Pathology of Rheumatoid Arthritis

Question 1

Describe the genetics of RA

Answer 1

• Complex polygenetic disorder - genetic markers explain 30% of the risk of developing RA
• RA patients have increased HLA DR4 serotype (set of alleles at HLA DRB1 gene locus strongly associated with RA)
• RA related to MHC class II

Question 2

What are HLA genes?

Answer 2

Group of genes that code cell surface markers (MHC molecules), proteins involved in immune function

Question 3

Describe the interaction in RA of genes and smoking?

Answer 3

• Cigarette smoking (and gingivitis) leads to increased citrullination of proteins
• In RA, an autoimmune response develops against citrullinated peptides via production of anti-CCP (cyclic citrullinated protein) antibodies
• Therefore, smoking + epitope producing anti-CCP means you are 40x more likely to develop RA
• Patients can also often present with new diagnosis of RA after infection/immunisation

Question 4

Which autoantibodies may be present in patients with RA up to 14 years before they present with symptoms?

Answer 4

• IgM RF

- Anti-CCP

Question 5

What does the immune system do in the synovium in RA?

Answer 5

1) Adaptive and innate immune pathways integrate
2) Pro-inflammatory cytokine milieu develops - TNFalpha, IL-6, GM-CSF
3) Stimulate macrophages, fibroblasts, mast cells and osteoclasts
4) Attract neutrophils
5) Promote tissue remodelling and damage

Question 6

How does bone damage occur in RA?

Answer 6

1) Inflammation and release of cytokines (RANKL) cause activation of osteoclasts (which differentiate from inflammatory cells that infiltrate the joint)
2) Angiogenesis also occurs, allowing further influx of inflammatory cells
3) Osteoclasts drive erosion of bone and mineralised cartilage
4) The pannus invades and erodes cartilage and bone

Question 7

What is the pannus?

Answer 7

The hypertrophied synovium in RA

Question 8

What does a normal synovial joint look like?

Answer 8

• Thin synovial membrane
• Preserved cartilage
• Small synoviocytes

Question 9

Describe the joint in early RA

Answer 9

• Angiogenesis (small capillaries)
• Thicker synovial membrane
• Influx of inflammatory cells

Question 10

Describe the joint in established RA

Answer 10

• Huge influx of inflammatory cells
• Extensive angiogenesis
• Beginning of bone erosion and pannus

Question 11

Why does the inflamed joint inhibit smooth movement?

Answer 11

• The synovial fluid contains inflammatory cells and is a lot more viscous
• Narrow joint space with worn down cartilage
• There is increased pain and swelling

Question 12

What happens to the synovial membrane in RA?

Answer 12

It becomes an inflammatory site that releases a range of inflammatory mediators which cause cartilage and joint degradation

Question 13

What are the inflammatory mediators in RA?

Answer 13

• TNFalpha
• IL-1, IL-6, IL-8, IL-10, IL-17
• PGE2

Question 14

Describe the actions of the mediators/cytokines in RA?

Answer 14

1) TNFα is produced by inflammatory cells and starts to induce the release of other mediators/cytokines e.g. IL-1
2) These can act on each other to stimulate inflammation and on synovial sites which release IL-6, IL-8, IL-10 (anti-inflammatory) and IL-17
3) The cytokines (TNFα and IL-1) can act to degrade the cartilage and bone

Question 15

What is the action of PGE2 in RA?

Answer 15

Cytokines release prostaglandins which are involved in mediating some of the pain and swelling observed in arthritis

Question 16

What are the cytokines driving inflammation in RA?

Answer 16

TNF and IL-6

Question 17

What is the most abundant cytokine within the RA synovium?

Answer 17

IL-6

Question 18

What are the effects of IL-6?

Answer 18

1) Drives acute phase response (CRP)
2) Mediates chemokine driven lymphocyte trafficking - helps bring in lymphocytes
3) Induction fo RANK-L (cytokine which activates osteoclasts) through JAK/STAT signalling

Question 19

What types of hypersensitivity is involved in RA?

Answer 19

Type II, III and IV

Question 20

Which type of hypersensitivity mediates joint and tissue damage?

Answer 20

Type III

Question 21

How thick is the synovial membrane usually?

Answer 21

1-2 cells thick (in RA, proliferates and becomes much thicker)

Question 22

Why is mast cell and their mediators involvement in RA not type 1 hypersensitivity?

Answer 22

Bc it is not triggered by IgE

Question 23

Describe synovial membrane cellular involvement in RA

Answer 23

• Macrophages = type A synoviocyte
• Fibroblasts = type B synoviocyte (FLS)
• Synovectomy relieves symptoms for several years

Question 24

What mediators are present in the RA joint?

Answer 24

• MMP-1,3 and 9
• Cytokines = TNF, IL-1, IL-6
• Chemokines = CCL2, CCL5, IL-8

Question 25

What are environmental risk factors for RA?

Answer 25

1) Infections e.g. EBV

2) Smoking

Question 26

What is the association of anti-CCP with genetics?

Answer 26

Highly significant association between anti-CCP and HLA-DR4 (may predict erosive disease)

Question 27

What happens in the rheumatoid synovial membrane?

Answer 27

1) Thickening of the synovial lining layer - proliferation fo fibroblast-like synoviocytes
2) Angiogenesis
3) Influx of mononuclear cells - T and B cells and monocytes
4) Production of cytokines, chemokines and matrix metalloproteinases

Question 28

Is RF present in the blood before RA presents?

Answer 28

Yes

Question 29

What do osteoclasts do?

Answer 29

• Multinucleated osteoclast likes to bind to bone
• High level of ROS
• ROS and enzymes cause resorption/resolving

Question 30

Describe the importance of the balance between pro-inflammatory and anti-inflammatory mediators in RA?

Answer 30

• In disease the pro-inflammatory mediators far outweigh the quantity and action of the anti-inflammatory mediators
• In treatment, want to restore this balance by either blocking pro-inflammatory mediators or enhancing the anti-inflammatory mediators e..g. IL-10