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Aims: To investigate the diagnostic accuracy of fecal calprotectin (FC) for inflammatory bowel disease (IBD) and organic gastrointestinal disease (OGID) in primary care. To examine the association with demographic factors, symptoms and concomitant medical therapy., Methods: A retrospective analysis of data on all semiquantitative FC tests from individuals ≥18 years conducted in primary care in Östergötland County in 2010. A 5-year follow-up with inclusion of new gastrointestinal diagnoses., Results: A total of 1293 eligible patients were included. IBD was found in 8.8% and other OGID in 30.8% of patients with positive FC. Positive FC was associated with diarrhea, age >60 years, duration <3 months, use of nonsteroidal anti-inflammatory drug (NSAID), and proton pump inhibitor (PPI). Predictors of IBD were positive FC, diarrhea, rectal bleeding, and male sex; predictors of OGID positive FC, age >35 years, abnormal clinical findings, and duration <3 months. FC yielded the highest sensitivity and negative predictive value compared with demographic factors, symptoms, and duration. Use of NSAID and PPI showed a marginal increase in the sensitivity, positive predictive value, and decrease in the specificity of FC. Within 5 years, 4.0% had a new gastrointestinal diagnosis among patients with positive FC (0.6% IBD)., Conclusions: FC reliably rules out IBD and contradicts the presence of other OGID in primary care patients. Positive FC test together with other predictors, such as diarrhea, rectal bleeding, short duration, or age >35 years, should encourage a prioritized investigation. Use of NSAID, PPI, and ASA may affect the diagnostic accuracy of FC for IBD and OGID., (© 2023 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Health-related quality of life (hrQoL) may be the most important patient-reported outcome for patients with chronic disorders. The Short Health Scale (SHS) is a brief four-item instrument to assess hrQoL in patients with bowel disorders. This study examined the validity, reliability and sensitivity of the German translation of the SHS in a cohort of outpatients with inflammatory bowel diseases (IBD)., Methods: The study was preregistered in April 2021 (https://doi.org/10.17605/OSF.IO/S82D9). Outpatients with IBD (n=225) in different stages of disease activity (as determined by the Harvey-Bradshaw index or partial Mayo score) completed the German SHS and the short Inflammatory Bowel Disease Questionnaire (sIBDQ) as an established measure of hrQoL to examine the convergent validity. To assess reliability, a subset of patients (n=30) in remission completed the same questionnaires after 4-8 weeks. Sensitivity to change was established from questionnaires of patients with either decreased (n=15) or increased (n=16) disease activity after 3-6 months., Results: The internal consistency of the German SHS was high (Cronbach's α=0.860). SHS total scores correlated strongly with sIBDQ scores (ρ=-0.760, p<0.001) and disease activity (ρ=0.590, p<0.001). Retest reliability was high (ρ=0.695, p<0.001). Sensitivity to change was statistically significant for patients with decreased (p=0.013) but not increased (p=0.134) disease activity., Conclusion: The German version of the SHS is a valid and reliable tool to measure hrQoL in persons with IBD., Competing Interests: The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Introduction: Fecal calprotectin (FC) is a noninvasive tool for examining response to biologics in inflammatory bowel disease (IBD), but its performance in relation to other novel fecal markers of various cellular origins is unknown., Methods: We performed a prospective multicenter cohort study and included patients with active IBD who provided a fecal sample at initiation of biological therapy. Levels of FC, myeloperoxidase (MPO), human neutrophil lipocalin (HNL), and eosinophil-derived neurotoxin (EDN) were analyzed and related to clinical remission status at 3 months. Changes in levels of markers at 3 months were calculated, and the impact of concomitant use of corticosteroids at baseline was estimated., Results: In patients achieving clinical remission (n = 27), a decrease in levels of FC ( P = 0.005), MPO ( P < 0.001), HNL ( P < 0.001), and EDN ( P < 0.001) was observed, whereas no significant decrease was seen in patients not achieving remission (n = 39). There was a significant difference in the change in the level of MPO ( P = 0.01) and HNL ( P = 0.02) between patients achieving clinical remission and those who did not, but changes in FC and EDN could not differentiate between these groups. Patients with concomitant systemic corticosteroids at inclusion had lower levels of HNL ( P = 0.01) and EDN ( P < 0.001) at baseline, compared with patients without corticosteroids., Discussion: Fecal MPO, HNL, and EDN are all promising biomarkers for assessing the treatment outcome of biologics in patients with IBD. Fecal levels of EDN and HNL are significantly affected by corticosteroids indicating a greater sensitivity to the effects of corticosteroids compared with levels of FC and MPO., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background: Serious infections have been observed in patients with inflammatory bowel disease (IBD) on anti-TNF use-but to what extent these infections are due to anti-TNF or the disease activity per se is hard to disentangle. We aimed to describe how the rates of serious infections change over time both before and after starting anti-TNF in IBD., Methods: Inflammatory bowel disease patients naïve to anti-TNF treatment were identified at 5 centers participating in the Swedish IBD Quality Register, and their medical records examined in detail. Serious infections, defined as infections requiring in-patient care, the year before and after the start of anti-TNF treatment were evaluated., Results: Among 980 patients who started their first anti-TNF therapy between 1999 and 2016, the incidence rate of serious infections was 2.19 (95% CI,1.43-3.36) per 100 person years the year before and 2.11 (95% CI, 1.33-3.34) per 100 person years 1 year after treatment start. This corresponded to an incidence rate ratio 1 year after anti-TNF treatment of 0.97 (95% CI, 0.51-1.84). Compared with before anti-TNF therapy, the incidence of serious infection was significantly decreased more than 1 year after treatment (incidence rate ratio 0.56; 95% CI, 0.33-0.95; P = .03)., Conclusions: In routine clinical practice in Sweden, the incidence rate of serious infection among IBD patients did not increase with anti-TNF therapy. Instead, serious infections seemed to decrease more than 1 year after initiation of anti-TNF treatment., (© 2022 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Background and Aim: Nonsteroidal anti-inflammatory drugs and proton pump inhibitors are known to affect the diagnostics of gastrointestinal disorders. The aim of this study was to investigate to what extent omeprazole, diclofenac or co-administration of these affects faecal calprotectin levels and the normalisation interval after cessation., Methods: Participants received 20 mg omeprazole daily for 2 weeks in the first sequence, 50 mg oral diclofenac three times daily for 2 weeks in the second and co-administration of these for 2 weeks in the third, with washout periods in between. The first two sequences were randomised to a different order. Faecal calprotectin was measured on days 0, 4, 7, 14, 21, 28 and 35 and thereafter at 7-day intervals until normalisation in each sequence., Results: Thirty-two healthy volunteers were included. During drug intake, 39% on diclofenac (median 70.8 µg/g; range 50.2-1080 µg/g), 53% on omeprazole (median 85.3 µg/g; range 51.1-249 µg/g) and 69% on omeprazole + diclofenac (median 101.5 µg/g; range 51.5-532 µg/g) had faecal calprotectin levels above normal. In the diclofenac sequence, faecal calprotectin returned to normal in all participants within 2 weeks of cessation and in the omeprazole and co-administration sequences, within 3 weeks of cessation. No statistical significant difference was found with respect to drug order., Conclusion: Short-term intake of omeprazole, diclofenac or co-administration appears to increase faecal calprotectin levels. In patients with increased faecal calprotectin on omeprazole alone or in combination with diclofenac, a repeated faecal calprotectin test is recommended at least 3 weeks after cessation. On diclofenac alone, it is sufficient to repeat the faecal calprotectin test 2 weeks after cessation., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Collagenous colitis (CC) is an inflammatory bowel disease, which usually responds to budesonide treatment. Our aim was to study the immunological background of the disease., Methods: Analyses of peripheral and mucosal MAIT (mucosa associated invariant T cells) and NK (natural killer) cells were performed with flow cytometry. Numbers of mucosal cells were calculated using immunohistochemistry. We studied the same patients with active untreated CC (au-CC) and again while in remission on budesonide treatment. Budesonide refractory patients and healthy controls were also included. The memory marker CD45R0 and activation marker CD154 and CD69 were used to further study the cells. Finally B cells, CD4 + and CD8 + T cells were also analysed., Results: The percentages of circulating CD56 dim CD16 + NK cells as well as MAIT cells (CD3 + TCRVa7.2 + CD161 + ) were decreased in au-CC compared to healthy controls. This difference was not seen in the mucosa; where we instead found increased numbers of mucosal CD4 + T cells and CD8 + T cells in au-CC. Mucosal immune cell numbers were not affected by budesonide treatment. In refractory CC we found increased mucosal numbers of MAIT cells, CD4 + and CD8 + T cells compared to au-CC., Discussion: Patients with active collagenous colitis have lower percentages of circulating MAIT and NK cells. However, there was no change of these cells in the colonic mucosa. Most mucosal cell populations were increased in budesonide refractory as compared to au-CC patients, particularly the number of MAIT cells. This may indicate that T cell targeting therapy could be an alternative in budesonide refractory CC., Competing Interests: AM has received salary for consultancies from Tillotts, Ferring, Vifor and Dr Falk Pharma; speaker’s honoraria from Tillotts and Vifor. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Daferera, Nyström, Hjortswang, Ignatova, Jenmalm, Ström and Münch.)

Iron deficiency, defined as ferritin <100 µg/L or ferritin 100-299 µg/L if the transferrin saturation is <20 %, with or without anaemia is a common comorbidity in patients with acute and chronic heart failure. International and Swedish guidelines recommend treatment of iron deficiency with intravenous iron in patients with symptomatic heart failure and ejection fraction <50 %. Controlled studies document positive effects from treatment with iron carboxymaltose on symptoms, quality of life, functional parameters and risk of hospitalisation. We present a simple algoritm based on published data to help the responsible physician to manage these patients in clinical practice.

Background: Real-world data on clinical outcomes of ustekinumab in ulcerative colitis are lacking., Objective: To assess short- and long-term clinical outcomes of ustekinumab in ulcerative colitis., Methods: Adult ulcerative colitis patients without previous colectomy starting ustekinumab treatment up until 11 December 2020 were identified through the Swedish Inflammatory Bowel Disease Register (SWIBREG). Prospectively recorded data were extracted from the SWIBREG. The primary outcome was persistence to ustekinumab 16 weeks after treatment initiation. Secondary outcomes included drug persistence beyond week 16, clinical remission (defined as a patient-reported Mayo rectal bleeding subscore = 0 and stool frequency subscore ≤1), biochemical remission (defined as faecal-calprotectin <250 μg/g) and changes in health-related quality of life (HRQoL), as measured by the Short Health Scale (SHS). Logistic regression was used to identify potential predictors of ustekinumab persistence at 16 weeks., Results: Of the 133 patients with ulcerative colitis, only three were naïve to biologics and tofacitinib. The persistence rates of ustekinumab were 115/133 (86%) at 16 weeks and 89/133 (67%) at last follow-up, that is, after a median follow-up of 32 (interquartile range 19-56) weeks. The clinical remission rates were 17% at 16 weeks and 32% at the last follow-up. The corresponding rates for biochemical remission were 14% and 23%. The median faecal-calprotectin concentration decreased from 740 μg/g at baseline to 98 μg/g at the last follow-up (p < 0.01, n = 37). Improvement was seen in each dimension of the SHS between baseline and last follow-up (p < 0.01 for each dimension, n = 46). Male sex was associated with ustekinumab persistence at 16 weeks (adjusted odds ratio = 4.00, 95% confidence interval: 1.35-11.83)., Conclusion: In this nationwide real-world cohort of ulcerative colitis patients with prior drug failures, including other biologics and tofacitinib, ustekinumab was associated with high drug persistence rates and improvements in clinical, biochemical and HRQoL measures., (© 2022 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background and Aims: Inflammatory bowel disease [IBD] is a chronic relapsing disorder of the gastrointestinal tract, which generally manifests as Crohn's disease [CD] or ulcerative colitis [UC]. These subtypes are heterogeneous in terms of disease location and histological features, while sharing common clinical presentation, genetic associations and, thus, common immune regulatory pathways., Methods: Using miRNA and mRNA coupled transcriptome profiling and systems biology approaches, we report a comprehensive analysis of blood transcriptomes from treatment-naïve [n = 110] and treatment-exposed [n = 177] IBD patients as well as symptomatic [n = 65] and healthy controls [n = 95]., Results: Broadly, the peripheral blood transcriptomes of CD and UC patients were similar. However, there was an extensive gene deregulation in the blood of IBD patients, while only a slight deregulation in symptomatic controls, when compared with healthy controls. The deregulated mRNAs and miRNAs are mainly involved in the innate immunity and are especially enriched in neutrophil activation-related pathways. Oxidative phosphorylation and neutrophil activation-related modules were found to be differentially co-expressed among treatment-naïve IBD as compared to healthy controls. In the deregulated neutrophil activation-related co-expression module, IL1B was identified as the central gene. Levels of co-expression among IL1B and chemosensing receptor [CXCR1/2 and FPR1/2] genes were reduced in the blood of IBD patients when compared with healthy controls., Conclusions: Immune dysregulation seen in peripheral blood transcriptomes of treatment-naïve IBD patients is mainly driven by neutrophil activation., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background and Aims: Patient-reported outcome measures [PROMs] aim to measure patients' perception of how their disorder influences everyday functioning. The objective of this study was to develop a PROM to assess disease activity in microscopic colitis [MC] fulfilling the requirements of the Food and Drug Administration [FDA]., Methods: The European Microscopic Colitis Activity Index [E-MCAI] was developed in four steps. [1] A list of symptoms associated with active MC was created by a group of experts in the field. [2] Content validity of the symptoms was performed by experts [n = 14] and patients [n = 79] using the Content Validity Index. [3] Questions and response alternatives were created for each symptom, and validity of the E-MCAI was evaluated with cognitive interviews with patients [n = 7] and by the experts. [4] A pilot postal survey was performed to ensure usability., Results: Seven of the symptoms related to active MC fulfilled the criteria for content validity and were included in the E-MCAI: stool consistency, stool frequency, stools at night, feel a need to pass more stools shortly after a bowel movement, urgent need to empty the bowel, leakage of stool and abdominal pain. The development and validation process resulted in the current version of the E-MCAI consisting of six questions related to MC., Conclusions: The E-MCAI was developed using the methods advocated by the FDA. The evaluation indicates good content validity. Further evaluation will be performed to achieve construct validity, reliability and responsiveness in future cross-sectional and longitudinal studies., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aim: Increased frequencies of T regulatory (Treg) cells, key players in immune regulation, have been reported in inflammatory bowel diseases, including collagenous colitis (CC). However, traditional Treg identification techniques might have misinterpreted the frequencies of Treg cells in CC. Thus, we investigated the presence of genuine Treg cells in CC., Methods: Treg cells were analyzed in mucosal and peripheral blood samples of CC patients before and during treatment with the corticosteroid drug budesonide and in healthy controls. Samples were analyzed by flow cytometry by classifying CD3+CD4+ cells as activated FoxP3highCD45RA- Treg cells, resting FoxP3dimCD45RA+ Treg cells, and nonsuppressive FoxP3dimCD45RA- T helper cells. Traditional gating strategies that classified Treg cells as CD25highCD127low, FoxP3+CD127low, and CD4+CD25+FoxP3+ were also used to facilitate comparison with previous studies., Results: Activated and resting Treg cell frequencies did not change in active CC mucosa or peripheral blood and were not affected by budesonide treatment. Instead, nonsuppressive FoxP3dimCD45RA- T helper cells were increased in active CC mucosa, and budesonide helped restore them to normal levels. In contrast, traditional Treg cell gating strategies resulted in increased Treg cell frequencies in active CC mucosa. No alterations were found in peripheral blood samples, independently of patient treatment or gating techniques., Conclusion: Previously reported increase of Treg cells is a result of incomplete Treg phenotyping, which included nonsuppressive FoxP3dimCD45RA- T helper cells. Because budesonide did not affect Treg percentage, its therapeutic effect in CC might involve alternative mechanisms., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Barrier dysfunction is recognized as a pathogenic factor in ulcerative colitis (UC) and irritable bowel syndrome (IBS), but it is unclear to what extent the factors related to barrier dysfunction are disease-specific. The aim of this study was to compare these aspects in UC patients in remission, IBS patients, and healthy controls (HCs)., Methods: Colonic biopsies were collected from 13 patients with UC in remission, 15 patients with IBS-mixed, and 15 HCs. Ulcerative colitis patients had recently been treated for relapse, and biopsies were taken from earlier inflamed areas. Biopsies were mounted in Ussing chambers for measurements of intestinal paracellular permeability to 51chromium (Cr)-ethylenediaminetetraacetic acid (EDTA). In addition, biopsies were analyzed for mast cells and eosinophils by histological procedures, and plasma tumor necrosis factor (TNF)-α was assessed by ELISA., Results: Ussing chamber experiments revealed an increased 51Cr-EDTA permeability in UC and IBS (P < 0.05). The 51Cr-EDTA permeability was higher in UC compared with IBS (P < 0.005). There were increased numbers of mucosal mast cells and eosinophils in UC and IBS and more eosinophils in UC compared with IBS (P < 0.05). Also, increased extracellular granule content was found in UC compared with HCs (P < 0.05). The 51Cr-EDTA permeability correlated significantly with eosinophils in all groups. Plasma TNF-α concentration was higher in UC compared with IBS and HCs (P < 0.0005)., Conclusions: Results indicate a more permeable intestinal epithelium in inactive UC and IBS compared with HCs. Ulcerative colitis patients, even during remission, demonstrate a leakier barrier compared with IBS. Both eosinophil numbers and activation state might be involved in the increased barrier function seen in UC patients in remission., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Objective: To evaluate the prevalence of anemia and iron deficiency (ID) among patients with inflammatory bowel disease (IBD) in the Scandinavian countries., Material and Methods: A cross-sectional study including 429 IBD patients from six centers in Denmark, Norway and Sweden. Patients were screened for anemia and ID. Each center included ~5% of their IBD cohort. Patients were consecutively seen in the outpatient clinic, regardless of disease activity and whether the visits were scheduled or not., Results: The overall prevalence of anemia was 19% (95% CI: 16-23%). The prevalence was higher among patients with Crohn's disease than among patients with ulcerative colitis (p = 0.01). The etiology of anemia was as follows: iron deficiency anemia (20%), anemia of chronic disease (12%), and both conditions (68%). Less than 5% had folate acid or vitamin B12 deficiency. ID was found in 35% (CI: 31-40%) of the patients., Conclusions: Anemia was present in every fifth IBD patient and ID in every third IBD patient.

Objectives: The association between abdominal symptoms, disease severity of fecal incontinence (FI), and quality of life (QoL) is not yet clear. We hypothesized that it would become clearer by prospective diary data. We also aimed to compare QoL of FI patients with ulcerative colitis (UC) patients in relapse and remission., Material and Methods: Sixty-five consecutive female patients with FI recorded bowel symptoms prospectively on diary cards. QoL was evaluated with the disease specific short health scale questionnaire (SHS). Patients with UC in remission and relapse were used as a reference group regarding SHS., Results: FI patients had median 3.5 leakage episodes/week. In all, 48% of bowel movements were associated with urgency. Urgency was correlated to decreased QoL according to SHS domains: symptoms (Rho = 0.54, p = 0.0002), function (Rho = 0.48, p = 0.0008), and disease related worry (Rho = 0.32, p = 0.027). Abdominal pain and bloating, reported by nearly half of patients, correlated to deceased QoL but not to number of leakages. QoL of patients with FI compared to UC in active phase (n = 35) was similar. FI patients had decreased QoL compared to UC in remission (n = 94) in all dimensions of SHS: symptoms (p < 0.0001), function (p < 0.0001), disease related worry (p < 0.0001), and general well being (p = 0.03)., Conclusion: Urgency and irritable bowel syndrome (IBS)-like symptoms were associated with decreased QoL in FI. Therefore, IBS should be considered as an important confounding factor in FI QoL studies. QoL in patients with FI was considerably decreased, in a similar extent as in patients with UC in relapse.

Objective: Health-related quality of life (HRQoL) is an important measure of inflammatory bowel disease (IBD) health outcome. The Inflammatory Bowel Disease Questionnaire (IBDQ) comprising 32 items grouped into four dimensions is a widely used IBD-specific HRQoL instrument. The purpose of this study was to evaluate the validity, reliability and responsiveness of the Swedish translation of the IBDQ in patients with Crohn's disease (CD)., Material and Methods: Four hundred and forty-eight patients with CD completed the IBDQ and three other HRQoL questionnaires (Rating Form of IBD Patient Concerns; Short Form-36; and the Psychological General Well-Being Index) in connection with their regular visit at the outpatient clinic. Disease activity was assessed by the physician on a 4-point Likert scale. Thirty-two patients who were stable in remission completed the questionnaires a second time, 4 weeks later. A total of 418 patients repeated all measurements after 6 months., Results: The dimensional scores were highly correlated with other measures of corresponding aspects of HRQoL and were significantly better in remission than in relapse. High test-retest correlations indicated good reliability. Responsiveness was confirmed in patients whose disease activity changed over time. However, high correlations between the dimensions, poor correlations between items within each dimension, and factor analysis all indicated that the original grouping of the items is not valid for Swedish CD patients., Conclusions: Although the Swedish IBDQ has good external validity, reliability and responsiveness for patients with CD, our results did not support the original grouping of the items.