RESEARCH ACCOMPLISHMENTS NOMID STUDIES: CLINICAL: 1. We analyzed 5 year outcome data in 20 patients and 3 year outcome data in 26 patients with NOMID who have been receiving escalating doses of anakinra. The initially observed good clinical response to anakinra persists, the drug is overall well tolerated. In most patients hearing and vision was persevered over 3 and 5 years, however patients who experienced hearing loss on anakinra had already significant hearing loss at baseline and more persistent enhancement on MRI. Low grade leptomeningeal inflammation was seen in up to 50% of patients at 3 years but dropped further at 5years. Although no new bone lesions occurred with anakinra treatment, preexisting bony lesions continued to expand on treatment. These data suggest that treatment with anakinra not only controls disease symptoms and inflammatory blood markers but can also prevent the progression of organ damage. Studies to assess the prevention of any organ damage in very young children are ongoing. 2. Disability on treatment with anakinra significantly improvement and persisted up to 3 and 5 years. 3. Chronic inflammation leads to growth retardation, osteoporosis. We showed that bone mineral density increases above the age-expected increase which correlate with a change in bone markers suggesting an increase in bone production and catch-up height and weight gains are seen in treated patients. 4. An ongoing study in patients with NOMID using the long acting IL-1 inhibitor canakinumab with the goal of finding an optimal dose regimen and monitoring long term outcome is currently ongoing. LABORATORY: 1. We have 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 and normal control tissue. 2. We studied a chondrocyte primary cell lines from a bone lesions from one patients with NOMID and in collaboration with Dr. Stratakis laboratory, their group identified that the cyclic adenosine-monophosphate (cAMP) signaling pathway is activated in patients with NOMID which is similar to bone lesions of other non-inflammatory conditions including fibrous dysplasia, osteochondromyxomas, and chondro- and osteo-sarcomas. These pathways all result in activation of the wnt signaling pathways and are dependent on active caspase-1 but not on IL-1. These findings explain our clinical findings that bone lesions once they have developed are non responsive to IL-1 blocking lessons. 4. In collaboration with Dr Nishikomoris group in Kyoto a number of our mutation negative patients analyzed by conventional methods are found to have somatic mosaicism. DIRA STUDIES: 1. Last year we published on a novel autoinflammatory disease DIRA, or deficiency of the IL-1 receptor antagonist and reported 4 founder mutations in the Newfoundland population, the Dutch, the Northern part of Puerto Rica around the city of Arecibo and Lebanon. Patients present with neonatal-onset multifocal osteomyelitis, periosteitis and pustulosis and systemic inflammation. The disease mimics infectious osteomyelitis and sepsis and has a high mortality if untreated. In collaboration with Dr. Jesus from Brazil and Dr. El-Shanti from Qatar a novel 15 basepair deletion in 2 unrelated Brazilian patients was found, suggesting a novel founder mutation in Brazil. Functional analyses indicated that the protein is expressed, but has no affinity to the IL-1 receptor and stimulation assay abnormalities are identical to those of the other DIRA patients As expected and similar to all other live children with DIRA, both patients had complete resolution of skin and bone lesions and a complete laboratory response. Similarities of the bone lesions in DIRA and patients with CRMO have spurred interest in the evaluation of the IL-1 pathway in patients with CRMO as well. ADULT ONSET STILL'S STUDIES We are closing out a pilot study of 5 patients with adult-onset Still's disease (AOSD) who were treated with the long acting IL-1 inhibitor rilonacept. We are assessing long term efficacy and safety. However, 3 patients had a satisfactory response to IL-1 TRAP and continue to be on treatment since the study stopped. A less uniform response to rilonacept was observed in 2 patients, one of them was subsequently switched to the commercially available IL-6 blocking agent tocilizumab. BEHCETS DISEASE A cohort of patients with Behcets disease has been recruited by Dr. Henderson and the clinical and laboratory manifestations of the diseases are being assessed. A treatment protocol to assess the role of a novel long acting IL-1 inhibitor XOMA 052 has been approved by the IRB and is expected to start recruitment soon. UNDIFFERENTIATED DISEASE We have accumulated a number of patients who have been referred with autoinflammatory disorders presenting early in life, who have clinical similarities with NOMID and DIRA patients but can clinically not be classified. We are using a genetic approach of whole genome sequencing in collaboration with Dr. Kastners group, an immunologic approach to characterize the immune deviation and a treatment approach using approved therapeutics in the treatment of these children to obtain answers to the underlying immune dysregulatory defect. 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. A novel founder mutation in 2 Brazil patients with DIRA has been identified and may raise the awareness of that disease in Brazil. 3. Somatic mosaicism in NLRP3 accounts for a large number of mutations in mutation negative patients assessed by conventional methods. 4. Long-term treatment effect of IL-1 blockade in patients with NOMID indicates that treatment of this devastating illness is safe and effective at least up to 5 years, improves disability and retards/stops progression of hearing loss and vision loss. 5. 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. 6. 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. A study evaluating the long term efficacy of the long acting IL-1 inhibitor canakinumab in patients with NOMID is ongoing. 7. The heterogeneous response to IL-1 blockade in patients with AOSD suggests a more complex cause for the inflammatory response in patients with AOSD. 8. The role of IL-1 in Behcets disease will be investigated with the newly approved protocol.

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