RA Introduction

Question 1

What is RA?

Answer 1

RA is an autoimmune disease affecting multiple joints, usually symmetrically. It affects the synovial and leads to its inflammation. More women are affected than man and predominantly affects hands and feet.

Question 2

How joint of RA patients look?

Answer 2

RA leads to inflammation of the synovial membrane which produces nutrients and lubrication to the joint. In RA synovium is characterised by infiltration and proliferation of macrophages, fibroblasts, T cells and B cells especially plasma cells. There is no high infiltration of neutrophils in the synovium but there is high infiltration of neutrophils in the synovial fluid. RA leads to bone erosion and cartilage loss within the joint.

Question 3

What genetic factors trigger RA?

Answer 3

Polymorphism of:
- HLA-DR4
- HLA-DR1
- PTPN22
- CTLA4

Question 4

What environmental factors trigger RA?

Answer 4

• Smoking
• Infections
• Vitamin D deficiency

Question 5

TNF in RA?

Answer 5

• Produced by macrophages and monocytes
• Regulator of other pro-inflammatory cytokines
• Up-regulates adhesion molecules
• Activates leukocytes, endothelial cells and synovial fibroblasts
• Promotes angiogenesis via VEGF
• Induces osteoclast differentiation and inhibits osteoblasts

Question 6

IL-6 in RA?

Answer 6

• Large amounts in RA synovium
• Stimulates proliferation and differentiation of B cells and T cells
• Regulates T cell migration and activation
• Promotes acute phase response and fever
• Drives osteoclast differentiation
• Promotes VEGF production

Question 7

GM-CSF in RA?

Answer 7

Involved in activation and differentiation of macrophages, neutrophils and DCs

Question 8

What autoantibodies are present in RA?

Answer 8

• Rheumatoid factor - IgM antibody which recognises FC portion of IgG, it forms immune complexes
• Anti-citrullinated antibodies (anti-CCP or ACPA) - target citrullinated proteins

Question 9

What is relevance of smoking in RA?

Answer 9

Patients with anti-CCP antibodies who smoke have higher chance of developing RA but patients with anti-CCP proteins who smoke and also have copies of HLA-DRB1 shared epitope have very high chances of developing RA (Klareskog 2006)

Question 10

Osteoclasts

Answer 10

Bone loss

Question 11

Osteoblasts

Answer 11

Bone formation

Question 12

Osteoclasts and RA

Answer 12

Osteoclasts precursors express PAD4 enzyme which promotes citrullination and they express citrullinated vimentin on their surface. When antibodies bind to citrullinated vimentin it leads to production of TNF and TNF drives differentiation of osteoclasts so it suggests that anti-CCP antibodies promote bone damage and pro-inflammatory cytokine production (Harre 2012)

Question 13

IL-23 in RA

Answer 13

IL-23 contributes to the initiation but not the effector phase of autoantibody mediated arthritis (Pfeifle 2017)

Question 14

Currently available treatments for RA?

Answer 14

• Disease modifying anti-rheumatic drugs e.g. methotrexate
• Adalimumab (anti-TNF)
• Corticosteroids
• Rituximab (anti-CD20)
• Tocilizumab (anti-IL-6R)
• Abatacept (CTLA4-Ig)

Question 15

Methotrexate

Answer 15

It was initially developed as anti-cancer drug but then it was used in RA. Methotrexate leads to production of adenosine which has highly anti-inflammatory properties. It affects rapidly dividing cells and can lead to various side effects e.g. alopecia but in RA doses are low so it usually does not happen plus patients receive folic acid the day after treatment to reduce side effects.

Question 16

What is the problem with currently available treatments?

Answer 16

Even though they are successful in around 50% patients, the problem is that if you stop treatment patients will relapse so these treatments don’t reverse the disease they just stop symptoms.