血清RANKL、OPG联合磁共振扫描在早期类风湿关节炎诊断与骨关节损伤中的研究
发布时间:2018-04-01 19:02
本文选题:类风湿关节炎 切入点:核因子KB受体活化因子配体 出处:《安徽医科大学》2015年硕士论文
【摘要】:研究背景类风湿关节炎(rheumatoid arthritis,RA)是一种慢性持续性以关节滑膜炎症为主要特征的自身免疫性疾病,主要累及双手、双足等小关节。局部骨侵蚀和全身骨质疏松是其骨与关节损伤的主要表现形式,最终导致关节破坏、功能的丧失。RA患者骨与关节损伤的主要表现形式为局部的骨侵蚀和全身骨质疏松(osteoporosis,OP),而这与成骨和破骨细胞有着密切的关系。人体的骨代谢是一个动态的平衡过程,主要包含骨形成和骨吸收,当平衡被破坏就会导致骨密度(bone mineral density,BMD)降低和骨结构的异常,从而表现为骨质破坏和OP等。近年来,对于RA骨与关节损伤的早期诊断的研究热点主要侧重于影像学研究,尤其是磁共振成像(magnetic resonance imaging,MRI)在RA的研究,可通过MRI上对滑膜炎、骨侵蚀、骨髓水肿等表现进行早期诊断,但MRI仍然只能发现影像学阳性的早期RA患者。核因子KB受体活化因子配体(receptor activator of nuclear factor KB ligand,RANKL)是目前发现的具有诱导破骨细胞分化、发育、发挥功能的因子,成骨细胞和激活的T淋巴细胞均可表达RANKL。RANKL与破骨细胞前体细胞或成熟破骨细胞表面的核因子-KB受体活化因子(receptor activator of nuclear factor KB,RANK)结合后,启动一系列信号传导通路,促进破骨细胞分化与骨吸收活性。成骨细胞和骨髓基质细胞分泌表达护骨素(osteoprotegerin,OPG)可与RANKL竞争性结合,从而抑制破骨细胞的成熟与分化,阻止骨的破坏。RA患者的骨与关节损伤的机制与破骨和成骨过程密切相关,但具体的机制仍不清楚,RANKL/RANK/OPG系统是近年来发现的在骨调节上发挥重要作用的系统,并认为是RA的关键性骨调节因子,可能与RA患者的早期骨与关节损伤有关。目的探讨血清RANKL和OPG水平联合MRI在早期RA诊断中的价值及骨与关节损伤中的价值。方法选择符合ACR 1987年诊断标准的RA患者232例,其中早期RA(≤1年)111例,非早期(1年)RA 121例,选择121例年龄性别匹配的正常对照组。详细记录RA患者各临床及实验室指标,232例RA患者和121例健康对照组的股骨(股骨颈、Ward区、大转子、总股骨区)和腰椎(lumbar spine,L2、L3、L4、L2-4)部位BMD使用双能X线骨密度仪(lunar Prodigy DF+310504,GE Healthcare,USA)测定,所有RA患者摄双手X线并进行Sharp评分。早期RA患者行双手MRI检查并进行RAMRIS积分。采用酶联免疫吸附试验(Enzyme Linked Immunosorbent Assay,ELISA)检测其中232例RA患者和121例正常人外周血RANKL、OPG水平。结果1.对照组、早期RA组、非早期RA组血清OPG、RANKL的水平差别有统计学意义(P0.05),且三组间血清RANKL水平呈逐渐升高趋势,但RANKL/OPG的比值三组间比较无统计学差异(P0.05)。2.对照组、早期RA组、非早期RA组在股骨颈区、Ward区、大转子区、总股骨区、L2、L 3、L 4和L2-4的BMD差异有统计学意义(P0.0001),且三组间BMD呈逐渐降低趋势。对照组、早期RA组、非早期RA组骨质疏松的发生率分别为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的表现:111例早期RA的X线分期结果提示:Ⅰ期82例,Ⅱ期29例,其Sharp评分结果均在10分以内;而37例行双手MRI的结果显示:有骨侵蚀33例、骨髓水肿21例、滑膜炎31例、肌腱炎11例。MRI各指标之间的相关分析显示肌腱炎与骨髓水肿(r=0.391,P0.05)、滑膜炎(r=0.330,P0.05)呈正相关,其余指标间无相关关系。4.早期RA患者MRI与血清RANKL/OPG水平、临床指标、BMD及Sharp评分间的相关性:早期RA(≤1年)患者MRI各指标与OPG、RANKL、RANKL/OPG比值间无相关关系(P0.05)。早期RA患者MRI骨侵蚀评分与大转子(r=-0.387,P0.05)和总股骨区(r=-0.358,P0.05)的BMD呈负相关,与Sharp评分呈正相关(r=0.721,P0.05)。MRI肌腱炎评分与关节肿胀数(r=0.371,P0.05)、关节压痛数(r=0.369,P0.05)、CRP(r=0.480,P0.05)呈正相关。MRI骨髓水肿评分、滑膜炎评分与各指标无相关关系。血清OPG水平与关节肿胀数(r=0.193,P0.05)、压痛数(r=0.209,P0.05)、VAS评分(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),骨侵蚀(r=0.339,P0.05)、Sharp评分(r=0.277,P0.05)呈正相关,与各部位骨密度无相关性。血清RANKL水平与各部位骨密度、临床指标、Sharp评分无相关性(P0.05)。5.非早期RA(1年)患者OPG、RANKL、RANKL/OPG比值与患者疾病活动性、骨与关节损伤的相关分析:血清OPG、RANKL、RANKL/OPG比值与非早期RA患者各部位的关节肿胀数、压痛数、VAS评分、ESR、CRP、DAS28、RF、抗CCP、HAQ、BMD、Sharp评分之间均无相关性(P0.05)。6.早期RA组与非早期RA组各诊断指标阳性率的比较:早期RA患者MRI上骨侵蚀、骨髓水肿、滑膜炎、肌腱炎的阳性率分别为89.19%(33/37)、56.76%(21/37)、83.78%(31/37)、29.73%(11/37)。四项指标中任一表现阳性率为97.30%(36/37)。非早期RA组RF、抗CCP阳性率高于早期RA组,阳性率分别为[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阴性组与阳性组间MRI上骨侵蚀、骨髓水肿、滑膜炎、肌腱炎的阳性率无统计学差异(P0.05)。7.血清OPG、RANKL水平在RF阴性(≤14 IU/ml)或低滴度阳性(≤42 IU/ml)中的比较:对照组、RF阴性的早期RA组、RF阴性的非早期RA组间血清OPG、RANKL水平单因素方差分析结果显示:对照组、早期RA组、非早期RA组血清RANKL水平差别有统计学意义(P0.05),且在三组间呈逐渐升高趋势,但血清OPG水平在三组间比较无统计学差异(P0.05)。对照组、RF低滴度阳性的早期RA组、RF低滴度阳性的非早期RA组间血清OPG、RANKL水平比较显示:血清OPG、RANKL水平三组间比较差异均有统计学意义(P0.05)。8.血清OPG、RANKL水平在抗CCP阴性(≤25RU/ml)或低滴度阳性(CCP≤75RU/ml)中的比较:对照组、抗CCP阴性的早期RA组、抗CCP阴性的非早期RA组间血清OPG、RANKL水平单因素方差分析结果显示:对照组、早期RA组、非早期RA组血清RANKL水平差异有统计学差异(P0.05),且血清RANKL水平呈逐渐升高趋势,但血清OPG水平三组间比较差异无统计学差异(P0.05)。对照组、抗CCP低滴度阳性的早期RA组、抗CCP低滴度阳性的非早期RA组间血清OPG、RANKL水平比较显示:对照组、早期RA组、非早期RA组血清RANKL水平差异有统计学差异(P0.05),且RANKL水平呈逐渐升高趋势,但OPG水平三组间比较差异无统计学差异(P0.05)。9.早期RA组中OPG阳性率(以降低计)和RANKL阳性率(以升高计)及联合MRI中各指标的阳性率。根据非正态分布资料的分析结果,以OPG≤178.80pg/ml,以RANKL≥109.56pg/ml为异常。OPG降低或存在骨侵蚀的早期RA患者数为31,占31/33=93.94%;OPG降低或存在骨髓水肿的患者24,占72.73%,OPG降低或存在滑膜炎患者为29例,占87.88%;OPG降低或存在腱鞘炎RA患者为18例,占54.55%;OPG降低或RAMRIS(3项)0的RA患者为33例,占100%;OPG降低或RAMRIS(4项)0分的患者为33例,为100%。RANKL升高或存在骨侵蚀患者30例,占90.91%,RANKL升高或存在骨髓水肿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RA患者19例,占57.57%,RANKL升高或RAMRIS(3项)0的RA患者32例,占96.97%,RANKL升高或RAMRIS(4项)0分的患者32例,占96.97%。结论1.早期RA患者OPG的水平低于正常对照组,且与疾病活动性和骨侵蚀相关,但随着病程的延长,OPG的水平逐渐升高;RA患者血清RANKL水平则随着病程的延长呈持续增高趋势。2.RA患者OP发生率随着病程的延长逐渐升高,早期RA患者即可出现各部位BMD明显的降低。3.MRI在RA显示出更高于X线改变的阳性率,RAMRIS评分异常在早期RA诊断中具有较好的诊断价值,单项以骨侵蚀阳性率最高,且与BMD及Sharp评分具有相关性;MRI上肌腱炎的表现可能具有一定的价值。4双手MRI表现联合血清OPG、RANKL异常改变能提高早期RA的诊断率。
[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h,
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