炎癥性腸病的診療進展

1、炎癥性腸病的研究進展,消化內科張文俊,IBD 概述,CD和UC是一種疾病的兩個階段或兩種疾病目前尚無定論,inflammatory bowel diseases,Crohn disease,Ulcerative colitis,,,,,,Undeterminated colitis,,CH/10/30,,,炎癥性腸病的復雜性,,對病因和發(fā)病機制進一步研究有助于預防和指導治療,IBD 現(xiàn)狀,病因尚不清楚 治療措施有限包括非特異性抗

2、炎和免疫抑制治療,,Epidemiology of IBD,1-2 million IBD patients in the U.S.Equal incidence of ulcerative colitis and Crohn’s diseaseApproximately 10,000 new cases diagnosed annually*,*Hanauer S. Inflammatory Bowel Disease. N En

3、gl J Med. 1996;334(13):841-8,VariableFindingTime trends in incidenceIncreased 1960s–80swith recent plateauIncidence (per 100,000)5-7Peak age at onset (y)15-30Female-to-male ratio1.1 to 1.8:1Racial/ethnic inci

4、denceHigh in whites, Jews,Epidemiology of IBD: Overview,,,Andres PG et al. Gastroenterol Clin N Am. 1999;28:255.,Age and Sex Incidence of IBD,IBD 病因,遺傳易感性,環(huán)境促發(fā)因素,精神因素免疫因素,IBD,GENETIC SUSCEPTIBILITY,種族的影響,Basu, D; Am

5、J Gastroenterology 100:2254-2261, 2005,A,Whites had stronger family history of IBD and colorectal cancer.African Americans with CD had higher incidence of arthritis. Disease severity similar across all groups. P-anca

6、 served as a sensitive maker for Mexican Americans as 100% with UC were positive compared with 40% in whites,識別的第一個IBD基因 –CARD15/NOD2,,,,,,,,,糖多肽,CD14,TLR4,TRAF6,NOD2,NF-kB,細胞核,,,,,,,,,,,,,,,炎癥,單核細胞,C-插入突

7、變 終止碼, NF-kB的異常激活,,,,IBD相關基因,Bamias. Ann Intern Med, 2005,143(12):895-904,IBD常見的免疫遺傳異常,p-ANCA (Peri-Nuclear Anti-Neutrophil Cytoplasmic Antibodies) ASCA (Anti-Saccharomyces cerevisiae antibodies) UC:

8、+p-ANCA, -ASCASens=57 Spec=97 CD: -p-ANCA, +ASCASens=47 Spec=97,pANCA 70% of UC,6% of CD；ASCA 50-60% of CD,基因型與IBD的關系,不同基因型不同IBD分型,,疾病易感性不同對藥物治療的反應不同,No contribution of NOD2,NOD2 contributes,NOD2 major factor

9、,,,M. CROHN AND NOD2/CARD15,CP/06/23,Environmental Triggers,Infections,NSAIDs,Stress,Smoking,Diet,Antibiotics,IBD,,,飲食因素,明確危險因素:過量攝入糖類，尤其是CD 可能危險因素:巧克力和可樂類飲料,高脂 可能保護因素:高纖維食物,水果和蔬菜 其他：丁酸，硫化物，谷氨酸鹽,Meta分析: 吸煙者發(fā)病危險性為從不吸煙者

10、的2倍吸煙增加CD復發(fā)可能性，女性多見（ 4倍）,過量吸煙,CD的危險因素，UC的保護因素,對于CD：,長期吸煙者發(fā)病危險性高 戒煙者患病的危險性為從不吸煙者的1.7倍 戒煙者重新吸煙(45％)可改善癥狀 尼古丁治療可增加活動期UC的癥狀緩解率,對于UC：,感染,外源性感染：沙門氏菌,志賀氏菌,副結核分枝桿菌, 產(chǎn)單核細胞的李斯特菌屬,纏繞桿菌屬,

11、 酵母菌,彎曲桿菌屬,耶爾森菌屬； 阿米巴; 麻疹病毒內源性細菌：大腸桿菌E.coli ?,微生物因素,微生物因素在IBD發(fā)生中的作用尚存在爭議缺乏足夠證據(jù)證明IBD的特異性病原體現(xiàn)有研究表明:病原微生物可能是本病的促發(fā)因素,J. Nutr. 1995;125:1401-12,The Human Gut Flora,Rapidly colonises gu

12、t after birth Comprises more than 1014 organisms Weighs 1-2 kgMore than 400 speciesAn individuals flora is immunologically distinctSymbiotic relationship with hostProbiotics,BALANCE OF COMMENSAL BACTERIAL COMPONE

13、NTS,,,,無菌腸道環(huán)境,細菌感染,未見炎癥,結腸炎癥,,免疫激活,基因易感宿主,No Bacteria, No IBD ？,麻疹病毒感染與IBD的相關研究,Ekbom A. Lancet 1996; 348. Lawrenson R. BMJ 1998; 316. Nielsen LLW. BMJ 1998; 316. Afzal MA. Lancet 1998; 351. Haga Y. Gut 1996; 38. Chad

14、wick N. J Med Virol 1998: 55.,假說一：持續(xù)麻疹病毒感染與CD相關,來自瑞士的研究: 麻疹流行期出生者CD患病率高在CD病人腸道組織中發(fā)現(xiàn)麻疹病毒蛋白和DNA,證據(jù),研究者Wakefield后續(xù)的研究不支持自己前期研究 當時檢測麻疹病毒的技術不夠可靠 來自英、美、日等國的研究存在分歧 血清中未檢測到抗麻疹病毒抗體,反證據(jù),麻疹病毒感染與IBD的相關研究,Thomspon NP. Lancet 1

15、995; 345. Gilat T. Scan J Gastroenterology 1987; 22.Pebody RG. BMJ 1998; 316. Feeney M. Lancet 1997; 350.,假說二：麻疹疫苗(非MMR)接種與CD相關,麻疹疫苗接種者IBD發(fā)病率較未接種者高,證據(jù),來自歐洲的病例對照研究不支持上述觀點 英國和芬蘭的研究顯示CD與疫苗接種無關,反證據(jù),麻疹病毒感染與IBD的相關研究,Montgom

16、ery SM. Gastroenterology 1999, 116; 796-803.Davids RL et al. Archives of Pediatric and Adolescent Medicine 2001; 155: 354-9.,假說三：IBD可能與早期病毒性腮腺炎有關,基于對70年代出生兒童的調查IBD與2歲前野生腮腺炎病毒或與麻疹病毒聯(lián)合感染相關,證據(jù),上述結果依據(jù)雙親對幼年時期患病的回憶調查

17、 （而病毒性腮腺炎多無癥狀） IBD患者未檢測到腮腺炎病毒或抗體 MMR疫苗接種后IBD發(fā)病率未見明顯升高,反證據(jù),,大腸桿菌與IBD的相關研究,假說：鞭毛蛋白在IBD中啟動獲得性免疫機制,,E. Coli,Flagella,,,,,,,,,,,,,,,,,,大腸桿菌與IBD的相關研究,假說：鞭毛蛋白在IBD中啟動獲得性免疫機制,常規(guī)革蘭染色陰性的鞭毛蛋白單體（如大腸桿菌）

18、 在CD中可作為抗原激發(fā)獲得性免疫反應 這種獲得性免疫反應受TLR5介導的先天性免疫調節(jié) 粘膜組織中可檢測到 非造血細胞產(chǎn)生的細胞因子（如IL-6和TNFa) 獲得性免疫與CD發(fā)生發(fā)展相關,大腸桿菌與IBD的相關研究,社會心理因素,45%的IBD患者認為應激促發(fā)IBD 胃腸病學專家認為 社會心理因素在IBD中起重要作用,“Stress…h(huán)as been positively co

19、rrelated with exacerbation of disease”,,依據(jù)：應激增強動物模型腸粘膜炎癥反應,Qui. Nature Med. 1999.,依據(jù)：無癥狀UC中應激與直腸炎癥有關,Levenstein S, et al. Am J Gastroenterol 1994;89:1219-25.,依據(jù)：應激對UC病情影響與持續(xù)時間有關,Levenstein S, et al. Am J Gastroenterol 20

20、00;95(5):1213-20.,Levenstein S, et al. Am J Gastroenterol 2000;95(5):1213-20.,依據(jù)：應激對UC病情影響與應激程度有關,不同IBD分型應激的影響不同,Maunder R. Dig Dis Sci 2000;45(11):2127-32.,機制：應激與循環(huán)遞質,機制：應激與腸壁通透性,Wilson LM. Microcirculation 1999;6:189.

21、.Meddings JB. Gastroent 2000;119:1019.,機制：應激與腸道局部介質,Soderholm JD. Am J Physiol Gastrointest Liver Physiol 2001;280:G7–G13.,Mawdsley J E. Gut. 2005,54(10):1481-91.,應激對胃腸道影響的多通路機制,Mawdsley J E. Gut. 2005,54(10):1481-91.,應激

22、與IBD,精神神經(jīng)免疫學機制,IBD處于血栓前狀態(tài) 凝血參數(shù)大多增高 血栓栓塞發(fā)生時給予抗凝治療 可同時改善IBD病情 血栓栓塞是IBD的嚴重并發(fā)癥 多發(fā)生于年輕患者急性期； 深靜脈血栓和肺栓塞常見； 動脈栓塞和其他

23、則少見,凝血和抗凝平衡紊亂,Schapira M. Acta Gastroenterol Belg. 1999, 62:182.Alfredo Guglielmi. World J Gastroenterol, 2005,7;11:2035.,凝血狀態(tài)異常是IBD的病因還是結果尚不確定,,UC患者腸系膜靜脈和門靜脈血栓形成,IBD 發(fā)病機制 (Pathogenesis),損傷機理： 粘膜屏障受損

24、 粘膜免疫異常 系統(tǒng)免疫失衡 IBD發(fā)病機制研究進展： 先天性免疫在IBD中的作用 IBD免疫效應分型－－Th1/Th2 CD是免疫亢進或免疫缺陷

25、 細胞因子及免疫遞質研究進展,ETIOLOGIC HYPOTHESES,,Pathogenesis of IBD,,,,,,,,,NSAIDsAntibioticsInfectionsViralBacterialParasitic,Luminal antigensFood antigensBacteriaBacterial productsFMLPLPSPGPS,,IL-2IFN-?IL-12T

26、NF-?IL-1TGF-? IL-4IL-5IL-10etc.,Translocation of luminal contents,InitiatingEvents,MucosalDamage,AbnormalImmune Response,ChronicInflammation,,Courtesy of R Baldassano, 2000.,Chronic Inflammation: Imbalance Bet

27、ween Mediators,,,,Pro-inflammatory,Anti-inflammatory,TNF-a,,IL-1b,,IL-8,,IL-12,,IFN-g,,TGF-b,,IL-10,,IL-1ra,,IL-4/IL-13,,,,,,,,,,,,,,,,,,,,,,"Target“,,PG,LTB,PAF,H2O2,Indirect,destruction,InterleukinschemokinesTNF

28、a,Release of factors,,,,,,,Virus,Bac-teria,Protein,,,,,Lymphocytes,Uncontrolled reactionto antigen,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Macrophages,PMN´s,Recruitment of cells,,,,,MHC,,,,4,,,,,,CP/03/48,PRINCIPLES

29、OF PATHOPHYSIOLOGY OF IBD,APC,Effector T-cell,Uncontrolled T-Cell Responses Induce Chronic Gut Inflammation,,,正常腸壁有生理性抗炎功能 IBD腸壁滲透性增加 損害腸粘膜屏障的因素： 遺傳易感性 環(huán)境促發(fā)因素,機制一：粘膜屏障受損,Mucosal Immune Syste

30、m,機制二：粘膜免疫失衡,腔內抗原浸潤并激活MC 效應細胞產(chǎn)生促炎細胞因子 減少調節(jié)性細胞因子產(chǎn)生 級聯(lián)反應促使炎癥反應擴大,粘膜免疫中的腸道微環(huán)境和相關基因,機制三：系統(tǒng)免疫失衡,遺傳、環(huán)境及社會心理等因素共同作用于免疫系統(tǒng),,先天性免疫是非特異性防御病原體的機制 —— 是機體的第一道防線 主要針對抗原產(chǎn)生的化學物質(而非抗原本身) 針對抗原的某種免

31、疫細胞選擇性增殖,The Role of the Innate Immune System in IBD,獲得性免疫與先天性免疫在IBD中的作用,傳統(tǒng)觀點認為 Acquired immune system IBD是獲得性免疫系統(tǒng)細胞介導的炎癥反應,主要識別抗原本身效應T細胞 (Teff) 和調節(jié)T細胞 (Treg),Defects in the innate immune system may play

32、an equal or even more important role in IBD,IBD可有原發(fā)性的調節(jié)性淋巴細胞和細胞因子 功能失調，如:IL-10、TGF-β,導致炎癥控制失靈 CD中存在激活的T細胞調亡抵抗,這些現(xiàn)象無法用現(xiàn)有的獲得性免疫機制解釋,,先天性免疫缺陷可能在IBD中起更重要的作用,進一步研究提示,Ann Intern Med, Volume 143(12).December 20, 2005.895

33、-904,NOD2蛋白是細胞內受體主要識別細菌胞壁成分在先天免疫中起作用被認為是IBD的易感基因NOD2突變見于1/3的CD而在UC不是危險因素,支持先天性免疫的證據(jù),先天性免疫中介導微生物-宿主反應的信號通路基因,膜耦聯(lián)受體 TLRs（toll-like receptors ） 識別脂多糖等微生物結構組分 細胞質蛋白家族成員： NBS/LRR (Nod1 and N

34、od2) 特異性識別肽聚糖,MediatesInnate Immune Defense,,IBD免疫效應分型－－Th1/Th2 paradigm,傳統(tǒng)觀點認為: CD為Th1優(yōu)勢反應 IL-12 和 IFN-γ等分泌增多,抗IL-12治療可減少固有層MC分泌細胞因子,傳統(tǒng)觀點認為: UC為Th2優(yōu)勢反應

35、 IL-5 和 IL-13等分泌增多,抗IL-13治療有助于改善結腸炎癥,,,,,,,,Th1,,Th2,Crohn’s Disease,BACTERIA,This will mean something unique to everyone. The bottom line is this: We’re sure that you’ll have a positive experience with DanActive and th

36、at you’ll be completely satisfied with it. We’re also confident that you’ll want to make DanActive a part of your family’s daily wellness routine.,Th1/Th2 新觀點的提出,UC和CD的研究發(fā)現(xiàn)Th1,Th2免疫分型界限不明顯各種細胞因子表達與原有分型差異甚至完全相反基于傳統(tǒng)Th1/T

37、h2觀點提出 抗TNF單克隆抗體 (Infliximab) 用于CD治療； 目前的研究發(fā)現(xiàn) Infliximab 對重癥UC同樣有效； 而對部分CD不能誘導緩解 抗IL-10的制劑不能誘導CD患者緩解,IBD存在免疫反應差異性,這些現(xiàn)象無法用傳統(tǒng)的Th1/Th2模式解釋,,其他T細胞免疫效應途徑,Am J Gastroenterol.2002,97:2820.

38、N Engl J Med,2002,347:417. Nat Rev Immunol,2003,3:521. J Exp Med,2002,195:1129. J Clin Invest. 2004;113:1490.,Th3 /Tr1與口服耐受相關,IBD病程不同免疫分型不同,急性期Th1為主,慢性期Th1/Th2混合型,自身免疫機制是CD發(fā)病的關鍵 遺傳易感的宿主對細菌抗原的免疫耐受終止 免疫過度激活導致慢性透壁性炎癥,CD

39、是免疫亢進或免疫缺陷,Sands, B E. Inflamm Bowel Dis,  2006,12(2),S 2:p S1,傳統(tǒng)觀點:IBD包括CD免疫亢進是其主要機制,細菌與腸粘膜粘附性增強 defensins表達降低 defensins治療有效 IBD存在體液,細胞免疫缺陷 NOD2/CARD15基因突變 損害細胞因子的轉錄表達GM-

40、CSF治療有效,支持CD存在免疫缺陷的證據(jù),Christian F. Eur J Gastroenterol Hepatol 2003 15:621–626,集落刺激因子改善粒細胞功能缺陷,KORZENIK JR. Dig Dis Sci, 2000 , 45, 6 :1121.,G-CSF and GM-CSF,KORZENIK JR. New Engl J Med, 2005, 352, 21 :2193.,Sargramostim

41、作為一種GM-CSF刺激腸道先天性免疫系統(tǒng)細胞,過氧化物酶增殖活化受體 PPAR- ?,Lewis, AJG 2001. Dubuquoy, Gastro 2003,,治療應用,外源物質代謝與IBD密切相關 Pregnane X receptor (PXR) 是配體激活的 轉錄因子家族成員 PXR可啟動外源物質代謝 PXR可被多種內源性或外源性物質激活， 如:激素，膽汁酸，抗生素

42、PXR 編碼基因NR1I2多態(tài)性與IBD相關,Pregnane X receptor and IBD,Dring MM. Gastrol, 2006, 130:341–348.,Vitamin D 和 IBD,Lim WC. J Gastro & Hepatol, 2005, 2:308.,Clinical Findings,,,,CD/05/105,STRICTURING STENOSIS AT THE ILEOCECAL

43、 BORDER,Presentation of UC,DiarrheaBleedingNO abdominal pain (cramps)Extraintestinal manifestations,Ulcerative Colitis: Bleeding,101402.7 Lindenbaum - On-screen 80,Complications of UC,Toxic MegacolonColonic Perforati

44、onDysplasia or CancerGrowth failure (pediatrics)Extraintestinal disorders(eg, arthritis, and dermatologic, musculoskeletal, ocular, renal, and hepatic disorders),Clinical Vignette: Ulcerative Colitis,22 yo mal

45、e presents with 15-20 bloody liquid bowel movements a day.He recently quit cigarette smokingHis mother has Crohn’s diseaseHe takes ibuprofen for left knee arthritisStool cultures are negative and colonoscopy reveals

46、colitis from the rectum to cecum.,Presentation of CD,DiarrheaChronic abdominal pain and tendernessLoss of appetite and weight lossFeverPerianal diseaseComplications such as fistulasExtraintestinal manifestations,Co

47、mplications of CD,FistulasAbscessesStricturesGrowth failure (pediatrics)MalnutritionExtraintestinal disorders,Crohn’s Disease Complications: Fistulas,A tunnel between two sections of the intestines or between the

48、intestines and other organs, including the skin,SmallIntestine,LargeIntestine(Colon),Fistula,,,,Fistula,,Crohn’s Disease Complications: Abscesses,A localized collection of pus within the tissue of the GI tract,Stom

49、ach,,SmallIntestine,LargeIntestine(Colon),,,Abscess froma fissure in thesmall intestineinto the peritoneal cavity,,Complications of CD: Fistulas,,,Abdominal Fistula,Perianal Fistula,Differential Diagnosis of IBD,L

50、ymphomaInfectious etiologiesAppendicitisDiverticulitisCarcinomaIschemic ColitisCeliac disease,Significant factorsUCCDAnatomic location Colon/rectumAny part of GI tractDistributionDiffuseFocal with “skip” ar

51、easFistula or abscessRareCommonStricturesUncommonCommonCurrent smokerRareCommonBloody diarrheaCommonRare,,Adapted from Surawicz CM. Contemp Intern Med. 1991;3:17.,,Differential Diagnosis,,Severe Crohn’s Colit

52、is,Reprinted by permission of Blackwell Science, Inc. Marion JF et al. In: Di Marino AJ, Benjamin SB (eds). Gastrointestinal Disease: An Endoscopic Approach. 1997:511.,Pseudopolyps in CD,Reprinted by permission of Black

53、well Science, Inc. Marion JF et al. In: Di Marino AJ, Benjamin SB (eds).Gastrointestinal Disease: An Endoscopic Approach. 1997:511.,Fibrostenosis in CD,Courtesy of J-F Colombel, MD.,Intestinal Complications of Ulcerativ

54、e Colitis Toxicity,101402.7 Lindenbaum - On-screen 95,Granuloma of the Ileum in CD,Courtesy of J-F Colombel, MD and K Geboes, MD.,Crypt Abscesses in IBD,Courtesy of J-F Colombel, MD.,ExtraintestinalManifestations,,Extra

55、intestinal Manifestations of IBD,Skin disordersErythema nodosumPyoderma gangrenosumJoint disordersPeripheral arthritisSacroiliitisAnkylosing spondylitisOcular disordersIritis, uveitis, and episcleritis,Extraintes

56、tinal Manifestations of IBD,HepatobiliaryGallstonesSclerosing cholangitisCholangiocarcinomaRenalRenal stonesAmyloidosisOther manifestationsAphthous stomatitisHypercoagulable state,Erythema Nodosum in IBD,Courtes

57、y of J-F Colombel, MD.,Pyoderma Gangrenosum in IBD,Courtesy of J-F Colombel, MD.,Pyoderma Gangrenosum in CD,Sacroiliitis in IBD,Courtesy of J-F Colombel, MD.,Reprinted from the Clinical Slide Collection on the Rheumatic

58、Diseases, copyright 1991, 1995, 1997.Used by permission of the American College of Rheumatology.,Ankylosing Spondylitis,Scleritis in IBD,Courtesy of J-F Colombel, MD.,Aphthous Stomatitis in IBD,Courtesy of J-F Colombel,

59、 MD.,Sclerosing Cholangitis in IBD,Courtesy of J-F Colombel, MD.,,CD/05/76,,SMALL LESIONS IN THE COLON IN CD – INVISIBLE IN MRI,,,CD/05/62,,WCE INSMALL BOWELCROHN´S DISEASE,,CD/05/97,CT-ENTEROCLYSIS – CROHN´

60、S DISEASE WITH STENOSIS AND PRESTENOTIC DILATATION,,n=41,*p<0.007,,,CD/05/73,COMPARISON OF WIRELESS CAPSULE ENDOS-COPY (WCE) – CT-ENTEROCLYSIS (CTE) IN IBD,Voderholzer, 2005,,,CD/06/22,,,DIAGNOSTIC ALGORITHM IN IBD,La

61、b test (blood count, CRP, lipase),microbiology, abdominal ultrasound,Inflammatory constellationpersistence of complaints,Ileocolonoscopysmall bowel X-ray / MRE / CTE,,Esophagogastroduodenoscopy,Goals of Treatment,Indu

62、ce response/remissionMaintain response/remissionHeal mucosal liningPrevent or cure complications (eg, fistulas)Improve quality of lifeRestore and maintain nutritionLimit surgery,Conventional Treatments for IBD,Amin

63、osalicylates (5-ASA)Glucocorticosteroids (GCS)ImmunosuppressantsAntibiotics (Cipro and Flagyl),Traditional Treatment Pyramid Based on Severity of CD,,SurgeryBowel restCyclosporineCorticosteroidsAzathioprine6-merc

64、aptopurineMethotrexateCorticosteroidsAntibioticsAminosalicylates,Disease Severity,,Mild,Moderate,Severe,Initial Treatment: Oral 5-ASA therapyTopical TherapyDisease Flare or Progression: Oral 5-ASA at higher do

65、se (>4g/d)CorticosteroidsImmunomodulatorsSteroid Dependent or Refractory or Severe Colitis:CyclosporineSurgery,Approach to Medical Treatment of UC,Early or Mild Disease: 5-ASA agents Antibiotics (Flagyl or C

66、ipro)Moderate to Severe Disease: Corticosteroids Immunomodulators Biologic Response Modifiers: Remicade Fistulizing Crohn’s Disease: Antibiotics: Flagyl, Cipro Immunomodulators: 6-MP/Imuran Remicade,Approach

67、 to Medical Treatment of Crohn’s disease,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,SASP,5-ASA,top. SASP/ASA,Prednisolone,Steroid Enema,0,20,40,60,80,100,% Success,,Drug,Placebo,,,,,TA,39%,TA,41%,TA,56%,TA,56%,TA,45%,,,CUT/03/21,META

68、-ANALYSIS OF DRUG TREATMENT OF ULCERATIVE COLITIS,Kornbluth, 1993,,,CUT/01/11,DOSE FINDING FOR 5-ASA IN ACTIVE ULCERATIVE COLITIS,Kruis, AGA 2000,8 weeks3 x 0.5 g3 x 1.0 g3 x 1.5 g(n = 104) (n = 104) (n = 104)R