title: Phenotype, genotype, and sustained response to anakinra in 22 patients with autoinflammatory disease associated with CIAS-1/NALP3 mutations.
abstract: OBJECTIVE
  To characterize the multisystem chronic inflammatory phenotype, dermatopathologic features, and response to therapy with interleukin 1 receptor antagonist (anakinra) in patients with mutations in the CIAS-1/NALP3 gene.
  
  
  METHODS
  Retrospective review of medical records and evaluation of histologic findings.
  
  
  METHODS
  The National Amyloidosis Centre, London, and a tertiary referral clinic for urticaria.
  
  
  METHODS
  Twenty-two individuals from 13 families with autoinflammatory disease associated with CIAS-1/NALP3 mutations.
  
  
  METHODS
  Phenotype, genotype, skin histologic findings, and response to treatment with anakinra.
  
  
  RESULTS
  Five heterozygous missense mutations were identified in CIAS-1/NALP3. Skin histologic findings revealed marked vascular dilatation and neutrophilic infiltration involving small vessels and eccrine glands. Serologic evidence of intense inflammation was present in untreated patients, with median serum amyloid A protein and C-reactive protein levels of 141 and 38 mg/L, respectively. Fifteen patients received anakinra for up to 39 months, all of whom achieved serologic remission and complete resolution of fever, rash, conjunctivitis, and rheumatic symptoms, without any adverse effects. Six patients had AA (reactive systemic) amyloidosis, 2 of whom died of renal failure complications before interleukin 1-inhibiting therapy was available; 1 patient underwent renal transplantation and remains clinically well taking anakinra, and in the remaining 3 patients, anakinra therapy resulted in remission of their nephrotic syndrome.
  
  
  CONCLUSIONS
  Anakinra therapy was well tolerated and has sustained efficacy on dermatologic and rheumatic manifestations in these patients with CIAS-1/NALP3 mutations. This treatment also resulted in resolution of AA amyloidosis-associated nephrotic syndrome in all affected patients.
authors.affiliation: Department of Dermatology, University of California, San Francisco, USA.
authors.forename: Kieron S
authors.initials: KS
authors.lastname: Leslie
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Lachmann
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bruning
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
authors.forename: Alison
authors.initials: A
authors.lastname: Bybee
authors.forename: J Ruth
authors.initials: JR
authors.lastname: Gallimore
authors.forename: Philip F
authors.initials: PF
authors.lastname: Roberts
authors.forename: Patricia
authors.initials: P
authors.lastname: Woo
authors.forename: Clive E
authors.initials: CE
authors.lastname: Grattan
authors.forename: Philip N
authors.initials: PN
authors.lastname: Hawkins
mesh_terms: D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D004247:DNA / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use*; D008297:Male; D020125:Mutation, Missense; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D016896:Treatment Outcome; D014581:Urticaria / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D004247:DNA