Increased Stroke Risk in Those With Familial Mediterranean Fever vs General Population

Patients with familial Mediterranean fever are at an increased risk for stroke.

Compared with the general population, patients with familial Mediterranean fever (FMF) are at an elevated risk for stroke, regardless of any known comorbidities, according to study findings published in Rheumatology (Oxford).

Although the link between chronic inflammatory disorders and cardiovascular (CV) disease has been well established, few analyses have evaluated the risk for ischemic heart disease and the risk for stroke among individuals with chronic inflammatory conditions, including FMF.

Using the Clalit Health Services database, researchers of the population-based study sought to assess the rates and risk for stroke among patients with FMF, as well as to examine predictors for stroke.

All individuals with an initial diagnosis of FMF between January 2000 and December 2016, were included in the study. Study participants were matched with control participants who did not have FMF, based on sex, age, and location of residence. Follow-up was conducted until initial diagnosis of stroke or death, whichever occurred first.

A total of 9769 patients with FMF and 9769 control participants without FMF were included in the analysis. At the index date of the study, the mean participant age was 25.7±18.0 years. Overall, the percentage of men in both groups was 49.0%.

Clinicians should be aware of these findings when managing these patients.

In the FMF vs control group, a significantly higher percentage of participants were from North Africa, the Middle East, and Turkey.

Regarding baseline CV risk factors between the groups, the only significant difference was with regard to history of smoking, which was reported more often among individuals with FMF vs those without (10.0% vs 9.1%, respectively; P =.032).

Researchers noted higher frequency in the FMF vs control group of amyloidosis (0.7% vs 0.3%); chronic kidney failure (3.8% vs 2.0%); need for dialysis (1.1% vs 0.2%); and kidney transplantation (0.6% vs 0.1%; P <.001 for all).

In the FMF group, 78.1% (n=7630) of the participants received treatment with colchicine, with a median duration of treatment of 10.2 years (range, 3.7-17.6 years).

Median follow-up was 12.4 years in the FMF cohort vs 12.5 years in the control cohort. During follow-up, a total of 208 participants with FMF vs 148 control participants were diagnosed with stroke, which resulted in stroke incidence rates per 10,000 person-years of 19.8 (95% CI, 17.2-22.7) and 13.9 (95% CI, 11.8-16.4), respectively. The crude hazard ratio (HR) was 1.42 (95% CI, 1.15-1.76; P <.001).

Following adjustments for sex and age (HR, 1.46; 95% CI, 1.18-1.80; P <.001) and for baseline CV risk factors (HR, 1.44; 95% CI, 1.16-1.78; P <.001), the results remained statistically significant. Participants with FMF vs control participants were diagnosed with stroke at a significantly younger age (59.8±15.9 vs 65.3±14.9 years, respectively; P <.001).

According to multivariate analysis, patients with FMF and disease-associated comorbidities, such as amyloidosis and kidney complications (HR, 2.16; 95% CI, 1.38-3.38; P <.001), and those with FMF without any disease-related complications (HR, 1.32; 95% CI, 1.04-1.67; P <.05) had an elevated risk for stroke. Patients with vs without FMF who had disease-associated comorbidities had a higher incidence rate of stroke (128.0 vs 15.4 stroke events per 10,000 person-years, respectively), which resulted in a higher difference in incidence rate (67.7 vs 3.7 stroke events per 10,000 person-years, respectively).

Study limitations included the inability to clinically differentiate between patients with FMF according to signs/symptoms of disease, frequency/severity of attacks, and levels of inflammatory markers; and the inability to retrieve any genetic information regarding participants’ baseline mutations due to privacy policies.

“North African and Middle Eastern origins are associated with higher stroke rates, illustrating a phenotypic-genotypic relation. Clinicians should be aware of these findings when managing these patients,” the study authors explained. “Further studies are warranted to decide on an effective primary prevention and screening strategy,” they concluded.


Ben-Shabat N, Gendelman O, Fisher L, et al. Increased risk for stroke in patients with familial Mediterranean fever: results from a large population-based study. Rheumatology (Oxford). Published online April 2, 2023. doi:10.1093/rheumatology/kead153