Clinical Decision Making in Inflammatory Bowel Disease Mimics: Practice Management from Inflammatory Bowel Disease LIVE.

Background: Since 2009, inflammatory bowel disease (IBD) specialists have utilized "IBD LIVE," a weekly live video conference with a global audience, to discuss the multidisciplinary management of their most challenging cases. While most cases presented were confirmed IBD, a substantial number were diseases that mimic IBD. We have categorized all IBD LIVE cases and identified "IBD-mimics" with consequent clinical management implications. Methods: Cases have been recorded/archived since May 2018; we reviewed all 371 cases from May 2018-February 2023. IBD-mimics were analyzed/categorized according to their diagnostic and therapeutic workup. Results: Confirmed IBD cases made up 82.5% (306/371; 193 Crohn's disease, 107 ulcerative colitis, and 6 IBD-unclassified). Sixty-five (17.5%) cases were found to be mimics, most commonly medication-induced (n = 8) or vasculitis (n = 7). The evaluations that ultimately resulted in correct diagnosis included additional endoscopic biopsies (n = 13, 21%), surgical exploration/pathology (n = 10, 16.5%), biopsies from outside the GI tract (n = 10, 16.5%), genetic/laboratory testing (n = 8, 13%), extensive review of patient history (n = 8, 13%), imaging (n = 5, 8%), balloon enteroscopy (n = 5, 8%), and capsule endoscopy (n = 2, 3%). Twenty-five patients (25/65, 38%) were treated with biologics for presumed IBD, 5 of whom subsequently experienced adverse events requiring discontinuation of the biologic. Many patients were prescribed steroids, azathioprine, mercaptopurine, or methotrexate, and 3 were trialed on tofacitinib. Conclusions: The diverse presentation of IBD and IBD-mimics necessitates periodic consideration of the differential diagnosis, and reassessment of treatment in presumed IBD patients without appropriate clinical response. The substantial differences and often conflicting treatment approaches to IBD versus IBD-mimics directly impact the quality and cost of patient care.

Surgery for Crohn's Disease Is Associated with a Dysbiotic Microbiome and Metabolome: Results from Two Prospective Cohorts.

BACKGROUND AND AIMS: Crohn's disease is associated with alterations in the gut microbiome and metabolome described as dysbiosis. We characterized the microbial and metabolic consequences of ileal resection, the most common Crohn's disease surgery. METHODS: Patients with and without intestinal resection were identified from the Diet to Induce Remission in Crohn's Disease and Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease studies. Stool samples were analyzed with shotgun metagenomics sequencing. Fecal butyrate was measured with 1H nuclear magnetic resonance spectroscopy. Fecal bile acids and plasma 7α-hydroxy-4-cholesten-3-one (C4) was measured with mass spectrometry. RESULTS: Intestinal resection was associated with reduced alpha diversity and altered beta diversity with increased Proteobacteria and reduced Bacteroidetes and Firmicutes. Surgery was associated with higher representation of genes in the KEGG pathway for ABC transporters and reduction in genes related to bacterial metabolism. Surgery was associated with reduced concentration of the But gene but this did not translate to reduced fecal butyrate concentration. Surgery was associated with decreased abundance of bai operon genes, with increased plasma C4 concentration, increased primary bile acids and reduced secondary bile acids, including isoLCA. Additionally, E lenta, A equalofaciens and G pamelaeae were lower in abundance among patients with prior surgery in both cohorts. CONCLUSIONS: In two different populations, prior surgery in Crohn's disease is associated with altered fecal microbiome. Patients who had undergone ileal resection had reduction in the potentially beneficial bacteria E lenta and related actinobacteria as well as secondary bile acids, including isoLCA, suggesting that these could be biomarkers of patients at higher risk for disease progression.

Cardiovascular Comorbidities and Inflammatory Bowel Disease: Causes and Consequences.

Patients with inflammatory bowel disease (IBD) have an increased risk of cardiovascular disease (CVD) such as myocardial infarction and stroke. CVD in patients with IBD might occur in those with younger age and active disease, which are not traditional risk factors of CVD. Atherosclerotic CVD (ASCVD) and IBD are both proinflammatory conditions, and the underlying chronic inflammation might drive ASCVD risk. Decreasing inflammation might reduce this risk; however, data are limited. IBD medications can increase or decrease ASCVD risk. There are no specific guidelines or modalities to assess ASCVD in IBD. Early detection and risk stratification strategies have been established in other chronic inflammatory disorders. This article discusses causes of CVD in IBD and strategies to modify the consequences.

Correlation Between Serum and Fecal Biomarkers and Patient-Reported Outcomes in Patients with Crohn's Disease and Ulcerative Colitis.

BACKGROUND: Patient-reported outcomes (PROs), such as the short CD activity index (sCDAI) and partial Mayo Score (PMS), are used to define clinical remission in IBD, but may not represent the true degree of inflammation and endoscopy is invasive. Non-invasive testing options include c-reactive protein (CRP) and fecal calprotectin (FCP). AIM: The aim of this study was to assess the degree of correlation of non-invasive biomarkers with PROs and the impact other clinical variables can have on their levels. METHODS: We reviewed data collected from the prospective cohort, Study of a Prospective Adult Research Cohort with IBD (SPARC-IBD), comprised of over 3000 patients from 17 tertiary referral centers. Demographic and clinical variables were analyzed by disease type, disease severity was based on PROs, and baseline CRP and FCP were measured. For comparative analysis, we performed Fisher's exact test and Welch's t test, where p < 0.05 was significant. RESULTS: 1547 patients were included; 63% had CD, 56% were female, with an average disease duration of 13.6 years. CRP and FCP were associated with symptom severity in inflammatory CD. CRP was useful to differentiate symptoms across different disease locations in CD, whereas FCP was associated with symptom severity in Crohn's colitis only. For UC, FCP was able to distinguish symptom severity better in distal UC, whereas in extensive or pancolitis, it was useful only to distinguish severe symptoms from other categories of symptom severity. CONCLUSION: PROs correlate with CRP and FCP; however, disease location and phenotype impact their ability to distinguish symptom severity.

Unraveling the Oral-Gut axis: Interconnection between Periodontitis and IBD, Current Challenges, and Future Perspective.

As the opposite ends of the orodigestive tract, the oral cavity and the intestine share anatomical, microbial, and immunological ties that have bidirectional health implications. A growing body of evidence suggests an interconnection between oral pathologies and Inflammatory Bowel Disease (IBD), implying a shift from the traditional concept of independent diseases to a complex, reciprocal cycle. This review outlines the evidence supporting an "Oral-Gut" axis, marked by a higher prevalence of periodontitis and other oral conditions in IBD patients and vice versa. We present an in-depth examination of the interconnection between oral pathologies and IBD, highlighting the shared microbiological and immunological pathways, and proposing a "multi-hit" hypothesis in the pathogenesis of periodontitis-mediated intestinal inflammation. Furthermore, the review underscores the critical need for a collaborative approach between dentists and gastroenterologists to provide holistic oral-systemic healthcare.

ExpLOring the role of the intestinal MiCrobiome in InflammATory bowel disease-AssocIated SpONdylarthritis (LOCATION-IBD).

Background: Inflammatory Bowel Disease (IBD)-associated arthritis is a frequent and potentially debilitating complication of IBD, that can affect those with or without active intestinal disease, and is often difficult to treat. The microbiome is known to play a role in IBD development and has been shown to be associated with inflammatory arthritis without concomitant IBD, but its role in IBD-associated arthritis is still unexplored. Further, disease localization is associated with development of IBD-associated arthritis, and stool compositional profiles are predictive of disease localization, yet mucosal location-specific microbiomes have not been well characterized. To address this gap in understanding, we designed a study (LOCATION-IBD) to characterize the mucosa-associated intestinal microbiome and metabolome in IBD-associated arthritis. Methods: Adults with an established diagnosis of IBD undergoing clinical colonoscopy between May of 2021 and February of 2023 were invited to participate in this study; those interested in participation who met inclusion criteria were enrolled. Prior to enrollment, participants were stratified into those with or without IBD-associated arthritis. All participants were interviewed and had clinical and demographic data collected, and 97.8% completed clinical colonoscopy with biopsy collection. Results and conclusion: A total of 182 participants, 53 with confirmed IBD-associated arthritis, were enrolled in this study, resulting in 1151 biopsies obtained for microbiome and metabolome analysis (median 6, mean 6.3 per participant). Clinical and demographic data obtained from the study population will be analyzed with microbiome and metabolome data obtained from biopsies, with the goal of better understanding the mechanisms underpinning the host-microbiome relationship associated the development of IBD-associated arthritis.

Humoral immune response and safety of SARS-CoV-2 vaccination in very early onset inflammatory bowel disease.

Children with very early onset inflammatory bowel disease (VEO-IBD) may respond differently to coronavirus disease 2019 (COVID-19) immunization compared to healthy children or other patients with IBD. We recruited children with VEO-IBD <6 years of age and younger following receipt of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Demographics, IBD characteristics, medication use, adverse events (AEs) and IBD exacerbations were collected. Blood draws (optional) were obtained for measurement of antireceptor binding domain (RBD) IgG antibodies following vaccination. Of 41 participants, none required emergency department visit or hospitalization due to AE, and only one experienced IBD exacerbation. Detectable antibody was present in 19/19 participants who provided blood sample; 6/7 participants (86%) had durable humoral response 12 months postvaccination. Children with VEO-IBD experience robust humoral immune response to COVID-19 immunization. Severe AEs were rare. These findings provide reassurance that children with VEO-IBD respond well and safely to SARS-CoV-2 vaccination.

Upadacitinib as Rescue Therapy for the Treatment of Acute Severe Colitis in an Acute Care Setting.

BACKGROUND: Inflammatory bowel disease is a chronic, relapsing, and remitting inflammatory disorder that despite advances in medical therapy often requires hospitalization for treatment of acute flares with intravenous corticosteroids. Many patients will not respond to corticosteroids and require infliximab or cyclosporine as rescue therapy. If medical therapy fails, definitive surgical management is required. Recently, Janus Kinase inhibitors, including upadacitinib, have been proposed as an alternative rescue therapy. AIMS: We hypothesized that upadacitinib may be effective in treating acute severe colitis. METHODS: A retrospective review of 12 inflammatory bowel disease patients admitted for acute severe colitis who received upadacitinib induction therapy was performed. The rates of surgery, repeat or prolonged steroid use, and re-admission within 90 days of index hospitalization were measured. The need for re-induction with upadacitinib, change in medical therapy, rates of clinical remission, change in 6-point partial Mayo score, and laboratory markers of inflammation were measured as secondary outcomes. RESULTS: Five patients met the primary composite endpoint including four patients requiring surgery and one additional patient being unable to withdraw steroids within 90 days of hospital discharge. One patient required re-induction with upadacitinib within 90 days and no patients required change in medical therapy within 90 days. Most patients who did not undergo surgery were in clinical remission within 90 days and showed clinical improvement with decreased 6-point partial Mayo scores. CONCLUSION: Upadacitinib may be effective salvage therapy for acute severe colitis, but larger controlled trials are required to validate these results.

Long-Term Effectiveness and Durability of COVID-19 Vaccination Among Patients With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: COVID-19 vaccination prevents severe disease in most patients with inflammatory bowel disease (IBD), but immunosuppressive medications can blunt serologic response. We followed adults with IBD for >1 year post-COVID-19 vaccination to describe factors associated with SARS-CoV-2 infection after vaccination, evaluate for a protective SARS-CoV-2 antibody level, characterize SARS-CoV-2 antibody persistence, and identify factors associated with humoral immune response durability. METHODS: Using a prospective cohort of COVID-19 immunized adults with IBD, we analyzed factors associated with SARS-CoV-2 infection after vaccination. We evaluated for an association between SARS-CoV-2 antibody level 12 weeks postvaccination and subsequent SARS-CoV-2 infection and assessed for a threshold of protection using receiver-operating characteristic curve analysis. We then conducted a separate analysis evaluating factors associated with persistence of SARS-CoV-2 antibodies 52 weeks postimmunization. RESULTS: Almost half (43%) of 1869 participants developed COVID-19 after vaccination, but most infections were mild, and <1% required hospitalization. Older age and corticosteroid use were associated with a decreased risk of SARS-CoV-2 infection postvaccination (50-59 years of age vs 18-29 years of age: adjusted hazard ratio, 0.57; 95% confidence interval, 0.44-0.74; steroid users vs nonusers: adjusted hazard ratio, 0.58; 95% confidence interval, 0.39-0.87). Most (98%) participants had detectable antibody levels at 52 weeks postvaccination. Antibody levels at 12 weeks and number of vaccine doses were positively associated with higher antibody levels at 52 weeks, while anti-tumor necrosis factor α therapy was negatively associated. CONCLUSIONS: COVID-19 vaccination generates an effective and durable protective response for the vast majority of adults with IBD, including vulnerable populations such as corticosteroid users and older individuals. Patients with IBD benefit from COVID-19 booster vaccination.

Changes in Therapy Are Not Associated With Increased Remission in Patients With Crohn's Disease of the Pouch.

INTRODUCTION: There is a paucity of data on the real-world effectiveness of therapies in patients with Crohn's disease of the pouch. METHODS: This was a prospective multicenter study evaluating the primary outcome of remission at 12 months of therapy for Crohn's disease of the pouch. RESULTS: One hundred thirty-four patients were enrolled. Among the 77 patients with symptoms at baseline, 35 (46.7%) achieved remission at 12 months. Of them, 12 (34.3%) changed therapy. There was no significant association between therapy patterns and remission status. DISCUSSION: Approximately 50% with symptoms at enrollment achieved clinical remission at 12 months, most of whom did so without a change in therapy.

Monitoring Patients With Inflammatory Bowel Disease at High Risk of Anal Cancer.

Anal cancer is a rare but deadly disease that disproportionately affects patients with inflammatory bowel disease (IBD). Rates of adenocarcinoma and human papillomavirus-related squamous cell carcinoma have been consistently demonstrated to be higher in patients with ulcerative colitis and Crohn's disease. Despite this increased risk, uniform screening, diagnosis, and treatment algorithms are lacking. This review describes the most recent literature surrounding anal cancer in the IBD population as well as the unique challenges inherent in diagnosing and treating this population. We conclude by proposing a new screening motif based off literature review and multidisciplinary clinical experience that aims to increase early detection of anal cancers in the IBD population.

Review of Adalimumab Biosimilar SB5 in Immune-Mediated Inflammatory Diseases.

SB5 is an approved biosimilar of adalimumab, a recombinant monoclonal anti-tumor necrosis factor (TNF) antibody. The approval of SB5 was based on the comparison with reference adalimumab in analytical studies, pharmacokinetic (PK) and immunogenicity assessments, and randomized controlled trials. Efficacy data was primarily obtained in patients with rheumatoid arthritis, and extended to include additional indications such as psoriasis, Crohn's disease, or ulcerative colitis by extrapolation. Following its approval, additional post-marketing data have been collected comparing SB5 with reference adalimumab. This review summarizes the clinical data on SB5 from randomized controlled trials and provides a comprehensive overview of the available post-approval data. In "real-world" settings, SB5 was as effective as its reference product across different indications and countries, treatment persistence was well maintained throughout studies, and no new safety concerns were identified. In both controlled and "real-world" settings, switching from reference adalimumab to SB5 was not associated with altered efficacy or clinical complications. In post-approval studies, the quality of SB5 was consistent over time, independent of the batch and process changes, and the SB5 autoinjector was preferred over other autoinjectors by both healthcare professionals and patients. Taken together, these data support the use of SB5 whenever reference adalimumab is appropriate and demonstrate that switching from reference adalimumab to SB5 is feasible.

Cardiovascular Safety of Ozanimod in Patients With Ulcerative Colitis: True North and Open-Label Extension Analyses.

BACKGROUND & AIMS: Evaluating cardiovascular safety of sphingosine 1-phosphate (S1P) receptor modulators is warranted due to S1P receptor expression on cardiomyocytes and vascular endothelial cells. This analysis reports the cardiovascular safety of ozanimod, an S1P receptor modulator, in patients with moderately to severely active ulcerative colitis from the phase 3 True North (TN) and open-label extension (OLE). METHODS: All patients who received ozanimod in TN (n = 796) and all eligible TN patients who entered the OLE (n = 823) were included. Cardiovascular-related adverse events were evaluated in patients with up to 146 weeks of ozanimod exposure (2219 patient-years), which included 52 weeks during TN. RESULTS: On TN day 1, first-dose ozanimod resulted in a 0.2 beats per minute mean decrease in heart rate from pretreatment to hour 6; 2 patients experienced bradycardia, which resolved without treatment modification. Mean systolic and diastolic blood pressure increases of 5.1 and 2.2 mm Hg, respectively, were observed at TN week 52. No second-degree Mobitz type II atrioventricular block events were reported; 1 third-degree atrioventricular block unrelated to ozanimod occurred in the OLE. Cardiac and vascular treatment-emergent adverse events were infrequent (3.8% [31 of 823] and 8.5% [70 of 823]); no ozanimod-related cardiovascular deaths occurred. The incidences of deep-vein thrombosis (0.2%; 2 of 823), pulmonary embolism (0.2%; 2 of 823), and ischemic stroke (0.4%; 3 of 823) in the OLE were low. CONCLUSIONS: No new cardiovascular safety signals were identified, consistent with findings from previous ozanimod studies. There were few major adverse cardiovascular events or thromboembolic events, which were unrelated or unlikely related to ozanimod. Ozanimod has a well-tolerated cardiovascular safety profile when prescribed in accordance with the label. Clinical trial registry website and trial numbers: ClinicalTrials.gov numbers: NCT02435992 and NCT02531126.

Personalized Treatment for Crohn's Disease: Current Approaches and Future Directions.

Crohn's disease is a complex, relapsing and remitting inflammatory disorder of the gastrointestinal tract with a variable disease course. While the treatment options for Crohn's disease have dramatically increased over the past two decades, predicting individual patient response to treatment remains a challenge. As a result, patients often cycle through multiple different therapies before finding an effective treatment which can lead to disease complications, increased costs, and decreased quality of life. Recently, there has been increased emphasis on personalized medicine in Crohn's disease to identify individual patients who require early advanced therapy to prevent complications of their disease. In this review, we summarize our current approach to management of Crohn's disease by identifying risk factors for severe or disabling disease and tailoring individual treatments to patient-specific goals. Lastly, we outline our knowledge gaps in implementing personalized Crohn's disease treatment and describe the future directions in precision medicine.

Factors Associated With Extraintestinal Manifestations of Inflammatory Bowel Disease in SPARC-IBD.

BACKGROUND: Extraintestinal manifestations (EIMs) of inflammatory bowel diseases (IBDs) are a common and debilitating feature of disease, occurring in up to 40% of patients with IBD, yet predicting who may develop them is difficult. The goal of our study was to better characterize which patients may be at highest risk of developing not only 1 EIM, but also multiple EIMs, across both diseases. METHODS: A retrospective study of participants enrolled in the SPARC IBD (Study of Prospective Adult Research Cohort with IBD) registry was performed, and demographic and clinical data were analyzed. A total of 1211 patients with data available on EIMs were included, and differences among variables with vs without EIMs were assessed. RESULTS: A total of 329 participants with at least 1 EIM were identified, compared with 882 participants without any EIMs. Crohn's disease patients and women were more likely to have 2 or more EIMs (P = .005 and P ≤ .001, respectively). Participants with ocular manifestations were likeliest to have at least 2 EIMs (P ≤ .001). Even when diagnosis was controlled for, involvement of the right colon (P = .021) was predictive of IBD-associated arthritis across both diseases in a multivariate generalized linear model. CONCLUSIONS: This is the first comprehensive large-cohort assessment of how EIMs relate to one another at the individual vs systems levels. Further, our analysis is the first to recognize specific locations of colon involvement associated with EIMs of IBD, regardless of IBD type. These results are important in identifying patients at risk of developing future EIMs and may help with risk stratification when choosing treatments.

Although extraintestinal manifestations frequently complicate inflammatory bowel disease, predicting those at highest risk of developing them is difficult. We found female patients with Crohn's disease, ocular, and dermatologic manifestations are likeliest to develop multiple extraintestinal manifestations. Further, we found right-sided involvement is predictive of inflammatory bowel disease­associated arthritis.

Extraintestinal Manifestations of Inflammatory Bowel Disease Are Associated With Increased Biologic Cycling.

Background: Extraintestinal manifestations (EIMs) of inflammatory bowel disease (IBD) are a common, frequently debilitating complication of the disease. Biologics are indicated and often required in patients with EIMs to control disease; however, little is known about whether patients with EIMs cycle through more therapies than their counterparts without EIMs. Methods: To address this question, we performed a retrospective analysis of patients enrolled in the Study of Prospective Adult Research Cohort with IBD registry seen at our University Medical Center, on data from December 2016 to January 2021. Four hundred fifty-six participants with information on EIMs and biologic use available were included, and demographic and clinical characteristics were analyzed. Results: Three hundred thirty-eight and 118 participants without and with EIMs were identified, respectively. Those with EIMs were likelier to have biologic exposure, and cycle through more biologics, both in univariate and multivariate analyses controlling for age, disease duration, sex, corticosteroid use, and IBD type (P-value = .006). In a subanalysis of patients with Crohn's disease (CD), EIMs were associated with increased biologic cycling in ileocolonic disease (P-value = .050). Conclusions: To our knowledge, this is the first study assessing biologic cycling in patients with EIMs. Our findings that patients with EIMs are likelier to cycle through biologics, particularly CD patients with ileocolonic disease, highlights the need for more research on which biologics may be most effective for specific subsets of IBD patients, including those with concurrent EIMs. The presence of EIMs is a marker of harder-to-treat IBD and may indicate earlier initiation of advanced therapies.

Histologic Inflammation can Predict Future Clinical Relapse in Ulcerative Colitis Patients in Endoscopic Remission.

Background: In ulcerative colitis (UC), endoscopic improvement, defined as a Mayo Endoscopic Score (MES) of 0 or 1, is a target of treatment. The aim of our study was to evaluate the risk of clinical relapse between patients with an MES of 0 or 1 and determine if histologic activity using the Robarts Histopathologic Index (RHI) was predictive of clinical relapse. Methods: UC patients with an MES score of 0 or 1, no prior colectomy, and at least 1 year of outpatient follow-up after colonoscopy were included. Demographic, clinical characteristics, and clinical relapse were retrospectively collected. Biopsy specimens were read by a gastrointestinal pathologist. Primary outcome was defined as a composite of relapse requiring change in medical therapy, new steroid use, UC-related hospitalization, and/or colectomy. Results: Four hundred and forty-five UC patients were identified. Ninety-five percent of patients with MES 0 were in histologic remission by the RHI whereas only 35% of patients with MES 1 were in histologic remission. Twenty-six percent of patients experienced a clinical relapse; patients with MES 1 or RHI > 3 were significantly more likely to relapse (P < .01) compared to patients with MES 0 or RHI ≤ 3. When patients were stratified into 4 groups (MES 0, RHI ≤ 3; MES 0, RHI > 3; MES 1, RHI ≤ 3; MES 1, RHI > 3) and adjusted for age and sex, RHI > 3 was predictive of relapse (P = .008). Conclusions: UC patients with endoscopic improvement have a high rate of clinical relapse over time. Histologic activity is a predictor of clinical relapse.

Unraveling the Link between Periodontitis and Inflammatory Bowel Disease: Challenges and Outlook.

Periodontitis and Inflammatory Bowel Disease (IBD) are chronic inflammatory conditions, characterized by microbial dysbiosis and hyper-immunoinflammatory responses. Growing evidence suggest an interconnection between periodontitis and IBD, implying a shift from the traditional concept of independent diseases to a complex, reciprocal cycle. This review outlines the evidence supporting an "Oral-Gut" axis, marked by a higher prevalence of periodontitis in IBD patients and vice versa. The specific mechanisms linking periodontitis and IBD remain to be fully elucidated, but emerging evidence points to the ectopic colonization of the gut by oral bacteria, which promote intestinal inflammation by activating host immune responses. This review presents an in-depth examination of the interconnection between periodontitis and IBD, highlighting the shared microbiological and immunological pathways, and proposing a "multi-hit" hypothesis in the pathogenesis of periodontitis-mediated intestinal inflammation. Furthermore, the review underscores the critical need for a collaborative approach between dentists and gastroenterologists to provide holistic oral-systemic healthcare.