克羅恩病研究進展 彭 孝 緯 福建省立醫院 福建省胃腸病研究所,流行病學研究概況,發病率分別為 4-12/105 近20年來CD增加明顯 歐美多見,中國和亞洲國家少見, 青壯年多見,兒童和老年人少見,流行病學研究概況,經濟發達地區的發病危險性高于落后地區 城市地區高于農村 當人群從疾病低發區移居到高發區后,發病率也會上升,亞洲國家克羅恩病發病率在上升,國內近15年克羅恩病病例數,小計 2910,提高城市化：公共衛生水平,增加CD的發病率 飲用熱水成為習慣：OR 5.0 (95%CI1.4-17.3) 不再使用公共浴室：OR 3.3 (95%CI1.38.3) 兒童期胃腸道感染可能是 CD的保護因素? Gent Lancet 1994,克 羅 恩 病,病因、發病機制迄今未明。 主要集中在環境、遺傳和免疫異常等方面。,Genetic Linkages and CD,Chr. 16q12 - IBD1 NOD2 6p - IBD3 MHC 和 14q - IBD4 TCR /復合體 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相關基因 Hugot等1996年發現在IBD1位點 僅見于CD而非UC，約20%-30%的CD患者 歐美澳三洲12個研究組613個家庭研究證實,NOD2基因產物是一種細胞內的內毒素結合蛋白 ,野生型能清除入侵病原體. NOD2突變可引起腸道菌群改變導致的免疫激活異常 NOD2突變還可使細胞凋亡機制失常 導致CD慢性炎癥和組織破壞 突變雜合子患病危險性增加3倍,純合子增加23倍.,NOD2突變破壞了細胞對細菌的天然(先天性)免疫反應 特異性獲得性免疫反應增強引起CD的組織損傷 編碼蛋白在單核細胞表達可使NF-B活化，對LPS反應,免 疫 異 常,細胞中介免疫反應異常 T細胞中心地位，激活后產生各種細胞因子、炎性介質，引起和放大粘膜炎癥-Th1類型免疫反應 遺傳決定因素使普通腸菌抗原引起上調的細胞免疫反應,克羅恩病的粘膜免疫反應,Role for Targeted Biologic Therapy in Crohns Disease (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),臨床表現和診斷,腸道慢性肉芽腫性疾病，常累及從食管到肛門的多個部位，使臨床癥狀多樣化，診斷變得困難。文獻報道手術前的誤診率高達66.7% . 臨床可分為兩型，一為頑疾型，癥狀輕而不典型，以腸梗阻為主，另一型為侵襲型，癥狀較重而典型，以潰瘍和腸瘺為主。,臨床表現和診斷,國外學者總結10年經驗，發現內鏡對潰瘍性結腸炎確診率達93.9%，對克羅恩病只有77.3% . 最難區別的還是克羅恩病和腸結核，因腸結核分布特點也是在右側結腸，跳躍和區域性分布，若潰瘍形態典型者尚能區別，而多數病變是呈非特異性的假息肉，無規律的潰瘍和充血糜爛改變。其與腸結核在臨床表現、結腸鏡下所見及病理改變等方面均有許多相似之處。因此，兩者的鑒別診斷十分困難，是臨床上的一大難題。文獻報道兩者相互誤診率高達49%-65。,臨床表現和診斷,病理改變是主要的鑒別要點，如裂隙樣潰瘍，非干酪樣肉芽腫，黏膜下層淋巴細胞聚集是克羅病恩病比較特異的改變。而較大的常融合成團的干酪樣肉芽腫則僅見于腸結核。但常常由于活檢組織太小，這些比較特異的病理改變不明顯或難于發現，特別對于只有肉芽腫，但沒有干酪樣壞死的腸結核。 國外報道，約60%的克羅恩病存在結節病樣肉芽腫，約30%的克羅恩病可見裂隙樣潰瘍。國內報道30例克羅恩病，活檢肉芽腫的陽性率為30.8%。,治 療,目標:控制發作 維持緩解 預防復發 防治并發癥 保證生活質量 原則: Witkison 早期控制癥狀 維持緩解 確定內外科治療界限,克羅恩病-Cochrane Library系統評價,糖皮質激素應用24月不減少復發 布的奈德 亦不能預防復發 Aza 維持緩解有效 Aza 或6-MP 誘導緩解有效,基于發病機理的靶向治療途徑,1.細菌抗原：直接穿過腸上皮，逞遞至固有膜免疫細胞，巨噬細胞加工逞遞給CD4+ T細胞，相互作用后產生促炎細胞因子 2.TNF-、IL-12， 引起Th1反應,新型生物治療劑,生物治療劑 作用 a NF-B抑制劑或細胞因子單抗 抑制IL-12、IL-13 b 47整合素單抗、趨化因子抑制劑 抑制效應細胞移動 c TNF特異性抗體 抑制TNF表達 d 調節性T細胞因子 抑制效應性T細胞 F 選擇性黏附分子抑制劑(SAM) 抑制免疫細胞向炎癥部位聚集,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,Cy