英夫利西单用和联合硫唑嘌呤诱导及维持克罗恩病患者深度缓解的疗效分析

发布时间：2017-12-28 16:20

本文关键词：英夫利西单用和联合硫唑嘌呤诱导及维持克罗恩病患者深度缓解的疗效分析　出处：《南方医科大学》2016年硕士论文　论文类型：学位论文

【摘要】：背景和目的：克罗恩病(Crohn's disease, CD)是一种可累及全消化道的慢性炎症性疾病。其治疗药物主要有5-氨基水杨酸(5-ASA)、糖皮质激素、免疫抑制剂(硫唑嘌呤、巯嘌呤、甲氨蝶呤)、生物制剂(肿瘤坏死因子拮抗剂)。伴随着新型抗TNF-α药物的生产和发展、内镜技术的进展和对CD疾病认识的深入,CD的治疗目标也逐步发生改变,由临床缓解、黏膜愈合发展到深度缓解和组织缓解。其中,深度缓解已应用于描述接受免疫抑制剂或TNF-α拮抗剂或两者联合治疗的CD患者没有临床症状和客观炎症表现的状态(定义为克罗恩病活动指数小于150分,并内镜下缓解)。国外已有研究证实英夫利西(Infliximab, IFX)可以诱导和维持CD患者获得深度缓解。然而,目前我国关于IFX对于CD患者获得深度缓解的作用和意义报道甚少,并且关于IFX单药治疗和IFX联合硫唑嘌呤(Azathioprine, AZA)治疗对CD患者获得深度缓解的疗效比较方面更缺乏大样本的相关临床研究数据。同时也尚不清楚升阶梯治疗方案和降阶梯治疗方案对深度缓解疗效等影响。基于以上研究背景,本研究通过回顾南方医科大学南方医院消化内科2011年5月至2015年5月期间住院诊治确诊为CD并且接受IFX单药或者IFX+AZA两药联合治疗的82例患者的人口学特点、临床表现、内镜表现、药物治疗方案和治疗效果等临床资料,分析比较IFX单药治疗和IFX+AZA两药联合治疗对诱导和维持CD患者临床缓解、黏膜愈合和深度缓解的疗效及安全性,同时分析升阶梯和降阶梯治疗对诱导和维持CD患者深度缓解的影响,从而为CD的治疗提供更多的依据。对象与方法：1.研究对象选取2011年5月至2015年5月期间在南方医科大学南方医院消化内科住院诊治确诊为CD并且接受IFX单药或者IFX+AZA两药联合治疗的患者为研究对象。患者CD的诊断综合了临床表现、影像学、消化内镜、病理组织学检查及随访观察结果等,并且符合中华医学会消化病学分会炎症性肠病协作组《炎症性肠病诊断与治疗的共识意见(2012年·广州)》有关CD的诊断标准。2.研究方法按照治疗方式的不同,将患者分为IFX单药治疗组和IFX+AZA两药联合治疗组。采用回顾性调查方法,记录并统计两组患者的临床资料,并计算患者克罗恩病活动度指数(CDAI)、临床缓解率、克罗恩病简化内镜评分(SES-CD)、黏膜愈合率、深度缓解率以及不良反应率。3.统计学处理采用SPSS20.0统计学软件进行分析,正态分布计量资料以x±s表示,计数资料以n和%表示;治疗前后的比较采用t检验；非正态分布的计量资料以中位数(M)[下四分位数(QL),上四分位数(QU)]表示,治疗前后的比较采用Wilcoxon非参数符号秩检验进行比较；率的比较使用卡方检验或Fisher确切概率法。P0.05为差异有统计学意义。结果：1.患者分组情况2011年5月至2015年5月在南方医科大学南方医院确诊CD并接受IFX治疗的患者共计82例,其中男54例,女28例,确诊年龄12-57岁,平均确诊年龄为(26.0±10.5)岁,其中79例患者为中度克罗恩病,3例患者为重度克罗恩病。根据治疗方案不同,患者分为IFX组和IFX+AZA组,其中48.8%(40/82)为IFX组,51.2%(42/82)为IFX+AZA组。2.两组患者基本情况比较IFX组40例患者中男性28例,女性12例,平均确诊年龄为(27.3±9.5)岁,平均治疗年龄为(28.0±9.6)岁,平均BMI为(18.5±3.1)kg/m2,既往有CD相关肠道手术者占22.5%(9/40),有肠外表现者占15.0%(6/40),其中2例为口腔溃疡,4例为关节痛。IFX+AZA组42例患者中男性26例,女性16例,平均确诊为(24.8±11.2)岁,平均治疗年龄为(25.4±11.3)岁,平均BMI为(17.5±2.7)kg/m2,既往有CD相关肠道手术者占19.0%(8/42),有肠外表现者占19.0%(8/42),其中1例为关节痛并结节性红斑,1例为关节痛并双侧眼巩膜炎,3例为口腔溃疡,3例为关节痛。两组患者的性别、年龄、肠外表现等资料对比差异无统计学意义(P0.05),具有可比性。3.两组患者实验室指标笔体重指数比较第14周和第30周时,IFX组和IFX+AZA组患者的WBC水平、CRP水平和ESR水平均较治疗前明显下降,患者炎症得到控制；而两组患者的HGB水平、ALB水平和体重指数均较治疗前升高,患者营养状态得到明显改善。但两组患者治疗后组间实验室指标和体重指数比较差异无统计学意义。4.两组患者临床缓解疗效比较第14周时,IFX组CDAI评分由[254.0(231.2,268.0]分下降为[87.5(55.5,118.0)]分,P0.05：IFX+AZA组CDAI评分由[256.0(231.7,346.7)]分下降为[85.0(49.8,121.0)]分,P0.05;但是两组间CDAI评分差异无统计学意义(P0.05)。两组的临床缓解率分别为90.0%86/40 vs.83.3%85/42)P0.05,差异无统计学意义,但数据显示IFX组的临床缓解率高。第30周时,IFX组CDAI评分由[254.0(231.2,268.0]分下降为[75.0(32.9,101.8)]分,P0.05；IFX+AZA组CDAI评分由[256.0(231.7,346.7)]分下降为[79.6(51.5,142.4)]分,P0.05：但是两组间CDAI评分差异没有统计学意义(P0.05)。两组的临床缓解率分别为92.5%87/40 vs.83.3%85/42)P0.05,差异无统计学意义,但数据显示IFX组的临床缓解率高。5.两组患者黏膜愈合疗效比较第14周时,IFX组有22例患者复查内镜,SES-CD评分由[10.9(7.1,17.1)]分下降为[3.6(0,5.3)]分,P0.05；IFX+AZA组有33例患者复查内镜,SES-CD评分由[12.0(6.8,15.2)]分下降为[2.8(0,6.6)]分,P0.05；但是两组间SES-CD评分比较差异没有统计学意义(P0.05)；两组的黏膜愈合率分别为：40.9%(9/22)vs.48.5%(16/33),P0.05,差异没有统计学意义,但数据显示IFX+AZA组黏膜愈合率较高。第30周时,IFX组SES-CD评分由[7.9(5.7,11.6)]分下降为[0.6(0,5.5)]分,P0.05；IFX+AZA组SES-CD评分由[11.0(6.5,15.0)]分下降为[0.1(0,5.3)]分,P0.05；然而两组间SES-CD评分比较差异没有统计学意义(P0.05)：两组的黏膜愈合率分别为：60.0%(24/40)vs.64.3%(27/42),P0.05,差异没有统计学意义,但数据显示IFX+AZA组黏膜愈合率较高。6.两组患者深度缓解疗效比较：6.1两组患者深度缓解率比较第14周时,IFX组有22例复查内镜,IFX+AZA组有33例复查内镜,两组的深度缓解率分别为：36.4%(8/22)vs.45.5%(15/33),P0.05。第30周时,两组患者均复查内镜,两组的深度缓解率分别为：57.5%(23/40)vs.59.5%(25/42),P0.05。两组深度缓解率的差异没有统计学意义,但数据显示IFX+AZA组深度缓解率较高。第14周和第30周时,IFX组和IFX+AZA组中,各组内获得深度缓解的患者中CRP水平5mg/L的比例明显均高于未获得深度缓解的患者。然而两组患者组间比较差异无统计学意义。6.2早期获得深度缓解与未获得深度缓解疗效分析根据患者第14周时深度缓解情况,将每组患者再分为早期获得深度缓解组和早期未获得深度缓解组。第30周时,IFX组有87.5%(7/8)早期获得深度缓解的患者在30周时维持深度缓解;IFX+AZA组有93.3%(14/15)早期获得深度缓解的患者在30周时维持深度缓解。且IFX组和IFX+AZA组中早期获得深度缓解的患者的CDAI评分、SES-CD评分、WBC水平、CRP水平和ESR水平均低于早期未获得深度缓解的患者,而HGB水平、ALB水平和BMI值均高于早期未获得深度缓解的患者,提示早期获得深度缓解有利于控制炎症和改善患者营养状态。6.3升或降阶梯治疗方案对深度缓解的影响IFX组有27.5%(11/40)患者采用升阶梯治疗方案,IFX+AZA组有28.6%(12/42)患者采用升阶梯治疗方案,在治疗后第14周和第30周,IFX组中升阶梯治疗患者和降阶梯治疗患者的深度缓解率分别为[33.3%(2/6)vs.37.5%(6/16),P0.05]和[54.5%(6/11)vs.58.6%(17/29),P0.05]；第14周时IFX+AZA组中升阶梯治疗患者均未获得深度缓解,而采用降阶梯治疗患者中有60.0%(15/25)获得深度缓解率,第30周时IFX+AZA组中升阶梯治疗患者和降阶梯治疗患者的深度缓解率分别为41.7%(5/12)vs.66.7%(20/30),P0.05：数据显示两组患者组内均是采用降阶梯治疗方案患者的深度缓解率高于采用升阶梯治疗方案的患者,但是差异无统计学意义。两组组间比较差异也无统计学意义。7.不良反应IFX组有25.0%(10/40)患者出现不良反应,IFX+AZA组有26.2%(11／42)患者出现不良反应,两组不良反应发生率比较差异没有统计学意义。两组患者均未出现其他严重不良反应。结论：本次回顾性研究发现,IFX和IFX+AZA两种方法均可有效诱导和维持中度CD患者临床缓解、黏膜愈合和深度缓解,两组患者的临床缓解率、黏膜愈合率和深度缓解率比较差异无统计学意义,但数据显示IFX+AZA组的黏膜愈合率和深度缓解率均高于IFX组,IFX+AZA两药联合治疗可能在促进黏膜愈合和深度缓解方面有更优趋势。并且,早期获得深度缓解有助于患者炎症控制和营养改善,本研究发现,降阶梯治疗方案有助于患者获得深度缓解,可能有较好优势。
[Abstract]:Background and purpose: Crohn's disease (CD) is a chronic inflammatory disease that can involve the whole digestive tract. The drugs are mainly 5- aminosalicylic acid (5-ASA), corticosteroids, immunosuppressants (azathioprine, mercaptopurine, methotrexate), biological agents (tumor necrosis factor antagonist). Along with the production and development of new anti TNF- drugs, the progress of endoscopic technology and the recognition of CD disease, the therapeutic targets of CD have gradually changed, from clinical alleviation, mucosal healing to deep remission and tissue remission. Deep remission has been applied to describe the situation of CD patients who received immunosuppressive drugs or TNF- alpha antagonists or combination therapy without clinical symptoms and objective inflammatory manifestations (defined as Crohn disease activity index less than 150 points, and endoscopic remission). Studies have shown that Indira J Lici (Infliximab, IFX) can induce and maintain the depth remission of CD patients. However, at present our country about IFX for patients with CD depth relief function and significance of the report is very little, and on the IFX and IFX combined with azathioprine monotherapy (Azathioprine, AZA) after the treatment of CD with effective depth relief and lack of relevant clinical research data of large sample comparison. At the same time, it is not clear that the escalation treatment plan and the step down treatment plan on the effect of depth remission. Based on the above research background, this study by reviewing the South Hospital of Southern Medical University from May 2011 to May 2015 during the period of hospitalization were diagnosed as CD and received IFX monotherapy or IFX+AZA two drugs in the treatment of 82 cases of patients with the demographic characteristics, clinical manifestations, clinical data, endoscopic table of drug treatment and the treatment results were compared between IFX single drug IFX+AZA treatment and two drugs in the treatment of the efficacy and safety of induction and maintenance of clinical remission in patients with CD in remission, mucosal healing and depth, and analysis step up and step-down therapy effect on the induction and maintenance of remission in patients with CD depth, so as to provide more evidence for the treatment of CD. Participants and methods: 1. the subjects were selected from May 2011 to May 2015, who were diagnosed as CD in the Department of Gastroenterology, Nanfang Hospital of Southern Medical University, and were treated with IFX single or IFX+AZA two drugs. The diagnosis of CD the clinical manifestations, imaging, endoscopy and pathological examination and follow-up results, and in line with the branch of inflammatory bowel disease group "diagnosis and treatment of inflammatory bowel disease consensus on digestive diseases of Chinese Medical Association (2012 - Guangzhou)" diagnostic criteria for CD. 2. in accordance with the different methods of treatment, the patients were divided into IFX single drug treatment group and IFX+AZA two medicine group. The clinical data of two groups of patients were recorded and counted by retrospective investigation method, and the activity index (CDAI), clinical remission rate, Crohn disease simplified endoscopic score (SES-CD), mucosal healing rate, depth remission rate and adverse reaction rate were calculated. 3. statistical analysis using SPSS20.0 statistical software, the normal distribution of measurement data with x + s said the count data expressed in N and% compared with before and after treatment; t test; non normal distribution of measurement data with median (M) [four quantile (QL), four (the number of bits QU)] said, before and after treatment were compared by comparing the nonparametric Wilcoxon signed rank test; were compared using chi square test or Fisher exact probability method. The difference was statistically significant in P0.05. Results: 1. patients were grouped and treated by IFX from May 2011 to May 2015 in Nanfang Hospital of Southern Medical University diagnosed CD patients a total of 82 cases, male 54 cases, female 28 cases, with age 12-57 years old, the average age of diagnosis was (26 + 10.5) years old, among them 79 cases of Crohn's disease, 3 patients severe Crohn's disease. According to the different treatments, the patients were divided into group IFX and group IFX+AZA, of which 48.8% (40/82) was group IFX and 51.2% (42/82) was group IFX+AZA. The basic situation of the 2. patients in the two groups compared with IFX group of 40 patients, 28 were male, 12 females, the average age of diagnosis was (27.3 + 9.5) years old, the average age for the treatment of (28 + 9.6) years old, the average BMI (18.5 + 3.1) kg/m2, with a history of CD related intestinal surgery accounted for 22.5% (9/40), performance of parenteral accounted for 15% (6/40), including 2 cases of oral ulcer, 4 cases of joint pain. IFX+AZA group of 42 patients, male 26 cases, female 16 cases, average diagnosed (24.8 + 11.2) years old, the average age for the treatment of (25.4 + 11.3) years old, the average BMI (17.5 + 2.7) kg/m2, with a history of CD related intestinal surgery accounted for 19% (8/42), parenteral for performance 19% (8/42), including 1 cases of joint pain and erythema nodosum, 1 cases of joint pain and bilateral ocular scleritis, 3 cases of oral ulcer, 3 cases of joint pain. There was no significant difference in the sex, age, and expression of the two groups of patients (P0.05), which was comparable. 3. two groups of patients with laboratory indexes pen body mass index comparison of fourteenth and thirtieth weeks, IFX group and IFX+AZA group were WBC, CRP and ESR level were significantly decreased compared with before treatment, patients with inflammation under control; and the two group of patients with HGB and ALB levels and body mass index were higher than that before treatment, nutrition the state of patients improved obviously. However, there was no significant difference in the laboratory index and body mass index between the two groups after treatment. 4. of the two groups of patients with clinical remission compared to fourteenth weeks, IFX group CDAI score by [254.0 (231.2268.0] (55.5118.0)] decreased to [87.5, P0.05:IFX+AZA group CDAI score by [256.0 (231.7346.7)] decreased [85.0 (49.8121.0)], P0.05; but there was no significant difference of CDAI score between the two groups (P0.05). The clinical remission rate of the two groups was 90.0%86/40 vs.83.3%85/42) P0.05 respectively, the difference was not statistically significant, but the data showed that the clinical remission rate of the IFX group was high. At thirtieth weeks, IF
【学位授予单位】：南方医科大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R574.62

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