本文選題：系統(tǒng)性紅斑狼瘡 + 假性腸梗阻��； 參考：《北京協(xié)和醫(yī)學院》2017年博士論文

【摘要】：目的:1.通過建立單中心系統(tǒng)性紅斑狼瘡相關(guān)假性腸梗阻及失蛋白腸病的臨床研究隊列,探討疾病的臨床特征、危險因素、生存情況及預(yù)后因素。2.分析不同表型系統(tǒng)性紅斑狼瘡患者的腸道微生物,揭示其與系統(tǒng)性紅斑狼瘡不同表型間存在的規(guī)律,探討腸道微生物在狼瘡發(fā)病、診斷及治療中的價值。3.建立多中心系統(tǒng)性紅斑狼瘡研究的起始隊列,進行橫斷面分析,為預(yù)后研究打下堅實基礎(chǔ)。方法:1.回顧性納入1997年至2016年間于北京協(xié)和醫(yī)院住院診治的系統(tǒng)性紅斑狼瘡相關(guān)假性腸梗阻及系統(tǒng)性紅斑狼瘡相關(guān)失蛋白腸病患者,以系統(tǒng)性紅斑狼瘡相關(guān)胃腸道受累的臨床確診時間為基線時間,收集人口學、家族史、臨床特征、免疫學指標等基線資料并進行隨訪,分別以死亡和出現(xiàn)復(fù)發(fā)或死亡作為研究終點。采用壽命表法及Kaplan-Meier曲線描述及分析,分層Kaplan-Meier曲線應(yīng)用Log-Rank法檢驗,對其中具有統(tǒng)計學意義的指標及Cox單因素回歸分析具有統(tǒng)計學意義的指標進一步進行Cox多因素回歸分析。2.腸道微生物研究方面,收集2016年5月至2017年3月于北京協(xié)和醫(yī)院住院治療的狼瘡胃腸道受累、狼瘡腎炎及神經(jīng)精神狼瘡患者的糞便,通過16srDNA測序鑒定并劃分細菌類群,比較系統(tǒng)性紅斑狼瘡各表型與健康對照間腸道菌群的差異。3.多中心預(yù)后研究方面,納入中國系統(tǒng)性紅斑狼瘡協(xié)作組平臺中SLE發(fā)病至登記入組時間小于6個月的患者,收集入組時人口學信息、家族史、臨床表現(xiàn)、免疫指標作為基線資料,對基線資料進行橫斷面分析。結(jié)果:1.系統(tǒng)性紅斑狼瘡胃腸道受累主要包括系統(tǒng)性紅斑狼瘡相關(guān)假性腸梗阻及系統(tǒng)性紅斑狼瘡相關(guān)失蛋白腸病兩種類型,分別入組133例和58例患者,女性均為主要發(fā)病人群,分別占92.48%和79.31%,年齡分布在11歲至71歲之間,43.61%至53.45%患者以狼瘡胃腸道損害作為狼瘡首發(fā)表現(xiàn)出現(xiàn)。(1)SLE-IPO主要表現(xiàn)為腸梗阻癥狀,21.05%至24.06%患者存在泌尿系統(tǒng)癥狀,漿膜炎為最常見合并受累系統(tǒng),見于63.91%患者,分別有63.16%、21.80%、57.14%患者合并腎臟、神經(jīng)、血液系統(tǒng)病變。抗SSA抗體陽性率最高,為66.17%,補體減低患者占84.96%。52.63%的患者合并腎盂輸尿管擴張,這部分患者中,膀胱壁受累(42.86%vs 6.35%,P0.001)、肝膽管擴張(14.29%vs 3.17%,P=0.026)及漿膜炎(78.57%vs 47.62%,P0.001)的比例均顯著高于無腎盂輸尿管擴張的患者,部分患者表現(xiàn)為廣泛空腔臟器擴張的三聯(lián)征。漿膜炎(OR=10.114,P=0.000),神經(jīng)病變(OR=4.336,P=0.000),抗 SSA 抗體陽性(OR=2.092,P=0.014),抗 SSB 抗體陽性(OR=2.433,P=0.035),補體減低(OR=2.685,P=0.003)是 SLE患者發(fā)生IPO的危險因素�；�糖皮質(zhì)激素使用率為100%,50.38%患者進行激素沖擊治療,85.71%應(yīng)用環(huán)磷酰胺。SLE-IPO的預(yù)后較差,1年、3年、5年生存率分別為91.51%、89.46%、86.73%。感染為主要死亡原因,占53.33%。1年、2年、3年的累積復(fù)發(fā)率分別為14.71%、26.32%、37.04%。預(yù)后不良的獨立危險因素包括起病晚(HR=1.051,P=0.027)、合并神經(jīng)系統(tǒng)病變(HR=4.621,P=0.017),保護性因素包括抗SSA抗體陽性(HR=0.530,P=0.039),疾病早期給予一線免疫抑制劑治療(HR=0.209,P=0.020)、達到早期緩解(HR=0.530,P=0.039)則可提高SLE-IPO患者的長期生存率并改善預(yù)后。(2)SLE-PLE以低白蛋白(100%)、水腫(89.66%)、漿膜腔積液(77.59%)為特點,1/3患者無消化系統(tǒng)癥狀。診斷性實驗锝99標記的白蛋白核素閃爍顯像顯示蛋白漏出部位多為小腸。抗SSA抗體陽性率為51.72%,87.93%的患者出現(xiàn)補體降低。SLE-PLE患者的1年、3年、5年生存率分別為91.49%、91.49%、88.54%。感染(40.00%)、狼瘡活動(40.00%)為主要死亡原因。嚴重的低白蛋白血癥(χ2=9.061,P=0.003)、24h尿蛋白升高(HR=1.553,P=0.012)為預(yù)后不良相關(guān)因素,早期識別、診斷并加強支持治療將改善SLE-PLE患者的預(yù)后。2.入組狼瘡胃腸道受累、狼瘡腎炎及神經(jīng)精神狼瘡患者各4例、健康對照7例,分別從門、科、屬、種的水平上對正常人和系統(tǒng)性紅斑狼瘡的不同臨床表型患者的腸道菌群結(jié)構(gòu)進行分析,不同表型的狼瘡患者腸道微生物的多樣性較健康人群存在不同的差異。狼瘡腎炎及狼瘡胃腸道損害的患者厚壁菌門減少(42.48%、49.37%vs 60.61%)、變形菌門增多(43.29%、17.61%vs 8.72%),尤其狼瘡胃腸道損害的患者中腸道微生態(tài)嚴重紊亂,厚壁菌門及擬桿菌門所占比例僅占50.39%,而變形菌門(43.29%vs 8.73%,P=0.021)、腸桿菌科(42.54%vs 6.79%,P=0.018)及大腸志賀菌(36.03%vs 2.61%,P=0.040)顯著富集。3.多中心系統(tǒng)性紅斑狼瘡起始隊列部分,隊列中共有患者1514人,女性為1370人,男性144人,平均發(fā)病年齡31.36歲,5.22%有風濕免疫病家族史,有異常生育史患者占16.24%。與我中心前期包含2104例患者的患病隊列相比,SLE起病年齡(P0.001)、確診年齡(P=0.003)更晚。出現(xiàn)頰部紅斑及盤狀紅斑患者分別占49.47%和10.30%,光過敏占24.97%,23.98%患者有口腔潰瘍,53.30%的患者存在關(guān)節(jié)炎,漿膜炎的比例為22.85%,腎臟受累和神經(jīng)受累的比例分別為46.10%和6.93%,67.70%患者有血液系統(tǒng)病變。較患病隊列,起始隊列的漿膜炎(P0.001)、神經(jīng)病變(P0.001)、血液系統(tǒng)病變比例更高(P0.001)。在自身抗體的檢查中,抗dsDNA抗體、抗Sm抗體、抗SSA抗體與抗SSB抗體的陽性率分別為39.36%、22.66%、32.16%與10.96%。起始隊列中抗核抗體陽性率較患病隊列低(P0.001)。結(jié)論:1.本研究首次建立了系統(tǒng)性紅斑狼瘡相關(guān)胃腸道受累的臨床研究隊列,全面描述狼瘡這一少見表型的臨床特點,發(fā)現(xiàn)SLE-IPO患者漿膜炎、抗SSA抗體陽性率高,SLE患者發(fā)生IPO的危險因素包括漿膜炎、神經(jīng)病變、抗SSA抗體陽性、抗SSB抗體陽性及補體減低,5年生存率為86.73%,3年累積復(fù)發(fā)率為37.04%,起病晚、合并神經(jīng)系統(tǒng)病變是預(yù)后不良的危險因素,抗SSA抗體陽性為保護性因素,疾病早期給予一線免疫抑制劑治療、達到早期緩解可提高SLE-IPO患者的長期生存率并改善預(yù)后。SLE-PLE以低白蛋白、7水腫、多漿膜腔積液為特點,1/3患者無消化系統(tǒng)癥狀。診斷性實驗锝99標記的白蛋白核素閃爍顯像顯示蛋白漏出部位多為小腸。5年生存率為88.54%。嚴重的低白蛋白血癥、24h尿蛋白升高為預(yù)后不良相關(guān)因素,早期識別、診斷并加強支持治療將改善SLE-PLE患者的預(yù)后。2.腸道微生態(tài)在狼瘡不同表型的患者中存在不同程度的紊亂,狼瘡腎炎及狼瘡胃腸道損害的患者中腸道菌群多樣性顯著下降,并出現(xiàn)厚壁菌門減少、變形菌門增多,重建微生態(tài)平衡有望使狼瘡患者獲益。3.建立系統(tǒng)性紅斑狼瘡起始隊列,通過橫斷面研究揭示了亞洲中國人SLE起病初期的臨床特點,為今后的預(yù)后研究打下堅實基礎(chǔ)。
[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.
【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R593.241

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