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Year 3: Block 1: MSK system > Rheumatoid arthritis: The science > Flashcards

Rheumatoid arthritis: The science Flashcards

1
Q

Features of a rheumatoid joint? (4)

A
  • erosion into corner of bone
  • thinning of cartilage
  • inflamed synovial - spreads across joint surface
  • inflamed tendon sheath
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2
Q

Define Rheumatoid arthritis

A

chronic symmetric polyarticular inflammatory joint disease, which primarily affects the small joints of the hands and feet

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3
Q

The rheumatoid synovitis (pannus) is characterised by ?

A

inflammatory cell infiltration, synoviocyte proliferation and neoangiogenesis

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4
Q

What does the joint cavity contain?

A

synovial fluid

- neutrophils, particularly during acute flares of RA

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5
Q

What causes bone and cartilage destruction (deformities)?

A

synovial pannus

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6
Q

What can be present in RA many years before the onset of clinical arthritis?

A

Auto immunity

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7
Q

what Autoantibodies are are commonly associated with RA (2)

A

as RFs and anti-citrullinated protein antibodies

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8
Q

When do autoantibodies occur in RA?

A

When either joint antigens, such as type II collagen, or systemic antigens, such as glucose phosphate isomerase are recognised

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9
Q

Describe features of seropositive RA? - what antibody is circulated?

A

Rheumatoid factor
Anti-citrullinated protein antibody (ACPA)
Diagnostic anti-CCP assays recognise citrullinated self-proteins
α-enolase, keratin, fibrinogen, fibronectin, collagen, vimentin

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10
Q

Patients who have what antibody of seropositive RA will have a ..?

A

ACPA+ disease
(Anti-citrullinated protein antibody (ACPA)

A less favourable diagnosis

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11
Q

2 types of autoantibody production ?

A

Seropositive rheumatoid arthritis

Seronegative rheumatoid arthritis

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12
Q

What is rheumatoid factor a auto-antibody to ?

A

self IgG Fc

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13
Q

What plays a key role in susceptibility to RA and disease severity?

A

genes

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14
Q

Concordance rates in twins - mono and dizygotic

A

15-30% among monozygotic (identic) twins

rates 5% among dizygotic twins

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15
Q

RA has an association with what serotype?

what do the alleles contain that confers susceptibility?

A

Association with HLA-DRB1 locus (HLA-DR4 serotype)

  • common amino acid motif (QKRAA – shared epitope) in the HLA-DRB1 region
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16
Q

What do the alleles provide? (2)

A
  • Role in promoting autoimmunity (e.g. altered antigen presentation)
  • Molecular mimicry (e.g. with microbial proteins)
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17
Q

What genetic associations are there?

what do they help function ?

A

polymorphisms in PTPN22, CTLA4, c-REL etc. aggregate

  • functionally with immune regulation
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18
Q

There are distinct genetic associations for ?

A

ACPA-positive and ACPA-negative RA

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19
Q

Environmental factors affecting the chances of developing RA?

GIVE examples of infectious agents (5)

A

Smoking and bronchial stress (exposure to silica)

Infectious agents have been associated with RA

  • Viruses (EBV, CMV)
  • E. Coli
  • Mycoplasma
  • Periodontal disease (Porphyromonas gingivalis)
  • Microbiome (gut microbes)
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20
Q

Repeated insults in a genetically susceptible individual would lead to? (2)

A

Formation of immune complexes and rheumatoid factor (high-affinity autoAb against the Fc portion of Ig)
Altered citrullination of proteins and breakdown of tolerance, with resulting ACPA response

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21
Q

What is Citrullination?

A

conversion of the amino acid arginine in a protein into the amino acid citrulline

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22
Q

What activation is there in genetically susceptible individuals?

A

T cell activation

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23
Q

Describe epigenetic modification

A
  • altered post transcriptional regulation
  • self protein Citrullination
  • loss of tolerance
  • transition of arthritis
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24
Q

Coexisting conditions relating to RA (6)

A
  • vascular disease
  • osteoporosis and fracture
  • metabolic syndrome
  • cog dysfunction and depression
  • disability and decline
  • socioeconomic status
25
Q

What cells are involved in the loss of tolerance

A 
dendritic 
B cell
T cell 
autoantibodies
sec lymphoid tissues
26
Q

Cells involved in Synovitis in RA?

A

Intimal lining hyperplasia and sublining infiltration (migration) with mononuclear cells, especially CD4 + T cells, macrophages, and B cells

27
Q

In Synovitis what proliferates ?
what are activated ?

what can the lymphocytes do ?

A

Lining FLS - become aggressive

  • macrophages

Lymphocytes

  • diffusely infiltrate the sublining
  • form lymphoid aggregates with germinal centres
28
Q

what cells display the memory cell phenotype

A

Sublining CD4+ T cells

29
Q

What cells exhibit evidence of antigen-driven maturation and antibody production?

A

Synovial B cells and plasma cells

30
Q

How is Neoangiogenesis induced

A

local hypoxic conditions and cytokines

31
Q

What is Synovitis

A

= inflammation of the synovium

32
Q

Describe the features of Pathogenesis of Rheumatoid Arthritis (6)

A
  • Villous hyperplasia
  • Infiltration of T cells, B cells,
    macrophages and plasma cells
  • Intimal cell proliferation (fibroblasts)
  • Production of cytokines and proteases
  • Increased vascularity
  • Self-amplifying process
33
Q

Low levels of T cell cytokines are present in ?

A

RA synovium

34
Q

What is efficacious in RA?

A

Abatacept (fusion protein CTLA4-IgG1 Fc that blocks T-cell costimulation

35
Q

Synovial B cells are mainly localised in?

A

T-cell-B-cell-aggregates

- Ectopic lymphoid follicles

36
Q

Role of B cells ? (3)

A
  • production of autoAb
  • Autoantigen presentation
  • Cytokines (IL-6, TNF-α)
37
Q

What cells are abundant in RA synovium ?

what do they go on to produce?

A

Macrophage and fibroblast cytokines

Chemokines that recruit inflammatory cells into the joint

38
Q

Macrophages (M1) are activated by?

A

TLRs and NLRs

39
Q

What networks perpetuate synovial inflammation?

A

Cytokine

40
Q

What Anti-inflammatory cytokines is produced in rheumatoid synovium ?

A

IL-10

41
Q

Describe some features of Inflammatory cytokines? (6)

A
  • Induce expression of endothelial-cell adhesion molecules
  • Activate synovial fibroblasts, chondrocytes, osteoclasts
  • Promote angiogenesis
  • Suppress T-regs
  • Activate leukocytes
  • Promote autoAb production
42
Q

IL-6 mediates systemic effects

4

A

Acute-phase response
Anaemia
Cognitive dysfunction
Lipid metabolism dysregulation

43
Q

What does Neo-angiogenesis provide?

A

nutrients to the hyperplastic synovium

44
Q

What enhances blood vessel proliferation in the synovium (2)

A

Hypoxic conditions and angiogenic factors such as IL-8 and VEGF

45
Q

Microvascular endothelia in the synovium express ?

A

adhesion molecules that guide circulating cells into the joint under the influence of chemoattractants

46
Q

What regulates cartilage degradation and bone destruction in RA

A

Distinct mechanisms and cell types

47
Q

what attaches to and invades cartilage in RA?

A

Synovial lining cells, especially FLS,

48
Q

What is bone destruction mediated by?

A

osteoclasts that are activated under the influence of RANKL produced by RA synovium

49
Q

Factors that regulate osteoclast differentiation in RA?

A

RANKL - M- csf

50
Q

Systemic consequences of RA (GENERAL) (4)

A

Vasculitis, nodules, scleritis, amyloidosis = secondary to uncontrolled chronic inflammation

  • Lungs (interstitial lung disease, fibrosis)
  • Muscles (sarcopoenia)
  • Bone (osteoporosis)
  • Secondary Sjogren’s syndrome
51
Q

Systemic consequences of RA (Cardiovascular) (3)

A
  • Altered lipid metabolism
  • Elevated acute-phase reactants
  • Increased endothelial activation
52
Q

Systemic consequences of RA (fatigue)

A
  • reduced cognitive function (secondary fibromyalgia)

Dysregulation of the HPA axis

53
Q

Systemic consequences of RA (liver) (3)

A

Elevated acute-phase response

Anaemia of chronic disease (IL-6 increases hepatocyte production of hepcidin, an iron-regulatory hormone)

54
Q

Several genes are implicated in susceptibility to RA and severity of disease, including?

A

class II major histocompatibility complex genes and PTPN22

55
Q

Repeated insults (smoking, infectious agents) in genetically susceptible individuals would lead to loss of ?

A

tolerance and autoimmunity

56
Q

Evidence of autoimmunity -when can this be present?

A

including high serum levels of autoAb (RFs and anti-CCP), can be present for many years before the onset of clinical arthritis

57
Q

What has been implicated in the pathogenesis?

A

Adaptive and innate immune responses in the synovium

58
Q

What cytokine networks participate in disease perpetuation (therapeutic targets) (2)

A

TNF-α, IL-6,

59
Q

Bone and cartilage destruction are primarily mediated by ?

A

osteoclasts and fibroblast-like synoviocytes

Year 3: Block 1: MSK system (22 decks)

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