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 In 11 patients, anakinra was withdrawn at three months until a flare occurred.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

Figure 1. Inflammatory Organ Manifestations in Neonatal-Onset Multisystem Inflammatory Disease before (Panels A, C, E, and G) and after (Panels B, D, F, and H) Treatment with Anakinra

The severity of rash, conjunctivitis, and leptomeningeal and cochlear enhancement on MRI is shown at baseline (Panels A, C, E, and G [arrow], respectively) and after three months (Panels B, D, F, and H) of anakinra therapy.

Figure 2. Mean (±SE) Serologic and Cellular Responses to Treatment

Panel A shows levels of interleukin-1β in supernatants of cultures of peripheral-blood mononuclear cells (10⁶ cells per milliliter), cultured for 24 hours with and without lipopolysaccharide (final concentration, 2 μg per milliliter), control subjects and patients at baseline; at one month, three months, and six months; and during a flare in the disease, during which time therapy with anakinra was intentionally withheld. Panels B and C show quantitative reverse-transcriptase–polymerase-chain-reaction analysis of gene products that are involved in the regulation of interleukin-1β activation, including CIAS1 encoding cryopyrin and genes encoding activation and recruitment domain (CARD) inhibitor of NF-κB–activating ligand (CARDINAL), apoptosis-associated speck-like protein with a CARD (ASC), and caspase 1; and molecules involved in the downstream response to interleukin-1β — interleukin 1α, 1β, 6, 18, and 10; TNF-α; interferon-γ and interferon-α; interleukin-1 receptor 1 and 2; and interleukin-1–receptor antagonist. NF-κB and inhibitor of kappa light polypeptide gene enhancer in B cells, kinase B (IKBKB) can be involved in both the regulation of and response to interleukin-1β. In Panel B, the level of expression of gene products in blood samples from the patients is expressed on a log (base-10) scale relative to the level of expression of gene products in blood samples from control subjects (assigned a value of 1) at baseline. Panel C shows the changes in the level of expression of gene products in blood samples from the patients from baseline to month 3 (in 18 patients) and from month 3 until two to seven days after the withdrawal of anakinra (in 11 patients).