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Original Investigation
May 4, 2020

Evaluating the Risk of Macrovascular Events and Mortality Among People With Multiple Sclerosis in England

Author Affiliations
  • 1Department of Primary Care and Public Health, School of Public Health, Imperial College of London, London, United Kingdom
  • 2Department of Public Health, Federico II University, Naples, Italy
  • 3Department of Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
  • 4Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
  • 5Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, United Kingdom
  • 6National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, United Kingdom
JAMA Neurol. Published online May 4, 2020. doi:10.1001/jamaneurol.2020.0664
Key Points

Question  Do people with multiple sclerosis have an increased risk of macrovascular disease and mortality?

Findings  In this population-based matched cohort study of 84 823 people with or without multiple sclerosis, those with multiple sclerosis were associated with an increased risk of macrovascular disease, even after controlling for sociodemographic variables and traditional vascular risk factors. People with multiple sclerosis were also associated with a 3.5-fold increased risk of all-cause mortality and a 1.5-fold increased risk of cardiovascular disease mortality; treatment with statins was associated with lower mortality rates among people with multiple sclerosis.

Meaning  These findings show that multiple sclerosis is associated with an increased risk of cardiovascular and cerebrovascular disease, which is not completely accounted for by traditional vascular risk factors.


Importance  People with multiple sclerosis (MS) are associated with an increased risk of cardiovascular disease and mortality; however, evidence from population-based studies is sparse.

Objective  To assess whether the risk of macrovascular events and mortality differs among people with MS compared with a matched population without MS in England.

Design, Setting, and Participants  A population-based retrospective matched cohort study was conducted in general practices registered with the Clinical Practice Research Datalink in England between January 1, 1987, and September 30, 2018, with a mean (SD) follow-up of 11.3 (6.5) years. A total of 12 251 patients with MS were matched with up to 6 people without MS (n = 72 572) by age, sex, and general practice. People with 3 or more diagnoses of MS recorded during the study period were included. The first MS diagnosis was considered as index date.

Exposures  Multiple sclerosis status. Analyses were also stratified by sex.

Main Outcomes and Measures  Main outcomes were acute coronary syndrome, cerebrovascular disease, any macrovascular disease (including peripheral arterial disease), and mortality (all-cause mortality and cardiovascular disease–specific mortality). Cox proportional hazards regression and Fine and Gray proportional subhazard regression models were used to assess differences in rates.

Results  A total of 12 251 people with MS (66.9% women; mean [SD] age, 44.9 [13.3] years) were matched with 72 572 people without MS (69.8% women; mean [SD] age, 44.9 [13.3] years). As compared with people without MS, people with MS were associated with a 28% increased hazard of acute coronary syndrome (hazard ratio [HR], 1.28; 95% CI, 1.09-1.51), 59% increased hazard of cerebrovascular disease (HR, 1.59; 95% CI, 1.32-1.92), 32% increased hazard of any macrovascular disease (HR, 1.32; 95% CI, 1.15-1.52), 3.5-fold increased hazard of all-cause mortality (HR, 3.46; 95% CI, 3.28-3.65), and 1.5-fold increased hazard in cardiovascular disease mortality (HR, 1.47; 95% CI, 1.27-1.71). Differences in macrovascular events were more pronounced among women than men. Mortality risk was also higher for women than men. Treatment with lipid-lowering medications (mainly statins) was associated with lower mortality rates among people with MS.

Conclusions and Relevance  This study suggests that MS is associated with an increased risk of cardiovascular and cerebrovascular disease that is not completely accounted for by traditional vascular risk factors. Given the adverse effects of these comorbidities on outcomes in patients with MS, further investigation is needed.

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    1 Comment for this article
    Mechanisms and Risk Factors
    Tomoyuki Kawada, MD | Nippon Medical School
    Palladino et al. evaluate the risk of macrovascular events and mortality in patients with multiple sclerosis (MS) (1). Hazard ratios of patients with MS for some macrovascular events and mortality significantly increased. Risk was more pronounced among women than men, and treatment with lipid-lowering medications was associated with lower mortality. I want to present some information.

    First, Habek et al. investigated the effect of adrenergic baroreflex sensitivity (BRSa) indices on blood pressure values after 2 years in patients with MS (2). α-BRSa at baseline significantly predicted the value of tilted systolic and diastolic blood pressure, presenting the effect of
    adrenergic hyperactivity. The increased risk for cardiovascular diseases in patients with MS should be verified by multivariate analysis.

    Second, Spencer et al. reviewed the changes of blood-brain barrier (BBB) function and cerebral perfusion in patients with MS (3). They considered the mechanism of MS pathogenesis by vascular changes via BBB disruption in combination with neuro-inflammation or neurodegeneration by-product of the myelin-specific immune response. Genetic and environmental factors modulate immune and vascular function via BBB malfunction, and there are disease-modifying therapies having an effect on the BBB. Although they could not fully explain the mechanism, Ishii and Iadecola presented hypothesis regarding the effect of gene variant APOE4 on Alzheimer’s disease incidence (4). There is evidence that ApoE4 protein is secreted by pericytes, and it affects endothelial cell function of cerebral capillaries at BBB. Secreted ApoE4 activates the protein cyclophilin A in the pericytes, and activates the inflammatory protein matrix metalloproteinase-9 in pericytes. This causes disruption of junctions between adjoining endothelial cells and disruption of the BBB might be associated with subsequent cognitive impairment and Alzheimer’s disease, because the lesion in brain involves learning and memory regions.

    Regarding APOE epsilon4 and the cognitive impairment of MS, Ghaffar and Feinstein reviewed the possible association between APOE epsilon4 and cognitive dysfunction in MS, finding no consistent results of the association (5). The same authors also conducted a case-control study to investigate the association of the epsilon4 allele of APOE with cognitive deficits in patients with MS, based on the past evidence of APOE, myelin repair, neuronal plasticity, and cerebral inflammation (6). This study did not support a role for the epsilon4 allele in cognitive dysfunction in patients with MS.

    Macrovascular events and mortality study in patients with MS should be evaluated by traditional vascular risk factors including lipid metabolism, genetic and environmental factors, and neuro-cognition status.

    1. Palladino R, Marrie RA, Majeed A, et al. JAMA Neurol. 2020 May 4. doi: 10.1001/jamaneurol.2020.0664
    2. Habek M, Pucić D, Mutak T, et al. Neurol Sci. 2020 Apr 29. doi: 10.1007/s10072-020-04432-3
    3. Spencer JI, Bell JS, DeLuca GC. J Neurol Neurosurg Psychiatry. 2018;89(1):42-52. doi: 10.1136/jnnp-2017-316011
    4. Ishii M, Iadecola C. Nature. 2020;581(7806):31-32. doi: 10.1038/d41586-020-01152-8
    5. Ghaffar O, Feinstein A. J Neuropsychiatry Clin Neurosci. 2010;22(2):155-165. doi: 10.1176/appi.neuropsych.22.2.155
    6. Ghaffar O, Reis M, Pennell N, et al. Neurology. 2010;74(20):1611-1618. doi: 10.1212/WNL.0b013e3181e074a7