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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 in the near future. The aim of this study was to compare vedolizumab and ustekinumab in CD patients using a quasi-experimental study design in a prospective registry specifically developed for comparative studies. Methods CD patients who failed anti-TNF treatment and started vedolizumab or ustekinumab in standard care as second-line biological and naïve to the latter two therapies, were identified in the observational prospective ICC Registry. Corticosteroid-free clinical remission (Harvey Bradshaw Index ≤4), biochemical remission (C-reactive protein ≤5 mg/l and faecal 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 (correcting for current smoker, disease duration, complicated disease (stricturing or penetrating behaviour), prior CD-related surgery, number of prior anti-TNF treatments, HBI at baseline and biochemical disease at baseline) and propensity score matching (variables include the same variables as logistic regression analysis with addition of disease location and behaviour, corticosteroid and immunosuppressant use at baseline). Results In total, 128 vedolizumab- and 85 ustekinumab-treated patients fulfilled the inclusion criteria. By using propensity score matching, 69 vedolizumab-treated patients were matched with 69 ustekinumab-treated patients. After adjusting for confounders, ustekinumab-treated patients were more likely to achieve corticosteroid-free clinical remission (OR: 2.56, 95% CI: 1.35–4.87, p = 0.004), biochemical remission (OR: 2.22, 95% CI: 1.04–4.74, p = 0.040), and combined corticosteroid-free clinical and biochemical remission (OR: 2.58, 95% CI: 1.15–5.78, p = 0.022), 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 showed comparable results. Conclusion In this prospective, comparative analysis ustekinumab was associated with higher effectiveness outcomes of ustekinumab when compared with vedolizumab. Safety outcomes were comparable after 52 weeks of treatment in CD patients who have failed anti-TNF treatment.

Background The goal of this study was to determine long-term mortality and causes of death in patients after hospitalization for inflammatory bowel disease (IBD). Methods A cohort of patients admitted to the hospital because of IBD for the first time between 1998 and 2010 was identified by linkage of nationwide Dutch registries. Mortality risks and causes of death in Crohn’s disease (CD) and ulcerative colitis (UC) patients were compared with a large random sample of individuals from the general population. Multivariable Cox regression models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Results In total, 23,003 patients (56.1% women; mean age, 44.8 years) were hospitalized for IBD. Patients admitted for IBD had a higher risk of death than those from the general population. Adjusted HRs for 5-year all-cause mortality were 2.42 (95% CI, 1.15–5.12) and 1.45 (95% CI, 1.26–1.66) in men and women hospitalized for CD, respectively. Corresponding HRs for UC were 1.59 (95% CI, 1.39–1.83) and 1.13 (95% CI, 0.98–1.31). Mortality among patients after hospitalization for IBD decreased between 1998–2004 and 2005–2010. Patients admitted for UC had a higher risk of all-cause mortality than those admitted for CD. Inflammatory bowel disease patients died more often from (colorectal) cancer and gastrointestinal disease and less often from cardiovascular disease relative to the general population. Conclusions Mortality of patients after hospitalization for IBD has decreased over time. Causes of death in CD and UC patients differ from those in the general population., Opstelten et al. report that mortality of patients after hospital admission for inflammatory bowel disease has decreased over time. The results from this study help inform caregivers about the long-term prognosis of patients with inflammatory bowel disease requiring hospitalization.

BACKGROUND & AIMS: Higher infliximab trough levels are associated with clinical and endoscopic remission in patients with Crohn's disease (CD). We investigated pharmacodynamic features of infliximab and radiological healing. METHODS: We performed a substudy of the TAILORIX trial (patients with active luminal CD in Europe, treated with infliximab), analyzing baseline and week 54 magnetic resonance enterography (MRE) data. MREs were scored using the MaRIA score by blinded central readers. Radiologic response and remission were defined, based on MaRIA criteria in all segments, as scores below 11 and 7, respectively. We collected data on infliximab trough levels, biomarkers, and endoscopic findings. Our primary aim was to evaluate pharmacodynamic features associated with radiologic response and remission, based on MRE assessments at baseline and at 54 weeks after initiation of infliximab therapy. RESULTS: We analyzed data from 36 patients (50% female; median age 35.7 years; interquartile age range, 25.6-48.6 years; median disease duration, 1.5 months; interquartile duration range, 0.6-22.4 months). At week 54 of treatment, 36.4% of patients had a radiologic response, 30.3% of patients were in remission, and 71% had endoscopic features of remission. At baseline, there was a correlation between the CD endoscopic index of severity and MaRIA scores (κ = 0.46; P = .008), but we found no correlation at week 54 (κ = 0.06; P = .75). Radiologic remission correlated with infliximab trough level at week 14 (P = .049) when the infliximab trough level cut-off value was set at 7.8 μg/mL (area under the curve, 0.74; 75% sensitivity; 86% specificity; 90% negative predictive value; 57% positive predictive value). Radiologic response correlated with infliximab trough levels at week 14 (P = .048) when the infliximab trough level cut-off value was set at 7.8 μg/mL (area under the curve, 0.73; 70% sensitivity; 90% specificity; 86% negative predictive value; 78% positive predictive value) and with continuous pharmacologic evidence of response (infliximab trough levels above 5.0 μg/mL at all time points) (P = .034). CONCLUSIONS: In a substudy of data from the TAILORIX trial of patients with active luminal CD, we identified a relationship between exposure to infliximab and radiologic evidence of outcomes. ispartof: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY vol:19 issue:5 pages:947-+ ispartof: location:United States status: published

Background Visualizing and quantifying cellular heterogeneity is of central importance to study tissue complexity, development, and physiology and has a vital role in understanding pathologies. Mass spectrometry-based methods including imaging mass cytometry (IMC) have in recent years emerged as powerful approaches for assessing cellular heterogeneity in tissues. IMC is an innovative multiplex imaging method that combines imaging using up to 40 metal conjugated antibodies and provides distributions of protein markers in tissues with a resolution of 1 μm2 area. However, resolving the output signals of individual cells within the tissue sample, i.e., single cell segmentation, remains challenging. To address this problem, we developed MATISSE (iMaging mAss cyTometry mIcroscopy Single cell SegmEntation), a method that combines high-resolution fluorescence microscopy with the multiplex capability of IMC into a single workflow to achieve improved segmentation over the current state-of-the-art. Results MATISSE results in improved quality and quantity of segmented cells when compared to IMC-only segmentation in sections of heterogeneous tissues. Additionally, MATISSE enables more complete and accurate identification of epithelial cells, fibroblasts, and infiltrating immune cells in densely packed cellular areas in tissue sections. MATISSE has been designed based on commonly used open-access tools and regular fluorescence microscopy, allowing easy implementation by labs using multiplex IMC into their analysis methods. Conclusion MATISSE allows segmentation of densely packed cellular areas and provides a qualitative and quantitative improvement when compared to IMC-based segmentation. We expect that implementing MATISSE into tissue section analysis pipelines will yield improved cell segmentation and enable more accurate analysis of the tissue microenvironment in epithelial tissue pathologies, such as autoimmunity and cancer.

Contains fulltext : 235673.pdf (Publisher’s version ) (Open Access) 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 & aims: It is currently unclear whether reported changes in the gut microbiome are cause or consequence of inflammatory bowel disease (IBD). Therefore, we studied the gut microbiome of IBD-discordant and -concordant twin pairs, which offers the unique opportunity to assess individuals at increased risk of developing IBD, namely healthy cotwins from IBD-discordant twin pairs. Methods: Fecal samples were obtained from 99 twins (belonging to 51 twin pairs), 495 healthy age-, sex-, and body mass index–matched controls, and 99 unrelated patients with IBD. Whole-genome metagenomic shotgun sequencing was performed. Taxonomic and functional (pathways) composition was compared among healthy cotwins, IBD-twins, unrelated patients with IBD, and healthy controls with multivariable (ie, adjusted for potential confounding) generalized linear models. Results: No significant differences were observed in the relative abundance of species and pathways between healthy cotwins and their IBD-twins (false discovery rate

Background & Aims Tissue-resident memory T (Trm) cells, both of the CD4 and CD8 lineage, have been implicated in disease flares in inflammatory bowel disease. However, data are conflicting regarding the profile of human CD8+ Trm cells, with studies suggesting both proinflammatory and regulatory functions. It is crucial to understand the functional profile of these cells in the context of (new) therapeutic strategies targeting (trafficking of) gut Trm cells. Methods Here, we performed imaging mass cytometry, flow cytometry, and RNA-sequencing to compare lamina propria and intraepithelial CD103+/–CD69+CD8+ Trm cells in healthy control subjects and patients with active ileal Crohn’s disease. Results Our data revealed that lamina propria CD103+CD69+CD8+ T cells have a classical Trm cell profile with active pathways for regulating cell survival/death and cytokine signaling, whereas intraepithelial CD103+CD69+CD8+ T cells display tightly regulated innate-like cytotoxic profile. Furthermore, within lamina propria CD8+CD103– Trm cells, an Itgb2+GzmK+KLRG1+ population distinct from CD103+ CD8+ Trm cells is found. During chronic inflammation, especially intraepithelial CD103+CD69+CD8+ T cells displayed an innate proinflammatory profile with concurrent loss of homeostatic functions. Conclusions Altogether, these compartmental and inflammation-induced differences indicate that therapeutic strategies could have a different impact on the same immune cells depending on the local compartment and presence of an inflammatory milieu, and should be taken into account when investigating short- and long-term effects of new gut T cell–targeting drugs.

Contains fulltext : 220028.pdf (Publisher’s version ) (Open Access) 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.

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.

Background: The understanding of gender differences in inflammatory bowel disease (IBD) patients is an important step towards tailored treatment for the individual patient. The aim of this study was to compare disease phenotype, clinical manifestations, disease activity, and healthcare utilization between men and women with Crohn's disease (CD) and ulcerative colitis (UC).Methods: Two multicenter observational cohort studies with a prospective design were used to explore the differences between men and women regarding demographic and phenotypic characteristics and healthcare utilization. Detailed data on IBD-phenotype was mainly available from the Dutch IBD Biobank, while the COIN cohort provided healthcare utilization data.Results: In the Dutch IBD Biobank study, 2118 CD patients and 1269 UC patients were analyzed. Female CD patients were more often current smokers, and male UC patients were more often previous smokers. Early onset CD (Conclusions: Sex differences in patients with IBD include age of onset, disease location, and EIM prevalence. No large differences in therapeutic management of IBD were observed between men and women with IBD.

Background: A low vitamin D status has been put forward as a potential risk factor for the development of inflammatory bowel disease (IBD). This study investigated the association between prediagnostic circulating vitamin D concentrations and dietary intakes of vitamin D, and the risk of Crohn’s disease (CD) and ulcerative colitis (UC).Methods: Among 359,728 participants of the European Prospective Investigation into Cancer and Nutrition cohort, individuals who developed CD or UC after enrollment were identified. Each case was matched with2 controls by center, gender, age, date of recruitment, and follow-up time. At cohort entry, blood samples were collected and dietary vitamin D intakes were obtained from validated food frequency questionnaires. Serum 25-hydroxyvitamin D levels were measured using liquid chromatography-tandem mass spectrometry. Conditional logistic regression was performed to determine the odds of CD and UC.Results: Seventy-two participants developed CD and 169 participants developed UC after a median follow-up of 4.7 and 4.1 years, respectively. Compared with the lowest quartile, no associations with the 3 higher quartiles of vitamin D concentrations were observed for CD (p trend = 0.34) or UC (p trend = 0.66). Similarly, no associations were detected when serum vitamin D levels were analyzed as a continuous variable. Dietary vitamin D intakes were not associated with CD (p trend = 0.39) or UC (p trend = 0.83).Conclusions: Vitamin D status was not associated with the development of CD or UC. This does not suggest a major role for vitamin D deficiency in the etiology of IBD, although larger studies are needed to confirm these findings.

Item does not contain fulltext Nodular regenerative hyperplasia (NRH) is a poorly understood liver condition, which is increasingly recognized in thiopurine-treated patients with inflammatory bowel disease (IBD).(1) It is difficult to establish an optimal approach to NRH patients, because its manifestations are highly variable (from asymptomatic to symptoms of noncirrhotic portal hypertension [NCPH]) and the prognosis is unknown.(2) The aim of this study was to identify NRH cases in IBD patients treated with azathioprine, mercaptopurine, and/or thioguanine, and to describe its clinical course.

Background 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 Crohn’s disease (CD) and ulcerative colitis. We assessed the two-year efficacy and safety of ustekinumab in a real world, prospective cohort of CD patients. Methods CD patients who started ustekinumab in regular care were prospectively enrolled in the nationwide Initiative on Crohn and Colitis Registry. At week 0, 12, 24, 52 and 104, clinical remission (HBI ≤ 4 points), biochemical remission (fecal calprotectin (FC) ≤200 μg/g and/or CRP ≤5 mg/L), peri-anal fistula remission, extra-intestinal manifestations, ustekinumab dosage and safety outcomes were determined. Patients starting therapy less than two years ago were excluded for the current evaluation. The primary outcome was corticosteroid-free clinical remission at week 104. Results In total, 252 CD patient with at least two years of follow up were included. Of all included patients, the proportion of patients in corticosteroid-free clinical remission at week 12, 24, 52 and 104 was 32.3% (81/251), 41.4% (104/251), 39% (97/249) and 34.0% (84/247), respectively. Of the 97 patients in corticosteroid free clinical remission at week 52, 58 (59.8%) were still in corticosteroid-free clinical remission at week 104. 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 week 12, 24, 52 and 104, respectively. The probability of remaining on ustekinumab treatment after 52 and 104 weeks was 64.3% and 54.8%, respectively. There were no predictive factors associated with corticosteroid-free clinical remission at week 104 on univariate and multivariate analysis. Most common adverse events were headache, skin reaction and musculoskeletal complaints. Two patients stopped ustekinumab due to an infection after 8 and 30 weeks of treatment (mild fever syndrome and moderate upper airway infection, respectively). The main reason for discontinuing treatment after 52 weeks was loss of response (66.7%). Conclusion Ustekinumab was effective and relatively safe in our real world, prospective cohort of CD patients. After 104 weeks of ustekinumab treatment, one third of patients were in corticosteroid-free clinical remission.

Background Inflammatory bowel disease (IBD) is often managed with anti-tumour necrosis factor-α (anti-TNFα) compounds, but only few studies have reported on long-term outcomes. We aimed to determine whether the incidence of loss-of-response decreases with longer treatment duration. Methods In a multicentre, retrospective cohort study of patients with IBD who received anti-TNFα for at least 4 months between 2011-2019, we compared incidence rates of loss-of-response between different intervals of treatment duration and performed parametric survival modelling to assess changes with longer treatment duration. Cox regression analysis was performed to identify predictors of loss-of-response. Secondary outcomes included overall anti-TNFα discontinuation and dose escalation. Results We included 900 anti-TNFα treatment episodes in 746 individual patients, with up to 9 years of follow-up. During follow-up, the most frequently observed reason for anti-TNFα discontinuation was loss-of-response (Figure 1), which occurred in 231 (25.7%) episodes, with presence of anti-drug antibodies in 67/231 (29%). Within the first year, the incidence of loss-of-response was threefold higher than after four years of treatment (17.3% versus 4.7% per patient-year, p Conclusion Long-term use of anti-TNFα maintenance treatment is associated with a reduced risk of loss-of-response in patients with IBD.

Item does not contain fulltext Objective: Inflammatory bowel disease [IBD] entails a high economic burden to society. We aimed to estimate the current and future impact of the introduction of biosimilars for infliximab on IBD-related health care costs. Methods: We designed a stochastic economic model to simulate the introduction of biosimilars in IBD, using a 5-year time horizon, based on the Dutch situation. Prevalence data on ulcerative colitis [UC] and Crohn's disease [CD] and IBD-related health care costs data were used as input. Assumptions were made on price reductions of anti-tumour necrosis factor [TNF] therapy, increase of anti-TNF prescription rate, and development of hospitalization costs. The base case scenario included a gradual decrease in prices of biosimilars up to 60%, a gradual decrease in prices of original anti-TNF compounds up to 50%, and an annual increase of anti-TNF prescription rate of 1%, and this was compared with no introduction of biosimilars. Sensitivity analyses were performed. Results: For the base case, cost savings over the total of 5 years were on average euro9,850 per CD patient and euro2,250 per UC patient, yielding in euro493 million total cost savings [a reduction of 28%] for The Netherlands. Results were predominantly determined by price reduction of anti-TNF therapy, threshold price reduction at which physicians switch patients towards biosimilars and the extent to which switching will take place. Conclusions: The introduction of biosimilars for infliximab can be expected to have a major impact on the cost profile of IBD. The economic impact will depend on local pricing, procurement policies and the physician's willingness to switch patients to biosimilars.

Background Treatment of patients with ileocaecal Crohn's disease who have not responded to conventional therapy is commonly scaled up to biological agents, but surgery can also offer excellent short-term and long-term results. We compared laparoscopic ileocaecal resection with infliximab to assess how they affect health-related quality of life. Methods In this randomised controlled, open-label trial, in 29 teaching hospitals and tertiary care centres in the Netherlands and the UK, adults with non-stricturing, ileocaecal Crohn's disease, in whom conventional therapy has failed were randomly allocated (1:1) by an internet randomisation module with biased-coin minimisation for participating centres and perianal fistula to receive laparoscopic ileocaecal resection or infliximab. Eligible patients were aged 18–80 years, had active Crohn's disease of the terminal ileum, and had not responded to at least 3 months of conventional therapy with glucocorticosteroids, thiopurines, or methotrexate. Patients with diseased terminal ileum longer than 40 cm or abdominal abscesses were excluded. The primary outcome was quality of life on the Inflammatory Bowel Disease Questionnaire (IBDQ) at 12 months. Secondary outcomes were general quality of life, measured by the Short Form-36 (SF-36) health survey and its physical and mental component subscales, days unable to participate in social life, days on sick leave, morbidity (additional procedures and hospital admissions), and body image and cosmesis. Analyses of the primary outcome were done in the intention-to-treat population, and safety analyses were done in the per-protocol population. This trial is registered at the Dutch Trial Registry (NTR1150). Findings Between May 2, 2008, and October 14, 2015, 73 patients were allocated to have resection and 70 to receive infliximab. Corrected for baseline differences, the mean IBDQ score at 12 months was 178·1 (95% CI 171·1–185·0) in the resection group versus 172·0 (164·3–179·6) in the infliximab group (mean difference 6·1 points, 95% CI −4·2 to 16·4; p=0·25). At 12 months, the mean SF-36 total score was 112·1 (95% CI 108·0–116·2) in the resection group versus 106·5 (102·1–110·9) in the infliximab group (mean difference 5·6, 95% CI −0·4 to 11·6), the mean physical component score was 47·7 (45·7–49·7) versus 44·6 (42·5–46·8; mean difference 3·1, 4·2 to 6·0), and the mean mental component score was 49·5 (47·0–52·1) versus 46·1 (43·3–48·9; mean difference 3·5, −0·3 to 7·3). Mean numbers of days of sick leave were 3·4 days (SD 7·1) in the resection group versus 1·4 days (4·7) in the infliximab group (p

Background and aim Vulval Crohn's disease (VCD) is a rare extraintestinal cutaneous manifestation of Crohn's disease. No consensus on the diagnostic workup and therapeutic management of this condition has been provided in the current literature. Patients and methods Retrospective, multicentre descriptive case series of female patients diagnosed and treated with VCD. By chart review, data on initial symptoms, clinical courses, histologic findings and therapeutic management were collected. Results Fifteen female patients with a median age of 28 years (interquartile range: 28-44 years) suffering from Crohn's disease of the ileum (27%), colon (33%) and ileocolon (40%) were included. VCD manifested most frequently with vulval swelling (93%), pain (80%) and erythema (73%). Histologic analysis demonstrated granulomatous inflammation in 78% and a mixed inflammatory cell infiltrate in 67% of cases. In eight (53%) cases, topical therapy resulted in temporary reduction of vulval symptoms. Combotreatment with immunosuppressive agents and tumour necrosis factor a inhibitors was the most effective second-line therapy: five (33%) patients achieved sustained clinical remission with this therapeutic strategy. Conclusion The diagnostic workup of VCD is challenging and should be approached in a multidisciplinary manner. Histopathologic analysis of the vulva supports the diagnosis. Topical therapy and systemic treatment with immunosuppressive agents and tumour necrosis factor a inhibitors are advised to treat this condition. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved

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

Background The pathogenesis of inflammatory bowel disease (IBD) is thought to result from an interplay between microbiota, the immune system and the environment in genetically susceptible hosts. Immunoglobulin A (IgA) produced by the immune system can be specifically directed against bacteria. The IgA-coating pattern of intestinal bacteria thus reflects interactions between the immune system and specific bacteria. Studying IBD in twins, concordant and discordant for IBD, reduces the impact of genetic predisposition and childhood exposures and therefore offers the unique opportunity to focus on other factors such as intestinal microbiota composition and immune-interactions in IBD. Methods Faecal samples from twin pairs discordant for Crohn’s disease (CD) or ulcerative colitis (UC) were collected. Employing fluorescence-activated cell sorting, IgA+ and IgA− bacteria from the intestinal microbiota were sorted. Subsequently, (1) the total, (2) IgA+ and (3) IgA− microbial composition was determined by 16S rRNA sequencing (IgA-SEQ). We estimated the relative IgA coating per bacterial species by dividing the abundance of that species in the IgA+ fraction over the abundance in the IgA- fraction, representing the IgA coating index. Linear discriminant analyses were performed with LefSE. Results We included 31 twin pairs (62 individuals) discordant for IBD (CD: 15, UC: 16). 15/32 twin pairs were monozygotic, 43/62 of participants were female, the median age was 47 years (interquartile range: 34–58.5). Of 31 participants with IBD, 7 had signs of active inflammation based on endoscopy, Harvey–Bradshaw index or short clinical colitis activity index. Differences (log-linear discriminant analysis score >3) in the microbial composition of IgA-coated bacteria were observed between CD patients and their twin-siblings not affected by IBD: Dorea formicigenerans (increased in IgA coating), Parabacteroides sp., Christensenellaceae sp., Clostridium sp. and Mollicutes RF39 sp. (decreased in IgA coating). In ulcerative colitis patients, an increase in IgA-coating was observed for Ruminococcus gnavus and Dorea formicigenerans, while Turicibacter sp., Barnesiellaceae sp. and an unclassified Clostridiales sp. were decreased in IgA-coating compared with their twin-siblings not affected by IBD. Conclusion In twins affected by IBD, the pattern of IgA-coated bacteria differs between IBD and non-IBD affected individuals. These data on immune-bacteria interactions could serve as a starting point for the elucidation of the immune-responses triggered by specific bacteria in IBD.

Background In current clinical practice, patients with inflammatory bowel disease (IBD) treated with originator infliximab (IFX) have been or are being switched to biosimilar infliximab (CT-P13) because of lower costs and seemingly similar effectiveness of biosimilars. Over a one-year follow-up, 7%-26% of the patients discontinue CT-P13 treatment. Common reasons for CT-P13 discontinuation are (subjective) loss of response or adverse events. As a result of these newly experienced symptoms, patients are occasionally switched back to treatment with originator IFX. However, not much is currently known regarding reverse switching to originator IFX. We aimed to assess the prevalence of and the specific reasons for reverse switching to originator infliximab within 52-weeks after an initial conversion from originator infliximab to CT-P13 in patients with IBD. Additionally, we evaluated whether reinitiating originator infliximab led to the desired favourable effect and sustained infliximab use. Methods In this retrospective, multicentre cohort study, data of IBD patients from eight hospitals in the Netherlands were collected. Adult patients with IBD were eligible for inclusion if they were switched from infliximab originator to CT-P13 and had a follow-up time of at least 52 weeks after initial conversion. Reasons for re-switching were categorised into adverse events or loss of response on the biosimilar. Drug survival was analysed with a time-varying Cox proportional hazards model. Results A total of 684 patients with IBD were switched (516 Crohn’s disease, 168 ulcerative colitis). Reverse switching was seen in 74 (10.8%) patients after a median of 140 days (IQR 86–231). Reverse switchers were more often females (70.3% vs. 49.7%, p < 0.001) and had shorter originator treatment (4.0 [IQR 2.6–6.5] vs. 5.2 [IQR 3.0–7.5] years, p = 0.037) than those who stayed on CT-P13. A total of 105 symptoms for switching were reported. IBD-like symptoms (25.7%) and dermatological symptoms (21.9%) were the most common. Four patients had objectified loss of response. All regained response after switching back. IBD-like symptoms and dermatological symptoms were reversible in 74.1% and 87%, respectively. Overall reversibility of symptoms was 73.3%. Cox proportional hazards model with CT-P13/originator infliximab as time-varying covariate, yielded no difference in survival risk (hazard ratio 1.23, 95% CI 0.65–2.33). Conclusion Switching back to originator infliximab seems effective in patients with IBD, who experience adverse effects or loss of response after switching from originator to CT-P13. Switching patients back to originator infliximab might, therefore, be justified in case patients experience new side effects or loss of response after switching to CT-P13.

Background & Aims: Endoscopic healing, an important target of treatment for Crohn's disease (CD), requires ileocolonoscopy, which is costly and burdensome. We investigated whether published noninvasive models (based on symptoms and biomarkers) to evaluate CD activity have sufficient accuracy to replace ileocolonoscopy. Methods: We performed a systematic review of published noninvasive diagnostic models to evaluate CD activity that used endoscopic features of activity (endoscopic activity) or healing as the reference standard. We externally validated these models for the outcome endoscopic activity (CD endoscopic index of severity scores, ≥3) using data from the a randomized controlled trial investigating tailored treatment with infliximab for active luminal Crohn's disease (TAILORIX) study (346 ileocolonoscopies in 155 patients) and the Utrecht Activity Index (UAI) study (93 ileocolonoscopies in 82 patients). We calculated the area under the receiver operating characteristic curves (AUROCs) for the models using data from these studies, and compared the performance of these models against measurements of fecal calprotectin (FC) and C-reactive protein (CRP). Results: We screened 5303 articles and identified 27 models (from 21 studies) for our analysis. Seven models could be validated externally; in the TAILORIX data set, these models identified patients with endoscopic activity with AUROC values ranging from 0.61 (95% CI, 0.51–0.70) to 0.81 (95% CI, 0.76–0.86). In this data set, the AUROC value for FC concentration was 0.79 (95% CI, 0.74–0.85) and the AUROC value for CRP level was 0.72 (95% CI, 0.66–0.77). The AUROC values for the validation in the UAI data set were similar. In the TAILORIX and/or UAI data set, 4 of the 7 models, as well as the FC and CRP assays, were able to identify patients with endoscopic activity with positive predictive values of 90% or more. Two of the 7 models (but not the FC or CRP values) identified patients without endoscopic activity with a negative predictive value (NPV) of 90% or more, leading to correct prediction of endoscopic healing in 3.2% to 11.3% of all patients. For example, applying the Herranz–Bachiller model (1 of 7 models) at a NPV of 92.1% and a positive predictive value of 91.9% correctly identified 35.7% of all patients in whom ileocolonoscopy could be avoided for expected endoscopic activity or healing but incorrectly identified 3.2% of all patients. Most ileocolonoscopies (66.5% in TAILORIX and 72.6% in the UAI of all ileocolonoscopies) could be avoided correctly based on concentrations of FC of 100 μg/g or less and 250 μg/g or higher. However, using this range of FC concentrations to identify patients who do not require ileocolonoscopy caused 18.7% of all patients in the TAILORIX cohort and 19.8% of all patients in the UAI cohort to be predicted incorrectly to have endoscopic activity or healing. Conclusions: In a systematic review and external validation of noninvasive models to identify patients with endoscopic activity of CD, we found only 2 of 7 models evaluated to have NPVs of 90% or more, however, leading to correctly predicted EH in only a small proportion of patients. Ileocolonoscopy therefore remains the mainstay to evaluate CD mucosal disease activity and healing.

Item does not contain fulltext BACKGROUND AND AIMS: Individuals with inflammatory bowel disease (IBD) often hold strong beliefs on how diet impacts their disease. This study aimed to compare dietary intakes between IBD patients and individuals from the general population and to assess associations of dietary factors with relapse in patients with IBD. METHODS: Patients with longstanding Crohn's disease and ulcerative colitis (n = 165) filled out food frequency questionnaires, as did individuals participating in a Dutch population-based study (controls) (n = 1469). Multivariable regression analyses were used to assess differences in habitual dietary intake between IBD patients and controls, and to estimate associations of dietary factors in patients in remission with the development of disease relapse at follow-up. RESULTS: IBD patients had higher intakes of animal protein (3.50 g/d, 95% confidence interval (CI) 1.67-5.34) and carbohydrate (10.1 g/d, 95% CI 5.23-14.9) than controls and lower intakes of (unsaturated) fat (-3.53 g/d, 95% CI -5.57- -1.50), dietary fiber (-2.19 g/d, 95% CI -3.05- -1.32) and alcohol (-0.84 g/d, 95% CI -1.46- -0.22). This was explained by a higher consumption of carbonated beverages, meat and poultry and lower consumption of fruit, vegetables and dairy products (except cheese) by IBD patients compared with controls. Several dietary factors, particularly (saturated) fat and fiber, appeared to be associated with risk of relapse. CONCLUSIONS: IBD patients had higher dietary intakes of (animal) protein and carbohydrate and lower intakes of (unsaturated) fat, dietary fiber and alcohol compared with a general Dutch population. The results further underscore that dietary factors may have a role in disease course.

ObjectivesSurveillance 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.DesignA 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.ResultsOf 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.ConclusionWithin 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.

Background & Aims Patients with inflammatory bowel diseases who have postinflammatory polyps (PIPs) have an increased risk of colorectal neoplasia (CRN). European guidelines propose that patients with PIPs receive more frequent surveillance colonoscopies, despite limited evidence of this increased risk. We aimed to define the risk of CRN and colectomy in patients with inflammatory bowel diseases and PIPs. Methods We conducted a multicenter retrospective cohort study of patients with inflammatory bowel diseases who underwent colonoscopic surveillance for CRN, from January 1997 through January 2017, at 5 academic hospitals and 2 large nonacademic hospitals in New York or the Netherlands. Eligible patients had confirmed colonic disease with duration of at least 8 years (or any duration, if they also had primary sclerosing cholangitis) and no history of advanced CRN (high-grade dysplasia or colorectal cancer) or colectomy. The primary outcome was occurrence of advanced CRN according to PIP status; secondary outcomes were occurrence of CRN (inclusive of low-grade dysplasia) and colectomy. Results Of 1582 eligible patients, 462 (29.2%) had PIPs. PIPs were associated with more severe inflammation (adjusted odds ratio 1.32; 95% confidence interval [CI] 1.13–1.55), greater disease extent (adjusted odds ratio 1.92; 95% CI 1.34–2.74), and lower likelihood of primary sclerosing cholangitis (adjusted odds ratio 0.38; 95% CI 0.26–0.55). During a median follow-up period of 4.8 years, the time until development of advanced CRN did not differ significantly between patients with and those without PIPs. PIPs did not independently increase the risk of advanced CRN (adjusted hazard ratio 1.17; 95% CI 0.59–2.31). The colectomy rate was significantly higher in patients with PIPs (P = .01). Conclusions In a retrospective analysis of data from 2 large independent surveillance cohorts, PIPs were associated with greater severity and extent of colon inflammation and higher rates of colectomy, but were not associated with development of any degree of CRN. Therefore, intervals for surveillance should not be shortened based solely on the presence of PIPs.

Background In rheumatoid arthritis and psoriasis female sex has been shown to be associated with discontinuation of anti-tumour necrosis factor-α (TNF-α) therapy. Aim To retrospectively assess the association between sex and TNF-α drug persistence in patients with inflammatory bowel disease (IBD). Methods All IBD patients on anti-TNF-α therapy with a minimum follow-up of 12 months in a single tertiary centre were identified. Patient and treatment characteristics and reasons for anti-TNF-α discontinuation were recorded. Overall and cause-specific drug persistence was analysed with Kaplan-Meier followed by Cox proportional hazards regression models. Results We included 529 patients (49.9% male) with 631 treatment episodes (2280 anti-TNF-α treatment years) and 289 discontinuations of therapy. Female sex (adjusted hazard ratio [aHR] 1.42, 95% confidence interval [CI] 1.16-1.74), greater age at start of therapy per decade (aHR 1.15, 95% CI 1.04-1.27] and dose escalation (aHR 3.74, 95% CI 2.78-5.02) were associated with TNF-α inhibitor discontinuation. Total cohort cause-specific analysis identified female sex to be associated with side effects (aHR 4.05, 95% CI 2.36-6.98) but not to other discontinuation reasons. Adalimumab (aHR 1.70, 95% CI 1.11-2.60) and golimumab (aHR 4.97, 95% CI 2.30-10.74) use and dose-escalation (aHR 7.71, 95% CI 5.28-11.26) were associated with secondary loss of response. Conclusion Drug persistence of anti-TNF-α therapy is lower in females as compared to males, mainly because of higher rates of side effects in females. Understanding the sex specific differences in effectiveness and safety of anti-TNF-α compounds can aid physicians in clinical decision-making.

Contains fulltext : 205172.pdf (Publisher’s version ) (Closed access) Background: Patients with refractory inflammatory bowel disease (IBD) might require a subtotal colectomy with construction of an ileostomy. Due to the risk of nerve damage and pelvic sepsis, the diverted rectum is often left in situ. Evidence on long-term complications of this rectal stump is limited, particularly in patients with Crohn's disease (CD). In addition to the risk of development of neoplasia, diversion proctitis is a frequently reported rectal stump associated complication. Surprisingly, clear recommendations concerning rectal stump surveillance and timing of proctectomy are lacking. Methods: Through the use of a pathology database and a review of medical records, we established a cohort of IBD patients with a diverted rectum. Among these patients, long-term complications of the rectal stump were identified. Main endpoint was advanced neoplasia (carcinoma or high-grade dysplasia [HGD]) in the rectal stump. Risk factors for advanced neoplasia were identified using Cox regression modeling. In the second, prospective part of the study, a questionnaire was sent out to 165 patients with either a rectal stump in situ or who had undergone a proctectomy, in order to identify differences in patient-reported outcome measures associated with the excision of the rectal stump. Results: From 530 patients with IBD and a (temporal) diversion of the rectum, we included 250 patients in whom the rectal stump was left in situ for more than 12 months. The majority of patients was female (61%) and had Crohn's disease (67%). On follow-up (median 8 years), 8 carcinomas, 2 cases of high-grade dysplasia, and 7 cases of low-grade dysplasia were found with incidence rates of 3.9 and 8.5 per 1000 patient-years of follow-up for cancer and all neoplasia, respectively. The 8 cases of rectal stump cancer (RSC) were diagnosed after a median of 15 years after colectomy. A history of colorectal neoplasia was associated with advanced rectal stump neoplasia. Out of 191 patients with endoscopic follow-up, rectal stump inflammation occurred in 161 (88.5%) patients. Results of the questionnaire did not show a significant difference in quality of life between patients with and patients without a rectal stump, although the latter group reported significantly more sexual and urinary symptoms than patients with a rectal stump in situ. The majority of rectal stump patients reported rectal blood loss, but 65.5% of them were not or barely limited in daily life by their rectal stumprelated problems. Conclusion: Rectal stump cancer has a low incidence rate, with patients with a history of colonic neoplasia carrying the highest risk of developing this severe complication. We observed no significant differences in quality of life between rectal stump and postproctectomy patients, but proctectomy surgery is associated with sexual and urinary complications.

BackgroundIleocaecal resection is the most commonly performed operation for Crohn’s disease (CD), but it is presently unclear if this affects the gut microbiome. This study aims to compare the gut microbiota composition between CD patients with and without an ileocaecal resection.MethodsStool samples and clinical data were collected from 30 patients with ileal CD in remission with a history of ileocaecal resection and without previous bowel surgery (control group), matched for gender and age. The faecal microbiota composition was characterised by 16S ribosomal RNA sequencing. Microbial diversity was assessed using the Shannon index and principal component analysis. Taxonomic differences between the two groups were determined using the statistical framework analysis of composition of microbiomes (ANCOM).ResultsIn total, 15 patients with and 15 patients without a previous ileocaecal resection were included. The median time between surgery and study enrolment was 12 years. Gut microbial diversity was significantly reduced in patients who underwent an ileocaecal resection compared with the control group. This was accompanied by an increased relative abundance of the family Veillonellaceae and a decreased relative abundance of the family Ruminococcaceae and the genus Faecalibacterium in patients with a history of an ileocaecal resection.ConclusionsGut microbial diversity is decreased in ileal CD patients who previously underwent an ileocaecal resection relative to ileal CD patients without a history of intestinal resection. This is associated with differences in the proportion of several bacterial taxa and suggests that ileocaecal resection has a profound impact on the gut microbiota in patients with CD.

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 and preference heterogeneity for CRC surveillance in IBD. Methods We conducted a web-based, multicentre, discrete choice experiment among adult IBD patients with an indication for surveillance, treated in two academic and one general teaching hospital in The Netherlands. Individuals were repeatedly asked to choose between three hypothetical surveillance scenarios and indicate if they would prefer this option in real-life. The choice tasks were based on bowel preparation (0.3-4L), 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, 301 of 386 questionnaires sent out were completed and included in the study. The attributes and levels in the choice tasks significantly affected patients’ preferences. Bowel preparation was the most valued attribute (importance score 40.0%), followed by surveillance interval and CRC risk reduction (respectively 30.9% and 29.0%). Maximal CRC risk reduction, low-volume bowel preparation (0.3L laxative with 2L clear liquid) with two-yearly surveillance was the most preferred combination. Patients were willing to exchange a surveillance interval from three-yearly to annually for a CRC risk reduction of 2.9%. In latent class analysis, three subgroups were identified (figure 1). Willingness to participate in CRC surveillance was high, with only five patients (1.7%) always choosing ‘no surveillance’. Perceived high burden of bowel preparation and lower age were significantly associated with the ‘laxative avoidant’ group compared to the reference group ‘surveillance preferent’ (univariable odds ratio (OR) 2.92, 95% CI (confidence interval) 1.63–5.23 and OR 0.96, 95% CI 0.94–0.98, respectively). High level of education and age significantly differed in the ‘CRC risk avoidant’ group (univariable OR 3.77, 95% CI 2.11–6.75 and 0.94, 95% CI 0.92–0.96). Figure 1: Attribute importance scores Higher scores indicate more relative importance [0=not important at all; 100=most important] Conclusion Bowel preparation is seen as the most important factor by patients in CRC surveillance in IBD. Heterogeneity in preferences can be explained by three latent subgroups. Surveillance adherence could benefit from these findings.

Background Methotrexate (MTX) is an immunomodulatory drug for patients with Crohn’s Disease (CD), used as first-line therapy, as a second-line in case of failure to thiopurine, and concomitantly with anti-TNFα agents to decrease production of anti-drug antibodies. Nevertheless, MTX is underutilised in the treatment of CD, despite its proven efficacy and good safety profile. This is for a large part due to the lack of therapeutic drug monitoring (TDM) of MTX because no stable plasma MTX levels are reached. Intracellular MTX-polyglutamates (MTX-PGs), formed after folylpolyglutamate synthetase attaches glutamate residues to MTX, could be used as a TDM tool as MTX-PG is thought to mediate MTX’s efficacy. We present the results of our cross-sectional study in CD patients, aiming to gain insight into erythrocyte MTX-PG levels. Methods CD adults on MTX treatment who visited the outpatient clinic of Amsterdam UMC between May 2019 and February 2020 were included consecutively. An established LC-ESI-MS/MS method1 was used to measure erythrocyte MTX-PGs. Results Nineteen patients were included. Mean disease duration was 17 years (SD±13.7). Montreal disease location and behaviour were as follows (n=): L1 = 2, L2 = 4, L3 = 13; B1 = 11, B2 = 5, B3 = 3. Only 4 patients had a flare according to Physician Global Assessment. Twelve patients received MTX monotherapy, whereas 7 patients were on concomitant anti-TNFα agents. The mean dose of MTX was 15.5 mg (SD±2.8) and 12 (63%) patients had subcutaneous (sc.) MTX. We successfully measured MTX-PG2-5 in 18 patients, showing substantial variability in measured concentrations of total MTX-PG(tot) and the individual species. The median MTX-PGtot was 117.1 nmol/L [min:46.4-max:358.7] with preferential accumulation of MTX-PG3 (43.1 [15.3-96.1]); the least predominant species being MTX-PG5 (9.4 [1.1-24.1]). Patients on sc. compared to oral MTX had higher MTX-PGtot levels (177.8 [58.8-358.7] vs. 93.2 [46.4-120.8] nmol/L, p=0.067) and significantly higher long-chain MTX-PG4-5 levels (55 [3.7-84.3] vs. 8.9 [2.4-15.0] nmol/L, p=0.010); see figure. Conclusion We showed that erythrocyte MTX-PGs can be measured in CD patients by tandem MS. Large variability in concentrations was demonstrated, similar to our previously published results in rheumatoid and juvenile arthritis2,3 which is a pre-requisite for MTX-PG use as a TDM tool. We showed for the first time that MTX-PG accumulation was higher in sc. MTX vs. oral MTX treatment. This work provides the first step towards establishing TDM for MTX in CD, a goal we aim to realize in our upcoming longitudinal study. References

Background There is an increasing demand of agents that can promote mucosal healing in Inflammatory Bowel Disease (IBD). Wnt/β-catenin signaling plays a critical role in epithelial regeneration and repair, and stimulating regeneration in the damaged epithelium by modulating Wnt signaling has been suggested as a potential treatment option for IBD. To guide development of Wnt modulating therapeutic molecules for IBD, an understanding of how Wnt signaling may be altered in IBD tissues is required. While earlier work showed altered Wnt pathway gene expression in UC tissues, these studies failed to consider disease conditions (moderate vs severe) and patient treatment history on expression of the Wnt family genes. These previous studies utilized RT-qPCR or microarray and did not reveal how Wnt pathway gene expression might be affected specifically in the epithelium and in the adjacent stromal stem cell niche. Here we report our work investigating expression patterns of Wnt pathway genes in UC biopsies from 12 patients with moderate and severe disease. Patients had either received no anti-TNF treatment or had gone through anti-TNF treatment and partially responded to the treatment. Methods Expression of a set of Wnt pathway genes was assessed in UC colon and rectum biopsies by RNAscope in situ hybridization and compared to expression patterns in normal control colon. The genes included the Wnt target genes AXIN2, LGR5 and RNF43, Wnt ligands and the FZD5 and LRP6 receptors enriched in the intestinal epithelium as well as key Wnt signal modulators RSPO1-4. Results Expression of Wnt target genes were mildly reduced in the UC colon epithelium, while their expression in some crypts appeared much lower. Overall expression levels of Wnt pathway genes did not differ between moderate and severe UC colon and Wnt target gene expression was more affected in the anti-TNF treated colons, which may reflect more refractory disease. Expression of FZD5, LRP6 and the key niche factor RSPO2, was reduced in the UC colon. RSPOs are normally expressed in the stromal cells next to the crypt bottom stem cell compartment but this expression pattern was disrupted in the UC colon as a result of immune cell infiltration. Although expression of Wnts was induced in the UC colon tissues, the location of expression was altered due to tissue damage, potentially making the Wnts less accessible to the intestinal stem cells. Conclusion Reduced expression of Wnt receptors, RSPOs and Wnt target genes indicate insufficient Wnt signal induction in the damaged colon epithelium of UC patients. This suggests that repair of the damaged epithelium by Wnt agonist treatment may constitute a new mechanism of action and benefit patients with UC.

Background Combination therapy with anti-TNF compounds and immunomodulators (IMM; thiopurine or methotrexate) is superior to IMM or anti-TNF monotherapy in patients with inflammatory bowel disease (IBD). IMMs are frequently discontinued during the maintenance phase to mitigate the risk of adverse events, but long-term consequences of this practice are not well studied. We explored the real-world outcomes after IMM discontinuation, including loss-of-response (LOR), dose escalations, immunogenicity and trough levels. Methods This was a multicenter, retrospective cohort study in a general hospital and a tertiary referral center. We included adult patients with IBD, treated >4 months with infliximab (IFX) or adalimumab (ADA) and an IMM at baseline between 2011–2019. The IMM had to be started within 30 days of anti-TNF initiation, or continued for >30 days in case of prior IMM monotherapy. LOR was defined as anti-TNF discontinuation due to disease activity. Adjusted hazards rates (aHR) were calculated using mixed-effects Cox regression analysis with time-varying covariates, accounting for follow-up prior to and after IMM cessation. We adjusted for sex, age, BMI, smoking, Crohn’s disease (CD) vs ulcerative colitis (UC), disease duration, primary sclerosing cholangitis, rheumatological comorbidity, ADA vs IFX, and prior anti-TNF exposure. Results We included 615 episodes of combination therapy (543 individual patients; CD, n=382, 70%). The IMM was discontinued in 296 (48%) episodes after a median of 0.9 (IQR: 0.6 – 2.1) years, at which point 252 (85%) patients were in clinical remission. IMM withdrawal was performed as part of a de-escalation strategy (n=158, 53%), for intolerance (n=86, 29%) or for miscellaneous reasons (n=52, 18%). During a median follow-up of 1.7 (IQR 0.8 – 3.5) years after IMM withdrawal, 46 (16%) patients experienced LOR, 79 (32%) required dose-escalation and 31 (10.3%) developed anti-drug antibodies. Compared to IMM continuation, withdrawal did not significantly increase the risk of LOR (aHR 1.10, 95%CI: 0.74 – 1.64), but more patients required dose escalations (aHR 1.42, 95%CI 1.02 – 1.97) or developed anti-drug antibodies (aHR 2.22, 95%CI 1.21 – 4.08). Among patients who stopped the IMM, clinical remission at IMM withdrawal was the only predictor of LOR (aHR 0.48, 95%CI 0.23 – 0.99), while higher BMI (aHR 1.09, 95%CI 1.01 – 1.17) and shorter duration of combination therapy (Figure 1, aHR 0.57 per year, 95%CI 0.33 – 0.96) increased the risk of immunogenicity. IFX, but not ADA, trough levels decreased significantly after IMM withdrawal. Conclusion Withdrawal of immunomodulators is not associated with higher risk of LOR, but does increase the risk of dose-escalation and unfavorable pharmacokinetics.

BACKGROUND & AIMS: Ulcerative proctitis (UP) refractory to 5-aminosalicylic acid (5-ASA) suppositories is a challenge to treat, often requiring step up to immunomodulator or biological therapy. Topical tacrolimus is effective and safe in patients with refractory UP. However, it is not clear how tacrolimus suppositories fit into in the treatment algorithm of UP. METHODS: We performed a randomized controlled, double-blind study at 8 hospitals in the Netherlands and Belgium from 2014 through 2017. Eighty-five patients with refractory UP (65% women) were randomly assigned to groups given once daily tacrolimus suppositories (2 mg; n = 43) or beclomethasone (3 mg; n = 42) for 4 weeks. The primary outcome was clinical response (decrease in Mayo score of 3 or more). Secondary outcomes included clinical remission, endoscopic response and remission, adverse events and quality of life. Outcomes were compared using Fisher's exact test and Mann-Whitney U test. RESULTS: Proportions of patients with clinical responses were 63% in the tacrolimus group and 59% in the beclomethasone group (P = .812); proportions of patients in clinical remission were 46% and 38%, respectively (P = .638). Proportions of patients with an endoscopic response were 68% and 60% in the tacrolimus group and in the beclomethasone group (P = .636); proportions in endoscopic remission rates were 30% and 13%, respectively (P = .092) Median increases in the inflammatory bowel disease questionnaire score were 18.0 in the tacrolimus group and 20.5 in the beclomethasone group (P = .395). Adverse event rates did not differ significantly between groups. CONCLUSIONS: In a 4-week randomized controlled trial, tacrolimus and beclomethasone suppositories induce comparable clinical and endoscopic responses in patients with UP refractory to 5-ASA. There were no significant differences in adverse events rates. Tacrolimus and beclomethasone suppositories are therefore each safe and effective treatment options for 5-ASA refractory disease. EUDRACT 2013-001259-11; Netherlands Trial Register NL4205/NTR4416. ispartof: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY vol:18 issue:8 pages:1777-+ ispartof: location:United States status: published

Background & Aims Little is known about the clinical significance of indefinite dysplasia (IND) in patients with inflammatory bowel diseases (IBD) undergoing colonoscopic surveillance for colorectal neoplasia. Methods We conducted a retrospective cohort analysis of 492 patients with colonic IBD for 8 or more years or concomitant primary sclerosing cholangitis, with no history of advanced colorectal neoplasia (high-grade dysplasia or colorectal cancer) or colectomy, undergoing colorectal neoplasia surveillance at a tertiary IBD referral center from 2001 through 2017. Subjects received consistent histopathologic grading of dysplasia. We collected data on time to development of (advanced) colorectal neoplasia or colectomy using Kaplan Meier methods. We identified factors independently associated with (advanced) colorectal neoplasia with multivariable Cox regression analysis. Results After 2149 person-years of follow-up, 53 patients (10.8%) received a diagnosis of IND without prior or synchronous low-grade dysplasia (LGD). Compared to patients without dysplasia, patients with IND had a significantly higher risk of advanced colorectal neoplasia (adjusted hazard ratio, 6.85; 95% CI, 1.78–26.4) and colorectal neoplasia (adjusted hazard ratio, 3.25; 95% CI, 1.50–7.05), but not colectomy (P = .78). Compared to IND, LGD was associated with a significantly higher risk of advanced colorectal neoplasia (P = .05). Following a diagnosis of no dysplasia, IND only, or LGD, the incidence rates of advanced colorectal neoplasia were 0.4% per patient-year, 3.1% per patient-year, and 8.4% per patient-year, respectively. Conclusions In a retrospective analysis of patients with IBD undergoing colorectal neoplasia surveillance with consistent histopathologic grading of dysplasia, IND was independently associated with a significant increase in risk of advanced colorectal neoplasia. These findings require validation and if confirmed, a reappraisal of the colorectal neoplasia surveillance guidelines.

BACKGROUND & AIMS: In the TAILORIX trial, no benefit could be shown by infliximab dose escalation based on pharmacokinetic (infliximab serum concentrations) and pharmacodynamic (biomarkers and symptoms) monitoring compared with dose escalation based on symptoms alone in patients with Crohn's disease (CD). We investigated whether integration of pharmacokinetic and pharmacodynamic monitoring can be used to evaluate responses to infliximab induction and maintenance therapy, based on findings from endoscopy. METHODS: We performed a post hoc analysis of patients with CD included in a trial to test the effects of infliximab dose escalation, based on biomarkers and serum concentrations of infliximab, on symptoms (the Study Investigating Tailored Treatment With Infliximab for Active Crohn's Disease trial; n = 122). We analyzed data from this study to determine whether concentrations of biomarkers and serum concentrations of infliximab were associated with endoscopic outcomes (n = 116). The primary end points were endoscopic response (CD endoscopic index of severity decrease ≥50% from baseline), endoscopic remission (CD endoscopic index of severity

Chronic inflammatory diseases are characterized by recurrent inflammatory attacks in the tissues mediated by autoreactive T cells. Identity and functional programming of CD8+ T cells at the target site of inflammation still remain elusive. One key question is whether, in these antigen-rich environments, chronic stimulation leads to CD8+ T cell exhaustion comparable to what is observed in infectious disease contexts. In the synovial fluid (SF) of juvenile idiopathic arthritis (JIA) patients, a model of chronic inflammation, an overrepresentation of PD-1+CD8+ T cells was found. Gene expression profiling, gene set enrichment analysis, functional studies, and extracellular flux analysis identified PD-1+CD8+ T cells as metabolically active effectors, with no sign of exhaustion. Furthermore, PD-1+CD8+ T cells were enriched for a tissue-resident memory (Trm) cell transcriptional profile and demonstrated increased clonal expansion compared with the PD-1- counterpart, suggesting antigen-driven expansion of locally adapted cells. Interestingly, this subset was also found increased in target tissues in other human chronic inflammatory diseases. These data indicate that local chronic inflammation drives the induction and expansion of CD8+ T cells endowed with potential detrimental properties. Together, these findings lay the basis for investigation of PD-1-expressing CD8+ T cell targeting strategies in human chronic inflammatory diseases.

The epithelial barrier of the gastrointestinal tract is home to numerous intraepithelial T cells (IETs). IETs are functionally adapted to the mucosal environment and are among the first adaptive immune cells to encounter microbial and dietary antigens. They possess hallmark features of tissue-resident T cells: they are long-lived nonmigratory cells capable of rapidly responding to antigen challenges independent of T cell recruitment from the periphery. Gut-resident T cells have been implicated in the relapsing and remitting course and persisting low-grade inflammation of chronic gastrointestinal diseases, including IBD and coeliac disease. So far, most data IETs have been derived from experimental animal models; however, IETs and the environmental makeup differ between mice and humans. With advances in techniques, the number of human studies has grown exponentially in the past 5 years. Here, we review the literature on the involvement of human IETs in gut homeostasis and inflammation, and how these cells are influenced by the microbiota and dietary antigens. Finally, targeting of IETs in therapeutic interventions is discussed. Broad insight into the function and role of human IETs in gut homeostasis and inflammation is essential to identify future diagnostic, prognostic and therapeutic strategies.