?
Early treatment
Demographics (higher Socioeconomic Status)
Health behaviors (adherence to medications, weight management, exercise)
No co-morbid illness
Rheumatoid Arthritis - What leads to poorer outcomes?
Delayed treatment
Demographics (lower Socioeconomic Status)
Affective (Depression)
Poor health behaviors
Co-morbid illnesses (Cardiovascular disease)
Rheumatoid Arthritis - Kinetics
Non-acute
Rheumatoid Arthritis - Phenotype
Clinical:
Polyarthritis
Systemic and extraarticular features
Pathological:
Synovial hypertrophy
Rheumatoid Arthritis - Immune/inflammatory effector pathways
MHC-T cell contribution
Autoantibodies/immune complexes
Macrophage/fibroblast derived cytokines (TNF-α, IL-1, IL-6)
Rheumatoid Arthritis - What is the cause?
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Rheumatoid Arthritis - Who will get it?
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Rheumatoid Arthritis - How do we cure it?
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Rheumatoid Arthritis - How do we prevent it?
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