【作者】 李静；

【导师】 王俊祥；

【作者基本信息】 河北医科大学 ， 内科学， 2011， 硕士

【摘要】 目的:类风湿关节炎(rheumatoid arthritis,RA)是最常见的炎症性自身免疫性疾病之一,可侵犯骨、关节及全身各系统,在发病以及病情发展过程中会出现关节侵蚀破坏,导致骨量丢失、骨密度(bone mineral density,BMD)下降并有可能导致骨质疏松症(osteoporosis,OP)。RA继发OP的具体机制尚未明确,在其过程中伴随的骨代谢水平的变化存在不同程度争议,治疗亦无明确的规范化标准。二膦酸盐(bisphosphonates,BPs)已作为一种新型抗RA药用于临床。本文通过分析女性RA患者骨代谢相关参数、BMD、临床指标之间的相关性并对比治疗前后各指标的变化情况,初步探寻RA发病及病情发展过程中骨代谢水平的变化、继发OP的发病机制以及Bps的治疗作用,为RA继发OP的防治提供新的理论依据。方法:RA组44例,其中按是否联合应用BPs分为BPs组和非BPs组。所有女性RA患者均符合2009年美国风湿病协会(ACR)与欧洲风湿病学会(EULAR)联合提出的RA分类标准,患者均应用一种非甾体抗炎药(NSAIDs),并合用两种改善病情的抗风湿药物(DMARDs),均未曾持续应用过糖皮质激素(glucocorticoid,GC)、生物制剂,观察过程中上述药物的剂量不变,且不加用新的药物,疗程约9个月。对照组36例均来自女性健康体检者。采用双抗体夹心酶联免疫吸附法(ABC-ELISA)测定RA患者外周血清中骨代谢指标的水平,包括骨形成标志物:成纤维细胞生长因子23(Fibroblast growth factor-23,FGF-23)、骨碱性磷酸酶(Bone alkalin pho- sphatase,BALP),骨吸收标志物:抗酒石酸酸性磷酸酶5b (Tartrate resitant- acid phosphatase,TRACP-5b)、白介素-23 (interleukin-23,IL-23)。采用双能X线吸收法(dual-energy X-Ray absorption- metry,DEXA)来检测患者的BMD。所有RA患者均记录发病年龄、病程(月),分别于治疗前及治疗后记录晨僵时间(分钟)、关节肿胀数、关节疼痛数、患者疼痛自主评分、ESR、CRP、RF、抗CCP、血常规、生化、免疫五项等指标,并记录治疗过程中出现的不良反应。利用SPSS13.0 for Windows统计软件进行数据分析,计量资料分析符合正态分布时采用均数±标准差(x±s)表示,偏态分布时采用中位数、四分位数间距(M,QR)表示;符合正态分布的两组间比较采用两样本均数比较的t或t’检验,治疗前后比较采用配对t检验,偏态分布时采用非参数秩和检验的方法进行分析。计数资料组间比较利用χ2检验。利用直线相关分析的方法比较指标的相关性,P<0.05时差异有统计学意义。结果:1基础资料的描述:对照组36例,均为女性,平均年龄为(57.03±10.61)岁;RA组44例,均为女性,平均年龄为(53.58±7.25)岁,平均病程为(62.45±10.48)月,其中BPs组22例,平均年龄为(57.93±8.67)岁,平均病程为(68.32±11.65)月;非BPs组22例,平均年龄为(50.78±8.13)岁,平均病程为(59.31±12.48)月。对照组年龄、性别与RA组差异无统计学意义(P>0.05),BPs组和非BPs组在年龄、病程、ESR、CRP、RF等方面差异无统计学意义(P>0.05)。2治疗前骨密度检测情况:在44例治疗前RA患者中OP、骨量减少、骨量正常的发生率为63.64%、22.73%、13.64%;不同部位骨质疏松的发生率不同,在大转子处最高(χ2=14.29,P =0.02);治疗之前BPs组和非BPs组各部位BMD差异无统计学意义(P>0.05)。3治疗前骨代谢指标的检测情况:与对照组相比,RA患者血清中FGF-23水平下降,差异无统计学意义(t=-1.361,P=0.088),TRACP-5b、BALP、IL-23水平均显著升高,差异均有统计学意义(P<0.05)。BPs组与非BPs组各骨代谢指标之间差异无统计学意义(P>0.05)。4治疗前后BMD变化:治疗后BPs组腰椎、大转子、股骨颈BMD与治疗前相比均有所升高,其中腰椎及大转子的升高具有统计学意义(P<0.05);治疗后非BPs组大转子BMD降低,有统计学意义(t=-2.464,P=0.033),腰椎及转子间治疗前后变化无统计学意义(P>0.05)。5治疗前后骨代谢指标的变化:经过约9个月治疗后RA患者血清中BALP水平升高,有统计学意义(t=-2.874,P=0.011);TRACP-5b、IL-23、FGF-23水平均降低,除TRACP-5b外差异均有统计学意义(P<0.05)。Bps组治疗后血清中TRACP-5b、IL-23水平、FGF-23与治疗前相比水平下降,而BALP水平升高,其差异均具有统计学意义(P<0.05);非BPs组与治疗前相比各项骨代谢指标水平变化均并无统计学意义(P>0.05)。为了比较不同组别治疗前后各骨代谢指标水平的变化幅度,将两组上述各组治疗前后的差值进行比较,结果显示:BPs组各项指标变化幅度都大于非BPs组,其中TRAP-5b、BALP、IL-23变化幅度具有统计学差异(P<0.05),而FGF-23变化幅度无统计学差异(P>0.05)。6治疗前后临床指标的变化:RA患者治疗后RF、ESR、CRP、PLT、IgG、IgM、IgA、C3、C4、晨僵时间、DAS28等治疗后均显著降低(P<0.05),BPs组DAS28、ESR、CRP、PLT、RF变化幅度较非BPs组大,其中DAS28、晨僵时间有统计学意义(P<0.05)。其余临床指标治疗前后变化无统计学意义(P>0.05)。7 BMD、骨代谢指标、临床指标的相关性:血清TRACP-5b水平分别与IL-23、RF之间呈高度正相关(P<0.05);血清BALP水平分别与FGF-23呈负相关、与AKLP呈高度正相关(P<0.05);FGF-23与病程、DAS28及ESR均呈负相关(P<0.05);大转子BMD与血清中BALP水平呈负相关,与BMI呈正相关(P<0.05);余指标之间未发现明显相关。8不良反应:治疗过程中未出现静脉炎、皮疹、发热、黏膜溃疡、胃肠道症状等不良反应,另外在治疗过程中注意监测血尿便常规、肝肾功能等未发现特殊异常。结论:1女性RA患者大多数存在骨量减少或OP,各部位骨量变化的情况不同,RA的各个部位都有可能会出现骨丢失。2 RA发展过程中伴随着骨代谢水平的变化,女性RA患者骨吸收与骨形成同时增强,属于高骨转换型,骨吸收增强的程度大于骨形成程度。3 RA患者BMD、骨代谢指标、临床指标之间均只有少数存在统计学上的相关性,提示RA并发OP可能是多因素长期共同作用的结果。4 BPs可以改善骨密度,降低骨转化率,主要以降低骨吸收为主,可能能促进骨形成。5应用抗RA药物的同时联用BPs能更好的降低炎性指标,有一定的改善病情作用。更多还原

【Abstract】 Objective: Rheumatoid arthritis (RA) is a kind of inflammatory autoim- mune diseases, which can encroach bones, joints and systems, lead to bones and joints destruction, bone mass and bone strength loss, osteopenia or even osteoporosis (OP). However, the mechanism of OP complicated with RA was unresolved, the changes of bone metabolism in RA patients were still controversial, and there was no specific standardization criterion for the treatment of OP complicated with RA. Bisphosphonates (BPs) were used for the treatment of RA. The objective of this study was to investigate the relationship between RA and bone metabolism condition, the role of BPs in treatment through determining bone mineral density (BMD), the levels of parameter of bone metabolism and clinical index before and after treatment, and provide new evidence for the treatment of RA patients.Methods: 36 healthy people were selected as control group. While 44 RA patients were envolved in this study. The diagnosis of RA patients was consistent with the major classification criteria revised by American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR). 44 RA patients were allocated into two groups: BPs and non-BPs treatment group. All the patients took one kind of NSAIDs and one or two kinds of disease modifying antirheumatic drugs (DMARD), and glucocor- ticoid or biologic agent were never continuously used. Serum levels of bone alkalin phosphatase (BALP), soluble fibroblast growth factor-23 (FGF-23), tartrate-resistant acid phosphatase 5b (TRACP-5b) and interleukin -23(IL-23) were assessment by avidin biotin peroxidase complex enzyme-linked imm- unosorbent assay (ABC-ELISA). The BMD were measured with dual-energy X-ray absorptiometry (DEXA). The clinical data associated were collected such as disease duration, age, erythrocyte sedimentation rate (ESR), rheuma- toid factor (RF), C-reactive protein (CRP), alkaline phosphatase (AKLP). These data of RA group were collected at baseline and at 9 months endpoint.Statistical analyses were performed with SPSS 13.0 software for Windows. All the measurement data which met normal distribution were expressed as mean number±standard deviation ( x±s). The t or t’test was adopted for comparison between groups, and paired t test was adopted for data of pre and post treatment.The measurement data which did not meet normal distribution was expressed by median and quartile range (M, QR), and rank-sum test was adopted. Chi-square test was used to compare the ranked data. Linear correlation analysis was used for correlationship. P or Z values<0.05 were considered significant.Results: 1 The demographic details: All the subjects were female. In nor- mal controls, the mean age was (57.03±10.61) years. In RA group the mean age of was (53.58±7.25) years, and average disease duration of (62.45±10.48) months. In the group of 22 patients with BPs treatment, the mean age was (57.93±8.67) years, and average disease duration of (68.33±11.65) months. In the group of 22 patients with non-BPs treatment, the mean age was (50.78±8.13) years, and average disease duration of (59.31±12.49) months. There were no differences between control group and RA group in age and gender(P>0.05), and also no significant differences between BPs group and non-BPs group in the traditional parameters of disease activity, such as ESR, CRP and RF(P>0.05).2 Results of bone density of RA group before treatment: The incidence of OP, osteopenia and normal BMD were 63.64%, 22.73% and 13.64% respectively. Among lumbar, greater trochanter and femoral neck, the incidence of OP had statistic significant differences (18.33%, 23.33% and 53.33% respectively), and the highest site was greater trochanter (50.00%). No statistical difference between BPs group and non-BPs group(P>0.05).3 Serum levels of bone metabolic indexes before treatment: Compared with normal controls, the serum level in RA group of TRACP-5b, BALP and IL-23 were significantly higher(P<0.05), and the level of FGF-23 was lower,but statistically significant (t=-1.361, P=0.088). There were no statistically different in bone metabolic indexes between BPs group and non-BPs group (P>0.05).4 The change of BMD before and after treatment:In BPs group,the BMD of lumbar and greater trochenter increased significantly after treatment of 9 months(P<0.05).There was no significantly change in non-BPs group except that BMD of greater trochanter was lower than pretreatment(P>0.05).5 The changes of the serum levels of bone metabolic indexes in RA group before and after treatment: Compared with pretreatment, the serum levels of IL-23, TRACP-5b and FGF-23 decreased, the level of BALP increased, and the different was significantly except TRACP-5b. Those changes in BPs group were significantly, while no statistical significance was obtained in non-BPs group. The range of changes in bone metabolic levels were significant different between BPs group and non-BPs group except FGF-23.6 The changes of clinical indexes in RA group before and after treatment: The levels of RF, ESR, CRP, PLT, IgG, IgM, IgA, C3, C4, morning stiffness duration and DAS28 were significant decreased after treatment. And the descent ranges of DAS28 and morning stiffness duration of were significant higher in BPs group.7 Correlation between bone metabolic indexe and clinical data: According to linear correlation analysis, there were positive correlation between TRACP-5b with IL-23 and RF. The level of BALP was positively correlated with AKLP while negatively correlated with FGF-23. The levels of ESR, disease duration and DAS28 were negatively correlated with the levels of FGF-23. The BMD of greater trochanter was positively correlated with BMI while negatively correlated with the levels of BALP.There were no significant linear correlation among other data.8 During treatment period, there were no adverse reactions such as phlebitis, rash, fever, mucosa ulcer, intestinal symptoms and drug-induced liver injury, etc. Conclusions: 1 Female RA patients had tendence of OP or osteopenia. The loss of bone mass could appear in every stage of RA, and it was different in diverse measurement sites.2 There was abnormality in bone metabolism of RA.The bone conversion of RA was high, both bone formation and bone resorption were strengthened at the same time, and the degree of bone resorption strengthened more than bone formation.3 Only seldom statistical correlations existed among bone metabolism indexes, BMD, and clinic datas. It suggested that multi-factors and long-term effectiveness led to the secondary OP of RA.4 BPs could enhance bone mass, decrease bone conversion. BPs were major restraint of bone resorption and might be promotion of bone formation.5 DMARDs treatment combined with BPs could decrease the levels of inflammatory index and effectively treat RA patients.更多还原