【作者】 王涛；

【导师】 李兴福；

【作者基本信息】 山东大学 ， 内科学（风湿病学）（专业学位）， 2018， 博士

【摘要】 研究背景系统性红斑狼疮(systemic lupus erythematosus,SLE)是一种自身免疫病,患者体内产生多种抗体,累及多个系统。如不早期发现并积极治疗,容易造成心、脑、肾、肺等重要脏器的严重并发症,严重危害患者生命及健康。而且SLE多发于年青育龄女性,影响患者的受孕及胎儿的发育和分娩。这些不仅给患者个人带来极大的痛苦,还给家庭和社会带来沉重的负担。由于目前SLE的病因及发病机制尚未完全清晰,因此治疗效果欠佳。进一步探索SLE的发病机制,积极寻找干预治疗的靶点一直是医学免疫学家和临床风湿免疫科医生面临的一项挑战性任务。目前一般认为在SLE的发病机制中,免疫细胞的活化和炎性因子的产生扮演着重要的角色。调节性B细胞(regulatory B cell,Bregs)的概念最初是在20世纪60年代由Morris等提出的,他们认为体内存在一群发挥免疫抑制功能的B淋巴细胞,可以分泌具有抑制作用的抗体。此后多种疾病模型中均观察到有可调节免疫反应的B细胞存在,这些B细胞的表型、来源、作用机制等差异较大。2006年,Mizoguchi等提出调节性B细胞这一概念,即一类不依赖于分泌免疫球蛋白且具有免疫调节功能的B细胞亚型。而Yanaba等在研究小鼠CHS模型时首次证实这种特殊细胞亚群的存在。这种调节性B细胞亚群又名B10细胞,在小鼠以CD19+CDldhighCD5+为表型特点,在人类以CD19+CD24highCD38high为表型特点。这些Bregs亚群可通过产生白细胞介素10(IL-10)或转化生长因子β1(TGF-β1)等抑制性细胞因子介导免疫耐受,抑制过度炎症反应。本研究拟通过流式细胞术及ELISA等技术检测SLE患者外周血CD19+CD24highCD38highBregs、IL-10 受体以及 IL-10、TGF-β1 等细胞因子的表达。将为深入、全面了解SLE发病机制,并通过Bregs信号通路干预治疗SLE等自身免疫病提供理论依据。目的本文目的旨在检测CD19+CD24highCD38high调节性B细胞(Bregs),血清白细胞介素(IL)-10,转化生长因子(TGF)-β,和IL-10受体(IL-10R)在SLE患者外周血的表达。方法1、本研究入组了 56例SLE患者和35例健康志愿者。根据SLE患者是否合并狼疮肾炎(lupus nephritis,LN),将56例SLE患者分为两组:合并LN组(LNgroup;N = 24),不合并 LN 组(nonLNgroup;N = 32)。2、收集了 SLEDAI等临床资料及实验室检查(血常规、尿常规、生化常规、红细胞沉降率、免疫球蛋白IgG\IgM\IgA补体C3\C4、间接荧光法抗核抗体\抗ds-DNA抗体半定量检测、免疫印迹法ANA谱12项定性检测)。流式细胞术检测了 CD19+CD24highCD38highBregs 和 IL-10R+细胞的比例。血清 IL-10 和 TGF-βl的检测采用了 ELISA方法。将上述检测指标与SLEDAI等临床资料及实验室检查指标作相关性分析。3、统计分析采用SPSS 18.0软件(GraphPad,La Jolla公司,CA,USA)。Kolmogorov-Smimov test检验数据是否正态分布。正态分布的计量资料,描述用均数±标准差(x±s)表示,两组间差异用two-tailed t-test检验。相关性检验(计算相关系数及P值)用two-tailed Pearson correlation检验。对于非正态分布的计量资料,描述用中位数[25th-75th百分位数]表示,两组间差异用Mann-Whitney U-test检验。相关性检验(计算相关系数及P值)用two-tailed Spearman’s Rho correlation检验。P值<0.05视为有统计学意义。结果1、SLE患者组CD19+CD24highCD38high Bregs在外周血中表达的比例,即CD19+CD24highCD38high Bregs细胞数/CD19+细胞数,高于正常对照组(39.83 ±21.39%vs.8.74 ± 3.97%;P<0.001)。在狼疮合并肾炎组与不合并肾炎组之间对比,无统计学差异。CD19+CD24highCD38high Bregs的表达与临床指标的相关性:与SLEDAI无明显相关性(r =-0.111,= 0.416),与外周血血清补体C3负相关(r =-0.432,P=0.002),与外周血血清补体C4负相关(r =-0.497,P<0.0.01),与外周血血清间接胆红素表达水平负相关(r =-0.335,P = 0.035)。2、SLE患者组IL-10R+细胞的比例明显低于正常对照组(23.76 ± 0.62%vs.51.01 ± 16.03%;P<0.001)。但IL-10R+细胞的比例在狼疮合并肾炎组与不合并肾炎组之间对比,无统计学差异(P>0.05)。另外,就IL-10R+细胞的平均荧光强度(MFI)比较,SLE患者组也明显低于正常对照组(20.18 ±3.88 vs.23.23 ±3.66;P<0.001)。进一步作相关性分析显示:IL-10R+细胞比例与SLEDAI无明显相关性(r = 0.093,P = 0.494),与ALT无明显相关性(r = 0.254,P = 0.075),与血清碱性磷酸酶(ALP)无明显相关性(r = 0.252,P=0.077);但与红细胞沉降率(ESR)呈负相关(r =-0.389,P= 0.016)。3、外周血血清IL-10浓度:SLE患者组高于健康对照组(3.65[2.22-9.17]pg/mLvs.1.04[0.43-1.46]pg/mL;P<0.001)。但外周血血清IL-10在狼疮合并肾炎组与不合并肾炎组之间对比,无统计学差异(P>0.05)。血清IL-10浓度与SLEDAI无明显相关性(P>0.05),但与血沉、ANA滴度、IgG、IgM和AST、ALT呈正相关,有统计学意义(P<0.05),与外周血淋巴细胞计数及红细胞计数呈负相关,有统计学意义(P<0.05)。4、外周血血清TGF-β1的浓度:在SLE患者组与正常对照组之间无明显差异(11262.02 ± 7784.17 pg/mLvs.13143.27 ±5559.21 pg/mL,P=0.239)。不过,我们发现SLE合并LN患者组外周血血清TGF-β1的表达低于健康对照组(9382.07 ±7558.16pg/mLvs.13143.27±5559.21 pg/mL,P= 0.038)。在SLE患者组,合并与未合并LN组之间TGF-β1的浓度没有统计学差异(9382.07 ± 7558.16 pg/mL vs.12671.98 ± 7767.39 pg/mL,P = 0.118)。相关性分析发现:患者外周血血清TGF-β1的浓度与SLEDAI无明显相关性,但是与外周血RBC计数呈正相关,与24小时尿蛋白定量、血清IgM和AST的浓度呈负相关。5、CD19+CD24highCD38high Bregs 的比例与IL-10R+ 淋巴细胞的比例及MFI均正相关,与外周血血清IL-10浓度正相关。另外,IL-10R+淋巴细胞的比例与其MFI正相关。而外周血血清TGF-β1浓度与IL-10浓度负相关。以上统计学分析均P<0.05。结论1、与正常对照相比,SLE患者组CD19+CD24highCD38high Bregs和IL-10在外周血中表达上调,IL-10 R的表达下调。这些指标参与SLE的免疫调节,CD19+CD24highCD38hig Bregs、IL-10的高表达可能是机体对IL-I0R低表达的代偿或中和。2、外周血血清TGF-β1的浓度在SLE患者组与正常对照组之间无明显差异,但SLE合并LN患者组外周血血清TGF-β1的表达低于健康对照组。TGF-β1对于LN具有一定的保护作用。3、CD19+CD24highCD38highBregs的表达与外周血血清补体C3、C4负相关。血清IL-10浓度与SLEDAI无明显相关性,但与血沉、ANA滴度、IgG、IgM和AST、ALT呈正相关,与外周血淋巴细胞计数及红细胞计数呈负相关。SLE患者组IL-10R的表达与ESR呈负相关。TGF-β1的浓度与外周血RBC计数呈正相关,与24小时尿蛋白定量负相关。因而,这些指标可以部分反映SLE患者病情活动情况。研究背景系统性红斑狼疮(Systemic lupus erythematosus,SLE)是一种异质性疾病且并发症多见。SLE相关的骨损害包括骨量减少、骨质疏松(osteoporosis,0P)、骨坏死(osteonecrosis,ON)和骨折。OP是一种以骨量减少和骨组织的细微结构破坏为特征的全身性疾病,最终导致骨脆性增加和骨折。ON是骨细胞成分死亡、骨结构破坏,继而导致关节疼痛及功能丧失。SLE的另一特点就是免疫紊乱,包括抗体和细胞因子的产生。有研究认为白细胞介素10(IL-10)和转化生长因子β1(TGF-β1)等抑制性细胞因子可以介导免疫耐受,抑制过度炎症反应,可能参与调节骨代谢和骨损害。但与SLE骨损害的相关性研究较少。本研究拟检测并比较SLE合并骨损害患者外周血IL-10、TGF-β1表达的的差异。将为深入、全面了解细胞因子参与SLE发病机制,并通过调节细胞因子表达干预治疗SLE等自身免疫病提供理论依据。目的本文目的旨在检测IL-10、TGF-β1在SLE合并骨损害患者外周血的表达并分析其临床意义。方法1、本研究入组了56例SLE患者。血清IL-10和TGF-β1的检测采用了ELISA方法。2、对56例患者临床资料进行回顾性分析,主要记录合并骨质疏松症及骨坏死情况。根据不同骨量分为:骨量正常组(14例),骨量减少组(26例),骨质疏松组(16例)。根据是否合并骨坏死分为:未发现骨坏死组(49例)和骨坏死组(7例)。3、统计分析采用SPSS 18.0软件(GraphPad,La Jolla公司,CA,USA)。Kolmogorov-Smirnov test检验数据是否正态分布。正态分布的计量资料,描述用均数±标准差(x±s)表示,两组间差异用two-tailed t-test检验。对于非正态分布的计量资料,描述用中位数[25th-75th百分位数]表示,两组间差异用Mann-Whitney U-test检验。P值<0.05视为有统计学意义。结果1、TGF-β1的表达,骨量正常组>骨量减少组>骨质疏松组,但差异仅在骨量正常组与骨质疏松组间有统计学意义(14778.93 ± 5188.10 vs 9289.53 ±6752.73 pg/mL,P=0.020)。IL-10的表达,骨量正常组<骨量减少组<骨质疏松组,但差异仅在骨量正常组与骨质疏松组间有统计学意义(0.12[0.01-2.74]vs 2.57[0.52-8.52]pg/mL,P=0.012)。2、TGF-β1的表达,无骨坏死组(11960.43 ±768.55 pg/mL)>有骨坏死组(6373.13 ± 5315.75 pg/mL),但差异无统计学意义(P=0.075)。IL-10的表达,无骨坏死组(0.87[0.21-4.56]pg/mL)<有骨坏死组(8.03[1.61-9.56]pg/mL),差异有统计学意义(P=0.017)。结论1、伴有骨质疏松的SLE患者组外周血血清TGF-β 1要明显低于骨量正常的SLE患者组。伴有骨坏死的SLE患者组外周血血清TGF-β 1要低于未伴有骨坏死的SLE患者组,尽管差异尚无统计学意义,但伴有骨坏死的SLE患者TGF-β 1表达有降低的趋势。提示我们TGF-β1表达的降低可能是SLE合并骨质代谢异常的发病环节之一。2、伴有骨质疏松的SLE患者组外周血血清IL-10要明显高于骨量正常的SLE患者组。伴有骨坏死的SLE患者组外周血血清IL-10要高于未伴有骨坏死的SLE患者组。这种IL-10表达增加可能是一种慢性炎症下的补偿性合成增加。研究背景系统性红斑狼疮(Systemic lupus erythematosus,SLE)是一种异质性疾病。骨坏死(osteonecrosis,ON)是骨细胞成分死亡、骨结构破坏,继而导致关节疼痛及功能丧失。ON是SLE的常见临床表现,致残率高。除了糖皮质激素治疗,其他临床指标也可能成为骨坏死的危险因素。目的评估分析除了糖皮质激素治疗外,SLE合并骨坏死的主要危险因素,为防控骨坏死提供决策依据。方法在 Cochrane library,PubMed,Ovid,和 Science Direct 等数据库检索关于 SLE合并ON的危险因素已发表的病例对照研究。对23篇符合纳入标准的文献进行了数据提取,共包含病例组(SLE合并ON)1071例和对照组(SLE不合并ON)23065例,应用Revman 5.3软件进行Meta分析。经过异质性分析,计算了每一个危险因素的OR值和95%可信区间。结果主要危险因素的OR[95%可信区间]如下:关节炎1.69[1.32,2.17],中枢神经系统损害 1.34[1.06,1.71]、糖尿病 1.59[1.03,2.46]、高血压 1.69[1.42,2.02]、口腔溃疡 1.48[1.06,2.08]、肾损害 1.53[1.27,1.83]、血管炎 2.45[1.54,3.89]、吸烟史 1.64[1.01,2.65]、白细胞下降 1.54[1.11,2.13]、血小板下降 1.63[1.14,2.32]、细胞毒药物1.79[1.25,2.57]、环磷酰胺治疗3.13[1.58,6.21]以及抗Sm抗体0.48[0.27,0.85]。结论除了糖皮质激素治疗,SLE合并ON的危险因素还包括:关节炎、中枢神经系统损害、糖尿病、高血压、口腔溃疡、肾损害、血管炎、吸烟史、白细胞下降、血小板下降、细胞毒药物、环磷酰胺治疗。抗虐药对SLE合并ON没有保护作用。更多还原

【Abstract】 BackgroundSystemic lupus erythematosus(SLE)is a chronic,systemic autoimmune inflammatory disease characterized by the production of numerous autoantibodies,particularly antinuclear antibodies(ANA),increased immune complex deposition,and multiple organ damage.Although both genetic and environmental factors may contribute to SLE development,the precise etiology of SLE is not fully understood.As a central player in SLE development,the immune system with both T and B cells contributes to the pathogenesis of human SLE.Historically,B cells are considered to be positive regulators of humoral immune responses because of their ability to terminally differentiate into plasma cells and produce antigen-specific antibodies.Specific B cell subsets,however,negatively regulate immune responses and have been termed regulatory B cells(Bregs).Bregs are associated with the CD19+CD24highCD38high phenotype and are characterized by the production of the immunoregulatory cytokines interleukin(IL)-10 and transforming growth factor(TGF)-β.Through the secretion of these immunosuppressive cytokines,Bregs suppress other immune cells and have been studied extensively for their potential role in the treatment of various autoimmune diseases.Recent studies indicate that Bregs are functionally impaired in SLE patients,suggesting their potential involvement in the pathogenesis of lupus.However,no studies have systematically characterized the status of Bregs,the levels of serum IL-10 or TGF-β,or IL-10 signaling.Moreover,their associations with the SLEDAI and other laboratory parameters in SLE patients have not been examined.Hence,we performed this study to address these questions in order to significantly improve our understanding of the pathogenesis of SLE as well as to justify targeting Bregs as a therapeutic approach for SLE and potentially other autoimmune diseases.ObjectiveThe aim of this study was to examine the status and clinical significance of CD 19+CD24thighCD38high regulatory B cells(Bregs),serum interleukin(IL)-10,serum transforming growth factor(TGF)-P,and IL-10 receptor(IL-10R)expression in peripheral blood from patients with systemic lupus erythematosus(SLE).Method1.A total of 56 SLE patients and 35 healthy individuals were recruited into this study.According to the presence of lupus nephritis(LN),the SLE patients were divided into two groups:those with lupus nephritis(LN group;N = 24)and those without(SLE group;N = 32).2.The SLE disease activity index(SLEDAI)was calculated,and other laboratory parameters were measured.Peripheral blood was collected from all participants.The frequency of CD19+CD24highCD38high Bregs and IL-10R+ expression on circulating lymphocytes was examined by flow cytometry.The serum levels of IL-10 and TGF-βwere measured using the enzyme-linked immunosorbent assay(ELISA).The associations between these measurements and SLED AI or other laboratory parameters were analyzed by correlation analysis.a portion for laboratory tests as follows:routine blood tests for ESR,red blood cell(RBC)count,and lymphocyte count;indirect immunofluorescence assay for ANA titer;automated immunofluorescence assay for anti-dsDNA antibody titer;liver function tests for CRP,complement components C3 and C4,IgG,IgM,IgA,and aspartate aminotransferase(AST)levels.3.Statistical analysis was performed using SPSS 18.0 software.Data distribution was checked for normality using the Kolmogorov-Smirnov test.Normally distributed data were expressed as the mean ± standard deviation,and the differences were examined using two-tailed t-tests.Correlation coefficients and their significance were calculated by two-tailed Pearson correlation.For nonparametric data,the results are presented as medians[25th-75th percentile].The Mann-Whitney U-test was used to compare the data between different groups of patients and controls.Correlation coefficients and their significance were calculated by two-tailed Spearman’s Rho correlation.P values of<0.05 were considered statistically significant.Results1.There was a higher percentage of CD19+CD24highCD38high Bregs among circulating lymphocytes from SLE patients than from healthy individuals(39.83 ±21.39%vs.8.74 ± 3.97%;P<0.001).Further analysis on the clinical significance of Bregs showed that the frequency of CD19+CD24highCD38high Bregs was not significantly correlated with the SLEDAI score(r =-0.111,P = 0.416)or the presence of LN in SLE patients(P>0.05,data not shown),but it was negatively correlated with the blood complement C3(r =-0.432,P = 0.002),complement C4(r =-0.497,P<0.001),and serum indirect bilirubin(r =-0.335,P = 0.035)levels.2.The percentage of IL-10R+ cells among circulating lymphocytes was dramatically lower in SLE patients than in healthy individuals(23.76 ± 0.62%vs.51.01 ± 16.03%;P<0.001).Furthermore,the expression level of IL-10F,based on the mean fluorescence intensity(MFI)of these cells,was also significantly lower in SLE patients compared to healthy individuals(20.18 ± 3.88 vs.23.23±3.66;P<0.001).Further correlation analysis showed that the MFI of IL10-R1+ lymphocytes did not significantly correlate with the presence of LN in SLE patients(P>0.05,data not shown),the SLEDAI(r = 0.093,P = 0.494),serum alanine transaminase(ALT)(r＝0.254,P = 0.075),or serum alkaline phosphatase(ALP)(r = 0.252,P = 0.077),but it negatively correlated with the ESR(r =-0.389,P = 0.016).3.The serum IL-10 concentration was significantly higher in the SLE patients than in the healthy controls(3.65[2.22-9.17]pg/mL in the SLE patients vs.1.04[0.43-1.46]pg/mL in the healthy controls;P<0.001).Correlation analysis showed that the serum IL-10 level did not correlate with the presence of LN in SLE patients(P>0.05),or the SLEDAI,but it positively correlated with the ESR,ANA titer,IgG,IgM,and AST and negatively correlated with the complement C3 level as well as red blood cell and lymphocyte counts.4.The serum TGF-β1 level was not significantly different between the SLE patients and the healthy controls(11262.02 ± 7784.17 pg/mL vs.13143.27 ± 5559.21 pg/mL,P-0.239).However,the serum TGF-βl level in the SLE patients with LN was significantly lower than in the healthy controls(9382.07 ± 7558,16 pg/mL vs.13143.27 ± 5559.21 p.g/mL,P=0.038),although there was also not a dramatic difference in the serum TGF-β1 level between the SLE patients with or without LN(9382.07 ± 7558.16 pg/mL vs.12671.98 ± 7767.39 pg/mL,P = 0.118).Correlation analysis showed that the serum TGF-β1 level was not significantly correlated with the SLEDAI score,but it was positively correlated with the red blood cell count and negatively correlated with globulin,24-h urine protein,IgM,and AST.5.The percentage of CD19+CD24highCD38high Bregs was positively correlated with the percentage of IL-10R+ lymphocytes,the MFI of IL-10R+ lymphocytes,and the serum IL-10 level.In addition,the percentage of IL-10R+ lymphocytes was positively correlated with its expression level(MFI),while the serum TGF-β1 level was negatively correlated with the serum IL-10 level.Conclusion1.Compared with normal control group,CD19+CD24higherCD38high Bregs and IL-10 in the peripheral blood of patients with SLE increased significantly,and IL-10 receptor decreased significantly.Deficient IL-10R expression may result in the compensatory enhanced expression of IL-10,expansion of Bregs,and/or compromise the functions of Bregs and IL-10,contributing to SLE development.2.The serum TGF-β1 level was not significantly different between the SLE patients and the healthy controls.However,the serum TGF-β1 level in the SLE patients with LN was significantly lower than in the healthy controls.The dysfunction of TGF-β1 in regulating the immune system leads to autoimmune disease.3.These results suggest that the expression of these immunological factors have correlations with clinical parameters and disease activity.They may play essential roles in SLE pathogenesis and be potential therapeutic targets or biomarkers in SLE.BackgroundSystemic lupus erythematosus(SLE)is a heterogeneous disease with many complications.The bone damage of SLE includes osteopenia,osteoporosis(OP),osteonecrosis(ON)and fractures.OP is a systemic disease characterized by bone loss and disruption of the microstructure.ON is the death of cellular elements of the bone,which leads to collapse of the bony structure,culminating in joint pain and loss of function.Another feature of SLE is immune disorders,including the production of antibodies and cytokines.Studies have suggested that interleukin 10(IL-10)and transforming growth factor β1(TGF-β1)are inhibitory cytokines which can mediate immune tolerance,inhibit excessive inflammation.They may be involved in the regulation of bone metabolism and bone damage.But the research about IL-10 and TGF-β1 in SLE with bone damage is not much.Hence,we performed this study to detect and compare the differences in IL-10 and TGF-β1 expression in peripheral blood of SLE patients with bone damage.We performed this study also in order to significantly improve our understanding of the inhibitory cytokines in the pathogenesis of SLE with bone damage,as well as to justify targeting them as a therapeutic approach for SLE with bone damage and potentially other autoimmune diseases.ObjectiveThe aim of this study was to investigate the expression of IL-10 and TGF-β1 in peripheral blood of patients with SLE complicated with bone lesions and to analyze their clinical significance.Method1.A total of 56 SLE patients were recruited into this study.Serum IL-10 and TGF-β1 were detected by ELISA.2.According to different bone mass,the SLE patients were divided into 3 groups:bone normal group(14 cases),bone loss group(26 cases),osteoporosis group(16 cases).According to whether the mergers of osteonecrosis,the SLE patients were divided into two groups:none osteonecrosis group(49 cases)and osteonecrosis group(7 cases).3.Statistical analysis was performed using SPSS 18.0 software.Data distribution was checked for normality using the Kolmogorov-Smirnov test.Normally distributed data were expressed as the mean ± standard deviation,and the differences were examined using two-tailed t-tests.For nonparametric data,the results are presented as medians[25th-75th percentile].The Mann-Whitney U-test was used to compare the data between different groups of patients and controls.P values of<0.05 were considered statistically significant.Results1.For TGF-β1 expression,bone mass normal group>osteopenia group>osteoporosis group,but only the difference between normal bone mass group and.osteoporosis group(14778.93 ± 5188.10 vs 9289.53± 6752.73 pg/mL,P = 0.020)was statistically significant.For IL-10 expression,bone mass normal group<osteopenia group<osteoporosis group,but only the difference between the normal bone group and osteoporosis group(0.12[0.01-2.74]vs 2.57[0.52-8.52]pg/mL,P =0.012)has statistical significance.2.For TGF-β1 expression,none osteonecrosis group(11960.43 ± 768.55 pg/mL)>bone necrosis group(6373.13 ± 5315.75 pg/mL),but the difference was not statistically significant(P = 0.075).For IL-10 expression,none osteonecrosis group(0.87[0.21-4.56]pg/mL)<bone necrosis group(8.03[1.61-9.56]pg/mL),the difference was statistically significant(P = 0.017).Conclusion1.The level of serum TGF-β1 in peripheral blood of SLE patients with osteoporosis was significantly lower than that of SLE patients with normal bone mass.Although the difference was not statistically significant,the expression of TGF-β1 in SLE patients with osteonecrosis has the trend of reduce.Suggesting that the reduction of TGF-β1 expression may be one of the pathogenesis of SLE complicated with abnormal bone metabolism.2.The level of serum IL-10 in peripheral blood of SLE patients with osteoporosis was significantly higher than that of SLE patients with normal bone mass.Serum IL-10 in peripheral blood of SLE patients with bone necrosis was higher than that of SLE patients without bone necrosis.This increase of IL-10 expression may be compensatory synthesis under chronic inflammation.BackgroundSystemic lupus erythematosus(SLE)is a heterogeneous disease,and differences in the clinical features may be risk factors for osteonecrosis(ON)in addition to treatment with glucocorticoids.ObjectiveTo assess the major risk factors for ON in SLE,and provide evidence for decision-making on prevention.MethodThe Cochrane library,PubMed,Ovid,and Science Direct were searched for published case-control studies on the risk factors of ON in SLE.A meta-analysis of 23 case-control studies(1,071 cases and 23,065 controls)that met the inclusion criteria was conducted using Revman 5.3 software.After analysis of homogeneity,the pooled odds ratios(OR)and 95%confidence intervals(CI)of each risk factor were calculated.ResultsThe pooled OR and 95%CI of each risk factor of ON in the patients with SLE were as follows:arthritis 1.69[1.32,2.17],central nervous system(CNS)involvement 1.34[1.06,1.71],diabetes mellitus 1.59[1.03,2.46],hypertension 1.69[1.42,2.02],oral ulcer 1.48[1.06,2.08],renal involvement 1.53[1.27,1.83],vasculitis 2.45[1.54,3.89],smoking history 1.64[1.01,2.65],leucopenia 1.54[1.11,2.13],thrombocytopenia 1.63[1.14,2.32],cytotoxic drugs 1.79[1.25,2.57],cyclophosphamide 3.13[1.58,6.21]and anti-Sm antibodies 0.48[0.27,0.85].Conclusion:In addition to glucocorticosteroids,other factors,including arthritis,CNS involvement,diabetes mellitus,hypertension,oral ulcer,renal involvement,vasculitis,smoking history,leucopenia,thrombocytopenia,cytotoxic drugs and cyclophosphamide are major risk factors of ON in patients with SLE.Antimalarial drugs are not protective factor against ON in patients with SLE.更多还原