Definition and genetics
Familial Mediterranean fever (FMF) is the prototypic monogenic autoinflammatory disease — recurrent, self-limited attacks of fever and polyserositis driven by dysregulated innate immunity, not autoantibodies or antigen-specific T cells. It is caused by mutations in MEFV (chromosome 16p13.3), which encodes pyrin. The classic inheritance is autosomal recessive, though a minority of symptomatic patients carry only a single demonstrable pathogenic variant. The most common disease-associated alleles cluster in exon 10 (M694V, M680I, V726A, M694I); M694V homozygosity carries the highest risk of severe disease and amyloidosis. FMF predominantly affects populations of the eastern Mediterranean basin — Sephardic and other Jews, Armenians, Turks, and Arabs — but is reported worldwide.
Episode pattern
The hallmark is brevity and stereotypy: attacks last 1–3 days (rarely up to 4) and resolve completely to baseline health, separated by symptom-free intervals of weeks to months. Onset is in childhood in the majority — about 90% before age 20, often before age 10. Triggers include physical exertion, emotional stress, menstruation, cold exposure, and infection, though many attacks are unprovoked. Unlike TRAPS or HIDS, FMF attacks are short.
Clinical features
Fever (often 38–40°C) accompanies serositis: sterile peritonitis (the most frequent feature — diffuse abdominal pain mimicking a surgical abdomen, sometimes leading to unnecessary laparotomy), unilateral pleuritis, and less commonly pericarditis. Acute, usually monoarticular arthritis of large lower-limb joints (hip, knee, ankle) is common. An erysipelas-like erythema over the lower leg or dorsum of the foot is characteristic. Exertional leg pain occurs in children. Acute-phase reactants (CRP, SAA, ESR) rise sharply during attacks and should normalise between them — persistent subclinical inflammation is a warning sign.
Diagnosis
Diagnosis is clinical, supported by ethnicity, family history, colchicine response, and MEFV genotyping (a confirmatory biallelic result strengthens but is not required, and a negative result does not exclude FMF). The Tel Hashomer criteria remain widely used; the 2019 Eurofever/PRINTO classification criteria integrate genetic and clinical variables to distinguish FMF from other hereditary recurrent fevers, reaching ~94% sensitivity / ~83% specificity with combined criteria.
See the full criteria: Familial Mediterranean Fever (FMF)
Red flags
- AA (secondary) amyloidosis — the most serious long-term complication, driven by chronic serum amyloid A elevation. Presents as proteinuria progressing to nephrotic syndrome and renal failure. Screen with periodic urinalysis and inter-attack SAA/CRP; persistent proteinuria warrants evaluation.
- Persistently elevated acute-phase reactants between attacks (ongoing subclinical inflammation).
- Atypically long attacks (>4 days), prominent periorbital oedema, or vaccination-triggered attacks — reconsider TRAPS or MKD/HIDS.
Management overview
Colchicine is the cornerstone — lifelong, taken continuously (not only during attacks) to prevent attacks and, critically, to prevent amyloidosis. It is effective in the large majority and adherence is central to outcome; dose is titrated to attack control and tolerability. For colchicine-resistant or colchicine-intolerant patients, IL-1 blockade (e.g. anakinra, canakinumab) is the established next step. Colchicine should be continued even when biologics are added, for ongoing amyloidosis protection. Manage acute attacks supportively. (Therapeutic classes only — confirm agent, dose, and monitoring against current formularies.)
References
- Gattorno M, et al. Ann Rheum Dis. 2019;78:1025–1032 (Eurofever/PRINTO).
- Livneh A, et al. Arthritis Rheum. 1997;40:1879–1885 (Tel Hashomer).
- Ozen S, et al. Ann Rheum Dis. 2016;75:644–651 (EULAR management).
- Nelson Textbook of Pediatrics, 21st ed.
Decision support for qualified clinicians only — verify against current primary guidelines and your clinical judgement.