Review Familial Mediterranean Fever: A review for clinical management Claudia Fonnesu, Claudia Cerquaglia, Maria Giovinale, Valentina Curigliano, Elena Verrecchia, Giuliana de Socio, Micaela La Regina, Giovanni Gasbarrini, Raffaele Manna * Department of Internal Medicine, Periodic Fevers Research Centre, Catholic University, Largo F.Vito 1, 00168 Rome, Italy Accepted 21 August 2008 Available online 16 December 2008 Abstract Familial Mediterranean Fever (FMF) is a hereditary autosomal recessive, autoinflammatory disorder characterized by recurrent, self-limiting episodes of short duration (mean 24e72 h) of fever and serositis. FMF is the most frequent periodic febrile syndrome among the auto- inflammatory syndromes (AS), a heterogeneous group of recently identified diseases clinically characterized by recurrent febrile attacks, in the absence of autoantibodies and antigen-specific T lymphocytes. In FMF, periodic attacks show inter- and intra-individual variability in terms of frequency and severity. Usually, they are triggered by apparently innocuous stimuli and may be preceded by a prodromal period. The Medi- terranean FeVer gene (MEFV) responsible gene maps on chromosome 16 (16p13) encoding the pyrinemarenostrin protein. The precise pathologic mechanism is still to be definitively elucidated; however a new macromolecular complex, called inflammasome, seems to play a major role in the control of inflammation and it might be involved in the pathogenesis of FMF. The most severe long-term complication is type AA amyloidosis, principally affecting the kidney and the cause of chronic renal failure. Two types of risk factors, genetic and non-genetic, have been identified for this complication. Currently, the only effective treatment of Familial Mediterranean Fever is the colchicine. New drugs in a few colchicine resistant patients have been tried, but additional studies on larger series are necessary to draw definitive conclusions. Ó 2008 Elsevier Masson SAS. All rights reserved. Keywords: Autoinflammatory disease; Geno-phenotypical correlations; Inflammasome; Trigger factors; Therapy 1. Introduction Familial Mediterranean Fever (FMF), called in the past ‘‘benign recurrent polyserositis and ‘‘familial paroxysmal polyserositis’’ [1], is the most frequent periodic febrile syndrome (about 100,000 subjects affected world-wide) among the autoinflammatory syndromes (AS) [2]. Besides Familial Mediterranean Fever, the following conditions also belong to this category [3]: the TNF-Receptor-Associated Periodic Syndrome (TRAPS); the Hyper-IgD with periodic fever Syndrome (HIDS); Cryopyrine-Associated Periodic Syndrome (CAPS) or cryopyrinopathies which include Familial Cold Autoinflammatory Syndrome (FCAS), Muck- leeWells Syndrome (MWS) and Chronic Infantile-Neuro- logiceCutaneouseArticular (CINCA) syndrome; Periodic Febrile syndrome with Aphthous stomatitis, Pharingitis and cervical Adenopathy (PFAPA); Pyogenic Arthritis, Pyoderma gangrenosum and Acne syndrome (PAPA). Due to the growing number of reports on patients affected by typical symptoms of different autoinflammatory disorders, recently, the concept of overlapping syndrome has been introduced [4,5]. Auto- inflammatory syndromes are caused by mutations of the so-called ‘‘autoinflammatory genes’’, whose mutation is trans- lated into an uncontrolled, aimless activation of the inflamma- tory process in response to innocuous stimuli [6]. Familial Mediterranean Fever has been proposed as proto- type of autoinflammatory syndromes. The first case has been described in 1908 by Janeway and Mosenthal, but the first series of affected patients was reported in 1945 by Siegal, a Jewish * Corresponding author. Tel.: þ39 06 30 15 5173/4335; fax: þ39 06 35 50 2775. E-mail address: rmanna@rm.unicatt.it (R. Manna). 1297-319X/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2008.08.004 Available online at www.sciencedirect.com Joint Bone Spine 76 (2009) 227e233