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102- Theme 1 > RA Symposium > Flashcards

RA Symposium Flashcards

1
Q

What is the goal of RA treatment/

A

Inflammation naturally fluctuates over time, the goal of treatment is to restore natural natural fluctuations below threshold

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2
Q

Describe the key characteristics of RA

What?Who?Where?,Impact?

A
  • Inflammation of synovial joints, systemic signs
  • 3:1 women, aged 40-50, affects 1% of population
  • most common, PIP, MCP, wrist
  • Increased mortality, reduced quality of life, disability
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3
Q

State three systemic signs of RA along with the cytokine associated

A
  • Low bone density, fractures (TNFa, RANKL)
  • Atherosclerosis, MI, stroke (IL6, complement, TNFa)
  • Insulin resistance (TNFa, IL1)
  • Low stress tolerance, depression (TNFa, IL1, IL6)
  • Acute phase response (CRP), iron distribution (hepcidin) (IL6)
    (Lipid particles altered, pro inflammatory HDL phenotype, total cholesterol decreased, small HDL increased)
  • Free fatty acid adipocytokines (TNFa, IL6)
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4
Q

Describe the joint damage in RA

A
  • symmetrical
  • morning stiffness
  • swelling
  • heat
  • pain
  • loss of function
  • redness
  • destruction process produces bone erosion and synovial and cartilage damage
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5
Q

What is synovitis?

A
  • swelling over extensor tendons, wrist and MCP joints
  • synovium hyperplasia and synovial fibroblasts have reduced apoptosis, enhanced anchorages, unregulated adhesion molecules and increased proliferation
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6
Q

Describe the differences between a normal joint and a rheumatoid joint

A 
Pannus - inflamed synovial membrane
Synovial fluid rich in neutrophils
Synovitis
Cartilage erosion
Bone erosion
Cartilage loss
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7
Q

What is the composition of synovial tissue in RA?

A
  • ACTIVATED T lymphocytes (40%)
  • macrophages (40%)
  • B lymphocytes and plasma cells (5%)
  • Fibroblasts and endothelial cells (10-15%)
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8
Q

Which immune component is key to RA?

How does this reflect in clinical practice?

A
  • Macrophages
  • Key effectors: phagocytosis, APC, cytokine production- TNF, IL1, IL6
  • Most therapies decrease macrophage cytokine production
  • Decreased macrophage infiltration strongly correlates with the degree of clinical improvement to therapies
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9
Q

Which pro inflammatory cytokines cause disequilibrium of inflammation

A

IL1
IL6
IL17

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10
Q

What is the role of IL17 in RA

A

Known to activate synovial fibroblasts and osteoclasts and favour cartilage resorption

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11
Q

Which immune cell is enriched in RA and defected in a way that can be blocked by TNF

A

Treg

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12
Q

What is the role of B cells in RA

A
  • make autoantibodies present before onset of symptoms
  • they form diffuse or follicular infiltrates in the RA synovium
  • depletion of B cells using monoclonal anti-CD20 is an effective treatment
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13
Q

Describe the cartilage erosion in RA

A
  • fibroblasts make MMPs which break down the collagen network in the cartilage
  • chondrocytes undergo apoptosis
  • fibroblasts adhere to and evade the cartilage
  • leads to biomechanical dysfunction and joint space narrowing
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14
Q

Which cytokines promote osteoclast differentiation and activation?

A
  • IL17
  • RANKL
  • TNFa
  • IL6
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15
Q

Describe the impact on bone physiology in RA?

A
  • Deep bone resorption pits develop, which become filled with inflammatory tissue
  • worse at mechanically vulnerable sites e.g. 2nd/3rd metacarpal
  • Little repair as cytokines inhibit differentiation of osteoblasts
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16
Q

Rheumatoid factors is a clinical marker

  • What is it?
  • Distribution in RA pop
  • Clinical relevance
A
  • AB against Fc of another AB –> immune complex formation
  • 60-70% patients
  • ## Non specific, present in other AID and in healthy people. Some RA patients are seronegative
  • Levels do not correlate with disease activity
  • RF positive have a more severe disease
17
Q

CCP anitbody is a clinical marker

  • Distribution in RA pop
  • Clinical relevance
A
  • 60-70% patients
  • High specificity
  • Detectable in blood many years before clinical onset
18
Q

What is citrullination

A
  • Process of replacing protein arginine residues with citrulline residues
  • If it occurs on an unusual part of protein it may be recognised as foreign e.g. of citrullinated self protein: a-enolase, keratin, fibrinogen, fibronectin, collagen and vimentin
19
Q

How might anti-CCP antibodies be considered pathogenic?

A
  1. Activation of inflammatory cells by anti-CCP immune complexes
  2. Anti-CCP mediated neutrophil cell death producing NETs
  3. Direct binding of anti-CCPs to drive osteoclastogenesis
20
Q

Consider the aetiology of RA

Polymorphisms are associated with RA. What is the role of HLA DRB1 SE?

A

Human leukocyte antigen, account for 30-50% of the overall genetic risk

21
Q

Consider the aetiology of RA

Polymorphisms are associated with RA. What is the role of PTPN22?

A

Regulates T cell activation

22
Q

Consider the aetiology of RA

Polymorphisms are associated with RA. What is the role of CTLA4?

A

Co stimulation suppressor that regulates interactions between T cells and APCs

23
Q

Consider the aetiology of RA

Polymorphisms are associated with RA. What is the role of STAT4?

A

Transducer of cytokine signals that regulates proliferation, survival and differentiation of lymphocytes

24
Q

Consider the aetiology of RA

Polymorphisms are associated with RA. What is the role of TRAF1?

A

Regulator of TNFa receptor superfamily signalling

25
Q

Consider the aetiology of RA

What can be said about the genetics of RA?

A
  • Weak genetic component, monozygotic twins 12-15% concordance
  • Carrying a risk gene doesn’t mean you will develop disease (epigenetic cause)
  • Genes have a low penetrance
26
Q

Consider the aetiology of RA

How is testosterone involved?
How is pregnancy involved?

A
  • Testosterone is considered to protect against AID….men who get RA usually have low testosterone levels
  • Risk of developing RA is increased during the period just after giving birth, breast feeding after the first pregnancy
  • RA patients often experience remission during pregnancy (less disease activity and have increased numbers of Treg)
  • risk of developing RA after menopause is not influences by hormone replacement therapy
27
Q

Consider the aetiology of RA

What is the role of smoking

A
  • Heavy smoking of both sexes increases the risk of RA amongst persons with susceptibility HLA DR4 alleles
  • HLA DRB1+ most susceptible if smoked and increases risk of being anti CCP+
  • TCDD in cigarette smoke has been shown to activate synovial fibroblasts to induces pro inflammatory cytokines
28
Q

Consider the aetiology of RA

Which infections are associated with RA

A 
Human parvovirus B19
Human retrovirus 5
Alphaviruses 
Hepatitis
Chronic hepatitis C
EBV
Mycoplasma
Ecoli
Rubella
Porphyromonas gingivitis- found in gums causing periodontitis by causing citrullinisation

102- Theme 1 (10 decks)

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