Defining the molecular and radiologic phenotype of progressive RA-ILD

定义进行性 RA-ILD 的分子和放射学表型

• 批准号: 10634344
• 负责人: Joyce Sujin Lee
• 金额: $ 65.3万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634344
• 关键词: Biological Markers; Blood; Cessation of life; Characteristics; Clinical; Clinical Trials; Collection; Combined Modality Therapy; Country; Data; Development; Diagnosis; Disease; Disease Progression; Epithelial Cells; Exposure to; Fibrosis; Foundations; Future; Gene Expression; Genes; Goals; Harm Reduction; Health; Heterogeneity; Histologic; Image; Imaging technology; Immunosuppression; Individual; Interstitial Lung Diseases; Intervention; Investigation; Knowledge; Length; Lung; Lung Transplantation; Lung diseases; Measures; Methods; Molecular; Morbidity - disease rate; Natural History; Outcome; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phenotype; Physiological; Prognosis; Progressive Disease; Public Health; Quality of life; Radiology Specialty; Research; Resolution; Rheumatoid Arthritis; Role; Sensitivity and Specificity; Structure of parenchyma of lung; Symptoms; Testing; Time; Tissues; Transplantation; Usual Interstitial Pneumonia; Work; alveolar epithelium; antifibrotic treatment; chest computed tomography; comparison control; deep learning; detection sensitivity; differential expression; disease diagnosis; disease heterogeneity; disease phenotype; experience; fibrotic interstitial lung disease; genetic risk factor; high risk; idiopathic pulmonary fibrosis; ineffective therapies; mortality; novel; novel therapeutics; participant enrollment; peripheral blood; precision medicine; prevent; prospective; proteomic signature; public health relevance; pulmonary function; quantitative imaging; radiologist; recruit; risk stratification; standard of care; targeted treatment; telomere; transcriptome; transcriptomics; treatment response

Research Objective: The objective of our proposed research is to identify patients with rheumatoid arthritis associated interstitial lung disease (RA-ILD) that are at the highest risk for progressive disease and may potentially benefit from more targeted, and potentially less harmful, treatment. Unmet Health Need: Deaths from RA-ILD are not improving despite an overall decline in RA mortality. Novel, noninvasive methods are urgently needed to identify those with progressive RA-ILD so that interventions can delay the development of end-stage lung disease. Rationale: RA-ILD is a heterogeneous condition and the majority will experience disease progression resulting in lung transplantation and/or death. Despite the heterogeneity of RA-ILD, all RA-ILD is treated the same without taking in to account the known heterogeneity of this disease. This immunosuppressive-based treatment approach has led to unpredictable natural histories, inconsistent responses to treatment, and ultimately irreversible fibrosis leading to increased symptom burden, worse quality of life, and ultimately death. Hypothesis: Our overall hypothesis is that novel quantitative imaging and specific blood markers will be associated with a progressive phenotype in RA-ILD. Aims: We will evaluate the role of novel quantitative imaging (Specific Aim 1), peripheral blood telomere length (Specific Aim 2) and peripheral blood mononuclear cell (PBMC) gene expression (Specific Aim 3) in predicting progressive RA-ILD as defined by 12-month change in FVC% predicted. We will also explore the overlap and additive strength of each of these predictors in a composite profile (Specific Aim 4). Approach: To achieve the proposed aims, we will recruit 364 subjects with RA-ILD at the time of ILD diagnosis by an ILD pulmonologist and prior to treatment with lung-specific immunosuppression. Recruitment will occur at 4 expert ILD centers across the country with longitudinal collection of clinical, physiologic, and radiologic data with collection of serial biospecimens. The overall goal of this proposal is to identify the subset of RA-ILD patients that are at highest risk for disease progression following diagnosis by using novel imaging and specific blood markers. This risk stratification will help us determine whether or not immunosuppression should be started on an RA-ILD patient at the time of diagnosis. This knowledge will ultimately lead to less harm to patients with RA-ILD by decreasing exposure to immunosuppression in the subset that is most vulnerable. This proposal will lead to future precision-medicine based investigations for RA-ILD treatment and will lay the foundation to perform clinical trials that will determine the role of additional treatment pathways (e.g., observation, antifibrotic therapy, novel therapeutics and/or combination therapy) in RA-ILD, leading to reduction in harm and delaying the development of end- stage lung disease.

研究目的：我们拟议的研究的目的是确定类风湿关节炎患者 相关的间质性肺疾病（RA-ELD）患有进行性疾病的风险最高，可能 有可能受益于更有针对性的危害治疗方法。未满足的健康需求：死亡 尽管RA死亡率总体下降，但RA-ULD并没有改善。新颖的无创方法是 迫切需要识别患有渐进式RA-ild的人，以便干预措施可以延迟 末期肺部疾病。理由：RA-sild是一种异质状况，大多数人会经历 疾病进展导致肺移植和/或死亡。尽管RA-ild的异质性，但 Ra-ild被对待相同，而无需考虑该疾病的已知异质性。这 基于免疫抑制的治疗方法导致了不可预测的自然历史，不一致 对治疗的反应，以及最终不可逆的纤维化，导致症状增加，质量较差 生命，最终死亡。假设：我们的总体假设是新颖的定量成像和特定的 血液标记将与RA-ELD中的进行性表型有关。目的：我们将评估 新颖的定量成像（特定目标1），外周血端粒长度（特定目标2）和外周 血液单核细胞（PBMC）基因表达（特定目的3）在预测定义的渐进性RA--ild中 FVC％预测的FVC％变化为12个月。我们还将探索每一个的重叠和加性强度 这些预测因子在复合曲线中（特定目标4）。方法：为了实现拟议的目标，我们将 ILD肺科医生和治疗前，在ILD诊断时招募364名受试者患有RA-ELD的受试者 与肺特异性免疫抑制。招聘将在全国4个专业ILD中心发生 纵向收集临床，生理和放射学数据，并收集了系列生物测量。这 该提案的总体目标是确定疾病风险最高的RA-ILD患者的子集 通过使用新型成像和特定的血液标记诊断后的进展。这种风险分层将 帮助我们确定是否应在RA-ELD患者开始进行免疫抑制 诊断。这些知识最终将通过减少接触暴露对RA-ELD的患者造成更少的伤害 最脆弱的子集中的免疫抑制。该提议将导致未来的精密中心 基于RA-ILD治疗的基础研究，并将为进行临床试验奠定基础 确定其他治疗途径的作用（例如，观察，抗纤维化疗法，新型治疗方法 和/或组合疗法）在RA-ild中，导致危害减少并延迟最终发展 肺部疾病。