克罗恩病研究进展课件

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 国家报告时间CD 日本19650.01 19790.78 19860.60 19910.51 19981.2 新加坡 1956 - 19700.04 19921.3 国内近15年克罗恩病病例数 年代 CD 89-93 236 94-98 1041 99-03 1633 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 巨噬 细胞 幼稚的 CD4细胞 凋亡 Th1 IFN- TNF IL-2 延迟超敏反 应肉芽肿 Th2 IL-4 IL-5 IL-10 体液免疫 变态反应 IL12 IFN- IL-4 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 Environmental factorsfactors Genetic Genetic factorsfactors 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 IL-1b IL-12 TNF- IL-8 IFN- TGF-b IL-10 IL-1ra IL-4 IL-13 adapted from Papachristou G et al. Pract Gastroenterol. 2004;28:18-30. Key Inflammatory Mediators in CD Antigen APC cell T cell CD4 APC cell Activated T cellTh1 cell TNF- TNF-Activated macrophage IL-12IFN- 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 Antigen APC cell T cell CD4 APC cell Activated T cell Th1 cell TNF- TNF-Activated macrophage IL-12IFN- Gately MK et al. Annu Rev Immunol. 1998;16:495-521; Podolsky DK. N Engl J Med. 2002;347:417-429 Resting memory Resting memory T cellsT cells IL-12IL-12 IFNIFN Th1 cellTh1 cell Nave T cellsNave T cells DifferentiationDifferentiation 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 Clinical EvidenceLocation/Cell Type IL-12 expressionMononuclear cells in actively inflamed tissue Clustered IL-12-positive cells Ileal lamina propria and gastric mucosa IL-12-containing macrophages Lamina/muscularis propria IL-12 mRNA expression Lamina propria and CD4+ T cells Kakazu T et al. Kakazu T et al. Am J Gastroenterol. Am J Gastroenterol. 1999;94: 2149-2155.1999;94: 2149-2155. Colpaert S et al. Colpaert S et al. Eur Cytokine NetwEur Cytokine Netw. 2002;13: 431-437 2002;13: 431-437. Berrebi D et al. Berrebi D et al. Am J PatholAm J Pathol. 1998;152:667-672 1998;152:667-672. Parronchi P et al. Parronchi P et al. Am J PatholAm J Pathol. 1997;150:823-832 1997;150:823-832. Monteleone G et al. Monteleone G et al. GastroenterologyGastroenterology. 1997;112: 1169-1178 1997;112: 1169-1178. Nielsen OH et al. Nielsen OH et al. Scand J GastroenterolScand J Gastroenterol. 2003;38:180-185 2003;38:180-185. Tumor Necrosis Factor (TNF) Sustains Th1 Responses in CD Antigen APC cell T cell CD4 APC cell Activated T cell Th1 cell TNF- TNF-Activated macrophage IL-12IFN- 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 339:89-91 1992;339:89-91. Reinecker HC et al. Reinecker HC et al. Clin Exp ImmunolClin Exp Immunol. 1993; 94:174-181. 1993; 94:174-181 Murch SH et al. Murch SH et al. Gut. Gut. 1993;34:1705-1709.1993;34:1705-1709. Breese EJ et al. Breese EJ et al. GastroenterologyGastroenterology. 1994;106:1455-1466 1994;106:1455-1466. MacDonald TT et al. MacDonald TT et al. Clin Exp ImmunolClin Exp Immunol. 1990;81: 301-305 1990;81: 301-305. Cappello M et al. Cappello M et al. GutGut. 1992;33:1214-1219 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. Cosnes J et al. Inflamm Bowel DisInflamm Bowel Dis. 2002;8:244-250 2002;8:244-250. Number of Number of patients at risk:patients at risk:2002200255255222922995953737 0 0 12122424363648486060727284849696 108108 120120 132132 144144 156156 168168 180180 192192 204204 216216 228228 240240 0 0 1010 2020 3030 4040 5050 6060 7070 8080 9090 100100 MonthsMonths Cumulative probability %Cumulative probability % penetratingpenetrating inflammatoryinflammatory stricturingstricturing 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. Bernell O et al. Ann Surg.Ann Surg. 2000;231:38-45. 2000;231:38-45. 0 0 2 2 4 4 6 6 8 8 101012121414 0 0 2020 4040 6060 8080 100100 Time (years)Time (years) Cumulative risk of surgery (%)Cumulative risk of surgery (%) 0 0 2 2 4 4 6 6 8 8 101012121414 0 0 2020 4040 6060 8080 100100 Time (years)Time (years) Cumulative risk of recurrence (%)Cumulative risk of recurrence (%) Risk of First ResectionRisk of First ResectionRisk of Recurrence After Risk of Recurrence After First ResectionFirst Resection The Proportion of Patients in Medical Remission Decreases Over Time Silverstein MD et al. Silverstein MD et al. Gastroenterology.Gastroenterology. 1999;117:49-57. 1999;117:49-57. Years After DiagnosisYears After Diagnosis Post Surgery RemissionPost Surgery Remission SurgerySurgery Drug RefractoryDrug Refractory Drug DependentDrug Dependent Drug ResponsiveDrug Responsive MildMild RemissionRemission ProbabilityProbability 0 0 101020203030404050506060 0 0 0.10.1 0.20.2 0.30.3 0.40.4 0.50.5 0.60.6 0.70.7 0.80.8 0.90.9 1 1 Markov analysis of the projected lifetime clinical course of CD in a population-based retrospective study of 174 patients (19701993) Veloso FT et al. Veloso FT et al. Inflamm Bowel Dis.Inflamm Bowel Dis. 2001;7:306-313. 2001;7:306-313. Remission Within the First Year of Diagnosis Remission Within the First Year of Diagnosis May Predict Future Disease BehaviorMay Predict Future Disease Behavior RemissionRemission Low ActivityLow Activity High ActivityHigh Activity 0%0% 20%20% 40%40% 60%60% 80%80% 100%100% 0 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 1010 1111 1212 1313 1414 1515 1616 1717 18181919 Years After DiagnosisYears 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 Progr