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

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 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， 人口（仅美国就有约200万成年人）。其特征在于慢性滑膜炎，如果不治疗， 可导致不可逆的关节破坏和畸形，导致发病率和全因死亡率增加。 在过去的三十年里，人们对疾病发病机制的理解取得了令人印象深刻的进展， 治疗结果。事实上，先使用甲氨蝶呤，再随后掺入抗肿瘤坏死因子（TNFi） 和其他“生物制剂”已经导致RA临床结果的实质性改善，提高了生活质量， 为数百万患有炎症性关节炎的患者提供治疗。然而，尽管取得了这些进展，一个重要的问题仍然存在。 仍然没有答案：为什么超过50%的中度至重度关节炎的RA患者没有反应 对这些探员来说合适吗药物微生物学-一个新兴的研究领域，调查的影响， 人类肠道微生物组的变化对药物的影响-有望克服这些障碍， 自身免疫性疾病的精准医疗方法。 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锚药： RA在全世界被广泛使用。虽然非常有效，口服MTX在更少的时间内取得了显着的效果。 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 MTX的生物利用度变化很大，范围为10 - 80%。其原因大概是 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， 根据我们的初步结果，并考虑到动物用抗生素治疗或保持在无菌条件下， 条件显示MTX代谢相对于对照动物的显著差异。 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首要目标，研究：a）如果基线肠道微生物组，其 基因和相关代谢产物可用于预测MTX的免疫调节反应， 初治、新发RA（诺拉）患者;和B）如果MTX无应答者的肠道微生物组可以 以调节MTX代谢和生物利用度。我们相信，我们的高度 翻译，创新的研究将直接影响治疗RA的治疗方法，并提供 一种更加个性化的方法，可以早期预测临床疗效反应（并可能 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卫生支出（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 在风湿病学和自身免疫的方法，可以更广泛地应用于研究和临床 其它类似小分子的最大化（例如，JAK抑制剂）或甚至生物制剂（例如，抗TNF mAb）。

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).