Gut Microbiome Signatures Forecast Clinical Response to Methotrexate in Treatment-Naive Early Rheumatoid Arthritis Patients

Oral methotrexate (MTX) is the first-line treatment for newly diagnosed rheumatoid arthritis (RA) patients. However, up to 50% of patients do not respond adequately to MTX and need other therapeutic interventions. Failure to respond to MTX during the first three months, which is known as the critical window of opportunity for effective RA treatment, can significantly impact disease progression. Therefore, accurately predicting MTX response is crucial for managing RA disease progression. Recent studies have revealed an association between the gut microbiome and the response to MTX in treatment-naive RA patients. However, most of these studies primarily used 16S rRNA gene amplicon sequencing data, which primarily provides taxonomic resolution at the genus level. One study utilized whole-genome shotgun (WGS) sequencing data, but it did not employ WGS-based taxonomic profiles to identify its association with the MTX response. Additionally, this study applied an arbitrary criterion to determine MTX response instead of using the standardized EULAR response criteria, which limits the clinical translation of its findings. Our study aims to address these limitations and more thoroughly investigate whether the gut microbiome can reliably predict MTX response in treatment-naive RA patients.

口服甲氨蝶呤（methotrexate, MTX）是初诊类风湿关节炎（rheumatoid arthritis, RA）患者的一线治疗方案。然而，高达50%的患者对甲氨蝶呤应答不充分，需采取其他治疗手段。在治疗最初三个月内对甲氨蝶呤无应答的情况（该时期被称为类风湿关节炎有效治疗的关键机遇窗），会显著影响疾病进展。因此，精准预测甲氨蝶呤应答对于管控类风湿关节炎疾病进展至关重要。近期研究已在初治类风湿关节炎患者中发现肠道菌群与甲氨蝶呤应答之间存在关联。然而，此类研究大多仅采用16S rRNA基因扩增子测序数据，这类数据仅能提供属水平的分类学分辨率。另有一项研究采用了全基因组鸟枪（whole-genome shotgun, WGS）测序数据，但未使用基于WGS的分类学特征来探究其与甲氨蝶呤应答的关联。此外，该研究采用了任意设定的判定标准来评估甲氨蝶呤应答，而非使用标准化的欧洲抗风湿病联盟（EULAR）应答标准，这限制了其研究结果的临床转化。本研究旨在克服上述局限，更全面地探究肠道菌群能否在初治类风湿关节炎患者中可靠预测甲氨蝶呤应答。