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1.  Gut Microbial Diversity Is Reduced in Smokers with Crohn's Disease 
Inflammatory Bowel Diseases  2016;22(9):2070-2077.
Article first published online 10 August 2016.
Background:
Smoking has a negative impact on Crohn's disease (CD), but the mechanisms underlying this association are unclear. We compared the gut microbiota composition of smoking with nonsmoking patients with CD using a metagenomic approach.
Methods:
Stool samples and clinical data were collected from current smokers and nonsmokers with CD from France and the Netherlands, matched for country, gender, age, disease activity, and body mass index. Fecal DNA was sequenced on an Illumina HiSeq 2500. On average, 40 million paired-end reads were generated per sample. Gene richness and the Shannon index were computed to assess microbial diversity. Wilcoxon's signed-rank tests for paired samples were performed to detect differences between the 2 groups.
Results:
In total, 21 smoking and 21 nonsmoking patients with CD were included. Compared with nonsmoking patients, gut microbial gene richness (P = 0.01), genus diversity (P < 0.01), and species diversity (P = 0.01) were decreased in smoking patients. This was accompanied by a reduced relative abundance of the genera Collinsella (P = 0.02), Enterorhabdus (P = 0.02), and Gordonibacter (P = 0.02) in smokers. No statistically significant differences at the species level were observed, although smokers had lower proportions of Faecalibacterium prausnitzii (P = 0.10).
Conclusions:
Gut microbial diversity is reduced in smokers with CD compared with nonsmokers with CD. The microbial profile differs between these groups at the genus level. Future studies should evaluate whether intestinal microbes mediate the adverse effects of smoking in CD.
doi:10.1097/MIB.0000000000000875
PMCID: PMC4991341  PMID: 27542127
smoking; microbiota; Crohn's disease; inflammatory bowel disease; sequencing
2.  Pooled Resequencing of 122 Ulcerative Colitis Genes in a Large Dutch Cohort Suggests Population-Specific Associations of Rare Variants in MUC2 
PLoS ONE  2016;11(8):e0159609.
Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC.
doi:10.1371/journal.pone.0159609
PMCID: PMC4973970  PMID: 27490946
3.  Exposure to Ambient Air Pollution and the Risk of Inflammatory Bowel Disease: A European Nested Case–Control Study 
Digestive Diseases and Sciences  2016;61(10):2963-2971.
Background
Industrialization has been linked to the etiology of inflammatory bowel disease (IBD).
Aim
We investigated the association between air pollution exposure and IBD.
Methods
The European Prospective Investigation into Cancer and Nutrition cohort was used to identify cases with Crohn’s disease (CD) (n = 38) and ulcerative colitis (UC) (n = 104) and controls (n = 568) from Denmark, France, the Netherlands, and the UK, matched for center, gender, age, and date of recruitment. Air pollution data were obtained from the European Study of Cohorts for Air Pollution Effects. Residential exposure was assessed with land-use regression models for particulate matter with diameters of <10 μm (PM10), <2.5 μm (PM2.5), and between 2.5 and 10 μm (PMcoarse), soot (PM2.5 absorbance), nitrogen oxides, and two traffic indicators. Conditional logistic regression analyses were performed to calculate odds ratios (ORs) with 95 % confidence intervals (CIs).
Results
Although air pollution was not significantly associated with CD or UC separately, the associations were mostly similar. Individuals with IBD were less likely to have higher exposure levels of PM2.5 and PM10, with ORs of 0.24 (95 % CI 0.07–0.81) per 5 μg/m3 and 0.25 (95 % CI 0.08–0.78) per 10 μg/m3, respectively. There was an inverse but nonsignificant association for PMcoarse. A higher nearby traffic load was positively associated with IBD [OR 1.60 (95 % CI 1.04–2.46) per 4,000,000 motor vehicles × m per day]. Other air pollutants were positively but not significantly associated with IBD.
Conclusion
Exposure to air pollution was not found to be consistently associated with IBD.
Electronic supplementary material
The online version of this article (doi:10.1007/s10620-016-4249-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s10620-016-4249-4
PMCID: PMC5020109  PMID: 27461060
Air pollution; Particulate matter; Inflammatory bowel disease; Crohn’s disease; Ulcerative colitis
4.  Evolution of Costs of Inflammatory Bowel Disease over Two Years of Follow-Up 
PLoS ONE  2016;11(4):e0142481.
Background
With the increasing use of anti-TNF therapy in inflammatory bowel disease (IBD), a shift of costs has been observed with medication costs replacing hospitalization and surgery as major cost driver. We aimed to explore the evolution of IBD-related costs over two years of follow-up.
Methods and Findings
In total 1,307 Crohn's disease (CD) patients and 915 ulcerative colitis (UC) patients were prospectively followed for two years by three-monthly web-based questionnaires. Changes of healthcare costs, productivity costs and out-of-pocket costs over time were assessed using mixed model analysis. Multivariable logistic regression analysis was used to identify costs drivers. In total 737 CD patients and 566 UC were included. Total costs were stable over two years of follow-up, with annual total costs of €7,835 in CD and €3,600 in UC. However, within healthcare costs, the proportion of anti-TNF therapy-related costs increased from 64% to 72% in CD (p<0.01) and from 31% to 39% in UC (p < 0.01). In contrast, the proportion of hospitalization costs decreased from 19% to 13% in CD (p<0.01), and 22% to 15% in UC (p < 0.01). Penetrating disease course predicted an increase of healthcare costs (adjusted odds ratio (adj. OR) 1.95 (95% CI 1.02–3.37) in CD and age <40 years in UC (adj. OR 4.72 (95% CI 1.61–13.86)).
Conclusions
BD-related costs remained stable over two years. However, the proportion of anti-TNF-related healthcare costs increased, while hospitalization costs decreased. Factors associated with increased costs were penetrating disease course in CD and age <40 in UC.
doi:10.1371/journal.pone.0142481
PMCID: PMC4839678  PMID: 27099937
5.  Multimodal treatment of perianal fistulas in Crohn’s disease: seton versus anti-TNF versus advancement plasty (PISA): study protocol for a randomized controlled trial 
Trials  2015;16:366.
Background
Currently there is no guideline for the treatment of patients with Crohn’s disease and high perianal fistulas. Most patients receive anti-TNF medication, but no long-term results of this expensive medication have been described, nor has its efficiency been compared to surgical strategies. With this study, we hope to provide treatment consensus for daily clinical practice with reduction in costs.
Methods/Design
This is a multicentre, randomized controlled trial. Patients with Crohn’s disease who are over 18 years of age, with newly diagnosed or recurrent active high perianal fistulas, with one internal opening and no anti-TNF usage in the past three months will be considered. Patients with proctitis, recto-vaginal fistulas or anal stenosis will be excluded. Prior to randomisation, an MRI and ileocolonoscopy are required. All treatment will start with seton placement and a course of antibiotics. Patients will then be randomised to: (1) chronic seton drainage (with oral 6-mercaptopurine (6MP)) for one year, (2) anti-TNF medication (with 6MP) for one year (seton removal after six weeks) or (3) advancement plasty after eight weeks of seton drainage (under four months anti-TNF and 6MP for one year). The primary outcome parameter is the number of patients needing fistula-related re-intervention(s). Secondary outcomes are the number of patients with closed fistulas (based on an evaluated MRI score) after 18 months, disease activity, quality of life and costs.
Discussion
The PISA trial is a multicentre, randomised controlled trial of patients with Crohn’s disease and high perianal fistulas. With the comparison of three generally accepted treatment strategies, we will be able to comment on the efficiency of the various treatment strategies, with respect to several long-term outcome parameters.
Trial registration
Nederlands Trial Register identifier: NTR4137 (registered on 23 August 2013).
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0831-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13063-015-0831-x
PMCID: PMC4545975  PMID: 26289163
Crohn’s disease; Perianal fistula; Seton; Anti-TNF; Advancement plasty; Quality of life; Cost-effectiveness
6.  Low rates of adherence for tumor necrosis factor-α inhibitors in Crohn’s disease and rheumatoid arthritis: Results of a systematic review 
AIM: To investigate adherence rates in tumor necrosis factor-α (TNF-α)-inhibitors in Crohn’s disease (CD) and rheumatoid arthritis (RA) by systematic review of medical literature.
METHODS: A structured search of PubMed between 2001 and 2011 was conducted to identify publications that assessed treatment with TNF-α inhibitors providing data about adherence in CD and RA. Therapeutic agents of interest where adalimumab, infliximab and etanercept, since these are most commonly used for both diseases. Studies assessing only drug survival or continuation rates were excluded. Data describing adherence with TNF-α inhibitors were extracted for each selected study. Given the large variation between definitions of measurement of adherence, the definitions as used by the authors where used in our calculations. Data were tabulated and also presented descriptively. Sample size-weighted pooled proportions of patients adherent to therapy and their 95%CI were calculated. To compare adherence between infliximab, adalimumab and etanercept, the adherence rates where graphed alongside two axes. Possible determinants of adherence were extracted from the selected studies and tabulated using the presented OR.
RESULTS: Three studies on CD and three on RA were identified, involving a total of 8147 patients (953 CD and 7194 RA). We identified considerable variation in the definitions and methodologies of measuring adherence between studies. The calculated overall sample size-weighted pooled proportion for adherence to TNF-α inhibitors in CD was 70% (95%CI: 67%-73%) and 59% in RA (95%CI: 58%-60%). In CD the adherence rate for infliximab (72%) was highercompared to adalimumab (55%), with a relative risk of 1.61 (95%CI: 1.27-2.03), whereas in RA adherence for adalimumab (67%) was higher compared to both infliximab (48%) and etanercept (59%), with a relative risk of 1.41 (95%CI: 1.3-1.52) and 1.13 (95%CI: 1.10-1.18) respectively. In comparative studies in RA adherence to infliximab was better than etanercept and etanercept did better than adalimumab. In three studies, the most consistent factor associated with lower adherence was female gender. Results for age, immunomodulator use and prior TNF-α inhibitors use were conflicting.
CONCLUSION: One-third of both CD and RA patients treated with TNF-α inhibitors are non-adherent. Female gender was consistently identified as a negative determinant of adherence.
doi:10.3748/wjg.v19.i27.4344
PMCID: PMC3718902  PMID: 23885145
Adherence; Tumor necrosis factor-α inhibitors; Systematic review; Crohn’s disease; Rheumatoid arthritis
7.  Pharmacological Activation of the Bile Acid Nuclear Farnesoid X Receptor Is Feasible in Patients with Quiescent Crohn's Colitis 
PLoS ONE  2012;7(11):e49706.
Background
The bile acid-activated nuclear receptor Farnesoid X Receptor (FXR) is critical in maintaining intestinal barrier integrity and preventing bacterial overgrowth. Patients with Crohn's colitis (CC) exhibit reduced ileal FXR target gene expression. FXR agonists have been shown to ameliorate inflammation in murine colitis models. We here explore the feasibility of pharmacological FXR activation in CC.
Methods
Nine patients with quiescent CC and 12 disease controls were treated with the FXR ligand chenodeoxycholic acid (CDCA; 15 mg/kg/day) for 8 days. Ileal FXR activation was assessed in the fasting state during 6 hrs after the first CDCA dose and on day 8, by quantification of serum levels of fibroblast growth factor (FGF) 19. Since FGF19 induces gallbladder (GB) refilling in murine models, we also determined concurrent GB volumes by ultrasound. On day 8 ileal and cecal biopsies were obtained and FXR target gene expression was determined.
Results
At baseline, FGF19 levels were not different between CC and disease controls. After the first CDCA dose, there were progressive increases of FGF19 levels and GB volumes during the next 6 hours in CC patients and disease controls (FGF19: 576 resp. 537% of basal; GB volumes: 190 resp. 178% of basal) without differences between both groups, and a further increase at day 8. In comparison with a separate untreated control group, CDCA affected FXR target gene expression in both CC and disease controls, without differences between both groups.
Conclusions
Pharmacological activation of FXR is feasible in patients with CC. These data provide a rationale to explore the anti-inflammatory properties of pharmacological activation of FXR in these patients.
Trial Registration
TrialRegister.nl NTR2009
doi:10.1371/journal.pone.0049706
PMCID: PMC3506649  PMID: 23189156
8.  Effect of adalimumab on work productivity and indirect costs in moderate to severe Crohn’s disease: A meta-analysis 
OBJECTIVE:
To assess the effect of adalimumab on work productivity and indirect costs in patients with Crohn’s disease (CD) using a meta-analysis of clinical trials.
METHODS:
Study-level results were pooled from all clinical trials of adalimumab for moderate to severe CD in which work productivity outcomes were evaluated. Work Productivity and Activity Impairment Questionnaire outcomes (absenteeism, presenteeism and total work productivity impairment [TWPI]) were extracted from adalimumab trials. Meta-analyses were used to estimate pooled averages and 95% CIs of one-year accumulated reductions in work productivity impairment with adalimumab. Pooled averages were multiplied by the 2008 United States national average annual salary ($44,101) to estimate per-patient indirect cost savings during the year following adalimumab initiation.
RESULTS:
The four included trials (ACCESS, CARE, CHOICE and EXTEND) represented a total of 1202 employed adalimumab-treated patients at baseline. Each study followed patients for a minimum of 20 weeks. Pooled estimates (95% CIs) of one-year accumulated work productivity improvements were as follows: −9% (−10% to −7%) for absenteeism; −22% (−26% to −18%) for presenteeism; and −25% (−30% to −20%) for TWPI. Reductions in absenteeism and TWPI translated into per-patient indirect cost savings (95% CI) of $3,856 ($3,183 to $4,529) and $10,964 ($8,833 to $13,096), respectively.
CONCLUSION:
Adalimumab provided clinically meaningful improvements in work productivity among patients with moderate to severe CD, which may translate into substantial indirect cost savings from an employer’s perspective.
PMCID: PMC3202356  PMID: 21912760
Adalimumab; Crohn’s disease; Indirect costs; Work productivity
9.  Farnesoid X Receptor (FXR) Activation and FXR Genetic Variation in Inflammatory Bowel Disease 
PLoS ONE  2011;6(8):e23745.
Background
We previously showed that activation of the bile salt nuclear receptor Farnesoid X Receptor (FXR) protects against intestinal inflammation in mice. Reciprocally, these inflammatory mediators may decrease FXR activation. We investigated whether FXR activation is repressed in the ileum and colon of inflammatory bowel disease (IBD) patients in remission. Additionally, we evaluated whether genetic variation in FXR is associated with IBD.
Methods
mRNA expression of FXR and FXR target gene SHP was determined in ileal and colonic biopsies of patients with Crohn's colitis (n = 15) and ulcerative colitis (UC; n = 12), all in clinical remission, and healthy controls (n = 17). Seven common tagging SNPs and two functional SNPs in FXR were genotyped in 2355 Dutch IBD patients (1162 Crohn's disease (CD) and 1193 UC) and in 853 healthy controls.
Results
mRNA expression of SHP in the ileum is reduced in patients with Crohn's colitis but not in patients with UC compared to controls. mRNA expression of villus marker Villin was correlated with FXR and SHP in healthy controls, a correlation that was weaker in UC patients and absent in CD patients. None of the SNPs was associated with IBD, UC or CD, nor with clinical subgroups of CD.
Conclusions
FXR activation in the ileum is decreased in patients with Crohn's colitis. This may be secondary to altered enterohepatic circulation of bile salts or transrepression by inflammatory signals but does not seem to be caused by the studied SNPs in FXR. Increasing FXR activity by synthetic FXR agonists may have benefit in CD patients.
doi:10.1371/journal.pone.0023745
PMCID: PMC3161760  PMID: 21887309
10.  Performance of EUS-FNA for mediastinal lymphadenopathy: impact on patient management and costs in low-volume EUS centers 
Surgical Endoscopy  2010;24(9):2260-2267.
Background
Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of mediastinal lymphadenopathy has been shown to be a valuable diagnostic tool in high-volume EUS centers (≥50 mediastinal EUS-FNA/endoscopist/year). Our goal was to assess the diagnostic accuracy of EUS-FNA and its impact on clinical management and costs in low-volume EUS centers (<50 mediastinal EUS-FNA/endoscopist/year).
Methods
Consecutive patients referred to two Dutch endoscopy centers in the period 2002–2008 for EUS-FNA of mediastinal lymphadenopathy were reviewed. The gold standard for a cytological diagnosis was histological confirmation or clinical follow-up of more than 6 months with repeat imaging. The impact of EUS-FNA on clinical management was subdivided into a positive impact by providing (1) adequate cytology that influenced the decision to perform surgery or (2) a diagnosis of a benign inflammatory disorder, and a negative impact which was subdivided into (1) false-negative or inconclusive cytology or (2) an adequate cytological diagnosis that did not influence patient management. Costs of an alternative diagnostic work-up without EUS-FNA, as established by an expert panel, were compared to costs of the actual work-up.
Results
In total, 213 patients (71% male, median age = 61 years, range = 23–88 years) underwent EUS-FNA. Sensitivity, specificity, and negative and positive predictive values were 89%, 100%, 80%, and 100%, respectively. EUS-FNA had a positive impact on clinical management in 84% of cases by either influencing the decision to perform surgery (49%) or excluding malignant lymphadenopathy (35%), and a negative impact in 7% of cases because of inadequate (3%) or false-negative (4%) cytology. In 9% of cases, EUS-FNA was performed without an established indication. Two nonfatal perforations occurred (0.9%). Total cost reduction was €100,593, with a mean cost reduction of €472 (SD = €607) per patient.
Conclusions
Mediastinal EUS-FNA can be performed in low-volume EUS centers without compromising diagnostic accuracy. Moreover, EUS-FNA plays an important role in the management of patients with mediastinal lymphadenopathy and reduces total diagnostic costs.
doi:10.1007/s00464-010-0946-9
PMCID: PMC2939341  PMID: 20177920
EUS-FNA; Costs; Accuracy; Mediastinal lymphadenopathy
11.  WNT-Pathway Activation in IBD-Associated Colorectal Carcinogenesis: Potential Biomarkers for Colonic Surveillance 
Objectives: The Wnt-pathway dominates the sporadic carcinogenesis whereas p53 plays a pivotal role in the colitis-associated counterpart. The expression of Wnt-signaling proteins and p53 during colitis-associated carcinogenesis was determined.
Methods: A tissue microarray was constructed with colonic samples from 5 groups of patients: controls (C, n=10), IBD without neoplasia (IBD, n=12), non-dysplastic IBD with neoplasia elsewhere in the colon (IBD-NE, n=12), dysplastic lesion in IBD (IBD-DYS, n=12), and IBD-associated colorectal cancer (IBD-CRC, n=10). Immunohistochemistry was performed for β-catenin, cyclin D1 and p53. p53 sequence analysis was performed in some cases.
Results: Nuclear β-catenin expression was found in 0%, 0%, 50%, 55% and 100% of the patients in the C-, IBD-, IBD-NE-, IBD-DYS- and IBD-CRC-groups, respectively. Non-dysplastic IBD mucosa with neoplasia detected elsewhere showed nuclear expression in 50% of the cases compared to 0% in IBD mucosa without neoplasia (p=0.02). Cyclin D1 staining had similar expression patterns. Overexpression of p53 was only detected in the IBD-DYS (66.7%) and IBD-CRC groups (50%).
Conclusion: In contrast to previous findings, our results suggest activation of the Wnt-pathway in the early phase of colitis-associated carcinogenesis. Furthermore, as Wnt activation was observed in 50% of the IBD-NE cases, nuclear β-catenin may facilitate detection of neoplasia.
doi:10.3233/CLO-2009-0503
PMCID: PMC4619233  PMID: 20208143
Colorectal cancer; inflammatory bowel disease; Wnt-pathway; surveillance; p53
12.  Prototype evaluation of a self-management Internet diary for patients with ulcerative colitis 
Objective:
To evaluate content, navigation, usability, and impact measurability of a prototype Internet-based self-management intervention for patients with ulcerative colitis.
Material and methods:
Analysis of 52 Internet diaries that were used in a six-month test trial. Analysis was done using an evaluation framework for eHealth applications that incorporates goals from theory and empirical studies on living with chronic illness, the software design industry, and health services research.
Results:
Content of the diary covered the intended functions of the Internet-based self-management intervention. The evaluation led to several refinement suggestions concerning navigation, usability, and impact measurability of the Internet diary.
Conclusion:
Psychosocial, medical, and scientific content as well as interface and design are equally important in the development of effective eHealth interventions.
PMCID: PMC2778412  PMID: 19936160
self-management; Internet diary; ulcerative colitis; eHealth; prototype
13.  Adherence to surveillance guidelines for dysplasia and colorectal carcinoma in ulcerative and Crohn’s colitis patients in the Netherlands 
AIM: To study adherence to the widely accepted surveillance guidelines for patients with long-standing colitis in the Netherlands.
METHODS: A questionnaire was sent to all 244 gastroenterologists in the Netherlands.
RESULTS: The response rate was 63%. Of all gastroenterologists, 95% performed endoscopic surveillance in ulcerative colitis (UC) patients and 65% in patients with Crohn’s colitis. The American Gastroenterological Association (AGA) guidelines were followed by 27%, while 27% and 46% followed their local hospital protocol or no specific protocol, respectively. The surveillance was correctly initiated in cases of pancolitis by 53%, and in cases of left-sided colitis by 44% of the gastroenterologists. Although guidelines recommend 4 biopsies every 10 cm, less than 30 biopsies per colonoscopy were taken by 73% of the responders. Only 31%, 68% and 58% of the gastroenterologists referred patients for colectomy when low-grade dysplasia, high-grade dysplasia (HGD) or Dysplasia Associated Lesion or Mass (DALM) was present, respectively.
CONCLUSION: Most Dutch gastroenterologists perform endoscopic surveillance without following international recommended guidelines. This practice potentially leads to a decreased sensitivity for dysplasia, rendering screening for colorectal cancer in this population highly ineffective.
doi:10.3748/wjg.15.226
PMCID: PMC2653310  PMID: 19132774
Colorectal cancer; Crohn’s disease; Dysplasia; Guidelines; Surveillance; Ulcerative colitis
14.  Laparoscopic ileocolic resection versus infliximab treatment of distal ileitis in Crohn's disease: a randomized multicenter trial (LIR!C-trial) 
BMC Surgery  2008;8:15.
Background
With the availability of infliximab, nowadays recurrent Crohn's disease, defined as disease refractory to immunomodulatory agents that has been treated with steroids, is generally treated with infliximab. Infliximab is an effective but expensive treatment and once started it is unclear when therapy can be discontinued. Surgical resection has been the golden standard in recurrent Crohn's disease. Laparoscopic ileocolic resection proved to be safe and is characterized by a quick symptom reduction.
The objective of this study is to compare infliximab treatment with laparoscopic ileocolic resection in patients with recurrent Crohn's disease of the distal ileum with respect to quality of life and costs.
Methods/design
The study is designed as a multicenter randomized clinical trial including patients with Crohn's disease located in the terminal ileum that require infliximab treatment following recent consensus statements on inflammatory bowel disease treatment: moderate to severe disease activity in patients that fail to respond to steroid therapy or immunomodulatory therapy. Patients will be randomized to receive either infliximab or undergo a laparoscopic ileocolic resection. Primary outcomes are quality of life and costs. Secondary outcomes are hospital stay, early and late morbidity, sick leave and surgical recurrence. In order to detect an effect size of 0.5 on the Inflammatory Bowel Disease Questionnaire at a 5% two sided significance level with a power of 80%, a sample size of 65 patients per treatment group can be calculated. An economic evaluation will be performed by assessing the marginal direct medical, non-medical and time costs and the costs per Quality Adjusted Life Year (QALY) will be calculated. For both treatment strategies a cost-utility ratio will be calculated. Patients will be included from December 2007.
Discussion
The LIR!C-trial is a randomized multicenter trial that will provide evidence whether infliximab treatment or surgery is the best treatment for recurrent distal ileitis in Crohn's disease.
Trial registration
Nederlands Trial Register NTR1150
doi:10.1186/1471-2482-8-15
PMCID: PMC2533646  PMID: 18721465
15.  C-reactive protein levels during a relapse of Crohn’s disease are associated with the clinical course of the disease 
AIM: To explore if C-reactive protein (CRP) levels might serve as a prognostic factor with respect to the clinical course of Crohn’s disease and might be useful for classification.
METHODS: In this retrospective cohort study we enrolled 94 patients from the inflammatory bowel disease (IBD) database of the University Medical Centre Utrecht. CRP levels during relapse were correlated with the number of relapses per year. Severity of relapses was based on endoscopic reports and prednisone use. Furthermore, patients were categorized in a low or high CRP group based on their CRP response during relapse and demographic and clinical features were compared.
RESULTS: Overall, a positive correlation between CRP levels, number of relapses, and severity of relapse was found (respectively rs = 0.31, P < 0.01 and rs = 0.50, P < 0.001). Employing a cut-off level of 15 mg/L, the index CRP level was found to discriminate patients with respect to the number of relapses per year, as well as for severity of relapses (respectively 0.25 ± 0.16 vs 0.36 ± 0.24, P < 0.05 and 4.4 ± 1.2 vs 3.2 ± 1.1 on a 10-point visual analogue scale, P < 0.001 for the high CRP and low CRP groups respectively). In addition, the high CRP group showed more cumulative days of prednisone use per year (107 ± 95 vs 58 ± 48, P < 0.05), as well as a better response to infliximab (93 % vs 33 %, P = 0.06).
CONCLUSION: A higher CRP level during relapse seems to be associated with a more severe clinical course of disease.
doi:10.3748/wjg.14.85
PMCID: PMC2673397  PMID: 18176967
Crohn’s disease; Infliximab; C-reactive protein; Prognosis; Clinical behaviour
16.  Colonic stenting as bridge to surgery versus emergency surgery for management of acute left-sided malignant colonic obstruction: a multicenter randomized trial (Stent-in 2 study) 
BMC Surgery  2007;7:12.
Background
Acute left-sided colonic obstruction is most often caused by malignancy and the surgical treatment is associated with a high mortality and morbidity rate. Moreover, these operated patients end up with a temporary or permanent stoma. Initial insertion of an enteral stent to decompress the obstructed colon, allowing for surgery to be performed electively, is gaining popularity. In uncontrolled studies stent placement before elective surgery has been suggested to decrease mortality, morbidity and number of colostomies. However stent perforation can lead to peritoneal tumor spill, changing a potentially curable disease in an incurable one. Therefore it is of paramount importance to compare the outcomes of colonic stenting followed by elective surgery with emergency surgery for the management of acute left-sided malignant colonic obstruction in a randomized multicenter fashion.
Methods/design
Patients with acute left-sided malignant colonic obstruction eligible for this study will be randomized to either emergency surgery (current standard treatment) or colonic stenting as bridge to elective surgery. Outcome measurements are effectiveness and costs of both strategies. Effectiveness will be evaluated in terms of quality of life, morbidity and mortality. Quality of life will be measured with standardized questionnaires (EORTC QLQ-C30, EORTC QLQ-CR38, EQ-5D and EQ-VAS). Morbidity is defined as every event leading to hospital admission or prolonging hospital stay. Mortality will be analyzed as total mortality as well as procedure-related mortality. The total costs of treatment will be evaluated by counting volumes and calculating unit prices. Including 120 patients on a 1:1 basis will have 80% power to detect an effect size of 0.5 on the EORTC QLQ-C30 global health scale, using a two group t-test with a 0.05 two-sided significance level. Differences in quality of life and morbidity will be analyzed using mixed-models repeated measures analysis of variance. Mortality will be compared using Kaplan-Meier curves and log-rank statistics.
Discussion
The Stent-in 2 study is a randomized controlled multicenter trial that will provide evidence whether or not colonic stenting as bridge to surgery is to be performed in patients with acute left-sided colonic obstruction.
Trial registration
Current Controlled Trials ISRCTN46462267.
doi:10.1186/1471-2482-7-12
PMCID: PMC1925059  PMID: 17608947
17.  Crohn’s disease, fatigue, and infliximab: Is there a role for cytokines in the pathogenesis of fatigue? 
AIM: To study the effect of infliximab on fatigue in relation to cytokine levels in Crohn’s disease (CD) patients.
METHODS: Fourteen CD patients were blinded for treatment and received placebo at baseline, and infliximab 2 wk later, with a follow-up of 4 wk. Blood samples were drawn on a regular basis, and questionnaires on fatigue, depression, quality of life, and clinical disease activity were completed at regular intervals.
RESULTS: After placebo infusion, fatigue scores decreased within 3 d (3.5 points ± 1.1, P ≤ 0.01), but returned to baseline values 14 d after this infusion. The drop of fatigue scores following infliximab infusion sustained until the end of the study (3.8 points ± 1.4, P≤ 0.05). Quality of life was increased at the end of the study compared to baseline values (138.6 ± 9.4 vs 179.4 ± 6.7; P ≤ 0.005), whereas depression scores were decreased (20.4 ± 9.4 vs 11.3 ± 2.2; P ≤ 0.01). No correlation between the severity of fatigue and the level of cytokines was observed.
CONCLUSION: The reduction of fatigue after infliximab infusion is subjective to a placebo effect. The effect of infliximab on fatigue, however, persists while the placebo effect disappears after a short period of time. A clear role of cytokines could not be substantiated.
doi:10.3748/wjg.v13.i14.2089
PMCID: PMC4319130  PMID: 17465453
Crohn’s disease; Fatigue; Infliximab; Cytokines
18.  Carbohydrate Intake in the Etiology of Crohn's Disease and Ulcerative Colitis 
Inflammatory Bowel Diseases  2014;20(11):2013-2021.
Article first published online 25 September 2014.
Supplemental Digital Content is Available in the Text.
Background:
Diet may have a role in the etiology of inflammatory bowel disease. In previous studies, the associations between increased intakes of carbohydrates, sugar, starch, and inflammatory bowel disease are inconsistent. However, few prospective studies have investigated the associations between these macronutrients and incident Crohn's disease (CD) or ulcerative colitis (UC).
Methods:
A total of 401,326 men and women were recruited between 1991 and 1998. At recruitment, dietary intakes of carbohydrate, sugar, and starch were measured using validated food frequency questionnaires. The cohort was monitored identifying participants who developed incident CD or UC. Cases were matched with 4 controls, and odds ratios were calculated for quintiles of total carbohydrate, sugar, and starch intakes adjusted for total energy intake, body mass index, and smoking.
Results:
One hundred ten participants developed CD, and 244 participants developed UC during follow-up. The adjusted odds ratio for the highest versus the lowest quintiles of total carbohydrate intake for CD was 0.87, 95% CI = 0.24 to 3.12 and for UC 1.46, 95% CI = 0.62 to 3.46, with no significant trends across quintiles for either (CD, Ptrend = 0.70; UC, Ptrend = 0.41). Similarly, no associations were observed with intakes of total sugar (CD, Ptrend = 0.50; UC, Ptrend = 0.71) or starch (CD, Ptrend = 0.69; UC, Ptrend = 0.17).
Conclusions:
The lack of associations with these nutrients is in agreement with many case–control studies that have not identified associations with CD or UC. As there is biological plausibility for how specific carbohydrates could have an etiological role in inflammatory bowel disease, future epidemiological work should assess individual carbohydrates, although there does not seem to be a macronutrient effect.
doi:10.1097/MIB.0000000000000168
PMCID: PMC4213135  PMID: 25265262
Crohn's disease; ulcerative colitis; etiology; sugar; carbohydrate; starch

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