title: Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition.
abstract: BACKGROUND
  Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation.
  
  
  METHODS
  We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare.
  
  
  RESULTS
  All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events.
  
  
  CONCLUSIONS
  Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations. (ClinicalTrials.gov number, NCT00069329 [ClinicalTrials.gov].).
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Md 20892, USA. goldbacr@mail.nih.gov
authors.forename: Raphaela
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authors.lastname: Goldbach-Mansky
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authors.lastname: Gelabert
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authors.forename: Suvimol
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authors.lastname: Pucino
authors.forename: Scott R
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authors.forename: Margje H
authors.initials: MH
authors.lastname: Haverkamp
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authors.lastname: Stein
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authors.lastname: Adams
authors.forename: Terry L
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authors.lastname: Moore
authors.forename: Robert C
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authors.lastname: Fuhlbrigge
authors.forename: Bracha
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authors.lastname: Shaham
authors.forename: James N
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authors.lastname: Jarvis
authors.forename: Kathleen
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authors.lastname: O'Neil
authors.forename: Richard K
authors.initials: RK
authors.lastname: Vehe
authors.forename: Laurie O
authors.initials: LO
authors.lastname: Beitz
authors.forename: Gregory
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authors.lastname: Gardner
authors.forename: William P
authors.initials: WP
authors.lastname: Hannan
authors.forename: Robert W
authors.initials: RW
authors.lastname: Warren
authors.forename: William
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authors.lastname: Horn
authors.forename: Joe L
authors.initials: JL
authors.lastname: Cole
authors.forename: Scott M
authors.initials: SM
authors.lastname: Paul
authors.forename: Philip N
authors.initials: PN
authors.lastname: Hawkins
authors.forename: Tuyet Hang
authors.initials: TH
authors.lastname: Pham
authors.forename: Christopher
authors.initials: C
authors.lastname: Snyder
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wesley
authors.forename: Steven C
authors.initials: SC
authors.lastname: Hoffmann
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: John A
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authors.lastname: Butman
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
mesh_terms: D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D034381:Hearing Loss / Q000188:drug therapy; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics; D008607:Intellectual Disability; D053590:Interleukin 1 Receptor Antagonist Protein; D008297:Male; D008581:Meningitis / Q000188:drug therapy; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010211:Papilledema / Q000188:drug therapy; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D012795:Sialoglycoproteins / Q000009:adverse effects / Q000627:therapeutic use*; D013577:Syndrome; D014581:Urticaria / Q000188:drug therapy*
chemical_list: D002352:Carrier Proteins; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins