發(fā)布時(shí)間：2018-03-16 14:41

  本文選題：中軸脊柱關(guān)節(jié)炎　切入點(diǎn)：DKK-1　出處：《鄭州大學(xué)》2015年碩士論文　論文類型：學(xué)位論文

【摘要】：背景脊柱關(guān)節(jié)炎(spondyloarthritis,SpA)是一組具有相似臨床表現(xiàn)、病理生理學(xué)特征和遺傳學(xué)特征的慢性炎性風(fēng)濕性疾病,主要以骶髂關(guān)節(jié)和脊柱受累為特征,部分病人還可以出現(xiàn)外周關(guān)節(jié)(如髖、膝、肩、踝關(guān)節(jié))和心、肺、腎和神經(jīng)系統(tǒng)等受累表現(xiàn)。我國(guó)SpA發(fā)病率發(fā)約為0.2%-0.54%,男性患者多發(fā)于女性患者,多見(jiàn)于具有一定遺傳素質(zhì)的10-30歲青少年,在一定的環(huán)境因素影響下,人體免疫和炎癥系統(tǒng)出現(xiàn)紊亂導(dǎo)致發(fā)病。Sp A根據(jù)臨床表現(xiàn)分為中軸型和外周型。中軸脊柱關(guān)節(jié)炎(ax-SpA)主要累及骶髂關(guān)節(jié)和脊柱,包括強(qiáng)直性脊柱炎(ankylosing spondylitis,AS)、非放射學(xué)中軸脊柱關(guān)節(jié)炎(nr-axSpA)等。SpA是一種異質(zhì)性疾病,疾病活動(dòng)情況個(gè)體差異很大,隨著病情逐漸進(jìn)展,部分患者會(huì)出現(xiàn)關(guān)節(jié)侵蝕及骨贅形成,最終導(dǎo)致患者殘疾、喪失勞動(dòng)能力,嚴(yán)重者影響到患者的生活質(zhì)量。所以SpA的治療目標(biāo)除了改善臨床癥狀,還需找到一種可以延緩關(guān)節(jié)破壞及新骨形成的治療方法。SpA的骨化機(jī)制可能與附著點(diǎn)和滑膜的炎癥、骨破壞以及骨形成三者之間平衡的紊亂有關(guān)。Wnt蛋白在骨重塑過(guò)程中至關(guān)重要,Dickopff相關(guān)蛋白1(DKK-1)是Wnt信號(hào)通路的天然抑制因子。研究表明AS的骨化與Wnt通路有關(guān),且AS患者中DKK-1表達(dá)失衡。近年有研究表明Wnt/?-連環(huán)蛋白(Wnt/?-catenin)途徑與前列腺素(prostaglandin,PG)通路存在關(guān)聯(lián),即前列腺素E2(prostaglandin E2,PGE2)可下調(diào)Wnt信號(hào)通路的負(fù)性調(diào)控因子DKK-1和硬骨素水平進(jìn)而上調(diào)Wnt途徑,啟動(dòng)成骨過(guò)程。提示前列腺素抑制劑(如NSAIDs)也許可以阻斷新骨形成。有研究報(bào)道選擇性COX-2抑制劑塞來(lái)昔布(西樂(lè)葆)可以延緩AS脊柱影像學(xué)進(jìn)展,但具體機(jī)制尚不明了。艾瑞昔布是與塞來(lái)昔布作用機(jī)制相似的藥物,該類藥物是否會(huì)影響血清DKK-1的水平進(jìn)而影響ax-SpA骨化機(jī)制,最終延緩骨贅的形成而達(dá)到改善病情的作用呢?觀察選擇性cox-2抑制劑對(duì)ax-spa的骨化機(jī)制及血清dkk-1水平的影響,為ax-spa的治療提供新的理論依據(jù),具有重要意義。目的1.觀察選擇性cox-2抑制劑艾瑞昔布和塞來(lái)昔布治療ax-spa患者在4周、12周的臨床指標(biāo)、炎癥指標(biāo)、影像學(xué)指標(biāo)的變化和不良反應(yīng);2.檢測(cè)使用選擇性cox-2抑制劑治療前后ax-spa患者血清dkk-1表達(dá)水平的差異;3.分析ax-spa患者血清dkk-1水平與臨床指標(biāo)、炎癥指標(biāo)、影像學(xué)評(píng)分之間的相關(guān)性。方法1.研究納入于鄭州大學(xué)第一附屬醫(yī)院風(fēng)濕免疫科門診就診的ax-spa患者60例,診斷符合2009年asas推薦的ax-spa分類標(biāo)準(zhǔn),符合相關(guān)入組排除標(biāo)準(zhǔn);入組患者隨機(jī)給予選擇性cox-2抑制劑艾瑞昔布或塞來(lái)昔布200mg每天兩次治療,分別于基線、4周、12周觀察記錄患者各項(xiàng)臨床指標(biāo)(basdai評(píng)分、basfi評(píng)分、患者總體評(píng)估、耳壁距、腰椎活動(dòng)度、schober試驗(yàn)、前指地距、踝間距)、炎癥指標(biāo)(esr、crp)的變化和不良反應(yīng);sparcc法對(duì)基線期、12周ax-spa骶髂關(guān)節(jié)核磁共振進(jìn)行評(píng)分。2.采用酶聯(lián)免疫吸附法檢測(cè)ax-spa患者基線期、12周血清dkk-1的表達(dá)水平。結(jié)果1.本研究共入組60例ax-spa患者,最終完成12周隨訪者51例,納入臨床療效及安全性分析,分別為艾瑞昔布組25例,塞來(lái)昔布組26例。4周時(shí)與基線期相比,艾瑞昔布組與塞來(lái)昔布組患者在臨床指標(biāo)(basdai評(píng)分、basfi評(píng)分、患者總體評(píng)估、耳壁距、腰椎活動(dòng)度、schober試驗(yàn)、前指地距、踝間距)和炎癥指標(biāo)esr方面均較基線期改善,兩組差異無(wú)統(tǒng)計(jì)學(xué)意義(p0.05);4周時(shí)crp在塞來(lái)昔布組較基線下降,艾瑞昔布組較基線期升高,兩組差異無(wú)統(tǒng)計(jì)學(xué)意義(P0.05)。12周時(shí)艾瑞昔布組、塞來(lái)昔布組患者在臨床指標(biāo)、炎癥指標(biāo)方面較基線期均有改善,兩組差異無(wú)統(tǒng)計(jì)學(xué)意義(P0.05)。隨訪12周兩組患者不良反應(yīng)發(fā)生率差異無(wú)統(tǒng)計(jì)學(xué)意義(P0.05)。2.艾瑞昔布組與塞來(lái)昔布組患者12周SPARCC評(píng)分較基線期下降,差異無(wú)統(tǒng)計(jì)學(xué)意義(P0.05);兩組患者12周與基線期血清DKK-1水平比較,差異無(wú)統(tǒng)計(jì)學(xué)意義(P0.05)。3.基線期艾瑞昔布組患者血清DKK-1水平與臨床指標(biāo)、炎癥指標(biāo)、影像學(xué)評(píng)分無(wú)相關(guān)性,塞來(lái)昔布組血清DKK-1水平與臨床指標(biāo)中BASFI評(píng)分、Schober試驗(yàn)呈相關(guān)性,分別為BASFI(r=-0.048,P=0.027)、Schober試驗(yàn)(r=0.437,P=0.048),與其余指標(biāo)不相關(guān)。結(jié)論 1.選擇性COX-2抑制劑能明顯減輕ax-SpA患者癥狀、改善功能,艾瑞昔布與塞來(lái)昔布療效相當(dāng);2.選擇性COX-2抑制劑艾瑞昔布和塞來(lái)昔布對(duì)血清DKK-1水平無(wú)影響。
[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.

【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：R593.2

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