Rheumatoid Arthritis - Pathogenesis Flashcards

1
Q

Function of synovium

A
Maintain intact tissue surface
Lubricate cartilage
Control synovial fluid volume
Control synovial fluid composition - hyaluronan, lubicin
Nutrition of chondrocytes
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2
Q

RA is a chronic, symmetric and polyarticular inflammatory joint disease. What are 3 features of rheumatoid synovitis?

A

Inflammatory cell infiltration
Synoviocyte proliferation
Neoangiogenesis

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3
Q

What cells are found in the synovial fluid of a rheumatoid joint?

A

Neutrophils

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4
Q

What is pannus?

A

An abnormal layer of fibrovascular or granulation tissue that forms over the articular surface
Causes bone and cartilage destruction leading to joint deformity

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5
Q

Which antibodies are associated with rheumatoid arthritis?

A

Rheumatoid Factor
Anticitrullinated protein
Autoantibodies to type II collagen and systemic antigens eg glucose phosphate isomerase

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6
Q

What process is activated by autoimmune responses in RA?

A

Complement

Leads to inflammation

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7
Q

Seropositive RA patients have which antibodies?

A

Rheumatoid Factor

Anticitrullinated Protein Antibodies ACPA

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8
Q

How is seropositive RA diagnosed?

A

Anti-CCP assays recognise self citrullinated proteins

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9
Q

Which proteins will be recognised to be self citrullinated in anti CCP diagnostic assays?

A

Keratin, fibrinogen, alpha enolose, fibronectin, collagen, vimentin

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10
Q

How does prognosis for patients compare between seropositive and seronegative cases of RA?

A

Seropositive have a less favourable prognosis

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11
Q

Which genetic polymorphism is associated with RA?

A

HLA DRB1 - promotes autoimmunity

Others -PTPN22, CTLA4, c-rel

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12
Q

What environmental factors may contribute to RA?

A

Smoking
Bronchial stress
Infection

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13
Q

Which infectious agents are associated with Rheumatoid arthritis?

A
Viruses
E.coli
Mycoplasma
Periodontal disease - Porphyromonas gingivalis
Gut microbes of the microbiome
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14
Q

3 events in pathogenesis of RA leading to ACPA response

A

Repeated insults in genetically susceptible individual
Formation of immune complexes and rheumatoid factor
Alteration in citrullination of proteins and breakdown of tolerance

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15
Q

What is citrullination?

A

Conversion of arginine to citrulline

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16
Q

What cells take up the citrullinated atingen in the ACPA response?

A

Antigen presenting cells

17
Q

Which cells are activated by the APCs in the ACPA response?

A

T cells and B cells resulting in antibody production

18
Q

Immune complexes are formed from the antibodies produced by activated B cells. What is the effect of the immune complexes in the ACPA response?

A

Inflammation of the joint

Cycle of complexes forming perpetuates inflammation

19
Q

What is synovitis?

A

Inflammation of the synovium

20
Q

Describe 6 cellular features of synovitis

A
Villous hyperplasia
Infiltration of B cells, T cells
Macrophage and plasma cell activation
Intimal cell proliferation
Production of cytokines and proteases
Increased vascularity 

Self ampifying process

21
Q

What cell involvement is there in rheumatoid arthritis?

A

T cells and their cytokines
B cells and cytokines
Stromal cell cytokines
Inflammatory cytokines

22
Q

What is the effect of T-cell targeted treatment in RA?

A

Little effect
Low level of cytokines in Synovium
Activation of B cells and macrophages

23
Q

Name a T-cell targeted medication

A

Abatacept

24
Q

What is the effect of a B-cell targeted treatment in RA?

A

Very effective against pathogenic CD20 + Bcells

25
Q

What do B cells produce and what is the function of this product?

A

Autoantibodies
Autoantigen presentation
Cytokines - IL-6, TNF alpha

26
Q

Which stromal cell cytokines are abundant in the RA synovium?

A

Macrophage and fibroblast cytokines

27
Q

Which cells are activated by TLR and NLRs?

A

Macrophage (M1)

28
Q

What is the function of chemokines produced in RA synovium?

A

Recruit inflammatory cells

29
Q

Anti-inflammatory IL-10 is also present in the synovium. Why does inflammation still occur?

A

Not produced at high enough levels to offset the proinflammatory cytokines

30
Q

Functions of inflammatory cytokines (6)

A

Promote expression of endothelial cell adhesion molecules
Activate synovial fibroblasts, chondrocytes and osteoclasts
Promote angiogenesis
Suppress T-regs
Activate leukocytes
Promote autoantibody production

31
Q

Which 4 systemic effects are mediated by IL-6?

A

Anaemia
Acute phase response
Cognitive dysfunction
Lipid metabolism dysregulation

32
Q

Why is neoangiogenesis crucial in driving RA?

A

Nutrients provided to hyperplastic synovium

33
Q

How is blood vessel proliferation enhanced on Rheumatoid synovium?

A

Hypoxic conditions

IL8 and VEGF - Angiogenic factors

34
Q

Which 3 cells are responsible for destruction of bonee and cartilage in RA?

A

Osteoclasts
Synovial lining cells (particularly FLS)- can invade cartilage
FLS - produce proteases

35
Q

What is produced in the RA synovium to activate osteoclasts?

A

RANKL

36
Q

Systemic consequences of RA

A

Vasculitis, nodules, scleritis, amyloidosis
Cardiovascular disease
Fatigue, reduced cognitive function
Liver - elevated acute phase response, anaemia
Lung - Interstitial lung disease, fibrosis
Muscles - sarcopenia
Bone - osteoporosis
Secondary Sjrogen’s Syndrome

37
Q

How can RA induce cardiovascular disease?

A

Altered lipid metabolism
Elevated acute phase reactants
Increased endothelial activation

38
Q

How can RA induce anaemia?

A

IL6 increases hepatocyte production of hepcidin which regulates iron levels