Variation in the Care of Children with Inflammatory Bowel Disease Within and Across Canadian Provinces: A Multi-Province Population-Based Cohort Study.

Purpose: The incidence of childhood-onset inflammatory bowel disease (IBD) is rising. We described variation in health services utilization and need for surgery among children with IBD between six and 60 months following IBD diagnosis across Canadian pediatric centers and evaluated the associations between care provided at diagnosis at each center and the variation in these outcomes. Patients and Methods: Using population-based deterministically-linked health administrative data from four Canadian provinces (Alberta, Manitoba, Nova Scotia, Ontario) we identified children diagnosed with IBD <16 years of age using validated algorithms. Children were assigned to a pediatric center of care using a hierarchical approach based on where they received their initial care. Outcomes included IBD-related hospitalizations, emergency department (ED) visits, and IBD-related abdominal surgery occurring between 6 and sixty months after diagnosis. Mixed-effects meta-analysis was used to pool results and examine the association between center-level care provision and outcomes. Results: We identified 3784 incident cases of pediatric IBD, of whom 2937 (77.6%) were treated at pediatric centers. Almost a third (31.4%) of children had ≥1 IBD-related hospitalization and there were 0.66 hospitalizations per person during follow-up. More than half (55.8%) of children had ≥1 ED visit and there were 1.64 ED visits per person. Between-center heterogeneity was high for both outcomes; centers where more children visited the ED at diagnosis had more IBD-related hospitalizations and more ED visits during follow-up. Between-center heterogeneity was high for intestinal resection in Crohn's disease but not colectomy in ulcerative colitis. Conclusion: There is variation in health services utilization among children with IBD and risk of undergoing intestinal resection in those with Crohn's disease, but not colectomy among children with ulcerative colitis, across Canadian pediatric tertiary-care centers. Improvements in clinical care pathways are needed to ensure all children have equitable and timely access to high quality care.

Health Services Utilization and Specialist Care in Pediatric Inflammatory Bowel Disease: A Multiprovince Population-Based Cohort Study.

BACKGROUND: Patterns of health services utilization among children with inflammatory bowel disease (IBD) are important to understand as the number of children with IBD continues to increase. We compared health services utilization and surgery among children diagnosed <10 years of age (Paris classification: A1a) and between 10 and <16 years of age (A1b). METHODS: Incident cases of IBD diagnosed <16 years of age were identified using validated algorithms from deterministically linked health administrative data in 5 Canadian provinces (Alberta, Manitoba, Nova Scotia, Ontario, Quebec) to conduct a retrospective cohort study. We compared the frequency of IBD-specific outpatient visits, emergency department visits, and hospitalizations across age groups (A1a vs A1b [reference]) using negative binomial regression. The risk of surgery was compared across age groups using Cox proportional hazards models. Models were adjusted for sex, rural/urban residence location, and mean neighborhood income quintile. Province-specific estimates were pooled using random-effects meta-analysis. RESULTS: Among the 1165 (65.7% Crohn's) children with IBD included in our study, there were no age differences in the frequency of hospitalizations (rate ratio [RR], 0.88; 95% confidence interval [CI], 0.74-1.06) or outpatient visits (RR, 0.95; 95% CI, 0.78-1.16). A1a children had fewer emergency department visits (RR, 0.70; 95% CI, 0.50-0.97) and were less likely to require a Crohn's-related surgery (hazard ratio, 0.49; 95% CI, 0.26-0.92). The risk of colectomy was similar among children with ulcerative colitis in both age groups (hazard ratio, 0.71; 95% CI, 0.49-1.01). CONCLUSIONS: Patterns of health services utilization are generally similar when comparing children diagnosed across age groups.

Among 1165 children with inflammatory bowel disease, health services utilization was similar for children diagnosed <10 years of age and those diagnosed ≥10 years of age, except younger children had fewer emergency department visits and Crohn's disease­related surgeries.

A randomized trial evaluating the utility of non-targeted biopsies for colorectal neoplasia detection in adults with inflammatory bowel disease: a pilot study protocol.

BACKGROUND: Persons with inflammatory bowel diseases are at increased risk of developing colorectal cancer and require frequent colonoscopy surveillance. Guidelines recommend taking 30 to 40 non-targeted biopsies throughout the colorectum to detect "invisible" neoplasia in this setting, despite a lack of evidence supporting this practice. We sought to assess the utility of this practice through a randomized controlled trial. We first propose an internal pilot study to assess recruitment potential, protocol adherence and data capture to guide the full trial. METHODS: We have designed a multi-centre, parallel-group, non-inferiority randomized controlled trial to test the utility of non-targeted biopsies as an adjunct to colonoscopy surveillance for neoplasia detection in persons with inflammatory bowel disease involving the colorectum in routine clinical practice. Participants are randomized 1:1, stratified by study site, to either standard of care high-definition white-light colonoscopy with 32 to 40 non-targeted biopsies of non-neoplastic-appearing mucosa along with a sampling of abnormal-appearing mucosa (control group) or modified colonoscopy with targeted sampling alone (intervention group). The primary outcome for the full trial will be the proportion of persons with ≥ 1 neoplastic focus detected during colonoscopy. For the pilot phase, we will assess the feasibility of recruiting a minimum of 15% of the estimated sample size within 1 year, under identical conditions as the full trial, while maintaining ≥ 90-95% rate of protocol adherence and data capture. These participants will contribute data to the full trial. The trial is being conducted at 12 centres across Canada, with a total sample size of 1952 persons. DISCUSSIONS: The trial protocol has been approved by the ethics committees of all participating sites, and the pilot study has received funding through the Canadian Institutes of Health Research (PJT 159607). If feasibility metrics are met during the pilot phase, we will complete the full trial. The trial outcomes will contribute to update the practice guidelines in this area. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04067778.

Significant Racial and Ethnic Disparities Exist in Health Care Utilization in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

BACKGROUND: The incidence of inflammatory bowel disease (IBD) is rising worldwide, though the differences in health care utilization among different races and ethnicities remains uncertain. We aimed to better define this through a systematic review and meta-analysis. METHODS: We explored the impact of race or ethnicity on the likelihood of needing an IBD-related surgery, hospitalization, and emergency department visit. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated with I2 values reporting heterogeneity. Differences in IBD phenotype and treatment between racial and ethnic groups of IBD were reported. RESULTS: Fifty-eight studies were included. Compared with White patients, Black patients were less likely to undergo a Crohn's disease (CD; OR, 0.69; 95% CI, 0.50-0.95; I2 = 68.0%) or ulcerative colitis (OR, 0.58; 95% CI, 0.40-0.83; I2 = 85.0%) surgery, more likely to have an IBD-hospitalization (OR, 1.54; 95% CI, 1.06-2.24; I2 = 77.0%), and more likely to visit the emergency department (OR, 1.74; 95% CI, 1.32-2.30; I2 = 0%). There were no significant differences in disease behavior or biologic exposure between Black and White patients. Hispanic patients were less likely to undergo a CD surgery (OR, 0.57; 95% CI, 0.48-0.68; I2 = 0%) but more likely to be hospitalized (OR, 1.38; 95% CI, 1.01-1.88; I2 = 37.0%) compared with White patients. There were no differences in health care utilization between White and Asian or South Asian patients with IBD. CONCLUSIONS: There remain significant differences in health care utilization among races and ethnicities in IBD. Future research is required to determine factors behind these differences to achieve equitable care for persons living with IBD.

Interim Analysis of a Trial Evaluating the Utility of Non-Targeted Biopsies for Colorectal Neoplasia Detection in Inflammatory Bowel Disease.

Persons with inflammatory bowel disease (IBD) affecting the colorectum (cIBD) have a 1.5- to 2-fold higher risk of developing colorectal cancer (CRC) relative to age- and sex-matched members of the general population.1 Intensive surveillance colonoscopy is recommended in this population to detect and treat early neoplastic lesions before they evolve to incurable cancers.2 Some societies advocate for widespread non-targeted ("random") biopsies throughout the colorectum to screen for "invisible" neoplastic lesions, in addition to targeted biopsies and/or resection of visible lesions.2 Despite the theoretical value of non-targeted biopsies in this setting, there are no high-quality, controlled data to support this practice. In addition to adding significant time and costs to colonoscopy screening, extensive biopsy sampling may also increase the risk of colorectal bleeding and bowel perforation, particularly in elderly patients and those receiving anticoagulant/antiplatelet therapies. With the widespread adoption of disease-modifying biologic and small molecule therapies,3 mucosal healing as a treatment end point,4 high-definition endoscopes,5 and endoscopy quality standards,6 as well as reports of very low neoplasia yield for non-targeted biopsies (0.1%-0.2% of biopsies),7 many experts have started to question the value of non-targeted biopsies as an adjunct for neoplasia surveillance in persons with cIBD.8 However, a recent large French cohort study reported that non-targeted biopsies still identify up to 20% of all neoplastic foci in persons with cIBD,9 albeit primarily in individuals with other major CRC risk factors.

Declining Corticosteroid Use for Inflammatory Bowel Disease Across Alberta: A Population-Based Cohort Study.

Background and Aims: Corticosteroid-free remission is a primary treatment goal in IBD which may be achieved with greater use of anti-TNF therapy. We defined temporal trends of corticosteroid use, anti-TNF use, hospitalization and surgery in a prevalent IBD cohort within the province of Alberta, Canada. Methods: Health administrative data were used to identify medication dispensing, hospitalizations and surgery in individuals with IBD from 2010 to 2015. Temporal trends were calculated using log-binomial regression for medications and log-linear models for hospitalizations and surgery rates. Analyses were stratified based on geographic location. Results: Of 28890 individuals with IBD, 50.3% had Crohn's disease. One in six individuals (15.45%) were dispensed a corticosteroid. Corticosteroid use decreased in both metropolitan areas (AAPC -20.08%, 95% CI: -21.78 to -18.04) and non-metropolitan areas (AAPC -18.14%, 95% CI: -20.78 to -18.04) with a similar pattern for corticosteroid dependence. Corticosteroid dependence was more prevalent in UC vs. CD (P < 0.05), and in the pediatric IBD cohort (13.45) compared to the adult (8.89) and elderly (7.54) cohorts (per 100 prevalent population, P < 0.001). The proportion of individuals dispensed an anti-TNF increased over the study period (AAPC 12.58%, 95% CI: 11.56 to 13.61). Significantly more non-metropolitan versus metropolitan residing individuals were hospitalized for any reason, for an IBD-related, or IBD-specific indication (all P < 0.001) though the proportion requiring IBD surgery was similar between groups. Conclusions: An increase in anti-TNF use corresponded to a decline in corticosteroid use and dependence in those with IBD. Inequities in IBD care still exist based on location and age.

Impact of adalimumab on disease burden in moderate-to-severe ulcerative colitis patients: The one-year, real-world UCanADA study.

BACKGROUND: A gap remains in documenting the impact of anti-tumor necrosis factor therapy on disease burden in ulcerative colitis (UC) patients treated in a real-world setting. The use of patient-reported outcomes (PROs) has been discussed as a primary endpoint in the context of the FDA PRO Guidance, for labelling purposes. Specifically, the efficacy and safety of adalimumab have been demonstrated in pivotal trials; however, data are needed to understand how clinical results translate into improvements in key aspects of the daily lives of UC patients, such as symptoms, health-related quality of life (HRQoL), and disability. AIM: To assess real-world effectiveness of adalimumab on PRO measures in patients with moderate-to-severe UC. METHODS: UCanADA was a single arm, prospective, 1-year multicenter Canadian post-marketing observational study in which multiple PRO questionnaires were completed-with psychologic distress/depression symptoms as the primary endpoint-by patients with moderate-to-severe UC. Assessments were performed during patients' routine care visit schedule, which was at the initiation of adalimumab (baseline), after induction (approximately 8 wk), and 52 wk after baseline. Additional optional assessments between weeks 8 and 52 were collected at least once but no more than two times during this period. Serious safety events and per-protocol adverse events were collected. RESULTS: From 23 Canadian centres, 100 patients were enrolled and 48 completed the study. Measured with the Patient Health Questionnaire-9 items at week 52, 61.5% (40/65) [95% confidence interval (CI): 49.7%-73.4%] of the patients improved in psychologic distress/depression symptoms, which was slightly higher in completers [65.9% (29/44); 95%CI: 51.9%-79.9%)]. At week 52, clinical response and clinical remission were achieved respectively by 65.7% (44/73) and 47.8% (32/73) of the patients. The odds of improving depressive symptoms for those achieving a clinical remission at week 52 was 7.94 higher compared with those not achieving a clinical remission (CI: 1.42, 44.41; P = 0.018). Significant changes from baseline to weeks 8 and 52 were observed in disability, HRQoL, and fatigue. Meaningful improvement was reported in work impairment. CONCLUSION: At week 52, over 60% of the UCanADA patients had depressive symptoms significantly reduced, as well as HRQoL, fatigue symptoms, and work impairment improved. No new safety signals were detected.

Hospitalization With Clostridioides difficile in Pediatric Inflammatory Bowel Disease: a Population-Based Study.

OBJECTIVES: Several studies have demonstrated higher rates of Clostridioides difficile infection (CDI) in adults with inflammatory bowel disease (IBD). We conducted a population-based study comparing the risk of hospitalization with CDI in children with and without IBD. METHODS: Using health administrative data and validated algorithms, we identified all children (<16 years) diagnosed with IBD in 5 Canadian provinces, then age and sex matched to 5 children without IBD. Province-specific 5-year incidence rates of hospitalization with CDI were pooled and generalized linear mixed-effects models were used to estimate the crude incidence rate ratio (IRR) comparing (1) children with and without IBD and (2) children with Crohn disease and ulcerative colitis. Hazard ratios (HR) from Cox proportional hazards models adjusting for age, sex, rural/urban household, and income were pooled using fixed-effects models. RESULTS: The incidence rate of CDI identified during hospitalization was 49.06 [95% confidence interval (CI), 39.40-61.08] per 10,000 person-years (PY) in 3593 children with IBD compared to 0.39 (95% CI, 0.13-1.21) per 10,000 PY in 16,284 children without IBD (crude IRR, 133.4, 95% CI, 42.1-422.7; adjusted HR, 68.2, 95% CI, 24.4-190.4). CDI was identified less often in children with Crohn disease than ulcerative colitis (crude IRR, 0.51, 95% CI, 0.32-0.82; adjusted HR, 0.69, 95% CI, 0.46-1.05). CONCLUSIONS: Children with IBD have a markedly higher incidence of CDI identified during a hospitalization relative to children without IBD. Consequently, symptomatic children with IBD who are hospitalized should be screened for CDI.

Periodic Colonoscopies Are Associated with Improved Survival and Prognosis of Colorectal Cancer in Ulcerative Colitis.

BACKGROUND AND STUDY AIMS: This study aimed to identify whether ulcerative colitis (UC) patients who develop colorectal cancer (CRC) present at earlier stages of CRC and have improved survival if prior to their CRC diagnosis, they underwent intermittent follow-up colonoscopies compared to those who have no follow-up colonoscopies. METHODS: Patients with UC who developed primary CRC were identified using data provided by the Institute for Clinical Evaluative Sciences. We defined low-risk CRC stage as estimated 5-year survival ≥ 80% compared to high-risk CRC as 5-year survival < 80%. RESULTS: A total of 421 patients were identified with UC and CRC. The 15-year mortality rate was significantly higher in those who did not have follow-up colonoscopy (33/74; 44.6%) compared to the follow-up group (105/347; 30.3%) (p = 0.0172). Among the 219 patients with UC with staging information available, patients who did not have follow-up colonoscopy were more likely to present with high-risk CRC (24/31; 77.4%) compared with patients who had follow-up colonoscopies (88/188; 44.4%) (p = 0.0016). Those who underwent follow-up colonoscopies at average intervals ≤ 3 years presented with high-risk CRC 41.3% of the time, which was less than the 48.6% in those with less frequent colonoscopies and 77.4% in those with no follow-up (p = 0.0048). CONCLUSIONS: Patients with UC who underwent intermittent follow-up colonoscopies had CRC detected at earlier stages and improvement in all-cause mortality, compared to those who with no follow-up colonoscopies. This may support regular surveillance colonoscopies for patients with UC.

AGA Clinical Practice Update on Endoscopic Surveillance and Management of Colorectal Dysplasia in Inflammatory Bowel Diseases: Expert Review.

Improvements in disease management, as well as endoscopic technology and quality, have dramatically changed the way in which we conceptualize and manage inflammatory bowel disease-related dysplasia over the past 20 years. Based on evolving literature, we propose a conceptual model and best practice advice statements for the prevention, detection, and management of colorectal dysplasia in people with inflammatory bowel disease. This expert review was commissioned and approved by the American Gastroenterological Association Institute Clinical Practice Updates Committee and the American Gastroenterological Association Governing Board to provide timely guidance on a topic of high clinical importance to the American Gastroenterological Association membership. It underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Gastroenterology.

Effectiveness of Dose De-escalation of Biologic Therapy in Inflammatory Bowel Disease: A Systematic Review.

INTRODUCTION: De-escalation of biologic therapy is a commonly encountered clinical scenario. Although biologic discontinuation has been associated with high rates of relapse, the effectiveness of dose de-escalation is unclear. This review was performed to determine the effectiveness of dose de-escalation of biologic therapy in inflammatory bowel disease. METHODS: We searched EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials from inception to October 2019. Randomized controlled trials and observational studies involving dose de-escalation of biologic therapy in adults with inflammatory bowel disease in remission were included. Studies involving biologic discontinuation only and those lacking outcomes after dose de-escalation were excluded. Risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS: We identified 1,537 unique citations with 20 eligible studies after full-text review. A total of 995 patients were included from 18 observational studies (4 prospective and 14 retrospective), 1 nonrandomized controlled trial, and 1 subgroup analysis of a randomized controlled trial. Seven studies included patients with Crohn's disease, 1 included patients with ulcerative colitis, and 12 included both. Overall, clinical relapse occurred in 0%-54% of patients who dose de-escalated biologic therapy (17 studies). The 1-year rate of clinical relapse ranged from 7% to 50% (6 studies). Eighteen studies were considered at high risk of bias, mostly because of the lack of a control group. DISCUSSION: Dose de-escalation seems to be associated with high rates of clinical relapse; however, the quality of the evidence was very low. Additional controlled prospective studies are needed to clarify the effectiveness of biologic de-escalation and identify predictors of success.

Colonoscopy-guided therapy for the prevention of post-operative recurrence of Crohn's disease.

BACKGROUND: About half of patients with Crohn's disease (CD) require surgery within 10 years of diagnosis. Resection of the affected segment is highly effective, however the majority of patients experience clinical recurrence after surgery. Most of these patients have asymptomatic endoscopic recurrence weeks or months before starting with symptoms. This inflammation can be detected by colonoscopy and is a good predictor of poor prognosis.Therapy guided by colonoscopy could tailor the management and improve the prognosis of postoperative CD. OBJECTIVES: To assess the effects of prophylactic therapy guided by colonoscopy in reducing the postoperative recurrence of CD in adults. SEARCH METHODS: The following electronic databases were searched up to 17 December 2019: MEDLINE, Embase, CENTRAL, Clinical Trials.gov, WHO Trial Registry and Cochrane IBD specialized register. Reference lists of included articles, as well as conference proceedings were handsearched. SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-RCTs and cohort studies comparing colonoscopy-guided management versus management non-guided by colonoscopy. DATA COLLECTION AND ANALYSIS: Two review authors independently considered studies for eligibility, extracted the data and assessed study quality. Methodological quality was assessed using both the Cochrane 'Risk of bias' tool for RCTs and Newcastle-Ottawa scale (NOS) for cohort studies. The primary outcome was clinical recurrence. Secondary outcomes included: endoscopic, surgical recurrence and adverse events. We calculated the risk ratio (RR) for each dichotomous outcome and extracted the hazard ratio (HR) for time-to-event outcomes. All estimates were reported with their corresponding 95% confidence interval (CI). Data were analysed on an intention-to-treat (ITT) basis. The overall quality of the evidence was evaluated using GRADE criteria. MAIN RESULTS: Two RCTs (237 participants) and five cohort studies (794 participants) met the inclusion criteria. Meta-analysis was not conducted as the studies were highly heterogeneous. We included two comparisons. Intensification of prophylactic-therapy guided by colonoscopy versus intensification guided by clinical recurrence One unblinded RCT and four retrospective cohort studies addressed this comparison. All participants received the same prophylactic therapy immediately after surgery. In the colonoscopy-based management group the therapy was intensified in case of endoscopic recurrence; in the control group the therapy was intensified only in case of symptoms. In the RCT, clinical recurrence (defined as Crohn's Disease Activity Index (CDAI) > 150 points) in the colonoscopy-based management group was 37.7% (46/122) compared to 46.1% (21/52) in the control group at 18 months' follow up (RR 0.82, 95% CI: 0.56 to 1.18, 174 participants, low-certainty evidence). There may be a reduction in endoscopic recurrence at 18 months with colonoscopy-based management (RR 0.73, 95% CI 0.56 to 0.95, 1 RCT, 174 participants, low-certainty evidence). The certainty of the evidence for surgical recurrence was very low, due to only four cohort studies with inconsistent results reporting this outcome. Adverse events at 18 months were similar in both groups, with 82% in the intervention group (100/122) and 86.5% in the control group (45/52) (RR 0.95, 95% CI:0.83 to 1.08, 1 RCT, 174 participants, low-certainty of evidence).The most common adverse events reported were alopecia, wound infection, sensory symptoms, systemic lupus, vasculitis and severe injection site reaction. Perforations or haemorrhages secondary to colonoscopy were not reported. Initiation of prophylactic-therapy guided by colonoscopy versus initiation immediately after surgery An unblinded RCT and two retrospective cohort studies addressed this comparison. The control group received prophylactic therapy immediately after surgery, and in the colonoscopy-based management group the therapy was delayed up to detection of endoscopic recurrence. The effects on clinical and endoscopic recurrence are uncertain (clinical recurrence until week 102: RR 1.16, 95% CI 0.73 to 1.84; endoscopic recurrence at week 102: RR 1.16, 95% CI 0.73 to 1.84; 1 RCT, 63 participants, very low-certainty evidence). Results from one cohort study were similarly uncertain (median follow-up 32 months, 199 participants). The effects on surgical recurrence at a median follow-up of 50 to 55 months were also uncertain in one cohort study (RR 0.79, 95% CI 0.38 to 1.62, 133 participants, very low-certainty evidence). There were fewer adverse events with colonoscopy-based management (54.8% (17/31)) compared with the control group (93.8% (30/32)) but the evidence is very uncertain (RR 0.58, 95% CI 0.42 to 0.82; 1 RCT, 63 participants). Common adverse events were infections, gastrointestinal intolerance, leukopenia, pancreatitis and skin lesions. Perforations or haemorrhages secondary to colonoscopy were not reported. AUTHORS' CONCLUSIONS: Intensification of prophylactic-therapy guided by colonoscopy may reduce clinical and endoscopic postoperative recurrence of CD compared to intensification guided by symptoms, and there may be little or no difference in adverse effects. We are uncertain whether initiation of therapy guided by colonoscopy impacts postoperative recurrence and adverse events when compared to initiation immediately after surgery, as the certainty of the evidence is very low. Further studies are necessary to improve the certainty of the evidence of this review.

Combined Biologic and Immunomodulatory Therapy is Superior to Monotherapy for Decreasing the Risk of Inflammatory Bowel Disease-Related Complications.

BACKGROUND AND AIMS: The combination of infliximab and azathioprine is more efficacious than either therapy alone for Crohn's disease [CD] and ulcerative colitis [UC]. However, it is uncertain whether these benefits extend to real-world clinical practice and to other combinations of biologics and immunomodulators. METHODS: We collected health administrative data from four Canadian provinces representing 78 413 patients with inflammatory bowel disease [IBD] of whom 11 244 were prescribed anti-tumour necrosis factor [anti-TNF] agents. The outcome of interest was the first occurrence of treatment failure: an unplanned IBD-related hospitalization, IBD-related resective surgery, new/recurrent corticosteroid use or anti-TNF switch. Multivariable Cox proportional hazards modelling was used to assess the association between the outcome of interest and receiving combination therapy vs anti-TNF monotherapy. Multivariable regression models were used to assess the impact of choice of immunomodulator or biologic on reaching the composite outcome, and random effects generic inverse variance meta-analysis of deterministically linked data was used to pool the results from the four provinces to obtain aggregate estimates of effect. RESULTS: In comparison with anti-TNF monotherapy, combination therapy was associated with a significant decrease in treatment ineffectiveness for both CD and UC (CD: adjusted hazard ratio [aHR] 0.77, 95% confidence interval [CI] 0.66-0.90; UC: aHR 0.72, 95% CI 0.62-0.84). Combination therapy was equally effective for adalimumab and infliximab in CD. In UC azathioprine was superior to methotrexate as the immunomodulatory agent (aHR = 1.52 [95% CI 1.02-2.28]) but not CD (aHR = 1.22 [95% CI 0.96-1.54]). CONCLUSION: In an analysis of a database of real-world patients with IBD, combination therapy decreased the likelihood of treatment failure in both CD and UC.

Aortic Stiffening Is an Extraintestinal Manifestation of Inflammatory Bowel Disease: Review of the Literature and Expert Panel Statement.

Current guidelines state that systemic inflammation, together with endothelial dysfunction, calcification, and hypercoagulability, predispose to premature atherosclerosis in patients with inflammatory bowel disease (IBD). We assessed whether IBD can affect aortic stiffness, a well-recognized vascular biomarker and an independent risk factor for cardiovascular (CV) disease (CVD) in several populations. Recent studies reported that aortic stiffness is increased in adults with IBD compared with matched controls. This association is dependent on inflammatory burden and disease duration, and is reduced by antitumor necrosis factor therapy. Considered together, current findings suggest that increased aortic stiffness is an extraintestinal manifestation of IBD. This is clinically relevant since measuring aortic stiffness in patients with IBD could improve risk assessment, especially in those without established CVD. Moreover, effective control of inflammation could lower CV risk in patients with IBD by reducing aortic stiffness. Further longitudinal studies are needed to better clarify (i) the relationship between disease duration and irreversible changes of the arterial wall, (ii) the clinical characteristics of patients with IBD that have an increased arterial stiffness at least in part reversible, and (iii) whether arterial stiffness is useful to evaluate the efficacy of immunosuppressive therapy.

Risk of Venous Thromboembolism After Hospital Discharge in Patients With Inflammatory Bowel Disease: A Population-based Study.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with a high risk of venous thromboembolism (VTE) during hospitalization. It is unclear if this association persists after discharge. We aimed to assess the incidence of postdischarge VTE in IBD patients and to determine if IBD is associated with increased VTE risk. METHODS: We performed a population-based cohort study between 2002 and 2016 using Ontario health administrative data sets. Hospitalized (≥72 hours) adults with IBD were stratified into nonsurgical and surgical cohorts and matched on propensity score to non-IBD controls. Time to postdischarge VTE was assessed by Kaplan-Meier methods, and VTE risk was assessed by Cox proportional hazard models. RESULTS: A total of 81,900 IBD discharges (62,848 nonsurgical and 19,052 surgical) were matched to non-IBD controls. The cumulative incidence of VTE at 12 months after discharge was 2.3% for nonsurgical IBD patients and 1.6% for surgical IBD patients. The incidence increased in the nonsurgical IBD cohort by 4% per year (incidence rate ratio, 1.04; 95% CI, 1.02-1.05). In our propensity score-matched analysis, the risk of VTE at 1-month postdischarge was greater in nonsurgical IBD patients (hazard ratio [HR], 1.72; 95% CI, 1.51-1.96) and surgical patients with ulcerative colitis (HR, 1.68; 95% CI, 1.16-2.45) but not surgical patients with Crohn's disease. These trends persisted through 12 months. CONCLUSIONS: Nonsurgical IBD patients and surgical patients with ulcerative colitis are 1.7-fold more likely to develop postdischarge VTE than non-IBD patients. These findings support the need for increased vigilance and consideration of thromboprophylaxis in this population.

Longitudinal Trends in the Direct Costs and Health Care Utilization Ascribable to Inflammatory Bowel Disease in the Biologic Era: Results From a Canadian Population-Based Analysis.

OBJECTIVES: The prevalence of inflammatory bowel disease (IBD) is increasing. The total direct costs of IBD have not been assessed on a population-wide level in the era of biologic therapy. DESIGN: We identified all persons with IBD in Manitoba between 2005 and 2015, with each matched to 10 controls on age, sex, and area of residence. We enumerated all hospitalizations, outpatient visits and prescription medications including biologics, and their associated direct costs. Total and per capita annual IBD-attributable costs and health care utilization (HCU) were determined by taking the difference between the costs/HCU accrued by an IBD case and their controls. Generalized linear modeling was used to evaluate trends in direct costs and Poisson regression for trends in HCU. RESULTS: 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 per capita annual anti-tumor necrosis factor costs, which rose from $181 in 2005 to $5,270 in 2015. There was a significant decline in inpatient costs for CD ($99 ± 25/yr. P < 0.0001), but not for ulcerative colitis ($8 increase ±$18/yr, P = 0.63). DISCUSSION: 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. IBD-attributable hospitalization costs have declined modestly over time for persons with CD, although no change was seen for patients with ulcerative colitis.

Utilization of Diagnostic Imaging and Ionization Radiation Exposure Among an Inflammatory Bowel Disease Inception Cohort.

BACKGROUND: Abdominal imaging is important in managing inflammatory bowel disease (IBD). We characterized utilization of imaging and exposure to ionizing radiation. METHODS: We enumerated abdominal diagnostic imaging in a population-based cohort of IBD patients between 1994 and 2016. Trends in utilization of abdominal computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound were characterized. Cumulative doses of ionizing radiation were compared between IBD patients and non-IBD controls and between Crohn's disease (CD) and ulcerative colitis (UC) patients. Regression models were constructed to assess predictors of high ionizing radiation exposure. RESULTS: There were 72,933 incident cases of IBD. During the first 5 years of diagnosis, IBD patients were exposed to nearly 6-fold higher exposure to cumulative ionizing radiation attributable to abdominal imaging compared with non-IBD controls (18.6 mSv vs 2.9 mSv). Cumulative ionizing radiation exposure was higher in CD than UC (26.0 mSv vs 12.0 mSv; P < 0.001). Crohn's disease patients were more than twice as likely as UC patients to exceed 50 mSv (15.6% vs 6.2%; P < 0.001) and 100 mSV (5.0% vs 2.1%; P < 0.001). There was geographic variation in ionizing radiation exposure, and individuals of lower income were more likely to have high exposure. Utilization of abdominal MRI has increased substantially, peaking between 2007 and 2012 and increasing annually at 34%, which coincided with an annual 2% decline in the use of abdominal CT. CONCLUSIONS: Crohn's disease patients are at highest risk for high exposure to ionizing radiation, with a subgroup receiving potentially harmful levels. Increasing utilization and access to abdominal MRI may alleviate exposure.

The Impact of Inflammatory Bowel Disease in Canada 2018: Epidemiology.

Canada has among the highest incidence and prevalence of inflammatory bowel disease (IBD) in the world. After decades of rising incidence of IBD in Canada during the 20th Century, the prevalence of IBD in 2018 is 0.7% of the Canadian population. Forecasting models predict that prevalence of IBD will continue to rise to 1.0% of the population by 2030. In 2018, the number of Canadians living with IBD is approximately 270,000 and is predicted to rise to 403,000 Canadians in 2030. Inflammatory bowel disease affects all age groups with adolescents and young adults at highest risk of diagnosis. Canadians of all ethnicities are being diagnosed with IBD including known high-risk groups such as Ashkenazi Jews and offspring of South Asian immigrants who were previously thought to be low risk. Moreover, IBD has evolved into a global disease with rising incidence in newly industrialized countries in Asia and South America. The causes of IBD remain unsolved; however, the high rates of disease in Western countries and its emergence in newly industrialized countries suggest that environmental factors associated with urbanization, modernization, or Western diets may be pertinent to understanding the pathogenesis of the disease. HIGHLIGHTS: 1. Canada continues to have among the highest prevalence of IBD in the world.2. Today, approximately 270,000 Canadians live with IBD. By 2030 it is estimated that nearly 403,000 Canadians will have a diagnosis of IBD.3. Inflammatory bowel disease has become a worldwide disease with increasing rates in Asia, Africa, and South America-continents where IBD was rarely diagnosed prior to 1990.4. The causes of IBD are unknown, but the high rates of disease over the past 60 years in Western countries and the emergence of disease in developing countries suggest that factors associated with urbanization, modernization, or Western diets may be pertinent to understanding the pathogenesis of the disease.5. Many of the leading hypotheses as to the causes of IBD tie in with alteration of the gut microbiome, the suite of organisms that reside in the bowel and maintain bowel health throughout life. KEY SUMMARY POINTS: 1. The incidence (the number of new diagnoses annually) of IBD rose throughout the 20th century in Canada and then stabilized at the turn of the 21st century.2. The prevalence (the total number of diagnosed persons in the population) of IBD in Canada is among the highest in the world.3. Today, 270,000 (0.7%, or 7 in 1000) Canadians are estimated to live with IBD. By 2030, that number is expected to rise to 403,000 Canadians (1% or 1 in 100).4. Inflammatory bowel disease can be diagnosed at any age. However, the age groups that are most likely to be diagnosed are adolescents and young adults from 20 to 30 years of age.5. Inflammatory bowel disease in Canada affects the lives of Canadians of all ethnicities, including known high-risk groups such as Ashkenazi Jews, and those thought previously to be at low risk, such as first-generation offspring of South Asian immigrants.6. Canadian health policy makers will need to prepare the Canadian health care system for the rising burden of IBD.7. As newly industrialized countries in Asia, Africa, and South America are transitioning to a Westernized society, IBD has emerged and its incidence in these countries is rising rapidly.8. The gut microbiome includes microorganisms that maintain digestive health. Thus, changes in the microbiome, which may change the immune system's response to triggers, may be important in initiating and perpetuating IBD.9. A number of factors can alter the gut microbiome and early childhood may be a particularly important time such that breastfeeding, early life diet, use of antibiotics, infections, and other environmental exposures may impact the gut microbiome in such a way that facilitates developing IBD.10. Smoking is associated with an increased risk and worsening disease course of Crohn's disease. Quitting smoking is associated with an increased risk of developing ulcerative colitis. Therefore, never initiating smoking can mitigate the risk for IBD. Educational programs aimed at those at-risk for IBD should emphasize the risk of starting to smoke tobacco.11. Modifying exposure to environmental risk factors associated with the Westernization of society (e.g., Western diet and lifestyles) may provide an avenue for reducing the risk of IBD in Canada and worldwide. GAPS IN KNOWLEDGE AND FUTURE DIRECTIONS: 1. While the incidence of IBD appears to be stabilizing in some regions in Canada, IBD may be occurring more frequently in certain populations such as in children, South Asians, Ashkenazi Jews, and immigrants. Future research should focus on the changing demographics of IBD in Canada.2. The prevalence of IBD will rise steadily over the next decade. To enable better health care system planning and to respond adequately to the increasing burden of IBD, ongoing surveillance of the epidemiology and health services utilization of IBD in Canada is necessary.3. Most studies have focused on the mortality associated with IBD. Future research is necessary to assess health-adjusted life expectancy and overall life expectancy for those living with IBD.4. Analyses of resources, infrastructure, and personnel need to be modeled into the future in order to prepare our health care system for the rising burden of IBD.5. Research on the interaction between genes, microbes, and our environment will inform our understanding of the pathogenesis of IBD, information necessary to prevent IBD in the future.

The Impact of Inflammatory Bowel Disease in Canada 2018: Direct Costs and Health Services Utilization.

Direct health care costs of illness reflect the costs of medically necessary services and treatments paid for by public and private payers, including hospital-based care, outpatient physician consultations, prescription medications, diagnostic testing, complex continuing care, and home care. The costs of caring for persons with inflammatory bowel disease (IBD) have been rising well above inflation over the past fifteen years in Canada, largely due to the introduction and penetration of expensive biologic therapies. Changing paradigms of care toward frequent patient monitoring and achievement of stricter endpoints for disease control have also increased health services utilization and costs among IBD patients. While the frequency and costs of surgeries and hospitalizations have declined slightly in parallel with increased biologic use (due to better overall disease control), the direct medical costs of care for IBD patients are largely dominated by prescription drug costs. Introduction and penetration of biosimilar agents (at a markedly lower price point than the originator drugs) and increasing gastroenterologist involvement in the care of IBD patients may help to balance rising health care costs while improving health outcomes and quality of life for IBD patients. Ultimately, however, the predicted rise in the prevalence of IBD over the next decade, combined with increasing use of expensive biologic therapies, will likely dictate a continued rise in the direct costs of IBD patient care in Canada for years to come. In 2018, direct health care costs of IBD are estimated to be at least $1 billion Canadian dollars (CAD) and possibly higher than $2 billion CAD. HIGHLIGHTS: 1. In Canada, the direct cost of caring for people living with IBD is estimated in 2018 to be close to $1.28 billion (roughly $4731 per person with IBD).2. The costs of caring for people living with IBD are dominated by prescription drugs, followed by hospitalization costs. There has been a shift away from hospitalizations and toward pharmaceuticals as the predominant driver of direct health care costs in IBD patients, due to the introduction and widespread use of expensive biologic therapies.3. The rates of hospitalizations and major abdominal surgeries have been declining in IBD patients in Canada over the past two decades, possibly due to penetration of biologic therapies and advances in patient management paradigms.4. Inflammatory bowel disease patients cared for by gastroenterologists have better outcomes, including lower risks of surgery and hospitalization. Canadians who live in rural and underserviced areas are less likely to receive gastroenterologist care, potentially due to care preferences or poorer access, which may result in poorer long-term outcomes.5. Introduction of biosimilar agents at a lower price point than originator biologic therapies, increased gastroenterologist care of IBD patients, and improvements in IBD care paradigms may balance overall treatment costs while improving health outcomes and quality of life for IBD patients. However, in the long-term, direct costs of care may continue to increase, dictated by a rising IBD prevalence and increasing use of biologic therapies. KEY SUMMARY POINTS: 1. The costs of health care for patients with IBD are more than double those without IBD.2. Prescription drug use accounts for 42% of total direct costs in IBD patients, and costs to treat IBD continue to rise due to increased use of existing biologic therapies and the introduction of several new biologic therapies in recent years.3. In Manitoba, the mean health care utilization and medication costs for persons with IBD in the year before beginning anti-TNF therapy was $10,206 and increased to $44,786 in the first year of therapy.4. Biosimilar agents to anti-TNF drugs are now entering the Canadian marketplace and may result in cost savings in patients using biologic agents to treat their IBD.5. Timely gastroenterologist care has been associated with reduced risks of requiring surgery and emergency care among ambulatory IBD patients and a reduced risk of death among hospitalized patients with ulcerative colitis.6. Inflammatory bowel disease care provided by gastroenterologists has increased over the past two decades. Even then, the average time from symptom onset to IBD diagnosis exceeds six months, and only one-third of IBD patients receive continuing care with a gastroenterologist during the first five years following diagnosis.7. Senior (age ≥65), rural-dwelling, and non-immigrant IBD patients have less frequent gastroenterologist care than other groups.8. About one in five adults with Crohn's disease and one in eight adults with ulcerative colitis are hospitalized in Ontario every year. Hospitalizations are most common during the first year following IBD diagnosis. Children with IBD (age <18) have the highest rates of hospitalizations and hospital re-admissions.9. In Canada, 16% of patients hospitalized for Crohn's disease undergo an intestinal resection, and 11% of patients hospitalized for ulcerative colitis undergo a colectomy during their initial hospitalization. Rates of intestinal resection and colectomy are declining in Canada in persons with Crohn's disease and ulcerative colitis, respectively.10. In Ontario, one-third of adult-onset Crohn's disease patients undergo intestinal resection within ten years of diagnosis. Among Canadian children with Crohn's disease, approximately one in fifteen children will require intestinal surgery within the first year of diagnosis, and up to one-third will require surgery within ten years of diagnosis.11. In Ontario, the ten-year colectomy risk following ulcerative colitis diagnosis is 13.3% among young persons and adults and 18.5% among individuals with senior-onset ulcerative colitis. In children with ulcerative colitis, the risk of colectomy is 4.8% to 6% in the first year following diagnosis and increases to 15% to 17% by ten years. GAPS IN KNOWLEDGE AND FUTURE DIRECTIONS: 1. Forecasting models are necessary to predict the rising costs attributable to biologics associated with increasing prevalence of IBD, more frequent use of these medications, and the introduction of newer agents.2. Research into ways to minimize the escalating costs associated with increasing use of biologic therapies to treat IBD (and other chronic diseases) is necessary to ensure sustainability of our publicly funded health care system. Biosimilars offer an opportunity to drive down the cost of biologic therapies, and future research should assess the uptake of biosimilars as new biosimilars are introduced into the marketplace.3. Cost-utility models and budget impact analyses that integrate changes in direct costs (i.e., reduced hospitalizations and increased pharmaceutical costs) with indirect cost savings from improved quality of life are necessary to inform policy decisions.4. Research into ways to reduce IBD hospitalizations further through targeted outpatient interventions is equally important for health system sustainability and to improve patient quality of life.5. Research into reasons for reduced gastroenterologist care among rural and underserviced IBD residents would allow targeted interventions to improve specialist care and thereby improve patient health outcomes and quality of life.