Related Subjects:Acute Cholecystitis
|Acute Appendicitis
|Chronic Peritonitis
|Abdominal Aortic Aneurysm
|Ectopic Pregnancy
|Acute Cholangitis
|Acute Abdominal Pain
|Penetrating Abdominal Trauma
|Acute Pancreatitis
|Acute Diverticulitis
🔥 Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disorder caused by MEFV mutations, leading to recurrent fever, serositis, arthritis, and rash.
⚠️ The major long-term complication is AA amyloidosis → progressive renal failure (preventable with colchicine).
Goal of therapy: suppress attacks + subclinical inflammation (elevated CRP/SAA between attacks) to prevent amyloidosis and organ damage (EULAR/PReS 2024 update).
📖 About
- Most common monogenic autoinflammatory disease worldwide.
- Prevalence highest in Eastern Mediterranean populations:
- Sephardic Jews (carrier rate up to 1:5–1:10) 🇮🇱
- Turks 🇹🇷
- Armenians 🇦🇲
- Arabs (esp. Lebanese, North African) 🇱🇧
- Onset typically in childhood (<10 years in ~65%; adolescence possible).
- Untreated: frequent attacks impair quality of life; amyloidosis risk ~2–60% (highest in M694V homozygotes, males, untreated/poorly adherent).
🧬 Aetiology & Pathophysiology
- Mutations in MEFV gene (chromosome 16p13.3) → pyrin (marenostrin) dysfunction.
- Pyrin regulates inflammasome (caspase-1/IL-1β pathway); loss-of-function → uncontrolled neutrophil activation and IL-1β overproduction.
- Most common pathogenic variants: M694V (severe, high amyloid risk), V726A, M680I, E148Q (often milder).
- Chronic/subclinical inflammation → serum amyloid A (SAA) overproduction → AA amyloid deposition (kidneys, spleen, thyroid, adrenals).
🩺 Clinical Features
- Attacks: self-limited (12–72 hours; average 1–3 days), triggered by stress, infection, exercise, menstruation, or cold.
- Fever ≥38–39°C (universal).
- Abdominal: severe peritonitis-like pain (rigid/tender abdomen; mimics acute abdomen → unnecessary surgery risk); recurrent → peritoneal adhesions, bowel obstruction, female infertility.
- Chest: pleurisy (unilateral pleuritic pain ± effusion), pericarditis (rare).
- Arthritis/arthralgia: monoarthritis (knee, ankle, hip; large joints; resolves without deformity).
- Other: erysipelas-like rash (lower legs), scrotal pain (tunica vaginalis; mimics torsion), myalgia, headache.
- Associated: Henoch-Schönlein purpura (IgA vasculitis), polyarteritis nodosa (rare).
- Between attacks: often asymptomatic; subclinical inflammation (↑CRP/SAA) common in untreated/poorly controlled.
🔬 Investigations
- During attack: neutrophilic leucocytosis, markedly ↑CRP/ESR/SAA, normal/raised ferritin.
- Between attacks: monitor CRP/SAA (persistent elevation → inadequate control/amyloid risk).
- Renal: urinalysis for proteinuria (early amyloid marker); serum creatinine/eGFR; 24h urine protein if positive.
- Genetic testing: MEFV sequencing (confirms diagnosis in atypical cases; identifies high-risk genotypes e.g. M694V homozygous).
- Amyloid confirmation: rectal/salivary gland/fat pad biopsy (Congo red + apple-green birefringence); renal biopsy if needed.
📊 Diagnosis (Tel Hashomer Criteria – Still Standard; EULAR 2024 Endorses Clinical + Genetic Approach)
| ✅ Tel Hashomer Criteria (Diagnosis if ≥1 major OR ≥2 minor criteria) |
|---|
| Major Criteria | Minor Criteria |
|---|
- Typical peritonitis (generalised)
- Typical pleuritis (unilateral) or pericarditis
- Typical monoarthritis (hip/knee/ankle)
- Typical fever alone (≥38°C)
- Incomplete abdominal attack
|
- Incomplete chest attack
- Incomplete monoarthritis
- Exertional leg pain
- Favourable response to colchicine
|
Supportive: family history, Mediterranean ancestry, response to colchicine, elevated acute-phase reactants during attacks. Genetic confirmation strengthens diagnosis but not mandatory in classic cases.
💊 Management (EULAR/PReS 2024 Compliant)
- Colchicine: First-line, lifelong prophylaxis (prevents attacks in >95% and amyloidosis in compliant patients).
- Starting dose (EULAR 2024/BNF-aligned):
- Children <5 years: ≤0.5 mg/day
- 5–10 years: 0.5–1.0 mg/day
- >10 years/adults: 1.0–1.5 mg/day (up to 1.8–2.0 mg if needed)
- Titrate by 0.5–0.6 mg increments (max 2 mg children; 3 mg adults) based on attacks/inflammation (CRP/SAA target: normal/low).
- GI side effects common (diarrhoea); divide doses, start low, lactose-free diet, treat bacterial overgrowth if needed.
- Safe in pregnancy/breastfeeding; discuss fertility (high doses may affect spermatogenesis in males → monitor).
- Colchicine-resistant/intolerant FMF (persistent attacks ≥1/year or subclinical inflammation despite max tolerated dose):
- IL-1 inhibitors preferred (EULAR 2024 strong recommendation):
- Anakinra (daily SC) first-line
- Canakinumab (every 4–8 weeks SC) alternative
- Rilonacept or other IL-1 blockers in select cases.
- Avoid routine thalidomide (toxicity).
- Amyloidosis management: Intensify colchicine (higher dose) or add IL-1 blocker; renal support; dialysis/transplant if ESRD (colchicine continues post-transplant).
- Monitoring: CRP/SAA every 3–6 months; annual renal function/proteinuria; adherence assessment (MASIF scale if available).
- Other: Vaccinations up-to-date; infection vigilance (immunosuppression risk with biologics); genetic counselling for family.
📌 Revision Pearls
- Classic triad: recurrent fever + serositis/arthritis + Mediterranean ancestry → think FMF.
- Colchicine lifelong (even asymptomatic) prevents amyloidosis (evidence level 1A).
- Persistent ↑CRP/SAA between attacks = subclinical inflammation → escalate therapy to prevent damage.
- High-risk genotypes (M694V homozygous) → earlier/more aggressive treatment.
- IL-1 blockers transform colchicine-resistant cases (attack-free in >80%).
📅 Revision Note
- Last updated: March 2026 (aligned with EULAR/PReS 2024 update; no major changes noted in 2025–2026).
📚 References (Current as of March 2026)
