- Email: [email protected]
Su1164 Diagnostic and Therapeutic Double Balloon Enteroscopy in Crohn's Disease Is Safe and Effective
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characteristic of Crohn's disease. Capsule endoscopy (CE) has been established as providing a higher detection rate for small bowel Crohn's disease, compared to ileo-colonoscopy (IC) and other imaging modalities. The aim of our study was to evaluate the accuracy of CE for detection of small bowel lesions in patients with SPA. Methods: This is a prospective cross-sectional study. The study cohort included patients ( . 18 y) followed by MUHC Rheumatology Center for known SpA or ankylosing spondylitis. The diagnosis of SpA was based on the ESSG criteria, while ankylosing spondylitis (AS) was based on the modified New York criteria. All patients were evaluated by CE, followed (within 4 weeks) by ileocolonoscopy (IC), performed blinded to CE results. NSAIDs were discontinued for a minimum of 4 weeks. The presence of small bowel mucosal inflammation on CE was quantified by the Lewis score (LS). Normal CE was defined as LS of , 135 , mild disease was defined as LS 135-790, while LS ≥790 was considered moderate to severe. Results: We report the preliminary results of the first 24 SPaCE study patients (age 39± 12, 54% male). 86% were HLA-B27 positive. Sixty three percent of the patients had gastrointestinal complaints, and 33.3% had elevated CRP levels. Recent therapy for SpA included etanercept (1 patient), methotrexate (1 patient) and NSAIDs in 58.3% of the patients. IC with biopsies demonstrated endoscopic and pathologic findings consistent with CD in 18.2% of the patients. None of the patients was diagnosed with ulcerative colitis. CE identified small bowel lesions consistent with CD in 33% of the patients (mean LS 1083 ±702), including all patients with ICdetected CD, and equivocal IC findings in additional 8.3% of the patients (LS of 168 and 225), respectively. In patients with equivocal CE results, CD was not demonstrated by IC. Gastrointestinal symptoms had a positive predictive value of 40% and 24%, and negative predictive value of 78.7% and 88.9% for findings on CE and IC, respectively. Following the diagnosis of small bowel inflammatory lesions, ant-TNF treatment was initiated in 4/8 patients. Conclusions: Small bowel lesions consistent with Crohn's disease are common in patients with spondyloarthropathies. These preliminary results suggest that CE of the SB is superior to IC in detecting CD in patients with known SpA. The findings obtained by CE are of clinical importance and resulted in a treatment change in 50% of the patients. Gastrointestinal complaints are a poor indicator for the presence Crohn's disease. These results merit verification on completion of the study.
AGA Abstracts
Risk of Solid Cancers With Tumor Necrosis Factor Alpha Inhibitor Therapy Among Inflammatory Bowel Disease Patients: An Analysis of the Food and Drug Administration Adverse Event Reporting System Derrick J. Stobaugh, Parakkal Deepak, Eli D. Ehrenpreis Background: The risk of solid cancers after exposure to tumor necrosis factor alpha (TNFα) inhibitors in inflammatory bowel disease (IBD) is unclear. We sought to examine the risk including with TNF-α monotherapy using the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: 3,171,655 files between January 2003 and June 2012 were downloaded and analyzed using SPSS 20 (IBM Co. Armonk, NY, USA). They were queried for Primary Suspect (PS) adverse events reports with TNF- α inhibitors (Adalimumab, Certolizumab, Infliximab), systemic corticosteroids, and immunomodulators (thiopurines, methotrexate and calcineurin inhibitors), using both trade and generic names, for IBD along with control drugs (5-aminosalicylic acid and sulphasalazine, including trade names) as a basis of comparison. These were further queried for outcomes of solid cancers as well as control reactions (syncope, hernia, deafness and vertigo, which were predefined to have no association with study drugs or control drugs) utilizing reactions terms from the Medical Dictionary for Regulatory Activities. Any reports with comorbidities of human immunodeficiency virus infection, organ transplantation or rheumatologic diseases associated with a risk of solid cancer as well as concomitant exposure to a non- TNF- α inhibitor biologic medication were excluded from analysis. The findings were further analyzed to determine the risk of the most commonly reported solid cancers. Odds ratios for the risk of solid cancers with TNF-α inhibitor monotherapy as well as combination therapy were calculated with the Fischer's exact test. Reports with more than one type of solid cancer within the same report were counted as a single entry for calculating overall odds ratios for individual drug categories, but separately for individual cancer categories. Results: 1741 PS solid cancers were reported with the study drugs, most commonly among Crohn's disease (1443, 83 %) patients. A female predominance (56 %) was seen with a mean age of 49 ± 16 years. Breast cancers (215, 12 %) were the most commonly reported (table 1) followed by colorectal cancers (211, 12 %). Analyzing for the most commonly reported solid cancers; significant odds of individual solid tumors were only seen for colorectal cancer (OR 4.5, 95% Confidence Interval 1.23-16.48) for TNF-α inhibitor usage in combination with corticosteroids and immunomodulators. Overall, significant odds (table 2) of developing a solid malignancy with TNF-α inhibitors were seen both with monotherapy and combinations including immunomodulators. Conclusion: Odds are elevated for developing a solid cancer with TNFα inhibitor usage both with monotherapy and in combinations including an immunomodulator, in IBD patients. Elevated odds of colorectal cancer were seen with TNF- α inhibitors in combination with immunomodulators and systemic corticosteroids.
Su1163 Utility of Homogenous Mobility Shift Assay for the Measurement of Protein Therapeutics in Serum Scott Hauenstein, Jared Salbato, Rukmini Reddy, Raymond Christie, Steven Lockton, Sharat Singh The importance of therapeutic drug monitoring has been shown to be advantageous for patient care in IBD patients. To date, assays have been developed to serum drug and antidrug antibody levels of anti-TNF antibodies such as infliximab (IFX) and adalimumab (ADA). We have previously shown the advantages of the homogenous mobility shift assay (HMSA) over assays such as ELISA and RIA used for therapeutic drug monitoring. Here we show that the HMSA can detect any protein therapeutic used for both IBD and RA as well as associated anti-drug antibodies in patients. Methods Patient serum used for assay development was from either residual samples collected at Prometheus during routine testing or from an IRB approved, single visit study of subjects treated with biologic therapy who initially achieved response/remission but are losing response or have recently lost response to treatment. Serum isolated from rabbits immunized with drug was used to generate polyclonal antibodies against the drug. The HMSA was performed as previously described (Wang, 2012). Briefly, serum samples and calibrators were mixed and incubated with the labeled antigen (drug or recombinant TNF/receptor). The immune complexes formed and the free label were separated and quantitated by a SEC-HPLC system equipped with a fluorescent detector. Analytical validation was performed for each drug to determine assay performance parameters. Results Method validation for the following drugs was performed: IFX, ADA, certolizumab pegol (CTZ), golimumab (GLM), natalizumab (NTZ), ustekinumab (UST), and tocolizumab (TLZ). Each assay demonstrated a lower limit of quantitation for each drug of 0.68-1.0 μg/mL and for anti-drug antibodies from 0.55-3.13 U/mL. The standard curves generated for each drug show high reproducibility, dynamic range, and sensitivity. Inter- and Intra-assay precision was less than 20% CV for both drug and anti-drug antibody assays and accuracy is within 20%. Drug tolerance in the anti-drug antibody levels was as high as 60 μg/mL. Anti-drug antibody levels in patients experiencing loss of response were inversely associated with drug levels (p ,0.05). Conclusions The homogenous mobility shift assay is a fluid-phase, highly sensitive method for monitoring serum levels of protein therapeutics and anti-drug antibodies. Monitoring drug and anti-drug antibody levels provides vital information about what drug may be appropriate for each patient.
Table 2: Reported odds of developing solid cancers with drug therapy among IBD patients
Su1164 Diagnostic and Therapeutic Double Balloon Enteroscopy in Crohn's Disease Is Safe and Effective Brendan P. Halloran, Gil Y. Melmed, Eric A. Vasiliauskas, Laith H. Jamil, Simon K. Lo, Neel K. Mann Background: Crohn's disease (CD) affects the small bowel in 80% of patients, and of those, 30% will have isolated small bowel stricturing complications. Small bowel imaging and capsule endoscopy are limited by the inability to obtain tissue and perform interventions. Double balloon enteroscopy (DBE) offers direct mucosal visualization with potential for diagnostic and therapeutic intervention. Aims: To investigate the safety and effectiveness of DBE in small bowel CD at our institution. Methods: From our DBE database, patients with CD at the time of index DBE (Jan 2004-Nov 2012) were identified. Data collection included demographics, CD phenotype (age of diagnosis, disease location, disease activity), complications (perforation, pancreatitis, death), therapeutic outcome (escalation or maintenance of existing therapy), and referral to surgery (resection or bowel-preserving, such as stricturoplasty or lysis of adhesions). Results: A total of 1596 DBEs were performed during the study period. Of those, 129 DBEs were performed in 79 patients with known CD (n=61) and in whom CD diagnosis was made at index DBE (n=18) for 115 endoscopic sessions. Overall, 38 % were women, the mean age was 43.8 years (11-78), and the mean CD duration was 18 years (0-50). Indications for DBE included assessment of disease activity (72%), hemorrhage
Su1162 Prevalence of Crohn's Disease in Patients With Spondyloarthropathies: Interim Analysis of the SPaCE study Uri Kopylov, Michael Starr, Craig Watts, Brandon A. Adelson, Ernest G. Seidman Background and aims: Inflammatory bowel disease (IBD) is clinically associated with spondylarthropathies (SpA) in 5-15% of cases. However, studies that employed colonoscopy systematically in SpA have shown a high prevalence (30-44 %) of asymptomatic inflammation
AGA Abstracts
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reviewed. The majority of tests (64%, 84/131) were ordered to help with initial clinical diagnosis, while 29% (38/131) of tests were used to confirm a previously existing diagnosis. The IBD-7 panel was ordered by the following specialties: gastroenterology 57%, primary care 30%, surgery 4%, and other 10%. The final clinical diagnosis was as follows: 43% were negative for IBD, 24% ulcerative colitis, 23% crohn's disease, 8% indeterminate colitis, and 2% unknown. The overall sensitivity and specificity of the IBD-7 panel was 66% and 66%, respectively. Of the individual markers within the IBD-7 panel, no one marker achieved a greater sensitivity; however, all individual markers had a greater specificity than the overall panel. The overall PPV and NPV of the IBD-7 panel was 72% and 60%, respectively. Sensitivity, specificity, PPV, and NPV of the test were all increased in patients with more severe disease. Conclusion: This is the first study to assess the clinical utility of the IBD-7 panel in a large adult population. Our reported sensitivity and specificity are consistent with previously reported results for the IBD-7 panel within the pediatric population. The IBD-7 serology continues to be a poor clinical tool in making the diagnosis of IBD, and should not be recommended as part of the initial diagnostic evaluation. Su1167 The Ultrasensitive C Reactive Protein (hs CRP) Is a Relapse Marker in Patients With Ulcerative Colitis and Correlates With the IL-6 Gene Expression in Colonic Mucosa Jesus K. Yamamoto-Furusho, Wendy Cedillo-Suarez, Carlos Campos Gonzalez Introduction: The ultrasensitive C reactive protein (hs CRP) is a reactant of acute phase produced by hepatocytes and is regulated by interleukin 1, interleukin 6, tumoral necrosis factor and interferon. The use of hsCRP has been increased in the follow-up of patients with UC. The aim of this study was to determine the role of hsCRP as endoscopic relapse marker in patients with UC and to explore the correlation between hs-CRP and grade of disease activity as well as the IL-6 gene expression in colonic mucosa. Patients and Methods: We evaluated a total of 450 patients with UC belonging to the IBD Clinic at the Instituto Nacional de Ciencias Médicas y Nutrición from january 2007 to december 2011. All patients with UC were in endoscopic remission at the basal colonoscopy and during the follow-up at least one colonoscopy was required. Full Mayo score and hs-CRP were evaluated. According to Mayo score, patients were grouped as remission, mild, moderate, or severe activity. Demographic, clinical and laboratory tests were evaluated in all patients. The SSPS version 17.0 statistical package was used for the analysis. Results: The mean age at diagnosis was 31+ 7 years old, 55.3% were female and 44.7% male. In relation to the extent of disease: 68.2% had pancolitis; 14.1% had distal colitis; 10.6% had proctosigmoiditis and 5.9% had left colitis. In 23.5% extraintestinal manifestations were present characterized by peripherical arthropathy, primary sclerosing colangitis, sacroileitis and uveitis. The medical treatment consisted of aminosalycilates all patients (100%); steroids in 30%, inmunomodulators in 25% and cyclosporin in 2%. The cut-off level of hsCRP was associated with the presence of endoscopic relapse without clinical activity: 0.34 mg/dL was associated with mild disease; 0.40 mg/dL for moderate disease and .0.65 mg/dL for severe disease. Nevertheless, 18% of the UC patients continued in endoscopic remission during the follow-up and the cut-off level of hs-CRP was below of 0.15 mg/dL. The levels of hs-CRP correlated in significant manner with the gene expression of interleukin 6 in the colonic mucosa (r=0.88, P ,00001). Conclusion: The hsCPR higher than 0.34 mg/dL is a factor associated with the presence of endoscopic relapse in patients with clinical remission of UC. Elevation of hsCRP correlated significantly with the grade of severity and the gene expression of IL-6 in the colonic mucosa.
Imaging included SBFT, CT, MRI Su1165 Serum Alpha-1-Antitrypsin: A Non-Invasive Marker of Pouchitis Shay Matalon, Hofit Elad, Eli Brazowski, Lael Werner, Erwin Santo, Hagit Tulchinsky, Iris Dotan Background: Ulcerative colitis patients undergoing total proctocolectomy with ileal pouchanal anastomosis are prone to develop pouch inflammation (pouchitis). Disease activity is determined by clinical, endoscopic and histologic criteria as none alone is enough to determine active inflammation. Alpha-1-antitrypsin (AAT) is an acute phase reactant produced mainly by hepatocytes, but, unlike C-reactive protein, it is also produced locally in the inflamed small intestine by neutophils, macrophages and Paneth cells. Vague data exist regarding non invasive biomarkers in pouchitis. Aim: To assess the ability of AAT to differentiate between inflamed and non-inflamed ileal pouches and to correlate AAT levels with inflammatory activity. Methods: Pouch patients were prospectively recruited and underwent clinical, endoscopic and histologic evaluation. Pouchitis disease activity index (PDAI) was calculated and a PDAI ≥7 defined acute pouchitis. Serum and fecal AAT levels were assessed using ELISA and CRP and fecal calprotectin were measured. Results: A total of 71 pouch patients (50.7% males) were included in the study. Their mean age was 43.8±8.3 years and the mean age at IBD diagnosis was 26.1±4.8 years. The indication for IPAA was intractable disease in 83.6% and neoplasia in 16.4% of UC patients. Mean time from IPAA to enrolling in the study was 9.1±2.9 years. Pouch patients were categorized by disease behavior : 26% had a normal pouch, 43% had recurrent acute pouchitis ( ≤ 4 flares of up to 2 weeks/year) and 31% had chronic pouchitis, with symptoms or anti-inflammatory therapy for≥ 4 weeks. AAT levels were significantly higher in patients with pouchitis and a PDAI≥7, compared to patients with PDAI ,7 (188.1±7.7mg/dL vs. 164.2±4.0 mg/dL, P= 0.05). Serum AAT and the PDAI significantly correlated (r=0.583, p ,0.001). This correlation was similar to the correlation between CRP and PDAI (r=0.584, p ,0.001). Serum AAT and CRP concentrations correlated closely (r=0.652; P ,0.001), as well as serum AAT and fecal calprotectin (r=0.725; P,0.001). In contrast, fecal AAT levels correlated with neither of the IBD biomarkers, nor with serum AAT levels. At serum AAT cutoff levels of 189 mg/dL, the receiver operating characteristic analysis demonstrated a sensitivity and specificity of 60 and 100%, respectively, for diagnosing pouchitis (PDAI≥7) . Conclusions: Serum AAT is a useful, non-invasive biomarker of pouch inflammation and its levels correlate with disease severity. Discordant serum and fecal AAT may suggest different mechanisms of production of local AAT.
Su1168 Neutrophil Gelatinase B-Associated Lipocalin - Matrix Metalloproteinase-9 (NGAL-MMP-9) Complex As a Surrogate Serum Marker for Mucosal Healing in Ulcerative Colitis Magali de Bruyn, Ingrid Arijs, Willem-jan Wollants, Kathleen Machiels, Kristel Van Steen, Marc Ferrante, Paul J. Rutgeerts, Severine Vermeire, Ghislain Opdenakker Introduction. The current standard for assessing intestinal inflammation and mucosal healing after therapy in inflammatory bowel diseases (IBD) is endoscopy. However, frequent assessments are costly and uncomfortable for the patient. Although C-reactive protein (CRP) is widely used as a marker of inflammation, half of the patients with active ulcerative colitis (UC) do not have elevated CRP levels. Therefore, we investigated NGAL-MMP-9 as a surrogate serum marker for mucosal healing after treatment with infliximab (IFX) in UC patients. Methods. NGAL-MMP-9 serum levels were determined with zymography analysis and sandwich ELISA before and 4-6 weeks after first IFX infusion from 66 IFX-Naïve patients with active UC (median age at first IFX 40.9 years, 39% female) as well as from 40 healthy controls (HC, median age 30.4 years, 38% female). The response to IFX was defined as complete mucosal healing (endoscopic Mayo score 0 or 1) at control endoscopy. Data were analyzed with SPSS statistics 20 using non-parametric tests and p-values of ,0.05 were considered significant. Results. From the 66 patients with active UC, 28 patients were classified as responder and 38 as non-responder. At baseline, median [interquartile range, IQR] NGAL-MMP-9 serum levels were found to be significantly higher in UC patients versus HC (103.8 [56.9-180.4] vs 42.4 [22.8-79.9] ng/ml; p,0.0001). After IFX therapy, median [IQR] NGAL-MMP-9 serum levels significantly decreased in UC responders (116.3 [58.6204.0] to 32.0 [22.4-64.2] ng/ml; p,0.0001), whereby only 3 patients (10%) had unchanged serum levels of NGAL-MMP-9 after therapy. For UC non-responders, median [IQR] NGALMMP-9 serum levels also significantly decreased after treatment with IFX (94.7 [53.2139.8] to 54.1 [35.9-103.9] ng/ml; p= 0.047), however, this decrease was significantly less pronounced in comparison with UC responders (p=0.0074). A strong correlation was found between results obtained from zymography analysis and sandwich ELISA (r=0.835, p,0.0001). NGAL-MMP-9 serum levels correlated with the amount of neutrophils (r=0.430, p,0.0001) and endoscopic Mayo scores (r=0.317, p ,0.0001). Moreover, we found that NGAL-MMP-9 serum levels correlate better with endoscopic Mayo scores than CRP levels (r=0.299, p,0.0001). Receiver operating characteristic (ROC) analysis defined a NGALMMP-9 serum level cut-off value of 97.7 ng/ml corresponding to mucosal healing (AUC= 0.75, 43% sensitivity, 93% specificity, 31% positive predictive value, 96% negative predictive value). Conclusion. In the search for surrogate markers assessing mucosal healing in UC,
Su1166 The Clinical Utility of the IBD-7 Screening Panel in Diagnosing Inflammatory Bowel Disease in an Adult Population Darren Spearman, Steven Armbruster, Corinne L. Maydonovitch, Ganesh R. Veerappan Background: Diagnosing inflammatory bowel disease (IBD) can be challenging, often relying on a combination of clinical, laboratory, radiologic, endoscopic, and histologic findings. IBD Serology 7 (Prometheus Laboratories; San Diego, CA) is a panel of seven antibodies touted to help establish a diagnosis of IBD; however, the utility of this test in clinical practice has been debated. The goal of this study was to evaluate the diagnostic utility of the IBD-7 panel in an adult population. Methods: All adult patients for whom an IBD-7 panel was ordered at our hospital between 15 November 2006 and 31 December 2010 were included for analysis. A detailed chart review was performed to determine the indication for each IBD panel (make a diagnosis of IBD, confirm a previous IBD diagnosis, or for prognosis). Additionally, the specific medical service ordering the test, demographic information, specific laboratory markers obtained within 30 days of the test (hematocrit, albumin, ESR, and CRP), and markers of severe disease (exposure to steroids, exposure to biologic therapy, IBDrelated surgeries and hospitalizations) were assessed. The final diagnosis (IBD or other) was determined by a review of the patient's entire diagnostic evaluation and electronic medical record by a gastroenterologist. Sensitivity, specificity, and negative and positive predictive values (NPV and PPV) were calculated for the IBD-7 panel. Results: A total of 131 records of adult patients (mean age 44 ± 15 years; male 58%; Caucasian 58%) were identified and
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AGA Abstracts
AGA Abstracts
(16%), mass/malignancy (10%), and capsule retention (1.6%). Of those with known CD, 106 DBEs were performed in 61 patients. (47 oral , 59 anal) with total enteroscopy achieved in 30%; 69% had history of previous surgical resection. Among those with established DBE, findings led to escalation of medical therapy in 30%, maintenance of therapy in 25%, and referral to surgery (25% resection, 8% bowel preservating). 4 patients underwent repeat DBE for disease monitoring after therapeutic escalation. Among 61 patients with known CD, 17 underwent dilation of 67 strictures during 32 endoscopic sessions. Of these patients, 65% were surgery-free during the study period. In those with CD diagnosis made at time of index DBE, 23 DBEs were performed in 18 patients (11 oral, 12 anal). Of these, 1 had total enteroscopy and 2/2 had successful capsule retrieval. All patients had previously undergone ileocolonoscopy and small bowel imaging without an established diagnosis (Table). Overall, there was one perforation in a patient with CD and a prior surgical resection; no patients developed DBE-associated pancreatitis or died during immediate followup period. Conclusions: Diagnostic and therapeutic DBE is safe and effective in patients with suspected or established CD, even in high risk patients with previous small bowel resection. DBE identified small bowel stricturing disease missed on prior ileocolonoscopy and small bowel imaging studies, and offers therapeutic potential for stricturing disease that might otherwise require surgery. Operating Characteristics of Small Bowel Imaging and Ileocolonoscopy for the Diagnosis of Isolated Small Bowel Crohn's Disease Using DBE as Reference
characteristic of Crohn's disease. Capsule endoscopy (CE) has been established as providing a higher detection rate for small bowel Crohn's disease, compared to ileo-colonoscopy (IC) and other imaging modalities. The aim of our study was to evaluate the accuracy of CE for detection of small bowel lesions in patients with SPA. Methods: This is a prospective cross-sectional study. The study cohort included patients ( . 18 y) followed by MUHC Rheumatology Center for known SpA or ankylosing spondylitis. The diagnosis of SpA was based on the ESSG criteria, while ankylosing spondylitis (AS) was based on the modified New York criteria. All patients were evaluated by CE, followed (within 4 weeks) by ileocolonoscopy (IC), performed blinded to CE results. NSAIDs were discontinued for a minimum of 4 weeks. The presence of small bowel mucosal inflammation on CE was quantified by the Lewis score (LS). Normal CE was defined as LS of , 135 , mild disease was defined as LS 135-790, while LS ≥790 was considered moderate to severe. Results: We report the preliminary results of the first 24 SPaCE study patients (age 39± 12, 54% male). 86% were HLA-B27 positive. Sixty three percent of the patients had gastrointestinal complaints, and 33.3% had elevated CRP levels. Recent therapy for SpA included etanercept (1 patient), methotrexate (1 patient) and NSAIDs in 58.3% of the patients. IC with biopsies demonstrated endoscopic and pathologic findings consistent with CD in 18.2% of the patients. None of the patients was diagnosed with ulcerative colitis. CE identified small bowel lesions consistent with CD in 33% of the patients (mean LS 1083 ±702), including all patients with ICdetected CD, and equivocal IC findings in additional 8.3% of the patients (LS of 168 and 225), respectively. In patients with equivocal CE results, CD was not demonstrated by IC. Gastrointestinal symptoms had a positive predictive value of 40% and 24%, and negative predictive value of 78.7% and 88.9% for findings on CE and IC, respectively. Following the diagnosis of small bowel inflammatory lesions, ant-TNF treatment was initiated in 4/8 patients. Conclusions: Small bowel lesions consistent with Crohn's disease are common in patients with spondyloarthropathies. These preliminary results suggest that CE of the SB is superior to IC in detecting CD in patients with known SpA. The findings obtained by CE are of clinical importance and resulted in a treatment change in 50% of the patients. Gastrointestinal complaints are a poor indicator for the presence Crohn's disease. These results merit verification on completion of the study.
AGA Abstracts
Risk of Solid Cancers With Tumor Necrosis Factor Alpha Inhibitor Therapy Among Inflammatory Bowel Disease Patients: An Analysis of the Food and Drug Administration Adverse Event Reporting System Derrick J. Stobaugh, Parakkal Deepak, Eli D. Ehrenpreis Background: The risk of solid cancers after exposure to tumor necrosis factor alpha (TNFα) inhibitors in inflammatory bowel disease (IBD) is unclear. We sought to examine the risk including with TNF-α monotherapy using the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: 3,171,655 files between January 2003 and June 2012 were downloaded and analyzed using SPSS 20 (IBM Co. Armonk, NY, USA). They were queried for Primary Suspect (PS) adverse events reports with TNF- α inhibitors (Adalimumab, Certolizumab, Infliximab), systemic corticosteroids, and immunomodulators (thiopurines, methotrexate and calcineurin inhibitors), using both trade and generic names, for IBD along with control drugs (5-aminosalicylic acid and sulphasalazine, including trade names) as a basis of comparison. These were further queried for outcomes of solid cancers as well as control reactions (syncope, hernia, deafness and vertigo, which were predefined to have no association with study drugs or control drugs) utilizing reactions terms from the Medical Dictionary for Regulatory Activities. Any reports with comorbidities of human immunodeficiency virus infection, organ transplantation or rheumatologic diseases associated with a risk of solid cancer as well as concomitant exposure to a non- TNF- α inhibitor biologic medication were excluded from analysis. The findings were further analyzed to determine the risk of the most commonly reported solid cancers. Odds ratios for the risk of solid cancers with TNF-α inhibitor monotherapy as well as combination therapy were calculated with the Fischer's exact test. Reports with more than one type of solid cancer within the same report were counted as a single entry for calculating overall odds ratios for individual drug categories, but separately for individual cancer categories. Results: 1741 PS solid cancers were reported with the study drugs, most commonly among Crohn's disease (1443, 83 %) patients. A female predominance (56 %) was seen with a mean age of 49 ± 16 years. Breast cancers (215, 12 %) were the most commonly reported (table 1) followed by colorectal cancers (211, 12 %). Analyzing for the most commonly reported solid cancers; significant odds of individual solid tumors were only seen for colorectal cancer (OR 4.5, 95% Confidence Interval 1.23-16.48) for TNF-α inhibitor usage in combination with corticosteroids and immunomodulators. Overall, significant odds (table 2) of developing a solid malignancy with TNF-α inhibitors were seen both with monotherapy and combinations including immunomodulators. Conclusion: Odds are elevated for developing a solid cancer with TNFα inhibitor usage both with monotherapy and in combinations including an immunomodulator, in IBD patients. Elevated odds of colorectal cancer were seen with TNF- α inhibitors in combination with immunomodulators and systemic corticosteroids.
Su1163 Utility of Homogenous Mobility Shift Assay for the Measurement of Protein Therapeutics in Serum Scott Hauenstein, Jared Salbato, Rukmini Reddy, Raymond Christie, Steven Lockton, Sharat Singh The importance of therapeutic drug monitoring has been shown to be advantageous for patient care in IBD patients. To date, assays have been developed to serum drug and antidrug antibody levels of anti-TNF antibodies such as infliximab (IFX) and adalimumab (ADA). We have previously shown the advantages of the homogenous mobility shift assay (HMSA) over assays such as ELISA and RIA used for therapeutic drug monitoring. Here we show that the HMSA can detect any protein therapeutic used for both IBD and RA as well as associated anti-drug antibodies in patients. Methods Patient serum used for assay development was from either residual samples collected at Prometheus during routine testing or from an IRB approved, single visit study of subjects treated with biologic therapy who initially achieved response/remission but are losing response or have recently lost response to treatment. Serum isolated from rabbits immunized with drug was used to generate polyclonal antibodies against the drug. The HMSA was performed as previously described (Wang, 2012). Briefly, serum samples and calibrators were mixed and incubated with the labeled antigen (drug or recombinant TNF/receptor). The immune complexes formed and the free label were separated and quantitated by a SEC-HPLC system equipped with a fluorescent detector. Analytical validation was performed for each drug to determine assay performance parameters. Results Method validation for the following drugs was performed: IFX, ADA, certolizumab pegol (CTZ), golimumab (GLM), natalizumab (NTZ), ustekinumab (UST), and tocolizumab (TLZ). Each assay demonstrated a lower limit of quantitation for each drug of 0.68-1.0 μg/mL and for anti-drug antibodies from 0.55-3.13 U/mL. The standard curves generated for each drug show high reproducibility, dynamic range, and sensitivity. Inter- and Intra-assay precision was less than 20% CV for both drug and anti-drug antibody assays and accuracy is within 20%. Drug tolerance in the anti-drug antibody levels was as high as 60 μg/mL. Anti-drug antibody levels in patients experiencing loss of response were inversely associated with drug levels (p ,0.05). Conclusions The homogenous mobility shift assay is a fluid-phase, highly sensitive method for monitoring serum levels of protein therapeutics and anti-drug antibodies. Monitoring drug and anti-drug antibody levels provides vital information about what drug may be appropriate for each patient.
Table 2: Reported odds of developing solid cancers with drug therapy among IBD patients
Su1164 Diagnostic and Therapeutic Double Balloon Enteroscopy in Crohn's Disease Is Safe and Effective Brendan P. Halloran, Gil Y. Melmed, Eric A. Vasiliauskas, Laith H. Jamil, Simon K. Lo, Neel K. Mann Background: Crohn's disease (CD) affects the small bowel in 80% of patients, and of those, 30% will have isolated small bowel stricturing complications. Small bowel imaging and capsule endoscopy are limited by the inability to obtain tissue and perform interventions. Double balloon enteroscopy (DBE) offers direct mucosal visualization with potential for diagnostic and therapeutic intervention. Aims: To investigate the safety and effectiveness of DBE in small bowel CD at our institution. Methods: From our DBE database, patients with CD at the time of index DBE (Jan 2004-Nov 2012) were identified. Data collection included demographics, CD phenotype (age of diagnosis, disease location, disease activity), complications (perforation, pancreatitis, death), therapeutic outcome (escalation or maintenance of existing therapy), and referral to surgery (resection or bowel-preserving, such as stricturoplasty or lysis of adhesions). Results: A total of 1596 DBEs were performed during the study period. Of those, 129 DBEs were performed in 79 patients with known CD (n=61) and in whom CD diagnosis was made at index DBE (n=18) for 115 endoscopic sessions. Overall, 38 % were women, the mean age was 43.8 years (11-78), and the mean CD duration was 18 years (0-50). Indications for DBE included assessment of disease activity (72%), hemorrhage
Su1162 Prevalence of Crohn's Disease in Patients With Spondyloarthropathies: Interim Analysis of the SPaCE study Uri Kopylov, Michael Starr, Craig Watts, Brandon A. Adelson, Ernest G. Seidman Background and aims: Inflammatory bowel disease (IBD) is clinically associated with spondylarthropathies (SpA) in 5-15% of cases. However, studies that employed colonoscopy systematically in SpA have shown a high prevalence (30-44 %) of asymptomatic inflammation
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reviewed. The majority of tests (64%, 84/131) were ordered to help with initial clinical diagnosis, while 29% (38/131) of tests were used to confirm a previously existing diagnosis. The IBD-7 panel was ordered by the following specialties: gastroenterology 57%, primary care 30%, surgery 4%, and other 10%. The final clinical diagnosis was as follows: 43% were negative for IBD, 24% ulcerative colitis, 23% crohn's disease, 8% indeterminate colitis, and 2% unknown. The overall sensitivity and specificity of the IBD-7 panel was 66% and 66%, respectively. Of the individual markers within the IBD-7 panel, no one marker achieved a greater sensitivity; however, all individual markers had a greater specificity than the overall panel. The overall PPV and NPV of the IBD-7 panel was 72% and 60%, respectively. Sensitivity, specificity, PPV, and NPV of the test were all increased in patients with more severe disease. Conclusion: This is the first study to assess the clinical utility of the IBD-7 panel in a large adult population. Our reported sensitivity and specificity are consistent with previously reported results for the IBD-7 panel within the pediatric population. The IBD-7 serology continues to be a poor clinical tool in making the diagnosis of IBD, and should not be recommended as part of the initial diagnostic evaluation. Su1167 The Ultrasensitive C Reactive Protein (hs CRP) Is a Relapse Marker in Patients With Ulcerative Colitis and Correlates With the IL-6 Gene Expression in Colonic Mucosa Jesus K. Yamamoto-Furusho, Wendy Cedillo-Suarez, Carlos Campos Gonzalez Introduction: The ultrasensitive C reactive protein (hs CRP) is a reactant of acute phase produced by hepatocytes and is regulated by interleukin 1, interleukin 6, tumoral necrosis factor and interferon. The use of hsCRP has been increased in the follow-up of patients with UC. The aim of this study was to determine the role of hsCRP as endoscopic relapse marker in patients with UC and to explore the correlation between hs-CRP and grade of disease activity as well as the IL-6 gene expression in colonic mucosa. Patients and Methods: We evaluated a total of 450 patients with UC belonging to the IBD Clinic at the Instituto Nacional de Ciencias Médicas y Nutrición from january 2007 to december 2011. All patients with UC were in endoscopic remission at the basal colonoscopy and during the follow-up at least one colonoscopy was required. Full Mayo score and hs-CRP were evaluated. According to Mayo score, patients were grouped as remission, mild, moderate, or severe activity. Demographic, clinical and laboratory tests were evaluated in all patients. The SSPS version 17.0 statistical package was used for the analysis. Results: The mean age at diagnosis was 31+ 7 years old, 55.3% were female and 44.7% male. In relation to the extent of disease: 68.2% had pancolitis; 14.1% had distal colitis; 10.6% had proctosigmoiditis and 5.9% had left colitis. In 23.5% extraintestinal manifestations were present characterized by peripherical arthropathy, primary sclerosing colangitis, sacroileitis and uveitis. The medical treatment consisted of aminosalycilates all patients (100%); steroids in 30%, inmunomodulators in 25% and cyclosporin in 2%. The cut-off level of hsCRP was associated with the presence of endoscopic relapse without clinical activity: 0.34 mg/dL was associated with mild disease; 0.40 mg/dL for moderate disease and .0.65 mg/dL for severe disease. Nevertheless, 18% of the UC patients continued in endoscopic remission during the follow-up and the cut-off level of hs-CRP was below of 0.15 mg/dL. The levels of hs-CRP correlated in significant manner with the gene expression of interleukin 6 in the colonic mucosa (r=0.88, P ,00001). Conclusion: The hsCPR higher than 0.34 mg/dL is a factor associated with the presence of endoscopic relapse in patients with clinical remission of UC. Elevation of hsCRP correlated significantly with the grade of severity and the gene expression of IL-6 in the colonic mucosa.
Imaging included SBFT, CT, MRI Su1165 Serum Alpha-1-Antitrypsin: A Non-Invasive Marker of Pouchitis Shay Matalon, Hofit Elad, Eli Brazowski, Lael Werner, Erwin Santo, Hagit Tulchinsky, Iris Dotan Background: Ulcerative colitis patients undergoing total proctocolectomy with ileal pouchanal anastomosis are prone to develop pouch inflammation (pouchitis). Disease activity is determined by clinical, endoscopic and histologic criteria as none alone is enough to determine active inflammation. Alpha-1-antitrypsin (AAT) is an acute phase reactant produced mainly by hepatocytes, but, unlike C-reactive protein, it is also produced locally in the inflamed small intestine by neutophils, macrophages and Paneth cells. Vague data exist regarding non invasive biomarkers in pouchitis. Aim: To assess the ability of AAT to differentiate between inflamed and non-inflamed ileal pouches and to correlate AAT levels with inflammatory activity. Methods: Pouch patients were prospectively recruited and underwent clinical, endoscopic and histologic evaluation. Pouchitis disease activity index (PDAI) was calculated and a PDAI ≥7 defined acute pouchitis. Serum and fecal AAT levels were assessed using ELISA and CRP and fecal calprotectin were measured. Results: A total of 71 pouch patients (50.7% males) were included in the study. Their mean age was 43.8±8.3 years and the mean age at IBD diagnosis was 26.1±4.8 years. The indication for IPAA was intractable disease in 83.6% and neoplasia in 16.4% of UC patients. Mean time from IPAA to enrolling in the study was 9.1±2.9 years. Pouch patients were categorized by disease behavior : 26% had a normal pouch, 43% had recurrent acute pouchitis ( ≤ 4 flares of up to 2 weeks/year) and 31% had chronic pouchitis, with symptoms or anti-inflammatory therapy for≥ 4 weeks. AAT levels were significantly higher in patients with pouchitis and a PDAI≥7, compared to patients with PDAI ,7 (188.1±7.7mg/dL vs. 164.2±4.0 mg/dL, P= 0.05). Serum AAT and the PDAI significantly correlated (r=0.583, p ,0.001). This correlation was similar to the correlation between CRP and PDAI (r=0.584, p ,0.001). Serum AAT and CRP concentrations correlated closely (r=0.652; P ,0.001), as well as serum AAT and fecal calprotectin (r=0.725; P,0.001). In contrast, fecal AAT levels correlated with neither of the IBD biomarkers, nor with serum AAT levels. At serum AAT cutoff levels of 189 mg/dL, the receiver operating characteristic analysis demonstrated a sensitivity and specificity of 60 and 100%, respectively, for diagnosing pouchitis (PDAI≥7) . Conclusions: Serum AAT is a useful, non-invasive biomarker of pouch inflammation and its levels correlate with disease severity. Discordant serum and fecal AAT may suggest different mechanisms of production of local AAT.
Su1168 Neutrophil Gelatinase B-Associated Lipocalin - Matrix Metalloproteinase-9 (NGAL-MMP-9) Complex As a Surrogate Serum Marker for Mucosal Healing in Ulcerative Colitis Magali de Bruyn, Ingrid Arijs, Willem-jan Wollants, Kathleen Machiels, Kristel Van Steen, Marc Ferrante, Paul J. Rutgeerts, Severine Vermeire, Ghislain Opdenakker Introduction. The current standard for assessing intestinal inflammation and mucosal healing after therapy in inflammatory bowel diseases (IBD) is endoscopy. However, frequent assessments are costly and uncomfortable for the patient. Although C-reactive protein (CRP) is widely used as a marker of inflammation, half of the patients with active ulcerative colitis (UC) do not have elevated CRP levels. Therefore, we investigated NGAL-MMP-9 as a surrogate serum marker for mucosal healing after treatment with infliximab (IFX) in UC patients. Methods. NGAL-MMP-9 serum levels were determined with zymography analysis and sandwich ELISA before and 4-6 weeks after first IFX infusion from 66 IFX-Naïve patients with active UC (median age at first IFX 40.9 years, 39% female) as well as from 40 healthy controls (HC, median age 30.4 years, 38% female). The response to IFX was defined as complete mucosal healing (endoscopic Mayo score 0 or 1) at control endoscopy. Data were analyzed with SPSS statistics 20 using non-parametric tests and p-values of ,0.05 were considered significant. Results. From the 66 patients with active UC, 28 patients were classified as responder and 38 as non-responder. At baseline, median [interquartile range, IQR] NGAL-MMP-9 serum levels were found to be significantly higher in UC patients versus HC (103.8 [56.9-180.4] vs 42.4 [22.8-79.9] ng/ml; p,0.0001). After IFX therapy, median [IQR] NGAL-MMP-9 serum levels significantly decreased in UC responders (116.3 [58.6204.0] to 32.0 [22.4-64.2] ng/ml; p,0.0001), whereby only 3 patients (10%) had unchanged serum levels of NGAL-MMP-9 after therapy. For UC non-responders, median [IQR] NGALMMP-9 serum levels also significantly decreased after treatment with IFX (94.7 [53.2139.8] to 54.1 [35.9-103.9] ng/ml; p= 0.047), however, this decrease was significantly less pronounced in comparison with UC responders (p=0.0074). A strong correlation was found between results obtained from zymography analysis and sandwich ELISA (r=0.835, p,0.0001). NGAL-MMP-9 serum levels correlated with the amount of neutrophils (r=0.430, p,0.0001) and endoscopic Mayo scores (r=0.317, p ,0.0001). Moreover, we found that NGAL-MMP-9 serum levels correlate better with endoscopic Mayo scores than CRP levels (r=0.299, p,0.0001). Receiver operating characteristic (ROC) analysis defined a NGALMMP-9 serum level cut-off value of 97.7 ng/ml corresponding to mucosal healing (AUC= 0.75, 43% sensitivity, 93% specificity, 31% positive predictive value, 96% negative predictive value). Conclusion. In the search for surrogate markers assessing mucosal healing in UC,
Su1166 The Clinical Utility of the IBD-7 Screening Panel in Diagnosing Inflammatory Bowel Disease in an Adult Population Darren Spearman, Steven Armbruster, Corinne L. Maydonovitch, Ganesh R. Veerappan Background: Diagnosing inflammatory bowel disease (IBD) can be challenging, often relying on a combination of clinical, laboratory, radiologic, endoscopic, and histologic findings. IBD Serology 7 (Prometheus Laboratories; San Diego, CA) is a panel of seven antibodies touted to help establish a diagnosis of IBD; however, the utility of this test in clinical practice has been debated. The goal of this study was to evaluate the diagnostic utility of the IBD-7 panel in an adult population. Methods: All adult patients for whom an IBD-7 panel was ordered at our hospital between 15 November 2006 and 31 December 2010 were included for analysis. A detailed chart review was performed to determine the indication for each IBD panel (make a diagnosis of IBD, confirm a previous IBD diagnosis, or for prognosis). Additionally, the specific medical service ordering the test, demographic information, specific laboratory markers obtained within 30 days of the test (hematocrit, albumin, ESR, and CRP), and markers of severe disease (exposure to steroids, exposure to biologic therapy, IBDrelated surgeries and hospitalizations) were assessed. The final diagnosis (IBD or other) was determined by a review of the patient's entire diagnostic evaluation and electronic medical record by a gastroenterologist. Sensitivity, specificity, and negative and positive predictive values (NPV and PPV) were calculated for the IBD-7 panel. Results: A total of 131 records of adult patients (mean age 44 ± 15 years; male 58%; Caucasian 58%) were identified and
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AGA Abstracts
(16%), mass/malignancy (10%), and capsule retention (1.6%). Of those with known CD, 106 DBEs were performed in 61 patients. (47 oral , 59 anal) with total enteroscopy achieved in 30%; 69% had history of previous surgical resection. Among those with established DBE, findings led to escalation of medical therapy in 30%, maintenance of therapy in 25%, and referral to surgery (25% resection, 8% bowel preservating). 4 patients underwent repeat DBE for disease monitoring after therapeutic escalation. Among 61 patients with known CD, 17 underwent dilation of 67 strictures during 32 endoscopic sessions. Of these patients, 65% were surgery-free during the study period. In those with CD diagnosis made at time of index DBE, 23 DBEs were performed in 18 patients (11 oral, 12 anal). Of these, 1 had total enteroscopy and 2/2 had successful capsule retrieval. All patients had previously undergone ileocolonoscopy and small bowel imaging without an established diagnosis (Table). Overall, there was one perforation in a patient with CD and a prior surgical resection; no patients developed DBE-associated pancreatitis or died during immediate followup period. Conclusions: Diagnostic and therapeutic DBE is safe and effective in patients with suspected or established CD, even in high risk patients with previous small bowel resection. DBE identified small bowel stricturing disease missed on prior ileocolonoscopy and small bowel imaging studies, and offers therapeutic potential for stricturing disease that might otherwise require surgery. Operating Characteristics of Small Bowel Imaging and Ileocolonoscopy for the Diagnosis of Isolated Small Bowel Crohn's Disease Using DBE as Reference