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 HISTORY OF SAIDs: 1. CANDLE, SAVI: We have assessed geno-phenotype correlations in CANDLE and SAVI patients using data pre-JAK inhibitor treatment to characterize the spectrum of inflammatory disease manifestations, the impact of untreated inflammation on accumulating organ damage, the rate of perinatal morbidity and mortality and assessed cytokine and other biomarker dysregulation. 2. We have clinically characterized the disease manifestations of a novel disease Lyn associated autoinflammatory disease. B. DEVELOPMENT AND VALIDATION OF OUTCOME CRITERIA: We have developed outcome parameters for several autoinflammatory diseases and have 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 TREAT-MENTS ON PATIENTS ENROLLED IN PREVIOUS TREATMENT PROTOCOLS. 1. SAVI and CANDLE/PRAAS patients require long-term treatment and currently JAK inhibitors (JAKi) provide the most consistent benefit. Our studies with the small molecule JAKi, baricitinib, identified that BK reactivation in urine in most patients and in blood (3). We follow patients long-term on the natural history study and developed guidance to monitor BK viruria and viremia in patients requiring higher doses of JAK inhibitors. 2. Follow-up of a cohort of NOMID patients we characterized a long-term efficacy and side effects and identified the development of amyloidosis in a subset of patients who are receiving long-term high dose anakinra at the injections site. We evaluating the extend of this side effect. D. GENETIC DISCOVERY AND CHARACTERIZATION OF NOVEL AUTO-INFLAMMATORY DISEASES AND CLINICAL AND GENETIC EVALUATION OF PATIENTS WITH NOT YET CHARACTERIZED EARLY-ONSET AUTOINFLAMMATORY DISEASES 1. We characterized 2 novel autoinflammatory diseases, one that clinically mimics CANDLE, NEMO exon5 deleted autoinflammatory syndrome (NEMO-NDAS) (4, 5) and another disease caused by GOF mutations in Lyn kinase. 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, (currently 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 comparing IFN production, the source of IFN and of the IFN response gene signature in peripheral blood and tissues. We are validating the IFN signature in other monogenic and complex diseases including in adult and pediatric patients with COVID-19. 2. We collaborated with Dr. Scott Canna and a wider group to characterize biomarkers that allow the identification of patients with IL-18 PAP-MAS (4) now referred to as SOJIA-LD who develop pulmonary alveolar proteinosis and are at risk for the development of macrophage activation syndrome. F. EXPLORE MONOCYTE AND MACROPHAGE DIFFERENTIATION TO IMPROVE DIAGNOSIS AND UNDERSTAND PATHOGENIC IMPACT 1. We established that monocyte differentiation in the IL-1 mediated disease and compared monocyte differentiation in NEMO-NDAS and CANDLE patients. We are describing the immunological impact of the disease-causing NEMO-NDAS mutations on monocyte and macrophage differentiation and function. G. USE OF IN VITRO CELL CULTURE SYSTEMS TO MODEL ORGAN-SPECIFIC IMMUNE DYSREGULATION AND ORGAN DAMAGE IN SELECTED AUTOINFLAMMATORY DISEASES. We modeled aspects of organ inflammation and damage in two diseases, SAVI and LYN kinase mediated disease. 1. The interstitial lung disease in patients with SAVI with predominantly p.V155M mutations in STING1 are severe, and the predominant cause for mortality in SAVI. Complications and progression of lung fibrosis occur despite JAKis. In collaboration with the Boehm laboratory (NHLBI) we developed iPSC model to assess endothelial cells differentiation. 2. We developed iPScells from a patient with a GOF mutation in Lyn kinase to investigate small vessel vasculitis THE NATURAL HISTORY PROTOCOL was developed for initial and follow-up evaluations of patients with autoinflammatory diseases. Affected participants (enrollment ceiling of n = 1000) are clinically evaluated and phenotyped at the NIH CC which includes state of the art radiologic molecular imaging. Research samples are collected and include blood, skin, saliva, urine, and CSF as well as skin swabs and stool samples for microbiome analyses. Unaffected relatives and unrelated healthy volunteers (n = 500 of each) are enrolled for the collection of control biological samples. All affected patients and their parents undergo genetic evaluation. The frequency of the follow-up visits is based on the participants clinical status and the scientific objective related to the patient's disease. We collect and store samples including DNA for comprehensive genetic analyses, RNA for gene expression profiling, serum, plasma and cells for biomarker analysis and biopsy material if left over from clinically indicated procedures. We generate fibroblast cells lines from selected patients, and in selective patients we may generate iPSCs to model disease pathogenesis in organs and tissues. We obtain imaging to evaluate organs that are inflamed or damaged. During the COVID pandemic we closed a compassionate use program and we follow patients with CANDLE, SAVI and with other autoinflammatory interferonopathies on the natural history protocol.