Increased Risk of Stroke With Herpes Zoster in Autoimmune Disease

Herpes zoster increases the time-dependent risk of stroke requiring hospitalization among older patients with autoimmune and inflammatory diseases, according to a study recently published in Arthritis & Rheumatology.¹ This increased risk is most pronounced in patients who develop zoster-related complications, peaking early after appearance of zoster.

Prior population studies have linked zoster with increased incidence of stroke in the general population.²  A team of investigators from the University of Alabama at Birmingham and the Cleveland Clinic sought to evaluate whether this increased risk persisted in patients with autoimmune diseases, and whether antiviral therapy modified this risk. 

The researchers retrospectively examined US Medicare claims of a cohort of patients with zoster as identified by the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code, who had concurrent ankylosing spondylitis (AS), inflammatory bowel disease (IBD), psoriasis (PSO), psoriatic arthritis (PSA), or rheumatoid arthritis (RA) for at least 12 observable months. Patients with a history of stroke or having received antiviral treatment for zoster were excluded from study participation.

Three categories were created to delineate zoster phenotypes and to allow for subgroup analysis:  zoster with cranial nerve complication, zoster with other complication, and zoster without complication.  Risk windows for when stroke occurred were also defined from the time of index presentation of zoster (0 to 90 days, 91 to 365 days, and 366 to 733 days). The primary outcome was defined by researchers as stroke requiring hospitalization.

A total of 43,527 patients were included in the final cohort, each having developed zoster and with 1 of the 5 inflammatory diseases defined above. 

Of these patients, 3080 were included into the subgroup of zoster with cranial nerve complications, 4494 into zoster with other complications, and 35,953 into zoster without complication.

In the general cohort of patients with zoster, crude incidence rates (IR) of stroke were 1.24 (95% [confidence interval], 1.05-1.49) per 100 patient-years within 90 days of presentation of zoster and 0.94 (95% CI, 0.83-1.06) during days 366 to 730  following zoster presentation.

Antiviral therapy appeared to reduce the incidence rate of stroke in the general cohort from 1.13 (95% CI, 0.92-1.39) in the 0-to-90-day risk window to 0.89 (95% CI, 0.77-1.03) in the 366-to-730-day risk window.

A crude incidence of stroke peaked at 2.30 (0.96-5.52) per 100 patient-per 100 patient-years during the time frame of 90 days following zoster presentation in the subgroup of patients with zoster-related cranial nerve complications who did not receive antiviral therapy.  The crude incidence of stroke declined to 0.87 (0.75-1.02) per 100 patient-years (more than 1 year after uncomplicated zoster).

The incidence rate ratio (IRR) for stroke presenting in the first 90 days compared with more than 1 year after zoster appearance was 1.36 (1.10-1.68) after multivariate analysis. This IRR increased to a greater extent for those patients who had zoster with cranial nerve complications (IRR 2.08, 95%  CI, 0.99-4.36).  

“Given the public health implications of these observations, new urgency should be directed at increasing the administration rate of vaccination for zoster in vulnerable populations,” the authors wrote. 

A renewed focus on the prevention of zoster, including the promotion of vaccination in particularly susceptible populations, may help to decrease further morbidity associated with autoimmune disease. 

Summary and Clinical Applicability

Data from a large cohort of patients from a Medicare database suggest that patients with autoimmune disease have an increased risk of stroke after zoster presentation, a risk that is further increased in those who had developed complications related to zoster. 

Limitations and Disclosures

• The diagnoses of zoster was made by ICD codes and therefore could not be confirmed

• Insufficient data existed to precisely identify the anatomic distribution of the strokes that did occur

References

1. Calabrese LH, Xie F, Yun H, et al. Herpes zoster and the risk for stroke in patients with autoimmune diseases. Arthritis Rheumatol. 2016 Sep 2. doi: 10.1002/art.39855 [Epub ahead of print]
2. Sundström K, Weibull CE, Söderberg-löfdal K, Bergström T, Sparén P, Arnheim-dahlström L. Incidence of herpes zoster and associated events including stroke–a population-based cohort study. BMC Infect Dis.2015;15:488.

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