1) BACKGROUND NOMID, an acronym for """"""""Neonatal Onset Multisystem Inflammatory Disease"""""""", is a rare chronic, systemic inflammatory disease leading to major disability in affected individuals. This syndrome is also known as chronic infantile neurological, cutaneous and arthropathy (CINCA) syndrome. Recently, we and others discovered that missense mutations in the NACHT domain of CIAS1, a gene located on chromosome 1, area causing the disease. The discovery of a genetic defect has shed light on the pathogenesis of this condition. These spontaneously occurring mutations are present in about 50% of patients with NOMID/CINCA syndrome. Less than 60 cases of NOMID have been reported in the literature, but milder and incomplete forms of the disease may be difficult to recognize because of poorly defined disease criteria. To date, 13 patients have been clinically and genetically evaluated at the National Institutes of Health. The disease affects multiple ethnic groups and both sexes equally. The gene that is mutated,CIAS1, encodes a protein, cryopyrin that is associated with up-regulation of IL-1 production in vitro and in vivo. Upregulation of IL-1 is present in patients with and without detectable mutations in CIAS1. This has formed the rationale to develop a treatment approach targeting the IL-1 pathway in the affected children. 2) OBJECTIVE OF PRESENT STUDIES: To evaluate the impact of IL-1 blockade in patients with NOMID, we initiated a multi-center pilot study using the IL-1 receptor antagonist anakinra. We plan to enroll a total number of 20 patients into this study. During a 3- week enrollment period before initiating therapy, we collect self/parent reported daily diary data and serological samples on 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 1mg/kg/day by regular daily subcutaneous injections (study phase 1). Patients will be re-evaluated after one month and every month thereafter. If patients do not fulfill improvement criteria at 1 month, the dose will be escalated to 2.0 mg/kg/day with a maximum dose of 200 mg/day, while patients fulfilling response criteria will maintain on 1mg/kg/dose (study phase 2). At three months, patients enter phase 3 of the study. Patients with stable disease and patients with significant improvement will be randomized to receive placebo or active study drug in a double-blinded manner and monitored for the occurrence of disease flares. The proportion of patients flaring in the two treatment arms and drug safety are the primary clinical outcomes of this study. At the time of flare anakinra will be re-started at the same dose as before drug was withdrawn. Patients who did not flare will also be restarted or continued, on medication at 2 months after randomization. All patients will be observed during this open label extension phase of the study until the end of 12 month calculated from the initiation of anakinra treatment (phase 4). During the open label extension phase we will assess long-term safety and continued efficacy. Clinical and laboratory parameters will be assessed for response to treatment and safety data and efficacy data will be collected throughout the trial. 3) RESULTS DURING THE PAST YEAR AND ONGOING INITIATIVES The NOMID anakinra trial recently started to recruit patients. We published our results on the genetic evaluation of a total of 13 children, 6 children had heterozygous missense mutations in CIAS1. Five of the 6 mutations are novel. We recently identified two new mutations in CIAS1 in two additional NOMID patients that were evaluated at the NIH. The genetic analysis was performed in Dr Daniel Kastner's laboratory. We evaluated a number of biomarkers and associated those with disease expression. We found evidence of increased IL-1 as well as TNF, IL-3, IL-5 and IL-6 but not TGF B in mutation positive and mutation negative children, which indicates that the genetic defect yet to be identified in the mutation negative children is likely associated with a gene that also regulates the IL-1 pathway. 4) CONCLUSIONS AND SIGNIFICANCE In children with NOMID the identification of the associated gene defect will undoubtedly improve the diagnosis of this disease. The development of prognostic criteria and the initiation of a treatment trial will allow us to test our concept that IL-1 may be the pivotal pathway that leads to disease expression and constitute a desperately needed effective therapeutic option in this disease where no good treatment options currently exist.
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