The enteric nervous system relays psychological stress to intestinal inflammation.

Mental health profoundly impacts inflammatory responses in the body. This is particularly apparent in inflammatory bowel disease (IBD), in which psychological stress is associated with exacerbated disease flares. Here, we discover a critical role for the enteric nervous system (ENS) in mediating the aggravating effect of chronic stress on intestinal inflammation. We find that chronically elevated levels of glucocorticoids drive the generation of an inflammatory subset of enteric glia that promotes monocyte- and TNF-mediated inflammation via CSF1. Additionally, glucocorticoids cause transcriptional immaturity in enteric neurons, acetylcholine deficiency, and dysmotility via TGF-ß2. We verify the connection between the psychological state, intestinal inflammation, and dysmotility in three cohorts of IBD patients. Together, these findings offer a mechanistic explanation for the impact of the brain on peripheral inflammation, define the ENS as a relay between psychological stress and gut inflammation, and suggest that stress management could serve as a valuable component of IBD care.

Fatigue and Physical Activity Patterns in Children With Inflammatory Bowel Disease.

OBJECTIVES: Fatigue is a common symptom in children with inflammatory bowel disease (IBD). Diagnostic tests to evaluate biological causes of fatigue commonly include markers of inflammation and hemoglobin (Hb), yet functional parameters have been inadequately studied in pediatric IBD. In this study, we compared fatigued and non-fatigued children with IBD from both a biological and functional point of view. METHODS: A cross-sectional study of 104 pediatric IBD patients with mild to moderately active IBD was conducted. Fatigued children were defined as those with a Pediatric Quality of Life Inventory Multidimensional Fatigue Scale z score <-2.0. Non-fatigued children had a z score ≥-2.0. Disease-specific quality of life (measured with IMPACT-III score), C-reactive protein (CRP), fecal calprotectin (FC), hemoglobin z score (Hb z score), and physical activity tests including 6-minute walking distance z score (6MWD z score) and triaxial accelerometry (TA) were evaluated. RESULTS: Fatigued children (n = 24) had a significant lower IMPACT-III score than non-fatigued children (n = 80). Hb z scores, CRP, FC, and 6MWD z scores were not significantly different between groups. TA was performed in 71 patients. Wear time validation requirements were met in only 31 patients. Fatigued patients spent significant shorter median time in moderate-to-vigorous activity than non-fatigued patients (18.3 vs 37.3 minutes per day, P = 0.008). CONCLUSION: Biological parameters did not discriminate fatigued from non-fatigued patients. TA possibly distinguishes fatigued from non-fatigued patients; the potential association may provide a target for interventions to combat fatigue and improve quality of life.

Decreasing Trends in Intestinal Resection and Re-Resection in Crohn's Disease: A Nationwide Cohort Study.

OBJECTIVE: To assess time trends in intestinal resection and re-resection in Crohn's disease (CD) patients. SUMMARY OF BACKGROUND DATA: CD treatment has changed considerably over the past decades. The effect of these advances on the necessity of intestinal resections and the risk of re-resection is unclear. METHODS: In this nationwide cohort study, adult CD patients with ileocolonic, small bowel, colon, or rectum resections between 1991 and 2015 were included. Data were retrieved from the Dutch nationwide network and registry of histopathology and cytopathology (PALGA). Time trends were analyzed with a broken stick model and Cox proportional hazard model with smoothing splines. RESULTS: The identified cohort comprised 8172 CD patients (3293/4879 male/female) in whom 10,315 intestinal resections were performed. The annual intestinal resection rate decreased nonlinearly from 1.9/100,000 (1991) to 0.2/100,000 (2015). A significantly steeper-decrease was observed before 1999 (slope ­0.13) as compared to subsequent years (slope ­0.03) (p<0.001). Analogous trends were observed for ileocolonic, small bowel, and colon resections. Overall cumulative risk of re-resection was 10.9% at 5 years, 18.6% at 10 years, and 28.3% at 20 years after intestinal resection. The hazard for intestinal re-resection showed a nonlinear decreasing trend, with hazard ratio 0.39 (95% confidence interval 0.36-0.44) in 2000 and hazard ratio 0.25 (95% confidence interval 0.18-0.34) in 2015 as compared to 1991. CONCLUSION: Over the past 25 years, intestinal resection rate has decreased significantly for ileocolonic, small bowel, and colonic CD. In addition, current postoperative CD patients are at 75% lower risk of intestinal re-resection.

Cost-effectiveness of Telemedicine-directed Specialized vs Standard Care for Patients With Inflammatory Bowel Diseases in a Randomized Trial.

BACKGROUND & AIMS: Telemedicine can be used to monitor determinants and outcomes of patients with chronic diseases, possibly increasing the quality and value of care. Telemedicine was found to reduce outpatient visits and hospital admissions for patients with inflammatory bowel diseases (IBD). We performed a full economic evaluation of telemedicine interventions in patients with IBD, comparing the cost-utility of telemedicine vs standard care. METHODS: We performed a randomized trial of 909 patients with IBD at 2 academic and 2 non-academic hospitals in The Netherlands. Patients were randomly assigned to groups that received telemedicine (myIBDcoach; n = 465) or standard outpatient care (n = 444) and followed for 12 months. Costs were measured from a societal perspective. Direct healthcare costs were based on actual resource use. Indirect costs comprised self-reported hours sick leave from work, intervention costs (annual license fee of €40 per patient [$45]), and utility costs (assessed using EQ5D). Cost-utility and uncertainty were estimated using the non-parametric bootstrapping method. RESULTS: Telemedicine resulted in lower mean annual costs of €547/patient [$612] (95% CI, €1029-2143 [$1150-2393]; mean costs of €9481 [$10,587] for standard care and €8924 [$9965] for telemedicine) without changing quality adjusted life years. At the Dutch threshold of €80,000 [$89,335] per quality adjusted life year, the intervention had increased incremental cost-effectiveness over standard care in 83% of replications and an incremental net monetary benefit of €707/patient [$790] (95% CI, €1241-2544 [$1386-2841]). CONCLUSIONS: Telemedicine with myIBDcoach is cost saving and has a high probability of being cost effective for patients with IBD. This self-management tool enables continuous registration of quality indicators and (patient-reported) outcomes and might help reorganize IBD care toward value-based healthcare. ClinicalTrials.gov no: NCT02173002.

The reproducibility of skeletal muscle signal intensity on routine magnetic resonance imaging in Crohn's disease.

BACKGROUND AND AIM: Myosteatosis is a prognostic factor in cancer and liver cirrhosis. It can be determined noninvasively using computed tomography or, as shown recently, by magnetic resonance (MR) imaging. The primary aim was to analyze the reproducibility of skeletal muscle signal intensity on routine MR-enterographies, as indicator of myosteatosis, in Crohn's disease (CD) and to explore the association between skeletal muscle signal intensity at diagnosis with time to intestinal resection. METHODS: CD patients undergoing MR-enterography within 6 months from diagnosis and having a maximum of 5 years follow-up were included. Skeletal muscle signal intensity was analyzed on T1-weighted fat-saturated post-contrast images. Intra-observer and inter-observer reproducibilities were assessed by intra-class correlation coefficient and Cohen's kappa. Intra-observer and inter-observer variabilities were determined by Pearson correlation coefficient and displayed by Bland-Altman plots. Time to intestinal resection was studied by Kaplan-Meier analysis. RESULTS: Median time between diagnosis and MR-enterography was 5 weeks (inter-quartile range 1-9) in 35 CD patients. Skeletal muscle signal intensity showed good intra-class correlation and substantial agreement (for intra-observer, intraclass correlation coefficient = 0.948, κ = 0.677; and inter-observer reproducibility, intraclass correlation coefficient = 0.858, κ = 0.622). Resection free survival was shorter in the low skeletal muscle signal intensity group (P = 0.037). CONCLUSION: Skeletal muscle signal intensity on routine MR-enterographies is reproducible and was associated with unfavorable disease outcome, indicating potential clinical relevance.

Telemedicine for management of inflammatory bowel disease (myIBDcoach): a pragmatic, multicentre, randomised controlled trial.

BACKGROUND: Tight and personalised control of inflammatory bowel disease in a traditional setting is challenging because of the disease complexity, high pressure on outpatient clinics, and rising incidence. We compared the effects of self-management with a telemedicine system, which was developed for all subtypes of inflammatory bowel disease, on health-care utilisation and patient-reported quality of care versus standard care. METHODS: We did this pragmatic, randomised trial in two academic and two non-academic hospitals in the Netherlands. Outpatients aged 18-75 years with inflammatory bowel disease and without an ileoanal or ileorectal pouch anastomosis, who had internet access and Dutch proficiency, were randomly assigned (1:1) to care via a telemedicine system (myIBDcoach) that monitors and registers disease activity or standard care and followed up for 12 months. Randomisation was done with a computer-generated sequence and used the minimisation method. Participants, health-care providers, and staff who assessed outcome measures were not masked to treatment allocation. Primary outcomes were the number of outpatient visits and patient-reported quality of care (assessed by visual analogue scale score 0-10). Safety endpoints were the numbers of flares, corticosteroid courses, hospital admissions, emergency visits, and surgeries. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02173002. FINDINGS: Between Sept 9, 2014, and May 18, 2015, 909 patients were randomly assigned to telemedicine (n=465) or standard care (n=444). At 12 months, the mean number of outpatient visits to the gastroenterologist or nurse was significantly lower in the telemedicine group (1·55 [SD 1·50]) than in the standard care group (2·34 [1·64]; difference -0·79 [95% CI -0·98 to -0·59]; p<0·0001), as was the mean number of hospital admissions (0·05 [0·28] vs 0·10 [0·43]; difference -0·05 [-0·10 to 0·00]; p=0·046). At 12 months, both groups reported high mean patient-reported quality of care scores (8·16 [1·37] in the telemedicine group vs 8·27 [1·28] in the standard care group; difference 0·10 [-0·13 to 0·32]; p=0·411). The mean numbers of flares, corticosteroid courses, emergency visits, and surgeries did not differ between groups. INTERPRETATION: Telemedicine was safe and reduced outpatient visits and hospital admissions compared with standard care. This self-management tool might be useful for reorganising care of inflammatory bowel disease towards personalised and value-based health care. FUNDING: Maastricht University Medical Centre and Ferring.

Patient-Reported Outcome Measures for Use in Clinical Trials and Clinical Practice in Inflammatory Bowel Diseases: A Systematic Review.

BACKGROUND & AIMS: Mucosal inflammation must be carefully monitored to improve the long-term outcomes of patients with inflammatory bowel diseases (IBD). Patient-reported outcome measures (PROMs) are used increasingly to monitor disease activity in clinical practice and as endpoints in clinical trials. We performed a systematic review to provide an overview of the available PROMs on IBD activity and to evaluate their diagnostic value. METHODS: A systematic search of the PubMed, Medline, Cochrane library, and Embase databases using defined keywords, identified 973 articles. These were screened by 2 independent reviewers, and 37 articles on development or validation of PROMs to assess IBD activity were identified for further analysis. Based on the recommendations of the Food and Drug Administration (FDA), the following measurement properties were evaluated: content, construct, and criterion validity; reliability; and responsiveness to change. In addition, data on ease of use in clinical practice were collected. RESULTS: Seventeen articles presenting 20 different PROMs were included the final analysis, although none met all the FDA-recommended criteria. Only 2 PROMs (patient-reported Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores) reported patient involvement during its development. Only 6 PROMs (patient-reported global assessment, patient assessment of disease activity, mobile health index for Crohn's disease, mobile health index for ulcerative colitis, patient-reported outcome derived from the Mayo score, and the 6-point Mayo score) were validated as markers of IBD activity, using findings from endoscopy as the reference standard; these PROMs identified patients with mucosal inflammation with area under the curve values of 0.63-0.82. The mobile health index for CD and UC scores had the best measurement properties for use in clinical practice and in clinical trials. CONCLUSIONS: In a systematic review, we identified more than 20 PROMS that have been developed and tested for their ability to determine IBD activity. Further studies are needed to determine their accuracy and whether they can be used effectively in routine practice, clinical trials, telemedicine systems, and value-based healthcare programs.

High Percentage of IBD Patients with Indefinite Fecal Calprotectin Levels: Additional Value of a Combination Score.

BACKGROUND AND AIM: Monitoring mucosal inflammation in inflammatory bowel disease (IBD) is of major importance to prevent complications and improve long-term disease outcome. The correlation of clinical activity indices with endoscopic disease activity is, however, moderate. Fecal calprotectin (FC) is a better predictor of mucosal inflammation, but values between 100 and 250 µg/g are difficult to interpret in clinical practice. We aimed to evaluate the occurrence of indefinite FC levels in a real-life IBD cohort and study the additional value of a combination of biochemical markers and clinical activity indices. METHODS: In total, 148 Crohn's disease (CD) and 80 ulcerative colitis (UC) patients visiting the outpatient clinic were enrolled. FC, clinical disease activity scored by the Harvey-Bradshaw index or Simple Clinical Colitis Activity Index, and C-reactive protein (CRP) were assessed. In a subset of patients, endoscopic activity was scored by the simple endoscopic score-Crohn's disease and Mayo endoscopic subscore. Clinical activity index, CRP, and FC were integrated in a combination score and compared with endoscopy. RESULTS: Indefinite FC values were present in 24% of CD and 15% of UC. In the cohort of patients with endoscopy scores available, the combination score predicted endoscopic disease activity in CD with a sensitivity of 83% and specificity of 69% [positive predictive value (PPV) 58%, negative predictive value (NPV) 89%]. In UC, this was 88 and 75% (PPV 93%, NPV 60%). CONCLUSIONS: A combination of FC with clinical activity indices or CRP may aid in classifying patients with indefinite disease activity according to FC alone.

Inflammatory bowel disease, cancer and medication: Cancer risk in the Dutch population-based IBDSL cohort.

The management of inflammatory bowel disease (IBD) has changed since the mid-1990s (e.g., use of thiopurines/anti-TNFα agents, improved surveillance programs), possibly affecting cancer risk. To establish current cancer risk in IBD, updates are warranted from cohorts covering this time span, and detailed enough to study associations with phenotype and medication. We studied intestinal-, extra-intestinal- and overall cancer risk in the Dutch population-based IBDSL cohort. In total, 1,157 Crohn's disease (CD) and 1,644 ulcerative colitis (UC) patients were diagnosed between 1991 and 2011, and followed until 2013. Standardized incidence ratios (SIRs) were calculated for CD and UC separately, as well as for gender-, phenotype-, disease duration-, diagnosis era- and medication groups. We found an increased risk for colorectal cancer in CD patients with colon involvement (SIR 2.97; 95% CI 1.08-6.46), but not in the total CD or UC population. In addition, CD patients were at increased risk for hematologic- (2.41; 1.04-4.76), overall skin- (1.55; 1.06-2.19), skin squamous cell- (SCC; 3.83; 1.83-7.04) and overall cancer (1.28; 1.01-1.60), whereas UC patients had no increased risk for extra-intestinal- and overall cancer. Finally, in a medication analysis on CD and UC together, long-term immunosuppression exposure (>12 months) was associated with an increased risk for hematologic cancer, non-Hodgkin lymphoma, SCC and overall cancer, and this increase was mainly attributed to thiopurines. IBD patients with long-term immunosuppression exposure can be considered as having a higher cancer risk, and our data support the advice in recent IBD guidelines to consider skin cancer screening in these patients.

A Systematic Review on Long-Term Efficacy Outcome Measures in Crohn's Disease Patients.

BACKGROUND: The traditional long-term treatment goal of Crohn's disease [CD] is maintenance of corticosteroid-free clinical remission. Additional treatment targets, such as biochemical, endoscopic and patient-reported remission, are advocated. The relapsing-remitting nature of CD provides a challenge to the timing of target assessment. Cross-sectional assessment at predetermined moments disregards the health state in between measurements. In this systematic review, we provide an overview of outcomes used to assess long-term efficacy in clinical trials in CD. METHODS: A systematic search of the PubMed and EMBASE databases was performed to identify clinical trials in luminal CD reporting on maintenance treatment [strategies] since 1995. Two independent reviewers selected eligible articles for full text retrieval, and assessed if long-term corticosteroid-free clinical, biochemical, endoscopic or patient-reported efficacy outcomes were used. RESULTS: The search resulted in 2452 hits and 82 articles were included. Clinical activity was used in 80 studies [98%] as the long-term efficacy outcome, and in 21 [26%] of these concomitant corticosteroid use was taken into account. C-reactive protein was used in 32 studies [41%], faecal calprotectin in 15 studies [18%], endoscopic activity in 34 studies [41%] and patient-reported outcome in 32 studies [39%]. In seven studies, clinical, biochemical, endoscopic activity and the patient's perspective were measured. In most studies cross-sectional measures or multiple measurements over time were used. CONCLUSION: In none of the published clinical trials in CD was sustained remission on all treatment targets reported. Cross-sectional outcomes at predetermined times were widely applied, leading to lack of information regarding sustained corticosteroid-free remission for this relapsing-remitting chronic disease.

Development and Validation of a Remote Monitoring Tool for Assessment of Mild, Moderate, and Severe Infections in Inflammatory Bowel Disease.

BACKGROUND: Immunomodulators and biologics are cornerstones in the management of inflammatory bowel disease [IBD], but are associated with increased risk of infections. Post-marketing surveillance registries are pivotal to assess this risk, yet mainly focus on severe infections. Data on the prevalence of mild and moderate infections are scarce. We developed and validated a remote monitoring tool for real-world assessment of infections in IBD patients. METHODS: A 7-item Patient-Reported Infections Questionnaire [PRIQ] covering 15 infection categories was developed with a 3-month recall period. Infection severity was defined as mild [self-limiting or topical treatment], moderate [oral antibiotics, antivirals, or antifungals], or severe [hospitalisation or intravenous treatment]. Comprehensiveness and comprehensibility were ascertained through cognitive interviewing of 36 IBD outpatients. After implementation in the telemedicine platform myIBDcoach, a prospective, multicentre cohort study was performed between June 2020 and June 2021 in 584 patients, to assess diagnostic accuracy. Events were cross-checked with general practitioner and pharmacy data [gold standard]. Agreement was evaluated using linear-weighted kappa with cluster-bootstrapping to account for within-patient level correlation. RESULTS: Patient understanding was good and interviews did not result in reduction of PRIQ items. During validation, 584 IBD patients {57.8% female, mean age 48.6 (standard deviaton [SD]: 14.8), disease duration 12.6 years [SD: 10.9]} completed 1386 periodic assessments, reporting 1626 events. Linear-weighted kappa for agreement between PRIQ and gold standard was 0.92 (95% confidence interval [CI] 0.89-0.94). Sensitivity and specificity for infection [yes/no] were 93.9% [95% CI 91.8-96.0] and 98.5% [95% CI 97.5-99.4], respectively. CONCLUSIONS: The PRIQ is a valid and accurate remote monitoring tool to assess infections in IBD patients, providing means to personalise medicine based on adequate benefit-risk assessments.

Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome.

BACKGROUND: Epigenetic alterations may provide valuable insights into gene-environment interactions in the pathogenesis of inflammatory bowel disease [IBD]. METHODS: Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 Crohn's disease [CD], 161 ulcerative colitis [UC], 28 IBD unclassified [IBD-U)] with covariates of age, sex and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using the Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. RESULTS: A total of 137 differentially methylated positions [DMPs] were identified in IBD, including VMP1/MIR21 [p = 9.11 × 10-15] and RPS6KA2 [6.43 × 10-13], with consistency seen across Scandinavia and the UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 [p = 1.53 × 10-15]. Age acceleration is seen in IBD [coefficient 0.94, p < 2.2 × 10-16]. Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r = -0.32, p = 3.64 × 10-7 vs non-IBD r = -0.14, p = 0.77]. Multi-omic integration of the methylome, genome and transcriptome also implicated specific pathways that associate with immune activation, response and regulation at disease inception. At follow-up, a signature of three DMPs [TAP1, TESPA1, RPTOR] were associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 [CI: 2.14-12.56], logrank p = 9.70 × 10-4). CONCLUSION: These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease.

Histopathological Features in Colonic Biopsies at Diagnosis Predict Long-term Disease Course in Patients with Crohn's Disease.

BACKGROUND AND AIMS: Crohn's disease [CD] is characterised by a heterogeneous disease course. Patient stratification at diagnosis using clinical, serological, or genetic markers does not predict disease course sufficiently to facilitate clinical decision making. The current study aimed to investigate the additive predictive value of histopathological features to discriminate between a long-term mild and severe disease course. METHODS: Diagnostic biopsies from treatment-naïve CD patients with mild or severe disease courses in the first 10 years after diagnosis were reviewed by two gastrointestinal pathologists after developing a standardised form comprising 15 histopathological features. Multivariable logistic regression models were built to identify predictive features and compute receiver operating characteristic [ROC] curves. Models were internally validated using bootstrapping to obtain optimism-corrected performance estimates. RESULTS: In total, 817 biopsies from 137 patients [64 mild, 73 severe cases] were included. Using clinical baseline characteristics, disease course could only moderately be predicted (area under receiver operating characteristic curve [AUROC]: 0.738 [optimism 0.018], 95% confidence interval [CI] 0.65-0.83, sensitivity 83.6%, specificity 53.1%). When adding histopathological features, in colonic biopsies a combination of [1] basal plasmacytosis, [2] severe lymphocyte infiltration in lamina propria, [3] Paneth cell metaplasia, and [4] absence of ulcers were identified and resulted in significantly better prediction of a severe course (AUROC: 0.883 [optimism 0.033], 95% CI 0.82-0.94, sensitivity 80.4%, specificity 84.2%). CONCLUSIONS: In this first study investigating the additive predictive value of histopathological features in biopsies at CD diagnosis, we found that certain features of chronic inflammation in colonic biopsies contributed to prediction of a severe disease course, thereby presenting a novel approach to improving stratification and facilitating clinical decision making.

Disease Activity Patterns of Crohn's Disease in the First Ten Years After Diagnosis in the Population-based IBD South Limburg Cohort.

BACKGROUND AND AIMS: Real-life data on long-term disease activity in Crohn's disease [CD] are scarce. Most studies describe disease course by using proxies, such as drug exposure, need for surgery or hospitalisations, and disease progression. We aimed to describe disease course by long-term disease activity and to identify distinctive disease activity patterns in the population-based IBD South Limburg cohort [IBDSL]. METHODS: All CD patients in IBDSL with ≥10 years follow-up [n = 432] were included. Disease activity was defined for each yearly quarter by mucosal inflammation on endoscopy or imaging, hospitalisation, surgery, or treatment adjustment for increased symptoms. Six distinct disease activity clusters were defined. Subsequently, the associations between clinical characteristics and the patterns were assessed using multivariable logistic regression models. RESULTS: On average, patients experienced 5.44 (standard deviation [SD] 3.96) quarters of disease activity during the first 10 years after diagnosis. Notably, 28.2% of the patients were classified to a quiescent pattern [≤2 active quarters in 10 years], and 89.8% of those never received immunomodulators nor biologics. Surgery at diagnosis (odds ratio [OR] 2.99; 95% confidence interval [CI] 1.07-8.34) and higher age [OR 1.03; 95% CI 1.01-1.06] were positively associated with the quiescent pattern, whereas inverse associations were observed for ileocolonic location [OR 0.44; 95% CI 0.19-1.00], smoking [OR 0.43; 95% CI 0.24-0.76] and need for steroids <6 months [OR 0.24; 95% CI 0.11-0.52]. CONCLUSIONS: Considering long-term disease activity, 28.2% of CD patients were classified to a quiescent cluster. Given the complex risk-benefit balance of immunosuppressive drugs, our findings underline the importance of identifying better predictive markers to prevent both over-treatment and under-treatment.

Higher Prevalence of Bacteroides fragilis in Crohn's Disease Exacerbations and Strain-Dependent Increase of Epithelial Resistance.

Bacteroides fragilis has previously been linked to Crohn's disease (CD) exacerbations, but results are inconsistent and underlying mechanisms unknown. This study investigates the epidemiology of B. fragilis and its virulence factors bft (enterotoxin) and ubiquitin among 181 CD patients and the impact on the intestinal epithelial barrier in vitro. The prevalence of B. fragilis was significantly higher in active (n = 69/88, 78.4%) as compared to remissive (n = 58/93, 62.4%, p = 0.018) CD patients. Moreover, B. fragilis was associated with intestinal strictures. Interestingly, the intestinal barrier function, as examined by transepithelial electrical resistance (TEER) measurements of Caco-2 monolayers, increased when exposed to secretomes of bft-positive (bft-1 and bft-2 isotype; increased TEER ∼160%, p < 0.001) but not when exposed to bft-negative strains. Whole metagenome sequencing and metabolomics, respectively, identified nine coding sequences and two metabolites that discriminated TEER-increasing from non-TEER-increasing strains. This study revealed a higher B. fragilis prevalence during exacerbation. Surprisingly, bft-positive secretomes increased epithelial resistance, but we excluded Bft as the likely causative factor.

Severe COVID-19 in inflammatory bowel disease patients in a population-based setting.

OBJECTIVE: Data on the course of severe COVID-19 in inflammatory bowel disease (IBD) patients remains limited. We aimed to determine the incidence rate and clinical course of severe COVID-19 in the heavily affected South-Limburg region in the Netherlands. METHODS: All COVID-19 patients admitted to the only two hospitals covering the whole South-Limburg region between February 27, 2020 and January 4, 2021 were included. Incidence rates for hospitalization due to COVID-19 were determined for the IBD (n = 4980) and general population (n = 597,184) in South-Limburg. RESULTS: During a follow-up of 4254 and 510,120 person-years, 20 IBD patients (0.40%; 11 ulcerative colitis (UC), 9 Crohn's disease (CD)) and 1425 (0.24%) patients from the general population were hospitalized due to proven COVID-19 corresponding to an incidence rate of 4.7 (95% Confidence interval (CI) 3.0-7.1) and 2.8 (95% CI 2.6-2.9) per 1000 patient years, respectively (Incidence rate ratio: 1.68, 95% CI 1.08-2.62, p = 0.019). Median age (IBD: 63.0 (IQR 58.0-75.8) years vs. general population: 72.0 (IQR 62.0-80.0) years, p = 0.10) and mean BMI (IBD: 24.4 (SD 3.3) kg/m2 vs. general population 24.1 (SD 4.9) kg/m2, p = 0.79) at admission were comparable in both populations. As for course of severe COVID-19, similar rates of ICU admission (IBD: 12.5% vs. general population: 15.7%, p = 1.00), mechanical ventilation (6.3% vs. 11.2%, p = 1.00) and death were observed (6.3% vs. 21.8%, p = 0.22). CONCLUSION: We found a statistically significant higher rate of hospitalization due to COVID-19 in IBD patients in a population-based setting in a heavily impacted Dutch region. This finding reflects previous research that showed IBD patients using systemic medication were at an increased risk of serious infection. However, although at an increased risk of hospitalization, clinical course of severe COVID-19 was comparable to hospitalized patients without IBD.

Dietary Intake Pattern is Associated with Occurrence of Flares in IBD Patients.

BACKGROUND: Diet is associated with the onset of inflammatory bowel disease [IBD]. Up to half of IBD patients believe that diet contributes to flares. However, studies on this topic are sparse and merely focus on specific nutrients, food items or food groups. We aimed to analyse the association between dietary patterns and flare occurrence in two geographically distinct Dutch cohorts. METHODS: In this longitudinal study, 724 IBD patients [Northern cohort: n = 486, Southern cohort: n = 238] were included and followed for 2 years. Habitual dietary intake was obtained via semi-quantitative food frequency questionnaires at baseline. Principal component analysis [PCA] was conducted on 22 food groups to identify dietary patterns. Flare occurrence was analysed in 427 patients in remission at baseline, using multivariable Cox proportional hazards. RESULTS: Compared to the Southern cohort, patients in the Northern cohort were younger at diagnosis, comprised more females, and had lower overall energy intakes [all p < 0.05]. PCA revealed three dietary patterns explaining 28.8% of the total variance. The most pronounced pattern [explaining 11.6%] was characterized by intake of grain products, oils, potatoes, processed meat, red meat, condiments and sauces, and sugar, cakes and confectionery. Of the 427 patients, 106 [24.8%] developed an exacerbation during follow-up. The above dietary pattern was associated with flare occurrence (hazard ratio [HR]: 1.51, 95% confidence interval [CI]: 1.04-2.18, p = 0.029), as was female sex [HR: 1.63, 95% CI 1.04-2.55, p = 0.032]. CONCLUSIONS: A dietary pattern, which can be seen as a 'traditional [Dutch]' or "Western' pattern was associated with flare occurrence. Confirmation in prospective studies is needed.

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.

Clustering of (auto)immune diseases with early-onset and complicated inflammatory bowel disease.

Studies in adult inflammatory bowel disease (IBD) patients have highlighted associations with genetic and serologic markers and suggest an association with disease location, behaviour and natural history. Data on patients with Crohn's disease (CD, n=80), ulcerative colitis (UC, n=15) and indeterminate colitis (n=4) were collected. All individuals were analysed for CARD15 R702W, G908R and L1007fs for toll-like receptor 4 (TLR4) Asp299Gly and for anti-Saccharomyces cerevisiae antibodies (ASCA) and atypical perinuclear antineutrophil cytoplasmatic antibodies (pANCA). After a mean of 10.7 years of follow up, the disease behaviour changed in 45% of CD patients, in contrast to disease location, where only 12.5% had a change (p<0.001). The younger the age at diagnosis, the more patients presented with colonic disease (p=0.021). Also, more TLR4 Asp299 Gly variants were found when the age at onset was younger (p=0.018). A large number of concomitant diseases were observed. There was no difference in the prevalence of TLR4 variants nor ASCA or pANCA between the patients with or without concomitant diseases. Patients who progressed more often needed surgery as compared to patients who remained free of stenosing or fistulising disease (27/32 or 84% versus 3/35 or 8.6%, respectively, p<0.0001) and more often had concomitant immune-mediated diseases and a trend for more seroreactivity towards ASCA.