Pathogenesis of Rheumatoid Arthritis

Question 1

How many cells thick is the synovial membrane?

Answer 1

1-3

Question 2

What are the two types of synoviocytes?

Answer 2

A and B. A are macrophages and B are fibroblast-like cells which make hyaluronic acid.

Question 3

What are type A synoviocytes?

Answer 3

A form of bone-marrow derived macrophages

Question 4

What are type B synoviocytes?

Answer 4

Fibro-blast like connective tissue cells (makes hyaluronic acid)

Question 5

Does the synovial membrane have a basement membrane?

Answer 5

No, it allows better diffusion of nutrients

Question 6

What is synovial fluid?

Answer 6

An ultra-filtrate of blood with added hyaluronic acid

Question 7

How is synovial fluid produced?

Answer 7

1. Fenestrated capillaries allow plasma to leak out of the blood vessel, and the loose areolar connective tissue allows this plasma to move through the subintima.
2. There is no basement membrane between the subintima and the synoviocytes, and therefore this allows plasma to flow through to the joint cavity
3. The synovial fluid can flow easily into and out of the joint,

Question 8

What is the composition of synovial fluid?

Answer 8

White blood cells, hyaluronic acid, glucose, protein (albumin and globulin), lubricant and cations, lactate etc.

Question 9

What pH is synovial fluid?

Answer 9

7.38 = alkaline

Question 10

How does the viscosity of synovial fluid change with rest and compression?

Answer 10

Synovial fluid is a gel at rest (viscous) due to hyaluronan and lubricin, but is fluid when compressed

Question 11

How does synovial fluid respond to low/slow frequency movements?

Answer 11

The molecules of hyaluronan and lubricin align in the direction of movement so that energy is dissipated in the direction of viscous flow

Question 12

How does synovial fluid respond to high/fast frequency movement?

Answer 12

The molecules of hyaluronan and lubricin an entangled molecular network is formed which resists deformation and acts as a shock absorbed, and the energy is stored as elasticity.

Question 13

How does synovial fluid interact with articular cartilage?

Answer 13

A small amount of synovial fluid occupies all of the free spaces between articulating surfaces, and also seeps into the articular cartilage (weeping lubrication). This helps to reduce friction between cartilage, forms a reserve volume and helps to nourish the articular cartilage.

Question 14

What is the ‘string test’ and how is it used to assess synovial fluid?

Answer 14

Take a sample of synovial fluid and drop it from a pipette and see how long it will drop before the string breaks, this is normally 4-6cm.

Question 15

What is the ‘mucin clot test’ and how is it used to assess synovial fluid?

Answer 15

When 2-5% acetic acid is added, normal synovial fluid will form a clot surrounded by a clear fluid, this is a test for normal synovial fluid (indicates have sufficient hyaluronic acid). The tougher the ‘clot’ the less hydrolysed the hyaluronic acid.

Question 16

What is the normal colour of synovial fluid?

Answer 16

Colourless or pale yellow

Question 17

What does red/brown synovial fluid represent?

Answer 17

Haemorrhage into the joint

Question 18

What does yellow and cloudy synovial fluid represent?

Answer 18

Inflammation

Question 19

What does white/creamy/shiny/cloudy synovial fluid represent?

Answer 19

Crystal arthropathy

Question 20

What does lumpy (purulent) and yellow/clear synovial fluid represent?

Answer 20

Bacterial infection

Question 21

Which is the main inflammatory cell involved in the pathogenesis of rheumatoid arthritis?

Answer 21

Th17 cells (CD4+); it produces lots of IL-17

Question 22

Describe the pathophysiology of rheumatoid arthritis

Answer 22

Stimulus causes Th17 cells to produce IL-17 and interact with dendritic cells (including macrophages) to cause production of more cytokines. Activated T cells and macrophages then:
> Induce RANKL on synovial fibroblasts (degrades cartilage and bone matrix)
> Stimulates local inflammation
> Activates synovial macrophages (type A) to secrete pro-inflammatory cytokines e.g. TNFa, IL-1 and IL-6 –> these induce Dkk-1 in synovial fibroblasts which directly inhibits osteoblast differentiation and indirectly by inducing expression of sclerostin by osteocytes (which inhibits osteoblasts)

Question 23

Why are synovial joints susceptible to inflammatory injury?

Answer 23

They have a rich network of fenestrated capillaries and a limited number of ways in which the cells can respond

Question 24

What is the consequence of the secretion of IL-17 by Th17 cells in rheumatoid arthritis?

Answer 24

> Induces RANKL on fibroblasts
Stimulates local inflammation
Activates synovial macrophages to secrete TNF, IL-1, IL-6

Question 25

What is pannus in the context of rheumatoid arthritis?

Answer 25

Where the proliferating synovial membrane grows into the articular cartilage and underlying tissue. The CD4+ T-cells collect around the small blood vessels and form lymphoid nodules. This is destructive and involves the erosion of the articular cartilage and bone, eventually leading to the destruction of the joint.

Question 26

What are the most prevalent white blood cells in the synovium in the inflammatory response in rheumatoid arthritis?

Answer 26

Neutrophils

Question 27

How do synovial fluid levels differ between a healthy individual and those with rheumatoid arthritis?

Answer 27

In a normal individual you could extract ~2ml from the knee, in rheumatoid arthritis you could extract ~20ml

Question 28

How may the presence of neutrophils in the rheumatoid arthritic inflammatory reaction lead to further worsening of the condition?

Answer 28

Neutrophils mount a respiratory burst which causes the production of a superoxide anion radical which leads to more free radical damage.

Question 29

What are the consequences of pannus in rheumatoid arthritis?

Answer 29

The accumulation of CD4+ T cells forming lymphoid nodules leads to the erosion of the articular cartilage of bone and eventually the destruction of the joint due to the persistent inflammatory response.