选择性COX-2抑制剂对强直性脊柱炎的疗效及血清VEGF、BMP-2的影响

发布时间：2018-06-10 18:29

本文选题：强直性脊柱炎 + 选择性　；参考：《郑州大学》2016年硕士论文

【摘要】：背景:强直性脊柱炎(Ankylosing Spondylitis,AS)是一种常见的慢性、炎症性、进展性的风湿性疾病,属于脊柱关节炎的典型类型。以脊柱和骶髂关节受累最为常见,部分患者也可出现外周关节炎及关节外的表现,如髋、膝、肩关节、心、肺、肾等;AS特征性的表现是慢性炎症、新骨形成、脊柱关节强直,如竹节样变,髋关节的强直等,严重影响患者的正常活动,引起生活质量下降。非甾体类抗炎药(non-steroidal anti-inflammatory drugs,NSAIDs)是治疗AS的一线用药,其不仅具有抗炎止痛、改善功能的作用,同时有研究发现持续应用塞来昔布可以延缓脊柱影像学进展。艾瑞昔布是中国原研的少有的药物之一,目前缺乏其在AS方面的相关研究,那么它是否可以同塞来昔布一样具有同样的疗效呢?AS骨赘形成是最主要的致残原因,寻求影响AS骨赘形成的因素具有重要的临床意义。骨形态发生蛋白(bone morphogenetic protein,BMP)是参与骨形成的最重要的活性物质,诱导骨形成、促进成骨细胞分化,并能够诱导血管、间充质细胞以及纤维细胞等转化为不可逆的骨系细胞。AS骨化的发生主要是软骨内成骨,而血管内皮生长因子对于血管的生成以及软骨内骨化均具有重要的作用,同时也可能参与了AS新骨形成。AS的炎症过程与环氧化酶病理性的表达密切相关,非甾体类抗炎药作为AS的一线用药,主要通过抑制环氧化酶的活性,减少前列腺素的合成,而发挥抗炎和改善病情的作用。已有研究发现环氧化酶可通过影响VEGF、BMP的表达参与血管内皮的损伤、肿瘤的发生发展以及骨转移等;COX-2选择性抑制剂塞来昔布可以缓解AS患者脊柱影像学的进展,但其具体作用机制尚不是十分清楚。血清VEGF和BMP-2的水平是否与骶髂关节影像学进展相关?并且选择性COX-2抑制剂是否对VEGF和BMP-2的表达有影响呢?因此,我们进行了此次研究。目的:1.评价COX-2选择性抑制剂对于AS患者的疗效,并比较艾瑞昔布和塞来昔布间疗效差异。2.评价COX-2选择性抑制剂对AS患者影像学评分的影响。3.观察COX-2选择性抑制剂对AS患者血清VEGF、BMP-2水平的影响,以及血清VEGF、BMP-2与影像学的关系。方法:选取2014年10月至2015年10月于郑州大学第一附属医院风湿免疫科门诊就诊的AS患者120例,要求其均符合一定的纳入排除标准。将入组患者随机分组,分别给予COX-2选择性抑制剂艾瑞昔布或塞来昔布200mg,每天两次口服。治疗前记录患者的基本特征(年龄、性别、病程、入组前治疗情况),分别记录治疗前、治疗后4周、治疗后12周时患者的实验室指标(血尿常规、肝肾功能、ESR、CRP)、病情活动度(BASDAI评分)以及功能评价指标(BASFI评分、患者总体评估、耳壁距、腰椎侧弯度、踝间距、Schober试验、前指地距)的情况,以及治疗前和治疗后12周的骶髂关节SPARCC评分,并通过酶联免疫吸附试验(ELISA)的方法检测治疗前、治疗后12周时血清VEGF、BMP-2的水平。结果:1.本研究共纳入120例AS患者,完成12周随访116例,其中包括艾瑞昔布组57例,塞来昔布组59例。两组在性别、年龄上无显著差异。治疗后4周以及12周,ESR、BASDAI评分、患者总体评估、踝间距、Schober和前指地距的变化情况差异均具有统计学意义(P0.05),而CRP在治疗后4周其变化情况无统计学意义(P0.05),在治疗后12周变化情况差异有统计学意义(P0.05)。艾瑞昔布与塞来昔布组进行比较,CRP在治疗后4周时变化情况差异具有统计学意义(P0.05),其余各项指标在两个时间点的变化情况差异均无统计学意义(P0.05)。重复测量方差分析,结果显示ESR、CRP、BASDAI、患者总体评估、踝间距、前指地距在时间主效应上差异具有统计学意义(P0.05),可以认为两组以上指标在各个时间点上的总体均数不全相同,其中ESR、BASDAI、患者总体评估、前指地距均数随治疗时间增长而下降,踝间距则呈增长趋势;而CRP结果显示时间主效应与处理主效应对其均值变化的差异均具有统计学意义(P0.05)。2.经选择性COX-2抑制剂治疗后12周,骶髂关节SPARCC评分均较前下降,差异具有统计学意义(11.99±12.76 vs 7.11±9.7,P=0.000);艾瑞昔布与塞来昔布组进行比较,SPARCC评分变化情况差异无统计学意义(-4.01±8.88 vs-5.71±10.6,P0.05)。Spearman相关性分析结果显示SPARCC评分与Schobber试验、腰椎活动度、ESR呈正相关(Schober试验:r=0.283,P=0.006;腰椎侧弯度左侧:r=0.315,P=0.002,右侧:r=0.357,P=0.000;ESR:r=0.236,P=0.022),与年龄、病程、耳壁距呈负相关(年龄r=-0.388,P=0.000;病程r=-0.335,P=0.001;耳壁距r=-0.245,P=0.018),与CRP、BASDAI、BASFI、患者总体评估等无明显相关性(P0.05)。3.经选择性COX-2抑制剂治疗后12周,血清VEGF水平较治疗前降低,差异具有统计学意义(VEGF:243.82±19.09 vs 191.29±12.09pg/ml,P=0.002);血清BMP-2水平较治疗前降低,但差异无统计学意义(BMP-2:2.29±1.09 vs 2.23±1.19 pg/ml,P=0.421)。Spearman相关性分析结果显示血清VEGF与BMP-2呈正相关(P0.05),血清VEGF水平与PLT、ESR、CRP、BASFI、耳壁距、前指地距呈正相关(P0.05),与HGB、腰椎侧弯度、Schober试验、踝间距呈负相关;血清BMP-2水平与ESR呈正相关(P0.05),与腰椎侧弯度呈负相关(P0.05)。结论:1选择性COX-2抑制剂对AS具有较好的疗效并且可以减少骶髂关节的炎症;并且艾瑞昔布与塞来昔布疗效相当。2血清VEGF可以作为评价AS病情活动的指标,但非影像学进展的标志物,选择性COX-2抑制剂可以降低血清VEGF的水平。而BMP-2对AS的影响需要进一步研究。
[Abstract]:Background: Ankylosing Spondylitis (AS) is a common chronic, inflammatory, progressive rheumatic disease, which belongs to the typical type of spinal arthritis. It is the most common type of spinal and sacroiliac joint involvement. Some patients can also appear peripheral arthritis and out of joint manifestations, such as hip, knee, shoulder joint, heart, lung, and kidney, and so on; AS The manifestations are chronic inflammation, new bone formation and ankylosis of the spine, such as slub like change and the ankylosis of the hip joint, which seriously affect the normal activities of the patients and cause a decline in the quality of life. Non steroidal anti-inflammatory drugs (non-steroidal anti-inflammatory drugs, NSAIDs) are the first-line drugs for the treatment of AS, which not only have anti-inflammatory analgesic pain and improve function. At the same time, it has been found that continuous use of celecoxib can delay the progression of spinal imaging. Alimioxib is one of the most rare drugs in China and is lacking in AS related studies. Is it as effective as celecoxib? AS osteophyte formation is the main cause of disability and search for shadow The factors affecting the formation of AS osteophyte have important clinical significance. Bone morphogenetic protein (BMP) is the most important active substance involved in bone formation, induces bone formation, promotes osteoblast differentiation, and can induce blood vessels, mesenchymal cells and fibrous cells to convert to irreversible ossification of irreversible bone cell cells. The pathogenesis is mainly endochondral osteogenesis, and vascular endothelial growth factor plays an important role in angiogenesis and endochondral ossification, and it may also be involved in the inflammatory process of the AS new bone formation of.AS and the pathological expression of cyclooxygenase. Non steroidal anti-inflammatory drugs are used as the front-line use of AS, mainly by inhibiting the epoxidation of cyclooxygenase. Enzyme activity, which reduces the synthesis of prostaglandins, plays the role of anti-inflammatory and improving the disease. It has been found that cyclooxygenase can be involved in vascular endothelial damage, tumor development and bone metastasis by influencing the expression of VEGF, BMP expression, and COX-2 Selective Inhibitor Celecoxib can relieve the progress of spinal imaging in AS patients, but it can be used to reduce the progress of spinal imaging. The specific mechanism is not yet very clear. Is the level of serum VEGF and BMP-2 related to the imaging progress of the sacroiliac joint? And is selective COX-2 inhibitors affect the expression of VEGF and BMP-2? Therefore, we conducted this study. Objective: 1. to evaluate the efficacy of COX-2 selective inhibitors in AS patients and to compare Ai Ruixi. Effect difference between cloth and celecoxib.2. evaluation of the effect of COX-2 selective inhibitors on the imaging score of AS patients.3. observation of the effect of COX-2 selective inhibitors on serum VEGF, BMP-2 level in AS patients and the relationship between serum VEGF, BMP-2 and imaging. Methods: from October 2014 to October 2015 at the First Affiliated Hospital of Zhengzhou University rheumatism 120 patients with AS in the Department of immunology were asked to conform to a certain inclusion criteria. The patients were divided into groups randomly and were given COX-2 selective inhibitors alisoxib or celecoxib 200mg each day for oral administration. The basic characteristics of the patients were recorded before treatment (age, sex, course of disease, before group treatment), and the treatment was recorded respectively. 4 weeks after treatment, 4 weeks after treatment, the patient's laboratory indexes (hematuria routine, liver and kidney function, ESR, CRP), disease activity (BASDAI score) and functional evaluation index (BASFI score, overall assessment of the patient, ear wall distance, lumbar lateral curvature, ankle distance, Schober test, anterior finger distance), and sacroiliac before and after treatment 12 weeks after treatment, and 12 weeks after treatment and after treatment, and the sacroiliac clearance before and after treatment. SPARCC scores and serum VEGF and BMP-2 levels at 12 weeks after treatment were detected by enzyme linked immunosorbent assay (ELISA). Results: 1. this study included 120 cases of AS patients and 116 cases were followed up for 12 weeks, including 57 of the elioxib group and 59 cases in the celecoxib group. The two groups had no significant difference in sex and age for 4 weeks after the treatment. And 12 weeks, ESR, BASDAI score, the overall assessment of patients, the gap between the ankle, Schober and the distance of the anterior finger were statistically significant (P0.05), but there was no significant difference in the change of CRP at the 4 week after the treatment (P0.05). The difference between the 12 weeks after the treatment was statistically significant (P0.05). The variation of CRP at 4 weeks after treatment was statistically significant (P0.05), and the changes of the other indexes at two time points were not statistically significant (P0.05). Repeated measurements of variance analysis showed that the overall assessment of ESR, CRP, and BASDAI, the difference between the ankle distance and the anterior finger distance was statistically significant (P 0.05), it can be considered that the total average number of all the two sets of indicators at all time points is not the same, in which ESR, BASDAI, the overall assessment of the patients, the average number of the anterior finger distance decreases with the growth of the treatment time, and the distance between the ankle is increasing, and the CRP result shows that the difference between the time main effect and the principal effect on the mean change of the mean time is statistically significant. The SPARCC score of sacroiliac joint was decreased at 12 weeks after the treatment of selective COX-2 inhibitor, and the difference was statistically significant (11.99 + 12.76 vs 7.11 + 9.7, P=0.000). Compared with the celecoxib group, the difference of the SPARCC score was not statistically significant (-4.01 + 8.88 vs-5.71 + 10.6, P0.05).Spearman correlation The results showed that the SPARCC score was positively correlated with the Schobber test, the lumbar activity and the ESR (Schober test: r=0.283, P=0.006; the left side of the lumbar spine: r=0.315, P=0.002, and the right: r=0.357, P=0.000; ESR:r=0.236, P=0.022). 018), there was no significant correlation with CRP, BASDAI, BASFI, and the overall assessment of patients (P0.05). The serum VEGF level was lower than before the treatment (VEGF:243.82 + 19.09 vs 191.29 + 12.09pg/ml, P=0.002) after 12 weeks after the treatment of selective COX-2 inhibitors (VEGF:243.82 + 19.09 vs 191.29 + 12.09pg/ml, P=0.002), but there was no significant difference in the level of serum BMP-2. .29 + 1.09 vs 2.23 + 1.19 pg/ml, P=0.421).Spearman correlation analysis showed that serum VEGF and BMP-2 had positive correlation (P0.05). The level of serum VEGF was positively correlated with PLT, ESR, CRP, ear wall distance, and the distance between the anterior finger, and the lateral curvature of the lumbar vertebrae. The side curvature of the vertebral side is negatively correlated (P0.05). Conclusion: 1 selective COX-2 inhibitors have a good effect on AS and can reduce the inflammation of the sacroiliac joint; and the effect of alisoxib and celecoxib is equivalent to.2 serum VEGF as a marker for evaluating the activity of the AS disease, but the selective COX-2 inhibitor can be reduced. The level of serum VEGF, while the effect of BMP-2 on AS needs further study.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R593.23

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