Sunanda Kane, MD, MSPH, FACG, FACP, AGAF Associate Professor of Medicine Mayo Clinic

Transcription

1 Serum Markers: What, Who, When and Why? Sunanda Kane, MD, MSPH, FACG, FACP, AGAF Associate Professor of Medicine Mayo Clinic

2 Crohn s Disease: Microbial Antibodies ASCA Anti-I2 Anti-OmpC Bir1 Flagellin Anti- Saccharomyces cerevisiae Protein from pseudomonas fluorescens Escherichia coli outer membrane porin Antibodies to CBir Flagellin Targan S. Gastroenterology 2005;128(7):

3 Combining Markers Improves Sensitivity but Not Overall Accuracy Relationships of Serum Responses in CD Total = 68% Total = 84% Adapted from Landers CJ, et al. Gastroenterology. 2002;123:

4 Antibodies to CBir1 Flagellin Antigen of the gut flora Induces a strong B cell and CD4+ T cell response in colitic mice 50% of patients with Crohn s disease have serum reactivity Little or no reactivity in UC, inflammatory controls, and normal controls Targan S. Gastroenterology 2005;128(7):

5 Immune Response CD Patients % of Patients ASCA 1 Anti-OmpC 1 panca 1 Anti-CBir Adapted from Landers CJ, et al. Gastroenterology. 2002;123: Targan SR, et al. Gastroenterology. 2005;128:

6 Anti-CBir1 Presence CD Patients.) Anti-CB Bir1 Antibo ody (O.D Normal Controls 8% 14% 6% Inflammatory Controls UC CD n=40 n=21 n=50 n=100 P vs CD: % Positive <0.001 <0.02 <0.001 n/a Level <0.001 <0.003 <0.001 n/a Targan SR, et al. Gastroenterology. 2005;128: %

7 Anti-CBir1 Helps Distinguish Between panca+ Patients ) Anti-CB Bir1 (O.D P<0.001 (level) 4% 1/25 44% 11/ panca + UC panca + CD Targan SR, et al. Gastroenterology. 2005;128:

8 Performance Comparison: Crohn s Disease ASCA+ 88% ASCA+ & panca- 97% 61% 49% Sensitivity Specificity Sensitivity Specificity N=391 (51% IBD, 50% CD, 50% UC) In a clinical study, serum samples from 100 CD,101 UC and 27 colitides/diarrheal id l patients and 163 controls were analyzed using panca IFA and ASCA ELISA Quinton JF, et al. Gut. 1998;42:

9 Performance Comparison Ulcerative Colitis panca+ 65% 85% panca+ & ASCA- 97% 57% Sensitivity Specificity Sensitivity Specificity N=391 ( 51% IBD, 50% CD, 50% UC) In a clinical study, serum samples from 100 CD,101 UC and 27 colitides/diarrheal patients and 163 controls were analyzed using panca IFA and ASCA ELISA. Quinton JF, et al. Gut. 1998:42:

10 Prometheus IBD Serology 7 Test Result IBD Predicted IBD Not Predicted PROMETHEUS IBD Serology 7 Overall Performance IBD CD UC Sensitivity 93% 88% 93% Specificity 95% 98% 97% PPV 96% 96% 89% NPV 90% 93% 98% Assay Assay Value : Ulcerative Colitis Predicted Crohn s Disease Predicted ASCA lga ASCA lgg Anti-OmpC Anti-CBir1 ELISA ELISA lga Elisa ELISA PROMETHEUS Predictive Algorithm Description: Utilizes Smart Diagnostic Algorithm (SDA) technology to charecterize complex relationships between markers to produce a diagnosic prediction with greater accuracy than simple comparison of assay results to a reference range. Developed (n=1813; 36% CD, 24% UC, 20% IBS, 20% normal) and validated (n=500; 38% CD, 21% UC, 41% normal) using serology results for samples with a known diagnosis Assay Information Neutrophi-Specific Nuclear Auto Antibodies (NSNA) (IBO Specific panca) Auto Antibody IFA Perinuclear DNAse ELISA Pattern Sensitivity EU/ml EU/ml 26.0 EU/ml 50.2 EU/ml <12.1 EU/ml NOT Detected NOT Detected Note: Test result determined by the PROMETHEUS Predictive Algorithm without direct consideration of assay values relative to reference values. However, interpretation of prognostic information should be made based on relative differences between assay values and reference values Reference Values <20.0 EU/ml <40.0 EU/ml <16.5 EU/ml <21.0 EU/ml < 12.1 EU/ml Not Detected Not Detected

11 Progression of CD and Response to Microbial Antigens Scottish Population Number of Positive Antibodies* (%) P Value OR (3:0) Disease Progression < Surgery < *Antibodies tested: ASCA, anti-ompc, anti-i2 Adapted from Arnott ID, et al. Am J Gastroenterol. 2004;99:

12 Association of ASCA and Early Surgery Newly Diagnosed CD Patients Early Surgery (n=35) No Early Surgery (n=35) P Value OR ASCA IgA 63% 20% ASCA IgG 40% 14% ASCA IgA & IgG 37% 14% Adapted from Forcione DG, et al. Gut. 2004;53:

13 High ASCA IgA & IgG in CD Associated With More Aggressive Small Bowel Disease Bowel gery With Small uiring Surg Patients W ease Requ % of P Dise P< % 57% 29% CD Subgroup panca+ ( 40) & ASCA- All Others ASCA IgG & IgA + ( 50) and ANCA- n=7 n=99 n=14 Adapted from Vasiliauskas EA, et al. Gut. 2000;47: *Other Investigators: Sands, Dassopoulos, Riis Similar results

14 Frequency of Complications Increases With Number of Serologic Markers Children With CD Nonperforating Nonstenotic Perianal Perforating Only Internal Perforating/Stenotic Only Frequ uency of Di isease Beh avior (%) *Odds ratios (P trend=0.002) 1.9* 2.3* 5.5* * n=40 n=60 n=42 n=29 n=12 No. of Immune Responses Serologic markers: ASCA Anti-OmpC Anti-CBir1 Anti-I2 Dubinsky M, et al. Am J Gastroenterol. 2006;101:

15 Anti-microbial responsiveness is increased in NOD2 mutant carriers Mutations in Nod2 may decrease innate immune clearance of bacteria leading to secondary increase in adaptive immune responses Analyzed 732 Crohn s disease patients, 220 healthy relatives, 200 controls Nod2 mutant carriers have higher titers of anti-microbial antibodies: CBir1, I2, ASCA, OmpC sum n quartile Mea One way ANOVA Devlin S, et al. DDW 2006, Los Angeles. Abstract #442 p-trend = n=499 n=194 n=39 WT 1 mut 2 mut NOD2/CARD15 Variant status

16 Potential Roles for IBD Serology Help identify IBD in patients with unclear diagnosis (but chronic inflammation already established) Help assess the need for endoscopy in patients who are suspected of having IBD (pediatric population) Help differentiate between CD and UC Help improve the accuracy of diagnosis prior to surgery (eg, colectomy, IPAA) Help identify patients at risk for aggressive disease behavior

17 Indeterminate Colitis: Value of Serology % 80% Leuven, Lille, Vienna 97pt Definite Diagnosis 31pt panca- / ASCA - 40pt UC panca+/asca- CD panca-/asca+ Joossens S. Gastroenterology (5): Joossens S. Gastroenterology : A323

18 IBD Serologies: When to order? IC / Colectomy is planned (UC vs CD, pouchitis risk) Pediatric: low suspicion Mainly extra-intestinal manifestations (is it IBD?) Ankylosing spondylitis Athiti Arthritis Pyoderma gangenosum Uveitis Second opinion / questionable diagnosis Prognostication: ready for prime time? Expensive: will insurance cover?

19 IBD Serologies: Summary Identify IBD in cases of diagnostic uncertainty Assess the need for invasive endoscopy in patients who are suspected of having IBD Differentiate between CD and UC Identify patients at risk for aggressive disease behavior Insurance / cost still an issue