Science of Rheumatoid Arthritis

Question 1

What is RA

Answer 1

Rheumatoid arthritis is a chronic symmetric polyarticular inflammatory joint disease, which primarily affects the small joints of the hands and feet

Question 2

Is RA common?

Answer 2

Rheumatoid Arthritis is one of the commonest, severe, chronic conditions of adulthood with potentially progressive, disabling arthritis and a range of systemic effects

Question 3

What are the layers of the synovium

Answer 3

Intimal lining

Sub-intimal

Question 4

What is contained in the intimal lining

Answer 4

• Thin 2 or 3 layers of cells

- Two cell types (fibroblast and macrophages)

Question 5

What is contained in the sub intimal lining

Answer 5

• Connective tissue containing blood vessesl, fibroblasts and macrophages

Question 6

Whats the function of the synovium

Answer 6

Maintenance of intact tissue surface
Lubrication of cartilage
Control of synovial fluid volume and composition (hyaluronan, lubricin)
nutrition of chondrocytes within joints

Question 7

What antibodies are commonly associated with RA

Answer 7

Autoantibodies, such as Rheumatoid Factor and anti-citrullinated protein antibodies, are commonly associated with RA

Question 8

What groups are people with RA split into

Answer 8

Seronegative rheumatoid arthritis

Seropositive rheumatoid arthritis

Question 9

What is Seropositive rheumatoid arthritis

Answer 9

Patients have - Rheumatoid factor

and/or

Anti-citrullinated protein antibody (ACPA) – less favourable prognosis

Question 10

What is Seronegative rheumatoid arthritis

Answer 10

Autoantibodies are not detectable

Question 11

What are environmental triggers that causes RA

Answer 11

Smoking and bronchial stress

Infectious agents

Question 12

What infectious agents can cause RA (x5)

Answer 12

• Viruses (EBV, CMV)
• E. Coli
• Mycoplasma
• Periodontal disease (Porphyromonas gingivalis)
• Microbiome (gut microbes)

Question 13

What are the genetics of RA

Answer 13

Genetic contribution to RA estimated to be ~50-60%

Overall incidence of RA ~1% rises to 2-4% in siblings and 12-15% in monozygotic twins

Question 14

What can happen when a genetically susceptible individual has repeated insults of an environmental trigger

Answer 14

Formation of immune complexes and rheumatoid factor

and/or

Altered citrullination of proteins and breakdown of tolerance, with resulting ACPA response

Question 15

What % of patients is RF found

Answer 15

70%

Question 16

What do RF autoantibodies target

Answer 16

They target the Fc portion of Gg antibodies

Question 17

What is an Fc portion on an antibody

Answer 17

All antibodies have an Fc antibody. It is were immune cells bind to the antibody.

Question 18

What happens when the Fc portion of the antibody has been targeted

Answer 18

The bodies immune system cant recognise the antibody and attacks it.

Question 19

What does the Anti-citrullinate protein antibody target

Answer 19

Targets citrullinated proteins such as fibrin and fillagrin

Question 20

What is a citrullinated protein

Answer 20

Citruliinated proteins are proteins that have arignated AA converted to citrullinate (making it seem foreign)

Question 21

What antibody is more sensitive and specific to RA

Answer 21

Anti-citrullinate protein antibody

Question 22

What is the pathological hallmark of RA

Answer 22

Synovitis

Question 23

What cells are found in an inflamed synovium due to RA

Answer 23

Macrophages 
Cytokines 
Fibroblast like Synoviocytes (type A)
T-cells 
Plasma cells

Question 24

What cells are found in an inflamed synovial fluid due to RA

Answer 24

Neutrophils

immune complexes

Question 25

What do macrophages do to cause RA in the synovium

Answer 25

Make cytokines (TNF-a, IL-1 and IL-6) which cause inflammation

Question 26

What do the cytokines secreted by macrophages do to cause RA in the synovium

Answer 26

Stimulate FLS which activate and proliferate They also stimulate rankl expression which act with the cytokines to activate osteoclasts which then cause bone erosion

Question 27

What do fibroblast like synoviocytes do to cause RA in the synovium

Answer 27

Stimulate rankl expression which act with the cytokines to activate osteoclasts which then cause bone erosion Also secrete proteases which cause the cartilage to break down (cartilage degredation).

Question 28

What can fibroblast like synoviocytes do which gives a typical feature of RA

Answer 28

When FLS are activated they can migrate from joint to joint (one hand to the other) – WHY IS SYMETTRICAL

Question 29

How does the cartilage respond to its breakdown via FLS

Answer 29

The cartilage also secretes proteases creating a positive feedback loop of degradation

Question 30

What do T cells do to cause RA in the synovium

Answer 30

They promote inflammation - They secrete interleukin 17 which promotes macrophage activity and also stimulate the FLS They also help in expression in RANKL (bone erosion

Question 31

What do plasma cells do to cause RA in the synovium

Answer 31

They assist in inflammation through cytokines and antibodies

Question 32

What do neutrophils do to cause RA in the synovium

Answer 32

Contain proteases and reactive oxygen species which cause bone and collagen degradation (inflammation)

Question 33

What do immune complexes do to cause RA in the synovium

Answer 33

These are complexes which bind to each other and promote inflammation

Question 34

What causes increased angiogenesis at the synovium in RA

Answer 34

The cytokines produces by the cells increases vascular permeability and expression of adhesion molecules in the vasulature allowing the immune cells to migrate into the joints