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Systems: MSK AB > The Science of Rheumatoid Arthritis > Flashcards

The Science of Rheumatoid Arthritis Flashcards

1
Q

What are the function of the synovium?

A
  • Maintenance of intact tissue surface
  • Lubrication of cartilage
  • Control of synovial fluid volume and composition (hyaluronan, lubricin)
  • Nutrition of chondrocytes within joints
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2
Q

Describe the joint affected by rheumatoid arthritis.

A
  • Erosion into corner of bone
  • Thinning of cartilage
  • Inflammed synovium spreading across joint surface
  • Inflammed tendon sheath
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3
Q

What is rheumatoid arthritis?

A

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

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4
Q

What is rheumatoid synovitis (pannus) characterised by?

A

Inflammatory cell infiltration, synoviocyte proliferation and neoangiogenesis

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5
Q

In rheumatoid arthritis, what does the synovial fluid in the joint cavity contain?

A

Neutrophils, particularly during acute flares

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6
Q

What does the synovial pannus cause?

A

Bone and cartilage destruction (deformities)

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7
Q

When can evidence of autoimmunity be present?

A

Evidence of autoimmunity can be present in RA many years before the onset of clinical arthritis

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8
Q

What autoantibodies are commonly associated with RA?

A
  • Rheumatoid factors

- Anti-citrullinated protein

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9
Q

What do autoantibodies recognise in RA?

A

Either joint antigens such as type II collagen or systemic antigens such as glucose phosphate isomerase

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10
Q

How can autoantibodies contribute to inflammation?

A

Through several mechanisms including activation of complement

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11
Q

What autoantibodies are produced in seropositive RA?

A
  • Rheumatoid factor

- Anti-cirtullinated protein antibody (ACPA)

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12
Q

What do diagnostic anti-CCP assays recognise in seropositive antibody production?

A
  • Citrullinated self-proteins
  • α-enolase
  • Keratin
  • Fibrinogen
  • Fibronectin
  • Collagen
  • Vimentin
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13
Q

What seropositive RA patients have a poorer prognosis?

A

Patients with ACPA disease

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14
Q

What is rheumatoid factor?

A

An auto-antibody to self IgG Fc

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15
Q

What genetic factors contribute to RA?

A
  • Concordance rates 15-30% in monozygotic twins and 5% in dizygotic twins
  • Association with HLA-DRB1 locus (HLA-DR4 serotype)
  • Other genetic associations including polymorphisms in PTPN22, CTLA4, c-REL etc. aggregate functionally with immune regulation
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16
Q

What environmental factors contribute to RA?

A
  • Smoking and bronchial stress (exposure to silica)

- Infectious agents (viruses, E.coli, mycoplasma, periodontal disease, microbiome)

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17
Q

What would repeated environmental insults in a genetically susceptible individual lead to?

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
18
Q

What is citrullination?

A
  • (Or deimination) is the conversion of the amino acid arginine in a protein into the amino acid citrulline.
  • Enzymes called peptidylarginine deiminases (PADs) replace the primary ketimine group (=NH) by a ketone group (=O).
19
Q

Why does synovitis occur in RA?

A
  • Intimal lining hyperplasia and sublining infiltration (migration) with mononuclear cells, especially CD4 + T cells, macrophages, and B cells
  • Lining FLS proliferate, become activated and “aggressive”
  • Macrophages in lining activated
  • Lymphocytes can either diffusely infiltrate the sublining or form lymphoid aggregates with germinal centres
  • Sublining CD4+ T cells mainly display the memory cell phenotype
  • Synovial B cells and plasma cells exhibit evidence of antigen-driven maturation and antibody production
  • DCs can present antigens to T cells in synovial germinal centres
  • Neoangiogenesis induced by local hypoxic conditions and cytokines
  • Insufficient lymphangiogenesis limits cellular egress
  • Neutrophils in synovial fluid
20
Q

What is synovitis?

A

Inflammation of the synovium

21
Q

What is the pathogenesis of RA?

A
  • Synovitis
  • 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
22
Q

What role do T cells play in RA?

A

Relatively low levels of T cell cytokines are present in RA synovium

Shift from homeostasis to inflammation

  • T-cell cytokines, such as IFN- γ and IL-17, are produced by Th1 cells or Th17 cells
  • Regulatory T cell function, which suppresses activation of other T cells, is reduced

T cell mediated B cell activation

Direct cell to cell contact with macrophages

23
Q

How can T cells be targeted in RA?

A
  • T-cell depleting strategies have limited efficacy

- Abatacept (fusion protein CTLA4-IgG1 Fc that blocks T-cell costimulation) is efficacious in RA

24
Q

What role do B cells play in RA?

A
  • Synovial B cells are mainly localised in T cell B cell aggregates (ectopic lymphoid follicles)
  • Pathogenic role for CD20+ B cells is confirmed by the efficacy of rituximab
  • Plasma cells are widely distributed and are not targeted by anti-CD20 antibodies
  • Role of B cells goes beyond production of autoAb (autoantigen presentation, cytokines IL-6 and TNFa)
25
Q

What are abundant in RA?

A

Macrophage and fibroblast cytokines

26
Q

What are macrophages activated by?

A

TLRs and NLRs

27
Q

What perpetuates synovial inflammation?

A

Cytokine networks including TNF-α, IL-6, IL-1, IL-15, IL-18, IL-23

28
Q

What do the macrophages and fibroblasts produce?

A

Chemokines that recruit inflammatory cells into the joints

29
Q

What anti-inflammatory response does the synovium have?

A

Anti-inflammatory cytokines such as IL-10 are produced in rheumatoid synovium but in amounts insufficient to offset proinflammatory cytokines

30
Q

What do inflammatory cytokines do?

A
  • Induce expression of endothelial-cell adhesion molecules
  • Activate synovial fibroblasts, chondrocytes, osteoclasts
  • Promote angiogenesis
  • Suppress T-regs
  • Activate leukocytes
  • Promtoe autoAb production
31
Q

What role does IL6 play in RA?

A

Mediates systemic effects

  • Acute-phase response
  • Anaemia
  • Cognitive dysfunction
  • Lipid metabolism dysregulation
32
Q

What is the role of eo-angiogenesis?

A

Provide nutrients to the hyperplastic synovium

33
Q

What enhances blood vessel proliferation in the synovium?

A

Hypoxic conditions and angiogenic factors such as IL-8

34
Q

What does the microvascular endothelial of the synovium express?

A

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

35
Q

How does cartilage and bone destruction occur in RA?

A
  • Several classes of proteases, including metalloproteinases and aggrecanases are produced by FLS in the intimal lining layer
  • Synovial lining cells, especially FLS, can attach to and invade cartilage in RA
  • Bone destruction is mediated by osteoclasts that are activated under the influence of RANKL produced by RA synovium
36
Q

What does cartilage and bone destruction lead to?

A

Joint space narrowing and erosions

37
Q

What factors regulate osteoclast differentiation in RA?

A

RANKL M-CSF

38
Q

What systemic consequences are there in RA?

A
  • Vasculitis, nodules, scleritis, amyloidosis = secondary to uncontrolled chronic inflammation
  • Cardiovascular disease
  • Fatigue and reduced cognitive function, secondary fibromyalgia due to dysregulation of the HPA axis
  • Liver problems
  • Lungs (interstitial lung disease, fibrosis)
  • Muscles (sarcpoenia)
  • Bone (osteoporosis)
  • Secondary Sjogren’s syndrome
39
Q

What cardiovascular involvement can occur in RA?

A
  • Altered lipid metabolism
  • Elevated acute-phase reactants
  • Increased endothelial activation
40
Q

What liver problems can occur in RA?

A
  • Elevated acute-phase response

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

Systems: MSK AB (43 decks)

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