Inflammation of Bone & Joint (RA)- Gravallese

Question 1

Summarize Inflammatory Arthritis

Answer 1

• Multiple etiologies
• Progressive inflammation leading to synovial proliferation and cytokine induced injury.
• Damage to articular cartilage and bone- joint is, thus, destroyed.

Question 2

What is Rheumatoid Arthritis?

Answer 2

A systemic disease manifested by Polyarthritis with:

• Destruction
• Inflammation
• Pain
• Swelling

DIPS

Question 3

Describe the Epidemiology of RA

Answer 3

• F > M (2.5:1)
• Cigarette smoking
• Genetic predisposition

Question 4

Describe Clinical features of RA

Answer 4

• Symmetric Arthritis
• Early peri-articular demineralization
• Early Joint Destruction
• DIP joints spared
• MCP and PIP heavily damaged

Question 5

What is Pannus?

Answer 5

• Pannus is Latin for Clot.

- In RA, it used to describe the Inflamed Synovial tissue.

Question 6

Describe Pathogenesis of RA

Answer 6

Environment:

• Smoking (may induce CCP)*
• Microorganisms

Genetics:
-HLADR4 (Highest risk for developing RA)

Autoimmunity:

• RF
• Anti-CCP antibodies

Note: Smoking is thought to induce the amount of CCP made; the body recognizes CCPs as foreign and creates ABs against them.

Question 7

Describe Genetic Predisposition to RA

Answer 7

• HLADR4 (Main)
• HLADRB1

T-Cells and the MHC locus are placed at the center of the RA Pathogenesis.

Question 8

What is the Shared Epitope? How does it relate to RA risk?

Answer 8

• This is the portion of the antigen that lends itself to the pathogenesis of RA.
• Comes from Cyclic Citrilinated Protein (CCP)

Note: Risk of developing RA increases in proportion to the amount of copies of Shared epitope.

Question 9

Discuss the spontaneous arthritis Mouse model and how it relates to RA

Answer 9

• The spontaneous arthritis in the mice resembled that seen in RA
• T and B cell interaction required.
• Antibodies that were generated against GPI led to the destruction of the joints.

Question 10

APC cells stimulate T cells, and T cells release which interleukins to activate B cells?

Answer 10

IL-4 and IL-10

Note: B cells become plasma cells that release RF and anti-CCP antibodies.

Question 11

What are the proteases implicated in the cartilage destruction?

Answer 11

SCAM

Serine
-PMN Elastase, Mast cell chymase, grandzymes

Cystein
-Cathepsin B, L, K

Aspartic
-Cathepsin D

Matrix Metalloproteinases

• MMP 1
• MMP 3
• MMP 8

Question 12

What are the factors produces by the RA synovium tissue with Osteoclastic activity?

Answer 12

RANKL !
TNF-a
IL-1, 6, 7, 15, 17
PTHrP

What is the name of this inflamed tissue? Pannus, dude. Pannus.

Question 13

What condition did the mice have that did not have mature osteoclasts? How did their bones look?

Answer 13

• Osteopetrosis

- Trumpet Bones

Question 14

What is Osteoprotegrin?

Answer 14

• Osteoclast inhibitory factor
• Binds RANKL (decoy receptor)

Thus, it blocks RANKL induced osteoclast differentiation and activation.

Question 15

Name 2 entities that can release RANKL

Answer 15

• Pannus
• T cells

Can you name others?

Question 16

Name the crucial cytokines released by the Pannus tissue that contributes to the pathogenesis of bone erosion in RA.

Answer 16

• RANKL
• TNF-a
• IL-1
• IL-6

This results in increased osteoclast bone resorption.

Question 17

Name the therapies for inhibiting osteoclastic bone resorption in RA

Answer 17

Denosumab
-Works as an OPG to block osteoclast differentiation

Protease Inhibitors
-works on Cathepsin K to inhibit Matrix resorption

Question 18

The inflammation seen in RA is driven by what? And where does it come from?

Answer 18

1. Pro-inflammatory cytokines

2. Inflammatory Cells in the Synovial Tissues

Question 19

Which cytokines upregulate proteinase production by synovial fibroblasts and chondrocytes?

Answer 19

TNF

IL-1beta

Question 20

Tight control of what process will attenuate joint destruction?

Answer 20

Inflammation

Question 21

Bone destruction leads to what?

Answer 21

1. Release of more cytokines
2. Which upregulate RANKL
3. Which leads to Osteoclastogenesis
4. Which leads to more bone destruction