MSK L11 Rheumatoid Arthritis Flashcards Preview

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Flashcards in MSK L11 Rheumatoid Arthritis Deck (29):
1

Definition

Autoimmune, chronic inflammatory disease, primarily affects the synovial joints

2

Clinical signs

➢ Soft tissue swelling
• Effusion
• Warmth
• Erythema
➢ Joint deformity
➢ Reduced range of movement
➢ Muscle wasting

3

Radiological signs

Erosion of bone
Deformity

4

Symptoms

1. Pain
2. Stiffness
3. Unpredictable ‘flare’ of inflammation
4. Fatigue
5. Disability
6. Psychological effects
• Anxiety
• Depression
• Helplessness

5

Epi

Half a million in UK have RA
Prevalence worldwide → 0.5-1% WW
40% of patients are registered disabled within 3 years
Cost of treating RA in the UK is £0.8-£1.3 million

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Population

Indians highest prevalence

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Causes →
Possible antigenic targets in RA:

Microbial antigens:
Self antigens

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Microbial antigens causing RA examples

1. Super antigens (doesn’t require processing recognised by T-cell immediately) e.g. staphylococcal toxins
2. Epstein-Barr virus antigens
3. Heat shock proteins (HSPs)
4. Parvovirus antigens

9

Self antigen associated with RA

• Collagen e.g. type II
• Cartilage link protein
• HSPS
• Aggrecan (cartilage matrix)
• Class II MHC shared epitope
• IgG Fc portion

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Pannus: Formed from

Synovial hyperplasia containing many inflammatory cells (pannus) that erodes cartilage and bone.

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Pannus function

Main form of joint destruction in RA

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Panus contains

Abundant cell population:
1. Lymphocytes
2. Macrophages
3. Fibroblasts*
Other cell population:
1. B lymphocytes – antigen processing
2. Dendritic cells
3. Plasma cells
4. Mast cells – pro-inflammatory

13

*Fibroblast cells →

apoptosis is delayed in RA therefore the fibroblasts continue to produce cytokines and enzymes continuing to erode the joint.

14

Role of B cells →

Auto antibodies:
1. Antibodies to the Fc (Rhuematoid factor), Fac and F(ab)2 of the self IgG molecule
2. Antibodies to Cellular antigens histone, ssDNA, RA nucleus antigen etc.
3. Anti-collagen antibodies
4. Antibodies to HSPs

15

Role of B cells in pathology→ Rheumatoid factors

1. Ig classes of IgM, IgG, IgA and IgE
2. RF found in 7-% of RA patients
3. Not useful in diagnosis but is a good prognostic marker

16

B cell functions summary:

1. Production of autoantibodies
2. Secrete cytokines IL-6, THF-alpha and IL-10
3. B-cells; can maintain T-cell activation in the RA synovium

17

Role of T-cells

1. Efficacy of t-cell directed treatment in RA (e.g. Anti-CD4 treatment)
2. Beneficial effects of cyclosporine
3. Prominence of T-cell in the pannus and expression of IL-2 receptor in RA synovium
4. Resolution of RA in patients with developing AIDS and during pregnancy

18

Small joints →

most of joint damage done by the pannus.

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Large joints →

e.g.. Hip or knee → cytokines and enzymes released from cartilage contribute to destruction.

20

Rheumatoid Arthritis → Joint destruction - cartilage

a. Cytokines and other inflammatory mediators
b. Chemokines – presence augments inflammation
c. Enzymes

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Cytokines and other mediators in the joint

1. TNF alpha
2. IL-1 beta
3. Gamma-INF
4. IL-6

22

Chemokines

IL-8 → attract neutrophils
IL-16 → attract eosinophils

23

Enzymes

Four classes of proteases have been recognised which degrade cartilage in RA:
1. Cysteine
2. Aspartate
3. Serine
4. Metallo- proteases (main group)

24

Role of TNF-alpha:

1. Induces production of pro-inflammatory cytokines e.g. IL-1, IL-6, chemokines
2. Activates endothelial cells, leading to further recruitment of cell within the joint
3. Stimulate cells within the joint to break down the matrix which surround them
4. Stimulate macrophages to produce matrix MMPs and free radicals

25

Metallopreoteases

Collagenase
Stromelysin
Gelatinase

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Collagenase

MMP-1,8 and 13 → degrade type II collagen

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Stromelysin

MMP-3,10 and 11 → proteoglycan degradation

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Gelatinase

MMP-2 and 9 → further degrade the products of collagenase.

29


Changes in Bone:

1. Osteoclasts (multinuclear) bind to bone surface via integrins
2. The cells lower the pH of the bone by releasing hydrogen ions
a. Loss of mineral part of bone → hydroxyappetite
b. Organic part → collagen and bone matrix (BSP, osteocalcin etc.) → destroyed by proteolytic enzymes like in cartilage.
3. Gradually destroy both mineral and organic bone
a. Hydroxyapitite

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