Employing the gut microbiome to accelerate effective initiation of rheumatoid arthritis therapy

利用肠道微生物组加速类风湿关节炎治疗的有效启动

• 批准号: 10240299
• 负责人: Jose U. Scher
• 金额: $ 64.79万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240299
• 关键词: Address; Adherence; Adjuvant Therapy; Adult; Affect; Animals; Antibiotics; Arthritis; Autoimmune Diseases; Autoimmunity; Bioinformatics; Biological; Biological Assay; Biological Availability; Biological Markers; Biological Products; Biological Response Modifier Therapy; Biometry; Cells; Chronic; Clinical; Complex; Control Animal; Coupled; Data; Deformity; Diagnosis; Dihydrofolate Reductase Inhibitor; Direct Costs; Disease; Disease Progression; Disease remission; Drug Kinetics; Engraftment; Excess Mortality; Exposure to; Foundations; Genes; Genetic Polymorphism; Genotype; Germ-Free; Goals; Health Expenditures; Human; Human Microbiome; Immunophenotyping; Individual; Individual Differences; Inflammation; Inflammatory Arthritis; Intervention; Intervention Studies; Knowledge; Lead; Left; Link; Literature; Machine Learning; Measures; Metabolism; Metagenomics; Methotrexate; Modeling; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mus; Musculoskeletal; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Oral; Outcome; Pathogenesis; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Play; Population; Positioning Attribute; Prediction of Response to Therapy; Prospective Studies; Protocols documentation; Publishing; Quality of life; Reproducibility; Research; Research Personnel; Research Project Grants; Rheumatoid Arthritis; Rheumatology; Role; Series; Structure; Symptoms; Synovitis; TNF gene; Techniques; Therapeutic; Transplantation; Validation; Variant; absorption; arthritis therapy; bacterial community; base; biomarker identification; chronic autoimmune disease; clinical efficacy; clinical practice; cohort; cost; cost effective; disability; drug disposition; drug metabolism; effective therapy; experience; experimental study; field study; follow-up; germ free condition; gut bacteria; gut microbiome; gut microbiota; immunoregulation; improved; inhibitor/antagonist; innovation; insight; inter-individual variation; joint destruction; joint injury; metabolomics; microbial; microbiome; microbiome components; mortality; multidisciplinary; multiple omics; novel; personalized approach; personalized medicine; polyglutamates; pre-clinical; precision medicine; prevent; rRNA Genes; recruit; response; response biomarker; rheumatologist; sample collection; small molecule; therapy outcome

Title: Employing the gut microbiome to accelerate effective initiation of rheumatoid arthritis therapy ABSTRACT Rheumatoid arthritis (RA) is a complex, multifactorial, autoimmune disorder that affects ~1% of the worldwide population (~2 million adults in the US alone). It is characterized by chronic synovitis that, when left untreated, can result in irreversible joint destruction and deformity, leading to increased morbidity and all-cause mortality. The last three decades have witnessed impressive advances in the understanding of disease pathogenesis and therapeutic outcomes. In fact, the use of methotrexate first, and the subsequent incorporation of anti-TNF (TNFi) and other “biologics” have led to substantial improvements in RA clinical outcomes, enhancing the quality of life for millions of patients with inflammatory arthritis. Despite this progress, however, a significant question still remains unanswered: why do over 50% of RA patients with moderate to severe arthritis fail to respond appropriately to these agents? Pharmacomicrobiomics – an emerging field of study that investigates the effect of variations within the human gut microbiome on drugs – promises to overcome these barriers and facilitate precision medicine approaches in autoimmune disease. Methotrexate (MTX), a dihydrofolate (DHF) reductase inhibitor, remains the anchor drug for the treatment of RA and is used widely throughout the world. While quite effective, oral MTX achieves significant results in less than 50% of patients and remission in only a quarter of them. It is well established that the inter-individual bioavailability of MTX is extremely variable, ranging from 10 to 80%. The reasons for this are presumably multifactorial. However, the intestinal microbiome and its enzymatic machinery are likely to play a significant role, based on our Preliminary Results and given that animals treated with antibiotics or kept under germ-free conditions show significant differences in MTX metabolism relative to control animals. Our multidisciplinary team composed of rheumatologists, bioinformaticians, pharmacologists and microbiome researchers will address our overarching goal to study: a) if baseline intestinal microbiome, its genes, and associated metabolites can be used to predict the immunomodulatory responses to MTX in treatment-naïve, new-onset RA (NORA) patients; and b) if the gut microbiomes of MTX non-responders can be manipulated to modulate MTX metabolism and bioavailability. We believe that the results of our highly translational, innovative studies will directly influence therapeutic approaches for the treatment of RA and offer a more personalized approach in which the clinical efficacy response would be predicted early (and potentially improved by microbiome-targeted adjuvant therapies) in any given patient about to initiate MTX, limiting or preventing disease progression and ultimately avoiding wasteful health expenditures (estimated as ~$50,000/year/patient in direct costs). Importantly, we anticipate that our studies will establish generalizable approaches in rheumatology and autoimmunity that could be more broadly applied to the study and clinical maximization of other similar small molecules (e.g., JAK inhibitors) or even biologic agents (e.g., anti-TNF mAbs).

标题：利用肠道微生物组加速类风湿关节炎治疗的有效启动 抽象的 类风湿性关节炎 (RA) 是一种复杂的、多因素的自身免疫性疾病，影响全球约 1% 的人 人口（仅美国就有约 200 万成年人）。其特点是慢性滑膜炎，如果不及时治疗， 可能导致不可逆转的关节破坏和畸形，导致发病率和全因死亡率增加。 过去三十年，人们对疾病发病机制和疾病的认识取得了令人瞩目的进展。 治疗结果。事实上，首先使用甲氨蝶呤，然后加入抗肿瘤坏死因子 (TNFi) 和其他“生物制剂”已显着改善 RA 临床结果，提高生活质量 为数百万炎症性关节炎患者提供帮助。然而，尽管取得了这些进展，仍然存在一个重大问题 仍然没有答案：为什么超过 50% 的患有中重度关节炎的 RA 患者没有反应 适合这些代理吗？药物微生物组学——一个研究其影响的新兴研究领域 人类肠道微生物组内的变化对药物的影响——有望克服这些障碍并促进 自身免疫性疾病的精准医学方法。 甲氨蝶呤 (MTX) 是一种二氢叶酸 (DHF) 还原酶抑制剂，仍然是治疗以下疾病的主力药物： RA 在世界各地广泛使用。口服 MTX 虽然非常有效，但只需更少的时间即可取得显着效果 超过 50% 的患者，其中只有四分之一得到缓解。众所周知，个体之间 MTX 的生物利用度变化很大，从 10% 到 80% 不等。造成这种情况的原因大概是 多因素的。然而，肠道微生物组及其酶机制可能发挥重要作用， 基于我们的初步结果，并考虑到动物经过抗生素治疗或无菌保存 与对照动物相比，条件显示 MTX 代谢存在显着差异。 我们的多学科团队由风湿病学家、生物信息学家、药理学家和 微生物组研究人员将解决我们的总体研究目标：a) 如果基线肠道微生物组，其 基因和相关代谢物可用于预测 MTX 的免疫调节反应 未接受过治疗的新发 RA (NORA) 患者； b) MTX 无反应者的肠道微生物组是否可以 操纵调节 MTX 代谢和生物利用度。我们相信，我们高度重视的结果 转化、创新研究将直接影响 RA 的治疗方法并提供 一种更加个性化的方法，可以尽早预测临床疗效反应（并且可能 在任何即将开始 MTX 的特定患者中，通过微生物组靶向辅助疗法改善），限制或 预防疾病进展并最终避免浪费的医疗支出（估计为 直接成本约为 50,000 美元/年/患者）。重要的是，我们预计我们的研究将建立可推广的 风湿病学和自身免疫学的方法可以更广泛地应用于研究和临床 其他类似小分子（例如 JAK 抑制剂）甚至生物制剂（例如抗 TNF 单克隆抗体）的最大化。