Conditions: Nervous System Malformations Arthropathy, Neurogenic Urticaria Papilledema
Keywords: Central Nervous System Abnormalities Arthropathy Urticaria Papilledema Auto-Inflammation Inflammatory Disease Neonatal Onset Multisystem Inflammatory Disease NOMID CINCA Syndrome
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 43
Healthy volunteers: no

Brief summary:
This study will evaluate the safety and effectiveness of anakinra (Kineret) for treating patients with neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurological, cutaneous and arthropathy (CINCA) syndrome. This disease can cause rash, joint deformities, brain inflammation, eye problems, and learning difficulties. Immune suppressing medicines commonly used to treat other pediatric rheumatologic diseases do not suppress NOMID symptoms and, if used long-term and in high doses, can cause harmful side effects. Anakinra, approved by The Food and Drug Administration for treating rheumatoid arthritis in adults, blocks a substance called IL-1 that may be an important factor in causing the inflammation in NOMID.

Detailed description:
This study uses the IL-1 receptor antagonist anakinra to treat children and adults with Neonatal-Onset Multisystem Inflammatory Disease (NOMID), also known as chronic infantile neurological, cutaneous and arthropathy (CINCA) syndrome. NOMID/CINCA syndrome is a rare genetic systemic auto-inflammatory disease that is characterized by a triad of symptoms, including a persistent urticaria-like skin rash, an arthropathy associated with patellar and epiphyseal osseous overgrowth, and neurological manifestations, including chronic aseptic meningitis, optic disc edema, high frequency hearing loss, and mental retardation. Spontaneous genetic mutations in the NACHT domain of CIAS1, a gene located on chromosome 1 have been recently identified in about half of the patients with NOMID/CINCA syndrome. CIAS1 encodes a protein, cryopyrin that is associated with up-regulation of IL-1 production in vitro, which has formed the rationale to target the IL-1 pathway in children with NOMID. During an up to 3- week enrollment period before initiating therapy, we will collect self/parent reported daily diary data and serological samples on up to 3 occasions one week apart, to determine baseline disease activity. These data may be gathered by collaborating centers. At the end of the observation period, patients will be admitted to the NIH for a standardized clinical evaluation and initiation of treatment with anakinra administered at 1 mg/kg/day by regular daily subcutaneous injections. If patients do not fulfill improvement criteria at 1 month, the dose will be escalated between 0.5 and 1 mg/kg/day increments to obtain inflammatory remission. An initial withdrawal study in a subset of 11 patients was performed. The clinical improvement at 3-4 months and the change in serum amyloid A levels (SAA) (a sensitive inflammatory marker) from before treatment to 3-4 months post treatment, and drug safety are the primary clinical outcomes of this study. To assess long-term safety and efficacy, all patients will be observed during an open ended extension phase of the study. Clinical and laboratory parameters will be used to assess safety and efficacy throughout the trial. All patients will be seen every 6 months and annually (as calculated from initiation of anakinra treatment) to further evaluate safety and long term outcomes. During the open ended extension phase of the study, patients who have residual clinical or laboratory evidence of active inflammation may have their dose increased between 0.5 and 1 mg/kg/day increments to a maximum dose of 10 mg/kg/per day to achieve clinical remission. In addition, since no data on the pharmacokinetics (PK) of anakinra in pediatric patients is available with doses exceeding 2 mg/kg/day, we plan to determine the PK of anakinra with each dose escalation.

Arms:
arm 1: All patients enrolled received daily doses of subcutaneous injection of increased doses of anakinra starting at 0.5mg/kg/day up to a maximum 10mg/kg/day to achieve disease remission.

Interventions: intervention 1: anakinra
Intervention descriptions: intervention 1: daily injection of subcutaneous injection

Protocol document: