Serum Metabolites Relate to Mucosal and Transmural Inflammation in Pediatric Crohn Disease.

BACKGROUND AND AIMS: We aimed to identify serum metabolites associated with mucosal and transmural inflammation in pediatric Crohn disease (pCD). METHODS: Fifty-six pCD patients were included through a pre-planned sub-study of the multicenter, prospective, ImageKids cohort, designed to develop the Pediatric Inflammatory Crohn's MRE Index (PICMI). Children were included throughout their disease course when undergoing ileocolonoscopy and magnetic resonance enterography (MRE) and followed for 18 months when MRE was repeated. Serum metabolites were identified using liquid chromatography/mass spectroscopy. Outcomes included: PICMI, the simple endoscopic score (SES), faecal calprotectin (FCP), and C-reactive protein (CRP), to assess transmural, mucosal, and systemic inflammation, respectively. Random forest models were built by outcome. Maximum relevance minimum redundancy (mRMR) feature selection with a j-fold cross validation scheme identified the best subset of features and hyperparameter settings. RESULTS: Tryptophan and glutarylcarnitine were the top common mRMR metabolites linked to pCD inflammation. Random forest models established that amino acids and amines were among the most influential metabolites for predicting transmural and mucosal inflammation. Predictive models performed well, each with an area under the curve (AUC) > 70%. In addition, serum metabolites linked with pCD inflammation mainly related to perturbations in citrate cycle (TCA cycle), aminoacyl-tRNA biosynthesis, tryptophan metabolism, butanoate metabolism, and tyrosine metabolism. CONCLUSIONS: We extend on recent studies, observing differences in serum metabolite between healthy controls and Crohn disease patients, and suggest various associations of serum metabolites with transmural and mucosal inflammation. These metabolites could improve the understanding of pCD pathogenesis and assess disease severity.

Postoperative Crohn's Disease Recurrence Risk and Optimal Biologic Timing After Temporary Diversion Following Ileocolic Resection.

BACKGROUND: Postoperative recurrence of Crohn's disease (CD) is common. While most patients undergo resection with undiverted anastomosis (UA), some individuals also have creation of an intended temporary diversion (ITD) with an ileostomy followed by ostomy takedown (OT) due to increased risk of anastomotic complications. We assessed the association of diversion with subsequent CD recurrence risk and the influence of biologic prophylaxis timing to prevent recurrence in this population. METHODS: This was a retrospective cohort study of CD patients who underwent ileocolic resection between 2009 and 2020 at a large quaternary health system. Patients were grouped by continuity status after index resection (primary anastomosis or ITD). The outcomes of the study were radiographic, endoscopic, and surgical recurrence as well as composite recurrence postoperatively (after OT in the ITD group). Propensity score-weighted matching was performed based on risk factors for diversion and recurrence. Multivariable regression and a Cox proportional hazards model adjusting for recurrence risk factors were used to assess association with outcomes. Subgroup analysis in the ITD group was performed to assess the impact of biologic timing relative to OT (no biologic, biologic before OT, after OT) on composite recurrence. RESULTS: A total of 793 CD patients were included (mean age 38 years, body mass index 23.7 kg/m2, 52% female, 23% active smoker, 50% penetrating disease). Primary anastomosis was performed in 67.5% (n = 535) and ITD in 32.5% (n = 258; 79% loop, 21% end) of patients. Diverted patients were more likely to have been males and to have had penetrating and perianal disease, prior biologic use, lower body mass index, and lower preoperative hemoglobin and albumin (all P < .01). After a median follow-up of 44 months, postoperative recurrence was identified in 83.3% patients (radiographic 40.4%, endoscopic 39.5%, surgical 13.3%). After propensity score matching and adjusting for recurrence risk factors, no significant differences were seen between continuity groups in radiographic (adjusted hazard ratio [aHR], 1.32; 95% confidence interval [CI], 0.91-1.91) or endoscopic recurrence (aHR, 1.196; 95% CI, 0.84-1.73), but an increased risk of surgical recurrence was noted in the ITD group (aHR, 1.61; 95% CI, 1.02-2.54). Most (56.1%) ITD patients started biologic prophylaxis after OT, 11.4% before OT, and 32.4% had no postoperative biologic prophylaxis. Biologic prophylaxis in ITD was associated with younger age (P < .001), perianal disease (P = .04), and prior biologic use (P < .001) but not in recurrence (P = .12). Despite higher rates of objective disease activity identified before OT, biologic exposure before OT was not associated with a significant reduction in composite post-OT recurrence compared with starting a biologic after OT (52% vs 70.7%; P = 0.09). CONCLUSIONS: Diversion of an ileocolic resection is not consistently associated with a risk of postoperative recurrence and should be performed when clinically appropriate. Patients requiring diversion at time of ileocolic resection are at high risk for recurrence, and biologic initiation prior to stoma reversal may be considered.

Diversion of an ileocolic resection is not consistently associated with a risk of postoperative recurrence and should be performed when clinically appropriate. Patients requiring diversion at time of ileocolic resection are high risk for recurrence, and biologic initiation prior to stoma reversal may be considered.

Influence of multidisciplinary team care with abundant nurse staffing on patient-reported outcomes among patients with inflammatory bowel disease in clinical remission.

BACKGROUND: Patients with inflammatory bowel disease (IBD) experience difficulties in daily life and demanding self-care needs. The goal of our support for patients is to ease their difficulties and improve their belief in their capacity to self-manage their disease (self-efficacy), by increasing their ability for self-care. The nurse's contribution is vital in empowering patients and supporting them to better manage their disease. There is evidence that higher nurse staffing levels are associated with better patient outcomes in acute care settings, but little is known about the outpatient setting. The objective of this study was to explore the impact of multidisciplinary team care with abundant nurse staffing levels on patient-reported outcome measures (PROMs) among patients with IBD, encompassing Crohn's disease (CD) and ulcerative colitis (UC), in clinical remission. METHODS: Patients with IBD in clinical remission were included because disease activity influences the patient's subjective evaluation. A total of 499 valid responses from two different sources were analyzed: 318 from a specialized IBD clinic with abundant nurse staffing and a multidisciplinary care team (UC: 83, CD: 235) and 181 from an online survey panel (UC: 109, CD: 72). The IBD Self-Efficacy Scale (IBD-SES) and the difficulty of life scale (DLS) were used as disease-specific PROMs. RESULTS: In two multiple regression models adjusted by background characteristics (age, sex, diagnosis [UC/CD], employment status, use of biologics, and disease duration) using the IBD-SES or DLS as a dependent variable, the responses from clinic patients showed a more favorable score (higher self-efficacy or lower difficulty) than the online responses. CONCLUSIONS: Multidisciplinary team care with abundant nurse staffing may improve self-efficacy and ease difficulties of life among patients with IBD in clinical remission. These results could help bring attention to nurse staffing in an outpatient setting, which has previously been overlooked, and be the first to provide evidence of its importance in encouraging enhanced staffing levels.

Leukocytoclastic Vasculitis-Associated Myocarditis as an Extraintestinal Manifestation of Crohn's Disease.

Cardiac extraintestinal manifestations (EIMs) of Crohn's disease (CD) are uncommon. They include pericarditis, myocarditis, and arrhythmias; however, distinguishing these from alternative causes including medication-related adverse effects is often challenging. Leukocytoclastic vasculitis is another uncommon EIM of CD that may present with systemic involvement. We present a rare case of myocarditis associated with leukocytoclastic vasculitis occurring as EIMs of CD. The myocarditis proved refractory to standard therapy and biologics targeting underlying gut inflammation. She developed an inflammatory cardiomyopathy and symptoms consistent with heart failure with preserved ejection fraction. Anakinra was tried, but despite the initial response, it should be used cautiously in patients with CD.

Association between 23 drugs and inflammatory bowel disease: a two-sample Mendelian randomization study.

Background: Inflammatory bowel disease (IBD) is a group of diseases characterized by chronic and recurrent inflammation of the gastrointestinal tract. The etiology of IBD remains multifaceted and poorly understood, resulting in limited treatment options that primarily target disease induction and remission maintenance. Thus, the exploration of novel therapeutic options for IBD among existing medications is advantageous. Mendelian randomization analysis (MR) serves as a valuable tool in investigating the relationship between drugs and diseases. In this study, MR analysis was employed to investigate the potential causal relationship between 23 approved drugs for the treatment of various diseases and IBD. Method: We performed a two-sample MR analysis using publicly available genome-wide association study (GWAS) statistics. The inverse variance weighting (IVW) method was used as the main analysis method, supplemented by the remaining four methods (weighted median, MR Egger regression, simple and weighted models), and Meta-analysis was performed to expand the sample size to obtain a more reliable composite causal effect. Finally, Cochran's Q statistic and the MR-Egger test for directed pleiotropy were applied to determine whether significant heterogeneity or directed pleiotropy existed. Results: In the main MR analysis (IVW), drugs with a negative causal association with the risk of IBD were immunosuppressant {OR (95% CI) = 0.7389 [0.6311-0.8651], p = 0.0046} and diabetes drugs {OR (95% CI) = 0.9266 [0.8876-0.9674], p = 0.0058}. A positive causal association with the risk of IBD was found for salicylic acid and derivatives {OR (95% CI) = 1.2737 [1.0778-1.5053], p = 0.0345}. Negative causal associations with UC risk were identified for immunosuppressants {OR (95% CI) = 0.6660 [0.5133-0.8640], p = 0.0169} and diabetes medications {OR (95% CI) = 0.9020 [0.8508-0.9551], p = 0.0046}; positive causal associations with UC risk were found for ß-receptor blockers {OR (95% CI) = 1.1893 [1.0823-1.3070], p = 0.0046}. A negative causal association with the risk of CD was found for immunosuppressants {OR (95% CI) = 0.6957 [0.5803-0.8341], p = 0.0023}. There was no statistically significant association between the remaining 19 drugs and IBD and subtypes. Conclusion: This MR study provides evidence suggesting that immunosuppressants have a mitigating effect on the risk of IBD and demonstrate consistent efficacy in subtypes of ulcerative colitis (UC) and Crohn's disease (CD). Additionally, diabetes medications show potential in reducing the risk of IBD, particularly in cases of UC, while ß-blockers may elevate the risk of UC. Conversely, salicylic acid and its derivatives may increase the risk of IBD, although this effect is not consistently observed in the subtypes of the disease. These findings offer new insights into the prevention and management of IBD.

Identifying hub genes in response to ustekinumab and the impact of ustekinumab treatment on fibrosis in Crohn's disease.

Introduction: Crohn's disease (CD) is a chronic inflammatory disease. Approximately 50% of patients with CD progressed from inflammation to fibrosis. Currently, there are no effective drugs for treating intestinal fibrosis. Biologic therapies for CD such as ustekinumab have benefited patients; however, up to 30% of patients with CD have no response to initial treatment, and the effect of ustekinumab on intestinal fibrosis is still uncertain. Therefore, it is of great significance to explore the predictive factors of ustekinumab treatment response and the effect of ustekinumab on intestinal fibrosis. Materials and methods: Public datasets-GSE207465 (blood samples) and GSE112366 and GSE207022 (intestinal samples)-were downloaded and analyzed individually (unmerged) based on the treatment response. Differentially expressed genes (DEGs) were identified by the "limma" R package and changes in immune cell infiltration were determined by the "CIBERSORT" R package in both blood and intestinal samples at week 0 (before treatment). To find predictive factors of ustekinumab treatment response, the weighted gene co-expression network analysis (WGCNA) R package was used to identify hub genes in GSE112366. Hub genes were then verified in GSE207022, and a prediction model was built by random forest algorithm. Furthermore, fibrosis-related gene changes were analyzed in ileal samples before and after treatment with ustekinumab. Results: (1) Our analysis found that MUC1, DUOX2, LCN2, and PDZK1IP1 were hub genes in GSE112366. GSE207022 revealed that MUC1 (AUC:0.761), LCN2 (AUC:0.79), and PDZK1IP1 (AUC:0.731) were also lower in the response group. Moreover, the random forest model was shown to have strong predictive capabilities in identifying responders (AUC = 0.875). To explore the relationship between intestinal tissue and blood, we found that ITGA4 had lower expression in the intestinal and blood samples of responders. The expression of IL18R1 is also lower in responders' intestines. IL18, the ligand of IL18R1, was also found to have lower expression in the blood samples from responders vs. non-responders. (2) GSE112366 revealed a significant decrease in fibrosis-related module genes (COL4A1, TUBB6, IFITM2, SERPING1, DRAM1, NAMPT, MMP1, ZEB2, ICAM1, PFKFB3, and ACTA2) and fibrosis-related pathways (ECM-receptor interaction and PI3K-AKT pathways) after ustekinumab treatment. Conclusion: MUC1, LCN2, and PDZK1IP1 were identified as hub genes in intestinal samples, with lower expression indicating a positive prediction of ustekinumab treatment response. Moreover, ITGA4 and IL18/IL18R1 may be involved in the treatment response in blood and intestinal samples. Finally, ustekinumab treatment was shown to significantly alter fibrotic genes and pathways.

Differentiation Between Ulcerative Colitis and Crohn's Disease Using Abdominal Computed Tomography in Patients With First-Time Inflammatory Bowel Disease.

Background Ulcerative colitis (UC) and Crohn's disease (CD) are classified as inflammatory bowel diseases (IBDs). However, they have different pathogeneses and treatment strategies and need to be differentiated. Purpose To determine the feasibility of differentiating UC from CD in patients with first-time IBD based on simple abdominal computed tomography (CT) findings. Methods We conducted a retrospective study of patients diagnosed with IBD for the first time at our hospital between January and December 2021. Age, sex, white blood cell count, albumin concentration, C-reactive protein concentration, visceral fat area, subcutaneous fat area, and psoas major volume were extracted and used to differentiate the two groups. Results Forty-three patients were selected. Their mean age was 35.60 ± 17.19 years, and 32 were male, while 11 were female. The visceral fat cross-sectional area was 51.80 cm2 for UC and 21.10 cm2 for CD (p < 0.01). The subcutaneous fat cross-sectional area was 108.30 cm2 for UC and 66.30 cm2 for CD (p = 0.049). The total protein concentration was 6.15 g/L for UC and 6.60 g/L for CD (p = 0.012). Receiver operating characteristic curve analysis of the visceral and subcutaneous fat cross-sectional areas showed areas under the curve, 95% confidence intervals, sensitivities, and specificities of 0.750 and 0.675, 0.603-0.897 and 0.507-0.844, 0.810 and 1.00, and 0.591 and 0.409, respectively, at cutoffs of 26.53 and 36.6 cm2. Conclusions  The visceral and subcutaneous fat cross-sectional areas determined with simple abdominal CT can differentiate UC from CD in patients with first-time IBD.

Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn's Disease.

OBJECTIVE: Epigenetic mechanisms, including DNA methylation (DNAm), have been proposed to play a key role in Crohn's disease (CD) pathogenesis. However, the specific cell types and pathways affected as well as their potential impact on disease phenotype and outcome remain unknown. We set out to investigate the role of intestinal epithelial DNAm in CD pathogenesis. DESIGN: We generated 312 intestinal epithelial organoids (IEOs) from mucosal biopsies of 168 patients with CD (n=72), UC (n=23) and healthy controls (n=73). We performed genome-wide molecular profiling including DNAm, bulk as well as single-cell RNA sequencing. Organoids were subjected to gene editing and the functional consequences of DNAm changes evaluated using an organoid-lymphocyte coculture and a nucleotide-binding oligomerisation domain, leucine-rich repeat and CARD domain containing 5 (NLRC5) dextran sulphate sodium (DSS) colitis knock-out mouse model. RESULTS: We identified highly stable, CD-associated loss of DNAm at major histocompatibility complex (MHC) class 1 loci including NLRC5 and cognate gene upregulation. Single-cell RNA sequencing of primary mucosal tissue and IEOs confirmed the role of NLRC5 as transcriptional transactivator in the intestinal epithelium. Increased mucosal MHC-I and NLRC5 expression in adult and paediatric patients with CD was validated in additional cohorts and the functional role of MHC-I highlighted by demonstrating a relative protection from DSS-mediated mucosal inflammation in NLRC5-deficient mice. MHC-I DNAm in IEOs showed a significant correlation with CD disease phenotype and outcomes. Application of machine learning approaches enabled the development of a disease prognostic epigenetic molecular signature. CONCLUSIONS: Our study has identified epigenetically regulated intestinal epithelial MHC-I as a novel mechanism in CD pathogenesis.

Brain network topological changes in inflammatory bowel disease: an exploratory study.

Although the aetio-pathogenesis of inflammatory bowel diseases (IBD) is not entirely clear, the interaction between genetic and adverse environmental factors may induce an intestinal dysbiosis, resulting in chronic inflammation having effects on the large-scale brain network. Here, we hypothesized inflammation-related changes in brain topology of IBD patients, regardless of the clinical form [ulcerative colitis (UC) or Crohn's disease (CD)]. To test this hypothesis, we analysed source-reconstructed magnetoencephalography (MEG) signals in 25 IBD patients (15 males, 10 females; mean age ± SD, 42.28 ± 13.15; mean education ± SD, 14.36 ± 3.58) and 28 healthy controls (HC) (16 males, 12 females; mean age ± SD, 45.18 ± 12.26; mean education ± SD, 16.25 ± 2.59), evaluating the brain topology. The betweenness centrality (BC) of the left hippocampus was higher in patients as compared with controls, in the gamma frequency band. It indicates how much a brain region is involved in the flow of information through the brain network. Furthermore, the comparison among UC, CD and HC showed statistically significant differences between UC and HC and between CD and HC, but not between the two clinical forms. Our results demonstrated that these topological changes were not dependent on the specific clinical form, but due to the inflammatory process itself. Broader future studies involving panels of inflammatory factors and metabolomic analyses on biological samples could help to monitor the brain involvement in IBD and to clarify the clinical impact.

Treatment of inflammatory bowel disease with steroid-sparing medications is age-dependent - Results from a Danish nationwide cohort study, 2000-2018.

BACKGROUND: Paediatric-onset and elderly-onset inflammatory bowel disease (IBD) present unique treatment challenges. AIMS: We investigated treatment patterns following a first and second course of systemic steroids in paediatric- and elderly-onset IBD and compared them to adult-onset IBD. METHODS: All patients diagnosed with Crohn's disease (CD) or ulcerative colitis (UC) between 2000 and 2018 were identified through the Danish healthcare registries. Patients were divided into groups based on their age at diagnosis. Kaplan-Meier plots were prepared for medications and surgeries after diagnosis and after the first and second courses of systemic steroids. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using multivariate Cox regression analysis for steroid-sparing medications. RESULTS: 1851 CD (13%) and 1687 (6%) UC patients were paediatric-onset, while 2952 (20%) CD and 5812 (23%) UC patients were elderly-onset. Paediatric-onset more frequently received immunomodulators [CD: HR: 1.64, CI: 1.52-1.77, UC: HR: 2.29, CI: 2.02-2.61] and biologics [CD: HR: 1.43, CI: 1.25-1.65, UC: HR: 1.27, CI: 0.99-1.64], while elderly-onset less frequently received immunomodulators [CD: HR: 0.39, CI: 0.35-0.44, UC: HR: 0.58, CI: 0.50-0.67] and biologics [CD: HR: 0.19, CI: 0.14-0.25, UC: HR: 0.36, CI: 0.27-0.48] compared to adult-onset age groups. After two courses of systemic steroids, elderly-onset still received less steroid-sparing medications. High frailty was associated with lower usage of medications for elderly-onset. CONCLUSION: There are significant differences in the use of steroid-sparing medication between age of onset, even after two courses with systemic steroids. High frailty could account for some of these differences in elderly-onset IBD.

Baseline Assessment of Serum Cytokines Predicts Clinical and Endoscopic Response to Ustekinumab in Patients With Crohn's Disease: A Prospective Pilot Study.

BACKGROUND: No biomarkers are currently available to predict therapeutic response to ustekinumab (UST) in Crohn's disease (CD). The aim of this prospective study was to identify 1 or more cytokines able to predict mucosal healing in patients with CD treated with UST. METHODS: We prospectively enrolled consecutive CD patients treated with UST. At weeks 0 (baseline), 24, and 48, a panel of serum cytokines was measured by a fluorescence assay. At the same time points, fecal calprotectin (FC) was assessed. A colonoscopy was performed at baseline and at week 48, where therapeutic outcome was evaluated in terms of mucosal healing. RESULTS: Out of 44 patients enrolled, 22 (50%) achieved mucosal healing at the end of follow-up. Response was associated with higher interleukin (IL)-23 levels (P < .01). Fecal calprotectin levels decreased over time in responders but did not change in nonresponders (test for the interaction between time and mucosal healing, P < .001). CONCLUSIONS: This pilot study showed that IL-23 and FC could be reliable biomarkers in predicting therapeutic outcome to UST therapy in CD. In particular, the correlation between baseline serum levels of IL-23 and mucosal healing at 48 weeks is particularly strong, paving the way for its use to drive therapeutic decisions.

This prospective pilot study showed that the assessment of IL-23 levels at baseline could predict clinical and endoscopic outcomes to ustekinumab therapy in Crohn's disease. Testing this biomarker before starting a biological therapy could be useful for a personalized choice.

Impact of Obesity and Metabolic Syndrome on IBD Outcomes.

PURPOSE OF REVIEW: The recent surge in inflammatory bowel disease (IBD) cases has paralleled a significant rise in obesity and metabolic comorbidities rates. In this article, we explore the potential influence of obesity and associated metabolic comorbidities on disease progression, complications, treatment response, surgical outcomes, health economics, and the potential impact of obesity treatment on the course of IBD. FINDINGS: Contrary to visceral adiposity, obesity does not consistently result in an increased risk of IBD-related complications. Patients with IBD have a higher risk of acute arterial events, likely linked to systemic inflammation. Substantial evidence suggests that obesity has a negative impact on the response to IBD treatment, with this effect being most thoroughly studied in biologics and immunomodulators. The rates of overall complications and post-operative infections are higher in patients who are obese. There are limited but promising data regarding the impact of weight loss techniques, including exercise, medications, and bariatric interventions, on the outcomes in IBD. Both obesity and diabetes have adverse effects on the overall quality of life and place an increased financial burden on the IBD population. A growing body of evidence indicates a connection between obesity and associated metabolic comorbidities and negative outcomes in IBD, yet further efforts are required to fully understand this relationship.

Mesenchymal stem cell therapy for therapy refractory complex Crohn's perianal fistulas: a case series.

BACKGROUND: Mesenchymal stem cell treatment (MST) has emerged as a new therapeutic strategy for Crohn's perianal fistulas. It has been demonstrated that a fibrotic tract on MRI with a MAGNIFI-CD score ≤ 6 is the best predictor for long-term clinical closure. Therefore, the aim of the current study was to analyse the effectiveness of MST for complex Crohn's perianal fistulas based on MRI. METHODS: Consecutive patients with complex Crohn's perianal fistulas, previously failing both anti-TNF treatment and surgical closure, who had surgical closure of the internal opening with MST were included. The primary endpoint was radiological remission of the fistula(s) defined as a MAGNIFI-CD ≤ 6 on MRI, read by an experienced radiologist. RESULTS: Between December 2019 and March 2023, 30 patients (15 males) with 48 fistula tracts were included with a median follow-up of 16.5 months. Radiological remission was achieved in thirteen patients (43.3%) after a median follow-up of 5.0 months (IQR 3.0-6.0). The median MAGNIFI-CD at baseline was 15.0 (IQR 7.0-20.0) which significantly decreased to 8.0 (IQR 3.0-15.0) after treatment (p = 0.001). Clinical closure was achieved in 21 patients (70.0%). Three patients (14.3%) developed a recurrence during long-term FU, all with clinically closed fistula(s), but no radiological remission. The median PDAI decreased significantly from 10.5 (IQR 7.0-14.0) to 4.0 (IQR 0.0-7.3) (p = 0.001). CONCLUSION: MST is a promising treatment strategy for therapy refractory Crohn's perianal fistulas, resulting in > 40% radiological remission, clinical closure in 70% and a significant improvement in quality of life. No recurrences were seen in patients with radiological remission.

The Efficacy of Combination Therapy with Ustekinumab and Budesonide for Crohn's Disease: A Randomized Controlled Trial.

Introduction: Limited data exist on the efficacy of combination therapy with ustekinumab and budesonide in patients with Crohn's disease. Our objective was to compare the clinical outcomes of ustekinumab and budesonide combination therapy with those of ustekinumab monotherapy. Methods: In this phase 2 single-center, double-blind, randomized controlled trial, we assigned 19 patients with Crohn's disease with a Crohn's disease activity index (CDAI) equal to or greater than 220 and less than 450 in a 1:1 ratio to receive ustekinumab and budesonide or ustekinumab for 32 weeks. The primary endpoint was the clinical remission rate at 8 weeks. The secondary endpoints were the clinical remission rate at 32 weeks and mucosal healing rates at 8 and 32 weeks. Results: Of 19 patients, the mean age was 37.8 years, and 42.1% were women (CDAI ≥220 and <450). There was no difference between combination therapy and ustekinumab monotherapy in terms of clinical remission rates (50.0% vs. 30.0%, p = 0.39 at 8 weeks and 37.5% vs. 20.0%, p = 0.41) and mucosal healing rates (75.0% vs. 90.0%, p = 0.40 and 37.5% vs. 60.0%, p = 0.34 at 8 and 32 weeks, respectively). The most common adverse event was an exacerbation of Crohn's. There were no differences in safety profiles between the two groups. Conclusions: Our study showed no difference between ustekinumab monotherapy and ustekinumab and budesonide combination therapy in terms of the induction and maintenance of remission (trial registration number: jRCTs021200013).

The association between circulating leukocytes and inflammatory bowel disease: a two-sample Mendelian randomization study.

Background: Inflammatory bowel disease (IBD) is a highly prevalent, recurrent, chronic intestinal inflammatory disease. Several observational studies have shown that circulating leukocytes are strongly associated with IBD. However, whether alterations in leukocytes are causally related to IBD remains uncertain. The present study explores this issue with the Mendelian randomization (MR) analysis method. Methods: The Genome wide association study (GWAS) statistical data related to circulating leukocytes and IBD were obtained from the Blood Cell Consortium and the IEU Qpen GWAS project, respectively. Inverse variance weighting (IVW) was used as the main MR analytical method, coupled with a series of sensitivity analyses to ensure the reliability of the results. Results: The results of IVW showed that increased monocyte count (especially CD14- CD16+ monocyte absolute counts) was negatively correlated with the risk of IBD and its main subtypes. Increased neutrophil count was positively associated with the risk of IBD and ulcerative colitis. Meanwhile, there was no causal relationship between basophil, eosinophil, lymphocyte counts and IBD risk. Conclusion: These results indicate that a causal relationship exists between circulating leukocytes and the risk of IBD and its subtypes, which confirms the important role that the leukocyte immune system plays in IBD. Our findings provide additional research directions for the clinical prevention and treatment of IBD.

Excess non-COVID-19-related mortality among inflammatory bowel disease decedents during the COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic disrupted healthcare in the United States. AIM: To investigate COVID-19-related and non-COVID-19-related death and characteristics associated with excess death among inflammatory bowel disease (IBD) decedents. METHODS: We performed a register-based study using data from the National Vital Statistics System, which reports death data from over 99% of the United States population, from January 1, 2006 through December 31, 2021. IBD-related deaths among adults 25 years and older were stratified by age, sex, race/ethnicity, place of death, and primary cause of death. Predicted and actual age-standardized mortality rates (ASMRs) per 100000 persons were compared. RESULTS: 49782 IBD-related deaths occurred during the study period. Non-COVID-19-related deaths increased by 13.14% in 2020 and 18.12% in 2021 [2020 ASMR: 1.55 actual vs 1.37 predicted, 95% confidence interval (CI): 1.26-1.49; 2021 ASMR: 1.63 actual vs 1.38 predicted, 95%CI: 1.26-1.49]. In 2020, non-COVID-19-related mortality increased by 17.65% in ulcerative colitis (UC) patients between the ages of 25 and 65 and 36.36% in non-Hispanic black (NHB) Crohn's disease (CD) patients. During the pandemic, deaths at home or on arrival and at medical facilities as well as deaths due to neoplasms also increased. CONCLUSION: IBD patients suffered excess non-COVID-19-related death during the pandemic. Excess death was associated with younger age among UC patients, and with NHB race among CD patients. Increased death at home or on arrival and due to neoplasms suggests that delayed presentation and difficulty accessing healthcare may have led to increased IBD mortality.

Safety and Effectiveness of Ustekinumab for Crohn's Disease With Perianal Manifestations: Ad hoc Analysis Data From 1-Year Post-Marketing Surveillance Study in Japan.

Background: Crohn's disease (CD) is an immune-mediated inflammatory disorder of the gastrointestinal tract with perianal disease being one of the challenging possible manifestations. Here, we report, an ad hoc analysis of the safety and effectiveness of 1-year use of ustekinumab (UST) for CD in patients with perianal manifestations using post-marketing surveillance (PMS) data in Japan. Methods: Among 341 patients enrolled in the PMS, 229 and 224 patients who had baseline Crohn's Disease Activity Index (CDAI) data used for evaluating perianal manifestations were included in the safety and efficacy analysis sets, respectively. Incidence of adverse drug reactions, clinical remission, the mean or its change in CDAI scores, and CDAI items were evaluated through week 52 in the presence or absence of perianal manifestations at baseline. The prevalence of perianal manifestations was also described. Results: Comparing patients with and without baseline perianal manifestations at week 52, there was no difference in ADR incidence (9.1% [n = 66] vs. 15.3% [n = 163]), no difference in clinical remission (68.3% vs. 59.9%; P = 0.269), and decreased mean change of CDAI score (-82.9 [n = 60] vs. -68.8 [n = 137]). The proportion of patients with perianal manifestations decreased after UST treatment in both biologics-naïve patients (23.5% [n = 4/17]) and patients who had received biologics (35.0% [n = 14/40]) at week 52. Conclusions: In Japanese clinical practice, UST is safe and effective in CD patients with and without perianal manifestations. The therapy might be also beneficial in those with manifestations regardless of prior use of other biologics.

Pediatric inflammatory bowel disease: What's new and what has changed?

The incidence and prevalence of inflammatory bowel disease (IBD) is on the rise in North America and worldwide, with young children being the fastest growing patient population. It is therefore essential for pediatricians and pediatric sub-specialists to be able to recognize signs and symptoms suspicious for a new diagnosis of IBD, as well as potential complications associated with IBD or its treatment. This article reviews the most recent literature regarding clinical presentation, helpful diagnostic clues, newer monitoring tools being used by pediatric gastroenterologists, and emerging new biologic and small molecule treatments.

Obstetric outcomes of patients with inflammatory bowel disease.

INTRODUCTION: Inflammatory bowel diseases (IBD) are frequently diagnosed between the ages of 20 and 40, i.e. the most fertile period for women. The potential impact of IBD on pregnancy is therefore a frequent issue. STUDY OBJECTIVE: To determine the impact of disease activity during pregnancy on the obstetric prognosis of women with IBD. METHODS: Gastroenterological and obstetric data were collected for patients for all consecutive patients with IBD and pregnancy followed up at Amiens University Hospital (Amiens, France) between 2007 and 2021. Obstetrics outcome of patients with and without active disease were compared. RESULTS: One hundred patients were included (81 with Crohn's Disease for 198 pregnancies, 19 with Ulcerative Colitis for 37 pregnancies). Patients with active IBD (21 patients, 24 pregnancies) were more likely to be admitted to hospital during pregnancy (66.6, vs. 5.2% in the inactive IBD group; p < 0.001), to give birth prematurely (mean term: 36.77 weeks of amenorrhoea (WA) vs. 38.7 WA, respectively; p = 0.02) and to experience very premature delivery (before 32 WA: 12.5 vs. 1.4%, respectively; p = 0.02). Patients with active disease had a shorter term at birth (38.4 WA, vs. 39.8 WA in the inactive disease group; p < 0.0001), a lower birth weight (2707 g vs. 3129 g, respectively; p = 0.01) and higher caesarean section rate (54.2 vs. 16.9%, respectively; p = 0.03). CONCLUSION: Women with IBD patients are at risk of pregnancy related complications, especially when IBD is active. Controlling disease activity at conception and close monitoring of the pregnancy is essential to improve both gastroenterological and obstetric outcome.

Complex dichotomous links of nonalcoholic fatty liver disease and inflammatory bowel disease: exploring risks, mechanisms, and management modalities.

Nonalcoholic fatty liver disease (NAFLD) has been shown to be linked to inflammatory bowel disease (IBD) due to established risk factors such as obesity, age, and type 2 diabetes in numerous studies. However, alternative research suggests that factors related to IBD, such as disease activity, duration, and drug-induced toxicity, can contribute to NAFLD. Recent research findings suggest IBD relapses are correlated with dysbiosis, mucosal damage, and an increase in cytokines. In contrast, remission periods are characterized by reduced metabolic risk factors. There is a dichotomy evident in the associations between NAFLD and IBD during relapses and remissions. This warrants a nuanced understanding of the diverse influences on disease manifestation and progression. It is possible to provide a holistic approach to care for patients with IBD by emphasizing the interdependence between metabolic and inflammatory disorders.