Autoinflammatory: Hereditary, AOSD, Gout Flashcards
L1 hereditary fevers
broad definition, What are auto-inflammatory conditions?
group of diseases that manifest as recurrent fevers and episodes of inflammation
What are the 4 characteristics of auto-inflammatory conditions?
- skin rashes
- joint inflammation
- no infection
- absence of auto-antibodies
What parts of the immune system are typically involved in auto-inflammatory conditions?
- high acute phase responses
- innate immune system
How do autoimmune diseases differ from autoinflammatory conditions?
- autoimmune involves T and and B cells, autoinflammatory involves innate + acute phase response
- autoimmune has female prevalence, autoinflammatory has equal
What are hereditary fever syndromes?
Group of disorders characterised by episodic fevers without infections
What distinguishes hereditary fever syndromes from typical fevers?
- no infectious cause (negative serology)
- periodic
- genetic mutation in innate system
3 examples of hereditary fever syndromes?
- Familial Mediterranean Fever (FMF)
- HIDS (hyperimmunoglobulinemia D syndrome or hyper IgD syndrome)
- TNF receptor–associated periodic syndrome (TRAPS)
What has been genetically discovered to play a pathogenic role in hereditary fever syndromes?
mutations in genes linked to dysfunction in innate immune system
What do bloods of hereditary fever syndrome patients show?
+3 examples
increase in acute phase response proteins:
- ESR
- CRP
- serum amyloid A (SAA)
Where in the world is FMF most prevalent?
eastern Mediterranean region
What symptoms are found within all hereditary fever syndromes?
- fever of varying persistence
- severe abdominal pain
- joint swelling/pain and inflammation
- rash of some form
What symptoms are exclusive to FMF?
- fever is episodic, lasting 12hrs to 3 days
- rash found on feet and lower legs
- amyloidosis
What is amyloidosis and what can it result in?
amyloid build up in kidneys, -> kidney failure
What is the genetic basis of FMF?
linked to>180 mutations in MEFV gene
-> abnormal Pyrin protein: which is a pattern recognition receptor
What symptoms are exclusive to HIDS/MKD?
- fever is periodic, lasting 1 week
- enlarged liver and spleen
- swollen lymph notes
What ethnic group does HIDS most affect? What is its prevalence?
- mostly Europeans
- extremely rare: only 200 reported cases
What is found in the blood of HIDS patients?
high levels of IgD
What is the genetic basis for HIDS?
Mutation in the MVK (mevalonate kinase) gene
What ethnic group does TRAPS most affect? What is its prevalence?
- mostly Europeans
- extremely rare: 1 per 10 million
What symptoms are exclusive to TRAPS?
- 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
What is the genetic basis of TRAPS?
mutations in TNF receptor
Summarise the causes of all hereditary fever syndromes.
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
Summarise the difference in fever of all hereditary fever syndromes.
FMF: episodic, 12hrs-3 days
HID: periodic, 1 week
TRAPS: more persistent, 1-4 weeks
Explain the molecular mechanism behind FMF.
- mutated pyrin -> activation of NAPL3 inflammasome
- activates Caspase-1
- increased secretion of IL-1B
-> increases migration of neutrophils to body cavities
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
What are the 4 different categories of therapies of hereditary fever syndromes?
- symptomatic
- preventative
- IL-1B biologics
- TNF biologics
What are the symptomatic treatments used to treat hereditary fever syndromes? and role
- NSAIDs
- glucocorticoids
both reduce pain and inflammation
preventative treatment for hereditary fever syndromes?
colchicine
How does colchicine work?
- inhibits NALP3 inflammasome
-> reduces caspase-1 activation and hence reduces IL-1B release
-> also inhibits neutrophil migration
What is the typical dose of colchicine? How long for?
1-2mg daily, life-long
What are the main side-effects of colchicine?
GI: diarrhoea, nausea, vomiting
what does colchicine reduce long term risk of?
amyloidosis and kidney failure
What is used for colchicine resistant patients?
IL-1B therapy
3 examples of IL-1B therapies?
- rilonacept (Arcalyst)
- canakinumab
- anakinra
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)
What is canakinumab and how does it work?
- monoclonal antibody
- mops up IL-1B by binding to it directly + neutralising in system
What is anakinra and how does it work?
- recombinant protein
- acts as a IL-1 receptor antagonist
so it cant bind and be activated
2 examples of anti TNF therapies?
- etanercept
- infliximab
been used to limited effect for patients with hereditary fever syndromes
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
What is infliximab and how does it work?
- chimeric monoclonal antibody
- binds to TNF
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
L2: AOSD
What is AOSD and prevalence?
Adult onset still disease
rare
AOSD symptoms? 6
- intermittent fever lasting a week
- arthritis
- salmon-coloured rash
- sore throat
- enlarged liver/spleen
- muscle pain
AOSD symptoms? what would indicate liver dysfunction in the blood results?
increased liver enzymes and ferritin
what colour is the rash described as that patients present with in AOSD?
salmon
how long does intermittent fever last in AOSD?
a week
effect of AOSD on px liver and spleen?
enlarged
Would the blood results be positive or negative for autoantibodies? AOSD
negative
What is the first line treatment for AOSD? (2) and what do they do?
NSAIDs
Glucocorticoids
-> reduce pain and inflamation
What is the second line treatment for AOSD? class
disease modifying treatments
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)
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
what are CRP and ESR?
and what drugs reduce levels?
acute phase response proteins…
Rilonacept and canakinumab in AOSD therapy
L3 Gout
What is gout the accumulation of?
deposition of MonoSodium Urate (MSU) crystals in joints
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%)
What are the common joint sites of gout?
Most common: big toe
Knee, ankle, instep, elbow
Less common in shoulder, wrist, finger
how many joints involved/ affected in early stages of gout?
only 1-2
What are risk factors of gout? 7
- Male gender
- Increased age
- diet: Obesity / metabolic syndrome
- HTN
- CKD
- OA
- Genetics
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
4 dietary purine examples… that leas to over production of uric acid?
- meat
- seafood
- beer
- drinks with fructose
2 conditions that may result in increased purine synthesis -> overproduction of uric acid?
malignancy (lymphoproliferative diseases)
HGPRT deficiency
underexcretion is the reason for 90% of gout cases.
what 2 things can it be caused by?
renal failure
diuretic drugs
name 2 diuretic drugs that may cause under excretion ..-> gout?
HTZ (hydrochlorothiazide)
aspirin
What are feature of acute gout attacks?
Sudden onset usually night
Acute inflammation
Completely resolved between 5-10 days
Usually only 1 joint affected
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
chronic gout is polyarticular. What is meant by polyarticular?
acute attacks more frequent and involve more joints
Where might patients with chronic gout find tophus (deposits of sodium urate)? 3
joints, kidneys and external ear
tophus (deposits of sodium urate) in kidneys can lead to (2)?
kidney stones
nephropathy
what diagnostic method can detect the prescence of MSU?
ultrasound of joint
what diagnostic method can detect tophi deposits, calcifications and erosions of the joint?
x rays
what parameters are measured via blood tests/ elevated levels of what are being investigated?
acute phase proteins such as ESR and CRP and uricaemia
what is the study of joint fluid analysis?
when joint fluid can be aspirated and MSU crystals can be observed by microscopy.
what do MSU crystals activate (innate immue system)?
tissue resident macrophages
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
MOA of gout- both mechansims (signal 1 + 2) lead to what 2 things?
inflammasome activation and IL-1B release
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
what drug class are patients w gout first treated with when they have acute attacks?
NSAIDs
what drug can be used for acute attacks where NSAIDS are contraindicated? gout
colchicine
for acute attacks of gout, what may be given into affected joint?
oral corticosteroids or corticosteroid injections
What is the second line treatment drug if gout acute attacks are frequent?
canakinumab (IL-1b therapy mab)
what is chronic gout characterised by?
frequent occurence and the prescence of tophi
How is the frequent occurence of tophi managed? (chronic gout) 2
need to manage hyperuricaemia…
- xanthine oxidase inhibitors
- uricosuric agent
name 2 xanthine oxidase inhibitors which may be used in the management of chronic gout?
allopurinol and febuostat
name a uricosuric agent that may be used in the management of chronic gout?
probenecid
why can xanthine oxidiase inhibitors or uricosuric agents not be given during an attack?
can precipitate further attacks
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
what does IL-1rilonacept do in gout?
reduced gout flares
why does chronic gout require the management of hyperuricaemia?
protect kidneys
Rheumatology SGT ————
IL-1B therapies: anakinra, canakinumab, rilonacept all prevention action of what?
IL1 receptor… redcuing pain, inflammation, fever
anakinra and rilonacept both target…
IL-1a and IL-1b cytokines
canakinumab targets..
IL-1b cytokine
What factors distinguish hereditary fever syndromes from typical fevers
Cause: Typical fever caused by infection but hereditary: gen mutations
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
characteristic rash in FMF?
ankle and foot rash
what would result in raised ESP and CRP in FMF?
- Joint swelling and inflammation
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.
Pyrin detects intracellular pattern rec. receptor in cytoskeleton
Inactivated by what, in FMF?
by the activation of GTPases from infection.
what pathwya affected in FMF?
IL1
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
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.
what to monitor in FMF px?
renal function through urine and blood tests. Key markers: abnormal urine albumin levels and persistent reduction in eGFR
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
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)
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
how is AOSD diagnosed?
in adults
* Intermittent fever lasting a week
* Arthralgia/ arthritis
* Salmon coloured rash
* Muscle pain
* Negative for auto-antibodies
