RheumatologyTier 2Disease (DEADMAN)

Periodic fever syndromes

Description

Autoinflammatory, not autoimmune: innate immune dysregulation with excess IL-1beta
- *No autoantibodies, no autoreactive T cells* - the discriminator from CTD
Stereotyped, self-limiting, recurrent attacks of fever + serositis + rash + arthritis, with complete wellness between attacks
Acute phase reactants rise during attacks and should normalise between them - persistent elevation between attacks predicts amyloidosis

	Gene / protein	Inheritance	Attack duration	Distinctive feature
FMF	**MEFV / pyrin**	AR	1-3 days	Erysipeloid rash on the lower leg/ankle; peritonitis
TRAPS	TNFRSF1A / TNF receptor 1	AD	>7 days (weeks)	Migratory myalgia with overlying rash, periorbital oedema
HIDS / mevalonate kinase deficiency	MVK	AR	3-7 days	Cervical lymphadenopathy, oral/genital ulcers, high IgD; triggered by vaccination
CAPS (FCAS, Muckle-Wells, NOMID/CINCA)	**NLRP3 / cryopyrin**	AD	Hours-days (often continuous)	Urticarial rash, sensorineural deafness; cold-triggered (FCAS)
PFAPA	Non-genetic	-	3-5 days, clockwork	Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis; children; aborts with a single steroid dose
DADA2	ADA2	AR	Variable	PAN-like vasculitis + early lacunar strokes; treat with TNF inhibitors
VEXAS	**UBA1 somatic**	Acquired, men >50	Continuous	Chondritis, vacuoles in myeloid precursors, macrocytic anaemia, MDS

Epidemiology

FMF is by far the commonest
- Mediterranean ancestry: Sephardic Jewish, Armenian, Turkish, Arab - carrier rate up to 1 in 5
- Onset <20 years in ~90%, <10 years in ~65%
PFAPA is the commonest periodic fever syndrome in children overall and is not genetic
VEXAS - adult-onset, essentially confined to men over 50 (X-linked somatic UBA1 mutation in haematopoietic cells)

Aetiopathogenesis

The common pathway

Inflammasome dysregulation -> caspase-1 -> uncontrolled IL-1beta release
-> fever, serositis, neutrophilia, acute phase response
*This is why IL-1 blockade works across almost the whole group*

FMF

*Loss-of-function MEFV mutations -> abnormal pyrin*
Pyrin normally restrains inflammasome activation -> dysregulated pyrin inflammasome -> excess IL-1beta
Common mutations: M694V (most severe, highest amyloidosis risk), V726A, M680I, E148Q
Autosomal recessive, but heterozygotes can have a mild phenotype

TRAPS

TNFRSF1A misfolding -> impaired receptor shedding + ER stress -> sustained inflammatory signalling

CAPS

*Gain-of-function NLRP3 -> constitutive inflammasome activation*

AA amyloidosis - the shared endpoint

Chronic elevation of serum amyloid A (SAA) during and between attacks
-> AA fibril deposition, predominantly renal -> proteinuria -> nephrotic syndrome -> ESKD
The reason to suppress subclinical inflammation, not just attacks

Diagnosis

When to suspect

>=3 stereotyped episodes of unexplained fever with complete resolution between
Onset in childhood or adolescence (except VEXAS)
Family history and ethnicity
Raised CRP/ESR/SAA and neutrophilia during attacks
Negative autoantibody and infectious workup

FMF clinical picture

Fever 38-40 C lasting 1-3 days, abrupt onset
Serositis
- Peritonitis (~90%) - frequently mistaken for appendicitis; many patients have had a negative laparotomy
- Pleuritis (~40%) - unilateral pleuritic chest pain
- Pericarditis (rare)
Mono- or pauciarticular arthritis of large lower-limb joints - non-erosive, resolves completely
- A protracted arthritis of the hip or knee is a recognised chronic variant
Erysipeloid erythema over the lower leg, ankle or dorsum of the foot - the pathognomonic rash
Scrotal pain (tunica vaginalis serositis), exertional myalgia, splenomegaly
Attacks triggered by stress, menstruation, infection, cold, exercise

Investigations

Genetic testing - MEFV panel for FMF; targeted or gene-panel testing for the others
- *FMF remains a clinical diagnosis - up to 20-30% of clinically definite cases have only one identifiable mutation*
CRP, ESR, SAA, FBE during AND between attacks
- A persistently raised SAA between attacks is the key amyloidosis risk marker
Urinalysis and UPCR at every review - proteinuria is the first sign of AA amyloidosis
Serum IgD and urinary mevalonic acid (HIDS)
Renal or fat-pad biopsy with Congo red if proteinuria - apple-green birefringence, AA typing
Bone marrow with attention to vacuoles in myeloid and erythroid precursors if VEXAS suspected

Differential

Recurrent infection, Still disease (adult and systemic JIA), Behcet disease, IBD, cyclical neutropenia, malignancy (lymphoma), factitious fever
Behcet overlaps heavily with FMF in the same populations - oral and genital ulcers, uveitis, pathergy

Management

Axis: attack prevention first (which also prevents amyloidosis), then escalation for colchicine resistance, then treatment of established complications.

A. FMF - colchicine is the whole treatment

Colchicine 1-2 mg daily (up to 2.4 mg), lifelong, from diagnosis
- Prevents attacks in ~60% completely and reduces them in a further ~30%
- *Prevents AA amyloidosis - the single most important reason to take it*
- *Much less effective at aborting an attack once it has started* - it is prophylactic, not abortive
- *Does not reverse established joint damage or established amyloid nephropathy*
Adherence is the main determinant of outcome - most "colchicine resistance" is non-adherence
- Check for it explicitly before escalating
Dose-limiting: diarrhoea (divide the dose, reduce lactose), nausea
- Reduce in renal impairment; beware CYP3A4/P-gp inhibitors (clarithromycin, ciclosporin, verapamil)
Continue colchicine through pregnancy and breastfeeding - it is safe and stopping it risks flare and amyloidosis

B. Colchicine-resistant or intolerant FMF (~5-10%)

IL-1 blockade: anakinra (daily) or canakinumab (8-weekly)
- Continue colchicine alongside where tolerated - it retains an amyloid-protective effect
Definition of resistance: >=1 attack per month over 3 months on maximum tolerated colchicine, or persistently raised CRP/SAA between attacks

C. Other syndromes

CAPS: IL-1 blockade is the treatment of choice - anakinra, canakinumab, rilonacept; transforms the disease and prevents deafness and amyloidosis
TRAPS: glucocorticoid for attacks; IL-1 blockade for frequent attacks (etanercept has modest, declining efficacy; anti-TNF monoclonals are contraindicated - they worsen TRAPS)
HIDS/MKD: IL-1 blockade; glucocorticoid at attack onset
PFAPA: a single dose of prednisolone aborts the attack (though it may shorten the interval); cimetidine, colchicine; tonsillectomy is curative in most
DADA2: TNF inhibitors - prevent strokes; steroids and other immunosuppressants do not
VEXAS: glucocorticoid-dependent; JAK inhibitors (ruxolitinib) and IL-6 blockade have partial effect; allogeneic stem cell transplantation is the only curative option

D. Monitoring and complication prevention

CRP and SAA between attacks - the target is normalisation, not just fewer attacks
Annual (or more frequent) urinalysis and UPCR for amyloid nephropathy
Growth and puberty in children; fertility (colchicine does not impair it)
Genetic counselling and family cascade testing
Established AA amyloidosis: suppress inflammation maximally with IL-1 blockade, ACE inhibitor/ARB for proteinuria, renal replacement or transplantation (colchicine must continue after transplant)

Associations

AA (reactive) amyloidosis - the defining complication
Vasculitis - FMF is associated with Henoch-Schonlein purpura (IgA vasculitis) and polyarteritis nodosa
Behcet disease - overlapping populations and features
Sacroiliitis and spondyloarthritis - in FMF, often HLA-B27 negative
Sensorineural deafness - CAPS (Muckle-Wells, NOMID)
Chronic aseptic meningitis, papilloedema, bony overgrowth - NOMID/CINCA
Early lacunar stroke, immunodeficiency, cytopenias - DADA2
Myelodysplastic syndrome and monoclonal gammopathy - VEXAS
Infertility and adhesions from recurrent peritonitis (historically)
Anaemia of chronic disease, growth failure in children

Natural history & complications

Attacks recur lifelong without treatment, decreasing somewhat with age
Colchicine-treated FMF has a normal life expectancy
*Untreated FMF: AA amyloidosis in up to 60-75% of high-risk genotypes* -> nephrotic syndrome -> ESKD -> death in the 4th-5th decade

Amyloidosis risk factors

M694V homozygosity
Male sex
Non-adherence or delayed diagnosis
Persistently raised SAA/CRP between attacks
Family history of amyloidosis
Certain ethnic backgrounds (higher in North African Jewish, Turkish and Armenian populations)
Amyloidosis can be the presenting feature - "phenotype II" FMF with amyloid nephropathy and no attack history

Complications

AA amyloid nephropathy -> nephrotic syndrome -> ESKD (also GI, hepatic, cardiac, adrenal, thyroid deposition)
Chronic destructive arthritis (protracted FMF arthritis of hip or knee)
Peritoneal adhesions and small bowel obstruction
Sensorineural deafness, blindness, CNS damage in CAPS
Growth failure and delayed puberty in children
Unnecessary surgery - appendicectomy, laparotomy
Colchicine toxicity: diarrhoea, myopathy, neuropathy, marrow suppression

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