Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent bouts of fever and peritonitis, sometimes with pleuritis, skin lesions, arthritis, and, very rarely, pericarditis. Renal amyloidosis may develop, sometimes leading to renal failure. People with genetic origins in the Mediterranean basin are more frequently affected than other ethnic groups. Diagnosis is largely clinical, although genetic testing is available. Treatment with prophylactic colchicine prevents acute attacks as well as amyloidosis in almost all patients. Prognosis is excellent with treatment.

FMF is a disease of people with genetic origins in the Mediterranean basin, predominantly Sephardic Jews, North African Arabs, Armenians, Turks, Greeks, and Italians. However, cases have occurred among enough other groups (eg, Ashkenazi Jews, Cubans, Japanese) to caution against excluding the diagnosis solely on the basis of ancestry. Up to 50% of patients have a family history of the disorder, usually involving siblings.

Etiology

FMF is caused by mutations in the MEFV gene on the short arm of chromosome 16 and is inherited in an autosomal recessive manner. The MEFV gene normally codes a protein named pyrin, which is expressed in circulating neutrophils. Its presumed action is to blunt the inflammatory response, possibly by inhibiting neutrophil activation and chemotaxis. Gene mutations result in defective pyrin molecules; it is hypothesized that the altered pyrin cannot suppress minor, unknown triggers to inflammation that are normally checked by intact pyrin. The clinical consequence is spontaneous bouts of neutrophil-predominant inflammation in the abdominal cavity as well as in other sites.

Symptoms and Signs

Onset is usually between the ages of 5 and 15 yr but may be much later or earlier, even during infancy. Attacks have no regular pattern of recurrence. They usually last 24 to 72 h but may last longer. Frequency ranges from 2 attacks/wk to 1 attack/yr (most commonly, once every 2 to 6 wk). Severity and frequency tend to decrease during pregnancy and in patients with amyloidosis. Spontaneous remissions may last years.

Fever as high as 40° C, usually accompanied by peritonitis, is the major manifestation. Abdominal pain (usually starting in one quadrant and spreading to the whole abdomen) occurs in about 95% of patients and can vary in severity with each attack. Decreased bowel sounds, distention, guarding, and rebound tenderness are likely to occur at the peak of an attack and cannot be differentiated from a perforated viscus by physical examination. Consequently, some patients have undergone urgent laparotomy before the correct diagnosis was made. With diaphragmatic involvement, splinting of the chest and pain in one or both shoulders may occur.

Other manifestations include acute pleurisy (in 30%); arthritis (in 25%), usually involving the knee, ankle, and hip; an erysipelas-like rash of the lower leg; and scrotal swelling and pain caused by inflammation of the tunica vaginalis of the testis. Pericarditis occurs very rarely. The pleural, synovial, and skin manifestations of FMF vary in frequency among different populations and are less frequently encountered in the US than elsewhere.

The most significant long-term complication is chronic renal failure caused by deposition of amyloid protein in the kidneys. Amyloid may also be deposited in the GI tract, liver, spleen, heart, testes, and thyroid.

FMF causes infertility or spontaneous abortion in about one third of women because peritoneal pelvic adhesions form, interfering with conception. In women with FMF, about 20 to 30% of pregnancies end in fetal loss.

Despite the severity of symptoms during acute attacks, most patients recover swiftly and remain free of illness until their next attack.

Diagnosis

• Clinical evaluation
• Genetic testing

Diagnosis is mainly clinical, but genetic testing is available and is particularly useful in evaluation of atypical cases. However, current genetic testing is not infallible; some patients with phenotypically unmistakeable FMF have only a single mutated gene or occasionally no evident pyrin mutations.

Nonspecific findings include elevations in WBCs with neutrophil predominance, ESR, C-reactive protein, and fibrinogen. Urinary excretion of > 0.5 g protein/24 h suggests renal amyloidosis. Differential diagnosis includes acute intermittent porphyria, hereditary angioedema with abdominal attacks, relapsing pancreatitis, and other hereditary relapsing fevers.

Treatment

• ColchicineSome Trade Names
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Prophylactic colchicineSome Trade Names
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0.6 mg po bid (some patients require qid dosing; others a single daily dose) provides complete remission or distinct improvement in about 85% of patients. For patients with infrequent attacks that have an insidious onset, colchicineSome Trade Names
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can be reserved until initial symptoms occur and then begun at 0.6 mg po q 1 h for 4 h, then q 2 h for 4 h, then q 12 h for 48 h. Initiation of colchicineSome Trade Names
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at the peak of an attack is unlikely to be beneficial. Children often require adult dosages for effective prophylaxis. Widespread use of prophylactic colchicineSome Trade Names
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has led to a dramatic reduction in the incidence of amyloidosis and subsequent renal failure.

ColchicineSome Trade Names
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does not add to the increased risk of infertility and miscarriage among affected women; when taken during pregnancy, it does not increase the risk of teratogenic events. Lack of response to colchicineSome Trade Names
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is often caused by poor adherence to the drug regimen, but a correlation has also been noted between poor response and diminished colchicineSome Trade Names
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concentration in circulating monocytes. Alternative therapies for nonresponders include infliximabSome Trade Names
REMICADE
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5 mg/kg IV q 8 wk, anakinraSome Trade Names
KINERET
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100 mg sc once/day, and rilonacept 2.2 mg/kg sc weekly.

Opioids are sometimes needed for pain relief but should be used prudently to avoid addiction.

Key Points

• Familial Mediterranean fever is caused by an autosomal recessive mutation in a protein that helps modulate the inflammatory response in neutrophils.
• People with genetic origins in the Mediterranean basin are more commonly (but not exclusively) affected.
• Patients have brief episodes of fever, abdominal pain, and sometimes other symptoms such as pleuritis, arthritis, and rash.
• Renal amyloidosis, sometimes causing renal failure, is the most common complication, but prophylactic colchicineSome Trade Names
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  provides protection against amyloidosis.
• Diagnose clinically, but consider genetic testing for atypical cases.
• Daily colchicineSome Trade Names
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  results in significant protection against attacks in most patients, but a few require an immunomodulator such as infliximabSome Trade Names
  REMICADE
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  , anakinraSome Trade Names
  KINERET
  Click for Drug Monograph
  , or rilonacept.

Last full review/revision February 2013 by Stephen E. Goldfinger, MD

Content last modified March 2013