Cerebrospinal Fluid Cytokines Correlate With Aseptic Meningitis and Blood–Brain Barrier Function in Neonatal-Onset Multisystem Inflammatory Disease

Central Nervous System Biomarkers in Neonatal-Onset Multisystem Inflammatory Disease Correlate With Central Nervous System Inflammation

Jackeline Rodriguez-Smith, Yen Chih Lin, Wanxia Li Tsai, Hanna Kim, Gina Montealegre-Sanchez, Dawn Chapelle, Yan Huang, Cailin Sibley, Massimo Gadina, Robert Wesley, Bibiana Bielekova, Raphaela Goldbach-Mansky

Research output: Contribution to journalArticle

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Abstract

Objective: To evaluate proinflammatory cytokines and leukocyte subpopulations in the cerebrospinal fluid (CSF) and blood of patients with neonatal-onset multisystem inflammatory disease (NOMID) after treatment, and to compare inflammatory cytokines in the CSF and blood in 6 patients treated with 2 interleukin-1 (IL-1) blockers—anakinra and canakinumab. Methods: During routine follow-up visits between December 2011 and October 2013, we immunophenotyped the CSF of 17 pediatric NOMID patients who were treated with anakinra, and analyzed CSF cytokine levels in samples obtained at baseline and at 3–5-year follow-up visits and compared them to samples from healthy controls. Results: CSF levels of IL-6, interferon-γ–inducible 10-kd protein (IP-10/CXCL10), and IL-18 and monocyte and granulocyte counts significantly decreased with anakinra treatment but did not normalize to levels in the controls, even in patients fulfilling criteria for clinical remission. CSF IL-6 and IL-18 levels significantly correlated with measures of blood–brain barrier function, specifically CSF protein (r = 0.75 and r = 0.81, respectively) and albumin quotient (r = 0.79 and r = 0.68, respectively). When patients were treated with canakinumab versus anakinra, median CSF white blood cell counts and IL-6 levels were significantly higher with canakinumab treatment (10.2 cells/mm3 versus 3.7 cells/mm3 and 150.7 pg/ml versus 28.5 pg/ml, respectively) despite similar serum cytokine levels. Conclusion: CSF leukocyte subpopulations and cytokine levels significantly improve with optimized IL-1 blocking treatment, but do not normalize. The correlation of CSF IL-6, IP-10/CXCL10, and IL-18 levels with clinical laboratory measures of inflammation and blood–brain barrier function suggests that they may have a role as biomarkers in central nervous system (CNS) inflammation. The difference in inhibition of CSF biomarkers between 2 IL-1 blocking agents, anakinra and canakinumab, suggests differences in efficacy in the intrathecal compartment, with anakinra being more effective. Our data indicate that intrathecal immune responses shape CNS inflammation and should be assessed in addition to blood markers.

Original languageEnglish (US)
Pages (from-to)1325-1336
Number of pages12
JournalArthritis and Rheumatology
Volume69
Issue number6
DOIs
StatePublished - Jun 1 2017

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Cryopyrin-Associated Periodic Syndromes
Aseptic Meningitis
Cerebrospinal Fluid
Central Nervous System
Biomarkers
Cytokines
Interleukin 1 Receptor Antagonist Protein
Inflammation
Interleukin-18
Interleukin-6
Interleukin-1
Leukocytes
Chemokine CXCL10
Cerebrospinal Fluid Proteins
Therapeutics
Leukocyte Count
Granulocytes
Monocytes
Albumins

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Cite this

Cerebrospinal Fluid Cytokines Correlate With Aseptic Meningitis and Blood–Brain Barrier Function in Neonatal-Onset Multisystem Inflammatory Disease : Central Nervous System Biomarkers in Neonatal-Onset Multisystem Inflammatory Disease Correlate With Central Nervous System Inflammation. / Rodriguez-Smith, Jackeline; Lin, Yen Chih; Tsai, Wanxia Li; Kim, Hanna; Montealegre-Sanchez, Gina; Chapelle, Dawn; Huang, Yan; Sibley, Cailin; Gadina, Massimo; Wesley, Robert; Bielekova, Bibiana; Goldbach-Mansky, Raphaela.

In: Arthritis and Rheumatology, Vol. 69, No. 6, 01.06.2017, p. 1325-1336.

Research output: Contribution to journalArticle

Rodriguez-Smith, Jackeline ; Lin, Yen Chih ; Tsai, Wanxia Li ; Kim, Hanna ; Montealegre-Sanchez, Gina ; Chapelle, Dawn ; Huang, Yan ; Sibley, Cailin ; Gadina, Massimo ; Wesley, Robert ; Bielekova, Bibiana ; Goldbach-Mansky, Raphaela. / Cerebrospinal Fluid Cytokines Correlate With Aseptic Meningitis and Blood–Brain Barrier Function in Neonatal-Onset Multisystem Inflammatory Disease : Central Nervous System Biomarkers in Neonatal-Onset Multisystem Inflammatory Disease Correlate With Central Nervous System Inflammation. In: Arthritis and Rheumatology. 2017 ; Vol. 69, No. 6. pp. 1325-1336.
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abstract = "Objective: To evaluate proinflammatory cytokines and leukocyte subpopulations in the cerebrospinal fluid (CSF) and blood of patients with neonatal-onset multisystem inflammatory disease (NOMID) after treatment, and to compare inflammatory cytokines in the CSF and blood in 6 patients treated with 2 interleukin-1 (IL-1) blockers—anakinra and canakinumab. Methods: During routine follow-up visits between December 2011 and October 2013, we immunophenotyped the CSF of 17 pediatric NOMID patients who were treated with anakinra, and analyzed CSF cytokine levels in samples obtained at baseline and at 3–5-year follow-up visits and compared them to samples from healthy controls. Results: CSF levels of IL-6, interferon-γ–inducible 10-kd protein (IP-10/CXCL10), and IL-18 and monocyte and granulocyte counts significantly decreased with anakinra treatment but did not normalize to levels in the controls, even in patients fulfilling criteria for clinical remission. CSF IL-6 and IL-18 levels significantly correlated with measures of blood–brain barrier function, specifically CSF protein (r = 0.75 and r = 0.81, respectively) and albumin quotient (r = 0.79 and r = 0.68, respectively). When patients were treated with canakinumab versus anakinra, median CSF white blood cell counts and IL-6 levels were significantly higher with canakinumab treatment (10.2 cells/mm3 versus 3.7 cells/mm3 and 150.7 pg/ml versus 28.5 pg/ml, respectively) despite similar serum cytokine levels. Conclusion: CSF leukocyte subpopulations and cytokine levels significantly improve with optimized IL-1 blocking treatment, but do not normalize. The correlation of CSF IL-6, IP-10/CXCL10, and IL-18 levels with clinical laboratory measures of inflammation and blood–brain barrier function suggests that they may have a role as biomarkers in central nervous system (CNS) inflammation. The difference in inhibition of CSF biomarkers between 2 IL-1 blocking agents, anakinra and canakinumab, suggests differences in efficacy in the intrathecal compartment, with anakinra being more effective. Our data indicate that intrathecal immune responses shape CNS inflammation and should be assessed in addition to blood markers.",
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T2 - Central Nervous System Biomarkers in Neonatal-Onset Multisystem Inflammatory Disease Correlate With Central Nervous System Inflammation

AU - Rodriguez-Smith, Jackeline

AU - Lin, Yen Chih

AU - Tsai, Wanxia Li

AU - Kim, Hanna

AU - Montealegre-Sanchez, Gina

AU - Chapelle, Dawn

AU - Huang, Yan

AU - Sibley, Cailin

AU - Gadina, Massimo

AU - Wesley, Robert

AU - Bielekova, Bibiana

AU - Goldbach-Mansky, Raphaela

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N2 - Objective: To evaluate proinflammatory cytokines and leukocyte subpopulations in the cerebrospinal fluid (CSF) and blood of patients with neonatal-onset multisystem inflammatory disease (NOMID) after treatment, and to compare inflammatory cytokines in the CSF and blood in 6 patients treated with 2 interleukin-1 (IL-1) blockers—anakinra and canakinumab. Methods: During routine follow-up visits between December 2011 and October 2013, we immunophenotyped the CSF of 17 pediatric NOMID patients who were treated with anakinra, and analyzed CSF cytokine levels in samples obtained at baseline and at 3–5-year follow-up visits and compared them to samples from healthy controls. Results: CSF levels of IL-6, interferon-γ–inducible 10-kd protein (IP-10/CXCL10), and IL-18 and monocyte and granulocyte counts significantly decreased with anakinra treatment but did not normalize to levels in the controls, even in patients fulfilling criteria for clinical remission. CSF IL-6 and IL-18 levels significantly correlated with measures of blood–brain barrier function, specifically CSF protein (r = 0.75 and r = 0.81, respectively) and albumin quotient (r = 0.79 and r = 0.68, respectively). When patients were treated with canakinumab versus anakinra, median CSF white blood cell counts and IL-6 levels were significantly higher with canakinumab treatment (10.2 cells/mm3 versus 3.7 cells/mm3 and 150.7 pg/ml versus 28.5 pg/ml, respectively) despite similar serum cytokine levels. Conclusion: CSF leukocyte subpopulations and cytokine levels significantly improve with optimized IL-1 blocking treatment, but do not normalize. The correlation of CSF IL-6, IP-10/CXCL10, and IL-18 levels with clinical laboratory measures of inflammation and blood–brain barrier function suggests that they may have a role as biomarkers in central nervous system (CNS) inflammation. The difference in inhibition of CSF biomarkers between 2 IL-1 blocking agents, anakinra and canakinumab, suggests differences in efficacy in the intrathecal compartment, with anakinra being more effective. Our data indicate that intrathecal immune responses shape CNS inflammation and should be assessed in addition to blood markers.

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