Familial Mediterranean Fever; Recent Advances, Future Prospectives

Abstract

Familial Mediterranean Fever (FMF) is the prototype and most common autoinflammatory disease that is particularly frequent in populations originating from the Mediterranean basin. It is characterized by episodes of recurrent inflammation lasting 2-3 days. Colchicine is the mainstay therapy, which decreases the number of attacks and eventually prevents amyloidosis, the most worrisome complication of uncontrolled FMF. It is an autosomal recessive disease. The high rate of MEFV gene mutations in specific populations has been discussed as the result of an evolutionary advantage. Tel-Hashomer criteria were the first set of criteria primarily designed for adults. Recently, the Eurofever/PRINTO group has validated a new set of classification criteria for FMF, including clinical and genetic variables. Colchicine intolerance is an important problem and limits the ability to reach an effective dose. In these groups of patients, adding an alternative biological treatment (anti IL-1 agents) is recommended. Several tools such as FMF50, AIDAI, ADDI, ISSF and MASIF have been proposed to evaluate and quantify the disease activity and organ damage. Ongoing research should clarify the exact mechanisms causing FMF attacks and phenotypic variabilities between the patients; further translational research requires the implementation of proteomics and epigenetics signatures to elucidate the pathogenesis.

Keywords: Familial Mediterranean Fever; Interleukin-1 inhibitor; autoinflammation; classification; colchicine.

Figure 1

The pathophysiology of the inflammatory response in FMF and the structure of pyrin with its interacting proteins. Pyrin (top left) consists of five domains: the Pyrin domain (PYD), bZip transcription factor basic domain (bZip), B-box zinc finger domain, alpha-helical (coiled coil) domain and B30.2 domain. Each domain has a regulatory role in diverse protein–protein interactions of pyrin with proteins connected to the inflammatory pathways through cell death and apoptosis, secretion of cytokines, chemokines, and adhesion molecules, and cytoskeletal signaling. In the inflammasome (bottom right), active forms of caspase-1 subunits, p20 and p10, are produced. In the cases without any FMF-associated MEFV mutations, the pyrin B30.2 domain interacts with p20 and p10 molecules, preventing their assembly into active p20/p10 heterodimers, which activate the caspase-1 mediated cleavage of pyrin. The caspase-1 mediated cleavage site of pyrin is located between the bZip transcription factor basic domain and the B-box zinc finger domain.