在银屑病关节炎的早期概念验证试验中，软骨和骨代谢的可溶性生物标志物：阿达木单抗与安慰剂的疗效比较。
Soluble biomarkers of cartilage and bone metabolism in early proof of concept trials in psoriatic arthritis: effects of adalimumab versus placebo.
机构信息
Division of Clinical Immunology and Rheumatology, F4-218, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
出版信息
PLoS One. 2010 Sep 3;5(9):e12556. doi: 10.1371/journal.pone.0012556.
BACKGROUND
There is growing interest in soluble biomarkers that could be used on the group level for screening purposes in small proof of principle studies during early drug development. We investigated early changes in serum levels of several candidate biomarkers involved in cartilage and bone metabolism following the initiation of adalimumab as a prototypic active treatment in psoriatic arthritis (PsA) compared to placebo.
MATERIALS AND METHODS
Twenty-four PsA patients were randomized to receive either adalimumab 40 mg s.c. every other week or placebo for 4 weeks, followed by an open label extension phase. Serum samples were obtained at baseline and after 4 and 12 weeks of treatment and analyzed for levels of CPII and PINP (synthesis of type II and type I procollagen), melanoma inhibitory activity (MIA) (chondrocyte anabolism), matrix metalloproteinase (MMP)-3, C2C and cartilage oligomeric matrix protein (COMP) (type II collagen degradation), osteocalcin (OC) (bone formation), NTX-I and ICTP (both type I collagen degradation).
RESULTS
After 4 weeks, there was a significant decrease in serum MMP-3 levels in adalimumab-treated patients (P<0.005), while no change was observed in the placebo group. A significant increase in serum MIA was noted after adalimumab therapy (P<0.005) but not after placebo treatment. After 12 weeks, there was a marked reduction in serum MMP-3 in both groups (P<0.005), whereas other markers did not show significant changes compared to baseline.
CONCLUSION
MMP-3 and MIA could serve as soluble biomarkers associated with inflammation as well as joint remodelling and destruction and may, together with clinical evaluation and in combination with other biomarkers, assist in distinguishing between effective and ineffective therapy in small, proof-of-principle studies of short duration in PsA.
TRIAL REGISTRATION
Current Controlled Trials ISRCTN23328456.
背景
人们对可用于群体水平的可溶性生物标志物越来越感兴趣，这些标志物可用于在早期药物开发的小原理验证研究中进行筛查。我们研究了在银屑病关节炎（PsA）中，与安慰剂相比，起始阿达木单抗治疗后，几种参与软骨和骨代谢的候选生物标志物的血清水平的早期变化。
材料和方法
24 例 PsA 患者被随机分配接受阿达木单抗 40mg sc，每两周一次或安慰剂治疗 4 周，随后进入开放标签扩展阶段。在基线时以及治疗 4 周和 12 周后采集血清样本，并分析 CPII 和 PINP（II 型和 I 型前胶原合成）、黑色素瘤抑制活性（MIA）（软骨细胞合成代谢）、基质金属蛋白酶（MMP）-3、C2C 和软骨寡聚基质蛋白（COMP）（II 型胶原降解）、骨钙素（OC）（骨形成）、NTX-I 和 ICTP（均为 I 型胶原降解）的水平。
结果
4 周后，阿达木单抗治疗组患者血清 MMP-3 水平显著下降（P<0.005），而安慰剂组无变化。阿达木单抗治疗后血清 MIA 显著增加（P<0.005），但安慰剂治疗后无变化。12 周后，两组血清 MMP-3 均明显下降（P<0.005），而其他标志物与基线相比无显著变化。
结论
MMP-3 和 MIA 可作为与炎症以及关节重塑和破坏相关的可溶性生物标志物，可能与临床评估一起，并与其他生物标志物相结合，有助于在短时间、小原理验证研究中区分有效和无效治疗。
试验注册
当前对照试验 ISRCTN23328456。
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