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Familial Mediterranean Fever: From Pathogenesis to Treatment

David QH Wang, Leonilde Bonfrate, Ornella de Bari, Tony Y Wang and Piero Portincasa

Familial Mediterranean Fever (FMF) is rare autosomal recessive autoinflammatory disorder characterized by periodic bouts of fever, serositis, synovitis, and/or cutaneous inflammation. Painful febrile attacks last 1 to 3 days and can vary in severity. FMF is almost exclusively affecting subjects with Mediterranean origin, especially Armenian, Arab, Jewish, Turkish, North Africans and Arabic descents. Cases have been reported in Italian population with a cluster of Italians patients living in Apulia and Basilicata. FMF results from the mutations in the MEFV (Mediterranean Fever) gene, consisting of 10 exons located on chromosome 16p13.3. MEFV encodes a 781 amino acid (86kDa) protein (pyrin or marenostrin) expressed in granulocytes, monocytes, serosal and synovial fibroblasts. In FMF, pyrin function is dysregulated with abnormal transcription of intranuclear peptides involved in inflammation. During acute attacks, a marked acute-phase response leads in leukocytosis, and elevated erythrocyte sedimentation rate, fibrinogen, C reactive protein, Serum Amyloid A protein. A worrisome manifestation of FMF is the evolution towards the secondary AA glomerular amyloidosis which puts a subgroup of patients at risk of end-stage kidney disease. Treatment of symptomatic FMF patients is aimed to prevent the acute attacks, and the development and progression of amyloidosis. Colchicine treatment given lifelong is the safe and effective in FMF patients at any age. In the few colchicine-resistant/ intolerant FMF patients, experimental off-label treatments include IL-1β inhibitors (anakinra, rilonacept, canakinumab), and anti-TNF-α agents (etanercept). This review describes pathophysiologic, diagnostic, and therapeutic aspects of FMF.