选择性COX-2抑制剂对中轴脊柱关节炎的疗效及血清DKK-1水平的影响

发布时间：2018-03-16 14:41

本文选题：中轴脊柱关节炎　切入点：DKK-1　出处：《郑州大学》2015年硕士论文　论文类型：学位论文

【摘要】：背景脊柱关节炎(spondyloarthritis,SpA)是一组具有相似临床表现、病理生理学特征和遗传学特征的慢性炎性风湿性疾病,主要以骶髂关节和脊柱受累为特征,部分病人还可以出现外周关节(如髋、膝、肩、踝关节)和心、肺、肾和神经系统等受累表现。我国SpA发病率发约为0.2%-0.54%,男性患者多发于女性患者,多见于具有一定遗传素质的10-30岁青少年,在一定的环境因素影响下,人体免疫和炎症系统出现紊乱导致发病。Sp A根据临床表现分为中轴型和外周型。中轴脊柱关节炎(ax-SpA)主要累及骶髂关节和脊柱,包括强直性脊柱炎(ankylosing spondylitis,AS)、非放射学中轴脊柱关节炎(nr-axSpA)等。SpA是一种异质性疾病,疾病活动情况个体差异很大,随着病情逐渐进展,部分患者会出现关节侵蚀及骨赘形成,最终导致患者残疾、丧失劳动能力,严重者影响到患者的生活质量。所以SpA的治疗目标除了改善临床症状,还需找到一种可以延缓关节破坏及新骨形成的治疗方法。SpA的骨化机制可能与附着点和滑膜的炎症、骨破坏以及骨形成三者之间平衡的紊乱有关。Wnt蛋白在骨重塑过程中至关重要,Dickopff相关蛋白1(DKK-1)是Wnt信号通路的天然抑制因子。研究表明AS的骨化与Wnt通路有关,且AS患者中DKK-1表达失衡。近年有研究表明Wnt/?-连环蛋白(Wnt/?-catenin)途径与前列腺素(prostaglandin,PG)通路存在关联,即前列腺素E2(prostaglandin E2,PGE2)可下调Wnt信号通路的负性调控因子DKK-1和硬骨素水平进而上调Wnt途径,启动成骨过程。提示前列腺素抑制剂(如NSAIDs)也许可以阻断新骨形成。有研究报道选择性COX-2抑制剂塞来昔布(西乐葆)可以延缓AS脊柱影像学进展,但具体机制尚不明了。艾瑞昔布是与塞来昔布作用机制相似的药物,该类药物是否会影响血清DKK-1的水平进而影响ax-SpA骨化机制,最终延缓骨赘的形成而达到改善病情的作用呢?观察选择性cox-2抑制剂对ax-spa的骨化机制及血清dkk-1水平的影响,为ax-spa的治疗提供新的理论依据,具有重要意义。目的1.观察选择性cox-2抑制剂艾瑞昔布和塞来昔布治疗ax-spa患者在4周、12周的临床指标、炎症指标、影像学指标的变化和不良反应;2.检测使用选择性cox-2抑制剂治疗前后ax-spa患者血清dkk-1表达水平的差异;3.分析ax-spa患者血清dkk-1水平与临床指标、炎症指标、影像学评分之间的相关性。方法1.研究纳入于郑州大学第一附属医院风湿免疫科门诊就诊的ax-spa患者60例,诊断符合2009年asas推荐的ax-spa分类标准,符合相关入组排除标准;入组患者随机给予选择性cox-2抑制剂艾瑞昔布或塞来昔布200mg每天两次治疗,分别于基线、4周、12周观察记录患者各项临床指标(basdai评分、basfi评分、患者总体评估、耳壁距、腰椎活动度、schober试验、前指地距、踝间距)、炎症指标(esr、crp)的变化和不良反应;sparcc法对基线期、12周ax-spa骶髂关节核磁共振进行评分。2.采用酶联免疫吸附法检测ax-spa患者基线期、12周血清dkk-1的表达水平。结果1.本研究共入组60例ax-spa患者,最终完成12周随访者51例,纳入临床疗效及安全性分析,分别为艾瑞昔布组25例,塞来昔布组26例。4周时与基线期相比,艾瑞昔布组与塞来昔布组患者在临床指标(basdai评分、basfi评分、患者总体评估、耳壁距、腰椎活动度、schober试验、前指地距、踝间距)和炎症指标esr方面均较基线期改善,两组差异无统计学意义(p0.05);4周时crp在塞来昔布组较基线下降,艾瑞昔布组较基线期升高,两组差异无统计学意义(P0.05)。12周时艾瑞昔布组、塞来昔布组患者在临床指标、炎症指标方面较基线期均有改善,两组差异无统计学意义(P0.05)。随访12周两组患者不良反应发生率差异无统计学意义(P0.05)。2.艾瑞昔布组与塞来昔布组患者12周SPARCC评分较基线期下降,差异无统计学意义(P0.05);两组患者12周与基线期血清DKK-1水平比较,差异无统计学意义(P0.05)。3.基线期艾瑞昔布组患者血清DKK-1水平与临床指标、炎症指标、影像学评分无相关性,塞来昔布组血清DKK-1水平与临床指标中BASFI评分、Schober试验呈相关性,分别为BASFI(r=-0.048,P=0.027)、Schober试验(r=0.437,P=0.048),与其余指标不相关。结论 1.选择性COX-2抑制剂能明显减轻ax-SpA患者症状、改善功能,艾瑞昔布与塞来昔布疗效相当;2.选择性COX-2抑制剂艾瑞昔布和塞来昔布对血清DKK-1水平无影响。
[Abstract]:Background spondylarthritis (spondyloarthritis, SpA) is a group with similar clinical manifestations, characteristics and genetic characteristics of pathophysiology of chronic inflammatory rheumatic disease, mainly in the sacroiliac joint and spinal involvement as the characteristic, some patients can appear peripheral joints (such as hip, knee, shoulder, ankle and heart) lung, kidney, and nervous system involvement in our country. The incidence of SpA hair is about 0.2%-0.54%, male patients with multiple female patients, more common in certain genetic quality of 10-30 year olds, in certain environmental factors, the human immune system disorders and inflammation contributes to the pathogenesis of.Sp A according to clinical features central type and peripheral type. The axial spondyloarthritis (ax-SpA) mainly involving the sacroiliac joints and the spine, including ankylosing spondylitis (ankylosing spondylitis, AS), non radiographic axial spondyloarthritis (nr-axSpA).SpA is a kind of heterogeneity Disease, disease activity of individual differences, as the disease progresses, some patients will be joint erosion and osteophyte formation, resulting in disability, loss of ability to work, seriously affect the quality of life of patients. So the treatment of SpA in improving clinical symptoms, but also need to find a possible mechanism of.SpA inflammatory ossification can delay the joint destruction and the formation of new bone treatment methods and attachment points and synovium, bone destruction and bone formation in the balance between the three disorders.Wnt protein is crucial in the process of bone remodeling, Dickopff related protein 1 (DKK-1) is a natural inhibitor of the Wnt signaling pathway. The research showed that AS ossification associated with Wnt AS in the DKK-1 pathway, and the expression imbalance. Recent studies show that Wnt/? - Catenin (Wnt/? -catenin) pathway and prostaglandin (prostaglandin, PG) associated pathways, namely prostaglandin E2 (prostaglandin E2 PGE2) can regulate Wnt signaling pathway negative regulatory factor DKK-1 and sclerostin levels and the up regulation of the Wnt pathway, start the osteogenesis process. It is suggested that prostaglandin inhibitors (such as NSAIDs) may block the formation of new bone. Studies have reported that selective COX-2 Inhibitor Celecoxib (Celebrex) can delay AS spinal images study progress, but the specific mechanism is still unknown. Imrecoxib is similar to the drug celecoxib mechanism, whether the drugs will influence the level of serum DKK-1 and ax-SpA ossification, formation of osteophyte and ultimately slow to improve the effect of the illness? To observe the effects of selective COX-2 inhibitor on ax-spa ossification the mechanism and the level of serum DKK-1, provide a new theoretical basis for the treatment of ax-spa, which is of great significance. Objective: 1. to observe the selective COX-2 Inhibitor Celecoxib and celecoxib in the treatment of ax-spa patients In 4 weeks, 12 weeks of clinical indicators, inflammatory markers, changes in imaging indexes and adverse reactions; 2. detection before and after using selective COX-2 inhibitors for the treatment of ax-spa patients with serum DKK-1 expression; 3. ax-spa analysis of serum DKK-1 level and clinical index, inflammation index, imaging score correlation between 60 ax-spa. Methods 1. patients enrolled in the First Affiliated Hospital of Zhengzhou University Department of rheumatology outpatient clinic were diagnosed according to the ax-spa classification standard recommended by ASAS in 2009, in accordance with the relevant group exclusion criteria; group were treated with selective COX-2 Inhibitor Celecoxib or celecoxib 200mg two times a day for 4 weeks, respectively at baseline. 12 weeks were observed the clinical indicators (BASDAI score, BASFI score, overall patient assessment, ear wall distance, lumbar activity, Schober test, anaphora from the ankle, spacing), inflammatory markers (ESR, C RP) changes and adverse reactions; the method of sparcc baseline, 12 week ax-spa sacroiliac joint MRI score of.2. were detected by enzyme-linked immunosorbent assay in patients with ax-spa at baseline, the expression level of serum DKK-1 in 12 weeks. 1. results of this study included 60 ax-spa patients completed 12 weeks of follow-up, the final 51 were included in the analysis of clinical efficacy and safety, respectively Imrecoxib group 25 cases, celecoxib group and 26 cases of.4 weeks when compared with baseline Imrecoxib group and celecoxib group of patients in the clinical index (BASDAI score, BASFI score, overall patient assessment, ear wall distance, lumbar the activity of Schober test, spinal distance, ankle spacing) and inflammatory indexes of ESR were improved compared to the baseline period, no significant difference between two groups (P0.05); CRP 4 in the celecoxib group decreased compared with baseline, Imrecoxib group compared with the baseline period increased, no significant differences between the two groups (P0.05).12 weeks Celecoxib group, celecoxib group of patients in the clinical indicators of inflammation index from baseline were improved, with no significant difference between two groups (P0.05). After 12 weeks of follow-up of two groups of patients with adverse reaction rate had no significant difference (P0.05).2. Imrecoxib group and celecoxib group were 12 week SPARCC score from baseline decreased, the difference was not statistically significant (P0.05); comparison of serum DKK-1 levels in 12 weeks and two groups of patients at baseline, there was no statistically significant difference (P0.05).3. baseline Ai Rui celecoxib group serum DKK-1 level and clinical index, inflammation index, imaging scores no correlation between celecoxib and BASFI cloth serum DKK-1 level and clinical index score, Schober test positive, respectively BASFI (r=-0.048, P=0.027), Schober test (r=0.437, P=0.048), not associated with other indexes. Conclusion 1. selective COX-2 inhibitors can significantly reduce the patients with ax-SpA disease Alisoxib has the same effect as celecoxib, and 2. selective COX-2 inhibitor alisoxib and celecoxib have no effect on serum DKK-1 level.

【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R593.2

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