Strategies for changing the course of Crohn s disease

Transcription

1 Strategies for changing the course of Crohn s disease Maria T. Abreu, MD University of Miami Miller School of Medicine Miami, Florida Where we are now and where we want to be Diagnosis (usually endoscopy) Serology (children) CRP/ESR Disease prognosis (clinical parameters) First visit: IBD panel Serotype Genotype Phenotype IBD subtype Disease prognosis Treatment based on symptoms +/- endoscopic inflammation Patient-specific treatment plan Integrated target-specific therapy 1 Abreu 1

2 Aggressive disease does not mean it doesn t respond to therapy Mild disease Responds well to therapy Does not respond well to therapy Aggressive disease Genetics of IBD: 163 confirmed loci NOD2 PTPN22 CD genes 3 CD specific loci 11 IBD loci Common pathways: Leprosy Mycobacterial susceptibility Other immunemediated disease UC genes 23 UC specific loci MHC Genes in common Jostins, L. et al. Nature 491, (1 November 212) 2 Abreu 2

3 IBD pathogenesis Crohn s disease-like Ulcerative colitis-like Crohn s activating infections Colonization (bacteria, viruses, fungi, worms) Loss of protective flora Crohn s specific genes (Nod2) Core genes Regulating Inflammation, Epithelial barrier, autophagy, etc UC specific genes Can we use serologies and genetic markers to predict disease behavior? 3 Abreu 3

4 Impact of Therapy will Depend on Degree of Structural Damage & Velocity of Progression 1 9 High Potential Low Potential Cum mulative Probability (%) Penetrating Inflammatory Stricturing Months Patients at risk: N = Cosnes J et al. Inflamm Bowel Dis. 22;8:244. Cumulative Probability of Surgical Intervention in CD 1 8 Probability (%) ±2 SD 3 surgeries later Who cares? D Years Events (no.) Munkholm P, et al. Gastroenterology. 1993;15: Abreu 4

5 How do biomarkers hold up Test Diagnosis Prognosis Active disease Serologies Good Better So-so Genetics Not good Best in No role combination with serologies CRP Not good Not good Ok in an individual patient if tracks with disease Stool studies Good in right clinical setting Not good Good for colonic disease; less for (children) ileal disease Are serological markers such as anti-glycan antibodies, anti- saccharomyces, ASCA, etc. useful in defining disease activity and response to therapy? Not useful for disease activity or response to therapy 5 Abreu 5

6 Innate and Adaptive Immune Responses/ Acute and Chronic Inflammation Hypothesis: IBD arises from inappropriate handling of intestinal bacteria Defective innate immunity followed by exuberant adaptive immune response IBD Specific Serologic Immune Markers Antibody DNase Sensitive panca ASCA Antigen Histone H 1, bacterial antigen? Saccharomyces cerevisiae (oligomannans) Non- IBD (%) CD (%) UC (%) <5% 1 25% 5 65% 5% 55 65% 5% OmpC Anti-Ι2 E. Coli <5% 38 5% 2% Pseudomonas fluorescens <5% 54% 2% Anti-Flagellin CBir 1 Antigen 8-14% 5% 6% Anti-ALCA IgG Anti-ACCA IgA laminaribioside Glc(β1,3)Glc(β) Chitobioside GlcNAc(β1,4)GlcNAc(β) 2% 27% 9% 12% 25% 25% 6 Abreu 6

7 IBD Specific Serologic Immune Markers Antibody DNase Sensitive panca ASCA Antigen Histone H 1, bacterial antigen? Saccharomyces cerevisiae (oligomannans) CD (%) UC (%) <5% 1 25% 5 65% 5% 55 65% 5% OmpC Anti-Ι2 E. Coli <5% 38 5% 2% Pseudomonas fluorescens <5% 54% 2% Anti-Flagellin CBir 1 Antigen 8-14% 5% 6% Anti-ALCA IgG Anti-ACCA IgA laminaribioside Glc(β1,3)Glc(β) Chitobioside GlcNAc(β1,4)GlcNAc(β) 2% 27% 9% 12% 25% 25% IBD Specific Serologic Immune Markers Antibody DNase Sensitive panca ASCA Antigen Histone H 1, bacterial antigen? Saccharomyces cerevisiae (oligomannans) Non- IBD (%) Non- IBD (%) CD (%) UC (%) <5% 1 25% 5 65% 5% 55 65% 5% OmpC Anti-Ι2 E. Coli <5% 38 5% 2% Pseudomonas fluorescens <5% 54% 2% Anti-Flagellin CBir 1 Antigen 8-14% 5% 6% Anti-ALCA IgG Anti-ACCA IgA laminaribioside Glc(β1,3)Glc(β) Chitobioside GlcNAc(β1,4)GlcNAc(β) 2% 27% 9% 12% 25% 25% 7 Abreu 7

8 The main targets to anti micro organism antibodies are actually fungal cell wall glycans β-glucans Mannan Chitosan Dotan I. et al, Gastroenterology 26 Ferrante M. et al, Gut 27 Seow CH. et al, Am J Gastroenterol 29 Description: Quartile Sum Scores (QSS) The magnitude of individual antigen responses is grouped by Quartile Score Quartile 1 <25% 2 25% - <5% 3 5% - <75% 4 75% - 1% The sum of all the individual antigen quartiles is expressed as the QSS ASCA- IgA 2 ASCA - IgG 2 Anti-OmpC 3 Anti-CBir1 4 Anti-I2 4 = QSS = 15 Mow WS, et al. Gastroenterology. 24;126: CD August 4, 21 8 Abreu 8

9 Quartile Sum Score Examples QSS = 6 Antibody 1 = 1 Antibody 2 = 1 Antibody 3 = 1 Antibody 4 = 1 QSS = 2 Antibody 1 = 4 Antibody 2 = 3 Antibody 3 = 4 Antibody 4 = 4 Antibody 5 = 1 Antibody 5 = 3 Antibody 6 = 1 Antibody 6 = CD August 4, 21 Prediction of Complicated Disease Behavior Quantitative Assessment with QSS Freq quency of disease behav vior, % * Patented P trend <.1 <.1 < q u a r t i l e s u m q u a r t i l e s u m q u a r t i l e s u m Fibrostenosing disease Small bowel surgery Internal-perforating disease Markers: ASCA Anti-OmpC* Anti-I2* Adapted from Mow WS, et al. Gastroenterology. 24;126: CD August 4, 21 9 Abreu 9

10 Antibody Sum and Surgery ability of non-progres ssive CD Prob P<.1 ab_sum= ab_sum=1 ab_sum=2 ab_sum=3 N= 47 N= 189 N= 243 N= Time to surgery (months) Dubinsky MC et al CGH 28;6:115 % patients Serological markers to carbohydrate Ags (ACCA, ALCA, ASCA) can be used to predict CD course Complicated disease course OR: 2. p=.1 OR: 1.96 p=.1 OR: 1.76 p=.6 OR: 1.56 p=.33 Need for abdominal surgery OR: 1.45 p=.72 OR: 2.81 p<.1 Score <1.5 Score Score 1.5 or or 3. Score >3. Score <1.5 Score Score 1.5 or or 3. Score >3. Ferrante M, et al. Gut 27 Oct;56(1): OR=odds ratio; p-value (Chi-square) 1 Abreu 1

11 Antibody Reactivity to Microbial Products Increases With Decreased NOD2 Function Leve el of Anti-microbial Ab bs P trend = N=499 N=194 N= NOD2/CARD15 Variant Status (number of mutations) Devlin, S. M., et al. (27). Gastroenterology 132(2): Are there genetic and/or biochemical markers that indicate disease prognosis? 11 Abreu 11

12 NOD2 Role in Pathogenesis Maeda S, Hsu LC, et al. Science. 25;37: NOD2 Allelic Variants More Frequent in Fibrostenosing vs. Perforating Disease 8 ency of NOD2 Varian nt Carriers (%) Frequ Fibro- stenosing Fib + Perf p=.2 Perforating 1 Abreu, M. T., et al. Gastroenterology 22, v Abreu 12

13 NOD2/CARD15 and need for surgery Probability of remaining free of surgery Cumulative survival Probability of remaining free of surgical recurrence Cumulative survival p value=.89 p value= No variants Nod2/Card15 gene variants Months Alvarez-Lobos et al, Annals of Surgery 25; 242: 693 Radlmayr et al, Gastroenterol 22; 122: 291 Buning et al, AP&T 24; 19: 173 The more Crohn s disease risk genes you carry, the more complicated the disease Characteristic All (n = 1353) Follow-up >5 years (n = 172) Follow-up >1 years n = 763 Age at diagnosis <4 years Familial occurrence Stricturing and/or penetrating behavior Perianal disease Operation NOD2, IBD5, ATG16L1, DLG5, IL23R R K Weersma, et al Gut 29;58: Abreu 13

14 Predicting response to anti-tnf therapy CLINICAL VARIABLE NON RESPONSE RESPONSE P Value UC vs. CD 14:8 6:66 <.1 Mean age at diagnosis i (years) Gender M:F 8:14 4:32.12 Disease duration at start of IFX (months) IMM use at start of IFX (% ) 79% 92.8%.1 Duration of IMM at start of IFX (months) panca % 29%.1 ASCA+ % 46.9%.3 Dubinsky MC. Inflamm Bowel Dis. 21 Aug;16(8): Endoscopic markers that predict poor prognosis 14 Abreu 14

15 Prognosis for Patients With CD and Severe Ulcerations Retrospective cohort 12 Patients with active CD SEL defined as deep ulcerations > 1% of mucosal area with at least 1 colonic segment Risk of colectomy associated with SELs, high CDAI score, and absence of immunosuppression Prob bability of Colectomy, % No SEL SEL Years CDAI = Crohn s Disease Activity Index; SEL = severe endoscopic lesions. Allez M, et al. Am J Gastro. 22;97: Synergism Between NOD2 Variants and Ab Levels in Fibrostenosis The odds ratio for fibrostenosis increases with QSS and increases even more in patients who have NOD2 variants 12 P=.1 1 P=.3 s Ratio (OR) Odd P=.4 NOD 2 Variant Present? No Yes Quartile Sum Ippoliti A, et al. Inflamm Bowel Dis. 21, 16: N= Abreu 15

16 Synergism between Serology and Genetics Serology NOD2 (-) Serology NOD2 (+) % complication QSS 24 QSS % complication 92% complication QSS 24 QSS 15 QSS 6 C om plications, cumulative risk % complication 16% complication QSS 6 P<.1 Com plications, cumulative risk % complication P< Years after DX Years after DX Lichtenstein, G.R. et al. Inflamm Bowel Dis. 211 Dec;17(12): Genetic factors influence disease phenotype in CD: The European IBD immunochip project IL23, LOC44118, PRDM1, NOD2 IRGM, TNFS15, C13RF31, NOD2 Cleynen I et al. Gut Abreu 16

17 So how do you stop progression of disease? SONIC Clinical Remission Without Corticosteroids at Week 26 Primary Endpoint tion of Patients (%) Proport p=.9 p<.1 45 p= /17 75/169 96/169 AZA + placebo IFX + placebo IFX+ AZA Colombel, J.F., et al., N Engl J Med. 362(15): p Abreu 17

18 healing ) ents with mucosal at week 12 (%) Patie The best opportunity to induce mucosal healing is early in Crohn s disease (EXTEND study) 5 45 Adalimumab, induction-only (placebo) Adalimumab, every other week /9 1/14 4/1 7/39 9/43 <2 years 2 to <5 years 5 years p=.29 for adalimumab vs placebo for disease duration <5 years vs. 5years All patients (n=135) received open-label adalimumab 16-/8-mg induction therapy at Weeks /2 and 129 patients were randomised at Week 4 to maintenance therapy with adalimumab 4 mg every other week or placebo Sandborn WJ, et al. J Crohn s Colitis 21; 4:S36 (Abstract P6) Patient Population for Model Development 796 well-characterized pediatric CD patients Enrolled from 21 centers from North America Demographic, clinical, genetic, and immune response data were prospectively collected Treatment data collected Steroids, immunomodulators (IMs), anti tumor necrosis factor (anti-tnf) agents Timing in relationship to a disease complication Model concordance index (Harrell s C =.81) Siegel CA et al. Inflamm Bowel Dis. 211;17:3. 18 Abreu 18

19 Control Panel and Output 16-year-old girl, small bowel and perianal disease, QSS group = No treatment Risk of Complication 5 25 Early IM treatment Year From Present Siegel CA et al. Inflamm Bowel Dis. 211;17:3. Post-op Ileocecectomy is the Perfect Opportunity for Prevention! Health Subclinical Inflammation Symptomatic Inflammation Complications Disability Disease Prevention Prevention of Complications Prevention of Symptomatic Disease Prevention of Relapse 19 Abreu 19

20 Recurrence After Surgery in Crohn s Disease 1 8 Survival without surgery N=89 Patients (%) 6 4 Survival without laboratory recurrence Survival without symptoms 2 Survival without endoscopic lesions Years Rutgeerts P et al. Gastroenterol. 199;99(4): Risk Stratification for Recurrence in Post-operative Crohn s disease Smoking Perforating-type of disease Small bowel disease Ileocolonic disease Perianal fistulas Duration of disease Age? Clear margins? Length of resection?type of anastomosis Greenstein AJ et al. Gut. 1988;29(5): Bernell O et al. Ann Surg. 2;231(1): Bernell O et al. Br J Surg. 2;87(12): D'Haens GR et al. Gut. 1995;36(5): Lautenbach E et al. Gastroenterol.1998;115(2): Moskovitz D et al. Int J Colorectal Dis. 1999;14(4-5): Kono T et al. Dis Colon Rectum 211 May;54(5): Abreu 2

21 The Neo-TI: The Rutgeerts Score Patients should be scoped 6 months after surgery to re-stratify risk Rutgeert s Rutgeerts 1 Rutgeerts 2 Normal ileal mucosa <5 aphthous ulcers >5 aphthous ulcers, normal intervening mucosa Ulceration without normal intervening mucosa Severe ulceration with nodules, cobblestoning, or stricture Rutgeerts 3 Rutgeerts 4 The neo-terminal ileum is not the anastomosis! Suture-related trauma Marginal ulcerations/ischemia 21 Abreu 21

22 Symptoms after Crohn s Surgery are Not Always Inflammatory! Symptom/Cause Post-operative operati e pain Post-resection diarrhesis (rapid transit due to absence of obstruction and muscular hypertrophy) Bile salts Narcotic bowel Bacterial overgrowth Treatments Limited analgesia, regional anesthesia when possible Anti-diarrheals Bile acid sequestrant NO narcotics! antibiotics Medical Prevention of Clinical and Endoscopic Recurrence of Crohn s Disease Clinical Recurrence Endoscopic recurrence Placebo 25% 77% 53% - 79% 5 ASA 24% - 58% 63% - 66% Budesonide 19% - 32% 52% - 57% Nitroimidazole 7% - 8% 52% - 54% AZA/6MP 34% 5% 42 44% Infliximab % 9.1% Regueiro M. Inflamm Bowel Dis. 29 Oct;15(1): Abreu 22

23 Scientific Integration: Practical Aspects First Visit: Diagnosis Early serologies/microbiome in young patients Disease Prognosis genes, multiple/hi titer Abs, microbiome, predict aggressive disease Top down or similar approach In future, check for adverse event genes 23 Abreu 23