Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease (a disease with a known etiology caused by a mutation in a single gene). In this case, it is the MEFV gene, which encodes the protein pyrin (also known as marenostrin). The mutated protein affects the regulation of the inflammatory response, leading to excessive production of the proinflammatory cytokine IL-1β, resulting in a systemic inflammatory reaction. Mutations are inherited in an autosomal recessive manner, meaning both parents are carriers of the mutation but may not exhibit symptoms. A person with FMF carries two mutations (one from each parent – homozygous). Rarely, literature suggests that a single mutation (heterozygous) may be sufficient to develop the disease.
FMF is most common among populations in the eastern Mediterranean region: non-Ashkenazi Jews, Turks, Armenians, and Arabs. It is estimated that 1 in 5-7 people in these ethnic groups is a carrier of the mutation, and 1 in 200 individuals has FMF. In Ukraine, the disease is relevant, but it is often diagnosed late—sometimes after many years.
Clinical Manifestations
FMF classically presents with paroxysmal episodes of fever lasting from 12 hours to 3 days (often high fever) accompanied by abdominal pain, occurring in 95% of cases. The abdominal pain results from non-infectious peritonitis (sterile peritonitis), which can be intense, mimicking acute abdomen, often leading patients to consult a surgeon. In some cases, appendectomy (with a normal appendix) or diagnostic laparotomy is performed. Studies indicate that 40% of patients undergo surgical interventions before receiving a diagnosis. Vomiting and diarrhea are common symptoms.
FMF episodes often involve arthritis of large joints (ankle, knee, hip), and in some cases, pleuritis or pericarditis. Erysipelas-like erythema is observed in 25% of patients, usually on the lower legs. Symptoms resolve spontaneously, even without treatment, after an episode ends.
The frequency and severity of episodes vary among patients—some experience several attacks per year, while others have multiple episodes per month. The disease typically manifests in early childhood, though rarely, onset may occur in adulthood.
Laboratory Findings
- Marked inflammatory response: Leukocytosis, left shift, elevated ESR, and CRP.
- Increased serum amyloid A (AA) levels.
- Such findings often mislead physicians into suspecting a bacterial infection, leading to unnecessary antibiotic therapy.
- Patients undergo extensive testing for viruses, fungi, parasites, and often visit surgeons, oncologists, hematologists, and rheumatologists, with numerous hospitalizations and instrumental examinations.
- Between FMF episodes, patients generally feel well, though subclinical inflammation may be present in laboratory tests.
The Most Severe Complication: Amyloidosis
The most significant danger of FMF is gradual amyloid deposition in internal organs due to excessive production during the disease course. The kidneys are the primary target, potentially leading to chronic kidney failure.
Diagnosis
FMF diagnosis is primarily clinical. A detailed medical history often reveals a patterned recurrence of episodes and a lack of response to antibiotics, diets, vitamins, or antiviral treatments.
Diagnostic Criteria (Yalçinkaya et al., 2009, for children):
- Fever (>38°C, duration 6-72 hours, at least 3 episodes)
- Abdominal pain (duration 6-72 hours, at least 3 episodes)
- Chest pain (duration 6-72 hours, at least 3 episodes)
- Oligoarthritis (duration 6-72 hours, at least 3 episodes)
- Family history of FMF
- Diagnosis is confirmed if ≥2 criteria are present.
Diagnostic Criteria (Livneh et al., 1997):
Major Criteria:
- Typical attacks (>3 similar episodes, fever >38°C, duration 12-72 hours), associated with:
- Peritonitis
- Unilateral pleuritis or pericarditis
- Monoarthritis (hip, knee, ankle)
- Isolated fever
Minor Criteria:
- Incomplete attacks (typical but with one or two variations):
- Fever <38°C
- Duration 6-12 hours or 3-7 days
- No peritonitis despite abdominal pain
- Localized abdominal pain
- Arthritis in other joints than hip, knee, or ankle
Additional Criteria:
- Family history of FMF
- Relevant ethnic background
- Onset before age 20
- Severe attacks requiring bed rest
- Spontaneous remission between episodes
- Transient inflammatory response (elevated WBC, ESR, serum amyloid A, fibrinogen, etc.)
- Episodic proteinuria/hematuria
- Sterile peritonitis upon laparotomy (with or without normal appendix removal)
- Consanguinity
A clinical diagnosis of FMF requires:
- ≥1 major criteria, or
- ≥2 minor criteria, or
- 1 minor + ≥5 additional criteria, or
- 1 minor + 4 of the first 5 additional criteria
Confirmatory Testing:
Final diagnosis is confirmed through genetic testing detecting MEFV mutations.
Treatment
Colchicine is the lifelong treatment, reducing episodes and significantly lowering amyloidosis risk. In most cases, colchicine allows complete disease control. If colchicine is ineffective, IL-1β inhibitors (anakinra, canakinumab) are used. NSAIDs and steroids may help during attacks but do not prevent future episodes or amyloidosis development.
Prepared by Stepanovskyi Yurii
References:
- Yalcinkaya F et al., 2009. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford), 48:395–8.
- De Jesus AA, Goldbach-Mansky R, 2013. Clin Immunol, 147(3):155–174.
- Ozen S, Bilginer Y, 2014. Nat Rev Rheumatol, 10(3):135.
- Livneh A et al., 1997. Arthritis Rheum, 40:1879–85.
- http://www.nomidalliance.org/fmf.php
- Pediatric Immunology: Textbook, L. I. Chernyshova et al., 2013.
- Chernyshova L. I. et al., 2015. Familial Mediterranean Fever. Modern Pediatrics Journal (4), 68.