MacIsaac Kenzie D, Baumgartner Richard, Kang Jia, Loboda Andrey, Peterfy Charles, DiCarlo Julie, Riek Jonathan, Beals Chan
Merck & Co. Inc., Department of Genetics and Pharmacogenomics, Boston, Massachusetts, United States of America.
Merck & Co. Inc., Department of Biometrics Research, Whitehouse Station, New Jersey, United States of America.
PLoS One. 2014 Dec 12;9(12):e113937. doi: 10.1371/journal.pone.0113937. eCollection 2014.
Approximately 30% of rheumatoid arthritis patients achieve inadequate response to anti-TNF biologics. Attempts to identify molecular biomarkers predicting response have met with mixed success. This may be attributable, in part, to the variable and subjective disease assessment endpoints with large placebo effects typically used to classify patient response. Sixty-one patients with active RA despite methotrexate treatment, and with MRI-documented synovitis, were randomized to receive infliximab or placebo. Blood was collected at baseline and genome-wide transcription in whole blood was measured using microarrays. The primary endpoint in this study was determined by measuring the transfer rate constant (Ktrans) of a gadolinium-based contrast agent from plasma to synovium using MRI. Secondary endpoints included repeated clinical assessments with DAS28(CRP), and assessments of osteitis and synovitis by the RAMRIS method. Infliximab showed greater decrease from baseline in DCE-MRI Ktrans of wrist and MCP at all visits compared with placebo (P<0.001). Statistical analysis was performed to identify genes associated with treatment-specific 14-week change in Ktrans. The 256 genes identified were used to derive a gene signature score by averaging their log expression within each patient. The resulting score correlated with improvement of Ktrans in infliximab-treated patients and with deterioration of Ktrans in placebo-treated subjects. Poor responders showed high expression of activated B-cell genes whereas good responders exhibited a gene expression pattern consistent with mobilization of neutrophils and monocytes and high levels of reticulated platelets. This gene signature was significantly associated with clinical response in two previously published whole blood gene expression studies using anti-TNF therapies. These data provide support for the hypothesis that anti-TNF inadequate responders comprise a distinct molecular subtype of RA characterized by differences in pre-treatment blood mRNA expression. They also highlight the importance of placebo controls and robust, objective endpoints in biomarker discovery.
ClinicalTrials.gov NCT01313520.
约30%的类风湿关节炎患者对抗肿瘤坏死因子（TNF）生物制剂反应不足。识别预测反应的分子生物标志物的尝试取得了喜忧参半的成果。这可能部分归因于通常用于分类患者反应的具有大安慰剂效应的可变且主观的疾病评估终点。61例尽管接受了甲氨蝶呤治疗但仍患有活动性类风湿关节炎且有MRI记录的滑膜炎的患者被随机分配接受英夫利昔单抗或安慰剂。在基线时采集血液，并使用微阵列测量全血中的全基因组转录。本研究的主要终点是通过MRI测量钆基造影剂从血浆到滑膜的转运速率常数（Ktrans）来确定的。次要终点包括使用DAS28（CRP）进行重复临床评估，以及通过RAMRIS方法评估骨炎和滑膜炎。与安慰剂相比，英夫利昔单抗在所有访视时手腕和掌指关节的动态对比增强MRI Ktrans较基线有更大程度的降低（P<0.001）。进行统计分析以识别与治疗特异性的14周Ktrans变化相关的基因。所识别的256个基因用于通过计算每个患者体内它们的对数表达的平均值来得出基因特征评分。所得评分与英夫利昔单抗治疗患者中Ktrans的改善以及安慰剂治疗受试者中Ktrans的恶化相关。反应不佳者显示活化B细胞基因的高表达，而反应良好者表现出与中性粒细胞和单核细胞动员以及高水平网状血小板一致的基因表达模式。在两项先前发表的使用抗TNF疗法的全血基因表达研究中，这种基因特征与临床反应显著相关。这些数据为以下假设提供了支持，即抗TNF反应不足者构成类风湿关节炎的一种独特分子亚型，其特征在于治疗前血液mRNA表达的差异。它们还强调了安慰剂对照以及在生物标志物发现中稳健、客观终点的重要性。
ClinicalTrials.gov NCT01313520。
