ibd腸外表現(xiàn)的新視角

1、炎癥性腸?。↖BD）的腸外表現(xiàn),Daniel C. Baumgart, MD, PhD, FACP, AGAFProfessor of MedicineCharité Medical Center – Virchow HospitalMedical School of the Humboldt-University of Berlinwww.danielbaumgart.de,www.danielba

2、umgart.de,Baumgart DC et al. Lancet. 2012 Nov 3;380(9853):1606-19.,,,,www.danielbaumgart.de,流行病學具有相關腸外表現(xiàn)的比值比（95%置信區(qū)間）,Bernstein CN et al. Am J Gastro 2001;96:1116-1122.,虹膜炎/葡萄膜炎原發(fā)性硬化性膽管炎（PSC）強直性脊柱炎壞

3、疽性膿皮病結節(jié)性紅斑,性別女男女男女男女男女男,CD4.5 (2.2–9.4)p < 0.00013.1 (1.2–7.9)p < 0.054.7 (0.9–29.7)NS6.2 (1.0–37.2)NS3.9 (1.4–11.2)p < 0.0517.7

4、 (7.0–44.5)p < 0.00012.9 (1.3–6.5)p < 0.054.0 (1.5–10.5)p < 0.011.8 (1.0–3.3)NS1.3 (0.4–4.2)NS,UC8.6 (4.4–17.0)p < 0.00013.3 (1.2–9.2)p < 0.059.

5、5 (2.7–32.9)p < 0.000130.3 (11.0–83.0)p < 0.00017.6 (2.0–28.3)p < 0.017.5 (2.9–19.0)p < 0.00012.9 (0.9–9.0)NS1.3 (0.4–3.6)NS2.2 (1.1–4.4)p < 0.052.5 (0.8–

6、7.4)NS,IBD6.3 (3.9–10.3)p < 0.00013.2 (1.6–6.4)p < 0.0017.3 (2.7–19.7)p < 0.000121.1 (9.2–48.7)p < 0.00015.0 (2.2–11.2)p < 0.000111.6 (6.1–22.1)p &l

7、t; 0.00012.9 (1.5–5.6)p < 0.012.2 (1.1–4.3)p < 0.052.0, (1.3–3.1)p < 0.011.8 (0.8–3.9)NS,,,,,不同種族間腸外表現(xiàn)的多樣性,特征關節(jié)炎強直性脊柱炎葡萄膜炎結節(jié)性紅斑壞疽性膿皮病PSC,全部2.1%1.3

8、2.24.32.11.8,白人1.7%1.51.63.41.91.3,非洲人5.8% a1.78.1 c1.72.53.2,西班牙人1.2% b01.2 d10.7 d,e2.43.0,bp=<0.05,dp=<0.01,,comparing

9、Hispanics to African-Americanscomparing Hispanics to African-Americanswww.danielbaumgart.de,ap=<0.01, comparingAfrican-Americans to whitescp=<0.001, comparingAfrican-Americans to whitesep=<0.01, comparing

10、 Hispanics to whitesNguyen GC et al. Am J Gastro 2006;101:1012-1023.,www.danielbaumgart.de,??,多種腸外表現(xiàn)的預測因子與關聯(lián)性克羅恩病的腸外表現(xiàn)預測因子(多變量分析):? 活動性疾病(OR=1.95, 95% CI = 1.17–3.23, p=0.01)? 腸外表現(xiàn)家族史陽性 (OR=1.77,

11、95% CI=1.07–2.92,P=0.025) 關聯(lián)性:? 結節(jié)性紅斑與外周關節(jié)炎常并發(fā)? 壞疽性膿皮病與外周關節(jié)炎、結節(jié)性紅斑常并發(fā)? 銀屑病或PSC常獨立發(fā)生,Vavricka S et al. Am J Gastroenterol 2011; 106:110–119.,?????,導航流行病學原發(fā)病變的處理抗TNF治療相關病變的處理

12、治療相關的皮膚病變?yōu)楹纬霈F(xiàn)？重點總結www.danielbaumgart.de,?????,導航流行病學原發(fā)病灶的處理抗TNF治療相關病灶的處理治療相關的皮膚病變?yōu)楹纬霈F(xiàn)？重點總結www.danielbaumgart.de,www.danielbaumgart.de,皮膚表現(xiàn)壞疽性膿皮病 – 經(jīng)典位置,Baumga

13、rt, DC et al. Am J Gastroenterol 2006;101:1048–1056,www.danielbaumgart.de,皮膚表現(xiàn)壞疽性膿皮病 – 造口周圍與陰莖疾病,www.danielbaumgart.de,??,皮膚表現(xiàn)壞疽性膿皮病——其他病因常見相關因素 (除IBD外)? 關節(jié)炎： 血清陰性，對稱多發(fā)關節(jié)炎，類風濕關節(jié)炎? 血液： 粒細胞性白血??；毛細胞白血病

14、；骨髓纖維化，髓樣化生；單克隆丙種球蛋白病(IgA)有報道的罕見相關因素? 關節(jié)炎: 脊柱炎；骨關節(jié)炎；銀屑病關節(jié)炎,????,肝臟：慢性活動性肝炎；HCV感染；原發(fā)性膽汁性肝硬化（PBC）血液：骨髓瘤；真性紅細胞增多癥；陣發(fā)性睡眠性血紅蛋白尿（PNH)；淋巴瘤免疫：系統(tǒng)性紅斑狼瘡； 補體C7缺乏；低丙種球蛋白血癥；高IgE綜合征；AIDS；類肉瘤病混合：多發(fā)性大動脈炎；化膿性汗腺炎； 聚合性

15、痤瘡；實體腫瘤；慢性阻塞性肺疾?。–OPD）,Callen JP Lancet 1998;351:581-585.,www.danielbaumgart.de,?沒有隨機對照的臨床試驗數(shù)據(jù)！,皮膚表現(xiàn)壞疽性膿皮病——傳統(tǒng)治療,?傷口護理?清洗，濕—干敷料，殺菌劑（過氧化氫，碘伏）?局部治療?激素 (氟羥氫化潑尼松，潑尼松)或他克莫司,?系統(tǒng)治療 ?激素，胺苯砜，米諾環(huán)素，環(huán)孢素A， FK506，霉酚酸酯，硫

16、唑嘌呤，甲氨蝶呤,Callen JP Lancet 1998;351:581-585.,www.danielbaumgart.de,初始,應用英夫利昔單抗2周后,Regueiro et al. Am J Gastroenterol. 2003;98(8):1821-6,皮膚表現(xiàn)壞疽性膿皮病——生物制劑,應用英夫利昔單抗8周后,,,,,,,,,,,,% 患者改善,www.danielbaumgart.de,1008060

17、40200,p = 0.025安慰劑n=13,英夫利昔單抗n=17,Brooklyn TN et al. Gut 2006;55:505-509.,皮膚表現(xiàn)壞疽性膿皮病——生物制劑主要終點：臨床改善在第2周,www.danielbaumgart.de,皮膚表現(xiàn)結節(jié)性紅斑,www.danielbaumgart.de,皮膚表現(xiàn)結節(jié)性紅斑——其他病因?感染?結核分枝

18、桿菌，鏈球菌，肺炎支原體，EB病毒?自身免疫性疾病?類肉瘤病，白塞病?妊娠,?藥物?磺胺類藥物，口服避孕藥，溴化物,?,惡性腫瘤（副癌）,www.danielbaumgart.de,Hände AP這是哪種皮膚表現(xiàn)？,www.danielbaumgart.de,???,銀屑病關節(jié)炎預測/篩查預測? 頭部受累 HR 3.89? 指甲受累 HR 2.

19、93? 臀部/肛周病變 HR 2.35? ≥3個區(qū)域受累 HR 2.24? 頭部，面部，四肢，軀干，臀部/肛周，掌跖，腋窩，生殖器銀屑病關節(jié)炎篩查與評估（PASE）調(diào)查問卷多倫多銀屑病關節(jié)炎篩選（ToPAS）附插圖調(diào)查問卷,Dominguez P et al. J Rheumatol. 2011 Mar;38(3):548-50.Husni ME et al. J Am Acad Dermatol.

20、2007 Oct;57(4):581-7Wilkens FC Arthritis Rheum. 2009 Feb 15;61(2):233-9.Gladman DD et al. Ann Rheum Dis. 2009 Apr;68(4):497-501.,www.danielbaumgart.de,這是哪種皮膚表現(xiàn)？,?????,導航流行病學原發(fā)病變的處理抗TNF治

21、療相關病變的處理治療相關的皮膚病變?yōu)楹纬霈F(xiàn)？重點總結www.danielbaumgart.de,www.danielbaumgart.de,???,抗TNF相關的皮膚反應風濕免疫學與皮膚病學的Meta分析數(shù)據(jù)1990-2007: 127例 Ko et al. 2009? 英夫利昔55%，依那西普 28%，阿達木單抗 17%1996-2009: 207例

22、 Collamer et al. 2008? 英夫利昔59%，阿達木單抗 22%，依那西普19%2008: 120例: Wollina et al.? 英夫利昔 52%，依那西普 31%，阿達木單抗 31%,www.danielbaumgart.de,?,抗TNF相關的皮膚反應風濕免疫學與皮膚病學的前瞻性數(shù)據(jù),???,62% 風濕病Flendrie et al. 200825% 風濕病 Lee HH et a

23、l. 200723% 皮膚病 Lee HH et al. 2007,?,起始,???,6個月 [IQR 2-17] 風濕病 Harrison et al. 20096個月 [IQR 4-10] 風濕病 & 皮膚病 Lee HH et al. 20079.1個月 [Range 0.1-113] 風濕病 Flendrie et al. 2007,發(fā)生率,www.danielbaumgart.de,????

24、?,阿達木單抗相關皮膚反應前瞻性連續(xù)性IBD隊列研究n=50單中心中位年齡 32½ 歲，病程: 7年CD (n=46) 與UC (n=4)疾病活動性,??,MC HBSI: 中位數(shù) 13 [6.75-21.25]CU MTWSI: 中位數(shù) 9.5,?,阿達木單抗,???,82% 誘導緩解 160/80 mg s.c.94% 維持治療 40 mg s.c. 隔周一次隨訪: 17個月 [IQR 12

25、–21],Baumgart DC et al. Inflamm Bowel Dis. 2011 Dec;17(12):2512-20. Epub 2011 Feb 23.,www.danielbaumgart.de,皮膚反應的多種表現(xiàn),Baumgart DC et al. Inflamm Bowel Dis. 2011 Dec;17(12):2512-20. Epub 2011 Feb 23.,www.danielbaumgart.de

26、,62%出現(xiàn)皮膚反應,??????????,濕疹樣皮損 n=9痤瘡樣皮損 n=9銀屑病樣皮損 n=6局部紅腫 n = 1干性皮炎 n=1酒渣鼻 n=1單純性癢疹 n=1單純癬 n=1單純皰疹 n=1念珠菌 n=1,???,疾病活動性? CD HBSI：中位數(shù) 6? UC MTWSI：中位數(shù) 410%停用阿達木單抗29% 皮科

27、會診? 42%皮科科干預? 32%局部激素? 10%抗菌治療,Baumgart DC et al. Inflamm Bowel Dis. 2011 Dec;17(12):2512-20. Epub 2011 Feb 23.,www.danielbaumgart.de,無皮膚反應的生存中位時間12個月 [IQR 30–5],Baumgart DC et al. Inflamm Bowel Dis. 2011 De

28、c;17(12):2512-20. Epub 2011 Feb 23,隨訪: 17個月 [12-21]22%停用阿達木單抗停藥更常發(fā)生在：,www.danielbaumgart.de,皮膚反應隨訪,???,???,長病程低誘導劑量激素或免疫調(diào)節(jié)劑平行使用,Baumgart DC et al. Inflamm Bowel Dis. 2011 Dec;17(12):2512-20. Epu

29、b 2011 Feb 23.,www.danielbaumgart.de,GETAID回顧性研究阿達木單抗，賽妥珠單抗，英夫利昔單抗,?,n=85,?,MC n= 69, CU n= 15, CI n= 1,?????,69例皮膚反應62例銀屑病樣與23例濕疹樣皮損41例皮膚反應在局部治療后獲得緩解29例由于皮膚反應停用抗TNF易感因素：,???,女性有過敏體質(zhì)家族史與疾病活動性無關,Rahier

30、 JF et al. Clin Gastroenterol Hepatol. 2010 Dec;8(12):1048-55.,?????,導航流行病學原發(fā)病灶的處理抗TNF治療相關病灶的處理治療相關的皮膚病變?yōu)楹纬霈F(xiàn)?重點總結www.danielbaumgart.de,www.danielbaumgart.de,Tree of Life: Cic

31、carelli F.D. et al. Science DOI: 10.1126/science.1123061,綠色: 古生菌,紅色: 真核微生物,藍色:細菌,www.danielbaumgart.de,在銀屑病中厚壁菌是皮膚菌群中的優(yōu)勢菌,Gao Z et al. PLoS ONE 3(7): e2719. doi:10.1371/journal.pone.0002719,健康皮膚,銀屑病皮膚,www.danielbaumgart

32、.de,Gao Z et al. PLoS ONE 3(7): e2719. doi:10.1371/journal.pone.0002719,L = 左上肢R = 右上肢A – F = 健康對照1,2,3,4,6,8 = 銀屑病PN = 銀屑病正常皮膚PP = 銀屑病皮損,在銀屑病中厚壁菌是皮膚菌群中的優(yōu)勢菌,TNFα 與IFNα在自身免疫性疾病中是交叉調(diào)節(jié)的系統(tǒng)幼年特發(fā)性關節(jié)炎(SOJIA)患者使用抗

33、TNF 治療后IFNα-調(diào)節(jié)基因的轉錄增加,健康對照 狼瘡 (SLE)Palucka A K et al. PNAS 2005;102:3372-3377,SOJIA無αTNF SOJIA有 αTNFwww.danielbaumgart.de,www.danielbaumgart.de,IBD中漿細胞樹突樣細胞（pDC）產(chǎn)生的IFNα,Baumgart DC et al

34、. Clin Exp Immunol. 2011 Oct;166(1):46-54. Epub 2011 Jul 15.,www.danielbaumgart.de,阻斷內(nèi)源性TNF誘導pDC持續(xù)性釋放IFN-α,Palucka A K et al. PNAS 2005;102:3372-3377,www.danielbaumgart.de,釋放IFN-α 的細胞在抗TNF相關銀屑病皮損處蓄積,Tillack C, et al. Gu

35、t 2013;00:1–21,www.danielbaumgart.de,Tillack C, et al. Gut 2013;00:1–21,釋放IL-17 的細胞在抗TNF相關銀屑病皮損處蓄積,www.danielbaumgart.de,Baumgart DC et al. Lancet. 2012 Nov 3;380(9853):1590-605.,我們?nèi)绾巫钄?TH17 細胞?不是使用sekuinumab，而是使用抗-IL1

36、2/IL23等ustekinumab!,???,重點總結IBD是一種系統(tǒng)性炎癥疾病炎癥狀態(tài)（皮膚）通常是相互關聯(lián)的? 事先主動檢查腸外表現(xiàn)? 通常多于一種表現(xiàn)? 選擇某種藥物時，盡量發(fā)揮治療的協(xié)同效應皮膚病變也可發(fā)生在抗TNF治療中? 皮膚反應更常見，出現(xiàn)晚于風濕病與皮膚病? 推薦皮科就診，指導繼續(xù)使用抗TNF? 轉換抗TNFs對銀屑病樣皮損治療無意義? Ustek

37、inuma對銀屑病樣皮損治療有效（以及克羅恩病)? 我們的前瞻性全國研究將會解釋一些尚未解決的問題www.danielbaumgart.de,想知道更多?,??,Daniel K. Podolsky, Judy H. Cho, Morten H. Vatn, Per Brandtzaeg, Jerrold R.Turner, Alan Walker, Kenya Honda, R

38、ichard Flavell, Charles L. Bevins, D.Neil Granger, Scott Snapper, Atsushi Mizoguchi, Atul K. Bhan, Kevin JWoollard, Lloyd Mayer, Yasuhiro Nemoto, Mamoru Watanabe, Matthew B.Grisham, Ra

39、lf Kiesslich, Patrik Rogalla, Joel G. Fletcher, Michael Gebel, IrisDotan, Edouard Louis, Haruhiko Ogata, Toshifumi Hibi, Pia Munkholm,Charles N. Bernstein, Miquel A. Gassull, A. Hil

40、lary Steinhart, LloydSutherland, Laurence Egan, Remo Panaccione, Gary R. Lichtenstein,Stephen Hanauer, Peter Mannon, Peter Gibson, John K. Marshall, Edward V.Loftus, Jr., Gert Van Assch

41、e, Walter Reinisch, Julián Panés, PaoloGionchetti, Daniel W. Hommes, Robert R. Cima, John H. Pemberton, MichaelManns, Roger W Chapman, Terumi Kamisawa, Sue Burge, Roger Sturrock,Alan Buchman

42、, Sunanda Kane, Jeffrey S. Hyams, Kristine Macartney,Francis A. Farraye, Jacques Cosnes, Marjorie Merrick, Ben WilsonCrohn’s Disease and Ulcerative Colitis serves as a uniquecombined resource for

43、 physicians and scientistsaddressing the needs of both groups. It will stimulateexchange and collaboration and shorten the path betweendiscovery and application of new knowledge and al

44、sohelp clinicians understand new therapeutic concepts fromtheir origins. This volume provides an introduction tomucosal immunology which forms the basis of modernimmunotherapy. It also serves as a

45、 comprehensive guideto the current diagnostic modalities, including enhancedimaging techniques such as MRI and CT enterography,virtual colonoscopy, ultrasound, and endomicroscopy aswell as conventio

46、nal and complex immunomodulatoryprinciples. Each chapter is written by experts in their fieldand includes the most up to date information. Crohn’sDisease and Ulcerative Colitis will be of great v

47、alue togastroenterologists, surgeons, internists, pediatriciansand gynecologists trainees, as well as all those involvedin Crohn’s disease, ulcerative colitis and relatedautoimm