3 - Rheumatoid Arthritis Epidemiology, Features, Pathogenesis Flashcards Preview

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Flashcards in 3 - Rheumatoid Arthritis Epidemiology, Features, Pathogenesis Deck (48):
1

Rheumatoid Arthritis - Inflammation

Edema
Warmth
Erythema
Pain

2

Rheumatoid Arthritis - Joint Destruction

Bone Erosion
Cartilage Erosion
Ligamentous laxity/rupture

3

Rheumatoid Arthritis - Major Features

Genetic predisposition
Environment
Autoimmunity
Inflammation

4

Rheumatoid Arthritis - Epidemiology

Prevalence ~ 1%
Peak incidence 35 - 60 years
Women 2 - 4x greater risk than men

5

Rheumatoid Arthritis - Joint Involvement (Most common to least)

MCP/PIP
Wrists
Knees
Shoulders
Ankles
Feet
Elbows
Hips

DIPs are spared

6

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

7

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:

8

Pannus

Synovium that has hypertrophied in response to inflammation

9

Radiographic features of Rheumatoid Arthritis

Bone erosion
Loss of cartilage
Osteopenia

10

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

11

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

12

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

13

Rheumatoid Arthritis - Systemic Symptoms

Constitutional - Fever, Weight loss
Cachexia - Muscle atrophy, osteopenia
Extra-articular involvement

14

Rheumatoid Arthritis - Systemic Serological Indicators

Elevated ESR and CRP
Decreased albumin
Polyclonal gammopathy
Anemia (normochromic normocytic)

Thought mostly to be due to IL-6

15

RA - Other involvement

Rheumatoid scleritis
Rheumatoid vasculitis
Rheumatoid nodules (Subcutaneous, Pulmonary)
Higher mortality rate (one of the major causes is cardiovascular disease)

16

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)

17

Rheumatoid Arthritis - Genetic Predisposition

Familial Clustering
Monozygotic > Dizygotic twins
Major histocompatibility Ag, DR4

18

MHC Association with Rheumatoid Arthritis

DR4 (Relative Risk 4)

19

MHC Association with Systemic Lupus Erythematosus

DR3 (Relative Risk 3)

20

MHC Association with Reactive Arthritis

B27 (Relative Risk 37)

21

MHC Association with Ankylosing Spondylitis

B27 (Relative Risk 69)

22

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

23

T-Cell Antigens in RA that are now targets for biologic therapies

CD4
CD-28
CTLA-4
CD-W52
CD8
CD5
CD7
IL-2R

24

Rheumatoid Arthritis - Environmental Triggers

Smoking?
Periodontal Disease?
Gut Microbiome?

25

Rheumatoid Arthritis - Autoantibodies

Rheumatoid Factor (RF)
Anti-citrullinated protein antibodies (ACPA)
Antibodies against cartilage-derived proteins
Antibodies against G6P Isomerase

26

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

27

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

28

Antibodies against cartilage derived proteins

Type II Collagen
Aggrecan
Glycoprotein 39

29

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.

30

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.

31

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.

32

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

33

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

34

Cellular Sources of Synovial Cytokines in RA - Macrophage Products

IL-1
IL-6
TNF-α
M-CSF
IFN-α (+/-)
GM-CSF

35

Cellular Sources of Synovial Cytokines in RA - Fibroblast Products

IL-6
GM-CSF

36

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

37

Anti-Inflammatory Molecules we normally have

IL-1ra
sIL-1R
sTNFR
IL-10
IL-4
IL-11

38

Cytokine Disequilibrium in Rheumatoid Arthritis

TNF-α and IL-1 just outweigh our anti-inflammatory mechanisms. There is too much to overcome!

39

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

40

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

41

Rheumatoid Arthritis - What leads to poorer outcomes?

Delayed treatment
Demographics (lower Socioeconomic Status)
Affective (Depression)
Poor health behaviors
Co-morbid illnesses (Cardiovascular disease)

42

Rheumatoid Arthritis - Kinetics

Non-acute

43

Rheumatoid Arthritis - Phenotype

Clinical:
Polyarthritis
Systemic and extraarticular features

Pathological:
Synovial hypertrophy

44

Rheumatoid Arthritis - Immune/inflammatory effector pathways

MHC-T cell contribution
Autoantibodies/immune complexes
Macrophage/fibroblast derived cytokines (TNF-α, IL-1, IL-6)

45

Rheumatoid Arthritis - What is the cause?

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46

Rheumatoid Arthritis - Who will get it?

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47

Rheumatoid Arthritis - How do we cure it?

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48

Rheumatoid Arthritis - How do we prevent it?

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