Does TNFi Use Alter the Incidence of Ischemic Stroke in RA?

ischemic stroke of brain
Incidence of ischemic stroke does not appear to be influenced by exposure to tumor necrosis factor(TNF)-inhibitor use in patients with rheumatoid arthritis

Incidence rates of ischemic stroke do not appear to be influenced by exposure to tumor necrosis factor(TNF)-inhibitors in patients with rheumatoid arthritis (RA), according to a study which analyzed prospectively acquired data from a large biologics registry in the UK.1  It was hypothesized that the use of TNFis may decrease activation of inflammatory cascades, thus decreasing formation of atherosclerotic plaques that are implicated in pathogenesis of ischemic stroke. 

Audrey Low, MD, University of Manchester and Salford Royal Hospital NHS Foundation Trust, UK, and colleagues utilized patient data included in the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA), a national observational study including patients with RA who had been prescribed TNFis or other biologic disease-modifying antirheumatic drugs (bDMARDs). 

Patients with RA enrolled in the BSRBR-RA who were later included in the TNFi cohort were naive to prior biologics, with active disease as defined by Disease Activity Score in 28 joints (DAS28) > 5.1. These patients had previously been treated with 2 synthetic DMARDs (sDMARDs) and were subsequently registered within 6 months of adalimumab, etanercept, or infliximab treatment.

High Yield Data Summary

  • Patients with RA taking TNFis included in a UK national biologics register did not have different occurrences of ischemic stroke compared with those taking synthetic DMARDs

A comparator cohort of patients with active RA (defined by DAS28 ≥ 4.2) who had no prior exposure to biologics but had taken synthetic DMARDs was also identified.  

The same questionnaire was then sent to both cohorts of patients and their treating rheumatologists, assessing disease activity, medication, hospitalizations, presence of comorbidities, and adverse effects. 

If death occurred during the study period, death certificates containing International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes were sent for inclusion into the BSBR-RA.

Researchers defined the primary outcome of the study to be occurrence of the first ischemic stroke in each patient as defined by the World Health Organization criteria.  A TNFi “ever-exposed” model was selected for primary analysis.  Any instance of taking adalimumab, etanercept, or infliximab resulted in a patient being added for analysis as part of the TNFi single exposure group. 

Final analysis included 14 913 patients, of which 3271 patients received sDMARDs and 11 642 received TNFis. Patients receiving TNFis tended to be younger with longer disease duration and functional disability as compared with those taking sDMARDs.  The use of glucocorticoids and antiinflammatory drugs was also higher in the TNFi treatment cohort. 

Two hundred twenty two verified strokes were noted during the study period, of which 134 were ischemic, 25 hemorrhagic, and 63 “unclassifiable”.  Of the ischemic strokes, 127 were first-ever ischemic strokes – 21 in patients treated with sDMARDs and 106 in patients treated with TNFis.  This translated into a crude ischemic stroke incidence rate of 175 per 100 000 PYs for those in the sDMARD cohort and 173 per 100 000 for those in the TNFi cohort. 

The unadjusted hazard ratio (HR) for risk of developing first-ever ischemic stroke in the TNFi cohort compared to the sDMARD cohort was 1.04 (95% CI 0.65–1.66).  No significant association was found between risk of first-ever ischemic stroke and TNFi ever-exposure after adjustments utilizing deciles of propensity score (HR 0.99 [95% confidence interval (95% CI) 0.54–1.81]).   

No association was found between TNFi ever-exposure and mortality at both 30 days and 1 year (odds ratio [OR] 0.18 [95% CI 0.03–1.21] and 0.60 [95% CI 0.16–2.28], respectively).  A statistically nonsignificant decrease in mortality in the TNFi cohort of patients at time of ischemic stroke as compared with the sDMARD cohort was noted (OR 0.60 [95% CI 0.16–2.28]). 

‘Atherosclerotic processes… may not account for systemic cerebral hypoperfusion and TNF may not play a role in this situation,” the authors stated. 

Summary and Clinical Applicability

Data from a large, prospective registry suggest that TNFi exposure is not associated with incidence of ischemic stroke in patients with RA.  Absolute risk of ischemic stroke remained low in both the TNFi cohort and the sDMARD cohort.

Limitations and Disclosures

  • ICD diagnosis codes in death certificates were used to quantify stroke incidence 
  • Longer followup period with larger patient sample size is required to increase statistical power of study

The British Society for Rheumatology receives restricted funding from AbbVie, Pfizer, UCB, and Roche, and in the past Swedish Orphan Biovitrum and Merck. Dr Hyrich has received honoraria from Pfizer and AbbVie.

Related Articles


1.  Low AS, Lunt M, Mercer LK, et al. Association Between Ischemic Stroke and Tumor Necrosis Factor Inhibitor Therapy in Patients With Rheumatoid Arthritis. Arthritis Rheumatol. 2016;68(6):1337-45.

follow @RheumAdvisor