ImmunologyTier 1Medical Sciences concept

Autoinflammatory syndromes and the inflammasome (FMF, gout, Blau, Schnitzler, CAPS)

Core concept

Autoinflammatory = INNATE immune activation without autoantibody or autoreactive T cells
- Contrast autoimmune: adaptive, antibodies/T cells, HLA-linked, responds to B/T-cell-directed therapy
Inflammasome = a cytosolic multiprotein complex that activates caspase-1
- NOD-like receptors (NLRs) are cytosolic sensors - they patrol the cytoplasm for PAMPs and DAMPs, the counterpart of the surface/endosomal TLRs
- Sensor (NLRP3, pyrin, NLRC4, AIM2) + adaptor ASC + pro-caspase-1
Two-signal model for NLRP3
- Signal 1 (priming) - NF-kB via TLR/IL-1R -> transcription of pro-IL-1beta and NLRP3
- Signal 2 (activation) - K+ efflux, lysosomal rupture from phagocytosed crystals, ROS, ATP, pore-forming toxins -> assembly
- -> caspase-1 cleaves pro-IL-1beta and pro-IL-18 to their active forms, and cleaves gasdermin D -> pyroptosis
-> IL-1beta is the final common effector - and that is why IL-1 blockade works across the whole family

Key detail

Syndrome	Gene / protein	Inheritance	Attack pattern	Signature
FMF	MEFV -> pyrin	AR (M694V worst)	12-72 h, brief	Serositis - peritonitis, pleuritis; erysipeloid rash on the shin/ankle; monoarthritis; AA amyloidosis
CAPS (FCAS / Muckle-Wells / NOMID-CINCA)	NLRP3 -> cryopyrin	AD	Minutes-days, cold-triggered in FCAS	Urticarial (non-pruritic, neutrophilic) rash; sensorineural deafness and AA amyloid in Muckle-Wells; NOMID adds chronic meningitis, papilloedema, bony overgrowth
TRAPS	TNFRSF1A	AD	>7 days - the long one	Migratory myalgia with overlying erythema, periorbital oedema, conjunctivitis
Hyper-IgD / MKD	MVK (mevalonate kinase)	AR	3-7 days, triggered by vaccination	Cervical lymphadenopathy, abdominal pain, aphthous ulcers, high IgD (IgD is neither sensitive nor specific); urinary mevalonic acid in attacks
Blau syndrome / early-onset sarcoidosis	NOD2 (CARD15) - the same gene as Crohn's susceptibility	AD	Chronic	Granulomatous triad: arthritis + uveitis + dermatitis, no lung involvement
Schnitzler syndrome	Acquired, monoclonal IgM	-	Chronic/intermittent	Chronic urticarial rash + IgM paraprotein + fever + bone pain/osteosclerosis; dramatic response to anakinra
PFAPA	Not monogenic	-	Every 3-6 weeks, clockwork	Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis; children; aborts with a single steroid dose - which shortens the interval
Still's disease (AOSD/sJIA)	Polygenic	-	Daily quotidian fever	Salmon-pink evanescent rash, arthritis, sore throat, very high ferritin with low glycosylated fraction; MAS risk
DIRA / DITRA	IL1RN / IL36RN	AR	-	Sterile osteomyelitis / generalised pustular psoriasis
VEXAS	Somatic UBA1 in myeloid cells	Acquired, men >50	Chronic	Vacuoles in myeloid precursors, macrocytic anaemia, chondritis, neutrophilic dermatosis, VTE, MDS

Common to all: fever, high CRP/SAA/ferritin, neutrophilia, NO autoantibodies, no HLA association, and risk of AA amyloidosis with uncontrolled disease
Attack duration is the most useful clinical discriminator: FMF short, TRAPS long, PFAPA clockwork

Clinical relevance

Crystal arthritis is an inflammasome disease

Monosodium urate and CPPD crystals are phagocytosed -> lysosomal destabilisation -> NLRP3 activation -> IL-1beta
- -> explains why IL-1 blockade (anakinra, canakinumab) aborts an acute gout flare when NSAIDs, colchicine and steroids are contraindicated
- Colchicine works by disrupting microtubules -> blocks NLRP3 assembly/trafficking and neutrophil chemotaxis - not by affecting urate at all
- This is also why colchicine is effective in FMF and in recurrent pericarditis

Therapy by mechanism

IL-1 blockade
- Anakinra - recombinant IL-1 receptor antagonist, short t1/2, daily injection with painful injection-site reactions; useful diagnostically as a rapid trial
- Canakinumab - anti-IL-1beta mAb, monthly; CAPS, FMF, TRAPS, MKD, Still's, gout
- Rilonacept - IL-1 trap; recurrent pericarditis
Colchicine - first-line for FMF (prevents attacks and amyloidosis), gout, pericarditis; diarrhoea is dose-limiting; toxic in renal impairment and with CYP3A4/P-gp inhibitors (clarithromycin, ciclosporin)
IL-6 (tocilizumab) for Still's; TNF inhibition for TRAPS and Blau; JAK inhibition for interferonopathies (SAVI, CANDLE, STING)
AA amyloidosis is the shared long-term complication - monitor SAA and urine protein in every uncontrolled autoinflammatory patient
Broader relevance of NLRP3: implicated in gout, type 2 diabetes, atherosclerosis (CANTOS - canakinumab reduced cardiovascular events), and NASH

Correlations

Interleukin functions - IL-1, IL-6, IL-18
Gout and pseudogout; crystal arthropathy microscopy
Amyloidosis - AA type
Innate immunity - PRRs, TLRs, PAMPs and DAMPs
Adult-onset Still's disease; HLH/macrophage activation syndrome
Recurrent pericarditis
Periodic fever in the returning traveller - differential of fever without a source

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