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Su1161 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
Su1161
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
S-416
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
S-416