Neurology: Independent of traditional vascular risk factors, circulating interleukin-6 (IL-6) levels are positively and linearly associated with long-term risk of developing ischemic stroke!

      Stroke is the leading cause of disability and death in adults worldwide
.
Identifying risk factors for stroke is important for developing effective primary and secondary prevention strategies
.
Inflammation has recently gained attention as a potential target for reducing ischemic stroke risk
.
Data from large trials provide some evidence that anti-inflammatory treatment can reduce the risk of cardiovascular disease
.
Nonetheless, there is little evidence that these trials tested cardiovascular endpoints and efficacy of anti-inflammatory approaches specifically for stroke prevention
.

     The development of effective anti-inflammatory therapeutic pathways to prevent stroke will require identification of key inflammatory mediators associated with stroke pathogenesis
.
While there is extensive literature showing the association of C-reactive protein (CRP) levels, a general marker of inflammation, with stroke, data on other inflammatory cytokines are limited
.
Data from human genetics studies suggest the potential pathogenic role of the pro-inflammatory cytokine interleukin-6 (IL-6) in vascular disease as a promising new drug target
.

      Identifying the association and related mechanisms between circulating IL-6 levels and ischemic stroke will drive further progress in anti-inflammatory therapy for IL-6 signaling
.
Although prospective cohort studies have identified a clear association between circulating IL-6 levels and risk of coronary artery disease, evidence for an association with ischemic stroke is limited and mechanisms other than atherosclerosis are implicated
.
We conducted a systematic review and meta-analysis using pooled data from the published literature and unpublished cohort studies to explore the association of circulating IL-6 levels with the risk of ischemic stroke in a population-based prospective cohort study
.

     Following Prisma guidelines, we systematically screened the PubMed search engine, from inception to March 2021, to conduct a population-based prospective cohort study to explore the relationship between circulating IL-6 levels and the risk of ischemic stroke
.
Combined association estimates for ischemic stroke risk with random-effects models and explored non-linear effects in dose-response meta-analyses
.
Risk of bias was assessed using the Newcastle-Ottawa Scale (NOS)
.
Publication bias was assessed using funnel plots and trim-to-fill analyses
.

• Eleven studies (27,411; 2,669 stroke events) were identified as meeting the inclusion criteria
  .
  
• The average age was 60.
  5 years, and 54.
  8% were women
  .
  Overall, the quality of included studies was high (median 8/9, interquartile range 7 to 9)
  .
  
• In the meta-analysis, a 1-standard deviation increase in circulating log-transformed IL-6 levels was associated with a 19% increased risk of ischemic stroke at a mean follow-up of 12.
  4 years (RR 1.
  19; 95% CI 1.
  10-1.
  28)
  .
  
• A dose-response meta-analysis showed that circulating IL-6 levels were linearly associated with ischemic stroke risk
  .
  

• There was only modest heterogeneity among studies limited to low risk of bias and studies that fully adjusted for demographic and vascular risk factors, and the results of sensitivity analyses were consistent
  .
  

• The results also remained stable after adjusting for publication bias
  .
  

There was only modest heterogeneity among studies limited to low risk of bias and studies that fully adjusted for demographic and vascular risk factors, and the results of sensitivity analyses were consistent
.

      Among community residents, higher circulating IL-6 levels were linearly associated with higher long-term risk of developing ischemic stroke, independent of traditional vascular risk factors
.
Combined with findings from genetic studies and clinical trials, these results provide additional support for the critical role of IL-6 signaling in ischemic stroke
.

Source: Papadopoulos A, Palaiopanos K, Björkbacka H, ​​et al.
Circulating Interleukin-6 Levels and Incident Ischemic Stroke: A Systematic Review and Meta-analysis of Prospective Studies [published online ahead of print, 2021 Dec 30].
Neurology.
2021 ;10.
1212/WNL.
0000000000013274.
doi:10.
1212/WNL.
0000000000013274