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The clinical presentation of familial Mediterranean fever (FMF) is remarkably variable, ranging from a quiescent to a severe and disabling disease. The M694V mutation is one of approximately 300 published genetic variations in the FMF gene. While some studies have reported a more severe phenotype for the homozygous M694V mutation, studies dedicated solely to featuring the phenotype of homozygous M694V genotype are meager. The objective of the study was to present a comprehensive characterization of the homozygous M694V mutation associated phenotype, compared to the phenotypes of other FMF genotypes. For that aim, we compared between the demographic and clinical characteristics of 57 FMF patients, homozygous for the M694V MEFV mutation, and 56 patients with other MEFV genotypes. A questionnaire, detailing demographic and clinical features was completed for each patient based on an interview, physical examination and medical file data. Compared with the control group, the double M694V MEFV mutation group comprised more patients with severe disease (89.4 vs. 32.1%, p < 0.0001) and affected with FMF-related comorbidities (29.8 vs. 12.5%, p = 0.0373). The mean frequency of attacks per year was higher for patients with the double M694V MEFV mutation, before and during colchicine treatment (23.6 ± 9.3 vs.15.6 ± 11.7, p = 0.0001 and 7.2 ± 7.8 vs. 3.5 ± 5.5, p = 0.0007, respectively); and the mean dose of colchicine used was higher (1.9 ± 0.48 vs.1.48 ± 0.54 mg/day, p = 0.0001). Among the genotypes tested, homozygosity to the M694V MEFV mutation was found to be associated with the most grievous phenotype in the clinical spectrum of FMF., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Objectives: Familial Mediterranean fever (FMF) is an autoinflammatory disorder with episodic and persistent inflammation, which is only partially suppressed by continuous colchicine treatment. While chronic inflammation is considered an important cardiovascular risk factor in many inflammatory disorders, its impact in FMF is still disputed. We measured arterial stiffness, a marker of atherosclerotic cardiovascular disease, in a group of FMF patients, in order to evaluate the cardiovascular consequences of inflammation in FMF and the role of colchicine in their development., Methods: Eighty colchicine treated FMF patients, without known traditional cardiovascular risk factors, were randomly enrolled in the study. Demographic, genetic, clinical and laboratory data were retrieved from patient files and examinations. Arterial stiffness was measured using pulse wave velocity (PWV). The recorded values of PWV were compared with those of an age and blood pressure adjusted normal population, using internationally endorsed values., Results: FMF patients displayed normal PWV values, with an even smaller than expected proportion of patients deviating from the 90th percentile of the reference population (5% vs. 10%, p=0.02). The lowest PWV values were recorded in patients receiving the highest dose of colchicine (≥2 mg vs. 0-1 mg, p=0.038), and in patients of North African Jewish origin, whose disease was typically more severe than that of patients of other ethnicities; both observations supporting an ameliorating colchicine effect (p=0.043)., Conclusions: Though subjected to chronic inflammation, colchicine treated FMF patients have normal PWV. Our findings provide direct evidence for a cardiovascular protective role of colchicine in FMF.

Background: Although familial Mediterranean fever (FMF) was originally defined as an autosomal recessive disorder, approximately 10-20% of FMF patients do not carry any FMF gene (MEFV) mutations. Fine phenotype characterization may facilitate the elucidation of the genetic background of the so called "FMF without MEFV mutations". In this study we clinically and demographically characterize this subset., Methods: MEFV mutation-negative FMF and control patients were recruited randomly from a cohort followed in a dedicated FMF clinic. The control subjects comprised 2 groups: 1. typical population of FMF, consisting of genetically heterogeneous patients manifesting the classical spectrum of FMF phenotype and 2. a severe phenotype of FMF, consisting of FMF patients homozygous for the p.M694V mutation., Results: Forty-seven genetic-negative, 60 genetically heterogeneous and 57 p.M694V homozygous FMF patients were enrolled to the study. MEFV-mutation negative FMF patients showed a phenotype closely resembling that of the other 2 populations. It differed however from the p.M694V homozygous subset by its milder severity (using Mor et al. scoring method), as determined by the lower proportion of patients with chest and erysipelas like attacks, lower frequency of some of the chronic manifestations, lower colchicine dose and older age of disease onset., Conclusions: MEFV mutation-negative FMF by virtue of its classical FMF phenotype is probably associated with a genetic defect upstream or downstream to MEFV related metabolic pathway.