What is Familial Mediterranean Fever?
Familial Mediterranean Fever (FMF) is a monogenic autoinflammatory disease characterized by recurrent, self-limited attacks of fever and serosal inflammation lasting 1-3 days, with marked elevation of acute phase reactants, and if left untreated, can lead to life-threatening AA amyloidosis. 1
Disease Characteristics
Genetic Basis and Epidemiology
- FMF is an autosomal recessive disorder caused by mutations in the MEFV gene located on chromosome 16p13, which encodes the pyrin-marenostrin protein 2, 3
- It is the most common monogenic autoinflammatory disease, particularly prevalent in Mediterranean and Middle Eastern populations including non-Ashkenazi Jews, Arabs, Armenians, Turks, and increasingly recognized in Ashkenazi Jewish and Italian populations 4, 5
- The disease requires mutations on both chromosomes for manifestation, with carrier parents typically remaining asymptomatic 5
Clinical Presentation
Attack Characteristics:
- Episodes are brief, recurring, and self-limited, typically lasting 1-3 days (mean 24-72 hours) 4, 2
- Attacks are accompanied by fever and inflammation of serosal surfaces 4
- Marked elevation of acute phase reactants occurs during attacks 4
- Joint pain (arthritis/synovitis) is a common manifestation 4
Disease Patterns:
- FMF follows three distinct clinical patterns, each affecting approximately one-third of patients: monocyclic, polycyclic/intermittent, and chronic patterns 4
- Attacks show inter- and intra-individual variability in frequency and severity 3, 6
- Episodes are typically triggered by apparently innocuous stimuli and may be preceded by a prodromal period 3
Genotype-Phenotype Correlations
- The M694V mutation demonstrates more severe phenotypic expression compared to V726A 2
- Patients with M694V/M694V homozygosity face higher risk of developing renal amyloidosis, arthritis, dermatologic and oral lesions, higher fever, and more frequent painful attacks 2
Diagnosis
Clinical Approach
- Diagnosis is primarily clinical, though genetic testing for MEFV gene mutations can confirm the diagnosis 4
- Ethnicity serves as a critical predictor for finding known MEFV mutations and guides which genes to test first 5
Differential Diagnosis
- Other periodic fever syndromes including TRAPS and hyper-IgD syndrome (MKD) must be excluded 4
- Infectious diseases and neoplastic disorders should be considered 4
Genetic Testing Indications
- Testing is indicated when family history reveals similar periodic fever patterns, even in patients with atypical or partial clinical symptoms 5
- Testing asymptomatic family members is recommended when a severe genotype is identified in a symptomatic relative or when family history includes amyloidosis, enabling monitoring of acute phase reactants and kidney function 5
- A family history of similar symptoms, specific ethnic backgrounds, or amyloidosis should prompt genetic testing 5
Most Severe Complication
AA Amyloidosis:
- The most severe long-term complication is type AA amyloidosis, which principally affects the kidney and causes chronic renal failure 3, 6
- Without treatment, the risk of amyloidosis is 60%, but regular colchicine treatment reduces this to less than 13% 4, 7
- Both genetic (particularly M694V/M694V genotype) and non-genetic risk factors have been identified 2, 3
Treatment Approach
First-Line Therapy
- Colchicine treatment should begin immediately upon clinical diagnosis, even before genetic confirmation, to prevent inflammatory attacks and complications 7
- This is the only currently effective treatment and must be lifelong 3, 6
Weight-Based Dosing: 7
- Children <5 years: ≤0.5 mg/day
- Children 5-10 years: 0.5-1.0 mg/day
- Children >10 years and adults: 1.0-1.5 mg/day
Treatment Goals
- The primary goal is achieving minimal or no clinical activity and complete control of subclinical inflammation to prevent associated damage 7
- Regular monitoring of acute phase reactants is necessary even during asymptomatic periods to detect subclinical inflammation 4, 7
- Adherence assessment is crucial, especially in adolescents and adults 7
Colchicine-Resistant Cases
- In adherent patients with persistent attacks or subclinical inflammation, increase colchicine dose within the recommended range 7
- Biologics have become the main therapeutic choice in colchicine-resistant FMF patients 1
- Canakinumab (ILARIS), an IL-1β blocker, is FDA-approved for FMF treatment in adults and children 8
- For FMF, canakinumab dosing is 150 mg subcutaneously every 4 weeks for patients >40 kg, with possible increase to 300 mg if clinical response is inadequate 8
Special Considerations
- Colchicine should be used with caution in patients with renal impairment 4
- FMF requires lifelong management with regular follow-up visits and patient education 7