Long-term rheumatologic comorbidities in familial Mediterranean fever

Familial Mediterranean fever (FMF) is characterized by pyrin inflammasome dysregulation and chronic subclinical inflammation. Whether FMF carries an increased long-term burden of rheumatologic and autoimmune inflammatory disease is unclear. We evaluated baseline and long-term occurrence of rheumatologic and selected autoimmune comorbidities in FMF.

This was a nationwide, retrospective, population-based matched-cohort study using electronic health records from Leumit Health Services in Israel (2001-2024). Patients with confirmed FMF were matched 1:4 with controls by age, sex, and socioeconomic status. Rheumatologic and selected autoimmune comorbidities, including inflammatory bowel disease and autoimmune thyroid disease, were identified using International Classification of Diseases, 9th Revision (ICD-9) codes. Baseline prevalence and cumulative occurrence over up to 20 years were assessed, with a 12-month washout. A composite endpoint of any prespecified rheumatologic or autoimmune diagnosis was evaluated. Multivariable logistic regression was adjusted for demographic and clinical covariates, with false discovery rate correction.

The cohort included 3324 FMF patients and 13,296 controls (mean age 24.5 years; 51% female). At baseline, FMF was associated with Behçet disease, rheumatoid arthritis, fibromyalgia, gout, osteoarthritis, and connective tissue disease (all q < 0.05). During follow-up, FMF was further associated with ankylosing spondylitis, lupus, vasculitis, psoriatic arthritis, and Crohn's disease (adjusted odds ratios 1.31-12.7; all q < 0.05). Amyloidosis was markedly more frequent in FMF (1.26%vs. 0.015%; q < 0.001). The composite endpoint was higher in FMF (17.0%vs. 7.4%; adjusted odds ratio 2.18).

FMF is associated with a selective, persistent excess of rheumatologic and autoimmune diseases despite colchicine, supporting long-term rheumatologic surveillance.