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Health 31 > Autoinflammatory: Hereditary, AOSD, Gout > Flashcards

Autoinflammatory: Hereditary, AOSD, Gout Flashcards

1
Q

L1 hereditary fevers
broad definition, What are auto-inflammatory conditions?

A

group of diseases that manifest as recurrent fevers and episodes of inflammation

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2
Q

What are the 4 characteristics of auto-inflammatory conditions?

A
  • skin rashes
  • joint inflammation
  • no infection
  • absence of auto-antibodies
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3
Q

What parts of the immune system are typically involved in auto-inflammatory conditions?

A
  • high acute phase responses
  • innate immune system
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4
Q

How do autoimmune diseases differ from autoinflammatory conditions?

A
  • autoimmune involves T and and B cells, autoinflammatory involves innate + acute phase response
  • autoimmune has female prevalence, autoinflammatory has equal
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5
Q

What are hereditary fever syndromes?

A

Group of disorders characterised by episodic fevers without infections

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6
Q

What distinguishes hereditary fever syndromes from typical fevers?

A
  • no infectious cause (negative serology)
  • periodic
  • genetic mutation in innate system
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7
Q

3 examples of hereditary fever syndromes?

A
  • Familial Mediterranean Fever (FMF)
  • HIDS (hyperimmunoglobulinemia D syndrome or hyper IgD syndrome)
  • TNF receptor–associated periodic syndrome (TRAPS)
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8
Q

What has been genetically discovered to play a pathogenic role in hereditary fever syndromes?

A

mutations in genes linked to dysfunction in innate immune system

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9
Q

What do bloods of hereditary fever syndrome patients show?
+3 examples

A

increase in acute phase response proteins:

  • ESR
  • CRP
  • serum amyloid A (SAA)
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10
Q

Where in the world is FMF most prevalent?

A

eastern Mediterranean region

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11
Q

What symptoms are found within all hereditary fever syndromes?

A
  • fever of varying persistence
  • severe abdominal pain
  • joint swelling/pain and inflammation
  • rash of some form
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12
Q

What symptoms are exclusive to FMF?

A
  • fever is episodic, lasting 12hrs to 3 days
  • rash found on feet and lower legs
  • amyloidosis
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13
Q

What is amyloidosis and what can it result in?

A

amyloid build up in kidneys, -> kidney failure

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14
Q

What is the genetic basis of FMF?

A

linked to>180 mutations in MEFV gene

-> abnormal Pyrin protein: which is a pattern recognition receptor

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15
Q

What symptoms are exclusive to HIDS/MKD?

A
  • fever is periodic, lasting 1 week
  • enlarged liver and spleen
  • swollen lymph notes
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16
Q

What ethnic group does HIDS most affect? What is its prevalence?

A
  • mostly Europeans
  • extremely rare: only 200 reported cases
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17
Q

What is found in the blood of HIDS patients?

A

high levels of IgD

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18
Q

What is the genetic basis for HIDS?

A

Mutation in the MVK (mevalonate kinase) gene

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19
Q

What ethnic group does TRAPS most affect? What is its prevalence?

A
  • mostly Europeans
  • extremely rare: 1 per 10 million
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20
Q

What symptoms are exclusive to TRAPS?

A
  • more persistent fever, typically lasting 1-4 weeks
  • Swollen eyes and conjunctivitis
  • Painful migrating rash on upper body and/or arms and legs
  • can -> amyloidosis
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21
Q

What is the genetic basis of TRAPS?

A

mutations in TNF receptor

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22
Q

Summarise the causes of all hereditary fever syndromes.

A

all caused by mutation in gene -> dysfunction in innate immune system:

  • FMF - >180 mutations in MEFV gene leading to abnormal pyrin protein
  • HIDS - mutation in MVK gene
  • TRAPS - mutations in TNF receptor
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23
Q

Summarise the difference in fever of all hereditary fever syndromes.

A

FMF: episodic, 12hrs-3 days

HID: periodic, 1 week

TRAPS: more persistent, 1-4 weeks

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24
Q

Explain the molecular mechanism behind FMF.

A
  • mutated pyrin -> activation of NAPL3 inflammasome
  • activates Caspase-1
  • increased secretion of IL-1B

-> increases migration of neutrophils to body cavities

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25
Q

Explain the molecular mechanism behind TRAPS.
although not clear

A
  • TNFR mutation impairs shedding of receptor
  • so less mopping up of soluble TNF-a ligand
  • defective trafficking
  • ligand independent signalling
  • impaired TNF binding
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26
Q

What are the 4 different categories of therapies of hereditary fever syndromes?

A
  • symptomatic
  • preventative
  • IL-1B biologics
  • TNF biologics
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27
Q

What are the symptomatic treatments used to treat hereditary fever syndromes? and role

A
  • NSAIDs
  • glucocorticoids

both reduce pain and inflammation

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28
Q

preventative treatment for hereditary fever syndromes?

A

colchicine

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29
Q

How does colchicine work?

A
  • inhibits NALP3 inflammasome

-> reduces caspase-1 activation and hence reduces IL-1B release

-> also inhibits neutrophil migration

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30
Q

What is the typical dose of colchicine? How long for?

A

1-2mg daily, life-long

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31
Q

What are the main side-effects of colchicine?

A

GI: diarrhoea, nausea, vomiting

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32
Q

what does colchicine reduce long term risk of?

A

amyloidosis and kidney failure

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33
Q

What is used for colchicine resistant patients?

A

IL-1B therapy

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34
Q

3 examples of IL-1B therapies?

A
  • rilonacept (Arcalyst)
  • canakinumab
  • anakinra
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35
Q

What is rilonacept and how does it work?

A
  • fusion protein w domains of IL-1B receptors
  • traps IL-1B by acting as a ‘decoy’ receptor (IL-1b TRAP)
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36
Q

What is canakinumab and how does it work?

A
  • monoclonal antibody
  • mops up IL-1B by binding to it directly + neutralising in system
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37
Q

What is anakinra and how does it work?

A
  • recombinant protein
  • acts as a IL-1 receptor antagonist
    so it cant bind and be activated
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38
Q

2 examples of anti TNF therapies?

A
  • etanercept
  • infliximab

been used to limited effect for patients with hereditary fever syndromes

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39
Q

What is etanercept and how does it work?

A
  • dimeric fusion protein composed of 2x human TNF receptors fused to Fc portion of IgG1
  • decoy receptor for TNF
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40
Q

What is infliximab and how does it work?

A
  • chimeric monoclonal antibody
  • binds to TNF
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41
Q

pharmacological treatment for hereditary fever syndromes: summarise first and second line treatment

A

first: colchicine (inhibits inflammasome and IL-1B release)

second: use IL-1B targeted therapy

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42
Q

L2: AOSD

What is AOSD and prevalence?

A

Adult onset still disease
rare

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43
Q

AOSD symptoms? 6

A
  • intermittent fever lasting a week
  • arthritis
  • salmon-coloured rash
  • sore throat
  • enlarged liver/spleen
  • muscle pain
44
Q

AOSD symptoms? what would indicate liver dysfunction in the blood results?

A

increased liver enzymes and ferritin

45
Q

what colour is the rash described as that patients present with in AOSD?

A

salmon

46
Q

how long does intermittent fever last in AOSD?

A

a week

47
Q

effect of AOSD on px liver and spleen?

A

enlarged

48
Q

Would the blood results be positive or negative for autoantibodies? AOSD

A

negative

49
Q

What is the first line treatment for AOSD? (2) and what do they do?

A

NSAIDs

Glucocorticoids

-> reduce pain and inflamation

50
Q

What is the second line treatment for AOSD? class

A

disease modifying treatments

51
Q

3 examples of second line treatment for AOSD? and for which tyoe of AOSD?

A

-Methotrexate

-IL-1B targeting agents: systemic AOSD

-(Anti TNF therapy: articular AOSD)

52
Q

What are examples of IL1B agents in AOSD and what 2 blood results does it reduce the levels of?

A

Rilonacept and canakinumab

  • reduces the levels of CRP and ESR
53
Q

what are CRP and ESR?
and what drugs reduce levels?

A

acute phase response proteins…
Rilonacept and canakinumab in AOSD therapy

54
Q

L3 Gout

What is gout the accumulation of?

A

deposition of MonoSodium Urate (MSU) crystals in joints

55
Q

what causes the MSU crystal accumulation in joints in gout? 2, and what % of each

A
  • hyperuricaemia: excess uric acid production (10%)
  • inefficient processing by kidneys/ under excretion (90%)
56
Q

What are the common joint sites of gout?

A

Most common: big toe

Knee, ankle, instep, elbow

Less common in shoulder, wrist, finger

57
Q

how many joints involved/ affected in early stages of gout?

A

only 1-2

58
Q

What are risk factors of gout? 7

A
  • Male gender
  • Increased age
  • diet: Obesity / metabolic syndrome
  • HTN
  • CKD
  • OA
  • Genetics
59
Q

gout cause: over production of uric acid accounts for 10% of cases.
in this, what 2 things is there an increase in?

A

dietary purines

purine synthesis

60
Q

4 dietary purine examples… that leas to over production of uric acid?

A
  • meat
  • seafood
  • beer
  • drinks with fructose
61
Q

2 conditions that may result in increased purine synthesis -> overproduction of uric acid?

A

malignancy (lymphoproliferative diseases)

HGPRT deficiency

62
Q

underexcretion is the reason for 90% of gout cases.
what 2 things can it be caused by?

A

renal failure
diuretic drugs

63
Q

name 2 diuretic drugs that may cause under excretion ..-> gout?

A

HTZ (hydrochlorothiazide)
aspirin

64
Q

What are feature of acute gout attacks?

A

Sudden onset usually night

Acute inflammation

Completely resolved between 5-10 days

Usually only 1 joint affected

65
Q

acute attacks have a sudden onset and are common during the night. Although only 1 joint is usually affected how long can complete resolution take?

A

5-10 days

66
Q

chronic gout is polyarticular. What is meant by polyarticular?

A

acute attacks more frequent and involve more joints

67
Q

Where might patients with chronic gout find tophus (deposits of sodium urate)? 3

A

joints, kidneys and external ear

68
Q

tophus (deposits of sodium urate) in kidneys can lead to (2)?

A

kidney stones
nephropathy

69
Q

what diagnostic method can detect the prescence of MSU?

A

ultrasound of joint

70
Q

what diagnostic method can detect tophi deposits, calcifications and erosions of the joint?

A

x rays

71
Q

what parameters are measured via blood tests/ elevated levels of what are being investigated?

A

acute phase proteins such as ESR and CRP and uricaemia

72
Q

what is the study of joint fluid analysis?

A

when joint fluid can be aspirated and MSU crystals can be observed by microscopy.

73
Q

what do MSU crystals activate (innate immue system)?

A

tissue resident macrophages

74
Q

What is the MOA of gout? Mechanism of inflammation from immune system
Signal1&2

A

Signal 1
MSU is phagocytosed by macrophage -> inflammasome activation +release of IL-1B

Signal 2
Also there is binding to TLR2/TLR4 on macrophage - -> inflammasome activation and IL-1B release

75
Q

MOA of gout- both mechansims (signal 1 + 2) lead to what 2 things?

A

inflammasome activation and IL-1B release

76
Q

How are acute attacks of gout treated? (1st lines and 2nd line)

A

NSAIDs

Colchicine where NSAIDs are contraindicated

Oral corticosteroids or injections into the affected joint

2nd line - canakinumab

77
Q

what drug class are patients w gout first treated with when they have acute attacks?

A

NSAIDs

78
Q

what drug can be used for acute attacks where NSAIDS are contraindicated? gout

A

colchicine

79
Q

for acute attacks of gout, what may be given into affected joint?

A

oral corticosteroids or corticosteroid injections

80
Q

What is the second line treatment drug if gout acute attacks are frequent?

A

canakinumab (IL-1b therapy mab)

81
Q

what is chronic gout characterised by?

A

frequent occurence and the prescence of tophi

82
Q

How is the frequent occurence of tophi managed? (chronic gout) 2

A

need to manage hyperuricaemia…
- xanthine oxidase inhibitors
- uricosuric agent

83
Q

name 2 xanthine oxidase inhibitors which may be used in the management of chronic gout?

A

allopurinol and febuostat

84
Q

name a uricosuric agent that may be used in the management of chronic gout?

A

probenecid

85
Q

why can xanthine oxidiase inhibitors or uricosuric agents not be given during an attack?

A

can precipitate further attacks

86
Q

what does IL-1B monoclonal antibody do in gout and give an example

A

Canakinumab
reduces pain
and risk of flares in px initiating allopurinol treatment

87
Q

what does IL-1rilonacept do in gout?

A

reduced gout flares

88
Q

why does chronic gout require the management of hyperuricaemia?

A

protect kidneys

89
Q

Rheumatology SGT ————

IL-1B therapies: anakinra, canakinumab, rilonacept all prevention action of what?

A

IL1 receptor… redcuing pain, inflammation, fever

90
Q

anakinra and rilonacept both target…

A

IL-1a and IL-1b cytokines

91
Q

canakinumab targets..

A

IL-1b cytokine

92
Q

What factors distinguish hereditary fever syndromes from typical fevers

A

Cause: Typical fever caused by infection but hereditary: gen mutations

93
Q

Familial Mediterranean Fever (FMF) symptoms/ results?

A
  • Most prevalent in eastern mediterranean region
  • Skin rashes on feet and lower legs
  • Severe abdominal pain
  • Episodic fever 12 hours – 3 days
  • Linked to >180 mutations in MEFV gene … -> abnormal Pyrin protein
  • Joint swelling and inflammation ( raised ESP and CRP)
    Negative serology likely auto immune disorder not infection
    Negative autoantibodies, likely not immune disease (but can be)

Can affect joint and lunga
mainly early childhood

94
Q

characteristic rash in FMF?

A

ankle and foot rash

95
Q

what would result in raised ESP and CRP in FMF?

A
  • Joint swelling and inflammation
96
Q

cause of FMF?

A
  • Gene mutation passed from parents to children

change happens in MEFV gene. = abnormal pyrin (a pattern recognition receptor) detects PAMPs and DAMPs. Detect anything unusual. E.g. outside of bacterium not normally there and danger/ damage damps. Cell death and necrosis.

97
Q

Pyrin detects intracellular pattern rec. receptor in cytoskeleton
Inactivated by what, in FMF?

A

by the activation of GTPases from infection.

98
Q

what pathwya affected in FMF?

A

IL1

99
Q

clinical tests could be performed to provide a more definitive diagnosis of FMF?

A

Molecular genetic testing:
* Identifies characteristic MEFV gene mutations that cause the disorder.
But often get false negatives.
Not everyone with FMF has same mutation

100
Q

long term risks of FMF

A

Amyloidosis and kidney failure: due to production and build up of protein amyloid A during FMF attacks, not normally found in the body. Buildup causes inflammation .. organ damage and kidney damage, causing nephrotic syndrome.

101
Q

what to monitor in FMF px?

A

renal function through urine and blood tests. Key markers: abnormal urine albumin levels and persistent reduction in eGFR

102
Q

treatment to start in FMF px asap?

A

Colchicine
prophylactic treatment for the FMF attacks
Recommended in all patients regardless of the frequency and intensity of attacks

103
Q

why is Colchicine used in FMF? (MoA)

A

Inhibits NALP3 inflammasome and reduces IL-1b release due to reducing caspase-1 activation
Also inhibits neutrophil migration
Reduced long term risk of amyloidosis and kidney failure

(Inhibits microtubule polymerisation
Stops activation of inflammasones)

104
Q

second line treatment for FMF: IL-1b targeted therapy.
who is it used in and what does it treat?

A

For colchicine resistant patients: therapies that target IL-1b directly e.g. rilonacept, canakinumab, anakinra

Used to treat cause

105
Q

how is AOSD diagnosed?

A

in adults
* Intermittent fever lasting a week
* Arthralgia/ arthritis
* Salmon coloured rash
* Muscle pain
* Negative for auto-antibodies

Health 31 (16 decks)

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