Triggering Factors in Pediatric Familial Mediterranean Fever: A New Perspective on Colchicine Resistance

In our study, we aimed to determine the frequency of attack-triggering factors in pediatric patients with colchicine-resistant familial Mediterranean fever (FMF), to examine their relationship with genotype, and to evaluate changes in these factors following treatment with an IL-1 antagonist.

Between January 2024 and February 2025, 86 pediatric FMF patients (36 colchicine-resistant, 50 colchicine-responsive) who met the Eurofever criteria were included in this study. Patients were questioned for the presence of potential attack-triggering factors, including psychological stress, cold exposure, seasonal changes, physical activity, infections, fatigue, prolonged standing, long-distance travel, menstruation, starvation, sleeplessness, and the consumption of high-fat foods. In the colchicine-resistant group, triggering factors were assessed before and after anti-IL-1 treatment.

At least one triggering factor was identified in 82.6% of patients, which was more common in colchicine-resistant patients than in colchicine-responsive patients (94.4% vs. 74%, p=0.014). The most common triggers in resistant patients were cold exposure (88.2%), stress (70.6%), physical activity (67.6%), seasonal changes (65.6%), and infection (58.8%). Following IL-1 antagonist treatment, the frequency of patient-reported attacks associated with triggering factors decreased significantly (mean 29% to 14%, p<0.001). M694V homozygosity was associated with a higher frequency of specific triggering factors, including cold exposure, physical activity, and fatigue. Multivariable analysis revealed that severe disease activity (ISSF) (OR: 6.23) and longer disease duration (OR: 1.22) were independent predictors of the presence of triggering factors.

Although triggering factors were more frequently reported in patients with colchicine-resistant pediatric FMF, disease severity and disease duration were independently associated with their presence. IL-1 antagonist therapy substantially reduced both trigger-associated attacks and triggering factors. Recognition of modifiable triggers and their genetic associations may support personalized management and improved disease control.