Interleukin-6 as a Prognostic Biomarker in Ruptured Intracranial Aneurysms

Kao, Hung Wen; Lee, Kwo Whei; Kuo, Chen Ling; Huang, Ching Shan; Tseng, Wan Min; Liu, Chin San; Lin, Ching Po

doi:10.1371/journal.pone.0132115

Cited by 44 publications

(31 citation statements)

References 27 publications

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“…Inflammation mediated by IL-1 is increasingly recognized as an important contributor to neurodegeneration after acute cerebrovascular events. Al- 20,30,37 We demonstrated previously that IL-1 antagonism using IV anakinra is a safe and effective way to reduce IL-6 following cerebral ischemic stroke 7 and SAH. 32 In this study, we have proven that administration of SC IL-1Ra, starting within 72 hours and continued for a maximum period of 21 days postictus, is safe and significantly reduces plasma concentrations of IL-6 following aSAH.…”

Section: Discussionmentioning

confidence: 97%

Reduction of inflammation after administration of interleukin-1 receptor antagonist following aneurysmal subarachnoid hemorrhage: results of the Subcutaneous Interleukin-1Ra in SAH (SCIL-SAH) study

Galea

Ogungbenro²,

Hulme

et al. 2018

Journal of Neurosurgery

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OBJECTIVE Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating cerebrovascular event with long-term morbidity and mortality. Patients who survive the initial bleeding are likely to suffer further early brain injury arising from a plethora of pathological processes. These may result in a worsening of outcome or death in approximately 25% of patients and may contribute to longer-term cognitive dysfunction in survivors. Inflammation, mediated by the cytokine interleukin-1 (IL-1), is an important contributor to cerebral ischemia after diverse forms of brain injury, including aSAH. Its effects are attenuated by its naturally occurring antagonist, IL-1 receptor antagonist (IL-1Ra [anakinra]). The authors hypothesized that administration of additional subcutaneous IL-1Ra would reduce inflammation and associated plasma markers associated with poor outcome following aSAH. METHODS This was a randomized, open-label, single-blinded study of 100 mg subcutaneous IL-1Ra, administered twice daily in patients with aSAH, starting within 3 days of ictus and continuing until 21 days postictus or discharge from the neurosurgical center, whichever was earlier. Blood samples were taken at admission (baseline) and at Days 3-8, 14, and 21 postictus for measurement of inflammatory markers. The primary outcome was difference in plasma IL-6 measured as area under the curve between Days 3 and 8, corrected for baseline value. Secondary outcome measures included similar area under the curve analyses for other inflammatory markers, plasma pharmacokinetics for IL-1Ra, and clinical outcome at 6 months. RESULTS Interleukin-1Ra significantly reduced levels of IL-6 and C-reactive protein (p < 0.001). Fibrinogen levels were also reduced in the active arm of the study (p < 0.002). Subcutaneous IL-1Ra was safe, well tolerated, and had a predictable plasma pharmacokinetic profile. Although the study was not powered to investigate clinical effect, scores of the Glasgow Outcome Scale-extended at 6 months were better in the active group; however, this outcome did not reach statistical significance. CONCLUSIONS Subcutaneous IL-1Ra is safe and well tolerated in aSAH. It is effective in reducing peripheral inflammation. These data support a Phase III study investigating the effect of IL-1Ra on outcome following aSAH. Clinical trial registration no.: EudraCT: 2011-001855-35 ( www.clinicaltrialsregister.eu ).

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Section: Discussionmentioning

confidence: 97%

Reduction of inflammation after administration of interleukin-1 receptor antagonist following aneurysmal subarachnoid hemorrhage: results of the Subcutaneous Interleukin-1Ra in SAH (SCIL-SAH) study

Galea

Ogungbenro²,

Hulme

et al. 2018

Journal of Neurosurgery

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“…IL-6 binding to a soluble IL6R (sIL6R) complex with ubiquitously expressed membrane-bound signaling protein gp130 can initiate pro-inflammatory signaling in cells that do not express IL6R [ 30 ]. Increased systemic and local tissue expression of IL-6 has been well-characterized in clinical studies of IA, and although some suggest that lower IL-6 levels are synonymous with lower rates of IA rupture [ 31 , 32 ], other studies have shown that certain polymorphisms in the IL-6 gene can be protective against IA [ 33 ]. A meta-analysis of IA in a Southern Indian population showed that genetic variants in TNF and IFNγ but not IL-6 were associated with IA [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Lymphocytes influence intracranial aneurysm formation and rupture: role of extracellular matrix remodeling and phenotypic modulation of vascular smooth muscle cells

Sawyer

Pace

Pascale

et al. 2016

J Neuroinflammation

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BackgroundIntracranial aneurysms (IA) are increasingly recognized as a disease driven by chronic inflammation. Recent research has identified key mediators and processes underlying IA pathogenesis, but mechanistic understanding remains incomplete. Lymphocytic infiltrates have been demonstrated in patient IA tissue specimens and have also been shown to play an important role in abdominal aortic aneurysms (AAA) and related diseases such as atherosclerosis. However, no study has systematically examined the contribution of lymphocytes in a model of IA.MethodsLymphocyte-deficient (Rag1) and wild-type (WT; C57BL/6 strain) mice were subjected to a robust IA induction protocol. Rates of IA formation and rupture were measured, and cerebral artery tissue was collected and utilized for histology and gene expression analysis.ResultsAt 2 weeks, the Rag1 group had significantly fewer IA formations and ruptures than the WT group. Histological analysis of unruptured IA tissue showed robust B and T lymphocyte infiltration in the WT group, while there were no differences in macrophage infiltration, IA diameter, and wall thickness. Significant differences in interleukin-6 (IL-6), matrix metalloproteinases 2 (MMP2) and 9 (MMP9), and smooth muscle myosin heavy chain (MHC) were observed between the groups.ConclusionsLymphocytes are key contributors to IA pathogenesis and provide a novel target for the prevention of IA progression and rupture in patients.

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“…The standard endovascular procedures and adjunctive therapies were detailed in our previous study. 21 In addition to recording the aneurysmal location, number, size, and morphology, the neuroradiologist gauged the vasospasm grade, on a scale of 0 to 4. 22…”

Section: Methodsmentioning

confidence: 99%

Cyclophilin A in Ruptured Intracranial Aneurysm

et al. 2015

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Cyclophilin A (CyPA), an oxidative stress-induced factor, was found to play an important role in the aneurysm formation. Our working hypothesis was that the plasma level of CyPA in ruptured intracranial aneurysm could predict the neurological outcome.From 2011 to 2013, a total of 36 patients with ruptured saccular intracranial aneurysm were recruited in our study. Before coil embolization, we draw blood samples at the orifice of a culprit aneurysm and in the remote peripheral vein for measurements of the CyPA levels. We utilized the modified Rankin scale 30 days after aneurysm rupture as the outcome measure. Generalized linear models were used to estimate the adjusted odds ratios of the poor neurological outcome given the presence of high plasma level of CyPA.The aneurysmal and venous CyPA levels were significantly associated with the initial clinical severity (P = 0.004 and 0.03, respectively) and 30-day outcome (P = 0.01 and 0.02, respectively). The aneurysmal CyPA levels modestly correlated with age and high Fisher grade (ρ = 0.39 and 0.41; P = 0.02 and 0.01, respectively). The aneurysmal CyPA levels strongly correlated with the venous counterpart (ρ = 0.89; P < 0.001). Patients with high levels of aneurysmal CyPA were 15.66 times (95% CI, 1.48–166.24; P = 0.02) more likely to have worse neurological outcome than those with the low levels after adjustment of the age, gender, and the documented confounding factors.High plasma level of CyPA is a significant prognostic biomarker for poor neurological outcome in patients with ruptured intracranial aneurysm.

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Interleukin-6 as a Prognostic Biomarker in Ruptured Intracranial Aneurysms

Cited by 44 publications

References 27 publications

Reduction of inflammation after administration of interleukin-1 receptor antagonist following aneurysmal subarachnoid hemorrhage: results of the Subcutaneous Interleukin-1Ra in SAH (SCIL-SAH) study

Reduction of inflammation after administration of interleukin-1 receptor antagonist following aneurysmal subarachnoid hemorrhage: results of the Subcutaneous Interleukin-1Ra in SAH (SCIL-SAH) study

Lymphocytes influence intracranial aneurysm formation and rupture: role of extracellular matrix remodeling and phenotypic modulation of vascular smooth muscle cells

Cyclophilin A in Ruptured Intracranial Aneurysm

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