Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review

Abstract

Familial Mediterranean fever (FMF) (OMIM #249100) is the most common hereditary autoinflammatory disease in the world. FMF is caused by gain of function mutations of MEFV gene which encodes an immune regulatory protein, pyrin. Over the last few years, we have witnessed several new developments in the pathogenesis, genetic testing, diagnosis, comorbidities, disease related damage and treatment approaches to FMF. Elucidation of some of the pathogenic mechanisms has led to the discovery of pathways involved in inflammatory, metabolic, cardiovascular and degenerative diseases. The use of next generation sequencing in FMF has revealed many new gene variants whose clinical significance may be clarified by developing functional assays and biomarkers. Clinically, although FMF is considered an episodic disease characterized by brief attacks, recent systematic studies have defined several associated chronic inflammatory conditions. Colchicine is the mainstay of FMF treatment, and interleukin (IL)-1 antagonists are the treatment of choice in refractory or intolerant cases. Experience of IL-1 antagonists, anakinra and canakinumab, is now available in thousands of colchicine resistant or intolerant FMF patients. In this contemporary review, we surveyed current FMF knowledge in the light of these recent advances.

M680I/M694V Heterozygous Mutation in Early Onset Familial Mediterranean Fever

“…FMF is caused by gain of function mutations in the MEFV gene located on chromosome 16 [ 18 ]. MEFV gene encodes pyrin, a protein which through interaction with GTPases results in inflammasome activation and modulates production of interleukin-1β (IL-1β) and in turn prevents inappropriate inflammatory reactions [ 19 , 20 ].…”

“…MEFV gene encodes pyrin, a protein which through interaction with GTPases results in inflammasome activation and modulates production of interleukin-1β (IL-1β) and in turn prevents inappropriate inflammatory reactions [ 19 , 20 ]. An increase in IL-1β and IL-18 causes cells to undergo pyroptosis, a process of inflammatory death [ 18 ]. The rise in pro-inflammatory cytokines gives rise to the inflammatory presentation seen in FMF patients.…”

Phenotypic characterization of Familial Mediterranean Fever patients harboring variants of uncertain significance

“…Persistent inflammation was defined as an increased serum C-reactive protein (CRP) levels during the attack-free period (at least 2 weeks apart from attack) and in more than 75% of follow-up visits was [13]. We defined colchicine non-responsiveness as having more than one attack per month for 3 months duration despite the use of maximal tolerated dose of colchicine [14].…”

Appendectomy history is associated with severe disease and colchicine resistance in adult familial Mediterranean fever patients

“…The most common cause of acute surgical abdomen in childhood is acute appendicitis with a peak incidence between 10-19 years. The lifetime risk of acute appendicitis is 7-9%, which is far beyond the prevalence of FMF [7] which has a prevalence of 1/400-1/1000 in endemic countries [8].…”