Divine Tanyingoh

Effects of Concomitant Immunomodulator Therapy on Efficacy and Safety of Anti–Tumor Necrosis Factor Therapy for Crohn’s Disease: A Meta-analysis of Placebo-controlled Trials

BACKGROUND & AIMS There is debate over whether patients with Crohns disease who start anti-tumor necrosis factor (TNF) therapy after failed immunomodulator therapy should continue to receive concomitant immunomodulators. We conducted a meta-analysis of subgroups from randomized controlled trials (RCTs) of anti-TNF agents to compare the efficacy and safety of concomitant immunomodulator therapy vs anti-TNF monotherapy. METHODS We performed a systematic review of literature published from 1980 through 2008 and identified 11 RCTs of anti-TNF agents in patients with luminal or fistulizing Crohns disease. We excluded RCTs of patients who were naive to anti-TNF and immunomodulator therapy. The primary end points were clinical response at weeks 4-14 and 24-30 and remission at weeks 24-30. Secondary end points included infusion site or injection site reactions and selected adverse events. A priori subgroup analyses were performed to evaluate fistula closure and the efficacy and safety of combination therapy with different anti-TNF agents. RESULTS Overall, combination therapy was no more effective than monotherapy in inducing 6-month remission (odds ratio [OR], 1.02; 95% confidence interval [CI], 0.80-1.31), inducing a response (OR, 1.08; 95% CI, 0.79-1.48), maintaining a response (OR, 1.53; 95% CI, 0.67-3.49), or inducing partial (OR, 1.25; 95% CI, 0.84-1.88) or complete fistula closure (OR, 1.10; 95% CI, 0.68-1.78). In subgroup analyses of individual anti-TNF agents, combination therapy was not more effective than monotherapy in inducing 6-month remission in those treated with infliximab (OR, 1.73; 95% CI, 0.97-3.07), adalimumab (OR, 0.88; 95% CI, 0.58-1.35), or certolizumab (OR, 0.93; 95% CI, 0.65-1.34). Overall, combination therapy was not associated with an increase in adverse events, but inclusion of infliximab was associated with fewer injection site reactions (OR, 0.46; 95% CI, 0.26-0.79.) CONCLUSIONS On the basis of a meta-analysis, continued use of immunomodulator therapy after starting anti-TNF therapy is no more effective than anti-TNF monotherapy in inducing or maintaining response or remission. RCTs are needed to adequately assess the efficacy of continued immunomodulator therapy after anti-TNF therapy is initiated.

Trends in Epidemiology of Pediatric Inflammatory Bowel Disease in Canada: Distributed Network Analysis of Multiple Population-Based Provincial Health Administrative Databases

Objectives:The incidence of pediatric-onset inflammatory bowel disease (IBD) is increasing worldwide. We used population-based health administrative data to determine national Canadian IBD incidence, prevalence, and trends over time of childhood-onset IBD.Methods:We identified children <16 years (y) diagnosed with IBD 1999–2010 from health administrative data in five provinces (Alberta, Manitoba, Nova Scotia, Ontario, Quebec), comprising 79.2% of the Canadian population. Standardized incidence and prevalence were calculated per 100,000 children. Annual percentage change (APC) in incidence and prevalence were determined using Poisson regression analysis. Provincial estimates were meta-analyzed using random-effects models to produce national estimates.Results: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 (95% CI 9.11 to 10.25) per 100,000 children. Incidence was similar amongst most provinces, but higher in Nova Scotia. APC in incidence did not significantly change over the study period in the overall cohort (+2.06%, 95% CI −0.64% to +4.76%). However, incidence significantly increased in children aged 0–5y (+7.19%, 95% +2.82% to +11.56%). Prevalence at the end of the study period in Canada was 38.25 (95% CI 35.78 to 40.73) per 100,000 children. Prevalence increased significantly over time, APC +4.56% (95% CI +3.71% to +5.42%).Conclusions: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.

Ambient Ozone Concentrations and the Risk of Perforated and Nonperforated Appendicitis: A Multicity Case-Crossover Study

Background: Environmental determinants of appendicitis are poorly understood. Past work suggests that air pollution may increase the risk of appendicitis. Objectives: We investigated whether ambient ground-level ozone (O3) concentrations were associated with appendicitis and whether these associations varied between perforated and nonperforated appendicitis. Methods: We based this time-stratified case-crossover study on 35,811 patients hospitalized with appendicitis from 2004 to 2008 in 12 Canadian cities. Data from a national network of fixed-site monitors were used to calculate daily maximum O3 concentrations for each city. Conditional logistic regression was used to estimate city-specific odds ratios (ORs) relative to an interquartile range (IQR) increase in O3 adjusted for temperature and relative humidity. A random-effects meta-analysis was used to derive a pooled risk estimate. Stratified analyses were used to estimate associations separately for perforated and nonperforated appendicitis. Results: Overall, a 16-ppb increase in the 7-day cumulative average daily maximum O3 concentration was associated with all appendicitis cases across the 12 cities (pooled OR = 1.07; 95% CI: 1.02, 1.13). The association was stronger among patients presenting with perforated appendicitis for the 7-day average (pooled OR = 1.22; 95% CI: 1.09, 1.36) when compared with the corresponding estimate for nonperforated appendicitis [7-day average (pooled OR = 1.02, 95% CI: 0.95, 1.09)]. Heterogeneity was not statistically significant across cities for either perforated or nonperforated appendicitis (p > 0.20). Conclusions: Higher levels of ambient O3 exposure may increase the risk of perforated appendicitis.

979 Impact of Concomitant Immunomodulator Treatment on Efficacy and Safety of Anti-TNF Therapy in Crohn's Disease: A Meta-Analysis of Placebo Controlled Trials With Individual Patient-Level Data

Background: Objective markers of Crohns Disease (CD) activity have been sought as diagnostic, phenotypic, prognostic and disease activity markers. Complications such as stricture and fistula and characteristics such as TNF-antagonist responsiveness have been suggested as discreet mechanistic CD subtypes. This study explored the ability of genome wide expression profiling in whole blood to differentiate CD sub-populations. Methods: In the previously reported Phase 2b ustekinumab CERTIFI study of patients with moderate to severely active CDwho had failed or were intolerant to TNF-antagonists, whole blood samples were collected from a subset for mRNA expression profiling using Affymetrix HG-U133+ PM arrays. Baseline expression profiles were compared between patient sub-groups characterized by defined baseline disease attributes; and compared with those from samples obtained independently from healthy subjects. Expression modulations of .+/-1.5x and false discovery rate (FDR) p-value , 0.05 were considered significant. Results: Patients (n=204) with moderate to severe CD had significant expression modulations in 1725 transcripts in the whole blood compared with healthy subjects (n=49), including genes involved in inflammatory response and connective tissue disorders. A panel of 20 transcripts (including GAB2 and IL18R1) discriminated patients with only colonic (n=49) vs. strictly ileal (n=60) disease involvement. Significantly different expression modulations of 169, 321, and 151 transcripts, respectively, were identified in patients with high baseline CRP ( ≥10 mg/dL, n=97), fecal calprotectin (≥850 mg/g, n=80) or lactoferrin (. 100 mg/g, n=89) compared with patients with low baseline CRP ( ≤3 mg/dL, n=45), fecal calprotectin (≤250 mg/g, n=58), or lactoferrin (≤100 mg/g, n=107). As expected, patients with high baseline CRP, fecal calprotectin, or lactoferrin had elevated gene expressions in inflammatory pathways such as IL-6 and acute phase response signaling. In contrast, gene expression profiles did not differentiate between patients with different durations of disease (long [≥15yrs] vs. short [≤5yrs]); prior treatment response (Primary responder vs. non-responder) and treatment history (number of TNFs failed); and the presence or absence of complications (stricture/stenosis, fistula). Conclusion: Genomewide expression profiling of peripheral blood samples provides the understanding of CD at the molecular level in circulation. This is a new, non-invasive method that can be used to identify systemic markers of local pathological alterations in CD and to discriminate clinically between different CD sub-types. Table: Number of significant expression modulations between CD sub-populations

Clinic-based Point of Care Transabdominal Ultrasound for Monitoring Crohn’s Disease: Impact on Clinical Decision Making

BACKGROUND AND AIMS The use of cross-sectional imaging is important to characterise inflammatory bowel disease [IBD] activity, extent, and location and to exclude complications, regardless of symptoms. The aim of this study was to evaluate the impact of routine use of sonography in the management of inflammatory bowel disease. METHODS A total of 49 patients with Crohns disease were prospectively evaluated. Clinical symptoms (Harvey-Bradshaw Index [HBI]), disease character, serological markers of inflammation [C-reactive protein], and endoscopic evaluation were collected and reviewed by two independent IBD-specialty physicians. Clinical decisions regarding management were recorded. A separate, blinded physician then performed bowel ultrasound [US] and graded disease activity:] as inactive, mild, or active. A second blinded physician read and graded a sub-set of the US images. Clinical decisions of both IBD-physicians after US were independently recorded. Changes in clinical management following US information and inter-rater agreement on US disease activity parameters were evaluated. The concordance between US, CRP and clinical symptoms [HBI] were analysed. Follow-up data after US evaluation were collected. RESULTS Clinical decisions were changed after ultrasound assessment in 30/49 [60%] and 28/48 [58%] of cases, for each physician respectively [p < 0.0001 for each]. Many [59%] of the patients seen in clinic were asymptomatic with an HBI of 3 or less [n = 29]; however, 52% [n = 15] of these had active disease found on US, resulting in alterations in clinical management. The agreement in overall score between the US reviewers was good, ĸ = 0.749 [0.5814, 0.9180], p < 0.001. CONCLUSIONS Clinic-based point of care US can play a significant role in guiding therapeutic management and is an important adjunct to routine clinical and laboratory assessment.

The effects of pregnancy on the pharmacokinetics of infliximab and adalimumab in inflammatory bowel disease

Transplacental transfer of infliximab and adalimumab results in detectable drug levels in the cord blood and infant.

Corrigendum: 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.

Objectives:To determine the association between inflammatory bowel disease (IBD) and rural/urban household at the time of diagnosis, or within the first 5 years (y) of life.Methods:Population-based cohorts of residents of four Canadian provinces were created using health administrative data. Rural/urban status was derived from postal codes based on population density and distance to metropolitan areas. Validated algorithms identified all incident IBD cases from administrative data (Alberta: 1999–2008, Manitoba and Ontario: 1999–2010, and Nova Scotia: 2000–2008). We determined sex-standardized incidence (per 100,000 patient-years) and incident rate ratios (IRR) using Poisson regression. A birth cohort was created of children in whom full administrative data were available from birth (Alberta 1996–2010, Manitoba 1988–2010, and Ontario 1991–2010). IRR was calculated for residents who lived continuously in rural/urban households during each of the first 5 years of life.Results:There were 6,662 rural residents and 38,905 urban residents with IBD. Incidence of IBD per 100,000 was 33.16 (95% CI 27.24–39.08) in urban residents, and 30.72 (95% CI 23.81–37.64) in rural 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).Conclusions: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.

Intrapartum corticosteroid use significantly increases the risk of gestational diabetes in women with inflammatory bowel disease.

BACKGROUND AND AIMS Women with inflammatory bowel disease (IBD) may be at higher risk of adverse pregnancy outcomes. This study compared perinatal outcomes in women with and without IBD. METHODS The population-based Data Integration, Measurement, and Reporting (DIMR) administrative discharge database was used to identify women (≥18 years of age) in Alberta, Canada, with IBD who delivered a baby between 2006 and 2009 inclusive. Women without IBD were randomly sampled and matched in a 3:1 ratio to IBD cases by age at conception (±1 year). Odds ratios of gestational diabetes, preterm birth, low birth weight, cesarean section, and neonatal intensive care unit admission were calculated. RESULTS One hundred and sixteen IBD patients were age-matched to 381 pregnant women without IBD. Gestational diabetes, preterm birth, and cesarean section were more common in women with IBD compared with controls (6.9 versus 1.8%, p = 0.03; 12.9 versus 0.3%, p < 0.0001; 43.1 versus 21.0%, p = 0.009, respectively). On multivariate analysis, women with IBD were independently more likely to have gestational diabetes (odds ratio [OR] = 4.3; 95% confidence interval [CI] 1.2-16.3), preterm birth (OR = 19.7, 95% CI 2.2-173.9), and to deliver by cesarean section (OR = 2.7, 95% CI 1.6-4.6) after adjusting for age and smoking status. CONCLUSION Intrapartum corticosteroid use significantly increases the risk of gestational diabetes in women with IBD. Furthermore, IBD patients are at higher risk of preterm delivery and are more likely to undergo cesarean section compared with a healthy age-matched population. The finding of a higher risk of gestational diabetes is a novel finding not previously reported in the IBD literature.

Upper gastrointestinal bleeding due to peptic ulcer disease is not associated with air pollution: a case-crossover study.

BackgroundRecent studies have demonstrated an association between short-term elevations in air pollution and an increased risk of exacerbating gastrointestinal disease. The objective of the study was to evaluate if day-to-day increases in air pollution concentrations were positively associated with upper gastrointestinal bleeding (UGIB) secondary to peptic ulcer disease (PUD).MethodsA time-stratified case-crossover study design was used. Adults presenting to hospitals with their first UGIB secondary to PUD from 2004–2010 were identified using administrative databases from Calgary (n = 1374; discovery cohort) and Edmonton (n = 1159; replication cohort). Daily concentrations of ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide, and particulate matter (PM10 and PM2.5) were estimated in these two cities. Conditional logistic regression models were employed, adjusting for temperature and humidity. Odds ratios (OR) with 95 % confidence intervals (CI) were expressed relative to an interquartile range increase in the concentration of each pollutant.ResultsNo statistically significant associations were observed for any of the individual pollutants based on same-day, or 1-day lag effects within the Calgary discovery cohort. When the air pollution exposures were assessed as 3-, 5-, and 7-day averages, some pollutants were inversely associated with UGIB in the discovery cohort; for example, 5-day averages of nitrogen dioxide (OR = 0.68; 95 % CI: 0.53–0.88), and particulate matter <2.5 μm (OR = 0.75; 95 % CI: 0.61–0.90). However, these findings could not be reproduced in the replication cohort.ConclusionOur findings suggest that short-term elevations in the level of ambient air pollutants does not increase the incidence of UGIB secondary to PUD.

Mo1297 Mode of Delivery in Inflammatory Bowel Disease Patients: A Population-Based Study

disease. The 5-, 10-, and 20-year actuarial risk of colectomy was 2.6%, 4%, and 5% respectively. Of note, 48 patients (75%) received a proctocolectomy with ileo-anal anastomosis, and 12 (25%) developed a chromic recurrent pouchitis. In addition, more than 80% of patients received maintenance therapy with mesalazine at least 1.6 gr/daily, and 43% of patients used combined oral and topical (1-2/week) maintenance therapy. Male sex (hazard ratio [HR] = 3.5; 95% confidence interval [CI] 1.5-5.5) and pancolitis (HR = 2.5; 95% CI 1.2-4.3) were predictive for EC, after adjustment for confounders. Age at diagnosis older than 40 yrs (HR = 2.5; 95% CI 1.4-3.8) and intolerance/inefficacy of thiopurines (HR = 3.1; 95% CI 1.45.1) were predictive of LC. Conclusions: Colectomy was rather infrequent in our cohort, being more often performed for chronically active disease. The incidence of cancer an dysplasia was also low, probably because the extensive use and adherence to mesalazine maintenance therapy. The introduction of anti-TNF-alpha therapy in the last five years have not changed this figure so far.