RESEARCH ACCOMPLISHMENTS NOMID STUDIES: Neonatal-onset multisystem inflammatory disease (NOMID) is a rare autoinflammatory/ autoimmune disorder characterized by urticarial rash, fever, aseptic meningitis, papilledema, sensorineural hearing loss, epiphyseal overgrowth of the long bones, growth retardation, and, in some cases, mental impairment. NOMID is at the severe end of a spectrum of disorders caused by mutations in CIAS1, which encodes a protein, cryopyrin, that is a key regulator of interleukin 1 (IL-1) beta activation. Results over the last year: CLINICAL: 1. We analyzed 3 year outcome data in 26 patients with NOMID who have been receiving escalating doses of anakinra in the attempt to achieve clinical complete remission of inflammatory symptoms. The initially observed good clinical response persists and the drug is overall well tolerated. However, in 3 patients with severe hearing loss at the beginning of the study, hearing loss progressed and intermittent low grade leptomeningeal inflammation was seen in up to 50% of patients at 3 years. Although no new bone lesions occurred with anakinra treatment, preexisting bony lesions continued to expand on treatment. 2. We assessed disability on treatment with anakinra and have seen significant improvement in pain and motor disability but not cognitive function for up to 3 years. 3. In untreated patients, the chronic inflammation leads to significant metabolic changes that include growth retardation, bone loss and anemia. We showed that bone mineral density increases above the age-expected increase and see a rapid and sustained change in bone markers that indicate an increase in bone production. Anemia rapidly resolves and catch-up height and weight gains are seen when the inflammation is suppressed. LABORATORY: 1. We characterized the inflammatory skin lesions in collaboration with Dr. Lowes at Rockefeller by comparing lesional and nonlesional pretreatment skin biopsy samples to post treatment skin biopsies. 2. Dr. Kastners laboratory identified a specific microarray signature that distinguishes NOMID patients from patients with other autoinflammatory diseases. The disease specific gene expression profile will allow us to define an IL-1 signature that may support the identification of shared immune pathways in other yet uncharacterized inflammatory diseases. DIRA STUDIES: 1. The referral of a child with presumed mutation negative NOMID led to an interesting finding of a novel autoinflammatory disease, DIRA. We recently published 4 mutations that led to the development of DIRA. These mutations are prevalent in the several founder populations but a disease state so for is only observed when 2 disease alleles are inherited. Affected patients present clinically with neonatal-onset multifocal osteomyelitis, periostitis and pustulosis and severe systemic inflammation. Treatment with the IL-1 inhibitor, anakinra, leads to rapid resolution of the clinical symptoms and the systemic inflammation. Sequencing of candidate genes in the IL-1 signaling pathway led to the identification of so far 4 different mutations in the IL1RN gene. In some cases a homozygous frameshift mutation (N52KfsX25) and two missense mutation (E77X) and (Q54X) lead to premature truncation of the IL-1 receptor antagonist protein. Another mutation is caused by a homozygous, 175kb deletion which includes the IL1RN gene. Functional studies confirmed absent or very low expression of the mutant protein and complete loss of function. LPS or IL-1beta stimulation lead to increased expression of the pro-inflammatory cytokines and chemokines, IL-6, IL-8, MIP-1 alpha, TNF, and MCP-1, which are associated with neutrophil activation and recruitment upon stimulation of whole blood cells. All children have been unresponsive to several DMARDs including high doses of steroids but had a uniformly rapid clinical response with complete resolution of skin and bone lesions and complete normalization of inflammatory markers including ESR and CRP, leukocytosis, anemia and thrombocytosis within 7-14 days of treatment with the IL-1 receptor antagonist anakinra. Deficiency of the Interleukin-1 Receptor Antagonist, DIRA, is a novel autoinflammatory syndrome that exemplifies once more the crucial role of IL-1 and expands the organ- specific disease manifestations to aseptic osteomyelitis, periostitis, pustulosis and vasculitis (in one patient). ADULT ONSET STILL'S STUDIES We are studying the long term efficacy and safety of the long acting IL-1 inhibitor rilonacept on 5 patients with adult-onset Still's disease (AOSD). A less uniform response to rilonacept with inflammatory remission in 2 out of 5 patients was observed. Biomarker studies that help distinguish patients with and without an immediate response to IL-1 blockade are ongoing. BEHCETS DISEASE A protocol to characterize the clinical and immunological manifestations of Behcets disease has been approved and patients are being actively recruited. CONCLUSIONS AND SIGNIFICANCE 1. In now 2 severe autoinflammatory syndromes, cryopyrin associated periodic syndromes, CAPS (which includes FACS, MWS and NOMID), and deficiency of the IL-1 receptor antagonist syndrome, DIRA, the crucial role for IL-1 in the pathophysiology of these illnesses with multiorgan involvement has been demonstrated. 2. Our studies on the long-term treatment effect of IL-1 blockade in patients with NOMID indicate that treatment of this devastating illness seems safe and effective at least up to 5 years and improves disability and retards/stops progression of hearing loss and vision loss. Patients treated with this agent for longer periods of time have continued to show significant improvement in their symptoms, and we will continue to evaluate patients for long term efficacy and safety. 3. A primary prevention protocol targets very young children with NOMID and will allow us to determine how effective early therapy is in the primary prevention of permanent organ damage that would develop if children remained untreated or partially treated with other DMARDs and steroids. 4. The phenotypic difference between NOMID and DIRA (no CNS, eye and ear inflammation in DIRA, compared to NOMID) and difference in skin manifestations, urticaria-like versus pustulosis, allow us to study the organ- specific immune responses downstream of IL-1 and may shed light on processes that determine specific organ manifestations. 5. The development of long acting IL-1 inhibitors may allow for better disease control in those patients who are not in complete remission and offer more convenient treatment options particularly in children in whom daily injections can be quite traumatic. 6. The heterogeneous response to IL-1 blockade in patients with AOSD suggests a more complex cause for the inflammatory response in patients with AOSD. 7. The role of IL-1 in aseptic multifocal osteomyelitis, pustulosis, hyperostosis and vasculitis suggests the evaluation of the contribution of IL-1 in other diseases with inflammatory bone lesions including CRMO/SAPHO.

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