Genotype-phenotype Interactions and Autoimmune Comorbidities in Adult Familial Mediterranean Fever: A Retrospective Cohort Study of 786 Patients

Background: Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disorder characterised by recurrent febrile attacks and serosal inflammation. Although Mediterranean fever gene (MEFV) gene mutations are central to disease pathogenesis, considerable phenotypic heterogeneity exists and the contribution of autoimmune comorbidities to disease expression remains insufficiently characterised in adult populations. Objective: This study aimed to evaluate genotype-phenotype associations and to assess the frequency and clinical impact of autoimmune comorbidities in a large cohort of adult patients with FMF. Methods: We retrospectively analysed 786 adult FMF patients diagnosed according to the Tel-Hashomer criteria. Demographic characteristics, MEFV mutation profiles, clinical manifestations during attacks, acute-phase reactants, treatment regimens and response to colchicine were systematically recorded. Genetic analyses were performed using sequencing-based methods. Statistical analyses were conducted using Statistical Package for the Social Sciences software. Results: Arthralgia was the most frequent clinical manifestation (89.8%), followed by abdominal pain and myalgia. Homozygous MEFV mutations, particularly M694V homozygosity, were significantly associated with increased disease severity, higher attack frequency and colchicine resistance. Autoimmune comorbidities were identified in 30.4% of patients, with ankylosing spondylitis being the most common (19.8%). Patients with homozygous M694V mutations exhibited higher rates of colchicine resistance ( P = .021) and required interleukin-1 inhibitors more frequently ( P = .003). Conclusion: FMF exhibits marked clinical heterogeneity influenced by both genetic background and coexisting autoimmune conditions. Homozygous M694V mutations are associated with severe disease and treatment resistance. Routine evaluation for autoimmune comorbidities may facilitate individualised treatment strategies in adult FMF patients.