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.

Dynamic Prediction of Advanced Colorectal Neoplasia in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Colonoscopic surveillance is recommended in patients with colonic inflammatory bowel disease (IBD) given their increased risk of colorectal cancer (CRC). We aimed to develop and validate a dynamic prediction model for the occurrence of advanced colorectal neoplasia (aCRN, including high-grade dysplasia and CRC) in IBD. METHODS: We pooled data from 6 existing cohort studies from Canada, The Netherlands, the United Kingdom, and the United States. Patients with IBD and an indication for CRC surveillance were included if they underwent at least 1 follow-up procedure. Exclusion criteria included prior aCRN, prior colectomy, or an unclear indication for surveillance. Predictor variables were selected based on the literature. A dynamic prediction model was developed using a landmarking approach based on Cox proportional hazard modeling. Model performance was assessed with Harrell's concordance-statistic (discrimination) and by calibration curves. Generalizability across surveillance cohorts was evaluated by internal-external cross-validation. RESULTS: The surveillance cohorts comprised 3731 patients, enrolled and followed-up in the time period from 1973 to 2021, with a median follow-up period of 5.7 years (26,336 patient-years of follow-up evaluation); 146 individuals were diagnosed with aCRN. The model contained 8 predictors, with a cross-validation median concordance statistic of 0.74 and 0.75 for a 5- and 10-year prediction window, respectively. Calibration plots showed good calibration. Internal-external cross-validation results showed medium discrimination and reasonable to good calibration. CONCLUSIONS: The new prediction model showed good discrimination and calibration, however, generalizability results varied. Future research should focus on formal external validation and relate predicted aCRN risks to surveillance intervals before clinical application.

The Efficacy of an Over-the-Counter Multivitamin and Mineral Supplement to Prevent Infections in Patients With Inflammatory Bowel Disease in Remission With Immunomodulators and/or Biological Agents: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: Patients with inflammatory bowel disease (IBD) treated with immunomodulators or biologic therapy are at increased risk of infections. Malnutrition and vitamin or mineral deficiencies are common among patients with IBD. The results of various studies have indicate that vitamin deficiencies might increase the risk of infections. To evaluate the efficacy of a multivitamin and mineral supplement on the incidence of infections in patients with IBD treated with immunomodulators, biologic therapy, or combination therapy. METHODS: This was a single-center, randomized, double-blind, placebo-controlled clinical trial to compare a multivitamin and mineral supplement (supplemented group) vs identical-in-appearance placebo (placebo group) in a total of 320 non-vitamin-deficient patients with IBD (Crohn's disease or ulcerative colitis) in remission with immunomodulators, biologic therapy, or combination therapy. Participants were asked to take a daily multivitamin and mineral supplement or placebo and report the occurrence of infections during a 24-week period of follow-up. RESULTS: Treatment arms consisted of 162 and 158 patients for the supplement and placebo, respectively. In both treatment groups, 107 patients reported an infection during the 24-week follow-up period (unadjusted odds ratio, 0.93; 95% confidence interval, 0.56-1.48). In the supplemented group, 32 patients received antibiotics for an infection compared with 21 patients in the placebo group (unadjusted odds ratio, 1.61; 95% confidence interval, 0.88-2.93). CONCLUSIONS: An over-the-counter multivitamin and mineral supplement did not reduce the risk of infection for patients with IBD in remission with immunomodulators, biologic therapy, or combination therapy.

Patients with inflammatory bowel disease are at increased risk of infections due to vitamin or mineral deficiencies. An over-the-counter supplement did not reduce the risk of infection for patients with inflammatory bowel disease in remission with immunomodulators and/or biologic therapy.

Therapeutic drug monitoring of methotrexate in patients with Crohn's disease.

BACKGROUND: Therapeutic drug monitoring (TDM) has the potential to improve efficacy and diminish side effects. Measuring methotrexate-polyglutamate (MTX-PG) in erythrocytes might enable TDM for methotrexate in patients with Crohn's disease (CD). AIM: To investigate the relationship between MTX-PGs and methotrexate drug survival, efficacy and toxicity METHODS: In a multicentre prospective cohort study, patients with CD starting subcutaneous methotrexate without biologics were included and followed for 12 months. Primary outcome was subcutaneous methotrexate discontinuation or requirement for step-up therapy. Secondary outcomes included faecal calprotectin (FCP), Harvey Bradshaw Index (HBI), hepatotoxicity and gastrointestinal intolerance. Erythrocyte MTX-PGs were analysed at weeks 8, 12, 24 and 52 or upon treatment discontinuation. RESULTS: We included 80 patients with CD (mean age 55 ± 13y, 35% male) with a median FCP of 268 µg/g (IQR 73-480). After the 12-month visit, 21 patients (26%) were still on subcutaneous methotrexate monotherapy. Twenty-one patients stopped because of disease activity, 29 because of toxicity, and four for both reasons. Five patients ended study participation or stopped methotrexate for another reason. A higher MTX-PG3 concentration was associated with a higher rate of methotrexate drug survival (HR 0.86, 95% CI 0.75-0.99), lower FCP (ß -3.7, SE 1.3, p < 0.01) and with biochemical response (FCP ≤250 if baseline >250 µg/g; OR 1.1, 95% CI 1.0-1.3). Higher MTX-PGs were associated with less gastrointestinal intolerance. There was no robust association between MTX-PGs and HBI or hepatotoxicity. CONCLUSIONS: Higher MTX-PG3 concentrations are related to better methotrexate drug survival and decreased FCP levels. Therefore, MTX-PG3 could be used for TDM if a target concentration can be established.

Cost-Effectiveness Analysis of Increased Adalimumab Dose Intervals in Crohn's Disease Patients in Stable Remission: The Randomized Controlled LADI Trial.

BACKGROUND AND AIMS: We aimed to assess cost-effectiveness of increasing adalimumab dose intervals compared to the conventional dosing interval in patients with Crohn's disease [CD] in stable clinical and biochemical remission. DESIGN: We conducted a pragmatic, open-label, randomized controlled non-inferiority trial, comparing increased adalimumab intervals with the 2-weekly interval in adult CD patients in clinical remission. Quality of life was measured with the EQ-5D-5L. Costs were measured from a societal perspective. Results are shown as differences and incremental net monetary benefit [iNMB] at relevant willingness to accept [WTA] levels. RESULTS: We randomized 174 patients to the intervention [n = 113] and control [n = 61] groups. No difference was found in utility (difference: -0.017, 95% confidence interval [-0.044; 0.004]) and total costs (-€943, [-€2226; €1367]) over the 48-week study period between the two groups. Medication costs per patient were lower (-€2545, [-€2780; -€2192]) in the intervention group, but non-medication healthcare (+€474, [+€149; +€952]) and patient costs (+€365 [+€92; €1058]) were higher. Cost-utility analysis showed that the iNMB was €594 [-€2099; €2050], €69 [-€2908; €1965] and -€455 [-€4,096; €1984] at WTA levels of €20 000, €50 000 and €80 000, respectively. Increasing adalimumab dose intervals was more likely to be cost-effective at WTA levels below €53 960 per quality-adjusted life year. Above €53 960 continuing the conventional dose interval was more likely to be cost-effective. CONCLUSION: When the loss of a quality-adjusted life year is valued at less than €53 960, increasing the adalimumab dose interval is a cost-effective strategy in CD patients in stable clinical and biochemical remission. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT03172377.

Increased versus conventional adalimumab dose interval for patients with Crohn's disease in stable remission (LADI): a pragmatic, open-label, non-inferiority, randomised controlled trial.

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 <5, faecal calprotectin <150 µg/g, and C-reactive protein <10 mg/L) for at least 9 months on a stable dose of 40 mg subcutaneous adalimumab every 2 weeks. Patients were randomly assigned (2:1) to the intervention group or control group by the coordinating investigator using a secure web-based system with variable block randomisation (block sizes of 6, 9, and 12). Randomisation was stratified on concomitant use of thiopurines and methotrexate. Patients and health-care providers were not masked to group assignment. Patients allocated to the intervention group increased adalimumab dose intervals to 40 mg every 3 weeks at baseline and further to every 4 weeks if they remained in clinical and biochemical remission at week 24. Patients in the control group continued their 2-weekly dose interval. The primary outcome was the cumulative incidence of persistent flares at week 48 defined as the presence of at least two of the following criteria: HBI score of 5 or more, C-reactive protein 10 mg/L or more, and faecal calprotectin more than 250 µg/g for more than 8 weeks and a concurrent decrease in the adalimumab dose interval or start of escape medication. The non-inferiority margin was 15% on a risk difference scale. All analyses were done in the intention-to-treat and per-protocol populations. This trial was registered at ClinicalTrials.gov, NCT03172377, and is not recruiting. FINDINGS: Between May 3, 2017, and July 6, 2020, 174 patients were randomly assigned to the intervention group (n=113) or the control group (n=61). Four patients from the intervention group and one patient from the control group were excluded from the analysis for not meeting inclusion criteria. 85 (50%) of 169 participants were female and 84 (50%) were male. At week 48, the cumulative incidence of persistent flares in the intervention group (three [3%] of 109) was non-inferior compared with the control group (zero; pooled adjusted risk difference 1·86% [90% CI -0·35 to 4·07). Seven serious adverse events occurred, all in the intervention group, of which two (both patients with intestinal obstruction) were possibly related to the intervention. Per 100 person-years, 168·35 total adverse events, 59·99 infection-related adverse events, and 42·57 gastrointestinal adverse events occurred in the intervention group versus 134·67, 75·03, and 5·77 in the control group, respectively. INTERPRETATION: The individual benefit of increasing adalimumab dose intervals versus the risk of disease recurrence is a trade-off that should take patient preferences regarding medication and the risk of a flare into account. FUNDING: Netherlands Organisation for Health Research and Development.

Exposure to Thioguanine During 117 Pregnancies in Women With Inflammatory Bowel Disease.

BACKGROUND: Safety of thioguanine in pregnant patients with inflammatory bowel disease [IBD] is sparsely recorded. This study was aimed to document the safety of thioguanine during pregnancy and birth. METHODS: In this multicentre case series, IBD patients treated with thioguanine during pregnancy were included. Data regarding disease and medication history, pregnancy course, obstetric complications, and neonatal outcomes were collected. RESULTS: Data on 117 thioguanine-exposed pregnancies in 99 women were collected. Most [78%] had Crohn's disease and the mean age at delivery was 31 years. In 18 pregnancies [15%], IBD flared. Obstetric and infectious complications were seen in 15% [n = 17] and 7% [n = 8] of pregnancies, respectively. Ten pregnancies [8.5%] resulted in a first trimester miscarriage, one in a stillbirth at 22 weeks of gestational age and one in an induced abortion due to trisomy 21. In total, 109 neonates were born from 101 singleton pregnancies and four twin pregnancies. One child was born with a congenital abnormality [cleft palate]. In the singleton pregnancies, 10 children were born prematurely and 10 were born small for gestational age. Screening for myelosuppresion was performed in 16 neonates [14.7%]; two had anaemia in umbilical cord blood. All outcomes were comparable to either the general Dutch population or to data from three Dutch cohort studies on the use of conventional thiopurines in pregnant IBD patients. CONCLUSION: In this large case series, the use of thioguanine during pregnancy is not associated in excess with adverse maternal or neonatal 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.

Patients Prioritize a Low-volume Bowel Preparation in Colitis-associated Colorectal Cancer Surveillance: A Discrete Choice Experiment.

BACKGROUND: Patients with inflammatory bowel disease (IBD) undergo surveillance colonoscopies at fixed intervals to reduce the risk of colorectal cancer (CRC). Taking patients' preferences for determining surveillance strategies into account could improve adherence and patient satisfaction. This study aimed to determine patient preferences for CRC surveillance in IBD. METHODS: We conducted a web-based, multicenter, discrete choice experiment among adult IBD patients with an indication for surveillance. Individuals were repeatedly asked to choose between 3 hypothetical surveillance scenarios. The choice tasks were based on bowel preparation (0.3-4 L), CRC risk reduction (8% to 1%-6%), and interval (1-10 years). Attribute importance scores, trade-offs, and willingness to participate were calculated using a multinomial logit model. Latent class analysis was used to identify subgroups with similar preferences. RESULTS: In total, 310 of 386 sent out questionnaires were completed and included in the study. Bowel preparation was prioritized (attribute importance score 40.5%) over surveillance interval and CRC risk reduction (31.1% and 28.4%, respectively). Maximal CRC risk reduction, low-volume bowel preparation (0.3 L laxative with 2 L clear liquid) with 2-year surveillance was the most preferred combination. Three subgroups were identified: a "surveillance avoidant," "CRC risk avoidant," and "surveillance preferring" groups. Membership was correlated with age, educational level, perceived CRC risk, the burden of bowel preparation, and colonoscopies. CONCLUSIONS: Inflammatory bowel disease patients consider bowel preparation as the most important element in acceptance of CRC surveillance. Heterogeneity in preferences was explained by 3 latent subgroups. These findings may help to develop an individualized endoscopic surveillance strategy in IBD patients.

This discrete choice experiment identified volume of bowel preparation as the attribute impacting patients' preferences regarding colitis-associated colorectal cancer surveillance most. Three subgroups were identified with similar preferences and distinct clinical characteristics.

Surveillance and management of colorectal dysplasia and cancer in inflammatory bowel disease: Current practice and future perspectives.

Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC). Current guidelines recommend frequent surveillance colonoscopies for patients with at least left-sided ulcerative colitis, or Crohn's disease involving more than 30% of the colon. Surveillance allows for early detection and treatment of colorectal dysplasia and cancer. The first colonoscopy should be performed 8 to 10 years after onset of disease symptoms. European and British guidelines employ a risk-stratification algorithm that assigns patients to surveillance intervals of one, three or five years, whereas American guidelines recommend to perform surveillance every 1 to 3 years based on the (combined) presence of risk factors. Patients with concomitant primary sclerosing cholangitis are at an additionally increased risk, and should undergo annual surveillance starting immediately after the diagnosis. The current practice of surveillance is based on limited evidence, is resource intensive and cannot preclude the occurrence of interval carcinomas. Fortunately, advances in endoscopic techniques for mucosal visualisation, along with better control of inflammation, have resulted in a declining incidence of CRC in patients with IBD. Furthermore, advanced endoscopic resection techniques can be expected to result in a shift from surgical to endoscopic management of dysplastic lesions. In this review, we provide an up-to-date overview of colitis-associated CRC pathophysiology, epidemiology, surveillance practices, and management of dysplasia.

Outcome of Reverse Switching From CT-P13 to Originator Infliximab in Patients With Inflammatory Bowel Disease.

BACKGROUND: Patients suffering from inflammatory bowel diseases (IBD) and treated with originator infliximab are increasingly being switched to biosimilars. Some patients, however, are "reverse switched" to treatment with the originator. Here we assess the prevalence of reverse switching, including its indication and outcomes. METHODS: In this retrospective multicenter cohort study, data on patients with IBD from 9 hospitals in the Netherlands were collected. All adult patients with IBD were included if they previously had been switched from originator infliximab to the biosimilar CT-P13 and had a follow-up time of at least 52 weeks after the initial switch. The reasons for reverse switching were categorized into worsening gastrointestinal symptoms, adverse effects, or loss of response to CT-P13. Drug persistence was analyzed through survival analyses. RESULTS: A total of 758 patients with IBD were identified. Reverse switching was observed in 75 patients (9.9%). Patients with reverse switching were predominantly female (70.7%). Gastrointestinal symptoms (25.5%) and dermatological symptoms (21.8%) were the most commonly reported reasons for reverse switching. In 9 patients (12.0%), loss of response to CT-P13 was the reason for reverse switching. Improvement of reported symptoms was seen in 73.3% of patients after reverse switching and 7 out of 9 patients (77.8%) with loss of response regained response. Infliximab persistence was equal between patients who were reverse-switched and those who were maintained on CT-P13. CONCLUSIONS: Reverse switching occurred in 9.9% of patients, predominantly for biosimilar-attributed adverse effects. Switching back to originator infliximab seems effective in patients who experience adverse effects, worsening gastrointestinal symptoms, or loss of response after switching from originator infliximab to CT-P13.

Prognostic Factors for Advanced Colorectal Neoplasia in Inflammatory Bowel Disease: Systematic Review and Meta-analysis.

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.

Clinical Outcomes of Covid-19 in Patients With Inflammatory Bowel Disease: A Nationwide Cohort Study.

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.

Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies.

BACKGROUND: Recently reported risks of colorectal cancer (CRC) in inflammatory bowel disease (IBD) have been lower than those reported before 2000. The aim of this meta-analysis was to update the CRC risk of ulcerative and Crohn's colitis, investigate time trends, and identify high-risk modifiers. METHODS: The MEDLINE search engine was used to identify all published cohort studies on CRC risk in IBD. Publications were critically appraised for study population, Crohn's disease localization, censoring for colectomy, and patient inclusion methods. The following data were extracted: total and stratified person-years at risk, number of observed CRC, number of expected CRC in background population, time period of inclusion, and geographical location. Pooled standardized incidence ratios and cumulative risks for 10-year disease intervals were calculated. Results were corrected for colectomy and isolated small bowel Crohn's disease. RESULTS: The pooled standardized incidence ratio of CRC in all patients with IBD in population-based studies was 1.7 (95% confidence interval [CI], 1.2-2.2 ). High-risk groups were patients with extensive colitis and an IBD diagnosis before age 30 with standardized incidence ratios of 6.4 (95% confidence interval, 2.4-17.5) and 7.2 (95% confidence interval, 2.9-17.8), respectively. Cumulative risks of CRC were 1%, 2%, and 5% after 10, 20, and >20 years of disease duration, respectively. CONCLUSIONS: The risk of CRC is increased in patients with IBD but not as high as previously reported and not in all patients. This decline could be the result of aged cohorts. The risk of CRC is significantly higher in patients with longer disease duration, extensive disease, and IBD diagnosis at young age.

Disease severity does not affect the interval between IBD diagnosis and the development of CRC: results from two large, Dutch case series.

BACKGROUND: The increased risk of colorectal cancer (CRC) in patients with inflammatory bowel disease (IBD) is well established. The incidence of IBD-related CRC however, differs markedly between cohorts from referral centers and population-based studies. In the present study we aimed to identify characteristics potentially explaining these differences in two cohorts of patients with IBD-related CRC. METHODS: PALGA, a nationwide pathology network and registry in The Netherlands, was used to search for patients with IBD-associated CRC between 1990 and 2006. Patients from 7 referral hospitals and 78 general hospitals were included. Demographic and disease specific parameters were collected retrospectively using patient charts. RESULTS: A total of 281 patients with IBD-associated CRC were identified. Patients from referral hospitals had a lower median age at IBD diagnosis (26 years vs. 28 years (p=0.02)), while having more IBD-relapses before CRC diagnosis than patients from general hospitals (3.8 vs. 1.5 (p<0.01)). In patients from referral hospitals, CRC was diagnosed at a younger age (47 years vs. 51 years (p=0.01)). However, the median interval between IBD diagnosis and diagnosis of CRC was similar in both cohorts (19 years in referral hospitals vs. 17 years in general hospitals (p=0.13)). CONCLUSIONS: IBD patients diagnosed with CRC treated in referral hospitals in The Netherlands are younger at both the diagnosis of IBD and CRC than IBD patients with CRC treated in general hospitals. Although patients from referral centers appeared to have a more severe course of IBD, the interval between IBD and CRC diagnosis was similar.

Risk factors for rectal stump cancer in inflammatory bowel disease.

BACKGROUND: Patients with long-standing colitis carry an increased risk of colorectal cancer and are therefore enrolled in colonoscopic surveillance programs. It is presently not known if endoscopic surveillance of patients with colitis with a closed rectal stump after a subtotal colectomy is justified. Neither is it clear which of these patients might be at increased risk for rectal stump cancer. OBJECTIVE: The aim of this study is to identify the risk factors for rectal stump cancer. DESIGN: This investigation is a retrospective descriptive case-control study. SETTINGS: This study was conducted at tertiary referral centers in the Netherlands. PATIENTS: Colorectal cancer cases associated with inflammatory bowel disease diagnosed between 1990 and 2006 were selected in a nationwide pathology archive. Patients with rectal stump cancer were selected from this group. The pathology archive was also used to identify inflammatory bowel disease controls matched for referral center with a closed rectal stump after subtotal colectomy, but without neoplasia. Follow-up started at the date of subtotal colectomy with the formation of a rectal stump. Demographic and disease characteristics were collected at baseline. MAIN OUTCOME MEASUREMENTS: Hazard ratios with 95% confidence intervals were calculated for factors associated with the development of rectal stump cancer with the use of univariate Cox regression analysis. End points were rectal stump cancer, end of follow-up, or death. RESULTS: A total of 12 patients with rectal stump cancer and 18 matching controls without neoplasia were identified. Univariate analysis showed an association between rectal stump cancer and primary sclerosing cholangitis, and disease duration until subtotal colectomy. LIMITATIONS: This study is limited by its retrospective design, and, despite being the largest series to date, it still has a limited number of cases. CONCLUSIONS: Risk factors for rectal stump cancer in a closed rectal stump after subtotal colectomy were primary sclerosing cholangitis and disease duration until subtotal colectomy.

Easily obtainable clinical features increase the diagnostic accuracy for latent autoimmune diabetes in adults: an evidence-based report.

BACKGROUND: Latent autoimmune diabetes in adults (LADA) represents a subgroup of diabetes mellitus. LADA is characterised by adult-onset diabetes and circulating autoimmune antibodies. LADA patients may need a different therapeutic approach than the usual type 2 diabetes mellitus. When LADA is inadequately diagnosed as type 2 diabetes mellitus, LADA patients will mistakenly be exposed to a high dose of oral glucose lowering drugs and their possible side effects. AIM: To assess which clinical features predict the presence or absence of LADA in patients older than 25 years presenting with hyperglycemia. METHODS: A structured Medline and Embase search was conducted. Titles and abstracts were screened using predetermined selection criteria. Critical appraisal was based on standardized validity criteria for diagnostic research. RESULTS: One-hundred and eighty-four papers were retrieved of which after assessment of relevance and validity 2 studies remained for further analysis. One study reported a probability of LADA of 0.99 with one or two out of the following five clinical features: age at onset <50 years; acute symptoms; BMI<25 kg/m(2); a history of autoimmune disease; a family history positive for diabetes mellitus. The other study reported a probability of LADA of zero with none of the following clinical features and of 0.32 with one out of three: fasting blood glucose> or =15 mmol/l and/or HbA(1c)> or =10%; 10% reduction in body weight in the previous 3 months; BMI<25 kg/m(2). CONCLUSION: Further testing for LADA by measurement of autoimmune antibodies appears to be unnecessary in the absence of a specific set of clinical features. Before initiating therapy applying the above criteria may help to separate LADA from usual type 2 diabetes.