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 In 11 patients, anakinra was withdrawn at three months until a flare occurred.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

SUBMITTER: Goldbach-Mansky R

PROVIDER: S-EPMC4178954 | biostudies-literature | 2006 Aug

REPOSITORIES: biostudies-literature

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

Goldbach-Mansky Raphaela R 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

The New England journal of medicine 20060801 6

<h4>Background</h4>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.<h4>Methods</h4>We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an int ...[more]

PMID: 16899778

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Project description:OBJECTIVE:To evaluate proinflammatory cytokines and leukocyte subpopulations in the cerebrospinal fluid (CSF) and blood of patients with neonatal-onset multisystem inflammatory disease (NOMID) after treatment, and to compare inflammatory cytokines in the CSF and blood in 6 patients treated with 2 interleukin-1 (IL-1) blockers-anakinra and canakinumab. METHODS:During routine follow-up visits between December 2011 and October 2013, we immunophenotyped the CSF of 17 pediatric NOMID patients who were treated with anakinra, and analyzed CSF cytokine levels in samples obtained at baseline and at 3-5-year follow-up visits and compared them to samples from healthy controls. RESULTS:CSF levels of IL-6, interferon-?-inducible 10-kd protein (IP-10/CXCL10), and IL-18 and monocyte and granulocyte counts significantly decreased with anakinra treatment but did not normalize to levels in the controls, even in patients fulfilling criteria for clinical remission. CSF IL-6 and IL-18 levels significantly correlated with measures of blood-brain barrier function, specifically CSF protein (r?=?0.75 and r?=?0.81, respectively) and albumin quotient (r?=?0.79 and r?=?0.68, respectively). When patients were treated with canakinumab versus anakinra, median CSF white blood cell counts and IL-6 levels were significantly higher with canakinumab treatment (10.2 cells/mm3 versus 3.7 cells/mm3 and 150.7 pg/ml versus 28.5 pg/ml, respectively) despite similar serum cytokine levels. CONCLUSION:CSF leukocyte subpopulations and cytokine levels significantly improve with optimized IL-1 blocking treatment, but do not normalize. The correlation of CSF IL-6, IP-10/CXCL10, and IL-18 levels with clinical laboratory measures of inflammation and blood-brain barrier function suggests that they may have a role as biomarkers in central nervous system (CNS) inflammation. The difference in inhibition of CSF biomarkers between 2 IL-1 blocking agents, anakinra and canakinumab, suggests differences in efficacy in the intrathecal compartment, with anakinra being more effective. Our data indicate that intrathecal immune responses shape CNS inflammation and should be assessed in addition to blood markers.

Dataset Information

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

Publications

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

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