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Molecule to Malady > RA - L1 > Flashcards

RA - L1 Flashcards

1
Q

What is RA?

A

Chronic inflammatory autoimmune disease

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2
Q

Incidence & Prevelance

A

8-98/100,00 per annum
0.5 to 1%
1-3x more common in females

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3
Q

Principles of Autoimmune Disease

A

Genetic Susceptibility + Environmental Trigger

leads to break down of immune tolerance (self reactive anitbody or T cells)

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4
Q

Risk Factors

A 
Genetics - 50-60%
    HLA - 12.7%
    Non-HLA - 4%
Epigenetic
Hormonal
(Citrullination)
Stochastic Environmental Triggers
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5
Q

What is HLA?

A

Region of genes at 6p21.31 that are involved in encoding cell surface molecules (antigen presenting molecules) and proteins involved in immune function

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6
Q

What HLA gene is susceptible?

A

HLA Class II
DRB1 gene
variants DRB1 *0401 & DRB1 *0404

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7
Q

What is the shared epitope?

A

The five amino acid sequence that the HLA-DRB1 alleles encode
QKRAA
positions 70-74 of the beta chain
surrounds peptide binding groove (determines antigen binding specificity & CD4 presentation)

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8
Q

What is the significance of the shared epitope?

A

It is shared by all the DRB1 alleles that have been implicated in RA and is not found in other DRB1 alleles, is said to cause the disease

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9
Q

Proposed roles of shared epitope?

A

Marker of Immunoreactivity (ACPA)
Efficient binding of arthritogenic (citrulline) peptides
Thymic selection of autoimmune T cells
Target for T cell
Polarises T cell differentiation to TH17 type

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10
Q

Is SE a good predictor is disease severity?

A

Yes, but not a good predictor of disease progression

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11
Q

What is microchimerism?

A

The state where maternally-derived cells persist in the offspring

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12
Q

What is the relevance of microchimerism?

A

May explain variability of RA. T cells from mother expressing SE may have survived in the offspring. Can also work in reverse, non-inherited maternal anitgens (NIMA)

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13
Q

What are non-HLA risk factors?

A

PTPN22
gene coding for a tyrosine phosphatase found in lympoid tissue that is involved in B and T cell signalling (non Asians)
PADI4
asians

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14
Q

What is epigenetics?

A

modification of a chromosome that leads to altered gene expression, without changing DNA

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15
Q

What are some epigenetic mechanisms?

A

Histone deacetylase increased in RA
DNA methylation
microRNAs
all involved in down regulation or silencing of gene expression

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16
Q

What are some hormonal risk factors?

A 
oestrogen exposure
   B cells more resistant to apoptosis
   FLS produce metalloproteinases and cause bone degradation
   bind macrophages and they secrete TNF
pregnancy
17
Q

What is citrullination?

A

the post-translational conversion of arginine (+ve charge) to citrulline (no charge) by peptidyl-arginine deiminase (PADI) enzymes

18
Q

Why is citrullination relevant?

A

new tertiary structure, autoimmune response
citrulline binds SE more avidly
leads to immune tolerance breakdown –> ACPA increased

19
Q

What isoforms of PADI do humans have?

A

Four

PADI2 & PADI4 abundant in inflamed synovium

20
Q

What are some stochastic triggers? (~40%)

A

new world pathogen
smoking (PADI2)
bronchiol stress
microbiome

21
Q

What are the articular manifestations of RA?

A

pain
swelling
morning stiffness
symmetrical distribution

22
Q

What joints are affected in RA and what are there deformities?

A 
Upper limbs
MCP - swan neck deformity
PIP - Boutonniere deformity
wrist
Lower limbs
MTP
23
Q

What are some extra-articular manifestations?

A 
nodules
pulmonary
ocular
vasulitis
neurological
cardivascular
cutaneous
malignancy
24
Q

How is RA diagnosed?

A

X-ray then blood work

25
Q

What antibodies are looked for in diagnosis?

A

Rheumatoid factor and ACPA

antibodies develop before symptoms present

26
Q

What is RF?

A

a high affinity antibody against the Fc portion of IgG

27
Q

What is sensitivity?

A

patients with the disease that test positive

A/(A+C)

28
Q

What is specificity?

A

patients without the disease that have a negative result

D/(B+D)

29
Q

What is the positive likelihood ratio?

A

true positives / false positives (high the better)

30
Q

What is the negative likelihood ratio?

A

false negatives / true negatives (smaller the better)

31
Q

How to RF and ACPA compare?

A

RF more sensitive
ACPA more specific
ACPA better PLR

32
Q

What are the ACR/EULAR classification criteria?

A

joint involvement
serology (RF & CCP)
acute phase reactants (CRP & ESR)
duration of symptoms

greater than 6 = RA

33
Q

How is severity of RA assessed?

A

DAS28-ESR Calculator

34
Q

What does the DAS28-ESR consider?

A 
joint counts
global assessment
pain score
morning stiffness
laboratory (ESR & CRP)
disability
fatigue
radiologica damage
35
Q

What are the DAS28-ESR thresholds?

A

5.1: high disease activity

36
Q

What are the differences between RA & osteoarthritis?

A 
age at onset
predisposing factors
early symptoms
joints involved
physical findings
radiological findings
laboratory findings

Molecule to Malady (29 decks)

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