Abstract
Fatigue is a common and clinically challenging symptom in patients with inflammatory bowel diseases (IBD), occurring in ~ 50% of patients with quiescent disease. In this study, we aimed to ...investigate whether fatigue in patients with clinically quiescent IBD is reflected by circulating inflammatory proteins, which might reflect ongoing subclinical inflammation. Ninety-two (92) different inflammation-related proteins were measured in plasma of 350 patients with clinically quiescent IBD. Quiescent IBD was defined as clinical (Harvey-Bradshaw Index < 5 or Simple Clinical Colitis Activity Index < 2.5) and biochemical remission (C-reactive protein < 5 mg/L and absence of anemia) at time of fatigue assessment. Leukemia inhibitory factor receptor (LIF-R) concentrations were inversely associated with severe fatigue, also after adjustment for confounding factors (nominal
P
< 0.05). Although solely LIF-R showed weak ability to discriminate between mild and severe fatigue (area under the curve AUC = 0.61, 95%CI: 0.53–0.69,
P
< 0.05), a combined set of the top seven (7) fatigue-associated proteins (all
P
< 0.10) was observed to have reasonable discriminative performance (AUC = 0.82 95%CI: 0.74–0.91,
P
< 0.01). Fatigue in patients with IBD is not clearly reflected by distinct protein signatures, suggesting there is no subclinical inflammation defined by the studied inflammatory proteins. Future studies are warranted to investigate other proteomic markers that may reflect fatigue in clinically quiescent IBD.
Background In multiple endocrine neoplasia type 1 (MEN1), pancreatic neuroendocrine tumors (pNETs) are the leading MEN1-related cause of death. Objective To evaluate EUS and11 C-5-hydroxytryptophan ...positron emission tomography (11 C-5-HTP PET), compared with the recommended screening techniques in MEN1 patients for early detection of pNETs. Design Cross-sectional study. Setting Tertiary-care university medical center. Patients This study involved 41 patients with a proven MEN1 mutation or with one MEN1 manifestation and a mutation carrier as a first-degree family member, with recent screening by abdominal CT or magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS). Interventions EUS by using a linear Pentax echoendoscope and Hitachi EUB-525 and11 C-5-HTP PET. Main Outcome Measurements Patient-based and lesion-based positivity for pNET was calculated for all imaging techniques. The McNemar test was used to compare the yield of the 4 imaging techniques. Results In 35 of 41 patients, 107 pancreatic lesions were detected in total. EUS detected 101 pancreatic lesions in 34 patients,11 C-5-HTP PET detected 35 lesions in 19 patients, and CT/MRI + SRS detected 32 lesions in 18 patients ( P < .001).11 C-5-HTP PET performed similarly to CT/MRI + SRS and better compared with SRS only (13 lesions in 12 patients), both at a patient-based and lesion-based level ( P < .05). Limitations Single-center study. Conclusion EUS is superior to CT/MRI + SRS for pancreatic lesion detection in patients with MEN1. In this setting,11 C-5-HTP PET is not useful. We recommend EUS as the first-choice pancreas imaging technique in patients with MEN1. (Clinical trial registration number: NTR1668 .)
Inflammatory bowel diseases (IBDs), e.g., Crohn’s disease (CD) and ulcerative colitis (UC), are chronic immune-mediated inflammatory diseases. A comprehensive overview of an IBD-specific antibody ...epitope repertoire is, however, lacking. Using high-throughput phage-display immunoprecipitation sequencing (PhIP-Seq), we identified antibodies against 344,000 antimicrobial, immune, and food antigens in 497 individuals with IBD compared with 1,326 controls. IBD was characterized by 373 differentially abundant antibody responses (202 overrepresented and 171 underrepresented), with 17% shared by both IBDs, 55% unique to CD, and 28% unique to UC. Antibody reactivities against bacterial flagellins dominated in CD and were associated with ileal involvement, fibrostenotic disease, and anti-Saccharomyces cerevisiae antibody positivity, but not with fecal microbiome composition. Antibody epitope repertoires accurately discriminated CD from controls (area under the curve AUC = 0.89), and similar discrimination was achieved when using only ten antibodies (AUC = 0.87). Individuals with IBD thus show a distinct antibody repertoire against selected peptides, allowing clinical stratification and discovery of immunological targets.
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•Characterized antibody (Ab) epitope repertoires in-depth in 497 individuals with IBD•Identified distinct Ab responses in people with IBD against 344,000 antigenic targets•Flagellin-directed antibodies dominate in CD and associate with complicated disease•Selected antibodies accurately discriminate individuals with IBD from controls
Inflammatory bowel diseases (IBDs) feature antibody responses against antigens that are generally not recognized by the host immune system. Bourgonje et al. investigated serum antibody responses against 344,000 microbial-, food-, and self-antigens in individuals with and without IBD using PhIP-Seq. They uncovered distinct antibody responses that were associated with IBD and specific disease characteristics.
Abstract
Background
Fatigue is one of the most frequently reported symptoms by patients with inflammatory bowel disease (IBD), both during active disease phases as well as during clinical remission. ...This study addressed whether different trajectories of fatigue over time can be identified among patients with IBD. Subsequently, we compared the demographic and clinical characteristics between trajectories.
Methods
The current study included 849 patients with IBD diagnosed with either Crohn disease (CD; n = 511) or ulcerative colitis (UC; n = 338) who visited the University Medical Center in Groningen (the Netherlands) at least 3 times during a 9-year follow-up. We conducted latent class growth analyses to identify distinct trajectories.
Results
In all patients with IBD (and in the subgroup with CD), we found 5 trajectories for fatigue. In the UC subgroup, we found 4 fatigue trajectories. One trajectory present in both patients with CD (11.45%) and patients with UC (4.75%) was characterized by chronic elevated levels of fatigue across time. Women and parents were more prevalent in trajectories with higher fatigue severity. We also found significant associations among the fatigue trajectories with disease activity and psychological well-being.
Conclusions
The results clearly showed the existence of distinct fatigue paths over time in patients with IBD. Those reporting more chronic elevated levels of fatigue also reported greater disease activity and reduced well-being. Therefore, reducing disease activity may be important for the treatment of fatigue. In addition, given the significant association with well-being, it is possible that reducing fatigue may improve self-reported well-being.
Patients with inflammatory bowel disease are at increased risk of colorectal neoplasia (CRN) due to mucosal inflammation. As current surveillance guidelines form a burden on patients and healthcare ...costs, stratification of high-risk patients is crucial. Cigarette smoke reduces inflammation in ulcerative colitis (UC) but not Crohn’s disease (CD) and forms a known risk factor for CRN in the general population. Due to this divergent association, the effect of smoking on CRN in IBD is unclear and subject of this study.
In this retrospective cohort study, 1,386 IBD patients with previous biopsies analyzed and reported in the PALGA register were screened for development of CRN. Clinical factors and cigarette smoke were evaluated. Patients were stratified for guideline-based risk of CRN. Cox-regression modeling was used to estimate the effect of cigarette smoke and its additive effect within the current risk stratification for prediction of CRN.
153 (11.5%) patients developed CRN. Previously described risk factors, i.e. first-degree family member with CRN in CD (p-value=.001), presence of post-inflammatory polyps in UC (p-value=.005), were replicated. Former smoking increased risk of CRN in UC (HR 1.73; 1.05-2.85), whereas passive smoke exposure yielded no effect. For CD, active smoking (2.20; 1.02–4.76) and passive smoke exposure (1.87; 1.09-3.20) significantly increased CRN risk. Addition of smoke exposure to the current risk-stratification model significantly improved model fit for CD.
This study is the first to describe the important role of cigarette smoke in CRN development in IBD patients. Adding this risk factor improves the current risk stratification for CRN surveillance strategies.
Background and Aim
While major efforts were made studying the complex etiology of inflammatory bowel disease (IBD) including environmental factors, less is known about underlying causes leading to ...the heterogeneous and highly variable course of disease. As cigarette smoking cessation is the best‐known environmental factor with beneficial effect in Crohn's disease (CD), more exposome factors are likely involved. Further insights into the role of the exposome in heterogeneity of disease might not only further knowledge of underlying pathways, but also allow for better risk stratification.
Methods
Seven hundred twenty‐eight IBD patients completed the validated Groningen IBD Environmental Questionnaire, collecting exposome data for 93 exposome factors. Associations with disease course, that is, for need for surgery or biological therapy, were evaluated using univariate and multivariate‐adjusted logistic regression modeling.
Results
No significant associations were seen after Bonferroni correction. However, 11 novel exposome factors were identified with P < 0.05. Two factors were associated with course of CD and ulcerative colitis (UC): beer (CD OR0.3/UC OR0.3) and cannabis (0.5/2.2). While in CD, carpet flooring (0.5) was associated with biological use, and four factors were associated with surgery: working shifts (1.8), appendectomy (2.4), frequent tooth brushing (2.8), and large household size (0.1). For UC, migrants more often required biologicals (10.2). Childhood underweight (3.4), amphetamine use (6.2), and cocaine use (4.8) were associated with surgery. Five factors were replicated.
Conclusions
We identified 16 environmental factors nominally associated with biological use and surgery in established IBD. These new insights form an important stepping stone to guide research on biological pathways involved, risk stratification, tailor‐made interventions, and preventive strategies in IBD.
Introduction
Patients with Inflammatory Bowel Disease (IBD) frequently receive immunomodulating treatment, which may render them at increased risk of an attenuated immune response upon vaccination. ...In this study, we assessed the effects of different types of commonly prescribed immunosuppressive medications on the serological response after vaccination against SARS-CoV-2 in patients with IBD.
Methods
In this prospective observational cohort study, IgG antibody titers against SARS-CoV-2 were measured 2-10 weeks after completion of standard vaccination regimens in patients with IBD. Clinical characteristics, previous history of SARS-CoV-2 infection, type of vaccine (mRNA- or vector-based) and medication use were recorded at the time of sampling. Subsequently, a chemiluminescent microparticle immunoassay was used for the quantitative determination of IgG antibodies against the receptor-binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2.
Results
Three hundred and twelve (312) patients with IBD were included (172 Crohn’s disease CD and 140 ulcerative colitis UC). Seroconversion (defined as titer of >50 AU/ml) was achieved in 98.3% of patients. Antibody concentrations were significantly lower in patients treated with TNF-α-antagonists
vs
. non-users of TNF-α-antagonists (geometric mean 95% confidence interval: 2204 1655-2935
vs
. 5002 4089-6116 AU/ml,
P
<0.001). In multivariable models, use of TNF-α-antagonists (
P
<0.001), vector vaccines (
P
<0.001), age (>50 years) (
P
<0.01) and CD (
P
<0.05) were independently associated with lower anti-SARS-CoV-2 antibody titers. In patients who received mRNA vaccines, users of thiopurines (either prescribed as monotherapy or in combination with biologicals) demonstrated significantly lower antibody titers compared to thiopurine non-users (
P
<0.05).
Conclusion
Despite reassuring findings that most patients with IBD have detectable antibodies after anti-SARS-CoV-2 vaccination, TNF-α-antagonists were found to be strongly associated with an attenuated IgG antibody response after vaccination against SARS-CoV-2, independent of vaccine type, the time elapsed after vaccination and blood sampling, prior SARS-CoV-2 infection and patient age. Patients treated with thiopurines and receiving mRNA-based vaccines demonstrated lower anti-SARS-CoV-2 antibody titers compared with non-users.
Abstract
Background
Hepcidin, the systemic iron regulator, could be critical in differentiating iron deficiency (ID) from functional iron restriction in inflammatory bowel disease (IBD). We assessed ...hepcidin as a diagnostic ID marker and explored the relationship between hepcidin and its regulators in patients with IBD undergoing induction therapy with infliximab (IFX) or vedolizumab (VEDO).
Methods
Patients with active IBD receiving induction therapy with IFX or VEDO were included. Serum samples at baseline and after 6 weeks of induction therapy were analyzed for hepcidin, inflammation- and hypoxia-associated cytokines, and oxidative stress. Data were analyzed by stratifying based on the response at week 14. Results were compared with samples from age- and sex-matched healthy control subjects.
Results
Patients receiving induction therapy with IFX (n = 71) or VEDO (n = 51) and healthy control subjects (n = 50) were included. At baseline, hepcidin correlated positively with ferritin and negatively with soluble transferrin receptor/log ferritin index (P < .001). ID was prevalent in 96.7% of patients who had hepcidin levels below the median. Hepcidin accurately identified ID: the area under the curve (hepcidin) was 0.89 (95% confidence interval, 0.82-0.95; P < .001). In total, 75.4% of patients responded to induction therapy; inflammation, hepcidin, and ferritin decreased significantly, while transferrin increased during induction therapy. These changes were observed only in patients who responded to the therapy.
Conclusions
Hepcidin levels in IBD are primarily determined by ID, even in an inflammatory state. In addition, induction therapy can decrease hepcidin levels, which might lead to better bioavailability of iron supplements. Therefore, hepcidin is a potential diagnostic ID biomarker that could assist therapeutic decision making.
Lay Summary
Absolute iron deficiency is the primary determinant of hepcidin levels, even in an inflammatory state. Induction therapy can decrease hepcidin levels, which might improve iron bioavailability. Hence, hepcidin is a potential diagnostic iron deficiency biomarker that could assist therapeutic decision making.
Graphical Abstract
Graphical Abstract
Abstract
Background and Aims
Crohn’s disease CD is characterised by chronic intestinal inflammation and dysbiosis in the gut. Riboflavin vitamin B2 has anti-inflammatory, antioxidant and ...microbiome-modulatory properties. Here, we analysed the effect of riboflavin on oxidative stress, markers of inflammation, clinical symptoms, and faecal microbiome in patients with CD.
Methods
In this prospective clinical intervention study, patients received 100 mg riboflavin DSM, Nutritional Products Ltd daily for 3 weeks. Clinical disease activity Harvey-Bradshaw Index: HBI, serum biomarkers of inflammation and redox status plasma free thiols, and faecal microbiome taxonomical composition and functionality fluorescent in situ hybridisation: FISH; and metagenomic shotgun sequencing: MGS, were analysed before and after riboflavin intervention.
Results
In total, 70 patients with CD with varying disease activity were included. Riboflavin supplementation significantly decreased serum levels of inflammatory markers. In patients with low faecal calprotectin FC levels, IL-2 decreased, and in patients with high FC levels, C-reactive protein CRP was reduced and free thiols significantly increased after supplementation. Moreover, HBI was significantly decreased by riboflavin supplementation. Riboflavin supplementation led to decreased Enterobacteriaceae in patients with low FC levels as determined by FISH; however, MGS analysis showed no effects on diversity, taxonomy, or metabolic pathways of the faecal microbiome.
Conclusions
Three weeks of riboflavin supplementation resulted in a reduction in systemic oxidative stress, mixed anti-inflammatory effects, and a reduction in clinical symptoms HBI. FISH analysis showed decreased Enterobacteriaceae in patients with CD with low FC levels, though this was not observed in MGS analysis. Our data demonstrate that riboflavin supplementation has a number of anti-inflammatory and anti-oxidant effects in CD.
ObjectiveRoutine urgent endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic biliary sphincterotomy (ES) does not improve outcome in patients with predicted severe acute biliary ...pancreatitis. Improved patient selection for ERCP by means of endoscopic ultrasonography (EUS) for stone/sludge detection may challenge these findings.DesignA multicentre, prospective cohort study included patients with predicted severe acute biliary pancreatitis without cholangitis. Patients underwent urgent EUS, followed by ERCP with ES in case of common bile duct stones/sludge, within 24 hours after hospital presentation and within 72 hours after symptom onset. The primary endpoint was a composite of major complications or mortality within 6 months after inclusion. The historical control group was the conservative treatment arm (n=113) of the randomised APEC trial (Acute biliary Pancreatitis: urgent ERCP with sphincterotomy versus conservative treatment, patient inclusion 2013–2017) applying the same study design.ResultsOverall, 83 patients underwent urgent EUS at a median of 21 hours (IQR 17–23) after hospital presentation and at a median of 29 hours (IQR 23–41) after start of symptoms. Gallstones/sludge in the bile ducts were detected by EUS in 48/83 patients (58%), all of whom underwent immediate ERCP with ES. The primary endpoint occurred in 34/83 patients (41%) in the urgent EUS-guided ERCP group. This was not different from the 44% rate (50/113 patients) in the historical conservative treatment group (risk ratio (RR) 0.93, 95% CI 0.67 to 1.29; p=0.65). Sensitivity analysis to correct for baseline differences using a logistic regression model also showed no significant beneficial effect of the intervention on the primary outcome (adjusted OR 1.03, 95% CI 0.56 to 1.90, p=0.92).ConclusionIn patients with predicted severe acute biliary pancreatitis without cholangitis, urgent EUS-guided ERCP with ES did not reduce the composite endpoint of major complications or mortality, as compared with conservative treatment in a historical control group.Trial registration numberISRCTN15545919.
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