Rheumatoid Arthritis - Pathogenesis

Question 1

Function of synovium

Answer 1

Maintain intact tissue surface
Lubricate cartilage
Control synovial fluid volume
Control synovial fluid composition - hyaluronan, lubicin
Nutrition of chondrocytes

Question 2

RA is a chronic, symmetric and polyarticular inflammatory joint disease. What are 3 features of rheumatoid synovitis?

Answer 2

Inflammatory cell infiltration
Synoviocyte proliferation
Neoangiogenesis

Question 3

What cells are found in the synovial fluid of a rheumatoid joint?

Answer 3

Neutrophils

Question 4

What is pannus?

Answer 4

An abnormal layer of fibrovascular or granulation tissue that forms over the articular surface
Causes bone and cartilage destruction leading to joint deformity

Question 5

Which antibodies are associated with rheumatoid arthritis?

Answer 5

Rheumatoid Factor
Anticitrullinated protein
Autoantibodies to type II collagen and systemic antigens eg glucose phosphate isomerase

Question 6

What process is activated by autoimmune responses in RA?

Answer 6

Complement

Leads to inflammation

Question 7

Seropositive RA patients have which antibodies?

Answer 7

Rheumatoid Factor

Anticitrullinated Protein Antibodies ACPA

Question 8

How is seropositive RA diagnosed?

Answer 8

Anti-CCP assays recognise self citrullinated proteins

Question 9

Which proteins will be recognised to be self citrullinated in anti CCP diagnostic assays?

Answer 9

Keratin, fibrinogen, alpha enolose, fibronectin, collagen, vimentin

Question 10

How does prognosis for patients compare between seropositive and seronegative cases of RA?

Answer 10

Seropositive have a less favourable prognosis

Question 11

Which genetic polymorphism is associated with RA?

Answer 11

HLA DRB1 - promotes autoimmunity

Others -PTPN22, CTLA4, c-rel

Question 12

What environmental factors may contribute to RA?

Answer 12

Smoking
Bronchial stress
Infection

Question 13

Which infectious agents are associated with Rheumatoid arthritis?

Answer 13

Viruses
E.coli
Mycoplasma
Periodontal disease - Porphyromonas gingivalis
Gut microbes of the microbiome

Question 14

3 events in pathogenesis of RA leading to ACPA response

Answer 14

Repeated insults in genetically susceptible individual
Formation of immune complexes and rheumatoid factor
Alteration in citrullination of proteins and breakdown of tolerance

Question 15

What is citrullination?

Answer 15

Conversion of arginine to citrulline

Question 16

What cells take up the citrullinated atingen in the ACPA response?

Answer 16

Antigen presenting cells

Question 17

Which cells are activated by the APCs in the ACPA response?

Answer 17

T cells and B cells resulting in antibody production

Question 18

Immune complexes are formed from the antibodies produced by activated B cells. What is the effect of the immune complexes in the ACPA response?

Answer 18

Inflammation of the joint

Cycle of complexes forming perpetuates inflammation

Question 19

What is synovitis?

Answer 19

Inflammation of the synovium

Question 20

Describe 6 cellular features of synovitis

Answer 20

Villous hyperplasia
Infiltration of B cells, T cells
Macrophage and plasma cell activation
Intimal cell proliferation
Production of cytokines and proteases
Increased vascularity 

Self ampifying process

Question 21

What cell involvement is there in rheumatoid arthritis?

Answer 21

T cells and their cytokines
B cells and cytokines
Stromal cell cytokines
Inflammatory cytokines

Question 22

What is the effect of T-cell targeted treatment in RA?

Answer 22

Little effect
Low level of cytokines in Synovium
Activation of B cells and macrophages

Question 23

Name a T-cell targeted medication

Answer 23

Abatacept

Question 24

What is the effect of a B-cell targeted treatment in RA?

Answer 24

Very effective against pathogenic CD20 + Bcells

Question 25

What do B cells produce and what is the function of this product?

Answer 25

Autoantibodies Autoantigen presentation Cytokines - IL-6, TNF alpha

Question 26

Which stromal cell cytokines are abundant in the RA synovium?

Answer 26

Macrophage and fibroblast cytokines

Question 27

Which cells are activated by TLR and NLRs?

Answer 27

Macrophage (M1)

Question 28

What is the function of chemokines produced in RA synovium?

Answer 28

Recruit inflammatory cells

Question 29

Anti-inflammatory IL-10 is also present in the synovium. Why does inflammation still occur?

Answer 29

Not produced at high enough levels to offset the proinflammatory cytokines

Question 30

Functions of inflammatory cytokines (6)

Answer 30

Promote expression of endothelial cell adhesion molecules Activate synovial fibroblasts, chondrocytes and osteoclasts Promote angiogenesis Suppress T-regs Activate leukocytes Promote autoantibody production

Question 31

Which 4 systemic effects are mediated by IL-6?

Answer 31

Anaemia Acute phase response Cognitive dysfunction Lipid metabolism dysregulation

Question 32

Why is neoangiogenesis crucial in driving RA?

Answer 32

Nutrients provided to hyperplastic synovium

Question 33

How is blood vessel proliferation enhanced on Rheumatoid synovium?

Answer 33

Hypoxic conditions | IL8 and VEGF - Angiogenic factors

Question 34

Which 3 cells are responsible for destruction of bonee and cartilage in RA?

Answer 34

Osteoclasts Synovial lining cells (particularly FLS)- can invade cartilage FLS - produce proteases

Question 35

What is produced in the RA synovium to activate osteoclasts?

Answer 35

RANKL

Question 36

Systemic consequences of RA

Answer 36

Vasculitis, nodules, scleritis, amyloidosis Cardiovascular disease Fatigue, reduced cognitive function Liver - elevated acute phase response, anaemia Lung - Interstitial lung disease, fibrosis Muscles - sarcopenia Bone - osteoporosis Secondary Sjrogen's Syndrome

Question 37

How can RA induce cardiovascular disease?

Answer 37

Altered lipid metabolism Elevated acute phase reactants Increased endothelial activation

Question 38

How can RA induce anaemia?

Answer 38

IL6 increases hepatocyte production of hepcidin which regulates iron levels