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.

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.

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.

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.

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.

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.

Faecal Microbiota Dynamics and their Relation to Disease Course in Crohn's Disease.

BACKGROUND: Microbial shifts have been associated with disease activity in Crohn's disease [CD], but findings on specific taxa are inconsistent. This may be due to differences in applied methods and cross-sectional study designs. We prospectively examined the faecal microbiota in adult CD patients with changing or stable disease course over time. METHODS: Faeces were collected at two time-points from 15 healthy control individuals [HCs], 35 CD patients who were in remission and who maintained remission [RRs], and 22 CD patients during remission and also during subsequent exacerbation [RAs]. The microbial composition was assessed by 16S rRNA [V4] gene sequencing. RESULTS: Compared with HCs, patients with CD had a lower microbial richness [p = 0.0002] and diversity [p = 0.005]. Moreover, the microbial community structure of a subset of patients, clustered apart from HCs, was characterized by low microbial diversity and Faecalibacterium abundance. Patients within this cluster did not differ with respect to long-term disease course compared with patients with a 'healthy-appearing' microbiota.Over time, microbial richness and diversity did not change in RR versus RA patients. Although the microbial community structure of both RR and RA patients was less stable over time compared with that of HCs, no differences were observed between the patient groups [p = 0.17]; nor was the stability impacted by Montreal classification, medication use, or surgery. CONCLUSION: The altered microbiota composition and stability in CD was neither associated with disease activity nor long-term disease course, questioning its involvement in the development of an exacerbation. The aberrant microbiota composition in a subset of CD patients warrants further exploration of a more microbiota-driven etiology in this group.

Development and Validation of a Patient-reported Score to Screen for Mucosal Inflammation in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Patient-reported outcome measures [PROMs] assessing inflammatory bowel disease [IBD] activity are of interest for monitoring in clinical practice, telemedicine systems, or trials. Different PROMs for follow-up of disease activity are available; however, none was developed with endoscopy as gold standard. The objective of this study was to develop and validate a PROM to predict endoscopic disease activity, following the recommendations of the Food and Drug Administration. METHODS: During development, 178 IBD patients undergoing a colonoscopy were asked to fill out 13 clinical questions derived from the literature. During endoscopy, inflammation was assessed with the simplified endoscopic score for Crohn's disease [CD] and the Mayo endoscopic subscore for ulcerative colitis [UC]. Based on correlation with endoscopic inflammation, questions were reduced to a total of six for CD and five for UC. The newly developed Monitor IBD At Home questionnaire [MIAH] was validated in an independent cohort of 135 CD and 131 UC patients. Additionally, diagnostic accuracy of the MIAH combined with a calprotectin home test [CHT] was assessed. RESULTS: The MIAH-CD includes questions on rectal bleeding, mucus, stool frequency, urgency, fatigue, and patient-reported disease activity. The MIAH-UC contains items on rectal bleeding, stool frequency, urgency, abdominal pain, and patient-reported disease activity. Both questionnaires showed to be valid, reliable, and responsive to changes. The MIAH and CHT combined had a sensitivity, specificity, negative predictive value [NPV], and positive predicitive value [PPV] of 96.7%, 66.7%, 94.7%, and 76.3% for CD and of 88.2%, 81.4%, 95.6%, and 60.0% for UC, respectively, compared with endoscopy. CONCLUSIONS: The MIAH is the first PROM developed to predict endoscopic inflammation in IBD patients. A combination of this questionnaire and a CHT shows excellent diagnostic accuracy to screen for patients who need further assessment of disease activity, and can be used in daily practice, telemedicine systems, and trials.

Incidence and Classification of Postcolonoscopy Colorectal Cancers in Inflammatory Bowel Disease: A Dutch Population-Based Cohort Study.

BACKGROUND AND AIMS: Patients with inflammatory bowel disease [IBD] colitis are at increased risk for colorectal cancer [CRC]. We examined the proportion and most likely aetiology of potentially preventable postcolonoscopy CRCs [PCCRCs] in a population-based cohort. Furthermore, adherence to IBD surveillance guidelines was evaluated in both PCCRCs and the remainder of prevalent CRCs. METHODS: All IBD patients diagnosed from 1991 to 2011 in the South Limburg region of The Netherlands [i.e. IBDSL cohort] were included. CRC cases were cross-checked with the Dutch pathology database and cancer registry. PCCRCs were defined as cancers diagnosed within 6-60 months after a colonoscopy and were classified as attributable to 'inappropriate surveillance interval', 'inadequate bowel examination', 'incomplete resection', 'missed lesion' or 'newly developed cancer'. RESULTS: Twenty CRC cases were identified during 25,931 patient years of follow-up in 2,801 patients. The proportion of PCCRCs was 45.0%. Of these, 55.6% could be considered a 'missed lesion', while other possible aetiologies occurred only once. Considering both PCCRCs [n=9] and prevalent CRCs [n=11], ten were detected after publication of the surveillance guideline, but only three patients were enrolled. Moreover, 6 CRCs [30.0%] were detected before the recommended start of surveillance. CONCLUSIONS: In the IBDSL cohort, 45.0% of all CRCs were considered to be PCCRCs, mainly classified as missed lesions. Additionally, a large proportion of CRCs in our cohort were observed before a surveillance endoscopy was performed. Therefore, stringent adherence to IBD surveillance guidelines, improving endoscopy techniques and adjusting the surveillance program may lead to a decrease in CRC incidence.

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.

Plasma intestinal fatty acid-binding protein fails to predict endoscopic disease activity in inflammatory bowel disease patients.

BACKGROUND: Monitoring disease activity in inflammatory bowel disease (IBD) is of major importance to prevent long-term complications. Intestinal fatty acid-binding protein (I-FABP) has been identified as a marker for intestinal damage and correlates with the degree of inflammation. The aim of the present study was to evaluate whether I-FABP can predict active disease or remission in Crohn's disease (CD) and ulcerative colitis (UC) in a real-life IBD cohort. METHODS: In total, 70 patients with endoscopic disease activity available and 194 patients with disease activity on the basis of a stringent combi-score of clinical activity index, C-reactive protein, and fecal calprotectin were included. Plasma I-FABP was compared between patients with active disease and remission. In a small subgroup of CD patients, follow-up samples were analyzed. RESULTS: In CD (139.2 vs. 119.2 pg/ml; P=0.37) and UC (107.8 vs. 151.8 pg/ml; P=0.33), the median I-FABP did not differ in endoscopic active disease versus remission. In UC patients with active disease on the basis of the combi-score, the median I-FABP (106.8 vs. 172.0 pg/ml; P=0.03) was significantly lower than in patients in remission, but not in CD (145.5 vs. 157.5 pg/ml; P=0.29). Neither disease location in CD nor extent of disease in UC influenced I-FABP significantly. I-FABP was not different (P=0.78) in CD patients with a change in disease activity over time. CONCLUSION: Plasma I-FABP did not differ between endoscopic active disease and remission in both CD and UC. I-FABP was lower in active UC but not CD on the basis of the combi-score. On the basis of these findings, I-FABP has no potential as a novel noninvasive biomarker for disease activity in IBD.

Concordance in Anti-OmpC and Anti-I2 Indicate the Influence of Genetic Predisposition: Results of a European Study of Twins with Crohn's Disease.

BACKGROUND AND AIMS: An adaptive immunological response to microbial antigens has been observed in Crohn's disease (CD). Intriguingly, this serological response precedes the diagnosis in some patients and has also been observed in healthy relatives. We aimed to determine whether genetic factors are implicated in this response in a CD twin cohort. METHODS: In total, 82 twin pairs (Leuven n = 13, Maastricht n = 8, Örebro n = 61) took part: 81 pairs with CD (concordant monozygotic n = 16, discordant monozygotic n = 22, concordant dizygotic n = 3, discordant dizygotic n = 40) and 1 monozygotic pair with both CD and ulcerative colitis. Serology for Pseudomonas fluorescens-related protein (anti-I2), Escherichia coli outer membrane porin C (anti-OmpC), CBir1flagellin (anti-CBir1) and antibodies to oligomannan (anti-Saccharomyces cerevisiae antibody [ASCA]) was determined by standardized enzyme-linked immunoassay. RESULTS: All markers were more often present in CD twins than in their healthy twin siblings. Using the intraclass correlation coefficient (ICC), agreements in concentrations of anti-OmpC and anti-I2 were observed in discordant monozygotic but not in discordant dizygotic twin pairs with CD (anti-OmpC, ICC 0.80 and -0.02, respectively) and (anti-I2, ICC 0.56 and 0.05, respectively). In contrast, no agreements were found in anti-CBir, immunoglobulin (Ig) G ASCA and ASCA IgA. CONCLUSIONS: We show that anti-I2 and anti-CBir1 statuses have specificity for CD and confirm previous reported specificities for anti-OmpC and ASCA. Based on quantitative analyses and observed ICCs, genetics seems to predispose to the anti-OmpC and anti-I2 response but less to ASCA and anti-CBir1 responses.

Volatile Organic Compounds in Exhaled Air as Novel Marker for Disease Activity in Crohn's Disease: A Metabolomic Approach.

BACKGROUND: Disappearance of macroscopic mucosal inflammation predicts long-term outcome in Crohn's disease (CD). It can be assessed by ileocolonoscopy, which is, however, an invasive and expensive procedure. Disease activity indices do not correlate well with endoscopic activity and noninvasive markers have a low sensitivity in subgroups of patients. Volatile organic compounds (VOCs) in breath are of increasing interest as noninvasive markers. The aim of this study was to investigate whether VOCs can accurately differentiate between active CD and remission. METHODS: Patients participated in a 1-year follow-up study and Harvey-Bradshaw index, blood, fecal, and breath samples were collected at regular intervals. Patients were stratified into 2 groups: active (fecal calprotectin >250 µg/g) or inactive (Harvey-Bradshaw index <4, C-reactive protein <5 mg/L, and fecal calprotectin <100 µg/g) disease. Breath samples were analyzed by gas chromatography-time-of-flight mass spectrometry. Random forest analyses were used to find the most discriminatory VOCs. RESULTS: Eight hundred thirty-five breath-o-grams were measured, 140 samples were assigned as active, 135 as inactive disease, and 110 samples of healthy controls. A set of 10 discriminatory VOCs correctly predicted active CD in 81.5% and remission in 86.4% (sensitivity 0.81, specificity 0.80, AUC 0.80). These VOCs were combined into a single disease activity score that classified disease activity in more than 60% of the previously undetermined individuals. CONCLUSIONS: We showed that VOCs can separate healthy controls and patients with active CD and CD in remission in a real-life cohort. Analysis of exhaled air is an interesting new noninvasive application for monitoring mucosal inflammation in inflammatory bowel disease.

Is clostridium difficile associated with relapse of inflammatory bowel disease? results from a retrospective and prospective cohort study in the Netherlands.

BACKGROUND: Although Clostridium difficile may be associated with exacerbations in inflammatory bowel diseases (IBD), prospective studies identifying the role of C. difficile in disease activity are currently lacking. We examined the prevalence of C. difficile in feces of (1) symptomatic IBD patients retrospectively and (2) consecutive outpatients in relation to disease activity prospectively. METHODS: From adult IBD patients with increase of symptoms, fecal samples collected between November 2010 and 2011 were tested for C. difficile, Salmonella, Shigella, Yersinia, and Campylobacter spp. Within a prospective IBD cohort, fecal samples, clinical data, and disease activity scores were collected every 3 months and during relapses. Baseline samples from all subjects (170 Crohn's disease, 116 ulcerative colitis) and additional samples from patients with changing disease activity during follow-up (57 Crohn's disease, 31 ulcerative colitis) were tested for C. difficile and when positive for toxin A and B genes by quantitative polymerase chain reaction. RESULTS: From 104 symptomatic patients, 139 fecal samples were analyzed. Toxinogenic C. difficile and Campylobacter jejuni were detected in 3.6% and 1.8%. In the prospective cohort, C. difficile prevalence at baseline was significantly different neither between ulcerative colitis (3.4%) and Crohn's disease patients (5.9%) nor between active (8.2%) and quiescent (3.3%) disease. In multivariable analysis, C. difficile was not associated with disease activity, disease subtype, gender, antibiotic, and immunosuppressive therapy. Clostridium difficile was also not associated with disease activity within patients with changing disease activity over time (P = 0.45). CONCLUSIONS: We found a low prevalence of C. difficile, and our findings indicate that C. difficile is not a common trigger for exacerbations of IBD in clinical practice in the Netherlands.

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.