Pretreatment synovial transcriptional pro le is associated with early and late clinical response in rheumatoid arthritis patients treated with rituximab
Pretreatment synovial transcriptional pro le is associated with early and late clinical response in rheumatoid arthritis patients treated with rituximab
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DOI：
10.1136/annrheumdis-2011-201115
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发表时间：
2012-11-01
影响因子：
27.4
通讯作者：
van Laar, Jacob M.
中科院分区：
文献类型：
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作者：
Hogan, Vanessa E.;Holweg, Cecile T. J.;van Laar, Jacob M.
目的个性化医疗保健取决于代表疾病相关途径和预测药物反应的生物标志物的鉴定。作者的目的是开发一种基因表达的签名，在滑膜组织中，可以丰富的类风湿关节炎（RA）患者的临床反应rituximab.Methods的作者研究了滑膜基因的表达，使用高通量定量实时PCR在20例RA患者接受关节镜手术治疗之前和之后与利妥昔单抗。几个客观的方法被用来探索模式的数据，并找到与疾病活动的变化，由于treatment.Results的基因分析揭示了两个患者人群与不同的临床，实验室和组织学特征，重要的是，显示丰富的响应（60%的无应答者与90%的应答者）。复合基线基因评分（GS）与基线和第3个月之间的疾病活动评分（Delta DAS）变化相关（r=0.74，p=0.0002），但也与以后时间点的Delta DAS相关（第9个月，r=0.54，p=0.016;第15个月，r=0.45，p=0.06;第21个月，r=0.72，p=0.003）。值得注意的是，GS与基线红细胞沉降率显著相关（r=0.69，p=0.0008），但与其他DAS组分无关。GS基因代表T细胞、巨噬细胞、重塑和干扰素-α生物学。应答者表现出更高的巨噬细胞和T细胞基因的表达，而无应答者表现出更高的表达干扰素-α和modeling genes.Conclusions本研究揭示了一个基线滑膜GS与早期和晚期的临床反应利妥昔单抗。GS生物学表明T细胞和巨噬细胞对于B细胞耗竭疗法的应答是重要的，而重塑和干扰素-α基因的表达与不良应答相关。
Objective Personalised healthcare is contingent on the identification of biomarkers that represent disease relevant pathways and predict drug response. The authors aimed to develop a gene expression signature in synovial tissue that could enrich clinical response of rheumatoid arthritis (RA) patients to rituximab.Methods The authors studied synovial gene expression using high-throughput quantitative real-time-PCR in 20 RA patients who underwent arthroscopy before and after treatment with rituximab. Several objective approaches were used to explore patterns in the data and to find genes associated with changes in disease activity due to treatment.Results This analysis revealed two patient populations associated with distinct clinical, laboratory and histological features and, importantly, showed enrichment for response (60% non-responders vs 90% responders). A composite baseline gene score (GS) correlated with change in disease activity score (Delta DAS) between baseline and month 3 (r=0.74, p=0.0002), but also with Delta DAS at later time-points (month 9, r=0.54, p=0.016; month 15, r=0.45, p=0.06; month 21, r=0.72, p=0.003). Notably, the GS significantly correlated with baseline erythrocyte sedimentation rate (r=0.69, p=0.0008), but not with other DAS components. The GS genes represented T cell, macrophage, remodelling and interferon-a biology. Responders demonstrated higher expression of macrophage and T cell genes, while non-responders showed higher expression of interferon-alpha and remodelling genes.Conclusions This study reveals a baseline synovial GS that correlates with early and late clinical responses to rituximab. The GS biology suggests that T cells and macrophages are important for response to B cell depleting therapy, while expression of remodelling and interferon-alpha genes correlates with poor response.