CANADIAN WOMEN WITH IBD ARE MORE LIKELY TO GIVE BIRTH TO LOW BIRTH WEIGHT INFANTS

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Targownik L. E.

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Background: Inflammatory bowel disease (IBD), a chronic inflammatory disease, often develops in adolescence and young adulthood, thus affecting many women in their childbearing years. Data are conflicting on the effect of IBD on gestational outcomes. Population-based data evaluating perinatal outcomes among Canadian women with IBD in the modern era are lacking. Aims: We sought to determine whether there is an increased likelihood of prematurity and/or low birth weight among infants born to Canadian women with IBD in a population based provincial dataset. Methods: We used the University of Manitoba IBD Epidemiology Database to identify all women in Manitoba between the ages of 15 to 45 with either Crohn's disease (CD) or ulcerative colitis (UC) between 1984-2014. Women with IBD were matched to non-IBD controls in a 1:10 ratio on age and neighborhood of residence at the time of IBD diagnosis. Live birth events were identified in the maternal record and linked to the neonatal record to obtain the estimated gestational age and birth weight. Prematurity was defined as gestational age less than 37 weeks. Infants weighing less than 2500g at birth were considered to have low birth weight (LBW), and those weighing between 2500-3000g were classified as low-normal birth weight (LNBW). The proportion of all LBW and premature babies among all babies born was calculated for IBD (stratified for CD and UC)  and controls. Results: There were 3172 women with IBD (1,827 CD, 1,345 UC) matched to 27,184 non-IBD controls (15,802 matched to CD cases, 11,382 matched to UC cases), 1495 infants (878 CD, 617 UC) were born to women with IBD, compared with 14,006 infants born to controls (8,362 controls, 5,644 UC controls. 3.5% of infants born to women with CD were premature, compared with 1.9% of controls (p=0.0043); There was no significant difference in the likelihood of prematurity among babies born to women with UC vs. CD (2.9% vs. 2.3%, p>0.2). The probability of having a LBW infant was higher among both women with CD and UC compared with controls (CD: 7.8% vs 3.4%, p=0.0004; UC: 7.0% vs 3.1%, p=0.0033). There was also a higher prevalence of LNBW babies among CD (17.5% vs 10.9%, p=0.0008) and UC (18.2% vs 12.5%, p=0.009). Neither maternal age at birth nor era of birth influenced the likelihood of prematurity, LBW, or LNBW. Conclusions: Canadian women with IBD are at increased risk of having LBW and LNBW infants, and women with CD specifically have a higher chance of giving birth prematurely. Further work is required to determine the disease and treatment related factors which may predispose to the development of these adverse birth outcomes.

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CANADIANS WITH CELIAC DISEASE MISINTERPRET PRODUCT LABEL INFORMATION WHICH MAY LEAD TO UNSAFE FOOD CHOICES DESPITE ALLERGEN LABELLING LAWS

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Emily Gutowski, Jocelyn Silvester, Lisa Rigaux, Kathy Green, Dayna Weiten, Charles N. Bernstein, John R. Walker, Lesley A. Graff, Donald Duerksen

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Background: Patients with celiac disease (CD) often report challenges reading labels as well as inadvertent gluten exposures and the most common cause of non-responsive CD is gluten exposure. Aims: To assess whether patients with CD can proficiently assess product labelling to determine if a product is gluten-free. Methods: The Manitoba Celiac Disease Cohort includes newly diagnosed adults with elevated TTG and/or EMA antibodies and Marsh III histology. At each follow-up visit (6, 12 and 24 months), participants were presented with 25 grocery items purchased at a local supermarket (different items at each time point) and asked to determine whether each was gluten-free based upon labeling information. The Celiac Diet Assessment Tool (CDAT) and Gluten-Free Eating Assessment Tool (GF-EAT) were used to assess GFD adherence. Results: There were 78 participants (62% female, mean age 40 years) who completed the 24 month study visit, of whom 70 also completed the 6 month assessment and 62 the 12 month assessment. Participants generally reported good adherence (median CDAT score < 13 at each time point); however, at 24 months 73% reported rare gluten exposure less than once per month on the GF-EAT. Grocery Quiz scores were [median (IQR)]: 6 months, 22 (21-23); 12 months, 21 (20-22); 24 months, 18 (18-19). Participants were more likely to make errors with gluten-containing items and least likely to make errors with gluten-free products with explicit “gluten-free” labelling claims. There were no significant correlations between quiz scores and either tTG antibody levels or standardized assessment tools. Conclusions: Patients who are trying to follow a gluten-free diet may not be able to consistently choose appropriate gluten-free foods based upon product labeling information. The ability to correctly read food labels does not appear to improve with time.  Further studies are needed to evaluate whether insufficient label reading skills are associated with persistent villous atrophy.

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ANTI-TNF DOSE AUGMENTATION FREQUENTLY OCCURS IN THE ABSENCE OF OBJECTIVE EVIDENCE OF DISEASE ACTIVITY

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Evan D. Elias, Adebanke Oketola, Harminder Singh, Charles N. Bernstein, Laura E. Targownik

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Background: Anti tumor necrosis factor therapy (anti-TNF) is widely used in patients with moderate to severe CD and UC. When symptoms persist, anti-TNF dose is often increased or the dosing interval shortened. Evidence supporting the effectiveness of dose augmentation is of low quality and dose augmentation imparts a significant additional cost of care. Persons with persistent gastrointestinal symptoms ascribed to IBD may not have evidence of ongoing inflammation; hence, dose augmentation may not be expected to benefit those without inflammation Therefore, we sought to determine the extent to which clinicians routinely assessed the presence of active inflammation prior to undertaking anti-TNF dose augmentation. Methods: Medical records of all IBD patients prescribed anti-TNF therapy from 2007-2016 by 8 of 23 Manitoba gastroenterologists were reviewed and demographics, disease characteristics, and IBD treatments recorded. Patients who underwent anti-TNF dose augmentation were further reviewed for the presence of any objective assessment of inflammatory activity, including laboratory investigations (CRP, ESR, albumin, ferritin, hemoglobin, fecal calprotectin), cross-sectional abdominal imaging, and endoscopy. Results: 529 patients receiving anti-TNF therapy were identified, of whom 151 had anti-TNF doses increased on 195 occasions (117 CD, 34 UC). 51 patients (43.6%) with CD had penetrating disease while 16 patients (47.1%) with UC had pancolitis. Mean age at diagnosis was 25.5 years and 50.3% of patients were female. There was no difference in demographics, disease phenotype, or baseline lab values between patients who received dose augmentation and those who did not.

Patients were assessed for biochemical evidence of disease activity in the 90 days preceding dose augmentation on 134 of 195 occasions (68.7%), however the results of these investigations were abnormal in only 23 cases (11.8%). Cross-sectional imaging was performed in 11 cases (5.6%) and revealed active disease in 8 (4.1%). Endoscopy was performed prior to dose augmentation on 28 occasions (14.4%) with 24 (12.3%) revealing active disease. Overall, objective evidence of inflammatory activity was present in only 48 of 195 dose augmentation events (24.6%), no objective evidence of inflammation was present in 95 (48.7%), and in 52 (26.7%), anti-TNF dose was increased without any investigation being performed. Conclusion: Anti-TNF dose augmentation routinely occurs in the absence of objective evidence of active inflammatory disease. This represents a target for ongoing quality improvement to optimize care of persons with IBD requiring anti-TNF based therapies, given the significant economic burden of unjustified and potentially unnecessary dose augmentation.

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NO INCREASE IN IMMUNOMODULATOR USE IN COMBINATION WITH ANTI-TNF THERAPY IN THE POST SONIC ERA

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Evan D. Elias, Adebanke Oketola, Laura E. Targownik, Harminder Singh, Charles N. Bernstein

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Background: The SONIC trial in 2010 definitively proved the superiority of anti tumor necrosis factor (anti-TNF) therapy in combination with thiopurines over anti-TNF monotherapy in persons with moderate to severe CD. Despite high-quality evidence supporting combination therapy, there is a scarcity of data about the impact of this trial on the utilization of combination therapy (anti-TNF plus thiopurines or methotrexate) in clinical practice. Therefore, we assessed the prevalence of combination therapy usage by all Manitoba gastroenterologists both pre and post publication of the landmark SONIC trial in 2010. Methods: All 23 prescribers of anti-TNF medications for IBD in Manitoba agreed to participate in the study. Patient charts were reviewed, with demographics, disease characteristics, and prior IBD treatments recorded from time of first contact with a gastroenterologist. The pre-SONIC group was defined as persons who received their first anti TNF treatment between 2005 and 2009, and the post-SONIC group as those who started treatment between 2011 and 2015; subjects starting therapy in 2010 were excluded. The proportion of subjects using combination therapy was compared between the pre-SONIC and post-SONIC patient populations. Results: 1,070 patients were identified, of whom 673 met the inclusion criteria . 226 patients started treatment pre SONIC and 447 post SONIC. Pre SONIC, 50.0% received combination therapy compared with 48.3% post SONIC (p=0.68). The proportion of patients receiving adalimumab increased from 12.3% in the pre-SONIC period to 33.2% post-SONIC (p<0.00001); Adalimumab users were as likely as infliximab users to receive combination therapy. Choice of immunomodulator differed pre and post SONIC. Of those who received combination therapy pre SONIC 80.0% received a thiopurine, versus 91.2% post SONIC (p=0.04). Of patients treated with anti-TNF monotherapy, 41.9% pre SONIC and 41.4% post SONIC had no record of any immunomodulator therapy before starting anti-TNF treatment (p=0.94). There were no differences in demographics, clinical characteristics, or markers of disease activity/severity between pre and post SONIC groups, or between combination therapy and anti-TNF monotherapy groups. Conclusion: We were unable to detect increased prevalence of combination therapy among anti-TNF users in the post-SONIC era. This represents a potential opportunity for quality improvement initiatives to optimize care of persons with IBD requiring anti-TNF based therapy.

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THE INCIDENCE OF DEEP REMISSION INCLUDING HISTOLOGIC NORMALIZATION IN LONGSTANDING UC

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Shaffer, S.

 

Background: The primary treatment goal in UC is to maintain clinical remission, and endoscopic mucosal healing. Up to 40% of those with mucosal healing have persistent histologic inflammation. Reduced histologic inflammation is associated with decreased risks of relapse, hospitalization, corticosteroid use, colectomy, and neoplasia. Some persons with UC may completely normalize their colon histology. It is unknown what patient characteristics, disease extent, or treatment characteristics are associated with histologic normalization and whether normalization can impact on clinical outcomes. Aims: To assess the rate of dysplasia in patients with UC who achieve endoscopic and histologic normalization on at least two consecutive colonoscopies compared to the rest of the cohort. Methods: A retrospective chart review was undertaken, of a referral clinic’s patients from 1994 to 2017. Patients included were those diagnosed with UC, with at least 1 colonoscopy undertaken in the referral clinic. Data extracted from the chart included: age, sex, date of diagnosis, date of last follow-up, endoscopic extent of disease, severity of disease, colon histology, medication history, all dysplasia surveillance colonoscopies, and presence/absence of dysplasia. Dedicated GI pathologists then reviewed biopsies to confirm normalization. Results: A total of 350 individuals’ charts were reviewed, with 294 meeting the inclusion criteria. 108 patients had at least 1 normal colonoscopy with normal histology. 28 of these 108 had two consecutive normal colonoscopies and histology. Comparing those with 2 normal colonoscopies to all others (including with 1 normal colonoscopy) there was no statistical difference in the medications used, duration of medications or age at diagnosis, but disease duration was longer for those with 2 consecutive normal colonoscopies (20.5 years vs 15.7, p = 0.02). The mean number of colonoscopies was 5.4 for those with two consecutive normal colonoscopies, vs 3.1. No dysplasia occurred after 2 consecutive normal endoscopies compared to 20 (7.5%) cases of dysplasia in the comparison cohort. For those with at least one normal colonoscopy, 7 (6.5%)developed dysplasia at some point. Conclusions: Persons who develop deep remission manifested by 2 consecutive colonoscopies with normal endoscopy and normal histology have a lower risk of dysplasia (0 in this cohort). Having 1 colonoscopy with normal histology was not protective against developing dysplasia. In persons with 2 consecutive normal colonoscopies by endoscopy and histology dysplasia surveillance intervals should be lengthened.

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THE USE OF CAPSULE ENDOSCOPY FOR DIAGNOSIS OF IRON DEFICIENCY ANEMIA- A RETROSPECTIVE ANALYSIS

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Stone J., Grover, K., and Bernstein, C. N.

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Introduction: Many patients who present with undiagnosed iron deficiency anemia (IDA) are presumed to have occult gastrointestinal (GI) bleeding as the cause. When investigations include a negative upper endoscopy and colonoscopy, a negative celiac antibody screen and there is no obvious GI source of blood loss, occult GI bleeding from a small bowel source is considered and capsule endoscopy (CE) is pursued. Recent Canadian Association of Gastroenterology guidelines on the use of CE suggested that CE is indicated in only selected cases of iron deficiency anemia; however, evidence on the yield of CE in IDA and how to optimally select cases is limited. We aimed to examine the yield of CE in diagnosing the cause of IDA and to define clinical parameters that predict higher diagnostic yields. Methods: 1351 individuals underwent CE in Manitoba between the years of 2005-2016. All studies were reported by one reading physician and all requisitions included demographics and requested information on medication use, prior imaging studies, and hemoglobin and ferritin levels. 620 (46%) CE was indicated for occult GI bleeding or IDA. Positive findings on CE were separated into ‘definite’ and ‘possible’. Descriptive statistics are reported and multinomial regression analysis was used to determine the variables correlated with definite CE findings. Results: Of the 620 included subjects, mean age was 62.9 years, and mean hemoglobin was 89 and mean ferritin was 32. 210 (33.9%) had positive findings (definite; 23%, possible;10.8%).  107 (17.2%) of all patients were taking ASA, 31 (5%) were on an antiplatelet, and 33 (5.3%) on an anticoagulant. Vascular ectasias were the majority of definite findings (47.5%). Predictors of definite findings were age (Relative risk (RR) 1.04; 95% CI 1.02-1.06) and male sex (RR 1.88; 95%CI 1.25-2.83). None of serum Hg or ferritin, rural vs urban residence, number of prior upper or lower endoscopies, prior small bowel enteroscopy, use of ASA, anti-platelet, anticoagulant or PPI medications predicted a positive CE. Conclusions: To our knowledge, this is the largest study examining the use of CE in iron deficiency anemia and occult GI bleeding. The diagnostic yield of 33.9% and more importantly 23% for definite lesions is within the range of previously reported yields. Within this cohort, age and male sex are predictors of definite findings on CE. Anti-platelet agents and anticoagulants did not predict positive findings in our study. Further research is needed to determine which findings lead to interventions that positively impact on patient outcomes.

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IPILIMUMAB INDUCED ENTEROCOLITIS: A SYSTEMATIC REVIEW AND META-ANALYSIS

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Kelcie Witges, Ryan Zarychanski, Ahmed M. Abou-Setta, Rasheda Rabbani, Orvie Dingwall, Charles N. Bernstein

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Introduction: Ipilimumab is a human monoclonal cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody used to treat patients with stage III/IV melanoma and other solid tumors. Although treatment from an oncologic perspective may be successful, ipilimumab (a type of (CTLA-4 antibody)  is associated with considerable drug-related adverse events, many serious events occurring in the gastrointestinal (GI) tract; including, enteritis, colitis, and enterocolitis. Until the introduction of ipilimumab and nivolumab (PD-1 antibody), no drugs have been reported to cause an enterocolitis that resembles inflammatory bowel disease (IBD), especially the chronic aspect of IBD. Aim: The objective of this study is to evaluate the risk of chronic (> 6 weeks) enterocolitis following ipilimumab administration. Methods: We searched MEDLINE, EMBASE, CENTRAL, and reference lists of relevant articles for citations. We included only randomized controlled trials comparing ipilimumab administration with placebo/standard of care/other active chemotherapy regimens. Two reviewers independently identified trials, extracted trial-level data and performed risk of bias assessments using the Cochrane Risk of Bias tool. The primary outcome was number of individuals with enterocolits both a) acute and b) chronic reported at longest follow-up. Meta-analysis was performed using a random-effects model. Results: Of 1282 records identified, we included 7 unique trials enrolling a total of 4160 subjects. The mean age of subjects was 60 years. Five trials were evaluated as low risk of bias and two trials were evaluated as high risk of bias. Trials did not distinguish between acute enterocolitis and chronic enterocolitis. Trials did not distinguish between enteritis (small bowel involvement) and colitis. Ipilimumab was associated with an increased risk of enterocolitis (RR 11.93, 95% CI 1.51 to 94.17, I2 0%, 2 trials) and colitis (RR 10.29, 95% CI 5.92 to 17.88, I2 0%, 7 trials). Conclusions: Insufficient data exist to distinguish the risk of acute enterocolitis from the risk of chronic enterocolits after ipilmumab use. Due to the serious impact of chronic enterocolitis on quality of life, future randomized controlled trials evaluating the safety of ipilimumab and other checkpoint inhibitors should be required to report gastrointestinal events in greater detail.

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