系统性红斑狼疮的预后及肠道微生物研究

发布时间：2018-06-15 04:35

本文选题：系统性红斑狼疮 + 假性肠梗阻　；参考：《北京协和医学院》2017年博士论文

【摘要】：目的:1.通过建立单中心系统性红斑狼疮相关假性肠梗阻及失蛋白肠病的临床研究队列,探讨疾病的临床特征、危险因素、生存情况及预后因素。2.分析不同表型系统性红斑狼疮患者的肠道微生物,揭示其与系统性红斑狼疮不同表型间存在的规律,探讨肠道微生物在狼疮发病、诊断及治疗中的价值。3.建立多中心系统性红斑狼疮研究的起始队列,进行横断面分析,为预后研究打下坚实基础。方法:1.回顾性纳入1997年至2016年间于北京协和医院住院诊治的系统性红斑狼疮相关假性肠梗阻及系统性红斑狼疮相关失蛋白肠病患者,以系统性红斑狼疮相关胃肠道受累的临床确诊时间为基线时间,收集人口学、家族史、临床特征、免疫学指标等基线资料并进行随访,分别以死亡和出现复发或死亡作为研究终点。采用寿命表法及Kaplan-Meier曲线描述及分析,分层Kaplan-Meier曲线应用Log-Rank法检验,对其中具有统计学意义的指标及Cox单因素回归分析具有统计学意义的指标进一步进行Cox多因素回归分析。2.肠道微生物研究方面,收集2016年5月至2017年3月于北京协和医院住院治疗的狼疮胃肠道受累、狼疮肾炎及神经精神狼疮患者的粪便,通过16srDNA测序鉴定并划分细菌类群,比较系统性红斑狼疮各表型与健康对照间肠道菌群的差异。3.多中心预后研究方面,纳入中国系统性红斑狼疮协作组平台中SLE发病至登记入组时间小于6个月的患者,收集入组时人口学信息、家族史、临床表现、免疫指标作为基线资料,对基线资料进行横断面分析。结果:1.系统性红斑狼疮胃肠道受累主要包括系统性红斑狼疮相关假性肠梗阻及系统性红斑狼疮相关失蛋白肠病两种类型,分别入组133例和58例患者,女性均为主要发病人群,分别占92.48%和79.31%,年龄分布在11岁至71岁之间,43.61%至53.45%患者以狼疮胃肠道损害作为狼疮首发表现出现。(1)SLE-IPO主要表现为肠梗阻症状,21.05%至24.06%患者存在泌尿系统症状,浆膜炎为最常见合并受累系统,见于63.91%患者,分别有63.16%、21.80%、57.14%患者合并肾脏、神经、血液系统病变。抗SSA抗体阳性率最高,为66.17%,补体减低患者占84.96%。52.63%的患者合并肾盂输尿管扩张,这部分患者中,膀胱壁受累(42.86%vs 6.35%,P0.001)、肝胆管扩张(14.29%vs 3.17%,P=0.026)及浆膜炎(78.57%vs 47.62%,P0.001)的比例均显著高于无肾盂输尿管扩张的患者,部分患者表现为广泛空腔脏器扩张的三联征。浆膜炎(OR=10.114,P=0.000),神经病变(OR=4.336,P=0.000),抗 SSA 抗体阳性(OR=2.092,P=0.014),抗 SSB 抗体阳性(OR=2.433,P=0.035),补体减低(OR=2.685,P=0.003)是 SLE患者发生IPO的危险因素。基线糖皮质激素使用率为100%,50.38%患者进行激素冲击治疗,85.71%应用环磷酰胺。SLE-IPO的预后较差,1年、3年、5年生存率分别为91.51%、89.46%、86.73%。感染为主要死亡原因,占53.33%。1年、2年、3年的累积复发率分别为14.71%、26.32%、37.04%。预后不良的独立危险因素包括起病晚(HR=1.051,P=0.027)、合并神经系统病变(HR=4.621,P=0.017),保护性因素包括抗SSA抗体阳性(HR=0.530,P=0.039),疾病早期给予一线免疫抑制剂治疗(HR=0.209,P=0.020)、达到早期缓解(HR=0.530,P=0.039)则可提高SLE-IPO患者的长期生存率并改善预后。(2)SLE-PLE以低白蛋白(100%)、水肿(89.66%)、浆膜腔积液(77.59%)为特点,1/3患者无消化系统症状。诊断性实验锝99标记的白蛋白核素闪烁显像显示蛋白漏出部位多为小肠。抗SSA抗体阳性率为51.72%,87.93%的患者出现补体降低。SLE-PLE患者的1年、3年、5年生存率分别为91.49%、91.49%、88.54%。感染(40.00%)、狼疮活动(40.00%)为主要死亡原因。严重的低白蛋白血症(χ2=9.061,P=0.003)、24h尿蛋白升高(HR=1.553,P=0.012)为预后不良相关因素,早期识别、诊断并加强支持治疗将改善SLE-PLE患者的预后。2.入组狼疮胃肠道受累、狼疮肾炎及神经精神狼疮患者各4例、健康对照7例,分别从门、科、属、种的水平上对正常人和系统性红斑狼疮的不同临床表型患者的肠道菌群结构进行分析,不同表型的狼疮患者肠道微生物的多样性较健康人群存在不同的差异。狼疮肾炎及狼疮胃肠道损害的患者厚壁菌门减少(42.48%、49.37%vs 60.61%)、变形菌门增多(43.29%、17.61%vs 8.72%),尤其狼疮胃肠道损害的患者中肠道微生态严重紊乱,厚壁菌门及拟杆菌门所占比例仅占50.39%,而变形菌门(43.29%vs 8.73%,P=0.021)、肠杆菌科(42.54%vs 6.79%,P=0.018)及大肠志贺菌(36.03%vs 2.61%,P=0.040)显著富集。3.多中心系统性红斑狼疮起始队列部分,队列中共有患者1514人,女性为1370人,男性144人,平均发病年龄31.36岁,5.22%有风湿免疫病家族史,有异常生育史患者占16.24%。与我中心前期包含2104例患者的患病队列相比,SLE起病年龄(P0.001)、确诊年龄(P=0.003)更晚。出现颊部红斑及盘状红斑患者分别占49.47%和10.30%,光过敏占24.97%,23.98%患者有口腔溃疡,53.30%的患者存在关节炎,浆膜炎的比例为22.85%,肾脏受累和神经受累的比例分别为46.10%和6.93%,67.70%患者有血液系统病变。较患病队列,起始队列的浆膜炎(P0.001)、神经病变(P0.001)、血液系统病变比例更高(P0.001)。在自身抗体的检查中,抗dsDNA抗体、抗Sm抗体、抗SSA抗体与抗SSB抗体的阳性率分别为39.36%、22.66%、32.16%与10.96%。起始队列中抗核抗体阳性率较患病队列低(P0.001)。结论:1.本研究首次建立了系统性红斑狼疮相关胃肠道受累的临床研究队列,全面描述狼疮这一少见表型的临床特点,发现SLE-IPO患者浆膜炎、抗SSA抗体阳性率高,SLE患者发生IPO的危险因素包括浆膜炎、神经病变、抗SSA抗体阳性、抗SSB抗体阳性及补体减低,5年生存率为86.73%,3年累积复发率为37.04%,起病晚、合并神经系统病变是预后不良的危险因素,抗SSA抗体阳性为保护性因素,疾病早期给予一线免疫抑制剂治疗、达到早期缓解可提高SLE-IPO患者的长期生存率并改善预后。SLE-PLE以低白蛋白、7水肿、多浆膜腔积液为特点,1/3患者无消化系统症状。诊断性实验锝99标记的白蛋白核素闪烁显像显示蛋白漏出部位多为小肠。5年生存率为88.54%。严重的低白蛋白血症、24h尿蛋白升高为预后不良相关因素,早期识别、诊断并加强支持治疗将改善SLE-PLE患者的预后。2.肠道微生态在狼疮不同表型的患者中存在不同程度的紊乱,狼疮肾炎及狼疮胃肠道损害的患者中肠道菌群多样性显著下降,并出现厚壁菌门减少、变形菌门增多,重建微生态平衡有望使狼疮患者获益。3.建立系统性红斑狼疮起始队列,通过横断面研究揭示了亚洲中国人SLE起病初期的临床特点,为今后的预后研究打下坚实基础。
[Abstract]:Objective: 1. to explore the clinical characteristics, risk factors, survival and prognostic factors of systemic lupus erythematosus patients with different phenotypes by establishing a clinical cohort of single central systemic lupus erythematosus associated with Pseudointestinal obstruction and inprotein enteropathy, and to reveal the intestinal microbes in patients with systemic lupus erythematosus with different phenotypes, and to reveal the different phenotypes of.2. with systemic lupus erythematosus. The value of intestinal microorganism in the pathogenesis, diagnosis and treatment of lupus erythematosus.3. established the initial cohort of multicentre systemic lupus erythematosus studies, and made a cross-sectional analysis to lay a solid foundation for the prognosis of the study. Methods: 1. a retrospective review of systemic lupus erythematosus, which was hospitalized in Peking Union Medical College Hospital from 1997 to 2016, was reviewed. Pseudointestinal obstruction and systemic lupus erythematosus associated inprotein enteropathy, baseline time for the diagnosis of systemic lupus erythematosus associated gastrointestinal involvement, the baseline data of demography, family history, clinical features, immunological indicators and so on were collected and followed up with death and recurrence or death as the end point of the study. Using the life table method and the Kaplan-Meier curve description and analysis, the stratified Kaplan-Meier curve is tested by the Log-Rank method. The statistical significance index and the Cox single factor regression analysis are statistically significant for the Cox multiple factor regression analysis of the.2. intestinal microorganism research, collected from May 2016 to March 2017. The excrement of lupus gastrointestinal tract, lupus nephritis and neuropsychic lupus patients hospitalized in Peking Union Medical College Hospital was identified and divided by 16srDNA sequencing, and the difference between the phenotypes of systemic lupus erythematosus and the healthy control intestinal flora was compared with the.3. multicenter prognosis study, which included the cooperation of systemic lupus erythematosus in China. In group SLE, the patients who had been enrolled in the group for less than 6 months were enrolled in the group. The demographic information, family history, clinical manifestations, and immunological indicators were used as baseline data, and the baseline data were analyzed. Results: 1. the gastrointestinal tract involvement of systemic lupus erythematosus included systemic lupus erythematosus associated Pseudointestinal obstruction and systematic nature. Two types of SLE related inprotein enteropathy were included in 133 cases and 58 patients respectively, women were the main groups, accounting for 92.48% and 79.31%, age distribution from 11 to 71 years, 43.61% to 53.45% in patients with lupus gastrointestinal damage as the first manifestation of lupus. (1) SLE-IPO mainly manifested as intestinal obstruction symptoms, 21.05% to 24. 06% patients have urinary system symptoms, serotis is the most common combined involvement system, seen in 63.91% patients, 63.16%, 21.80%, 57.14% patients with kidney, nerve, and blood system lesions. The highest anti SSA antibody positive rate, 66.17%, patients with 84.96%.52.63% complements with renal pelvis ureteral dilatation, this part of the patients, bladder Cystine wall involvement (42.86%vs 6.35%, P0.001), hepatic bile duct dilatation (14.29%vs 3.17%, P=0.026) and serotitis (78.57%vs 47.62%, P0.001) were significantly higher than those without ureteropelvic dilatation. Some of the patients showed a triple sign of extensive cavity and visceral dilatation. Serotitis (OR=10.114, P=0.000), neuropathy (OR=4.336, P=0.000), anti SSA resistance. Body positive (OR=2.092, P=0.014), anti SSB antibody positive (OR=2.433, P=0.035), and complements (OR=2.685, P=0.003) were the risk factors for IPO in SLE patients. Baseline glucocorticoid use rate was 100%, 50.38% patients were treated with hormone shock, 85.71% used cyclophosphamide.SLE-IPO for poor prognosis, 1 years, 3 years, 5 year survival rate 91.51%, 89 respectively. .46%, 86.73%. infection is the main cause of death, accounting for 53.33%.1 years, 2 years, 3 years of cumulative recurrence rate of 14.71%, 26.32%, 37.04%. independent risk factors including late onset (HR=1.051, P=0.027), combined with nervous system lesions (HR=4.621, P=0.017), protective factors including anti SSA antibody positive (HR=0.530, P=0.039), early disease given to the disease. HR=0.209 (P=0.020) and early remission (HR=0.530, P=0.039) can improve the long-term survival rate of SLE-IPO patients and improve the prognosis. (2) SLE-PLE with low albumin (100%), edema (89.66%), serous cavity effusion (77.59%), 1/3 patients without digestive system symptoms. Diagnostic experimental technetium 99 labeled albumin nuclide flicker The scintigraphy showed that the leakage site of protein was mostly small intestine. The positive rate of anti SSA antibody was 51.72%, and 87.93% of patients had 1 years of complement reduction in.SLE-PLE patients and 3 years, 5 year survival rate was 91.49%, 91.49%, 88.54%. infection (40%), and lupus activity (40%) as the main cause of death. Severe hypoalbuminemia (x 2=9.061, P=0.003), 24h urine protein liter High (HR=1.553, P=0.012) is associated with poor prognosis. Early identification, diagnosis and strengthening of support therapy will improve the prognosis of SLE-PLE patients with.2. into the group of lupus gastrointestinal tract, lupus nephritis and neuromental lupus, 4 cases in each, 7 healthy controls, from the portal, family, genus and species level to normal people and systemic lupus erythematosus. The intestinal microflora structure of patients with bed phenotype was analyzed. The diversity of intestinal microflora in patients with lupus with different phenotypes was different from that of healthy people. Patients with lupus nephritis and lupus gastrointestinal damage were reduced (42.48%, 49.37%vs 60.61%), more Proteus (43.29%, 17.61%vs 8.72%), especially the gastrointestinal tract damage in lupus. In the patients, the intestinal microecology was seriously disturbed, the proportion of the bacilli and the bacteriobacteria was only 50.39%, while the Proteus (43.29%vs 8.73%, P=0.021), the Enterobacteriaceae (42.54%vs 6.79%, P=0.018) and the Shigella coliformis (36.03%vs 2.61%, P=0.040) were significantly enriched in the starting part of the.3. multiple middle heart lupus erythematosus, with a cohort of 1514 patients. There were 1370 women and 144 men, with an average age of 31.36 years and 5.22% family history of rheumatic immune disease. The patients with abnormal birth history accounted for 16.24%. and the cohort of 2104 patients in the early stage of my center. The age of SLE onset (P0.001) and the age of diagnosis (P=0.003) were later. 49.47% and 10. of the buccal erythema and discoid erythema were found, respectively. 30%, light allergy accounted for 24.97%, 23.98% patients had oral ulcers, 53.30% of the patients had arthritis, the proportion of serotis was 22.85%, the proportion of renal involvement and nerve involvement was 46.10% and 6.93%, and 67.70% of the patients had hematological changes. The incidence of serotis (P0.001), neuropathy (P0.001), and the proportion of blood system lesions in the onset cohort were compared with those in the onset cohort. Higher (P0.001). In the examination of autoantibodies, the positive rates of anti dsDNA, anti Sm, SSA and SSB antibodies were 39.36%, 22.66%, 32.16% and 10.96%. in the initial cohort were lower than those of the disease cohort (P0.001). Conclusion: the clinical study of systemic lupus erythematosus associated gastrointestinal involvement was first established in the 1. study. The cohort described the clinical features of the rare phenotypes of lupus, and found that SLE-IPO patients were serous and anti SSA positive. The risk factors for IPO in SLE patients included serotis, neuropathy, anti SSA antibody positive, anti SSB antibody positive and complements, the 5 year survival rate was 86.73%, the 3 year cumulative recurrence rate was 37.04%, the onset was late, merged late. Neuropathy is a risk factor for poor prognosis. Anti SSA antibody positive is a protective factor. Early stage of the disease is treated with a first-line immunosuppressive agent. Early remission can improve the long-term survival rate of SLE-IPO patients and improve the prognosis of.SLE-PLE with low albumin, 7 edema, multiple plasma membrane effusion, and no digestive system symptoms in 1/3 patients. The albumin nuclide scintigraphy labeled with technetium 99 showed that the leakage site of the protein was mostly low.5 years of small intestine with 88.54%. severe hypoalbuminemia, and the increase of 24h urine protein was the associated factor of poor prognosis. Early recognition, diagnosis and strengthening support therapy would improve the prognosis of SLE-PLE patients with.2. intestinal microecology in the different phenotypes of lupus The diversity of intestinal flora in patients with different degrees of disorder, lupus nephritis and lupus gastrointestinal damage decreased significantly in patients with lupus nephritis, thicker phylum and Proteus, and the reconstructive microecological balance was expected to benefit lupus patients to establish the initial cohort of systemic lupus erythematosus, which was revealed through cross-sectional study in Asia. The clinical characteristics of SLE at the early stage of onset of illness in Chinese people lay a solid foundation for future prognosis research.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R593.241

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