本文選題：類風(fēng)濕關(guān)節(jié)炎　切入點(diǎn)：核因子KB受體活化因子配體　出處：《安徽醫(yī)科大學(xué)》2015年碩士論文

【摘要】：研究背景類風(fēng)濕關(guān)節(jié)炎(rheumatoid arthritis,RA)是一種慢性持續(xù)性以關(guān)節(jié)滑膜炎癥為主要特征的自身免疫性疾病,主要累及雙手、雙足等小關(guān)節(jié)。局部骨侵蝕和全身骨質(zhì)疏松是其骨與關(guān)節(jié)損傷的主要表現(xiàn)形式,最終導(dǎo)致關(guān)節(jié)破壞、功能的喪失。RA患者骨與關(guān)節(jié)損傷的主要表現(xiàn)形式為局部的骨侵蝕和全身骨質(zhì)疏松(osteoporosis,OP),而這與成骨和破骨細(xì)胞有著密切的關(guān)系。人體的骨代謝是一個(gè)動(dòng)態(tài)的平衡過程,主要包含骨形成和骨吸收,當(dāng)平衡被破壞就會(huì)導(dǎo)致骨密度(bone mineral density,BMD)降低和骨結(jié)構(gòu)的異常,從而表現(xiàn)為骨質(zhì)破壞和OP等。近年來,對(duì)于RA骨與關(guān)節(jié)損傷的早期診斷的研究熱點(diǎn)主要側(cè)重于影像學(xué)研究,尤其是磁共振成像(magnetic resonance imaging,MRI)在RA的研究,可通過MRI上對(duì)滑膜炎、骨侵蝕、骨髓水腫等表現(xiàn)進(jìn)行早期診斷,但MRI仍然只能發(fā)現(xiàn)影像學(xué)陽性的早期RA患者。核因子KB受體活化因子配體(receptor activator of nuclear factor KB ligand,RANKL)是目前發(fā)現(xiàn)的具有誘導(dǎo)破骨細(xì)胞分化、發(fā)育、發(fā)揮功能的因子,成骨細(xì)胞和激活的T淋巴細(xì)胞均可表達(dá)RANKL。RANKL與破骨細(xì)胞前體細(xì)胞或成熟破骨細(xì)胞表面的核因子-KB受體活化因子(receptor activator of nuclear factor KB,RANK)結(jié)合后,啟動(dòng)一系列信號(hào)傳導(dǎo)通路,促進(jìn)破骨細(xì)胞分化與骨吸收活性。成骨細(xì)胞和骨髓基質(zhì)細(xì)胞分泌表達(dá)護(hù)骨素(osteoprotegerin,OPG)可與RANKL競(jìng)爭(zhēng)性結(jié)合,從而抑制破骨細(xì)胞的成熟與分化,阻止骨的破壞。RA患者的骨與關(guān)節(jié)損傷的機(jī)制與破骨和成骨過程密切相關(guān),但具體的機(jī)制仍不清楚,RANKL/RANK/OPG系統(tǒng)是近年來發(fā)現(xiàn)的在骨調(diào)節(jié)上發(fā)揮重要作用的系統(tǒng),并認(rèn)為是RA的關(guān)鍵性骨調(diào)節(jié)因子,可能與RA患者的早期骨與關(guān)節(jié)損傷有關(guān)。目的探討血清RANKL和OPG水平聯(lián)合MRI在早期RA診斷中的價(jià)值及骨與關(guān)節(jié)損傷中的價(jià)值。方法選擇符合ACR 1987年診斷標(biāo)準(zhǔn)的RA患者232例,其中早期RA(≤1年)111例,非早期(1年)RA 121例,選擇121例年齡性別匹配的正常對(duì)照組。詳細(xì)記錄RA患者各臨床及實(shí)驗(yàn)室指標(biāo),232例RA患者和121例健康對(duì)照組的股骨(股骨頸、Ward區(qū)、大轉(zhuǎn)子、總股骨區(qū))和腰椎(lumbar spine,L2、L3、L4、L2-4)部位BMD使用雙能X線骨密度儀(lunar Prodigy DF+310504,GE Healthcare,USA)測(cè)定,所有RA患者攝雙手X線并進(jìn)行Sharp評(píng)分。早期RA患者行雙手MRI檢查并進(jìn)行RAMRIS積分。采用酶聯(lián)免疫吸附試驗(yàn)(Enzyme Linked Immunosorbent Assay,ELISA)檢測(cè)其中232例RA患者和121例正常人外周血RANKL、OPG水平。結(jié)果1.對(duì)照組、早期RA組、非早期RA組血清OPG、RANKL的水平差別有統(tǒng)計(jì)學(xué)意義(P0.05),且三組間血清RANKL水平呈逐漸升高趨勢(shì),但RANKL/OPG的比值三組間比較無統(tǒng)計(jì)學(xué)差異(P0.05)。2.對(duì)照組、早期RA組、非早期RA組在股骨頸區(qū)、Ward區(qū)、大轉(zhuǎn)子區(qū)、總股骨區(qū)、L2、L 3、L 4和L2-4的BMD差異有統(tǒng)計(jì)學(xué)意義(P0.0001),且三組間BMD呈逐漸降低趨勢(shì)。對(duì)照組、早期RA組、非早期RA組骨質(zhì)疏松的發(fā)生率分別為13.92%(22/158)、23.39%(29/124)、35.69%(101/283)(χ2=42.137,P0.0001)。3.早期RA患者的MRI的表現(xiàn):111例早期RA的X線分期結(jié)果提示:Ⅰ期82例,Ⅱ期29例,其Sharp評(píng)分結(jié)果均在10分以內(nèi);而37例行雙手MRI的結(jié)果顯示:有骨侵蝕33例、骨髓水腫21例、滑膜炎31例、肌腱炎11例。MRI各指標(biāo)之間的相關(guān)分析顯示肌腱炎與骨髓水腫(r=0.391,P0.05)、滑膜炎(r=0.330,P0.05)呈正相關(guān),其余指標(biāo)間無相關(guān)關(guān)系。4.早期RA患者M(jìn)RI與血清RANKL/OPG水平、臨床指標(biāo)、BMD及Sharp評(píng)分間的相關(guān)性:早期RA(≤1年)患者M(jìn)RI各指標(biāo)與OPG、RANKL、RANKL/OPG比值間無相關(guān)關(guān)系(P0.05)。早期RA患者M(jìn)RI骨侵蝕評(píng)分與大轉(zhuǎn)子(r=-0.387,P0.05)和總股骨區(qū)(r=-0.358,P0.05)的BMD呈負(fù)相關(guān),與Sharp評(píng)分呈正相關(guān)(r=0.721,P0.05)。MRI肌腱炎評(píng)分與關(guān)節(jié)腫脹數(shù)(r=0.371,P0.05)、關(guān)節(jié)壓痛數(shù)(r=0.369,P0.05)、CRP(r=0.480,P0.05)呈正相關(guān)。MRI骨髓水腫評(píng)分、滑膜炎評(píng)分與各指標(biāo)無相關(guān)關(guān)系。血清OPG水平與關(guān)節(jié)腫脹數(shù)(r=0.193,P0.05)、壓痛數(shù)(r=0.209,P0.05)、VAS評(píng)分(r=0.264,P0.05)、HAQ(r=0.337,P0.05)、DAS28(r=0.277,P0.05)、ESR(r=0.194,P0.05)、CRP(r=0.349,P0.05)、抗CCP(r=0.212,P0.05),骨侵蝕(r=0.339,P0.05)、Sharp評(píng)分(r=0.277,P0.05)呈正相關(guān),與各部位骨密度無相關(guān)性。血清RANKL水平與各部位骨密度、臨床指標(biāo)、Sharp評(píng)分無相關(guān)性(P0.05)。5.非早期RA(1年)患者OPG、RANKL、RANKL/OPG比值與患者疾病活動(dòng)性、骨與關(guān)節(jié)損傷的相關(guān)分析:血清OPG、RANKL、RANKL/OPG比值與非早期RA患者各部位的關(guān)節(jié)腫脹數(shù)、壓痛數(shù)、VAS評(píng)分、ESR、CRP、DAS28、RF、抗CCP、HAQ、BMD、Sharp評(píng)分之間均無相關(guān)性(P0.05)。6.早期RA組與非早期RA組各診斷指標(biāo)陽性率的比較:早期RA患者M(jìn)RI上骨侵蝕、骨髓水腫、滑膜炎、肌腱炎的陽性率分別為89.19%(33/37)、56.76%(21/37)、83.78%(31/37)、29.73%(11/37)。四項(xiàng)指標(biāo)中任一表現(xiàn)陽性率為97.30%(36/37)。非早期RA組RF、抗CCP陽性率高于早期RA組,陽性率分別為[88.56%(325/367)vs 75.41%(138/183),χ2=28.348,P0.0001;86.08%(266/309)vs 72.78%(123/169),χ2=12.760,P0.0001]。RF、抗CCP陰性組與陽性組間MRI上骨侵蝕、骨髓水腫、滑膜炎、肌腱炎的陽性率無統(tǒng)計(jì)學(xué)差異(P0.05)。7.血清OPG、RANKL水平在RF陰性(≤14 IU/ml)或低滴度陽性(≤42 IU/ml)中的比較:對(duì)照組、RF陰性的早期RA組、RF陰性的非早期RA組間血清OPG、RANKL水平單因素方差分析結(jié)果顯示:對(duì)照組、早期RA組、非早期RA組血清RANKL水平差別有統(tǒng)計(jì)學(xué)意義(P0.05),且在三組間呈逐漸升高趨勢(shì),但血清OPG水平在三組間比較無統(tǒng)計(jì)學(xué)差異(P0.05)。對(duì)照組、RF低滴度陽性的早期RA組、RF低滴度陽性的非早期RA組間血清OPG、RANKL水平比較顯示:血清OPG、RANKL水平三組間比較差異均有統(tǒng)計(jì)學(xué)意義(P0.05)。8.血清OPG、RANKL水平在抗CCP陰性(≤25RU/ml)或低滴度陽性(CCP≤75RU/ml)中的比較:對(duì)照組、抗CCP陰性的早期RA組、抗CCP陰性的非早期RA組間血清OPG、RANKL水平單因素方差分析結(jié)果顯示:對(duì)照組、早期RA組、非早期RA組血清RANKL水平差異有統(tǒng)計(jì)學(xué)差異(P0.05),且血清RANKL水平呈逐漸升高趨勢(shì),但血清OPG水平三組間比較差異無統(tǒng)計(jì)學(xué)差異(P0.05)。對(duì)照組、抗CCP低滴度陽性的早期RA組、抗CCP低滴度陽性的非早期RA組間血清OPG、RANKL水平比較顯示:對(duì)照組、早期RA組、非早期RA組血清RANKL水平差異有統(tǒng)計(jì)學(xué)差異(P0.05),且RANKL水平呈逐漸升高趨勢(shì),但OPG水平三組間比較差異無統(tǒng)計(jì)學(xué)差異(P0.05)。9.早期RA組中OPG陽性率(以降低計(jì))和RANKL陽性率(以升高計(jì))及聯(lián)合MRI中各指標(biāo)的陽性率。根據(jù)非正態(tài)分布資料的分析結(jié)果,以O(shè)PG≤178.80pg/ml,以RANKL≥109.56pg/ml為異常。OPG降低或存在骨侵蝕的早期RA患者數(shù)為31,占31/33=93.94%;OPG降低或存在骨髓水腫的患者24,占72.73%,OPG降低或存在滑膜炎患者為29例,占87.88%;OPG降低或存在腱鞘炎R(shí)A患者為18例,占54.55%;OPG降低或RAMRIS(3項(xiàng))0的RA患者為33例,占100%;OPG降低或RAMRIS(4項(xiàng))0分的患者為33例,為100%。RANKL升高或存在骨侵蝕患者30例,占90.91%,RANKL升高或存在骨髓水腫RA患者24例,占72.73%,RANKL升高或存在滑膜炎患者29例,占87.88%,RANKL升高或存在腱鞘炎R(shí)A患者19例,占57.57%,RANKL升高或RAMRIS(3項(xiàng))0的RA患者32例,占96.97%,RANKL升高或RAMRIS(4項(xiàng))0分的患者32例,占96.97%。結(jié)論1.早期RA患者OPG的水平低于正常對(duì)照組,且與疾病活動(dòng)性和骨侵蝕相關(guān),但隨著病程的延長(zhǎng),OPG的水平逐漸升高;RA患者血清RANKL水平則隨著病程的延長(zhǎng)呈持續(xù)增高趨勢(shì)。2.RA患者OP發(fā)生率隨著病程的延長(zhǎng)逐漸升高,早期RA患者即可出現(xiàn)各部位BMD明顯的降低。3.MRI在RA顯示出更高于X線改變的陽性率,RAMRIS評(píng)分異常在早期RA診斷中具有較好的診斷價(jià)值,單項(xiàng)以骨侵蝕陽性率最高,且與BMD及Sharp評(píng)分具有相關(guān)性;MRI上肌腱炎的表現(xiàn)可能具有一定的價(jià)值。4雙手MRI表現(xiàn)聯(lián)合血清OPG、RANKL異常改變能提高早期RA的診斷率。
[Abstract]:The research background of rheumatoid arthritis (rheumatoid arthritis RA) is a chronic persistent synovitis with the main features of the autoimmune disease, mainly involving the hands, feet and other small joints. Local bone erosion and osteoporosis is a major manifestation of bone and joint injury, eventually leading to joint destruction. Loss of function of the main manifestations of.RA patients with bone and joint injury for local bone erosion and osteoporosis (osteoporosis, OP), and that osteoblasts and osteoclasts are closely related to bone metabolism. The human body is a dynamic equilibrium process, including bone formation and bone resorption, when the destruction of balance will lead to bone mineral density (bone mineral density, BMD) and reduce the abnormal bone structure, which showed bone destruction and OP. In recent years, research focus for the early diagnosis of RA injury of bone and joints of the main side In imaging studies, especially magnetic resonance imaging (magnetic resonance, imaging, MRI) in the RA study, through the MRI of synovitis, bone erosion, bone marrow edema in early diagnosis of MRI, but still only found positive imaging in patients with early RA. Receptor activator of nuclear factor KB ligand (receptor activator of nuclear factor KB ligand, RANKL) is found in inducing osteoclast differentiation, development, functional factor, osteoblasts and T cells can activate the expression of RANKL.RANKL and osteoclast precursor cells or mature osteoclast surface receptor activator of nuclear factor -KB (receptor activator of nuclear factor KB RANK), after the combination of initiating a series of signal transduction pathways, promote osteoclast differentiation and bone resorption activity of osteoblasts and bone marrow stromal cells secreting expression of osteoprotegerin (osteoprotegerin, OPG ) can compete with RANKL for binding, thereby inhibiting osteoclast maturation and differentiation, prevent bone destruction in.RA patients with bone and joint injury mechanism is closely related with the broken bone and bone formation, but the mechanism is still not clear, RANKL/RANK/OPG is found in recent years play an important role in the regulation of bone, and that is a key regulator of bone RA, and early bone and joint injury related RA patients. Objective to investigate the serum levels of OPG and RANKL combined with MRI in the early diagnosis of RA value and the value of bone and joint injury. Methods 232 RA patients met the criteria for diagnosis of ACR cases in 1987. Early RA (less than 1 years) in 111 cases, non early (1 years) and 121 cases of RA, 121 cases of age and gender matched normal control group. RA were recorded in details of various clinical and laboratory indicators of 232 cases of RA patients and 121 healthy controls of the femur (femoral neck, The greater trochanter area Ward, total area), femur and lumbar (lumbar spine, L2, L3, L4, L2-4) BMD site using dual energy X-ray absorptiometry (lunar Prodigy DF+310504, GE Healthcare, USA) were all RA patients by hands X-ray and Sharp score. Early RA patients underwent MRI examination and hands RAMRIS integral. Using enzyme-linked immunosorbent assay (Enzyme Linked Immunosorbent Assay, ELISA) in peripheral blood RANKL detection, including 232 cases of RA patients and 121 normal people. The OPG level of 1. in the control group, the early RA group, non RA group early serum OPG, there was a significant difference between the level of RANKL (P0.05). And the serum RANKL levels of the three groups increased gradually, but the ratio of RANKL/OPG between the three groups had no significant difference (P0.05).2. control group, early RA group, non RA group early in the femoral neck area, Ward area, the total area of femoral trochanter, L2, L, 3, there were significant differences in BMD L 4 and L2-4 (P0. 0001), and BMD between the three groups was gradually decreased. The control group, the early RA group, non RA group early osteoporosis incidence rate were 13.92% (22/158), 23.39% (29/124), 35.69% (101/283) (2=42.137, P0.0001) MRI in patients with early RA.3. early X-ray manifestations: 111 cases the results suggest that RA staging: stage I in 82 cases, 29 cases of stage II, the Sharp score results in less than 10 minutes; and 37 cases of MRI hands showed that the bone erosion in 33 cases, bone marrow edema in 21 cases, 31 cases of synovitis, correlation analysis between each index of 11.MRI cases showed tendinitis and tendon inflammation bone marrow edema (r=0.391, P0.05), synovitis (r=0.330, P0.05) was positively related to the clinical index of.4. was not correlated with early RA MRI and serum level of RANKL/OPG, BMD and other indexes, the correlation among Sharp score: early RA (less than 1 years) with MRI indexes and OPG, RANKL, no correlation between RANKL/OPG the ratio between early RA (P0.05). 鎮(zhèn)ｈ，

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