Lecture 24 - Rheumatoid Arthritis Flashcards Preview

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Flashcards in Lecture 24 - Rheumatoid Arthritis Deck (79):
1

Arthritis definition

Literally means 'inflamed joint'
Umbrella term for over 100 joint-inflammation diseases

2

Number of Australians suffering from arthritis in 2011-2012

~3.3 million

3

Diseases causing 95% of arthritis cases

Osteoarthritis, rheumatoid arthritis, gout

4

Cost of arthritis and musculoskeletal condition treatment in 2012

$55.1 bilion

5

Rheumatoid arthritis

Chronic autoinflammatory disease of unknown aetiology
Associated with articular manifestations

6

Synovitis
1)
2)

1) A primary manifestation of RA
2) Leads to erosion of bone cartilage and peri-articular structures

7

Incidence

Number of cases diagnosed in a year

8

Prevalence

Number of cases within a set period of time

9

Incidence of RA in adult caucasian populations

8 to 98 cases/100,000 per year

10

Prevalence of RA in adult caucasian populations

0.5-1%

11

Which gender is more at risk of RA?

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

12

Peak age of RA onset

40 years (40-70 year range)

13

RA risk factors
1)
2)
3)
4)

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

14

Most powerful genetic factor in RA

HLA type

15

HLA types most associated with RA

DRB1 gene of HLA2 locus

16

DRB1 alleles associated with RA

DRB1 0401
DRB1 0404

17

Amount that genetics contributes to RA susceptibility

~60%

18

Proportion of genetic RA cases that are caused by HLA

12.7%

19

Which chromosome is HLA locus on?

p arm of chromosome 6

20

Aspect of HLA DRB1 that makes one more susceptible to RA

Encodes shared epitope

21

What is the shared epitope?
1)
2)
3)
4)

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

Amino acid sequence of shared epitope

Glutamine-leucine-arginine-alanine-alanine
QKRAA

23

How does the shared epitope contribute to RA?
1)
2)
3)
4)
5)

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

ACPA

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

RA environmental factors
1)
2)
3)
4)
5)

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

44

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

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

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

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

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

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

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