Crohn's disease after surgery: Changes in post-operative management strategies over time and their impact on long-term re-operation rate-A retrospective multicentre real-world study.

BACKGROUND: Few data are available addressing the impact of post-operative management of Crohn's disease (CD) on long-term clinical course. AIM: To assess the evolution of post-operative management strategies over the last 40 years and their impact on the re-operation rate of CD. METHODS: We included 657 patients with CD who had undergone their first radical ileo-caecal resection between 1980 and 2020. Three cohorts were defined according to year of surgery: cohort 1 (1980-1998; n = 198), cohort 2 (1999-2009; n = 218) and cohort 3 (2010-2020; n = 241). We estimated exposure to immunomodulators and anti-TNFα agents after surgery and rates of re-operation using Kaplan-Meier survival analyses. We used Cox proportional hazards regression to assess the association of clinical variables with time to re-operation. RESULTS: Immunosuppressants, (IMMs) and anti-TNFα exposure within 5 years after surgery increased significantly from cohort 1 to cohort 2 and cohort 3 (IMMs: 1.6%, 38.2% and 28.0%, respectively, p < 0.001; anti-TNFα: 0.0%, 20.7% and 52.0%, respectively, p < 0.001). There was no significant difference across cohorts regarding the cumulative probability of re-operation within 5 and 10 years. Multivariate analysis identified IMMs/anti-TNFα exposure before the first surgery (HR 9.15; 95% CI 2.77-30.21) and post-operatively (HR: 0.24; 95% CI 0.07-0.74) as variables associated with the risk of re-operation. However, these associations had a time-varying effect and become non-significant after 5 and 2 years after surgery, respectively. CONCLUSION: Despite increased post-operative use of IMMs and anti-TNFα agents in the last two decades, the impact of these strategies on the risk of long-term re-operation rate has been modest.

Real-World Treatment Patterns and Healthcare Resource Use for Ulcerative Colitis and Crohn's Disease in Italy.

INTRODUCTION: Real-world data are used to inform decision-makers and optimise therapeutic management for patients with ulcerative colitis (UC) and Crohn's disease (CD). We analysed data on the epidemiology (by using proxies of prevalence and incidence), patient characteristics, treatment patterns and associated healthcare direct costs for the management of patients with UC and patients with CD in Italy. METHODS: This retrospective observational study used administrative databases from eight Local Health Units geographically distributed across Italy. Adult patients with a hospitalisation and/or an exemption for UC or CD were included. Study outcomes were summarised descriptively, and limited statistical tests were performed. RESULTS: At baseline, 9255 adults with UC and 4747 adults with CD were included. Mean (standard deviation) age at inclusion was 54.0 (18.4)/48.6 (18.1) years, for UC/CD. The estimated average incidence of UC and CD for the period 2013-2020 was 36.5 and 18.7 per 100,000, respectively. The most frequently prescribed drug category for patients with UC/CD was conventional treatment [mesalazine and topical corticosteroids (67.4%/61.1%), immunomodulators and systemic corticosteroids (43.2%/47.7%)], followed by biologic treatments (2.1%/5.1%). The mean annual total direct cost per patient was 7678 euro (€), for UC and €6925 for CD. CONCLUSION: This analysis, carried-out in an Italian clinical setting, may help to optimise therapy for patients with UC and CD and provide relevant clinical practice data to inform decision-makers.

Data from clinical practice can be used to guide healthcare decisions and optimise treatment for patients with ulcerative colitis and Crohn's disease. This study used anonymised patient information from almost four million individuals across Italy to describe the epidemiology, patient characteristics, treatment patterns and healthcare costs of patients with ulcerative colitis and Crohn's disease. Adults with an Italian National Health System code in their records associated with the diagnosis of ulcerative colitis or Crohn's disease were included. Baseline characteristics were balanced between groups and rates of perceived incidence were numerically similar to the results reported in similar Italian studies. This study found that patients with ulcerative colitis and Crohn's disease were most often prescribed conventional treatments, and biological treatments were least-commonly prescribed. More than half of patients with ulcerative colitis and nearly half of those with Crohn's disease were persistent with first (index) treatment of mesalazine and topical corticosteroids and with biologic index treatment during the follow-up period. Switch occurred in up to approximately a quarter of patients with ulcerative colitis and Crohn's disease. The main factors that predicted switch were index biologic for ulcerative colitis and baseline comorbidities for Crohn's disease. The average direct cost per patient in 1 year was 7678 euro (€) for ulcerative colitis and €6925 for Crohn's disease. The results of this analysis may help to optimise therapy for patients with ulcerative colitis and Crohn's disease, and to inform decision-makers in healthcare systems on which treatment options provide value for money and benefit patients.

The management of patients with inflammatory bowel disease-associated spondyloarthritis: Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) and Italian Society of Rheumatology (SIR) recommendations based on a pseudo-Delphi consensus.

Spondyloarthritis (SpA) is the most frequent extraintestinal manifestation in patients with inflammatory bowel diseases (IBD). When IBD and spondyloarthritis coexist, musculoskeletal and intestinal disease features should be considered when planning a therapeutic strategy. Treatment options for IBD and SpA have expanded enormously over the last few years, but randomized controlled trials with specific endpoints focused on SpA are not available in the IBD setting. To address this important clinical topic, the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) and the Italian Society of Rheumatology (SIR) jointly planned to draw updated therapeutic recommendations for IBD-associated SpA using a pseudo-Delphi method. This document presents the official recommendations of IG-IBD and SIR on the management of IBD-associated SpA in the form of 34 statements and 4 therapeutic algorithms. It is intended to be a reference guide for gastroenterologists and rheumatologists dealing with IBD-associated SpA.

Comparative efficacy and safety of subcutaneous infliximab and vedolizumab in patients with Crohn's disease and ulcerative colitis included in randomised controlled trials.

BACKGROUND: While indirect comparison of infliximab (IFX) and vedolizumab (VDZ) in adults with Crohn's disease (CD) or ulcerative colitis (UC) shows that IFX has better effectiveness during induction, and comparable efficacy during maintenance treatment, comparative data specific to subcutaneous (SC) IFX (i.e., CT-P13 SC) versus VDZ are limited. AIM: Pooled analysis of randomised studies to compare efficacy and safety with IFX SC and VDZ in moderate-to-severe inflammatory bowel disease. METHODS: Parallel-group, randomised studies evaluating IFX SC and VDZ in patients with moderate-to-severe CD or UC were identified. Eligible studies reported ≥ 1 prespecified outcome of interest at Week 6 (reflecting treatment during the induction phase) and/or at 1 year (Weeks 50-54; reflecting treatment during the maintenance phase). Prespecified efficacy and safety outcomes considered in this pooled analysis included the proportions of patients achieving disease-specific clinical responses, clinical remission, or discontinuing due to lack of efficacy, and the proportions of patients experiencing adverse events (AEs), serious AEs, infections, serious infections, or discontinuing due to AEs. Data from multiple studies or study arms were extracted and pooled using a random-effect model; comparative analyses were performed separately for patients with CD and UC. RESULTS: We identified three eligible CD trials and four eligible UC trials that assigned over 1200 participants per disease cohort to either IFX SC or VDZ. In patients with CD, intravenous induction therapy with IFX demonstrated better efficacy (non-overlapping 95% confidence intervals [CIs]) compared with VDZ; during the maintenance phase, IFX SC showed numerically better efficacy (overlapping 95% CIs) than VDZ. A lower proportion of IFX SC-treated patients discontinued therapy due to lack of efficacy over 1 year. In patients with UC, efficacy profiles were similar with IFX SC and VDZ during the induction and maintenance phases, and a lower proportion of IFX SC-treated patients discontinued therapy due to lack of efficacy over 1 year. In both cohorts, safety profiles for IFX SC and VDZ were generally comparable during 1 year. CONCLUSION: IFX SC demonstrated better efficacy than VDZ in patients with CD, and similar efficacy to VDZ in patients with UC; 1-year safety was comparable with IFX SC and VDZ.

Optimising surgical anastomosis in ileocolic resection for Crohn's disease with respect to recurrence and functionality: two international parallel randomized controlled trials comparing handsewn (END-to-end or Kono-S) to stapled anastomosis (HAND2END and the End2End STUDIES).

BACKGROUND: The most common intestinal operation in Crohn's disease (CD) is an ileocolic resection. Despite optimal surgical and medical management, recurrent disease after surgery is common. Different types of anastomoses with respect to configuration and construction can be made after resection for example, handsewn (end-to-end and Kono-S) and stapled (side-to-side). The various types of anastomoses might affect endoscopic recurrence and its assessment, the functional outcome, and costs. The objective of the present study is to compare the three types of anastomoses with respect to endoscopic recurrence at 6 months, gastrointestinal function, and health care consumption. METHODS: This is a randomized controlled multicentre superiority trial, allocating patients either to side-to-side stapled anastomosis as advised in current guidelines or a handsewn anastomoses (an end-to-end or Kono-S). It is hypothesized that handsewn anastomoses do better than stapled, and end-to-end perform better than the saccular Kono-S. Two international studies with a similar setup will be conducted mainly in the Netherlands (End2End) and Italy (HAND2END). Patients diagnosed with CD, aged over 16 years in the Netherlands and 18 years in Italy requiring (re)resection of the (neo)terminal ileum are eligible. The first part of the study compares the two handsewn anastomoses with the stapled anastomosis. To detect a clinically relevant difference of 25% in endoscopic recurrence, a total of 165 patients will be needed in the Netherlands and 189 patients in Italy. Primary outcome is postoperative endoscopic recurrence (defined as Rutgeerts score ≥ i2b) at 6 months. Secondary outcomes are postoperative morbidity, gastrointestinal function, quality of life (QoL) and costs. DISCUSSION: The research question addresses a knowledge gap within the general practice elucidating which type of anastomosis is superior in terms of endoscopic and clinical recurrence, functionality, QoL and health care consumption. The results of the proposed study might change current practice in contrast to what is advised by the guidelines. TRIAL REGISTRATION: NCT05246917 for HAND2END and NCT05578235 for End2End ( http://www. CLINICALTRIALS: gov/ ).

Rates of Adverse Events in Patients With Ulcerative Colitis Undergoing Colectomy During Treatment With Tofacitinib vs Biologics: A Multicenter Observational Study.

INTRODUCTION: Patients with ulcerative colitis (UC) receiving immunosuppressive drugs are at substantial risk of colectomy. We aimed to assess the risk of postoperative complications of tofacitinib exposure before colectomy in comparison with biologics. METHODS: A multicenter, retrospective, observational study was conducted in patients with UC who underwent total colectomy for medically refractory disease, exposed to tofacitinib or a biologic before surgery. Primary outcome was the occurrence of any complication within 30 (early) and 90 (late) days after surgery. Secondary outcomes were the occurrence of infections, sepsis, surgical site complications, venous thromboembolic events (VTE), hospital readmissions, and redo surgery within the same timepoints. RESULTS: Three hundred one patients (64 tofacitinib, 162 anti-tumor necrosis factor-α agents, 54 vedolizumab, and 21 ustekinumab) were included. No significant differences were reported in any outcome, except for a higher rate of early VTE with anti-tumor necrosis factor-α agents ( P = 0.047) and of late VTE with vedolizumab ( P = 0.03). In the multivariate analysis, drug class was not associated with a higher risk of any early and late complications. Urgent colectomy increased the risk of any early (odds ratio [OR] 1.92, 95% confidence interval [CI] 1.06-3.48) complications, early hospital readmission (OR 4.79, 95% CI 1.12-20.58), and early redo surgery (OR 7.49, 95% CI 1.17-47.85). A high steroid dose increased the risk of any early complications (OR 1.96, 95% CI 1.08-3.57), early surgical site complications (OR 2.03, 95% CI 1.01-4.09), and early redo surgery (OR 7.52, 95% CI 1.42-39.82). Laparoscopic surgery decreased the risk of any early complications (OR 0.54, 95% CI 0.29-1.00), early infections (OR 0.39, 95% CI 0.18-0.85), and late hospital readmissions (OR 0.34, 95% CI 0.12-1.00). DISCUSSION: Preoperative tofacitinib treatment demonstrated a postoperative safety profile comparable with biologics in patients with UC undergoing colectomy.

Pragmatic trial design to compare real-world effectiveness of different treatments for inflammatory bowel diseases: the PRACTICE-IBD European consensus.

BACKGROUND AND AIMS: Pragmatic studies designed to test interventions in everyday clinical settings can successfully complement the evidence from registration and explanatory clinical trials. The European consensus project PRACTICE-IBD was developed to identify essential criteria and address key methodological issues needed to design valid comparative pragmatic studies in inflammatory bowel diseases (IBDs). METHODS: Statements were issued by a panel of 11 European experts in IBD management and trial methodology on four main topics: (I) study design; (II) eligibility, recruitment and organization, flexibility; (III) outcomes; (IV) analysis. The consensus process followed a modified Delphi approach, involving two rounds of assessment and rating of the level of agreement (1 to 9; cut-off ≥7 for approval) with the statements by 18 additional European experts in IBD. RESULTS: At the first voting round, 25 out of the 26 statements reached a mean score ≥7. Following the discussion that preceded the second round of voting, it was decided to eliminate two statements and to split one into two. At the second voting round, 25 final statements were approved: 7 for study design, 6 for eligibility, recruitment and organization, flexibility, 8 for outcomes, and 4 for analysis. CONCLUSIONS: Pragmatic randomized clinical trials can address important questions in IBD clinical practice, and may provide complementary high-level evidence, as long as they follow a methodologically rigorous approach. These 25 statements intend to offer practical guidance in the design of high-quality pragmatic clinical trials that can aid decision making in choosing a management strategy for IBDs.

The learning curve for using intestinal ultrasonography.

BACKGROUND AND AIMS: Intestinal ultrasonography (IUS) is challenging to learn. This prospective study examined how the accuracy of IUS increases with operator experience ("learning curve") and if prior abdominal ultrasound experience facilitates the learning process. METHODS: The study included two trainees with limited abdominal ultrasound experience (< 50 exams) and two with extensive experience (> 500 exams). Each trainee performed 99 examinations and reported four IUS findings. An expert sonographer repeated the exam, and concordance (k) between the expert and trainees was assessed in three consecutive testing periods of 33 exams each. RESULTS: A progressive improvement in concordance was observed for all IUS findings from Period 1 to Period 3, overall and for both groups of trainees, although those with experience in abdominal ultrasound had faster learning curves. The minimum number of examinations required to achieve concordance with the expert operator for detecting increased bowel wall thickness was 84 and detecting bowel dilatation was 79. However, a minimum of 97 examinations was necessary to achieve concordance for detecting intra-abdominal complications, considered an advanced IUS competence. CONCLUSION: Basic competence in IUS can be acquired with relatively few examinations, while advanced competence requires more extensive training, particularly for gastroenterologists without abdominal ultrasound experience.

Ophthalmological Manifestations in Inflammatory Bowel Diseases: Keep an Eye on It.

BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD) are multifactorial chronic inflammatory disorders affecting the gastrointestinal tract. However, a broad spectrum of extraintestinal manifestations (EIMs) is associated with IBD, affecting several organs and systems, such as the skin, musculoskeletal and hepatobiliary systems, and, not least, the eye. Approximately 10% of IBD patients can develop ocular EIMs (O-EIMs) with a higher prevalence in Crohn's disease (CD). Eye-redness, photophobia, pain, and blurred vision are the common symptoms, with a wide rate of severity and clinical impact on the quality of life. This narrative review aims to summarize the prevalence, pathogenesis, and current evidence-based management of O-EIMs, underlying the importance of a holistic approach and specialties collaboration for a prompt diagnosis and treatment. METHODS: PubMed was searched up to December 2023 to identify relevant studies investigating the pathogenesis, epidemiology, and treatment of O-EIMs in IBD patients. RESULTS: The mechanisms underlying O-EIMs are partially unknown, encompassing immune dysregulation, shared antigens between the eye and the gut, genetic predisposition, and systemic inflammation driven by high levels of interleukins and cytokines in IBD patients. The complexity of O-EIMs' pathogenesis reflects in the management of these conditions, varying from topical and systemic steroids to immunomodulatory molecules and biologic therapy, such as anti-tumor necrosis factor (TNF)-alpha. A multidisciplinary approach is the backbone of the management of O-EIMs.

The gut-brain axis: Correlation of choroid plexus volume and permeability with inflammatory biomarkers in Crohn's disease.

BACKGROUND: The dysregulation of the gut-brain axis in chronic inflammatory bowel diseases can cause neuro-psychological disturbances, but the underlying mechanisms are still not fully understood. The choroid plexus (CP) maintains brain homeostasis and nourishment through the secretion and clearance of cerebrospinal fluid. Recent research has demonstrated the existence of a CP vascular barrier in mice which is modulated during intestinal inflammation. This study investigates possible correlations between CP modifications and inflammatory activity in patients with Crohn's disease (CD). METHODS: In this prospective study, 17 patients with CD underwent concomitant abdominal and brain 3 T MRI. The volume and permeability of CP were compared with levels of C-reactive protein (CRP), fecal calprotectin (FC), sMARIA and SES-CD scores. RESULTS: The CP volume was negatively correlated with CRP levels (R = -0.643, p-value = 0.024) and FC (R = -0.571, p-value = 0.050). DCE metrics normalized by CP volume were positively correlated with CRP (K-trans: R = 0.587, p-value = 0.045; Vp: R = 0.706, p-value = 0.010; T1: R = 0.699, p-value = 0.011), and FC (Vp: R = 0.606, p-value = 0.037). CONCLUSIONS: Inflammatory activity in patients with CD is associated with changes in CP volume and permeability, thus supporting the hypothesis that intestinal inflammation could affect the brain through the modulation of CP vascular barrier also in humans.

Estimation of patients affected by inflammatory bowel disease potentially eligible for biological treatment in a real-world setting.

BACKGROUND/AIMS: This analysis estimated the number of inflammatory bowel disease (IBD) patients presenting criteria of eligibility for biological therapies in an Italian real-world setting. METHODS: An observational analysis was performed on administrative databases of a sample of Local Health Units, covering 11.3% of the national population. Adult IBD patients (CD or UC) from 2010 to the end of data availability were included. Eligibility criteria for biologics were the following: Criterion A, steroid-refractory active disease; Criterion B, steroid-dependent patients; Criterion C, intolerance or contraindication to conventional therapies; Criterion D, severe relapsing disease; Criterion E (CD only), highly active CD disease and poor prognosis. RESULTS: Of 26,781 IBD patient identified, 18,264 (68.2%) were treated: 3,125 (11.7%) with biologics and 15,139 (56.5%) non-biotreated. Among non-biotreated, 7,651 (28.6%) met at least one eligibility criterion for biologics, with criterion B (steroid-dependence) and criterion D (relapse) as the most represented (58-27% and 56-76%, respectively). Data reportioned to the Italian population estimated 67,635 patients as potentially eligible for biologics. CONCLUSIONS: This real-world analysis showed a trend towards undertreatment with biologics in IBD patients with 28.6% being potentially eligible, suggesting that an unmet medical need still exists among the Italian general clinical practice for IBD management.

Clinical trial: Clinical and endoscopic outcomes with ustekinumab in patients with Crohn's disease: Results from the long-term extension period of STARDUST.

BACKGROUND: STARDUST, a phase 3b randomised trial, compared ustekinumab therapeutic strategies in patients with Crohn's disease (CD) using early endoscopic assessment and treat-to-target (T2T) versus standard of care (SoC). AIM: To assess the efficacy of ustekinumab extended treatment in a long-term extension (LTE) of up to 104 weeks with dosing adapted according to clinical, biomarker and endoscopy outcomes. METHODS: Adults with moderately-to-severely active CD received intravenous ustekinumab approximating 6 mg/kg at Week 0 and subcutaneous ustekinumab 90 mg at Week 8. At Week 16, 440 ≥70-point responders were randomised to T2T or SoC and 323 entered the LTE. At Week 48, a unified, protocol-defined ustekinumab dose frequency escalation/de-escalation was applied based on achieving endoscopic remission and corticosteroid-free clinical remission. Achieving corticosteroid-free clinical remission and biomarker remission at consecutive visits determined ustekinumab dosing frequency. Dichotomous variables were analysed using non-responder imputation. RESULTS: Among patients who entered the LTE, 7.7%, 48.6% and 43.7% received doses every 4, 8 and 12 weeks, respectively. Ustekinumab dose frequency was escalated in 23.5% and de-escalated in 19.7%. Endoscopic response and remission rates were 28.9% and 10.73% (all randomised) and 39.3% and 14.6% (patients entering the LTE), respectively, at Week 104. Clinical remissiona rates at week 104 were 50.2% (all randomised) and 68.4% (patients entering the LTE). There were no new safety signals. CONCLUSION: STARDUST LTE is the first interventional ustekinumab efficacy study to show a favourable benefit-risk profile with preservation of clinical and endoscopic outcomes through Week 104 using flexible, algorithm-driven dose adjustment including de-escalation.

Timing of proper introduction, optimization and maintenance of anti-TNF therapy in IBD: Results from a Delphi consensus.

BACKGROUND: Crohn's disease and ulcerative colitis are inflammatory bowel diseases (IBDs) with a rapidly growing worldwide incidence. The last decades presented rapid progress in pharmacological treatment leading in many cases to clinical and endoscopic remission, including biological treatment with anti-TNF agents. AIM: The exact timing of introduction, optimization and maintenance of anti-TNF therapy in IBDs is not thoroughly covered in current guidelines. METHODS: We used the Delphi panel methodology to gather the IBD experts' views and achieve consensus for clinical recommendations on introducing and maintaining anti-TNF therapy for patients with IBDs. RESULTS: Twelve recommendations achieved a high level of consensus in two assessment rounds by 52 (1st round) and 47 (2nd round) IBD experts. CONCLUSION: In many clinical situations, the early use of anti-TNF therapy is recommended. Nowadays, the cost-efficacy profile of anti-TNF biosimilars makes them the first-line drug in a substantial proportion of patients, thus providing the opportunity to increase access to biological therapy.

Exploring the link: Porto-sinusoidal vascular disorder and inflammatory bowel disease - A comprehensive narrative review.

Porto-sinusoidal vascular disorder (PSVD) encompasses a group of vascular disorders characterized by lesions involving the portal venules and sinusoids, independent of the presence of portal hypertension (PH), and for which liver biopsy is essential for diagnosis. PSVD has been shown to be common in patients with immune-mediated diseases, including inflammatory bowel disease (IBD). The association between PSVD and the use of thiopurines and thioguanine in patients with IBD has been well established. In addition, research suggests an association between PSVD and IBD, even in cases where patients haven't been exposed to specific medications, probably related to changes in intestinal permeability. The identification and management of patients with known IBD and PSVD is a challenge for gastroenterologists. This narrative review aims to summarize the currently available data on the association between IBD and PSVD and provide practical suggestions for the management of this group of patients.

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.

Transition care in patients with IBD: The pediatric and the adult gastroenterologist's perspective. Results from a national survey.

BACKGROUND: Transition is a crucial process in the care of IBD patients, although it remains largely heterogeneous. AIMS: To provide an overview of the transition process in Italy and to investigate the perspective of the paediatric and adult physicians. METHODS: An online survey was developed by the Italian Group for Inflammatory Bowel Diseases (IG-IBD) and the Italian Society of Paediatric Gastroenterology, Hepatology and Nutrition (SIGENP). RESULTS: 104 physicians (62 paediatric and 42 adult gastroenterologists) participated to the survey. The disease status was ranked with the highest priority among the key elements of the transition process. The age of the patient was perceived with a higher priority by paediatric gastroenterologists than by adult ones (p < 0.01). In most cases, the transition was organized through one or more joint meetings. Only less than 25 % of responders reported to involve other professions during transition. The struggle in leaving paediatric setting was perceived as the main obstacle to an effective transition process. Paediatric IBD gastroenterologists ranked the struggle in leaving the paediatric setting and the attending physician as higher critical point than adult gastroenterologists. CONCLUSIONS: The current survey provided a snapshot of the IBD transition process in Italy. The present findings highlight the need to embed transitional care in healthcare policy.

Epigenetic and metabolic reprogramming of fibroblasts in Crohn's disease strictures reveals histone deacetylases as therapeutic targets.

BACKGROUND & AIMS: No effective therapeutic intervention exists for intestinal fibrosis in Crohn's disease [CD]. We characterised fibroblast subtypes, epigenetic and metabolic changes, and signalling pathways in CD fibrosis to inform future therapeutic strategies. METHODS: We undertook immunohistochemistry, metabolic, signalling pathway and Epigenetic [Transposase-Accessible Chromatin using sequencing] analyses associated with collagen production in CCD-18Co intestinal fibroblasts and primary fibroblasts isolated from stricturing [SCD] and non-stricturing [NSCD] CD small intestine. SCD/ NSCD fibroblasts were cultured with TGFß and valproic acid [VPA]. RESULTS: Stricturing CD was characterised by distinct histone deacetylase [HDAC] expression profiles, particularly HDAC1, HDAC2, and HDAC7. As a proxy for HDAC activity, reduced numbers of H3K27ac+ cells were found in SCD compared to NSCD sections. Primary fibroblasts had increased extracellular lactate [increased glycolytic activity] and intracellular hydroxyproline [increased collagen production] in SCD compared to NSCD cultures. The metabolic effect of TGFß-stimulation was reversed by the HDAC inhibitor VPA. SCD fibroblasts appear "metabolically primed" and responded more strongly to both TGFß and VPA. Treatment with VPA revealed TGFß-dependent and independent Collagen-I production in CCD-18Co cells and primary fibroblasts. VPA altered the epigenetic landscape with reduced chromatin accessibility at the COL1A1 and COL1A2 promoters. CONCLUSIONS: Increased HDAC expression profiles, H3K27ac hypoacetylation, a significant glycolytic phenotype, and metabolic priming, characterise SCD-derived as compared to NSCD fibroblasts. Our results reveal a novel epigenetic component to Collagen-I regulation and TGFß-mediated CD fibrosis. HDAC inhibitor therapy may 'reset' the epigenetic changes associated with fibrosis.

Treat-to-Target and Regular Surveillance of Inflammatory Bowel Disease Are Associated with Low Incidence and Early-Stage Detection of Malignancies: A Retrospective Cohort Study.

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), increase the risk of malignancies, particularly colorectal cancer (CRC). We aimed to assess the incidence of malignancies in IBD patients managed using a treat-to-target approach and recommended surveillance. We retrospectively searched the electronic databases of two tertiary IBD centers in Milan from 2010 to 2019 for new diagnoses of malignancy in patients with pre-existing IBD. A total of 5239 patients with a follow-up of 19,820 years were included. In total, 71 malignancies were diagnosed in 70 patients (38 CD, 32 UC) with a mean age of 52.9 years, of whom 64% were former or active smokers. The annual incidence of all malignancies was 358 per 100,000 patient years (95% CI 275-444), and the standardized incidence rate (SIR) was 0.93 (95% CI 0.73-1.16). Gastrointestinal cancers were the most frequent (n = 17, 23.9%), in particular, CRC (n = 9), with an incidence of 45 per 100,000 (95% CI 15-74) and an SIR of 1.18 (95% CI 0.54-2.09). CRC occurred mainly in UC patients (6/8), while small bowel cancer was seen in CD patients (5/9). Melanoma and breast cancer (n = 8 each) were the most common non-GI cancers. No significant difference in incidence was found between CD or UC. Death occurred in nine patients (11%) and was due to cancer in eight of these cases, two of which were IBD-related. Most malignancies included in the surveillance were diagnosed at early (I-II) stages (20 vs. 4, p < 0.05). In patients with IBD, treat-to-target and strict surveillance were associated with a low incidence of cancer, similar to that of the general population, and the detection of malignancies at an early stage.

Effectiveness and Safety of Switching from Intravenous to Subcutaneous Vedolizumab Formulation in Inflammatory Bowel Disease Patients in Clinical Remission.

BACKGROUND AND AIMS: Subcutaneous vedolizumab formulation has been shown to be as effective and safe as the intravenous one in randomized control trials. Real-life data are limited especially for patients receiving long-term intravenous therapy. This study aimed to evaluate the safety and effectiveness of switching from intravenous to subcutaneous vedolizumab in a large cohort of patients with stable clinical remission. METHODS: In this prospective cohort study, we enrolled consecutive patients attending our center between September 2021 and April 2022. The baseline demographic characteristics, 12- and 24-weeks follow-up clinical activity, C-reactive protein levels, and adverse events were recorded. The primary endpoint was to assess combined steroid-free clinical remission plus biochemical remission 24-week after the switch. RESULTS: 93 patients (43 Crohn's disease, 50 ulcerative colitis), switched to subcutaneous vedolizumab after a median duration of intravenous treatment of 36 months [IQR 16-52]. At baseline, 80 patients (86%) had a combined remission. At 24-week, 89.2% (n=74) maintained combined steroid-free clinical remission plus biochemical remission. 25 adverse events were reported, mostly SARS-CoV-2 infections and injection site reactions, with a further four recurrence episodes. Twelve patients (12.9%) discontinued subcutaneous administration and restarted intravenous vedolizumab. CONCLUSIONS: Switching from intravenous to subcutaneous vedolizumab can be considered effective and safe for maintaining remission in patients with inflammatory bowel disease. In addition, this might reduce healthcare costs. However, large-scale real-life studies with long-term follow-up are necessary.

Mirikizumab Improves Quality of Life in Patients With Moderately-to-Severely Active Ulcerative Colitis: Results From the Phase 3 LUCENT-1 Induction and LUCENT-2 Maintenance Studies.

Background: Mirikizumab, an anti-IL-23p19 antibody, demonstrated efficacy in phase 3, randomized, double-blind, placebo-controlled LUCENT-1 (induction/NCT03518086) and LUCENT-2 (maintenance/NCT03524092) ulcerative colitis (UC) studies. We evaluated the effect of mirikizumab on quality-of-life (QoL) outcomes in these studies. Methods: In LUCENT-1, 1162 patients with moderately-to-severely active UC were randomized 3:1 to receive mirikizumab 300 mg intravenous or placebo every 4 weeks (Q4W) for 12 weeks. In LUCENT-2, mirikizumab induction responders (N = 544) were re-randomized 2:1 to receive mirikizumab 200 mg subcutaneous or placebo Q4W through week (W) 40 (W52 of treatment). QoL was assessed at W12 and W52 using patient-reported outcomes. Treatments were statistically compared using analysis of covariance model (continuous outcomes) and Cochran-Mantel-Haenszel test (binary outcomes). Results: At W12 and W52, mirikizumab showed significant improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) total and domain scores (P < .001); 36-Item Short Form Health Survey (SF-36) Physical Component Summary (PCS), Mental Component Summary (MCS), and domain scores (P < .05); EQ-5D-5L scores (P < .001); Work Productivity and Activity Impairment Questionnaire (UC) scores (P < .05); Patient Global Rating of Severity (P < .001); and Patient Global Rating of Change (P < .01) scores. A significantly higher proportion of mirikizumab-treated patients achieved IBDQ response (W12: 72.7% vs 55.8%; W52: 79.2% vs 49.2%; P < .001), IBDQ remission (W12: 57.5% vs 39.8%; W52: 72.3% vs 43.0%; P < .001), and clinically important improvements in PCS (W12: 50.6% vs 41.5%; W52: 61.9% vs 36.9%; P < .01) and MCS (W12: 44.2% vs 37.8%; W52: 51.2% vs 34.6%; P < .05) scores. Conclusions: Mirikizumab improved QoL in patients with moderately-to-severely active UC in phase 3 LUCENT-1 and LUCENT-2 studies. Clinical trials registration number: LUCENT-1: NCT03518086; LUCENT-2: NCT03524092.