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Loco > RA > Flashcards

RA Flashcards

1
Q

How many layers of synoviocytes are usually found in the synovial membrane?

A

1 - 3

cells are cuboidal

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2
Q

What are the different types of synoviocytes?

A

Type A = bone marrow derived

  • involved in immune surveillance
  • makes sure synovial fluid entering joint space is aseptic

Type B = fibroblast like connective tissue cell

  • makes hyaluronic acid which is added to synovial fluid
  • makes synovial fluid viscous
  • produces lubricin which acts as the barrier layer of synovial fluid
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3
Q

What is found below the layers of synoviocytes in the synovial membrane?

A

connective tissue subintima

- there is no basement layer/membrane

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4
Q

What composes the subintima layer in the synovial membrane?

A
  • dense network of fenestrated capillaries (semipermeable)

- loose areolar connective tissue

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5
Q

What should synovial fluid (SF) usually look like? What is indicated if it is:

a. red-brown
b. yellow and cloudy
c. white/creamy and cloudy/shiny
d. colourless to yellow and purulent

A

SF is usually colourless to pale yellow and clear (should be able to read through it)

a. haemorrhage into joint
b. inflammation (typical of RA0
c. presence of crystals (gout)
d. bacterial infection

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6
Q

What is the normal pH of SF?

A

~7.38

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7
Q

How long should a ‘string’ of SF be?

A

Usually 4-6cm, but anything over 2cm is considered healthy

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8
Q

Describe the mucin clot test. How would a result indicating RA compare to a normal result.

A

Add a sample of SF into acetic acid/vinegar
Normal result: clear fluid and solid clot
RA result: cloudy fluid + solid clot or crumbly/soft clot

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9
Q

What changes occur to the synovial in RA?

A
  • proliferation of synoviocytes (10-15 layers of cells)
  • infiltration of inflammatory cells
  • -> neutrophils in SF
  • -> lymphocytes in subintima
  • proliferation of fibroblasts in subintima causing thickening and fibrosis
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10
Q

What are Thelper 17 cells so important in the development of RA?

A

TH17 cells release/produce IL-17 and this stimulates osteoclast differentiation and maturation

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11
Q

How do synovial fibroblasts contribute to joint damage in RA?

A

secrete MMPs and cathespins

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12
Q

What upregulates the action of synovial fibroblasts in RA?

A

secretion of lymphotoxin-beta and TNF-alpha (cytokines) from T cell when presented with an antigen by B cells

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13
Q

What change can occur to macrophages under the influence of cytokines?

A

Macrophages in the synovial membrane and subintima can become osteoclasts

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14
Q

How is a pannus formed?

A
  • Subintima becomes fibrotic and the synoviocytes continue to proliferate
  • synovium becomes hyper plastic and a pannus is formed
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15
Q

Why is pannus formation such a problem?

A

Tidemark between bone and cartilage will disappear as pannus takes over

pannus is destructive – secretes cytokines and other signalling molecules and is involved in the erosion of articular cartilage

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16
Q

Explain the association between ACPAs and osteoclasts and bone erosion.

A
  • Anti-citrullinated protein antibodies (ACPAs) can stimulate osteoclast differentiation from monocytes leading to initial bone loss
  • osteoclasts produce IL-8 which induces MORE osteoclasts by AUTOCRINE feedback
  • IL-8 also sensitises nociceptors and contribute to increased pain
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17
Q

Which cell produces rheumatoid factor?

A

B cells

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18
Q

How can synovitis contribute to bone erosion?

A
  • synovitis leads to production of cytokines
  • this stimulates osteoclasts proliferation and differentiation
  • this induces the expression of RANKL and synergises with RANKL to enhance bone erosions filled with inflamed, synovial derived pannus tissue
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19
Q

What is citrullination?

A

changing arginine to citrulline by deamination by peptides arginine deaminase which occurs during apoptosis

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20
Q

How does CD4+ T-cell infiltration contribute to bone erosion in RA?

A

T-cell infiltration, particularly Th17 infiltration, is a hallmark of RA pathogenesis

  • th17 secrete IL-17
  • induces RANKL on synovial fibroblasts
  • activates synovial macrophages to secrete pro-inflammatory cytokines (TNF-alpha, IL-1, IL-6)
  • cytokines activate osteoclastogenesis either by directly acting on an osteoclast precursor or inducing of RANKL
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21
Q

What is DDK-1? How is its expression induced? What does it do?

A

DDK-1 = Dickkopf-related protein 1
Cytokines induce expression of DDK-1 by synovial fibroblasts
It directly inhibits osteoblast differentiation
DDK-1 also induces the expression of sclerotin by osteocytes - this acts to inhibit osteoblasts

22
Q

What changes occur in the synovial fluid in RA?

A
  • High abundance of neutrophils
  • Neutrophils mount a respiratory burst producing superoxide anion radical
  • Means more free radical damage
  • SF is less vicious (damage to hyaluronic acid –> shorter strands)
  • increased volume of SF
23
Q

What is NETosis?

A

Neutrophil Extracellular Trap
Unique form of cell death
There is decondensed chromatin and degranulation
This activates B-cells and released PAD citrullinated peptides

24
Q

What joints does RA commonly affect?

A

Usually small joints of small hands and feet, usually affect proximal joints
Can affect any synovial joint

25
Q

Does RA usually present unilaterally or bilaterally?

A

Bilaterally as it is an inflammatory process

26
Q

What other heath conditions are associated with RA?

A

Increased risk of coronary artery disease
Increased risk of kidney amyloidosis
Significant risk premature mortality
Can cause carpal tunnel syndrome

27
Q

What kind of deformities of the hands can RA cause?

A
  • dorsal subluxation of ulnar head
  • radial deviation at the wrist
  • ulnar deviation of fingers at MCPs
  • volar subluxations of MCPs (phalanges have subluxed under the metacarpal heads)
  • swan neck deformity (extension of PIP, flexion of DIP)
  • Z deformity of the thumb (flexion of MCP and expansion of IP)
28
Q

What are the risk factors for RA?

A
  • HLA DR4
  • Genetic predisposition
  • Gender and hormonal factors
  • Previous inflammatory disease
  • Environmental factors/gut flora/smoking
  • Post viral immunomodulation
29
Q

What is required for a diagnosis of RA?

A
  • > 6/10 score on the ACR/EULAR criteria
  • Blood sample for RF and ACPA
  • -> RF in 60-80% of RA patients
  • -> ACPA specificity for RA is 96%
  • Also test for CRP and ESR (markers of inflammation)
30
Q

What complications can arise with RA?

A
  1. Liver: acute phase response(CRP); iron redistribution (hepcidin)
  2. Fat: free fatty acid; adipocytokines
  3. Muscle: insulin resistance
  4. Bone: low BMD; fractures
  5. Brain: low stress tolerance; depression
  6. Blood vessels: atherogenesis; MI; stroke
  7. Eye: keratoconjunctivitis sick; scleritis + episcleritis; scleromalacia perforans
  8. Hypochromic normocytic anaemia
31
Q

How quickly should a DMARD be administered for RA?

A

Within 3 months of persistent symptoms

32
Q

What is the gold standard treatment for RA?

A

MTX

33
Q

How often should methotrexate (MTX) be taken, and how long before benefits should be seen?

A

Take orally once a week, on the same day
Given as 2.5 mg tablets
Start between 5-10mg a weak
3-12 weeks before benefit is seen

34
Q

What is the MOA of MTX?

A
  1. MTX enters the cell through a reduced folate carrier –> it is an folic acid antagonist
  2. after entering the cell, MTX is a polyglutamated (via folylpolyglutamate synthase)
  3. MTX and its polyglutamates inhibit the enzyme dihydrofolate reductase
  4. Blocks the conversion of dihydrofolate to tetrahydrofolate
  5. Tetrahydrofolate stores are depleted and this reduces thymidylate synthesis which ultimately inhibits DNA synthesis
  6. Long-chain polyglutamates of MTX have markedly increased inhibitory effects on both thymidylate synths and purine biosynthesis - required for RNA production
  7. Blocks immune cell proliferation

**can cause liver and blood count (WBC) problems

35
Q

What is sulfasalazine? How often should it be taken, and how long before benefit can be seen?

A

Antibiotic - combines sulfapyridine and salicylate via an ago bond

Taken orally

  • start with 500mg daily
  • gradually increase dosage over 4 weeks to 1g twice a day

12 weeks before any benefit is noted

36
Q

What is the MOA of sulfasalazine?

A
  • Metabolised into 5-aminosalicylic acid and sulfapyridine
  • 5_ASA can be absorbed across the gut, becomes concentrated in connective tissue and in serous fluid
  • -> inhibits COX, cytokines, IL-1 and TNF-alpha
  • -> reduces pain and inflammation
  • Sulfapyridine is absorbed rapidly in the colon and then acetylated in the liver by NAT-2 into N-acetylsulfapyridine
  • -> may help prevent local GI inflammation by reducing pro-inflammatory cytokines that are in the blood
37
Q

What is hydroxychloroquine? How often should it be taken, and how long before benefit can be seen?

A

Anti-malarial

Taken orally, with or after food

  • start with 400mg daily
  • reduce to 2-3 times per week

12 weeks before benefit is seen

38
Q

What is the MOA of hydroxychloroquine?

A
  • Accumulates in lysosomes increasing the pH and thus decreasing protein modifications –> less fibrosis
  • blocks TLR9 which recognises DNA containing immune complexes –> decreases activation of dendritic cells
39
Q

What is the main side effect of hydroxychloroquine?

A

Causes a rash in the flexor compartment - Never give to a patient with psoriasis

40
Q

How should leflunomide be taken?

A

10-20mg a day

for the first 3 days have a higher does of 100mg a day

41
Q

what is the MOA of leflunomide?

A
  • inhibits pyrimidine biosynthesis by inhibiting dihydroorotate dehydrogenase
  • blocks DNA and RNA synthesis
  • works synergistically with MTX
42
Q

What is Etanercept? How should it be taken? How long for there to be an effect?

A

TNF-alpha blocker + fusion protein human TNF receptor 2 and Fc human IgG1

Take 50mg once a weka via subcutaneous injection

1-4 weeks for effect
progressive improvement over 3-6 months

43
Q

What is Infliximab? How should it be taken? How long for there to be an effect?

A

TNF-alpha blocker (monoclonal antibody against TNF-alpha)
+ Antibody designed against the most binding site of TNF-alpha with remaining 75% human IgG1

Take 3mg/kg infusions for 2-3 hours, each infusion is 2-6 weeks apart

days to weeks to have effect

44
Q

What is Adalimumab? How should it be taken? How long for there to be an effect?

A

TNF-alpha blocker
+ human TNF-alpha monoclonal antibody

take 40mg via subcutaneous injection every other week

effect is seen between 1-4 weeks

45
Q

What is Anakinra? How should it be taken? How long for there to be an effect?

A

Human recombinant IL0-1 receptor antagonist

Take 100mg per day via subcutaneous injection

takes 2-4 weeks to have an effect

46
Q

What is Canakinumab?

A

Human monoclonal antibody targeting IL-1beta

47
Q

What is Rilanocept?

A

Dimeric fusion protein extracellular woman of IL1R1 and Fc human IgG1

48
Q

What is Rituximab? How should it taken? How long for there to be an effect?

A

Chimeric monoclonal antibody against CD20 primarily found on surface B-cells

  • destroys both normal and malignant B cells
  • used in combination with MTX
  • used if TNF-alpha blockers can’t be used/fail

Take as single course of 2 infusions of 1000mg given 2 weeks apart
- last for 6 months - 1 year

Effect seen ~3 months after infusions

49
Q

What is Abatacept? How should it taken? How long for there to be an effect?

A

Fusin protein IgG, fused to extracellular domain of CTLA-4
- prevents 2nd signal (co-stimulatory) from being delivered to T-cell

Dosage is dependent on body weight

  • IV infusions over 30 minutes-1 hour
  • once a month

Response ~3 months

50
Q

What is Belatacept?

A

Anti-CD28, which modulates T cell signalling

51
Q

What is Tocilizumab? How should it taken?

A

Humanised monoclonal antibody against membrane and soluble IL-6 receptor

  • used in combination with MTX
  • used when TNF-alpha blockers can’t be used/fail

Taken as 8mg/kg IV infusion monthly

Loco (19 decks)

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