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 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.
Familial Mediterranean fever is caused by
The mutation is inherited in an autosomal recessive manner. FMF mutations are gain-of-function, that is, they confer new or enhanced activity on a protein, with a gene dosage effect (ie, more copies of the abnormal gene convey a greater effect). The MEFV gene normally codes a protein named pyrin, which is expressed in circulating neutrophils.
Pyrin is part of the innate immune system and guards against bacterial toxins that depolymerize actin and activate inflammasomes. Bacteria that produce such toxins include Clostridium difficile, Burkholderia cenocepacia, and Vibrio cholerae (1). Pyrin is presumed to blunt the inflammatory response, possibly by inhibiting neutrophil activation and chemotaxis. Gene mutations result in altered pyrin molecules that do not inhibit inflammasome activation and thus 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.
Onset of familial Mediterranean fever is usually between the ages of 5 and 15 years but may be much later or earlier, even during infancy. Attacks have no regular pattern of recurrence. They usually last 24 to 72 hours but may last longer. Frequency ranges from 2 attacks/week to 1 attack/year (most commonly, once every 2 to 6 weeks). 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 of FMF 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 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.
Despite the severity of symptoms during acute attacks, most patients recover swiftly and remain free of illness until their next attack.
The most significant long-term complication of FMF is
Amyloid may also be deposited in the gastrointestinal 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.
Diagnosis of familial Mediterranean fever 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 mutations in the MEFV gene. About 10 to 20% of patients who meet the diagnostic criteria for FMF do not have MEFV mutations, which suggests epigenetic and environmental factors contribute to the disease pathogenesis (1).
Nonspecific findings include elevations in white blood cells with neutrophil predominance, erythrocyte sedimentation rate, C-reactive protein, and fibrinogen. Urinary excretion of > 0.5 g protein/24 hours suggests renal amyloidosis.
Prophylactic colchicine 0.6 mg orally 2 times a day (some patients require dosing 4 times a day; others a single daily dose) provides complete remission or distinct improvement in about 85% of patients. If attacks or subclinical inflammation persist, the colchicine dose should be increased. For patients with infrequent attacks that have a gradual onset, colchicine can be reserved until initial symptoms occur and then begun at 0.6 mg orally every hour for 4 hours, then every 2 hours for 4 hours, then every 12 hours for 48 hours. Initiation of colchicine at the peak of an attack is unlikely to be beneficial. Children often require adult dosages for effective prophylaxis. Widespread use of prophylactic colchicine has led to a dramatic reduction in the incidence of amyloidosis and subsequent renal failure.
Colchicine 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 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.
Opioids are sometimes needed for pain relief but should be used prudently to avoid addiction.
1. Ozen S, Demirkaya E, Erer B, et al: EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis 75(4):644–651, 2016. doi: 10.1136/annrheumdis-2015-208690.
2. De Benedetti F, Gattorno M, Anton J, et al: Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med 378(20):1908–1919, 2018. doi: 10.1056/NEJMoa1706314.
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 colchicine provides protection against amyloidosis.
Diagnose clinically, but consider genetic testing for atypical cases.
Daily colchicine results in significant protection against attacks in most patients, but a few require an immunomodulator such as anakinra, rilonacept, or canakinumab.
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