RESEARCH ACCOMPLISHMENTS A. STUDIES ON THE IL-1-MEDIATED DISEASES, NOMID AND DIRA: 1. We have developed a long-term follow up study and are evaluating patients with NOMID who have been treated for over ten years in long-term follow up. We also focus on children who were started on treatment early in life and are assessing the progression of organ damage. The evaluation of these patients is expected to provide us with data on the long-term outcome of NOMID patients treated with IL-1 blocking agents including the prevention of organ damage, and the long-term safety of chronic IL-1 blockade in NOMID patients. 2. We have identified novel mutations causing Majeed syndrome and are studying their role in causing osteomyelitis and bone inflammation. B. EVALUTION OF PHARMACOKINETIC PROFILE AND CLINICAL BENEFIT OF THE JAK INHIBITOR (BARICITINIB) IN A COMPASSIONATE USE STUDY IN PATIENTS WITH INTERFERONOPATHIES. We have treated 18 patients (11 CANDLE, 4 SAVI and 4 with other AIDs) in an ongoing compassionate use study with the Janus kinase (JAK) inhibitor, baricitinib (Eli Lilly) that can inhibit interferon signaling. All patients enrolled expressed high IP-10 (Interferon gamma-induced protein 10), MCP-1, and other chemokines and cytokines associated with interferon induced diseases and a strong interferon (IFN) response signature (IRS) with disease flares. We established the pharmacokinetic profile of baricitinib in these patients and assessed clinical benefit at optimized doses of baricitinib that had tolerable safety profiles. We developed a validated IFN score using nanostring that allows us to reliably measure and quantify chronic IFN signaling. On baricitinib treatment, the median daily symptom score, a measure that was developed to quantify daily disease symptoms, decreased from 1.3 (interquartile range IQR, 0.931.78) to 0.25 (IQR, 0.10.63) (P < 0.0001). Patients receiving corticosteroids at baseline, decreased prednisone doses from 0.44 mg/kg/day (IQR, 0.311.09) to 0.11 mg/kg/day (IQR, 0.020.24) (P < 0.01). 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom with genetically undefined conditions, discontinued treatment because of lack of efficacy. One CANDLE patient, discontinued treatment because of BK viremia and azotemia. The treatment was overall well tolerated and common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. These data suggest the use of JAK inhibitors in as therapeutic strategy for these patients with autoinflammatory interferonopathies including CANDLE, SAVI and others. C. COMPASSIONATE USE OF IL-18BP in NLRC4-MAS. The identification of gain-of-function mutations in the innate immune sensor, NLRC4 represents the first monogenic defect that may link high IL-18 levels and macrophage activation syndrome. Preliminary data in a patient with NLRC4 mutations with recombinant IL-18 binding protein (tadekinig, AB2bio) suggests that IL-18 blockade may be a rational therapeutic target in these patients. D. ONGING STUDY OF PATIENTS WITH UNDIFFERENTIATED AUTOINFLAMMTORY DISEASES Our findings of genetic defects that cause autoinflammatory disease manifestations revealed mutations in genes that lead to the IFN- mediated conditions (SAVI and CANDLE) and our biomarker and treatment data suggest a role of IFN overproduction in driving autoinflammatory/ autoimmune disease phenotypes. 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. CHARACTERIZATION OF GENETIC MUTATIONS AND PATHWAYS THAT LEAD TO TYPE-I IFN PRODUCTION IN PATIENTS WITH CANDLE/PRAAS 1. SAVI and CANDLE/PRAAS and are genetically defined rare autoinflammatory interferonopathies that are caused by gain-of-function mutations in TMEM173 encoding STING and genes encoding proteasome components or proteasome assembly genes (PSMB8, PSMB4, PSMA3, PSMB9 and POMP). We have identified mutations in known and in additional proteasome related genes that lead to the clinical phenotype of CANDLE/PRAAS with variable disease severity. These findings confirm and solidify the notion that progressive impairment of proteasome function to more than 50% leads to a triggering of and IFN stress response. The addition of additional genes to screening panels for CANDLE will facilitate early recognition of these diseases. 2. The source of IFN production varies in CANDLE and SAVI patients. While SAVI patients present with constitutive transcription of IFNB1 in peripheral blood monocytes, CANDLE and SAVI lesional skin samples show similar elevated transcription in IFNAs and IFNB1. IP- 10 levels were highest in CANDLE skin samples. Understanding differences in intracellular signaling pathways activating IFN production and the IFN loop is needed to design targeted treatment approaches for the different interferonopathies. F. USE OF IN VITRO MODELS TO STUDY ORGAN-SPECIFIC IMMUNE DYSREGULATION IN NOMID, DIRA, CANDLE, SAVI AND OTHER AUTOINFLAMMATORY DISEASES. 1. The severity of interstitial lung disease varies in patients with SAVI from being absent to being severe and the cause of death. We assessed chest computed tomography (CT) and pulmonary function tests (PFTs) and lung tissue where available in 12 SAVI patients and found a genetic modifying region to be associated with the severity of lung disease. Patients with two copies of the genetic modifiers had the most severe disease which was associated with the increased IFNbeta production. CONCLUSIONS AND SIGNIFICANCE Our program provides an integrative approach to the clinical, genetic and immunologic evaluation of patients with autoinflammatory diseases that continues to provide us with novel insights into the disease pathogenesis and into the use of targeted therapeutics to better treat patients and improve disease outcomes. Our studies have resulted in the discovery of novel autoinflammatory diseases that provided insights into the disease pathogenesis and revealed targets for treatment. 1. Two autoinflammatory diseases discovered in our group, SAVI caused by mutations in and NLRC4-MAS caused by gain-of-function mutations in NLRC4 shed light on basic disease mechanisms that cause autoinflammatory disease phenotypes and expanded the pathogenesis of of autoinflammatory diseases to include a role of Type-I IFN and IL-18 signaling. 2. Pathogenesis data in CANDLE, along with our findings that gain-of- function mutations in TMEM173 that cause SAVI encodes STING, a gatekeeper molecule for IFN beta transcription, suggest a causative role of IFN signaling in causing autoinflammatory disease phenotypes. We have developed an IFN response gene score to asses disease activity longitudinally and to screen patients with yet uncharacterized autoinflammatory diseases and assess the utility of the IFN score in making a diagnosis and in making treatment decisions. 4. In an ongoing compassionate use study using the JAK1/2 inhibitor baricitinib that inhibits IFN signaling we showed clinical benefit and collected safety data in patients with CANDLE and SAVI and in patients with clinical and laboratory evidence of IFN mediated disease. In a pharmacokinetic/dynamic study, we assessed the pharmacokinetic profile in children and young adults and provided a dosing regimen for patients with autoinflammatory interferonopathies. 5. The identification of mutations in NLRC4 th
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