Cam V, Cingoz E, Ercan Emreol H, Unal D, Bayindir Y , et al.
Rheumatology (Oxford, England) •
Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent febrile attacks and serositis, with a high prevalence and carrier frequency of MEFV variants in Eastern Mediterranean populations. In this setting, interpretation of MEFV variants of uncertain significance (VUS) is challenging, and their clinical relevance remains controversial. We aimed to describe the clinical characteristics of patients carrying mono- or biallelic MEFV VUS and to compare them with patients harboring biallelic pathogenic MEFV variants, including assessment of FMF and PFAPA classification according to Eurofever/PRINTO criteria. This retrospective study included pediatric patients with recurrent autoinflammatory manifestations who underwent MEFV genetic analysis and were receiving colchicine. Patients were stratified by MEFV genotype, and clinical features, attack characteristics, treatment profiles, and classification status were compared. Patients with MEFV VUS exhibited fewer classical FMF features, such as serositis-related chest pain and arthritis, but more frequent atypical manifestations, including diarrhea, oral aphthae, and lymphadenopathy, along with longer attack duration. Measures of disease burden, including age at onset and attack frequency, were similar between groups. FMF criteria were fulfilled by approximately half of patients with VUS. Patients with autoinflammatory disease carrying MEFV variants of uncertain significance may exhibit atypical clinical features. Alternative diagnoses should be considered, and further genetic evaluation may be required.
Yaglikara E, Boluk O, Bayindir Y, Bilginer Y, Tasar MA , et al.
Diagnostics (Basel, Switzerland) •
FMF is the most common autoinflammatory disease. The activation of the pyrin inflammasome is the mainstay of the pathogenesis, which might lead to a specific cell-death mechanism, pyroptosis. Pyroptosis is a programmed inflammatory cell death mediated by gasdermin proteins, featuring cell swelling, membrane rupture, and release of inflammatory contents Aim: In this study we aimed to analyze the cell-death mechanisms in the pathogenesis of FMF attacks. Twenty-five FMF patients were included, and PFAPA patients ( = 10) and healthy controls (HC, = 10) served as controls. We collected plasma samples from FMF and PFAPA patients during the attack and the attack-free period. We measured the soluble plasma levels of sFas, sFasL, granzyme A, granzyme B, perforin, granulysin, IL-2, IL-4, IL-10, IL-6, IL-17A, TNF-α, and IFN-γ by commercial pre-defined cytometric bead array kits. There was no significant difference between groups in terms of sex and age between FMF patients and HCs, but PFAPA patients were younger than other groups due to the nature of the disease. We then analyzed the components of apoptosis and pyroptosis. The levels of sFasL ( = 0.035) and granzyme A ( = 0.038) in FMF patients were significantly increased during the attack period and decreased to levels comparable to HCs during the attack-free period. This increase was not seen in the PFAPA patients, with comparable levels with the HC group both during attack period and attack-free period. During the attack period of FMF patients, granzyme B ( = 0.145) and perforin ( = 0.203) levels were also increased; however, the differences were not statistically significant. The levels of sFasL, granzyme A, granzyme B, and perforin were closely correlated with each other during the attack period of FMF patients. Our study on death pathways during an FMF attack, suggests an upregulation in both pyroptosis through the granzyme-gasdermin pathway and apoptosis with the increased FasL and perforin levels, which was different from PFAPA patients. These findings might shed light on the reason for the nature of self-limited attacks, but further studies are needed to prove this hypothesis.