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.

Familial Mediterranean fever (FMF) is the most inherited common autoinflammatory disease (AID) with mutations in the MEFV (MEditerraneanFeVer) gene.The Mor- and Pras-Score modified for children and C-reactive protein (CRP) were used to assess FMF disease severity in Germany. We evaluate the applicability of the 2 severity scores and the correlations between ethnic origin, phenotype, and genotype.Among 242 children (median 5 age at diagnosis), we detected 431 pyrin mutations and 22 different sequence variants, including one new mutation (p.Gly488Asp). The 5 most -frequent alterations were p.Met694Val (55.2%), p.Met680lle (11.8%), p.Val726Ala (10%), p.Glu148Gln (7.9%) and p.Met694IIe (2.3%). The prevailing ancestries of 223 cases were Turkish (82.5%) and Lebanese (8.1%). Homozygous p.Met694Val substitution (30.2%) was associated with a more severe disease activity by Mor-Score, as well as with a higher mean CRP (74 mg/l) compared to patients with other mutations. Indeed, Mor- and Pras-Score were inconsistent with each other. A typical distribution of mutations in different ethnic populations was obvious, but not statistically verifiable due to the low number of cases.The homozygous p.Met694Val substitution was associated with a more severe disease activity in our German cohort. The common severity scores were inconsistent in -children.

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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