Exploring the Role of Vitamin D in Familial Mediterranean Fever: Pathogenesis, Triggers, and Immune Modulation.

Familial Mediterranean Fever (FMF) is among the most frequent autoinflammatory diseases in populations originating from the area of Middle Eastern and Mediterranean countries. It is caused by mutations in the MEFV gene, which causes dysregulated pyrin expression and thus an immunologic anomaly. FMF is diagnosed by recurrent episodes of fever and serosal inflammation, predominantly peritonitis and pleuritis, as well as other systemic symptoms. Recent research is dedicated to searching for factors beyond genetic code contributing to how FMF evolves, the severity of its symptoms and response to conventional therapy-colchicine. These factors include epigenetic modifications of the MEFV gene and other environmental factors, such as cold exposure, stress, composition of gut flora and diet. Among these factors, vitamin D, best known for its classical role in musculoskeletal health, has emerged as a powerful immune modulator. It has been documented that vitamin D has been implicated in the regulation of pro-inflammatory cytokines and may modulate immune responses. Notably, in regions with some of the highest reported prevalences of MEFV mutations-likely reflecting Mediterranean populations more broadly-vitamin D concentrations are frequently low. This overlap raises the hypothesis that vitamin D deficiency may be associated with FMF pathogenesis, although current data are largely correlational and do not establish causality. In this review, we summarize current evidence on FMF pathogenesis, potential triggers, and vitamin D metabolism, and explore how vitamin D may modulate immune responses and intersect with key autoinflammatory pathways, considering whether adequate vitamin D supplementation could help reduce disease burden in some patients with FMF.