Review article: A practical approach to persistent gastrointestinal symptoms in inflammatory bowel disease in remission.

BACKGROUND: Persistent gastrointestinal symptoms are prevalent in adult patients with inflammatory bowel disease (IBD), even when endoscopic remission is reached. These symptoms can have profound negative effects on the quality of life of affected patients and can be difficult to treat. They may be caused by IBD-related complications or comorbid disorders, but they can also be explained by irritable bowel syndrome (IBS)-like symptoms. AIMS: To provide a practical step-by-step guide to diagnose and treat persistent gastrointestinal symptoms in patients with IBD in remission via a personalised approach. METHODS: We scrutinised relevant literature on causes, diagnostics and treatment of persistent gastrointestinal symptoms (abdominal pain or discomfort, bloating, abdominal distension, diarrhoea, constipation and faecal incontinence) in patients with IBD in remission. RESULTS: A graphical practical guide for several steps in diagnosing, identifying potential triggers and adequate treatment of persistent gastrointestinal symptoms in IBD in remission is provided based on supporting literature. The first part of this review focuses on the diagnostic and treatment approaches for potential IBD-related complications and comorbidities. The second part describes the approach to IBS-like symptoms in IBD in remission. CONCLUSIONS: Persistent gastrointestinal symptoms in IBD in remission can be traced back to potential pathophysiological mechanisms in individual patients and can be treated adequately. For both IBD-related complications and comorbidities and IBS-like symptoms in IBD in remission, pharmacological, dietary, lifestyle or psychological treatments can be effective. A systematic and personalised approach is required to reduce the burden for patients, healthcare systems, and society.

[How psychological stress aggravates intestinal inflammation]. / Hoe psychologische stress tot darmontstekingen leidt.

OBJECTIVE: To investigate the biological mechanisms underlying the associations of psychological stress and intestinal inflammation in inflammatory bowel disease (IBD). DESIGN: Experimental mouse models and large human cohorts have been used. METHOD: Consecutive mouse models with chemically induced colitis were used to investigate biological pathways though which psychological stress leads to gut inflammation. These results were validated in three human cohorts with patients with IBD. RESULTS: Stress induced elevated levels of glucocorticoids drive the generation of an inflammatory subset of enteric glia cells. These enteric glia cells produce the protein CSF1, that promotes monocyte accumulation in the intestinal mucosa and TNF-mediated intestinal inflammation. CONCLUSION: A pivotal role for the enteric nervous system (ENS) has been discovered in mediating the aggravating effect of psychological stress on intestinal inflammation.

Predicting response to iron supplementation in patients with active inflammatory bowel disease (PRIme): a randomised trial protocol.

INTRODUCTION: Iron deficiency anaemia (IDA) is the most common systemic manifestation of inflammatory bowel disease (IBD) that has detrimental effects on quality of life (QoL) and disease outcomes. Iron deficiency (ID), with or without anaemia, poses a diagnostic and therapeutic challenge in patients with IBD due to the multifactorial nature of ID(A) and its frequent recurrence. Elevated hepcidin-a systemic iron regulator that modulates systemic iron availability and intestinal iron absorption-has been associated with oral iron malabsorption in IBD. Therefore, hepcidin could assist in therapeutic decision-making. In this study, we investigate whether hepcidin can predict response to oral and intravenous iron supplementation in patients with active IBD undergoing anti-inflammatory treatment. METHODS AND ANALYSIS: PRIme is an exploratory, multicentre, open-label and randomised trial. All adult patients with active IBD and ID(A) will be assessed for eligibility. The participants (n=90) will be recruited at five academic hospitals within the Netherlands and randomised into three groups (1:1:1): oral ferrous fumarate, oral ferric maltol or intravenous iron. Clinical and biochemical data will be collected at the baseline and after 6, 14 and 24 weeks. Blood samples will be collected to measure hepcidin and other biomarkers related to iron status. In addition, patient-reported outcomes regarding QoL and disease burden will be evaluated. The primary outcome is the utility of hepcidin as a predictive biomarker for response to iron therapy, which will be assessed using receiver operating curve analysis. ETHICS AND DISSEMINATION: The study has been approved by the Institutional Review Board at the Leiden University Medical Center (IRB No. P21.109) and other study sites. All participants will provide written informed consent to enrol in the study. The findings will be published in a peer-reviewed journal and disseminated at scientific conferences; the dataset will be available on reasonable request. TRIAL REGISTRATION: Prospectively registered in the https://clinicaltrials.gov/ and the Eudra registries. First submitted on 10 May 2022 to the ClinicalTrials.gov (ID: NCT05456932) and on 3 March 2022 to the European Union Drug Regulating Authorities Clinical Trials Database (ID: 2022-000894-16).

Satisfaction With Life in IBS Is Associated With Psychological Burden Rather than Gastrointestinal Symptom Severity.

INTRODUCTION: Irritable bowel syndrome (IBS) has a major impact on emotional, social, and professional life. This study aimed to evaluate general life satisfaction, a subjective measure of well-being, in IBS patients, and to determine which factors are associated with higher life satisfaction. METHODS: IBS patients (n = 195, mean age 51.4 ± 16.5 years, 73.8% female) recruited from primary and secondary/tertiary care completed questionnaires regarding gastrointestinal symptoms, quality of life, psychological factors, and life satisfaction (Satisfaction With Life Scale, 5 items, range 5-35). A finite mixture model analysis was performed to identify latent classes. Multivariable linear regression was used to identify variables associated with life satisfaction. RESULTS: Overall, 71.3% of the patients were satisfied about their life (Satisfaction With Life Scale-score ≥21). Three latent subgroups could be identified with significantly higher life satisfaction in the subgroup with higher mental quality of life, fewer anxiety and depressive symptoms, lower gastrointestinal specific anxiety, and lower gastrointestinal symptom severity, compared with the other 2 groups. Multivariable linear regression showed that higher physical quality of life (B0.168, P < 0.001) and higher mental quality of life (B0.199, P < 0.001) were associated with higher life satisfaction. Using multivariable regression, no significant association was found between gastrointestinal symptom severity and life satisfaction. DISCUSSION: Higher physical and mental quality of life, but not gastrointestinal symptom severity, were independently associated with higher general life satisfaction in IBS. These findings reinforce the clinical need in IBS treatment to focus on the full extent of the disorder and not merely on gastrointestinal symptom improvement. ClinicalTrials.gov Identifier: NCT00775060.

[Irritable bowel syndrome]. / Prikkelbaredarmsyndroom.

Irritable bowel syndrome (IBS) is a prevalent disorder of the gut-brain interaction, of which the multifactorial pathophysiology is still incompletely understood. IBS is a symptom-based diagnosis based on the Rome IV criteria, and additional diagnostics are only indicated when history or physical examination point towards the presence of other (organic) disorders. Diagnosis and treatment should take place in primary care. However, management of IBS can be challenging due to the heterogenous clinical presentation. Furthermore, a variety of treatment options are available, yet only effective in subgroups of patients. Early positive diagnosis, patient education, and shared-decision making are of utmost importance in order to limit individual disease burden and the socioeconomic impact of IBS. In this review we discuss diagnosis, indications for additional investigations or referral to secondary care, and treatment of IBS, based on both the recently updated Dutch guideline and general practice standard on IBS.

Predictive Genetic Biomarkers for the Development of Peritoneal Metastases in Colorectal Cancer.

Metastatic colorectal cancer (CRC) is a common cause of cancer-related mortality, of which peritoneal metastases (PMs) have the worse outcome. Metastasis-specific markers may help predict the spread of tumor cells and select patients for preventive strategies. This exploratory pilot study aimed to gain more insight into genetic alterations in primary CRC tumors, which might be a predictive factor for the development of PM. Forty patients with T3 stage CRC were retrospectively divided in three groups: without metachronous metastases during 5-year follow-up (M0, n = 20), with metachronous liver metastases (LM, n = 10) and with metachronous PM (PM, n = 10). Patients with synchronous metastases were excluded. Primary formalin-fixed paraffin-embedded tumor samples were analyzed via comprehensive genome sequencing (TSO500 analysis) to identify DNA alterations and RNA fusion transcripts in 523 genes and 55 genes, respectively. Thirty-eight samples were included for final analysis. Four M0 tumors and one PM tumor were microsatellite instable. BRAF mutations were uniquely identified in three microsatellite-stable (MSS) PM tumors (37.5%, p = 0.010). RNA analysis showed an additional FAM198A-RAF1 fusion in one PM sample. BRAF p.V600E mutations were only present in PM patients with MSS tumors. Greater attention should be paid to BRAF-mutated tumors in relation to the development of metachronous PM.

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.

[Dietary interventions in irritable bowel syndrome: 10 tips]. / Voedingsinterventies voor het prikkelbaredarmsyndroom.

Diet plays an important role in the development of abdominal symptoms in Irritable Bowel Syndrome (IBS). Most patients indicate that their symptoms are triggered or modulated by specific food. Both, patients and treating physicians, often prefer dietary interventions as a treatment for IBS, when compared to pharmacological or psychotherapy. Selecting the most effective dietary intervention for an individual patient is a challenge. It is crucial to identify patient specific food related triggers and to evaluate the patients' treatment expectations prior to start of the intervention. In this article we will discuss the approaches that may lead to the most successful dietary intervention for IBS, via 10 tips for the daily practice.

The Socioeconomic Impact of Irritable Bowel Syndrome: An Analysis of Direct and Indirect Health Care Costs.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is associated with substantial costs to society. Extensive data on direct costs (health care consumption) and indirect costs (health-related productivity loss) are lacking. Hence, we examined the socioeconomic costs of IBS and assessed which patient characteristics are associated with higher costs. METHODS: Cross-sectional data from 3 Rome-defined Dutch IBS patient cohorts (n = 419) were collected. Bootstrapped mean direct and indirect costs were evaluated per patient with IBS using validated questionnaires (ie, medical cost questionnaire and productivity cost questionnaire, respectively). Multivariable regression analyses were performed to identify variables associated with higher costs. RESULTS: Quarterly mean total costs per patient were €2.156 (95% confidence interval (CI), €1793-€2541 [$2444]), consisting of €802 (95% CI, €625-€1010 [$909]) direct costs and €1.354 (95% CI, €1072-€1670 [$1535]) indirect costs. Direct costs consisted primarily of health care professional consultations, with costs related to gastrointestinal clinic visits accounting for 6% and costs related to mental health care visits for 20%. Higher direct costs were significantly associated with older age (P = .007), unemployment (P = .001), IBS subtypes other than constipation (P = .033), lower disease-specific quality of life (P = .027), and more severe depressive symptoms (P = .001). Indirect costs consisted of absenteeism (45%), presenteeism (42%), and productivity loss related to unpaid labor (13%) and were significantly associated with the male sex (P = .014) and more severe depressive symptoms (P = .047). CONCLUSIONS: Productivity loss is the main contributor to the socioeconomic burden of IBS. Direct costs were not predominantly related to gastrointestinal care, but rather to mental health care. Awareness of the nature of costs and contributing patient factors should lead to significant socioeconomic benefits for society.

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.

Colonic permeability is increased in non-cirrhotic patients with nonalcoholic fatty liver disease.

BACKGROUND AND AIM: Intestinal permeability (IP) plays an important role in the pathophysiology of nonalcoholic fatty liver disease (NAFLD). We assessed site-specific (gastroduodenum, small intestine, colon and whole gut) IP in NAFLD patients and healthy controls (HC) and its association with the degree of hepatic steatosis, hepatic fibrosis and dietary composition in these NAFLD patients. METHODS: In vivo site-specific IP was analysed with a validated multi-sugar test in NAFLD patients and HC. Furthermore, in NAFLD patients, hepatic steatosis (chemical shift MRI), hepatic fibrosis (transient elastography) and dietary composition (food frequency questionnaire) were assessed. RESULTS: Fifty-two NAFLD patients and forty-six HC were included in this study. Small intestinal (P <0.001), colonic (P = 0.004) and whole gut (P <0.001) permeability were increased in NAFLD patients compared to HC. Furthermore, colonic permeability (P = 0.029) was significantly higher in NAFLD patients with clinically significant fibrosis compared to those without. Colonic permeability remained positively associated with the presence of clinically significant fibrosis (P = 0.017) after adjustment for age, sex and BMI. CONCLUSION: Colonic permeability is increased in at least a subset of NAFLD patients compared to HC and is independently associated with clinically significant NAFLD fibrosis.

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

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

Anemia and Iron Deficiency in Outpatients with Inflammatory Bowel Disease: Ubiquitous Yet Suboptimally Managed.

Background: Iron deficiency (ID) and anemia in patients with Inflammatory Bowel Disease (IBD) are associated with a reduced quality of life. We assessed the prevalence of ID and anemia in Dutch outpatients with IBD and compared routine ID(A) management among medical professionals to the European Crohn's and Colitis Organisation (ECCO) treatment guidelines. Methods: Between January and November 2021, consecutive adult outpatients with IBD were included in this study across 16 Dutch hospitals. Clinical and biochemical data were extracted from medical records. Additionally, medical professionals filled out questionnaires regarding routine ID(A) management. Results: In total, 2197 patients (1271 Crohn's Disease, 849 Ulcerative Colitis, and 77 IBD-unclassified) were included. Iron parameters were available in 59.3% of cases. The overall prevalence of anemia, ID, and IDA was: 18.0%, 43.4%, and 12.2%, respectively. The prevalence of all three conditions did not differ between IBD subtypes. ID(A) was observed more frequently in patients with biochemically active IBD than in quiescent IBD (ID: 70.8% versus 23.9%; p < 0.001). Contrary to the guidelines, most respondents prescribed standard doses of intravenous or oral iron regardless of biochemical parameters or inflammation. Lastly, 25% of respondents reported not treating non-anemic ID. Conclusions: One in five patients with IBD suffers from anemia that­despite inconsistently measured iron parameters­is primarily caused by ID. Most medical professionals treat IDA with oral iron or standard doses of intravenous iron regardless of biochemical inflammation; however, non-anemic ID is often overlooked. Raising awareness about the management of ID(A) is needed to optimize and personalize routine care.

Detecting Colorectal Adenomas and Cancer Using Volatile Organic Compounds in Exhaled Breath: A Proof-of-Principle Study to Improve Screening.

INTRODUCTION: Early detection of colorectal cancer (CRC) by screening programs is crucial because survival rates worsen at advanced stages. However, the currently used screening method, the fecal immunochemical test (FIT), suffers from a high number of false-positives and is insensitive for detecting advanced adenomas (AAs), resulting in false-negatives for these premalignant lesions. Therefore, more accurate, noninvasive screening tools are needed. In this study, the utility of analyzing volatile organic compounds (VOCs) in exhaled breath in a FIT-positive population to detect the presence of colorectal neoplasia was studied. METHODS: In this multicenter prospective study, breath samples were collected from 382 FIT-positive patients with subsequent colonoscopy participating in the national Dutch bowel screening program (n = 84 negative controls, n = 130 non-AAs, n = 138 AAs, and n = 30 CRCs). Precolonoscopy exhaled VOCs were analyzed using thermal desorption-gas chromatography-mass spectrometry, and the data were preprocessed and analyzed using machine learning techniques. RESULTS: Using 10 discriminatory VOCs, AAs could be distinguished from negative controls with a sensitivity and specificity of 79% and 70%, respectively. Based on this biomarker profile, CRC and AA combined could be discriminated from controls with a sensitivity and specificity of 77% and 70%, respectively, and CRC alone could be discriminated from controls with a sensitivity and specificity of 80% and 70%, respectively. Moreover, the feasibility to discriminate non-AAs from controls and AAs was shown. DISCUSSION: VOCs in exhaled breath can detect the presence of AAs and CRC in a CRC screening population and may improve CRC screening in the future.

Classic drugs in the time of new drugs: real-world, long-term outcomes of thiopurine monotherapy in 1016 patients with inflammatory bowel disease.

BACKGROUND: Thiopurines remain recommended as maintenance therapy in patients with inflammatory bowel disease (IBD). Despite their widespread use, long-term effectiveness data are sparse and safety is an increasingly debated topic which thwarts proper delineation in the current IBD treatment algorithm. AIMS: To document effectiveness and safety of thiopurine monotherapy in patients with IBD, using the population-based IBD South-Limburg (IBDSL) cohort METHODS: All patients starting thiopurine monotherapy as maintenance between 1991 and 2014 were included. Therapy was defined as effective if there was no escalation to biologicals, no course of corticosteroids, no surgery and no hospitalisation for active disease during treatment. Long-term effectiveness was assessed by adjusting for differences in follow-up using Kaplan-Meier analyses. Mid- to long-term safety regarding cancer incidence and clinically relevant liver disease was documented. RESULTS: In total, 1016 patients (643 Crohn's disease [CD]; 373 ulcerative colitis [UC]) received thiopurine monotherapy at a median of 15.2 (Q1-Q3 4.2-48.5) months after diagnosis. During follow-up, effectiveness rates at 1, 5 and 10 years were 64%, 45%, 32%, respectively, in CD and and 66%, 41%, 36%, respectively in UC. No statistically significant differences in effectiveness were observed after stratification for era of initiation (pre-biological vs biological, CD: p = 0.56; UC: p = 0.43). Sixteen non-melanoma skin cancers (incidence rate [IR] 3.33/1000 PY), five lymphomas (IR 1.04/1000 PY) and one urinary tract cancer (IR 0.21/1000 PY) were recorded. Two cases of portal hypertension were identified. CONCLUSION: In real-world practice, thiopurine monotherapy remains effective, safe and durable for patients with CD or UC, including in the era of biologics.

Diet Quality and Dietary Inflammatory Index in Dutch Inflammatory Bowel Disease and Irritable Bowel Syndrome Patients.

Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) share common culprit foods and potential pathophysiological factors. However, how diet may contribute to disease course and whether this differs between both entities is unclear. We therefore investigated the association of dietary indices with intestinal inflammation and gastrointestinal symptoms in both IBD and IBS patients. Food frequency questionnaires from 238 IBD, 261 IBS and 195 healthy controls (HC) were available to calculate the overall diet quality by the Dutch Healthy Diet-Index 2015 (DHD-2015) and its inflammatory potential by the Adapted Dietary Inflammatory Index (ADII). Intestinal inflammation and symptoms were evaluated by faecal calprotectin and the Gastrointestinal Symptom Rating Scale, respectively. The DHD-2015 was lower in IBD and IBS versus HC (p < 0.001), being associated with calprotectin levels in IBD (b = −4.009, p = 0.006), and with abdominal pain (b = −0.012, p = 0.023) and reflux syndrome (b = −0.016, p = 0.004) in IBS. ADII scores were comparable between groups and were only associated with abdominal pain in IBD (b = 0.194, p = 0.004). In this side-by-side comparison, we found a lower diet quality that was differentially associated with disease characteristics in IBD versus IBS patients. Longitudinal studies are needed to further investigate the role of dietary factors in the development of flares and predominant symptoms.