KCP: Rheumatoid Arthritis (Pathogenesis)

Question 1

Overview of three stages of RA?

Answer 1

Question 1

What happens in stage 1 RA?

Answer 1

Antibodies develop against citrullinated and carbamylated proteins

Question 2

Why is there a strong association between RA and Human Leucocyte Antigen (HLA) class II genotypes

Answer 2

Antigens are presented to T-cells bound to HLA Class II proteins

Question 3

What is Citrullination and what promotes it?

Answer 3

Protein citrullination is promoted by smoking, infection, microbiome at mucosal sites

Question 4

What happens in normal antigen prensenting?

Answer 4

Signal 1 is the presentation of the antibody to the T cell. Signal 2 is the presentation of CD 80/86 - known as co-stimulation, this is signalling not only the antigen but also danger and is required to activate the T-cell

Question 5

What happens in autoimmune antigen presenting?

Answer 5

Question 6

What happens in stage 2 of rheumatoid arthritis?

Answer 6

Tissue Invasion

• Initial clinical presentation of disease is with synovitis when inflammatory cells enter the synovial membrane
• Loss of resident macrophages which maintain immune privilege
• Pro-inflammatory CD4 positive short lived effector T cells (SLEC) are key
  1. Show evidence of immuno-senescence
  2. Proliferate
  3. Poor ATP production
  4. Undergo pyroptosis-cell death that triggers inflammation

Question 7

What happens in stage 3 of rheumatoid arthritis?

Answer 7

Chronic inflammation and progressive damage

1. Activation of synovial fibroblasts & infiltration by macrophages
   * Pro-inflammatory cytokines produced such as IL-1, TNF, IL-6
   * T cells also produce RANKL which stimulates osteoclasts
2. Angiogenesis
   * Increased blood flow and synovial swelling
3. Chronic synovitis, cartilage damage and bone erosions

Question 8

Overview of RA

Answer 8

Question 9

Reminder: Diagnoses of RA

Answer 9

Prescence of anti-cyclic citrullinated peptide antibodies

Gull-wing appearance in joints

Question 10

Reminder: RA Treatment

Answer 10

• Start immunosuppressive treatment early
• Short term course of prednisolone (corticosteroid)
• Methotrexate

Question 11

4 examples of common disease modifying anti-rheumatic drugs (DMARDs)

Answer 11

a. Methotrexate
b. Hydroxychloroquine
c. Sulfasalazine
d. Leflunomide

Question 12

What is immune tolerance and what is the significance to RA?

Answer 12

Immune tolerance is the prevention of an immune response against a particular antigen.

Normally the body will develop peripheral tolerance to the autoimmune antibodies however in RA stage 1 this breaks down

Question 13

What is biological therapy?

Answer 13

A type of treatment that uses substances made from living organisms to treat disease.

Question 14

TNF inhibitor are a type of biological therey for RA. What are TNF inhibitors?

Answer 14

They block tumor necrosis factor alpha. A protein in the body’s immune system that causes inflamation. It is a pro-inflammatory cytokine

Question 15

Why do the antibodies produced in response to citrullinated proteins in the mucosa then cause a response in the synovium of the joints?

Answer 15

These antibodies become systemically circulated. A citrullinated protein then can get stuck in the synovium of joints (like hair in a sink). Now lets say a rouge neutrophil passes by and detects it or if it is called there because of damage and then detects it it will attack it. But it can’t engulf it because it is stuck. This causes more and more aggrivation and the neutrophil might release more citrullinated proteins in response cause more of a response.

At this point you have swarming and inflamation and more damage and more immune response and it cascades into dog shit.

Question 16

Why is RA symmetrical?

Answer 16

Rheumatoid is symmetrical because it is a systemic response

Question 17

Why do you give the short course of prednisolone as well as DMARDs?

Answer 17

DMARDs take 8-12 weeks to start working, this is a lot of time of pain and time for things to get worse. So giving corticosteroids before the DMARDs kick in gets them into remission really quickly.

Question 18

Most common RA related antibody and second most common?

Answer 18

1. Anti CCP
2. RF rheumatoid factor

Question 19

Joints that are first affected

Answer 19

Radiocarpal
Metacarpophalangeal joints