Upadacitinib Achieves Clinical and Endoscopic Outcomes in Crohn's Disease Regardless of Prior Biologic Exposure.

BACKGROUND & AIMS: Upadacitinib, an oral Janus kinase inhibitor, achieved significantly higher rates of clinical remission and endoscopic response vs placebo during induction (U-EXCEL [NCT03345849], U-EXCEED [NCT03345836]) and maintenance (U-ENDURE [NCT03345823]) treatment in patients with moderate-to-severe Crohn's disease. Prior biologic failure is often associated with reduced responses to subsequent therapies. This post hoc analysis assessed upadacitinib efficacy by prior biologic failure status. METHODS: Patients were randomized to placebo or upadacitinib 45 mg (UPA45) for 12 weeks (induction). UPA45 clinical responders were enrolled in U-ENDURE and rerandomized to placebo, upadacitinib 15 mg, or upadacitinib 30 mg (UPA30) for 52 weeks. Assessments were by prior biologic failure. RESULTS: Of 1021 patients, 733 (71.8%) had prior biologic failure. Across outcomes and subgroups, upadacitinib-treated patients achieved higher rates vs placebo. During induction, upadacitinib had higher rates vs placebo for clinical remission based on stool frequency/abdominal pain score (without failure: 54.0% vs 28.3%; with failure: 42.2% vs 14.1%) and endoscopic response (without failure: 52.0% vs 16.2%; with failure: 35.7% vs 5.3%). In maintenance, the greatest treatment effect (upadacitinib vs placebo) was among patients with prior biologic failure treated with UPA30 (clinical remission without failure: 58.5% vs 32.7%; with failure: 42.5% vs 8.7%; endoscopic response without failure: 43.9% vs 17.9%; with failure: 38.9% vs 4.0%). Patients without vs with prior biologic failure had fewer adverse events. CONCLUSIONS: Upadacitinib led to higher absolutes rates of clinical and endoscopic outcomes in patients without vs with prior biologic failure. Patients treated with upadacitinib achieved greater rates of clinical and endoscopic improvements vs placebo, regardless of prior biologic exposure. CLINICALTRIALS: gov: NCT03345849, NCT03345836, NCT03345823.

Safety of Immunosuppression in a Prospective Cohort of Inflammatory Bowel Disease Patients With a HIstoRy of CancEr: SAPPHIRE Registry.

BACKGROUND & AIMS: In patients with inflammatory bowel disease (IBD) and a history of cancer, retrospective studies have suggested that exposure to immunosuppressive agents does not increase the risk of incident (recurrent or new) cancer compared with unexposed patients. SAPPHIRE is a prospective registry aimed at addressing this issue. METHODS: Since 2016, patients with IBD and confirmed index cancer before enrollment were followed up annually. Patients receiving chemotherapy or radiation at enrollment, or recurrent cancer within 5 years, were excluded. The primary outcome was development of incident cancer related to exposure to immunosuppressive medications. RESULTS: Among 305 patients (47% male, 88% white), the median age at IBD diagnosis and cancer were 32 and 52 years, respectively. Index cancers were solid organ (46%), dermatologic (32%), gastrointestinal (13%), and hematologic (9%). During a median follow-up period of 4.8 years, 210 patients (69%) were exposed to immunosuppressive therapy and 46 patients (15%) developed incident cancers (25 new, 21 recurrent). In unadjusted analysis, the crude rate of incident cancer in unexposed patients was 2.58 per 100 person-years vs 4.78 per 100 person-years (relative risk, 1.85; 95% CI, 0.92-3.73) for immunosuppression-exposed patients. In a proportional hazards model adjusting for sex, smoking history, age and stage at index malignancy, and nonmelanoma skin cancer, no significant association was found between receipt of immunosuppression and incident cancer (adjusted hazard ratio, 1.41; 95% CI, 0.69-2.90), or with any major drug class. CONCLUSIONS: In this interim analysis of patients with IBD and a history of cancer, despite numerically increased adjusted hazard ratios, we did not find a statistically significant association between subsequent exposure to immunosuppressive therapies and development of incident cancers.

Predicting inpatient mortality in patients with inflammatory bowel disease: A machine learning approach.

BACKGROUND AND AIM: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Impact of Inflammatory Bowel Disease Therapies on Durability of Humoral Response to SARS-CoV-2 Vaccination.

Immunization against the spike protein of SARS-CoV-2 reduces transmission1,2 and severe outcomes. However, little is known regarding the impact of immune-mediated diseases and immunosuppressive medications on the efficacy of vaccination. Vaccination immunity is transient, with breakthrough cases increasing at longer time intervals since the last dose.3,4 Although there are data on SARS-CoV-2 vaccine on early seroconversion in patients with inflammatory bowel disease (IBD),5 no data in the same cohort exist describing the durability of these antibodies over time. We sought to investigate the impact of IBD and its therapies on postvaccination antibody response and kinetics of immunogenicity decline, because these findings may better inform clinical guidelines and recommendations on precautions and booster vaccination.

Dual Biologic or Small Molecule Therapy for Treatment of Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

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.

Bacterial Swarmers Enriched During Intestinal Stress Ameliorate Damage.

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.

Article Topic: Positioning Ulcerative Colitis Therapies in 2022 and Beyond.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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.

Deciphering structural bases of intestinal and hepatic selectivity in targeting pregnane X receptor with indole-based microbial mimics.

Microbial metabolite mimicry is a new concept that promises to deliver compounds that have minimal liabilities and enhanced therapeutic effects in a host. In a previous publication, we have shown that microbial metabolites of L-tryptophan, indoles, when chemically altered, yielded potent anti-inflammatory pregnane X Receptor (PXR)-targeting lead compounds, FKK5 and FKK6, targeting intestinal inflammation. Our aim in this study was to further define structure-activity relationships between indole analogs and PXR, we removed the phenyl-sulfonyl group or replaced the pyridyl residue with imidazolopyridyl of FKK6. Our results showed that while removal of the phenyl-sulfonyl group from FKK6 (now called CVK003) shifts agonist activity away from PXR towards the aryl hydrocarbon receptor (AhR), the imidazolopyridyl addition preserves PXR activity in vitro. However, when these compounds are administered to mice, that unlike the parent molecule, FKK6, they exhibit poor induction of PXR target genes in the intestines and the liver. These data suggest that modifications of FKK6 specifically in the pyridyl moiety can result in compounds with weak PXR activity in vivo. These observations are a significant step forward for understanding the structure-activity relationships (SAR) between indole mimics and receptors, PXR and AhR.

Comorbid Diabetes in Inflammatory Bowel Disease Predicts Adverse Disease-Related Outcomes and Infectious Complications.

BACKGROUND: 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. AIM: To investigate the impact of DM on IBD-related disease outcomes, mortality, and infections in patients with IBD. METHODS: 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. RESULTS: 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. CONCLUSION: Comorbid diabetes in patients with IBD is a predictor of poor disease-related and infectious outcomes.

An Unusual Hiccup: Severe Singultus as a Symptom in Ulcerative Colitis.

Inflammatory bowel disease encompasses a group of chronic inflammatory conditions associated with both intestinal and extraintestinal manifestations. We present a 26-year-old man with a history of ulcerative colitis who presented with a disease exacerbation associated with severe intractable hiccups. We report a unique clinical symptom associated with severe ulcerative colitis and the diagnostic dilemma associated with this presentation. This case highlights the importance of recognizing unusual symptoms that can be associated with inflammatory bowel disease exacerbations and demonstrates the therapeutic potential of effective therapy of the underlying inflammatory disease.

Diagnosis of Inflammatory Bowel Disease-Associated Peripheral Arthritis: A Systematic Review.

BACKGROUND: Inflammatory bowel disease (IBD)-associated peripheral spondyloarthritis (pSpA) decreases quality of life and remains poorly understood. Given the prevalence of this condition and its negative impact, it is surprising that evidence-based disease definitions and diagnostic strategies are lacking. This systematic review summarizes available data to facilitate development and validation of diagnostics, patient-reported outcomes, and imaging indices specific to this condition. METHODS: A literature search was conducted. Consensus or classification criteria, case series, cross-sectional studies, cohort studies, and randomized controlled trials related to diagnosis were included. RESULTS: A total of 44 studies reporting data on approximately 1500 patients with pSpA were eligible for analysis. Data quality across studies was only graded as fair to good. Due to large heterogeneity, meta-analysis was not possible. The majority of studies incorporated patient-reported outcomes and a physical examination. A total of 13 studies proposed or validated screening tools, consensus, classification, or consensus criteria. A total of 28 studies assessed the role of laboratory tests, none of which were considered sufficiently accurate for use in diagnosis. A total of 17 studies assessed the role of imaging, with the available literature insufficient to fully endorse any imaging modality as a robust diagnostic tool. CONCLUSIONS: This review highlights existing inconsistency and lack of a clear diagnostic approach for IBD-associated pSpA. Given the absence of an evidence-based approach, a combination of existing criteria and physician assessment should be utilized. To address this issue comprehensively, our future efforts will be directed toward pursuit of a multidisciplinary approach aimed at standardizing evaluation and diagnosis of IBD-associated pSpA.

This systematic review highlights the lack of an evidence-based approach to the diagnosis of inflammatory bowel disease­associated peripheral spondyloarthritis and the need to standardize evaluation and diagnosis via multidisciplinary collaboration with development of patient-reported outcomes and imaging indices.

p53 basic C terminus regulates p53 functions through DNA binding modulation of subset of target genes.

The p53 gene encodes a transcription factor that is composed of several functional domains: the N-terminal transactivation domain, the central sequence-specific DNA binding domain, the tetramerization domain, and the highly basic C-terminal regulatory domain (CTD). The p53 CTD is a nonspecific DNA binding domain that is subject to extensive post-translational modifications. However, the functional significance of the p53 CTD remains unclear. The role of this domain in the regulation of p53 functions is explored by comparing the activity of ectopically expressed wild-type (WT) p53 protein to that of a truncated mutant lacking the 24 terminal amino acids (Δ24). Using quantitative real time PCR and chromatin Immuno-Precipitation experiments, a p53 CTD deletion is shown to alter the p53-dependent induction of a subset of its target genes due to impaired specific DNA binding. Moreover, p53-induced growth arrest and apoptosis both require an intact p53 CTD. These data indicate that the p53 CTD is a positive regulator of p53 tumor suppressor functions.

Mycobacterium avium subspecies paratuberculosis (MAP) and Crohn's disease: the debate continues.

Crohn's disease (CD) in humans and Johne's disease (JD) in ruminants share numerous clinical and pathologic similarities. As Mycobacteria avium subspecies paratuberculosis (MAP) is known to fulfill Koch's postulates as the cause of JD, there has been considerable debate over the past century about whether MAP also plays a role in CD. With recent advances in MAP identification techniques, we can now demonstrate a higher presence of MAP in CD patients compared to the general population. However, it remains unclear if MAP is playing a bystander role or is directly pathogenic in these patients. Studies have shown that there may be an immune response targeting MAP in these patients, which may underlie a pathologic role in CD. Clinical studies have yielded conflicting results as to whether anti-MAP therapy improves clinical outcomes in CD, leading to the lack of its inclusion within evidence-based clinical guidelines. Additionally, many of these studies have been small case series, with only a few randomized controlled trials published to date. In this article, we will discuss the historical context of MAP in CD, review clinical and laboratory data surrounding detection of MAP and possible pathogenesis in human disease, and suggest future directions which may finally provide some clarity to this debate.

Effect of comorbid conditions on adherence to colorectal cancer screening.

Potential barriers to colorectal cancer (CRC) screening include preexisting medical conditions (comorbidities), physician recommendation, psychosocial factors, and screening preparedness. This study's purpose was to investigate the impact of comorbid conditions on CRC screening among African Americans. A stage-matched randomized clinical trial was performed. Asymptomatic African Americans over age 50, with a primary care physician, and eligible for CRC screening were recruited at The Mount Sinai Hospital from 2005 to 2008. One hundred sixty-one patients were assessed for referral for, and completion of, CRC screening, comorbid conditions, "readiness to change," and number of physician visits within the observation period. Data was compared to a pretrial index to predict the likely effect of comorbid conditions on CRC screening. One hundred fifty-nine patients completed the study; 108 (68.9%) were referred for and 34 (21.2%) completed CRC screening. No demographic characteristics were associated with CRC screening completion. CRC screening referrals were similar for all patients, regardless of comorbidities or clinical visits. Comorbidities rated as having extreme influence on CRC screening showed a trend toward lower screening rates. There was a significant increase in screening rates among participants in advanced stages of readiness at enrollment. These data suggest that while comorbidities did not predict colonoscopy completion, they may play a role in concert with other factors. This is the only study to assess the effect of screening colonoscopy in an African American primary care setting. We must continue to explore interventions to narrow the disparate gap in screening and mortality rates.

COVID-19 is not associated with worse long-term inflammatory bowel disease outcomes: a multicenter case-control study.

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.

Incident heart failure is a predictor of adverse outcomes in inflammatory bowel disease.

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.