Guidelines Summary
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Ideally, FMF should be diagnosed and initially treated by a physician with experience in FMF; after diagnosis and initiation of therapy, patients can also be followed by their primary care physician in conjunction with the referral center, but if possible, patientsshould be seen by a physician with experience of FMF at least once per year in the long term.
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The ultimate goal of treatment in FMF is to obtain complete control of unprovoked attacks and minimize subclinical inflammation between attacks.
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Treatment with colchicine should be started as soon as a clinical diagnosis is made.
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Colchicine can be given in single or divided doses, depending on tolerance and compliance.
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Persistent attacks or subclinical inflammation represent an indication to increase the colchicine dose.
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Compliant patients who continue to have one or more attacks each month despite receiving the maximally tolerated dose of colchicine for at least 6 months can be considered nonresponders or resistant; alternative biological treatments are indicated in these patients; colchicine should be coadministered with biological therapies, as it may reduce the risk of amyloidosis despite persistence of attacks
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FMF treatment needs to be intensified in AA amyloidosis, using the maximal tolerated dose of colchicine and supplemented with biologics as required.
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Periods of physical or emotional stress can trigger FMF attacks, and it may be worth temporarily increasing the dose of colchicine.
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Response, toxicity, and compliance should be monitored every 6 months.
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Liver enzymes should be monitored regularly in patients with FMF treated with colchicine; if elevations greater than twofold the upper limit of normal occur, the colchicine dose should be reduced and the cause further investigated.
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In patients with decreased renal function, the risk of colchicine toxicity is very high, so evidence of toxicity should routinely be sought and if found, the colchicine dose should be reduced accordingly.
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Colchicine toxicity is a serious complication that should be given adequate consideration and be prevented; potential causes include exceeding the recommended dose (maximum recommended oral doses for treatment of FMF are 3 mg daily in adults and 2 mg daily in children), liver or renal failure, and concomitant administration of other drugs metabolized by cytochrome 3A4.
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If an attack is suspected, always consider other possible causes; during attacks, continue the usual dose of colchicine and use nonsteroidal anti inflammatory drugs (NSAIDs).
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Colchicine should not be discontinued during conception, pregnancy, or lactation; current evidence does not justify amniocentesis.
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In general, men need not stop colchicine prior to conception; in the rare case of azoospermia or oligospermia proven to be related to colchicine, temporary dose reduction or discontinuation may be required.
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Chronic arthritis in a patient with FMF might need additional medications, such as disease-modifying antirheumatic drugs (DMARDs), intra-articular steroid injections, or biologics.
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In protracted febrile myalgia, glucocorticoids lead to the resolution of symptoms; NSAID and interleukin-1 blockade might also be a treatment option; NSAIDs are suggested for the treatment of exertional leg pain.
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If a patient is stable, with no attacks for more than 5 years and no elevation in acute phase reactants (eg, serum amyloid A protein, C-reactive protein), dose reduction could be considered after expert consultation and with continued monitoring.
Medication Summary
The goals of therapy are to reduce morbidity and to prevent complications. Colchicine is the drug of choice; patients who do not respond to colchicine or cannot tolerate it may benefit from the addition or substitution of biologic agents that inhibit interleukin-1. Of those, canakinumab, anakinra, and rilonacept have demonstrated efficacy, but only canakinumab is approved for use in the United States.
Anti-inflammatory agents
Class Summary
Colchicine is the drug of choice for familial Mediterranean fever (FMF).
Colchicine (Colcrys)
Decreases leukocyte motility and phagocytosis in inflammatory responses.
Interleukin Inhibitors
Class Summary
In patients with 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.
Canakinumab (Ilaris)
Human monoclonal anti-human IL-1beta antibody of the IgG1/kappa isotype. It binds to human IL1beta and neutralizes its activity by blocking its interaction with IL-1 receptors. It is indicated for the treatment of FMF in adult and pediatric patients.
Further Outpatient Care
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. [18] 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
Complications
Patients with amyloidosis may develop an acute onset of renal failure if they are stressed by dehydration, infection, or both.
Renal vein thrombosis may occur in nephrotic patients. This condition may manifest as abdominal or flank pain, increasing proteinuria, and worsening renal function. Acute anticoagulation may stabilize or improve renal function.
Prognosis
Patients who are compliant with daily colchicine can probably expect to have a normal lifespan if colchicine is started before proteinuria develops.
Even with amyloidosis, the use of colchicine, dialysis, and renal transplantation should extend a patient's life beyond age 50 years.
Patient Education
Patients with FMF need to understand the importance of strict compliance with daily colchicine therapy. Patient education information on FMF is available through the American College of Rheumatology.