The FMF phenotype is known to be more severe in patients carrying the p.M694V mutation. This report describes 2 molecules secreted by unconventional secretory pathways, S100A12 and IL-18, whose concentrations correlated with clinical disease activity and genotype in patients with FMF. In this clinically and genetically heterogeneous disease, management of these surrogate markers might help to improve patient care and outcomes.

Co-culture with colchicine and/or stimulation with adenosine triphosphate (ATP) and lipopolysaccharide (LPS) led to a significant increase in receptor shedding. Neutrophils were not prevented from spontaneous shedding by blocking IL-1 or the NLRP3 inflammasome. In summary, the data demonstrate that ex vivo cultured neutrophils derived from FMF patients display a unique phenotype with spontaneous release of high amounts of IL-18, S100A12, MPO, caspase-1, and proteinase 3 and spontaneous activation as demonstrated by the loss of CD62L. Neutrophilic activation seems to be independent from IL-1 activation and displays a gene-dose effect that may be responsible for genotype-dependent phenotypes.

Familial Mediterranean fever (FMF) is caused by mutations within the Mediterranean fever (MEFV) gene. These gain of function mutations lead to an increased activation of the inflammasome pyrin with a subsequent disproportional proinflammatory reaction. Classically, in FMF patients two pathogenic mutations affecting both alleles are found in the molecular genetic analysis; however, it is well known that the phenotype can also be caused either by mutations with lower penetrance or unknown significance. Furthermore, in a significant number of patients only one or even no MEFV mutations can be detected. Heterozygous mutation carriers who do not suffer from classical FMF, can also present with other signs of inflammation, e. g. subclinical increased inflammation markers, associated inflammatory diseases or unclassified symptoms. Thus, FMF does not follow a classical autosomal recessive inheritance and a variable gene dose effect has to be considered, which is furthermore modulated by other mostly unknown genetic variants and environmental factors. This article summarizes the broad spectrum of clinical presentations associated with MEFV mutations and analyzes the effect of the gene dose on the phenotypical expression. Furthermore, the impact of the molecular genetic analysis on the diagnostics of a patient and on the individualized management of the disease is discussed.

ME, et al. International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-Workgroup Report of the Adverse Reactions to Foods Committee,

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BackgroundFamilial Mediterranean Fever (FMF) is an autoinflammatory disorder associated with MEFV pyrin-encoding gene mutations. S100A12 is a pro-inflammatory “damage associated molecular pattern” molecule and is strongly elevated in active FMFObjectivesTo investigate the association between genotype and S100A12 secretion in clinically active, inactive and subclinical disease in vitro and ex vivo.MethodsSerum S100A12 concentration was retrospectively analysed for 125 patients in the German Auto-Inflammatory Diseases Network (AID-Net) Registry according to disease activity and genotype. In vitro, secretion of S100A12, IL-18, IL-1beta and caspase-1 was measured after stimulation of neutrophils from six M694V-positive patients and four healthy controls (HC).ResultsS100A12 hypersecretion correlated significantly with clinical disease activity and also with genotype in a “gene-dosing” way, being highest in homozygotes > compound heterozygotes > heterozygotes. M694V-positive heterozygous, compound heterozygous or homozygous patients h had higher S100A12 concentration during inactive and subclinical disease than M694V-negative heterozygous, compound heterozygous or homozygous patients respectively. In vitro, unstimulated neutrophils from M694V-positive patient spontaneously secreted higher S100A12, IL-8 and caspase-1 compared to healthy controls. Colchicine significantly inhibited secretion of S100A12 from stimulated and unstimulated patient neutrophils.ConclusionsFMF phenotype is known to be more severe in patients with M694V mutations. We describe for the first time a biomarker that correlates with clinical disease activity and FMF genotype both ex vivo and in vitro, which has implications for clinical management.ReferencesWittkowski H. et al. Pediatr Rheumatol 2008.Kallinich T. et al. ARD 2010.Jeske M et al. Klin Pädiatrie 2013.Disclosure of InterestNone declared

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