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Sensor drift is a well-known disadvantage of electronic nose (eNose) technology and may affect the accuracy of diagnostic algorithms. Correction for this phenomenon is not routinely performed. The aim of this study was to investigate the influence of eNose sensor drift on the development of a disease-specific algorithm in a real-life cohort of inflammatory bowel disease patients (IBD). In this multi-center cohort, patients undergoing colonoscopy collected a fecal sample prior to bowel lavage. Mucosal disease activity was assessed based on endoscopy. Controls underwent colonoscopy for various reasons and had no endoscopic abnormalities. Fecal eNose profiles were measured using Cyranose 320®. Fecal samples of 63 IBD patients and 63 controls were measured on four subsequent days. Sensor data displayed associations with date of measurement, which was reproducible across all samples irrespective of disease state, disease activity state, disease localization and diet of participants. Based on logistic regression, corrections for sensor drift improved accuracy to differentiate between IBD patients and controls based on the significant differences of six sensors (p = 0.004; p < 0.001; p = 0.001; p = 0.028; p < 0.001 and p = 0.005) with an accuracy of 0.68. In this clinical study, short-term sensor drift affected fecal eNose profiles more profoundly than clinical features. These outcomes emphasize the importance of sensor drift correction to improve reliability and repeatability, both within and across eNose studies.

Patients with inflammatory bowel disease (IBD) produce enhanced immunoglobulin A (IgA) against the microbiota compared to healthy individuals, which has been correlated with disease severity. Since IgA complexes can potently activate myeloid cells via the IgA receptor FcαRI (CD89), excessive IgA production may contribute to IBD pathology. However, the cellular mechanisms that contribute to dysregulated IgA production in IBD are poorly understood. Here, we demonstrate that intestinal FcαRI-expressing myeloid cells (i.e., monocytes and neutrophils) are in close contact with B lymphocytes in the lamina propria of IBD patients. Furthermore, stimulation of FcαRI-on monocytes triggered production of cytokines and chemokines that regulate B-cell differentiation and migration, including interleukin-6 (IL6), interleukin-10 (IL10), tumour necrosis factor-α (TNFα), a proliferation-inducing ligand (APRIL), and chemokine ligand-20 (CCL20). In vitro, these cytokines promoted IgA isotype switching in human B cells. Moreover, when naïve B lymphocytes were cultured in vitro in the presence of FcαRI-stimulated monocytes, enhanced IgA isotype switching was observed compared to B cells that were cultured with non-stimulated monocytes. Taken together, FcαRI-activated monocytes produced a cocktail of cytokines, as well as chemokines, that stimulated IgA switching in B cells, and close contact between B cells and myeloid cells was observed in the colons of IBD patients. As such, we hypothesize that, in IBD, IgA complexes activate myeloid cells, which in turn can result in excessive IgA production, likely contributing to disease pathology. Interrupting this loop may, therefore, represent a novel therapeutic strategy.

Background and Aims: Non-invasive biomarkers are gaining interest for monitoring disease activity in patients with inflammatory bowel diseases (IBD). Fecal calprotectin is a reliable biomarker but patients often report the collection of feces being unpleasant and cumbersome. In this study, we aimed to assess if salivary calprotectin could be used as a non-invasive biomarker to determine disease activity instead of fecal calprotectin., Methods: In this cross-sectional explorative cohort study, stimulated saliva was collected from patients with an established IBD diagnosis and healthy controls. The concentration of calprotectin in saliva was determined by a particle-enhanced turbidimetric immunoassay. Intestinal disease activity was assessed with fecal calprotectin levels and the Harvey-Bradshaw Index (HBI) or Simple Clinical Colitis Activity Index (SCCAI). Missing data were handled using multiple imputation., Results: Sixty-three patients (41 Crohn's disease and 22 ulcerative colitis) and 11 controls were included. Patients had a mean fecal calprotectin of 138.78 µg/g and a median salivary calprotectin of 1.87 mg/L. No significant correlation was found between salivary calprotectin and fecal calprotectin levels (p=0.495). When patients were stratified in two subgroups based on a fecal calprotectin cut-off value of 250 µg/g, there were no significant differences in salivary calprotectin levels between both patient groups (p=0.641) and between patients and healthy controls (p=0.248). Also, salivary, and fecal calprotectin levels were not significantly different when stratifying patients in two subgroups, active disease and remission, using HBI/SCCAI scores., Conclusions: Salivary calprotectin does not correlate to fecal calprotectin and disease activity scores in patients, making it unreliable for assessing IBD activity.

Background: To timely detect myelotoxicity and hepatotoxicity, laboratory monitoring at 3-month intervals is advised throughout thiopurine maintenance treatment for IBD. However, reported incidence rates of myelotoxicity and hepatotoxicity in maintenance treatment are low., Aim: To assess incidence rates and clinical consequences of myelotoxicity and hepatotoxicity in thiopurine maintenance therapy after at least 1 year of thiopurine treatment., Methods: Retrospective analysis of therapy adjustment for laboratory toxicity in adult IBD patients after 12 consecutive months of azathioprine (AZA) or mercaptopurine monotherapy (ie baseline) between 2000 and 2016. Incidence rates of laboratory toxicity (ie myelotoxicity [leucocyte count <4.0 × 10e9/L, and/or platelet count <150 × 10e9/L] and/or hepatotoxicity (gamma-glutamyltransferase [GGT], alkaline phosphatase [AP], ALT and/or AST above ULN, excluding isolated increased AST/AP]) and associated diagnostic procedures and complications were assessed., Results: In total, 12,391 laboratory assessments were performed on 1132 patients (56% female, AZA 74%) during 3.3 years of median follow-up. Median monitoring frequency was 3.1 assessments/treatment year. Only 83/12,391 (0.7%) assessments resulted in therapy adjustment, dose reduction in 46 patients, cessation in 28 and allopurinol initiation in nine; risk of therapy adjustment was 1.9% per treatment year. Incidence rates of myelotoxicity were 7.1% (5.1% mild/1.8% moderate/0.1% severe) and hepatotoxicity 5.1% (3.8% mild/1.1% moderate/0.2% severe) per treatment year. Treatment-related complications with concurrent laboratory toxicity occurred in 12 patients (1.1%) and would not have been prevented by monitoring., Conclusion: Severe laboratory toxicity is uncommon after 1 year of thiopurine monotherapy at 4-month monitoring intervals. Therapy adjustments are rare after detection of laboratory toxicity. After 1 year of thiopurine monotherapy, laboratory monitoring may be lowered to less than a 4-month interval., (© 2020 John Wiley & Sons Ltd.)

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., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.

Purpose: The Dutch IBD Biobank aims to facilitate the discovery of predictors for individual disease course and treatment response in patients with inflammatory bowel disease (IBD). In this paper, we aim to describe the establishment of the Dutch IBD Biobank, including the facilitators and barriers to establishment. Moreover, we aim to provide a complete overview of the content of the Dutch IBD Biobank., Participants: Since 2007, every patient with IBD treated in one of the eight Dutch university medical centres is asked to participate in the Dutch IBD Biobank in which 225 standardised IBD-related data items and biomaterials, such as serum, DNA, biopsies and a stool sample, are collected., Findings to Date: As of June 2014, the Dutch IBD Biobank had enrolled 3388 patients with IBD: 2118 Crohn's disease (62.5%), 1190 ulcerative colitis (35.1%), 74 IBD-unclassified (2.2%) and 6 IBD-indeterminate (0.2%). The inclusion of patients with IBD is ongoing. The quality of the biomaterials is good and serum, DNA and biopsies have been used in newly published studies., Future Plans: The genotyping (750 000 genetic variants) of all participants of the Dutch IBD Biobank is currently ongoing, enabling more genetic research. In addition, all participants will start reporting disease activity and outcome measures using an online platform and mobile app ., Competing Interests: Competing interests: FI reports personal fees for speaking from AbbVie. AAvB reports personal fees for consultation or speaking from AbbVie, Ferring, MSD, Takeda, Tramedico and VIFOR, he is member of the Committee on Drugs of the Dutch Society for Gastroenterology (NVMDL). RKW reports unrestricted research grants from Ferring and Tramedico, and personal fees during the conduct of the study from Abbott but outside the submitted work. AEvdMdJ reports unrestricted research grants from Takeda and Abbott, and personal fees during the conduct of the study from Abbott, Takeda and Tramedico outside the submitted work. NKHdB reports unrestricted research grant from FALK outside the submitted work, personal fees for consultation or speaking from AbbVie and Teva Pharma, and he is a member of the Advisory Board of MSD., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Both, autologous and allogeneic hematopoietic stem cell transplantation (HSCT) can be used to cure or ameliorate a variety of malignant and non-malignant diseases. The rationale behind this strategy is based on the concept of immunoablation using high-dose chemotherapy, with subsequent regeneration of naive T-lymphocytes derived from reinfused hematopoietic progenitor cells. In addition, the use of HSCT allows for the administration of high-dose chemotherapy (whether or not combined with immunomodulating agents such as antithymocyte globulin) resulting in a prompt remission in therapy-refractory patients. This review gives an update of the major areas of successful uses of HSCT in non-malignant gastrointestinal disorders. A Medline search has been conducted and all relevant published data were analyzed. HSCT has been proved successful in treating refractory Crohn's disease (CD). Patients with refractory celiac disease type II and a high risk of developing enteropathy associated T-cell lymphoma have shown promising improvement. Data concerning HSCT and mesenchymal SCT in end-stage chronic liver diseases are encouraging. In refractory autoimmune gastrointestinal diseases high-dose chemotherapy followed by HSCT seems feasible and safe and might result in long-term improvement of disease activity. Mesenchymal SCT for a selected group of CD is promising and may represent a significant therapeutic alternative in treating fistulas in CD.

Aims: In immune‐mediated inflammatory diseases (IMIDs), early symptom control is a key therapeutic goal. Methotrexate (MTX) is the first‐line treatment across IMIDs. However, MTX is underutilized and suboptimally dosed, partly due to the inability of making individualized treatment decisions through therapeutic drug monitoring (TDM). To implement TDM in clinical practice, establishing a relationship between drug concentration and disease activity is paramount. In this meta‐analysis, we investigated the relationship between concentrations of MTX polyglutamates (MTX‐PG) in erythrocytes and efficacy as well as toxicity across IMIDs. Methods: Studies analysing MTX‐PG in relation to disease activity and/or toxicity were included for inflammatory arthritis (rheumatoid [RA] and juvenile idiopathic arthritis [JIA]), inflammatory bowel disease (Crohn's and ulcerative colitis) and dermatitis (psoriasis and atopic dermatitis). Meta‐analyses were performed resulting in several summary effect measures: regression coefficient (β), correlation coefficient and mean difference (of MTX‐PG in responders vs. nonresponders) for IMIDs separately and collectively. Results: Twenty‐five studies were included. In RA and JIA, higher MTX‐PG was significantly associated with lower disease activity at 3 months (β: −0.002; 95% confidence interval [CI]: −0.004 to −0.001) and after 4 months of MTX use (β: −0.003; 95% CI: −0.005 to −0.002). Similarly, higher MTX‐PG correlated with lower disease activity in psoriasis (R: −0.82; 95% CI: −0.976 to −0.102). Higher MTX‐PG was observed in RA, JIA and psoriasis responders (mean difference: 5.2 nmol/L MTX‐PGtotal; P <.01). Conclusion: We showed that higher concentrations of erythrocyte MTX‐PG were associated with lower disease activity in RA, JIA and psoriasis. These findings are an important step towards implementation of TDM for MTX treatment across IMIDs. [ABSTRACT FROM AUTHOR]

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach. [ABSTRACT FROM AUTHOR]