Defining the molecular and radiologic phenotype of progressive RA-ILD

研究目的：我们建议的研究的目的是识别类风湿关节炎患者。 相关间质性肺病(RA-ILD)是进展性疾病风险最高的疾病，可能 可能受益于更有针对性、可能危害更小的治疗。未满足的健康需求：死亡 尽管RA死亡率总体下降，但RA-ILD的发病率并没有改善。新的非侵入性方法是 迫切需要确定那些患有进展性RA-ILD的人，以便干预措施可以延缓 终末期肺部疾病。理论基础：RA-ILD是一种异质性疾病，大多数人将经历 疾病进展导致肺移植和/或死亡。尽管RA-ILD具有异质性，但所有 RA-ILD的治疗相同，没有考虑到这种疾病的已知异质性。这 以免疫抑制为基础的治疗方法导致了不可预测的自然病史，不一致 治疗反应，最终导致不可逆转的纤维化，导致症状负担增加，质量下降 生命，最终是死亡。假设：我们的总体假设是新的定量成像和特异性 血液标记物将与RA-ILD的进行性表型相关。目标：我们将评估 新型定量成像(特异靶1)、外周血端粒长度(特异靶2)和外周血细胞 血单个核细胞(PBMC)基因表达(特异靶3)在预测进展性RA-ILD中的作用 按12个月FVC%变化预测。我们还将探讨每个组件的重叠和附加强度 综合概况中的这些预测因素(具体目标4)。方针：为达致建议的目标，我们会 在ILD肺科医生诊断ILD时和治疗前招募364名RA-ILD患者 肺部特异性免疫抑制。招聘将在全国4个ILD专家中心进行， 通过收集系列生物显微镜纵向收集临床、生理和放射学数据。这个 这项提案的总体目标是确定RA-ILD患者中患病风险最高的子集 通过使用新的成像和特异性血液标记物进行诊断后的进展。这种风险分层将 帮助我们确定是否应该在RA-ILD患者接受治疗时开始免疫抑制 诊断。这一知识最终将通过减少接触以下物质而减少对RA-ILD患者的伤害 最脆弱的子集的免疫抑制。这项提议将导致未来的精准医学 以RA-ILD治疗为基础的研究，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、抗肝纤维化治疗、新疗法 和/或联合治疗)，可减少危害并延缓终末期肾病的发展。 肺部疾病的阶段。

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.