克罗恩病研究进展.ppt

克罗恩病研究进展 彭 孝 纬 福建省立医院 福建省胃肠病研究所,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-5 19p - IBD6 TB4H,C3 Others:- 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),Disease Mechanisms: Chronic Immune Activation Natural History of Crohns Disease: Chronic Progression Monoclonal 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,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. 1999;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 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 Reponses,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;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 Holtmann 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. Lancet. 1992;339:89-91. Reinecker HC et al. Clin Exp Immunol. 1993; 94:174-181 Murch 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 Mechanisms: Chronic Immune Activation Natural History of Crohns Disease: Chronic Progression Monoclonal 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:,2002 552 229 95 37,0,12,24,36,48,60,72,84,96,108,120,132,144,156,168,180,192,204,216,228,240,0,10,20,30,40,50,60,70,80,90,100,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 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 75% of CD patients will require at least 1 intestinal resection Nearly 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 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 retrospective 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 Diagnosis,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，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-13 b 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 Activation Natural History of Crohns Disease: Chronic Progression Monoclonal Antibodies for the Treatment of CD,Monoclonal antibody,No signal,Cytokine (IL-12 or TNF),Monoclonal Antibodies Prevent Interactions of Cytokines With Cellular Receptors,Cytokin