Familial Mediterranean Fever

FMF is caused by

• Mutations in the MEFV gene on the short arm of chromosome 16

The mutation is classically inherited in an autosomal recessive manner, but heterozygotes may manifest a clinical phenotype. 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 plays a role in innate immunity. It senses modifications in the activity of the small GTPase RhoA, a molecular switch that regulates a variety of signal transduction pathways including cytoskeletal organization. Pathogen virulence toxins (such as Clostridioides difficile, Burkholderia cenocepacia, and Vibrio cholera) downregulate RhoA activity and cause an assembly pyrin along with other proteins into a pyrin inflammasome, which eventually results in the production of the proinflammatory cytokine interleukin-1 beta (IL-1 beta). MEFV pathogenic variants favor the active state of pyrin and give rise to cell membrane rupture (pyroptosis) and the release of proinflammatory cytokines (1).

There is strong evidence that Yersinia pestis, the cause of bubonic plague, led to the positive selection of FMF-associated MEFV mutations. These mutations confer a survival advantage to certain people who harbor Yersinia pestis (2).

Onset of FMF 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 12 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). Physical and emotional stressors (eg, physical trauma, infection, menstruation) may trigger attacks (1). 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 undergo urgent laparotomy before the correct diagnosis is made. With pleural involvement, dyspnea due to pleuritic pain may occur.

Other manifestations of FMF include 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 (2).

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

Autoinflammatory Periodic Fever Disorders

CAPS = cryopyrin-associated periodic syndromes; FMF = familial Mediterranean fever; NOMID = neonatal-onset multisystem inflammatory disease; PFAPA = periodic fevers with aphthous stomatitis, pharyngitis, and adenitis; TRAPS = tumor necrosis factor receptor–associated periodic syndrome. Adapted from Sag E, Bilginer Y, Ozen S: Autoinflammatory diseases with periodic fevers. Curr Rheumatol Rep 19(7):41, 2017. doi: 10.1007/s11926-017-0670-8

• Clinical evaluation

• Genetic testing

Diagnosis of familial Mediterranean fever is mainly clinical based on Tel HaShomer criteria (see table Tel HaShomer Criteria for the Diagnosis of Familial Mediterranean Fever) (1), 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 (2).

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 may suggest renal amyloidosis.

Differential diagnosis includes acute intermittent porphyria, hereditary angioedema with abdominal attacks, relapsing pancreatitis, and other hereditary relapsing fevers.

• Daily colchicine

• In patients who are colchicine-resistant or -intolerant, interleukin-1 (IL-1) inhibitors

amyloidosis (1). Colchicine provides complete remission or distinct improvement in almost 95% of patients. If attacks or subclinical inflammation persist, the colchicine dose should be increased. Initiation of colchicine at the peak of an attack is not beneficial. Children require a dose adjustment for colchicine that is typically based on age, weight, and severity of phenotype and genotype (2

colchicine is often caused by poor adherence to the regimen.

Patients who are colchicine3, 4