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The tumor suppressor p53 (TP53) has a well-studied role in triggering cell-cycle checkpoint in response to DNA damage. Previous studies have suggested that functional p53 enhances chemosensitivity. In contrast, data are presented to show that p53 can be required for cell survival following DNA damage due to activation of reversible cell-cycle checkpoints. The cellular outcome to DNA damage is determined by the duration and extent of the stimulus in a p53-dependent manner. In response to transient or low levels of DNA damage, p53 triggers a reversible G2 arrest, whereas a sustained p53-dependent cell-cycle arrest and senescence follows prolonged or high levels of DNA damage. Regardless of the length of treatment, p53-null cells arrest in G2, but ultimately adapt and proceed into mitosis. Interestingly, they fail to undergo cytokinesis, become multinucleated, and then die from apoptosis. Upon transient treatment with DNA-damaging agents, wild-type p53 cells reversibly arrest and repair the damage, whereas p53-null cells fail to do so and die. These data indicate that p53 can promote cell survival by inducing reversible cell-cycle arrest, thereby allowing for DNA repair. Thus, transient treatments may exploit differences between wild-type p53 and p53-null cells.Implications: Although p53 status has been suggested as a clinical predictor of chemotherapeutic efficacy, studies to date have not always supported this. This study demonstrates that p53 is still an important determinant of cell fate in response to chemotherapy, under the appropriate treatment conditions. Mol Cancer Res; 13(1); 16–28. ©2014 AACR.

Supplemental Material. Supplemental Figure S1. A: Doxorubicin treatment leads to the concentration-dependent induction of p53 and p21 in parental U2OS cells. U2OS cells were treated with doxorubicin at concentrations ranging from 0.05 μg/ml to 0.2 μg/ml for 24 hours and harvested. Cell extracts were analyzed by immunoblotting for expression of p53, p21, and β-actin (loading control). B: Responses of control and p53-ablated cells to doxorubicin are not clonal in nature. U2OS derivatives expressing either a control shRNA (clone 1 and clone 4) or p53 shRNA (clone 7 and clone 8) were untreated or treated with 0.05 μg/ml doxorubicin for 1-6 days, and then analyzed by flow cytometry. The percentage of cells in each phase of the cell cycle or with a DNA content of less than 2N (

BACKGROUND: Disability in patients with medically refractory ulcerative colitis (UC) after total proctocolectomy (TPC) with ileal pouch anal anastomosis (IPAA) is not well understood. The aim of this study was to compare disability in patients with IPAA vs medically managed UC, and identify predictors of disability. METHODS: This was a multi-center cross-sectional study performed at five academic institutions in New York City. Patients with medically or surgically treated UC were recruited. Clinical and socioeconomic data were collected and the inflammatory bowel disease disability index (IBD-DI) was administered to eligible patients. Predictors of moderate-severe disability (IBD-DI≥35) were assessed in univariable and multivariable models. RESULTS: A total of 94 patients with IPAA and 128 patients with medically managed UC completed the IBD-DI. Among patients with IPAA and UC, 35 (37.2%) and 30 (23.4%) had moderate-severe disability, respectively. Patients with IPAA had significantly greater IBD-DI scores compared to patients with medically managed UC (29.8 vs 17.9, p

Background and Aims We conducted a systematic review and meta-analysis to summarize emerging data on the safety and effectiveness of dual biologic therapy in combination or with tofacitinib in patients with refractory inflammatory bowel disease (IBD). Methods Through a systematic search of multiple electronic databases through November 9, 2020, we identified cohort studies or case series (>10 patients) reporting the safety and effectiveness of simultaneous use of biologic agents in combination or with tofacitinib in patients with IBD. Rates of adverse events, clinical remission, and endoscopic remission were synthesized using pooled data, and we identified factors associated with successful dual therapy. Results We identified 30 studies reporting 288 trials of dual biologic or small molecule therapy in 279 patients (76% Crohn’s disease; median duration of treatment 24 weeks (IQR25-IQR75 1332)). The main indications for dual therapy included medically refractory IBD (81%) and concurrent extra-intestinal manifestations or rheumatologic disease (12%). The most common combinations of dual therapy included tumor necrosis factor-α antagonists & anti-integrins (48%), ustekinumab & anti-integrins (19%); 61% of patients had previously failed at least one of the two therapies used in combination. Over a median follow-up of 32 weeks (IQR25-IQR75 24-52), pooled rates of adverse and serious adverse events were 31% (95% CI, 13%-54%) and 6.5% (95% CI, 2.1%-13.1%); pooled rates of clinical and endoscopic remission were 59% (95% CI, 42%-74%), and 34% (95% CI, 23%-46%), respectively. 12% (95% CI, 4%-24%) of patients required surgery. Rates of success were higher in patients on dual therapy due to EIM. Heterogeneity was not significant for endoscopic response (P = .88, I2 = 0%), endoscopic remission (P = .44, I2 = 0%), and malignancy (P = .87, I2 = 0%). However, significant heterogeneity existed for other outcomes. Conclusions Dual biologic or small molecule therapy may be a possible option in highly selected, refractory IBD patients at specialized centers. Higher quality combination of therapies with a significant improvement in the quality of data is required prior to more widespread use.

Background & Aims We aimed to compare safety and effectiveness of vedolizumab to tumor necrosis factor (TNF)-antagonist therapy in ulcerative colitis in routine practice. Methods A multicenter, retrospective, observational cohort study (May 2014 to December 2017) of ulcerative colitis patients treated with vedolizumab or TNF-antagonist therapy. Propensity score weighted comparisons for development of serious adverse events and achievement of clinical remission, steroid-free clinical remission, and steroid-free deep remission. A priori determined subgroup comparisons in TNF-antagonist–naive and –exposed patients, and for vedolizumab against infliximab and subcutaneous TNF-antagonists separately. Results A total of 722 (454 vedolizumab, 268 TNF antagonist) patients were included. Vedolizumab-treated patients were more likely to achieve clinical remission (hazard ratio [HR], 1.651; 95% confidence interval [CI], 1.229-2.217), steroid-free clinical remission (HR, 1.828; 95% CI, 1.135-2.944), and steroid-free deep remission (HR, 2.819; 95% CI, 1.496-5.310) than those treated with TNF antagonists. Results were consistent across subgroup analyses in TNF-antagonist–naive and −exposed patients, and for vedolizumab vs infliximab and vs subcutaneous TNF-antagonist agents separately. Overall, there were no statistically significant differences in the risk of serious adverse events (HR, 0.899; 95% CI, 0.502-1.612) or serious infections (HR, 1.235; 95% CI, 0.608-2.511) between vedolizumab-treated and TNF-antagonist−treated patients. However, in TNF-antagonist−naive patients, vedolizumab was less likely to be associated with serious adverse events than TNF antagonists (HR, 0.192; 95% CI, 0.049-0.754). Conclusions Treatment of ulcerative colitis with vedolizumab is associated with higher rates of remission than treatment with TNF-antagonist therapy in routine practice, and lower rates of serious adverse events in TNF-antagonist−naive patients.

Ulcerative colitis (UC) is a chronic disease with an increasing incidence. Recent guidelines emphasize treating toward objective targets, requiring the use of effective, steroid-sparing therapies. This review summarizes the safety and efficacy data of available therapies as well comparative effectiveness studies in order to help the reader make rational treatment decisions.Following the approval of tumor necrosis factor alpha antagonists, we have seen recent regulatory approval of several additional biologic and small molecule agents from several therapeutic classes (integrin antagonists, interleukin 12/23 antagonists, Janus kinase inhibitors, and sphingosine-1-phosphate receptor antagonists) for UC. Randomized, controlled trials, real-world analyses, and network meta-analyses have investigated the comparative safety and efficacy of these therapies in order to help clinicians better position these therapies in clinical practice. Numerous agents are now approved for the treatment of UC. This evidence-based review will help the reader understand the important factors weighing into treatment decisions for patients with UC and enable patient education and discussion with a focus on a shared decision-making approach.

Background and Aims Bacterial swarming, a collective movement on a surface, has rarely been associated with human pathophysiology. This study aims to define a role for bacterial swarmers in amelioration of intestinal stress. Methods We developed a polymicrobial plate agar assay to detect swarming and screened mice and humans with intestinal stress and inflammation. From chemically induced colitis in mice, as well as humans with inflammatory bowel disease, we developed techniques to isolate the dominant swarmers. We developed swarm-deficient but growth and swim-competent mutant bacteria as isogenic controls. We performed bacterial reinoculation studies in mice with colitis, fecal 16S, and meta-transcriptomic analyses, as well as in vitro microbial interaction studies. Results We show that bacterial swarmers are highly predictive of intestinal stress in mice and humans. We isolated a novel Enterobacter swarming strain, SM3, from mouse feces. SM3 and other known commensal swarmers, in contrast to their mutant strains, abrogated intestinal inflammation in mice. Treatment of colitic mice with SM3, but not its mutants, enriched beneficial fecal anaerobes belonging to the family of Bacteroidales S24-7. We observed SM3 swarming associated pathways in the in vivo fecal meta-transcriptomes. In vitro growth of S24-7 was enriched in presence of SM3 or its mutants; however, because SM3, but not mutants, induced S24-7 in vivo, we concluded that swarming plays an essential role in disseminating SM3 in vivo. Conclusions Overall, our work identified a new but counterintuitive paradigm in which intestinal stress allows for the emergence of swarming bacteria; however, these bacteria act to heal intestinal inflammation.

Data are lacking on predicting inpatient mortality (IM) in patients admitted for inflammatory bowel disease (IBD). IM is a critical outcome; however, difficulty in its prediction exists due to infrequent occurrence. We assessed IM predictors and developed a predictive model for IM using machine-learning (ML).Using the National Inpatient Sample (NIS) database (2005-2017), we extracted adults admitted for IBD. After ML-guided predictor selection, we trained and internally validated multiple algorithms, targeting minimum sensitivity and positive likelihood ratio (+LR) ≥ 80% and ≥ 3, respectively. Diagnostic odds ratio (DOR) compared algorithm performance. The best performing algorithm was additionally trained and validated for an IBD-related surgery sub-cohort. External validation was done using NIS 2018.In 398 426 adult IBD admissions, IM was 0.32% overall, and 0.87% among the surgical cohort (n = 40 784). Increasing age, ulcerative colitis, IBD-related surgery, pneumonia, chronic lung disease, acute kidney injury, malnutrition, frailty, heart failure, blood transfusion, sepsis/septic shock and thromboembolism were associated with increased IM. The QLattice algorithm, provided the highest performance model (+LR: 3.2, 95% CI 3.0-3.3; area-under-curve [AUC]:0.87, 85% sensitivity, 73% specificity), distinguishing IM patients by 15.6-fold when comparing high to low-risk patients. The surgical cohort model (+LR: 8.5, AUC: 0.94, 85% sensitivity, 90% specificity), distinguished IM patients by 49-fold. Both models performed excellently in external validation. An online calculator (https://clinicalc.ai/im-ibd/) was developed allowing bedside model predictions.An online prediction-model calculator captured 80% IM cases during IBD-related admissions, with high discriminatory effectiveness. This allows for risk stratification and provides a basis for assessing interventions to reduce mortality in high-risk patients.

BACKGROUND: Delays in biologic or small molecule medication administration are associated with increased adverse events, hospitalization, and surgery in inflammatory bowel disease (IBD). We evaluated the impact of a quality improvement (QI) intervention on the time to administration of biologics or small molecules (TABS) in IBD. METHODS: Data were retrospectively extracted for IBD patients prescribed biologics or small molecules from a convenience sample of providers participating in an accredited QI educational intervention (baseline cohort). Subsequent to the intervention, data were prospectively collected from patients prescribed these medications (post-intervention cohort). Dates related to steps between a treatment decision to medication administration were collected. The primary outcome compared TABS in baseline and post-intervention cohorts. RESULTS: Eighteen physicians provided survey- and patient data for 200 patients in each cohort (n=400). The median time to medication administration (TABS) decreased from baseline to post-intervention cohorts (30 days vs. 26 days, p=0.04). Emergency room visits prior to medication administration also decreased (25.5% vs. 12.5%, p=0.001). Similar numerical TABS reductions were observed in subgroups limited to physicians providing patients to both cohorts and for individual medications prescribed. Primary contributors to delays included filling prescriptions subsequent to insurance approval and dispensation subsequent to this. CONCLUSION: A QI intervention successfully reduced medication administration times (TABS) by accelerating provider-dependent steps. This intervention was associated with reduced emergency room visits. We propose TABS as a quality metric to assess effective delivery of therapies in IBD. Further evaluation of QI interventions, patient education on prescription drug insurance, and quality metrics are warranted.

Background Infliximab and adalimumab concentrations are associated with important outcomes in inflammatory bowel disease (IBD). Antibodies to infliximab (ATI) and adalimumab (ATA) are associated with reduced drug concentrations and worse outcomes. Because the efficacy of dose escalation to overcome antibodies is unclear, we assessed the impact of this strategy to overcome immunogenicity in IBD. Methods Infliximab and adalimumab dosing, drug, and antibody concentrations were extracted from a database of patients with IBD having specimens collected for therapeutic drug monitoring. The primary outcome compared proportions with either infliximab ≥5 μg/mL or adalimumab ≥7.5 μg/mL and undetectable antibodies between dose-escalated and non-escalated patients. Area under the receiver operating characteristic curve analyses determined antibody concentrations below which dose escalation was associated with the primary outcome. Results The study included 63,176 patients treated with infliximab and 46,429 patients treated with adalimumab. We detected ATI and ATA in 23.6% (n = 14,900) of patients treated with infliximab and 19.6% (n = 9101) of patients treated with adalimumab. In patients with ATI, infliximab dose escalation (n = 453) yielded higher proportions achieving the primary outcome (47.5% vs 30.9%; P < 0.001), greater drug concentration increases (5.9 μg/mL vs 0.2 μg/mL; P < 0.001), and ATI reductions (4.3 U/mL vs 1.9 U/mL; P = 0.002) compared to no escalation (n = 204). An ATI threshold of 8.55 U/mL was associated with achieving the primary outcome with dose escalation (area under the curve = 0.66). For patients with ATI ≤8.55 U/mL (n = 274), higher proportions (59.1% vs 29.6%; P < 0.001) achieved the primary outcome compared with those with ATI >8.55 U/mL (n = 179). No patients treated with adalimumab achieved the primary outcome (0/390), regardless of dose escalation (n = 87). Conclusion Dose escalation increased drug concentrations and eliminated antibodies with infliximab but not adalimumab. Initial ATI ≤8.55 U/mL was associated with increased efficacy of dose escalation using this assay.

Peripheral and axial spondyloarthritis are the most common extra-intestinal manifestations reported in patients with Crohn’s disease. Despite the frequency of Crohn’s disease associated spondyloarthritis, clinical diagnostic tools are variably applied in these cohorts and further characterization with validated spondyloarthritis disease activity indexes are needed. In addition, the pathogenesis of Crohn’s disease associated spondyloarthritis is not well understood. Evidence of shared genetic, cellular, and microbial mechanisms underlying both Crohn’s disease and spondyloarthritis highlight the potential for a distinct clinicopathologic entity. Existing treatment paradigms for Crohn’s disease associated spondyloarthritis focus on symptom control and management of luminal inflammation. A better understanding of the underlying pathogenic mechanisms in Crohn’s disease associated spondyloarthritis and the link between the gut microbiome and systemic immunity will help pave the way for more targeted and effective therapies. This review highlights recent work that has provided a framework for clinical characterization and pathogenesis of Crohn’s disease associated spondyloarthritis and helps identify critical gaps that will help shape treatment paradigms.

OBJECTIVE Heart failure (HF) exerts deleterious effects on the gastrointestinal tract and the gut microbiome, yet its impact on inflammatory bowel disease (IBD) is unknown. This study was performed to evaluate the impact of HF on disease course and outcomes in patients with IBD. METHODS Using a large institutional database, we identified patients aged 18-65 years diagnosed with IBD and incident HF (IBD-HF), IBD without HF (IBD), and HF without IBD (HF). Patients were followed longitudinally, and IBD-related outcomes were compared between the IBD-HF and IBD cohorts using multivariable cox regression. General clinical outcomes were compared between all three cohorts using Kaplan-Meier survival analysis. RESULTS A total of 271, 2449, and 20,444 patients were included in the IBD-HF, IBD, and HF cohorts. Compared with IBD, IBD-HF had significantly higher risk of IBD-related hospitalization [hazard ratio (HR): 1.42; (95% confidence interval, CI: 1.2-1.69)], flare [HR 1.32 (1.09-1.58)], complication [HR 1.7 (1.33-2.17)], pancolitis [HR 1.55 (1.04-2.3)], and escalation to nonbiologic therapy. No significant difference was observed in the incidence of IBD-related surgery or Clostridium difficile infection. New biologic use was less frequent in IBD-HF [HR 0.52 (0.36-0.77)]. IBD-HF, compared with the other two groups, had reduced event-free survival for all-cause hospitalization (P < 0.001), emergency department visits (P = 001), and venous thromboembolism (P < 0.05). Mortality risk in IBD-HF was elevated compared to IBD but was similar to that within HF cohort. CONCLUSION Incident HF in patients with IBD is a predictor of adverse IBD-related and overall clinical outcomes.

Immunization against the spike protein of SARS-CoV-2 reduces transmission

Background Previous retrospective studies have demonstrated that patients with inflammatory bowel disease (IBD) exposed to anti-TNF and/or immunomodulators (IMM) following a diagnosis of cancer were not at an increased risk of new or recurrent cancer compared with those unexposed to these agents. Prospective studies are lacking and little is known about cancer risk with ustekinumab and vedolizumab. The SAPPHIRE Registry was developed to prospectively examine whether patients with IBD and a history of cancer subsequently exposed to immunosuppressive IBD therapies are at greater risk of new or recurrent cancer compared with those not exposed to immunosuppression. Methods We are longitudinally following patients with IBD and a histologically confirmed first cancer within the last five years from 8 centres affiliated with the New York Crohn’s and Colitis Organization (NYCCO) between 2017 and 2019. Patients receiving chemotherapy or radiation at enrolment, a first cancer more than 5 years prior to study entry, or recurrent cancer within the last 5 years are excluded. Cancers are categorised into luminal gastrointestinal (GI), hematologic, dermatologic, and other solid malignancies. Our primary outcome is the development of new or recurrent cancer stratified by immunosuppression exposure. Results We identified 170 patients with IBD and a history of a first cancer within the last 5 years (Table 1). The average age at IBD diagnosis was 36 years; average age at cancer diagnosis was 54 years. Patients were 49% male, 91% white, and 39% former smokers. Prior cancers were solid (78; 46%), GI (23; 14%), dermatologic (59; 35%), and hematologic (12; 7%) malignancies. Following a diagnosis of cancer, patients were exposed to IMM (38; 22%), anti-TNF (45; 26%), vedolizumab (41; 23%), ustekinumab (17; 10%), or no immunosuppression (33; 19%; Table 2). During follow-up, 13 (8%) patients developed 14 subsequent cancers (6 new, 8 recurrent) comprising 6 (43%) solid, 1 (7%) gastrointestinal, and 7 (50%) dermatologic malignancies. Compared to patients not exposed to immunosuppression, exposure to an IMM (RR 4.94, 95% CI 0.50, 48.6) or a biologic (RR 3.53, 95% CI 0.71, 17.5) was not associated with an increased risk of new or recurrent cancer. However, exposure to combination therapy with an IMM and a biologic (RR 6.81, 95% CI 1.40, 33.2) was associated with an increased risk in this small sample. Conclusion In this ongoing prospective study, exposure to immunosuppressive IBD monotherapies in patients with IBD and a recent history of cancer has so far conferred no increased risk of new or recurrent cancer. Continued enrolment will enable a more refined estimate of the safety of combination therapies.

Significant gaps in knowledge and utilization of vaccinations exist among practitioners providing care for patients with IBD. This review is intended to update the reader on best practices for vaccination within the IBD population with a specific focus on the elderly. Advances in IBD therapeutics have recently increased the number of immunosuppressive therapies available to practitioners. Differences in mechanisms of action of these medications have led to differential implications pertaining to vaccination strategies. Additionally, new vaccines, including the recombinant zoster vaccine, have recently become available for the use in the IBD population. Given the prominent role the IBD provider plays in the management of patients with IBD, a clear understanding of best practices is essential. This review provides a framework for the integration of optimal vaccination strategies for practitioners caring for adult and elderly patients with IBD.

Background Vedolizumab effectiveness estimates immediately after Food and Drug Administration (FDA) approval for ulcerative colitis (UC) and Crohn’s disease (CD) are limited by use in refractory populations. We aimed to compare treatment patterns and outcomes of vedolizumab in 2 time frames after FDA approval. Methods We used 2 data sets for time trend analysis, an academic multicenter vedolizumab consortium (VICTORY) and the Truven MarketScan database, and 2 time periods, May 2014–June 2015 (Era 1) and July 2015–June 2017 (Era 2). VICTORY cumulative 12-month clinical remission, corticosteroid-free remission, and mucosal healing rates, and Truven 12-month hospitalization and surgery rates, were compared between Eras 1 and 2 using time-to-event analyses. Results A total of 3661 vedolizumab-treated patients were included (n = 1087 VICTORY, n = 2574 Truven). In both cohorts, CD and UC patients treated during Era 2 were more likely to be biologic naïve. Compared with Era 1, Era 2 CD patients in the VICTORY consortium had higher rates of clinical remission (31% vs 40%, P = 0.03) and mucosal healing (42% vs 58%, P < 0.01). These trends were not observed for UC. In the Truven database, UC patients treated during Era 2 had lower rates of inflammatory bowel disease–related hospitalization (22.4% vs 9.6%, P < 0.001) and surgery (17.2% vs 9.4%, P = 0.008), which was not observed for CD. Conclusion Since FDA approval, remission and mucosal healing rates have increased for vedolizumab-treated CD patients, and vedolizumab-treated UC patients have had fewer hospitalizations and surgeries. This is likely due to differences between patient populations treated immediately after drug approval and those treated later., There has been a shift in utilization of vedolizumab in both Crohn’s disease and ulcerative colitis toward earlier use in the treatment sequencing algorithm. This shift in utilization is associated with improvements in response and disease outcomes.

BACKGROUND Race, ethnicity and socio-economic status impact clinical outcomes in inflammatory bowel disease (IBD) patients. However, their impact on disability has not been studied. AIM To determine the association between race, ethnicity and socio-economic factors with disability in IBD, using the validated IBD disability index (IBD-DI). METHODS Ambulatory IBD patients were enrolled at five academic centres participating in the New York Crohn's and Colitis Organization. We assessed the IBD-DI, and collected clinical and socio-economic data. Factors associated with moderate-to-severe disability (IBD-DI score > 35) on univariable analysis were tested in multivariable models with adjusted odds ratios (aOR) and 95% confidence intervals (CI) reported. RESULTS In this study, 323 patients (57.3% CD, 51.4% female) were enrolled; 17.7% were Hispanic, 17% were non-Hispanic black, 56.0% were non-Hispanic Caucasian and 9.3% belonged to non-Hispanic non-black minority races. However, 39.0% of patients were publicly insured and 38.4% of patients had low annual household income (

Background Nonadherence to biologic therapy in inflammatory bowel disease (IBD) is associated with risk of relapse, immunogenicity, and disease complications. Significant nonadherence prevalence is reported with tumor necrosis factor (TNF) antagonists but the risk of nonadherence with newer biologics with better safety profiles is unknown. This study aimed to investigate if IBD patient-preferences favoring biologic discontinuation vary by biologic class and analyze factors associated with such preferences. Methods A convenience sample of 200 adults with IBD on biologic therapy treated at an academic outpatient center was surveyed using a 22-point questionnaire. Patient-preference favoring treatment discontinuation between TNF-antagonist and non-TNF-antagonist biologics [vedolizumab (VDZ)/ustekinumab (UST)] was compared using χ 2 test. Risk factors associated with a preference to discontinue biologic therapy were evaluated using univariable and multivariable logistic regression, and Spearman rank correlation analyses. Results A total of 190 questionnaires were analyzed that contained data on preferences regarding biologic discontinuation (median age 36 years, 62% were females; 63% had Crohn disease; 56% were receiving a TNF antagonist, 31% VDZ, and 14% UST). Overall, 32% patients reported a preference to discontinue biologic treatment with a higher proportion among those receiving a TNF antagonist compared with VDZ/UST (39.6% vs 21.4%; P < 0.01). Current VDZ/UST use was independently associated with a reduced odds of patient-preference favoring biologic discontinuation [adjusted odds ratio: 2.67 (1.42–5.01); P < 0.01]. The most concerning factor to patients was the perceived risk of side effects. Patients on VDZ/UST perceived their therapy to be safer than those receiving a TNF antagonist (r = 0.2, P = 0.04). Conclusions Patient-preference favoring treatment discontinuation is improved with VDZ/UST compared with TNF-antagonist biologic therapy.

Diabetes mellitus (DM) and inflammatory bowel diseases (IBD) are chronic systemic illnesses associated with chronic inflammation, dysbiosis, impaired immune function, and infection risk. The impact of DM in modifying disease activity in patients with IBD remains largely unknown. To investigate the impact of DM on IBD-related disease outcomes, mortality, and infections in patients with IBD. We performed a longitudinal cohort analysis. Using a large institutional database, patients with concurrent IBD and DM (IBD–DM), and IBD without DM (IBD cohort), were identified and followed longitudinally to evaluate for primary (IBD-related) and secondary (mortality and infections) outcomes. Cox proportional hazards models were used to determine the independent effect of DM on each outcome, adjusting for confounding effects of covariates. A total of 901 and 1584 patients were included in the IBD–DM and DM cohorts. Compared with IBD, IBD–DM had significantly higher risk of IBD-related hospitalization [adjusted hazard ratio (HR) 1.97, 95% confidence interval (1.71–2.28)], disease flare [HR 2.05 (1.75–2.39)], and complication [HR 1.54 (1.29–1.85)]. No significant difference was observed in the incidence of IBD-related surgery. All-cause mortality, sepsis, Clostridioides difficile infection (CDI), pneumonia, urinary tract infection, and skin infection were also more frequent in the IBD–DM than the IBD cohort (all p ≤ 0.05). Subgroup analysis of Crohn’s disease (CD) and ulcerative colitis patients showed similar associations, except with an additional risk of surgery and no association with CDI in the CD–DM cohort. Comorbid diabetes in patients with IBD is a predictor of poor disease-related and infectious outcomes.

Diabetes mellitus (DM) and inflammatory bowel diseases (IBD) are chronic systemic illnesses associated with chronic inflammation, dysbiosis, impaired immune function, and infection risk. The impact of DM in modifying disease activity in patients with IBD remains largely unknown.To investigate the impact of DM on IBD-related disease outcomes, mortality, and infections in patients with IBD.We performed a longitudinal cohort analysis. Using a large institutional database, patients with concurrent IBD and DM (IBD-DM), and IBD without DM (IBD cohort), were identified and followed longitudinally to evaluate for primary (IBD-related) and secondary (mortality and infections) outcomes. Cox proportional hazards models were used to determine the independent effect of DM on each outcome, adjusting for confounding effects of covariates.A total of 901 and 1584 patients were included in the IBD-DM and DM cohorts. Compared with IBD, IBD-DM had significantly higher risk of IBD-related hospitalization [adjusted hazard ratio (HR) 1.97, 95% confidence interval (1.71-2.28)], disease flare [HR 2.05 (1.75-2.39)], and complication [HR 1.54 (1.29-1.85)]. No significant difference was observed in the incidence of IBD-related surgery. All-cause mortality, sepsis, Clostridioides difficile infection (CDI), pneumonia, urinary tract infection, and skin infection were also more frequent in the IBD-DM than the IBD cohort (all p ≤ 0.05). Subgroup analysis of Crohn's disease (CD) and ulcerative colitis patients showed similar associations, except with an additional risk of surgery and no association with CDI in the CD-DM cohort.Comorbid diabetes in patients with IBD is a predictor of poor disease-related and infectious outcomes.

Bacterial swarming, a collective movement on a surface, in contrast to sessile biofilms, has rarely been associated with human pathophysiology in health and disease. Here, we report for the first time that bacterial swarmers are associated with protection against intestinal inflammation in a murine model of acute colitis. We show, the presence of bacterial swarmers is highly predictive of intestinal stress in mice, pigs, and humans. We isolated a novel Enterobacter swarming strain, SM3 from mouse feces. In mice, SM3 and other known commensal swarmers, in contrast to their respective swarming-deficient but swimming-competent isogenic strains, demonstrated significant protection from intestinal inflammation. Treatment with SM3 in colitic mice also paralleled a significant reduction in luminal oxygen concentration and enrichment of beneficial anaerobes. Overall, our work identifies a new paradigm in which intestinal stress, allows for the emergence of swarming bacteria, which in turn can protect and heal from intestinal inflammation.

Background:Inflammatory bowel disease (IBD) is not associated with worse coronavirus disease 2019 (COVID-19) outcomes. However, data are lacking regarding the long-term impact of severe acute respiratory syndrome coronavirus 2 infection on the disease course of IBD.Objectives:We aimed to investigate the effect of COVID-19 on long-term outcomes of IBD.Design:We performed a multicenter case–control study of patients with IBD and COVID-19 between February 2020 and December 2020.Methods:Cases and controls were individuals with IBD with presence or absence, respectively, of COVID-19-related symptoms and confirmatory testing. The primary composite outcome was IBD-related hospitalization or surgery.Results:We identified 251 cases [ulcerative colitis ( n = 111, 45%), Crohn’s disease ( n = 139, 55%)] and 251 controls, with a median follow-up of 394 days. The primary composite outcome of IBD-related hospitalization or surgery occurred in 29 (12%) cases versus 38 (15%) controls ( p = 0.24) and on multivariate Cox regression, COVID-19 was not associated with increased risk of adverse IBD outcomes [adjusted hazard ratio (aHR): 0.84, 95% confidence interval [CI]: 0.44–1.42]. When stratified by infection severity, severe COVID-19 was associated with a numerically increased risk of adverse IBD outcomes (aHR: 2.43, 95% CI: 1.00–5.86), whereas mild-to-moderate COVID-19 was not (aHR: 0.68, 95% CI: 0.38–1.23).Conclusion:In this case–control study, COVID-19 did not have a long-term impact on the disease course of IBD. However, severe COVID-19 was numerically associated with worse IBD outcomes, underscoring the continued importance of risk mitigation and prevention strategies for patients with IBD during the ongoing COVID-19 pandemic.

Background We quantified loss of response (LOR) to vedolizumab (VDZ) in clinical practice and assessed the effectiveness of VDZ dose intensification for managing LOR. Methods Retrospective review (May 2014–December 2016) of a prospectively maintained inflammatory bowel disease (IBD) registry. Kaplan-Meier estimates were used to determine rates of LOR to VDZ . Independent predictors of LOR were identified using univariate and multivariable Cox proportional hazard regression. Success of recapturing response (>50% reduction in symptoms from baseline) and remission (complete resolution of symptoms) after dose intensification was quantified. Results Cumulative rates for VDZ LOR were 20% at 6 months and 35% at 12 months, with slightly lower rates in Crohn’s disease than in ulcerative colitis (6 months 15% vs 18% and 12 months 30% vs 39%, P = 0.03). On multivariable analysis, LOR to a tumor necrosis factor (TNF) antagonist before VDZ use was associated with an increased risk for LOR to VDZ [hazard ratio (HR) 1.93; 95% confidence interval (CI) 1.25–2.97] in all patients. For Crohn’s disease patients specifically, higher baseline C-reactive protein concentration was associated with increased risk for LOR to VDZ (HR 1.01 per mg/dL increase, 95% CI 1.01–1.02). Shortening of VDZ infusion interval from 8 to every 4 or 6 weeks recaptured response in 49% and remission in 18% of patients. Conclusions LOR to a TNF antagonist before VDZ use and higher baseline C-reactive protein are important predictors of VDZ LOR. Treatment response can be recaptured in almost half of these patients with VDZ infusion interval shortening.

Sessile serrated adenomas (SSA) and traditional serrated adenomas (TSA) are recognized precursors of colorectal cancer, but their risk factors are not well established. We investigated the association between Helicobacter pylori infection (HPI) and the development of SSA and TSA. Retrospective data were collected on patients aged ≥ 18 years that underwent colonoscopy with biopsy between 2006 and 2016. Based on histology, patients were classified into three groups: those with SSA and/or TSA, (serrated neoplasia group, SN); conventional adenomas only (CA); and with no polyps (NP). Gastric HPI status, demographic, and clinical risk factors were compared between groups using bivariate and multivariable analysis. HPI was significantly associated with increased risk of SN (SN vs. NP: OR 1.71 [95% CI 1.29–2.27]; SN vs. CA: 1.49 [1.14–1.96]). Additional factors associated with increased risk of SN included the following: age 50–75 years, compared to younger age (SN vs. NP: 2.83 [1.69–4.74]), female gender (SN vs. CA: 1.28 [0.99–1.64]), White race, compared to Blacks (SN vs. CA: 1.52 [1.07–2.15)], overweight and obese body mass index [SN vs. NP: p

Background Although patients with inflammatory bowel disease (IBD) reported an increased frequency of gastrointestinal (GI) symptoms following infection, the durable impact of COVID-19 on underlying IBD is not well defined. Methods In 118 IBD patients with COVID-19, clinical and endoscopic IBD activity, laboratory markers (ESR, CRP, hemoglobin (Hb), fecal calprotectin(FCP)), and medication utilization was assessed up to 6 months post-infection and compared to during infection or up to 6 months prior to infection. Active disease was defined by a Harvey Bradshaw Index > 4, Mayo Score ≥2, SES-CD ≥2, Mayo endoscopic score ≥1. 16S rRNA analysis was used to evaluate microbiome composition in a subset of 12 patients before and after COVID-19. Results Although upper respiratory (86.6%) and new GI symptoms (39.1%) were common in patients with IBD, there was no significant change in IBD clinical disease activity (Pre vs. Post-COVID-19 HBI: 4.7 vs. 4.9; partial Mayo: 3.0 vs. 2.1), endoscopic evaluation (Pre vs. Post-COVID-19 SES-CD: 7.2 vs. 8.9, Mayo endoscopic score: 1.5 vs. 1.7), or laboratory markers (Pre vs. Post-COVID-19 CRP: 1.2 vs. 1.3; ESR: 25 vs. 26; Hb 12.8 vs. 13.2; FCP: 388 vs. 250) up to 7 months post-COVID-19 compared to the 6 months prior to infection (Table 1). Overall active disease was present in 60% of the cohort prior to COVID-19 and 55% and 59% during and post-COVID-19, respectively. More subjects (8.5%) reported a delay in medical therapy during COVID-19, but there were no differences in the need for corticosteroids, a change in medical therapy, or IBD-related surgery or hospitalization during or post-COVID-19 compared to the prior 6 months. Microbiome composition stratified by underlying IBD disease activity, but did not show significant change post-COVID-19 (Figure 1). Conclusion COVID-19 showed no durable impact on clinical IBD disease activity or microbiome composition supporting guidelines for continued maintenance care.

Background Treatment options in Crohn’s disease (CD) are limited. Tofacitinib, a Janus Kinase 1–3 inhibitor, is not currently approved for use in CD, however, its effect on biochemical markers suggests that tofacitinib does impact disease activity in CD. Aim To evaluate the real-world experience with off-label tofacitinib in the treatment of Crohn’s colitis at a large inflammatory bowel disease center. Methods We evaluated 5 adult patients with moderate-to-severely active Crohn’s colitis who were started on tofacitinib therapy after failing ≥2 biologic agents. Pre- and post-tofacitinib treatment characteristics including clinical, endoscopic and biochemical disease activity, presence of extra-intestinal manifestations, and potential adverse effects were recorded (figure 1). Endpoints evaluated were clinical remission [defined as Harvey Bradshaw index (HBI) 50% reduction in HBI); endoscopic remission (simple endoscopic score (SES)-CD50% reduction in SES-CD); and biochemical remission [fecal calprotectin (FC) Results Post-tofacitinib, patients were followed for a median period of 18 weeks (range 8–34 weeks). Four of the 5 (80%) patients achieved clinical remission, 4/5 (80%) achieved clinical response. All patients that underwent a follow-up endoscopy (n=3) achieved endoscopic response and 2/3 (67%) achieved endoscopic remission (figure 2). Three of the 4 patients with a follow-up FC (75%) achieved biochemical remission. Of the 4 patients on baseline corticosteroids, 3 (75%) were corticosteroid-free by week 18. Four of the 5 (80%) patients exhibited improvement in CD-related arthropathy. No significant treatment-emergent adverse events were observed. Conclusions In this case series, use of tofacitinib was safe and effective in the treatment of refractory Crohn’s colitis and CD-related arthropathy. Further investigation of tofacitinib in CD, particularly involving the colon, is warranted.

Bacterial swarming is a conserved and distinct form of bacterial motility that is often regulated differently than biofilm communities. While bacterial biofilms are associated with pathogenesis and pathobiology of human diseases, there are very few examples of swarming behaviors that uniquely define or align with human pathophysiology. Here we report that bacterial swarmers are associated with protection against intestinal inflammation in a murine model of acute colitis. Using feces in soft-agar plate assay, we showed bacterial spreading harboring swarmers, is highly predictive of the presence of intestinal stress in mice, pigs, and humans. From murine feces, we isolated a novel Enterobacter swarming strain, SM3, which demonstrated significant protection from intestinal inflammation when compared to its swarming deficient but swimming competent transposon mutants in a DSS-induced intestinal inflammation model of mice. Known commensal swarmers also protected against intestinal inflammation when compared to swarming deficient isogenic mutants. When treated with SM3, its anti-inflammatory properties paralleled a significant reduction of luminal oxygen concentration in colitic mice as observed in real time using a microsensor probe. This led to a favorable anaerobic environment conducive to the growth of beneficial anaerobes as demonstrated by 16S profiling of feces. This work identifies a new paradigm in which intestinal stress, specifically inflammation, allows for the emergence of swarming bacteria, which in turn can protect and heal from intestinal inflammation.