Familial Mediterranean fever association with schizophrenia: insights from big data analysis
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University of Leeds, United Kingdom
Sheba Medical Centre, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
University of Genoa, Italy
Clalit Health Services, Israel
Submission date: 2019-08-15
Final revision date: 2020-02-11
Acceptance date: 2020-02-26
Online publication date: 2020-05-27
Several autoimmune diseases have been associated with schi¬zophrenia; however, little is known about putative links with auto-inflam¬matory 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.

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]).

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.