Comparative Efficacy of Subcutaneous and Intravenous Infliximab and Vedolizumab for Maintenance Treatment of TNF-naive Adult Patients with Inflammatory Bowel Disease: A Systematic Literature Review and Network Meta-analysis.

BACKGROUND: Infliximab and vedolizumab are widely used to treat Crohn's disease (CD) and ulcerative colitis (UC). AIMS: This systematic review and network meta-analysis evaluated comparative efficacy of various regimens for intravenous or subcutaneous infliximab and vedolizumab during maintenance treatment in CD and UC. METHODS: Parallel-group randomized controlled trials (RCTs) were identified by a systematic literature review (CRD42022383401) and included if they evaluated therapeutics of interest for maintenance treatment of adults with moderate-to-severe luminal CD or UC and assessed clinical remission between Weeks 30 and 60. Clinical remission rates in CD or UC and mucosal healing rates in UC were analyzed in a Bayesian network meta-analysis model. Endoscopic outcomes in CD were synthesized by proportional meta-analysis. RESULTS: Overall, 13 RCTs were included in the analyses. All vedolizumab studies randomized induction responders to maintenance treatment; infliximab studies used a treat-through design. Subcutaneous infliximab 120 mg every 2 weeks had the highest odds ratio (OR) [95% credible interval] versus placebo for clinical remission during the maintenance phase (CD: 5.90 [1.90-18.2]; UC: 5.45 [1.94-15.3]), with surface under the cumulative ranking curve (SUCRA) values of 0.91 and 0.82, respectively. For mucosal healing in UC, subcutaneous infliximab 120 mg every 2 weeks showed the highest OR (4.90 [1.63-14.1]), with SUCRA value of 0.73, followed by intravenous vedolizumab 300 mg every 4 weeks (SUCRA value, 0.70). Endoscopic outcomes in CD were better with subcutaneous infliximab 120 mg every 2 weeks than intravenous infliximab 5 mg/kg every 8 weeks. CONCLUSIONS: Subcutaneous infliximab showed a favorable efficacy profile for achieving clinical remission and endoscopic outcomes during maintenance treatment in CD or UC.

Long-term outcomes after close rectal dissection and total mesorectal excision in ileal pouch-anal anastomosis for ulcerative colitis.

BACKGROUND: During ileal pouch-anal anastomosis (IPAA) surgery for ulcerative colitis (UC), rectal dissection can be performed via close rectal dissection (CRD) or in a total mesorectal excision plane (TME). Although CRD should protect autonomic nerve function, this technique may be more challenging than TME. The aim of this study was to compare long-term outcomes of patients undergoing CRD and TME. METHODS: This single-centre retrospective cohort study included consecutive patients who underwent IPAA surgery for UC between January 2002 and October 2017. Primary outcomes were chronic pouch failure (PF) among patients who underwent CRD and TME and the association between CRD and developing chronic PF. Chronic PF was defined as a pouch-related complication occurring ≥ 3 months after primary IPAA surgery requiring redo pouch surgery, pouch excision or permanent defunctioning ileostomy. Secondary outcomes were risk factors and causes for chronic PF. Pouch function and quality of life were assessed via the Pouch dysfunction score and Cleveland global quality of life score. RESULTS: Out of 289 patients (155 males, median age 37 years [interquartile range 26.5-45.5 years]), 128 underwent CRD. There was a shorter median postoperative follow-up for CRD patients than for TME patients (3.7 vs 10.9 years, p < 0.01). Chronic PF occurred in 6 (4.7%) CRD patients and 20 (12.4%) TME patients. The failure-free pouch survival rate 3 years after IPAA surgery was comparable among CRD and TME patients (96.1% vs. 93.5%, p = 0.5). CRD was a no predictor for developing chronic PF on univariate analyses (HR 0.7 CI-95 0.3-2.0, p = 0.54). A lower proportion of CRD patients developed chronic PF due to a septic cause (1% vs 6%, p = 0.03). CONCLUSIONS: Although differences in chronic PF among CRD and TME patients were not observed, a trend toward TME patients developing chronic pelvic sepsis was detected. Surgeons may consider performing CRD during IPAA surgery for UC.

ImmUniverse Consortium: Multi-omics integrative approach in personalized medicine for immune-mediated inflammatory diseases.

Immune mediated inflammatory diseases (IMIDs) are a heterogeneous group of debilitating, multifactorial and unrelated conditions featured by a dysregulated immune response leading to destructive chronic inflammation. The immune dysregulation can affect various organ systems: gut (e.g., inflammatory bowel disease), joints (e.g., rheumatoid arthritis), skin (e.g., psoriasis, atopic dermatitis), resulting in significant morbidity, reduced quality of life, increased risk for comorbidities, and premature death. As there are no reliable disease progression and therapy response biomarkers currently available, it is very hard to predict how the disease will develop and which treatments will be effective in a given patient. In addition, a considerable proportion of patients do not respond sufficiently to the treatment. ImmUniverse is a large collaborative consortium of 27 partners funded by the Innovative Medicine Initiative (IMI), which is sponsored by the European Union (Horizon 2020) and in-kind contributions of participating pharmaceutical companies within the European Federation of Pharmaceutical Industries and Associations (EFPIA). ImmUniverse aims to advance our understanding of the molecular mechanisms underlying two immune-mediated diseases, ulcerative colitis (UC) and atopic dermatitis (AD), by pursuing an integrative multi-omics approach. As a consequence of the heterogeneity among IMIDs patients, a comprehensive, evidence-based identification of novel biomarkers is necessary to enable appropriate patient stratification that would account for the inter-individual differences in disease severity, drug efficacy, side effects or prognosis. This would guide clinicians in the management of patients and represent a major step towards personalized medicine. ImmUniverse will combine the existing and novel advanced technologies, including multi-omics, to characterize both the tissue microenvironment and blood. This comprehensive, systems biology-oriented approach will allow for identification and validation of tissue and circulating biomarker signatures as well as mechanistic principles, which will provide information about disease severity and future disease progression. This truly makes the ImmUniverse Consortium an unparalleled approach.

Intestinal Ultrasound Early on in Treatment Follow-up Predicts Endoscopic Response to Anti-TNFα Treatment in Crohn's Disease.

BACKGROUND: To assess treatment response, objective measures are superior to clinical improvement in Crohn's disease [CD]. Intestinal ultrasound [IUS] is an attractive, non-invasive alternative to endoscopy, demonstrating early transmural changes after treatment initiation. Therefore, we investigated IUS and contrast-enhanced ultrasound [CEUS] to predict [early] endoscopic treatment response. METHODS: Consecutive patients with endoscopically active CD, starting anti-TNFα therapy, were included. Clinical, biochemical, IUS, and CEUS parameters at baseline [T0], after 4-8 weeks [T1] and 12-34 weeks [T2] were collected. The most severely inflamed segment at endoscopy (highest segmental Simplified Endoscopic Score for Crohn's Disease [SES-CD]) and IUS (highest segmental bowel wall thickness [BWT]) was identified. At T2, endoscopic response [decrease in SES-CD ≥ 50%] and remission [SES-CD = 0] were scored. RESULTS: A total of 40 patients were included: 14 reached endoscopic remission and 17 endoscopic response. At T1 (3.1 mm [1.9-4.2] vs 5.3 mm [3.8-6.9], p = 0.005) and T2 (2.0 mm [1.8-3.1] vs 5.1 [3.0-6.3] mm, p = 0.002) BWT was lower in patients with endoscopic remission. At T1 and T2, 18% (area under the receiver operating curve [AUROC]: 0.77; odds ratio [OR]: 10.80, p = 0.012) and 29% [AUROC: 0.833; OR: 37.50, p = 0.006] BWT decrease predicted endoscopic response, respectively. To determine endoscopic remission, BWT 3.2 mm was most accurate [AUROC: 0.94; OR: 39.42, p < 0.0001] at T2. In addition, absence of colour Doppler signal [OR: 13.76, p = 0.03] and the CEUS parameter wash-out rate [OR: 0.76, p = 0.019] improved the prediction model. CONCLUSIONS: Reduction in BWT, already after 4-8 weeks of follow-up, predicted endoscopic response and remission. CEUS parameters were of limited value. Furthermore, we have provided accurate cut-offs for BWT reflecting endoscopic response and remission at different time points.

Point-of-care Intestinal Ultrasound in IBD Patients: Disease Management and Diagnostic Yield in a Real-world Cohort and Proposal of a Point-of-care Algorithm.

INTRODUCTION: Intestinal ultrasound [IUS] is useful for assessment of inflammation, complications, and treatment follow-up in inflammatory bowel disease [IBD] patients. We aimed to study outcomes and impact on disease management for point-of-care [POC] IUS in IBD patients. METHODS: Two patient cohorts undergoing POC IUS [January 2016-July 2018 and October 2019-December 2019] were included retrospectively. Disease management after IUS was analysed and IUS outcomes were compared with symptoms, biomarkers, and additional imaging within 8 weeks from IUS. To study differences in use of IUS over time, cohorts were compared. RESULTS: In total, 345 examinations (280 in Crohn's disease [CD]/65 in ulcerative colitis [UC]) were performed. Present inflammation on IUS was comparable between symptomatic and asymptomatic CD [67.6% vs 60.5%; p = 0.291]. In 60%, IUS had impact on disease management with change in medication in 47.8%. Additional endoscopy/magnetic resonance imaging [MRI] was planned after 32.8% examinations, showing good correlation with IUS in 86.3% [ρ = 0.70, p <0.0001] and 80.0% [ρ = 0.75, p <0.0001] of cases, respectively. Faecal calprotectin was higher in active versus inactive disease on IUS [664 µg/g vs 79 µg/g; p <0.001]. Over the years, IUS was performed more frequently to monitor treatment response and the use of MRI was reduced within the cohort. CONCLUSIONS: POC IUS affects clinical decision making and could detect preclinical relapse in CD patients, with potential to reduce additional endoscopy or MRI. In addition, the paradigm expands towards monitoring treatment and close follow-up for IUS. Based on our results, we propose a POC IUS algorithm for follow-up of IBD patients.

Hyperbaric oxygen therapy for the treatment of rectovaginal fistulas in patients with Crohn's disease: results of the HOT-REVA pilot study.

BACKGROUND: Positive effects of hyperbaric oxygen (HBO) on perianal fistulas in Crohn's disease (CD) have been described, but the effect on rectovaginal fistulas (RVFs) has not yet been studied. The aim was to investigate the efficacy, safety and feasibility of HBO in patients with RVF in CD. METHODS: In this prospective study, consecutive CD patients between November 2018 and February 2020 presenting with RVF at the outpatient fistula clinic of the Amsterdam University Medical Centre were included and selected to receive treatment with 30 daily HBO sessions, if fistulas were actively draining and any concomitant treatment regimen was stable at least 6 weeks prior to start of HBO. Patients with a stoma were excluded. The primary endpoint was clinical closure at 3-month follow-up, defined as cessation of complaints and/or closure of the external orifice if visible at baseline. Secondary outcomes were improvement of concomitant perianal fistulas as measured by the perianal disease activity index (PDAI) and fistula drainage assessment (FDA), as well as improvement in patient-reported outcomes (visual analogue scale (VAS), inflammatory bowel disease questionnaire (IBDQ), faecal incontinence quality of life scale (FIQL) and female sexual functioning index (FSFI)) at 3-month follow-up. RESULTS: Out of 14 eligible patients, nine patients (median age 50 years) were treated, all of whom had previously had one or more unsuccessful medical and/or surgical treatments for their RVF. Clinical closure occurred in none of the patients at 3-month follow-up. There was no improvement in PDAI and patient-reported outcomes (VAS, IBDQ, FIQL and FSFI). Two patients had concomitant perianal fistulas; using FDA, one patient had a clinical response and one patient was in clinical remission 3 months after HBO. There were two treatment-related adverse events during HBO concerning claustrophobia and fatigue. Furthermore, two patients had a surgical intervention due to RVF and two patients were treated with antibiotics for a urinary tract infection during follow-up. One patient had a dose reduction of ustekinumab because of decreased luminal complaints. CONCLUSION: Treatment with HBO was feasible, but in this therapy-refractory cohort without deviating ostomy no clinical closure of RVF or improvement in quality of life was seen 3 months after HBO. Treatment with HBO alone in this specific group of patients therefore appears to be ineffective.

A nationwide database study on colectomy and colorectal cancer in ulcerative colitis: what is the role of appendectomy?

AIM: Although has been suggested that an appendectomy has a positive effect on the disease course in patients with ulcerative colitis (UC), recent studies indicate a potential increase in risk of colectomy and colorectal cancer (CRC). This study aimed to evaluate the rates of colectomy and CRC after appendectomy in UC patients using a nationwide prospective database [the Initiative on Crohn and Colitis Parelsnoer Institute - Inflammatory Bowel Disease (ICC PSI-IBD) database]. METHOD: All UC patients were retrieved from the ICC PSI-IBD database between January 2007 and May 2018. Primary outcomes were colectomy and CRC. Outcomes were compared in patients with and without appendectomy, with a separate analysis for timing of appendectomy (before or after UC diagnosis). RESULTS: A total of 826 UC patients (54.7% female; median age 46 years, range 18-89 years) were included. Sixty-three (7.6%) patients had previously undergone appendectomy: 24 (38.1%) before and 33 (52.4%) after their diagnosis of UC. In multivariate analysis, appendectomy after UC diagnosis was associated with a significantly lower colectomy rate compared with no appendectomy [hazard ratio (HR) 0.16, 95% C: 0.04-0.66, P = 0.011], and the same nonsignificant trend was seen in patients with an appendectomy before UC diagnosis (HR 0.35, 95% CI 0.08-1.41, P = 0.138). Appendectomy was associated with delayed colectomy, particularly when it was performed after diagnosis of UC (P = 0.009). No significant differences were found in the CRC rate between patients with and without appendectomy (1.6% vs 1.2%; P = 0.555). CONCLUSION: Appendectomy in established UC is associated with an 84% decreased risk of colectomy and a delay in surgery. Since the colon is in situ for longer, the risk of developing CRC remains, which underscores the importance of endoscopic surveillance programmes.

Systematic Review: Histological Scoring of Strictures in Crohn's Disease.

BACKGROUND AND AIMS: In Crohn's disease, many patients develop a stricture, which can due to inflammation, fibrosis and muscular changes or all at the same time. Determining the predominant component has therapeutic consequences but remains challenging. To develop imaging techniques that assess the nature of a stricture, a gold standard is needed and histopathology is considered as such. This paper provides an overview of published histological scoring systems for strictures in Crohn's disease. METHODS: A systematic literature review according to PRISMA guidelines was performed of histological scoring indices that assessed whether a stricture was inflammation-predominant or fibrosis-predominant. Multiple libraries were searched from inception to December 2018. Two reviewers independently assessed abstracts and full-texts. RESULTS: Sixteen articles were identified as suitable for this systematic review. A large number of parameters were reported. Extent of neutrophil infiltration and extent of fibrosis in the bowel wall were most frequently described to reflect severity of inflammation and fibrosis, respectively. Among the 16 studies, only two described a numerical scoring system for the inflammatory and fibrotic component separately. Smooth muscle changes were scored in a minority of studies. CONCLUSIONS: Multiple scoring systems have been developed. There was large heterogeneity in scoring per parameter and construction of numerical scoring systems. Therefore, we feel that none of the systems is suitable to be used as gold standard. We offer an overview of histological parameters that could be incorporated in a future histological scoring index for strictures.

Prospective cohort study of appendicectomy for treatment of therapy-refractory ulcerative colitis.

INTRODUCTION: Appendicectomy may reduce relapses and need for medication in patients with ulcerative colitis, but long-term prospective data are lacking. This study aimed to analyse the effect of appendicectomy in patients with refractory ulcerative colitis. METHODS: In this prospective multicentre cohort series, all consecutive patients with refractory ulcerative colitis referred for proctocolectomy between November 2012 and June 2015 were counselled to undergo laparoscopic appendicectomy instead. The primary endpoint was clinical response (reduction of at least 3 points in the partial Mayo score) at 12 months and long-term follow-up. Secondary endpoints included endoscopic remission (endoscopic Mayo score of 1 or less), failure (colectomy or start of experimental medication), and changes in Inflammatory Bowel Disease Questionnaire (IBDQ) (range 32-224), EQ-5D™ and EORTC-QLQ-C30-QL scores. RESULTS: A total of 28 patients (13 women; median age 40·5 years) underwent appendicectomy. The mean baseline IBDQ score was 127·0, the EQ-5D™ score was 0·65, and the EORTC-QLQ-C30-QL score was 41·1. At 12 months, 13 patients had a clinical response, five were in endoscopic remission, and nine required a colectomy (6 patients) or started new experimental medical therapy (3). IBDQ, EQ-5D™ and EORTC-QLQ-C30-QL scores improved to 167·1 (P < 0·001), 0·80 (P = 0·003) and 61·0 (P < 0·001) respectively. After a median of 3·7 (range 2·3-5·2) years, a further four patients required a colectomy (2) or new experimental medical therapy (2). Thirteen patients had a clinical response and seven were in endoscopic remission. The improvement in IBDQ, EQ-5D™ and the EORTC-QLQ-C30-QL scores remained stable over time. CONCLUSION: Appendicectomy resulted in a clinical response in nearly half of patients with refractory ulcerative colitis and a substantial proportion were in endoscopic remission. Elective appendicectomy should be considered before proctocolectomy in patients with therapy-refractory ulcerative colitis.

ANTECEDENTES: La apendicectomía puede reducir las recaídas y la necesidad de medicación en pacientes con colitis ulcerosa (ulcerative colitis, UC), sin embargo, faltan datos a largo plazo obtenidos de forma prospectiva. El objetivo de este estudio fue analizar el efecto de la apendicectomía en pacientes con UC refractarios al tratamiento. MÉTODOS: En esta serie prospectiva de cohortes multicéntrica, a todos los pacientes consecutivos con UC refractaria remitidos para proctocolectomía entre noviembre de 2012 y junio de 2015 se les recomendó en su lugar someterse a una apendicectomía laparoscópica. El criterio de valoración principal fue la respuesta clínica (disminución de ≥ 3 puntos del sistema de puntuación parcial de Mayo que varía de 0 a 9) a los 12 meses y en el seguimiento a largo plazo. Los criterios de valoración secundarios incluyeron la remisión endoscópica (puntuación endoscópica de Mayo ≤ 1), fracaso (colectomía o inicio de medicación experimental) y cambios en el IBDQ (rango 32-224), EQ-5D y EORTC-QLQ-C30-QL. RESULTADOS: En total, 28 pacientes (13 mujeres, mediana de edad 40,5) se sometieron a una apendicectomía. El IBDQ de referencia promedio fue de 127,0; el EQ-5D 0,65 y el EORTC-QLQ-C30-QL 41,1. A los 12 meses, 13 pacientes presentaban una respuesta clínica, cinco estaban en remisión endoscópica y nueve precisaron colectomía (n = 6) o un nuevo tratamiento médico experimental (n = 3). El IBDQ, EQ-5D y EORTC-QLQ-C30-QL mejoraron a 167,1 (P < 0,001); 0,80 (P = 0,003) y 61,0 (P < 0,001) respectivamente. Después de una mediana de 3,7 años (rango 2,3-5,2), otros cuatro pacientes requirieron una colectomía (n = 2) o un nuevo tratamiento médico experimental (n = 2). Trece pacientes presentaron respuesta clínica y siete se encontraban en remisión endoscópica. La mejora del IBDQ, el EQ-5D y el EORTC-QLQ-C30-QL se mantuvo estable a lo largo del tiempo. CONCLUSIÓN: La apendicectomía consiguió una respuesta clínica en casi la mitad de los pacientes con UC refractaria. La apendicectomía electiva debería ser considerada antes que la proctocolectomía en pacientes con UC refractaria al tratamiento.

Hyperbaric oxygen therapy for the treatment of perianal fistulas in Crohn's disease (HOT-TOPIC): study protocol of a prospective interventional cohort study with one-year follow-up.

Background: Perianal fistulizing Crohn's disease (pCD) has a significant impact on patients' health and quality of life. Current treatment options have a relatively low success rate and a high recurrence risk. Positive effects of hyperbaric oxygen (HBO2) therapy have been indicated in animal studies as well as in small case series. Methods/Design: This is a non-randomized, controlled pilot study. A total of 20 patients with pCD who have been refractory to standard therapy for at least six months will be included. Patients with a seton and stable treatment regimen will be included. Patients with anal strictures, rectovaginal fistulas, stoma or deep ulceration of the rectum will be excluded. Patients who are eligible but refuse HBO2 will be asked to serve as controls. Patients in the HBO2 group will be treated with 40 sessions of HBO2 therapy at 243-253 kPa, with the seton being removed after 30 sessions. Co-primary endpoints are changes in the perianal disease activity index and MRI-scores. Secondary outcomes are fistula drainage assessment, laboratory findings and patient-reported outcomes. Assessment will be done at baseline, 16 weeks, 34 weeks and 60 weeks after finishing HBO2. Discussion: The aim of this study is to investigate the feasibility and therapeutic effect of HBO2 on pCD. The one-year follow-up should provide information on the effect durability. A comparison between patients treated with HBO2 and patients who continue to receive standard care will be made. The risk of bias will be limited by using clearly defined inclusion and exclusion criteria, baseline characteristics and consecutive recruitment of patients through an outpatient fistula clinic. Trial registration: The HOT-TOPIC trial has been approved by the local Medical Ethical Committee of the Academic Medical Centre in Amsterdam, the Netherlands. The trial has been registered at the Netherlands Trial Register (www.trialregister.nl), registration number: NTR 6676. Protocol version: August 2017, version 3.0.

A JAK1 Selective Kinase Inhibitor and Tofacitinib Affect Macrophage Activation and Function.

BACKGROUND: Janus kinases (JAKs) mediate cytokine signaling involved in inflammatory bowel disease. The pan-JAK inhibitor tofacitinib has shown efficacy in the treatment of ulcerative colitis. However, concerns regarding adverse events due to their wide spectrum inhibition fueled efforts to develop selective JAK inhibitors. Given the crucial role of myeloid cells in intestinal immune homeostasis, we evaluated the effect of pan-JAK and selective JAK inhibitors on pro- and anti-inflammatory macrophage polarization and function (M1/M2) and in experimental colitis. METHODS: Murine bone marrow-derived macrophages or human monocytes were treated using JAK1 and JAK3 selective inhibitors (JAK1i;JAK3i) and tofacitinib and were evaluated by transcriptional, functional, and metabolic analyses. In vivo, oral administration of JAK1i and tofacitinib (10 or 30 mg/kg) was tested in both acute and acute rescue dextran sodium sulfate (DSS) colitis. RESULTS: Both tofacitinib and JAK1i but not JAK3i effectively inhibited STAT1 phosphorylation and interferon gamma-induced transcripts in M1 polarized macrophages. Strikingly, transcriptional profiling suggested a switch from M1 to M2 type macrophages, which was supported by increased protein expression of M2-associated markers. In addition, both inhibitors enhanced oxidative phosphorylation rates. In vivo, JAK1i and tofacitinib did not protect mice from acute DSS-induced colitis but ameliorated recovery from weight loss and disease activity during acute rescue DSS-induced colitis at the highest dose. CONCLUSION: JAK1i and tofacitinib but not JAK3i induce phenotypical and functional characteristics of anti-inflammatory macrophages, suggesting JAK1 as the main effector pathway for tofacitinib in these cells. In vivo, JAK1i and tofacitinib modestly affect acute rescue DSS-induced colitis.

Appendectomy for Therapy-Refractory Ulcerative Colitis Results in Pathological Improvement of Colonic Inflammation: Short-Term Results of the PASSION Study.

BACKGROUND AND AIMS: The objective of this study was to examine the modulating effect of an appendectomy on the disease course of therapy-refractory ulcerative colitis [UC] patients, and to analyse appendiceal pathological characteristics predictive of pathological response. METHODS: Patients with therapy-refractory UC, and referred for proctocolectomy, were invited to undergo laparoscopic appendectomy first. The primary end points were clinical response after 3 and 12 months. Secondary end points were endoscopic remission, failure, and pathologic response. Appendiceal specimens, and pre- and post-operative biopsies were histologically graded according to the validated Geboes score. RESULTS: Thirty patients [53% male] with a median age of 40 (interquartile range [IQR], 33-47) underwent appendectomy, with a median preoperative total Mayo score of 9 [IQR, 8-11]. After 12 months, 9 patients [30%] had lasting clinical response, of whom 5 [17%] were in endoscopic remission. Pathological evaluation was possible in 28 patients. After a median of 13.0 weeks [range 7-51], pathological response was seen in 13 patients [46%], with a median decrease of 2 points [range 1-3]. Appendiceal inflammation was highly predictive of pathological response when compared with no inflammation or extensive ulcerations [85% vs 20%, p = 0.001]. CONCLUSIONS: Appendectomy was effective in one-third of therapy-refractory UC patients, with a substantial proportion of patients demonstrating complete endoscopic remission after 1 year. Pathological response was seen in almost 50% of patients and was related to active inflammation in the appendix, limited disease, and shorter disease duration. These early results suggest that there is a UC patient group that may benefit from appendectomy.

Antigenic response to CT-P13 and infliximab originator in inflammatory bowel disease patients shows similar epitope recognition.

AIM: To test the cross-immunogenicity of anti-CT-P13 IBD patients' sera to CT-P13/infliximab originator and the comparative antigenicity evoked by CT-P13/infliximab originator sera. METHODS: Sera of patients with IBD with measurable anti-CT-P13 antibodies were tested for their cross-reactivity to 5 batches of infliximab originator and CT-P13. Anti-drug antibody positive sera from treated patients were used to compare antigenic epitopes. RESULTS: All 42 anti-CT-P13 and 37 anti-infliximab originator IBD sera were cross-reactive with infliximab originator and CT-P13 respectively. Concentration of anti-drug antibodies against infliximab originator or CT-P13 were strongly correlated both for IgG1 and IgG4 (P < 0.001). Anti-CT-P13 sera of patients with IBD (n = 32) exerted similar functional inhibition on CT-P13 or infliximab originator TNF binding capacity and showed reduced binding to CT-P13 in the presence of five different batches of CT-P13 and infliximab originator. Anti-CT-P13 and anti-infliximab originator IBD sera selectively enriched phage-peptides from the VH (CDR1 and CDR3) and VL domains (CDR2 and CDR3) of infliximab. Sera reactivity detected major infliximab epitopes in these regions of infliximab in 60%-79% of patients, and no significant differences were identified between CT-P13 and infliximab originator immunogenic sera. Minor epitopes were localised in framework regions of infliximab with reduced antibody reactivity shown, in 30%-50% of patients. Monoclonal antibodies derived from naïve individuals and ADA-positive IBD patients treated with CT-P13 provided comparable epitope specificity to five different batches of CT-P13 and infliximab originator. CONCLUSIONS: These results strongly support a similar antigenic profile for infliximab originator and CT-P13, and point toward a safe switching between the two drugs in anti-drug antibody negative patients.

Subcutaneous rather than intravenous ustekinumab induction is associated with comparable circulating drug levels and early clinical response: a pilot study.

BACKGROUND: Ustekinumab (USK) is licenced for intravenous induction and subcutaneous (S/C) maintenance in Crohn's disease. AIM: To evaluate ustekinumab trough concentrations and clinical response with exclusive subcutaneous ustekinumab induction. METHODS: Patients with Crohn's disease who initiated treatment with subcutaneous ustekinumab at a single academic centre were included in this pilot study. A dosage of 360 mg ustekinumab was given subcutaneously in divided doses; 180 mg at Week 0, 90 mg at Week 1 and 90 mg at Week 2, with corresponding ustekinumab trough concentrations assessed to Week 8. The primary outcome measures were trough serum ustekinumab levels and clinical remission at Week 8. Secondary outcome measures were trough serum ustekinumab levels at Week 1 & 2 and changes in C-reactive protein, albumin and faecal calprotectin at Week 8. RESULTS: Nineteen patients were included. Median Week 8 ustekinumab trough concentrations were 6.1 µg/mL (Inter-quartile range 4-9.8 µg/mL). There was a significant improvement in Harvey Bradshaw index from Week 0 (median HBI 5; interquartile range 2-8) to Week 8 (median HBI 1; interquartile range 0-3) (P = 0.002). C-reactive protein levels did not change significantly but faecal calprotectin improved significantly; median faecal calprotectin at Week 0 was 533 µg/g; at Week 8, it was 278 µg/g (P = 0.038). CONCLUSIONS: Ustekinumab trough concentrations are comparable whether ustekinumab induction treatment was administered subcutaneously or intravenously. A significant improvement in symptoms and faecal calprotectin was noted. These results support the use of subcutaneous induction as an alternative if there are barriers to intravenous induction.

Systematic review with meta-analysis: endoscopic and histologic placebo rates in induction and maintenance trials of ulcerative colitis.

BACKGROUND: Regulatory requirements for claims of mucosal healing in ulcerative colitis (UC) will require demonstration of both endoscopic and histologic healing. Quantifying these rates is essential for future drug development. AIMS: To meta-analyse endoscopic and histologic placebo response and remission rates in UC randomised controlled trials (RCTs) and identify factors influencing these rates. METHODS: MEDLINE, EMBASE and the Cochrane Library were searched from inception to March 2017 for placebo-controlled trials of pharmacological interventions for UC. Endoscopic and histologic placebo rates were pooled by random effects. Mixed effects univariable and multivariable meta-regression was used to evaluate the influence of patient, intervention and trial-related study-level covariates on these rates. RESULTS: Fifty-six induction (placebo n = 4171) and 8 maintenance trials (placebo n = 1011) were included. Pooled placebo endoscopic remission and response rates for induction trials were 23% [95 confidence interval (CI) 19-28%] and 35% [95% CI 27-42%] respectively, and 20% [95% CI 16-24%] for maintenance of remission. The pooled histologic placebo remission rate was 14% [95% CI 8-22%] for induction trials. High heterogeneity was observed for all outcomes (I2 56.2%-88.3%). On multivariable meta-regression, central endoscopy reading was associated with significantly lower endoscopic placebo remission rates (16% vs 25%; OR = 0.52, [95% CI 0.29-0.92], P = 0.03). On univariable meta-regression, higher histologic placebo remission was associated with concomitant corticosteroids (OR = 1.17 [95% CI 1.08-1.26], P < 0.0001, per 10% increase in corticosteroid use). CONCLUSIONS: Placebo endoscopic and histologic rates range from 14% to 35% in UC RCTs but are highly heterogeneous. Outcome standardisation may reduce heterogeneity and is needed in this field.

Ultrasound for Assessing Disease Activity in IBD Patients: A Systematic Review of Activity Scores.

BACKGROUND AND AIMS: Ultrasound [US] indices for assessing disease activity in IBD patients have never been critically reviewed. We aimed to systematically review the quality and reliability of available ultrasound [US] indices compared with reference standards for grading disease activity in IBD patients. METHODS: Pubmed, Embase and Medline were searched for relevant literature published within the period 1990 to June 2017. Relevant publications were identified through full text review after initial screening by two investigators. Data on methodology and index characteristics were collected. Study quality was assessed using a modified version of the Quadas-2 tool for risk of bias assessment. RESULTS: Of 20 studies with an US index, 11 studies met the inclusion criteria. Out of these 11 studies, 7 and 4 studied Crohn's disease [CD] and ulcerative colitis [UC0 activity indices, respectively. Parameters that were used in these indices included bowel wall thickness [BWT], Doppler signal [DS], wall layer stratification [WLS], compressibility, peristalsis, haustrations, fatty wrapping, contrast enhancement [CE], and strain pattern. Study quality was graded high in 5 studies, moderate in 3 studies and low in 3 studies. Ileocolonoscopy was used as the reference standard in 9 studies. In 1 study a combined index of ileocolonoscopy and barium contrast radiography and in 1 study histology was used as the reference standard. Only 5 studies used an established endoscopic index for comparison with US. CONCLUSIONS: Several US indices for assessing disease activity in IBD are available; however, the methodology for development was suboptimal in most studies. For the development of future indices, stringent methodological design is required.

Reliability of histologic assessment in patients with eosinophilic oesophagitis.

BACKGROUND: The validity of the eosinophilic oesophagitis (EoE) histologic scoring system (EoEHSS) has been demonstrated, but only preliminary reliability data exist. AIM: Formally assess the reliability of the EoEHSS and additional histologic features. METHODS: Four expert gastrointestinal pathologists independently reviewed slides from adult patients with EoE (N = 45) twice, in random order, using standardised training materials and scoring conventions for the EoEHSS and additional histologic features agreed upon during a modified Delphi process. Intra- and inter-rater reliability for scoring the EoEHSS, a visual analogue scale (VAS) of overall histopathologic disease severity, and additional histologic features were assessed using intra-class correlation coefficients (ICCs). RESULTS: Almost perfect intra-rater reliability was observed for the composite EoEHSS scores and the VAS. Inter-rater reliability was also almost perfect for the composite EoEHSS scores and substantial for the VAS. Of the EoEHSS items, eosinophilic inflammation was associated with the highest ICC estimates and consistent with almost perfect intra- and inter-rater reliability. With the exception of dyskeratotic epithelial cells and surface epithelial alteration, ICC estimates for the remaining EoEHSS items were above the benchmarks for substantial intra-rater, and moderate inter-rater reliability. Estimation of peak eosinophil count and number of lamina propria eosinophils were associated with the highest ICC estimates among the exploratory items. CONCLUSION: The composite EoEHSS and most component items are associated with substantial reliability when assessed by central pathologists. Future studies should assess responsiveness of the score to change after a therapeutic intervention to facilitate its use in clinical trials.

Physicians' perspective on the clinical meaningfulness of inflammatory bowel disease trial results: an International Organization for the Study of Inflammatory Bowel Disease (IOIBD) survey.

BACKGROUND: Several novel compounds are being developed for inflammatory bowel diseases (IBD). In addition, biosimilar drugs are being approved. An increasing number of head-to-head, superiority and non-inferiority trials in patients with IBD are expected in the future. The clinical relevance of the magnitude of the effect size is often debated. AIM: To better understand physicians' perspectives on the clinical meaningfulness of IBD trial results. METHODS: We conducted an online survey among all IOIBD (International Organization for the Study of Inflammatory Bowel Diseases) members, asking their opinion on the clinical relevance of the results of IBD trials. RESULTS: Forty-six IOIBD members responded to the survey (52.3%). In biologic-naïve ulcerative colitis (UC) and Crohn's disease (CD) patients, most of the participants considered a 15% difference with placebo for clinical remission and endoscopic remission to be clinically relevant. In head-to-head trials, most of participants considerer a 10% difference between groups for clinical remission and endoscopic remission to be clinically relevant. Half of respondents considered 10% to be an adequate margin in non-inferiority trials. In bioequivalence studies, most of the participants considered adequate a ± 5% difference between a biosimilar and the originator for pharmacokinetic parameters, efficacy, safety and immunogenicity. Regarding safety, the difference between two drugs considered clinically relevant varied from 1% to 5%, depending on the type of adverse event. CONCLUSIONS: This is the first survey exploring how physicians perceive IBD trial results, providing an estimation of the magnitude of the difference between treatment arms that may directly influence clinical practice.

Patterns of anti-TNF use and associated treatment outcomes in inflammatory bowel disease patients: results from an analysis of Dutch health insurance claims data.

INTRODUCTION: Real-life patterns of anti-tumour necrosis factor (anti-TNF) use remain largely unknown. We aimed to investigate survival rates, clinical outcomes and costs of anti-TNF agents in a large population of patients with inflammatory bowel disease (IBD). METHODS: Health insurance data from 22,082 IBD patients were provided by Achmea Healthcare. Time to anti-TNF discontinuation, treatment intensification, corticosteroid initiation and hospitalisation were analysed in patients starting on anti-TNF treatment from January 2008 until December 2014. Treatment regimens were analysed at different time points. RESULTS: In this cohort, 855 and 1199 subjects started infliximab and adalimumab treatment, respectively. The median time to anti-TNF discontinuation was 600 days (IQR 156-1693). The proportion of subjects receiving intensified treatment increased over time (infliximab at 3 vs. 24 months: 22.2% vs. 33.6%, p = 0.01; adalimumab at 3 vs. 24 months: 10.5% vs. 19.3%, p < 0.001). Cessation of anti-TNF treatment was less common in Crohn's disease patients (HR 0.79, p = 0.001) and in patients receiving intensified treatment (HR 0.62, p = 0.001). Immunomodulator use was associated with a longer time to corticosteroid initiation (HR 0.80, p = 0.048), but not with longer drug survival (HR 0.99, p = 0.617). Hospitalisation was more common in Crohn's patients (HR 1.49, p = 0.011). Corticosteroid initiation was lower in Crohn's patients (HR 0.57, p < 0.001) and in patients using infliximab (HR 0.55, p < 0.001). CONCLUSIONS: Discontinuation of anti-TNF therapy occurred earlier than previously reported and was associated with a diagnosis of ulcerative colitis and non-intensified anti-TNF treatment. Immunomodulator use at the start of anti-TNF treatment was associated with a longer time to corticosteroid initiation, but not with longer drug survival.