临床无肌病型皮肌炎合并急性间质性肺病预后相关危险因素及中性粒细胞、Th17细胞在疾病发病机制中作用的研究

发布时间：2018-03-10 00:22

本文选题：无肌病型皮肌炎　切入点：间质性肺病　出处：《上海交通大学》2015年博士论文　论文类型：学位论文

【摘要】：背景和目的临床无肌病型皮肌炎(Clinically amyopathic dermatomyositis,CADM)是近年来备受瞩目的一种风湿免疫病,属于特发性肌炎之中皮肌炎(dermatomyositis,DM)的一种特殊亚型。CADM具有典型的皮肌炎的皮肤损害,伴有轻微或没有肌炎的临床表现,并且实验室检查如血清酶学、肌电图和肌肉活检有轻微或无异常。虽然CADM的发病率为2.08/100万人,但具有易合并间质性肺病(interstitial lung disease,ILD)的特点,ILD的发生率为57%,其ILD病程及严重度也是多变的。然而,快速进展型间质性肺病(rapidly progressive interstitial lung disease,RPILD)并伴有急性呼吸衰竭却最多见于CADM。即使在大剂量的糖皮质激素及免疫抑制剂的干预下,RPILD在1-3个月内发生急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS),导致患者死亡。这种情况特别多见于东亚人群(中国,日本),明显高于高加索人群。对这类病人随访的研究发现,CADM合并RPILD在确诊后的第一年,其生存曲线呈几乎直线下降,随后进入平台期。仁济风湿科的回顾研究亦发现,这类患者6月生存率仅为41%。回顾仁济医院2012-2014年住院患者死亡率为1.42%,其中CADM-ILD死亡率占总体死亡患者的26.7%。CADM合并RPILD治疗非常棘手,即便使用大剂量糖皮质激素疗效甚微,目前尚无针对这类患者可推荐的治疗方案。与其他结缔组织病相比,虽然cadm的发病率比较低,然而这类患者在诊断初期所面临的死亡风险更高,是一项巨大医学的挑战,因此需要投入更多关注。有研究发现,中性粒细胞可能参与炎性肌病合并ild的发生,为明确中性粒细胞在cadm-ild的作用,本研究第一部分系统地回顾并分析了55例患者的临床资料及转归,寻找并发现中性粒细胞与疾病的预后具有一定的关联。第二部分研究cadm-ild患者中性粒细胞活化分子的表达、t辅助细胞(thelpercell,th)是否与cadm-ild疾病活动存在关联,并研究它们在疾病中的作用。方法1)回顾2012-2014年,仁济医院风湿科诊断明确的cadm合并ild活动期患者。使用cox生存回归分析法分析入选患者的临床资料,分析与死亡相关的危险因素。2)cadm合并ild患者和经典皮肌炎合并ild患者为对照组各18例,检测血清il8;中性粒细胞活化标志物的mrna表达水平;th细胞比例;比较两组间的差异。使用偏最小二乘法(partialleastsquares,pls)模型分析各检测指标对疾病活动度的权重。结果cox单因素生存回归分析提示急性间质性肺炎(acuteinterstitialpneumonia,aip),中性粒细胞/淋巴细胞比例(neutrophillymphocyteratio,nlr),血清铁蛋白,血清乳酸脱氢酶(lactatedehydrogenase,ldh)、用量肺活量(forcedpercentualvitalcapacity,fvc%),一氧化碳弥散功能(carbon monoxide diffusing capacity,DLCO%)和胸部HRCT评分是与CADM-ILD患者生存相关的危险因素。COX多因素生存回归分析提示AIP、高NLR和高HRCT评分是CADM-ILD患者1年生存率密切相关的因素。大剂量糖皮质激素不能改善患者总体及急性ILD生存率。钙调磷酸酶抑制剂改善患者总体生存率及AIP生存率。早期使用巴利昔单抗可能改善CADM-ILD活动期患者预后。CADM-ILD患者的血清IL-8水平、外周血中性粒细胞CD11b、MCL1和IL18的mRNA表达水平和Th17细胞比例与DM-ILD相比明显升高;血清IL-8水平、外周血中性粒细胞CD11b、MCL1和IL18的mRNA表达水平和Th17细胞比例在疾病缓解期明显下降。外周血中性粒细胞CD11b的mRNA表达水平与胸部HRCT评分呈正性相关。PLS模型分析提示,中性粒细胞CD11b和IL18的mRNA表达水平及Th17细胞比例是与疾病活动度相关的前三位主要因子。结论AIP、高NLR和高胸部HRCT评分是CADM-ILD患者1年不良预后密切相关的因素。大剂量糖皮质激素不能改善患者总体生存率及AIP生存率;钙调磷酸酶抑制剂可改善患者总体生存率及AIP生存率;早期使用巴利昔单抗可能改善CADM-ILD活动期患者预后。外周血中性粒细胞活化与Th17细胞比例在CADM的急性间质性肺炎发生、发展中具有一定的作用。
[Abstract]:Background and objective: the clinical amyopathic dermatomyositis (Clinically amyopathic, dermatomyositis, CADM) is a recent high-profile rheumatic disease, belong to idiopathic myositis in dermatomyositis (dermatomyositis, DM) skin lesions in a special subtype.CADM has typical dermatomyositis, with mild or no myositis and clinical manifestations. Laboratory tests such as serum enzymes, electromyography and muscle biopsy with mild or no abnormalities. Although the incidence of CADM was 2.08/100 million, but is easily complicated with interstitial lung disease (interstitial lung, disease, ILD) characteristics, the incidence of ILD was 57% in the course of ILD and the severity is also variable. However, fast progressive interstitial lung disease (rapidly progressive interstitial lung disease, RPILD) accompanied by acute respiratory failure is most common in CADM. even in large doses of glucocorticoids and immunosuppressive Agent under the intervention of RPILD occurred within 1-3 months of acute respiratory distress syndrome (acute respiratory distress syndrome, ARDS), cause the death of the patient. This situation is particularly prevalent in East Asian populations (China, Japan), was significantly higher than that in Caucasian population. Research on this type of follow-up found that CADM combined with RPILD diagnosed in the first year the survival curve was almost straight down, then into the platform. The Department of rheumatism Renji retrospective study also found that this kind of patient survival rate is only 41%. in June 2012-2014 years review of Renji Hospital inpatient mortality rate was 1.42%, which accounted for the overall mortality of CADM-ILD death in 26.7%.CADM patients with RPILD treated patients is very difficult, even if the use of large doses of sugar corticosteroids have little effect, there is no treatment options for these patients can be recommended. Compared with other connective tissue diseases, although the incidence of CADM is relatively low, but this The risk of death in patients with early diagnosis in the face of higher, is a huge medical challenge, so it needs more attention. Studies have found that the occurrence of neutrophils may participate in inflammatory myopathy with ILD, clear neutrophils in the role of the cadm-ild, the first part of this study is a systematic review and prognosis analysis of the clinical data of 55 patients, find out its relationship with the prognosis of neutrophil activation and disease. The second part studies the cadm-ild of neutrophils in patients with molecular expression of T helper cells (thelpercell, th) is associated with cadm-ild disease activity, and to study their roles in diseases. Methods 1 review of 2012-2014 years), Renji Hospital Department of rheumatism diagnosed CADM and ILD patients. The clinical data of patients with Cox survival regression analysis, correlation analysis and death The risk factors of.2) in patients with CADM in patients with ILD and ILD for the classic dermatomyositis and control group of 18 cases, the detection of serum IL8; activation marker mRNA expression level of neutrophil ratio; Th cells; compare the differences between the two groups. Using partial least squares (partialleastsquares, PLS) model analysis indexes weight of disease the activity of Cox. The results of single factor regression analysis showed that the survival of acute interstitial pneumonia (acuteinterstitialpneumonia, AIP), neutrophil / lymphocyte ratio (neutrophillymphocyteratio, NLR), serum ferritin, serum lactate dehydrogenase (LactateDehydrogenase, LDH), the amount of vital capacity (forcedpercentualvitalcapacity, fvc%), carbon monoxide diffusing (carbon monoxide diffusion function capacity DLCO%), and chest HRCT score is related to the risk factors of.COX multivariate regression analysis showed that AIP survival in patients with CADM-ILD, High NLR and high HRCT score is CADM-ILD, the 1 year survival rate of patients is closely related to the factors. High dose corticosteroids did not improve the overall survival rate of patients with acute and ILD. Calcineurin inhibitors improve patient survival rate and overall survival rate of AIP. The early use of basiliximab may improve the level of serum IL-8 CADM-ILD in patients with the prognosis of patients with.CADM-ILD the peripheral blood neutrophil CD11b, MCL1 and IL18 mRNA expression level and the percentage of Th17 cells compared with DM-ILD significantly increased; the level of serum IL-8, peripheral blood neutrophil CD11b, MCL1 and IL18 mRNA expression level and the percentage of Th17 cells in disease remission decreased significantly. Peripheral blood neutrophils the CD11b expression of mRNA and HRCT were positively related to chest.PLS model analysis showed that IL18, CD11b and neutrophil mRNA expression level and the percentage of Th17 cells is associated with disease activity The three major factor. Conclusion AIP, high NLR and high HRCT score are the 1 Factors in the chest is closely related to the poor prognosis of CADM-ILD patients. High dose corticosteroids did not improve the overall patient survival rate and the survival rate of AIP; calcineurin inhibitors can improve overall patient survival rate and survival rate of AIP; the early use of basiliximab monoclonal antibody may improve the prognosis of patients with active CADM-ILD. Peripheral blood neutrophil activation and Th17 cell ratio in CADM acute interstitial pneumonia, has a certain role in the development.

【学位授予单位】：上海交通大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R593.26;R563

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