1027 A Single Biomarker Panel Predicts Response to Infliximab in Patients With Crohn's Disease and...
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AGA Abstracts 1027 A Single Biomarker Panel Predicts Response to Infliximab in Patients With Crohn's Disease and Ulcerative Colitis Willem Westra, Vy Hoang, Daphna Laifenfeld Background: Anti-TNF therapies are an important treatment for Crohn's disease (CD) or ulcerative colitis (UC) patients, yet not all respond to these drugs. Developing biomarkers to predict response prior to anti-TNF therapy is important to avoid ineffective treatment and adverse events. A related question is whether the same biomarker panel can predict response to anti-TNF treatment in both IBD subforms. Objectives: The objectives of this research were to: 1. Develop mechanistic gene-based biomarker panels to predict response to infliximab in CD and UC patients based on TNF signaling; 2. Compare biomarkers for the different IBD subforms; and 3. Determine whether a pan-IBD biomarker can predict response in both subforms. Methods: A panel of 1853 TNF-regulated genes from 691 publications was customized to UC and CD by constraining to genes that are 1) TNF- regulated in IBD-relevant experimental contexts and 2) differentially regulated in CD or UC compared to controls. This resulted in a biomarker panel of 123 TNF-regulated genes for CD and 542 for UC. The 117 gene overlap between these panels was used as a pan-IBD panel. All three biomarkers were subsequently tested on GSE16879, a transcriptomic data set from mucosal biopsies obtained by endoscopy in actively inflamed colonic mucosa of 24 patients with active UC and 19 with CD. Patients were treatment-Naïve to anti-TNF therapy and refractory to corticosteroids and/or immunosuppresants. Response to infliximab was defined as complete mucosal healing with a decrease of at least 3 points on the histological score for CD (12 responders, 7 non-responders) and as a decrease to a Mayo endoscopic subscore of 0 or 1 with a decrease to grade 0 or 1 on the histological score for UC (8 responders, 16 non-responders), 4-6 weeks after treatment (Arijs et al. 2009). Individual patients were stratified for TNF signaling strength by a quantitative scoring algorithm applied to the genes within the three biomarker panels. Results: Stratifying patients for TNF signaling strength with the individual CD or UC biomarker panels accurately predicted infliximab response (AUROC=0.96, specificity=80%/sensitivity=92% and AUROC=0.88, specificity= 80%/sensitivity=88%, respectively). In addition, the pan-IBD biomarker panel accurately predicted infliximab response for both CD (AUROC=0.98, specificity=100%/sensitivity= 83%) and UC (AUROC=0.88, specificity=80%/sensitivity=88%). Conclusions: this study demonstrates that 1. An a-priori approach assessing TNF signaling can predict response to anti-TNF therapy in IBD and 2. That identification of infliximab responders is possible using a single pan-IBD gene expression panel reflecting TNF signaling strength. Additional independent cohorts will be required to further assess and validate the feasibility of predicting response to infliximab in CD and UC with a single biomarker. S-192 AGA Abstracts 1028 Novel Proteomic Assessment for the Development of IBD in Active Duty US Military Personnel Ganesh R. Veerappan, Mary Beth Yacyshyn, Corinne Maydonovitch, John Betteridge, Feng Wang, Bruce R. Yacyshyn Introduction: Environment and genetics are involved in the development of inflammatory bowel diseases (IBD). The onset of IBD might be predicted before obvious clinical changes or detection of antibody titers to autoimmune and bacterial components. The environment may be triggering production of specific proteins, which may be participatory in the develop- ment of IBD. Our goal for this case-control study is to identify a population at risk for the development of either Crohn's disease (CD) or ulcerative colitis (UC) based on the presence of proteins in IBD patients compared to a control population. Methods: We identified active duty personnel with IBD using multiple ICD-9 codes at 2 different outpatient encounters. We analyzed 50 patients each with CD, UC and 50 age, race, gender and time-matched controls. Samples came from the Department of Defense serum repository (DoDSR), which routinely stores serum from active duty military. We obtained serum samples from 2 time points (1st before diagnosis; 2nd within a year of diagnosis of IBD) of these individuals from the DoDSR in Silver Spring, MD. Serum samples were analyzed for specific proteins using multiplexed Luminex and traditional single ELISAs. The protein panel was chosen based on previous non-published IBD proteomic data. Results: Using a targeted panel of serum proteins, the adipokine, resistin, is significantly different at baseline in IBD, both CD (.01, p , .05) and UC (.0005 , p ,.0001) samples, when compared to the baseline control samples. Although this marker has been linked to active disease, this is the first report of it differentiating IBD prior to diagnosis. This marker remained stable over the two times measured. Another well-documented measure of inflammation is CRP. A statistically significant Increase in CRP levels was detected in CD baseline samples (.0005 ,p, .0001) when compared to controls and UC (.01 ,p,.05). Interestingly, at time of diagnosis (time 2), this difference was lost. SCL70, an anti-nuclear autoantibody, demonstrated significant changes between the two time points (baseline and diagnosis) in both UC (p , .05) and Crohns (p, .05). Serum pANCA also demonstrated a significant change (.01 , p, .05) in Crohn's patients between time point 1 and 2. pANCA in UC patients remained constant over time (p=.695 between time point 1 and 2). Conclusion: Further development of serum proteomic analysis of specific markers may aid in determining risk for IBD development as well understanding early mechanisms associated with disease by demonstrating changes in serum proteins over time. Early stage proteomics may be beneficial in early diagnosis and treatment before clinically evident IBD. 1029 Serological and Inflammatory IBD Marker Prevalence As Function of Age in a Large Cohort of Patients Presenting IBD-Like Gastrointestinal Symptoms Scott E. Plevy, Steven Lockton, Fred Princen, Sharat Singh Background: Around 1.4 million Americans suffer from Crohn's disease or ulcerative colitis. Approximately 10 % of cases occur in individuals younger than 17 years old. Endoscopy and biopsies are traditionally used to diagnose pediatric IBD but less invasive testing methods can be especially valuable for younger patients. The use of serological and inflammatory markers to assist in IBD diagnosis has been extensively described in the literature. However, the prevalence of these markers in adults compared to children is not well established. Aim: To analyze serological and inflammatory marker prevalence as function of age in patients presenting with a suspected diagnosis of IBD in clinical practice. Methods: Marker data from 43,679 de-identified patients with unknown diagnostic samples between ages 2 and 85 year-old were collected from Prometheus Labs CLIA laboratory. The prevalence of serological markers (ASCA-A, ASCA-G, ANCA, pANCA & anti-OmpC), anti-flagelins (CBir1, A4-Fla2 & FlaX) and inflammatory markers (CRP, SAA, ICAM, VCAM & VEGF) were compared between different age groups: 2-7 year-olds (n = 932), 8-17 year-olds (n = 5907) and 18 year-old and above (n = 36,840). Results: In this large sample of subjects, 16.7% were under 18 year old and 3.5% of the patients were under 7 years old. The prevalence of ASCA-A was 6.2% in the 2-7 year-old group and 22.6 % in the ≥ 18 year old group. ASCA-G follows a similar trend, with 3.9% and 21.6% of patients positive, respectively (Table 1). Anti- OmpC also increased in prevalence from 8.5 % in the 2-7 year-old group to 23.1 % in the ≥ 18 year old and above group. Interestingly, the flagellin marker anti-CBir-1 demonstrated the opposite trend with 61.2% of younger patients positive, decreasing to 22.9% at ages ≥ 18 (Table 1). Anti-flagellins A4-Fla2 and FlaX follow similar trends as CBir-1. ANCA did not display significant variation amongst age groups. Inflammatory markers CRP and SAA increased in prevalence with age, while ICAM-1 and VCAM-1 prevalence decreased (Table 1). These results have been validated in a smaller cohort of age-matched patients with known CD. Conclusion: A distinct serological marker pattern distinguishes pediatric and adult patients in this cohort. The two ASCA markers and anti-OmpC are more prevalent in adult patients while anti-flagellins are dominant in pediatric patients. The inflammatory markers CRP and SAA increase with age. These results demonstrate the potential clinical value of anti-flagellin serological markers in pediatric IBD. Age Group (years)
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1027
A Single Biomarker Panel Predicts Response to Infliximab in Patients WithCrohn's Disease and Ulcerative ColitisWillem Westra, Vy Hoang, Daphna Laifenfeld
Background: Anti-TNF therapies are an important treatment for Crohn's disease (CD) orulcerative colitis (UC) patients, yet not all respond to these drugs. Developing biomarkersto predict response prior to anti-TNF therapy is important to avoid ineffective treatmentand adverse events. A related question is whether the same biomarker panel can predictresponse to anti-TNF treatment in both IBD subforms. Objectives: The objectives of thisresearch were to: 1. Develop mechanistic gene-based biomarker panels to predict responseto infliximab in CD and UC patients based on TNF signaling; 2. Compare biomarkers forthe different IBD subforms; and 3. Determine whether a pan-IBD biomarker can predictresponse in both subforms. Methods: A panel of 1853 TNF-regulated genes from 691publications was customized to UC and CD by constraining to genes that are 1) TNF-regulated in IBD-relevant experimental contexts and 2) differentially regulated in CD or UCcompared to controls. This resulted in a biomarker panel of 123 TNF-regulated genes forCD and 542 for UC. The 117 gene overlap between these panels was used as a pan-IBDpanel. All three biomarkers were subsequently tested on GSE16879, a transcriptomic dataset from mucosal biopsies obtained by endoscopy in actively inflamed colonic mucosa of24 patients with active UC and 19 with CD. Patients were treatment-Naïve to anti-TNFtherapy and refractory to corticosteroids and/or immunosuppresants. Response to infliximabwas defined as complete mucosal healing with a decrease of at least 3 points on the histologicalscore for CD (12 responders, 7 non-responders) and as a decrease to a Mayo endoscopicsubscore of 0 or 1 with a decrease to grade 0 or 1 on the histological score for UC (8responders, 16 non-responders), 4-6 weeks after treatment (Arijs et al. 2009). Individualpatients were stratified for TNF signaling strength by a quantitative scoring algorithm appliedto the genes within the three biomarker panels. Results: Stratifying patients for TNF signalingstrength with the individual CD or UC biomarker panels accurately predicted infliximabresponse (AUROC=0.96, specificity=80%/sensitivity=92% and AUROC=0.88, specificity=80%/sensitivity=88%, respectively). In addition, the pan-IBD biomarker panel accuratelypredicted infliximab response for both CD (AUROC=0.98, specificity=100%/sensitivity=83%) and UC (AUROC=0.88, specificity=80%/sensitivity=88%). Conclusions: this studydemonstrates that 1. An a-priori approach assessing TNF signaling can predict response toanti-TNF therapy in IBD and 2. That identification of infliximab responders is possibleusing a single pan-IBD gene expression panel reflecting TNF signaling strength. Additionalindependent cohorts will be required to further assess and validate the feasibility of predictingresponse to infliximab in CD and UC with a single biomarker.
S-192AGA Abstracts
1028
Novel Proteomic Assessment for the Development of IBD in Active Duty USMilitary PersonnelGanesh R. Veerappan, Mary Beth Yacyshyn, Corinne Maydonovitch, John Betteridge, FengWang, Bruce R. Yacyshyn
Introduction: Environment and genetics are involved in the development of inflammatorybowel diseases (IBD). The onset of IBD might be predicted before obvious clinical changesor detection of antibody titers to autoimmune and bacterial components. The environmentmay be triggering production of specific proteins, which may be participatory in the develop-ment of IBD. Our goal for this case-control study is to identify a population at risk for thedevelopment of either Crohn's disease (CD) or ulcerative colitis (UC) based on the presenceof proteins in IBD patients compared to a control population. Methods: We identified activeduty personnel with IBD using multiple ICD-9 codes at 2 different outpatient encounters.We analyzed 50 patients each with CD, UC and 50 age, race, gender and time-matchedcontrols. Samples came from the Department of Defense serum repository (DoDSR), whichroutinely stores serum from active duty military. We obtained serum samples from 2 timepoints (1st before diagnosis; 2nd within a year of diagnosis of IBD) of these individualsfrom the DoDSR in Silver Spring, MD. Serum samples were analyzed for specific proteinsusing multiplexed Luminex and traditional single ELISAs. The protein panel was chosenbased on previous non-published IBD proteomic data. Results: Using a targeted panel ofserum proteins, the adipokine, resistin, is significantly different at baseline in IBD, both CD(.01, p , .05) and UC (.0005, p ,.0001) samples, when compared to the baselinecontrol samples. Although this marker has been linked to active disease, this is the firstreport of it differentiating IBD prior to diagnosis. This marker remained stable over the twotimes measured. Another well-documented measure of inflammation is CRP. A statisticallysignificant Increase in CRP levels was detected in CD baseline samples (.0005 ,p, .0001)when compared to controls and UC (.01,p,.05). Interestingly, at time of diagnosis (time2), this difference was lost. SCL70, an anti-nuclear autoantibody, demonstrated significantchanges between the two time points (baseline and diagnosis) in both UC (p , .05) andCrohns (p, .05). Serum pANCA also demonstrated a significant change (.01 , p, .05) inCrohn's patients between time point 1 and 2. pANCA in UC patients remained constantover time (p=.695 between time point 1 and 2). Conclusion: Further development of serumproteomic analysis of specific markers may aid in determining risk for IBD development aswell understanding early mechanisms associated with disease by demonstrating changes inserum proteins over time. Early stage proteomics may be beneficial in early diagnosis andtreatment before clinically evident IBD.
1029
Serological and Inflammatory IBD Marker Prevalence As Function of Age in aLarge Cohort of Patients Presenting IBD-Like Gastrointestinal SymptomsScott E. Plevy, Steven Lockton, Fred Princen, Sharat Singh
Background: Around 1.4 million Americans suffer from Crohn's disease or ulcerative colitis.Approximately 10 % of cases occur in individuals younger than 17 years old. Endoscopyand biopsies are traditionally used to diagnose pediatric IBD but less invasive testing methodscan be especially valuable for younger patients. The use of serological and inflammatorymarkers to assist in IBD diagnosis has been extensively described in the literature. However,the prevalence of these markers in adults compared to children is not well established. Aim:To analyze serological and inflammatory marker prevalence as function of age in patientspresenting with a suspected diagnosis of IBD in clinical practice. Methods: Marker data from43,679 de-identified patients with unknown diagnostic samples between ages 2 and 85year-old were collected from Prometheus Labs CLIA laboratory. The prevalence of serologicalmarkers (ASCA-A, ASCA-G, ANCA, pANCA& anti-OmpC), anti-flagelins (CBir1, A4-Fla2 &FlaX) and inflammatory markers (CRP, SAA, ICAM, VCAM&VEGF) were compared betweendifferent age groups: 2-7 year-olds (n = 932), 8-17 year-olds (n = 5907) and 18 year-oldand above (n = 36,840). Results: In this large sample of subjects, 16.7% were under 18year old and 3.5% of the patients were under 7 years old. The prevalence of ASCA-A was6.2% in the 2-7 year-old group and 22.6 % in the ≥ 18 year old group. ASCA-G followsa similar trend, with 3.9% and 21.6% of patients positive, respectively (Table 1). Anti-OmpC also increased in prevalence from 8.5 % in the 2-7 year-old group to 23.1 % in the≥ 18 year old and above group. Interestingly, the flagellin marker anti-CBir-1 demonstratedthe opposite trend with 61.2% of younger patients positive, decreasing to 22.9% at ages ≥18 (Table 1). Anti-flagellins A4-Fla2 and FlaX follow similar trends as CBir-1. ANCA didnot display significant variation amongst age groups. Inflammatory markers CRP and SAAincreased in prevalence with age, while ICAM-1 and VCAM-1 prevalence decreased (Table1). These results have been validated in a smaller cohort of age-matched patients with knownCD. Conclusion: A distinct serological marker pattern distinguishes pediatric and adultpatients in this cohort. The two ASCA markers and anti-OmpC are more prevalent in adultpatients while anti-flagellins are dominant in pediatric patients. The inflammatory markersCRP and SAA increase with age. These results demonstrate the potential clinical value ofanti-flagellin serological markers in pediatric IBD.Age Group (years)
