Familial Mediterranean fever

Background

• One of the periodic fever syndromes
• Caused by an autosomal recessive gain-of-function mutations in MEFV gene on 16p13 that encodes pyrin
• May be associated with vasculitides (HSP and PAN) or Behçet disease

Types

• Type 1: acute attacks of fever plus the classical symptoms of painful serositis and arthritis
• Type 2: kidney amyloidosis, without other symptoms of FMF and without fever attacks
• Type 3: patients with two mutations of MEFV gene, without fever, other symptoms of FMF, nor amyloidosis

Epidemiology

• First found among Armenians, Arabs, Turks, and non-Ashkenazi Jews in North Africa and Iraq, but now also known to be found in Ashkenazi Jews, Italians, and other Mediterranean people
• Rarely found in people without Mediterranean ancestry

Clinical Manifestations

• Attacks consist of fever (96%), abdominal pain (90%), arthritis (45%), aphthous changes in lips and oral mucosa, erysipelas-like erythema (7-40%), and headache
  • Fever up to 40ºC, may be preceded by chills
  • Abdominal pain either diffuse or localized, may mimic acute abdomen or appendicitis, but can also cause intestinal obstruction
    • May have unnecessary surgery or laparoscopy
    • May have diarrhea or vomiting, or constipation
  • Arthritis is usually monoarticular in the large joints of the lower limbs and may last longer than other attacks
  • Myalgias usually in the legs
  • Pericarditis or pleuritis
  • Headache from aseptic meningitis
  • Unilateral acute scrotal inflammation in prepubertal boys
  • May have prodrome of myalgias, arthralgias, lumbar pain, headache, dyspnea, nausea, asthenia
  • Length of episodes 24 to 72 hours, occuring every 1 week to 1 decade
• Elevated CRP, ESR, serum amyloid A, leukocytosis and neutrophilia
• Onset usually before age 20 years
• Severity of attacks is inversely proportional to the age at onset (earlier is more severe)
• Attacks may be triggered by infections, stress, menses, exposure to cold, fat-rich food, or drugs
  • Pregnancy may be protective

Differential Diagnosis

• Infection
• Autoimmune diseases
• Juvenile idiopathic arthritis
• Inflammatory bowel disease

Diagnosis

• Requires clinical criteria confirmed by genetic testing

Tel Hashomer Criteria

• Must exclude other causes
• Must meet two major criteria, or one major and two minor criteria
• Major criteria
  • Recurrent febrile episodes accompanied by peritonitis, synovitis, pleurisy
  • AA amyloidosis without a predisposing disease
  • Response to continuous colchicine administration
• Minor criteria
  • Recurrent febrile episodes
  • Erysipelas-like erythema
  • FMF diagnosed in a first-degree relative

Turkish FMF Paediatric Criteria

• Must meet at least two out of five criteria:
  • Fever >38ºC
  • Abdominal pain
  • Chest pain
  • Oligoarthritis
  • Family history of FMF
• Duration of the symptoms must be 6 to 72 hours, ≥3 hours

Management

• Goal is to reduce recurrence of attacks, normalize inflammatory markers, and minimize subclinical inflammation
• First-line treatment is colchicine 0.5 to 1 mg/day for at least 3 to 6 months to determine efficacy
  • Can start ≤0.5 mg/day if younger than 5 years, 0.5-1 mg/day for 5-10 years old, 1-1.5 mg/day for children >10 years and adults
  • May be gradually titrated up to 2 mg/day in children or 3 mg/day in adults
• May need NSAIDs or corticosteroids for arthritis and myalgias
• Second-line treatments include corticosteroids and IL-1β inhibitors like canakinumab