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Molecule to Malady > Lecture 24 - Rheumatoid Arthritis > Flashcards

Lecture 24 - Rheumatoid Arthritis Flashcards

1
Q

Arthritis definition

A

Literally means ‘inflamed joint’

Umbrella term for over 100 joint-inflammation diseases

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2
Q

Number of Australians suffering from arthritis in 2011-2012

A

~3.3 million

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3
Q

Diseases causing 95% of arthritis cases

A

Osteoarthritis, rheumatoid arthritis, gout

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4
Q

Cost of arthritis and musculoskeletal condition treatment in 2012

A

$55.1 bilion

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5
Q

Rheumatoid arthritis

A

Chronic autoinflammatory disease of unknown aetiology

Associated with articular manifestations

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6
Q

Synovitis
1)
2)

A

1) A primary manifestation of RA

2) Leads to erosion of bone cartilage and peri-articular structures

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7
Q

Incidence

A

Number of cases diagnosed in a year

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8
Q

Prevalence

A

Number of cases within a set period of time

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9
Q

Incidence of RA in adult caucasian populations

A

8 to 98 cases/100,000 per year

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10
Q

Prevalence of RA in adult caucasian populations

A

0.5-1%

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11
Q

Which gender is more at risk of RA?

A

Females 2-3x more likely to develop RA than males

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12
Q

Peak age of RA onset

A

40 years (40-70 year range)

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13
Q 
RA risk factors
1)
2)
3)
4)
A

1) Genetic
2) Epigenetic
3) Hormonal
4) Stochastic triggers

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14
Q

Most powerful genetic factor in RA

A

HLA type

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15
Q

HLA types most associated with RA

A

DRB1 gene of HLA2 locus

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16
Q

DRB1 alleles associated with RA

A

DRB1 0401

DRB1 0404

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17
Q

Amount that genetics contributes to RA susceptibility

A

~60%

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18
Q

Proportion of genetic RA cases that are caused by HLA

A

12.7%

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19
Q

Which chromosome is HLA locus on?

A

p arm of chromosome 6

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20
Q

Aspect of HLA DRB1 that makes one more susceptible to RA

A

Encodes shared epitope

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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

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22
Q

Amino acid sequence of shared epitope

A

Glutamine-leucine-arginine-alanine-alanine

QKRAA

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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

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24
Q

ACPA

A

Anti-citrullinated protein antibodies

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25
Q

What can be inferred from the presence of shared epitope?
1)
2)

A

1) Doesn’t necessarily predict RA

2) Could indicate severity of RA - With two copies, increases bone erosion, extra-articular manifestations

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26
Q

HLA-DRB1 RA odds ratio

A

4-5 fold increase

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27
Q

Gene that is a RA risk factor in Asian populations

A

PADI4

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28
Q

Gene that is a RA risk factor in caucasian populations

A

PTPN22

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29
Q

PTPN22

A

Encodes lymphoid tyrosine phosphatase

RA risk factor in non-Asian populations

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30
Q

An explanation why shared epitope is not a RA risk factor in certain ethnic groups

A

Microchimerism

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31
Q

Microchimerism

A

Maternal cells of shared-epitope-expressing women persist in child’s circulation throughout adulthood

Non-inherited maternal antigens

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32
Q

Epigenetic mechanisms that might contribute to RA susceptibility
1)
2)
3)

A

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
Q

Hormonal risk factor in RA

A

Oestrogen exposure

34
Q

How can oestrogen exposure contribute to RA susceptibility?
1)
2)
3)

A

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
Q

Effect of metalloproteases on RA

A

Damage synovium, bones, tendons

36
Q

How is pregnancy a hormaonal risk factor in RA?
1)
2)
3)

A

1) 1st and second trimerster - Over 75% report improvement in RA
2) 3rd trimester - Remission
3) Postpartum - 90% flare

37
Q

What is citrullination?

A

Post-translational conversion of arginine to citrulline.

Catalysed by peptidyl-arginine deiminase

38
Q

How does citrullination contribute to RA?
1)
2)
3)

A

1) Citrullinated protein forms a neoepitope
2) Citrulline binds shared epitope more avidly
3) This can lead to autoimmune activation

39
Q

PADI

A

Peptidyl-arginine deiminase

Converts arginine to citrulline

40
Q

Is PADI expression specific to RA joint symptoms?

A

No

Citrullination occurs in many different settings of tissue stress and inflammation

41
Q

Number of human PADI isoforms

A

Four

42
Q

Human PADI isoforms associated with RA

A

Isoforms 2 and 4 are abundant in inflamed synovium

43
Q 
RA environmental factors
1)
2)
3)
4)
5)
A

1) Smoking
2) Bronchial stress
3) Infections
4) TLR activation
5) Microbiome

44
Q 
Infections that can increase RA risk
1)
2)
3)
4)
5)
A

1) Porphyromonas gingivalis
2) EBV
3) Cytomegalovirus
4) Proteus species
5) E coli

45
Q

How can TLR activation lead to RA?
1)
2)

A

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
Q

Contributors to synovitis in RA

A

Macrohpages and fibroblasts erode bone in joints

47
Q 
Articular manifestations of RA
1)
2)
3)
4)
A

1) Pain
2) Morning stiffness (over an hour each morning, for over 6 weeks)
3) Swelling
4) Distribution

48
Q

Distribution of affected joints in RA
1)
2) a,b,c
3) a

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
Q

Deformity caused by proximal interphalangeal swelling

A

Boutonierre deformity

50
Q

Deformity caused by metacarpophalangeal swelling

A

Swan neck deformity, subluxation, ulnar deformity

51
Q

Ulnar deformity

A

Bending of the hand towards ulna bone because of metacarpophalangeal swelling

52
Q

Boutonierre deformity

A

Caused by proximal interphalangeal swelling

53
Q 
Features by which to distinguish between RA and osteoarthritis 
1)
2)
3)
4)
5)
6)
7)
A

1) Age of onset
2) Predisposing factors
3) Early symptoms
4) Joints affected
5) Physical findings
6) Radiological findings
7) Lab findings

54
Q

Difference between RA and OA in age of onset

A

RA onset is childhood, adulthood

OA risk increases with age

55
Q

Difference between RA and OA in predisposing factors

A

RA - Susceptibility epitopes (HLA-DRB1)

OA - Trauma, congenital abnormalities

56
Q

Difference between RA and OA in early symptoms

A

RA - Morning stiffness

OA - Pain increases during the day

57
Q

Difference between RA and OA in physical findings

A

RA - Soft tissue swelling, warmth

OA - Bony osteophytes (bony swelling), minimal soft tissue swelling early

58
Q

Difference between RA and OA in lab findings

A

RA - Increased C-reactive protein, rheumatoid factor, anti-citrullinated protein antibodies
OA - Normal

59
Q

Difference between RA and OA in affected joints

A

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
Q

Ways to diagnose RA
1)
2)

A

1) Physical analysis

2) Presence of autoantibodies (RF, ACPA)

61
Q

Rheumatoid factor

A

High-affinity autoantibody against Fc portion of IgG

Prior to RA onset, increases in IgM or IgA isotype of RH

62
Q

Anti-citrullinated protein antibodies
1)
2)

A

1) Before onset of RA, increase in titre, avidity, epitope spreading, isotype change
2) Against citrullinated self proteins

63
Q

Way to detect presence of anti-citrullinated protein antibodies

A

Anti-cyclic citrullinated peptide assay

64
Q

Potential targets of anti-citrullinated protein antibodies

A

Alpha-enolase, keratin, fibrinogen, fibronectin, type II collaged, vimentin

65
Q

How long before infection can autoantibodies appear?

A

Several years
Anti-citrullinated protein antibodies appear ~14 years before symptoms
IgM rheumatoid factor antibodies appear ~10 years before symptoms

66
Q

SpIn

A

When a test has a high specificity (EG: over 95%), a positive result is taken as a diagnosis

67
Q

SnNout

A

When a test has a high sensitivity, a negative result rules out a diagnosis

68
Q

Positive likelihood ratio

A

Sensitivity/(1-specificity)

69
Q

Negative likelihood ratio

A

(1-specificity)/sensitivity

70
Q

IgM rheumatoid factor sensitivity

A

70%

71
Q

ACPA specificity

A

95%

72
Q

Positive likelihood ratio

A

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
Q

Two subsets of RA

A

1) Seropositive for RF and ACPA

2) Seronegative

74
Q

Implications of seropositive RA

A

More aggressive disease

Worse radiographic impressions, extra-articular manifestations, functional impairment

75
Q

DAS28 ESR calculator
1)
2)

A

1) Give scores for things such as joint soreness

2) Program calculates a score to measure severity of RA at time of testing

76
Q 
Factors used to calculate DAS28 score
1)
2)
3)
4)
5)
A

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
Q 
Das28 cutoffs for either C-reactive protein or erythrocyte sedimentation rates
1)
2)
3)
4)
A

1) Remission - Under 2.6
2) Low - 2.6 - 3.2
3) Moderate - 3.2 - 5.1
4) High - Over 5.1

78
Q

What can persist during clinical remission?

A

Subclinical inflammation, that can only be viewed using MRI or other imaging techniques

79
Q

What can and can’t autoantibodies be used to determine in RA?

A

Can be used to diagnose RA

Can’t be used to determine disease activity

Molecule to Malady (35 decks)

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