A Gene Expression Based Blood Test for Rheumatic Disease Diagnosis

描述(由申请人提供)：临床困境：风湿病生物疗法的最新进展为更深入的疾病管理提供了一种手段。正确的诊断是选择适当的生物治疗方法的必要方面。虽然基于临床结果和实验室测试的疾病诊断对相当数量的患者有效，但对于早期疾病、症状轻微或表现不清楚的患者，这种诊断可能会出现问题，导致延迟或不适当的治疗，导致患者预后不良和/或暴露于不必要的药物毒性。这一问题部分是由于目前风湿病诊断实验室检测的特异性和敏感性的局限性。其中许多测试旨在包括或排除一种疾病，如果结果为阴性，这可能不足以获得诊断。我们的初步数据表明，可以开发一种单一的血液检测方法，它能够利用外周血的基因表达谱来敏感和特异地诊断许多常见的风湿性疾病。我们也有数据表明，这种多疾病测试在临床完全分化之前的早期疾病患者中是有效的，并可能有助于指导早期治疗，从而显着改善结果。 方法：为了评估基于基因表达的诊断测试的可能性，从一组明确形式的炎症性疾病患者中收集临床样本，并进行广泛的基因表达谱分析。多变量算法确定了38个区分对照和四种炎症性疾病的基因，并进行了高度特异性和敏感性的测试。随后，我们从第二个更大的患者队列中收集了足够大的RNA，以支持一项研究，以区分一组难以区分的风湿性疾病，即类风湿性关节炎、骨关节炎、系统性红斑狼疮和强直性脊柱炎。基因表达谱的生物统计分析将使我们能够将这些发现转化为两项高通量临床测试，第一项基于基因表达结果，第二项基于血清蛋白质生物标记物。最后，我们将通过检查患有未分化关节炎的疾病周期早期患者的结果来评估基因表达谱的预后能力，以确定谁可能发展为侵蚀性疾病，谁可能进入缓解状态。这些发现将使医生能够在早期未分化关节炎中使用更积极的治疗形式，以推迟侵蚀性疾病的发病，并为可能缓解的患者使用更便宜、副作用更少的药物。公共卫生相关性：这项研究将为一些更常见的风湿性疾病确定新的血液标记物(生物标记物)。这些生物标志物将被医生用来准确诊断这些疾病，并帮助区分更有可能发展为严重疾病的患者和那些可能进入缓解状态的患者。更早的诊断和治疗与患者更好的结果有关。

DESCRIPTION (provided by applicant): Clinical dilemma: Recent advances in biologic therapies for rheumatic diseases provide a means for more profound disease management. Proper diagnosis is a necessary aspect of choosing the proper biologic therapy. While disease diagnosis, based on clinical findings and laboratory tests, is effective in a significant number of patients, it can be problematic in patients with early disease, mild symptoms, or unclear presentation, leading to delayed or inappropriate treatment with poor patient outcomes and/or exposures to unnecessary drug toxicities. This problem is due in part to limitations of specificity and sensitivity of current rheumatology diagnostic laboratory tests. Many of these tests are designed to include or rule out one disease, which may be inadequate to obtain a diagnosis if the results are negative. Our preliminary data suggest that a single blood test can be developed which is capable of sensitive and specific disease diagnosis of many common rheumatic diseases using gene expression profiling of peripheral blood. We also have data suggesting that this multi-disease test is effective in patients with early disease prior to full clinical differentiation and may aid in guiding earlier treatment which can dramatically improve outcomes. Approach: To assess the potential of gene expression-based diagnostic testing, clinical samples were collected from a cohort of patients with definitive forms of inflammatory disease, and broad-based gene expression profiling was performed. Multivariate algorithms identified 38 genes that distinguished controls and the four inflammatory diseases tested with high specificity and sensitivity. We have subsequently collected RNA from a second larger patient cohort with sufficient size to power a study to distinguish among a set of rheumatic diseases that can be difficult to distinguish, namely rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, and ankylosing spondylitis. Biostatistical analyses of gene expression profiles will allow us to translate these findings into two high throughput clinical tests, the first based on gene expression results and the second based on serum protein biomarkers. Finally, we will assess the prognostic power of gene expression profiling by examining results from patients early in their disease cycle with undifferentiated arthritis to determine who is likely to develop erosive disease and who is likely to go into remission. These findings will allow physicians to use more proactive forms of therapy in early undifferentiated arthritis to delay onset of erosive disease and to use less expensive drugs with fewer side effects for patients that are likely to remit. PUBLIC HEALTH RELEVANCE: This study will identify novel blood markers (biomarkers) for some of the more common forms of rheumatic diseases. These biomarkers will be used by physicians to accurately diagnose these diseases and to help distinguish patients who are more likely to develop severe forms of disease from those likely to go into remission. Earlier diagnosis and treatment are linked to better outcome in patients.