A novel smartphone application for the tracking of procedural numbers and trainee experience in gastrointestinal endoscopy.

OBJECTIVES: The tracking and documentation of procedures in gastrointestinal endoscopy including therapeutic interventions is an essential but challenging process. The University of Alberta has developed a smartphone app to help facilitate this task. This study evaluated the functionality, usefulness, and user satisfaction of this app. METHODS: Four Gastroenterology (GI) residents and two therapeutic endoscopy fellows participated in the study. The trainees submitted all their data into the app from the procedures in which they participated hands-on for one year, data was collected and analyzed on the app and the website associated with it. RESULTS: Trainees were able to register the procedures immediately after each procedure without difficulty, this data was available to be reviewed at anytime in the app and associated website. Furthermore, the data collected was able to be transformed into tables and graphs on the app website. The total number of procedures and therapeutic interventions performed were easily accessed in the app and website at anytime. The app facilitated the calculation of the cecal intubation rate in colonoscopy and the cannulation rate in ERCP for the therapeutic endoscopy trainee. Trainees reported excellent experience with the app capabilities. CONCLUSIONS: A novel smartphone app was useful in collecting meaningful data submitted by gastrointestinal endoscopy trainees, furthermore, through an associated website, it was capable to create graphs and tables to show and facilitate the calculation of meaningful data such as key performance indicators.

Pregnancy-Related Beliefs and Concerns of Inflammatory Bowel Disease Patients Modified After Accessing e-Health Portal.

OBJECTIVE: Poor inflammatory bowel disease (IBD)-specific reproductive knowledge is associated with concerns and medication noncompliance. Having shown an educational portal can improve knowledge, we evaluated its effectiveness for addressing IBD patients' reproductive and medication concerns. METHODS: Adult IBD participants (aged 18 to 45 years) were invited to access an e-health portal providing information on heritability, fertility, surgery, pregnancy outcomes, delivery, postpartum, and breastfeeding in the context of IBD and IBD medications. At pre-, post-, and 6+-month postintervention, participants completed a questionnaire on IBD-specific pregnancy concerns, medication concerns from the Beliefs About Medicines Questionnaire (BMQ), and medication adherence via the Medication Adherence Rating Scale (MARS). The Wilcoxon signed-rank test was used to compare median differences between scores (95% confidence). RESULTS: Demographics for 78 (70.3%) participants completing postintervention questionnaires: median age 29.3 (interquartile range: 25.6 to 32.9) years; 54 (69.2%) Crohn's disease; 21 (26.9%) ulcerative colitis; 63 (80.3%) females, 5 (7.9%) pregnant; and 19 (30.2%) previously pregnant. Postintervention, the median number of reproductive concerns decreased from 3 to 1, and remained stable 6+ months later (P < 0.001*). The median BMQ score decreased from 28 to 25, and remained stable 6+ months later (P = 0.032*). Participants adherent to medications increased from 82.4% to 87.8% postintervention (P = 0.099). CONCLUSION: Using an e-health portal may potentially reduce IBD-specific reproductive and medications concerns. An e-health portal is feasible as one component of managing IBD patient's reproductive and medication concerns during preconception and pregnancy.

Double-Balloon Endoscopy in Crohn Disease: A Tertiary Referral Center Experience.

BACKGROUND: Crohn disease (CD) affects the small bowel in 80% of patients. Double balloon endoscopy (DBE) provides the potential for direct and extensive mucosal visualization with the potential for diagnostic monitoring and therapeutic intervention. This study aimed to investigate the safety and effectiveness of DBE in small-bowel CD. METHODS: From our DBE database, patients with CD at the time of index DBE (January 2004-January 2013) were identified. Data collection included demographics, CD phenotype (age at diagnosis, disease location, disease activity), procedural information, adverse events (perforation, pancreatitis, death), therapeutic intervention (stricture dilation), and outcome (escalation or maintenance of existing therapy, referral to surgery). RESULTS: A total of 184 DBEs were performed in patients with inflammatory bowel disease over 162 endoscopic sessions. In this cohort, 115 patients had previously diagnosed CD. A diagnosis of CD was made in 22 patients. Of those with known CD, 140 DBEs were performed in 82 patients; DBE findings led to escalation of medical therapy in 26% of patients, maintenance of therapy in 26% of patients, and surgery in 18% of patients. We considered DBE to have failed in 11% (n = 18) of patients. During 46 endoscopic sessions, in 29 patients, 103 strictures were dilated via balloon dilation. Of patients undergoing dilation with clinical follow-up, 19 of 24 (79%) patients were surgery-free during the study period. Overall, there were 2 perforations. CONCLUSIONS: We found that DBE is a safe and effective procedure in patients with suspected or established CD. Furthermore, patients undergoing dilation of strictures via DBE had an 80% surgery-free rate within the follow-up period.

Preoperative Ustekinumab Treatment Is Not Associated With Increased Postoperative Complications in Crohn's Disease: A Canadian Multi-Centre Observational Cohort Study.

BACKGROUND: Ustekinumab (UST), an anti-IL12/23 inhibitor is indicated for moderate-to-severe Crohn's disease (CD). However, it is unclear if patients treated with UST are at increased risk for postoperative complications. AIM: To evaluate the postoperative safety outcomes in UST-treated CD patients. METHODS: A multicentre cohort study of UST-treated CD patients at two tertiary care centres (University of Calgary, University of Alberta, Canada) undergoing abdominal surgery between 2009 and 2016 was performed. Postoperative outcomes were compared against a control cohort of anti-TNF-treated patients over the same time-period. The primary outcome was occurrence of postoperative complications up to six months postoperatively, stratified by timing (early <30 days vs. late complications ≥30 days). RESULTS: Twenty UST-treated patients and 40 anti-TNF-treated patients were included with a median preoperative treatment exposure of 6.5 months and 18 months, respectively (p=0.01). Bowel obstruction was the most common surgical indication in both cohorts. UST-treated patients were more likely to require an ostomy (70.0% vs. 12.5%, p<0.001) and be on combination therapy with either systemic corticosteroids or concurrent immunomodulators (azathioprine or methotrexate) (25.0% vs. 2.5%, p=0.01). Despite the increased concomitant use of immunosuppression in the UST-treated cohort, there were no significant differences in early or late postoperative wound infections (1/20 in UST-cohort, 2/40 in anti-TNF cohort, p=1.00), anastomotic leak (0/20 in UST-cohort, 3/40 in anti-TNF cohort, p=0.54), or postoperative ileus/obstruction (3/20 in UST-cohort, 4/40 in anti-TNF cohort, p=0.67). CONCLUSIONS: CD patients receiving preoperative UST did not experience an increase in postoperative complications, despite increased use of concurrent immunosuppression.

Noninvasive Fecal Immunochemical Testing and Fecal Calprotectin Predict Mucosal Healing in Inflammatory Bowel Disease: A Prospective Cohort Study.

BACKGROUND: The noninvasive biomarkers fecal immunochemical testing (FIT) and fecal calprotectin (FCP) are sensitive for prediction of mucosal inflammation in inflammatory bowel disease. However, neither test has yet been shown to independently and accurately predict mucosal healing (MH). We aimed to assess the specificity of noninvasive FIT and FCP for MH prediction. METHODS: In this prospective cohort study of adult inflammatory bowel disease outpatients presenting for colonoscopy, stool samples for FIT and FCP were collected 48 hours before endoscopy. Using MH defined by Simple Endoscopic Score for Crohn's disease (SES-CD = 0), Rutgeert's score (i0), and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS = 3), receiver operator characteristic curves were plotted, and sensitivity, specificity, positive and negative predictive values, and areas under the curve were calculated. Multivariate logistic regression analysis was used to develop a clinical model for noninvasively predicting MH. RESULTS: Eighty patients (40 Crohn's disease and 40 ulcerative colitis) were enrolled. The specificities of FIT <100 ng/mL and FCP <250 µg/g for MH were 0.57 (95% confidence interval, 0.38-0.74) and 0.77 (0.57-0.89), respectively. Positive predictive values for MH for FIT <100 ng/mL and FCP <250 µg/g were 0.78 (0.64-0.87) and 0.77 (0.58-0.90), respectively. In multivariate modeling, combining FIT, FCP, and clinical symptomatic remission improved specificity for MH to 0.90 (0.72-0.97) with positive predictive values of 0.84 (0.60-0.96). Areas under the curve for FIT was higher for patients with ulcerative colitis (0.88) than for patients with Crohn's disease (0.69, P = 0.05). CONCLUSIONS: FIT and FCP have similar performance characteristics for identifying MH. Combined, low FIT, low FCP, and clinical remission are specific for MH.

Long-term Maintenance of Clinical, Endoscopic, and Radiographic Response to Ustekinumab in Moderate-to-Severe Crohn's Disease: Real-world Experience from a Multicenter Cohort Study.

BACKGROUND: Ustekinumab is a monoclonal antibody targeting interleukins 12 and 23. While effective in clinical trials for Crohn's disease (CD), long-term maintenance of response in the real-world setting is unclear. We aim to assess the efficacy of ustekinumab for maintaining clinical, endoscopic, and radiographic response in CD. METHODS: A retrospective multicenter cohort study was performed on patients with CD achieving steroid-free clinical response to ustekinumab induction, and advanced onto a regularly scheduled maintenance ustekinumab regimen between 2011 and 2016. The primary outcome was loss of response, defined by an increase in Harvey Bradshaw Index of >3 points from baseline requiring ustekinumab dose escalation, reinduction, rescue corticosteroids, immunomodulators, surgery, or ustekinumab discontinuation. Multivariate Cox proportional hazards regression was used to identify clinical factors associated with loss of response. RESULTS: One hundred four patients with CD achieving steroid-free response with ustekinumab induction were included; 92.3% (96/104) had previously failed antitumor necrosis factor therapy. Median follow-up was 57.2 weeks (interquartile range (IQR): 36.7-103.4). Cumulative probability of maintained response at 52 weeks was 71.8%. Sixty-seven patients (64.4%) maintained endoscopic or radiographic response. Thirty-five patients (33.7%) lost response at a median time of 47.4 weeks (IQR: 35.3-68.4). Dose escalation was required in 17 patients (16.3%); response was recaptured in 9/17 (52.9%). Nine patients (8.7%) required surgery. In Cox multivariate regression, concurrent immunomodulation was associated with reduced risk of loss of response (hazards ratio 0.39 (95% CI, 0.17-0.92)). CONCLUSIONS: Subcutaneous ustekinumab is an effective treatment option for maintaining long-term clinical, endoscopic, and radiographic response in patients with moderate-to-severe CD failing antitumor necrosis factor therapy.

Similar Clinical and Surgical Outcomes Achieved with Early Compared to Late Anti-TNF Induction in Mild-to-Moderate Ulcerative Colitis: A Retrospective Cohort Study.

Background. Biologic agents targeting tumor necrosis factor alpha are effective in the management of ulcerative colitis (UC), but their use is often postponed until after failure of other treatment modalities. Objectives. We aim to determine if earlier treatment with infliximab or adalimumab alters clinical and surgical outcomes in UC patients. Methods. A retrospective cohort study was conducted evaluating UC outpatients treated with infliximab or adalimumab from 2003 to 2014. Patients were stratified by time to first anti-TNF exposure; early initiation was defined as starting treatment within three years of diagnosis. Primary outcomes were colectomy, UC-related hospitalization, and clinical secondary loss of response. Kaplan-Meier analysis was used to assess time to the primary outcomes. Results. 115 patients were included (78 infliximab, 37 adalimumab). Median follow-up was 175.6 weeks (IQR 72.4-228.4 weeks). Fifty-seven (49.6%) patients received early anti-TNF therapy; median time to treatment in this group was 38.1 (23.3-91.0) weeks compared to 414.0 (254.0-561.3) weeks in the late initiator cohort (p < 0.0001). Patients treated with early anti-TNF therapy had more severe endoscopic disease at induction (mean Mayo endoscopy subscore 2.46 (SD ± 0.66) versus 1.86 (±0.67), p < 0.001) and trended towards increased risk of colectomy (17.5% versus 8.6%, p = 0.16) and UC-related hospitalization (43.9% versus 27.6%, p = 0.07). In multivariate regression analysis, early anti-TNF induction was not associated with colectomy (HR 2.02 [95% CI: 0.57-7.20]), hospitalization (HR 1.66 [0.84-3.30]), or secondary loss of response (HR 0.86 [0.52-1.42]). Conclusions. Anti-TNF therapy is initiated earlier in patients with severe UC but earlier treatment does not prevent hospitalization, colectomy, or secondary loss of response.

Anti-TNF Therapy Within 2 Years of Crohn's Disease Diagnosis Improves Patient Outcomes: A Retrospective Cohort Study.

BACKGROUND: Although biological agents targeting tumor necrosis factor (TNF) alpha are effective in the management of Crohn's disease (CD), use of anti-TNF agents is often delayed until after failure of other treatment modalities, resulting in potentially long delays between diagnosis and initiation of infliximab or adalimumab. We aim to determine if early treatment with anti-TNF agents reduces the rate of surgical resection and clinical secondary loss of response in CD patients. METHODS: A retrospective cohort study was conducted evaluating CD outpatients who were primary responders to anti-TNF therapy, on a maintenance regimen with infliximab or adalimumab from 2003 to 2014. Patients were stratified by time to first dose of anti-TNF therapy; early initiation was defined as starting anti-TNF therapy within 2 years of diagnosis. The primary outcome was occurrence of surgical resection or clinical secondary loss of response requiring dose escalation. Kaplan-Meier analysis was used to assess time to the primary outcomes. RESULTS: One hundred ninety CD patients met inclusion criteria (100 infliximab, 90 adalimumab). Median follow-up duration was 154.4 weeks (inter quartile range, 106.4-227.8). Fifty-three patients (27.9%) had early initiation of anti-TNF therapy. Fewer patients in the early initiation group required surgery (5.7% versus 30.7%, P < 0.001) or experienced clinical secondary loss of response (45.3% versus 67.2%, P = 0.006). In Kaplan-Meier analysis, early initiation of anti-TNF therapy prolonged time to surgery (P = 0.001) and secondary loss of response (P = 0.006). CONCLUSIONS: In CD patients, early initiation of infliximab or adalimumab within the first 2 years of diagnosis reduces the rate of surgery and secondary loss of response requiring dose escalation.

Lymphoproliferative disorders in inflammatory bowel disease patients on immunosuppression: Lessons from other inflammatory disorders.

Immunosuppressive agents, such as thiopurines, methotrexate, and biologics, have revolutionized the treatment of inflammatory bowel disease (IBD). However, a number of case reports, case control studies and retrospective studies over the last decade have identified a concerning link between immunosuppression and lymphoproliferative disorders (LPDs), the oncological phenomenon whereby lymphocytes divide uncontrollably. These LPDs have been associated with Epstein-Barr virus (EBV) infection in which the virus provides the impetus for malignant transformation while immunosuppression hampers the immune system's ability to detect and clear these malignant cells. As such, the use of immunosuppressive agents may come at the cost of increased risk of developing LPD. While little is known about the LPD risk in IBD, more is known about immunosuppression in the post-transplantation setting and the development of EBV associated post-transplantation lymphoproliferative disorders (PTLD). In review of the PTLD literature, evidence is available to demonstrate that certain immune suppressants such as cyclosporine and T-lymphocyte modulators in particular are associated with an increased risk of PTLD development. As well, high doses of immunosuppressive agents and multiple immunosuppressive agent use are also linked to increased PTLD development. Here, we discuss these findings in context of IBD and what future studies can be taken to understand and reduce the risk of EBV-associated LPD development from immunosuppression use in IBD.

A study investigating the association of dermatological and infusion reactions to infliximab and infliximab trough levels.

BACKGROUND: Although infliximab is an effective therapy for inflammatory bowel disease (IBD), it is associated with dermatological events and infusion reactions. It is not known whether a relationship between these adverse events (AEs) and infliximab trough levels (ITLs) exists. OBJECTIVES: To report the prevalence of infliximab-associated AEs in IBD patients receiving stable maintenance infliximab therapy, and to correlate ITLs with dermatological and infusion reactions to infliximab. METHODS: Adult IBD patients receiving stable maintenance infliximab therapy were recruited from the University of Alberta Infusion Clinic (Edmonton, Alberta). ITLs were measured in blood samples collected before infusion, and the patients' records were reviewed for dermatological and infusion reactions to infliximab. RESULTS: One-quarter (18 of 71 [25.4%]) of patients experienced dermatological or infusion reactions to infliximab: nine (12.7%) dermatological events and nine (12.7%) infusion reactions. The median ITL was similar among patients with and without these AEs (7.2 µg/mL [interquartile range (IQR) 2.0 µg/mL to 13.3 µg/mL] versus 6.6 µg/mL [IQR 3.2 µg/mL to 12.7 µg/mL]; P=0.648). The median ITL of patients who experienced infusion reactions (2.0 µg/mL [IQR 0.1 µg/mL to 5.7 µg/mL]) was lower than that of patients who experienced no such AEs (6.6 µg/mL [IQR 3.2 µg/mL to 12.7 µg/mL]; P=0.008]) and lower than that of patients who experienced dermatological AEs (13.3 µg/mL [IQR 8.8 µg/mL to 17.4 µg/mL]; P<0.001). CONCLUSION: One-quarter of IBD outpatients receiving stable maintenance infliximab therapy experienced dermatological and infusion reactions. Low ITLs were correlated with infusion reactions, and normal or high ITLs with dermatological events.

Outpatient Ulcerative Colitis Primary Anti-TNF Responders Receiving Adalimumab or Infliximab Maintenance Therapy Have Similar Rates of Secondary Loss of Response.

GOALS: To compare the proportion of secondary loss of response to adalimumab and infliximab during maintenance treatment of ulcerative colitis (UC) after primary response to induction therapy. BACKGROUND: The efficacy of anti-tumor necrosis factor-α (TNF-α) therapy used to maintain response in patients with UC after primary response to induction therapy wanes with time, resulting in secondary loss of response. METHODS: A retrospective cohort study evaluating anti-TNF-naive UC outpatients who were primary responders to adalimumab and infliximab induction therapy and who advanced onto a maintenance regimen with the respective anti-TNF agent from 2003 to 2013 was conducted. The primary outcome was the proportion of patients in each treatment group that had secondary loss of response. The secondary outcome was time to secondary loss of response, analyzed by the Kaplan-Meier method analysis. RESULTS: A total of 102 UC primary anti-TNF responders met inclusion criteria. Thirty-six patients (35.3%) were treated with adalimumab and 66 patients (64.7%) with infliximab. Mean follow-up was 139.0 weeks for adalimumab and 158.8 weeks for infliximab. A total of 21/36 (58.3%) adalimumab-treated patients and 39/66 (59.1%) infliximab-treated patients experienced a secondary loss of response during maintenance therapy. Mean time to secondary loss of response was similar for adalimumab (55.8 wk) and infliximab (59.4 wk) (P=0.82). Sex, extent of colitis, previous or concomitant azathioprine, and concurrent corticosteroids with anti-TNF induction were not associated with increased risk of secondary loss of response. CONCLUSIONS: In this real-life cohort of anti-TNF-naive primary responders with UC, the proportion of secondary loss of response and the time to secondary loss of response are similar for adalimumab and infliximab.

Crohn's disease outpatients treated with adalimumab have an earlier secondary loss of response and requirement for dose escalation compared to infliximab: a real life cohort study.

BACKGROUND: The efficacy of anti-tumor necrosis factor alpha agents in maintaining remission in Crohn's disease may wane over time, leading to secondary loss of response that can often be overcome with dose escalation. Comparison of secondary loss of response of adalimumab and infliximab during long-term treatment of CD in a real-life IBD clinic has not been previously evaluated. METHODS: A retrospective cohort study was conducted evaluating outpatients with CD on a maintenance regimen with adalimumab or infliximab from 200 to 2013 and who experienced a secondary loss of response. All infliximab-treated patients were anti-TNF naïve. Adalimumab-treated patients were stratified by prior anti-TNF exposure. Kaplan-Meier analysis was conducted to compare time to loss of response. RESULTS: 218 CD patients met inclusion criteria (117 infliximab, 101 adalimumab). Median follow-up duration was 170.0weeks for infliximab and 122.0weeks for adalimumab (p=0.61). The proportion of patients with secondary loss of response was similar for infliximab-treated - 51.3% (60/117) compared to adalimumab patients naïve to anti-TNF therapy - 60.5% (23/38) (p=0.32), and adalimumab patients with prior anti-TNF exposure - 65.1% (41/63) (p=0.08). Median time to secondary loss of response was longer for infliximab patients (99.3wk, IQR 55.7-168.5) compared to both adalimumab patients naïve to anti-TNF therapy (58.9wk, IQR 29.0-85.7) (p=0.03), and adalimumab patients with prior anti-TNF exposure (52.7wk, IQR 20.1-85.0) (p<0.001). CONCLUSIONS: Over 50% of CD patients treated with infliximab and adalimumab develop secondary loss of response. Time to loss of response was shorter in patients treated with adalimumab compared to those treated with infliximab. Prior anti-TNF exposure further accelerated time to loss of response.

Comparison of MR enteroclysis with video capsule endoscopy in the investigation of small-intestinal disease.

PURPOSE: To evaluate the diagnostic accuracy of MR enteroclysis and to compare it to video capsule endoscopy (VCE) in the analysis of suspected small-bowel disease. METHODS: We performed a retrospective analysis of 77 patients who underwent both MR enteroclysis and VCE and compared the findings of these studies with the findings of enteroscopy, surgery, or with the results of clinical follow-up lasting ≥2 years. RESULTS: Findings included malignant neoplasms (n = 13), benign neoplasms (n = 10), refractory celiac disease (n = 4), Crohn's disease (n = 2) and miscellaneous conditions (n = 10). Specificity of MR enteroclysis was higher than that of VCE (0.97 vs. 0.84, P = 0.047), whereas sensitivity was similar (0.79 vs. 0.74, P = 0.591). In 2/32 (6.3%) patients with both negative VCE and negative MR enteroclysis a positive diagnosis was established, compared to 5/11 (45.5%) patients in whom VCE was positive and MR enteroclysis was negative (likelihood ratio 8.1; P = 0.004), 9/11 (81.8%) patients in whom MR enteroclysis was positive and VCE was negative (likelihood ratio 23.5; P < 0.0001), and all 23 patients in whom both VCE and MR enteroclysis showed abnormalities (likelihood ratio 60.8; P < 0.0001). CONCLUSIONS: VCE and MR enteroclysis are complementary modalities. In our study-population, MR enteroclysis was more specific than VCE, while both produced the same sensitivity.

Lesions of T-cell-mediated kidney allograft rejection in mice do not require perforin or granzymes A and B.

Organ allograft rejection is strongly associated with the presence of alloreactive cytotoxic T cells but the role of cytotoxicity in the pathologic lesions is unclear. Previous studies showed that the principal lesions of kidney rejection - interstitial infiltration, tubulitis, and endothelial arteritis - are T-cell-dependent and antibody-independent. We studied the role of cytotoxic granule components perforin and granzymes A and B in the evolution of the T-cell-mediated lesions of mouse kidney transplant rejection. By real-time RT-PCR, allografts rejecting in wild-type hosts at days 5, 7, 21, and 42 showed massively elevated and persistent expression of perforin and granzymes A and B, but evolution of tubulitis and arteritis did not correlate with increasing granzyme or perforin expression. Allografts transplanted into hosts with disrupted genes for perforin or granzymes A and B showed no change in tubulitis, arteritis, or MHC induction. Thus the development of the histologic lesions diagnostic of T-cell-mediated kidney transplant rejection are associated with but not mediated by perforin or granzyme A or B. Together with previous graft survival studies, these results indicate that the granule-associated cytotoxic mechanisms of T cells are not the effectors of T-cell-mediated allograft rejection.