What is the recommended treatment for Familial Mediterranean Fever (FMF)?

Treatment of Familial Mediterranean Fever

First-Line Treatment: Colchicine

Colchicine should be initiated immediately upon clinical diagnosis of FMF, even before genetic confirmation is obtained, as it is the definitive first-line treatment to prevent attacks and amyloidosis. 1, 2

Starting Doses by Age

The initial colchicine dosing is age-based and should be titrated to the maximum tolerated dose 1, 2, 3:

• Children <5 years: Start with ≤0.5 mg/day (≤0.6 mg/day if using 0.6 mg tablets); maximum 1.2 mg/day 2, 3, 4
• Children 5-10 years: Start with 0.5-1.0 mg/day; maximum 1.8 mg/day 2, 3, 4
• Children >10 years and adults: Start with 1.0-1.5 mg/day; maximum 3 mg/day for adults, 2 mg/day for all children 1, 2, 3, 4

Dose Administration and Titration

• Colchicine can be given once daily or divided into two doses based on gastrointestinal tolerance, though single daily dosing may improve adherence 2
• If attacks persist or subclinical inflammation continues, increase the dose gradually by 0.5 mg increments no more frequently than once weekly until reaching the maximum tolerated dose 1, 2, 3
• Never use intravenous colchicine due to substantially increased toxicity risk 1, 2

Monitoring Requirements

Regular monitoring is essential to optimize treatment 2, 3:

• Initial phase: Assess every 3-6 months for response, toxicity, and adherence 2
• Stable disease: Monitor every 6 months 2
• Laboratory surveillance: Check CRP and/or serum amyloid A (SAA) every 3 months during dose escalation, plus regular monitoring of liver enzymes, complete blood count, renal function, and CPK 2

Critical Pitfall: Subclinical Inflammation

Do not ignore elevated acute phase reactants between attacks—persistent subclinical inflammation increases amyloidosis risk even without clinical attacks and requires dose escalation. 1, 2

Second-Line Treatment: IL-1 Inhibitors

Defining Treatment Failure

A patient is considered colchicine-resistant when 1, 2, 3:

• ≥1 attack per month over 3 months despite maximum tolerated dose with confirmed adherence, OR
• >3 attacks over 6 months, OR
• Persistent laboratory inflammation between attacks

Always systematically verify adherence before concluding colchicine resistance, as non-adherence is the most frequent cause of apparent therapeutic failure. 2, 5

IL-1 Inhibitor Therapy

For adherent patients not responding adequately to maximum tolerated colchicine, IL-1 inhibitors are the treatment of choice, with the highest level of evidence from six randomized controlled trials. 1, 2

Initial biologic dosing 1, 2:

• Anakinra: 100 mg/day or 2 mg/kg subcutaneously daily
• Canakinumab: 150-300 mg or 2-4 mg/kg subcutaneously every 4-8 weeks
• Rilonacept: 2.2 mg/kg (maximum 160 mg) subcutaneously weekly

Colchicine Continuation with Biologics

While traditional practice maintains colchicine alongside IL-1 inhibitors, recent evidence suggests that for patients truly intolerant to effective colchicine doses, IL-1 antagonist monotherapy may effectively control FMF disease activity with comparable inflammatory markers and disease activity scores. 6

Special Clinical Situations

Amyloidosis

• Intensify treatment with maximum tolerated colchicine dose 2
• Add biologics if necessary to maintain normal SAA levels, which can prevent amyloid deposit progression or promote regression 2

Chronic Musculoskeletal Manifestations

• May require additional treatments beyond colchicine and IL-1 inhibitors, including conventional DMARDs, other biologics, or intra-articular corticosteroid injections 1, 2

Acute Attack Management

• Continue the usual colchicine dose during attacks and add NSAIDs for symptomatic relief 2
• Always exclude other possible causes before attributing symptoms to an FMF attack 2

Prolonged Febrile Myalgia

• Glucocorticoids are the treatment of choice, with NSAIDs and IL-1 blockade as alternatives 2

Important Drug Interactions

Coadministration with strong CYP3A4 or P-gp inhibitors (clarithromycin, ketoconazole, ritonavir, atazanavir, etc.) is contraindicated due to risk of fatal colchicine toxicity. 4

For patients requiring moderate CYP3A4 inhibitors (diltiazem, verapamil, erythromycin, fluconazole), reduce colchicine dose by 50% 4

Pregnancy and Breastfeeding

Colchicine should not be stopped during conception, pregnancy, or breastfeeding, as current data do not justify discontinuation or amniocentesis. 2

Renal and Hepatic Impairment

Patients with renal insufficiency are at high risk of toxicity and require dose reduction with close monitoring for signs of toxicity 2, 4