Magnetic Resonance Enterography and Histology in Patients With Fibrostenotic Crohn's Disease: A Multicenter Study.

INTRODUCTION: Magnetic resonance enterography (MRE) is useful for detecting bowel strictures, whereas a number of imaging biomarkers may reflect severity of fibrosis burden in Crohn's disease (CD). This study aimed to verify the association of MRE metrics with histologic fibrosis independent of inflammation. METHODS: This prospective European multicenter study performed MRE imaging on 60 patients with CD with bowel strictures before surgical resection. Locations of 61 histological samples were annotated on MRE examinations, followed by central readings using the Chiorean score and measurement of delayed gain of enhancement (DGE), magnetization transfer ratio, T2-weighted MRI sequences (T2R), apparent diffusion coefficient (ADC), and the magnetic resonance index of activity (MaRIA). Correlations of histology and MRE metrics were assessed. Least Absolute Shrinkage and Selection Operator and receiver operator characteristic (ROC) curve analyses were used to select composite MRE scores predictive of histology and to estimate their predictive value. RESULTS: ADC and MaRIA correlated with fibrosis (R = -0.71, P < 0.0001, and 0.59, P < 0.001) and more moderately with inflammation (R = -0.35, P < 0.01, and R = 0.53, P < 0.001). Lower or no correlations of fibrosis or inflammation were found with DGE, magnetization transfer ratio, or T2R. Least Absolute Shrinkage and Selection Operator and ROC identified a composite score of MaRIA, ADC, and DGE as a very good predictor of histologic fibrosis (ROC area under the curve = 0.910). MaRIA alone was the best predictor of histologic inflammation with excellent performance in identifying active histologic inflammation (ROC area under the curve = 0.966). DISCUSSION: MRE-based scores for histologic fibrosis and inflammation may assist in the characterization of CD stenosis and enable development of fibrosis-targeted therapies and clinical treatment of stenotic patients.

Inflammatory Bowel Disease-related Behaviours [IBD-Bx] Questionnaire: Development, Validation and Prospective Associations with Fatigue.

BACKGROUND AND AIMS: Disease-related behaviours that may maintain or worsen symptom burden remain largely unexplored in inflammatory bowel disease [IBD]. In this study, we developed and validated an instrument assessing IBD-related, modifiable behaviours and explored which behaviours prospectively correlate with fatigue, a debilitating and common symptom in IBD. METHODS: Initially, 72 items reflecting IBD-related behaviours were generated based on literature review and input from clinicians and people diagnosed with IBD. During wave 1, 495 IBD patients rated to what extent each behaviour was applicable to them. Additionally, disease activity, fatigue, IBD-related concerns and psychological variables were assessed. During a follow-up visit 4-12 weeks later [wave 2], a random selection of 92 patients from wave 1 completed the measures assessing the IBD-related behaviours, disease activity and fatigue once more. RESULTS: A principal component analysis with oblique rotation revealed seven components in the 72 IBD behaviours, which could be interpreted as: [1] Avoiding food and activities, [2] Access to toilets, [3] Avoidance of sex, [4] Cognitive avoidance, [5] Not sharing with others, [6] Alternative treatments and [7] Disease management. Each component was reduced to three to five representative items, resulting in a final, 25-item IBD-Bx questionnaire showing good concurrent validity [alphas > 0.63] and reliability. Almost all components were cross-sectionally related to levels of fatigue. Avoiding food and activities and Access to toilets significantly predicted fatigue at wave 2 when controlling for baseline fatigue. CONCLUSIONS: The IBD-Bx is a valid and reliable questionnaire of IBD-related behaviours, some of which predict future fatigue burden.

What Are the Most Challenging Aspects of Inflammatory Bowel Disease? An International Survey of Gastroenterologists Comparing Developed and Developing Countries.

BACKGROUND AND AIMS: As inflammatory bowel disease (IBD) becomes more prevalent, the challenges that gastroenterologists face in managing these patients evolve. We aimed to describe the most important challenges facing gastroenterologists from around the world and compare these between those working in developed and developing countries. METHODS: An online questionnaire was developed, and a link distributed to gastroenterologists. Data were analyzed descriptively using Friedman and Wilcoxon matched-pair signed rank tests to compare rankings for responses. Mann-Whitney U tests were used to compare rankings between responses from gastroenterologists from developed and developing countries. Lower scores reflected greater challenges. RESULTS: Of 872 who started, 397 gastroenterologists (45.5%) completed the survey. Respondents represented 65 countries (226 [56.9%] from developed countries). Overall, the challenge ranked most important (smallest number) was increasing IBD prevalence (13.6%). There were significant differences in mean ranking scores for many simple aspects of care for those from developing countries compared to providers from developed countries, such as access to simple IBD treatments (5.52 vs. 6.02, p = 0.01), access to anti-TNF drugs including dose escalation (3.33 vs. 3.93, p < 0.01), access to good stoma care (2.57 vs. 3.03, p < 0.001), access to therapeutic drug monitoring (1.47 vs. 1.84, p < 0.001), and access to care for people from low socioeconomic status (2.77 vs. 3.37, p < 0.001). CONCLUSIONS: Increasing IBD prevalence is seen by gastroenterologists as the greatest challenge facing them. There are significant differences between the IBD challenges facing gastroenterologists from developed and developing countries that reflect inequities in access to health care.

Implementing capnography to help improve patient safety during procedural sedation: quality improvement in a high-volume gastroenterology department.

OBJECTIVE: Respiratory compromise is a major cause of adverse events during procedural sedation; continuous monitoring is vital for identifying and halting decompensation. We performed a quality improvement investigation to assess patient safety during procedural sedation in gastroenterology and the impact of implementing capnography monitoring. PATIENTS AND METHODS: Sedation-related adverse events and interventions were prospectively recorded during the endoscopic procedure and in recovery. Assuming rates in published literature, power analysis determined that at least 1332 patients were required to show a 20% improvement in patient safety. Recorded sedation-related adverse events (mild and severe oxygen desaturations, bradycardia and tachycardia) and interventions were anonymized and aggregated to evaluate the quality improvement. Patient safety under current care was determined before capnography (Medtronic) was implemented in combination with training. RESULTS: Between February 2018 and April 2018, a baseline (1092 patients) for outcomes under current care was completed, with 11.45 events per 100 procedures recorded. Between May 2018 and July 2018, 1044 procedures including capnography monitoring were performed with 5.08 events per 100 procedures recorded. The distribution of American Society of Anesthesiologists scores and procedure types between baseline and capnography were comparable. The absolute difference between baseline and capnography was -6.4 events per 100 procedures [95% confidence interval (CI), -4.1 to -8.7; P ≤ 0.0001]. The 55% reduction in adverse events surpassed the 20% improvement in patient safety set as the goal of this quality improvement. After multivariate regression, the adjusted odds ratio for events after implementation of capnography was 0.46 (95% CI, 0.32-0.66). CONCLUSIONS: Addition of capnography to current care significantly decreased procedure-related safety events.

Evolution of Endoscopic Lesions in Steroid-Refractory Acute Severe Ulcerative Colitis Responding to Infliximab or Cyclosporine.

BACKGROUND/AIMS: Few data on the evolution of endoscopic findings are available in patients with acute severe ulcerative colitis (ASUC). The aim of this study was to describe this evolution in a prospective cohort. METHODS: Patients admitted for a steroid-refractory ASUC and included in a randomized trial comparing infliximab and cyclosporine were eligible if they achieved steroid-free clinical remission at day 98. Flexible sigmoidoscopies were performed at baseline, days 7, 42 and 98. Ulcerative colitis endoscopic index of severity (UCEIS) and its sub-scores - vascular pattern, bleeding and ulceration/erosion - were post-hoc calculated. Global endoscopic remission was defined by a UCEIS of 0, and partial endoscopic remission by any UCEIS sub-score of 0. RESULTS: Among the 55 patients analyzed (29 infliximab and 26 cyclosporine), 49 (83%) had UCEIS ≥6 at baseline at baseline. Partial endoscopic remission rates were higher for bleeding than for vascular pattern and for ulcerations/erosions at day 7 (20% vs. 4% and 5% (n = 55); p = .004 and p=.04), for bleeding and ulceration/erosion than for vascular pattern at day 42 [63% and 65% vs. 33% (n=54); p<.001 for both] and at day 98 [78% and 92% vs. 56% (n = 50); p = .007 and p < .001]. Global endoscopic remission rates at day 98 were higher in patients treated with infliximab than with cyclosporine [73% vs. 25% (n = 26 and 24); p < .001]. CONCLUSION: In steroid-refractory ASUC patients responding to a second-line medical therapy, endoscopic remission process started with bleeding remission and was not achieved in half the patients at day 98 for vascular pattern. Infliximab provided a higher endoscopic remission rate than cyclosporine at day 98.

Rates of Postoperative Recurrence of Crohn's Disease and Effects of Immunosuppressive and Biologic Therapies.

BACKGROUND & AIMS: The Rutgeerts' scoring system is used to evaluate patients with Crohn's disease (CD) following ileocolic resection, based on endoscopic findings at the anastomosis and in the neoterminal ileum. We investigated rates of clinical and surgical recurrence of CD after surgery and effect of therapy modification based on post-operative endoscopic findings. METHODS: We collected data from 365 adults with CD (20% with Rutgeerts' score i0, 10% with score i1, 49% with score i2, 12% with score i3, 9% with score i4) who underwent ileocolonoscopy within 12 months of ileocolic resection with anastomosis from 2000 through 2013 at 2 centers in Belgium and France. Patients were followed for 3 y or more after the ileocolonoscopy. Clinical post-operative recurrence (POR) was defined as occurrence of CD symptoms along with biologic, radiologic, and/or endoscopic features of disease activity; modified surgical POR was defined as either an endoscopic or surgical intervention. RESULTS: After a median follow-up time of 88 months, 48% of patients had clinical POR and 26% had modified surgical POR. Rates of survival without clinical POR or a modified surgical POR were lower in patients with Rutgeerts' scores of i2, i3, or i4 compared to patients with scores of i0 or i1 (P < .001 and P = .02). New immunosuppressant or biological therapy was initiated following endoscopy in 129/254 patients (51%) with Rutgeerts' score of i2, i3, or i4 vs 7/111 patients (6%) with scores of i0 or i1 (odds ratio for new therapy, 14.9; 95% CI, 7.1-36.8; P < .001). A modest decrease in risk of clinical POR was observed for patients with Rutgeerts scores of i3 or i4 after initiation of immunosuppressive or biological therapy based on endoscopic findings (Breslow P = .03), but this was not observed for patients with scores of i2 (Breslow P = .46). CONCLUSIONS: Use of immunosuppressants and tumor necrosis factor antagonists to treat patients with an asymptomatic endoscopic post-operative recurrence of CD did not reduce long-term risk of clinical recurrence in patients with Rutgeerts' scores of i2, but it had a small effect in patients with scores of i3 or i4.

A Multicentre, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy, Safety, and Tolerability of the S1P Receptor Agonist KRP203 in Patients with Moderately Active Refractory Ulcerative Colitis.

BACKGROUND AND AIMS: KRP203 is a potent oral agonist of the sphingosine-1-phosphate receptor subtype 1 that induces the sequestration of peripheral lymphocytes, thereby potentially reducing the number of activated lymphocytes circulating to the gastrointestinal tract. METHODS: We conducted a multicentre, double-blind, placebo-controlled, parallel-group, proof-of-concept study to evaluate the efficacy, safety, and tolerability of KRP203 in patients with moderately active 5-aminosalicylate-refractory ulcerative colitis (UC). Patients were randomly assigned to receive 1.2 mg KRP203 or placebo daily for 8 weeks. Primary efficacy variable was clinical remission, defined as partial Mayo Score 0-1 and modified Baron Score 0-1 with rectal bleeding subscore 0. RESULTS: KRP203 was safe and well tolerated overall. The most common adverse events (AEs) were gastrointestinal disorders and headache. Importantly, no KRP203-related cardiac AEs were reported. Total peripheral lymphocytes and selectively affected lymphocyte subtypes decreased, causing marked decreases in naive and central memory CD4+ and CD8+ T cells, and also in B cells. Clinical remission occurred in 2/14 (14%) patients under KRP203, compared with 0/8 (0%) under placebo. CONCLUSIONS: Overall, KRP203 was safe and well tolerated by patients with UC. Importantly, no cardiac AEs were reported. Although KRP203 did not meet the minimum clinically relevant threshold for efficacy, the results may suggest that KRP203 treatment is superior to placebo. However, in this small study population, the difference was insignificant. Based on these data, studies with an improved design and a larger population should be considered.

Worries and concerns of inflammatory bowel disease (IBD) patients in Belgium - a validation of the Dutch rating form.

OBJECTIVES: Worry is the most common psychological complaint among patients with Inflammatory Bowel Disease (IBD). This study aimed to translate and test the psychometric properties the Rating Form of IBD Patient Concerns (RFIPC) among Dutch-speaking patients with IBD in Belgium. It also aimed to describe worries and concerns, and to examine possible differences in worry patterns between patients with different disease types and disease activities. METHODS: The RFIPC was translated into Dutch following the guidelines of the Rome Foundation and was completed by patients with Crohn's disease (CD, n = 336) and ulcerative colitis (UC, n = 160). To test concurrent validity, the Depression Anxiety Stress Scales (DASS-21) were used. Factor structure was examined with confirmatory factor analysis. RESULTS: The four-factor structure including subscales 'impact of the disease', 'sexual intimacy', 'complications of the disease' and 'body stigma' was confirmed in the Dutch sample. All factors had high internal consistency (>.70). Correlations with DASS-21 suggest good concurrent validity, all rs>.30, ps<.001. No differences in the RFIPC scores were observed between patients with CD and UC. Patients with active disease (53%) had higher scores than patients in remission (47%). Across all groups, the order of top concerns was consistent and included worries about energy level, side effects of medication, having an ostomy bag/surgery, and uncertain nature of the disease. CONCLUSIONS: The Dutch version of the RFIPC is a valid and reliable measure of IBD-specific worries and concerns which can be used in both research and clinical settings.

Biological Therapy in Inflammatory Bowel Disease Patients Partly Restores Intestinal Innate Lymphoid Cell Subtype Equilibrium.

Patients with Crohn disease (CD) and ulcerative colitis (UC) suffer from chronic relapsing intestinal inflammation. While many studies focused on adaptive immunity, less is known about the role of innate immune cells in these diseases. Innate lymphoid cells (ILCs) are recently identified cells with a high cytokine-producing capacity at mucosal barriers. The aim was to study the impact of biological treatment on ILC in CD and UC. Patients initiating anti-tumor necrosis factor (TNF), ustekinumab, or vedolizumab treatment were prospectively followed up and peripheral and intestinal ILCs were determined. In the inflamed gut tissue of patients with inflammatory bowel disease, we found an increase of ILC1 and in immature NKp44- ILC3, whereas there was a decrease of mature NKp44+ ILC3 when compared to healthy controls (HCs). Similar but less pronounced changes in ILC1 were observed in blood, whereas circulating NKp44- ILC3 were decreased. Fifteen percent of CD patients had NKp44+ ILC3 in blood and these cells were not detected in blood of HCs or UC patients. Therapy with three different biologicals (ustekinumab targeting the IL-12/23 cytokines, anti-TNF and vedolizumab) partly restored intestinal ILC subset equilibrium with a decrease of ILC1 (except for ustekinumab) and an increase of NKp44+ ILC3. Anti-TNF also mobilized more NKp44+ ILC3 in circulation. As ILC1 are proinflammatory cells and as NKp44+ ILC3 contribute to homeostasis of intestinal mucosa, the observed effects of biologicals on ILCs might contribute to their clinical efficacy.

Fibrogenesis in chronic murine colitis is independent of innate lymphoid cells.

INTRODUCTION: Insight in the pathogenesis of intestinal fibrosis is an unmet medical need in inflammatory bowel diseases. Studies in murine models and human organ fibrosis point to a potential role of innate lymphoid cells (ILC) in chronic intestinal inflammation and fibrosis. MATERIALS AND METHODS: Dextran sodium sulfate (DSS) in drinking water was used to induce chronic colitis and remodeling in C57Bl/6 wild type (WT), RAG-deficient, RAG-/- common γ chain deficient and anti-CD90.2 monoclonal antibody treated RAG-/- mice. Inflammation was scored by macroscopic and histological examination and fibrosis was evaluated by hydroxyproline quantification and histology. RESULTS: In RAG-/- mice (which have a normal ILC population but no adaptive immunity), chronic intestinal inflammation and fibrosis developed similarly as in WT mice, with a relative increase in ILC2 during repeated DSS exposure. Chronic colitis could also be induced in the absence of ILC (RAG-/- γc-/- or anti-CD90.2 treated RAG-/- mice) with no attenuation of fibrosis. Importantly, clinical recovery based on weight gain after stopping DSS exposure was impaired in ILC-deficient or ILC-depleted mice. CONCLUSION: These data argue against a profibrotic effect of ILC in chronic colitis, but rather suggest that ILC have a protective and recovery-enhancing effect after repeated intestinal injury.

Development and feasibility of a telemonitoring tool with full integration in the electronic medical record: a proof of concept study for patients with inflammatory bowel disease in remission on biological therapy.

Objectives: Telemonitoring can be implemented to enhance disease monitoring and ultimately reduce the number of outpatient visits and associated costs. We developed an in house IBD mobile app and established a proof of concept study to demonstrate the effectiveness and accuracy of the telemonitoring tool for monitoring of disease activity.Methods: An IBD mobile app was designed through close collaboration between the Information Technology and Gastroenterology department of University Hospitals of Leuven. The study was proposed to all patients in remission under stable biological therapy visiting the outpatient clinic. During one-year follow-up, patients completed weekly and monthly questionnaires on their mobile device or on a website. Entered data were directly sent to the electronic medical record. Predefined red flags or alerts, generated by the answers to the questionnaires, were monitored daily.Results: The pilot study in 45 patients demonstrated accurate monitoring of disease activity with fast intervention during flares. During the 12-months follow-up period, an alert for disease activity was generated for 9 different patients out of 1296 completions of the questionnaire. Symptoms resolved spontaneously in 8 patients. One patient reported consecutive PRO-2 increase, endoscopy confirmed an IBD flare and therapy was switched. For the remaining 36 included patients, no alerts indicating disease activity increase were reported. Median compliance to all weekly and monthly questionnaires during 1 year was 52% (IQR: 24-91).Conclusions: We developed the mynexuzhealth IBD app with full integration in the electronic medical record. The app enabled continuous remote monitoring and showed accurate detection of flares.

Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients With Crohn's Disease.

BACKGROUND & AIMS: We evaluated the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, in a randomized trial of patients with Crohn's disease (CD). METHODS: We performed a double-blind, phase 2 trial in adults with moderate to severe CD and inadequate response or intolerance to immunosuppressants or tumor necrosis factor antagonists. Patients were randomly assigned (1:1:1:1:1:1) to groups given placebo; or 3 mg, 6 mg, 12 mg, or 24 mg upadacitinib twice daily; or 24 mg upadacitinib once daily and were evaluated by ileocolonoscopy at weeks 12 or 16 of the induction period. Patients who completed week 16 were re-randomized to a 36-week period of maintenance therapy with upadacitinib. The primary endpoints were clinical remission at week 16 and endoscopic remission at week 12 or 16 using the multiple comparison procedure and modeling and the Cochran-Mantel-Haenszel test, with a 2-sided level of 10%. RESULTS: Among the 220 patients in the study, clinical remission was achieved by 13% of patients receiving 3 mg upadacitinib, 27% of patients receiving 6 mg upadacitinib (P < .1 vs placebo), 11% of patients receiving 12 mg upadacitinib, and 22% of patients receiving 24 mg upadacitinib twice daily, and by 14% of patients receiving 24 mg upadacitinib once daily, vs 11% of patients receiving placebo. Endoscopic remission was achieved by 10% (P < .1 vs placebo), 8%, 8% (P < .1 vs placebo), 22% (P < .01 vs placebo), and 14% (P < .05 vs placebo) of patients receiving upadacitinib, respectively, vs none of the patients receiving placebo. Endoscopic but not clinical remission increased with dose during the induction period. Efficacy was maintained for most endpoints through week 52. During the induction period, patients in the upadacitinib groups had higher incidences of infections and serious infections vs placebo. Patients in the twice-daily 12 mg and 24 mg upadacitinib groups had significant increases in total, high-density lipoprotein, and low-density lipoprotein cholesterol levels compared with patients in the placebo group. CONCLUSIONS: In a phase 2 trial of patients with CD, upadacitinib induced endoscopic remission in a significant proportion of patients compared with placebo. Upadacitinib's benefit/risk profile supports further development for treatment of CD. (Clinicaltrials.gov, Number: NCT02365649).

Treatment Algorithm for Mild and Moderate-to-Severe Ulcerative Colitis: An Update.

BACKGROUND: Patient care in ulcerative colitis (UC) remains challenging despite an array of established treatment options and emerging new therapies. The management of UC therapy should be guided by the endoscopic extent of inflammation, disease severity, and prognostic factors of poor outcome. Complete remission, defined as durable symptomatic and endoscopic remission without corticosteroid therapy, is the desired treatment goal. SUMMARY: This review focuses on treatment recommendations for different clinical scenarios in moderate-to-severe UC: Active UC of any extent not responding to aminosalicylates, steroid-dependent UC, steroid-refractory UC, immunomodulator-refractory UC, and acute severe UC. Comprehensive treatment algorithms for daily clinical practice were developed based on published guidelines and current literature. Key Messages: While current treatment options including a number of biologicals and small molecules have evolved UC treatment to achieve sustained remission in a majority of patients, upcoming treatment options with different molecular pathways and different modes of actions will further increase the need for personalized medicine.

Expression Levels of 4 Genes in Colon Tissue Might Be Used to Predict Which Patients Will Enter Endoscopic Remission After Vedolizumab Therapy for Inflammatory Bowel Diseases.

BACKGROUND & AIMS: We aimed to identify biomarkers that might be used to predict responses of patients with inflammatory bowel diseases (IBD) to vedolizumab therapy. METHODS: We obtained biopsies from inflamed colon of patients with IBD who began treatment with vedolizumab (n = 31) or tumor necrosis factor (TNF) antagonists (n = 20) and performed RNA-sequencing analyses. We compared gene expression patterns between patients who did and did not enter endoscopic remission (absence of ulcerations at month 6 for patients with Crohn's disease or Mayo endoscopic subscore ≤1 at week 14 for patients with ulcerative colitis) and performed pathway analysis and cell deconvolution for training (n = 20) and validation (n = 11) datasets. Colon biopsies were also analyzed by immunohistochemistry. We validated a baseline gene expression pattern associated with endoscopic remission after vedolizumab therapy using 3 independent datasets (n = 66). RESULTS: We identified significant differences in expression levels of 44 genes between patients who entered remission after vedolizumab and those who did not; we found significant increases in leukocyte migration in colon tissues from patients who did not enter remission (P < .006). Deconvolution methods identified a significant enrichment of monocytes (P = .005), M1-macrophages (P = .05), and CD4+ T cells (P = .008) in colon tissues from patients who did not enter remission, whereas colon tissues from patients in remission had higher numbers of naïve B cells before treatment (P = .05). Baseline expression levels of PIWIL1, MAATS1, RGS13, and DCHS2 identified patients who did vs did not enter remission with 80% accuracy in the training set and 100% accuracy in validation dataset 1. We validated these findings in the 3 independent datasets by microarray, RNA sequencing and quantitative PCR analysis (P = .003). Expression levels of these 4 genes did not associate with response to anti-TNF agents. We confirmed the presence of proteins encoded by mRNAs using immunohistochemistry. CONCLUSIONS: We identified 4 genes whose baseline expression levels in colon tissues of patients with IBD associate with endoscopic remission after vedolizumab, but not anti-TNF, treatment. We validated this signature in 4 independent datasets and also at the protein level. Studies of these genes might provide insights into the mechanisms of action of vedolizumab.

Evaluating Efficacy, Safety, and Pharmacokinetics After Switching From Infliximab Originator to Biosimilar CT-P13: Experience From a Large Tertiary Referral Center.

BACKGROUND: The use of infliximab biosimilar CT-P13 has increased in patients with inflammatory bowel disease. Nevertheless, doubts about switching from infliximab originator to biosimilar still exist among patients and health care professionals. METHODS: Our tertiary referral center underwent a mandatory switch from infliximab originator to CT-P13 in 2017. We investigated pharmacokinetics, efficacy, and safety of this switch. The primary endpoint was infliximab discontinuation within 6 months of switching. Secondary endpoints included loss of clinical remission, need for treatment optimization, adverse events, evolution of patient-reported outcome, C-reactive protein, infliximab trough levels, and antidrug-antibodies. RESULTS: A total of 361 patients (54.0% male, 70.0% Crohn's disease, 55.6% in clinical remission) were enrolled. Infliximab discontinuation within 6 months was observed in 4%. Loss of clinical remission, adverse events, and antidrug-antibodies were identified in only 2.0%, 2.2%, and 1.1% of patients, respectively. C-reactive protein concentrations and infliximab trough levels remained stable. Independent factors associated with remission at 6 months were lower PRO2 at switch (HR 6.024; 95% CI, 4.878-8.000; P < 0.0001) and higher hemoglobin levels (HR 1.383; 95% CI, 1.044-2.299; P = 0.018). CONCLUSIONS: Switching from infliximab originator to CT-P13 was not associated with an increased risk of treatment discontinuation, loss of clinical remission, or adverse events. No significant changes in infliximab trough levels or immunogenicity could be identified.

Influence of Drug Exposure on Vedolizumab-Induced Endoscopic Remission in Anti-Tumour Necrosis Factor [TNF] Naïve and Anti-TNF Exposed IBD Patients.

BACKGROUND AND OBJECTIVES: Vedolizumab has demonstrated efficacy and safety in patients with Crohn's disease [CD] and ulcerative colitis [UC]. Endoscopic outcome data are limited, especially in anti-tumour necrosis factor [TNF] naïve patients. The present study compared endoscopic outcome in anti-TNF naïve and exposed patients, and explored if this was affected by drug exposure. METHODS: We retrospectively analysed all patients initiating vedolizumab at our tertiary referral centre since 2015. For UC, endoscopic improvement was defined as a Mayo endoscopic subscore ≤1 at week 14. For CD, endoscopic remission was defined as absence of ulcerations at week 22. Vedolizumab trough concentrations were measured at week 6, week 14 and during maintenance. RESULTS: A total of 336 patients were identified [53.3% CD], 20% of them being anti-TNF naïve. Endoscopic improvement was achieved by 56.1% of UC patients and endoscopic remission by 39.1% of CD patients. Endoscopic outcomes were significantly better in anti-TNF naïve vs exposed patients [all: 67.2% vs 42.0%, p = 0.0002; UC: 74.4% vs 50.0%, p = 0.02; CD: 57.1% vs 35.8%, p = 0.03]. Achievement of endoscopic end points significantly impacted long-term treatment continuation [p = 9.7 × 10-13]. A better endoscopic outcome was associated with significantly higher drug exposure in both CD and UC. CONCLUSIONS: The results of this observational, single-centre real-life study suggest that vedolizumab may induce endoscopic remission in both CD and UC. Although anti-TNF naïve patients had a significantly better outcome, 42% of anti-TNF exposed patients still benefited endoscopically. A clear exposure-endoscopic response relationship exists, but not all patients will benefit from treatment intensification. Hence, predictive biomarkers remain necessary. PODCAST: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

Ustekinumab Pharmacokinetics and Exposure Response in a Phase 3 Randomized Trial of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: The efficacy of antibody-based therapeutics depends on their pharmacokinetics. The pharmacokinetic and exposure response profiles of ustekinumab, a monoclonal antibody against interleukin 12/interleukin 23, are known in patients with Crohn's disease, yet there are few data from patients with ulcerative colitis. We characterized ustekinumab's pharmacokinetics, exposure response, and optimal serum concentrations in patients with ulcerative colitis. METHODS: We collected data from 2 phase 3 trials (1 induction and 1 maintenance), in which patients with moderate to severe ulcerative colitis received an intravenous induction dose of ustekinumab (130 mg, n = 320; or approximately 6 mg/kg, n = 322). Responders were assigned randomly to groups that received subcutaneous maintenance ustekinumab (90 mg) every 8 weeks (n = 176) or 12 weeks (n = 172), or placebo (n = 175). We evaluated the association between ustekinumab concentration and efficacy, serum based on clinical effects (Mayo score), histologic features, and inflammation (measurement of C-reactive protein, fecal calprotectin, and fecal lactoferrin), as well as safety (infections, serious infections, and serious adverse events), during induction and maintenance therapy. Optimal serum concentrations of ustekinumab were identified using receiver operating characteristic curve analyses. RESULTS: In patients with ulcerative colitis, dose-proportional serum concentrations of ustekinumab, unaffected by prior biologic or concomitant immunomodulator therapy, reached steady state by the second maintenance dose; the median trough concentration for dosing every 8 weeks was approximately 3-fold that of dosing every 12 weeks. Serum concentrations were associated with clinical and histologic features of efficacy and normalization of inflammation markers. The week-8 concentration threshold for induction of response was 3.7 µg/mL. A steady-state trough serum concentration of 1.3 µg/mL or higher was associated with a higher rate of clinical remission compared with patients who had lower serum concentrations. Serum concentrations of ustekinumab were not associated with infections, serious infections, or serious adverse events. CONCLUSIONS: In an analysis of data from 2 phase 3 trials of patients with ulcerative colitis, we found that serum concentrations of ustekinumab were proportional to dose, unaffected by prior biologic or concomitant immunomodulator therapies, associated with clinical and histologic efficacy and markers of inflammation, and were not associated with safety events at doses evaluated. Ustekinumab pharmacokinetics are consistent between patients with Crohn's disease vs ulcerative colitis.

No Superiority of Tacrolimus Suppositories vs Beclomethasone Suppositories in a Randomized Trial of Patients With Refractory Ulcerative Proctitis.

BACKGROUND & AIMS: Ulcerative proctitis (UP) refractory to 5-aminosalicylic acid (5-ASA) suppositories is a challenge to treat, often requiring step up to immunomodulator or biological therapy. Topical tacrolimus is effective and safe in patients with refractory UP. However, it is not clear how tacrolimus suppositories fit into in the treatment algorithm of UP. METHODS: We performed a randomized controlled, double-blind study at 8 hospitals in the Netherlands and Belgium from 2014 through 2017. Eighty-five patients with refractory UP (65% women) were randomly assigned to groups given once daily tacrolimus suppositories (2 mg; n = 43) or beclomethasone (3 mg; n = 42) for 4 weeks. The primary outcome was clinical response (decrease in Mayo score of 3 or more). Secondary outcomes included clinical remission, endoscopic response and remission, adverse events and quality of life. Outcomes were compared using Fisher's exact test and Mann-Whitney U test. RESULTS: Proportions of patients with clinical responses were 63% in the tacrolimus group and 59% in the beclomethasone group (P = .812); proportions of patients in clinical remission were 46% and 38%, respectively (P = .638). Proportions of patients with an endoscopic response were 68% and 60% in the tacrolimus group and in the beclomethasone group (P = .636); proportions in endoscopic remission rates were 30% and 13%, respectively (P = .092) Median increases in the inflammatory bowel disease questionnaire score were 18.0 in the tacrolimus group and 20.5 in the beclomethasone group (P = .395). Adverse event rates did not differ significantly between groups. CONCLUSIONS: In a 4-week randomized controlled trial, tacrolimus and beclomethasone suppositories induce comparable clinical and endoscopic responses in patients with UP refractory to 5-ASA. There were no significant differences in adverse events rates. Tacrolimus and beclomethasone suppositories are therefore each safe and effective treatment options for 5-ASA refractory disease. EUDRACT 2013-001259-11; Netherlands Trial Register NL4205/NTR4416.