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1、克罗恩病研究进展,流行病学研究概况,发病率分别为 4-12/105 近20年来CD增加明显欧美多见,中国和亚洲国家少见,青壮年多见,儿童和老年人少见,流行病学研究概况,经济发达地区的发病危险性高于落后地区城市地区高于农村当人群从疾病低发区移居到高发区后,发病率也会上升,亚洲国家克罗恩病发病率在上升,国内近15年克罗恩病病例数,小计 2910,提高城市化：公共卫生水平,增加CD的发病率饮用热水成为习惯：OR 5.0(95%CI1.4-17.3)不再使用公共浴室：OR 3.3(95%CI1.38.3)儿童期胃肠道感染可能是 CD的保护因素?Gent Lancet 1994,克 罗 恩 病,病因、发
2、病机制迄今未明。主要集中在环境、遗传和免疫异常等方面。,Genetic Linkages and CD,Chr.16q12-IBD1 NOD2 6p-IBD3 MHC 和 14q-IBD4 TCR/复合体5q-IBD5 IL-3,IL-4,IL-519p-IBD6 TB4H,C3Others:-Chr 1,2,3,7,X,NOD2 基因,NOD2/CARD15基因CD相关基因Hugot等1996年发现在IBD1位点仅见于CD而非UC，约20%-30%的CD患者欧美澳三洲12个研究组613个家庭研究证实,NOD2基因产物是一种细胞内的内毒素结合蛋白,野生型能清除入侵病原体.NOD2突变可引起肠道
3、菌群改变导致的免疫激活异常 NOD2突变还可使细胞凋亡机制失常导致CD慢性炎症和组织破坏突变杂合子患病危险性增加3倍,纯合子增加23倍.,NOD2突变破坏了细胞对细菌的天然(先天性)免疫反应特异性获得性免疫反应增强引起CD的组织损伤编码蛋白在单核细胞表达可使NF-B活化，对LPS反应,免 疫 异 常,细胞中介免疫反应异常T细胞中心地位，激活后产生各种细胞因子、炎性介质，引起和放大粘膜炎症-Th1类型免疫反应遗传决定因素使普通肠菌抗原引起上调的细胞免疫反应,克罗恩病的粘膜免疫反应,Role for Targeted Biologic Therapy in Crohns Disease(CD),D
4、isease Mechanisms:Chronic Immune ActivationNatural History of Crohns Disease:Chronic ProgressionMonoclonal Antibodies for the Treatment of CD,Etiology of CD:Chronic Activation of the Mucosal Immune Response,Environmental factors,Genetic factors,T cell,Th1 cell,TNF-,IL-12,IFN-,Macrophage,Inflammation
5、,Th1 cell,Th1 cell,Th1 cell,TNF-,IFN-,IL-12,Crohns disease state,Normal state,Chronic uncontrolled inflammation due to Th1 cell apoptotic defect,Normal controlled inflammation via apoptosis of Th1 cells(programmed cell death),Gately MK et al.Annu Rev Immunol.1998;16:495-521;Ina K et al.J Immunol.199
6、9;163:1081-1090;Podolsky DK.N Engl J Med.2002;347:417-429,Cytokine Imbalance in Chronic Inflammation,Pro-inflammatory,Anti-inflammatory,adapted from Papachristou G et al.Pract Gastroenterol.2004;28:18-30.,Key Inflammatory Mediators in CD,Gately MK et al.Annu Rev Immunol.1998;16:495-521;Podolsky DK.N
7、 Engl J Med.2002;347:417-429,Interleukin 12(IL-12)Promotes Th1 Responses in CD,Gately MK et al.Annu Rev Immunol.1998;16:495-521;Podolsky DK.N Engl J Med.2002;347:417-429,IL-12,IFN,Th1 cell,Differentiation,Gately MK et al.Annu Rev Immunol.1998;16:495-521,Additional Mechanisms for IL-12-induced Th1 Re
8、ponses,Clinical Evidence of Increased Expression of IL-12 in CD,Kakazu T et al.Am J Gastroenterol.1999;94:2149-2155.Colpaert S et al.Eur Cytokine Netw.2002;13:431-437.Berrebi D et al.Am J Pathol.1998;152:667-672.,Parronchi P et al.Am J Pathol.1997;150:823-832.Monteleone G et al.Gastroenterology.1997
9、;112:1169-1178.Nielsen OH et al.Scand J Gastroenterol.2003;38:180-185.,Tumor Necrosis Factor(TNF)Sustains Th1 Responses in CD,Gately MK et al.Annu Rev Immunol.1998;16:495-521;Podolsky DK.N Engl J Med.2002;347:417-429,TNF Promotes CD Activity and Pathogenesis Through Multiple Pathways,Adapted from Ho
10、ltmann et al.Z Gastroenterol.2002;40:587-600.,Tissue destruction&inflammation,Macrophage,TNF-,TNF-,TNF-,IFN-,IL-12,Activated T cell,Th1 cell,Coagulation(increased production of thrombin),Ulcer,Inflammation,Inflammatory cells,Clinical Evidence of Increased Expression of TNF in CD,Braegger CP al.Lance
11、t.1992;339:89-91.Reinecker HC et al.Clin Exp Immunol.1993;94:174-181Murch SH et al.Gut.1993;34:1705-1709.,Breese EJ et al.Gastroenterology.1994;106:1455-1466.MacDonald TT et al.Clin Exp Immunol.1990;81:301-305.Cappello M et al.Gut.1992;33:1214-1219.,Current Concepts in Crohns Disease(CD),Disease Mec
12、hanisms:Chronic Immune ActivationNatural History of Crohns Disease:Chronic ProgressionMonoclonal Antibodies for the Treatment of CD,The Likelihood for Disease Complications in CD Increases Over Time,Cosnes J et al.Inflamm Bowel Dis.2002;8:244-250.,Number of patients at risk:,20025522299537,0,12,24,3
13、6,48,60,72,84,96,108,120,132,144,156,168,180,192,204,216,228,240,0,10,20,30,40,50,60,70,80,90,100,Months,Cumulative probability%,penetrating,inflammatory,stricturing,Occurrence of a stricturing and/or penetrating complication was assessed retrospectively in 2,002 consecutive CD patients(19742000)The
14、 estimated risks for penetrating CD at 5 and 20 years after diagnosis are 40%and 70%,Most Patients Will Progress to Surgery,Data on initial intestinal resection and postoperative recurrence were evaluated retrospectively in a population-based cohort of 1,936 CD patients(19551989)It is estimated that
15、 75%of CD patients will require at least 1 intestinal resectionNearly 50%of these patients will have a clinical relapse,Bernell O et al.Ann Surg.2000;231:38-45.,0,2,4,6,8,10,12,14,0,20,40,60,80,100,Time(years),Cumulative risk of surgery(%),0,2,4,6,8,10,12,14,0,20,40,60,80,100,Time(years),Cumulative
16、risk of recurrence(%),Risk of First Resection,Risk of Recurrence After First Resection,The Proportion of Patients in Medical Remission Decreases Over Time,Silverstein MD et al.Gastroenterology.1999;117:49-57.,Markov analysis of the projected lifetime clinical course of CD in a population-based retro
17、spective study of 174 patients(19701993),Veloso FT et al.Inflamm Bowel Dis.2001;7:306-313.,Remission Within the First Year of Diagnosis May Predict Future Disease Behavior,Remission,Low Activity,High Activity,0%,20%,40%,60%,80%,100%,0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,Years After Diagn
18、osis,The clinical course of CD was studied in a cohort of 480 consecutive patients followed from diagnosis up to 20 years(19801999),临床表现和诊断,肠道慢性肉芽肿性疾病，常累及从食管到肛门的多个部位，使临床症状多样化，诊断变得困难。文献报道手术前的误诊率高达66.7%.临床可分为两型，一为顽疾型，症状轻而不典型，以肠梗阻为主，另一型为侵袭型，症状较重而典型，以溃疡和肠瘘为主。,临床表现和诊断,国外学者总结10年经验，发现内镜对溃疡性结肠炎确诊率达93.9%，对克罗
19、恩病只有77.3%.最难区别的还是克罗恩病和肠结核，因肠结核分布特点也是在右侧结肠，跳跃和区域性分布，若溃疡形态典型者尚能区别，而多数病变是呈非特异性的假息肉，无规律的溃疡和充血糜烂改变。其与肠结核在临床表现、结肠镜下所见及病理改变等方面均有许多相似之处。因此，两者的鉴别诊断十分困难，是临床上的一大难题。文献报道两者相互误诊率高达49%-65。,临床表现和诊断,病理改变是主要的鉴别要点，如裂隙样溃疡，非干酪样肉芽肿，黏膜下层淋巴细胞聚集是克罗病恩病比较特异的改变。而较大的常融合成团的干酪样肉芽肿则仅见于肠结核。但常常由于活检组织太小，这些比较特异的病理改变不明显或难于发现，特别对于只有肉芽肿，
20、但没有干酪样坏死的肠结核。国外报道，约60%的克罗恩病存在结节病样肉芽肿，约30%的克罗恩病可见裂隙样溃疡。国内报道30例克罗恩病，活检肉芽肿的阳性率为30.8%。,治 疗,目标:控制发作 维持缓解 预防复发 防治并发症 保证生活质量原则:Witkison 早期控制症状 维持缓解 确定内外科治疗界限,克罗恩病-Cochrane Library系统评价,糖皮质激素应用24月不减少复发布的奈德 亦不能预防复发Aza 维持缓解有效Aza 或6-MP 诱导缓解有效,基于发病机理的靶向治疗途径,1.细菌抗原：直接穿过肠上皮，逞递至固有膜免疫细胞，巨噬细胞加工逞递给CD4+T细胞，相互作用后产生促炎细胞因
21、子2.TNF-、IL-12，引起Th1反应,新型生物治疗剂,生物治疗剂 作用a NF-B抑制剂或细胞因子单抗 抑制IL-12、IL-13b 47整合素单抗、趋化因子抑制剂 抑制效应细胞移动c TNF特异性抗体 抑制TNF表达d 调节性T细胞因子 抑制效应性T细胞F 选择性黏附分子抑制剂(SAM)抑制免疫细胞向炎症部位聚集,Role for Targeted Biologic Therapy in Crohns Disease(CD),Disease Mechanisms:Chronic Immune ActivationNatural History of Crohns Disease:Chr
22、onic ProgressionMonoclonal Antibodies for the Treatment of CD,Monoclonalantibody,No signal,Cytokine(IL-12 or TNF),Monoclonal Antibodies Prevent Interactions of Cytokines With Cellular Receptors,Cytokine receptor,Choy EHS et al.N Engl J Med.2001;344:90716.,Evolution of Monoclonal Antibodies,Adalimuma
23、b(D2E7),Fully Human,Murine,Chimeric,Humanized,510%Mouse Protein,Human(No Mouse Protein),25%Mouse Protein,100%Mouse Protein,抗TNF在炎症性肠病中的应用,2001-2003年欧洲使用指南 Infliximab 是唯一注册药物 剂量：5mg/Kg 适应症：难治性CD、瘘(术前或再治疗)美国最新资料 15,000次 静脉滴注(147,000)对CD伴瘘管特别有效,明显优于UC 70%有效,治 疗 策 略,1.Step up strategy 5-氨基水杨酸 糖皮质类固醇 免疫抑
24、制剂 TNF-单抗2.Top down strategy 有效的控制和维持 良好的临床过程 减少并发症 减少药物的副作用 减少外科手术率,Therapeutic Pyramid for Active Crohns Disease,Severe,Moderate,Mild,Surgery,Corticosteroids,Aminosalicylates/Antibiotics,Immunomodulators,Infliximab,Infliximab,Surgery,Steroids,AZA/6-MP/MTX,Early,Reversing the Crohns Disease Pyramid,
