Objective The diagnosis of inflammatory bowel disease (IBD) associated with high-grade dysplasia (HGD) has a significant impact on clinical management, including colectomy. However, the prognosis of HGD remains unclear due to diagnostic uncertainty and low-quality data on subsequent synchronous and metachronous neoplasia. We aimed to evaluate a diagnostic strategy with dedicated gastrointestinal (GI) pathologist consensus of revised HGD and the impact on synchronous and metachronous neoplasia rates. Methods In this retrospective multicenter cohort study, we used the Dutch Nationwide Pathology Databank to identify IBD patients with HGD in seven hospitals. Histopathological specimens of the initial HGD were independently revised by two dedicated GI pathologists. Definitive diagnosis was established in a consensus meeting. Synchronous and metachronous neoplasia incidences were assessed with a competing risk analysis. Results We included 54 IBD patients with HGD, of whom 33 (61.1%) with ulcerative colitis and 42 (77.8%) with extensive disease. After consensus, 18 (33.3%) lesions were downgraded to indefinite/low-grade dysplasia, and 6 (11.1%) were revised to colorectal cancer (CRC). Seven patients (13.0%) had synchronous CRC. Patients with downgraded lesions showed a lower cumulative advanced neoplasia (HGD/CRC) incidence compared with confirmed HGD [(Gray’s test P < 0.01), 5-year cumulative incidence 0.0% vs. 26.6%]. Conclusions We demonstrated frequent downgrading of HGD, associated with lower metachronous neoplasia rates. This underlines the potential impact of dedicated GI pathologist consensus meetings. The high and synchronous and metachronous neoplasia rates after HGD underline the need for close surveillance.

BACKGROUND AND AIMS: Although colorectal cancer (CRC) surveillance is embedded in clinical inflammatory bowel disease (IBD) practice, a subset of patients still develops advanced neoplasia (AN) (high-grade dysplasia [HGD] and/or CRC). We aimed to assess the impact of surveillance quality on AN risk in IBD. METHODS: In this multicenter case-control study, we searched the Dutch nationwide pathology databank to identify IBD cases with AN and controls with indefinite or low-grade dysplasia. The surveillance colonoscopy preceding the index lesion (first indefinite for dysplasia [IND]/low-grade dysplasia [LGD] or AN) was used to assess the impact of surveillance quality. We assessed intervals, bowel preparation, cecal intubation, and absence of inflammation as primary quality indicators. In addition, we assessed chromoendoscopy, endoscopist expertise, hospital setting, and biopsy strategy. Associations of quality indicators with AN risk were determined with multivariable logistic regression analyses with Firth's correction. RESULTS: We included 137 cases and 138 controls. Delayed intervals (58.2% vs 39.6%) and active inflammation (65.3% vs 41.8%) were frequently present in cases and controls and were associated with AN (delayed interval: adjusted odds ratio [aOR], 2.00; 95% confidence interval [CI], 1.07-3.81; P = .03; active inflammation: aOR, 2.46; 95% CI, 1.33-4.61; P < .01). Surveillance compliant with primary quality indicators was associated with a reduced AN risk (aOR, 0.43; 95% CI, 0.22-0.91; P = .03), similar to chromoendoscopy (OR, 0.11; 95% CI, 0.01-0.89; P = .01). Other indicators were not significantly associated with AN. CONCLUSIONS: Surveillance compliant with primary quality indicators is associated with a reduced colitis-associated AN risk. Delayed surveillance intervals and active inflammation were associated with an increased AN risk. This underlines the importance of procedural quality, including endoscopic remission to optimize the effectiveness of endoscopic surveillance.

Abstract Background Although colorectal cancer (CRC) surveillance is embedded in IBD practice, a subset of patients still develops advanced neoplasia (AN; high-grade dysplasia (HGD) and/or CRC). We aimed to determine the most plausible explanations for AN in IBD patients through assessment of inadequate surveillance. Methods A search of the nationwide histopathology registry of the Netherlands (PALGA) was used to identify IBD patients with AN in seven hospitals. Patients with ulcerative colitis (UC), Crohn’s disease (CD), or IBD-unclassified (IBD-U) from 1 January 1991 until 1 October 2020 were eligible for inclusion. Exclusion criteria comprised familial CRC or AN prior to IBD diagnosis. A root-cause analysis based on the World Endoscopy Organizations’ recommendations was performed to determine inadequate surveillance prior to the first AN, including lack of cecal intubation, insufficient bowel preparation (BBPS<6 or according to colonoscopy report) and active endoscopic inflammation. Interval inadequacy was assessed according to most recent BSG guideline including a six month margin. Associations were assessed with a binary regression model. Results We included 179 patients with AN (figure 1). Of these, 22 patients (12.3%) were diagnosed with AN before surveillance was indicated. Inadequate surveillance was present in 122 patients (68.2%, n=50 HGD, n=72 CRC), of whom 47 patients (26.3%) did not receive any surveillance colonoscopy before AN diagnosis. A delayed surveillance interval was identified in 44 patients (24.6%), with a median deviation from surveillance recommendations of 19.0 months (IQR 9.5–28.5 months). Furthermore, 56 patients (31.3%) had active inflammation, three had insufficient bowel preparation, and two patients had an incomplete colonoscopy. Younger age at diagnosis (annual OR 0.96, 95% CI 0.94–0.98, p<0.01) and post-inflammatory polyps (OR 2.14 95% CI 1.06–4.32, p=0.03) were independently associated with inadequate surveillance. By contrast, prior indefinite for dysplasia or low-grade dysplasia was associated with adequate surveillance (OR 0.36, 95% CI 0.17–0.76, p<0.01). Finally, 35 patients (19.6%) had interval or surveillance AN despite adequate surveillance (diagnosed during a diagnostic procedure or surveillance colonoscopy, respectively). Figure 1. Root-cause analysis flowchart Conclusion The majority of IBD patients with AN in our cohort had prior inadequate surveillance. This observation underlines the importance of adequate surveillance and guideline adherence.

The impact of serrated polyps on the advanced colorectal neoplasia (CRN) risk in inflammatory bowel disease (IBD) patients is unknown. Serrated polyps are histologically categorized as hyperplastic polyps (HPs), sessile serrated lesions (SSLs), and traditional serrated adenomas (TSAs). We aimed (1) to characterize the serrated polyps in IBD patients, (2) to identify factors associated with the presence of serrated polyps in IBD, and (3) to assess the CRN risk in IBD patients with serrated polyps. We established a retrospective cohort of IBD patients with and without colonic serrated polyps. Cox-regression analysis with time-dependent variables was used to compare advanced CRN risk in IBD patients with and without serrated polyps. Of the 621 enrolled IBD patients, 198 had a serrated polyp (92 HPs, 88 SSLs without dysplasia, 13 SSLs with dysplasia, and 5 TSAs). Independent factors associated with serrated polyps were ulcerative colitis (UC) (odds ratio (OR) 1.77, 95

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.

BACKGROUND AND AIMS:Patients with inflammatory bowel disease (IBD) have an increased risk of colorectal cancer (CRC). We performed a systematic review and meta-analysis to identify all prognostic factors for advanced colorectal neoplasia (aCRN, high-grade dysplasia, or CRC) in patients with IBD.METHODS:A systematic literature search was conducted according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. Risk of bias was assessed using the Quality in Prognostic Studies tool. Random-effects models were created separately for odds and hazard ratios, different study designs, and univariable or multivariable data. The evidence for all prognostic factors was categorized as "weak", "moderate", or "strong", based on estimate of effect sizes, heterogeneity, and risk of bias.RESULTS:A total of 164 studies were included, allowing pooled analysis of 31 potential prognostic factors. In the univariable analysis, the evidence for extensive disease was classified as strong while evidence for low-grade dysplasia, strictures, primary sclerosing cholangitis, post-inflammatory polyps, family history of CRC, and ulcerative colitis versus Crohn's disease was considered moderate. Evidence for any dysplasia, colon segment resection, aneuploidy, male sex, and age was classified as weak. In addition, histologic inflammation was identified as a risk factor in multivariable analysis (weak evidence). The evidence for the protective factors colonoscopic surveillance, 5-Aminosalicylic Acid, thiopurines, and smoking was moderate in univariable analysis. Multivariable analysis provided weak evidence for statin use.CONCLUSIONS:In this systematic review and meta-analysis, we identified 13 risk factors and 5 protective factors for aCRN in IBD patients, based on univariable and/or multivariable pooled analyses. These findings might lay the groundwork for an improved CRC risk stratification-based surveillance in IBD.

BACKGROUND AND AIMS:The impact of recurrent low-grade dysplasia (LGD) on the risk of advanced neoplasia (high-grade dysplasia and colorectal cancer) in inflammatory bowel disease (IBD) patients is unknown. In addition, it is unclear how a neoplasia-free period after index LGD impacts this risk. We aimed to determine whether recurrent LGD is a risk factor for advanced neoplasia development and to evaluate the impact of a neoplasia-free time period after initial LGD diagnosis on the advanced neoplasia risk. METHODS:This is a nationwide cohort study using data from the Dutch National Pathology Registry to identify all IBD patients with LGD and ≥1 follow-up colonoscopy between 1991 and 2010 in the Netherlands. Follow-up data were collected until January 2016. We compared the cumulative advanced neoplasia incidence between patients with and without recurrent LGD at first follow-up colonoscopy using log-rank analysis. We subsequently studied the impact of a neoplasia-free period after initial LGD on the advanced neoplasia incidence. RESULTS:We identified 4284 IBD patients with colonic LGD with a median follow-up of 6.4 years. Recurrent LGD was a risk factor for advanced neoplasia (hazard ratio, 1.66; 95% confidence interval, 1.22-2.25; P = .001). A neoplasia-free period of at least 3 years after LGD protected against advanced neoplasia. CONCLUSIONS:Recurrent LGD at follow-up colonoscopy after initial LGD was a risk factor for advanced neoplasia. A neoplasia-free period of at least 3 years after initial LGD was associated with a reduced subsequent risk of advanced neoplasia.

BACKGROUND:Patients with inflammatory bowel disease (IBD) who have postinflammatory polyps (PIPs) may have an increased risk of developing colorectal neoplasia. Current guidelines recommend an intensified surveillance strategy in these patients, although the evidence for this recommendation is conflicting. The aim of our study was to assess whether IBD patients with PIPs are at increased risk of colorectal neoplasia.METHODS:We established a retrospective cohort in a tertiary IBD center with IBD patients undergoing colorectal cancer (CRC) surveillance in the current era. We compared cumulative incidences of colorectal neoplasia since IBD diagnosis between patients with and without PIPs and corrected for confounders. Second, we compared the risk of receiving a colectomy.RESULTS:In our cohort with >22 years of median follow-up, 154 of 519 patients had PIPs. PIPs were associated with extensive disease (odds ratio [OR], 2.76; 95% confidence interval [CI], 1.61-4.42; P < 0.001) and with more severe inflammation at colonoscopy (OR, 3.54; 95% CI, 2.28-5.50; P < 0.001). After correction for confounders, the presence of PIPs was not associated with development of colorectal neoplasia (hazard ratio [HR], 1.28; 95% CI, 0.85-1.93; P = 0.24) or with development of advanced neoplasia (HR, 1.38; 95% CI, 0.52-3.68; P = 0.52). There was a higher risk of colectomy in patients with PIPs (HR, 3.41; 95% CI, 1.55-7.54; P = 0.002).CONCLUSION:In this cohort, PIPs were associated with disease extent, inflammation, and higher rates of colectomy. However, the presence of PIPs was not associated with the development of neoplasia. These findings suggest that patients with PIPs may not need an intensified surveillance strategy.

Abstract Background and Aims The 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. Methods This 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. Results We 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. Conclusions In 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.

Increasing life expectancy and IBD incidence will result in more elderly IBD patients. There is paucity of data on safety and efficacy of anti-TNF in the elderly since this group is underrepresented in clinical studies. We aimed to compare the long-term effectiveness and safety of first anti-TNF treatment in IBD patients per age group (20–40 years/41–60 years/>60 years), by assessment of drug survival and reasons for discontinuation. Patients on first anti-TNF treatment were identified through IBDREAM, a multi-centre prospective IBD registry in 5 hospitals in the Netherlands. Data on demographics, medical history, drug survival and adverse events were extracted from IBDREAM. STATA 11.2’s competing risk regression was used to study time to drug discontinuation due to adverse events or lack of effectiveness, with discontinuation due to remission as a competing risk. The following predictors were considered in the analysis, corrected for age group: gender, IBD-type, anti-TNF type (infliximab or adalimumab), co-medication at baseline, disease duration, malignancies and surgery in medical history. A total of 895 patients were included, 679 had Crohn’s disease, 200 ulcerative colitis and 16 IBD unclassified. Male represented 42%, median age at diagnosis was 26 years (IQR 19–38) and median follow-up was 46 months (IQR 18–97). 546 patients started anti-TNF at an age between 20 and 40 (61%), 268 at age 41–60 (30%) and 81 at age >60 (9%). Infliximab was the first anti-TNF in 75%, 71%, and 67% of patients, respectively, per age group. A total of 450 patients discontinued first anti-TNF therapy, 284 (52%), 133 (50%) and 33 (41%) per group. Reasons for discontinuation were adverse events in 27%, 29% and 39%, respectively per age group, lack of effectiveness in 40%, 47% and 32% and remission in 15%, 30% and 3%. Competing-risks regression analysis, with discontinuation due to adverse events/ lack of effectiveness as the outcome of interest and discontinuation due to remission as a competing event, showed a shorter drug survival in the two older groups (subhazard rate (SHR) age >60 1.46, SHR age 41–60 1.21; p = 0.03, both SHR compared with age <40) (Figure 1). Risk factor for discontinuation was prednisone use at baseline (SHR: 2.78; p < 0.001). IBD patients starting the first anti-TNF agent at higher age showed a higher discontinuation rate due to adverse events or lack of effectiveness, with patients >60 years having the highest rate of discontinuation. Prednisone use at baseline was the only other predictor found for discontinuation. Figure 1. Cumulative incidence function of discontinuation in patients who started anti-TNF at age 20–40/41–60/>60 as estimated by the competing risk regression model.

maintenance regimen to treat IBD from 11/01/2016 to 04/30/2017 were screened and prospectively followed.Clinical and biological data, infectious events and trough level of infliximab were collected at each infusion visit.The exposure to infliximab during the study period was estimated by the area under curve (AUC) of the concentration of the drug according to a compartment model using a Bayesian approach.Then the individual exposure over the 6-month was estimated by the sum of AUC (cAUC).Independent risk factors of infection were identified by logistic regression.Results: A total of 209 patients were included: 102 men (49%), mean age 39 (±14) years old, 159 Crohn's diseases (76%) and 50 ulcerative colitis (24%).A total of 54 (26%) patients received combination therapy.The mean dose of infliximab was 455 (±197) mg, with a mean infusion interval of 8 (±1.6) weeks.The mean cAUC was 3964 (±444) mg.d/L, corresponding to a mean period of exposure to infliximab of 24.7 (±3.5) weeks.A total of 215 infections were collected from the 640 infusion visits (63 [29%] bacterial infections, 143 [67%] viral infections and 9 [4%] fungal infections).At least one infection occurred in 123 patients (59%), more than one infection in 64 patients (30 %), and 46 patients (22%) received antibiotics.Only two factors were independently associated with the occurrence of an infection after multivariate analysis: IBD activity (OR=2.7,IC95=[1.31-5.55],p=0.007) and cAUC for infliximab >5261 mg.d/L (OR= 2.28, IC95=[1.1-5.09],p= 0.04).Furthermore, the cumulated individual AUC was significantly and positively linked to the number of infections (p=0.005), the bacterial infections (p=0.023), the viral infections (p=0.024), the disease activity (p=0.007), the combination therapy (p=0.029), the absence of perianal disease (p=0.017) and the absence of prior digestive surgery (p=0.014).The trough level of infliximab at each infusion visit solely was not associated with an infection since the last infusion.Conclusions Almost two thirds of patients underwent at least one infectious event over the 6-month follow-up, and the risk of infection was linked with higher cumulative exposure to infliximab.As the cAUC accounts for the infusion interval length, it better reflects the exposure between two infusions than the trough.This result should encourage starting treatment de-escalation as soon as possible to prevent the infection risk.

Background & Aims Polycystic liver disease (PLD) occurs in two genetic disorders, autosomal-dominant polycystic kidney disease (ADPKD) and autosomal-dominant polycystic liver disease (ADPLD). The aim of this study is to compare disease severity between ADPKD and ADPLD by determining the association between diagnosis and height-adjusted total liver volume (hTLV). Methods We performed a cross-sectional analysis with hTLV as endpoint. Patients were identified from the International PLD Registry (>10 liver cysts) and included in our analysis when PLD diagnosis was made prior to September 2017, hTLV was available before volume-reducing therapy (measured on computed tomography or magnetic resonance imaging) and when patients were tertiary referred. Data from the registry were retrieved for age, diagnosis (ADPKD or ADPLD), gender, height and hTLV. Results A total of 360 patients (ADPKD n = 241; ADPLD n = 119) met our inclusion criteria. Female ADPKD patients had larger hTLV compared with ADPLD (P = 0.008). In a multivariate regression analysis, ADPKD and lower age at index CT were independently associated with larger hTLV in females, whereas in males a higher age was associated with larger hTLV. Young females (<= 51 years) had larger liver volumes compared with older females (>51 years) in ADPKD. Conclusion Aetiology is presented as a new risk factor associated with PLD severity. Young females with ADPKD represent a subgroup of PLD patients with the most severe phenotype expressed in hTLV.

Approximately 30% of patients with ulcerative colitis require a colectomy during their disease course. This substantially reduces colorectal cancer risk, although it is still possible to develop colorectal neoplasia in the remaining rectum. Although clear and well-accepted surveillance guidelines exist for patients with inflammatory bowel disease with an intact colon, specific surveillance recommendations following colectomy are less clear. Here, we aim to summarize the prevalence, incidence, and risk factors for developing colorectal cancer in patients with inflammatory bowel disease who underwent subtotal colectomy with a permanent end ileostomy and rectal stump, or with ileorectal anastomosis. Subsequently, gained insights are integrated into a proposed endoscopic surveillance strategy of the residual rectum.

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.