Autoinflammatory disorders Flashcards by Anish Khakhria

what are autoinflammatory disorders?

A group of diseases that manifest as recurrent fevers and episodes of inflammation
* Presence of skin rashes and joint inflammation and No infection
* Absence of auto- antibodies that are typical of autoimmune diseases
* Typically high acute phase
responses and involvement of innate
immune system

How well did you know this?

Not at all

Perfectly

what are some examples of auto inflammatory conditions?

IBD
behcet’s disease
gout
psoriasis

How well did you know this?

Not at all

Perfectly

what characteristics for auto inflammatory disease compared to autoimmune diseases?

inflammatory:
- use of innate immunity
-prevalent in both sex

immune:
- t and b cell involvement
- female predominantly

How well did you know this?

Not at all

Perfectly

what are hereditary fever syndromes?

disorders characterised by episodic fevers (irregular fevers)

How well did you know this?

Not at all

Perfectly

what are some examples of hereditary fever syndrome?

Familial Mediterranean Fever(FMF)
HIDS (hyperimmunoglobulinemia D syndrome)
TNF receptor- associated periodic syndrome (TRAPS)

How well did you know this?

Not at all

Perfectly

what is episodic fevers?

irregular fevers

How well did you know this?

Not at all

Perfectly

how does hereditary fever syndrome occur?

mutations in genes that are linked to dysfunction in an innate immune system

> 180 mutations in MEFV gene = abnormal pyrin protein

How well did you know this?

Not at all

Perfectly

how is hereditary fever syndrome detected?

blood increases acute phase response proteins
- elevated ESR/CRP/ serum amyloid A (SAA)

How well did you know this?

Not at all

Perfectly

what are the symptoms of hereditary fever syndrome?

Episodic fever lasting 12 hours to 3 days
Severe abdominal pain
Joint swelling and inflammation
Skin rashes-often on feet and lower legs
FMF can also lead to amyloidosis (build up of amyloid in kidneys), which can result in kidney failure

How well did you know this?

Not at all

Perfectly

what is pyrin?

pattern recognition receptor

How well did you know this?

Not at all

Perfectly

how does familia mediterranean fever (FMF) occur?

> 180 mutations in MEFV gene = abnormal pyrin protein

How well did you know this?

Not at all

Perfectly

what are the symptoms of hyperimmunoglobulinemia D syndrome (HIDS/MKD)?

Periodic fever, typically lasting 1 week
Rash
Severe abdominal pain
Joint pain and inflammation
Enlarged liver and spleen
Swollen lymph nodes
High levels of IgD in blood

How well did you know this?

Not at all

Perfectly

who is mainly succeptible to hyperimmunoglobulinemia D syndrome (HIDS/MKD)?

europeans

How well did you know this?

Not at all

Perfectly

who is mainly succeptible to familia mediterranean fever (FMF)?

eastern mediterranean

How well did you know this?

Not at all

Perfectly

who is mainly succeptible to TRAPS?

Europeans

How well did you know this?

Not at all

Perfectly

what are the symptoms of TRAPS?

More persistent fever, typically lasting 1-4 weeks
Severe abdominal pain
Joint and muscle pain
Swollen eyes and conjunctivitis
Painful migrating rash on upper body and/or arms and legs
TRAPS can also lead to amyloidosis

explain how FMF induces a disease state

mutated pyrin = activates NAPL3 inflammasome = activate Caspase-1 = secrete IL-1B = increase neutrophils to body cavities = inflammation induction

explain how TRAPS induces a disease state

TNFR mutation = TNF receptor inactive = less soluble TNF-a ligand signalling = impaired TNF binding

what is the treatment for hereditary disease?

FIRST LINE
symptomatic treatments - NSAIDs, GC’s to reduce pain/inflammation
& colchicine as a preventative
SECOND LINE
colchicine resistant - anti-IL-1B (anakinra/canakinumab/rilonacept)

what are the drug characteristics of colchicine? and side effects

1-2 mg/daily
life long treatment
reduces long term risk of amyloidosis and kidney failure

SIDE EFFETS:
Gastrointestinal side-effects (nausea,
vomiting and diarrhoea)

what is the mode of action of colchicine?

Inhibits the NALP3 inflammasome
* Reduces caspase-1 activation
* Results in a reduction in IL-1β release

Also inhibits neutrophil migration

what can you give as an alternative for colchicine resistant pts?

ANTI-IL1B TREATMENT:
Rilonacept (Arcalyst)
* Fusion protein with domains of IL-
1β receptors.
* Acts to trap IL-1β (IL-1TRAP)
Canakinumab
* Monoclonal Antibody that mops
up IL-1β
Anakinra
* Recombinant protein that acts as a IL-1 receptor antagonist

what can you give as an alternative for colchicine resistant pts ?

Rilonacept (Arcalyst)
* Fusion protein with domains of IL-
1β receptors.
* Acts to trap IL-1β (IL-1TRAP)
Canakinumab
* Monoclonal Antibody that mops
up IL-1β
Anakinra
* Recombinant protein that acts as a IL-1 receptor antagonist

what are anti-TNF treatments?

Etanercept
* Dimeric fusion protein composed of
2x human TNF receptors fused to
Fc portion of IgG1.
* Acts as a decoy receptor for TNF

Infliximab
* Chimeric monoclonal antibody
* Binds to TNF

what are the symptoms of adult onset stills disease (AOSD)?

* Intermittent fever lasting a week * Arthritis/arthralgia * Salmon-coloured rash * Sore throat * Enlarged liver/spleen * Muscle pain * Blood results * Indicates liver dysfunction - increase in liver enzymes and ferritin But negative for auto-antibodies

what is the first and second line treatment for AOSD?

1st line : NSAIDS/GCs to reduce pain/inflammation 2nd line: disease modifying treatments - MTX - IL-1B targeting agents for systemic AOSD Rilonacept or canakinumab - Anti-TNF for articular AOSD

what is gout? and how is it caused?

Gout is the deposition of MonoSodium Urate (MSU) crystals in the joints * excess uric acid production * inefficient processing by the kidneys

what are the common sites for gout to occur?

* Most common in big toe, but can affect multiple joints * Common in knee, ankle, instep, elbow * Less common in shoulder, wrist, finger * In early stage disease, usually only 1-2 joints are involved.

what are the risk factors of gout?

* Male gender (3.6 to 1) * Age * Diet -obesity/Metabolic syndrome * Higher prevalence in developed countries * Hypertension * Chronic Kidney Disease * Osteoarthritis * Genetics

what are the two classes of gout/ MSU crystal production?

1. over-production (10%) 2. under-excretion (90%) or 1. acute attacks 2. chronic gout

how does over-production MSU crystal production occur?

1. increase in dietary purines - meat (beef/pork/lamb) / seafood / beer / drinks with fructose 2. increase purine synthesis - malignancy - HGPRT deficiency

how does under-excretion MSU crystal production occur?

-renal failure -diuretics -hydrochlorothiazide (HTZ) -aspirin

what are acute attacks of gout?

Sudden onset, common during the night Acute inflammation Complete resolution 5-10 days Usually only 1 joint affected

what is chronic gout?

Polyarticular * more frequent and involve multiple joints (polyarticular) * Tophus (deposits of sodium urate) - Joints / External ear /Kidneys (Lead to kidney stones Nephropathy)

how do you detect gout?

* Ultrasound of the joint can detect presence of MSU * X-rays of joint can detect Tophi deposits, calcifications and erosions * Blood rests to examine elevated levels of acute phase response proteins (ESR, CRP) and elevated uricemia * Joint fluid analysis - fluid is aspirated and MSU crystals observed by microscopy

how does gout induce inflammation?

1. MSU crystals phagocytose by macrophages - activation of inflammasomes and release of IL-1B 2. Binding to TLR2/TLR4 on macrophage activation of NFkB, leads to activation of inflammasome and IL-1b release

what is the treatment for acute attacks of gout?

1st line: NSAIDs colchicine used if NSAIDs are contraindicated oral/inj corticosteroids 2nd line: canakinumab if frequent acute attacks

what is the treatment for chronic gout?

Frequent occurrence and presence of tophi requires therapeutic management of hyperuricemia * Xanthine oxidase inhibitors (Allopuriniol, Febuxostat) * Uricosuric agents (e.g probenecid) But not started during an attack since they can precipitate

name Xanthine oxidase inhibitors used for gout

Allopuriniol, Febuxostat