What is the Mediterranean autoinflammatory disease, its typical presentation, diagnostic approach, and first‑line and refractory treatment options?

Familial Mediterranean Fever (FMF)

What is FMF?

Familial Mediterranean Fever is the most common monogenic autoinflammatory disease, characterized by recurrent self-limited episodes of fever and serositis lasting 12-72 hours, primarily affecting Mediterranean populations (Arabs, Armenians, Turks, and Jews). 1, 2

• FMF results from mutations in the MEFV gene on chromosome 16p13.3, which encodes pyrin (marenostrin), leading to excessive activation of the pyrin inflammasome and uncontrolled IL-1β release 3, 4
• The disease is autosomal recessive, though heterozygous carriers may occasionally manifest symptoms 4

Clinical Presentation

The hallmark presentation includes recurrent fever episodes accompanied by:

• Peritonitis (abdominal pain mimicking acute abdomen) - most common manifestation 2, 5
• Pleuritis (chest pain with breathing) 2
• Arthritis/synovitis (joint pain and swelling, typically monoarticular) 2
• Erysipelas-like skin lesions on lower extremities 3
• Myalgia 3

Attack characteristics:

• Duration: 1-3 days (12-72 hours) 2, 3
• Marked elevation of acute phase reactants (CRP, SAA) during attacks 2
• Complete resolution between attacks, though subclinical inflammation may persist 1

Disease patterns (each affecting approximately one-third of patients): monocyclic, polycyclic/intermittent, and chronic 2

Diagnostic Approach

Diagnosis is primarily clinical, based on characteristic recurrent attacks, though genetic testing provides confirmatory support. 2, 6

Key diagnostic steps:

• Clinical criteria assessment using validated tools (Tel-Hashomer criteria historically; newer Eurofever/PRINTO classification criteria incorporating clinical and genetic variables) 5, 6
• Genetic testing for MEFV gene mutations to confirm diagnosis, particularly helpful in atypical presentations 2, 6
• Laboratory monitoring of acute phase reactants (CRP, SAA) during and between attacks 1, 2
• Differential diagnosis must exclude other periodic fever syndromes (TRAPS, hyper-IgD syndrome), infectious diseases, and neoplastic disorders 2

Critical pitfall: Do not delay treatment waiting for genetic confirmation - begin colchicine immediately upon clinical diagnosis 7

First-Line Treatment: Colchicine

Start colchicine immediately upon clinical diagnosis, even before genetic confirmation, to prevent inflammatory attacks and life-threatening complications including AA amyloidosis. 1, 7

Dosing regimen (weight-based and age-dependent): 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
• Can be given as single or divided doses depending on tolerance and compliance 1

Treatment goals: 1, 7

• Complete control of unprovoked attacks
• Minimize subclinical inflammation between attacks
• Prevent AA amyloidosis (colchicine reduces amyloidosis risk from 60% to <13%) 7, 2

Monitoring requirements: 1, 7

• Response, toxicity, and compliance every 6 months
• Regular monitoring of acute phase reactants (SAA, CRP) even during asymptomatic periods to detect subclinical inflammation
• Annual review by FMF-experienced physician recommended 1

Dose adjustment: 1, 7

• If attacks persist or subclinical inflammation continues, increase colchicine dose within recommended range
• Physical or emotional stress may trigger attacks; temporary dose increase may be appropriate 1

Important caveat: Use colchicine with caution in patients with renal impairment 2

Management of Colchicine Resistance or Intolerance

Patients who remain symptomatic despite maximum tolerated colchicine doses (and confirmed adherence) should be classified as colchicine-resistant and require biological therapy. 1

Biological treatment options for refractory disease: 1, 3

• IL-1 inhibitors are the preferred biologics for colchicine-resistant FMF
• Anakinra (IL-1 receptor antagonist) 3
• Canakinumab (IL-1β monoclonal antibody) 3
• Rilonacept (IL-1 trap) 3
• TNF-α inhibitors (etanercept, infliximab) as alternative options 3

Special consideration for AA amyloidosis: FMF treatment must be intensified using maximal tolerated colchicine dose supplemented with biologics as required 1

Critical adherence issue: Always assess compliance, especially in adolescents and adults, before labeling patients as colchicine-resistant 7 - non-adherence is a common cause of apparent treatment failure.

Long-Term Management

FMF requires lifelong treatment with continuous monitoring, as this is a chronic condition with serious complications if inadequately controlled. 7

• Regular follow-up visits with patient education 7
• Monitoring for subclinical inflammation even when asymptomatic 7, 2
• Patient-centered management to promote quality of life 7
• Ideally, initial diagnosis and treatment by physician experienced in FMF, with subsequent care coordinated with general practitioner 1