title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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/mm3versus 3.7 cells/mm3and 150.7 pg/ml versus 28.5 pg/ml, respectively) despite similar serum cytokine levels.
  
  
  
  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.
authors.affiliation: Translational Autoinflammatory Disease Studies, Intramural Research Program, NIH, Bethesda, Maryland.
authors.forename: Jackeline
authors.initials: J
authors.lastname: Rodriguez-Smith
authors.affiliation: Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland.
authors.forename: Yen-Chih
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland.
authors.forename: Wanxia Li
authors.initials: WL
authors.lastname: Tsai
authors.affiliation: Scholar's Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Kim
authors.affiliation: Translational Autoinflammatory Disease Studies, Intramural Research Program, NIH, Bethesda, Maryland.
authors.forename: Gina
authors.initials: G
authors.lastname: Montealegre-Sanchez
authors.affiliation: Translational Autoinflammatory Disease Studies, Intramural Research Program, NIH, Bethesda, Maryland.
authors.forename: Dawn
authors.initials: D
authors.lastname: Chapelle
authors.affiliation: Translational Autoinflammatory Disease Studies, Intramural Research Program, NIH, Bethesda, Maryland.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Oregon Health & Science University, Portland, Oregon.
authors.forename: Cailin H
authors.initials: CH
authors.lastname: Sibley
authors.affiliation: Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland.
authors.forename: Massimo
authors.initials: M
authors.lastname: Gadina
authors.affiliation: Clinical Center, NIH, Bethesda, Maryland.
authors.forename: Robert
authors.initials: R
authors.lastname: Wesley
authors.affiliation: Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland.
authors.forename: Bibiana
authors.initials: B
authors.lastname: Bielekova
authors.affiliation: Translational Autoinflammatory Disease Studies, Intramural Research Program, NIH, Bethesda, Maryland.
authors.forename: Raphaela
authors.initials: R
authors.lastname: Goldbach-Mansky
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002675:Child, Preschool; D056587:Cryopyrin-Associated Periodic Syndromes / Q000134:cerebrospinal fluid* / Q000188:drug therapy; D016207:Cytokines / Q000134:cerebrospinal fluid / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D008297:Male; D008582:Meningitis, Aseptic / Q000134:cerebrospinal fluid* / Q000188:drug therapy; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015415:Biomarkers; D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; C541220:canakinumab