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.

Variation Between Hospitals in Outcomes and Costs of IBD Care: Results From the IBD Value Study.

BACKGROUND: Data on variation in outcomes and costs of the treatment of inflammatory bowel disease (IBD) can be used to identify areas for cost and quality improvement. It can also help healthcare providers learn from each other and strive for equity in care. We aimed to assess the variation in outcomes and costs of IBD care between hospitals. METHODS: We conducted a 12-month cohort study in 8 hospitals in the Netherlands. Patients with IBD who were treated with biologics and new small molecules were included. The percentage of variation in outcomes (following the International Consortium for Health Outcomes Measurement standard set) and costs attributable to the treating hospital were analyzed with intraclass correlation coefficients (ICCs) from case mix-adjusted (generalized) linear mixed models. RESULTS: We included 1010 patients (median age 45 years, 55% female). Clinicians reported high remission rates (83%), while patient-reported rates were lower (40%). During the 12-month follow-up, 5.2% of patients used prednisolone for more than 3 months. Hospital costs (outpatient, inpatient, and medication costs) were substantial (median: €8323 per 6 months), mainly attributed to advanced therapies (€6611). Most of the variation in outcomes and costs among patients could not be attributed to the treating hospitals, with ICCs typically between 0% and 2%. Instead, patient-level characteristics, often with ICCs above 50%, accounted for these variations. CONCLUSIONS: Variation in outcomes and costs cannot be used to differentiate between hospitals for quality of care. Future quality improvement initiatives should look at differences in structure and process measures of care and implement patient-level interventions to improve quality of IBD care. TRIAL REGISTRATION NUMBER: NL8276.

Variation in outcomes and costs cannot be used to differentiate between hospitals for quality of inflammatory bowel disease care. Future quality improvement initiatives should look at differences in structure and process measures and implement patient-level interventions to improve quality of inflammatory bowel disease care.

Interobserver agreement of current and new proposed endoscopic scores for postoperative recurrence in Crohn's disease.

BACKGROUND AND AIMS: The modified Rutgeerts' score (mRS) is widely used for the assessment of endoscopic postoperative recurrence (ePOR) in Crohn's disease (CD) after ileocolic resection to guide therapeutic decisions. To improve the validity and prognostic value of this endoscopic assessment, two new scores have been proposed. This study assessed the interobserver agreement of the current (mRS) and new endoscopic scores for ePOR in CD. METHODS: Sixteen Dutch academic and non-academic IBD specialists assessed endoscopic videos (n=71) of postoperative CD patients (n=66) retrieved from nine Dutch centers. Each video was assessed for the degree of inflammation by four gastroenterologists using the mRS and the new proposed endoscopic score: REMIND score (separate score of anastomosis and neoterminal ileum) and updated Rutgeerts score (assessment of lesions at the anastomotic line, ileal inlet, ileal body and neoterminal ileum). In addition, lesions at the ileal body, ileal inlet, neoterminal ileum, colonic and/or ileal blind loop were separately assessed. Interobserver agreement was assessed using Fleiss' weighted kappa. RESULTS: Fleiss' weighted kappa for the mRS was 0.67 (95% confidence interval [CI] 0.59-0.74). The weighted kappa for the REMIND score was 0.73 (95% CI 0.65-0.80) for lesions in the neoterminal ileum and 0.46 (95% CI 0.35-0.58) for anastomotic lesions. The weighted kappa for the updated Rutgeerts' score was 0.69 (95% CI 0.62-0.77). The weighted kappa for lesions in the ileal body, ileal inlet, neoterminal ileum, colonic and ileal blind loop was 0.61 (95% CI 0.49-0.73), 0.63 (95% CI 0.54-0.72), 0.61 (95% CI 0.49-0.74), 0.83 (95% CI 0.62-1.00) and 0.68 (95% CI 0.46-0.89). CONCLUSION: The interobserver agreement of the mRS is substantial. Similarly, the interobserver agreement is substantial for the updated Rutgeerts' score. According to the REMIND score, the interobserver agreement was substantial for lesions in the neoterminal ileum, whereas only moderate for anastomotic lesions. Since therapeutic decisions in clinical practice are based on these assessments and these scores are used as outcome measure in clinical studies, further improvement of the interobserver agreement is essential.

Prognostic Value of the Modified Rutgeerts Score for Long-Term Outcomes After Primary Ileocecal Resection in Crohn's Disease.

INTRODUCTION: The prognostic value of the modified Rutgeerts score (mRS) in patients with Crohn's disease (CD) needs to be further elucidated. This study assessed the prognostic value of the mRS for long-term outcomes after primary ileocecal resection in patients with CD. METHODS: Patients with CD after primary ileocecal resection with an available mRS at first postoperative ileocolonoscopy (index mRS) were retrospectively included. The primary outcome was surgical recurrence. Secondary outcomes were clinical recurrence and progression to severe endoscopic recurrence (≥i3). Cox proportional hazard models were used to assess the association between index mRS and outcomes. RESULTS: Six hundred fifty-two patients were included (mean follow-up: 6.4 years, SD: 4.6). Surgical recurrence rates were 7.7%, 5.3%, 12.9%, 19.1%, 28.8%, 47.8% for index mRS i0, i1, i2a, i2b, i3, and i4, respectively. Clinical recurrence occurred in 42.2% (i0), 53.7% (i1), 58.5% (i2a), 80.2% (i2b), 79.4% (i3), and 95.3% (i4) of patients. Progression to severe endoscopic recurrence occurred in 21.1% (i0), 33.9% (i1), 26.8% (i2a), and 33.3% (i2b) of patients. An index mRS of i2b (adjusted hazard ratio [aHR] 3.0; 1.5-5.6), i3 (aHR 4.0; 2.0-7.9) and i4 (aHR 8.0; 4.0-16.0) were associated with surgical recurrence. An index mRS of i1 (aHR 1.7; 1.2-2.4), i2a (aHR 1.7; 1.2-2.4), i2b (aHR 4.4; 3.2-6.0), i3 (aHR 3.6; 2.5-5.2), and i4 (aHR 7.3; 4.8-10.9) were associated with clinical recurrence. An index mRS of i1 (aHR 2.0; 1.1-3.7) or i2b (aHR 2.5; 1.4-4.6) was associated with progression to severe endoscopic recurrence. DISCUSSION: The increasing mRS corresponds closely with the risk of surgical and clinical recurrence. An index mRS ≥ i2b is associated with surgical recurrence, an index mRS ≥ i1 is associated with clinical recurrence, and i1 or i2b with progression to severe endoscopic recurrence. These results support tight monitoring of disease activity and treatment optimization in patients with ileal lesions and a more conservative management in patients with anastomotic lesions.

Impact of timing of primary ileocecal resection on prognosis in patients with Crohn's disease.

BACKGROUND: The advantage of early ileocecal resection after Crohn's disease diagnosis is a matter of debate. This study aims to assess the timing of ileocecal resection on prognosis, after correction for possible confounders. METHODS: Patients with Crohn's disease with primary ileocecal resection between 2000 and 2019 were included in a retrospective multicentre cohort. The primary endpoint was endoscopic recurrence (Rutgeerts score ≥i2b) within 18 months. Secondary endpoints were escalation of inflammatory bowel disease medication within 18 months and re-resection during follow-up. The association between timing of ileocecal resection and these endpoints was investigated using multivariable proportional hazard models, corrected for covariates including Montreal classification, postoperative prophylaxis, smoking, indication for surgery, medication before ileocecal resection, perianal fistulas, surgical approach, histology, length of resected segment and calendar year. RESULTS: In 822 patients ileocecal resection was performed after a median of 3.1 years (i.q.r. 0.7-8.0) after Crohn's disease diagnosis. The lowest incidence of endoscopic recurrence, escalation of inflammatory bowel disease medication and re-resection was observed for patients undergoing ileocecal resection shortly after diagnosis (0-1 months). After correction for covariates, patients with ileocecal resection at 0, 4 and 12 months after diagnosis had a cumulative incidence of 35 per cent, 48 per cent and 39 per cent for endoscopic recurrence, 20 per cent, 29 per cent and 28 per cent for escalation of inflammatory bowel disease medication and 20 per cent, 30 per cent and 34 per cent for re-resection, respectively. In the multivariable model ileocolonic disease (HR 1.39 (95 per cent c.i. 1.05 to 1.86)), microscopic inflammation of proximal and distal resection margins (HR 2.20 (95 per cent c.i. 1.21 to 3.87)) and postoperative prophylactic biological and immunomodulator (HR 0.16 (95 per cent c.i. 0.05 to 0.43)) were associated with endoscopic recurrence. CONCLUSION: The timing of ileocecal resection was not associated with a change of disease course; in the multivariable model, the postoperative recurrence was not affected by timing of ileocecal resection.

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.

Effectiveness and safety of tofacitinib for ulcerative colitis: two-year results of the ICC Registry.

BACKGROUND: Tofacitinib is an oral Janus kinase (JAK) inhibitor and is registered for the treatment of ulcerative colitis (UC). The effectiveness of tofacitinib has been evaluated up to 12 months of treatment. AIM: The aim of this study was to assess the effectiveness and safety of 24 months of tofacitinib use in UC patients in the Netherlands. METHODS: Patients initiating tofacitinib treatment were included in the ICC Registry, a nationwide, observational registry. Patients were prospectively evaluated for up to 24 months. The primary outcome was corticosteroid-free clinical remission (CSFR, Simple Clinical Colitis Activity Index [SCCAI] ≤2) at week 104. Secondary outcomes included biochemical remission (C-reactive protein (CRP) ≤5 mg/L and faecal calprotectin (FC) ≤250 µg/g), safety, and discontinuation rate. RESULTS: We included 110 patients of whom 104 (94.5%) were anti-TNF experienced. After 104 weeks of tofacitinib, 31.8% (34/107) were in CSFR, 23.4% (25/107) in biochemical remission and 18.7% (20/107) in combined clinical and biochemical remission. Of the patients in CSFR at week 52, 76.5% (26/34) remained so after 104 weeks of treatment. Sixty-one patients (55.5%) discontinued tofacitinib after a median duration of 13 weeks (IQR 7-34). The main reasons for discontinuation were non-response (59%), loss of response (14.8%), and adverse events (18%). There were 33.9 possible tofacitinib-related adverse events per 100 patient-years during follow-up. Adverse events most probably related to tofacitinib were skin reactions and headaches. There were 6.4 herpes zoster infections per 100 patient-years. CONCLUSION: Tofacitinib was effective in 31.8% of patients after 24 months of treatment.

Validation and update of a prediction model for risk of relapse after cessation of anti-TNF treatment in Crohn's disease.

BACKGROUND: Anti-tumor necrosis factor (TNF) therapy is effective for the treatment of Crohn's disease. Cessation may be considered in patients with a low risk of relapse. We aimed to externally validate and update our previously developed prediction model to estimate the risk of relapse after cessation of anti-TNF therapy. METHODS: We performed a retrospective cohort study in 17 Dutch hospitals. Crohn's disease patients in clinical, biochemical or endoscopic remission were included after anti-TNF cessation. Primary outcome was a relapse necessitating treatment. Discrimination and calibration of the previously developed model were assessed. After external validation, the model was updated. The performance of the updated prediction model was assessed in internal-external validation and by using decision curve analysis. RESULTS: 486 patients were included with a median follow-up of 1.7 years. Relapse rates were 35 and 54% after 1 and 2 years. At external validation, the discriminative ability of the prediction model was equal to that found at the development of the model [c-statistic 0.58 (95% confidence interval (CI) 0.54-0.62)], though the model was not well-calibrated on our cohort [calibration slope: 0.52 (0.28-0.76)]. After an update, a c-statistic of 0.60 (0.58-0.63) and calibration slope of 0.89 (0.69-1.09) were reported in internal-external validation. CONCLUSION: Our previously developed and updated prediction model for the risk of relapse after cessation of anti-TNF in Crohn's disease shows reasonable performance. The use of the model may support clinical decision-making to optimize patient selection in whom anti-TNF can be withdrawn. Clinical validation is ongoing in a prospective randomized trial.

Indications, Postoperative Management, and Long-term Prognosis of Crohn's Disease After Ileocecal Resection: A Multicenter Study Comparing the East and West.

BACKGROUND: The Crohn's disease (CD) phenotype differs between Asian and Western countries and may affect disease management, including decisions on surgery. This study aimed to compare the indications, postoperative management, and long-term prognosis after ileocecal resection (ICR) in Hong Kong (HK) and the Netherlands (NL). METHODS: CD patients with primary ICR between 2000 and 2019 were included. The endpoints were endoscopic (Rutgeerts score ≥i2b and/or radiologic recurrence), clinical (start or switch of inflammatory bowel disease medication), and surgical recurrences. Cumulative incidences of recurrence were estimated with a Bayesian multivariable proportional hazards model. RESULTS: Eighty HK and 822 NL patients were included. The most common indication for ICR was penetrating disease (HK: 32.5%, NL: 22.5%) in HK vs stricturing disease (HK: 32.5%, NL: 48.8%) in the NL (P < .001). Postoperative prophylaxis was prescribed to 65 (81.3%) HK patients (28 [35.0%] aminosalicylates [5-aminosalicylic acid]; 30 [37.5%] immunomodulators; 0 biologicals) vs 388 (47.1%) NL patients (67 [8.2%] 5-aminosalicylic acid; 187 [22.8%] immunomodulators; 69 [8.4%] biologicals; 50 [6.1%] combination therapy) (P < .001). Endoscopic or radiologic evaluation within 18 months was performed in 36.3% HK vs 64.1% NL (P < .001) patients. No differences between both populations were observed for endoscopic (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.24-1.21), clinical (HR, 0.91; 95% CI, 0.62-1.32), or surgical (HR, 0.61; 95% CI, 0.31-1.13) recurrence risks. CONCLUSION: The main indication for ICR in CD patients is penetrating disease in HK patients and stricturing disease in NL patients. Although considerable pre- and postoperative management differences were observed between the two geographical areas, the long-term prognosis after ICR is similar.

This is the first study reporting similar long-term prognoses after ileocecal resection in Crohn's disease in low- and high-incidence countries despite differences in Crohn's disease phenotype at diagnosis, surgical approach, indications, and pre- and postoperative management including prophylactic medication.

Ustekinuma b for Crohn's Disease: Two-Year Results of the Initiative on Crohn and Colitis (ICC) Registry, a Nationwide Prospective Observational Cohort Study.

AIMS: Ustekinumab is a monoclonal antibody that selectively targets p40, a shared subunit of the cytokines interleukin [IL]-12 and IL-23. It is registered for the treatment of inflammatory bowel diseases. We assessed the 2-year effectiveness and safety of ustekinumab in a real world, prospective cohort of patients with Crohn's disease [CD]. METHODS: Patients who started ustekinumab were prospectively enrolled in the nationwide Initiative on Crohn and Colitis [ICC] Registry. At weeks 0, 12, 24, 52 and 104, clinical remission Harvey Bradshaw Index≤ 4 points], biochemical remission (faecal calprotectin ≤ 200 µg/g and/or C-reactive protein ≤5 mg/L], perianal fistula remission, extra-intestinal manifestations, ustekinumab dosage and safety outcomes were determined. The primary outcome was corticosteroid-free clinical remission at week 104. RESULTS: In total, 252 CD patients with at least 2 years of follow-up were included. Of all included patients, the proportion of patients in corticosteroid-free clinical remission was 32.3% [81/251], 41.4% [104/251], 39% [97/249] and 34.0% [84/247] at weeks 12, 24, 52 and 104, respectively. In patients with combined clinical and biochemical disease activity at baseline [n = 122], the corticosteroid-free clinical remission rates were 23.8% [29/122], 35.2% [43/122], 40.0% [48/120] and 32.8% [39/119] at weeks 12, 24, 52 and 104, respectively. The probability of remaining on ustekinumab treatment after 52 and 104 weeks in all patients was 64.3% and 54.8%, respectively. The main reason for discontinuing treatment after 52 weeks was loss of response [66.7%]. No new safety issues were observed. CONCLUSION: After 104 weeks of ustekinumab treatment, one-third of CD patients were in corticosteroid-free clinical remission.

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.

Comorbidity, not patient age, is associated with impaired safety outcomes in vedolizumab- and ustekinumab-treated patients with inflammatory bowel disease-a prospective multicentre cohort study.

BACKGROUND: Few data are available on the effects of age and comorbidity on treatment outcomes of vedolizumab and ustekinumab in inflammatory bowel disease (IBD). AIMS: To evaluate the association between age and comorbidity with safety and effectiveness outcomes of vedolizumab and ustekinumab in IBD. METHODS: IBD patients initiating vedolizumab or ustekinumab in regular care were enrolled prospectively. Comorbidity prevalence was assessed using the Charlson Comorbidity Index (CCI). Association between age and CCI, both continuously assessed, with safety outcomes (any infection, hospitalisation, adverse events) during treatment, and effectiveness outcomes (clinical response and remission, corticosteroid-free remission, clinical remission combined with biochemical remission) after 52 weeks of treatment were evaluated. Multivariable logistic regression was used to adjust for confounders. RESULTS: We included 203 vedolizumab- and 207 ustekinumab-treated IBD patients, mean age 42.2 (SD 16.0) and 41.6 (SD 14.4). Median treatment duration 54.0 (IQR 19.9-104.0) and 48.4 (IQR 24.4-55.1) weeks, median follow-up time 104.0 (IQR 103.1-104.0) and 52.0 weeks (IQR 49.3-100.4). On vedolizumab, CCI associated independently with any infection (OR 1.387, 95% CI 1.022-1.883, P = 0.036) and hospitalisation (OR 1.586, 95% CI 1.127-2.231, P = 0.008). On ustekinumab, CCI associated independently with hospitalisation (OR 1.621, 95% CI 1.034-2.541, P = 0.035). CCI was not associated with effectiveness, and age was not associated with any outcomes. CONCLUSIONS: Comorbidity - but not age - is associated with an increased risk of hospitalisations on either treatment, and with any infection on vedolizumab. This underlines the importance of comorbidity assessment and safety monitoring of IBD patients.

Ustekinumab is associated with superior effectiveness outcomes compared to vedolizumab in Crohn's disease patients with prior failure to anti-TNF treatment.

BACKGROUND: Both vedolizumab and ustekinumab can be considered for the treatment of Crohn's disease (CD) when anti-TNF treatment fails. However, head-to-head trials are currently not available or planned. AIM: To compare vedolizumab and ustekinumab in Crohn´s disease patients in a prospective registry specifically developed for comparative studies with correction for confounders. METHODS: Crohn´s disease patients, who failed anti-TNF treatment and started vedolizumab or ustekinumab in standard care as second-line biological, were identified in the observational prospective Dutch Initiative on Crohn and Colitis Registry. Corticosteroid-free clinical remission (Harvey Bradshaw Index ≤4), biochemical remission (C-reactive protein ≤5 mg/L and fecal calprotectin ≤250 µg/g), combined corticosteroid-free clinical and biochemical remission, and safety outcomes were compared after 52 weeks of treatment. To adjust for confounding and selection bias, we used multiple logistic regression and propensity score matching. RESULTS: In total, 128 vedolizumab- and 85 ustekinumab-treated patients fulfilled the inclusion criteria. After adjusting for confounders, ustekinumab-treated patients were more likely to achieve corticosteroid-free clinical remission (odds ratio [OR]: 2.58, 95% CI: 1.36-4.90, P = 0.004), biochemical remission (OR: 2.34, 95% CI: 1.10-4.96, P = 0.027), and combined corticosteroid-free clinical and biochemical remission (OR: 2.74, 95% CI: 1.23-6.09, P = 0.014), while safety outcomes (infections: OR: 1.26, 95% CI: 0.63-2.54, P = 0.517; adverse events: OR: 1.33, 95% CI: 0.62-2.81, P = 0.464; hospitalisations: OR: 0.67, 95% CI: 0.32-1.39, P = 0.282) were comparable between the two groups. The propensity score matched cohort with sensitivity analyses showed comparable results. CONCLUSIONS: Ustekinumab was associated with superior effectiveness outcomes when compared to vedolizumab, while safety outcomes were comparable after 52 weeks of treatment in CD patients who have failed anti-TNF treatment.

Tofacitinib for ulcerative colitis: results of the prospective Dutch Initiative on Crohn and Colitis (ICC) registry.

BACKGROUND: Tofacitinib is a Janus kinase inhibitor approved for the treatment of ulcerative colitis (UC). AIM: To evaluate effectiveness, safety and use of tofacitinib in daily practice. METHODS: UC patients initiating tofacitinib were prospectively enrolled in 15 hospitals in the Netherlands. Corticosteroid-free clinical remission (short clinical colitis activity index [SCCAI] ≤2), biochemical remission (faecal calprotectin level ≤250 µg/g), combined corticosteroid-free clinical and biochemical remission, predictors of remission, safety outcomes, treatment dose and effect on lipids were determined at weeks 12 and 24. Endoscopic outcomes were evaluated in centres with routine endoscopic evaluation. RESULTS: In total, 123 UC patients (95% anti-TNF, 62% vedolizumab and 3% ustekinumab experienced) were followed for a median duration of 24 weeks (interquartile range 12-26). The proportion of patients in corticosteroid-free clinical, biochemical, and combined corticosteroid-free clinical and biochemical remission rate at week 24 was 29% (n: 22/77), 25% (n: 14/57), and 19% (n: 11/57) respectively. Endoscopic remission (Mayo = 0) was achieved in 21% of patients at week 12 (n: 7/33). Prior vedolizumab exposure was associated with reduced clinical remission (odds ratio 0.33, 95% confidence interval [CI] 0.11-0.94). At week 24, 33% (n: 14/42) of patients still on tofacitinib treatment used 10 mg twice daily. In total, 33 tofacitinib-related adverse events (89 per 100 patient years) occurred, 7 (6% of total cohort) resulted in discontinuation. Cholesterol, HDL and LDL levels increased during induction treatment by 18% (95% CI 9-26), 18% (95% CI 8-28) and 21% (95% CI 14-39) respectively. CONCLUSION: Tofacitinib is an effective treatment for UC after anti-TNF and vedolizumab failure. However, a relatively high rate of adverse events was observed resulting in discontinuation in 6% of patients.

Ustekinumab for Crohn's Disease: Results of the ICC Registry, a Nationwide Prospective Observational Cohort Study.

BACKGROUND AND AIMS: Ustekinumab is approved for the treatment of Crohn's disease [CD]. Systematically registered prospective real-world data are scarce. We therefore aimed to study the effectiveness, safety and usage of ustekinumab for CD in everyday practice. METHODS: We prospectively enrolled CD patients initiating ustekinumab in regular care between December 2016 and January 2019. Clinical (Harvey Bradshaw Index [HBI]), biochemical (C-reactive protein [CRP] and faecal calprotectin [FCP]), extra-intestinal manifestations and, peri-anal fistula activity, ustekinumab dosage, concomitant medication use, and adverse events were documented at weeks 0, 12, 24, and 52. The primary outcome was corticosteroid-free clinical remission. RESULTS: In total, 221 CD patients were included (98.6% anti-tumour necrosis factor [TNF] and 46.6% vedolizumab exposed) with a median follow-up of 52.0 weeks [interquartile range 49.3-58.4]. Corticosteroid-free clinical remission rates at weeks 24 and 52 were 38.2% and 37.1%, respectively. An initial dosing schedule of 8 weeks, compared to 12 weeks, correlated with a lower discontinuation rate [20.0% vs 42.6%, p = 0.01], but comparable corticosteroid-free clinical remission at week 52 (46.3% [q8w] vs 34.6% [q12w], p = 0.20). There was no clinical benefit of combination therapy after 52 weeks when compared to ustekinumab monotherapy [combi 40.6% vs mono 36.0%, p = 0.64]. At baseline, 28 patients had active peri-anal fistula, of whom 35.7% showed complete clinical resolution after 24 weeks. During follow-up we encountered six severe infections [3.5 per 100 patient-years], with all patients being on concomitant immunosuppressant therapies. Ustekinumab treatment discontinuation was observed in 75 [33.9%] patients mainly due to lack of response. CONCLUSION: Ustekinumab is a relatively safe and effective treatment option for CD patients with prior failure of anti-TNF and anti-integrin therapies.

Vedolizumab for Inflammatory Bowel Disease: Two-Year Results of the Initiative on Crohn and Colitis (ICC) Registry, A Nationwide Prospective Observational Cohort Study: ICC Registry - Vedolizumab.

Prospective data of vedolizumab treatment for patients with inflammatory bowel disease (IBD) beyond 1 year of treatment is scarce but needed for clinical decision making. We prospectively enrolled 310 patients with IBD (191 with Crohn's disease (CD) and 119 patients with ulcerative colitis (UC)) with a follow-up period of 104 weeks (interquartile range: 103-104) in a nationwide registry. The corticosteroid-free clinical remission rate (Harvey Bradshaw Index ≤ 4, Short Clinical Colitis Activity index ≤ 2) at weeks 52 and 104 were 28% and 19% for CD and 27% and 28% for UC, respectively. Fifty-nine percent maintained corticosteroid-free clinical remission between weeks 52 and 104. Vedolizumab with concomitant immunosuppression showed comparable effectiveness outcomes compared with vedolizumab monotherapy (week 104: 21% vs. 23%; P = 0.77), whereas 8 of 13 severe infections occurred in patients treated with concomitant immunosuppression. To conclude, the clinical effect was 19% for CD and 28% for UC after 2 years of follow-up regardless of concomitant immunosuppression.

[Gastric perforation in Eastern European economic migrants]. / Maagperforatie bij Oost-Europese arbeidsmigranten.

The general prevalence of perforated peptic ulcers is decreasing and they are, therefore, more likely to be missed. In our hospital, Eastern European migrants are overrepresented in the population of patients with perforated gastric peptic ulcers; due to a higher prevalence of Helicobacter pylori in Eastern Europe, they have a higher chance of developing gastric peptic ulcers than patients of Dutch origin. Treatment is hampered by the language barrier and low compliance rates, with patients often leaving hospital against medical advice and not showing up for follow-up appointments. These patients should, therefore, be informed by an interpreter, so that they are well educated about the disease and its treatment. Furthermore, we advise determination of the presence of H. pylori in these patients either during or directly after surgery, and, if necessary, empirical eradication of the bacteria.

Faecal Microbiota Dynamics and their Relation to Disease Course in Crohn's Disease.

BACKGROUND: Microbial shifts have been associated with disease activity in Crohn's disease [CD], but findings on specific taxa are inconsistent. This may be due to differences in applied methods and cross-sectional study designs. We prospectively examined the faecal microbiota in adult CD patients with changing or stable disease course over time. METHODS: Faeces were collected at two time-points from 15 healthy control individuals [HCs], 35 CD patients who were in remission and who maintained remission [RRs], and 22 CD patients during remission and also during subsequent exacerbation [RAs]. The microbial composition was assessed by 16S rRNA [V4] gene sequencing. RESULTS: Compared with HCs, patients with CD had a lower microbial richness [p = 0.0002] and diversity [p = 0.005]. Moreover, the microbial community structure of a subset of patients, clustered apart from HCs, was characterized by low microbial diversity and Faecalibacterium abundance. Patients within this cluster did not differ with respect to long-term disease course compared with patients with a 'healthy-appearing' microbiota.Over time, microbial richness and diversity did not change in RR versus RA patients. Although the microbial community structure of both RR and RA patients was less stable over time compared with that of HCs, no differences were observed between the patient groups [p = 0.17]; nor was the stability impacted by Montreal classification, medication use, or surgery. CONCLUSION: The altered microbiota composition and stability in CD was neither associated with disease activity nor long-term disease course, questioning its involvement in the development of an exacerbation. The aberrant microbiota composition in a subset of CD patients warrants further exploration of a more microbiota-driven etiology in this group.

Development and Validation of a Patient-reported Score to Screen for Mucosal Inflammation in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Patient-reported outcome measures [PROMs] assessing inflammatory bowel disease [IBD] activity are of interest for monitoring in clinical practice, telemedicine systems, or trials. Different PROMs for follow-up of disease activity are available; however, none was developed with endoscopy as gold standard. The objective of this study was to develop and validate a PROM to predict endoscopic disease activity, following the recommendations of the Food and Drug Administration. METHODS: During development, 178 IBD patients undergoing a colonoscopy were asked to fill out 13 clinical questions derived from the literature. During endoscopy, inflammation was assessed with the simplified endoscopic score for Crohn's disease [CD] and the Mayo endoscopic subscore for ulcerative colitis [UC]. Based on correlation with endoscopic inflammation, questions were reduced to a total of six for CD and five for UC. The newly developed Monitor IBD At Home questionnaire [MIAH] was validated in an independent cohort of 135 CD and 131 UC patients. Additionally, diagnostic accuracy of the MIAH combined with a calprotectin home test [CHT] was assessed. RESULTS: The MIAH-CD includes questions on rectal bleeding, mucus, stool frequency, urgency, fatigue, and patient-reported disease activity. The MIAH-UC contains items on rectal bleeding, stool frequency, urgency, abdominal pain, and patient-reported disease activity. Both questionnaires showed to be valid, reliable, and responsive to changes. The MIAH and CHT combined had a sensitivity, specificity, negative predictive value [NPV], and positive predicitive value [PPV] of 96.7%, 66.7%, 94.7%, and 76.3% for CD and of 88.2%, 81.4%, 95.6%, and 60.0% for UC, respectively, compared with endoscopy. CONCLUSIONS: The MIAH is the first PROM developed to predict endoscopic inflammation in IBD patients. A combination of this questionnaire and a CHT shows excellent diagnostic accuracy to screen for patients who need further assessment of disease activity, and can be used in daily practice, telemedicine systems, and trials.