Marrie RA, Garland A, Peschken CA, Hitchon CA, Chen H, Fransoo R, Bernstein CN. Increased incidence of critical illness among patients with inflammatory bowel disease: A population-based study. Clinical Gastroenterology and Hepatology 2014; 12: 2063-2070.

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Little is known about intensive care unit (ICU) admission in IBD. We aimed to determine the incidence of, and mortality after ICU admission in IBD as compared to the general population, and the characteristics of critical illness (Critical illness refers to illness that leads to ICU admission) in the IBD population. We identified all persons with IBD in the province of Manitoba using a validated administrative definition of IBD for the period 1984 to 2010. Cases were considered newly diagnosed with IBD if their first health system contact for IBD was in 1989 or later. We identified a population-based control group, matched by age, sex and geography (postal code). Case and control cohorts were linked to the Manitoba ICU database containing clinical data from 93% of provincial high intensity adult ICUs. Incidence of ICU admission, reasons for ICU admission, and mortality after ICU admission were compared between groups. There were 8224 prevalent and 4580 incident cases of IBD. The risk for ICU admission was nearly twofold higher for IBD versus controls. From 2000-2010, the age and sex-standardized annual incidence of ICU admission among the prevalent IBD cohort was 0.55-1.12% (1 out of every 100 to 200 persons with IBD may get admitted to an ICU per year). Compared to controls admitted to ICUs, one year after ICU admission, mortality was increased by 32% in IBD.  We concluded that in IBD there is an increased risk for ICU admission and increased mortality at one year post-ICU admission. This underscores the potential severity of IBD.​

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Moffatt D, Yu BN, Yei W, Bernstein CN. Trends in utilization of diagnostic and therapeutic ERCP and cholecystectomy over the past 25 years: a population based study. Gastrointestinal Endoscopy 2014; 79: 615-622.

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ERCP is a test used to determine if gallstones are causing problems in the bile duct leading from the liver or from the pancreas. In the context of persons with IBD it can be used to determine if there is a condition called primary sclerosing cholangitis or complications of that condition are present. We aimed to establish crude and age-adjusted population-based rates of ERCP, evaluate for changing indications for ERCP, and evaluate for interactions between cholecystectomy (gall bladder removal) technique and ERCP use from 1984 to 2009 In Manitoba  The rate of ERCP/10,000 people increased from 7.70 (1984) to 13.86/10,000 (2009) (nearly doubled). Diagnostic ERCP declined from 7.28/10,000 (1984) to 1.11/10,000 (2009), and therapeutic ERCP increased from 0.42/10,000 (1984) to 12.75/10,000 (2009). ERCPs were more common in women (62%) and in older populations (60-79 years, >80 years), with rates of therapeutic ERCP reaching 62.58/10,000 in the elderly. The primary indication for ERCP has changed over time, with biliary indications increasing from 50.3% to 67.3% and pancreatic indications decreasing from 18.3% to 8.1%. The rate of therapeutic ERCP increased during the transition from open to laparoscopic cholecystectomy (1991-1994), whereas open bile duct exploration decreased from 2.0 to 0.18/10,000.We concluded that ERCP use increased steadily from 1984 to 2009, and changed from a diagnostic modality to a therapeutic one. Changes in cholecystectomy technique may have influenced therapeutic ERCP use and likewise, the availability of therapeutic ERCP has decreased the need for open bile duct exploration.

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​Israeli E, Ying S, Henderson B, Mottola JT, Strome T, Bernstein CN. The impact of abdominal computed tomography in a tertiary referral center emergency department on the management of patients with inflammatory bowel disease. Alimentary Pharmacology and Therapeutics 2013; 38: 513-21.

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Although exposure to diagnostic radiation may be associated with increased risk of malignancy, the use of abdominal CT (ACT) in the last decade has increased for patients in the emergency department (ED).We aimed to examine the impact of ACT ordered in the ED on management of patients with IBD, as well as to quantify the cumulative effective dose (CED) of radiation received by these patients. A total of 152 patients with Crohn's disease  and 130 patients with ulcerative colitis that presented to the ED in a tertiary centre between 2009 and 2011 were identified. For patients that had an ACT, chart review assessed if the ACT findings changed clinical management. CED of diagnostic radiation  was calculated for all imaging studies between 1 January 2006 and 30 August 2012. Abdominal CT use was 49% for CD and 19% for UC. ACTs with findings of penetrating/obstructive disease were 35% for Crohn’s disease. Urgent non-IBD-related diagnoses were found in 13% for Crohn’s disease and 28% for ulcerative coltis (P < 0.05). ACT caused a change in management in 81% of Crohn’s disease and 69% of ulcerative colitis patients. Average CED from diagnostic radtation was 77.4 ± 63.0 mSv for Crohn’s disease and 67.2 ± 51.0 mSv for ulcerative coltis (P = 0.47). The CED for the 80-month period exceeded 75 mSv in 35% and 36% respectively. We concluded that Although abdominal CT often changes management of IBD patients in the ED, this population carries a very high-risk of radiation exposure. Efforts should be made to decrease this risk by development of low-radiation protocols, and wider use of MRI/ultrasound.

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​Chisick L, Oleschuk C, Bernstein CN. The utility of TPMT testing in inflammatory bowel disease. Canadian Journal of Gastroenterology 2013; 27: 39-43.

This study aimed to assess the levels of red blood cell thiopurine methyltransferase (TPMT) in subjects with IBD and to determine how these levels impacted thiopurine dosing and leukopenia over the first six months of therapy. A retrospective chart review was performed on all adult IBD patients (n=423, 88.2% Caucasian) who had TPMT levels measured by 11 participating gastroenterologists in Manitoba between 2008 and 2010. In addition to descriptive data, white blood cell count, dose and reason for discontinuation were analyzed for the first six months of therapy. Patients receiving at least 2.0 mg/kg of azathioprine (AZA) or at least 1.0 mg/kg of 6-mercapatopurine were considered to be 'substantially' dosed. Of the 423 patients, 8.3% had intermediate levels and 93.4% had normal levels of TPMT. Only one subject had a low level. A total of 216 patients had sufficient data to be included for full analysis. Patients with intermediate TPMT levels were generally started at lower doses of thiopurine than patients with normal TPMT levels (average 1.0 mg/kg versus 1.8 mg/kg). Of the subjects with normal TPMT levels, only 37.8% were dosed with at least 2.0 mg/kg of AZA. Each month, approximately 5% of subjects were leukopenic (had low white blood cell counts). These subjects received an average overall AZA dose of 1.9 mg/kg and had an average white blood cell count of 3.8 x10(9)/L. We concluded that normal TPMT levels did not prevent the development of leukopenia, although life-threatening leukopenia was rare. Physicians are not using TPMT levels to substantially dose thiopurines at the outset, which may limit the speed at which adequate doses are reached to facilitate remission.

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Israeli E, Graff LA, Clara I, Walker JR, Lix LM, Targownik LE, Bernstein CN. Low prevalence of disability among patients with inflammatory bowel diseases a decade after diagnosis. Clinical Gastroenterology and Hepatology 2014; 12: 1330-7.

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Disability is defined by chronic limitations that preclude the ability to engage in usual daily activities. Studies of disability in patients with IBD have focused on work and employment, with few descriptions of more general disability among multiple domains. We examined disability and the factors associated with it a decade after diagnosis in a population-based cohort of IBD patients. We interviewed 125 patients with Crohn's disease  and 119 with ulcerative colitis from the Manitoba IBD Cohort study at 12 years after diagnosis. Disability was assessed by using 2 validated measures. Disease activity was assessed every 6 months, and long-term activity was defined as symptoms of active IBD at more than 65% of these 6 month assessments. Mean levels of disability were significantly higher among patients with Crohn's disease than those with UC. On the basis of the Work and Social Adjustment Scale, rates of disability were 19% among patients with Crohn's disease vs 11% among those with UC. Results from the World Health Organization Disability Assessment Schedule v.2 and the Work and Social Adjustment Scale correlated highly in both Crohn's disease and UC. Disability was associated with reduced quality of life. Long-term active disease and a lifetime history of major depression were associated with disability, whereas history of IBD-related surgeries or hospitalizations was not. We concluded that a minority of patients with IBD have significant disability after a decade of disease, although a higher proportion of patients with Crohn's disease are disabled than those with UC. Long-term active disease and psychological factors are important predictors of disability. Hence, depression in persons with IBD should be treated as aggressively as the IBD itself.

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Ungaro R, Bernstein CN, Gearry R, Hviid A, Kolho KL, Kronman M, Shaw S, Van Kruiningen H, Colombel JF. Antibiotics associated with increased risk of new onset Crohn's disease but not ulcerative colitis: A meta-analysis. American Journal of Gastroenterology 2014; 109: 1728-1738.

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The objective of this study was to perform a meta-analysis investigating antibiotic exposure as a risk factor for developing IBD. A literature search using Medline, Embase, and Cochrane databases was performed to identify studies providing data on the association between antibiotic use and newly diagnosed IBD. Included studies reported Crohn's disease, ulcerative colitis (UC), or a composite of both (IBD) as the primary outcome and evaluated antibiotic exposure before being diagnosed with IBD.  A total of 11 observational studies (8 case-control and 3 cohort) including 7,208 patients diagnosed with IBD were analyzed. The pooled increased likelihood for IBD patients to be exposed to any antibiotic was an increase of 57%. Antibiotic exposure was significantly associated with Crohn’s disease but was not significant for UC. Exposure to antibiotics most markedly increased the risk of CD in children by nearly threefold. All antibiotics were associated with IBD, with the exception of penicillin. Exposure to metronidazole was associated with a 5-fold risk for IBD and fluoroquinolones were associated with nearly a 2-fold risk for developing IBD.

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Ryan JD, Silverberg MS, Xu W, Graff LA, Targownik LE, Walker JR, Carr R, Clara I, Miller N, Rogala L, Bernstein CN. Predicting complicated Crohn’s disease and surgery: phenotypes, genetics, serology and psychological characteristics of a population based cohort. Alimentary Pharmacology and Therapeutics 2013; 38: 274-83.

We aimed to investigate whether serological markers, susceptibility genes or psychological characteristics are predictive of developing complicated Crohn’s disease or surgery. 182 members of the Manitoba IBD Cohort with Crohn’s disease were phenotyped using the Montreal classification which means that their disease presentation was carefully detailed. All underwent genetic and serological (blood) analysis at enrolment and after 5years. 127 had blood results available at baseline and 5 years later and their data were used to predict outcomes at nearly 10 years of disease duration. Serological analysis consisted of a seven antibody panel, and DNA was tested for Crohn’s disease-associated genes such as NOD2 variants (rs2066845,rs2076756,rs2066847), ATG16L1 (rs3828309, rs2241880) and IL23R (rs11465804). Psychological characteristics were assessed using semi-structured interviews and validated survey measures. 65% had complicated Crohn’ disease (meaning they had strictures or fistulas) and 42% underwent surgery. Multivariate analysis indicated that having a blood marker called ASCA IgG was 3 fold more likely of developing stricturing/penetrating behaviour and ileal Crohn’s disease was 2-fold more likely to develop stricturing/penetrating behaviour. Persons with this complicated Crohn’s disease behaviour had a 5-fold likelihood of surgery. Overall, though, the strongest predictor of complicated disease or surgery was having ASCA IgG antibody levels. Psychological characteristics were not significantly associated with disease behaviour, serological profile or genotype.  We also found that ASCA positivity was stable over time meaning that if positive at baseline it was highly likely to still be positive 5 years later. We also found that the gene markers we studied did not predict te development of complicated disease or surgery.

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Goldenberg BA, Graff LA, Clara I, Zarychanski R, Walker JR, Carr R, Rogala L, Miller N, Bernstein CN. Is iron deficiency in the absence of anemia associated with fatigue in inflammatory bowel disease? American Journal of Gastroenterology 2013; 108: 1392-7.

Fatigue is a common symptom in persons with IBD even if their disease is inactive. One cause of fatigue can be anemia or having a low hemoglobin level. It is uncertain if simply having low iron levels can cause fatigue. Many people who get an iron infusion may claim to get a boost of energy. We explored whether iron deficiency in the absence of anemia is associated with fatigue in IBD.  Fatigue was measured using the Multidimensional Fatigue Inventory survey. Iron deficiency was identified in 20% with Crohn's disease and 27% with ulcerative colitis. Anemia (low hemoglobin) was identified overall in18%, and 82% were nonanemic. In the nonanemic subgroup, there were no significant differences between persons with iron-deficiency and persons without iron deficiency for reported levels of fatigue or proportions with problematic fatigue. We concluded that there was no evidence of an association between iron deficiency and fatigue in the absence of anemia, suggesting that iron deficiency is not a clinically relevant contributor to fatigue in IBD.

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Graff LA, Clara I, Walker JR, Lix L, Carr R, Miller N, Rogala L, Bernstein CN. Changes in fatigue over 2 years are associated with activity of inflammatory bowel disease and psychological factors. Clinical Gastroenterology and Hepatology 2013; 11: 1140-6.

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We performed a longitudinal study of fatigue in patients with IBD to determine its course and contributing factors. Symptomatic disease activity was measured every 6 months for 2 years to characterize long-term disease patterns as active, fluctuating, or inactive, based on the validated Manitoba IBD Index. We collected data concurrently on fatigue using a survey called the Multidimensional Fatigue Inventory, psychological function, and laboratory biomarkers at the point of study entry and 1 and 2 years later. 26% had consistently inactive, 29% had fluctuating, and 45% had consistently active disease over the 2-year time period. Mean levels of fatigue were strongly associated with disease activity; participants with consistently inactive disease had the lowest level of fatigue at each time point. Fatigue levels increased over time regardless of disease activity pattern . Being female and having high psychological distress, reduced psychological well-being and poor sleep quality were associated independently with increases in fatigue over time. We concluded that fatigue can increase over time in patients with IBD, even when their disease is in remission. Psychological factors may be useful targets for intervention to reduce fatigue

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Graff LA, Clara I, Walker JR, Lix L, Carr R, Miller N, Rogala L, Bernstein CN. Fatigue, over 2 years, is associated with disease activity and psychological factors in longitudinal study of inflammatory bowel disease. Clinical Gastroenterology and  Hepatology 2013; 11: 1140-6.​
 

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Targownik LE, Bernstein CN, Nugent Z, Kanos J, Leslie WD. Inflammatory bowel disease and the risk of fracture after controlling for FRAX. Journal of Bone and Mineral Research 2013; 28: 1007-1013.

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Subjects with IBD are at increased risk for hip and other major osteoporotic fractures. However, previous analyses have not fully accounted for differences in bone mineral density (BMD) and other clinical factors that affect the risk of fracture. The World Health Organization Fracture Risk Assessment tool (FRAX) can be used to predict the 10-year fracture risk from BMD and clinical risk factors. A population based database containing clinical information on all IBD subjects in the province of Manitoba, Canada, was linked with the Manitoba Bone Mineral Density Database, which contains results of all dual X-ray absorptiometry (DXA) scans in the province.  FRAX probabilities were calculated for all subjects age at least age 50 undergoing baseline DXA testing. Subjects were followed for occurrence of major osteoporotic fractures  (hip, clinical spine, wrist, humerus). After controlling for FRAX fracture probability computed with BMD, IBD was not associated with a significantly increased risk for major osteoporotic fractures  but was associated with a twofold increased risk for hip fracture. The 10 year incidence of hip fracture following DXA among high risk subjects (hip fracture probability ≥3%) was significantly greater for IBD subjects than non-IBD subjects (12.1% vs. 7.1%, p=0.02). Therefore, FRAX will underestimate hip fracture risk in the presence of IBD.

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Targownik LE, Bernstein CN, Nugent Z, Leslie WD. Inflammatory bowel disease has a small effect on bone mineral density and risk for osteoporosis. Clinical Gastroenterology and Hepatology 2013; 11: 278-285.

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A high prevalence of osteoporosis has been reported in IBD. It is unclear whether IBD is itself a risk factor for low bone mineral density (BMD) or whether low BMD in IBD is related to other associated factors. Subjects with IBD were identified within the Manitoba BMD Database, containing results of BMD testing on all Manitobans since 1997. BMD was assessed at each of lumbar spine (L1-L4 mean), total hip, femoral neck, and trochanter. 45714 subjects underwent BMD testing (1230 with IBD). IBD was associated with a statistically significant, but small effect on T-score (a measure of change in BMD from the mean in healthy young adults), with no increased risk of osteoporosis at any measurement site. Crohn’s disease was associated with an increased risk of osteoporosis at the lumbar spine and trochanter, but ulcerative colitis was not associated with an increased risk of osteoporosis or lower T-score. No IBD-specific variables were associated with increased risk of osteoporosis or lower T-score. We concluded that IBD overall has only a marginal effect on BMD, though effects are more pronounced for Crohn’s disease versus ulcerative colitis. The risk of osteoporosis in IBD is related to other known osteoporosis risk factors.
 

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Shaw S, Blanchard JF, Bernstein CN. Association between early childhood otitis media and pediatric inflammatory bowel disease: an exploratory population-based analysis. Journal of Pediatrics 2013; 162: 510-514.

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The most common disease for which antibiotics are used in childhood is otitis media. Since our study exploring antibiotic use in early childhood and risk for IBD had a small sample size (because we could only access antibiotic use back to 1995) we aimed to determine if a diagnosis of otitis media in the first five years of childhood was associated with development of pediatric IBD. Otitis media was a proxy for antibiotic use since it is almost always treated with antibiotics and we could assess for otitis media diagnoses in cases and controls dating back to 1984. We assessed the population-based University of Manitoba IBD Database in Manitoba, Canada.  A total of 294 pediatric IBD cases diagnosed between 1989 and 2008 were matched to 2,377 controls, based on age, sex and geographic region (Total N=2,671). Otitis media diagnoses were based on physician claims.  IBD status was determined from a validated administrative database definition. By age of 5, 89% of IBD cases had at least one diagnosis of otitis media, compared to 82% of controls. Compared to cases and controls with no otitis media diagnoses, individuals with an otitis media diagnosis by the age of 5 were three times more likely of being an IBD case. This association was detected in stratified models examining Crohn’s disease and ulcerative colitis separately.  We concluded that compared to controls, subjects diagnosed with IBD were more likely to have had at least one early childhood episode of otitis media prior to their diagnosis. We suspect otitis media serves as a proxy of antibiotic use.

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Lix LM, Sajobi TT, Sawatzky R, Jiu J, Mayo NE, Huang Y, Graff LA, Walker JR, Ediger J, Clara I, Sexton K, Carr R, Bernstein CN. Relative importance measures for re-prioritization response shift. Quality of Life Research 2013; 22: 695-703.

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Response shift, a change in the meaning of an individual’s self-evaluation of a target construct, such as health-related quality of life (HRQOL), can affect the interpretation of change in measures of the construct collected over time. This study proposes new statistical methods to test for re-prioritization response shift, in which the relative importance of HRQOL domains changes over time. The methods use descriptive discriminant analysis or logistic regression models and bootstrap inference to test for change in relative importance weights (Method 1) or ranks (Method 2) for discriminating between patient groups at two occasions. The methods are demonstrated using data from the Manitoba IBD Cohort Study (n = 388). Re-prioritization of domains from the IBD Questionnaire (IBDQ) and SF-36 was investigated for groups with active and inactive disease symptoms.We found that the IBDQ bowel symptoms and SF-36 bodily pain domains had the highest ranks for group discrimination. Using Method 1, there was evidence of re-prioritization response shift in the IBDQ social functioning domain and the SF-36 bodily pain and social functioning domains. Method 2 did not detect change for any of the domains. We concluded that compared to IBD patients without active disease symptoms, those with active symptoms were likely to change the meaning of their self-evaluations of pain and social interactions. Further research is needed to compare these new response shift detection methods under a variety of data analytic conditions before recommendations about the optimal method can be made.

Publications // from the Manitoba IBD Epidemiology Database