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Familial
Mediterranean fever is an inherited disorder characterized by recurrent
bouts of fever and peritonitis, sometimes with pleuritis, skin lesions,
arthritis, and, very rarely, pericarditis. Renal amyloidosis may
develop, which may lead to renal failure. Descendants of inhabitants
of the Mediterranean basin are most 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, Belgians) to caution against excluding the diagnosis solely on the basis of ancestry. About 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 cause defective pyrin molecules; it is hypothesized that minor, unknown triggers to inflammation that are normally checked by intact pyrin cannot be suppressed by the altered protein. The clinical consequence is spontaneous bouts of neutrophil-predominant inflammation in the abdominal cavity as well as at 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 every 2 to 6 wk). Severity and frequency tend to decrease during pregnancy and 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 on 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. However, 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 of FMF is chronic renal failure caused by deposition of amyloid protein in the kidneys. Amyloid deposition may also occur in the GI tract, liver, spleen, heart, testes, and thyroid.
Diagnosis
Diagnosis is mainly clinical, but genetic testing is now available and is particularly useful in the evaluation of atypical cases. Nonspecific findings include elevated 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.
Prognosis
and Treatment
Despite the severity of symptoms during acute attacks, most patients recover swiftly and remain free of illness until their next attack. Widespread use of prophylactic colchicine has led to a dramatic reduction in the incidence of amyloidosis and subsequent renal failure.
Prophylactic colchicine 0.6 mg po bid (some patients require qid dosing and 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 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 at the peak of an attack, even if delivered IV, is unlikely to be beneficial. Children often require adult dosages to achieve effective prophylaxis. Colchicine does not add to the increased risk of infertility and miscarriage among affected women, nor does it increase the number of teratogenic events when taken during pregnancy.
Lack of response to colchicine is often caused by poor adherence to the drug regimen, but a correlation has also been noted between poor response and diminished colchicine concentration in circulating monocytes. Weekly IV colchicine may reduce attack frequency and severity in nonresponders. Untested alternatives in nonresponders include interferon-α 3 to 10 million units sc, prazosin 3 mg po bid, and thalidomide .
Opioids are sometimes needed for pain relief but should be administered prudently to avoid addiction.
Last full review/revision November 2005
Content last modified November 2005
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