Long-Term Outcome of Immediate Versus Postponed Intervention in Patients With Infected Necrotizing Pancreatitis (POINTER): Multicenter Randomized Trial.

OBJECTIVE: To compare the long-term outcomes of immediate drainage versus the postponed-drainage approach in patients with infected necrotizing pancreatitis. BACKGROUND: In the randomized POINTER trial, patients assigned to the postponed-drainage approach using antibiotic treatment required fewer interventions, as compared with immediate drainage, and over a third were treated without any intervention. METHODS: Clinical data of those patients alive after the initial 6-month follow-up were re-evaluated. The primary outcome was a composite of death and major complications. RESULTS: Out of 104 patients, 88 were re-evaluated with a median follow-up of 51 months. After the initial 6-month follow-up, the primary outcome occurred in 7 of 47 patients (15%) in the immediate-drainage group and 7 of 41 patients (17%) in the postponed-drainage group (RR 0.87, 95% CI 0.33-2.28; P =0.78). Additional drainage procedures were performed in 7 patients (15%) versus 3 patients (7%) (RR 2.03; 95% CI 0.56-7.37; P =0.34). The median number of additional interventions was 0 (IQR 0-0) in both groups ( P =0.028). In the total follow-up, the median number of interventions was higher in the immediate-drainage group than in the postponed-drainage group (4 vs. 1, P =0.001). Eventually, 14 of 15 patients (93%) in the postponed-drainage group who were successfully treated in the initial 6-month follow-up with antibiotics and without any intervention remained without intervention. At the end of follow-up, pancreatic function and quality of life were similar. CONCLUSIONS: Also, during long-term follow-up, a postponed-drainage approach using antibiotics in patients with infected necrotizing pancreatitis results in fewer interventions as compared with immediate drainage and should therefore be the preferred approach. TRIAL REGISTRATION: ISRCTN33682933.

Immediate versus Postponed Intervention for Infected Necrotizing Pancreatitis.

BACKGROUND: Infected necrotizing pancreatitis is a potentially lethal disease that is treated with the use of a step-up approach, with catheter drainage often delayed until the infected necrosis is encapsulated. Whether outcomes could be improved by earlier catheter drainage is unknown. METHODS: We conducted a multicenter, randomized superiority trial involving patients with infected necrotizing pancreatitis, in which we compared immediate drainage within 24 hours after randomization once infected necrosis was diagnosed with drainage that was postponed until the stage of walled-off necrosis was reached. The primary end point was the score on the Comprehensive Complication Index, which incorporates all complications over the course of 6 months of follow-up. RESULTS: A total of 104 patients were randomly assigned to immediate drainage (55 patients) or postponed drainage (49 patients). The mean score on the Comprehensive Complication Index (scores range from 0 to 100, with higher scores indicating more severe complications) was 57 in the immediate-drainage group and 58 in the postponed-drainage group (mean difference, -1; 95% confidence interval [CI], -12 to 10; P = 0.90). Mortality was 13% in the immediate-drainage group and 10% in the postponed-drainage group (relative risk, 1.25; 95% CI, 0.42 to 3.68). The mean number of interventions (catheter drainage and necrosectomy) was 4.4 in the immediate-drainage group and 2.6 in the postponed-drainage group (mean difference, 1.8; 95% CI, 0.6 to 3.0). In the postponed-drainage group, 19 patients (39%) were treated conservatively with antibiotics and did not require drainage; 17 of these patients survived. The incidence of adverse events was similar in the two groups. CONCLUSIONS: This trial did not show the superiority of immediate drainage over postponed drainage with regard to complications in patients with infected necrotizing pancreatitis. Patients randomly assigned to the postponed-drainage strategy received fewer invasive interventions. (Funded by Fonds NutsOhra and Amsterdam UMC; POINTER ISRCTN Registry number, ISRCTN33682933.).

A Prediction Model for Successful Increase of Adalimumab Dose Intervals in Patients with Crohn's Disease: Secondary Analysis of the Pragmatic Open-Label Randomised Controlled Non-inferiority LADI Trial.

BACKGROUND: In the pragmatic open-label randomised controlled non-inferiority LADI trial we showed that increasing adalimumab (ADA) dose intervals was non-inferior to conventional dosing for persistent flares in patients with Crohn's disease (CD) in clinical and biochemical remission. AIMS: To develop a prediction model to identify patients who can successfully increase their ADA dose interval based on secondary analysis of trial data. METHODS: Patients in the intervention group of the LADI trial increased ADA intervals to 3 and then to 4 weeks. The dose interval increase was defined as successful when patients had no persistent flare (> 8 weeks), no intervention-related severe adverse events, no rescue medication use during the study, and were on an increased dose interval while in clinical and biochemical remission at week 48. Prediction models were based on logistic regression with relaxed LASSO. Models were internally validated using bootstrap optimism correction. RESULTS: We included 109 patients, of which 60.6% successfully increased their dose interval. Patients that were active smokers (odds ratio [OR] 0.90), had previous CD-related intra-abdominal surgeries (OR 0.85), proximal small bowel disease (OR 0.92), an increased Harvey-Bradshaw Index (OR 0.99) or increased faecal calprotectin (OR 0.997) were less likely to successfully increase their dose interval. The model had fair discriminative ability (AUC = 0.63) and net benefit analysis showed that the model could be used to select patients who could increase their dose interval. CONCLUSION: The final prediction model seems promising to select patients who could successfully increase their ADA dose interval. The model should be validated externally before it may be applied in clinical practice. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT03172377.

Patient selection for urgent endoscopic retrograde cholangio-pancreatography by endoscopic ultrasound in predicted severe acute biliary pancreatitis (APEC-2): a multicentre prospective study.

OBJECTIVE: Routine urgent endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic biliary sphincterotomy (ES) does not improve outcome in patients with predicted severe acute biliary pancreatitis. Improved patient selection for ERCP by means of endoscopic ultrasonography (EUS) for stone/sludge detection may challenge these findings. DESIGN: A multicentre, prospective cohort study included patients with predicted severe acute biliary pancreatitis without cholangitis. Patients underwent urgent EUS, followed by ERCP with ES in case of common bile duct stones/sludge, within 24 hours after hospital presentation and within 72 hours after symptom onset. The primary endpoint was a composite of major complications or mortality within 6 months after inclusion. The historical control group was the conservative treatment arm (n=113) of the randomised APEC trial (Acute biliary Pancreatitis: urgent ERCP with sphincterotomy versus conservative treatment, patient inclusion 2013-2017) applying the same study design. RESULTS: Overall, 83 patients underwent urgent EUS at a median of 21 hours (IQR 17-23) after hospital presentation and at a median of 29 hours (IQR 23-41) after start of symptoms. Gallstones/sludge in the bile ducts were detected by EUS in 48/83 patients (58%), all of whom underwent immediate ERCP with ES. The primary endpoint occurred in 34/83 patients (41%) in the urgent EUS-guided ERCP group. This was not different from the 44% rate (50/113 patients) in the historical conservative treatment group (risk ratio (RR) 0.93, 95% CI 0.67 to 1.29; p=0.65). Sensitivity analysis to correct for baseline differences using a logistic regression model also showed no significant beneficial effect of the intervention on the primary outcome (adjusted OR 1.03, 95% CI 0.56 to 1.90, p=0.92). CONCLUSION: In patients with predicted severe acute biliary pancreatitis without cholangitis, urgent EUS-guided ERCP with ES did not reduce the composite endpoint of major complications or mortality, as compared with conservative treatment in a historical control group. TRIAL REGISTRATION NUMBER: ISRCTN15545919.

Overuse and Misuse of Antibiotics and the Clinical Consequence in Necrotizing Pancreatitis: An Observational Multicenter Study.

OBJECTIVE: The use and impact of antibiotics and the impact of causative pathogens on clinical outcomes in a large real-world cohort covering the entire clinical spectrum of necrotizing pancreatitis remain unknown. SUMMARY BACKGROUND DATA: International guidelines recommend broad-spectrum antibiotics in patients with suspected infected necrotizing pancreatitis. This recommendation is not based on high-level evidence and clinical effects are unknown. MATERIALS AND METHODS: This study is a post-hoc analysis of a nationwide prospective cohort of 401 patients with necrotizing pancreatitis in 15 Dutch centers (2010-2019). Across the patient population from the time of admission to 6 months postadmission, multivariable regression analyses were used to analyze (1) microbiological cultures and (2) antibiotic use. RESULTS: Antibiotics were started in 321/401 patients (80%) administered at a median of 5 days (P25-P75: 1-13) after admission. The median duration of antibiotics was 27 days (P25-P75: 15-48). In 221/321 patients (69%) infection was not proven by cultures at the time of initiation of antibiotics. Empirical antibiotics for infected necrosis provided insufficient coverage in 64/128 patients (50%) with a pancreatic culture. Prolonged antibiotic therapy was associated with Enterococcus infection (OR 1.08 [95% CI 1.03-1.16], P =0.01). Enterococcus infection was associated with new/persistent organ failure (OR 3.08 [95% CI 1.35-7.29], P <0.01) and mortality (OR 5.78 [95% CI 1.46-38.73], P =0.03). Yeast was found in 30/147 cultures (20%). DISCUSSION: In this nationwide study of patients with necrotizing pancreatitis, the vast majority received antibiotics, typically administered early in the disease course and without a proven infection. Empirical antibiotics were inappropriate based on pancreatic cultures in half the patients. Future clinical research and practice must consider antibiotic selective pressure due to prolonged therapy and coverage of Enterococcus and yeast. Improved guidelines on antimicrobial diagnostics and therapy could reduce inappropriate antibiotic use and improve clinical outcomes.

Complete Endoscopic Healing Is Associated With Lower Relapse Risk After Anti-TNF Withdrawal in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Discontinuation of anti-tumor necrosis factor-α treatment (anti-TNF) (infliximab and adalimumab) in patients with inflammatory bowel disease (IBD) is associated with a high relapse risk that may be influenced by endoscopic activity at the time of stopping. We assessed the relapse rate after anti-TNF withdrawal in patients with endoscopic healing and studied predictors of relapse including the depth of endoscopic healing. METHODS: This was a multicenter, prospective study in adult patients with Crohn's disease (CD), ulcerative colitis (UC), or IBD-unclassified (IBDU), with ≥6 months of corticosteroid-free clinical remission (confirmed at baseline) and endoscopic healing (Mayo <2/SES-CD <5 without large ulcers), who discontinued anti-TNF between 2018 and 2020 in the Netherlands. We performed Kaplan-Meier and Cox regression analyses to assess the relapse rate and evaluate potential predictors: partial (Mayo 1/SES-CD 3-4) versus complete (Mayo 0/SES-CD 0-2) endoscopic healing, anti-TNF trough levels, and immunomodulator and/or mesalamine use. RESULTS: Among 81 patients (CD: n = 41, 51%) with a median follow-up of 2.0 years (interquartile range, 1.6-2.1), 40 patients (49%) relapsed. Relapse rates in CD and UC/IBDU patients were comparable. At 12 months, 70% versus 35% of patients with partial versus complete endoscopic healing relapsed, respectively (adjusted hazard rate [aHR], 3.28; 95% confidence interval [CI], 1.43-7.50). Mesalamine use was associated with fewer relapses in UC/IBDU patients (aHR, 0.08; 95% CI, 0.01-0.67). Thirty patients restarted anti-TNF, and clinical remission was regained in 73% at 3 months. CONCLUSIONS: The relapse risk was high after anti-TNF withdrawal in IBD patients with endoscopic healing, but remission was regained in most cases after anti-TNF reintroduction. Complete endoscopic healing and mesalamine treatment in UC/IBDU patients decreased the risk of relapse.

Superior Effectiveness of Tofacitinib Compared to Vedolizumab in Anti-TNF-experienced Ulcerative Colitis Patients: A Nationwide Dutch Registry Study.

BACKGROUND & AIMS: Clinicians face difficulty in when and in what order to position biologics and Janus kinase inhibitors in patients with anti-tumor necrosis factor-alpha (TNF) refractory ulcerative colitis (UC). We aimed to compare the effectiveness and safety of vedolizumab and tofacitinib in anti-TNF-exposed patients with UC in our prospective nationwide Initiative on Crohn and Colitis Registry. METHODS: Patients with UC who failed anti-TNF treatment and initiated vedolizumab or tofacitinib treatment were identified in the Initiative on Crohn and Colitis Registry in the Netherlands. We selected patients with both clinical as well as biochemical or endoscopic disease activity at initiation of therapy. Patients previously treated with vedolizumab or tofacitinib were excluded. Corticosteroid-free clinical remission (Simple Clinical Colitis Activity Index ≤2), biochemical remission (C-reactive protein ≤5 mg/L or fecal calprotectin ≤250 µg/g), and safety outcomes were compared after 52 weeks of treatment. Inverse propensity score-weighted comparison was used to adjust for confounding and selection bias. RESULTS: Overall, 83 vedolizumab- and 65 tofacitinib-treated patients were included. Propensity score-weighted analysis showed that tofacitinib-treated patients were more likely to achieve corticosteroid-free clinical remission and biochemical remission at weeks 12, 24, and 52 compared with vedolizumab-treated patients (odds ratio [OR], 6.33; 95% confidence interval [CI], 3.81-10.50; P < .01; OR, 3.02; 95% CI, 1.89-4.84; P < .01; and OR, 1.86; 95% CI, 1.15-2.99; P = .01; and OR, 3.27; 95% CI, 1.96-5.45; P < .01; OR, 1.87; 95% CI, 1.14-3.07; P = .01; and OR, 1.81; 95% CI, 1.06-3.09; P = .03, respectively). There was no difference in infection rate or severe adverse events. CONCLUSIONS: Tofacitinib was associated with superior effectiveness outcomes compared with vedolizumab in anti-TNF-experienced patients with UC along with comparable safety outcomes.

Endoscopic Versus Surgical Step-Up Approach for Infected Necrotizing Pancreatitis (ExTENSION): Long-term Follow-up of a Randomized Trial.

BACKGROUND & AIMS: Previous randomized trials, including the Transluminal Endoscopic Step-Up Approach Versus Minimally Invasive Surgical Step-Up Approach in Patients With Infected Pancreatic Necrosis (TENSION) trial, demonstrated that the endoscopic step-up approach might be preferred over the surgical step-up approach in patients with infected necrotizing pancreatitis based on favorable short-term outcomes. We compared long-term clinical outcomes of both step-up approaches after a period of at least 5 years. METHODS: In this long-term follow-up study, we reevaluated all clinical data on 83 patients (of the originally 98 included patients) from the TENSION trial who were still alive after the initial 6-month follow-up. The primary end point, similar to the TENSION trial, was a composite of death and major complications. Secondary end points included individual major complications, pancreaticocutaneous fistula, reinterventions, pancreatic insufficiency, and quality of life. RESULTS: After a mean follow-up period of 7 years, the primary end point occurred in 27 patients (53%) in the endoscopy group and in 27 patients (57%) in the surgery group (risk ratio [RR], 0.93; 95% confidence interval [CI], 0.65-1.32; P = .688). Fewer pancreaticocutaneous fistulas were identified in the endoscopy group (8% vs 34%; RR, 0.23; 95% CI, 0.08-0.83). After the initial 6-month follow-up, the endoscopy group needed fewer reinterventions than the surgery group (7% vs 24%; RR, 0.29; 95% CI, 0.09-0.99). Pancreatic insufficiency and quality of life did not differ between groups. CONCLUSIONS: At long-term follow-up, the endoscopic step-up approach was not superior to the surgical step-up approach in reducing death or major complications in patients with infected necrotizing pancreatitis. However, patients assigned to the endoscopic approach developed overall fewer pancreaticocutaneous fistulas and needed fewer reinterventions after the initial 6-month follow-up. Netherlands Trial Register no: NL8571.

Health outcomes of 1000 children born to mothers with inflammatory bowel disease in their first 5 years of life.

OBJECTIVE: The aim of this study was to describe the long-term health outcomes of children born to mothers with inflammatory bowel disease (IBD) and to assess the impact of maternal IBD medication use on these outcomes. DESIGN: We performed a multicentre retrospective study in The Netherlands. Women with IBD who gave birth between 1999 and 2018 were enrolled from 20 participating hospitals. Information regarding disease characteristics, medication use, lifestyle, pregnancy outcomes and long-term health outcomes of children was retrieved from mothers and medical charts. After consent of both parents, outcomes until 5 years were also collected from general practitioners. Our primary aim was to assess infection rate and our secondary aims were to assess adverse reactions to vaccinations, growth, autoimmune diseases and malignancies. RESULTS: We included 1000 children born to 626 mothers (381 (61%) Crohn's disease, 225 (36%) ulcerative colitis and 20 (3%) IBD unclassified). In total, 196 (20%) had intrauterine exposure to anti-tumour necrosis factor-α (anti-TNF-α) (60 with concomitant thiopurine) and 240 (24%) were exposed to thiopurine monotherapy. The 564 children (56%) not exposed to anti-TNF-α and/or thiopurine served as control group. There was no association between adverse long-term health outcomes and in utero exposure to IBD treatment. We did find an increased rate of intrahepatic cholestasis of pregnancy (ICP) in case thiopurine was used during the pregnancy without affecting birth outcomes and long-term health outcomes of children. All outcomes correspond with the general age-adjusted population. CONCLUSION: In our study, we found no association between in utero exposure to anti-TNF-α and/or thiopurine and the long-term outcomes antibiotic-treated infections, severe infections needing hospital admission, adverse reactions to vaccinations, growth failure, autoimmune diseases and malignancies.

Urgent endoscopic retrograde cholangiopancreatography with sphincterotomy versus conservative treatment in predicted severe acute gallstone pancreatitis (APEC): a multicentre randomised controlled trial.

BACKGROUND: It remains unclear whether urgent endoscopic retrograde cholangiopancreatography (ERCP) with biliary sphincterotomy improves the outcome of patients with gallstone pancreatitis without concomitant cholangitis. We did a randomised trial to compare urgent ERCP with sphincterotomy versus conservative treatment in patients with predicted severe acute gallstone pancreatitis. METHODS: In this multicentre, parallel-group, assessor-masked, randomised controlled superiority trial, patients with predicted severe (Acute Physiology and Chronic Health Evaluation II score ≥8, Imrie score ≥3, or C-reactive protein concentration >150 mg/L) gallstone pancreatitis without cholangitis were assessed for eligibility in 26 hospitals in the Netherlands. Patients were randomly assigned (1:1) by a web-based randomisation module with randomly varying block sizes to urgent ERCP with sphincterotomy (within 24 h after hospital presentation) or conservative treatment. The primary endpoint was a composite of mortality or major complications (new-onset persistent organ failure, cholangitis, bacteraemia, pneumonia, pancreatic necrosis, or pancreatic insufficiency) within 6 months of randomisation. Analysis was by intention to treat. This trial is registered with the ISRCTN registry, ISRCTN97372133. FINDINGS: Between Feb 28, 2013, and March 1, 2017, 232 patients were randomly assigned to urgent ERCP with sphincterotomy (n=118) or conservative treatment (n=114). One patient from each group was excluded from the final analysis because of cholangitis (urgent ERCP group) and chronic pancreatitis (conservative treatment group) at admission. The primary endpoint occurred in 45 (38%) of 117 patients in the urgent ERCP group and in 50 (44%) of 113 patients in the conservative treatment group (risk ratio [RR] 0·87, 95% CI 0·64-1·18; p=0·37). No relevant differences in the individual components of the primary endpoint were recorded between groups, apart from the occurrence of cholangitis (two [2%] of 117 in the urgent ERCP group vs 11 [10%] of 113 in the conservative treatment group; RR 0·18, 95% CI 0·04-0·78; p=0·010). Adverse events were reported in 87 (74%) of 118 patients in the urgent ERCP group versus 91 (80%) of 114 patients in the conservative treatment group. INTERPRETATION: In patients with predicted severe gallstone pancreatitis but without cholangitis, urgent ERCP with sphincterotomy did not reduce the composite endpoint of major complications or mortality, compared with conservative treatment. Our findings support a conservative strategy in patients with predicted severe acute gallstone pancreatitis with an ERCP indicated only in patients with cholangitis or persistent cholestasis. FUNDING: The Netherlands Organization for Health Research and Development, Fonds NutsOhra, and the Dutch Patient Organization for Pancreatic Diseases.

Cross-cultural translation and validation of the IBD-control questionnaire in The Netherlands: a patient-reported outcome measure in inflammatory bowel disease.

BACKGROUND: There is a need for easy-to-use patient-reported outcome measures (PROMS) in inflammatory bowel disease (IBD) practice. The 'IBD-control' is a short IBD-specific questionnaire capturing disease control from the patient's perspective. The International Consortium for Health Outcomes Measurement (ICHOM) recommends the use of the IBD-control even though it has only been validated in the United Kingdom. We aimed to cross-culturally translate and validate the IBD-control in the Netherlands using IBDREAM, a prospective multicentre IBD registry. METHODS: Lack of ambiguity and acceptability were verified in a pilot patient group (n = 5) after forward-backward translation of the IBD-control. Prospective validation involved completion of the IBD-control, Short Form-36, short IBDQ and disease activity measurement by Physician Global Assessment (PGA) and Simple Clinical Colitis Activity Index or Harvey-Bradshaw Index. Test-retest (2-week repeat) was used for measuring reliability. RESULTS: Questionnaires were completed by 998 IBD patients (674 Crohn's disease, 324 ulcerative colitis). Internal consistency (Cronbach's alpha) was 0.82 for the sub-group of 8 questions (IBD-control-8-sub-score). Mean completion time was 105 s. Construct validity analyses demonstrated moderate-to-strong correlations of the IBD-control-8-subscore and the other instruments (0.49-0.81). Test-retest reliability for stable patients was high (intraclass correlation coefficient 0.95). The IBD-control-8-subscore showed good discriminant ability between the PGA categories (ANOVA, p<.001). Sensitivity to change analyses showed large effect sizes of 0.81-1.87 for the IBD-control-8 subscore. CONCLUSIONS: These results support the IBD-control as a rapid, reliable, valid and sensitive instrument for measuring disease control from an IBD patient's perspective in the Netherlands.

Efficacy of dashboard driven dosing of infliximab in inflammatory bowel disease patients; a randomized controlled trial.

OBJECTIVES: Loss of response (LOR) to infliximab (IFX) remains a challenge in the management of inflammatory bowel diseases (IBD). Proactive dosing strategies to achieve and maintain predefined IFX trough levels (TL) may prevent LOR. We aimed to investigate the efficacy of dashboard driven IFX dosing compared to standard dosing in a prospective trial in IBD patients. METHODS: In this multicentre 1:1 'PRECISION' trial, we randomized IBD patients in clinical remission (Harvey Bradshaw Index ≤4 for Crohn's disease (CD) or a partial Mayo score ≤2 for ulcerative colitis (UC)) receiving IFX maintenance treatment. The precision group (PG) received IFX dosing guided by a Bayesian pharmacokinetic model, aiming to achieve and maintain a TL of 3 µg/ml by treatment (de)escalation as indicated by the dashboard. Patients in the control group (CG) continued treatment without dose adaptations. The primary endpoint was the proportion of patients in sustained clinical remission after 1 year. RESULTS: Eighty patients were enrolled (66 CD, 14 UC), and the median [interquartile range] age was 37 years [27-51]). After one year, 28/32 (88%) of patients in the PG were in sustained clinical remission versus 25/39 (64%) in the CG (p = .017). PG patients had lower median faecal calprotectin levels after 1 year (p = .031), whereas no significant differences in median CRP levels were found. CONCLUSION: We demonstrated that the use of a Bayesian dashboard for IFX dosing in maintenance treatment for IBD reduced the incidence of LOR compared to standard dosing. Precision dosing also resulted in lower FCP levels. CLINICALTRIALS.GOV NUMBER: NCT02453776.

Inflammatory bowel disease patients provide reliable self-reported medical information: A multicentre prospective pharmacovigilance monitoring system.

PURPOSE: To assess the agreement between patient-reported and health care provider-reported medical information in inflammatory bowel disease (IBD). METHODS: This multicentre, prospective, event monitoring study enrolled adult Crohn's disease (CD) and ulcerative colitis (UC) patients treated with a biological in four medical centers in the Netherlands. At two-monthly intervals, patients completed questionnaires on biological use, combination therapy and indication. The patient-reported information was compared with their electronic health records (EHRs) and analysed for percentage agreement and Cohen's kappa. A reference population from a prospective IBD registry was used to assess the representativeness of the study population. RESULTS: In total, 182 patients (female 50.5%, mean age 42.2 years, CD 76.9%) were included in the analysis. At baseline, 51.0% of the patients were prescribed an immunomodulator (43.9% thiopurines, 7.1% methotrexate), and patients were prescribed biologicals as follows: 59.3% infliximab, 30.2% adalimumab, 9.3% vedolizumab, and 1.1% ustekinumab. Agreement on patient-reported indication and biological use was almost perfect (κ = 0.878 and κ = 1.000, respectively); substantial for combination therapy (κ = 0.672). Gender, age, type of IBD, biological use and combination therapy were comparable with the reference population. CONCLUSION: Systematic patient-reporting by questionnaires was reliable in retrieving indication and treatment specific information from IBD patients. These results indicate that the use of patient-reporting outcomes in daily IBD practice can ensure reliable information collection.

Consecutive negative findings on colonoscopy during surveillance predict a low risk of advanced neoplasia in patients with inflammatory bowel disease with long-standing colitis: results of a 15-year multicentre, multinational cohort study.

OBJECTIVES: Surveillance colonoscopy is thought to prevent colorectal cancer (CRC) in patients with long-standing colonic IBD, but data regarding the frequency of surveillance and the findings thereof are lacking. Our aim was to determine whether consecutive negative surveillance colonoscopies adequately predict low neoplastic risk. DESIGN: A multicentre, multinational database of patients with long-standing IBD colitis without high-risk features and undergoing regular CRC surveillance was constructed. A 'negative' surveillance colonoscopy was predefined as a technically adequate procedure having no postinflammatory polyps, no strictures, no endoscopic disease activity and no evidence of neoplasia; a 'positive' colonoscopy was a technically adequate procedure that included at least one of these criteria. The primary endpoint was advanced colorectal neoplasia (aCRN), defined as high-grade dysplasia or CRC. RESULTS: Of 775 patients with long-standing IBD colitis, 44% (n=340) had >1 negative colonoscopy. Patients with consecutive negative surveillance colonoscopies were compared with those who had at least one positive colonoscopy. Both groups had similar demographics, disease-related characteristics, number of surveillance colonoscopies and time intervals between colonoscopies. No aCRN occurred in those with consecutive negative surveillance, compared with an incidence rate of 0.29 to 0.76/100 patient-years (P=0.02) in those having >1 positive colonoscopy on follow-up of 6.1 (P25-P75: 4.6-8.2) years after the index procedure. CONCLUSION: Within this large surveillance cohort of patients with colonic IBD and no additional high-risk features, having two consecutive negative colonoscopies predicted a very low risk of aCRN occurrence on follow-up. Our findings suggest that longer surveillance intervals in this selected population may be safe.

Endoscopic or surgical step-up approach for infected necrotising pancreatitis: a multicentre randomised trial.

BACKGROUND: Infected necrotising pancreatitis is a potentially lethal disease and an indication for invasive intervention. The surgical step-up approach is the standard treatment. A promising alternative is the endoscopic step-up approach. We compared both approaches to see whether the endoscopic step-up approach was superior to the surgical step-up approach in terms of clinical and economic outcomes. METHODS: In this multicentre, randomised, superiority trial, we recruited adult patients with infected necrotising pancreatitis and an indication for invasive intervention from 19 hospitals in the Netherlands. Patients were randomly assigned to either the endoscopic or the surgical step-up approach. The endoscopic approach consisted of endoscopic ultrasound-guided transluminal drainage followed, if necessary, by endoscopic necrosectomy. The surgical approach consisted of percutaneous catheter drainage followed, if necessary, by video-assisted retroperitoneal debridement. The primary endpoint was a composite of major complications or death during 6-month follow-up. Analyses were by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN09186711. FINDINGS: Between Sept 20, 2011, and Jan 29, 2015, we screened 418 patients with pancreatic or extrapancreatic necrosis, of which 98 patients were enrolled and randomly assigned to the endoscopic step-up approach (n=51) or the surgical step-up approach (n=47). The primary endpoint occurred in 22 (43%) of 51 patients in the endoscopy group and in 21 (45%) of 47 patients in the surgery group (risk ratio [RR] 0·97, 95% CI 0·62-1·51; p=0·88). Mortality did not differ between groups (nine [18%] patients in the endoscopy group vs six [13%] patients in the surgery group; RR 1·38, 95% CI 0·53-3·59, p=0·50), nor did any of the major complications included in the primary endpoint. INTERPRETATION: In patients with infected necrotising pancreatitis, the endoscopic step-up approach was not superior to the surgical step-up approach in reducing major complications or death. The rate of pancreatic fistulas and length of hospital stay were lower in the endoscopy group. The outcome of this trial will probably result in a shift to the endoscopic step-up approach as treatment preference. FUNDING: The Dutch Digestive Disease Foundation, Fonds NutsOhra, and the Netherlands Organization for Health Research and Development.

Clinical Course of Nodular Regenerative Hyperplasia in Thiopurine Treated Inflammatory Bowel Disease Patients.

Nodular regenerative hyperplasia (NRH) is a poorly understood liver condition, which is increasingly recognized in thiopurine-treated patients with inflammatory bowel disease (IBD).1 It is difficult to establish an optimal approach to NRH patients, because its manifestations are highly variable (from asymptomatic to symptoms of noncirrhotic portal hypertension [NCPH]) and the prognosis is unknown.2 The aim of this study was to identify NRH cases in IBD patients treated with azathioprine, mercaptopurine, and/or thioguanine, and to describe its clinical course.

Pharmacokinetics of golimumab in moderate to severe ulcerative colitis: the GO-KINETIC study.

Background: Golimumab (GLM) is approved for the treatment of moderate to severe ulcerative colitis (UC). Higher serum concentrations of anti-tumor necrosis factor (TNF) agents are associated with improved clinical and endoscopic outcomes. Correlations between GLM serum concentrations and clinical and endoscopic outcomes were investigated during induction and maintenance treatment. In addition, a population pharmacokinetic model was developed to identify factors associated with the pharmacokinetics of GLM in UC. Methods: A prospective observational trial (GO-KINETIC) was conducted in patients with moderate to severe UC receiving induction and maintenance treatment with GLM. Clinical and endoscopic outcomes were evaluated, fecal GLM concentrations were measured and pharmacokinetic data were analyzed. Results: A total of 20 patients were enrolled. At week 8 (after induction treatment), 12 out of 20 patients (60%) showed an endoscopic response (≥1 point reduction in endoscopic Mayo score). Patients with endoscopic response at week 8 had numerically higher median GLM serum concentrations at week 2 compared to endoscopic non-responders: 9.1 µg/ml [5.9-12.3] vs. 7.1 µg/mL [5.2-9.0]; p = .384, respectively. At week 52, 3/20 patients (15%) achieved endoscopic remission (endoscopic Mayo score ≤1) and continued GLM treatment. Population pharmacokinetic analysis showed an inverse association between albumin concentrations and GLM clearance. GLM concentrations were undetectable in fecal samples. Conclusions: After induction therapy, 60% of the patients showed endoscopic response. During maintenance therapy, about one third of patients discontinued GLM treatment because of loss of response. These patients might benefit from dose optimization.

Randomised controlled trial of transanal endoscopic microsurgery versus endoscopic mucosal resection for large rectal adenomas (TREND Study).

OBJECTIVE: Non-randomised studies suggest that endoscopic mucosal resection (EMR) is equally effective in removing large rectal adenomas as transanal endoscopic microsurgery (TEM), but EMR might be more cost-effective and safer. This trial compares the clinical outcome and cost-effectiveness of TEM and EMR for large rectal adenomas. DESIGN: Patients with rectal adenomas ≥3 cm, without malignant features, were randomised (1:1) to EMR or TEM, allowing endoscopic removal of residual adenoma at 3 months. Unexpected malignancies were excluded postrandomisation. Primary outcomes were recurrence within 24 months (aiming to demonstrate non-inferiority of EMR, upper limit 10%) and the number of recurrence-free days alive and out of hospital. RESULTS: Two hundred and four patients were treated in 18 university and community hospitals. Twenty-seven (13%) had unexpected cancer and were excluded from further analysis. Overall recurrence rates were 15% after EMR and 11% after TEM; statistical non-inferiority was not reached. The numbers of recurrence-free days alive and out of hospital were similar (EMR 609±209, TEM 652±188, p=0.16). Complications occurred in 18% (EMR) versus 26% (TEM) (p=0.23), with major complications occurring in 1% (EMR) versus 8% (TEM) (p=0.064). Quality-adjusted life years were equal in both groups. EMR was approximately €3000 cheaper and therefore more cost-effective. CONCLUSION: Under the statistical assumptions of this study, non-inferiority of EMR could not be demonstrated. However, EMR may have potential as the primary method of choice due to a tendency of lower complication rates and a better cost-effectiveness ratio. The high rate of unexpected cancers should be dealt with in further studies.

High Risk of Advanced Colorectal Neoplasia in Patients With Primary Sclerosing Cholangitis Associated With Inflammatory Bowel Disease.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC, termed PSC-IBD) are at increased risk for colorectal cancer, but their risk following a diagnosis of low-grade dysplasia (LGD) is not well described. We aimed to determine the rate of advanced colorectal neoplasia (aCRN), defined as high-grade dysplasia and/or colorectal cancer, following a diagnosis of indefinite dysplasia or LGD in this population. METHODS: We performed a retrospective, longitudinal study of 1911 patients with colonic IBD (293 with PSC and 1618 without PSC) who underwent more than 2 surveillance colonoscopies from 2000 through 2015 in The Netherlands or the United States (9265 patient-years of follow-up evaluation). We collected data on clinical and demographic features of patients, as well as data from each surveillance colonoscopy and histologic report. For each surveillance colonoscopy, the severity of active inflammation was documented. The primary outcome was a diagnosis of aCRN during follow-up evaluation. We also investigated factors associated with aCRN in patients with or without a prior diagnosis of indefinite dysplasia or LGD. RESULTS: Patients with PSC-IBD had a 2-fold higher risk of developing aCRN than patients with non-PSC IBD. Mean inflammation scores did not differ significantly between patients with PSC-IBD (0.55) vs patients with non-PSC IBD (0.56) (P = .89), nor did proportions of patients with LGD (21% of patients with PSC-IBD vs 18% of patients with non-PSC IBD) differ significantly (P = .37). However, the rate of aCRN following a diagnosis of LGD was significantly higher in patients with PSC-IBD (8.4 per 100 patient-years) than patients with non-PSC IBD (3.0 per 100 patient-years; P = .01). PSC (adjusted hazard ratio [aHR], 2.01; 95% CI, 1.09-3.71), increasing age (aHR 1.03; 95% CI, 1.01-1.05), and active inflammation (aHR, 2.39; 95% CI, 1.63-3.49) were independent risk factors for aCRN. Dysplasia was more often endoscopically invisible in patients with PSC-IBD than in patients with non-PSC IBD. CONCLUSIONS: In a longitudinal study of almost 2000 patients with colonic IBD, PSC remained a strong independent risk factor for aCRN. Once LGD is detected, aCRN develops at a higher rate in patients with PSC and is more often endoscopically invisible than in patients with only IBD. Our findings support recommendations for careful annual colonoscopic surveillance for patients with IBD and PSC, and consideration of colectomy once LGD is detected.

Early versus on-demand nasoenteric tube feeding in acute pancreatitis.

BACKGROUND: Early enteral feeding through a nasoenteric feeding tube is often used in patients with severe acute pancreatitis to prevent gut-derived infections, but evidence to support this strategy is limited. We conducted a multicenter, randomized trial comparing early nasoenteric tube feeding with an oral diet at 72 hours after presentation to the emergency department in patients with acute pancreatitis. METHODS: We enrolled patients with acute pancreatitis who were at high risk for complications on the basis of an Acute Physiology and Chronic Health Evaluation II score of 8 or higher (on a scale of 0 to 71, with higher scores indicating more severe disease), an Imrie or modified Glasgow score of 3 or higher (on a scale of 0 to 8, with higher scores indicating more severe disease), or a serum C-reactive protein level of more than 150 mg per liter. Patients were randomly assigned to nasoenteric tube feeding within 24 hours after randomization (early group) or to an oral diet initiated 72 hours after presentation (on-demand group), with tube feeding provided if the oral diet was not tolerated. The primary end point was a composite of major infection (infected pancreatic necrosis, bacteremia, or pneumonia) or death during 6 months of follow-up. RESULTS: A total of 208 patients were enrolled at 19 Dutch hospitals. The primary end point occurred in 30 of 101 patients (30%) in the early group and in 28 of 104 (27%) in the on-demand group (risk ratio, 1.07; 95% confidence interval, 0.79 to 1.44; P=0.76). There were no significant differences between the early group and the on-demand group in the rate of major infection (25% and 26%, respectively; P=0.87) or death (11% and 7%, respectively; P=0.33). In the on-demand group, 72 patients (69%) tolerated an oral diet and did not require tube feeding. CONCLUSIONS: This trial did not show the superiority of early nasoenteric tube feeding, as compared with an oral diet after 72 hours, in reducing the rate of infection or death in patients with acute pancreatitis at high risk for complications. (Funded by the Netherlands Organization for Health Research and Development and others; PYTHON Current Controlled Trials number, ISRCTN18170985.).