Inflammatory bowel disease linked with increased stroke risk

Patients with inflammatory bowel disease (IBD) were 13% more likely to suffer a stroke than the general population, even decades after their diagnosis, according to a large national cohort study.

The study included all biopsy-confirmed IBD patients in Sweden from 1969 to 2019, representing approximately 85,000 individuals. The incidence rate of stroke in these patients was 32.6 per 10,000 person-years, compared with 27.7 for matched controls (HR 1.13, 95% CI 1.08-1.17), Jiangwei Sun, PhD, of the Karolinska Institutet in Stockholm, and colleagues reported in Neurologyopens in a new tab or window.

The risk remained elevated 25 years after diagnosis and corresponded to one additional stroke per 93 IBD patients. "Our study is the largest with the longest follow-up so far to investigate stroke risk in IBD patients," the researchers wrote. "These findings highlight the need for clinical vigilance about the long-term excess risk of cerebrovascular events in IBD patients."

The excess risk was mainly driven by ischemic stroke (HR 1.14, 95% CI 1.09-1.18) rather than hemorrhagic stroke (HR 1.06, 95% CI 0.97-1.15), and was significantly higher across IBD subtypes. The risk increase was 19% for Crohn's disease (95% CI 1.10-1.29), 9% for ulcerative colitis (95% CI 1.04-1.16), and 22% for unclassified IBD (95% CI 1.08-1.37), the study found.

Possible underlying mechanisms for stroke risk in IBD patients, the researchers said, include chronic systemic inflammation and a shifted microbiota-gut-brain axis. Chronic inflammation induces endothelial dysfunction, promotes plaque formation as well as platelet activation and aggregation, and contributes to atherosclerosis and arterial stiffness, the team explained.

Furthermore, disruptions in the microbiota-gut-brain-axis have been linked to neurodevelopmental disorders, neurodegenerative diseases, and stroke through various processes including modulated blood-brain barrier formation, myelination, microglia maturation, and neuroinflammation. Finally, IBD patients can be at higher risk for blood clots due to surgeries, immobilization due to fractures, and steroid therapy, the researchers noted.

The study found a higher relative risk for stroke in women with IBD (HR 1.20, 95% CI 1.14-1.27) than in men (HR 1.06, 95% CI 1.01-1.12). This could be explained by differences in risk factor profiles, sex hormone-dependent mechanisms, and stroke pathophysiology, the researchers said.

Sun and colleagues also reported a much higher relative risk of stroke in younger patients. For those with IBD onset at age 17 or younger, the risk was more than doubled (HR 2.35, 95% CI 1.52-3.62). Risk gradually decreased with age, suggesting that in older patients traditional cardiovascular risk factors become more prevalent and may outweigh the risk associated with IBD. In addition, more severe disease activity in younger-onset IBD patients could contribute to this trend, the study authors said.

Regarding implications, the team explained, "screening and management of traditional stroke risk factors in IBD patients could be more urgent than in the general population to prevent fatal CVD complications."

In addition, "for individuals with traditional CVD risk factors, optimal anti-inflammatory therapy aiming at clinical response and remission or even endoscopic healing but with less adverse cardiovascular effects should be encouraged to reduce the excess risk of ischemic stroke," Sun and co-authors advised.

They identified biopsy-confirmed patients with IBD in the ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) cohort. The team also identified stroke patients and analyzed medical records data in the Swedish National Patient Register. The researchers matched the IBD patients with up to five reference individuals randomly selected from the general population.

The primary outcome was incident overall stroke; secondary outcomes were ischemic and hemorrhagic stroke. The researchers estimated hazard ratios with flexible parametric survival models, adjusting for factors including hypertension, diabetes, obesity, dyslipidemia, chronic kidney disease, and chronic obstructive pulmonary disease. The investigators also performed an analysis comparing stroke risk in the IBD patients with their IBD-free siblings, in order to assess any familial factors. The sibling comparison confirmed the main findings, Sun and co-authors said.

Study limitations, the team said, included that there was a lack of complete data on lifestyle factors that can contribute to stroke risk, such as smoking and alcohol use. The diagnostic criteria for IBD and stroke also changed during the study period, which may have affected associations. In addition, the study lacked information on inflammatory markers such a C-reactive protein. The researchers also cautioned that the findings may not be able to be extrapolated to other settings due to differences in the incidence and prevalence of IBD and stroke across countries, regions, and ethnicities and the fact that the Swedish healthcare system offers universal access "practically free of charge."

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