Synovial tissue and serum biomarkers of disease activity, therapeutic response and radiographic progression: analysis of a proof-of-concept randomised clinical trial of cytokine blockade
Synovial tissue and serum biomarkers of disease activity, therapeutic response and radiographic progression: analysis of a proof-of-concept randomised clinical trial of cytokine blockade
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DOI：
10.1136/ard.2009.108324
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发表时间：
2010-04-01
影响因子：
27.4
通讯作者：
Bresnihan, Barry
中科院分区：
文献类型：
--
作者：
Rooney, Terence;Roux-Lombard, Pascale;Bresnihan, Barry
目的评价类风湿关节炎(RA)生物治疗过程中滑膜组织和血清生物标志物对疾病活动性、疗效和放射学进展的影响。方法活动期类风湿关节炎(RA)患者随机入组，每天服用阿纳金100 mg，单用或联合应用聚乙二醇单用，每周2次。关节镜下滑膜组织活检分别在基线和后续两个时间点进行。免疫组织化学染色后，选择RA病理生理介质，用数字图像分析进行定量。结果22例患者随机分为两组，其中11例接受单一治疗，11例接受联合治疗。美国风湿病学会联合治疗有效率分别为%、%和46%，单一治疗有效率分别为36%、9%和0%。在滑膜组织中，T细胞的浸润性、血管密度和转化生长因子β的表达作为疾病活动性和治疗反应的生物标志物具有重要的实用价值。在血清中，白介素6(IL-6)、基质金属蛋白酶(MMP1)、MMP3和TIMP-1在这方面的作用最大。早期血清TIMP-1水平的下降预示着后期的治疗结果。治疗前血清IL-6、IL-8、MMP-1、TIMP-1、可溶性肿瘤坏死因子受体I、II和IL-18水平与病情进展呈正相关。结论滑膜组织分析确定了疾病活动、疗效和放射学进展的生物标志物。生物标记物在组织中的表达与血清中测量的水平无关。
Objectives To evaluate synovial tissue and serum biomarkers of disease activity, therapeutic response and radiographic progression during biological therapy for rheumatoid arthritis (RA).Methods Patients with active RA entered a randomised study of anakinra 100 mg/day, administered as monotherapy or in combination with pegsunercept 800 mu g/kg twice a week. Arthroscopic synovial tissue biopsies were obtained at baseline and two further time points. Following immunohistochemical staining, selected mediators of RA pathophysiology were quantified using digital image analysis. Selected mediators were also measured in the serum.Results Twenty-two patients were randomly assigned: 11 received monotherapy and 11 combination therapy. American College of Rheumatology 20, 50 and 70 response rates were 64%, 64% and 46% with combination therapy and 36%, 9% and 0% with monotherapy, respectively. In synovial tissue, T-cell infiltration, vascularity and transforming growth factor beta (TGF beta) expression demonstrated significant utility as biomarkers of disease activity and therapeutic response. In serum, interleukin 6 (IL-6), matrix metalloproteinase (MMP) 1, MMP-3 and tissue inhibitor of metalloproteinase 1 (TIMP-1) were most useful in this regard. An early decrease in serum levels of TIMP-1 was predictive of the later therapeutic outcome. Pretreatment tissue levels of T-cell infiltration and the growth factors vascular endothelial growth factor/TGF beta, and serum levels of IL-6, IL-8, MMP-1, TIMP-1, soluble tumour necrosis factor receptor types I and II and IL-18 correlated with radiographic progression.Conclusions Synovial tissue analysis identified biomarkers of disease activity, therapeutic response and radiographic progression. Biomarker expression in tissue was independent of the levels measured in the serum.