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

NOMID、DIRA、CANDLE、SAVI等自身炎症性疾病的发病机制和治疗

• 批准号: 9359793
• 负责人: Raphaela Goldbach-Mansky
• 金额: $ 138.24万
• 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/9359793
• 关键词: Animal Model; Arthralgia; Autoimmune Diseases; Automobile Driving; Biological Markers; Biopsy; CCL2 gene; Cause of Death; Cells; Cerebrospinal Fluid; Chest; Chronic; Clinic; Clinical; Clinical Research; Clinical assessments; Cytokine Signaling; DNA Sequence Alteration; Data; Defect; Deficiency Diseases; Disease; Disease Outcome; Drug Kinetics; Effectiveness; Enrollment; Evaluation; Exanthema; Eye; FDA approved; Fatty acid glycerol esters; Fever; Flare; Future; Gatekeeping; Genes; Genetic; Genetic Transcription; Hematopoietic; Histologic; Human; Immune; Immunofluorescence Immunologic; Immunohistochemistry; Immunologics; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Ink; Interferon Type I; Interferon Type II; Interferon-beta; Interferons; Interleukin-1; Interleukin-18; Interstitial Lung Diseases; JAK1 gene; JAK2 gene; Janus kinase; Laboratories; Labyrinth; Lead; Life; Light; Link; Lipodystrophy; Lung diseases; Macrophage Activation; Mediating; Medical Genetics; Mendelian disorder; Modeling; Muscle; Mutation; National Institute of Allergy and Infectious Disease; Neonatal; Neuraxis; Organ; Organ Model; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Prevention; Production; Proteins; Pulmonary function tests; Recurrence; Reporting; Research; Role; Safety; Sampling; Severities; Signal Pathway; Signal Transduction; Skin; Skin Manifestations; Source; Staining method; Stains; Structure of parenchyma of lung; Syndrome; Temperature; Therapeutic; Tissues; Undifferentiated; Vascular Diseases; Work; X-Ray Computed Tomography; anakinra; autoinflammatory; base; bone; chemokine; cytokine; design; disability; disease phenotype; early onset; effective therapy; exome sequencing; gain of function mutation; genetic analysis; human disease; improved; infancy; inhibitor/antagonist; insight; kinase inhibitor; loss of function mutation; macrophage; monocyte; multicatalytic endopeptidase complex; neutrophil; next generation sequencing; novel; peripheral blood; prevent; programs; receptor; response; sensor; skin disorder; skin lesion; targeted treatment; tissue culture

RESEARCH ACCOMPLISHMENTS A. STUDIES ON THE IL-1-MEDIATED DISEASES, NOMID AND DIRA: 1. We evaluated biomarkers in the cerebrospinal fluid (CSF) that correlate with CNS inflammation and suggest a contribution on non-hematopoietic cells to the inflammatory response in the CNS. We validated these markers in patients treated with a short-acting IL-1 inhibitor anakinra and the long-acting IL-1 inhibitor canakinumab. 2. A study with the long-acting IL-1 blocking agent rilonacept in patients with DIRA was recently completed and our data suggest good inflammatory control and prevention of progression of organ damage in the six DIRA patients enrolled. B. EVALUTION OF PHARMACOKINETIC PROFILE AND CLINICAL BENEFIT OF THE JAK INHIBITOR (BARICITINIB) IN A COMPASSIONATE USE STUDY IN PATIENTS WITH INTERFERONOPATHIES. We are treating 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, and assessed clinical benefit and the pharmacokinetic profile of baricitinib. 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). Preliminary benefit and safety data are encouraging and suggest that targeting IFN signaling with a JAK1/JAK2 inhibitor may be a successful therapeutic strategy. 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 and is reported under in AR041202-03. 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 suggested a role of IFN overproduction as 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. In addition to a detailed immune evaluation, patients undergo genetic analyses through next generation sequencing, including whole exome sequencing (WES). E. CHARACTERIZATION OF GENETIC MUTATIONS AND PATHWAYS THAT LEAD TO TYPE-I IFN PRODUCTION IN PATIENTS WITH CANDLE/PRAAS 1. Most patients with CANDLE are homozygous or compound heterozygous for PSMB8 mutations. We recently found that combinations of mutations in PSMB9, PSMB4, PSMA3 and heterozygous loss-of-function mutations in POMP (2015) cause a digenic and autosomal dominant form of CANDLE. The discovery of loss-of function mutations in proteasome components suggest that reduction of proteasome function below a critical leve is associated with Type-I IFN production. 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. PATHOGENESIS OF SKIN MANIFESTATIONS OF IL-1 MEDIATED AND TYPE I IFN-MEDITATED AIDs AND EVALUATION OF VARIABLE INTERSITITAL LUNG DISEASE IN SAVI PATIENTS 1. Tissue from skin lesions of patients with NOMID (n=4), DIRA (n=4), SAVI (n=3), CANDLE (n=5) and other interferonopathies (UIFN) (n=7) were assessed by immunohistochemistry and immunofluorescence. A distinct histologic pattern of neutrophil and macrophage infiltration characterizes SAVI, CANDLE, NOMID and DIRA skin biopsies, while Mx-1 staining and the IFN scores distinguish IFN- and IL-1-mediated AIDs suggesting that the histologic and immunologic assessment of skin biopsies may aid in identifying relevant dysregulated immune pathways. 2. 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 that was inked to 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 may provide us with clues to the disease pathogenesis and to 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 novel recently identified autoinflammatory diseases, SAVI and NLRC4-MAS shed light on basic disease mechanisms that cause autoinflammatory disease phenotypes. 2. Our 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, suggested a causative role of IFN signaling in causing autoinflammatory disease phenotypes. 3. Our studies in CANDLE and SAVI provide a rationale for a compassionate use study with the JAK1/2 inhibitor baricitinib that inhibits IFN signaling and allows us to assess the clinical benefit and collect safety data in patients with CANDLE and SAVI and in patients with clinical and laboratory evidence of IFN mediated disease. 4. The identification of mutations in NLRC4 causing macrophage activation led to the exploration of the role of IL-18 in macrophage activation and suggests IL-18 as a potential target for treatment. 5. IL-1-blocking therapies are FDA-approved for the use in CAPS including NOMID based on work performed under this study. Our biomarker analyses aim to define markers that help us determine appropriate control of systemic and organ inflammation in NOMID and to identify potential differences in the effectiveness in controlling organ inflammation that may exist between different IL-1 blocking agents. 6. Data from a clinical study in patients with DIRA treated with the long-acting IL-1 inhibitor rilonacept (Regeneron) are being analyzed.

研究成就

项目成果

Alterations in peripheral blood memory B cells in patients with active rheumatoid arthritis are dependent on the action of tumour necrosis factor.

• DOI: 10.1186/ar2718
• 发表时间: 2009
• 期刊: Arthritis research & therapy
• 影响因子: 4.9
• 作者: Souto-Carneiro MM;Mahadevan V;Takada K;Fritsch-Stork R;Nanki T;Brown M;Fleisher TA;Wilson M;Goldbach-Mansky R;Lipsky PE
• 通讯作者: Lipsky PE

Molecular mechanisms in genetically defined autoinflammatory diseases: disorders of amplified danger signaling.

• DOI: 10.1146/annurev-immunol-032414-112227
• 发表时间: 2015
• 期刊: Annual review of immunology
• 影响因子: 29.7
• 作者: de Jesus AA;Canna SW;Liu Y;Goldbach-Mansky R
• 通讯作者: Goldbach-Mansky R

Anaphylactic reaction to anakinra in a rheumatoid arthritis patient intolerant to multiple nonbiologic and biologic disease-modifying antirheumatic drugs.

对多种非生物和生物疾病缓解抗风湿药物不耐受的类风湿性关节炎患者对阿那白滞素的过敏反应。

• DOI: 10.1345/aph.1l573
• 发表时间: 2009
• 期刊: The Annals of pharmacotherapy
• 作者: Desai,Ditina;Goldbach-Mansky,Raphaela;Milner,JoshuaD;Rabin,RonaldL;Hull,Keith;Pucino,Frank;Colburn,Nona
• 通讯作者: Colburn,Nona

IL-1 blockade in autoinflammatory syndromes.

• DOI: 10.1146/annurev-med-061512-150641
• 发表时间: 2014
• 期刊: Annual review of medicine
• 影响因子: 10.5
• 作者: Jesus AA;Goldbach-Mansky R
• 通讯作者: Goldbach-Mansky R

Newly recognized Mendelian disorders with rheumatic manifestations.

• DOI: 10.1097/bor.0000000000000207
• 发表时间: 2015-09
• 期刊: Current opinion in rheumatology
• 影响因子: 5.1
• 作者: de Jesus AA;Goldbach-Mansky R
• 通讯作者: Goldbach-Mansky R