Diagnostic Criteria and Treatment Options for Familial Mediterranean Fever (FMF)
Familial Mediterranean Fever (FMF) diagnosis is based on clinical symptoms, genetic testing, and exclusion of other conditions, with colchicine as first-line treatment and IL-1 inhibitors for colchicine-resistant cases.
Diagnostic Criteria
Clinical Diagnosis
- Recurrent short episodes (24-72 hours) of fever and serositis
- Manifestations include:
- Peritonitis (abdominal pain)
- Pleuritis (chest pain)
- Synovitis (joint pain)
- Erysipela-like erythema (mainly on feet and legs)
- Effort-induced myalgia
Laboratory Findings
- During attacks:
- Elevated white blood cell count with neutrophil predominance
- Elevated acute phase reactants (CRP, SAA, fibrinogen)
- Elevated erythrocyte sedimentation rate
- Decreased albumin concentrations
Genetic Testing
- MEFV gene testing is recommended for all patients with suspected FMF 1
- Most common mutations:
- M694V (associated with severe phenotype and amyloidosis risk)
- M694I, M680I, V726A, and E148Q
- Interpretation of genetic results 2:
- Two clearly pathogenic variants confirm FMF diagnosis
- One pathogenic variant + one variant of uncertain significance (VUS) could be consistent with FMF
- Two VUS require clinical judgment
- One pathogenic variant alone requires clinical judgment
Treatment Options
First-Line Treatment
- Colchicine should be started as soon as a clinical diagnosis is made 2, 3
- Dosing by age group 3:
- Children <5 years: 0.5-0.6 mg/day (max 1.2 mg/day)
- Children 5-10 years: 0.5-1.0 mg/day (max 1.8 mg/day)
- Children >10 years and adults: 1.0-1.5 mg/day (max 3.0 mg/day)
- Maximum recommended dose: 2 mg/day for children, 3 mg/day for adults 2
- Can be administered as single or divided doses based on tolerance and adherence 2
- Lifelong treatment required to prevent attacks and amyloidosis 2, 3
Monitoring and Dose Adjustment
- Regular monitoring every 3-6 months 3
- Assess:
- Attack frequency and severity
- Inflammatory markers (CRP, SAA)
- Liver enzymes (reduce dose if >2x upper limit)
- Complete blood count
- Renal function
- Increase dose if attacks persist or subclinical inflammation continues despite adherence 2
Management of Colchicine Resistance
- Defined as ≥1 attack per month over 3 months despite maximum tolerated dose 3
- Add IL-1 inhibitors as second-line treatment 2, 3:
Management of Acute Attacks
- Continue regular colchicine dose during attacks 2
- Add NSAIDs for symptomatic relief 2, 3
- Avoid glucocorticoids and opioids 2
Special Considerations
- Pregnancy: Continue colchicine during conception, pregnancy, and lactation 2, 3
- Chronic inflammatory musculoskeletal involvement may require additional treatments (DMARDs) 2
- Reduced renal function: Monitor closely for colchicine toxicity and adjust dose 3
Complications and Prognosis
- Most severe complication: AA amyloidosis leading to renal failure 5, 6
- Early diagnosis and treatment with colchicine prevents amyloidosis 6, 7
- Regular monitoring for proteinuria is essential 7
- Untreated FMF can lead to:
- End-stage renal disease
- Malabsorption due to amyloid deposition
- Infertility
- Growth retardation in children 8
Common Pitfalls in Diagnosis
- Nonspecific manifestations can mimic common disorders (infections, appendicitis, cholecystitis) 8
- Diagnosis may be delayed for years without genetic testing 1
- Relying solely on genetic testing without clinical correlation can be misleading, especially with VUS 2
- Failure to recognize atypical presentations, particularly in patients without Mediterranean ancestry
Early diagnosis and prompt initiation of colchicine therapy are essential to prevent long-term complications and improve quality of life in patients with FMF.