Familial Mediterranean fever association with schizophrenia: insights from big data analysis

Introduction: Several autoimmune diseases have been associated with schizophrenia; however, little is known about putative links with auto-inflammatory conditions. We investigated the association between familial Mediterranean fever (FMF), a paradigmatic auto-inflammatory disease, and schizophrenia and assessed the impact of the latter on the survival of FMF patients. Material and methods: A case-control study was performed by utilising the database of Clalit Health Services, the largest health maintenance organisation in Israel. Familial Mediterranean fever patients were compared to age- and sex-matched controls in terms of prevalence of schizophrenia. The χ² test was used to assess the distribution of categorical variables, while the t-test was applied for continuous variables. Analysis regarding survival was performed using Kaplan-Meier curves, log rank test, and multivariate Cox proportional-hazards method. Statistical analysis was performed using SPSS version 24.0, IBM, USA. Results: The study included 7747 FMF patients and 10,080 age- and sex-matched controls (case-control match 1: 1.3). On univariate analysis, 50 FMF patients (0.6%) and 89 controls (0.9%) had schizophrenia. On multiple logistic regression model, FMF was inversely associated with schizophrenia (OR = 0.64 [95% CI: 0.43–0.90], p = 0.0173). Familial Mediterranean fever (HR = 1.43 [95% CI: 1.23–1.66]) and schizophrenia (HR = 3.97 [95% CI: 1.47–10.70]) were independently associated with all-cause mortality. However, schizophrenia as a co-morbidity in FMF subjects did not worsen their prognosis (HR = 2.17 [95% CI: 0.60–7.86]). Conclusions: Familial Mediterranean fever patients have a significantly lower proportion of schizophrenia than controls. The current evidence shows that auto-inflammatory conditions confer protection against schizophrenia development. Patients with either FMF or schizophrenia are at higher risk of all-cause mortality, a finding that calls for assessment of better medical management of mortality outcomes.