How is Familial Mediterranean fever diagnosed and managed, including colchicine dosing, second‑line interleukin‑1 inhibitors, monitoring for amyloid A amyloidosis, and genetic counseling?

Familial Mediterranean Fever: Diagnosis and Management

Diagnosis

FMF should ideally be diagnosed by a physician with experience in FMF, typically at a referral center capable of managing autoinflammatory diseases and their differential diagnoses. 1

Clinical Diagnosis

• Diagnosis is primarily clinical, based on recurrent self-limited episodes of fever and painful serositis lasting 1-3 days 2
• Look specifically for: fever, peritonitis, pleuritis, arthritis, and characteristic ethnic background (Mediterranean basin populations: Armenian, Jewish, Turkish, Arab) 2, 3
• Genetic testing for MEFV mutations supports but does not replace clinical diagnosis—treatment should begin on clinical grounds alone 4
• M694V homozygosity indicates more severe phenotype with higher risk of amyloidosis, arthritis, and more frequent attacks 2

---

First-Line Treatment: Colchicine

Treatment with colchicine must start immediately upon clinical diagnosis, even before genetic confirmation is available. 1, 4

Colchicine Dosing

Weight-based and age-dependent dosing: 4

• 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 (up to 2.4 mg/day in some patients) 2
• Can be given as single or divided doses depending on tolerance and compliance 1

Treatment Goals

The ultimate goal is complete control of unprovoked attacks AND minimizing subclinical inflammation between attacks—both objectives are equally critical. 1

• Preventing clinical attacks improves quality of life 1
• Suppressing subclinical inflammation (particularly serum amyloid A protein elevation) prevents AA amyloidosis, which remains a major cause of mortality 1
• Colchicine reduces amyloidosis risk from 60% to less than 13% when used appropriately 1, 4

---

Monitoring Strategy

Monitor response, toxicity, and compliance every 6 months, with particular attention to adherence in adolescents and adults. 1, 4

Laboratory Monitoring

• Measure serum amyloid A (SAA) protein and/or CRP regularly, even during asymptomatic periods, to detect subclinical inflammation 1, 4
• Check urinary protein to screen for amyloidosis 2
• Annual review by an FMF-experienced physician is recommended long-term 1

Dose Adjustment Algorithm

If persistent attacks or subclinical inflammation occurs in compliant patients: 1, 4

1. First, verify adherence (critical step—many "resistant" patients are non-adherent)
2. Increase colchicine dose within recommended range (up to maximum tolerated dose)
3. Consider temporary dose increase during physical or emotional stress 1

---

Colchicine Resistance/Intolerance

Patients who remain symptomatic or have persistent subclinical inflammation despite maximum tolerated colchicine doses AND confirmed compliance should be classified as colchicine-resistant. 1, 5

Second-Line: IL-1 Inhibitors

Biological agents targeting IL-1β are indicated for colchicine-resistant or intolerant patients. 1, 6, 5

Available Options:

• Anakinra (IL-1 receptor antagonist): 1-2 mg/kg/day subcutaneously 6, 5
• Canakinumab (anti-IL-1β monoclonal antibody): 150 mg (or 2-8 mg/kg for children) subcutaneously every 8 weeks 7, 6
• Rilonacept (IL-1 decoy receptor): Loading dose 320 mg/week, then 160 mg/week subcutaneously (adults) 7, 2

Clinical evidence shows these agents achieve complete attack cessation or significant reduction in frequency, with improved quality of life and minimal side effects in pediatric and adult populations. 6, 5

---

AA Amyloidosis Management

FMF treatment must be intensified in patients with established AA amyloidosis using maximal tolerated colchicine dose supplemented with biologics as required. 1

Specific Considerations:

• Colchicine prevents new amyloid deposition if started before renal impairment develops 8
• In patients with amyloidosis but normal renal function, colchicine ameliorates disease course 8
• Once renal function is impaired, colchicine does not alter progression—early detection is critical 8
• Anti-IL-1 therapy shows benefit in FMF-related amyloidosis, including nephrotic syndrome and chronic kidney disease 6

Monitoring for Amyloidosis:

• Regular SAA protein measurement (most sensitive marker) 1
• Urinary protein screening 2, 8
• Maintaining normal SAA protein concentration between attacks is the key to preventing amyloidosis 1

---

Genetic Counseling

FMF is inherited as autosomal recessive, requiring counseling for family planning. 2, 3

• Patients should understand inheritance pattern and 25% recurrence risk for affected offspring when both parents are carriers 3
• Genetic testing identifies MEFV mutations but phenotypic expression varies (allelic heterogeneity and modulating genes) 3
• M694V/M694V homozygotes have more severe disease and higher amyloidosis risk—this information guides monitoring intensity 2

---

Critical Pitfalls to Avoid

• Never assume colchicine resistance without first confirming adherence—non-compliance is common, especially in adolescents 1, 4
• Do not wait for genetic confirmation to start colchicine—clinical diagnosis is sufficient and delays increase amyloidosis risk 4
• Do not rely solely on clinical attack frequency—subclinical inflammation persists between attacks and drives amyloidosis 1
• Colchicine dose reduction is rarely appropriate and should only be attempted by FMF experts with strict monitoring (SAA/CRP at 3 months, gradual reduction by ≤0.5 mg every 6 months) 1
• Complete attack cessation may not be achievable in severe phenotypes (e.g., M694V homozygotes), but subclinical inflammation control remains mandatory 1