Familial Mediterranean Fever Treatment & Management

Colchicine

Colchicine is so effective in preventing attacks of familial Mediterranean fever (FMF) and preventing the development of amyloidosis that the most important aspects of medical care are to make the correct diagnosis and to institute therapy.

Administer colchicine therapy daily in patients at risk of developing amyloidosis (eg, North African Jewish people, Turkish people, Armenian people living in Armenia). Other Sephardic Jewish people and Arabic people are at lower risk but also probably require daily colchicine therapy.

Daily colchicine is customarily given in a dosage of 0.6 or 0.5 mg twice daily, depending on the dosage form available. However, a study in treatment-naive pediatric patients newly diagnosed with FMF found that a single 1-g daily dose was noninferior to 0.5 mg given twice daily. ^[22] Guidelines from the European League Against Rheumatism (EULAR) recommend the following starting dosages of colchicine ^[23] :

• Children < 5 years of age: ≤0.5 mg/day (≤0.6 mg/day if tablets contain 0.6 mg)
• Children 5–10 years: 0.5–1.0 mg/day (1.2 mg/day if tablets contain 0.6 mg)
• Children >10 years and adults:1.0–1.5 mg/day (1.8 mg/day if tablets contain 0.6 mg)

After colchicine has been started, EULAR recommends following patients closely for 3–6 months to observe the therapeutic effect.

In patients who do not respond to twice-a-day dosing, administer colchicine three, or even four, times a day. In patients who have difficulty tolerating colchicine, start therapy at once-a-day dosing and gradually increase the dose. In patients whose conditions were not responsive to oral colchicine, the addition of 1 mg IV once a week reduced the number of attacks in 10 of 13 patients and the severity of attacks in 6 of 13 patients. ^[24]

Colchicine also stabilizes the amount of proteinuria in patients with amyloid nephropathy. Renal disease may resolve in patients with a creatinine level of less than 1.5 mg/dL who are treated with 1.5 mg/d of colchicine.

Ashkenazi Jewish people and Armenian people living in the United States seem to be at extremely low risk of amyloidosis and may need treatment only to prevent attacks. If attacks are rare and patients can determine when they are beginning, treatment with intermittent colchicine therapy at the onset of attacks may be sufficient.

The regimen for acute attacks in patients not taking daily colchicine is 0.6 mg every hour for 4 doses, then 0.6 mg every 2 hours for 2 doses and then 0.6 mg every 12 hours for 4 doses. Colchicine should be started as soon as the patient recognizes that an attack is occurring. If the initial doses are effective, patients may be able to do without the later doses, but this varies from patient to patient.

A Turkish study found that in children who were heterozygous for MEFV variants and required initiation of colchicine treatment after experiencing symptoms of FMF, colchicine may be successfully discontinued in some cases, if very careful follow-up is provided. In this study, the median duration of colchicine treatment was 36 (range, 24-110) months, and colchicine was discontinued after a median attack- and inflammation-free period of 27 (range, 24-84) months. Colchicine was restarted in 2 of the 22 patients because of symptom recurrence. ^[25]

A group from another Turkish hospital followed 69 children who were heterozygous for MEFV mutations and did not meet criteria for pediatric FMF. Of these, 39 had known pathogenic mutations and 30 had mutations of unknown significance (E148Q or P369S in 26 cases). None of these children developed persistent proteinuria and only 2 patients who were M694V heterozygous experienced febrile episodes often enough to be started on colchicine. ^[26]

Some patients treated with colchicine develop lactose intolerance and may respond to a lactose-free diet.

Biologics

In patients whose conditions do not respond to colchicine, biologic therapy—in particular, agents directed toward interleukin-1 (IL-1)—may be effective. In FMF, uninhibited pyrin activity results in uncontrolled production of IL-1, which causes inflammation and may be accompanied by joint pain, swelling, muscle pain, and skin rash. Biologic agents used for FMF include the following:

• Interferon-alpha
• The tumor necrosis factor (TNF)–blocking drug etanercept ^[27]
• The IL-1 receptor antagonists anakinra ^{[28, 29]} and rilonacept
• Canakinumab   

Rilonacept, given by once-weekly subcutaneous injection, has been shown, in combination with continuation of colchicine, to reduce the number of attacks in patients who did not respond optimally. ^[30] Interferon-alpha has been used in an intermittent fashion and as prophylaxis, with varying results. ^{[31, 32, 33]}

A systematic review found that in patients who do not respond to colchicine or cannot tolerate it, anti–IL-1 treatment resulted in a complete response to therapy, without a single attack during treatment, in 76.5% of patients treated with anakinra and 67.5% of those treated with canakinumab. In addition, anti–IL-1 treatment proved able to reverse proteinuria in patients with established type AA amyloidosis. ^[34]

Canakinumab

Canakinumab was approved by the US Food and Drug Administration for FMF in September 2016. Canakinumab is a human monoclonal anti-human IL-1β antibody of the IgG1/kappa isotype. It binds to human IL­1β and neutralizes its activity by blocking its interaction with IL-1 receptors. Approval was based on the phase 3 CLUSTER study, which showed disease control beginning at day 15 and lasting through 16 weeks when compared with placebo. ^[35]

A systematic review of the literature on canakinumab found that even though most patients included in the studies had a particularly severe phenotype, nearly 80% of patients did not experience a single attack after the initiation of therapy, and almost all the remaining patients had significantly reduced disease activity. Canakinumab therapy also appeared effective at limiting amyloidosis. The drug was also safe and well tolerated, with no patient discontinuing treatment due to adverse effects. ^[36]

Other therapeutic measures

Additional treatment options include the following:

• Hemodialysis can be used for patients who develop renal failure. Peritoneal dialysis tends to increase the number of abdominal attacks.
• Patients who experience episodes of prolonged myalgia with fever and severe pain may need treatment with prednisone (1 mg/kg) for as long as 6 weeks.
• Patients with exertional lower extremity muscle pain respond to rest.
• Treat patients with fibromyalgia with the usual agents for this condition.
• Treat patients who develop seronegative spondyloarthropathy with nonsteroidal anti-inflammatory drugs as first-line therapy. Some of these patients may require treatment with TNF-alpha blockers and should receive follow-up care by a rheumatologist. ^[37]

Before the advent of colchicine therapy, renal transplantation was performed in patients with end-stage renal disease due to amyloid nephropathy. Currently, renal failure develops only in patients who are not compliant with therapy or cannot tolerate it and those with disease refractory to therapy. 

Since the advent of colchicine therapy, most treated patients are asymptomatic and do not need consultation with a specialist.

Consultation with a rheumatologist is indicated in patients with the following conditions:

• Seronegative spondyloarthropathy not responsive to nonsteroidal anti-inflammatory drugs
• Fibromyalgia not responsive to the usual treatments
• Coexistent Henoch-Schönlein purpura, polyarteritis nodosa, or Behçet disease

Patients with familial Mediterranean fever (FMF) should be seen regularly to ensure compliance with therapy. In one study, only 2% of 906 patients who were at high risk and compliant developed amyloidosis, compared with 49% of 54 patients who admitted noncompliance.

Teenagers are typically a noncompliant group and need long-term daily therapy to prevent chronic complications. For many of these patients, noncompliance is associated with severe symptoms, which may reinforce the need for therapy. Communicating with patients' pharmacies to determine how often they are obtaining refills may be the best way to assess compliance.

Perform a urinalysis at every visit, particularly in patients at risk of developing amyloidosis. If proteinuria is present, assess patients carefully for compliance. Exclude other causes of proteinuria (eg, heavy sports activity). In patients with hypertension, proteinuria of greater than 3.5 g/24 h and severe FMF, amyloidosis is the more likely cause. However, in nonhypertensive patients with milder diseases, other causes of proteinuria may exist and a biopsy should be considered. ^[21]  If amyloidosis is confirmed, increase the daily dose of colchicine.

For unknown reasons, hematuria occurs in approximately 5% of patients. Its presence, along with prolonged abdominal or muscle pain, suggests the development of polyarteritis nodosa.