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Familial Mediterranean fever 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 most commonly affected. Diagnosis is largely clinical, although genetic testing is available. Treatment with prophylactic colchicine prevents acute attacks as well as renal amyloidosis in most patients. Prognosis is excellent with treatment.

Familial Mediterranean fever (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 in 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 (called pyrin or marenostrin) 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 and vary in the same patient. They usually last 24 to 72 h, but some last ≥ 1 wk. Frequency ranges from 2 attacks/wk to 1 attack/yr (most commonly, once q 2 to 6 wk). Severity and frequency tend to decrease during pregnancy and in patients with amyloidosis. Spontaneous remissions may last years. In some patients, the attacks have a prodromal phase.

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, many patients undergo urgent laparotomy before the correct diagnosis is 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 ¹/₃ 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. 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

• Colchicine Some Trade Names
  No US trade name
  Click for Drug Monograph
  

Prophylactic colchicine Some Trade Names
No US trade name
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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 involve a prodromal phase, colchicine Some Trade Names
No US trade name
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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 colchicine Some Trade Names
No US trade name
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at the peak of an attack, even if delivered IV, is unlikely to be beneficial. Children often require adult dosages for effective prophylaxis. Widespread use of prophylactic colchicine Some Trade Names
No US trade name
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has led to a dramatic reduction in the incidence of amyloidosis and subsequent renal failure.

Colchicine Some Trade Names
No US trade name
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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 colchicine Some Trade Names
No US trade name
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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 colchicine Some Trade Names
No US trade name
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concentration in circulating monocytes. Weekly IV colchicine Some Trade Names
No US trade name
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may reduce attack frequency and severity in patients who do not respond to oral colchicine Some Trade Names
No US trade name
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. Untested alternatives in nonresponders include interferon-α 3 to 10 million units sc, prazosin Some Trade Names
MINIPRESS
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3 mg po bid, infliximab Some Trade Names
REMICADE
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5 mg/kg IV q 8 wk, and thalidomide Some Trade Names
THALOMID
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initially 100 mg po once/day.

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

Last full review/revision January 2009 by Stephen E. Goldfinger, MD

Content last modified January 2009