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Epidemiology // the study of a specific group of people

In 1995 we developed The University of Manitoba IBD Epidemiology Database. This database utilized the Manitoba Health Database and harnessed the fact that all Manitobans have a unique personal health identification number (PHIN) through which all of their health care contacts can be tracked. After mailing out surveys through nearly 400 doctors offices in Manitoba approximately half of Manitoba’s IBD patients responded and were willing to self report on their IBD allowing themselves to be documented in an IBD Research Registry.

Through patients self report and after a chart review through doctors’ offices we were able to develop an administrative definition of IBD. This means that we could apply a certain rule (having at least 5 separate contacts with the health care system, either outpatient or hospital-based) to the Manitoba Health administrative database to identify all Manitobans with IBD. We could reapply this definition on a go-forward basis to anonymously document the incidence rates (number of new cases) and prevalence rates (number of all cases at any one time) of both Crohn’s disease and ulcerative colitis within Manitoba. We could determine the burden of disease by how many patients exist with these diseases. We could explore trends in incidence rates as well as patient demographics to potentially develop hypotheses as to disease causation.

We first reported the very high rates of IBD in Manitoba in 1999 (Bernstein et al American Journal of Epidemiology 1999) and in fact showed that Manitoba had the highest incidence rates of Crohn’s disease of anywhere in the world. We then wanted to explore whether this was specific to Manitoba or a sign of how widespread the disease was across Canada. In 2005 we got together with investigators in BC, Alberta, Saskatchewan and Nova Scotia and we applied the made in Manitoba administrative definition of being an IBD case and we found that the high rates of IBD in Manitoba were similar in the other provinces. Hence Canada was the hotspot for IBD in the world (not just Manitoba). Based on these data, and more recent data from Quebec, Ontario and Nova Scotia we estimate that approximately 280000 Canadians have IBD in 2017.

Epidemiology data can be used to study many things. We have not only reported on the burden of disease in terms of numbers of persons diagnosed with disease, we have also reported on the burden to patents in terms of concurrent other health issues and the burden to society in terms of health care utilization (how many doctor visits and hospitalizations were specifically for IBD) and costs.

 

Epidemiology data can also be used to report on adverse outcomes like death, or serious complications like cancer, blood clots, or fractures.

 

Epidemiology data can also be used to explore potential causes of IBD. We have undertaken such studies. We have determined that being born by cesarean section rather than vaginal delivery does not increase the risk for developing IBD. Neither does a mother receiving antibiotics before delivery or in the perinatal (period around time of birth) period. On the other hand we have shown that use of antibiotics in the first year of life increased the risk for children developing IBD.

Publications // from the Manitoba IBD Epidemiology Database

Publications // by category

Epidemiology // the burden of IBD and healthcare utilization

Bernstein CN, Longobardi T, Finlayson G, Blanchard JF. The direct medical cost of managing IBD patients: A Canadian population based study. Inflammatory Bowel Diseases 2012; 18: 1498-1508.

This study aimed to quantify the direct medical cost of treating IBD in Manitoba in 2005/2006. In all, 7375 individuals with IBD recorded in the University of Manitoba IBD Epidemiology Database were matched on age, gender, and geography to up to 10 non-IBD controls. Data for cases and controls were extracted from Manitoba Health databases in fiscal 2005/2006 for pharmaceutical, physician claims, and hospital abstracts. The average expenditure were computed for the annual cost of pharmaceuticals, hospitalizations (day surgery and inpatient), and physician office visits. We assessed costs based on age, sex, type of IBD, disease duration, and level of care provided. In 2005/2006 the average direct cost of an IBD case was $3896 which was twice that of controls (P < 0.05). Crohn's disease (n = 3735) was significantly more costly on average than ulcerative colitis (UC; n = 3640) ($4232 and $3552, respectively, P < 0.001). The most costly cases included those within 1 year of diagnosis ($6611; SE = $593), those hospitalized overnight (15%) ($13,495, maximum  costing  case= $130,332), those who had a surgical stay (2% of IBD cases) ($18,749, range = $13,413-$125,912), and those using infliximab (0.7%) ($31,440; maximum costing case= $96,328). For individuals using infliximab their direct annual average healthcare cost was $9683 (maximum costing case = $55,208) prior to using infliximab. We concluded that in Manitoba the direct average annual healthcare cost of Crohn’s disease is greater than UC and that of a patient using infliximab tends to be greater than one incurring a surgical stay.

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.

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.

Bernstein CN, Garland A, Peschken CA, Hitchon CA, Chen H, Fransoo R, Marrie RA. Predictors of ICU admission and outcomes one year post admission in persons with IBD: A population based study. Inflammatory Bowel Diseases 2015; 21: 1341-1347.

We aimed  to determine predictors of intensive care unit (ICU) admission and to assess health care utilization post-ICU admission among persons with IBD. We matched a population-based database of Manitobans with IBD to a general population cohort by age, sex and region of residence and linked these cohorts to a population-based ICU database. We compared the incidence rates of ICU admission among prevalent IBD cases according to health care utilization (HCU) in the year prior to admission adjusting for age, sex, socioeconomic status, region, and comorbidity. Among incident cases of IBD who survived their first ICU admission we compared HCU to matched controls who survived ICU admission. Risk factors for ICU admission from the year prior to admission included cumulative corticosteroid use and IBD-related surgery. Use of immunomodulatory therapies (azathioprine, 6-mercaptopurine, and methotrexate) within one year, or surgery for IBD beyond one year prior, were not associated with ICU admission. In those who used corticosteroids and immunomodulatory medications in the year prior to ICU admission, the use of immunomodulatory medications conferred a 30% risk reduction in ICU admission. Persons with IBD who survived ICU admission had higher health care utilization in the year following ICU discharge than controls. We concluded that corticosteroid use and surgery within the year are associated with ICU admission in IBD while immunomodulatory therapy is not. Surviving ICU admission is associated with high health care utilization in the year post-ICU discharge.

Bernstein CN, Nugent ZN, Targownik LE, Singh H, Lix L. Predictors and risks for death in a population based study of persons with IBD in Manitoba. Gut 2015; 64: 1403-1411.

We aimed to determine the predictors and risk for death among persons with either Crohn’s disease (CD) or ulcerative colitis (UC) compared to the general population.  We used the population based University of Manitoba IBD Epidemiology Database to calculate mortality rates in persons with IBD in relation to the general population. There were 10,788 prevalent cases of CD and UC and 101,860 matched controls.  Persons with CD had a 26% higher mortality rate than the general population but there was no difference in mortality for prevalent UC cases compared to matched controls. CD cases were more likely to die of colorectal cancer, non-Hodgkin lymphoma, digestive diseases, pulmonary embolism and sepsis and UC cases were more likely to die from colorectal cancer, digestive diseases, and respiratory diseases.  For incident cases there were significant effects on mortality by socioeconomic status, comorbidity score and surgery. The greatest risk for death in both CD and UC was within the first 30 days following gastrointestinal  surgery. The first year from diagnosis was also associated with increased risk of death in both CD and UC, but persisted after the 1st year only in CD. We concluded that there is a significantly increased risk of mortality in CD compared to controls while in UC an increased risk for death was only evident in the first year from diagnosis. Surgery poses an increased risk for death in both CD and UC for up to 1 year.

Nugent Z, Singh H, Targownik LE, Strome T, Snider C, Bernstein CN. Predictors of emergency department use by persons with IBD: A population based study. Inflammatory Bowel Diseases 2016; 22: 2907-2916.

We aimed to describe the patterns and predictors of Emergency Department (ED) attendance and post ED hospitalization by persons with inflammatory bowel disease (IBD). We linked the University of Manitoba IBD Epidemiology Database with the Emergency Department Information System of the Winnipeg Regional Health Authority to determine the rates of presentation to the ED by persons with IBD from 01/01/09 to 03/31/12. Incident cases were diagnosed during the study period and all others were considered prevalent cases. We determined predictors of attendance in the ED and for hospitalization within 2 days of ED attendance. The study population included 300 incident and 3394 prevalent cases, of whom 76% and 49%, respectively, attended the ED at least once during the study period. Incident cases with CD (as opposed to UC) or with a history of opioid use were more likely to attend the ED. Those who had seen a gastroenterologist within the preceding year were less likely to visit the ED. Among prevalent cases higher comorbidity, opioid or corticosteroid use, and recent hospital admission were predictive of ED attendance and those who saw only one physician in the preceding year had lower ED attendance. Presenting to the ED with a primary GI complaint was the strongest predictor of subsequent hospital admission.  We concluded that ED attendance by both incident and prevalent cases of IBD is high. We identified predictors of ED attendance and post ED hospitalization. This could guide the optimization of outpatient IBD care to limit ED attendance and potentially post ED hospitalization.

Melesse DY, Lix L, Nugent Z, Targownik LE, Singh H, Blanchard JF, Bernstein CN. Estimates of disease course in inflammatory bowel disease using administrative data: a population-level study. Journal of Crohn’s and Colitis 2017; 562-570.

In this study we aimed to develop a predictive model of disease course in IBD using health care utilization measures from administrative health data. In other words we wanted to determine if we could assess administrative health data and estimate disease activity status from it. Study participants were IBD patients who were prospectively followed for a one-year period between 2009 and 2010 in a Canadian clinic setting to assess their IBD disease course (i.e., remission, mild, moderate, severe). Clinic data were linked with population-based administrative health data of Manitoba Health. We developed a statistical model to identify patters of health care utilization that matched with each disease state. The model was applied to project the distribution of disease course for the Manitoba IBD population for 1995-2013. There were 407 participants. 41% of participants were clinically in remission, while 14.0% had severe IBD. Mild, moderate, or severe disease was associated with at least 3 gastroenterologist visits or at least 3 general practitioner visits with an IBD diagnosis and at least 1 radiology test .  The percentages of the Manitoba IBD population in remission steadily rose from 1995 to 2013 (43.6% to 59.9%), while the percentages of individuals with mild, moderate or severe disease declined. In summary, this study demonstrated that health care utilization measures from administrative data can be used to predict disease course in the IBD population.

Nguyen GC, Bernstein CN, Benchimol E. Risk of surgery and mortality in elderly-onset inflammatory bowel disease: A population-based cohort study. Inflammatory Bowel Disease 2017; 23:218-223.

In this study the administrative data of the province of Ontario was used and new IBD cases in diagnosed  between 1999 and 2008 were identified. Of 21,218 persons with IBD, there were 1749 cases of elderly-onset (at least 65 years) ulcerative colitis (UC) and 725 cases elderly-onset Crohn's disease (CD). Elderly UC had higher rates of IBD-related surgery than those with young-adult UC  (less than 40 years) (adjusted hazard ratio, 1.34; 95% CI, 1.16-1.55), although there was no difference in surgical rates between age groups in CD. IBD-specific mortality was higher in elderly-onset CD (33.1/10,000 person-year) compared with that in middle-age (40-64 years) CD (5.6/10,000 person-year, P < 0.0001) and young adult CD (1.0/10,000 person-year) but was not different by age in UC. The leading cause of death in elderly UC and CD was solid malignancies accounting for 22.9% and 26.4% of deaths, respectively, whereas IBD was third most frequent cause of death accounting for 6.3% and 9.1% of deaths, respectively.  We concluded that elderly-onset patients with UC were more likely to undergo surgery while elderly-onset patients with CD exhibited higher IBD-specific death rates than those with younger-onset disease. These findings should prompt more optimized disease management in elderly IBD since they are at higher risk for bad outcomes when they are newly diagnosed.

Benchimol EI, Kaplan GG, Otley AR, Nguyen GC, Underwood FE, Guttmann A, Jones JL, Potter BK, Catley CA, Nugent Z, Cui Y, Tanyingoh D, Mojaverian N, Bitton A, Carroll MW, deBruyn J, Dummer TJB, El-Matary W, Griffiths AM, Jacobson K, Kuenzig ME, Leddin D, Lix LM, Mack DR, Murthy S, Peña Sánchez JN, Singh H, Targownik L, Vutcovici M, Bernstein CN. Rural and urban residence during early life is associated with a lower risk of inflammatory bowel disease: A population-based inception and birth cohort study. American Journal of Gastroenterology 2017, 112:1412-1422.

We aimed to determine if growing up in an urban or rural household impacted on being diagnosed with IBD. Using administrative data in each of 4 Canadian provinces we created comprehensive datasets of all persons with IBD in those provinces dating back to 2000.  There were 6,662 rural residents and 38,905 urban residents with IBD. The incidence of IBD per 100,000 (number of new cases) was 30.72 in rural residents and 33.16 in urban residents, (IRR 0.90, 95% CI 0.81-0.99). The protective association was strongest in children <10 years (IRR 0.58, 95% CI 0.43-0.73) and 10-17.9 years (IRR 0.72, 95% CI 0.64-0.81). In the birth cohort, comprising 331 rural and 2,302 urban residents, rurality in the first 1-5 years of life was associated with lower risk of IBD (IRR 0.75-0.78). We concluded that people living in rural households had lower risk of developing IBD. This association is strongest in young children and adolescents, and in children exposed to the rural environment early in life.

Bernstein CN. Large registry epidemiology in IBD. Inflammatory Bowel Diseases 2017;23(11):1941-1949.

 

This review article discusses the exploration of the study of the epidemiology of IBD using large databases.

Bernstein CN. Changes in the epidemiology of inflammatory bowel disease - clues for aetiology. Alimentary Pharmacology and Therapeutics 2017;46(10):911-919.

 

This review article discusses how epidemiology studies can be used to search for clues as to what causes IBD.

Shah SC, Khalili H, Gower-Rousseau C, Olen O, Benchimol EI, Lynge E, Nielsen KR, Brassard P, Vutcovici M, Bitton A, Bernstein CN, Leddin D, Tamim H, Stefansson T, Loftus EV, Moum B, Tang W, Ng S, Gearry R, Sincic B, Bell S, Sands BE. Lakatos PL, Végh Z, Ott C, Kaplan GG, Burisch J, Colombel JF. Sex-based difference in the incidence of inflammatory bowel disease: a pooled analysis of population-based studies. Gastroenterology 2018 Oct;155(4): 1079-1089.

 

Although the incidence of IBD varies with age, few studies have examined variations between the sexes. We therefore used population data from established cohorts to analyze sex differences in IBD incidence according to age at diagnosis. We identified population-based cohorts of patients with IBD for which incidence and age data were available (17 distinct cohorts from 16 regions of Europe, North America, Australia, and New Zealand). We collected data through December 2016 on 95,605 incident cases of Crohn's disease (42,831 male and 52,774 female) and 112,004 incident cases of UC (61,672 male and 50,332 female). We pooled incidence rate ratios of Crohn’s disease and UC for the combined cohort and compared differences according to sex using random effects meta-analysis. Female patients had a lower risk of Crohn’s disease during childhood, until the age range of 10-14 years (incidence rate ratio, 0.70; 95% CI, 0.53-0.93), but they had a higher risk of Crohn’s disease thereafter, which was statistically significant for the age groups of 25-29 years and older than 35 years. The incidence of UC did not differ significantly for female vs male patients (except for the age group of 5-9 years) until age 45 years; thereafter, men had a significantly higher incidence of UC than women. We concluded that in a pooled analysis of population-based studies, we found age at IBD onset to vary with sex. Further studies are needed to investigate mechanisms of sex differences in IBD incidence.

Benchimol EI, Kuenzig MI, Bernstein CN, Nguyen GC, Guttmann A, Jones J, Potter BK, Targownik LE, Catley CA, Nugent Z, Tanyingoh D, Mojaverian N, Underwood FE, Siddiq S, Otley AR, Bitton A, Carroll MW, deBruyn J, Dummer TJB, El-Matary W, Griffiths AM, Jacobson K, Leddin D, Lix LM, Mack DR, Murthy SK, Peña-Sánchez JN, Singh H, Kaplan GG, on behalf of the Canadian Gastro-Intestinal Epidemiology Consortium. Rural and urban disparities in the care of Canadian patients with inflammatory bowel disease: A population-based study. Clinical Epidemiology 2018 Nov 8; 10:1613-1626.

 

Canada’s large geographic area and low population density pose challenges in access to specialized healthcare for remote and rural residents. We compared health services use, surgical rate and specialist gastroenterologist care in rural and urban IBD patients in Canada. We used validated algorithms applied to population-based health administrative data to identify all people living within 3 Canadian provinces: Alberta, Manitoba, and Ontario. We compared rural to urban residents for time to diagnosis, hospitalizations, outpatient visits, emergency department use, surgical rate, and gastroenterologist care. There were 36,656 urban and 5,223 rural residents with newly diagnosed IBD who were included. Outpatient physician visit rate was similar in rural and urban patients. IBD-specific and IBD-related hospitalization rates were higher in rural patients by 17%  and 27% (IRR 1.17, 95% CI 1.02-1.34, and IRR 1.27, 95% CI 1.04-1.56, respectively), Emergency Department in Ontario visit rate was 50% higher (IRR 1.53, 95% CI 1.42-1.65, and IRR 1.33, 95% CI 1.25-1.40) (Emergency Department visit rate could not be tracked in Alberta and Manitoba.  Surgical rates were not different between rural and urban patients, nor was pre-diagnosis lag time. Rural patients had 20% fewer IBD-specific gastroenterologist visits (IRR 0.79, 95% CI 0.73-0.84), and a smaller proportion of their IBD-specific care provided by gastroenterologists (28.3% vs. 55.2%, p<0.0001). This was less pronounced in children under age 10 at diagnosis (59.3% vs. 65.0%, p<0.0001), and the gap was widest in patients over age 65 (33.0% vs. 59.2%, p<0.0001). We concluded that rural IBD patients have less use of gastroenterologists, more hospitalizations and greater rates of Emergency Department visits. These health services use disparities result in costlier care for rural patients. Innovative methods of delivering gastroenterology care to rural IBD patients (such as telehealth, online support, and/or remote clinics) should be explored, especially for communities lacking easy access to gastroenterologists.

Ananthakrishnan A, Bernstein CN, Iliopoulos D, MacPherson A, Neurath M, Affendi RA, Vavricka S, Fiocchi C. Environmental triggers in inflammatory bowel disease: A review of progress and evidence. Nature Reviews Gastroenterology & Hepatology 2018; 15:39-49.

This review article written by authors from around the world discusses the environmental factors that may be important in causing IBD.

Coward S, Clement F, Benchimol EI, Bernstein CN, Avina-Zubieta JA, Bitton A, Carroll MW, Hazlewood G, Jacobson K, Jelinski S, Deardon R, Jones JL, Kuenzig ME, Leddin D, McBrien KA, Murthy SK, Nguyen GC, Otley AR, Panaccione R, Rezaie A, Rosenfeld G, Peña-Sánchez JN, Singh H, Targownik LE, Kaplan GG. Past and future burden of inflammatory bowel diseases based on modeling of population-based data. Gastroenterology 2019; 156:1345-1353.

 

Inflammatory bowel diseases exist worldwide, with high prevalence in North America. IBD is complex and costly, and its increasing prevalence places a greater stress on health care systems. In this study we aimed to determine the past current, and future prevalences of IBD in Canada. We used administrative health data from Alberta (2002-2015), British Columbia (1997-2014), Manitoba (1990-2013), Nova Scotia (1996-2009), Ontario (1999-2014), Quebec (2001-2008), and Saskatchewan (1998-2016). In 2018, the prevalence of IBD in Canada was estimated at 725 per 100,000 (95% PI 716-735) and the annual average percent change increase was nearly 3% per year. The prevalence in 2030 was forecasted to be 981 per 100,000 159 per 100,000 in children, 1118 per 100,000  in adults, and 1370 per 100,000 in the elderly. In 2018, 267,983 Canadians were estimated to be living with IBD, which was forecasted to increase to 402,853 by 2030.

The following series of articles was written to update the burden of IBD for Crohn’s and Colitis Canada as of the summer of 2018:

 

Benchimol E, Bernstein CN, Bitton A, Murthy SK, Nguyen GC, Lee K, Cooke-Lauder J, Siddq S, Windsor JW, Carroll M, Coward S, El-Matary W, Griffiths AM, Jones J, Kuenzig E, Lee L, Mack DR, Mawani M, Otley A, Singh H, Targownik LE, Weizman AV, Kaplan GG. The Impact of Inflammatory Bowel Disease in Canada 2018: A Scientific Report from the Canadian Gastro-Intestinal Epidemiology Consortium to Crohn's and Colitis Canada. Journal of the Canadian Association of Gastroenterology 2019; 2 Supplement 1: S1-S5.

 

Kaplan GG, Bernstein CN, Coward S, Bitton A, Murthy SK, Nguyen GC, Lee K, Cooke-Lauder J, Benchimol E. The Impact of Inflammatory Bowel Disease in Canada 2018: Epidemiology. Journal of the Canadian Association of Gastroenterology 2019; 2 Supplement 1: S6-S16.

 

Carroll M, Kuenzig E, Mack DR, Otley A, Griffiths AM, Kaplan GG, Bernstein CN, Bitton A, Murthy SK, Nguyen GC, Lee K, Cooke-Lauder J, Benchimol E. The Impact of Inflammatory Bowel Disease in Canada 2018: Children and Adolescents with IBD. Journal of the Canadian Association of Gastroenterology 2019; 2 Supplement 1: S49-S67.

 

Nguyen GC, Targownik LE, Singh H, Benchimol E, Bitton A, Murthy SK, Bernstein CN, Lee K, Cooke-Lauder J, Kaplan GG. The Impact of Inflammatory Bowel Disease in Canada 2018: IBD in Seniors. Journal of the Canadian Association of Gastroenterology 2019; 2 Supplement 1: S68-S72.

 

Bernstein CN, Benchimol E, Bitton A, Murthy SK, Nguyen GC, Lee K, Cooke-Lauder J, Kaplan GG. The Impact of Inflammatory Bowel Disease in Canada 2018: Extra-intestinal Diseases in IBD. Journal of the Canadian Association of Gastroenterology 2019; 2 Supplement 1: S73-S80.

 

Rose K, Sherman PM, Cooke-Lauder J, Mawani M, Benchimol E, Kaplan GG, Bernstein CN, Bitton A, Murthy SK, Nguyen GC, Lee K. The Impact of Inflammatory Bowel Disease in Canada 2018: IBD Research Landscape in Canada. Journal of the Canadian Association of Gastroenterology 2019; 2 Supplement 1: S81-S91.

Jones J, Nguyen GC, Benchimol E, Bernstein CN, Bitton A, Kaplan GG, Murthy SK, Lee K, Cooke-Lauder J, Otley A. The Impact of Inflammatory Bowel Disease in Canada 2018: Quality of Life. Journal of the Canadian Association of Gastroenterology. 2019; 2 Supplement 1: S42-S48.

Keunzig ME, Lee L, El-Matary W, Weizman AV, Benchimol EI, Targownik LE, Singh H, Kaplan GG, Bernstein CN, Bitton A, Nguyen GC, Lee K, Cooke-Lauder J, Murthy S. The Impact of Inflammatory Bowel Disease in Canada 2018: Direct Costs and Health Services Utilization. Journal of the Canadian Association of Gastroenterology. 2019; 2 Supplement 1: S17-S33.

 

Keunzig ME, Benchimol E, Lee L, Targownik LE, Singh H, Kaplan GG, Nguyen GC, Bernstein CN, Bitton A, Lee K, Cooke-Lauder J, Murthy S. The Impact of Inflammatory Bowel Disease in Canada 2018: Indirect costs of IBD care. Journal of the Canadian Association of Gastroenterology. 2019; 2 Supplement 1: S34-S41.

Epidemiology // pharmacoepidemiology

Targownik LE, Nugent Z, Singh H, Bugden S, Bernstein CN. The prevalence and predictors of opioid use in inflammatory bowel disease: a population based analysis. American Journal of Gastroenterology 2014; 109: 1613-1620.

Opioids are commonly used in the treatment of pain and associated symptoms of IBD. The continuous use of opioids has been associated with adverse outcomes, including death. The prevalence and the risk factors for opioid use in IBD are poorly characterized. We used the population based University of Manitoba IBD Epidemiology Database to identify all persons in Manitoba with IBD who were prescribed opioids both prior to and following diagnosis. We determined the point prevalence of any opioid use, as well as the risk of becoming a heavy opioid user (defined as continuous use for at least 30 days at a dose exceeding 50mg morphine/day or equivalent: Within 10 years of diagnosis, 5% of persons with IBD had become heavy opioid users. Moderate use of opioids prior to diagnosis was strongly predictive of future heavy use. Persons with IBD were significantly more likely to become heavy opioid users than their matched controls. Heavy opioid use was three times as likely to be associated with mortality. We concluded that IBD is an independent risk factor for becoming a heavy opioid user, and heavy opioid use is associated with excess mortality in IBD patients. Clinicians should recognize risk factors for future heavy opioid use among their patients with IBD.

Targownik LE, Singh H, Nugent Z, Bernstein CN. Prevalence of and outcomes associated with corticosteroid prescription in inflammatory bowel disease. Inflammatory Bowel Diseases 2014; 20: 622-630.

Corticosteroids are widely utilized in the management of inflammatory bowel disease (IBD), and are associated with significant side effects. The real world effectiveness of newer drug therapies at reducing corticosteroid use has yet to be reported. The overall burden of corticosteroid use and its effects are also poorly characterized. We used the population-based University of Manitoba IBD Epidemiology Database to evaluate the overall prevalence of corticosteroid exposure, time free of corticosteroid use, and heavy corticosteroid use over the course of disease. Heavy corticosteroid use was defined as more than 3000mg of prednisone or equivalent in a 365 day period. The proportion of persons with IBD who were prescribed corticosteroids within 1, 5 and 10 years of disease was 35.2%, 52.0%, and 62.8%, respectively. Persons with ulcerative colitis, males, and those diagnosed before age 25 were more likely to use corticosteroids and have higher cumulative corticosteroid exposure. Heavy corticosteroid use in the first year following IBD diagnosis was associated with nearly 3 times increased risk of resective surgery. Cumulative corticosteroid exposure did not decrease among those diagnosed with IBD in more recent years, in spite of increasing use of immunomodulator agents. We concluded that the majority of IBD patients will be exposed to corticosteroids over the course of disease, mostly in the first year. Heavy corticosteroid use in the first year of IBD is a strong predictor of subsequent surgery. Cumulative exposure to corticosteroids use is not decreasing despite increasing uptake of immunomodulators (azathioprine, 6-mercatopurine or methotrexate).

Melesse DY, Targownik LE, Singh H, Blanchard JF, Bernstein CN. Patterns and predictors of long term nonuse of medical therapy among persons with inflammatory bowel disease. Inflammatory Bowel Diseases 2015; 21: 1615-1622.

We aimed to describe the pattern and determine predictors of delayed initiation and long-term nonuse of IBD-specific medications among persons with IBD.  All incident cases of IBD diagnosed between1987-2012 were identified from the population-based University of Manitoba IBD Epidemiology Database. Point prevalence of long-term medication nonuse (defined as no receipt of IBD-specific medications for a year or longer) was determined over calendar time and the course of disease. Among 6451 persons with IBD followed since 1987 (46.8% male, 47.8% with Crohn’s disease (CD)), approximately 11.7% were not dispensed an IBD-specific medication within the first year. Within 5 years from diagnosis 6.2% were not dispensed an IBD-specific medication. Factors associated with delayed initiation included having CD, urban living at the time at diagnosis, lower socio-economic status (SES), age over 65 and having any medical comorbidity. The prevalence of long-term nonuse consistently remained between 40-50% of persons with IBD across the study years. Persons with CD, lower SES, IBD-associated surgery, or delayed initiation of first IBD medication were more likely to become long-term nonusers after initiation.  We concluded that at any given time, roughly half of all IBD patients have not used IBD specific medications in the previous year. We found that the majority of these persons did not have more than 2 visits within the past year for IBD and hence we concluded that it was likely that the majority of these nonusers of IBD-specific medications were in remission and not in need of an IBD-specific medication.

Bhasin S, Singh H, Targownik LE, Israeli E, Bernstein CN. Rates and reasons for nonuse of prescription medication for inflammatory bowel disease in a referral clinic. Inflammatory Bowel Disease 2016;22(4):919-24.

We aimed to determine the rates and reasons for nonuse of IBD-specific medication in a referral clinic. Consecutive persons with Crohn’s disease  (n=426) and UC (n=344) were followed in a single clinic over 2 years. At each patient visit it was determined whether and what type of IBD-specific medications were used at that visit. If medications were not used the reason for nonuse was recorded. Deep remission was considered a reason for nonuse if the attending physician believed the person was in deep remission and agreed for them to be off medications.  Nonuse of IBD-specific medication was seen in 126 persons with Crohn’s disease  (30%) and 65 persons with UC (19%). In Crohn’s disease increased age and disease duration were associated with nonuse; disease phenotype did not predict nonuse. In UC disease duration was associated with nonuse but age was not. In Crohn’s disease, the most common reason for medication nonuse was deep remission (51.6%), followed by not having seen a gastroenterologist for a lengthy period (17%), and nonadherence (16%). In UC 51.3% of nonuse was attributed to deep remission, followed by nonadherence (26.3%) and not having seen a gastroenterologist for a lengthy period (9.2%). We concluded that over a quarter of persons with IBD attending at a tertiary care practice do not use IBD-specific medications with a higher rate in CD than UC. The decision not to use medications was deemed to be appropriate in approximately one-half of all nonusers.

Targownik LE, Tenakaroon A, Leung S, Lix LM, Nugent Z, Singh H, Bernstein CN. Factors associated with discontinuation of anti-TNF inhibitors among persons with IBD: A population based analysis. Inflammatory Bowel Disease 2017; 23:409-420.

Anti-tumor necrosis factor (anti-TNF) medications (i.e. infliximab (IFX) and adalimumab (ADA)) are known to be highly efficacious in persons with moderate-to-severe IBD). There is little data from population based sources to that report on how common it is for users of these drugs to persist with them over time. Discontinuation of anti-TNF therapy is a marker of lack of effectiveness, intolerance and patient/physician practice preferences  We identified all persons with IBD in Manitoba who were dispensed infliximab (IFX) and adalimumab (ADA) between 2001 and 2014 through our University of Manitoba IBD Epidemiology Database. Subjects were followed longitudinally to assess rates of completion of anti-TNF induction and duration of continued use. Overall, 925 of 8651 persons with IBD were prescribed an anti-TNF drug (705 Crohn’s Disease [CD: 523 IFX, 182 ADA), 220 ulcerative colitis (UC: 214 IFX, 6 ADA). Approximately four-fifths of persons starting on anti-TNF therapy completed induction (induction refers to the first 6 weeks of drug treatment to get persons into remission). At 1 and 5 years, persistence rates with the original anti-TNF were approximately 60% and 40%, respectively. Immunomodulator use (such as azathioprine, 6-mercaptopurine and methotrexate) at the time of anti-TNF dispensation was associated with a decreased likelihood of anti-TNF discontinuation in both CD and UC. ADA users with CD who reached maintenance phase had a 65% higher risk of discontinuation than IFX users.  We concluded that approximately two fifths of anti-TNF users discontinue use within one year of initiation, and three-fifths will have discontinued at 5 years. Concomitant IM therapy decreased discontinuation rates.

Targownik LE, Tenakaroon A, Leung S, Lix LM, Singh H, Bernstein CN. Temporal Trends in Initiation of Therapy with Tumor Necrosis Factor Antagonists for Patients With Inflammatory Bowel Disease: A Population-Based Analysis. Clinical Gastroenterology and Hepatology 2017 Jul; 15(7): 1061-70.

We aimed to determine the patterns of use and changes over time of anti-TNFs and the use of immunomodulators (azathioprine, 6-mercaptopurine, and methotrexate) [and corticosteroids prior to starting anti-TNF therapy in persons with IBD. We used the University of Manitoba IBD Epidemiology Database to identify all anti-TNF users with Crohn’s disease (CD) and ulcerative colitis (UC) from 2001-2014. We assessed changes in the prevalence and incidence of anti-TNFs over time. We also characterized patterns of corticosteroid use, corticosteroid dependence, and immunomodulator use prior to anti-TNF administration, and how they have changed over time.  We identified 950 persons (761 CD, 189 UC) who received anti-TNF. The cumulative prevalence (number of users ever) of anti-TNF use in 2014 was 20.4% for CD and 6.0% for UC. Within 5 years of diagnosis, the cumulative incidence of anti-TNF exposure was 23.4% for CD and 7.8% for UC. The majority of anti-TNF users had evidence of corticosteroid dependence (>2g prednisone within any 12 month period) prior to anti-TNF initiation. Cumulative corticosteroid exposure prior to anti-TNF use decreased over time for UC, but not significantly for CD. There was no increase over time in the use of concomitant immunomodulators with anti-TNF therapy. We concluded that anti-TNF use is increasing over time. There was a significant decrease in cumulative corticosteroid use in UC prior to starting anti-TNF, but not in CD; and no change in immunomodulator use. This suggests the continuing need for optimizing the use of anti-TNFs in IBD.

Targownik LE, Leung S, Lix L, Singh H, Bernstein CN. Persistence with immunomodulator monotherapy use and incidence of therapeutic ineffectiveness among users of immunomodulator monotherapy in IBD. American Journal of Gastroenterology 2018; 113: 1206-12. 

Immunomodulator-based monotherapy with thiopurines (azathioprine and 6-mercaptopurine) or methotrexate has relatively low cost compared to biological therapy (i.e. infliximab or adalimumab). We used the population-based dataset of the University of Manitoba IBD Epidemiology Database spanning from 1996 until 2014 to assess the initiation and continued use and outcomes of immunomodulator monotherapy. We found that there were 3312 persons diagnosed with IBD (1480 CD, 1832 ulcerative colitis (UC)) in the study period. The cumulative incidence of immunomodulator monotherapy use at 5 years was 46% for CD and 24.9% for UC. Approximately one-third remained on immunomodulator monotherapy continuously for 5 years or more. Roughly three-quarters of immunomodulator users with a history of corticosteroid use had at least a 50% reduction in corticosteroid exposure in the year following immunomodulator initiation. We concluded that although the majority of persons who are initiated on immunomodulator monotherapy discontinue medications and/or have evidence of therapeutic ineffectiveness a significant minority remain free of any negative outcomes over many years of therapy.

 

 

Targownik LE, Benchimol EI, Bernstein CN, Singh H, Lix ML, Tennakoon A, Leung S, Aviña A, Coward S, Jones J, Kaplan G, Murthy SK, Nguyen GC, Peña-Sánchez JN. Upfront combination therapy, compared with monotherapy, for patients not previously treated with a biologic agent associates with reduced risk of inflammatory bowel disease-related complications in a population-based cohort study. Clinical Gastroenterology and Hepatology 2018; in press.

 

Although guidelines recommend inclusion of immunomodulators (azathioprine, 6-mercaptopurine or methotrexate) in anti-tumor necrosis factor (TNF) initiation therapy for Crohn's disease (CD) there are limited data on the incremental effectiveness of this treatment strategy from the real world. We collected data from the University of Manitoba Inflammatory Bowel Disease Epidemiology database on persons with CD (n=852) or UC (n=303), from 2001 through 2016, who began treatment with anti-TNF drugs (infliximab or adalimumab). New and/or continuing users of immunomodulators at the time anti-TNF therapy began were considered recipients of combination therapy. The main outcome was treatment ineffectiveness during TNF antagonist-based therapy or within 90 days after the anti-TNF agent was discontinued.  In patients with CD, combination therapy was associated with a nearly 40% decrease in likelihood of treatment ineffectiveness. In conclusion, in an analysis of a database of real-world patients with IBD, we associated initiation therapy with a combination immunomodulators and anti-TNF drugs with an increased likelihood of treatment effectiveness for patients with CD.

 

Targownik LE, Benchimol E, Witt J, Bernstein CN, Singh H, Lix L, Tennakoon A, Zubieta AA, Coward S, Jones J, Kuenzig E, Murthy S, Nguyen G, Peña Sánchez JN, Kaplan GG. The effect of initiation of anti-TNF therapy on the subsequent direct healthcare costs of inflammatory bowel disease. Inflammatory Bowel Diseases 2019; in press.

Background: The prevalence of inflammatory bowel disease (IBD) is known to be increasing. The total direct costs of IBD have not been assessed on a population wide level in the era of biologic therapy. We identified all persons with IBD in Manitoba in the University of Manitoba Inflammatory Bowel Disease Epidemiology Database between January 2005 and December 2015, with each matched to 10 controls on age, sex, and geographic area of residence. Costs of all hospitalizations, outpatient physician-patient contacts and prescription medication use were enumerated for cases and controls. Total and per-capital annual costs attributable to IBD were determined by taking the difference between the costs accrued by an IBD case and their control. The number of people with IBD in Manitoba increased from 6,323 to 7,603 between 2005 and 2015. The total per capita annual costs attributable to IBD rose from $3,354 in 2005 to $7,801 in 2015, primarily driven by an increase in pre capital annual anti-TNF drug (i.e. infliximab and adalimumab) costs, which rose from $181 in 2005 to  $5,270 in 2015.  There was a significant decline in inpatient costs for CD ($180±35/year. p=0.0006), but not for UC ($56±35/year, p=0.23), In summary, the direct health care costs attributable to IBD have more than doubled over the 10 years between 2005 and 2015, driven mostly by increasing expenditures on biological medications (i.e. anti-TNF drugs). IBD-attributable hospitalization costs have declined modestly over time for persons with CD, though no change was seen for patients with UC.

 

Murthy SK, Begum J, Benchimol EI, Kaplan GG, Targownik LE, Singh H, Bernstein CN, McCurdy JD, Taljaard. Introduction of anti-TNF therapy has not yielded expected declines in hospitalization and intestinal resection rates in inflammatory bowel diseases: a population-based interrupted time series study. Gut 2019; in press.

 

We evaluated the effect of introduction of infliximab in Ontario on the population rates of major health events and direct costs in persons with IBD. We studied all adult patients with Crohn’s disease (CD) and ulcerative colitis (UC) living in Ontario, Canada between July 1, 1995 and March 31, 2012 using population-level health administrative data. Marketplace introduction of infliximab in CD did not have a significant immediate  or gradual impact on the rate of IBD-related hospitalizations, nor an immediate or gradual impact on the rate of intestinal resections. Marketplace introduction of infliximab in UC was not associated with an immediate effect but was associated with a gradual decrease in IBD-related hospitalization rates. There were no significant persistent effects of infliximab availability on colectomy rates among UC patients nor on the rates of non-IBD hospitalizations or other major abdomino-thoracic surgeries (control outcomes) among CD or UC patients. We concluded that robust market penetration of infliximab among CD patients has not resulted in a meaningful reduction in the population rates of IBD-related hospitalizations or intestinal resections. Despite the absence of UC-related colectomies there was a reduction in UC-related hospitalization rates. Since we know these drugs can have dramatic effects in a substantial number of patients we believe that the absence of an impact of infliximab on key outcomes likely relates to underuse of this agent in the target populations.

Epidemiology // comorbidity

Targownik LE, Leslie WD, Carr R, Clara I, Miller N, Rogala L, Graff LA, Walker JR, Bernstein CN.  Longitudinal change in bone mineral density in a population-based cohort of patients with inflammatory bowel disease. Calcific Tissue International 2012; 91; 356-61.

Persons with IBD are reported to have a high prevalence of osteoporosis and reduced bone mineral density (BMD) and to be at higher risk of fracture. The course of BMD loss over time is poorly characterized in persons with IBD. Eighty-six persons, stratified by age, were enrolled from a population-based longitudinal IBD cohort study to undergo BMD testing at baseline, with final BMD testing a mean of 4.3 years later. The proportion of subjects with significant change in BMD at the lumbar spine, total hip, and femoral neck was assessed, as were clinical, biochemical, and anthropomorphic changes. Vertebral radiographs were also obtained at baseline and at the end of follow-up in those aged 50 years and above to detect vertebral fractures. The change in BMD seen in this cohort of IBD patients was similar to the expected rate of BMD loss in the general population. Age greater than 50 years, decreasing body mass index, and corticosteroid use were most notably correlated with BMD loss. Subjects aged less than 50 years did not have significant declines in BMD. IBD symptom activity scores correlated poorly with BMD loss. Vertebral fractures were uncommon, with only two subjects out of 41 greater than 50 years old developing a definite radiographic fracture over the course of follow-up. No major nonvertebral fractures were observed. Patients with IBD do not appear to have significantly accelerated BMD loss. Older age, decreasing body mass index, and corticosteroid use may identify IBD patients at greater risk for BMD loss.

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.

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.

Marrie RA, Walker JR, Graff LA, Lix LM, Bolton JM, Nugent Z, Targownik LE, Bernstein CN. Performance of administrative case definitions for depression and anxiety in inflammatory bowel disease. Journal of Psychosomatic Research 2016; 89: 107-113.

Comorbid depression and anxiety are common in IBD, but few population-based estimates of the burden of depression and anxiety exist. Methods to support population-based studies are needed. We aimed to test the performance of administrative case definitions (that are extracted from Manitoba Health administrative data) for depression and anxiety in IBD and to understand what the prevalence of these conditions are in IBD.  We linked administrative (health claims) data from the province of Manitoba, Canada with clinical data for 266 persons in the Manitoba IBD Cohort Study. We compared the performance of administrative case definitions for depression and anxiety with (a) diagnoses of depression and anxiety as identified based on the Composite International Diagnostic Interview (CIDI), which identifies disorders meeting formal diagnostic criteria, and (b) participant report of physician-diagnosed depression or anxiety. Administrative definitions for depression showed moderate agreement with the CIDI. Agreement was higher with participant report of physician-diagnosed depression. The lifetime prevalence of depression was 29.3% based on the CIDI, 17.7% based on participant report of physician-diagnosed depression, and 21.8-22.5% based on administrative data. Compared to the CIDI, administrative definitions for anxiety showed onlyfair agreement. The lifetime prevalence of anxiety was 31.2% based on the CIDI, 9.7% based on participant report of physician-diagnosed anxiety, and 24.4-31.9% based on administrative data. We concluded that administrative data may be used for population-level surveillance of depression and anxiety in IBD, although they will not capture undiagnosed or untreated cases.

Singh H, Nugent Z, Yu BN, Lix LM, Targownik LE, Bernstein CN. Higher Incidence of Clostridium difficile Infection Among Individuals With Inflammatory Bowel Disease. Gastroenterology 2017 Aug; 153(2): 430-438.

Studies of Clostridium difficile infections (CDIs) among individuals with IBD have used data from single centers or CDI administrative data codes of limited diagnostic accuracy. We determined the incidence, risk factors, and outcomes after CDI in a population-based cohort of patients with IBD and laboratory confirmation diagnoses of CDI. We searched the University of Manitoba IBD Epidemiology Database and Manitoba Health CDI databases to identify individuals with CDI, with or without IBD, from July 1, 2005 through March 31, 2014. Individuals with IBD had a 4.8-fold increase in risk of CDI than individuals without IBD; we found no difference between individuals with ulcerative colitis vs Crohn's disease. There was no increase in CDI incidence over the study time period in either group. Among individuals with IBD, exposure to corticosteroids, infliximab or adalimumab, metronidazole, hospitalizations, higher ambulatory care visits, shorter duration of IBD, and higher comorbidities were associated with an increased risk of CDI. Although CDI increased mortality among individuals with and without IBD, there was lower mortality after CDI among individuals with IBD than without IBD by 35%. We concluded that CDI incidence is no longer increasing among individuals with IBD. We identified unique risk factors for CDI in patients with IBD. CDI is associated with a greater increase in mortality among individuals without IBD than with IBD.

Nugent Z, Singh H, Targownik LE, Bernstein CN. Herpes Zoster infection and Herpes Zoster vaccination in a population based sample of persons with IBD: Is there still an unmet need? Inflammatory Bowel Disease 2019; 25:532-540.

In this study we aimed to report the rates of herpes zoster infection before and after the introduction of herpes zoster vaccine (HZVac) and to determine the rates of HZVac after it became available in Manitoba in 2009. We used the population-based University of Manitoba IBD Epidemiology Database to identify cases of IBD and controls (1984-2016) who were diagnosed with herpes zoster infection before and after 2009 and to determine the rate of HZVac in those older than age 50 years. Further, we explored predictors of receipt of HZVac among persons with IBD. Persons with IBD vs matched controls have higher rates of herpes zoster infection before diagnosis and postdiagnosis. Herpes zoster infection rates before 2009 per 1000 person-years were increased in persons with IBD (9.2) vs controls (7.2, P < 0.0001). Persons with IBD compared with controls were more likely to get HZVac (15.5 vs 12 per 1000 person-years). Persons newly diagnosed with IBD after 2009 and of higher socioeconomic status were more likely to get HZVac. Despite the introduction of HZVac, there was a steady rise in herpes zoster infection throughout the study period (annual percent change in infection rates of +0.54, P < 0.0001). The increased risk of herpes zoster infection in IBD may reflect an inherent risk associated with the disease or, in those already diagnosed, an increased risk secondary to the use of immunomodulating drugs. HZVac rates are very low, which may reflect physician and patient knowledge of the vaccine's availability and utility and the fact that it is not covered by the provincially provided health care plan.We must do better in encouraging patients with IBD, especially those using immunosuppressive drugs to get vaccinated against Herpes Zoster (shingles).

Epidemiology // risk factors for IBD

Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease. American Journal of Gastroenterology 2010 ;105(12):2687-92.

The development of commensal flora in infants has been shown to be sensitive to antibiotic use.  Altered intestinal flora is thought to contribute to the etiology of IBD, an idiopathic chronic condition.  We aimed to determine if early use of antibiotics was associated with development of IBD in childhood. We accessed the population-based University of Manitoba Inflammatory Bowel Disease Epidemiologic Database. IBD status was determined from a validated administrative database definition.  A total of 36 subjects diagnosed between 1996 and 2008 were matched to 360 controls, based on age, sex and geographic region. Antibiotic data were drawn from the Manitoba Drug Program Information Network, a comprehensive population-based database of all prescription drugs for all Manitobans dating back to 1995.  Antibiotic use in the first year of life was compared for IBD cases versus controls. The mean age at IBD diagnosis was 8.4 years. Twenty one cases (58%) had one or more antibiotic dispensations in their first year of life, versus 39% of controls.  Crohn’s disease was diagnosed in 75% of IBD cases. Those receiving one or more dispensations of antibiotics were 3 times more likely of being an IBD case than a control.  We concluded that subjects diagnosed with IBD in childhood are more likely to have used antibiotics in their first year of life.

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: 510-4.

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.

Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics and new diagnoses of Crohn's disease and ulcerative colitis. American Journal of  Gastroenterology 2011;106(12):2133-42.

We aimed to determine if use of antibiotics 2-5 years prior to diagnosis in adults was associated with development of IBD. We assessed the population-based University of Manitoba Inflammatory Bowel Disease Epidemiologic Database.  A total of 2,234 subjects diagnosed with IBD between 2001 and 2008 were matched to 22,346 controls, based on age, sex and geographic region. Antibiotic data were drawn from the Manitoba Drug Program Information Network, a comprehensive database of all prescription drugs for all Manitobans dating back to 1995.

The mean age at diagnosis was 43.4 years. 12% of cases had at least 3 prescriptions two years prior to the case date, compared to 7% of controls.  The likelihood for those receiving at least 3 dispensations 2 years prior to their study inclusion was 50% higher in IBD cases than controls. This difference in at least 3 dispensations between cases and controls was fairly consistent at 3, 4 and 5 years prior to IBD case date.  Antibiotic dispensations were associated with both Crohn's disease and UC, with the association nominally stronger in Crohn's disease cases for at least 1 and at least 2 dispensations, while the association was stronger in UC cases for at least 3 dispensations. A dose-dependent relationship between number of antibiotic dispensations, and the risk of IBD was observed across all years investigated. We concluded that subjects diagnosed with IBD were more likely to have been prescribed antibiotics 2-5 years prior to their diagnosis. This possibly implicates antibiotic use as a predisposing factor in IBD etiology.

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.

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.

Shaw S, Nugent Z, Targownik LE, Singh H, Bernstein CN. Spring season of birth and Crohn’s disease. Clinical Gastroenterology and Hepatology 2014; 12:277-282.

Similar to many complex diseases, seasonal variation in the incidence of IBD has been demonstrated. Persons born in different seasons may potentially have variable rates of exposures to various potential causative factors, such as sunlight, antibiotics and prevalent infections. This study sought to explore the relationship between season of birth, early childhood antibiotic exposure, and development of childhood IBD. We used the population-based University of Manitoba Inflammatory Bowel Disease Epidemiology Database. Seasons of birth for 11,145 IBD cases and 108,633 controls were compared. Antibiotic data in the first year of life for cases and controls were drawn from the Manitoba Drug Program Information Network, a comprehensive database of all prescription drugs for all Manitobans dating back to 1995. Approximately 27.0% of cases were born between April and June, compared to 25.6% of controls. While this difference seems small it was statistically significant, meaning that it was not likely to happen by chance. Stratification by sex (male vs. female) and type of IBD (ulcerative colitis vs. Crohn’s disease) revealed that only males with Crohn’s disease were more likely to be diagnosed in spring. Antibiotic use for both cases and controls showed a significantly higher amount of antibiotic prescriptions for those born between April and June at 6 months of age and older.  In summary, this study found male subjects diagnosed with Crohn’s disease were more likely to have been born between April and June. This raises questions as to whether the important risk for male babies is something in the environment during spring at time of birth or alternatively perhaps when male babies are 6 months of age this is more likely to occur during winter time where there may be an increased risk for flu like illnesses.

Bernstein CN, Banerjee A, Targownik LE, Singh H, Ghia JE, Burchill C, Chateau D, Roos LL.

Cesarean Section Delivery Is Not a Risk Factor for Development of Inflammatory Bowel Disease: A Population-based Analysis. Clinical Gastroenterology and Hepatology 2016;14(1):50-7.

We aimed to determine if mode of delivery (Cesarean section  versus vaginal delivery) impacted on the future risk of inflammatory bowel disease (IBD). The University of Manitoba IBD Epidemiology Database contains records on all Manitobans diagnosed with IBD between 1984-2010. From 1970, 6-digit family health registration numbers were used in Manitoba which allows linkage of mothers to their offspring. Maternal health records including dates and modes of delivery and siblings of individuals with IBD were identified.  1671 individuals with IBD and 10488 controls matched by age, gender, area of residence (at IBD diagnosis) could be linked to their mother’s obstetrical records. Urban versus rural residency was associated with higher likelihood of caesarean section for both IBD cases (12.8% vs. 9.7%) and for controls (13.3% vs 9.4%). In Crohn’s disease, males were more likely than females to have caesarean section (13.5% vs.8.4%). Overall, there was no difference in caesarean section for IBD (11.6%) versus controls (11.7%). In multivariate analysis, being born by caesarean section was not associated with an increased risk of subsequent IBD, controlling for age, sex, urban residence, and income. Persons with IBD were no more likely to have been born by caesarean section  than their unaffected siblings (1740 siblings from 1615 families) (11.6% vs.11.3%). We concluded that caesarean section  is not more common in IBD than in controls or in their siblings.

Bernstein CN, Burchill C, Targownik LE, Singh H, Ghia JE, Roos LL. Maternal Infections That Would Warrant Antibiotic Use Antepartum or Peripartum Are Not a Risk Factor for the Development of IBD: A Population-Based Analysis. Inflammatory Bowel Diseases 2017;23(4):635-640.

We aimed to determine if maternal antenatal or perinatal infections (and thereby use of antibiotics) increase the risk of developing IBD in their offspring. The rationale is that maternal use of antibiotics may change the baby’s gut microbiome and possibly make it more conducive for the baby to ultimately develop IBD. The University of Manitoba IBD Epidemiology Database includes all Manitobans with IBD dating back to 1984 and a control group matched by age, sex and geographic residence. Individuals born in 1970 and later are linkable to their mothers through a 6 digit family health registration number and cross referencing of mothers’ health identification number  on the child’s birth record.  We assessed antenatal (30 days and 9 months prior to delivery) and peripartum (in hospital) maternal infections identified by ICD-8 and ICD-9 codes as a proxy for antibiotic use. Of the 2487 IBD cases born after 1970, 1758 were born in Manitoba, of which 1671 were linkable to mothers (Crohn’s disease=973, ulcerative colitis=698). 10488 matched controls and 1740 siblings from 1615 families were identified. Maternal infections occurred with equal rates in mothers of IBD cases (21.7%) and mothers of controls (23.2%) within 9 months antepartum . Maternal infections occurred with equal rates in mothers of IBD cases (11.4%) and mothers of controls (12.4%) within 30 days antepartum Maternal infections occurred with equal rates in mothers of IBD cases (5.5%) and mothers of controls (7.5%)  peripartum. There was also no difference in the occurrence of antepartum or peripartum infections among mothers of IBD cases vs unaffected siblings. We concluded that maternal infections (and therefore antibiotic use) in the antepartum and peripartum periods do not affect the risk of development of IBD in offspring. Combined with our data that caesarean section is not a risk factor for developing IBD we further concluded that  it appears that events of the immediate postpartum period that shape the developing neonate gut microbiome may not be critical in the development of IBD.

Bernstein CN, Burchill C, Targownik LE, Singh H, Roos LL. Events within the first year of life, but not the neonatal period, affect risk for later development of inflammatory bowel diseases. Gastroenterology 2019; in press.

We performed a population-based study to determine whether there was an increased risk of inflammatory bowel diseases (IBD) in persons with critical events at birth and within 1 year of age. We collected data from the University of Manitoba IBD Epidemiology Database, which contains records on all Manitobans diagnosed with IBD from 1984 through 2010 and matched controls. From 1970 individuals' records can be linked with those of their mothers, so we were able to identify siblings. All health care visits or hospitalizations during the neonatal and postnatal periods were available from 1970 through 2010. In previous studies using this data source we showed that development of IBD was not associated with being born by caesarean section (versus vaginal delivery) and was not associated with mothers’ having antenatal or perinatal infections. In this study we collected data on infections, gastrointestinal illnesses, failure to thrive, and hospital readmission in the first year of life and sociodemographic factors at birth. From 1979, data were available on gestational age, Apgar score, neonatal admission to the intensive care unit, and birth weight. We compared incident rate of infections, gastrointestinal illnesses, and failure to thrive between IBD cases and matched controls as well as between IBD cases and siblings. Data on 825 IBD cases and 5999 matched controls were available from 1979. Maternal diagnosis of IBD was the greatest risk factor for IBD in offspring (increased the risk for IBD development in offspring 4.5x). When we assessed neonatal events, only being in the highest vs lowest socioeconomic quintile increased risk for later development of IBD. For events within the first year of life, being in the highest socioeconomic quintile at birth and infections increased risk for developing IBD at any age. Infection in the first year of life was associated with diagnosis of IBD before age 10 years (by 3x)  and before age 20 years (by 1.5x) Risk for IBD was not affected by gastrointestinal infections, gastrointestinal disease, or abdominal pain in the first year of life. In a population-based study, we concluded that infection within the first year of life was associated with a diagnosis of IBD. This might be due to use of antibiotics or a physiologic defect at a critical age for gut microbiome development.

Bernstein CN, Burchill C, Targownik LE, Singh H, Roos LL. Events within the first year of life, but not the neonatal period, affect risk for later development of inflammatory bowel diseases. Gastroenterology 2019; in press.

 

We performed a population-based study to determine whether there was an increased risk of inflammatory bowel diseases (IBD) in persons with critical events at birth and within 1 year of age. We collected data from the University of Manitoba IBD Epidemiology Database, which contains records on all Manitobans diagnosed with IBD from 1984 through 2010 and matched controls. From 1970 individuals' records can be linked with those of their mothers, so we were able to identify siblings. All health care visits or hospitalizations during the neonatal and postnatal periods were available from 1970 through 2010. In previous studies using this data source we showed that development of IBD was not associated with being born by caesarean section (versus vaginal delivery) and was not associated with mothers’ having antenatal or perinatal infections. In this study we collected data on infections, gastrointestinal illnesses, failure to thrive, and hospital readmission in the first year of life and sociodemographic factors at birth. From 1979, data were available on gestational age, Apgar score, neonatal admission to the intensive care unit, and birth weight. We compared incident rate of infections, gastrointestinal illnesses, and failure to thrive between IBD cases and matched controls as well as between IBD cases and siblings. Data on 825 IBD cases and 5999 matched controls were available from 1979. Maternal diagnosis of IBD was the greatest risk factor for IBD in offspring (increased the risk for IBD development in offspring 4.5x). When we assessed neonatal events, only being in the highest vs lowest socioeconomic quintile increased risk for later development of IBD. For events within the first year of life, being in the highest socioeconomic quintile at birth and infections increased risk for developing IBD at any age. Infection in the first year of life was associated with diagnosis of IBD before age 10 years (by 3x)  and before age 20 years (by 1.5x) Risk for IBD was not affected by gastrointestinal infections, gastrointestinal disease, or abdominal pain in the first year of life. In a population-based study, we concluded that infection within the first year of life was associated with a diagnosis of IBD. This might be due to use of antibiotics or a physiologic defect at a critical age for gut microbiome development.

Epidemiology // pediatric IBD

El-Matary W, Bernstein CN, Moroz S. Inflammatory bowel disease in children of Manitoba: 30 years' experience of a tertiary center. Journal of Pediatric Gastroenterology and Nutrition 2014; 59: 763-66.

The aim of this study was to describe the incidence and prevalence of IBD in children  less than17 years of age in the years from 1978 to 2007. From January 1, 1978, to December 31, 2007, the sex- and age-adjusted annual incidence and prevalence of pediatric IBD per 100,000 population were calculated based on the pediatric IBD database of the only pediatric tertiary center in the province. The annual health statistics records for the Province of Manitoba were used to calculate population estimates for the participants. To ensure validity of data, the University of Manitoba IBD Epidemiology Database was analyzed for patients less than 17 years of age from 1989 to 2000.  The sex- and age-adjusted incidence of pediatric Crohn disease increased from 1.2/100,000 in 1978 to 4.68/100,000 in 2007 (P < 0.001). For ulcerative colitis, the incidence has increased from 0.47/100,000 in 1978 to 1.64/100,000 in 2007 (P < 0.001). During the same time period, the prevalence of Crohn disease has increased from 3.1 to 18.9/100,000 (P < 0.001) and from 0.7 to 12.7/100,000 for ulcerative colitis (P < 0.001). During the last 5 years of the study the average annual incidence of IBD in urban patients was 8.69/100,000 as compared with 4.75/100,000 for rural patients (P < 0.001). We concluded that the incidence and prevalence of pediatric IBD are increasing. The majority of patients were residents of urban Manitoba, confirming the important role of environmental factors as causative in IBD.

Singh H, Nugent Z, Brownell M, Targownik L, Roos L, Bernstein CN. Academic performance among children with inflammatory bowel disease: A population based study. Journal of Pediatrics 2015; 166: 1128-33.

We aimed to determine grade 12 academic performance (and potential predictors) for children with IBD compared to population controls. Children diagnosed with IBD under age 17 years were identified from the population-based University of Manitoba IBD Epidemiology Database and were matched by age-, sex- and area of residence to 10 randomly selected controls. Grade 12 educational outcomes (scores on the provincial grade 12 language arts, mathematics standards tests and enrollment in grade12 by age 17) were determined by linkage to the province wide Manitoba Education Database. Grade 12 educational outcomes among 337 children with IBD were compared with 3093 without IBD. There were no significant differences among the two groups in the standardized scores for language arts and mathematics or enrollment in grade 12 by age 17. Lower socioeconomic status and diagnosis with mental health problems 6 months prior to 6 months post IBD diagnosis were independent predictors of worse educational outcomes.  There was no significant effect of age of diagnosis of IBD, type of IBD (UC vs. CD), use of corticosteroids or immunomodulator agents, hospitalizations or surgery for IBD.  It is reassuring that children with IBD on average achieve similar levels of academic achievement in grade 12 as those without IBD. This study identified the educational impact of mental health conditions at IBD diagnosis among children.

Singh H, Nugent Z, Targownik LE, El Matary W, Brownell M, Bernstein CN. Health care utilization among a population based cohort of children with inflammatory bowel disease. Clinical Gastroenterology and Hepatology 2015; 13: 1302-09.

We explored health care use by children with IBD. We identified all children with IBD in the population-based University of Manitoba IBD Epidemiology Database; 651 children with IBD were matched for age, sex, and area of residence with 5950 children without IBD (controls), and followed up for a total of 6419 and 53,875 person-years, respectively. We extracted and analyzed data on IBD type (Crohn's disease vs ulcerative colitis), diagnosis before or after 2002 (era of diagnosis), age, sex, ambulatory care visits and hospitalizations before and after diagnosis, comorbidities, exposure to IBD drugs, and surgeries. We found that children with IBD were more likely to have visits for gastrointestinal symptoms in each of the 4 years before IBD diagnosis than controls, with no significant effect of era of diagnosis. Children with IBD had more physician encounters for psychosocial diagnoses in the 6 months before or after the IBD diagnosis, as well as in the second year after IBD diagnosis, than controls; 56% of children with IBD were exposed to corticosteroids within the year after their diagnosis, with no decrease over eras of follow-up evaluation. Among children diagnosed from 2002 through 2010, the 8-year actuarial rate of colectomy for those with ulcerative colitis was 8%, and the rate of resective surgery for Crohn's disease was 10%; both of these values were lower than for children diagnosed from 1987 through 2001. We concluded that in a population-based study from Canada, children with IBD were more likely to have visits for gastrointestinal symptoms in each of the 4 years before IBD diagnosis than children without IBD, indicating a potential delay in diagnosis of this disease. Rates of surgery are decreasing among children with IBD.

Shaw S, Blanchard JF, Bernstein CN. Early Childhood Measles Vaccinations Are Not Associated With Pediatric IBD: A Population-Based Analysis. Journal of Crohn’s and Colitis 2015; 9: 334-8.

Early childhood vaccinations have been hypothesized to contribute to the emergence of paediatric IBD in developed countries. Using linked population-based administrative databases, we aimed to explore the association between vaccination with measles-containing vaccines and the risk for IBD. This was a case-control study using the University of Manitoba IBD Epidemiology Database. The database was linked to the Manitoba Immunization Monitoring System [MIMS], a population-based database of immunizations administered in Manitoba. All paediatric IBD cases in Manitoba, born after 1989 and diagnosed before March 31, 2008, were included. Controls were matched to cases on the basis of age, sex, and region of residence at time of diagnosis. Measles-containing vaccinations received in the first 2 years of life were documented, with vaccinations categorized as 'None' or 'Complete', with completeness defined according to Manitoba's vaccination schedule. A total of 951 individuals [117 cases and 834 controls] met eligibility criteria, with average age of diagnosis among cases at 11 years. The proportion of IBD cases with completed vaccinations was 97%, compared with 94% of controls. In models adjusted for physician visits and area-level socioeconomic status, no statistically significant association was detected between completed measles vaccinations and the risk of IBD  We concluded that no significant association between completed measles-containing vaccination in the first 2 years of life and paediatric IBD could be demonstrated in this population-based study.

El-Matary W, Dufault B, Moroz SP, Schellenberg J, Bernstein CN. Education, Employment, Income, and Marital Status Among Adults Diagnosed With Inflammatory Bowel Diseases During Childhood or Adolescence. Clinical Gastroenterology and Hepatology 2017 Apr;15(4):518-524.

We aimed to assess levels of education attained, employment, and marital status of adults diagnosed with IBD during childhood or adolescence, compared with healthy individuals in Canada. We performed a cross-sectional study of adults diagnosed with IBD in childhood or adolescence at Children's Hospital in Winnipeg, Manitoba from January 1978 through December 2007. Participants (n = 112) answered a semi-structured questionnaire on educational achievements, employment, and marital status. Patients were matched for age and sex with random healthy individuals from the 2012 Canadian Community Health Survey (controls, 5 per patient).  Patients were followed for a mean duration of 14.3 years (range, 3.1-34.5 years). Persons with IBD were nearly twice as likely to earn more money per year and nearly three times as likely to attain a post-secondary school degree or receive a diploma as controls There was no significant difference between patients and controls in employment or marital status. We concluded that adults diagnosed with IBD during childhood seem to achieve higher education levels than individuals without IBD. This observation should provide reassurance to children with IBD and their parents.

Benchimol EI, Bernstein CN, Bitton A, Carroll MW, Singh H, Otley AR, Vutcovici M, El-Matary W, Nguyen GC, Griffiths AM, Mack DR, Jacobson K, Mojaverian N, Divine Tanyingoh D, Cui Y, Nugent Z, Coulombe J, Targownik LE, Jones JL, Leddin D, Murthy SK, Kaplan GG. Trends in Epidemiology of Pediatric Inflammatory Bowel Disease in Canada: Distributed Network Analysis of Multiple Population-Based Provincial Health Administrative Databases. American Journal of Gastroenterology 2017 Jul; 112(7): 1120-1134.

The University of Manitoba IBD Clinical and Research Centre is one of 8 centres participating in Canada-wide network dedicated to the study of the epidemiology of IBD in Canada. The network is call CanGIEC (Canadian GastroIntestinal Epidemiology Consortium). The incidence of pediatric-onset IBD is increasing worldwide. In this study we used population-based health administrative data from Alberta, Manitoba, Nova Scotia, Ontario and Quebec, to determine national Canadian IBD incidence, prevalence, and trends over time of childhood-onset IBD. These 5 provinces comprise 79.2% of the Canadian population. We identified children less than16 years diagnosed with IBD 1999-2010. Standardized incidence and prevalence were calculated per 100,000 children.  5,214 incident cases were diagnosed during the study period (3,462 Crohn's disease, 1,382 ulcerative colitis, 279 type unclassifiable). The incidence in Canada was 9.68 per 100,000 children. Incidence was similar amongst most provinces, but higher in Nova Scotia. The  incidence did not significantly change over the study period in the overall cohort  However, the incidence significantly increased in children aged 0-5y (+7.19%). Prevalence at the end of the study period in Canada was 38.25 per 100,000 children. The prevalence increased significantly over time. We concluded that Canada has amongst the highest incidence of childhood-onset IBD in the world. Prevalence significantly increased over time. Incidence was not statistically changed with the exception of a rapid increase in incidence in the youngest group of children.

El Matary W, Nugent Z, Yu BN, Lix LM, Targwonik LE, Bernstein CN, Singh H. Trends and predictors of Clostridium difficile infection among children: A Canadian population-based study. Journal of Pediatrics 2019 Mar; 206:20-25.

 

In this paper we report on the incidence rates over time of children with IBD presenting with Clostridium difficile infection. We explored our provincial database on all persons with Clostridium difficile infection between 2005-2014 so that we could identify the rates of this infection in children and what diseases increased the risk for Clostridium difficile infection. In children. The overall Clostridium difficile infection rate over the study period was 7.77 per 100,000. There was no significant increase in Clostridium difficile infection rates over the observation period. Co-morbid conditions that were more prevalent among children with Clostridium difficile infection than matched controls included Hirschsprung’s disease (p<0.001) and IBD (p<0.0001). Recurrent Clostridium difficile infections were responsible for 10.4% of CDI episodes (range 2-6 infections). Children with cancer were 3 times as likely to have recurrent Clostridium difficile infection (Hazard ratio (HR) = 3.0, 95% confidence interval (CI) 1.1, 8.8), children with diabetes were nearly 5 times as likely to have recurrent Clostridium difficile infection (HR=4.8, 95% CI 1.1, 21.4) and children with neurodegenerative diseases were over 8 times as likely to have recurrent Clostridium difficile infection (HR=8.4, 95% CI 1.9, 37.5). We concluded that the incidence of Clostridium difficile infection was not increasing among children in Manitoba. Children with malignancy, diabetes and neurodegenerative disorders are more likely to have recurrent Clostridium difficile infection.

El-Matary W, Leung S, TennakoonA, Benchimol EI, Bernstein CN, Targownik LE. Trends of utilization of tumor necrosis factor antagonists in children with inflammatory bowel disease: A Canadian population-based study. Inflammatory Bowel Diseases 2019; in press.

We aimed to describe the trend of utilization of anti-TNF drugs (infliximab and adalimumab) in children with IBD over time. We assessed all persons diagnosed with IBD prior to age 18y identified in the University of Manitoba IBD Epidemiology Database to determine the time from diagnosis to first anti-TNF in different eras (2005-2008, 2008-2012, 2012-2016). There were 291 persons diagnosed with IBD (157 CD, 134 UC) prior to age 18y. The likelihood of being initiated on anti-TNFs by 1, 2 and 5 years post-diagnosis was 18.4%, 30.5% and 42.6% respectively. The proportion of persons <18 using anti-TNFs increased over time; in 2010, 13.0% of Crohn’s disease (CD) and 4.9% of ulcerative colitis (UC); by 2016 60.0% of CD and 25.5% of UC were actively using an anti-TNF agent. For those diagnosed after 2012, 42.5% of CD and 28.4% of UC had been started on an anti-TNF agent within 1 year of IBD diagnosis. The median cumulative dose of corticosteroids in the year prior to anti-TNF initiation significantly decreased over time (prior to 2008: 4360mg; 2008-2012: 2010mg, 2012-present 1395mg prednisone equivalents) meaning the use of anti-TNF drugs has likely translated into a reduced use of corticosteroids.

Epidemiology // cancer risk in IBD

Bernstein CN, Nugent Z, Blanchard JF. 5-aminosalicylate is not chemoprophylactic for colorectal cancer in IBD: a population based study. American Journal of Gastroenterology 2011; 106: 731-6.

People with UC or Crohn’s colitis are at increased risk of developing colorectal ancer compared to the general population. We aimed to determine if use of 5-aminosalicylates (5-ASA) was associated with a reduced risk of colorectal cancer (CRC) in people with IBD. We used the population-based University of Manitoba IBD Epidemiology Database from 1984 to 2008 and which includes all prescription medication use since 1995. In 2008, there were 8,744 subjects with IBD (ulcerative colitis 4,325, Crohn's disease 4,419, females 4,851, males 3,893). In study I, we assessed the incidence of colorectal cancer among 5-ASA users (at least 1 year, and at least 5 years of cumulative use) compared with nonusers. In study II, we assessed a cohort of those with colorectal cancer (n=101) diagnosed in 1995-2008, matched to a control cohort by age, sex, disease duration, and disease diagnosis without CRC (n=303) to assess use of 5ASA prior to colorectal cancer diagnosis. For study I, the risk for colorectal cancer among 5-ASA users was nearly identical to non users for persons with at least 1 year of use and was actually increased 2-fold for those with at least 5 years of use with no difference when assessing by diagnosis. Males, but not females, using 5-ASA for at least 5 years had an increased risk of colorectal cancer. In study II, colorectal cancer cases had similar use of any 5-ASA compared with controls for at least 1 year of use at least 5 years and a similar average number of 5-ASA prescriptions at 10 vs. 11  and a similar average number of dose days at 330 vs. 410 . We concluded that 5-ASA use does not prevent colorectal cancer in IBD.

Nguyen G, Gulamhusein A, Bernstein CN. 5-Aminosalicylic acid is not protective against colorectal cancer in inflammatory bowel disease: A meta-analysis of non-referral populations. American Journal of Gastroenterology 2012; 107: 1298-1304.

Some studies have demonstrated that 5-aminosalicylic acid (5-ASA) is associated with a reduced risk of colorectal cancer in IBD. However, as noted in our study above and in other population-based studies no protective association has been found. We conducted a systematic review that focused on non-referral studies to reassess the role of 5-ASA for prevetion of colorectal cancer in. We searched MEDLINE, EMBASE, and the Cochrane databases for studies of non-referral populations that assessed the association between 5-ASA use for at least 1 year and colorectal neoplasia between 1966 and 2011 and conducted a quantitative meta-analysis.

Four observational studies fulfilled inclusion criteria. While there was moderate heterogeneity between studies the overall pooled likelihood of 5ASA preventing colorectal cancer was not met. A series of sensitivity analyses in which each of the four studies was excluded one at a time did not show any significant change in the overall pooled odds ratio or likelihood that 5ASA was protective against colorectal cancer. We conducted a separate meta-analysis of nine clinic-based studies, which, in contrast, yielded  protection of 5ASA against colorectal cancer by almost half the rate. We concluded that our meta-analysis yielded inconsistent results that were dependent on the inclusion of either non-referral or clinic-based populations. Based on non-referral studies, there does not seem to be a protective effect of 5-ASA on development of colorectal cancer in IBD. However, heterogeneity among these studies limits their interpretation.

Samadder NJ, Valentine JF, Guthery S, Singh, H, Bernstein CN, Wan Y, Wong J, Boucher K, Pappas L, Rowe K, Bronner M, Ulrich N, Burt RW, Curtin K and Smith KR. Colorectal cancer in inflammatory bowel diseases: A population-based study in Utah. 2017;62: 2126-32.

 

All newly diagnosed cases of colorectal cancer between 1996 and 2011 were obtained from Utah Cancer Registry. IBD was identified using the validated algorithm developed in Manitoba, from statewide databases of Intermountain Healthcare, University of Utah Health Sciences, and the Utah Population Database. Among 12,578 patients diagnosed with colorectal cancer, 101 (0.8%) had a prior history of IBD (61 ulcerative colitis and 40 Crohn's disease). The mean age at colorectal caner was younger for patients with IBD than those without IBD (52.8 vs 67.1 years, P < 0.001). Individuals with IBD-associated colorectal cancer were nearly twice as likely to be men (odds ratio [OR] 1.90, 95% CI 1.23-2.92), nearly 7 times as likely to be aged less than 65 years (OR 6.77, 95% CI 4.06-11.27), and nearly 3 times as likely to have colorectal cancer located in the proximal colon (OR 2.79, 95% CI 1.85-4.20) than those with sporadic colorectal cancer. Nearly 20% of the IBD-associated colorectal cancers had evidence of primary sclerosing cholangitis. After adjustment for age, gender, and stage at diagnosis, the excess hazard of death after colorectal cancer diagnosis was nearly two times higher in IBD than in non-IBD patients (OR 1.7, 95% CI 1.27-2.33).

Samadder NJ, Valentine JF, Guthery S, Singh H, Bernstein CN, Leighton JA, Wan Y, Wong J, Boucher K, Pappas L, Rowe K, Burt RW, Curtin K, Smith KR. Family history is associated with increased risk of colorectal cancer in patients with inflammatory bowel disease. Clinical Gastroenterology and Hepatology 2018; in press .

 

This study relied on the population based database of IBD developed in the state of Utah using the administrative definition of IBD developed in Manitoba. Although family history of colorectal cancer is a well-established risk factor in healthy individuals, its role in patients with IBD is less clear. In this study we aimed to estimate the risk of colorectal cancer in a cohort of patients with IBD from Utah and the significance of family history of colorectal cancer in a first-degree relative. Utah residents with IBD were identified, using the Intermountain Healthcare and University of Utah Health Sciences databases, from January 1, 1996, through December 31, 2011. Colorectal cancers were identified using the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Colorectal cancer incidence was compared with that of the state population. A cohort of 9505 individuals with IBD was identified and 101 developed colorectal cancer during the study period. Colorectal cancer was over 3 times as common in patients with Crohn's disease ( SIR 3.4, 95% CI, 2.3-4.4), and 5 times as common in UC ( SIR 5.2, 95% CI, 3.9-6.6). Patients with IBD and a concurrent diagnosis of primary sclerosing cholangitis had the greatest risk of colorectal cancer and it was increased nearly 15-fold (SIR, 14.8; 95% CI, 8.3-21.2). A history of colorectal cancer in a first degree relative was associated with a nearly 8-fold increase in risk of CRC in patients with IBD (SIR, 7.9; 95% CI, 1.6-14.3), compared with the state population. We concluded that patients with IBD have a 3- to 5-fold increase in risk of colorectal cancer, and those with colorectal cancer in a first degree relative have an almost 8-fold increase in risk. Family history of colorectal cancer indicates the need for enhanced surveillance in this population.

ten Hove JR, Bernstein CN, Oldenburg B. Putting evidence into practice: IBD dysplasia surveillance, chromoendoscopy and future directions. American Journal of Gastroenterology 2018 Mar;113(3): 313-316.

 

 This review article discusses approaches to colonoscopy surveillance for colorectal cancer (and its precursor, dysplasia) in persons with IBD.

Samadder NJ, Valentine JF, Guthery S, Singh H, Bernstein CN, Leighton JA, Wan Y, Wong J, Boucher K, Pappas L, Rowe K, Burt RW, Curtin K, Smith KR. Family history is associated with increased risk of colorectal cancer in patients with inflammatory bowel disease. Clinical Gastroenterology and Hepatology 2018; in press .

Individuals with inflammatory bowel diseases have an increased risk of developing colorectal cancer. Although family history of colorectal cancer is a well-established risk factor in healthy individuals, its role in patients with IBD is less clear. We aimed to estimate the risk of colorectal cancer in a cohort of patients with IBD from Utah and the significance of family history of CRC in a first-degree relative (FDR). We identified Utah residents with IBD, using the Intermountain Healthcare and University of Utah Health Sciences databases, from January 1, 1996, through December 31, 2011. Colorectal cancers were identified using the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Colorectal cancer incidence was compared with that of the state population.A cohort of 9505 individuals with IBD was identified (using the administrative definition for IBD developed in Manitoba) and 101 developed CRC during the study period. Patients with Crohn's disease had 3.4X the likelihood of developing colorectal cancer and patients with ulcerative colitis had 5.2X the likelihood of developing colorectal cancer.  Patients with IBD and a concurrent diagnosis of primary sclerosing cholangitis had nearly 15x the risk of developing colorectal cancer. A history of colorectal cancer in a first degree relative was associated with a nearly 8-fold increase in risk of colorectal cancer in patients with IBD. Hence, family history may act as a simple measure to identify individuals with IBD at highest risk for CRC and indicates the need for enhanced surveillance in this population

ten Hove JR, Shah SC, Shaffer SR, Bernstein CN, Castaneda D, Palmela C, Mooiweer E, Elman J, Kumar A, Glass J, Ullman TA, Colombel JF, Torres J, van Bodegraven AA, Hoentjen F, Jansen JM, de Jong M, Mahmmod N, van der Meulen-de Jong AE, Ponsioen CY, van der Woude CJ, Itzkowitz SH, Oldenburg B. Consecutive negative findings on colonoscopy during surveillance predict a low risk of advanced neoplasia in patients with longstanding colitis: results of a 15-year multicenter, multinational cohort study. Gut 2019; 68: 615-622.

 

Surveillance colonoscopy is thought to prevent colorectal cancer in patients with long-standing colonic IBD, but data regarding the frequency of surveillance and the findings thereof are lacking. Our aim was to determine whether consecutive negative surveillance colonoscopies adequately predict low neoplastic risk. A multicentre (Manitoba, NY, Holland) database of patients with long-standing IBD colitis without high-risk features and undergoing regular colorectal cancer surveillance was constructed. A 'negative' surveillance colonoscopy was predefined as a technically adequate procedure having no postinflammatory polyps, no strictures, no endoscopic disease activity and no evidence of neoplasia; a 'positive' colonoscopy was a technically adequate procedure that included at least one of these criteria. The primary endpoint was advanced colorectal neoplasia defined as high-grade dysplasia or colorectal cancer. Of 775 patients with long-standing IBD colitis, 44% (n=340) had at least 1 negative colonoscopy. Patients with consecutive negative surveillance colonoscopies were compared with those who had at least one positive colonoscopy. Both groups had similar demographics, disease-related characteristics, number of surveillance colonoscopies and time intervals between colonoscopies. No advanced colorectal neoplasia occurred in those with consecutive negative surveillance, compared with an incidence rate of 0.29 to 0.76/100 patient-years (P=0.02) in those having at least 1 positive colonoscopy on follow-up of 6.1 years after the index procedure. Within this large surveillance cohort of patients with colonic IBD and no additional high-risk features, having two consecutive negative colonoscopies predicted a very low risk of advanced colorectal neoplasia occurrence on follow-up. Our findings suggest that longer surveillance intervals in this selected population may be safe.