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

标题：利用肠道微生物群加速类风湿关节炎治疗的有效启动 摘要 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 人口(仅在美国就有大约200万成年人)。它的特点是慢性滑膜炎，如果不治疗， 可能导致不可逆转的关节破坏和畸形，导致发病率和各种原因的死亡率增加。 在过去的三十年里，人们在了解疾病的发病机制和治疗方法方面取得了令人印象深刻的进展 治疗效果。事实上，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”导致类风湿性关节炎临床结果的显著改善，提高了生活质量 适用于数百万炎症性关节炎患者。然而，尽管取得了这一进展，一个重大问题仍然存在。 仍然没有答案：为什么50%以上的中到重度关节炎RA患者没有反应 对这些特工合适吗？药物微生物学--研究其影响的新兴研究领域 人类肠道微生物群对药物的变异-承诺克服这些障碍并促进 精准医学在自身免疫性疾病中的应用。 甲氨蝶呤(MTX)是一种二氢叶酸(DHF)还原酶抑制剂，仍是治疗糖尿病的主要药物。 RA和在世界各地被广泛使用。虽然相当有效，但口服MTX在更少的时间内取得显著效果 超过50%的患者，只有四分之一的患者得到缓解。众所周知，个体间的 甲氨蝶呤的生物利用度极不稳定，从10%到80%不等。造成这种情况的原因大概是 多因素。然而，肠道微生物组及其酶机制可能会发挥重要作用， 根据我们的初步结果，考虑到使用抗生素治疗的动物或在无菌条件下饲养的动物 与对照动物相比，条件下的甲氨蝶呤代谢有显著差异。 我们的多学科团队由风湿学家、生物信息学家、药理学家和 微生物组研究人员将致力于我们的首要目标来研究：a)如果肠道微生物组基线，其 基因和相关代谢产物可用于预测甲氨蝶呤的免疫调节反应。 治疗-幼稚的新发RA(NORA)患者；以及b)如果MTX无反应者的肠道微生物群可以 调节甲氨蝶呤的代谢和生物利用度。我们相信，我们高度重视的结果 翻译性、创新性研究将直接影响RA的治疗方法，并提供 一种更个性化的方法，在这种方法中，临床疗效反应将被及早(并可能)预测 通过微生物组靶向辅助治疗得到改善)任何即将启动MTX、限制或 预防疾病进展并最终避免浪费的医疗支出(估计为 约50,000美元/年/患者的直接成本)。重要的是，我们预计我们的研究将建立可推广的 风湿学和自身免疫的方法，可以更广泛地应用于研究和临床 最大化其他类似的小分子(例如JAK抑制剂)或甚至生物制剂(例如抗肿瘤坏死因子单抗)。

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).