Association Between Ischemic Stroke and Tumor Necrosis Factor Inhibitor Therapy in Patients With Rheumatoid Arthritis

Abstract

Objective: Patients with rheumatoid arthritis (RA) are at an increased risk of ischemic stroke. Tumor necrosis factor inhibitors (TNFi) may influence risk and mortality after ischemic stroke by reducing inflammation. This study was undertaken to examine the association of TNFi with the risk of incident ischemic stroke and with 30-day and 1-year mortality after ischemic stroke.

Methods: Patients with RA starting therapy with TNFi and a biologics-naive comparator group treated with synthetic disease-modifying antirheumatic drugs (DMARDs) only were recruited to the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis from 2001 to 2009. Patients were followed up via clinical and patient questionnaires as well as the national death register. Incident strokes were classified as ischemic if brain imaging reports suggested ischemia or if ischemic stroke was reported as the underlying cause of death on a death certificate. Patients with a previous stroke were excluded. Risk of ischemic stroke was compared between patients receiving synthetic DMARDs only and those ever-exposed to TNFi using a Cox proportional hazards regression model adjusted for potential confounders. Mortality after ischemic stroke was compared between synthetic DMARD-treated patients and TNFi-treated patients using logistic regression, adjusted for age and sex.

Results: To April 2010, 127 verified incident ischemic strokes (21 in 3,271 synthetic DMARD-treated patients and 106 in 11,642 TNFi-treated patients) occurred during 11,973 and 61,226 person-years of observation, respectively (incidence rate 175 versus 173 per 100,000 person-years). After adjustment for confounders, there was no association between ever-exposure to TNFi and ischemic stroke (hazard ratio 0.99 [95% confidence interval (95% CI) 0.54-1.81]). Mortality 30 days or 1 year after ischemic stroke was not associated with concurrent TNFi exposure (odds ratio 0.18 [95% CI 0.03-1.21] and 0.60 [95% CI 0.16-2.28], respectively).

Conclusion: Exposure to TNFi does not appear to influence the occurrence of ischemic stroke in the medium term in patients with RA. The impact on mortality after ischemic stroke remains inconclusive.

Figure 1

Patient selection for the analysis of ischemic stroke. BSRBR‐RA = British Society for Rheumatology Biologics Register for Rheumatoid Arthritis; DMARD = disease‐modifying antirheumatic drug; anti‐TNF = anti–tumor necrosis factor; DAS28 = Disease Activity Score in 28 joints.

Figure 2

Stroke verification process. BSRBR‐RA = British Society for Rheumatology Biologics Register for Rheumatoid Arthritis; WHO = World Health Organization; sDMARD = synthetic disease‐modifying antirheumatic drug; TNFi = tumor necrosis factor inhibitor; ICD‐10 = International Statistical Classification of Diseases and Related Health Problems, Tenth Revision; CT = computed tomography.