Autoinflammatory: Hereditary, AOSD, Gout Flashcards
(105 cards)
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
2
Q
What are the 4 characteristics of auto-inflammatory conditions?
A
- skin rashes
- joint inflammation
- no infection
- absence of auto-antibodies
3
Q
What parts of the immune system are typically involved in auto-inflammatory conditions?
A
- high acute phase responses
- innate immune system
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
5
Q
What are hereditary fever syndromes?
A
Group of disorders characterised by episodic fevers without infections
6
Q
What distinguishes hereditary fever syndromes from typical fevers?
A
- no infectious cause (negative serology)
- periodic
- genetic mutation in innate system
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)
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
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)
10
Q
Where in the world is FMF most prevalent?
A
eastern Mediterranean region
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
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
13
Q
What is amyloidosis and what can it result in?
A
amyloid build up in kidneys, -> kidney failure
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
15
Q
What symptoms are exclusive to HIDS/MKD?
A
- fever is periodic, lasting 1 week
- enlarged liver and spleen
- swollen lymph notes
16
Q
What ethnic group does HIDS most affect? What is its prevalence?
A
- mostly Europeans
- extremely rare: only 200 reported cases
17
Q
What is found in the blood of HIDS patients?
A
high levels of IgD
18
Q
What is the genetic basis for HIDS?
A
Mutation in the MVK (mevalonate kinase) gene
19
Q
What ethnic group does TRAPS most affect? What is its prevalence?
A
- mostly Europeans
- extremely rare: 1 per 10 million
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
21
Q
What is the genetic basis of TRAPS?
A
mutations in TNF receptor
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
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
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
25
Explain the molecular mechanism behind TRAPS.
although not clear
- TNFR mutation impairs shedding of receptor
- so less mopping up of soluble TNF-a ligand
- defective trafficking
- ligand independent signalling
- impaired TNF binding
26
What are the 4 different categories of therapies of hereditary fever syndromes?
- symptomatic
- preventative
- IL-1B biologics
- TNF biologics
27
What are the symptomatic treatments used to treat hereditary fever syndromes? and role
- NSAIDs
- glucocorticoids
both reduce pain and inflammation
28
preventative treatment for hereditary fever syndromes?
colchicine
29
How does colchicine work?
- inhibits NALP3 inflammasome
-> reduces caspase-1 activation and hence reduces IL-1B release
-> also inhibits neutrophil migration
30
What is the typical dose of colchicine? How long for?
1-2mg daily, life-long
31
What are the main side-effects of colchicine?
GI: diarrhoea, nausea, vomiting
32
what does colchicine reduce long term risk of?
amyloidosis and kidney failure
33
What is used for colchicine resistant patients?
IL-1B therapy
34
3 examples of IL-1B therapies?
- rilonacept (Arcalyst)
- canakinumab
- anakinra
35
What is rilonacept and how does it work?
- fusion protein w domains of IL-1B receptors
- traps IL-1B by acting as a 'decoy' receptor (IL-1b TRAP)
36
What is canakinumab and how does it work?
- monoclonal antibody
- mops up IL-1B by binding to it directly + neutralising in system
37
What is anakinra and how does it work?
- recombinant protein
- acts as a IL-1 receptor antagonist
so it cant bind and be activated
38
2 examples of anti TNF therapies?
- etanercept
- infliximab
been used to limited effect for patients with hereditary fever syndromes
39
What is etanercept and how does it work?
- dimeric fusion protein composed of 2x human TNF receptors fused to Fc portion of IgG1
- decoy receptor for TNF
40
What is infliximab and how does it work?
- chimeric monoclonal antibody
- binds to TNF
41
pharmacological treatment for hereditary fever syndromes: summarise first and second line treatment
first: colchicine (inhibits inflammasome and IL-1B release)
second: use IL-1B targeted therapy
42
L2: AOSD
What is AOSD and prevalence?
Adult onset still disease
rare
43
AOSD symptoms? 6
- intermittent fever lasting a week
- arthritis
- salmon-coloured rash
- sore throat
- enlarged liver/spleen
- muscle pain
44
AOSD symptoms? what would indicate liver dysfunction in the blood results?
increased liver enzymes and ferritin
45
what colour is the rash described as that patients present with in AOSD?
salmon
46
how long does intermittent fever last in AOSD?
a week
47
effect of AOSD on px liver and spleen?
enlarged
48
Would the blood results be positive or negative for autoantibodies? AOSD
negative
49
What is the first line treatment for AOSD? (2) and what do they do?
NSAIDs
Glucocorticoids
-> reduce pain and inflamation
50
What is the second line treatment for AOSD? class
disease modifying treatments
51
3 examples of second line treatment for AOSD? and for which tyoe of AOSD?
-Methotrexate
-IL-1B targeting agents: systemic AOSD
-(Anti TNF therapy: articular AOSD)
52
What are examples of IL1B agents in AOSD and what 2 blood results does it reduce the levels of?
Rilonacept and canakinumab
- reduces the levels of CRP and ESR
53
what are CRP and ESR?
and what drugs reduce levels?
acute phase response proteins...
Rilonacept and canakinumab in AOSD therapy
54
L3 Gout
What is gout the accumulation of?
deposition of MonoSodium Urate (MSU) crystals in joints
55
what causes the MSU crystal accumulation in joints in gout? 2, and what % of each
- hyperuricaemia: excess uric acid production (10%)
- inefficient processing by kidneys/ under excretion (90%)
56
What are the common joint sites of gout?
Most common: big toe
Knee, ankle, instep, elbow
Less common in shoulder, wrist, finger
57
how many joints involved/ affected in early stages of gout?
only 1-2
58
What are risk factors of gout? 7
- Male gender
- Increased age
- diet: Obesity / metabolic syndrome
- HTN
- CKD
- OA
- Genetics
59
gout cause: over production of uric acid accounts for 10% of cases.
in this, what 2 things is there an increase in?
dietary purines
purine synthesis
60
4 dietary purine examples... that leas to over production of uric acid?
- meat
- seafood
- beer
- drinks with fructose
61
2 conditions that may result in increased purine synthesis -> overproduction of uric acid?
malignancy (lymphoproliferative diseases)
HGPRT deficiency
62
underexcretion is the reason for 90% of gout cases.
what 2 things can it be caused by?
renal failure
diuretic drugs
63
name 2 diuretic drugs that may cause under excretion ..-> gout?
HTZ (hydrochlorothiazide)
aspirin
64
What are feature of acute gout attacks?
Sudden onset usually night
Acute inflammation
Completely resolved between 5-10 days
Usually only 1 joint affected
65
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?
5-10 days
66
chronic gout is polyarticular. What is meant by polyarticular?
acute attacks more frequent and involve more joints
67
Where might patients with chronic gout find tophus (deposits of sodium urate)? 3
joints, kidneys and external ear
68
tophus (deposits of sodium urate) in kidneys can lead to (2)?
kidney stones
nephropathy
69
what diagnostic method can detect the prescence of MSU?
ultrasound of joint
70
what diagnostic method can detect tophi deposits, calcifications and erosions of the joint?
x rays
71
what parameters are measured via blood tests/ elevated levels of what are being investigated?
acute phase proteins such as ESR and CRP and uricaemia
72
what is the study of joint fluid analysis?
when joint fluid can be aspirated and MSU crystals can be observed by microscopy.
73
what do MSU crystals activate (innate immue system)?
tissue resident macrophages
74
What is the MOA of gout? Mechanism of inflammation from immune system
Signal1&2
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
MOA of gout- both mechansims (signal 1 + 2) lead to what 2 things?
inflammasome activation and IL-1B release
76
How are acute attacks of gout treated? (1st lines and 2nd line)
NSAIDs
Colchicine where NSAIDs are contraindicated
Oral corticosteroids or injections into the affected joint
2nd line - canakinumab
77
what drug class are patients w gout first treated with when they have acute attacks?
NSAIDs
78
what drug can be used for acute attacks where NSAIDS are contraindicated? gout
colchicine
79
for acute attacks of gout, what may be given into affected joint?
oral corticosteroids or corticosteroid injections
80
What is the second line treatment drug if gout acute attacks are frequent?
canakinumab (IL-1b therapy mab)
81
what is chronic gout characterised by?
frequent occurence and the prescence of tophi
82
How is the frequent occurence of tophi managed? (chronic gout) 2
need to manage hyperuricaemia...
- xanthine oxidase inhibitors
- uricosuric agent
83
name 2 xanthine oxidase inhibitors which may be used in the management of chronic gout?
allopurinol and febuostat
84
name a uricosuric agent that may be used in the management of chronic gout?
probenecid
85
why can xanthine oxidiase inhibitors or uricosuric agents not be given during an attack?
can precipitate further attacks
86
what does IL-1B monoclonal antibody do in gout and give an example
Canakinumab
reduces pain
and risk of flares in px initiating allopurinol treatment
87
what does IL-1rilonacept do in gout?
reduced gout flares
88
why does chronic gout require the management of hyperuricaemia?
protect kidneys
89
Rheumatology SGT ------------
IL-1B therapies: anakinra, canakinumab, rilonacept all prevention action of what?
IL1 receptor... redcuing pain, inflammation, fever
90
anakinra and rilonacept both target...
IL-1a and IL-1b cytokines
91
canakinumab targets..
IL-1b cytokine
92
What factors distinguish hereditary fever syndromes from typical fevers
Cause: Typical fever caused by infection but hereditary: gen mutations
93
Familial Mediterranean Fever (FMF) symptoms/ results?
* 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
characteristic rash in FMF?
ankle and foot rash
95
what would result in raised ESP and CRP in FMF?
* Joint swelling and inflammation
96
cause of FMF?
* 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
Pyrin detects intracellular pattern rec. receptor in cytoskeleton
Inactivated by what, in FMF?
by the activation of GTPases from infection.
98
what pathwya affected in FMF?
IL1
99
clinical tests could be performed to provide a more definitive diagnosis of FMF?
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
long term risks of FMF
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
what to monitor in FMF px?
renal function through urine and blood tests. Key markers: abnormal urine albumin levels and persistent reduction in eGFR
102
treatment to start in FMF px asap?
Colchicine
prophylactic treatment for the FMF attacks
Recommended in all patients regardless of the frequency and intensity of attacks
103
why is Colchicine used in FMF? (MoA)
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
second line treatment for FMF: IL-1b targeted therapy.
who is it used in and what does it treat?
For colchicine resistant patients: therapies that target IL-1b directly e.g. rilonacept, canakinumab, anakinra
Used to treat cause
105
how is AOSD diagnosed?
in adults
* Intermittent fever lasting a week
* Arthralgia/ arthritis
* Salmon coloured rash
* Muscle pain
* Negative for auto-antibodies
