血清基质金属蛋白酶水平降低可预测膝骨关节炎患者定量 MRI 评估的骨关节炎药物的疾病修饰作用。

Decrease in serum level of matrix metalloproteinases is predictive of the disease-modifying effect of osteoarthritis drugs assessed by quantitative MRI in patients with knee osteoarthritis.

机构信息

Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Notre-Dame Hospital, Montreal, Quebec H2L 4M1, Canada.

出版信息

Ann Rheum Dis. 2010 Dec;69(12):2095-101. doi: 10.1136/ard.2009.122002. Epub 2010 Jun 22.

DOI:10.1136/ard.2009.122002

PMID:20570834

Abstract

OBJECTIVES

To explore the impact of disease-modifying osteoarthritis drug (DMOAD) treatment on biomarker levels and their correlation with cartilage volume loss and disease symptoms in a 2-year phase III clinical trial in patients with knee OA.

METHODS

161 patients with knee OA (according-to-protocol population) were selected from a 2-year DMOAD trial studying the effect of licofelone (200 mg twice daily) versus naproxen (500 mg twice daily). Clinical evaluation of patients was carried out using the Western Ontario and McMaster Universities (WOMAC) questionnaire. Biomarker measurements of matrix metalloproteinase (MMP)-1, MMP-3, interleukin (IL)-6, C reactive protein (CRP), cartilage oligomeric matrix protein (COMP) and type I collagen C-terminal telopeptide (CTX-I) in serum, type II collagen C-terminal telopeptide (CTX-II) in urine, and knee MRI were performed at baseline and 2 years.

RESULTS

Over time an increase occurred in all biomarker levels with the exception of IL-6, CRP and CTX-II which decreased. The increase in MMP-1 and MMP-3 was significantly less (p = 0.05; p < 0.01, respectively) in the licofelone group. The baseline MMP-1 level was significantly but inversely predictive of cartilage volume loss for the medial compartment in both univariate (p = 0.04) and multivariate (p ≤ 0.04) regression analyses, and COMP, a predictor for the lateral compartment, in both univariate and multivariate models (p < 0.01). Baseline levels of IL-6 and CRP also showed a significant relationship with volume loss for the medial compartment (univariate analysis, p = 0.04 and p = 0.01, respectively; multivariate analysis, p = 0.03, p = 0.01). A significant association (univariate) was observed between the change in the levels of MMP-1 (p = 0.03) and MMP-3 (p = 0.02) and cartilage volume loss (lateral compartment) over 2 years. Baseline levels of CTX-I correlated (p = 0.02) with an increase in the size of the bone marrow lesion in the medial compartment. The baseline CRP levels correlated with worsening of symptoms: WOMAC total index (p < 0.01), pain (p < 0.01) and function (p < 0.01).

CONCLUSION

Higher baseline values of IL-6, CRP and COMP are predictive of greater risk of cartilage loss in OA. However, over time a reduction in MMP-1 and MMP-3 levels correlated best with reduction in cartilage volume loss and the effect of drug treatment. Baseline CRP was found to be a good predictor of the symptomatic response to treatment.

摘要

目的

探讨在膝关节骨关节炎患者为期 2 年的 III 期临床试验中，疾病修饰性骨关节炎药物（DMOAD）治疗对生物标志物水平的影响及其与软骨体积损失和疾病症状的相关性。

方法

从一项为期 2 年的 DMOAD 试验中选择了 161 名膝关节骨关节炎患者（按方案人群），该试验研究了 licofelone（200mg 每日 2 次）与 naproxen（500mg 每日 2 次）的疗效。使用 Western Ontario 和 McMaster 大学（WOMAC）问卷对患者进行临床评估。在基线和 2 年时进行血清基质金属蛋白酶（MMP）-1、MMP-3、白细胞介素（IL）-6、C 反应蛋白（CRP）、软骨寡聚基质蛋白（COMP）和 I 型胶原 C 末端肽（CTX-I）、尿液 II 型胶原 C 末端肽（CTX-II）和膝关节 MRI 的生物标志物测量。

结果

随着时间的推移，除了 IL-6、CRP 和 CTX-II 降低外，所有生物标志物水平均升高。在 licofelone 组，MMP-1 和 MMP-3 的增加明显减少（p=0.05;p<0.01）。基线 MMP-1 水平在单变量（p=0.04）和多变量（p≤0.04）回归分析中均与内侧室软骨体积损失呈显著负相关，在单变量和多变量模型中均与 COMP（预测外侧室）呈显著相关（p<0.01）。基线 IL-6 和 CRP 水平也与内侧室的体积损失呈显著相关（单变量分析，p=0.04 和 p=0.01；多变量分析，p=0.03，p=0.01）。MMP-1（p=0.03）和 MMP-3（p=0.02）水平的变化与 2 年内软骨体积损失（外侧室）之间存在显著相关性（单变量）。CTX-I 的基线水平与内侧室骨髓病变的增大相关（p=0.02）。基线 CRP 水平与症状恶化相关：WOMAC 总指数（p<0.01）、疼痛（p<0.01）和功能（p<0.01）。