Pathogenesis and treatment of autoinflammatory diseases i.e.NOMID,DIRA,CANDLE

NOMID、DIRA、CANDLE等自身炎症性疾病的发病机制和治疗

• 批准号: 8746501
• 负责人: Raphaela Goldbach-Mansky
• 金额: $ 102.06万
• 依托单位: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8746501
• 关键词: Arthralgia; Aseptic Meningitis; CCL2 gene; Cardiac; Cells; Child; Chronic; Clinic; Clinical; Clinical Research; Collaborations; Contracture; Data; Deficiency Diseases; Development; Disease; Epidermis; Evaluation; Event; Exanthema; Eye; FDA approved; Fatty acid glycerol esters; Fever; Functional disorder; Gene Expression Profiling; Genes; Genetic; Goals; HIV-Associated Lipodystrophy Syndrome; Heart Diseases; Human; Hyperlipidemia; Immune; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Inherited; Injury; Interferon Type II; Interferons; Interleukin-1; Interleukin-1 alpha; Interleukin-6; Interleukin-8; International; JAK1 gene; Japan; Joints; Labyrinth; Lead; Life; Ligands; Lipodystrophy; Mediating; Metabolic; Metabolic Diseases; Metabolic Marker; Metabolic syndrome; Modeling; Muscle; Muscular Atrophy; Mutation; NF-kappa B; Natural regeneration; Neonatal; Neuraxis; Neurologic; Organ; Orphan; Outcome; Outcome Study; Panniculitis; Parents; Pathogenesis; Pathway interactions; Patients; Perinatal; Pharmaceutical Preparations; Phenotype; Prevention; Primary Prevention; Process; Proteins; Protocols documentation; Psoriasis; Pustular psoriasis; Rare Diseases; Recruitment Activity; Research; Residual state; Role; Safety; Secondary Prevention; Signal Transduction; Signs and Symptoms; Skin; Study Section; Syndrome; TNF gene; Temperature; Therapeutic; Therapeutic Effect; Tissues; Treatment Protocols; Undifferentiated; Up-Regulation; anakinra; base; beta-Chemokines; bone; carbamoyl phosphate synthetase deficiency; chemokine; clinical Diagnosis; clinical efficacy; clinical phenotype; cytokine; disability; disease phenotype; early onset; effective therapy; exome sequencing; follow-up; gain of function mutation; genetic analysis; improved; inhibitor/antagonist; keratinocyte; lipid metabolism; monocyte; multicatalytic endopeptidase complex; novel; prevent; programs; receptor; response; skin disorder; standard care; therapeutic target; vascular inflammation

RESEARCH ACCOMPLISHMENTS A. IL-1-MEDIATED DISEASES, NOMID and DIRA: 1. FDA submission of our long term outcome data using the short-acting IL-1 inhibitor anakinra (SOBI) in patients with neonatal-onset multisystem inflammatory disease (NOMID) led to FDA approval of anakinra for the treatment of NOMID in December 2012. 2. We initiated a 10-year follow up outcome study in patients with NOMID, focusing on residual organ inflammation in NOMID, particularly CNS inflammation (aseptic meningitis), inner ear inflammation, eye inflammation, as well as systemic inflammation using previously validated outcomes. 3. Uncontrolled inflammation and chronic IL-1 mediated inflammation can also lead to metabolic and cardiac disease, such that a secondary goal of our studies is to examine cardiac and vascular inflammation in collaboration with Dr. Nehal Mehta, as well as metabolic markers of lipid metabolism. 4. Analyses of long-term outcomes in patients with DIRA treated with the IL-1 blocking agent anakinra indicate good inflammatory control and prevention of organ damage in nine patients. 4. We initiated a novel study with the long term IL-1 inhibitor rilonacept that targets IL-1alpha and beta in patients with DIRA, and have started recruitment. B. NON-IL-1-MEDIATED DISEASES, CANDLE and CAMPS studies: 1. Chronic atypical neutrophilic dermatosis with lipodystrophy, and elevated temperature (CANDLE) is a novel autoinflammatory disease. In an international collaboration our group and others recently identified mutations in the proteasome subunit PSMB8 as a causative gene for this disease. These findings led to a unifying concept that a group of rare diseases described as JMP (joint contractures, muscle atrophy and panniculitis-induced lipodystrophy) syndrome, Nakajo Nishimura syndrome (NNS) in Japan and CANDLE syndrome are along one disease spectrum of proteasome-associated autoinflammatory syndromes (PRAAS). We recently identified that novel mutations in PSMB8 and in additional proteasome genes are genetic causes for CANDLE in those patients, who were either negative for mutations in PSMB8 or carry only one of the PSMB8 mutations. Functional studies showed that mutation-positive and mutation-negative patients expressed high IP-10 (Interferon gamma-induced protein 10), MCP-1, and other chemokines and cytokines associated with interferon induced diseases. Microarray profiles and monocyte stat-1 activation demonstrated an interferon (IFN) response signature (IRS). These observations led to the hypothesis that IFN may be a key inflammatory mediator of the inflammatory disease manifestations in CANDLE, and may be partially responsible for the inflammatory disease manifestations observed. We hypothesized that blockade of IFN signaling may improve the disease manifestations of CANDLE, and initiated a compassionate use study with the drug baricitinib (Eli Lilly), a JAK1/2 inhibitor that can inhibit interferon signaling, in patients with CANDLE. To date we have recruited 10 CANDLE patients who are unresponsive to IL-1 blocking therapy and have incomplete or only minimal responses to therapies blocking TNF and IL-6. We are studying the inflammatory phenotype as well as the metabolic changes that are prominent in CANDLE, including hyperlipidemias, metabolic syndrome and muscle atrophy. 2. CARD14-mediated pustulosis (CAMPS) is another autoinflammatory disease that is caused by autosomal dominant mutations in CARD14. In most instances it is autosomal dominantly inherited but can also be caused by de novo mutations; a G138A mutation that occurred de novo was detected in one of our patients with sporadic, early-onset, generalized pustular psoriasis. The gain of function mutation of CARD14 leads to nuclear factor kappa B (NF-kB) activation, and upregulation of a subset of psoriasis-associated genes in keratinocytes which include the chemokines, (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis. We propose that, after a triggering event that may include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration, a cycle which is the hallmark of psoriasis. Gene expression profiling suggests that CARD14-mediated pustular psoriasis is driven by pathomechanisms similar to those seen in psoriasis. C. UNDIFFERENTIATED AUTOINFLAMMTORY DISEASES Among the children seen in our clinic many do not have a genetic or specific clinical diagnosis. We are dedicated to evaluating and treating patients with severe inflammatory diseases of early onset in life. In addition to a detailed immune evaluation, patients undergo genetic analyses including whole exome sequencing (WES) in trios (patients and parents) and treatment with targeted therapies that all help to identify immune/cytokine dysregulatory pathways. By evaluating patients immunologically, genetically and using targeted therapies, we attempt a "clinical Gestalt" with the goal of identifying immune dysregulated pathways and better treatments. CONCLUSIONS AND SIGNIFICANCE 1. IL-1-blocking therapies have become the standard of treatment for patients with CAPS and DIRA and other autoinflammatory diseases with clinical similarities to the genetic IL-1 diseases. Based on our studies, anakinra (SOBI) was FDA-approved under the orphan program for the use in NOMID. We continue to evaluate the long term safety and efficacy of these agents in our protocols. 2. A study evaluating the efficacy of the long acting IL-1 inhibitor canakinumab in patients with NOMID indicates control of systemic inflammation and disease signs and symptoms, but raises the question about the complete inflammatory control of CNS inflammation that can be achieved in patients with severe disease. 3. We initiated a clinical study in patients with DIRA using the long-acting IL-1 inhibitor rilonacept (Regeneron) to assess its safety and efficacy in these patients with DIRA, who require lifelong therapy with IL-1 blocking agents. 4. In patients with CANDLE we identified additional proteasome mutations as the genetic cause in those patients with clinical disease who have been negative for mutations in PSMB8 or carry only one mutation. These findings allow us to extend our understanding of proteasome dysfunction and its relation to inflammatory disease in humans. 5. We initiated a clinical study using the JAK1/2 inhibitor baricitinib to investigate clinical efficacy and safety in patients with CANDLE to provide preliminary data whether blocking the IFN pathway may be beneficial in this disease. 6. The discovery that mutations in CARD14 cause CARD14-mediated pustulosis (CAMPS) points to a role of keratinocytes in triggering the inflammatory response, and gene expression profiling shows similarities to psoriasis, thus suggesting similar pathogenic pathways. 7. An integrative approach using immune evaluation, whole exome sequencing and targeted therapeutics is used in assessing patients with undifferentiated autoinflammatory disorders, which will lead to an improved understanding of the pathogenesis of severe autoinflammatory disease phenotypes and the development of novel therapies.

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