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There are limited data on therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients treated with vedolizumab (VDZ). Although an exposure–response relation has been demonstrated in the post-induction phase, this relationship is more uncertain in the maintenance phase of treatment. The aim of our study was to determine whether there is an association between VDZ trough concentration and clinical and biochemical remission in the maintenance phase. A prospective, observational multicenter study has been performed on patients with IBD on VDZ in the maintenance treatment (≥14 weeks). Patient demographics, biomarkers, and VDZ serum trough concentrations were collected. Clinical disease activity was scored by the Harvey Bradshaw Index (HBI) for Crohn’s disease (CD) and the Simple Clinical Colitis Activity Index (SCCAI) for ulcerative colitis (UC). Clinical remission was determined as HBI < 5 and SCCAI < 3. Biochemical remission was defined as fecal calprotectin

ObjectiveFollowing an episode of acute biliary pancreatitis, cholecystectomy is advised to prevent recurrent biliary events. There is limited evidence regarding the optimal timing and safety of cholecystectomy in patients with necrotising biliary pancreatitis.DesignA post hoc analysis of a multicentre prospective cohort. Patients with biliary pancreatitis and a CT severity score of three or more were included in 27 Dutch hospitals between 2005 and 2014. Primary outcome was the optimal timing of cholecystectomy in patients with necrotising biliary pancreatitis, defined as: the optimal point in time with the lowest risk of recurrent biliary events and the lowest risk of complications of cholecystectomy. Secondary outcomes were the number of recurrent biliary events, periprocedural complications of cholecystectomy and the protective value of endoscopic sphincterotomy for the recurrence of biliary events.ResultsOverall, 248 patients were included in the analysis. Cholecystectomy was performed in 191 patients (77%) at a median of 103 days (P25–P75: 46–222) after discharge. Infected necrosis after cholecystectomy occurred in four (2%) patients with persistent peripancreatic collections. Before cholecystectomy, 66 patients (27%) developed biliary events. The risk of overall recurrent biliary events prior to cholecystectomy was significantly lower before 10 weeks after discharge (risk ratio 0.49 (95% CI 0.27 to 0.90); p=0.02). The risk of recurrent pancreatitis before cholecystectomy was significantly lower before 8 weeks after discharge (risk ratio 0.14 (95% CI 0.02 to 1.0); p=0.02). The complication rate of cholecystectomy did not decrease over time. Endoscopic sphincterotomy did not reduce the risk of recurrent biliary events (OR 1.40 (95% CI 0.74 to 2.83)).ConclusionThe optimal timing of cholecystectomy after necrotising biliary pancreatitis, in the absence of peripancreatic collections, is within 8 weeks after discharge.

Item does not contain fulltext BACKGROUND: Despite its effectiveness in treating Crohn's disease, adalimumab is associated with an increased risk of infections and high health-care costs. We aimed to assess clinical outcomes of increased adalimumab dose intervals versus conventional dosing in patients with Crohn's disease in stable remission. METHODS: The LADI study was a pragmatic, open-label, multicentre, non-inferiority, parallel, randomised controlled trial, done in six academic hospitals and 14 general hospitals in the Netherlands. Adults (aged ≥18 years) diagnosed with luminal Crohn's disease (with or without concomitant perianal disease) were eligible when in steroid-free clinical and biochemical remission (defined as Harvey-Bradshaw Index [HBI] score

Item does not contain fulltext OBJECTIVES: We developed an epidemiological algorithm to classify types of diabetes mellitus (DM) in chronic pancreatitis (CP), and applied it to a nationwide prospective longitudinal cohort of CP patients. METHODS: Patients with definite CP (M-ANNHEIM criteria) were classified as having DM types 1, 2, or 3c, or no DM using an algorithm based on epidemiological characteristics: DM onset in relation to age, CP onset, exocrine insufficiency. Variables associated with development of DM were identified. RESULTS: Of 1130 included patients with CP between 2011 and 2018, 368 patients (33%) had DM at inclusion. Among patients with DM, 11 were classified as having type 1 (3%), 159 as type 2 (43%), and 191 as type 3c (52%). Patients with DM type 3c had longer duration of CP, more severe pain and lower physical quality of life. During longitudinal follow-up of median 47 months, 120 (20%) patients developed DM, of which 99 patients were classified as type 3c. This was independently associated with pancreatic endoscopy and surgery. CONCLUSIONS: The described algorithm based on epidemiological characteristics can help to classify types of DM in patients with CP. Diabetes mellitus type 3c is associated with longer duration of CP and more severe CP sequelae.

Background Loss of response to infliximab or adalimumab in ulcerative colitis occurs frequently, and dose escalation may aid in regaining clinical benefit. This study aimed to systematically assess the annual loss of response and dose escalation rates for infliximab and adalimumab in ulcerative colitis. Methods A systematic search was conducted from August 1999 to July 2021 for studies reporting loss of response and dose escalation during infliximab and/or adalimumab use in ulcerative colitis patients with primary response. Annual loss of response, dose escalation rates, and clinical benefit after dose escalation were calculated. Subgroup analyses were performed for studies with 1-year follow-up or less. Results We included 50 unique studies assessing loss of response (infliximab, n = 24; adalimumab, n = 21) or dose escalation (infliximab, n = 21; adalimumab, n = 16). The pooled annual loss of response for infliximab was 10.1% (95% confidence interval [CI], 7.1-14.3) and 13.6% (95% CI, 9.3-19.9) for studies with 1-year follow-up. The pooled annual loss of response for adalimumab was 13.4% (95% CI, 8.2-21.8) and 23.3% (95% CI, 15.4-35.1) for studies with 1-year follow-up. Annual pooled dose escalation rates were 13.8% (95% CI, 8.7-21.7) for infliximab and 21.3% (95% CI, 14.4-31.3) for adalimumab, regaining clinical benefit in 72.4% and 52.3%, respectively. Conclusions Annual loss of response was 10% for infliximab and 13% for adalimumab, with higher rates during the first year. Annual dose escalation rates were 14% (infliximab) and 21% (adalimumab), with clinical benefit in 72% and 52%, respectively. Uniform definitions are needed to facilitate more robust evaluations.

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.

Background and Aims There is paucity of data on safety and efficacy of anti-tumour necrosis factor [TNF] in elderly inflammatory bowel disease [IBD] patients. We aimed to compare the long-term treatment failure rates and safety of a first anti-TNF agent in IBD patients between different age groups [ Methods IBD patients who started a first anti-TNF agent were identified through IBDREAM, a multicentre prospective IBD registry. Competing risk regression was used to study treatment failure, defined as time to drug discontinuation due to adverse events [AEs] or lack of effectiveness, with discontinuation due to remission as a competing risk. Results A total of 895 IBD patients were included; 546 started anti-TNF at age 60] was 1.52 for discontinuation due to AEs and 1.11 for lack of effectiveness. Concomitant thiopurine use was associated with a lower treatment failure rate (SHR 0.78, 95% confidence interval [CI] 0.62–0.98, p = 0.031). Serious adverse event [SAE] rate, as well as serious infection rate, were significantly higher in elderly IBD patients [61.2 versus 16.0 and 12.4 per 1000 patient-years, respectively] whereas the malignancy rate was low in all age groups. Conclusions Elderly IBD patients starting a first anti-TNF agent showed higher treatment failure rates, but concomitant thiopurine use at baseline was associated with lower failure rates. Elderly IBD patients demonstrated higher rates of SAEs and serious infections.

Background There are limited real-world data on the change in total work impairment (TWI) in biological-treated patients with inflammatory bowel disease (IBD). This study aimed to evaluate the real-world effects of initiating biological therapy or tofacitinib on change in TWI in IBD patients. Methods This multicenter prospective cohort study enrolled IBD patients who started treatment with biological therapy or tofacitinib. Subjects completed the work productivity and activity impairment (WPAI) questionnaire and short inflammatory bowel disease questionnaire at therapy initiation and at week 26. Total work impairment comprises working hours missed due to sick leave and impact of disease during working hours (range 0%-100%). Clinical disease activity was assessed using the Harvey-Bradshaw Index and Simple Clinical Colitis Activity Index (SCCAI). Results We included 137 IBD patients for analyses (median age 38 years, 58% Crohn’s disease [CD]). The median baseline TWI was 50% and decreased by a median of 10%-points of points after 26 weeks. Patients with continued biological therapy or tofacitinib use, clinical disease activity at baseline, and clinical response or remission at week 26 showed a greater median TWI reduction (22%-points) than the remaining study patients (7%-points; P = .014). Ulcerative colitis (UC) and IBD-unclassified (IBD-U) patients showed a greater median TWI reduction (26%-points) than CD patients (6%-points); P = .041. Correlations were observed between decrease in TWI and decrease in SCCAI, decrease in fatigue and increase in quality of life. Conclusions Work impairment in IBD patients decreased following biological therapy or tofacitinib initiation. Patients achieving clinical remission or response showed the greatest improvement, especially UC and IBD-U patients.

Background and AimsThe long-term risk of high-grade dysplasia [HGD] and colorectal cancer [CRC] following low-grade dysplasia [LGD] in inflammatory bowel disease [IBD] patients is relatively unknown. We aimed to determine the long-term cumulative incidence of advanced neoplasia [HGD and/or CRC], and to identify risk factors for advanced neoplasia in a nationwide IBD cohort with a history of LGD.MethodsThis is a nationwide cohort study using data from the Dutch National Pathology Registry [PALGA] to identify all IBD patients with LGD between 1991 and 2010 in the Netherlands. Follow-up data were collected until January 2016. We determined the cumulative incidence of advanced neoplasia and identified risk factors via multivariable Cox regression analysis.ResultsWe identified 4284 patients with colonic LGD with a median follow-up of 6.4 years after initial LGD diagnosis. The cumulative incidence of subsequent advanced neoplasia was 3.6, 8.5, 14.4 and 21.7%, after 1, 5, 10 and 15 years, respectively. The median time to develop advanced neoplasia after LGD was 3.6 years. Older age [≥ 55 years] at moment of LGD (hazard ratio [HR] 1.73, 95% confidence interval [CI] 1.44–2.06), male sex [HR 1.33, 95% CI 1.10–1.60], and follow-up at an academic [vs non-academic] medical centre [HR 1.37, 95% CI 1.07–1.76] were independent risk factors for advanced neoplasia following LGD.ConclusionsIn a large nationwide cohort with long-term follow-up of IBD patients with LGD, the cumulative incidence of advanced neoplasia was 21.7% after 15 years. Older age at LGD [≥55 years], male sex and follow-up by a tertiary IBD referral centre were independent risk factors for advanced neoplasia development after initial LGD.

Contains fulltext : 235614.pdf (Publisher’s version ) (Open Access) 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

Background and Aims The COVID-19 risk and disease course in inflammatory bowel disease [IBD] patients remains uncertain. Therefore, we aimed to assess the clinical presentation, disease course, and outcomes of COVID-19 in IBD patients. Second, we determined COVID-19 incidences in IBD patients and compared this with the general population. Methods We conducted a multicentre, nationwide IBD cohort study in The Netherlands and identified patients with COVID-19. First, we assessed the COVID-19 disease course and outcomes. Second, we compared COVID-19 incidences between our IBD study cohort and the general Dutch population. Results We established an IBD cohort of 34 763 patients. COVID-19 was diagnosed in 100/34 763 patients [0.29%]; 20/100 of these patients [20%] had severe COVID-19 defined as admission to the intensive care unit, mechanical ventilation, and/or death. Hospitalisation occurred in 59/100 [59.0%] patients and 13/100 [13.0%] died. All patients who died had comorbidities and all but one were ≥65 years old. In line, we identified ≥1 comorbidity as an independent risk factor for hospitalisation (odds ratio [OR] 4.20, 95% confidence interval [CI] 1.58–11.17,; p = 0.004). Incidences of COVID-19 between the IBD study cohort and the general population were comparable (287.6 [95% CI 236.6–349.7] versus 333.0 [95% CI 329.3–336.7] per 100000 patients, respectively; p = 0.15). Conclusions Of 100 cases with IBD and COVID-19, 20% developed severe COVID-19, 59% were hospitalised and 13% died. A comparable COVID-19 risk was found between the IBD cohort [100/34 763 = 0.29%] and the general Dutch population. The presence of ≥1 comorbidities was an independent risk factor for hospitalisation due to COVID-19.

Introduction Inflammatory bowel disease (IBD) frequently requires chronic immunosuppressive treatment and active involvement from patients during treatment decision making. Information about the risk of developing adverse drug reactions (ADRs) to IBD therapies is required in this process. Objective The aim of this study was to describe the ADRs reported in IBD patients from real-world data, using the Dutch nationwide IBDREAM registry, and compare the occurrence and cumulative incidences with the Summary of Product Characteristics (SmPC) of the associated drugs. Methods In this retrospective multicentre study, ADRs related to IBD medication were assessed. Only reports associated with the use of drugs used for the maintenance treatment of IBD were included. All ADRs were verified by healthcare professionals and coded by trained pharmacovigilance assessors. Results In total, 3080 ADRs were reported in 1179 patients. Twenty-three new drug–ADR associations related to the use of azathioprine, mercaptopurine, infliximab, oral mesalamine and thioguanine were reported in the IBDREAM registry that were not mentioned in the corresponding SmPCs. The most frequently reported new association was pyrexia for azathioprine (3.1%) and mercaptopurine (4.9%). In addition, there were seven ADRs with a higher cumulative incidence in IBDREAM compared with the SmPC, and included, among others, arthralgia during mercaptopurine use (2.5%), and diarrhoea (1.4%), alopecia (1.2%) and infections (1.6%) during azathioprine use. Conclusions Based on real-world data, ADR reporting demonstrated new ADRs and higher incidences of ADRs to IBD therapies. This information will contribute to drug safety by updating the SmPCs, allowing better risk assessment and communication towards patients. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01045-3.

Background Only limited data is available on the extent and burden of adverse drug reactions (ADRs) to biological therapy in inflammatory bowel disease (IBD) patients in daily practice, especially from a patient's perspective. Objective The aim of this study was to systematically assess patient‐reported ADRs during biological therapy in IBD patients and compare these with healthcare provider (HCP)‐reported ADRs. Methods This multicentre, prospective, event monitoring study enrolled IBD patients on biological therapy. Patients completed bimonthly comprehensive web‐based questionnaires regarding description of biological induced ADRs, follow‐up of previous ADRs and experienced burden of the ADR using a five‐point Likert scale. The relationship between patient‐reported ADRs and biological therapy was assessed. HCP‐reported ADRs were extracted from the electronic healthcare records. Results In total, 182 patients (female 51%, mean age 42.2 [standard deviation 14.2] years, Crohn's disease 77%) were included and completed 728 questionnaires. At baseline, 60% of patients used infliximab, 30% adalimumab, 9% vedolizumab and 1% ustekinumab. Fifty percent of participants reported at least one ADR with a total of 239 unique ADRs. Fatigue (n = 26) and headache (n = 20) resulted in the highest burden and a correlation in time with the administration of the biological was described in 56% and 85% respectively. Out of 239 ADRs, 115 were considered biological‐related. HCPs reported 119 ADRs. Agreement between patient‐reported ADRs and HCP‐reported ADRs was only 13%. Conclusion IBD patients often report ADRs during biological therapy. We observed an important significant difference between the type and frequency of patient‐reported ADRs versus HCP‐reported ADRs, leading to an underestimation of more subjective ADRs and patients' ADR‐related burden., Key summary Summarise the established knowledge on this subject Adverse drug reactions (ADRs) are severely underreported by healthcare providers (HCP) and do not capture the full spectrum of biological‐related ADRs.Patient self‐reporting may be used to detect ADRs and offers more insight in the patient's perception and experience of an ADR.Data on self‐reporting ADRs in inflammatory bowel disease (IBD) patients is limited. What are the significant and/or new findings of this study? IBD patients frequently reported ADRs during biological use (50%) and 48% of these ADRs were considered biological‐related.Fatigue and headache resulted in the highest patient‐reported burden.Patients often reported a correlation in time (44%) for the top six patient‐reported ADRs.There was a significant difference between type and frequency of patient‐reported ADRs and HCP‐reported ADRs.

Phosphate binders such as sevelamer are widely used in patients with chronic kidney disease to lower serum phosphate levels. We present a case of a 67-year-old woman with lower gastrointestinal bleeding after 9 days of using sevelamer carbonate (Renvela®). Sigmoidoscopy revealed multiple deep ulcers (diameter 10–15 mm) and mucosal oedema. Histologic examination showed deposition of sevelamer crystals in these rectal ulcers. We hypothesized that the lower gastrointestinal bleeding was caused by deposition of sevelamer crystals. After cessation of sevelamer, gastrointestinal bleeding stopped. Deposition of sevelamer crystals in the gastrointestinal tract is a rare complication of sevelamer therapy. There are only 17 other recorded cases of gastrointestinal deposition of sevelamer crystals. This adverse effect should be considered in all patients taking sevelamer who present with gastrointestinal symptoms, such as gastrointestinal bleeding and abdominal pain. When sevelamer is discontinued, symptoms and mucosal damage appear to revert.

Contains fulltext : 235646.pdf (Publisher’s version ) (Open Access) 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.

Background Pancreatic cancer has a very poor prognosis. Best practices for the use of chemotherapy, enzyme replacement therapy, and biliary drainage have been identified but their implementation in daily clinical practice is often suboptimal. We hypothesized that a nationwide program to enhance implementation of these best practices in pancreatic cancer care would improve survival and quality of life. Methods/design PACAP-1 is a nationwide multicenter stepped-wedge cluster randomized controlled superiority trial. In a per-center stepwise and randomized manner, best practices in pancreatic cancer care regarding the use of (neo)adjuvant and palliative chemotherapy, pancreatic enzyme replacement therapy, and metal biliary stents are implemented in all 17 Dutch pancreatic centers and their regional referral networks during a 6-week initiation period. Per pancreatic center, one multidisciplinary team functions as reference for the other centers in the network. Key best practices were identified from the literature, 3 years of data from existing nationwide registries within the Dutch Pancreatic Cancer Project (PACAP), and national expert meetings. The best practices follow the Dutch guideline on pancreatic cancer and the current state of the literature, and can be executed within daily clinical practice. The implementation process includes monitoring, return visits, and provider feedback in combination with education and reminders. Patient outcomes and compliance are monitored within the PACAP registries. Primary outcome is 1-year overall survival (for all disease stages). Secondary outcomes include quality of life, 3- and 5-year overall survival, and guideline compliance. An improvement of 10% in 1-year overall survival is considered clinically relevant. A 25-month study duration was chosen, which provides 80% statistical power for a mortality reduction of 10.0% in the 17 pancreatic cancer centers, with a required sample size of 2142 patients, corresponding to a 6.6% mortality reduction and 4769 patients nationwide. Discussion The PACAP-1 trial is designed to evaluate whether a nationwide program for enhanced implementation of best practices in pancreatic cancer care can improve 1-year overall survival and quality of life. Trial registration ClinicalTrials.gov, NCT03513705. Trial opened for accrual on 22th May 2018.

Introduction: After standard diagnostic work-up, the aetiology of acute pancreatitis remains unknown in 16–27% of cases, a condition referred to as idiopathic acute pancreatitis (IAP). Determining the aetiology of pancreatitis is essential, as it may direct treatment in the acute phase and guides interventions to prevent recurrent pancreatitis. Methods: Between 2008 and 2015, patients with acute pancreatitis were registered prospectively in 19 Dutch hospitals. Patients who had a negative initial diagnostic work-up with regard to the underlying aetiology of their pancreatitis were labelled ‘presumed’ IAP. The aim of this study was to assess the use of diagnostic modalities and their yield to establish an aetiology in ‘presumed’ IAP, and to assess recurrence rates both with and without treatment. Results: Out of the 1632 registered patients, 191 patients had a first episode of ‘presumed’ IAP, of whom 176 (92%) underwent additional diagnostic testing: CT (n = 124, diagnostic yield 8%), EUS (n = 62, yield 35%), MRI/MRCP (n = 56, yield 33%), repeat ultrasound (n = 97, yield 21%), IgG4 (n = 54, yield 9%) and ERCP (n = 15, yield 47%). In 64 of 176 patients (36%) an aetiological diagnosis was established, mostly biliary (n = 39). In 13 out of 176 of patients (7%) a neoplasm was diagnosed. If additional diagnostic workup revealed an aetiology, the recurrence rate was lower in the treated patients than in the patients without a definite aetiology (15% versus 43%, p = 0.014). Conclusion: Additional diagnostic testing revealed an aetiology in one-third of ‘presumed’ IAP patients. The aetiology found was mostly biliary, but occasionally neoplasms were found. Identification of an aetiology with subsequent treatment reduced the rate of recurrence.

Adherence is pivotal but challenging in ulcerative colitis (UC) treatment. Many methods to assess adherence are subjective or have limitations. (Nac-)5-aminosalicylic acid (5-ASA) urinalysis by high-performance liquid chromatography (HPLC) seems feasible and reproducible in healthy volunteers. We performed a prospective study in adult quiescent UC patients to evaluate the feasibility of spot (Nac-)5-ASA urinalysis by HPLC to assess adherence in daily inflammatory bowel disease (IBD) care. Twenty-nine patients (51.7% male, mean age 52 ± 11 years) were included (median FU 9 months) and weekly spot urine samples were collected. We found large variation in spot (Nac-)5-ASA urinary excretion that was unrelated to brand, dosing schedule or dosage of 5-ASA. In conclusion, spot (Nac-)5-ASA urinalysis is not applicable to assess 5-ASA adherence in daily IBD care.

Background Both methotrexate (MTX) and tioguanine (TG) can be considered as viable treatment options before initiating biological therapy following failure of conventional thiopurines for Crohn’s disease. It is unclear how safety and effectiveness compare for both therapies. This study aimed to compare tolerability and drug survival of MTX and TG therapy after failure of conventional thiopurines in patients with Crohn′s disease. Methods We conducted a retrospective, multi-centre study in five Dutch hospitals, including patients initiating MTX or TG for Crohn’s disease after failure (all causes) of conventional thiopurines. Patients with prior MTX or TG use, MTX or TG not primarily prescribed for Crohn’s disease, or patients receiving concomitant biological treatment at baseline were excluded. Follow-up duration from starting treatment was 104 weeks or until treatment discontinuation. Primary outcome was therapy discontinuation rate due to adverse events (AE). Secondary outcome was ongoing treatment without initiation of biological treatment. Results In total, 221 patients with failure of conventional thiopurines and subsequent therapy with either MTX (n=106) or TG (n=115) were included. Median follow-up was 89 weeks (IQR 28-104). Previous biological failure was present in 28 (26%) MTX and 17 (15%) TG treated patients (p=0.044). Sixty-four (29%) patients (MTX 41.5%, TG 17.4%, p Conclusion Forty-two percent of MTX, compared to 17% of TG treated patients, discontinued therapy due to AE in patients with Crohn’s disease with prior failure of conventional thiopurines. These data may aid in the selection of subsequent therapy after failure of conventional thiopurine therapy.

Background Randomised controlled trials have reported improvement of work productivity and activity impairment (WPAI) as well as quality of life in biological-treated inflammatory bowel disease (IBD) patients. However, data beyond clinical trials are limited. Methods This multicentre prospective cohort study evaluated the effect of initiating biological or small molecule therapy on work impairment in IBD patients. Subjects completed the WPAI questionnaire and Short IBD questionnaire (SIBDQ) at biological therapy initiation and at week 26. Clinical disease activity was assessed using the Harvey Bradshaw Index and Simple Clinical Colitis Activity Index. Biochemical disease activity was assessed using C-reactive protein and faecal calprotectin. Data are presented as mean ± standard deviation. Results In total, 156 IBD patients were included for analysis (median age 40 years, 55% male, 55% Crohn’s disease). Of these patients, 28% started infliximab, 33% adalimumab, 19% vedolizumab, 18% ustekinumab, 1% tofacitinib and 1% golimumab. Concomitant medication use at baseline included 28% prednisone, 12% budesonide, 34% mesalamine, and 46% immunomodulator. At baseline, 58% had clinical disease activity and 58% had biochemical disease activity. In our cohort, 111 (71%) were employed and 17 (11%) patients reported partial or full occupational disability. The mean total work impairment at baseline was 52% ± 36%. During follow-up, 7 patients lost their job and 8 patients started employment. For the entire cohort, improvements in all WPAI domains were observed: mean 11%-points decrease in missed working hours, 4%-points decrease in impairment while working, 15%-points decrease in total work impairment and 15%-points decrease in total activity impairment. Parallel improvements were seen in SIBDQ scores (mean improvement 7.6 ± 11.3). At week 26, 66 (42%) patients achieved the minimal clinical important difference in total work impairment (improvement ≥7%-points). Patients with clinical disease activity at baseline and clinical response to the biological (n=32) showed a larger improvement in total work impairment compared with other subjects (n=86) (mean difference 29%-points versus 10%-points; p=0.036 (T-test)). Similarly, these patients showed greater improvement in SIBDQ scores compared to other subjects (mean 13.8 versus 5.4, respectively; p Conclusion IBD patients experienced substantial work impairment prior to initiating biological treatment. Improved work impairment scores were seen after initiation of biological therapy and patients with clinical response showed even greater improvements. These results underline the importance of IBD disease control to improve work productivity and participation.

Background Tofacitinib is a janus kinase 1 and 3 inhibitor approved for the treatment of ulcerative colitis (UC). Real-world evidence is needed to evaluate the effectiveness, usage and safety in daily practice. Methods UC patients in whom tofacitinib was started in 15 hospitals (8 academic, 7 non-academic) participated in the ICC Registry: a Dutch prospective, observational registry. Visits were planned at baseline, Week 12, and 24. Patients with both clinical (Short Clinical Colitis Activity Index (SCCAI) >2) and objective disease activity (endoscopy (Mayo >0), C-reactive protein (CRP) >5 mg/l or faecal calprotectin (FCP) >250 µg/g) were included. In this study, corticosteroid-free clinical remission (SCCAI ≤2), biochemical remission (FCP ≤250 µg/g), combined corticosteroid-free clinical and biochemical remission, predictors of remission, safety outcomes, dose optimisation, and effect on lipids were determined at Week 24. Only patients from centres with routine endoscopic follow-up (regardless of symptoms) were analysed to determine endoscopic remission (Mayo = 0) at Week 12. All analyses were done on an intention-to-treat basis. Results In total, 111 UC patients (95% anti-TNF, 60% vedolizumab, 4% ustekinumab exposed) were followed for a median of 24 weeks (IQR 12–26). All patients had both active clinical and objective disease (SCCAI 8 (IQR 5–11), FCP 1800µg/g (IQR 633–2682)). Corticosteroid-free clinical, biochemical, and combined corticosteroid-free clinical and biochemical remission rate at week 24 was 29%, 25%, and 19%, respectively. Endoscopic remission was achieved in 21% of patients (n = 33) at Week 12. Prior vedolizumab exposure was associated with a lower remission rate at week 24 (OR 0.33, 95% CI 0.11–0.94) in multivariable analysis. In total, 36 patients (88 per 100 patient-years) experienced tofacitinib-related adverse events (most common: cutaneous lesions and headache) of which 6 patients (18 per 100 patient-years) discontinued treatment. No thromboembolic events were reported. We observed 4 cases of herpes zoster re-activation but no severe infections (requiring hospitalisation). During follow-up 14 hospitalisations and 5 (4.5%) colectomies were performed. Cholesterol, HDL, and LDL increased between baseline and week 12 (18% (95% CI 9–26, n = 35), 18% (95% CI 8–28, n = 35) and 27% (95% CI 14–39, n = 35), respectively). At week 24, 33% of patients used 10 mg twice daily. Conclusion Tofacitinib is an effective treatment for UC after anti-TNF and/or vedolizumab failure. We did observe a relatively high rate of adverse events in this refractory UC cohort.

Background There are limited data available on de-escalation of biological therapy after prior escalation in inflammatory bowel disease (IBD) patients. The aim of this study was to assess the frequency and success rate of de-escalation of biological therapy in IBD patients after prior dose escalation and evaluate which measures are used prior to de-escalation. Methods This multicentre, prospective, cohort study enrolled IBD patients treated with infliximab (IFX), adalimumab (ADA) or vedolizumab (VEDO) in whom therapy was de-escalated at least once after prior biological escalation. Objective disease measures for de-escalation were defined as faecal calprotectin ≤ 200 µg/g and/or therapeutic or supratherapeutic trough levels and/or radiologic or endoscopic remission. Successful de-escalation was defined as remaining on the same or lower biological dose for ≥6 months after de-escalation. Results In total, 206 IFX users, 85 ADA users and 55 VEDO users underwent therapy escalation. Of these, 34 (17%) patients on IFX, 18 (21%) patients on ADA and 8 (15%) patients on VEDO had received at least one subsequent de-escalation. De-escalation was successful in 91% of IFX patients, 89% of ADA patients and 100% of VEDO patients. The probability of remaining on the de-escalated regimen or further de-escalation after 1 year was 85% for IFX, 62% for ADA and 100% for VEDO. De-escalation based on objective disease measures was performed in 67% of all de-escalations. Objective de-escalations were successful in 98% versus 80% of subjective de-escalations. Conclusion De-escalation after biological escalation is successful in the majority of patients. Objective markers of remission increase the likelihood of successful de-escalation.

Background: This review discusses current insights with regard to biliary tract management during and after acute biliary pancreatitis. Methods: A MEDLINE and EMBASE search was done and studies were selected based on methodological quality and publication date. The recommendations of recent guidelines are incorporated in this review. In absence of consensus in the literature, expert opinion is expressed. Results: There is no role for early endoscopic retrograde cholangiopancreatography (ERCP) in patients with (predicted) mild biliary pancreatitis to improve outcome. In case of persisting choledocholithiasis, ERCP with stone extraction is scheduled electively when the acute event has subsided. Whether early ERCP with sphincterotomy is beneficial in patients with predicted severe pancreatitis remains subject to debate. Regardless of disease severity, in case of concomitant cholangitis urgent endoscopic sphincterotomy (ES) is recommended. As a definitive treatment to reduce the risk of recurrent biliary events in the long term, ES is inferior to cholecystectomy and should be reserved for patients considered unfit for surgery. After severe biliary pancreatitis, cholecystectomy should be postponed until all signs of inflammation have subsided. In patients with mild pancreatitis, cholecystectomy during the primary admission reduces the risk of recurrent biliary complications. Conclusion: Recent research has provided valuable data to guide biliary tract management in the setting of acute biliary pancreatitis with great value and benefit for patients and clinicians. Some important clinical dilemmas remain, but it is anticipated that on-going clinical trials will deliver some important insights and additional guidance soon. (C) 2015 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.

IntroductionIdiopathic acute pancreatitis (IAP) remains a dilemma for physicians as it is uncertain whether patients with IAP may actually have an occult aetiology. It is unclear to what extent additional diagnostic modalities such as endoscopic ultrasonography (EUS) are warranted after a first episode of IAP in order to uncover this aetiology. Failure to timely determine treatable aetiologies delays appropriate treatment and might subsequently cause recurrence of acute pancreatitis. Therefore, the aim of the Pancreatitis of Idiopathic origin: Clinical added value of endoscopic UltraSonography (PICUS) Study is to determine the value of routine EUS in determining the aetiology of pancreatitis in patients with a first episode of IAP.Methods and analysisPICUS is designed as a multicentre prospective cohort study of 106 patients with a first episode of IAP after complete standard diagnostic work-up, in whom a diagnostic EUS will be performed. Standard diagnostic work-up will include a complete personal and family history, laboratory tests including serum alanine aminotransferase, calcium and triglyceride levels and imaging by transabdominal ultrasound, magnetic resonance imaging or magnetic resonance cholangiopancreaticography after clinical recovery from the acute pancreatitis episode. The primary outcome measure is detection of aetiology by EUS. Secondary outcome measures include pancreatitis recurrence rate, severity of recurrent pancreatitis, readmission, additional interventions, complications, length of hospital stay, quality of life, mortality and costs, during a follow-up period of 12 months.Ethics and disseminationPICUS is conducted according to the Declaration of Helsinki and Guideline for Good Clinical Practice. Five medical ethics review committees assessed PICUS (Medical Ethics Review Committee of Academic Medical Center, University Medical Center Utrecht, Radboud University Medical Center, Erasmus Medical Center and Maastricht University Medical Center). The results will be submitted for publication in an international peer-reviewed journal.Trial registration numberNetherlands Trial Registry (NL7066). Prospectively registered.

Background The use of biologicals has improved the treatment of IBD but the understanding of adverse drug reactions (ADRs) and the knowledge of patients’ perception on ADRs is poor. Patient-reporting may provide more insight in the extent and burden of ADRs in daily practice which in turn can lead to treatment optimisation. This study aimed to assess systematic patient-reported ADRs during biological therapy in IBD patients. Methods This multicentre, prospective, event monitoring study enrolled adult Crohn’s disease (CD) and ulcerative colitis (UC) patients treated with a biological between 1 January 2017 and 31 December 2018. Patients completed bimonthly comprehensive web-based questionnaires regarding indication and use of, description of biological induced ADRs, follow-up of previous ADRs, experienced burden of the ADR using a 5-point Likert scale, contact with a healthcare provider and therapeutic consequences due to the ADR. Patient-reported ADRs were MedDRA coded by trained pharmacovigilance assessors. MedDRA is a multi-hierarchical dictionary used to code reported ADRs into specific unambiguous terms (preferred terms). Preferred terms are subsequently grouped into high-level terms, high-level group terms and system organ classes. In total there are 26 system organ classes. Results In total, 182 patients in 4 centres (female 51%, mean (standard deviation) age 42.2 (14.2) years, CD 77%) were included and completed 750 questionnaires. At baseline, 49% used an immunomodulator (43% thiopurines, 6% methotrexate), while biologicals were documented as follows: 59% infliximab, 30% adalimumab, 9% vedolizumab, 1% ustekinumab. At least one ADR was reported by 50% of the participants, and 233 ADRs were reported in total with a median reported ADRs per participant of 2 (interquartile range, 1–3). Fatigue (n = 26), headache (n = 20), injection site reactions (n = 16) and arthralgia (n = 12) were most commonly reported, with a mean burden of 3.31, 1.63, 2.55 and 3.33, and a correlation in time with the administration of the biologic was described in 58%, 85%, 81% and 8% in these ADRs, respectively. Participants contacted a healthcare provider in 62% of all ADRs. In two out of 90 patients who reported an ADR, the biological was discontinued. Conclusion We established a patient-reported pharmacovigilance monitoring system and participants in this study frequently reported ADRs due to biologicals. Fatigue and arthralgia resulted in the highest burden. This reporting system may provide more understanding of patient-experienced ADRs which may ultimately lead to increased adherence of therapy and improved quality of life.

Contains fulltext : 181861.pdf (Publisher’s version ) (Closed access) 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.

Contains fulltext : 191267.pdf (Author’s version postprint ) (Open Access) Background and Aims: Histological remission [HR] is a potential treatment target in ulcerative colitis [UC]. Limited 'real world' data are available on the reliability of histological scoring when assessing minimal histological inflammation. The aim of this study was to investigate the reliability of UC histological scores in colonic biopsies showing mucosal healing [MH] and limited histological inflammation, and to compare the 'daily practice' histological assessment with expert reviews by gastrointestinal [GI] pathologists. Methods: We performed a retrospective single-centre study. Colonic biopsies from UC patients with MH [Mayo score

Background: Chronic pancreatitis is a complex disease with many unanswered questions regarding the natural history and therapy. Prospective longitudinal studies with long-term follow-up are warranted.Methods: The Dutch Chronic Pancreatitis Registry (CARE) is a nationwide registry aimed at prospective evaluation and follow-up of patients with chronic pancreatitis. All patients with (suspected) chronic or recurrent pancreatitis are eligible for CARE. Patients are followed-up by yearly questionnaires and review of medical records. Study outcomes are pain, disease complications, quality of life, and pancreatic function. The target sample size was set at 500 for the first year and 1000 patients within 3 years.Results: A total of 1218 patients were included from February 2010 until June 2013 by 76 participating surgeons and gastroenterologist from 33 hospitals. Participation rate was 90% of eligible patients. Eight academic centers included 761 (62%) patients, while 25 community hospitals included 457 (38%). Patient centered outcomes were assessed by yearly questionnaires, which had a response rate of 85 and 82% for year 1 and 2, respectively. The median age of patients was 58 years, 814 (67%) were male, and 38% had symptoms for less than 5 years.Discussion: The CARE registry has successfully recruited over 1200 patients with chronic and recurrent pancreatitis in about 3 years. The defined inclusion criteria ensure patients are included at an early disease stage. Participation and compliance rates are high. CARE offers a unique opportunity with sufficient power to investigate many clinical questions regarding natural course, complications, and efficacy and timing of treatment strategies. Copyright (C) 2014, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.

Adherence is pivotal but challenging in ulcerative colitis (UC) treatment. Many methods to assess adherence are subjective or have limitations. (Nac‐)5‐aminosalicylic acid (5‐ASA) urinalysis by high‐performance liquid chromatography (HPLC) seems feasible and reproducible in healthy volunteers. We performed a prospective study in adult quiescent UC patients to evaluate the feasibility of spot (Nac‐)5‐ASA urinalysis by HPLC to assess adherence in daily inflammatory bowel disease (IBD) care. Twenty‐nine patients (51.7% male, mean age 52 ± 11 years) were included (median FU 9 months) and weekly spot urine samples were collected. We found large variation in spot (Nac‐)5‐ASA urinary excretion that was unrelated to brand, dosing schedule or dosage of 5‐ASA. In conclusion, spot (Nac‐)5‐ASA urinalysis is not applicable to assess 5‐ASA adherence in daily IBD care.

Background & Aims: Recently, treatment goals in inflammatory bowel disease (IBD) in clinical trials have shifted from mainly symptom-based to more mucosa-driven. Real world data on treatment priorities are lacking. We aimed to investigate the current practice and most commonly used definitions of IBD treatment targets among Dutch gastroenterologists. Methods: Dutch gastroenterologists were asked to participate in a computer-based nation-wide survey. We asked questions on demographics, opinion and current practice regarding IBD treatment targets. Results: Twenty-four percent (134/556) of the respondents completed the survey. For both Crohn’s disease (CD) (47.3%, 61/129) and ulcerative colitis (UC)(45%, 58/129) the main treatment goal was to achieve and maintain deep remission, defined as clinical, biochemical and endoscopic remission. Seventy-six percent of the participants use mucosal healing (MH) as a potential treatment target for IBD, whereas 22.6% use histological remission. There is no single definition for MH in IBD. The majority use Mayo score ≤ 1 in UC (52%) and ‘macroscopic normal mucosa’ in CD (66%). Conclusion: More stringent and mucosa-driven treatment targets as ‘deep remission’ and ‘mucosal healing’ have found traction in clinical practice. The most commonly used definition for MH in routine practice is endoscopic MAYO score ≤ 1 in UC and ‘macroscopic normal mucosa’ in CD. Abbreviations: CD: Crohn’s disease; CDEIS: Crohn‘s Disease Endoscopic Index of Severity; IBD: Inflammatory Bowel Disease; IBDU: IBD unclassified; IOIBD: International Organization for the Study of Inflammatory Bowel Diseases; MH: Mucosal healing; MMH: Microscopic mucosal healing; PROMS: Patient reported outcome measures; SES-CD: Simple endoscopic score for Crohn’s disease; UC: ulcerative colitis; UCEIS: Ulcerative Colitis Endoscopic Index of Severity.

Contains fulltext : 172256.pdf (Publisher’s version ) (Open Access) AIM: To identify definitions of cytomegalovirus (CMV) infection and intestinal disease, in inflammatory bowel disease (IBD), to determine the prevalence associated with these definitions. METHODS: We conducted a systematic review and interrogated PubMed, EMBASE and Cochrane for literature on prevalence and diagnostics of CMV infection and intestinal disease in IBD patients. As medical headings we used "cytomegalovirus" OR "CMV" OR "cytomegalo virus" AND "inflammatory bowel disease" OR "IBD" OR "ulcerative colitis" OR "colitis ulcerosa" OR "Crohn's disease". Both MeSH-terms and free searches were performed. We included all types of English-language (clinical) trials concerning diagnostics and prevalence of CMV in IBD. RESULTS: The search strategy identified 924 citations, and 52 articles were eligible for inclusion. We identified 21 different definitions for CMV infection, 8 definitions for CMV intestinal disease and 3 definitions for CMV reactivation. Prevalence numbers depend on used definition, studied population and region. The highest prevalence for CMV infection was found when using positive serum PCR as a definition, whereas for CMV intestinal disease this applies to the use of tissue PCR > 10 copies/mg tissue. Most patients with CMV infection and intestinal disease had steroid refractory disease and came from East Asia. CONCLUSION: We detected multiple different definitions used for CMV infection and intestinal disease in IBD patients, which has an effect on prevalence numbers and eventually on outcome in different trials.

Background Acute pancreatitis is mostly caused by gallstones or sludge. Early decompression of the biliary tree by endoscopic retrograde cholangiography (ERC) with sphincterotomy may improve outcome in these patients. Whereas current guidelines recommend early ERC in patients with concomitant cholangitis, early ERC is not recommended in patients with mild biliary pancreatitis. Evidence on the role of routine early ERC with endoscopic sphincterotomy in patients without cholangitis but with biliary pancreatitis at high risk for complications is lacking. We hypothesize that early ERC with sphincterotomy improves outcome in these patients. Methods/Design The APEC trial is a randomized controlled, parallel group, superiority multicenter trial. Within 24 hours after presentation to the emergency department, patients with biliary pancreatitis without cholangitis and at high risk for complications, based on an Acute Physiology and Chronic Health Evaluation (APACHE-II) score of 8 or greater, Modified Glasgow score of 3 or greater, or serum C-reactive protein above 150 mg/L, will be randomized. In 27 hospitals of the Dutch Pancreatitis Study Group, 232 patients will be allocated to early ERC with sphincterotomy or to conservative treatment. The primary endpoint is a composite of major complications (that is, organ failure, pancreatic necrosis, pneumonia, bacteremia, cholangitis, pancreatic endocrine, or exocrine insufficiency) or death within 180 days after randomization. Secondary endpoints include ERC-related complications, infected necrotizing pancreatitis, length of hospital stay and an economical evaluation. Discussion The APEC trial investigates whether an early ERC with sphincterotomy reduces the composite endpoint of major complications or death compared with conservative treatment in patients with biliary pancreatitis at high risk of complications. Trial registration Current Controlled Trials ISRCTN97372133 (date registration: 17-12-2012) Electronic supplementary material The online version of this article (doi:10.1186/s13063-015-1132-0) contains supplementary material, which is available to authorized users.

Objective: 5-Amino salicylicacid (5-ASA) is the cornerstone of ulcerative colitis treatment, with (assessment of) non-adherence as a challenge. Multi-matrix release (MMX)-mesalazine has the advantage of once-daily (OD) dosing. Primarily we assessed urinary (NAc-) 5-ASA excretion, as measured by High-Performance Liquid Chromatography (HPLC), in order to monitor nonadherence, in healthy volunteers taking MMX-mesalazine. Secondly, we established urinary (NAc-)5-ASA cut-off levels for (partial) nonadherence. Method: We studied 25 healthy adult volunteers who used MMX-mesalazine 2400 mg OD (days 1-4), followed by 1200 mg twice daily (BID) (days 8-11), separated by a drug-free interval of 3 days. Daily morning urine spot samples were collected. The cut-off level for adherence was set at the lowest steady state (NAc-)5-ASA urinary concentration level. Results: Stability of urinary 5-ASA and NAc-5-ASA, stored at room temperature during 24 hours was 96.4 ± 8.3% and 96.4 ± 4.1%. Recovery of urinary 5-ASA and NAc-5-ASA was 114.3 ± 10.4% and 107.5 ± 6.4%. The limit of detection and quantification were 1.1 ug/ml and 3.5 ug/ml for NAc-5-ASA and 0.4 ug/ml and 1.3 ug/ml for 5-ASA. The maximal 5-ASA within-run and between-run relative SD were 10.4% and 12.5%. The cut-off level for non-adherence was determined at 9.67 (OD) and at 15.39 (BID) mg/mmol (NAc-) 5-ASA per mmol creatinine. Conclusion: HPLC is a feasible, sensitive and reproducible method to measure urinary (NAc-) 5-ASA excretion in volunteers taking MMX-mesalazine. This study establishes urinary (NAc-) 5-ASA cut-off levels for MMX-mesalazine non-adherence that may be useful in clinical practice and future trials.

Background and Aims: A fraction of patients with clinically type 2 diabetes have humoral immunological changes and requiring insulin therapy at short time. This type of diabetes is named Latent Autoimmune Diabetes of the Adult (LADA). Special attention should be paid to diagnose such patients because therapy may influence the speed of progression toward insulin dependency. In the Netherlands no epidemiological study exists on this diabetic population. The aim of the study is to determine prevalence of LADA on a diabetic outpatient clinical department of a Dutch, non-university hospital and describe patients characteristics in this population. Materials and Methods: During a four-month study period, we studied 407 consecutive patients with diabetes mellitus type 2 who visited the outpatient clinic. Blood tests for GAD-antibodies were performed from 230 patients, after informed consent was obtained. History, physical examination, and other laboratory results were obtained from the patients file. 177 Patients were excluded from the study because of refusal, suboptimal thyroidfunction, malignancy, the use of NSAIDs and/or acetylsalicylacid. These exclusion criteria were used because of further studies in the LADA population. Results: 26 (11.3%) patients had positive GAD-antibodies (anti-GAD level median 0.55 U). 27% was male. Mean age of this group 59.3±16.3 years. Median time before insulin requirement 18.5 months (range 3-396). BMI was 27.8±4.5 kg/m2. The prevalence of long-term complications was as follows: neuropathy: 30.8%, retinopathy 30.8%, hypertension 46.25%, peripheral vascular damage 30.7%. Laboratory results showed fasting glucose 11.7±4.8 mmol/I HbAlc 8.3±1.6 mmolll, total cholesterol 5.4±1.06 mmolll, HDL-cholesterol 1.73±0.53 mmolll, triglycerides median 1.1 mmolll (range 0.5-9.7), LDL 2.88±1.16 mmoi/l. The prevalence of hypothyreoidism was 19.2%. Conclusion: The prevalence of LADA in this Dutch patient group was 11.3%. This is comparable with previous study results in other countries. Concerning late complications, the LADA population has no major difference compared to a normal type 2 diabetes population. Striking is the high concentration of HDL-cholesterol and the high prevalence of hypothyreoidism.

Item does not contain fulltext BACKGROUND: Recently, mucosal healing (MH) is regarded as an important treatment goal in ulcerative colitis (UC). 5-Aminosalicylates (5-ASA) are the standard treatment in mild-to-moderate UC, but the effect on MH is less known. The aim of this study was to systematically review the medical literature in order to compare different preparations of 5-ASA for the effect on MH. METHODS: We conducted a structured search of PubMed and the Cochrane Central Register of Controlled Trials to identify randomized controlled clinical trials with 5-ASA in UC providing data about MH. We calculated the sample size-weighted pooled proportion of patients with MH, and performed meta-analysis of head-to-head comparisons. RESULTS: Out of 645 hits, we included 90 treatment arms, involving 3977 patients using oral 5-ASA (granulate and tablets) and 2513 patients using rectal 5-ASA (suppositories, enema, and foam). Overall, 43,7% of 5-ASA treated patients achieved MH (oral 36,9%; rectal 50,3%). In oral studies, 49% of patients using granulate (7 treatment-arms) achieved MH compared to 34,9% using tablets (43 treatment-arms). In rectal studies the proportion of MH was 62% for suppositories (eight treatment arms), 51% for foam (nine treatment arms), and 46% for enema (23 treatment arms), respectively. CONCLUSIONS: 5-ASA preparations achieved MH in nearly 50% of UC patients. There were no significant differences in MH between the various 5-ASA agents, either in the oral or the rectal treatment groups.

Item does not contain fulltext BACKGROUND AND AIMS: Many outpatients with Inflammatory Bowel Disease (IBD) complain about fatigue, even in a quiescent disease. The aim of this study is to examine prevalence of fatigue in IBD outpatients and define possible determinants of fatigue. METHODS: A case-control study was conducted in consecutive IBD outpatients, with Lynchsyndrome gene carriers (Lynch) as a control group. Demographics, laboratory results and Harvey Bradshaw Index (HBI) were obtained from medical records. Subjective fatigue was measured by the revised Piper Fatigue Scale (PFS). Mean PFS scores were compared between groups. Secondly, possible determinants of fatigue were assessed. RESULTS: Three hundred patients were enrolled. 74% returned the questionnaires (117 CD; 55 UC; and 50 Lynch). Demographics were not different between groups. Mean overall PFS is 4.03. PFS score in IBD patients was significantly higher compared to Lynch. Mean (SD) PFS score was 4.8 (2.09) for CD, 4.2 (2.3) for UC versus 1.9 (2.03) for Lynch (P

A patient who bred exotic turtles as a hobby presented with 2 episodes of severe diarrhea, the second of which was proven to be caused by turtle-associated salmonellosis that was contracted during treatment with a proton-pump inhibitor. The literature about reptile-associated salmonellosis is briefly reviewed.

Background: Many patients with Inflammatory Bowel Disease (IBD) complain about severe fatigue interfering with daily life, even if their disease is in remission. Therefore we performed a study to examine the prevalence and severity of fatigue in these IBD patients and to define possible determinants of fatigue. Methods: In a three month period we conducted a casecontrol study in consecutive patients at our outpatient clinic. Patients with confirmed Crohn's Disease (CD) andUlcerative Colitis (UC) were studied. Lynch syndrome gene carriers (Lynch), visiting the same out-patient clinic, served as a control group. Demographic variables, clinical history, laboratory results were obtained from the medical records. In IBD patients severity of disease was assessed by the Harvey Bradshaw Index. (Severity of) Fatigue was scored using the revised Piper Fatigue Scale (PFS), a validated questionnaire consisting of 22 numerically (0-10) scaled items, that measures four dimensions of subjective fatigue: (1) behavioral/severity; (2) affective meaning; (3)sensory and (4) cognitive/mood. Mean PFS scores were compared between the three groups for both overall score and dimensions. Within the IBD patient group we looked for possible determinants of fatigue, by comparing demographic and clinical variables between patients with a high (≥4) and low (