Lecture 24 - Rheumatoid Arthritis Flashcards
(79 cards)
1
Q
Arthritis definition
A
Literally means ‘inflamed joint’
Umbrella term for over 100 joint-inflammation diseases
2
Q
Number of Australians suffering from arthritis in 2011-2012
A
~3.3 million
3
Q
Diseases causing 95% of arthritis cases
A
Osteoarthritis, rheumatoid arthritis, gout
4
Q
Cost of arthritis and musculoskeletal condition treatment in 2012
A
$55.1 bilion
5
Q
Rheumatoid arthritis
A
Chronic autoinflammatory disease of unknown aetiology
Associated with articular manifestations
6
Q
Synovitis
1)
2)
A
1) A primary manifestation of RA
2) Leads to erosion of bone cartilage and peri-articular structures
7
Q
Incidence
A
Number of cases diagnosed in a year
8
Q
Prevalence
A
Number of cases within a set period of time
9
Q
Incidence of RA in adult caucasian populations
A
8 to 98 cases/100,000 per year
10
Q
Prevalence of RA in adult caucasian populations
A
0.5-1%
11
Q
Which gender is more at risk of RA?
A
Females 2-3x more likely to develop RA than males
12
Q
Peak age of RA onset
A
40 years (40-70 year range)
13
Q
RA risk factors 1) 2) 3) 4)
A
1) Genetic
2) Epigenetic
3) Hormonal
4) Stochastic triggers
14
Q
Most powerful genetic factor in RA
A
HLA type
15
Q
HLA types most associated with RA
A
DRB1 gene of HLA2 locus
16
Q
DRB1 alleles associated with RA
A
DRB1 0401
DRB1 0404
17
Q
Amount that genetics contributes to RA susceptibility
A
~60%
18
Q
Proportion of genetic RA cases that are caused by HLA
A
12.7%
19
Q
Which chromosome is HLA locus on?
A
p arm of chromosome 6
20
Q
Aspect of HLA DRB1 that makes one more susceptible to RA
A
Encodes shared epitope
21
Q
What is the shared epitope? 1) 2) 3) 4)
A
1) Encoded by HLA DRB1
2) Glutamine-leucine-arginine-alanine-alanine motif
3) Occupies position 70-74 of HLA-DRbeta chain
4) Surrounds peptide binding groove
22
Q
Amino acid sequence of shared epitope
A
Glutamine-leucine-arginine-alanine-alanine
QKRAA
23
Q
How does the shared epitope contribute to RA? 1) 2) 3) 4) 5)
A
1) Efficiently binds citrullinated residues
2) Thymic expression of autoimmune cells (positive, negative selection)
3) Target for T cells (molecular mimicry, EG: EBV)
4) Marker of immunoreactivity (ACPA)
5) Polarises T cell differentiation to Th17
24
Q
ACPA
A
Anti-citrullinated protein antibodies
25
What can be inferred from the presence of shared epitope?
1)
2)
1) Doesn't necessarily predict RA
| 2) Could indicate severity of RA - With two copies, increases bone erosion, extra-articular manifestations
26
HLA-DRB1 RA odds ratio
4-5 fold increase
27
Gene that is a RA risk factor in Asian populations
PADI4
28
Gene that is a RA risk factor in caucasian populations
PTPN22
29
PTPN22
Encodes lymphoid tyrosine phosphatase
| RA risk factor in non-Asian populations
30
An explanation why shared epitope is not a RA risk factor in certain ethnic groups
Microchimerism
31
Microchimerism
Maternal cells of shared-epitope-expressing women persist in child's circulation throughout adulthood
Non-inherited maternal antigens
32
Epigenetic mechanisms that might contribute to RA susceptibility
1)
2)
3)
1) Increased levels of histone deacetylase in RA synovia
2) DNA methylation in fibroblast-like synoviocytes and T cells
3) MicroRNAs (regulate protein expression)
33
Hormonal risk factor in RA
Oestrogen exposure
34
How can oestrogen exposure contribute to RA susceptibility?
1)
2)
3)
1) Oestrogen makes B cells more resistant to apoptosis (even if B cell makes autoantibodies)
2) Fibroblast-like synoviocytes increase levels of metalloproteases
3) Macrophages increase production of TNFa
35
Effect of metalloproteases on RA
Damage synovium, bones, tendons
36
How is pregnancy a hormaonal risk factor in RA?
1)
2)
3)
1) 1st and second trimerster - Over 75% report improvement in RA
2) 3rd trimester - Remission
3) Postpartum - 90% flare
37
What is citrullination?
Post-translational conversion of arginine to citrulline.
Catalysed by peptidyl-arginine deiminase
38
How does citrullination contribute to RA?
1)
2)
3)
1) Citrullinated protein forms a neoepitope
2) Citrulline binds shared epitope more avidly
3) This can lead to autoimmune activation
39
PADI
Peptidyl-arginine deiminase
Converts arginine to citrulline
40
Is PADI expression specific to RA joint symptoms?
No
| Citrullination occurs in many different settings of tissue stress and inflammation
41
Number of human PADI isoforms
Four
42
Human PADI isoforms associated with RA
Isoforms 2 and 4 are abundant in inflamed synovium
43
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RA environmental factors
1)
2)
3)
4)
5)
```
1) Smoking
2) Bronchial stress
3) Infections
4) TLR activation
5) Microbiome
44
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Infections that can increase RA risk
1)
2)
3)
4)
5)
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1) Porphyromonas gingivalis
2) EBV
3) Cytomegalovirus
4) Proteus species
5) E coli
45
How can TLR activation lead to RA?
1)
2)
1) TLR activation can lead to increased peptidyl-arginine deiminase expression
2) TLR2 activation can directly lead to arthritis (EG: TLR2 activation by strep)
46
Contributors to synovitis in RA
Macrohpages and fibroblasts erode bone in joints
47
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Articular manifestations of RA
1)
2)
3)
4)
```
1) Pain
2) Morning stiffness (over an hour each morning, for over 6 weeks)
3) Swelling
4) Distribution
48
Distribution of affected joints in RA
1)
2) a,b,c
3) a
1) Symmetrical
2) Upper limb joints most affected
a) Metacarpolphalangeal (MCP)
b) Proximal interphalangeal (PIP)
c) Wrist
3) Lower limb joints most affected
a) Metatarsophalangeal (MTP)
49
Deformity caused by proximal interphalangeal swelling
Boutonierre deformity
50
Deformity caused by metacarpophalangeal swelling
Swan neck deformity, subluxation, ulnar deformity
51
Ulnar deformity
Bending of the hand towards ulna bone because of metacarpophalangeal swelling
52
Boutonierre deformity
Caused by proximal interphalangeal swelling
53
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Features by which to distinguish between RA and osteoarthritis
1)
2)
3)
4)
5)
6)
7)
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1) Age of onset
2) Predisposing factors
3) Early symptoms
4) Joints affected
5) Physical findings
6) Radiological findings
7) Lab findings
54
Difference between RA and OA in age of onset
RA onset is childhood, adulthood
OA risk increases with age
55
Difference between RA and OA in predisposing factors
RA - Susceptibility epitopes (HLA-DRB1)
| OA - Trauma, congenital abnormalities
56
Difference between RA and OA in early symptoms
RA - Morning stiffness
| OA - Pain increases during the day
57
Difference between RA and OA in physical findings
RA - Soft tissue swelling, warmth
| OA - Bony osteophytes (bony swelling), minimal soft tissue swelling early
58
Difference between RA and OA in lab findings
RA - Increased C-reactive protein, rheumatoid factor, anti-citrullinated protein antibodies
OA - Normal
59
Difference between RA and OA in affected joints
RA - Wrist, MCP, PIP, symmetry. Distal interphalangeal joint is almost always spared
OA - Distal interphalangeal joint, base of thumb. Can affect the lumbar spine
60
Ways to diagnose RA
1)
2)
1) Physical analysis
| 2) Presence of autoantibodies (RF, ACPA)
61
Rheumatoid factor
High-affinity autoantibody against Fc portion of IgG
Prior to RA onset, increases in IgM or IgA isotype of RH
62
Anti-citrullinated protein antibodies
1)
2)
1) Before onset of RA, increase in titre, avidity, epitope spreading, isotype change
2) Against citrullinated self proteins
63
Way to detect presence of anti-citrullinated protein antibodies
Anti-cyclic citrullinated peptide assay
64
Potential targets of anti-citrullinated protein antibodies
Alpha-enolase, keratin, fibrinogen, fibronectin, type II collaged, vimentin
65
How long before infection can autoantibodies appear?
Several years
Anti-citrullinated protein antibodies appear ~14 years before symptoms
IgM rheumatoid factor antibodies appear ~10 years before symptoms
66
SpIn
When a test has a high specificity (EG: over 95%), a positive result is taken as a diagnosis
67
SnNout
When a test has a high sensitivity, a negative result rules out a diagnosis
68
Positive likelihood ratio
Sensitivity/(1-specificity)
69
Negative likelihood ratio
(1-specificity)/sensitivity
70
IgM rheumatoid factor sensitivity
70%
71
ACPA specificity
95%
72
Positive likelihood ratio
Chance that a person with a condition will receive a positive result, compared to someone without the condition.
EG: ACPA has a positive likelihood ratio of 14.4, so someone with RA is 14.4x more likely to receive a positive result than someone without RA
73
Two subsets of RA
1) Seropositive for RF and ACPA
| 2) Seronegative
74
Implications of seropositive RA
More aggressive disease
| Worse radiographic impressions, extra-articular manifestations, functional impairment
75
DAS28 ESR calculator
1)
2)
1) Give scores for things such as joint soreness
| 2) Program calculates a score to measure severity of RA at time of testing
76
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Factors used to calculate DAS28 score
1)
2)
3)
4)
5)
```
1) Lab results (C-reactive protein, erythrocyte sedimentation rate)
2) Count of sore joints
3) Pain score
4) length of morning stiffness
5) Radiological damage
77
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Das28 cutoffs for either C-reactive protein or erythrocyte sedimentation rates
1)
2)
3)
4)
```
1) Remission - Under 2.6
2) Low - 2.6 - 3.2
3) Moderate - 3.2 - 5.1
4) High - Over 5.1
78
What can persist during clinical remission?
Subclinical inflammation, that can only be viewed using MRI or other imaging techniques
79
What can and can't autoantibodies be used to determine in RA?
Can be used to diagnose RA
| Can't be used to determine disease activity
