title: A 24-month open-label study of canakinumab in neonatal-onset multisystem inflammatory disease.
abstract: OBJECTIVE
  To study efficacy and safety of escalating doses of canakinumab, a fully human anti-IL-1β monoclonal antibody in the severe cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease (NOMID).
  
  
  METHODS
  6 patients were enrolled in this 24-month, open-label phase I/II study. All underwent anakinra withdrawal. The initial subcutaneous canakinumab dose was 150 mg (or 2 mg/kg in patients ≤40 kg) or 300 mg (or 4 mg/kg) with escalation up to 600 mg (or 8 mg/kg) every 4 weeks. Full remission was remission of patient-reported clinical components and measures of systemic inflammation and CNS inflammation. Hearing, vision and safety were assessed. Primary endpoint was full remission at month 6.
  
  
  RESULTS
  All patients flared after anakinra withdrawal, and symptoms and serum inflammatory markers improved with canakinumab. All patients required dose escalation to the maximum dose. At month 6, none had full remission, although 4/6 achieved inflammatory remission, based on disease activity diary scores and normal C-reactive proteins. None had CNS remission; 5/6 due to persistent CNS leucocytosis. At the last study visit, 5/6 patients achieved inflammatory remission and 4/6 had continued CNS leucocytosis. Visual acuity and field were stable in all patients, progressive hearing loss occurred in 1/10 ears. Adverse events (AEs) were rare. One serious AE (abscess due to a methicillin-resistant Staphylococcus aureus infection) occurred.
  
  
  CONCLUSIONS
  Canakinumab at the studied doses improves symptoms and serum inflammatory features of NOMID, although low-grade CNS leukocytosis in four patients and headaches in one additional patient persisted. Whether further dose intensifications are beneficial in these cases remains to be assessed.
  
  
  BACKGROUND
  NCT00770601.
authors.affiliation: Translational Autoinflammatory Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Cailin H
authors.initials: CH
authors.lastname: Sibley
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Chioato
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Felix
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Laurence
authors.initials: L
authors.lastname: Colin
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Chakraborty
authors.affiliation: Translational Autoinflammatory Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Nikki
authors.initials: N
authors.lastname: Plass
authors.affiliation: Translational Autoinflammatory Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jackeline
authors.initials: J
authors.lastname: Rodriguez-Smith
authors.affiliation: Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Brewer
authors.affiliation: Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: King
authors.affiliation: Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Zalewski
authors.affiliation: Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: H Jeffrey
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Bishop
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Ken
authors.initials: K
authors.lastname: Abrams
authors.affiliation: Translational Autoinflammatory Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Stone
authors.affiliation: Translational Autoinflammatory Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Dawn
authors.initials: D
authors.lastname: Chapelle
authors.affiliation: Translational Autoinflammatory Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Bahar
authors.initials: B
authors.lastname: Kost
authors.affiliation: Translational Autoinflammatory Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Snyder
authors.affiliation: Diagnostic Radiology Department, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Butman
authors.affiliation: Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Wesley
authors.affiliation: Translational Autoinflammatory Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Raphaela
authors.initials: R
authors.lastname: Goldbach-Mansky
mesh_terms: D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D002097:C-Reactive Protein / Q000378:metabolism; D002555:Cerebrospinal Fluid / Q000166:cytology; D002648:Child; D056587:Cryopyrin-Associated Periodic Syndromes / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006261:Headache / Q000188:drug therapy / Q000209:etiology; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors*; D007958:Leukocyte Count; D008297:Male; D012074:Remission Induction; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053583:Interleukin-1beta; C541220:canakinumab; D002097:C-Reactive Protein
keywords: Cytokines; DMARDs (Biologic); Disease Activity; Inflammation