Pathogenesis, and Outcome of Autoinflammatory Diseases, NOMID/CAPS, DIRA, CANDLE, SAVI, NLRC4-MAS, Still's-like Diseases, and other Undifferentiated Autoinflammatory Diseases

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A. CHARACERIZATION OF THE NATURAL HISTROY OF AIDS: 1. DIRA, CANDLE, SAVI: We have summarized the natural history of untreated DIRA, CANDLE and SAVI to characterize the spectrum of inflammatory disease manifestations, the impact of untreated inflammation on accumulating organ damage, the impact on perinatal morbidity and mortality as well as on overall mortality and to establish genotype-phenotype correlations. 2. We have clinically characterized the disease manifestations of novel diseases including CCD42-AID, NEMO-NDAS, SAMD9L-SAAD and IL-18PAP-MAS. 3. We contributed to the development of clinical criteria to identify patients with IFN mediated autoinflammatory diseases (4). B. DEVELOPMENT AND VALIDATION OF OUTCOME CRITERIA: We have assessed various parameters as outcome in autoinflammatory diseases and have developed and validated the outcomes in the following areas for patients with DIRA and CANDLE: 1. parents/ patient outcomes, 2. remission, and 3. low disease activity. 4. Maintenance of a outcome inclusion of 5. growth and development parameters and 6. Ability to wean systemic glucocorticoids. C. LONG-TERM OUTCOME AND SAFETY EVALUATION ON TARGETED TREATMENT WITH JAK INHIBITROR BARICITINIB. 1. SAVI and CANDLE/PRAAS are genetically defined rare autoinflammatory interferonopathies that are caused by gain-of-function mutations in STING1 and in genes encoding proteasome components or proteasome assembly genes (PSMB8, PSMB4, PSMA3, PSMB9, PSMB10, PSMG2 and POMP). We have described the benefit of JAK inhibition with the small molecule baricitinib in patients with CANDLE and SAVI and that patients require life-long treatment (13,14). We follow patients long-term to characterize the safety profile on long-term treatment with baricitinib. As we previously described the development of BK viruria and viremia we monitor kidney function and hematologic parameters and infections. D. GENETIC DISCOVERY AND CHARACTERIZATION OF NOVEL AUTOINFLAMMATORY DISEASES AND CLINICAL AND GENETIC EVALUATION OF PATIENTS WITH NOT YET CHARACTERIZED EARLY-ONSET AUTOINFLAMMATORY DISEASES 1. We characterized 2 novel autoinflammatory diseases that are clinical mimics of CANDLE and include NEMO exon5 deleted autoinflammatory syndrome (NEMO-NDAS) and SAMD9L associated autoinflammatory disease (SAMD9L-SAAD) (13). The pathogenic pathways are broader than in CANDLE and involve increased IFN and NF-kB signaling as assessed in the peripheral blood. 2. We also identified a novel mutation in CDC42 that causes a high IL-18 state that in the context of stress and infections leads to the development of MAS (5). We have also identified and characterized a novel disease, IL-18 PAPMAS, which is not yet genetically characterized disease that presents with high IL-18 serum levels and with pulmonary alveolar proteinosis and predisposition to the development of MAS (13, 3). We continue to evaluate and treat patients with severe inflammatory diseases that present early in infancy particularly those with interferonopathies but yet unknown genetic mutations All patients undergo a detailed immune evaluation that includes assessment of their assessed their IFN response gene signature, genetic analyses using next generation sequencing, (whole exome sequencing (WES) and/or whole genome sequencing (WGS)). E. DEVELOPMENT AND VALIDATION OF BIOMARKERS AND FOCUS ON UNDERSTANDING MONOCYTE AND MACROPHAGE DIFFERENTIATION TO IMPROVE DIAGNOSIS AND MONITORING OF AUTOINFLMAMMTORY DISEASES. 1. We are assessing the source of IFN production and the source of the IFN response in peripheral blood and tissues. We are validating the IFN signature in other monogenic and complex diseases including in patients with COVID-19. F. UNDERSTAND MONOCYTE AND MACROPHAGE DIFFERENTIATION TO IMPROVE DIAGNOSIS AND IMPACT ON DISEASE PATHOGENESIS 1. We established that monocyte differentiation in the IL-1 mediated disease, Majeed syndrome and found that M2 differentiated cells produce pro-inflammatory cytokines and chemokines that can also drive osteoclastogenesis and provide a model for bone inflammation in patients with autoinflammatory bone diseases. G. USE OF IN VITRO CELL CULTURE SYSTEMS TO MODEL ORGAN-SPECIFIC IMMUNE DYSREGULATION AND ORGAN DAMAGE IN SELECTED AUTOINFLAMMATORY DISEASES. 1. The severity of interstitial lung disease varies in patients with SAVI from being absent to being severe. Complications from interstitial lung disease are the major cause of childhood mortality in SAVI. We assess chest computed tomography (CT) and pulmonary function tests (PFTs) and lung tissue in SAVI patients and found a genetic modifying region to be associated with the severity of lung disease. We identified genetic markers of disease severity that causes SAVI.