W3: Pathophysiology of RA Flashcards
What is rheumatoid arthiritis?
A type of inflammatory arthritis
A systemic autoimmune disease that is characterised by chronic inflammation of the synovial joints
What are the key features of rheumatoid arthiritis?
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.
What does rheumatoid arthritis increase the risk of?
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.**
What is the relevant epidemiology of rheumatoid arthiritis?
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.
Describe the structure of a synovial joint.
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.
Define synovium
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
What are the two different layers within the synovium?
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.
What are the features of type A synoviocytes?
Derived from bone marrow macrophage lineage
Responsible for cytokines release in response to an immune complex.
What are the features of type B synoviocytes?
Derived from fibroblast like mesenchymal lineages.
Produce large amounts of proteoglycan hyaluronic acid, which is secretes into the synovial fluid
What is the normal role of the synovial fluid?
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.
What is the basic change in the synovium during rheumatoid arthritis?
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.
What is a pannus?
What are its key features in RA?
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
What is the role of a pannus in rheumatoid arthritis?
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.
What are the five main stages in the pathophysiology of rheumatoid arthiritis?
- Infiltration of the synovium by inflammatory cells and proliferation of synovial cells
- Increase in angiogenesis
- Increased chemokine production and upregulated adhesion molecules on vascular endothelial cells
- Cytokines production activates MMPs to degrade matrix
- Pannus formation - further degrades cartilage and bone
Stage 1; Patho of RA
What is the intial inflammatory stage of rheumatoid arthiritis?
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.
What are the four stages of leukocyte extravasation?
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
Stage 2: pathophysiology in RA
What is the role of blood vessel formation in rheumatoid arthiritis?
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.
Why is increased angiogenesis a useful feature in Rheumatoid arthritis diagnosis?
Results in increased blood flow
Can be identified by a Doppler ultrasound
This aids clinical diagnosis.
Stage 3 in RA patho
What is the role of chemokines in Rheumatoid Arthiritis?
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
Stage 4 in RA pathophysiology
Describe how the tissue is destroyed in rheumatoid arthiritis?
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.
Stage 5 in RA pathophysiology:
Describe the process of pannus formation in rheumatoid arthiritis.
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.
Why is rheumatoid arthiritis often describe as joint soup?
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.
What type of T cell in linked to rheumatoid arthitis?
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.
What is rheumatoid factor?
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.
