Abstract
Recurrent self-limited attacks of fever and short-lived inflammation in the serosal membranes, joints, and skin are the leading features of familial Mediterranean fever (FMF), the most common autoinflammatory disorder in the world, transmitted as autosomal recessive trait caused by MEFV gene mutations. Their consequence is an abnormal function of pyrin, a natural repressor of inflammation, apoptosis, and release of cytokines. FMF-related mutant pyrins are hypophosphorylated following RhoA GTPases' impaired activity and show a propensity to relapsing uncontrolled systemic inflammation with inappropriate response to inflammatory stimuli and leukocyte spread to serosal membranes, joints or skin. Typical FMF phenotype 1 consists of brief episodes of inflammation and serositis, synovitis, and/or erysipelas-like eruption, whereas phenotype 2 is defined by reactive amyloid-associated (AA) amyloidosis, which is the most ominous complication of FMF, in otherwise asymptomatic individuals. Furthermore, FMF phenotype 3 is referred to the presence of two MEFV mutations with neither clinical signs of FMF nor AA amyloidosis. The influence of epigenetic and/or environmental factors can contribute to the variable penetrance and phenotypic heterogeneity of FMF. Colchicine, a tricyclic alkaloid with anti-microtubule and anti-inflammatory properties, is the bedrock of FMF management: daily administration of colchicine prevents the recurrence of FMF attacks and the development of secondary AA amyloidosis. Many recent studies have also shown that anti-interleukin-1 treatment is the best therapeutic option for FMF patients nonresponsive or intolerant to colchicine. This review aims to catch readers' attention to the clinical diversity of phenotypes, differential diagnosis, and management of patients with FMF.