Systemic Sclerosis Patients May Benefit from Targeted Stroke Screening

Systemic sclerosis (SSc), also known as scleroderma, causes collagen deposits in the skin and internal organs, as well as endothelial damage leading to vasculopathy. Originally, rheumatologists thought this rare, multisystem, autoimmune disease primarily affected the microvasculature. However, rheumatologists increasingly recognize SSc as having a macrovascular disease component that results from endothelial dysfunction and cerebral vasospasm.

An Independent Risk Factor for Stroke?
Previous studies have found SSc patients have an increased prevalence of subclinical cerebrovascular atherosclerotic disease. This increased risk can be documented by physiologic measurements of atherosclerosis and in population-based studies. The latter suggests cardiovascular and cerebrovascular disease may be responsible for 20–30% of SSc mortality. Despite this evidence, few studies have demonstrated an independent association between SSc and stroke.

David Ying, MD, a rheumatologist at University of California, San Francisco (UCSF), and colleagues designed a study using data from the Veterans Affairs (VA) Health System to directly assess this question. The VA Health System is the largest healthcare system in the U.S. and provides care to more than 5 million veterans nationwide.

The Ying et al. study reveals SSc is independently associated with a higher risk of ischemic stroke, a finding that led the authors to suggest patients with SSc may benefit from targeted stroke screening or prevention therapies. They published their results online June 2019 in the Journal of Rheumatology.¹

Study Design
The investigators conducted their retrospective cohort study using the administrative VA Corporate Data Warehouse, which contains data elements extracted from the national VA electronic health records. They followed 4,545 patients (83% male) with both prevalent and incident SSC for approximately five years. The authors acknowledge that, because the study used administrative data, there may be diagnostic inaccuracy and patients may have been misclassified as having SSc. Additionally, they acknowledge the possibility of missing any stroke diagnosis that occurred outside of the VA system.

The researchers obtained data for all patients with an SSc diagnosis and matched them with two controls, for a total of 9,090 controls. They used a Mahalanobis distance metric for date of birth and duration of VA enrollment, which allowed researchers to match the controls to SSc patients based on sex, race, smoking status and VA site. To be included in the analysis, healthy controls had to have at least one encounter with medical care system during the five-year period of the reference date, which was defined as the date of SSc diagnosis of their respective match. Patients were excluded from matching if they were younger than 18 years at the time of their first encounter or had an ICD-9 diagnosis code for morphea, eosinophilic fasciitis or nephrogenic systemic fibrosis.

The team followed patients until the development of ischemic stroke, death or their last encounter. They used a Cox proportional regression model to estimate risk of ischemic stroke. Next, they calculated an adjusted risk by adjusting for cardiovascular comorbidities of hypertension, diabetes, atrial fibrillation, non-cerebrovascular atherosclerotic disease and hyperlipidemia, as well as the baseline use of aspirin, non-steroidal anti-inflammatory drugs and Medicare enrollment.

Higher Risk in SSc Patients
The researchers documented an incidence rate of ischemic stroke of 15.3 per 1,000 person-years in SSc patients with 12.2 per 1,000 person-years in the control cohort. The incidence of ischemic stroke between the two groups diverged early in the follow-up period. The divergence translated into an unadjusted hazard ratio of 1.28 and an adjusted hazard ratio of 1.21. The hazard ratio remained consistent for all sensitivity analyses.

Investigators conclude the risk of incident stroke or transient ischemic attack was 20–30% higher in individuals with SSc than in matched controls. Additionally, although cases had a significantly higher prevalence of traditional cardiovascular risk factors than controls, researchers note the increased risk of cerebrovascular disease in SSc patients was independent of these traditional cardiovascular risk factors. 

“In this study, we found scleroderma is associated with ischemic stroke,” says Gabriela Schmajuk, MD, a rheumatologist at UCSF and co-author of the paper. “This [finding] is important because we don’t traditionally think about large vessel disease, such as stroke and heart attack, in these patients. We were surprised by the number of patients in the VA system who we found with this diagnosis. We were able to put together the largest cohort of patients with scleroderma to date.”

Dr. Schamjuk also emphasized that, although previous studies have found similar results in women, their study is much larger than any previously published research. This suggests rheumatologists should worry about ischemic stroke in women, as well as men.

Lara C. Pullen, PhD, is a medical writer based in the Chicago area.

References

1. Ying D, Gianfrancesco MA, Trupin L, et al. Increased risk of ischemic stroke in systemic sclerosis: A national cohort study of U.S. veterans. J Rheumatol. 2020 Jan;47(1):82–88.