Familial Mediterranean Fever and Autoinflammatory Syndromes
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Direct answer
Familial Mediterranean fever is an autosomal recessive autoinflammatory disorder caused by MEFV mutations, which alter the protein pyrin and produce recurrent fever with serositis. Attacks typically last one to three days, and colchicine given long term reduces attacks and prevents AA amyloidosis, the most feared complication. Colchicine-resistant disease responds to interleukin-1 blockade.
What you must remember
- Inheritance and gene: autosomal recessive, with MEFV on chromosome 16 encoding pyrin; M694V is the commonest variant.
- Attacks: fever lasting one to three days with serositis, such as peritonitis, pleuritis, pericarditis or synovitis, often with erysipelas-like erythema over the legs.
- Populations: higher prevalence among Armenians, Turks, Arabs and Sephardic Jews, though the disease occurs in other groups too.
- Colchicine: the mainstay of prevention, given long term to reduce attacks and protect against amyloid deposition, with the dose adjusted for renal function.
- Amyloidosis: AA amyloid deposits in the kidneys cause proteinuria that can progress to nephrotic syndrome and renal failure.
- Refractory disease: interleukin-1 blockade with anakinra or canakinumab is used when colchicine fails or is not tolerated.
- Related syndromes: TRAPS, hyper-IgD syndrome and cryopyrin-associated periodic syndromes, each with a different gene and inheritance pattern.
- Diagnosis: clinical, with acute-phase reactants raised during attacks and MEFV testing supporting the diagnosis.
Autoinflammatory syndromes compared
Autoinflammatory disease is driven by innate immune signalling rather than autoantibodies or T cells, which is why the fevers come in attacks with clean serology. Each syndrome has its own gene, so a clinician can often name the likely diagnosis from the pattern of attacks and the family history. The table compares the common periodic fever syndromes.
| Syndrome | Gene and inheritance | Key feature |
|---|---|---|
| Familial Mediterranean fever | MEFV (pyrin), autosomal recessive | Serositis, responds to colchicine |
| TRAPS | TNFRSF1A, autosomal dominant | Attacks lasting over a week, periorbital oedema, migratory myalgia |
| Hyper-IgD syndrome | MVK (mevalonate kinase), autosomal recessive | Attacks with raised IgD, lymphadenopathy and abdominal pain |
| Cryopyrin-associated syndromes | NLRP3, autosomal dominant | Urticarial rash, cold-triggered attacks in the familial cold form |
Colchicine works well for familial Mediterranean fever but is less reliable in the others, which respond more to interleukin-1 or TNF blockade. Attack duration is the first clue, since FMF attacks last a few days while TRAPS attacks often run for more than a week. Matching the syndrome to its gene and inheritance pattern is the examinable skill.
Where the exam tries to catch you
Autoinflammatory questions usually turn on the inheritance pattern, the treatment of attacks and the amyloid complication.
- Trap: calling familial Mediterranean fever autosomal dominant Correct: FMF is autosomal recessive, whereas TRAPS and cryopyrin-associated syndromes are autosomal dominant.
- Trap: treating every sterile fever with antibiotics Correct: FMF attacks are sterile, so antibiotics do not help, and NSAIDs or colchicine are the relevant agents.
- Trap: ignoring proteinuria in a patient with FMF Correct: proteinuria raises the possibility of AA amyloidosis, and renal function and urine protein need monitoring.
- Trap: assuming colchicine works for every periodic fever Correct: colchicine is the drug of choice for FMF, but the other syndromes need different biologic treatment.
Frequently asked questions
Which gene is mutated in familial Mediterranean fever?
The MEFV gene, which encodes the protein pyrin, is mutated in familial Mediterranean fever. The M694V variant is the commonest, and inheritance is autosomal recessive.
What is the main long-term complication of familial Mediterranean fever?
AA amyloidosis is the main long-term complication of familial Mediterranean fever, depositing in the kidneys and causing proteinuria, nephrotic syndrome and renal failure. Colchicine reduces this risk when it is given consistently.
Why is colchicine given long term in familial Mediterranean fever?
Colchicine is given long term to reduce the frequency of attacks and to prevent AA amyloidosis. Its dose is adjusted for renal function, and it is usually continued indefinitely once started.
Which biologic treats colchicine-resistant familial Mediterranean fever?
Interleukin-1 blockade with anakinra or canakinumab is used for colchicine-resistant familial Mediterranean fever. These agents target the cytokine that drives the inflammatory attacks in the autoinflammatory syndromes.