Lecture 25 - Rheumatoid Arthritis - Introduction Flashcards Preview

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Flashcards in Lecture 25 - Rheumatoid Arthritis - Introduction Deck (80):
1

How many different types of arthritis are there?

Over 100

2

What is the burden of arthritis?

• approx. 3.3 million
• $55 billion spent

3

What is the definition of RA?

Chronic inflammatory autoimmune disease of unknown aetiology

4

Describe the primary manifestation of RA

Synovitis (synovial inflammation)
Erosion of:
• Bone
• Cartilage
• Peri-articular structures

5

What is the incidence of RA?

0.5% - 1%

6

Is RA more common in males of females?

Females (2-3x more common)

7

What is the age of onset of RA?

40-70 years

8

What is the central paradigm of autoimmune disease?

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

9

Outline the categories of risk factors for RA

• Genetic
• Epigenetic
• Hormonal
• Environmental

10

Describe the genetic risk factors for RA

1. HLA class II
• DRB1 gene, which encodes HLA-DR
• Allelic variants

2. non-HLA II

11

What do twinning studies show about genetic risk of RA?

Genetics accounts for 50-60% of disease susceptibility

The remainder is due to other factors

12

On which chromosome are the genes for HLA class II?

Chromosome 6, p arm

13

Which alleles of HLA-DR predispose to RA?

HLA-DRB1* 0401
HLA-DRB1* 0404

14

What is the 'shared epitope'?

What is its role in RA?

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

15

What are the proposed roles of the SE?

SE: Shared epitope

• Target for T-cells (molecular mimicry)
• Marker of immunoreactivity
• Polarises T cell differentiation to Th17 (autoimmunity)

16

List some non-HLA genetic risk factors for RA

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

17

What is microchimerism?

Give an example of it in RA

What is NIMA?

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

18

What is epigenetics?

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

19

What are some epigenetic mechanisms seen in RA?

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

20

List some hormonal risk factors for RA

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

21

Describe how oestrogen exposure predisposes to RA

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

22

Describe how pregnancy exposure predisposes to RA

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?)

23

What is Citrullination?

Post-translational conversion of arginine to citrulline by PADI enzymes

24

What is the function of PADI enzymes?

Where are they active (on a cellular level)?

Conversion of arginine to citrulline
Occurs post-translation

Active intra- or extracellularly

25

What is the role of citrulline in RA?

1. Citrulline binds the Shared Epitope (SE) more avidly
2. Break down in tolerance
3. Presence of anti-citrullinated protein Ab

26

What is ACPA?

What are some of its targets?

Anti–citrullinated protein antibody

Some targets:
• α-enolase
• Keratin
• Fibrinogen
• Fibronectin
• Type II collagen

27

When is PADI expressed?

Not specific to joint or RA

Happens in many instances:
• Tissue stress
• Inflammation

28

How many isoforms of PADI are there in humans?
Which are abundant in inflamed synovium?

There are four isoforms

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

29

What does PADI stand for?

Peptidyl-arginine deiminase

30

Describe the citrullination reaction

Arginine → Citrulline

31

List some environmental risk factors for RA

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

32

Describe the features of synovitis

1. Inflammatory cell infiltration
• Fibroblasts
• Macrophages
• Lymphocytes
• Mast cells

2. Vascular neogenesis

3. Ectopic lymphoid neogenesis

4. Synoviocyte neogenesis

33

What are the articular manifestations of RA?

• Pain
• Morning stiffness
• Swelling

34

Which joints are most commonly affected by RA?

• Metacarpophalangeal (MCP)
• Proximal interphalangeal (PIP)
• Wrist
• Metatarsophalangeal (MTP)
• Distal interphalangeal

35

Compare the following in Osteoarthritis and RA:
• Age of onset
• Predisposing factors
• Symptoms
• Joints involved
• Symmetry
• Swelling

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

Describe presence of nodules in RA

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

37

List pulmonary features of RA

• Pleuritis
• Pleural effusion
• Fibrosing alveolitis

38

List ocular manifestations of RA

• Scleritis
• Episcleritis
• Keratoconjunctivitis sicca (KJS)

39

List vascular manifestations of RA

Vasculitis:
• Systemic
• Cutaneous
• Mononeuritis multiplex

40

List neurological manifestations of RA

• Nerve entrapment
• Cervical myelopathy

41

List cardiovascular manifestations of RA

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

42

List cutaneous manifestations of RA

• Palmar erythema
• Ulceration
• Pyoderma gangrenous
• Neutrophilic dermatoses

43

List haematologic manifestations of RA

• Anaemia
• Felty's syndrome
• Amyloidosis

44

List malignant manifestations in RA

• Lymphoma
• Lymphoproliferative disease
• Large granular lymphocyte syndrome
• Lung cancer
• Skin cancer

45

List the autoantibodies seen in RA
What are their specificities?

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

Why are they helpful?

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

Are autoantibodies present before or after onset of RA?

Both: before and after

Auto-Ab can be present years before onset

47

Compare sensitivity and specificity

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

What is the positive likelihood ratio?

Sensitivity ÷ (1 – specificity)

49

How is RA diagnosed?

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

50

Compare sensitivity and specificity of the two auto-Ab tests

1. IgM RF:
• More sensitive
• RF: 70
• ACPA: 67

2. ACPA:
• More specific
• RF: 79
• ACPA: 95

51

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

Give the ratios for both

ACPA by a long way

ACPA: 14.4
IgM RF: 3.3

52

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

1. Seropositive
• RF / ACPA positive

2. Seronegative
• RF / ACPA negative

53

How is RA disease activity assessed?

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

What is C-reactive protein?

• 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

Describe the results given by DAS28

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

What may still be occurring in clinical remission?

Inflammation

In a certain subset of patients

57

List some general extra-arthritic manifestations of RA

• Nodules
• Vasculitis
• Neurological manifestations
• Pulmonary manifestations
• Cardiovascular manifestations

58

What are 95% of cases of arthritis due to?

• Osteoarthritis
• RA
• Gout

59

Describe the structure of a synovial joint

• Articular cartilage
• Synovial fluid
• Synovial membrane
• Bone
• Periosteum

60

Which HLA gene is involved in RA?

HLA-DRB1

Allelic variants:
• 0401
• 0404

61

Which molecule does the Shared Epitope bind very effectively?

Citrulline (a self peptide)

62

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

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

Describe the effect of the Industrial revolution on RA

RA not observed before the industrial revolution

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

64

Describe the role of EBV and molecular mimicry in RA

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

65

Discuss the risk factor of the Microbiome in RA

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

Compare pain in OA and RA

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

67

Which joints are commonly affected in:
• OA
• RA

1. OA
• DIP
• PIP
• MCP
• MTP
• Wrist

2. OA
• DIP: base of thumb
Weight bearing joints:
• Hips
• Knees

68

What is the strength of ACPA Ab in diagnostics?

It is very specific:
i.e. not likely to give a false negative

69

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

Seropositivity of seronegativity gives prognostic information:

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

70

What are the parameters of DAS28?

• Joint tenderness
• Joint swelling
• ESR (Erythrocyte sedimentation rate)
• CRP

71

What is clinical remission?

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

72

What is the goal of treatment in RA?

Remission

73

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

In fibroblasts: increased Histone deacetylase

Leads to increased proliferation

74

What is the effect on gene expression of DNA methylation?

Silencing of the gene

75

What is the role of metalloproteinases in RA?

Destruction of the joint:
• Bone
• Cartilage
• Tendons

76

Describe the role of Porphyromonas gingivalis in RA

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

77

Describe the risk factor of TLR activation in RA

• TLR activation leads to increased expression of PADI
• Increased citrullination

78

Why is SE a good marker of immunoreactivity?

Leads to production of ACPA when it binds citrulline peptide

79

What are some common deformities seen in RA?
Describe the position of the affected joints

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

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

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