Familial mediterranean fever: a fascinating model of inherited autoinflammatory disorder Piero Portincasa*, Giuseppe Scaccianoce † and Giuseppe Palasciano* *Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy, † Gastrointestinal Endoscopy, “Umberto I” Hospital, Altamura, Bari, Italy ABSTRACT Background Familial Mediterranean fever (FMF) is a rare inherited autosomal recessive autoinflammatory disorder characterized by recurrent and self-limited episodes of fever and painful serositis, lasting 1–3 days. FMF occurs almost exclusively among ethnic groups of the Mediterranean basin, although cases have also been found in Japan and Korean populations. Diagnosis is based on clinical features, response to colchicine and genetic analysis. Novel drugs are emerging, allowing better management of colchicine-resistant/colchicine- intolerant patients. This review aims to attract the attention of the readers on differential diagnosis and management of patients with FMF. Methods The current state-of-the-art on FMF is outlined, with respect to epidemiological, genetic, patho- physiological and therapeutic characteristics, based on critical analysis of solid scientific literature. Results FMF is more frequent than it was thought before. The phenotypic expression of M694V is more severe than that of V726A. Patients with M694V/M694V homozygosity are exposed to a higher risk of developing renal amyloidosis, arthritis, dermatologic and oral lesions, higher fever and more frequent painful attacks. Life-long therapy with colchicine (10–24 mg/day) is effective and safe to prevent recurrent attacks and renal amyloidosis and to reverse proteinuria. In nonresponder patients, alternative novel approaches include interleukin-1 receptor antagonist anakinra and the interleukin-1 decoy receptor rilonacept. Conclusions The prognosis of FMF is normal if AA amyloidosis is prevented. Colchicine remains the first-line therapy to treat pain and prevent amyloidosis. A follow-up should include clinical evaluation, therapeutic adjustments, measurement of serum amyloid A and proteinuria. Keywords Amyloidosis, anakinra, colchicine, periodic fever, pyrin, serositis. Eur J Clin Invest 2013; 43 (12): 1314–1327 Introduction Familial Mediterranean fever (FMF) is a rare inherited autoso- mal recessive autoinflammatory disorder. Clinically, FMF is characterized by recurrent and self-limited attacks of fever and peritonitis, pleuritis, arthritis or erysipelas-like skin disease with a marked acute-phase response. Late complications of untreated patients are due to renal amyloidosis [1–4]. FMF occurs almost exclusively among ethnic groups of the Mediterranean basin with Armenian, Arab, Jewish, Turkish, North Africans and Arabic descent. The prevalence of FMF is estimated to be 1 per 250 to 1 per 1000 in non-Ashkenazi (Sephardic) Jews [5], 1 per 73 000 in Ashkenazi Jews [6], 1 per 500 Armenians [7], 1 per 1000 Turkish and 1 per 2600 Arabic people. The carrier frequency is estimated to be 1 in 3 Arme- nians [8], 1 in 5–10 Sephardic Jews [9], 1 in 5 Ashkenazi Jews [9] and Turks [10]. Due to advancement of gene testing and worldwide travelling and immigration, FMF cases have been reported in Italians [11]. A novel cluster of FMF patients living in Altamura (Apulia Region) in southern Italy has been recently identified [12–14]. FMF is also found in populations like Greeks, Cubans, Belgians [15], in countries like Sweden [16], Germany [17] and other unexpected locations, such as Japan [18–20] and Korea [21]. The worldwide prevalence is estimated at 100 000–150 000 patients [22]. FMF in adults appears to be more frequent in males with a ratio of M/F of 15–2 : 1. Historical landmarks for FMF include the early report in 1908 by Janeway and Mosenthal of a Jewish girl with episodic fever and abdominal pain (as outlined in ref. [1]); other cases were described later as ‘fever of unknown origin’ [23], while the first 1314 ª 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd DOI: 10.1111/eci.12170 REVIEW