Initiation of vedolizumab did not provoke new-onset spondylarthritis in patients with inflammatory bowel disease: A prospective 24-week study with imaging assessments.

BACKGROUND: A temporal relationship between vedolizumab and new-onset spondyloarthritis (SpA) has been suggested. AIMS: We evaluated the relationship between vedolizumab initiation and development of new-onset SpA in patients with inflammatory bowel disease (IBD) through serial clinical evaluation and magnetic resonance imaging (MRI). METHODS: A single-centre prospective observational study of 24 patients with IBD. Patients were eligible if they had active ulcerative colitis or Crohn's disease (CD), were initiating vedolizumab, had no prior history of arthritis or SpA and were suitable for serial MRI. A rheumatologist performed clinical evaluation prior to the first dose and 8 and 24 weeks. Axial MRI was evaluated by a blinded central reader and performed at baseline 8 and 24 weeks. RESULTS: Nine tumor necrosis factor (TNF) inhibitor-naïve patients (4 male; mean age 53.2 years; 6 UC; 3 CD) and eight TNF inhibitor-experienced patients (7 male; mean age 48 years; 3 UC; 5 CD) completed all assessments. No patients developed new features of axial arthritis or features of peripheral SpA (inflammatory oligoarthritis, enthesitis, dactylitis, or psoriasis (nail, body, or scalp)). Both groups demonstrated a good intestinal response. CONCLUSION: Vedolizumab initiation did not induce new features of axial or peripheral SpA after 24 weeks of treatment in TNF inhibitor-experienced or TNF inhibitor-naive patients with IBD.

Impact of CYP2C19 metabolizer status on esophageal mucosal inflammation, acid exposure, and motility among patients on chronic proton-pump inhibitor therapy with refractory symptoms of gastroesophageal reflux disease.

Background: The extent of disease severity remains unclear among CYP2C19 rapid and ultra-rapid metabolizers with refractory symptoms of gastroesophageal reflux disease (GERD) on chronic proton-pump inhibitors (PPIs). Aims: To determine the impact of CYP2C19 metabolizer status in relation to chronic PPI therapy with a focus on the extent of esophageal inflammation, acid exposure, and motor function. Methods: This retrospective study included 54 patients with refractory GERD symptoms who underwent CYP2C19 genotyping for PPI metabolism, esophagogastroduodenoscopy, ambulatory pH study, and high-resolution esophageal manometry. Patients were divided into three groups: normal metabolizer (NM) group, intermediate metabolizer/poor metabolizer (IM/PM) group, and rapid metabolizer/ultra-rapid metabolizer (RM/UM) group. The Chi-square test was used to analyze categorical variables, and one-way ANOVA for comparing means. Results: Rapid metabolizer/ultra-rapid metabolizer (RM/UM) group more frequently had either Los Angeles grade C or D GERD (7/19, 36.8% vs 1/21, 4.8%, P = 0.011) and metaplasia of the esophagus (9/19, 47.4% vs 2/21, 9.5%, P = 0.007) when compared to the NM group. RM/UM group were more frequently offered dilatation for nonobstructive dysphagia (8/19, 42.1% vs 3/21, 14.3%, P = 0.049) and more exhibited a hypotensive lower esophageal sphincter (LES) resting pressure compared to the NM group (10/19, 52.6% vs 4/21, 19%, P = 0.026). All three groups exhibited comparable DeMeester scores when PPIs were discontinued 72 hours before the ambulatory pH study. Conclusion: CYP2C19 RMs and UMs on chronic PPI with refractory GERD symptoms exhibited greater esophageal mucosal inflammation, as observed both endoscopically and histologically, and more were found to have hypotensive LES resting pressures and more were offered esophageal dilatation.

Cannabis Use in Patients With Inflammatory Bowel Disease Following Legalization of Cannabis in Canada.

Background: Cannabis is used by patients with Crohn's disease (CD) and ulcerative colitis (UC) as an alternative to, or in combination with, conventional therapies to treat symptoms such as abdominal pain, poor sleep, and reduced appetite. The clinical efficacy of cannabis for these disorders is controversial, with some studies showing harmful outcomes associated with its use. Previous studies suggest that cannabis is used by ~12% of patients with UC and ~16% of patients with CD in the USA despite legal prohibition. Methods: We conducted a prospective cohort study of adult patients with inflammatory bowel diseases (IBD) followed in a Canadian tertiary care center. Patients completed an online 40-question survey that included demographics, IBD disease history, cannabis use, and the Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Results: Completed surveys were obtained from 254 participants (148 with CD, 90 with UC, and 16 with indeterminate colitis). Recent cannabis use was reported by 41% of CD and 31% of UC participants. Interestingly, only 46% of participants who used cannabis discussed their use with their physician. Participants who recently used cannabis reported more abdominal pain, poor appetite, and flatulence, and importantly this was associated with lower SIBDQ scores (recent use 37 vs non-recent use 40). Conclusions: Cannabis use among patients with IBD has more than doubled since its legalization. Cannabis use is associated with worse abdominal symptoms and quality of life. Physicians should inquire about cannabis use and optimize symptom control with evidence-based therapies.

Clinical, Endoscopic, and Radiological Effectiveness of Ustekinumab in Bio-naïve Versus Bio-experienced Patients With Crohn's Disease: Real-world Experience From a Large Canadian Center.

INTRODUCTION: With the expanding therapeutic armamentarium for inflammatory bowel disease (IBD), real-world data may help inform drug positioning. We assessed clinical, endoscopic, imaging, and biochemical response/remission outcomes in patients with Crohn's disease (CD) treated with ustekinumab in a large Canadian IBD center. METHODS: A retrospective cohort study of CD patients was treated with ustekinumab. Clinical, endoscopic, radiological, and biochemical response and remission outcomes were stratified by prior biologic exposure status. Hazard ratios for biologic exposure status were estimated using Cox proportional hazard models and subgroup-specific incidence rates for healing. RESULTS: A total of 231 patients (55.9% female, median 45.8 years) were identified as receiving ustekinumab during the study period, with 2 patients subsequently excluded (N = 229). Of these patients, 79.0% (181 of 229) were bio-experienced, with 38.7% (70 of 181) having failed 1 biologic and 61.3% (111 of 181) having failed ≥2 biologics. At 3 months of follow-up after induction, clinical remission (Harvey-Bradshaw Index ≤4) was achieved by 59.1% (62 of 105) of bio-experienced patients and 79.4% (27 of 34) of bio-naïve patients (relative risk [RR], 1.34; 95% CI, 1.06-1.70; P = .013). Endoscopic remission (absence of mucosal ulcers) was achieved in 37.9% (33 of 87) cases. Rate of endoscopic healing (either endoscopic response or remission) per 1000 person-months was 72.7 (95% CI, 42.4-125.1) and 50.2 (37.9-66.4); and the median time to endoscopic response was 8.4 months (95% CI, 6.4-9.8) and 15.4 months (95% CI, 10.3-17.9) in bio-naïve vs bio-experienced patients, respectively. Imaging response/remission and steroid-free remission rates were higher in bio-naïve patients. CONCLUSION: In this large real-world cohort of CD patients with complex phenotypes and high rates of prior biologic exposure, we observed that ustekinumab was effective and safe with higher rates of improvement in bio-naïve subjects across a range of end points.

In this large real-world study of patients with Crohn's Disease treated with ustekinumab, we observed high rates of clinical, endoscopic, radiological, and biochemical response and remission rates. Effectiveness was greater in bio-naïve compared with bio-experienced patients.

Impact of inflammatory bowel disease on student experience in postsecondary education.

Objectives: This literature review seeks to identify based on the current literature how the burden of disease for IBD patients manifests itself as this cohort transitions simultaneously from pediatric to adult care and from secondary to post-secondary education. Methods: This paper reviews the current literature regarding postsecondary students with IBD and provides a summary of research regarding key factors in their quality of experience. The research was conducted through databases including Taylor & Francis, PubMed, as well as searches via Google Scholar. Results: Over the course of this search, thirty-three relevant studies were identified. These studies addressed the themes outlined in this paper, including academic performance, social adaptation, transition of care, as well as overall transition to a postsecondary institution. Each of these is further broken down to identify specific determinants of IBD student experience. Conclusions: Although students with IBD can demonstrate resilience and adaptive behavior, the evidence suggests there are significant limitations impacting their perceived experience. The barriers IBD students face impact their ability to experience postsecondary education as they intend to, forcing them to adjust in adaptive or maladaptive manners. This review also attempts to generate possible solutions to specific barriers identified from current research, generating directions of action for students, physicians, and academic supports.

High oncostatin M predicts lack of clinical remission for patients with inflammatory bowel disease on tumor necrosis factor α antagonists.

The interleukin-6 family cytokine, oncostatin-M (OSM) has been associated with response to tumor necrosis factor-α antagonists (anti-TNFs) in small cohorts of patients with inflammatory bowel disease (IBD). We aimed to evaluate the association between plasma OSM concentrations and response to anti-TNFs (infliximab and adalimumab) in both ulcerative colitis (UC) and Crohn's disease (CD). A retrospective cohort study was conducted in patients with IBD with a history of anti-TNF exposure. Blood samples, collected prior to anti-TNF exposure, were analyzed by enzyme-linked immunosorbent assay for the presence and quantity of OSM. Clinical remission was assessed at 1-year post anti-TNF exposure in addition to the occurrence of surgery, hospitalization, corticosteroid use, and adverse drug events. Lastly the threshold OSM plasma concentration associated with anti-TNF non-response was assessed by receiver operator characteristic (ROC) curve analysis. Patients with IBD (CD, n = 82; UC, n = 40) were assessed. In both UC and CD, mean pre-treatment OSM concentrations were significantly lower in those who achieved clinical remission at 1-year (p < 0.0001). A threshold plasma OSM concentration of 168.7 pg/ml and 233.6 pg/ml respectively separated those who achieved clinical remission at 1-year on an anti-TNF from those who did not in CD and UC respectively (CD: area under the receiver operator characteristic curve, AUROC = 0.880, 95% CI 0.79-0.96; UC: AUROC = 0.938, 95% CI 0.87-1.00). High OSM concentrations were associated with anti-TNF discontinuation and use of rescue steroids in CD and UC. High pre-treatment OSM concentrations identify IBD patients at-risk of anti-TNF non-response at 1-year as well as other deleterious clinical outcomes.

A Multicenter Randomized Controlled Trial Comparing Two Bowel Cleansing Regimens for Colonoscopy After Failed Bowel Preparation.

BACKGROUND & AIMS: Failed bowel preparation for colonoscopy occurs commonly, but the optimal regimen for the subsequent attempt is unknown. High-volume preparations often are used but are not well studied. The objective of this study was to compare the efficacy, tolerability, and safety of 2 regimens for use after failed bowel preparation. METHODS: A multicenter, endoscopist-blinded randomized controlled trial was conducted in patients who previously failed bowel preparation despite adequate compliance. Patients were randomized to 1 of 2 split polyethylene glycol (PEG) regimens, preceded by 15 mg bisacodyl: PEG 2 L the evening before and 2 L the day of colonoscopy (PEG 2+2L+bisacodyl), or 4 L and 2 L (PEG 4+2L+bisacodyl). All patients followed a low-fiber diet on both the third and second day before the procedure, followed by a clear fluid diet the day before and the morning of the colonoscopy. The primary outcome was adequate bowel preparation, defined as a Boston Bowel Preparation Scale total score of 6 or higher, with all segment scores of 2 or higher. Secondary outcomes included adenoma detection rate, advanced adenoma detection rate, sessile serrated lesion detection, cecal intubation rate, tolerability, and adverse events. RESULTS: A total of 196 subjects were randomized at 4 academic centers in Canada (mean age, 60.7 y; SD, 11.4 y; 44.9% were women). There were no significant differences between the PEG 2+2L+bisacodyl and the PEG 4+2L+bisacodyl groups in achieving adequate bowel preparation (91.2% vs 87.6%; P = .44). There were no significant differences with regard to mean adenoma detection rate (37.4% vs 31.5%; P = .41), advanced adenoma detection rate (18.7% vs 11.2%; P = .16), sessile serrated lesion detection (8.8% vs 5.6%; P = .41), and cecal intubation rate (96.7% vs 92.1%; P = .19). The 2 regimens were similarly well tolerated, but PEG 2+2L+bisacodyl was associated with a higher willingness to repeat the bowel preparation (91.2% vs 66.2%; P < .001). CONCLUSIONS: Split-dose 4 L-PEG with 15 mg bisacodyl, along with dietary restrictions, has similar efficacy as a higher-volume preparation, and should be considered for patients who previously failed bowel preparation (ClinicalTrials.gov number, NCT02976805).

Pretreatment HLADQA1-HLADRB1 Testing for the Prevention of Azathioprine-Induced Pancreatitis in Inflammatory Bowel Disease: A Prospective Cohort Study.

INTRODUCTION: Azathioprine-induced pancreatitis is an idiosyncratic and unpredictable response, occurring in up to 7% of azathioprine-exposed patients with inflammatory bowel disease (IBD). The haplotype HLADQA1-HLADRB1*07:01A>C is strongly associated with azathioprine-induced pancreatitis in IBD. We aimed to evaluate whether pretreatment HLADQA1-HLADRB1*07:01A>C screening will reduce the risk of azathioprine-induced pancreatitis. METHODS: Participants with IBD were screened for HLADQA1-HLADRB1*07:01A>C, and participants with a variant genotype were excluded from azathioprine treatment. Wild-type participants were started on azathioprine and followed for 3 months. The incidence of pancreatitis was compared with unscreened historical controls. RESULTS: HLADQA1-HLADRB1*07:01A>C screening resulted in an 11-fold reduction in the incidence of azathioprine-induced pancreatitis (n = 1/328 or 0.30% vs n = 13/373 or 3.4%). In propensity score-matched cohorts (age and sex), HLA DQA1-HLADRB1*07:01A>C screening was significantly associated with a reduction in the incidence of AZA-induced pancreatitis independent of weight, glucocorticoid exposure, and smoking status (adjusted odds ratio = 0.075, 95% confidence interval = 0.01-0.58, P = 0.01). Up to 45% (n = 271/599) of participants were excluded from azathioprine therapy based on the haplotype in the HLADQA1-HLADRB1*07:01A>C-screened cohort. DISCUSSION: HLADQA1-HLADRB1*07:01A>C screening reduced the risk of azathioprine-induced pancreatitis; however, using this strategy to guide the use of azathioprine therapy in IBD may eliminate a large proportion of patients from being eligible for treatment with azathioprine. In regions where there is access to other IBD therapies, and given the short-term and long-term toxicities associated with azathioprine, HLADQA1-HLADRB1*07:01A>C-screening may be a clinically relevant strategy for enhancing the safe use of azathioprine in IBD. In addition, cost-effectiveness analyses are needed to further solidify the utility of HLADQA1-HLADRB1*07:01A>C screening in IBD populations.

Pancreatitis associated with azathioprine and 6-mercaptopurine use in Crohn's disease: a systematic review.

Thiopurines are proven agents in the treatment of Crohn's disease. While pancreatitis is recognised as an adverse event associated with therapy, the effect size and morbidity of thiopurine-induced pancreatitis is not known. The aim of this systematic review and meta-analysis was to quantify the risk of pancreatitis with azathioprine and 6-mercaptopurine (6-MP) within Crohn's disease. We searched six electronic databases from inception to 29 October 2019. The primary outcomes measures were the occurrence of pancreatitis. We calculated pooled OR with corresponding 95% CIs for risk of pancreatitis. A number needed to harm analysis was performed. The search identified 4418 studies, of which 25 randomised controlled trials met the criteria for inclusion. The number of patients treated with azathioprine to cause an episode of pancreatitis was 36 (induction of remission) and 31 (maintenance of remission). The risk of pancreatitis in patients receiving azathioprine across all contexts was 3.80%, compared with a control risk of 0.2% (placebo) and 0.5% (5-aminosalicylic acid agents). There was no difference seen between 6-MP and placebo, although this was a low certainty result due to imprecision from very low event numbers and patient numbers. There is a probably increased occurrence of pancreatitis when azathioprine is used in Crohn's disease (moderate certainty), with incidence overall approximately 3.8%. Most cases are mild and resolve on cessation of therapy and no mortality was reported. There was no increased occurrence seen when using 6-MP, although this is a low certainty finding. PROSPERO prior to the study (CRD42019138065).

Biopsies From Ascending and Descending Colon Are Sufficient for Diagnosis of Microscopic Colitis.

BACKGROUND & AIMS: Lymphocytic and collagenous colitis are types of microscopic colitis (MC) that commonly cause chronic watery diarrhea, but there are no macroscopic features of MC that can be detected during colonoscopy. Endoscopists therefore often collect multiple random colonic biopsies, potentially oversampling, increasing times of colonoscopy and slide review. We sought to identify sites from which biopsies could be taken and analyzed to identify patients with MC with a high level of sensitivity and determine the appropriate number of biopsies to take at these sites. METHODS: We performed a retrospective study using biopsies from 101 consecutive patients with MC (52 cases of collagenous colitis, 42 cases of lymphocytic colitis, 7 combined cases), without comorbidities, from 2017 through 2018. Slides were reviewed, and the proportion of biopsies that were diagnostic of MC were calculated at each biopsy site. RESULTS: The proportions of biopsy fragments from each site of the colon found to be positive for MC were as follows: cecum, 90.0%; ascending colon, 96.9%; hepatic flexure, 77.8%; transverse colon, 95.7%; splenic flexure, 75.0%; descending colon, 85.0%; sigmoid colon, 90.9%; and rectum, 82.2%. For biopsies labeled random, 95.7% were positive for MC. When findings from ascending and descending colon biopsies were combined, 100% of MC cases were detected. CONCLUSIONS: MC can be detected with certainty by analyzing biopsies from the ascending and descending colon. Fewer biopsies than were collected from our cases are sufficient for diagnosis. We propose a Western protocol (taking 2 biopsies from each of the ascending and descending colon) in evaluation of patients for MC.

Safety of Combination Biologic and Antirejection Therapy Post-Liver Transplantation in Patients With Inflammatory Bowel Disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) post-liver transplant (LT) may have bowel inflammation requiring biologic therapy. We aimed to evaluate the safety of combination biologic and antirejection therapy in IBD patients after LT from a tertiary center case series and an updated literature review. METHODS: Inflammatory bowel disease patients undergoing LT between 1985 and 2018 and requiring combination biologic and antirejection therapy post-LT were identified from the London Health Sciences Transplant Registry (Ontario, Canada). Safety outcomes were extracted by medical chart review. For an updated literature review, EMBASE, Medline, and CENTRAL were searched to identify studies evaluating the safety of combination biologic and antirejection therapy in IBD patients. RESULTS: In the case series, 19 patients were identified. Most underwent LT for primary sclerosing cholangitis (PSC; 14/19, 74%) treated with anti-integrins (8/19, 42%) or tumor necrosis factor α (TNF) antagonists (6/19, 32%). Infections occurred in 11/19 (58%) patients, most commonly Clostridium difficile (4/19, 21%). Two patients required colectomy, and 1 patient required re-transplantation. In the literature review, 13 case series and 8 case reports reporting outcomes for 122 IBD patients treated with biologic and antirejection therapy post-LT were included. PSC was the indication for LT in 97/122 (80%) patients, and 91/122 (75%) patients were treated with TNF antagonists. Infections occurred in 32/122 (26%) patients, primarily Clostridium difficile (7/122, 6%). CONCLUSIONS: Inflammatory bowel disease patients receiving combination biologic and antirejection therapy post-LT appeared to be at increased risk of Clostridium difficile. Compared with the general liver transplant population in the published literature, there was no increased risk of serious infection.

Cannabis for the Treatment of Crohn's Disease and Ulcerative Colitis: Evidence From Cochrane Reviews.

BACKGROUND: We systematically reviewed the safety and effectiveness of cannabis and cannabinoids treatment for Crohn's disease (CD) and ulcerative colitis (UC). METHODS: MEDLINE, Embase, WHO ICTRP, AMED, PsychINFO, CENTRAL, ClinicalTrials.Gov, and the European Clinical Trials Register were searched for relevant studies. MAIN RESULTS: Five randomized controlled trials (3 CD and 2 UC studies, 185 participants) were included. One CD study (N = 21) showed 45% (5 of 11) of the cannabis cigarette group experienced clinical remission compared with 10% (1 of 10) of the placebo group (risk ratio [RR] 4.55; 95% CI, 0.63-32.56). Another CD study (N = 19) did not show significant rates of clinical remission. Forty percent (4 of 10) of participants in the cannabis oil group experienced remission compared with 33% (3 of 9) of the placebo group (RR 1.20; 95% CI, 0.36-3.97). A UC study (N = 60) did not have significant clinical remission rates. Twenty-four percent (7 of 29) of cannabis oil participants experienced remission compared with 26% (8 of 31) of placebo participants (RR 0.94; 95% CI, 0.39-2.25). A second UC study (N = 32) showed the effects on disease activity, C-reactive protein levels, and fecal calprotectin levels were uncertain. Adverse events were more prevalent in the cannabis groups for both CD and UC studies. GRADE analysis for the UC and CD studies ranged from very low to moderate. CONCLUSIONS: In summary, no firm conclusions can be made regarding the safety and effectiveness of cannabis and cannabinoids in adults with CD and UC.

Crohn's Disease Is Associated with Decreased CYP3A4 and P-Glycoprotein Protein Expression.

Cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) have broad substrate overlap and are involved in the metabolism and transport of nearly 50% of currently prescribed medications. In the intestine, CYP3A4 and P-gp are coexpressed in the enterocytes at the intestinal villous tip and act in a coordinated manner to limit drug and xenobiotic oral bioavailability prior to further metabolism and disposition in the liver. Crohn's disease (CD), a form of inflammatory bowel disease, introduces a transmural intestinal insult that disrupts the intestinal barrier function; it therefore has the potential to affect intestinal drug metabolism and transport. We hypothesized that individuals with CD have reduced intestinal expression of CYP3A4 and P-gp. We obtained intestinal biopsy samples from individuals with and without CD and quantified the expression of CYP3A4 and P-gp. When we carried out Western analysis for protein expression, we observed a significant reduction in ileal (45% decrease) and colonic (78% decrease) CYP3A4 protein expression in subjects with CD compared with those without. Similarly, an 85% reduction in colonic P-gp protein expression was seen in the CD patients. Our data highlight important and novel findings pertaining to CD-associated changes to the intestinal expression of CYP3A4 and P-gp that are of relevance to better predict substrate drug dosing for patients with CD.

Controversies in Inflammatory Bowel Disease: Exploring Clinical Dilemmas Using Cochrane Reviews.

A symposium organized by the Cochrane IBD Group and presented at the 2017 Digestive Disease Week annual meeting reviewed the recent literature on several controversial topics in inflammatory bowel disease (IBD) management including the efficacy of oral aminosalicylates for induction and maintenance of Crohn's disease (CD), the feasibility of drug withdrawal in patients with quiescent CD, and strategies for detecting colon cancer in patients with IBD. This article summarizes the data presented at that session.

Vedolizumab in Refractory Microscopic Colitis: An International Case Series.

BACKGROUND: Evidence for second-line therapy in patients with microscopic colitis [MC] failing budesonide is scarce, although anti-tumour necrosis factors [anti-TNFs], methotrexate and azathioprine have been reported to be effective in small cohort studies. Vedolizumab, a monoclonal antibody targeting α4ß7-integrin, prevents homing of T-cells to the gut. We evaluated clinical remission with vedolizumab in budesonide-refractory MC patients. METHODS: We solicited gastroenterologists in Europe and Canada for cases of MC treated with vedolizumab. Vedolizumab 300 mg IV was administered at weeks 0, 2 and 6, and then every 8 weeks. Clinical remission and histological remission were defined as less than three stools per day and normalization of histology, respectively, after induction treatment. RESULTS: Eleven cases were retrieved (nine females, lymphocytic colitis [LC] n = 5, collagenous colitis [CC] n = 6). Median [interquartile range] disease duration at vedolizumab initiation was 51 [29-70] months. Nine of 11 patients had failed one immunosuppressant and ten of 11 at least one anti-TNF agent. After three infusions of vedolizumab, clinical remission was observed in 5/11 patients [two LC and three CC] of whom three remained well with maintenance therapy [median duration of 13 months]. Biopsies were obtained from 9/11 patients. Histological remission was observed in 3/4 patients with clinical remission [2/3 CC, 1/1 LC] and 0/5 patients without clinical improvement. CONCLUSION: In a series of highly refractory MC patients, vedolizumab induced clinical remission in 5/11 subjects, of whom 75% showed normalized histology. Larger randomized trials are needed to assess the efficacy of vedolizumab in patients with MC.