W3: Pathophysiology of RA

Question 1

What is rheumatoid arthiritis?

Answer 1

A type of inflammatory arthritis
A systemic autoimmune disease that is characterised by chronic inflammation of the synovial joints

Question 2

What are the key features of rheumatoid arthiritis?

Answer 2

Can affect most synovial joints
Acts on symmetrical joints
Affects small joints - mainly MTC and PIP
Characterised by progressive destruction of synovial joints through loss of cartilage and bone.
Results in disability, deformity, loss of function, reduced quality of life, increased comorbidity and a shortened life expectancy.

Question 3

What does rheumatoid arthritis increase the risk of?

Answer 3

Doubles the risk of hip and vertebral fractures
Increase risk of falls
Risk of death from cardiovascular disease
Risk of death from pulmonary problems, including respiratory infection and lung cancer.**

Question 4

What is the relevant epidemiology of rheumatoid arthiritis?

Answer 4

Varies across population - may be due to frequency of HLA polymorphism
More common in women 3:1 ratio
Onset is often between 30 to 50 yrs but can develop at any age.

Question 5

Describe the structure of a synovial joint.

Answer 5

Bone lined by hyaline cartilage at the articular surface.
The Joint is surrounded by a joint capsule which has an outer fibrous layer and an inner synovial layer (synovium), which is made from synoviocytes.
The synovial layer secretes synovial fluid which fills the synovial cavity, the gap between the two articulating bones.

Question 6

Define synovium

Answer 6

A connective tissue between the outer fibrous layer of the joint capsule and the joint space
Lines all surfaces of the inner joint except the cartilage articular surface

Question 7

What are the two different layers within the synovium?

Answer 7

Inner-thin lining (1-2 cells thick) consisting of type 1/A synoviocytes (macrophage-like) and type 2/B synoviocytes (fibroblast-like)
Outer - synovial sublining (or subintima)- loose connective tissue with numerous blood vessels, nerves, lymphatics and scattered macrophages and fibroblasts.
Matrix of collagen and proteoglycan holds all cellular structures together.

Question 8

What are the features of type A synoviocytes?

Answer 8

Derived from bone marrow macrophage lineage
Responsible for cytokines release in response to an immune complex.

Question 9

What are the features of type B synoviocytes?

Answer 9

Derived from fibroblast like mesenchymal lineages.
Produce large amounts of proteoglycan hyaluronic acid, which is secretes into the synovial fluid

Question 10

What is the normal role of the synovial fluid?

Answer 10

In healthy joints - normally only present in small amounts
Is highly viscous - due to high hyaluronic acid content - this protects the articular surface
Acts as a medium of exchange between the synovium, blood vessels and articular cartilage.
Is an ultrafiltrate of blood plasma.

Question 11

What is the basic change in the synovium during rheumatoid arthritis?

Answer 11

The lining becomes thickened - due to hyperplasia and hypertrophy
Also, excess infiltration of the underlying subintima by macrophages, lymphocytes and plasma cells.
Increased angiogenesis.
Decreased hyaluronic acid production - leads to less protective synovial fluid, less lubrication and shock absoprtion.

Question 12

What is a pannus?
What are its key features in RA?

Answer 12

Is excessive growth of the synovial lining due to hyperplasia and hypertrophy
Contains active angiogenesis, immune celll migration and fibroblast activation - type of granulation tissue

Question 13

What is the role of a pannus in rheumatoid arthritis?

Answer 13

Begins to invade and degrade the surrounding bone and cartilage.
Consists of hyperplastic synovial lining, extensive angiogenesis, osteoclast activity, and immune cells (macrophage, dendritic cells, T cells, plasma cell, B cell and mast cell) and fibroblasts.

Is a sign of late and irreversible damage from RA.

Question 14

What are the five main stages in the pathophysiology of rheumatoid arthiritis?

Answer 14

1. Infiltration of the synovium by inflammatory cells and proliferation of synovial cells
2. Increase in angiogenesis
3. Increased chemokine production and upregulated adhesion molecules on vascular endothelial cells
4. Cytokines production activates MMPs to degrade matrix
5. Pannus formation - further degrades cartilage and bone

Question 15

Stage 1; Patho of RA
What is the intial inflammatory stage of rheumatoid arthiritis?

Answer 15

Inflammation is triggered by an unknown cause.
Adhesion molecules (ICAM and E-selectin) increase on endothelial cells in the subliming of the synovium, stimulates by TNFalpha
Vasodilation of bv - leukocytes extravasation into synovium occurs.
This includes neutrophils, monocytes, mast cells, T cells and B cells.

Question 16

What are the four stages of leukocyte extravasation?

Answer 16

Extravasation - movement from circulatory system to tissue of need/damage/infection

1) marginalisation of luekocytes
2) rolling - low affinity adhesion via selectin receptors and ligands, such as L-selectin on leukocytes, E-selectin on endothelial cells (which expression is caused by TNF-alpha activating the endothelium)
3) Tight binding - high affinity between IL8 receptor on leukocyte and ligand (CXCL8 bound to proteoglycan on endothelial cell) and LFA-1 on leukocyte and ICAM-1 on endothelial cells.
4) Diapedesis - facilitated by PECAM.
5) Migration in tissue down a chemokine gradient

Question 17

Stage 2: pathophysiology in RA
What is the role of blood vessel formation in rheumatoid arthiritis?

Answer 17

Synovium undergoes hyperproliferation and hypertrophy - results in hypoxia as reduced blood flow and increased oxygen demand
Activation of Hypoxia Inducible Factor leading to release of pro-angioegneic factors, such as VEGF
Pro-inflammatory cytokines are also pro-angiogenic - resulting in increased angiogenesis.

Question 18

Why is increased angiogenesis a useful feature in Rheumatoid arthritis diagnosis?

Answer 18

Results in increased blood flow
Can be identified by a Doppler ultrasound
This aids clinical diagnosis.

Question 19

Stage 3 in RA patho
What is the role of chemokines in Rheumatoid Arthiritis?

Answer 19

Chemokines are produces by macrophages - found in large numbers in the synovial tissue, fluid and blood.
CCL2 chemoattractant for monocytes
CCL3 attracts monocytes, leukocytes, basophils and eosinophils via CCR1,5
CCL5 recruites lymphocytes and monocytes via CCR1,3,5

Question 20

Stage 4 in RA pathophysiology
Describe how the tissue is destroyed in rheumatoid arthiritis?

Answer 20

Cytokines cause MMP release which degrades the bone and cartilage matrix.

TNFalpha and IL-1beta are produced by macrophages : cause chondrocytes to produce MMPs, activate osteoclases (degrade organic bone matrix)
T cells, B cells and synovial fibroblasts may also contribute to cytokine production.

Question 21

Stage 5 in RA pathophysiology:
Describe the process of pannus formation in rheumatoid arthiritis.

Answer 21

Develops from normal synovium - gradually invades bone and cartilage
Contains type A and B synoviocytes, alongside infiltrating immune cells.
Type B synoviocytes and activated chondrocytes to produce MMPs, pro-inflammatory cytokines, prostaglandins and ADAMTs which degrade cartilage
Type B synoviocytes and T cell secrete RANKL which activates osteoclasts to destroy bone by the release of lysosomal enzymes and acid secretion.

Question 22

Why is rheumatoid arthiritis often describe as joint soup?

Answer 22

The synovium will contain a large number of cells in the process
Includes: T cells, B cells, plasma cells, macrophages, dendritic cells, endothelial cells, fibroblasts, osteoclasts, chondrocytes, mast cells and neutrophils.

Question 23

What type of T cell in linked to rheumatoid arthitis?

Answer 23

CD4+ T Cell
Proliferation and differentiate in triggered by DCs and linked to rhematoid arthiritis
In particular Th17 which produce IL-23
Also Th1 have a proinflammatory phenotype.

Question 24

What is rheumatoid factor?

Answer 24

An antibody against an antibody
Can be IgM (most) alongside other classes Specific with high affinity for the Fc region of the IgG antibody.
Produced by autoreactive B cell.

Question 25

What is the function of the Rose-Waaler test?

Answer 25

Test to identify the presence of rheumatoid factor in blood
Sheep RBCs sensitised by IgG from rabbit.
Then add patient sample - if RF present will react with antibody and cause haemagglutination.

Question 26

What is the link between rheumatoid factor and rheumatoid arthiritis?

Answer 26

Positive rheumatoid factor is associated with increased severity, erosions, extraarticular manifestations and poor prognosis.
Present in 70% of RA patient, specificity of 60-80% - can be present in other diseases and healthy patients.

Question 27

What is the role of rheumatoid factor in healthy individuals?

Answer 27

Aid immune complex clearance and the uptake and processing of immune complexes by B cells.

Question 28

What are anti-citrullinated protein antibodies (ACPA)?
What is the link to Rheumatoid arthiritis?

Answer 28

ACPA or anti-CPP anitbodies
Recognise modified protein strucutres where an arginine has been changed to a citrulline during post translational modificiatio by peptidly arginine deaminases PADIs. (e.g fibrin in synovium)
PADI2 and PADI4 are abundant in RA

Question 29

What is the importance of anti-CPP antibodies in rheumatoid arthiritis?

Answer 29

Can appear up to ten years before symptomatic disease onset
Present in 80% of RA patients
Specificity of 90-95%
Associated with increased joint erosions, destruction, poor prognosis but not extra-articular manifestations.
Part of potential diagnositic criteria.

Question 30

What is the genetics underlying Rheumatoid arthiritis?

Answer 30

Genetics account for 30-50% of the total risk from Rheumatoid arthritis.
No specific known cause, genetic interactions are thought to increases susceptibility
Stong links to HLA and PADI mutations.

Question 31

What is the HLA mutation linked to rheumatoid arthiritis?

Answer 31

Mutation in the beta chain in HLA-DR loci (class 2 HLA)
The mutation is HLA-DR-1B-04 variant
Better at presenting self epitope in rheumatoid arthritis.

Question 32

What is the shared epitope in rheumatoid arthiritis?

Answer 32

A sequence of five amino acids common to HLA-DR-B1 alleles that are thought to increase the risk of RA
Located in amino acid 70-74, within the peptide binding groove of the MHC class 2 molecule.
Increases ability to present epitope to TCR and activate a T cell.

Question 33

What are some minor genetic changes linked to rheumatoid arthritis?

Answer 33

PTPN22 - norm - inhibits T cell activation
PAD14 - converts agininge to citruline
STAT4 - adis maturation of T cells
CTLA4 - T reg co-stimulation
IL2 - T reg develpment
CD40 - Co-stim expressed on B cells
Combined only 3-5% of genetic burden on RA

Question 34

What is the main environmental risk factor associated with rheumatoid arthiris?

Answer 34

Smoking

Question 35

What is the link between smoking and rheumatoid arthiritis?

Answer 35

Study found increased odds by 12-fold in susceptible people
by 1.8 fold in smokers with a pack year greater than 20.
Risk persists for 20 years after quit smoking
Associated with increased risk of disease, x-ray damage, more severe disease, higher mortality, increased nodular disease, increased rheumatoid factor and anti-CPP

Question 36

What are some environmental risk factors associated with rheumatoid arthritis?

Answer 36

Silica/asbestos
Pollutants
Diet
Role of gut microbiome (dysbiosis)
Peridontal disease (porphyromonas gingivalis)
Infection - epstein barr virus, E.coli, cytomegalovirus
Link through susceptibility to inflammation and molecular mimicry causing autoimmune conditions.

Question 37

What type of arthritis in rheumatoid arthritis?

Answer 37

Symmetric small join inflammatory polyarthritis.