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

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

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

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

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

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