Global Hospitalization Trends for Crohn's Disease and Ulcerative Colitis in the 21st Century: A Systematic Review With Temporal Analyses.

BACKGROUND & AIMS: The evolving epidemiologic patterns of inflammatory bowel disease (IBD) throughout the world, in conjunction with advances in therapeutic treatments, may influence hospitalization rates of IBD. We performed a systematic review with temporal analysis of hospitalization rates for IBD across the world in the 21st century. METHODS: We systematically reviewed Medline and Embase for population-based studies reporting hospitalization rates for IBD, Crohn's disease (CD), or ulcerative colitis (UC) in the 21st century. Log-linear models were used to calculate the average annual percentage change (AAPC) with associated 95% confidence intervals (95% CIs). Random-effects meta-analysis pooled country-level AAPCs. Data were stratified by the epidemiologic stage of a region: compounding prevalence (stage 3) in North America, Western Europe, and Oceania vs acceleration of incidence (stage 2) in Asia, Eastern Europe, and Latin America vs emergence (stage 1) in developing countries. RESULTS: Hospitalization rates for a primary diagnosis of IBD were stable in countries in stage 3 (AAPC, -0.13%; 95% CI, -0.72 to 0.97), CD (AAPC, 0.20%; 95% CI, -1.78 to 2.17), and UC (AAPC, 0.02%; 95% CI, -0.91 to 0.94). In contrast, hospitalization rates for a primary diagnosis were increasing in countries in stage 2 for IBD (AAPC, 4.44%; 95% CI, 2.75 to 6.14), CD (AAPC, 8.34%; 95% CI, 4.38 to 12.29), and UC (AAPC, 3.90; 95% CI, 1.29 to 6.52). No population-based studies were available for developing regions in stage 1 (emergence). CONCLUSIONS: Hospitalization rates for IBD are stabilizing in countries in stage 3, whereas newly industrialized countries in stage 2 have rapidly increasing hospitalization rates, contributing to an increasing burden on global health care systems.

Validation of stricture length, duration and obstructive symptoms as predictors for intervention in ileal stricturing Crohn's disease.

BACKGROUND: Risk factors for intervention in terminal ileal (TI) stricturing Crohn's disease (CD) are poorly defined. Novel and rigorous definitions for TI strictures recently became available. OBJECTIVE: We aimed to describe the rates of symptoms or need for endoscopic balloon dilation (EBD) or surgery as well as risk factors of progression in a well-defined stricturing CD cohort. METHODS: Consecutive adult patients with non-penetrating stricturing TI CD, as defined by centrally-read magnetic resonance enterography CONSTRICT criteria, were separated into a derivation and validation cohort. Clinical and imaging characteristics were collected following prespecified scoring conventions. Primary outcome was a composite endpoint of EBD or surgery ("intervention"). Multivariable analysis was performed. RESULTS: Eighty-six patients (48.8% female, median age 36 years) met selection criteria, 17.4% had prior EBD, 59.3% previously received biologics and 58.1% of strictures were anastomotic. Median follow-up was 63.4 [95% CI: 57, 68.9] months. In the derivation cohort, at 12 and 48 months, 26% and 45% of patients had intervention, respectively. Multivariable analysis showed obstructive symptoms (Hazard ratio [HR] 1.444; 95% CI 1.126-1.852), stricture duration (HR 0.974; 95% CI, 0.954-0.995) and length (HR 1.039; 95% CI, 1.011-1.069) predicted intervention. The concordance index for split-sample validation was 0.74 and 0.67, respectively. Biologics were not associated with intervention. An online risk calculator was constructed. CONCLUSION: In patients with TI stricturing CD, 26% and 45% required intervention at 1 and 4 years. Obstructive symptoms, stricture duration and length were independent and validated predictors of the need for intervention. These findings are important for clinical practice and aid in the design of future trials for CD strictures.

Patients With Inflammatory Bowel Disease on Treatment Have Lower Rates of Celiac Disease.

BACKGROUND: The association between celiac disease and inflammatory bowel disease (IBD) has been studied; however, the impact of IBD therapy on celiac disease is not known. Using a large database, we sought to describe the association of celiac disease and IBD and the impact of IBD treatment. METHODS: We queried a large multicenter database (Explorys Inc.), an electronic health record data aggregate from 26 American health care systems. We identified a cohort of patients with celiac disease and IBD between 1999 and 2020 and conducted a statistical analysis using a multivariate model. RESULTS: Of the 72,965,940 individuals in the database, 133,400 had celiac disease (0.18%), 191,570 (0.26%) had ulcerative colitis (UC), and 230,670 (0.32%) had Crohn disease (CD). Patients with IBD were more likely to have a diagnosis of celiac disease (odds ratio [OR], 13.680), with a greater association with CD. Treated patients with UC and with CD, respectively, had a lower risk association with celiac disease compared to those not undergoing IBD treatment, specifically corticosteroids (OR, 0.407 and 0.585), 5-aminosalicylates (OR, 0.124 and 0.127), immunomodulators (OR, 0.385 and 0.425), and anti-tumor necrosis factor drugs (OR, 0.215 and 0.242). There was no lower risk association in the vedolizumab group, but there was a higher risk association among the ustekinumab group. CONCLUSIONS: In this large dataset, we showed a bidirectional association between celiac disease and IBD that was stronger with CD. Patients with IBD treated using corticosteroids, 5-aminosalicylates, immunomodulators, or anti-tumor necrosis factor drugs had a lower association with celiac disease. Additional studies are required to determine the underlying mechanisms for IBD therapy-related modification of celiac disease incidence.

Optimal inflammatory bowel disease management during the global coronavirus disease 2019 pandemic.

PURPOSE OF REVIEW: This review aims to summarize the current evidence regarding the risks and implications of coronavirus disease 2019 (COVID-19) in patients with inflammatory bowel disease (IBD) and discuss optimal management of IBD during this pandemic. RECENT FINDINGS: Patients with IBD are not at increased risk of COVID-19 but several risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 infection) have been identified, such as active IBD, obesity, and corticosteroid use. COVID-19 outcomes are similar among patients with IBD and the overall population. Although biologics have not been shown to increase the risk of severe COVID-19 complications, several risk factors have been associated with negative COVID-19 outcomes in patients with IBD, including older age, obesity, the presence of comorbidities, active disease, and corticosteroid use. IBD therapy should, therefore, be continued with the aim of attaining or maintaining remission, except for corticosteroids, which should be held or reduced to the minimal effective dose. Although it has been recommended that immunosuppressive therapy be held during a case of COVID-19, the half-lives of these drugs and data on the timing of restarting therapy limit the strength of these recommendations. We recommend COVID-19 vaccination for IBD patients whenever available, as benefits to the individual and to society outweigh the risks. SUMMARY: As our understanding of SARS-CoV-2 and COVID-19 continues to evolve, we are learning more about its impact in patients with IBD and how to better manage patients in this setting. Managing IBD during this pandemic has also highlighted the importance of restructuring services in order to adapt to current and potential future outbreaks. The COVID-19 pandemic has transformed IBD care through the expansion of telemedicine and development of novel approaches to remote monitoring.

Gastrointestinal manifestations of COVID-19.

Gastrointestinal (GI) symptoms are seen in patients with COVID-19. The prevalence could be as high as 50%, but most studies show ranges from 16% to 33%. Presenting with GI symptoms increases the risk of testing positive for SARs-CoV-2. Approximately 50% of patients with COVID-19 have detectable virus in their stool. Having GI symptoms has been associated with more severe disease. Management of GI symptoms is mainly supportive. Healthcare providers should be aware of the GI manifestations of COVID-19 and perform SARS-CoV-2 testing for patients presenting with digestive changes, especially in those with respiratory symptoms.

Prevention and Treatment of Stricturing Crohn's Disease - Perspectives and Challenges.

Introduction: Fibrostenosis is a hallmark of Crohn's disease (CD), remains a challenge in today's clinical management of inflammatory bowel disease patients and represents a key event in the disease course necessitating improved preventative strategies and a multidisciplinary approach to diagnosis and management. With the advent of anti-fibrotic therapies and well-defined clinical endpoints for stricturing CD, there is promise to impact the natural history of disease.Areas covered: This review summarizes current evidence in the natural history of stricturing Crohn's disease, discusses management approaches as well as future perspectives on intestinal fibrosis.Expert opinion: Currently, there are no specific therapies to prevent progression to fibrosis or to treat it after it becomes clinically apparent. In addition to the international effort by the Stenosis Therapy and Anti-Fibrotic Research (STAR) consortium to standardize definitions and propose endpoints in the management of stricturing CD, further research to improve our understanding of mechanisms of intestinal fibrosis will help pave the way for the development of future anti-fibrotic therapies.

Systematic review with meta-analysis: efficacy of balloon-assisted enteroscopy for dilation of small bowel Crohn's disease strictures.

BACKGROUND: Evidence for endoscopic balloon dilation of small intestinal strictures in Crohn's disease (CD) using balloon-assisted enteroscopy is scarce. AIM: To evaluate endoscopic balloon dilation for the treatment of small intestinal CD strictures using balloon-assisted enteroscopy. METHODS: Citations in Embase, MEDLINE, and Cochrane were systematically reviewed. In a meta-analysis of 18 studies with 463 patients and 1189 endoscopic balloon dilations, technical success was defined as the ability to dilate a stricture. Individual data were also obtained on 218 patients to identify outcome-relevant risk factors. RESULTS: In the pooled per-study analysis, technical success rate of endoscopic balloon dilation was 94.9%, resulting in short-term clinical efficacy in 82.3% of patients. Major complications occurred in 5.3% of patients. During follow-up, 48.3% of patients reported symptom recurrence, 38.8% were re-dilated and 27.4% proceeded to surgery. On the per-patient-based multivariable analysis, that patients with disease activity in the small intestine had lower short-term clinical efficacy (odds ratio 0.32; 95% confidence interval 0.14-0.73, P = 0.007). Patients with concomitant active disease in the small and/or large intestine had an increased risk to proceed toward surgery (hazard ratio 1.85; 95% confidence interval 1.09-3.13, P = 0.02 and hazard ratio 1.77; 95% confidence interval 1.34-2.34, P < 0.001). CONCLUSIONS: Balloon-assisted enteroscopy for dilatation of CD-associated small intestinal strictures has high short-term technical and clinical efficacy and low complication rates. However, up to two-thirds of patients need re-dilation or surgery.

COVID-19 in patients with IBD and pancreaticobiliary disorders.

Evidence shows that COVID-19 can exacerbate symptoms of inflammatory bowel disease (IBD) and pancreaticobiliary disorders, and it is important to distinguish between an IBD exacerbation and symptoms caused by COVID-19. Although IBD does not appear to increase the risk for COVID-19 or worsen outcomes, corticosteroids can increase the risk and should be avoided when treating these patients. Pancreatic and biliary disease have been described in patients with COVID-19, but it is not clear whether COVID-19 induces these diseases. For facilities resuming endoscopic procedures, there are consensus guidelines for minimizing the COVID-19 transmission risks with these procedures.

Hepatic manifestations of COVID-19.

Patients with COVID-19 commonly have elevated liver enzyme levels, which is associated with adverse outcomes during hospitalization including increased risk of ICU admission, intubation, and mortality. When assessing these patients, it is important to consider causes of liver injury unrelated to COVID-19. Therapies for COVID-19 may increase liver enzyme levels but are not contraindicated in patients with baseline abnormal liver tests. Liver enzymes should be regularly monitored in all hospitalized patients with COVID-19. Patients with preexisting liver disease such as cirrhosis and those who have received a liver transplant may be an increased risk of severe COVID-19 outcomes.

Systematic review: medical therapy for fibrostenosing Crohn's disease.

BACKGROUND: Medical therapy and/or endoscopic balloon dilation with intralesional therapies are options for the treatment of small bowel fibrostenotic Crohn's disease (CD). AIM: To perform a systematic review summarising evidence for efficacy of systemic and endoscopic intralesional medical therapy in established small bowel strictures in adult CD patients. METHODS: A systematic search of MEDLINE, EMBASE, CENTRAL and Scopus was conducted. Primary outcomes were rates of surgical resection and repeat endoscopic dilation. Pooled event rates from random effects models across studies with 95% confidence intervals were reported. RESULTS: Ten studies describing systemic medical therapy and eight studies of intralesional injection were included. One randomised controlled trial each for systemic therapy and intrastricture injection were identified. Only observational studies were found for systemic biologic therapies, which exclusively included tumour necrosis factor (TNF) antagonists, while intralesional therapies all involved corticosteroids except for one study that evaluated infliximab. Pooled event rates for surgical resection after systemic and intralesional therapy were 28.3% (95% CI: 18.2%-41.3%) and 18.5% (95% CI: 8.3%-36.2%), respectively over a median follow-up of 23 months (range 5.5-105.8), and 21.8 months (range 5-47). Risk of repeat endoscopic balloon dilation in those with intralesional therapy was 58.3% (95% CI: 36.6%-77.3%) over a median follow-up of 21.8 months (range 5-47). CONCLUSIONS: There are no favoured therapies for patients with stricturing small bowel CD. Data are lacking for ustekinumab and vedolizumab. No endoscopic intralesional medications provided a clear benefit for prevention of repeat EBD or surgery.

Natural history, diagnosis and treatment approach to fibrostenosing Crohn's disease.

Stricturing Crohn's disease (CD) is a significant clinical problem. The presence of a stricture may be suggested by clinical symptoms. Cross-sectional imaging using computed tomography or magnetic resonance enterography is essential in diagnosing strictures as it allows further characterization and evaluation for complications such as abscess, fistulizing disease or malignancy. Managing small bowel stricturing CD should be approached in a multidisciplinary fashion. Medical therapy can be considered in strictures which are not associated with complications, with most of the data supporting anti-TNF strategies in this setting. If the disease is refractory to medical therapy, endoscopic therapy or surgery should be performed. Endoscopic balloon dilation (EBD) is an option for short, uncomplicated and straight strictures that are within reach of a colonoscope. Although EBD has good short-term outcomes, repeat dilation is often required. Surgical options mainly include resection and strictureplasty. Strictures refractory to medical therapy, not amenable or refractory to EBD, or associated with complications or malignancy should be managed surgically. However, surgery may also be considered at an earlier stage depending on disease characteristics and patient preference. Postoperative recurrence is common, highlighting the importance of careful monitoring of the patient postoperatively and optimization of medical management accordingly. There is a pressing need to develop anti-fibrotics for the treatment of stricturing CD. This requires the development of standardized diagnostic criteria, patient-reported outcome measures and validation of endpoints in fibrostenotic CD. The STAR consortium is pioneering this effort in order to allow development and testing of anti-fibrotics in future clinical trials.

Selective deletion of MyD88 signaling in α-SMA positive cells ameliorates experimental intestinal fibrosis via post-transcriptional regulation.

Intestinal fibrosis leading to strictures remains a significant clinical problem in inflammatory bowel diseases (IBD). The role of bacterial components in activating intestinal mesenchymal cells and driving fibrogenesis is largely unexplored. Tamoxifen-inducible α-SMA promoter Cre mice crossed with floxed MyD88 mice were subjected to chronic dextran sodium sulfate colitis. MyD88 was deleted prior to or after induction of colitis. Human intestinal myofibroblasts (HIMF) were exposed to various bacterial components and assessed for fibronectin (FN) and collagen I (Col1) production. RNA sequencing was performed. Post-transcriptional regulation was assessed by polysome profiling assay. Selective deletion of MyD88 in α-SMA-positive cells prior to, but not after induction of, experimental colitis decreased the degree of intestinal fibrosis. HIMF selectively responded to flagellin with enhanced FN or Col1 protein production in a MyD88-dependent manner. RNA sequencing suggested minimal transcriptional changes induced by flagellin in HIMF. Polysome profiling revealed higher proportions of FN and Col1 mRNA in the actively translated fractions of flagellin exposed HIMF, which was mediated by eIF2 alpha and 4EBP1. In conclusion, selectivity of flagellin-induced ECM secretion in HIMF is post-transcriptionally regulated. The results may represent a novel and targetable link between the gut microbiota and intestinal fibrogenesis.

Pilot Validation Study: Canadian Global Rating Scale for Colonoscopy Services.

Background. The United Kingdom Global Rating Scale (GRS-UK) measures unit-level quality metrics processes in digestive endoscopy. We evaluated the psychometric properties of its Canadian version (GRS-C), endorsed by the Canadian Association of Gastroenterology (CAG). Methods. Prospective data collection at three Canadian endoscopy units assessed GRS-C validity, reliability, and responsiveness to change according to responses provided by physicians, endoscopy nurses, and administrative personnel. These responses were compared to national CAG endoscopic quality guidelines and GRS-UK statements. Results. Most respondents identified the overarching theme each GRS-C item targeted, confirming face validity. Content validity was suggested as 18 out of 23 key CAG endoscopic quality indicators (78%, 95% CI: 56-93%) were addressed in the GRS-C; statements not included pertained to educational programs and competency monitoring. Concordance ranged 75-100% comparing GRS-C and GRS-UK ratings. Test-retest reliability Kappa scores ranged 0.60-0.83, while responsiveness to change scores at 6 months after intervention implementations were greater (P < 0.001) in two out of three units. Conclusion. The GRS-C exhibits satisfactory metrics, supporting its use in a national quality initiative aimed at improving processes in endoscopy units. Data collection from more units and linking to actual patient outcomes are required to ensure that GRS-C implementation facilitates improved patient care.

Timing of rebleeding in high-risk peptic ulcer bleeding after successful hemostasis: a systematic review.

BACKGROUND: Peptic ulcer rebleeding (PUR) usually occurs within three days following endoscopic hemostasis. However, recent data have increasingly suggested delayed rebleeding. OBJECTIVE: To better characterize the timing of PUR (Forrest Ia to IIb) following initially successful endoscopic hemostasis. METHODS: An exhaustive literature search (1989 to 2013), with cross-referencing, was performed to identify pertinent randomized controlled trial (RCT) arms. Patients receiving high-dose proton pump inhibitor (PPI) infusion following successful modern-day endoscopic hemostasis were included. A sensitivity analysis included any patients receiving PPI doses >40 mg daily. The main outcome measure was 30-day rebleeding, while weighted mean averages at t = three, seven, 14 and 28 to 30 days are also reported. RESULTS: Of 756 citations, six RCTs were included (561 patients; 58.5% to 89.5% male; 55.3 to 67.5 years of age). Among patients receiving high-dose PPI (five RCTs [393 patients]), 11.5% (95% CI 8.4% to 14.7%) experienced rebleeding, 55.6% (95% CI 41.1% to 70.1%) rebled within three days, 20% (95% CI 8.3% to 31.7%) between four and seven days, 17.8% (95% CI 6.6% to 28.9%) at eight to 14 days, and 6.7% (95% CI 0% to 14%) at 15 to 28 to 30 days. Using the relaxed lower PPI dosing threshold, similar respective rates were 14.4% (95% CI 11.5% to 17.3%) overall, with interval rates of 39.5% (95% CI 28.9% to 50.15%), 34.6% (95% CI 24.2% to 44.9%), 19.7% (95% CI 11% to 28.4%) and 6.2% (95% CI 0.95% to 11.5%). Qualitative review of patient characteristics, limited by small sample size, possible bias and study heterogeneity, suggested increased patient comorbidity and postendoscopic use of lower PPI dosing may predict delayed rebleeding. CONCLUSION: In patients with high-risk PUR undergoing successful endoscopic hemostasis, most rebled within three days, with many experiencing later rebleeding. Additional research is needed to better predict such an outcome.

Is routine second-look endoscopy effective after endoscopic hemostasis in acute peptic ulcer bleeding? A meta-analysis.

BACKGROUND: Routine second-look endoscopy in modern-era peptic ulcer bleeding (PUB) remains controversial. OBJECTIVE: To assess the effectiveness of routine second-look endoscopy in patients with PUB exhibiting high-risk stigmata after standard medical care and endoscopic therapy. DESIGN: Comprehensive literature searches (1990-2011) were performed, seeking randomized trials comparing a routine with an as-needed second endoscopy. MAIN OUTCOME MEASUREMENTS: The main outcome was rebleeding. Secondary outcomes were surgery and mortality. Subanalyses assessed the influence of study quality, rebleeding definitions, endoscopic hemostasis modality, and proton pump inhibitor (PPI) therapies. Analyses were performed with Revman 5.1. Results are shown as odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Only 4 published articles completely reporting studies and 4 abstracts (of 577 citations) were included (938 patients). Rebleeding was significantly decreased by a routine second-look endoscopy (OR 0.55; 95% CI, 0.37-0.81), as was surgery (OR 0.43; 95% CI, 0.19-0.96), but not mortality (OR 0.65; 95% CI, 0.26-1.62). Results remained robust with varying definitions of rebleeding, but not with varying endoscopic hemostasis modalities and PPI therapies; the only trial in which high-dose PPI was used did not show a benefit of a second-look endoscopy. When removing the 2 trials that included patients at highest risk of rebleeding, no significant benefit attributable to a second-look endoscopy was noted (OR 0.65; 95% CI, 0.42-1.00). LIMITATIONS: The small number of trials and patients in each of these studies. CONCLUSIONS: In the absence of high-dose PPI, especially in patients at very high risk (eg, active bleeding), routine second-look endoscopy appears effective in these selected patients with PUB. However, the generalizability of these results to the era of high-dose PPI and otherwise unselected patients with high-risk stigmata is unclear.