Ustekinumab Does Not Increase Risk of Adverse Events: A Meta-Analysis of Randomized Controlled Trials.

GOALS AND BACKGROUND: Ustekinumab (UST) is a monoclonal antibody inhibitor of IL-12/IL-23 approved for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). We conducted a meta-analysis to compare rates of adverse events (AEs) in randomized controlled trials (RCTs) of UST for all indications. STUDY: A systematic search was performed of MEDLINE, Embase, and PubMed databases through November 2019. Study inclusion included RCTs comparing UST to placebo or other biologics in patients aged 18 years or older with a diagnosis of an autoimmune condition. RESULTS: Thirty RCTs with 16,068 patients were included in our analysis. Nine thousand six hundred and twenty-six subjects were included in the UST vs placebo analysis. There was no significant difference in serious or mild/moderate AEs between UST and placebo with an OR of 0.83 (95% CI 0.66, 1.05) and 1.08 (95% CI 0.99, 1.18), respectively, over a median follow-up time of 16 weeks. In a sub-analysis of CD and UC trials, no difference in serious or mild/moderate AEs in UST versus placebo was seen. CONCLUSIONS: UST was not associated with an increase in short-term risk of AEs.

Testing and Treating Small Intestinal Bacterial Overgrowth Reduces Symptoms in Patients with Inflammatory Bowel Disease.

BACKGROUND: Common mechanisms against small intestinal bacterial overgrowth (SIBO), including an intact ileocecal valve, gastric acid secretion, intestinal motility, and an intact immune system, are compromised in inflammatory bowel disease (IBD), and therefore, a relatively high incidence of SIBO has been reported in this population. AIMS: We aimed to determine whether an improvement in IBD clinical activity scores is seen after testing and treating SIBO. METHODS: A retrospective cohort study of 147 patients with inflammatory bowel disease who were referred for SIBO breath testing from 1/2012 to 5/2016 was performed. Characteristics of SIBO positive and treated patients were compared to SIBO negative patients, including the changes in Partial Mayo Score or Harvey Bradshaw Index (HBI), using Student's t test for continuous variables and Chi-squared or Fisher's exact test for categorical variables. RESULTS: 61.9% were SIBO positive and treated, and 38.1% were SIBO negative. In Crohn's disease, the median HBI decreased from 5 to 3 and 5 to 4, in the SIBO positive and negative groups, respectively (p = 0.005). In ulcerative colitis, the Partial Mayo Score decreased from 2 to 1.5 and 2 to 1, respectively (p = 0.607). CONCLUSIONS: This study examines the clinical effect of testing and treating for SIBO in an IBD population. We see a significant reduction in HBI after testing for and treating SIBO. Future prospective studies are necessary to further investigate the role of SIBO in the evaluation and management of IBD.

Id1 expression in endothelial cells of the colon is required for normal response to injury.

Inhibitor of DNA binding (ID)-1 is important for angiogenesis during embryogenesis and tumor development. Whether ID1 expression in endothelial cells of the colon is required for normal response to injury is unknown. We demonstrate that Id1 is up-regulated in colonic endothelial cells in an experimental model of colitis and in the inflamed mucosa of patients with inflammatory bowel disease. Because prostaglandin E2 and tumor necrosis factor-α are also elevated in colitis, we determined whether these factors could induce ID1 transcription in cultured endothelial cells. Tumor necrosis factor-α stimulated ID1 transcription via early growth response 1 protein (Egr-1). By contrast, the induction of ID1 by prostaglandin E2 was mediated by cAMP response element-binding protein (CREB). To determine whether the increased ID1 levels in the endothelial cells of inflamed mucosa were an adaptive response that modulated the severity of tissue injury, Id1 was conditionally depleted in the endothelium of mice, which sensitized the mice to more severe chemical colitis, including more severe diarrhea, bleeding, and histological injury, and shorter colon compared with control mice. Moreover, depletion of Id1 in the vasculature was associated with increased CD31(+) aggregates and increased vascular permeability in inflamed mucosa compared with those in Id1 wild-type control mice. These results suggest that endothelial ID1 up-regulation in inflamed colonic mucosa is an adaptive response that modulates the severity of tissue injury.

Exercise and Self-Reported Limitations in Patients with Inflammatory Bowel Disease.

BACKGROUND: Limited evidence suggests that exercise may have beneficial, anti-inflammatory effects in patients with inflammatory bowel disease (IBD). AIMS: The purpose of this study was to evaluate the prevalence of exercise in patients with IBD and the limitations they experience secondary to their disease. METHODS: Two hundred and fifty IBD patients were prospectively enrolled in this study at an academic medical center at the time of their outpatient visits between March and October 2013. Subjects were asked to complete a one-time survey that asks questions about medical and surgical history, exercise frequency and intensity, and the limitations and barriers they experience. RESULTS: Two hundred and twenty-seven patients (148 female patients) completed the survey. Crohn's disease was present in 140 patients (61.5 %), while 87 had ulcerative colitis. Forty-one patients (16.4 %) never exercised, 82 patients (32.8 %) exercised 1-2 times per week, 59 (23.6 %) exercised 3-4 times per week, and 45 (18.0 %) exercised more than four times per week. Of the 186 who regularly exercise, 95 (51 %) reported moderate exercise intensity, 61 (33 %) reported light intensity, and 30 (16 %) reported vigorous intensity. Ninety-nine patients (44 %) reported that their IBD limited their exercise for reasons including fatigue (n = 81), joint pain (n = 37), embarrassment (n = 23), weakness (n = 21), and others. CONCLUSIONS: Although they may benefit from exercise, IBD patients experience considerable barriers to regular exercise secondary to the relapsing and remitting nature of IBD. Larger studies are needed to determine the effects of exercise on disease symptomatology and activity.

S1P1 localizes to the colonic vasculature in ulcerative colitis and maintains blood vessel integrity.

Signaling through sphingosine-1-phosphate receptor1 (S1P1) promotes blood vessel barrier function. Degradation of S1P1 results in increased vascular permeability in the lung and may explain side effects associated with administration of FTY720, a functional antagonist of the S1P1 receptor that is currently used to treat multiple sclerosis. Ulcerative colitis (UC) is characterized by an increased density of abnormal vessels. The expression or role of S1P1 in blood vessels in the colon has not been investigated. In the present study, we show that S1P1 is overexpressed in the colonic mucosa of UC patients. This increase in S1P1 levels reflects increased vascular density in the inflamed mucosa. Genetic deletion of S1pr1 in mice increases colonic vascular permeability under basal conditions and increases bleeding in experimental colitis. In contrast, neither FTY720 nor AUY954, two S1P receptor-targeting agents, increases bleeding in experimental colitis. Taken together, our findings demonstrate that S1P1 is critical to maintaining colonic vascular integrity and may play a role in UC pathogenesis.

Low prevalence of coeliac disease in patients with systemic sclerosis: a cross-sectional study of a registry cohort.

OBJECTIVES: Two prior studies suggested that coeliac disease (CD) has a higher prevalence rate (8%) in SSc than in the general population (1%), but these studies were limited by small numbers and the use of traditional coeliac screening antibody tests, where newer ones with improved accuracy have since emerged. Our aim was to determine the prevalence of CD in a larger SSc population using a more modern serological approach to coeliac testing and to correlate coeliac antibody status with gastrointestinal symptoms. METHODS: Stored sera from 72 SSc patients in the Scleroderma Registry at the Hospital for Special Surgery were tested for anti-tissue transglutaminase (traditional) and anti-deamidated gliadin peptide (novel) antibodies. If any of these antibodies were positive, anti-endomysial antibodies were tested and confirmatory small-bowel endoscopy and biopsy were obtained. Registry clinical data were used to determine whether antibody status correlated with gastrointestinal symptoms. RESULTS: The prevalence of coeliac antibodies in our SSc population was 3/72 (4%). No significant differences with respect to gastrointestinal symptoms were seen in the coeliac antibody-positive compared with -negative SSc patients. No cases of confirmed CD were seen in our cohort. CONCLUSION: Contrary to the only two previously published studies, the low prevalence of CD that we found does not suggest that concurrent CD is a common cause of gastrointestinal complaints in SSc patients.

The impact of COVID-19 monoclonal antibodies on clinical outcomes: A retrospective cohort study.

PURPOSE: Despite progress in the treatment of coronavirus disease 2019 (COVID-19), including the development of monoclonal antibodies (mAbs), more clinical data to support the use of mAbs in outpatients with COVID-19 is needed. This study is designed to determine the impact of bamlanivimab, bamlanivimab/etesevimab, or casirivimab/imdevimab on clinical outcomes within 30 days of COVID-19 diagnosis. METHODS: A retrospective cohort study was conducted at a single academic medical center with 3 campuses in Manhattan, Brooklyn, and Long Island, NY. Patients 12 years of age or older who tested positive for COVID-19 or were treated with a COVID-19-specific therapy, including COVID-19 mAb therapies, at the study site between November 24, 2020, and May 15, 2021, were included. The primary outcomes included rates of emergency department (ED) visit, inpatient admission, intensive care unit (ICU) admission, or death within 30 days from the date of COVID-19 diagnosis. RESULTS: A total of 1,344 mAb-treated patients were propensity matched to 1,344 patients with COVID-19 patients who were not treated with mAb therapy. Within 30 days of diagnosis, among the patients who received mAb therapy, 101 (7.5%) presented to the ED and 79 (5.9%) were admitted. Among the patients who did not receive mAb therapy, 165 (12.3%) presented to the ED and 156 (11.6%) were admitted (relative risk [RR], 0.61 [95% CI, 0.50-0.75] and 0.51 [95% CI, 0.40-0.64], respectively). Four mAb patients (0.3%) and 2.64 control patients (0.2%) were admitted to the ICU (RR, 01.51; 95% CI, 0.45-5.09). Six mAb-treated patients (0.4%) and 3.37 controls (0.3%) died and/or were admitted to hospice (RR, 1.61; 95% CI, 0.54-4.83). mAb therapy in ambulatory patients with COVID-19 decreases the risk of ED presentation and hospital admission within 30 days of diagnosis.

A Case-Based Approach to Constipation in Primary Care.

Primary care physicians frequently evaluate patients with constipation. The history is crucial in uncovering warning symptoms and signs that warrant colonoscopy. Particular elements in the history and rectal examination also can provide clues regarding the underlying etiology. Regardless of etiology, lifestyle modifications, fiber, and laxatives are first-line therapies. Patients who fail first-line therapies can be offered second-line treatments and/or referred for testing of defecatory function. In those with severely refractory symptoms, referrals to a gastroenterologist and a surgeon should be considered.

The COVID-19 Army: Experiences From the Deployment of Non-Hospitalist Physician Volunteers During the COVID-19 Pandemic.

OBJECTIVE: New York City was the epicenter of the outbreak of the 2019 coronavirus disease (COVID-19) pandemic in the United States. As a large, quaternary care medical center, NYU Langone Medical Center was one of many New York medical centers that experienced an unprecedented influx of patients during this time. Clinical leadership effectively identified, oriented, and rapidly deployed a "COVID Army," consisting of non-hospitalist physicians, to meet the needs of the patient influx. We share feedback from our providers on our processes and offer specific recommendations for systems experiencing a similar influx in the current and future pandemics. METHODS: To assess the experiences and perceived readiness of these physicians (n = 183), we distributed a 32-item survey between March and June of 2020. Thematic analyses and response rates were examined to develop results. RESULTS: Responses highlighted varying experiences and attitudes of our frontline physicians during an emerging pandemic. Thematic analyses revealed a series of lessons learned, including the need to (1) provide orientations, (2) clarify roles/workflow, (3) balance team workload, (4) keep teams updated on evolving policies, (5) make team members feel valued, and (6) ensure they have necessary tools available. CONCLUSIONS: Lessons from our deployment and assessment are scalable at other institutions.

Baseline Oral 5-ASA Use and Efficacy and Safety of Budesonide Foam in Patients with Ulcerative Proctitis and Ulcerative Proctosigmoiditis: Analysis of 2 Phase 3 Studies.

BACKGROUND: Rectal budesonide foam is a second-generation corticosteroid efficacious for active mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis. This subgroup analysis examined the impact of baseline oral 5-aminosalicylic acid (5-ASA) on the efficacy and safety of budesonide foam in patients with mild to moderate ulcerative proctitis or ulcerative proctosigmoiditis. METHODS: Patients received budesonide foam 2 mg/25 mL twice daily for 2 weeks, then once daily for 4 weeks, or placebo, with or without continued stable dosing of baseline oral 5-ASAs, for remission induction at week 6 (primary endpoint) in 2 identically designed, randomized, double-blind, phase 3 studies. RESULTS: Of the 267 and 279 patients randomized to treatment with budesonide foam or placebo (pooled population), 55.1% and 55.2%, respectively, reported baseline 5-ASA use. A significantly greater percentage of patients achieved remission with budesonide foam versus placebo, either with (42.2% versus 31.8%, respectively; P = 0.03) or without (40.0% versus 14.4%; P < 0.0001) baseline 5-ASA use at week 6. A significantly greater percentage of patients achieved a Modified Mayo Disease Activity Index rectal bleeding subscale score of 0 at week 6, regardless of baseline 5-ASA use (5-ASA, 50.3% versus 35.7%; P = 0.003: no 5-ASA, 45.8% versus 19.2%; P < 0.0001). The frequency of adverse events was comparable between groups, regardless of baseline 5-ASA use. CONCLUSIONS: Budesonide foam was efficacious and safe for induction of remission of mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis in patients receiving oral 5-ASA at baseline and those who were not (Clinicaltrials.gov: NCT01008410 and NCT01008423).

Cirrhotic Patients Have Worse Bowel Preparation at Screening Colonoscopy than Chronic Liver Disease Patients without Cirrhosis.

BACKGROUND: Cirrhosis has been shown in small studies to be a predictor of suboptimal bowel preparation at screening colonoscopy. It has yet to be established whether patients with chronic liver disease in the absence of cirrhosis experience equally poor colon cleansing. Intestinal dysmotility related to cirrhosis might impair bowel preparation in this population more than those with chronic liver disease without cirrhosis. OBJECTIVE: This study compared the quality of bowel preparation in cirrhotic and non-cirrhotic patients with chronic liver disease and determined whether this influenced polyp detection rate. METHODS: A retrospective study of patients with chronic liver disease, both cirrhotic and non-cirrhotic, who underwent screening colonoscopy was performed. Patient characteristics, concomitant medication use, adequacy of bowel preparation, and the total number and types of polyps found were compared between cirrhotic and non-cirrhotic groups. RESULTS: 330 patients fulfilled inclusion criteria; 36% (n = 120) were cirrhotic. Cirrhotic patients had significantly worse bowel preparation scores compared with non-cirrhotics (mean 3.4 ± 1.1 vs. 3.7 ± 0.9, P = 0.003). Worse bowel preparation scores in cirrhotics vs. non-cirrhotics persisted despite controlling for age, sex, and concomitant diabetes mellitus (DM) (P = 0.0027). Among the cirrhotics, 48% had the lowest preparation scores compared with 30% of non-cirrhotics. No difference in polyp detection rate was found between cirrhotics and non-cirrhotics. Severity of cirrhosis as assessed by the MELD score did not predict worse bowel preparation. CONCLUSIONS: Cirrhotics have significantly worse bowel preparation scores compared to non-cirrhotics with chronic liver disease. No correlation between MELD score and bowel preparation score was observed in the cirrhotic cohort.

Cerebral venous thrombosis in inflammatory bowel disease.

Cerebral venous thrombosis (CVT) is a rare but devastating complication of inflammatory bowel disease (IBD). Here we describe six IBD patients with cerebral venous thrombosis. The patients presented with hours to days of headache and were found to have venous thrombosis on imaging. Four of the six patients had ulcerative colitis and two had Crohn's disease. All six patients were treated with therapeutic anticoagulation. There were two deaths; one patient became comatose and died despite anticoagulation while the other recovered well from the sinus thrombosis but died after a bowel perforation 3 weeks later. This case series demonstrates the critical need for early recognition of neurological symptoms in patients with IBD during disease flares. It is important to recognize the clinical signs in order to start anticoagulation expeditiously and improve neurological outcomes.

The Effect of Breathing, Movement, and Meditation on Psychological and Physical Symptoms and Inflammatory Biomarkers in Inflammatory Bowel Disease: A Randomized Controlled Trial.

BACKGROUND: This study evaluated the effects of the Breath-Body-Mind Workshop (BBMW) (breathing, movement, and meditation) on psychological and physical symptoms and inflammatory biomarkers in inflammatory bowel disease (IBD). METHODS: Twenty-nine IBD patients from the Jill Roberts IBD Center were randomized to BBMW or an educational seminar. Beck Anxiety Inventory, Beck Depression Inventory, Brief Symptom Inventory 18, IBD Questionnaire, Perceived Disability Scale, Perceived Stress Questionnaire, Digestive Disease Acceptance Questionnaire, Brief Illness Perception Questionnaire, fecal calprotectin, C-reactive protein, and physiological measures were obtained at baseline and weeks 6 and 26. RESULTS: The BBMW group significantly improved between baseline and week 6 on Brief Symptom Inventory 18 (P = 0.02), Beck Anxiety Inventory (P = 0.02), and IBD Questionnaire (P = 0.01) and between baseline and week 26 on Brief Symptom Inventory 18 (P = 0.04), Beck Anxiety Inventory (P = 0.03), Beck Depression Inventory (P = 0.01), IBD Questionnaire (P = 0.01), Perceived Disability Scale (P = 0.001), and Perceived Stress Questionnaire (P = 0.01) by paired t tests. No significant changes occurred in the educational seminar group at week 6 or 26. By week 26, median C-reactive protein values decreased significantly in the BBMW group (P = 0.01 by Wilcoxon signed-rank test) versus no significant change in the educational seminar group. CONCLUSIONS: In patients with IBD, participation in the BBMW was associated with significant improvements in psychological and physical symptoms, quality of life, and C-reactive protein. Mind-body interventions, such as BBMW, which emphasize Voluntarily Regulated Breathing Practices, may have significant long-lasting benefits for IBD symptoms, anxiety, depression, quality of life, and inflammation. BBMW, a promising adjunctive treatment for IBD, warrants further study.

Early referral for esophageal pH monitoring is more cost-effective than prolonged empiric trials of proton-pump inhibitors for suspected gastroesophageal reflux disease.

INTRODUCTION: The most cost-effective diagnostic algorithm for gastroesophageal reflux disease (GERD) remains controversial. We hypothesized that prompt referral for esophageal pH monitoring is more cost-effective than prolonged empiric courses of proton-pump inhibitors (PPIs). DISCUSSION: A cost model was created based on a cohort of 100 patients with possible GERD who underwent pH monitoring. The additional costs incurred from pH monitoring were compared to the potential savings from avoiding unnecessary PPI usage in patients with a negative pH study. The costs of PPI therapy reach equivalence with pH monitoring after 6.4 to 23.7 weeks, depending on the PPI regimen. A total of 21,411 weeks of PPIs were prescribed beyond the recommended 8-week trial, of which 32 % were for patients who had a negative 24-h pH monitoring study. If the sensitivity of pH monitoring was 96 %, early referral for pH monitoring would have saved between $1,197 and $6,303 per patient over 10 years. This strategy remains cost-effective as long as the sensitivity of pH monitoring is above 35 %. Prompt referral for pH monitoring after a brief empiric PPI trial is a more cost-effective strategy than prolonged empiric PPI trials for patients with both esophageal and extraesophageal GERD symptoms.

ID1 is a functional marker for intestinal stem and progenitor cells required for normal response to injury.

LGR5 and BMI1 mark intestinal stem cells in crypt base columnar cells and +4 position cells, respectively, but characterization of functional markers in these cell populations is limited. ID1 maintains the stem cell potential of embryonic, neural, and long-term repopulating hematopoietic stem cells. Here, we show in both human and mouse intestine that ID1 is expressed in cycling columnar cells, +4 position cells, and transit-amplifying cells in the crypt. Lineage tracing revealed ID1+ cells to be self-renewing, multipotent stem/progenitor cells that are responsible for the long-term renewal of the intestinal epithelium. Single ID1+ cells can generate long-lived organoids resembling mature intestinal epithelium. Complete knockout of Id1 or selective deletion of Id1 in intestinal epithelium or in LGR5+ stem cells sensitizes mice to chemical-induced colon injury. These experiments identify ID1 as a marker for intestinal stem/progenitor cells and demonstrate a role for ID1 in maintaining the potential for repair in response to colonic injury.

Effect of zileuton and celecoxib on urinary LTE4 and PGE-M levels in smokers.

COX-2 and 5-lipoxygenase (5-LO) use arachidonic acid for the synthesis of eicosanoids that have been implicated in carcinogenesis and cardiovascular disease. The ability of celecoxib, a selective COX-2 inhibitor, to redirect arachidonic acid into the 5-LO pathway can potentially reduce its efficacy as a chemopreventive agent and increase the risk of cardiovascular complications. Levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E4 (LTE4), biomarkers of the COX and 5-LO pathways, are elevated in smokers. Here, we investigated the effects of zileuton, a 5-LO inhibitor, versus zileuton and celecoxib for 6 ± 1 days on urinary PGE-M and LTE4 levels in smokers. Treatment with zileuton led to an 18% decrease in PGE-M levels (P = 0.03); the combination of zileuton and celecoxib led to a 62% reduction in PGE-M levels (P < 0.001). Levels of LTE4 decreased by 61% in subjects treated with zileuton alone (P < 0.001) and were unaffected by the addition of celecoxib. Although zileuton use was associated with a small overall decrease in PGE-M levels, increased PGE-M levels were found in a subset (19 of 52) of subjects. Notably, the addition of celecoxib to the 5-LO inhibitor protected against the increase in urinary PGE-M levels (P = 0.03). In conclusion, zileuton was an effective inhibitor of 5-LO activity resulting in marked suppression of urinary LTE4 levels and possible redirection of arachidonic acid into the COX-2 pathway in a subset of subjects. Combining celecoxib and zileuton was associated with inhibition of both the COX-2 and 5-LO pathways manifested as reduced levels of urinary PGE-M and LTE4.

Peripheral neuropathic symptoms in celiac disease and inflammatory bowel disease.

OBJECTIVES: An association between celiac disease (CD) and peripheral neuropathy (PN) has been reported. METHODS: Patients with CD and/or inflammatory bowel disease (IBD) were recruited from the gastroenterology clinics at a medical center and local support groups. Control subjects without CD or IBD were recruited from the staff of the medical center as well as relatives and attendees at support groups. Each participant completed a survey that used two validated PN instruments to define and characterize PN. RESULTS: In the CD group, 38.9% met criteria for PN compared with 38.7% in the IBD group (P = 0.97) and 20.5% in the control group (P < 0.001). On multiple logistic regression, the odds of PN after adjusting for age, gender, diabetes, vitamin B12 deficiency, and cancer history were increased for CD (odds ratio, 2.51; 95% confidence interval, 1.82-3.47) and IBD (odds ratio, 2.78; 95% confidence interval, 1.85-4.18). CONCLUSIONS: PN is more often found in patients with CD and/or IBD than in the general population.