Pathogenesis of Behcet's disease and Still's disease

白塞病和斯蒂尔病的发病机制

• 批准号: 8344737
• 负责人: Raphaela Goldbach-Mansky
• 金额: $ 47.96万
• 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/8344737
• 关键词: Adult; Adult-Onset Still' s Disease; Affect; Age; American; Antigens; Arthritis; Autoantibodies; Autoimmune Diseases; Behcet Syndrome; Biopsy Specimen; Blood; Childhood; Clinical; Clinical Research; Collaborations; Communities; Complex; DNA; Data; Databases; Dermatologic; Development; Disease; Disease Marker; Enrollment; Functional disorder; Future; Gene Mutation; Genes; Genetic; Genital system; Goals; Inflammation; Inflammatory; Inflammatory Response; Institutional Review Boards; Interleukin-1; Interleukin-6; JAK3 gene; Juvenile-Onset Still' s Disease; Laboratories; Measurement; Measures; Meleagris gallopavo; Methods; Monitor; Mucous Membrane; National Human Genome Research Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Oral; Oral Ulcer; Oral mucous membrane structure; Organ; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Phase; Pilot Projects; Play; Production; Questionnaires; RNA; Randomized; Relapse; Reporting; Risk Factors; Role; Safety; Sampling; Serum; Specimen; T-Lymphocyte; Testing; Therapeutic Uses; Tissues; Travel; Ulcer; United States; Universities; Withdrawal; anakinra; arm; base; cohort; conventional therapy; cytokine; effective therapy; inhibitor/antagonist; insight; interest; microbiome; neutrophil; pathogen; receptor; response; therapeutic target; treatment strategy

RESEARCH ACCOMPLISHMENTS Behcet's Disease (a) Dr. Sibley traveled to Istanbul in December 2010 to collect patient disease questionnaire data, blood, DNA, RNA, and tissue specimens. (b) Preliminary analysis shows that organ manifestations and disease activity measurements differ in the United States compared to Turkey. Notably, Turkish patients have more severe organ manifestations whereas American patients report higher disease activity on questionnaires. (c) The first paired affected and unaffected samples for microbiome and RNA-Seq analyses have been successfully analyzed. This proves the feasibility of the projects with larger efforts now underway. (d) IRB approval has been obtained to begin a pilot clinical study of ankinra in the treatment of mucocutaneous BD. Patient enrollment will begin shortly. Adult Onset Stills Disease (a) The pilot study of rilonacept in AOSD has been completed. The data from this study has been monitored and the database is now locked. Preliminary analyses now underway showing that three patients responded well to rilonacept. The two non-responders were switched to tocilizumab, an IL-6 receptor blocker, and are now showing clinical benefit. CONCLUSIONS AND SIGNFICANCE Similar methods to those used in the monogenic auto-inflammatory disorders NOMID and DIRA are underway to characterize clinical and inflammatory pathways in Behcets Disease and AOSD, polygenic diseases in adults. 1. A pilot study of IL-1 inhibition with rilonacept has been completed in AOSD. 3/5 patients showed good response to IL-1 blockade whereas the remaining 2 patients responded well to a change of therapy to the IL-6 receptor blocker, tocilizumab. 2. Cytokine profiles will be analyzed from longitudinal serum samples collected from AOSD patients with an effort to better understand the underlying inflammatory pathophysiology of this disease. 3. Organ manifestations and disease activity measures of American BD patients have been summarized and will be compared to patients from more classically defined ethnic backgrounds. Data suggests that important differences exist between these groups. 4. Tissue microbiome and RNA-Seq characterization is underway in patients with active BD compared to ethnically matched controls. 5. A pilot study of IL-1 inhibition with anakinra in patients with mucocutaneous BD has been IRB approved with enrollment to begin shortly.

研究成果 白塞病 （一） 西布利博士于2010年12月前往伊斯坦布尔收集患者疾病问卷数据、血液、DNA、RNA和组织标本。 （B） 初步分析表明，与土耳其相比，美国的器官表现和疾病活动测量不同。 值得注意的是，土耳其患者有更严重的器官表现，而美国患者在问卷调查中报告了更高的疾病活动性。 （c）第（1）款 已成功分析了用于微生物组和RNA-Seq分析的第一对受影响和未受影响的样品。 这证明了目前正在进行的更大努力的项目的可行性。 （d）其他事项 已获得IRB批准，开始安白滞素治疗粘膜皮肤BD的初步临床研究。 患者入组将很快开始开始。 成人斯蒂尔病 （一） 利洛那塞治疗AOSD的中试研究已经完成。 对本研究的数据进行了监测，数据库现已锁定。 目前正在进行的初步分析显示，三名患者对利洛那西普反应良好。 两名无反应者改用tocilizumab，一种IL-6受体阻滞剂，现在显示出临床获益。 结论和意义 与单基因自身炎症性疾病NOMID和DIRA中使用的方法类似的方法正在进行中，以表征成人多基因疾病Behcets病和AOSD中的临床和炎症途径。 1. 已在AOSD中完成了利洛那塞抑制IL-1的初步研究。 3/5例患者显示对IL-1阻断的良好反应，而其余2例患者对IL-6受体阻断剂托珠单抗治疗的改变反应良好。 2. 将分析从AOSD患者采集的纵向血清样本的细胞因子谱，以更好地了解该疾病的潜在炎症病理生理学。 3. 美国BD患者的器官表现和疾病活动性指标已被总结，并将与来自更经典定义的种族背景的患者进行比较。 数据表明，这些群体之间存在着重大差异。 4. 与种族匹配的对照相比，活动性BD患者的组织微生物组和RNA-Seq表征正在进行中。 5. 一项在皮肤粘膜BD患者中使用阿那白滞素抑制IL-1的初步研究已获得IRB批准，招募工作将于开始。