Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

BIOM30002 - M2M > Lecture 25 - Rheumatoid Arthritis - Introduction > Flashcards

Lecture 25 - Rheumatoid Arthritis - Introduction Flashcards

1
Q

How many different types of arthritis are there?

A

Over 100

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is the burden of arthritis?

A
  • approx. 3.3 million

* $55 billion spent

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is the definition of RA?

A

Chronic inflammatory autoimmune disease of unknown aetiology

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Describe the primary manifestation of RA

A 
Synovitis (synovial inflammation)
Erosion of:
 • Bone
 • Cartilage
 • Peri-articular structures
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is the incidence of RA?

A

0.5% - 1%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Is RA more common in males of females?

A

Females (2-3x more common)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is the age of onset of RA?

A

40-70 years

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is the central paradigm of autoimmune disease?

A

Genetic susceptibility + Environmental trigger
→ Breakdown of immune tolerance
→ Autoimmune disease

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Outline the categories of risk factors for RA

A
  • Genetic
  • Epigenetic
  • Hormonal
  • Environmental
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Describe the genetic risk factors for RA

A 
1. HLA class II
 • DRB1 gene, which encodes HLA-DR
 • Allelic variants
  1. non-HLA II
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What do twinning studies show about genetic risk of RA?

A

Genetics accounts for 50-60% of disease susceptibility

The remainder is due to other factors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

On which chromosome are the genes for HLA class II?

A

Chromosome 6, p arm

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Which alleles of HLA-DR predispose to RA?

A

HLA-DRB1* 0401

HLA-DRB1* 0404

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is the ‘shared epitope’?

What is its role in RA?

A

Five aa sequence: QKRAA
Present in the HLA-DR β chain
Surrounds the peptide binding groove; thus determining antigen presentation in the context of HLA II)

Role in RA:
• Efficient binding of arthritogenic peptides
• Thymic selection of autoimmune T cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are the proposed roles of the SE?

A

SE: Shared epitope

  • Target for T-cells (molecular mimicry)
  • Marker of immunoreactivity
  • Polarises T cell differentiation to Th17 (autoimmunity)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

List some non-HLA genetic risk factors for RA

A

There are many other genes that have been identified
e.g.
PTPN22:
• has a role in B and T cell signalling
• Carries a 2 fold risk of RA in caucasians

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What is microchimerism?

Give an example of it in RA

What is NIMA?

A

Microchimerism:
• the presence of a small number of cells that originate from another individual (usually the mother)
• Genetically distinct from the cells of the host individual
• The cells often come from the mother during gestation
• Maybe responsible for autoimmune disease, however the mechanisms are still unclear

In RA:
NIMA: Non-inherited maternal antigens

Persistence of maternal antigens in a child throughout life (from gestation)
These antigens are not ‘inherited’
Cells expressing SE from mother persist

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What is epigenetics?

A

Modification of chromosome that leads to altered gene expression without changes to the DNA sequence

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What are some epigenetic mechanisms seen in RA?

A
  1. Increased histone deacetylase
    •In fibroblasts
    → increased cell proliferation
  2. DNA methylation
    (suppression of gene expression)
    • In RA, there is an abnormal pattern of DNA methylation
    of genes associated with RA
  3. microRNAs
    • Pre-translational modification of genes thought to be associated with RA
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

List some hormonal risk factors for RA

A
  1. Oestrogen exposure
    → Thus women more prone to RA
  2. Pregnancy
    • High levels of Oestrogen and Progesterone (as well as IL-10)
    • Immune suppressive effect during pregnancy
    • Relapse postpartum
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Describe how oestrogen exposure predisposes to RA

A
  1. B cells
    • Eostrogen exposure makes them become more resistant to apoptosis
    • These are the cells that are producing the auto-antibodies
  2. Fibroblasts
    • Eostrogen exposure leads to increased metalloproteinase secretion
    → damage of joints
  3. TNF
    • Eostrogen exposure to macrophages increases their release of TNF
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Describe how pregnancy exposure predisposes to RA

A

In pregnancy there are high levels of Oestrogen and Progesterone

1st & 2nd trimester: > 75% of the women have improvement of RA

3rd trimester: remission
• Lots of oestrogen circulating

**(is oestrogen beneficial or harmful?)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What is Citrullination?

A

Post-translational conversion of arginine to citrulline by PADI enzymes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What is the function of PADI enzymes?

Where are they active (on a cellular level)?

A

Conversion of arginine to citrulline
Occurs post-translation

Active intra- or extracellularly

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What is the role of citrulline in RA?

A
  1. Citrulline binds the Shared Epitope (SE) more avidly
  2. Break down in tolerance
  3. Presence of anti-citrullinated protein Ab
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

What is ACPA?

What are some of its targets?

A

Anti–citrullinated protein antibody

Some targets:
 • α-enolase
 • Keratin
 • Fibrinogen
 • Fibronectin
 • Type II collagen
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

When is PADI expressed?

A

Not specific to joint or RA

Happens in many instances:
• Tissue stress
• Inflammation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

How many isoforms of PADI are there in humans?

Which are abundant in inflamed synovium?

A

There are four isoforms

Abundant in inflamed synovium:
• PADI -2
• PADI -4

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

What does PADI stand for?

A

Peptidyl-arginine deiminase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

Describe the citrullination reaction

A

Arginine → Citrulline

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

List some environmental risk factors for RA

A
  1. Smoking
    • increased PADI 2 expression
  2. Microbiome
  3. Infections
    • Epstein-barr virus (molecular mimicry)
    • Porphyromonas gingivitis (increased PADI4 expression)
  4. Bronchial stress
    • Exposure to silica
  5. TLR activation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

Describe the features of synovitis

A 
1. Inflammatory cell infiltration
 • Fibroblasts
 • Macrophages
 • Lymphocytes
 • Mast cells
  1. Vascular neogenesis
  2. Ectopic lymphoid neogenesis
  3. Synoviocyte neogenesis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

What are the articular manifestations of RA?

A
  • Pain
  • Morning stiffness
  • Swelling
34
Q

Which joints are most commonly affected by RA?

A
  • Metacarpophalangeal (MCP)
  • Proximal interphalangeal (PIP)
  • Wrist
  • Metatarsophalangeal (MTP)
  • Distal interphalangeal
35
Q 
Compare the following in Osteoarthritis and RA:
 • Age of onset
 • Predisposing factors
 • Symptoms
 • Joints involved
 • Symmetry
 • Swelling
A
  1. Age of onset:
    • OA: 65 +
    • RA: Childhood and adults, peak around 50
  2. Predisposing factors
    • OA: Injury, increased body mass,
    • RA: Genetics (HLA-D1, HLA-D4), Smoking
  3. Symptoms:
    • OA: Pain in moving joints
    • RA: Morning stiffness
  4. Joints involved:
    • OA: Hips, knees (weight bearing joints)
    • RA: metacarpophalangeal, wrist,
  5. Symmetry
    • OA: asymetrical
    • RA: symmetrical
  6. Swelling
    • OA: Bony swelling
    • RA: Soft tissue swelling
36
Q

Describe presence of nodules in RA

A
  • Subcutaneous (e.g. Achilles tendon nodules)
  • Pulmonary
  • Cardiac
37
Q

List pulmonary features of RA

A
  • Pleuritis
  • Pleural effusion
  • Fibrosing alveolitis
38
Q

List ocular manifestations of RA

A
  • Scleritis
  • Episcleritis
  • Keratoconjunctivitis sicca (KJS)
39
Q

List vascular manifestations of RA

A

Vasculitis:
• Systemic
• Cutaneous
• Mononeuritis multiplex

40
Q

List neurological manifestations of RA

A
  • Nerve entrapment

* Cervical myelopathy

41
Q

List cardiovascular manifestations of RA

A
  • Ischemic heart disease (IHD)
  • Pericarditis
  • Pericardial effusion
  • Conduction defects
  • Stroke
42
Q

List cutaneous manifestations of RA

A
  • Palmar erythema
  • Ulceration
  • Pyoderma gangrenous
  • Neutrophilic dermatoses
43
Q

List haematologic manifestations of RA

A
  • Anaemia
  • Felty’s syndrome
  • Amyloidosis
44
Q

List malignant manifestations in RA

A
  • Lymphoma
  • Lymphoproliferative disease
  • Large granular lymphocyte syndrome
  • Lung cancer
  • Skin cancer
45
Q

List the autoantibodies seen in RA
What are their specificities?

What is the role of these auto-Abs in RA?

Why are they helpful?

A
  1. Rheumatoid Factor (RF)
    • auto-Ab against Fc portion of IgG
  2. ACPA: Anti-citrullinated protein antigen
    • against citrullinated self proteins

Role in RA:
• Indicate break down in tolerance
• Not part of pathogenesis

Helpful:
• Diagnostic and Prognostic information about the disease
• Not part of treatment

46
Q

Are autoantibodies present before or after onset of RA?

A

Both: before and after

Auto-Ab can be present years before onset

47
Q

Compare sensitivity and specificity

A

Sensitivity: probability of true positive
• Probability of those who have the disease testing positive

Specificity: probably of true negative
• Probability of those who don’t have the disease testing negative

48
Q

What is the positive likelihood ratio?

A

Sensitivity ÷ (1 – specificity)

49
Q

How is RA diagnosed?

A

Detection of auto-Ab:
• IgM RF (rheumatoid factor)
• ACPA

50
Q

Compare sensitivity and specificity of the two auto-Ab tests

A
  1. IgM RF:
    • More sensitive
    • RF: 70
    • ACPA: 67
  2. ACPA:
    • More specific
    • RF: 79
    • ACPA: 95
51
Q

Which auto-Ab test has a higher Positive Likelihood Ratio?

Give the ratios for both

A

ACPA by a long way

ACPA: 14.4
IgM RF: 3.3

52
Q

What are the two ‘sero-‘ subsets of RA?

A
  1. Seropositive
    • RF / ACPA positive
  2. Seronegative
    • RF / ACPA negative
53
Q

How is RA disease activity assessed?

A
  1. Joint counts
    • Tender / swollen
    • with DAS28-ESR Calculator
  2. Global assessment
    • Physician
  3. Pain score
  4. Morning stiffness
  5. Laboratory
    • Erythrocyte sedimentation rate
    • C-reactive protein
  6. Disability
  7. Fatigue
  8. Radiological damage
54
Q

What is C-reactive protein?

A
  • Protein made by the liver
  • Levels rise during inflammation
  • Bind to dying or dead cells
  • Triggers C’ activation
  • Thus, role in clearing apoptotic or necrotic cells
55
Q

Describe the results given by DAS28

A

DAS28 score:

  1. < 2.6: remission
  2. 2.6-3.2: low disease activity
  3. 3.2-5.1: moderate disease activity
  4. > 5.1: high disease activity
56
Q

What may still be occurring in clinical remission?

A

Inflammation

In a certain subset of patients

57
Q

List some general extra-arthritic manifestations of RA

A
  • Nodules
  • Vasculitis
  • Neurological manifestations
  • Pulmonary manifestations
  • Cardiovascular manifestations
58
Q

What are 95% of cases of arthritis due to?

A
  • Osteoarthritis
  • RA
  • Gout
59
Q

Describe the structure of a synovial joint

A
  • Articular cartilage
  • Synovial fluid
  • Synovial membrane
  • Bone
  • Periosteum
60
Q

Which HLA gene is involved in RA?

A

HLA-DRB1

Allelic variants:
• 0401
• 0404

61
Q

Which molecule does the Shared Epitope bind very effectively?

A

Citrulline (a self peptide)

62
Q

Describe the results of twinning studies in the context of the contribution of smoking to RA

A

Twinning studies
• Mono-zygotic twins that were discordant for smoking and RA
• The twin who smokes is much more likely to develop RA

Mechanism:
• Smoking interacts with PADI2
• Contributes to the citrullination process

63
Q

Describe the effect of the Industrial revolution on RA

A

RA not observed before the industrial revolution

Some environmental antigen associated with the new Industries that leads to RA?

64
Q

Describe the role of EBV and molecular mimicry in RA

A

SE a target for auto-reactivity itself:
• Similar sequence on EBV peptides to the SE (Shared Epitope)
→ Cross reaction

65
Q

Discuss the risk factor of the Microbiome in RA

A

Studies:
• Germ free mice raised
• Certain bacteria given to mice
• Induction of RA in the mice

Conclusion:
• Certain bacteria may play a role in development of RA

66
Q

Compare pain in OA and RA

A

RA: morning pain
OA: pain progresses in severity throughout the day. Normally at its worst in the evenings

67
Q

Which joints are commonly affected in:
• OA
• RA

A 
1. OA
 • DIP
 • PIP
 • MCP
 • MTP
 • Wrist
2. OA
 • DIP: base of thumb
Weight bearing joints:
 • Hips
 • Knees
68
Q

What is the strength of ACPA Ab in diagnostics?

A

It is very specific:

i.e. not likely to give a false negative

69
Q

Describe how auto-Abs can be used as a prognostic tool

A

Seropositivity of seronegativity gives prognostic information:

Seropositivity indicates:
• Radiographic progression
• Extra-articular manifestations
• Functional impairment

70
Q

What are the parameters of DAS28?

A
  • Joint tenderness
  • Joint swelling
  • ESR (Erythrocyte sedimentation rate)
  • CRP
71
Q

What is clinical remission?

A

The disease is not cured, but the disease process has gone away for the moment

72
Q

What is the goal of treatment in RA?

A

Remission

73
Q

Which epigenetic modification is seen in the fibroblasts in the inflamed synovium in RA?
What can this lead to?

A

In fibroblasts: increased Histone deacetylase

Leads to increased proliferation

74
Q

What is the effect on gene expression of DNA methylation?

A

Silencing of the gene

75
Q

What is the role of metalloproteinases in RA?

A

Destruction of the joint:
• Bone
• Cartilage
• Tendons

76
Q

Describe the role of Porphyromonas gingivalis in RA

A
  • This is a pathogen
  • Affects the function of PADI 4
  • Thus, affects the citrullination process
77
Q

Describe the risk factor of TLR activation in RA

A
  • TLR activation leads to increased expression of PADI

* Increased citrullination

78
Q

Why is SE a good marker of immunoreactivity?

A

Leads to production of ACPA when it binds citrulline peptide

79
Q

What are some common deformities seen in RA?

Describe the position of the affected joints

A
  1. Boutonniere deformity
    • Flexion of PIP
    • Extension of DIP
  2. Swan neck deformity
    • Hyper-extension of PIP
    • Hyper-flexion of DIP
  3. Ulnar deviation
    • Phalanges subluxed from the MCP
    • Phalanges drift outwards
80
Q

What is actually responsible for the bone and cartilage damage in RA?

A

Matrix metalloproteinases and cytokines (TNF) released by activated synovial fibroblasts and macrophages, and Th17 cells.

TNF in inflamed synovium stimulates osteoclasts and inhibits osteoblasts –> bone destruction

The arthritogenic Abs observed in RA are not thought to play a pathogenic role

BIOM30002 - M2M (36 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions