Systemic Inflammatory Disease Symposium Flashcards

1
Q

What is Rheumatoid arthritis?

A
  • an Autoimmune disease
    • women are 3x more affected than men
  • an increase in dysregulated and persistent inflammation
    • systemic inflammation is seen
  • Inflammation of the synovial joint
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2
Q

What are the key cytokines involved in RA pathophysiology? (3)

  • what are their main effects?
A
  • TNF, IL-1, IL-6
  • cytokines make atherosclerotic plaques unstable
    • MI and strokes
  • muscle and adipose tissue becomes insulin resistant
    • diabetes
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3
Q

Review the comorbidities in RA?

  • what is the cause of these?
A
  • MI’s Stroke (artherosclerotic plaque instability)
  • Diabetes due to adipose and muscle insulin resistance
  • causes by cytokines TNF, IL-1 and IL-6
    • TNF - causes negative mood affects
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4
Q

What is the joint damage pattern in RA?

  • how does it present
  • what are the process that cause this?
A
  • Usually multiple joints in a symmetrical fashion
  • Morning stiffness
  • Swelling, heat, redness and pain
  • Loss of function

Destructive process

  • Bone erosion
  • Synovial and cartilage damage

joint damage is irreversible and joint damage is mirrored across the body

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5
Q

What are the clinical markers of RA?

A
  • Elevated ESR (Erythrocyte sedimentation rate)
  • Elevated CRP (C-reactive protein)
  • Presence of autoantibodies:
    • Rheumatoid factor (RF)
    • Cyclic citrullinated peptide (anti-CCP) antibodies
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6
Q

What is Rheumatoid factor (RF)?

A
  • Rheumatoid factor are antibodies directed against the Fc portion of another antibody, leading to immune complex formation
  • Present in 60-70% of patients with RA
  • Of some use in diagnosis, but:
  • Not specific for RA (only 86%), also present in other autoimmune diseases, infectious diseases and some healthy individuals
    • RF also found in other diseases e.g., Sjogren’s syndrome, SLE and hepatitis B
  • Some RA patients are ‘seronegative’
  • Levels do not correlate with disease activity
  • RF+ patients have a more severe disease
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7
Q

What is Anti-cyclic citrullinated peptide (CCP) antibody?

A
  • Also known as ACPA (anti-citrullinated peptide antibodies)
  • Antibodies directed against CCP are found in 60-70% of patients with RA (anti-CCP+)
  • Very rarely found in healthy people who do not go on to develop RA (high specificity 98%)
  • Detectable in the blood many years before disease onset
  • Anti-CCP+ RA has a more aggressive clinical course of disease
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8
Q

What is Citrullination

  • how does it present in the body?
A
  • Process of replacing protein arginine residues with citrulline residues
  • Occurs normally in the body but if occurs on an unusual part of the protein, they may be recognised as foreign, leading to an antibody response
  • Citrullinated self-proteins are detected in RA patients by anti-CCP antibodies; examples are α-enolase, keratin, fibrinogen, fibronectin, collagen and vimentin
    • might be seen in joint synovial tissue
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9
Q

How might anti-CCP have a pathogenic role in RA?

A

Unable to induce arthritis alone, but can enhance the development and severity of inflammation in mice when mild synovitis is already present.

  • Possible mechanisms:
    1. Activation of inflammatory cells by anti-CCP immune complexes
    2. Anti-CCP mediated neutrophil cell death producing NETs
    3. Direct binding of anti-CCPs to drive osteoclastogenesis
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10
Q

Explain the genetic factor within RA

A
  • Most genes show a relatively low gene penetrance. Variants are not found in many of the RA patients.
  • No individual gene is necessary or sufficient
  • Susceptibility and severity is determined by a combination of genes
  • Must be other factors that in addition to genetics that have a role in the susceptibility and severity of autoimmune diseases.

Many of the genes identified regulate the immune system, possibly in response to environmental agents

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11
Q

What are some specific genes associated with RA (4)

A
  • HLA-DRB1 SE Human leukocyte antigen (HLA), accounts for 30-50% of the overall genetic risk
  • PTPN22 Negative regulator of antigen receptor signalling in T and B cells (protein tyrosine phosphatase 22)
  • CTLA4 Co-stimulation suppressor that regulates interactions between T cells and antigen presenting cells (downregulated in RA)
  • TNFAIP3 (A20) Inhibitor of NF-κB and TNFα mediated apoptosis (downregulated in RA)
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12
Q

Explain the hormonal factor within RA

A
  • Men who get RA usually have low testosterone levels
  • RA patients often experience remission during pregnancy
  • Early menopause (age <45 years) has been associated with both an increased risk of RA, as well as RF positivity
  • Use of oral contraceptives modestly decreases risk of anti-CCP+ RA
  • Mixed data on HRT - may reduced the risk of anti-CCP+ RA in postmenopausal women >50 years of age, many other studies show no effect
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13
Q

What is the association between smoking and RA?

A
  • Heavy smoking of both sexes increase the risk of RA among persons with susceptibility HLA-DR4 alleles.
  • Twin studies have demonstrated the gene–environment interaction by showing the effect of smoking is greater in genetically susceptible individuals, particularly if HLA DRB1+
  • Smoking and HLA-DRB1 alleles increase the risk of being anti-CCP+
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14
Q

How are infections associated with RA?

A
  • Viral/bacterial infections have been suggested for many decades as an initiating cause of autoimmunity
    • difficult to prove as infection may no longer be present once the disease is established
  • Porphyromonas gingivalis (P. gingivalis) has some indications of being linked with RA
    • has its own version of PAD (P-PAD) and can citrullinate our proteins but possibly in a different way to normal and thus activate the immune system which then triggers autoantibody formation that then also recognises normally citrullinated proteins.
    • this infection occurs in Periodontitis
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15
Q

Give an overview of Molecular mechanisms of joint destruction in RA

A
  • Swelling over extensor tendons, wrist and MCP joints
  • Synovium hyperplasia (an increase in cell numbers)
  • Synovial fibroblasts have reduced apoptosis, enhanced anchorage, upregulated adhesion molecules and increased proliferation
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16
Q

What is the difference between a normal joint and a rheumatoid joint?

A
17
Q

What is the composition of synovial tissues in the Pannus structure in RA

A
  • mainly macrophages (40%)
  • fibroblast (10-15%)
  • T lymphocytes (40%)
  • B lymphocytes (5%)
18
Q

How do cytokines affect the bone in RA?

A
  • Cytokines (IL-17, RANKL, TNF-alpha, IL-1 and IL-6) promote osteoclast differentiation and activation
  • Deep bone resorption pits develop, which become filled with inflammatory tissue
  • Worse at mechanically vulnerable sites, such as the 2nd/ 3rd metacarpal
  • Little repair as cytokines inhibit the differentiation of osteoblasts
  • Affects 80% RA patients within 1 year of diagnosis
19
Q

What happens to the cartilage in RA?

A
  • Chondrocytes undergo apoptosis
  • Fibroblasts adhere to and invade the cartilage
  • Fibroblasts make matrix metalloproteases (MMPs) which break down the collagen network in the cartilage
  • Leads to biomechanical dysfunction and joint space narrowing
20
Q

What is the role of T cells in RA

A
  • Human leukocyte antigen (HLA) associations suggest T cell role
  • RA synovium is rich in activated T cells
    • Th17 cells and Th1 cells predominate
  • Increasingly, Th17 cells have been suggested as a major pathogenic subset. IL-17 is known to:
    • Activate synovial fibroblasts and osteoclasts
    • Favour cartilage resorption
  • T regulatory cells are enriched in the RA joint but appear to have a defect that can be reversed by blocking TNF
21
Q

What is the role of B cells in RA?

A
  • Auto-antibodies associated with disease are usually present before onset of symptom
  • B cells form diffuse or follicular infiltrates in the RA synovium
  • B cell depletion using monoclonal anti-CD20 is an effective treatment
  • B cells also produce cytokines and are important for antigen presentation
22
Q

What is the role of Neutrophils in RA?

A
  • When activated neutrophils can undergo a special form of cell death termed ‘NETosis’ releasing nuclear chromatin
  • Neutrophils infiltrate synovial fluid
  • Enhanced NETosis correlates with the presence of anti-CCP antibodies
  • NETs release citrullinated proteins
    • these can activate and become immune complexes with autoantibodies already present
23
Q

What is the role of Innate immune cells in RA?

A
  • Infiltrating macrophages, mast cells, NK cells in synovium
  • Macrophages appear to be key effectors
    • Phagocytosis
    • Antigen presentation
    • TNF, IL-1 and IL-6
  • Most therapies decrease macrophage cytokine production
  • Decreased macrophage infiltration strongly correlates with the degree of clinical improvement to therapies
24
Q

Review the cellular interactions in RA

A
25
Q

Review the risk factors for RA and its presentation as it progresses

A
26
Q

What are signs and symptoms of RA?

A
  • Onset varies, can be acute or chronic
  • Symmetrical pain and boggy swelling of the small joints of the hands and feet (MCP, PIP, wrist, MTP, subtalar, rarely the DIPs)
  • Early morning stiffness > 1 Hour
  • An inflammatory pattern of pain
  • Systemically unwell – fatigue, weight loss, malaise, temperatures
  • Examination - look for pain, swelling and restriction of movement
  • Look for extra-articular symptoms because RA is a systemic disease
27
Q

What are extra-articular manifestations of RA?

A
  • Nodules (20%)
  • Bursitis / Tenosynovitis
  • Eyes: dry eyes (secondary Sjogren’s syndrome) / Scleritis / Scleromalacia
  • Splenomegaly (Felty’s)
  • Anaemia of chronic disease
  • Lung fibrosis /effusion /Nodules (Caplan’s)
  • Pericarditis
  • Neurological: Atlanto-axial subluxation / Carpal tunnel syndrome / Mononeuritis multiplex
  • Renal amyloidosis (AA)
  • Leg ulcers / Pyoderma gangenosum