一项315例克罗恩病患者首次手术危险因素的队列研究

发布时间：2018-05-29 10:55

本文选题：克罗恩病 + 蒙特利尔分型　；参考：《南方医科大学》2014年硕士论文

【摘要】：背景和目的克罗恩病(Crohn's Disease, CD)是炎症性肠病(Inflammatory Bowel Disease, IBD)的一个主要亚型,是一种慢性复发性、炎性肉芽肿性疾病,病变呈节段性分布,可累及全消化道,以回肠末端和邻近结肠多见。CD在欧美国家是常见病,其年发病率约为6-15/10万,患病率约为50-200/10万。新近一项亚洲-太平洋地区多中心合作的流行病学调查表明,2011年4月1日至2012年3月31日,亚洲地区的CD年发病率平均为0.54/10万,CD在亚洲地区平均发病率仍然远低于西方欧美国家,但近20年来的流行病学研究显示,CD在亚洲地区的发病率呈上升趋势。克罗恩病的病因复杂,发病机制至今尚不清楚。近年的观点认为,CD的发生与基因遗传、环境因素和免疫因素均有关系,携带遗传易感基因的宿主在环境因素参与下,免疫功能紊乱,最终导致疾病发生。西方的大规模的流行病学发现CD患者的家族阳性率高达13.4%-18.0%,并且CD患者的一级亲属患CD的危险比普通人群高6-10倍。日本、韩国、中国香港报道的CD家族阳性率为1.51-2.80%,明显要低于西方国家的报道。同时,欧美国家的分子遗传学研究发现16号染色体上的NOD2/CARD15基因与白种人的克罗恩病发病明显相关,然而在亚洲人群中并未发现这一现象,这也说明亚洲人群CD发病同西方白色人种存在着基因遗传学的差异。除了遗传背景不一样,亚洲人群CD的临床特征和疾病的自然病程可能与西方白种人也有差异。而2005年世界胃肠病大会上提出的蒙特利尔分型为我们提供了一种可用于比较不同人群之间CD特征的标准。同时,由于CD患者在整个病程中手术率非常高,有研究表明,有高达70-90%的CD患者在疾病发展进程中因为发生肠梗阻、瘘管形成、腹腔脓肿、消化道大出血等严重并发症而需要手术治疗。手术治疗仅仅是为了控制症状、恢复肠道功能,而并不能治愈本病。同时约有一半CD患者需要再次手术治疗。这种需要反复手术的病程严重危害患者的身心健康。目前关于预测CD首次手术危险因素的研究较少,NOD2/CARD15阳性、诊断年龄、累及上消化道、狭窄型、穿透型、肠外表现、肛周病变、吸烟行为被认为是CD患者的手术危险因素,但在各个独立的研究中的结果并不一致。目前我国关于CD的研究多数为临床病例报道,关于CD的临床特征、蒙特利尔分型和手术的危险因素的研究报道仍然较少。但是,明确CD患者的手术风险因素具有极其重要的临床意义。研究克罗恩病的疾病发展规律,确定CD手术率增高的危险因素,可以为临床上筛选出可能需要手术的高风险CD患者,并针对高危因素积极进行干预,以期降低CD患者的手术率,从而使患者从治疗中获得更大的益处。正是基于以上考虑,我们设计了本次华南地区单中心的回顾性历史队列研究,旨在了解CD的临床特征、蒙特利尔分型和疾病进程中的首次肠切除手术率,探讨导致CD患者手术率增高的危险因素,为临床上制定更有益于患者的治疗方案提供客观依据,同时也为将来多中心合作的前瞻性研究提供可以参考的数据。方法回顾性分析2003年1月1日-2012年12月31日在南方医科大学第一附属医院南方医院住院且既往无肠切除手术史的确诊为CD的连续性病例,收集患者的一般人口学资料、临床表现、实验室检查资料、影像学资料、内镜资料、病理资料、内科用药情况、手术情况,并对在我院住院期间未手术的CD患者进行电话随访。将疾病发生的时间点视为研究起点,首次肠切除手术或未手术的患者末次随访的时间点视为研究终点,研究起点到研究终点的时间间隔视为疾病病程,评估CD患者的首次肠切除手术率。应用Kaplan-Meier法估算年累积手术率,以log-rank检验各个临床变量是否均一,最后应用COX比例风险回归模型分析引起CD患者手术率升高的独立的危险因素,以相对危险度HR和95%的可信区间来衡量危险的大小,p0.05认为具有统计学差异。结果 1.共有315例CD患者纳入本次研究,男女性别比为2.6：1(228/87),91.9%的患者来自于华南地区。中位诊断年龄(32岁,9-69岁)比中位发病年龄(28岁,8-63岁)要晚4年。22例(7.0%)患者既往有阑尾切除史,30例(9.5%)患者有吸烟习惯且吸烟者均为男性,2例(0.6%)患者发现有克罗恩病阳性家族史。腹痛(87.6%)、腹泻(65.4%)、体重减轻(54.0%)是CD患者最常见的三大临床症状。 2.根据蒙特利尔分型,诊断年龄主要为A2型(17-40岁,66.0%)；疾病部位主要为回肠型(L1,50.5%),其次为回结肠型(L3,34.9%),结肠型(L2,14.6%)相对较少,有4.8%的患者累及上消化道(L4)；疾病行为主要为非狭窄非穿透型(B1,56.2%),其次为狭窄型(B2,36.5%),穿透型(B3,7.3%)较少,有18.1%的患者发现有肛周病变(P)。 3.纳入本次研究的CD患者的中位病程为4年(1-20年),整个疾病进程中,共有91例(28.9%)CD患者行手术治疗,其中14.3%的CD患者需要急诊手术,手术切除部位以“小肠(48.4%)”和“小肠+结肠(46.2%)”为主,单纯切除结肠(5.5%)的病例较少。CD患者首次手术原因有：肠梗阻(52例,57.14%)、肠道大出血(11例,12.09%)、肠穿孔(6例,6.59)、瘘管形成(6例,6.59)、回盲部包块(6例,6.59)、肠道巨大溃疡,内科药物治疗无效(6例,6.59)和其他(4例,4.40%)。 4.单变量分析 CD患者自发病起1年、2年、5年、10年、20年的累积手术率分别为12%、17%、26%、46%、82%。运用Kaplan-Meier法对各个临床分类变量进行分析,计算各自的5年累积手术率,以log-rank检验各个临床分类变量对累积手术率的影响是否具有统计学差异。单变量分析发现： (1)下列临床变量对CD患者首次肠切除的累积手术率的影响无统计学差异(均有p0.05)：诊断年龄分组(5年累及手术率：A1为40.0%,A2位30.1%,A3为36.7%,p=0.852)、累及上消化道(5年累及手术率：未累及上消化道为32.8%,累及上消化道为28.6%,p=0.813)、阑尾手术史(5年累及手术率：无阑尾手术史为33.3%,有阑尾切除史为25.0%,p=0.499)、肠外表现(5年累及手术率：无肠外表现为32.5%,有肠外表现为33.3%,p=0.740)； (2)下列临床变量与CD患者首次肠道手术率升高有关：性别(5年累积手术率：男性为34.3%,女性为28.0%,p=0.040)、病变部位(5年累积手术率：L1回肠型为37.5%,L2结肠型为12.0%,L3回结肠型为32.8%,p=0.015)、疾病行为(5年累积手术率：B1非狭窄非穿透型为12.3%,B2狭窄型为49.5%,B3穿透型为38.1%,p0.001)、吸烟(5年累积手术率：吸烟者为61.9%,不吸烟者为29.1%,p=0.002)。 (3)下列临床变量与首次肠切除手术率降低有关：肛周病变(5年累积手术率：有肛周病变者为10.7%,无肛周病变者36.4%,p=0.022)。此外,使用任何一种抗克罗恩病药物治疗的CD患者的累积手术率均显著低于未用药患者(p0.05)：氨基水杨酸类(5年累积手术率：未使用组为68.4%,使用组为17.6%,P0.001)、糖皮质激素(5年累积手术率：未使用组为50.5%,使用组为13.8%,P0.001,)、免疫抑制剂(5年累积手术率：未使用组为39.0%,使用组为2.9%,P0.001,)、生物制剂(5年累积手术率：未使用组为35.3%,使用组为13.0%,P=0.003)。 4.多变量分析进一步应用Cox比例风险回归模型(Cox proportional hazards regression model),将所有的临床变量代入同一个多变量分析模型,应用Wald检验各个临床变量有无统计学差异。在这个Cox多变量模型中,狭窄型(HR：4.803；95%CI：2.466-9.352；P0.001)、穿透型(HR：13.197；95%CI：5.938-29.330；P0.001)、吸烟(HR:1.932;95%CI:1.031-3.619;P=0.041)与首次肠切除手术率升高显著相关,而肛周病变与(HR:0.027;95%CI:0.193-0.889; P=0.024)和使用氨基水杨酸类制剂(HR:0.277;95%CI:0.162-0.474;P0.001)与首次肠切除手术率降低显著相关。结论本次华南地区单中心的队列研究发现,克罗恩病患者以男性多见,蒙特利尔分型中诊断年龄以A2型(17～40岁)为主,病变部位主要为L1型(回肠型),其次为L3型(回结肠型),疾病行为主要为B1型(非狭窄非穿透型)。在疾病发展进程中,克罗恩病患者的累积手术率逐年增高,狭窄型、穿透型和吸烟行为为首次肠切除手术的独立危险因素,肛周病变和氨基水杨酸制剂的使用则有可能降低CD患者首次肠切除手术的风险。
[Abstract]:Background and Objective Crohn ' s Disease ( CD ) is a major subtype of inflammatory bowel disease ( IBD ) . It is a chronic recurrent and inflammatory granulomas disease . The incidence of CD in Asia is still much lower than that of western European countries .

The etiology of Crohn ' s disease is complex and the pathogenesis is not clear . In recent years , the incidence of CD is related to genetic , environmental and immune factors . The positive rate of CD in CD patients is 1 . 51 - 2 . 80 % .

In addition to the genetic background , the clinical features of CD in Asian populations and the natural history of disease may differ from those in the West . The Montreal typing presented at the 2005 World Conference on Gastroenterology provides us with a standard that can be used to compare CD characteristics among different populations .

There are few studies on the risk factors of CD first operation , NOD2 / CARD15 positive , diagnosis age , upper gastrointestinal tract , narrow type , penetrating type , extraintestinal manifestation , perianal lesion , smoking behavior are considered to be the surgical risk factors of CD patients . However , the study of CD has very important clinical significance .

Based on the above considerations , we designed a retrospective historical cohort study of a single center in South China to understand the clinical features of the CD , the first bowel resection rate in the Montreal typing and disease progression , the risk factors leading to increased procedural rates in CD patients , an objective basis for the clinical setting of a treatment programme that is more beneficial to the patient , and data that can be referenced for prospective studies in future multi - center cooperation .

Methods A retrospective analysis was made on the continuous cases of CD in the southern hospital of the First Affiliated Hospital of South Medical University from January 1 , 2003 to December 31 , 2012 . The time point of the disease occurrence was considered as the study end point . The time interval between the starting point and the end of the study was considered as the study end point . The time interval between the starting point and the end of the study was regarded as the study end point . The time interval between the starting point and the end of the study was considered as the study end point .

Results

1 . A total of 315 CD patients were enrolled in the study , the sex ratio of male and female was 2.6 : 1 ( 228 / 87 ) , and 91.9 % of the patients were from southern China . The median diagnosis age ( 32 years , 9 - 69 years ) was 4 years later than the median age ( 28 years , 8 - 63 years ) . In 22 cases ( 7.0 % ) , there was a history of Crohn ' s disease . Abdominal pain ( 87.6 % ) , diarrhea ( 65.4 % ) , weight loss ( 54.0 % ) were the most common clinical symptoms in CD patients .

2 . According to the Montreal classification , the diagnosis age is mainly type A2 ( 17 - 40 years , 66.0 % ) ;
The disease site was mainly ileum type ( L1 , 50.5 % ) , followed by ileocolic ( L3 , 34.9 % ) , colon ( L2 , 14.6 % ) , and the upper digestive tract ( L4 ) was 4.8 % .
The disease behavior was mainly the non - narrow non - penetrating type ( B1 , 56.2 % ) , followed by the narrow ( B2 , 36 . 5 % ) , the penetrating type ( B3 , 7.3 % ) , and 18.1 % of the patients had perianal lesions ( P ) .

3 . The median course of CD patients included in this study was 4 years ( 1 - 20 years ) , and 91 ( 28 . 9 % ) CD patients were treated surgically in the whole disease course . Among them , 14.3 % of CD patients had fewer cases . The first operative reason for CD patients was : intestinal obstruction ( 52 cases , 57.14 % ) , intestinal bleeding ( 6 cases , 6.59 ) , ileocecal ligation ( 6 cases , 6.59 ) , intestinal large ulcer , ineffective internal medicine treatment ( 6 cases , 6.59 ) and other ( 4 cases , 4.40 % ) .

4 . Single variable analysis

The cumulative surgical rates of patients with CD were 12 % , 17 % , 26 % , 46 % and 82 % from 1 year , 2 years , 5 years , 10 years and 20 years , respectively .

( 1 ) The effect of the following clinical variables on the cumulative surgical rate of the first bowel resection of CD patients was not statistically different ( all p < 0.05 ) : the diagnostic age group ( 5years and operation rate : A1 was 40.0 % , A2 was 30.1 % , A3 was 33.7 % , p = 0.852 ) , and the upper gastrointestinal tract ( 5 years of progressive operation rate : not involving the upper gastrointestinal tract was 33.8 % , with appendix resection history of 25.0 % , p = 0.499 ) , and out - of - intestinal manifestations ( 5 years of progressive operation : no intestinal manifestations were 32.5 % , with an external appearance of 33.3 % , p = 0.740 ) ;

( 2 ) The following clinical variables were related to the increase in the first bowel operation rate in patients with CD : sex ( 5 years cumulative surgery rate : 36.3 % for men , 28 . 0 % for women , p = 0 . 040 ) , disease behavior ( cumulative surgical rate in 5 years : 38.8 % for L1 ileum , 12.0 % for L2 colonic type , 38.8 % for L3 ileocolic type , p = 0.015 ) , disease behavior ( 5 year cumulative surgery rate : 61.9 % for smokers and 29 . 1 % for non - smokers , p = 0.002 ) .

( 3 ) The following clinical variables were related to the reduction of the first bowel resection rate : perianal lesions ( 5 - year cumulative surgery rate : 10.7 % for perianal lesions , 36 . 4 % for perianal lesions , p = 0 . 022 ) . In addition , the cumulative surgical rates for CD patients treated with any one of the anti - Crohn ' s disease drugs were significantly lower than those in the untreated patients ( p 0.05 ) : aminosalicylic acid ( 5 - year cumulative surgery rate : 68.4 % in the unused group , 17.6 % in the use group , P0.001 ) , and the immune inhibitor ( 5 - year cumulative surgery rate : 39.0 % in the unused group , P = 0.001 , P = 0.003 ) , and the biological agent ( 5 - year cumulative surgery rate : 35 . 3 % in the unused group , 13.0 % in the use group , P = 0.003 ) .

4 . Multivariate analysis

Cox proportional hazards regression model ( Cox proportional hazards regression model ) was further applied to substitute all clinical variables into the same multivariate analysis model , and Wald was used to test whether there was statistical difference in each clinical variable . In this Cox multivariate model , the stenosis type ( HR : 4.803 ;
95 % CI : 2.466 - 9.352 ;
P0.001 ) , penetrating type ( HR : 13.197 ;
95 % CI : 5.938 - 29.330 ;
P0 . 001 ) , smoking ( HR : 1.932 ; 95 % CI : 1.031 - 3.619 ; P = 0.041 ) was significantly associated with the increase in the first bowel resection rate , while perianal lesions were significantly associated with the reduction in the first bowel resection rate ( HR : 0.027 ; 95 % CI : 0.193 - 0.889 ; P = 0 . 024 ) and the use of aminosalicylic acid preparations ( HR : 0.277 ; 95 % CI : 0.162 - 0.474 ; P0.001 ) .

Conclusion

According to cohort study of single center in South China , patients with Crohn ' s disease were mostly male with age A2 ( 17 - 40 years old ) . The lesion was mainly L1 type ( ileum type ) , followed by L3 type ( ileocolic ) , and the disease behavior was mainly B1 type ( non - narrow non - penetrating type ) . In the course of disease development , the cumulative surgical rate of patients with Crohn ' s disease was increased year by year .
【学位授予单位】：南方医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R574

【参考文献】