Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition.
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 In 11 patients, anakinra was withdrawn at three months until a flare occurred.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].).
Goldbach-Mansky
Raphaela
R
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Md 20892, USA. goldbacr@mail.nih.gov
Dailey
Natalie J
NJ
Canna
Scott W
SW
Gelabert
Ana
A
Jones
Janet
J
Rubin
Benjamin I
BI
Kim
H Jeffrey
HJ
Brewer
Carmen
C
Zalewski
Christopher
C
Wiggs
Edythe
E
Hill
Suvimol
S
Turner
Maria L
ML
Karp
Barbara I
BI
Aksentijevich
Ivona
I
Pucino
Frank
F
Penzak
Scott R
SR
Haverkamp
Margje H
MH
Stein
Leonard
L
Adams
Barbara S
BS
Moore
Terry L
TL
Fuhlbrigge
Robert C
RC
Shaham
Bracha
B
Jarvis
James N
JN
O'Neil
Kathleen
K
Vehe
Richard K
RK
Beitz
Laurie O
LO
Gardner
Gregory
G
Hannan
William P
WP
Warren
Robert W
RW
Horn
William
W
Cole
Joe L
JL
Paul
Scott M
SM
Hawkins
Philip N
PN
Pham
Tuyet Hang
TH
Snyder
Christopher
C
Wesley
Robert A
RA
Hoffmann
Steven C
SC
Holland
Steven M
SM
Butman
John A
JA
Kastner
Daniel L
DL
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*
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