Stephan R. Vavricka

Fecal calprotectin correlates more closely with the Simple Endoscopic Score for Crohn's disease (SES-CD) than CRP, blood leukocytes, and the CDAI

OBJECTIVES:Studies evaluating the correlation between the widely used Simple Endoscopic Score for Crohns disease (SES-CD) and noninvasive markers are scarce. The aim of this study was to evaluate the correlation between the SES-CD and fecal calprotectin, C-reactive protein (CRP), blood leukocytes, and the Crohns disease activity index (CDAI).METHODS:Crohns disease patients undergoing complete ileocolonoscopy were prospectively enrolled and scored independently according to the SES-CD and the CDAI. SES-CD was defined as follows: inactive 0–3; mild 4–10; moderate 11–19; and high ≥20.RESULTS:Values in CD patients (n=140 ileocolonoscopies) compared with controls (n=43) are as follows: calprotectin, 334±322 vs. 18±5 μg/g; CRP, 26±29 vs. 3±2 mg/l; and blood leukocytes, 9.1±3.4 vs. 5.4±1.9 g/l (all P<0.001). The SES-CD correlated closest with calprotectin (Spearmans rank correlation coefficient r=0.75), followed by CRP (r=0.53), blood leukocytes (r=0.42), and the CDAI (r=0.38). Calprotectin was the only marker that could discriminate inactive endoscopic disease from mild activity (104±138 vs. 231±244 μg/g, P<0.001), mild from moderate activity (231±244 vs. 395±256 μg/g, P=0.008), and moderate from high activity (395±256 vs. 718±320 μg/g, P<0.001). The overall accuracy for the detection of endoscopically active disease was 87% for calprotectin (cutoff 70 μg/g), 66% for elevated CRP, 54% for blood leukocytosis, and 40% for the CDAI ≥150.CONCLUSIONS:Fecal calprotectin correlated closest with SES-CD, followed by CRP, blood leukocytes, and the CDAI. Furthermore, fecal calprotectin was the only marker that reliably discriminated inactive from mild, moderate, and highly active disease, which underlines its usefulness for activity monitoring.

Frequency and risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort.

OBJECTIVES:Data on the frequency of extraintestinal manifestations (EIMs) in Crohns disease (CD) and ulcerative colitis (UC) and analyses of their risk factors are scarce. We evaluated their prevalence and risk factors in a large nationwide cohort of inflammatory bowel disease (IBD) patients.METHODS:IBD patients from an adult clinical cohort in Switzerland (Swiss IBD cohort study) were prospectively included. Data from validated physician enrolment questionnaires were analyzed.RESULTS:A total of 950 patients were included, 580 (61%) with CD (mean age 41 years) and 370 (39%) with UC (mean age 42 years). Of these, 249 (43%) of CD and 113 (31%) of UC patients had one to five EIMs. The following EIMs were found: arthritis (CD 33%, UC 21%), aphthous stomatitis (CD 10%, UC 4%), uveitis (CD 6%, UC 4%), erythema nodosum (CD 6%, UC 3%), ankylosing spondylitis (CD 6%, UC 2%), psoriasis (CD 2%, UC 1%), pyoderma gangrenosum (CD and UC each 2%), and primary sclerosing cholangitis (CD 1%, UC 4%). Multiple logistic regression identified the following risk factors for ongoing EIM in CD: active disease (odds ratio (OR)=1.95, 95% confidence interval (CI)=1.17–3.23, P=0.01), and positive IBD family history (OR=1.77, 95% CI=1.07–2.92, P=0.025). No risk factors were identified in UC patients.CONCLUSIONS:EIMs are a frequent problem in CD and UC patients. Active disease and positive IBD family history are associated with ongoing EIM in CD patients. Identification of EIM prevalence and associated risk factors may result in increased awareness for this problem and thereby facilitating their diagnosis and therapeutic management.

Regional Distribution of Solute Carrier mRNA Expression Along the Human Intestinal Tract

Intestinal absorption of drugs, nutrients, and other compounds is mediated by uptake transporters expressed at the apical enterocyte membrane. These compounds are returned to the intestinal lumen or released into portal circulation by intestinal efflux transporters expressed at apical or basolateral membranes, respectively. One important transporter superfamily, multiple members of which are intestinally expressed, are the solute carriers (SLCs). SLC expression levels may determine the pharmacokinetics of drugs that are substrates of these transporters. In this study we characterize the distribution of 15 human SLC transporter mRNAs in histologically normal biopsies from five regions of the intestine of 10 patients. The mRNA expression levels of CNT1, CNT2, apical sodium-dependent bile acid transporter (ABST), serotonin transporter (SERT), PEPT1, and OCTN2 exhibit marked differences between different regions of the intestine: the first five are predominantly expressed in the small intestine, whereas OCTN2 exhibits strongest expression in the colon. Two transporter mRNAs studied (OCTN1, OATP2B1) are expressed at similar levels in all gut sections. In addition, ENT2 mRNA is present at low levels across the colon, but not in the small intestine. The other six SLC mRNAs studied are not expressed in the intestine. Quantitative knowledge of transporter expression levels in different regions of the human gastrointestinal tract could be useful for designing intestinal delivery strategies for orally administered drugs. Furthermore, changes in transporter expression that occur in pathological states, such as inflammatory bowel disease, can now be defined more precisely by comparison with the expression levels measured in healthy individuals.

pH-dependent internalization of muramyl peptides from early endosomes enables Nod1 and Nod2 signaling

Nod1 and Nod2 are members of the Nod-like receptor family that detect intracellular bacterial peptidoglycan-derived muramyl peptides. The biological effects of muramyl peptides have been described for over three decades, but the mechanism underlying their internalization to the cytosol remains unclear. Using the human epithelial cell line HEK293T as a model system, we demonstrate here that Nod1-activating ligands entered cells through endocytosis, most likely by the clathrin-coated pit pathway, as internalization was dynamin-dependent but not inhibited by methyl-β-cyclodextrin. In the endocytic pathway, the cytosolic internalization of Nod1 ligands was pH-dependent, occurred prior to the acidification mediated by the vacuolar ATPase, and was optimal at pH ranging from 5.5 to 6. Similarly, the Nod2 ligand MDP was internalized into host cytosol through a similar pathway with optimal pH for internalization ranging from 5.5 to 6.5. Moreover, Nod1-activating muramyl peptides likely required processing by endosomal enzymes, prior to transport into the cytosol, suggesting the existence of a sterically gated endosomal transporter for Nod1 ligands. In support for this, we identified a role for SLC15A4, an oligopeptide transporter expressed in early endosomes, in Nod1-dependent NF-κB signaling. Interestingly, SLC15A4 expression was also up-regulated in colonic biopsies from patients with inflammatory bowel disease, a disorder associated with mutations in Nod1 and Nod2. Together, our results shed light on the mechanisms by which muramyl peptides get access to the host cytosol, where they are detected by Nod1 and Nod2, and might have implications for the understanding of human diseases, such as inflammatory bowel disease.

European consensus on the diagnosis and management of iron deficiency and anaemia in inflammatory bowel diseases

European Consensus on the Diagnosis and Management of Iron Deficiency and Anaemia in Inflammatory Bowel Diseases

Fecal calprotectin more accurately reflects endoscopic activity of ulcerative colitis than the Lichtiger Index, C-reactive protein, platelets, hemoglobin, and blood leukocytes

Background:The correlation between noninvasive markers with endoscopic activity according to the modified Baron Index in patients with ulcerative colitis (UC) is unknown. We aimed to evaluate the correlation between endoscopic activity and fecal calprotectin (FC), C-reactive protein (CRP), hemoglobin, platelets, blood leukocytes, and the Lichtiger Index (clinical score). Methods:UC patients undergoing complete colonoscopy were prospectively enrolled and scored clinically and endoscopically. Samples from feces and blood were analyzed in UC patients and controls. Results:We enrolled 228 UC patients and 52 healthy controls. Endoscopic disease activity correlated best with FC (Spearmans rank correlation coefficient r = 0.821), followed by the Lichtiger Index (r = 0.682), CRP (r = 0.556), platelets (r = 0.488), blood leukocytes (r = 0.401), and hemoglobin (r = −0.388). FC was the only marker that could discriminate between different grades of endoscopic activity (grade 0, 16 [10–30] &mgr;g/g; grade 1, 35 [25–48] &mgr;g/g; grade 2, 102 [44–159] &mgr;g/g; grade 3, 235 [176–319] &mgr;g/g; grade 4, 611 [406–868] &mgr;g/g; P < 0.001 for discriminating the different grades). FC with a cutoff of 57 &mgr;g/g had a sensitivity of 91% and a specificity of 90% to detect endoscopically active disease (modified Baron Index ≥2). Conclusions:FC correlated better with endoscopic disease activity than clinical activity, CRP, platelets, hemoglobin, and blood leukocytes. The strong correlation with endoscopic disease activity suggests that FC represents a useful biomarker for noninvasive monitoring of disease activity in UC patients.

Smoking cessation induces profound changes in the composition of the intestinal microbiota in humans.

Background The human intestinal microbiota is a crucial factor in the pathogenesis of various diseases, such as metabolic syndrome or inflammatory bowel disease (IBD). Yet, knowledge about the role of environmental factors such as smoking (which is known to influence theses aforementioned disease states) on the complex microbial composition is sparse. We aimed to investigate the role of smoking cessation on intestinal microbial composition in 10 healthy smoking subjects undergoing controlled smoking cessation. Methods During the observational period of 9 weeks repetitive stool samples were collected. Based on abundance of 16S rRNA genes bacterial composition was analysed and compared to 10 control subjects (5 continuing smokers and 5 non-smokers) by means of Terminal Restriction Fragment Length Polymorphism analysis and high-throughput sequencing. Results Profound shifts in the microbial composition after smoking cessation were observed with an increase of Firmicutes and Actinobacteria and a lower proportion of Bacteroidetes and Proteobacteria on the phylum level. In addition, after smoking cessation there was an increase in microbial diversity. Conclusions These results indicate that smoking is an environmental factor modulating the composition of human gut microbiota. The observed changes after smoking cessation revealed to be similar to the previously reported differences in obese compared to lean humans and mice respectively, suggesting a potential pathogenetic link between weight gain and smoking cessation. In addition they give rise to a potential association of smoking status and the course of IBD.

Changes in mRNA expression levels of solute carrier transporters in inflammatory bowel disease patients

Inflammatory bowel disease (IBD) is an inflammatory condition that affects the gastrointestinal tract. The solute carrier (SLC) superfamily of transporters comprise proteins involved in the uptake of drugs, hormones, and other biologically active compounds. The purpose of this study was to determine the mRNA expression levels of 15 solute carrier transporters in two regions of the intestine in IBD patients. Endoscopic biopsy specimens were taken from two locations (terminal ileum and colon) for histological examination and RNA extraction. We quantitatively measured the mRNA expression of 15 SLC transporters in 107 IBD patients (53 with Crohns disease and 54 with ulcerative colitis) and 23 control subjects. mRNA expression was evaluated using the quantitative reverse transcription-polymerase chain reaction technique. We observed that in the ileum of IBD patients, mRNA levels for serotonin transporter, equilibrative nucleoside transporter (ENT) 1, ENT2, and organic anion-transporting polypeptide (OATP) 2B1 were significantly elevated, whereas levels for apical sodium-dependent bile acid transporter (ASBT) and organic zwitterion/cation transporter (OCTN) 2 were significantly lower. In colon, mRNA levels for ENT1, ENT2, concentrative nucleoside transporter (CNT) 2, OATP2B1, and OATP4A1 were significantly higher, whereas mRNA levels for OCTN2 were significantly decreased. In inflamed colon of IBD patients the mRNA expression levels of ENT1, ENT2, CNT2, OATP2B1, OATP4A1, and peptide transporter 1 were significantly higher. We conclude that intestinal SLC mRNA levels are dysregulated in IBD patients, which may be linked to the inflammation of the tissue and provides an indication about the role of inflammatory signaling in regulation of SLC expression.

Systematic evaluation of risk factors for diagnostic delay in inflammatory bowel disease

Background: The diagnosis of inflammatory bowel disease (IBD), comprising Crohns disease (CD) and ulcerative colitis (UC), continues to present difficulties due to unspecific symptoms and limited test accuracies. We aimed to determine the diagnostic delay (time from first symptoms to IBD diagnosis) and to identify associated risk factors. Methods: A total of 1591 IBD patients (932 CD, 625 UC, 34 indeterminate colitis) from the Swiss IBD cohort study (SIBDCS) were evaluated. The SIBDCS collects data on a large sample of IBD patients from hospitals and private practice across Switzerland through physician and patient questionnaires. The primary outcome measure was diagnostic delay. Results: Diagnostic delay in CD patients was significantly longer compared to UC patients (median 9 versus 4 months, P < 0.001). Seventy‐five percent of CD patients were diagnosed within 24 months compared to 12 months for UC and 6 months for IC patients. Multivariate logistic regression identified age <40 years at diagnosis (odds ratio [OR] 2.15, P = 0.010) and ileal disease (OR 1.69, P = 0.025) as independent risk factors for long diagnostic delay in CD (>24 months). In UC patients, nonsteroidal antiinflammatory drug (NSAID intake (OR 1.75, P = 0.093) and male gender (OR 0.59, P = 0.079) were associated with long diagnostic delay (>12 months). Conclusions: Whereas the median delay for diagnosing CD, UC, and IC seems to be acceptable, there exists a long delay in a considerable proportion of CD patients. More public awareness work needs to be done in order to reduce patient and doctor delays in this target population. (Inflamm Bowel Dis 2012;)

3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn's Disease 2016: Part 2: Surgical Management and Special Situations

This paper is the second in a series of two publications relating to the European Crohns and Colitis Organisation [ECCO] evidence-based consensus on the diagnosis and management of Crohns disease [CD] and concerns the surgical management of CD as well as special situations including management of perianal CD and extraintestinal manifestations. Diagnostic approaches and medical management of CD of this ECCO Consensus are covered in the first paper [Gomollon et al JCC 2016].