Familial Mediterranean Fever

It is a monogenic disease, associated with an autosomal recessive transmission of mutated MEFV gene. This gene is made up of 10 exons located on the short arm of chromosome 16. Most of the mutations occur in exons 2, 3, 5, and 10. The most frequent mutations are M694V, M680I, V726A, and M694I in exon 10, and E148Q in exon 2 where M694 V is the most prevalent and pathogenic one.

The MEFV gene encodes mutated pyrin protein, which is a critical player in the innate immune response. Briefly, the Pyrin protein is part of the inflammasome complex that induces an outburst of the proinflammatory interleukin-1β and IL-18. This inflammatory response is associated with the pathogenesis of FMF.

FMF is characterized by the onset of repetitive short-lived fever attacks that resolve within 1-3 days. Such attacks start before age 20, however, some cases are diagnosed at an older age and have a milder phenotype. A typical attack would last from 12 hours to 4 days, associated with rectal fever F≥ 38°C, and the presence of abdominal pain, peritonitis, pleuritis, and arthritis (hip, ankle, and knee). Patients with FMF can detect attack triggers like emotional stress, menstruation, and cold before the attack. In addition, the severity and frequency of the attacks vary wildly between patients, varying from once every few months, to once or more every month.

FMF is diagnosed based on the patient’s history, inflammatory response to colchicine, and genetic testing. The change in the inflammatory mediators such as serum amyloid A (SAA), and CRP, is assessed between attacks and can signify ongoing inflammation. Different types of genetic tests can be used, ranging from analysis of only specific mutations (kit with known 12 mutations), analysis of specific exons, analysis of all exons and introns of MEFV gene, and finally, analysis of all genes using Next generation sequencing.

FMF treatment aims to prevent the recurrence of attacks, decrease inflammation between attacks, and prevent the formation of amyloidosis. Colchicine is the mainstay treatment in FMF patients. It is known to suppress pyrin oligomerization, interfere with neutrophil migration, and prevents cytoskeletal changes that lead to pyrin inflammasome assembly. It improves the patient’s quality of life, decreases fever episodes, and prevents amyloidosis, and it should be prescribed once the diagnosis is done. However,  cases of intolerance or resistance to colchicine are seen in some patients, and in this case, IL-1 Antagonists such as Anakinra and canakinumab are prescribed.