Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Ann Rheum Dis. 2011 Jun;70(6):1153-9. doi: 10.1136/ard.2010.147199. Epub 2011 Mar 27.
Despite the fact that rituximab depletes B cells in all treated patients with RA, not all patients show a favourable clinical response. The goal of this study was to provide insight into pharmacological changes in peripheral blood that are associated with clinical response to rituximab.
Gene expression profiling was performed on peripheral blood RNA of 13 patients with RA (test group) using Illumina HumanHT beadchip microarrays. An independent group of nine patients was used for validation using TaqMan quantitative PCR. Clinical responder status was determined after 6 months using change in 28-joint Disease Activity Score (ΔDAS28) and European League Against Rheumatism (EULAR) response criteria. Significance analysis of microarrays and ontology analysis were used for data analysis and interpretation.
Pharmacogenomic analyses demonstrated marked interindividual differences in the pharmacological responses at 3 and 6 months after start of treatment with rituximab. Interestingly, only differences in the regulation of type I interferon (IFN)-response genes after 3 months correlated with the ΔDAS28 response. Good responders (DAS>1.2; n=7) exhibited a selective increase in the expression of type I IFN-response genes, whereas this activity was unchanged or hardly changed in non-responders (DAS<1.2; n=6) (p=0.0040 at a cut-off of 1.1-fold induction). Similar results were obtained using EULAR response criteria. These results were validated in an independent cohort of nine patients (five non-responders and four responders, p=0.0317).
A good clinical response to rituximab in RA is associated with a selective drug-induced increase in type I IFN-response activity in patients with RA. This finding may provide insight in the biological mechanism underlying the therapeutic response to rituximab.
尽管利妥昔单抗会使所有接受 RA 治疗的患者的 B 细胞耗竭，但并非所有患者都表现出有利的临床反应。本研究的目的是深入了解与利妥昔单抗临床反应相关的外周血药理学变化。
使用 Illumina HumanHT beadchip 微阵列对 13 例 RA 患者（实验组）的外周血 RNA 进行基因表达谱分析。使用 TaqMan 定量 PCR 对 9 例独立患者进行验证。6 个月后，根据 28 关节疾病活动评分（ΔDAS28）和欧洲抗风湿病联盟（EULAR）反应标准的变化来确定临床反应者的状态。使用微阵列的显著性分析和本体论分析进行数据分析和解释。
药物基因组学分析表明，利妥昔单抗治疗 3 个月和 6 个月后，药物反应存在明显的个体间差异。有趣的是，仅在治疗 3 个月后 I 型干扰素（IFN）反应基因的调节差异与 ΔDAS28 反应相关。良好反应者（DAS>1.2；n=7）表现出 I 型 IFN 反应基因表达的选择性增加，而无反应者（DAS<1.2；n=6）则无变化或几乎不变（p=0.0040，在 1.1 倍诱导的截止值）。使用 EULAR 反应标准也得到了类似的结果。这些结果在 9 例患者的独立队列中得到了验证（5 例无反应者和 4 例反应者，p=0.0317）。
RA 患者对利妥昔单抗的良好临床反应与患者中 I 型 IFN 反应活性的选择性药物诱导增加相关。这一发现可能为利妥昔单抗治疗反应的生物学机制提供了新的见解。
