Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition

N Engl J Med. 2006 Aug 10;355(6):581-92. doi: 10.1056/NEJMoa055137.

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 In 11 patients, anakinra was withdrawn at three months until a flare occurred.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].).

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Adult
  • Carrier Proteins / genetics
  • Child
  • Child, Preschool
  • Female
  • Hearing Loss / drug therapy
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / genetics
  • Intellectual Disability
  • Interleukin 1 Receptor Antagonist Protein
  • Male
  • Meningitis / drug therapy
  • Mutation
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Papilledema / drug therapy
  • Receptors, Interleukin-1 / antagonists & inhibitors*
  • Sialoglycoproteins / adverse effects
  • Sialoglycoproteins / therapeutic use*
  • Syndrome
  • Urticaria / drug therapy*

Substances

  • Carrier Proteins
  • IL1RN protein, human
  • Interleukin 1 Receptor Antagonist Protein
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Receptors, Interleukin-1
  • Sialoglycoproteins

Associated data

  • ClinicalTrials.gov/NCT00069329