DAMP-ing IBD: Extinguish the Fire and Prevent Smoldering.

In inflammatory bowel diseases (IBD), the most promising therapies targeting cytokines or immune cell trafficking demonstrate around 40% efficacy. As IBD is a multifactorial inflammation of the intestinal tract, a single-target approach is unlikely to solve this problem, necessitating an alternative strategy that addresses its variability. One approach often overlooked by the pharmaceutically driven therapeutic options is to address the impact of environmental factors. This is somewhat surprising considering that IBD is increasingly viewed as a condition heavily influenced by such factors, including diet, stress, and environmental pollution-often referred to as the "Western lifestyle". In IBD, intestinal responses result from a complex interplay among the genetic background of the patient, molecules, cells, and the local inflammatory microenvironment where danger- and microbe-associated molecular patterns (D/MAMPs) provide an adjuvant-rich environment. Through activating DAMP receptors, this array of pro-inflammatory factors can stimulate, for example, the NLRP3 inflammasome-a major amplifier of the inflammatory response in IBD, and various immune cells via non-specific bystander activation of myeloid cells (e.g., macrophages) and lymphocytes (e.g., tissue-resident memory T cells). Current single-target biological treatment approaches can dampen the immune response, but without reducing exposure to environmental factors of IBD, e.g., by changing diet (reducing ultra-processed foods), the adjuvant-rich landscape is never resolved and continues to drive intestinal mucosal dysregulation. Thus, such treatment approaches are not enough to put out the inflammatory fire. The resultant smoldering, low-grade inflammation diminishes physiological resilience of the intestinal (micro)environment, perpetuating the state of chronic disease. Therefore, our hypothesis posits that successful interventions for IBD must address the complexity of the disease by simultaneously targeting all modifiable aspects: innate immunity cytokines and microbiota, adaptive immunity cells and cytokines, and factors that relate to the (micro)environment. Thus the disease can be comprehensively treated across the nano-, meso-, and microscales, rather than with a focus on single targets. A broader perspective on IBD treatment that also includes options to adapt the DAMPing (micro)environment is warranted.

Electronic Nose Sensor Drift Affects Diagnostic Reliability and Accuracy of Disease-Specific Algorithms.

Sensor drift is a well-known disadvantage of electronic nose (eNose) technology and may affect the accuracy of diagnostic algorithms. Correction for this phenomenon is not routinely performed. The aim of this study was to investigate the influence of eNose sensor drift on the development of a disease-specific algorithm in a real-life cohort of inflammatory bowel disease patients (IBD). In this multi-center cohort, patients undergoing colonoscopy collected a fecal sample prior to bowel lavage. Mucosal disease activity was assessed based on endoscopy. Controls underwent colonoscopy for various reasons and had no endoscopic abnormalities. Fecal eNose profiles were measured using Cyranose 320®. Fecal samples of 63 IBD patients and 63 controls were measured on four subsequent days. Sensor data displayed associations with date of measurement, which was reproducible across all samples irrespective of disease state, disease activity state, disease localization and diet of participants. Based on logistic regression, corrections for sensor drift improved accuracy to differentiate between IBD patients and controls based on the significant differences of six sensors (p = 0.004; p < 0.001; p = 0.001; p = 0.028; p < 0.001 and p = 0.005) with an accuracy of 0.68. In this clinical study, short-term sensor drift affected fecal eNose profiles more profoundly than clinical features. These outcomes emphasize the importance of sensor drift correction to improve reliability and repeatability, both within and across eNose studies.

Hypnotherapy for Irritable Bowel Syndrome-Type Symptoms in Patients with Quiescent Inflammatory Bowel Disease: A Randomized, Controlled Trial.

BACKGROUND AND AIMS: Many inflammatory bowel disease [IBD] patients in remission have persisting symptoms, compatible with irritable bowel syndrome [IBS-type symptoms]. We aimed to compare the effectiveness of gut-directed hypnotherapy vs standard medical treatment [SMT] for IBS-type symptoms in IBD patients. METHODS: In this multicentre, randomized, controlled, open-label trial, patients aged 12-65 years with IBD in clinical remission [global assessment] and biochemical remission [faecal calprotectin ≤100 µg/g, or ≤200 µg/g without inflammation at endoscopy] with IBS according to Rome III criteria were randomized to hypnotherapy or SMT. Primary outcome was the proportion with ≥50% reduction on a visual analog scale for symptom severity, as measured with the Irritable Bowel Syndrome Severity Scoring System [IBS-SSS] at week 40 [i.e. 6 months after finishing the intervention], compared to baseline. Secondary outcomes included total IBS-SSS score, quality of life, adequate relief, IBS-related cognitions, and depression and anxiety scores. RESULTS: Eighty patients were included, of whom 70 received at least one session of the allocated treatment and were included in the modified intention-to-treat-population. Seven patients were excluded because of missing baseline data required for the primary outcome. The primary outcome was met in nine [27%] of 33 patients randomized to SMT and nine [30%] of 30 patients randomized to hypnotherapy [p = 0.81]. Adequate relief was reported in 60% and 40% of subjects, respectively. Exploratory analyses of secondary outcomes revealed no apparent differences between the two treatment groups. CONCLUSIONS: Hypnotherapy was not superior to SMT in the treatment of IBS-type symptoms in IBD patients. Both treatment strategies are reasonable options from a clinical perspective.

Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn's disease: retrospective long-term follow-up of the LIR!C trial.

BACKGROUND: The LIR!C trial showed that laparoscopic ileocaecal resection is a cost-effective treatment that has similar quality-of-life outcomes to treatment with infliximab, an anti-tumour necrosis factor (TNF) drug. We aimed to compare long-term outcomes of both interventions and identify baseline factors associated with the duration of treatment effect in each group. METHODS: In this retrospective follow-up study, we collected data from patients who participated in the LIR!C trial, a multicentre randomised controlled trial that compared quality of life after surgical resection versus infliximab in adult patients with non-stricturing and immunomodulator-refractory ileocaecal Crohn's disease. From Jan 1 to May 1, 2018, we collected follow-up data from the time from enrolment in the LIR!C trial until the last visit at either the gastrointestinal surgeon or gastroenterologist. In this study, outcomes of interest were need for surgery or repeat surgery or anti-TNF therapy, duration of treatment effect, and identification of factors associated with the duration of treatment effect. Duration of treatment effect was defined as the time without need for additional Crohn's disease-related treatment (corticosteroids, immunomodulators, biologics, or surgery). FINDINGS: We collected long-term follow-up data for 134 (94%) of 143 patients included in the LIR!C trial, of whom 69 were in the resection group and 65 were in the infliximab group. Median follow-up was 63·5 months (IQR 39·0-94·5). In the resection group, 18 (26%) of 69 patients started anti-TNF therapy and none required a second resection. 29 (42%) patients in the resection group did not require additional Crohn's disease-related medication, although 14 (48%) of these patients were given prophylactic immunomodulator therapy. In the infliximab group, 31 (48%) of 65 patients had a Crohn's disease-related resection, and the remaining 34 patients maintained, switched, or escalated their anti-TNF therapy. Duration of treatment effect was similar in both groups, with a median time without additional Crohn's disease-related treatment of 33·0 months (95% CI 15·1-50·9) in the resection group and 34·0 months (0·0-69·3) in the infliximab group (log-rank p=0·52). In both groups, therapy with an immunomodulator, in addition to the allocated treatment, was associated with duration of treatment effect (hazard ratio for resection group 0·34 [95% CI 0·16-0·69] and for infliximab group 0·49 [0·26-0·93]). INTERPRETATION: These findings further support laparoscopic ileocaecal resection as a treatment option in patients with Crohn's disease with limited (affected segment ≤40 cm) and predominantly inflammatory terminal ileitis for whom conventional treatment is not successful. FUNDING: None.

I am a total failure: associations between beliefs and anxiety and depression in patients with inflammatory bowel disease with poor mental quality of life.

BACKGROUND: According to cognitive behavioural theory, cognitive factors (i.e. underlying general dysfunctional beliefs and (situation) specific illness beliefs) are theorized to lead to outcomes like anxiety and depression. In clinical practice, general dysfunctional beliefs are generally not tackled directly in short-term-therapy. AIMS: The goal of the present study was to investigate the associations of general versus specific illness beliefs on anxiety and depressive symptoms and psychiatric disorders among a subgroup of patients with inflammatory bowel disease (IBD) with poor mental quality of life (QoL). METHOD: This study concerns cross-sectional data, collected at baseline from a randomized clinical trial. One hundred and eighteen patients, recruited at four Dutch hospitals, with poor QoL (score ≤23 on the mental health subscale of the Short-Form 36-item Health-Survey; SF-36) were included. General dysfunctional beliefs were measured by the Dysfunctional Attitude Scale (DAS), specific illness beliefs by the Illness Perceptions Questionnaire-Revised (IPQ-R), anxiety and depressive symptoms by the Hospital Anxiety and Depression Scale (HADS), and psychiatric disorders by the Structured Clinical Interview for DSM-IV Axis-I Disorders (SCID-I). RESULTS: Univariate analyses showed associations between the level of anxiety and/or depression and general dysfunctional beliefs and four specific illness beliefs (consequences, personal control, emotional representations and treatment control). Among patients with IBD with psychiatric disorders, only the DAS was significantly associated with anxiety and depression (DAS added to IPQ-R and IPQ-R added to DAS). CONCLUSIONS: Psychological interventions may have to target general dysfunctional beliefs of patients with IBD with co-morbid psychiatric disorders to be effective. These patients with IBD are especially in need of psychological treatment.

Cost-effectiveness of laparoscopic ileocaecal resection versus infliximab treatment of terminal ileitis in Crohn's disease: the LIR!C Trial.

OBJECTIVE: Evaluate the cost-effectiveness of laparoscopic ileocaecal resection compared with infliximab in patients with ileocaecal Crohn's disease failing conventional therapy. DESIGN: A multicentre randomised controlled trial was performed in 29 centres in The Netherlands and the UK. Adult patients with Crohn's disease of the terminal ileum who failed >3 months of conventional immunomodulators or steroids without signs of critical strictures were randomised to laparoscopic ileocaecal resection or infliximab. Outcome measures included quality-adjusted life-years (QALYs) based on the EuroQol (EQ) 5D-3L Questionnaire and the Inflammatory Bowel Disease Questionnaire (IBDQ). Costs were measured from a societal perspective. Analyses were performed according to the intention-to-treat principle. Missing cost and effect data were imputed using multiple imputation. Cost-effectiveness planes and cost-effectiveness acceptability curves were estimated to show uncertainty. RESULTS: In total, 143 patients were randomised. Mean Crohn's disease total direct healthcare costs per patient at 1 year were lower in the resection group compared with the infliximab group (mean difference €-8931; 95% CI €-12 087 to €-5097). Total societal costs in the resection group were lower than in the infliximab group, however not statistically significant (mean difference €-5729, 95% CI €-10 606 to €172). The probability of resection being cost-effective compared with infliximab was 0.96 at a willingness to pay (WTP) of €0 per QALY gained and per point improvement in IBDQ Score. This probability increased to 0.98 at a WTP of €20 000/QALY gained and 0.99 at a WTP of €500/point of improvement in IBDQ Score. CONCLUSION: Laparoscopic ileocaecal resection is a cost-effective treatment option compared with infliximab. CLINICAL TRIAL REGISTRATION NUMBER: Dutch Trial Registry NTR1150; EudraCT number 2007-005042-20 (closed on 14 October 2015).

Cohort profile: design and first results of the Dutch IBD Biobank: a prospective, nationwide biobank of patients with inflammatory bowel disease.

PURPOSE: The Dutch IBD Biobank aims to facilitate the discovery of predictors for individual disease course and treatment response in patients with inflammatory bowel disease (IBD). In this paper, we aim to describe the establishment of the Dutch IBD Biobank, including the facilitators and barriers to establishment. Moreover, we aim to provide a complete overview of the content of the Dutch IBD Biobank. PARTICIPANTS: Since 2007, every patient with IBD treated in one of the eight Dutch university medical centres is asked to participate in the Dutch IBD Biobank in which 225 standardised IBD-related data items and biomaterials, such as serum, DNA, biopsies and a stool sample, are collected. FINDINGS TO DATE: As of June 2014, the Dutch IBD Biobank had enrolled 3388 patients with IBD: 2118 Crohn's disease (62.5%), 1190 ulcerative colitis (35.1%), 74 IBD-unclassified (2.2%) and 6 IBD-indeterminate (0.2%). The inclusion of patients with IBD is ongoing. The quality of the biomaterials is good and serum, DNA and biopsies have been used in newly published studies. FUTURE PLANS: The genotyping (750 000 genetic variants) of all participants of the Dutch IBD Biobank is currently ongoing, enabling more genetic research. In addition, all participants will start reporting disease activity and outcome measures using an online platform and mobile app.

Effectiveness of cognitive-behavioral therapy on quality of life, anxiety, and depressive symptoms among patients with inflammatory bowel disease: A multicenter randomized controlled trial.

OBJECTIVE: Inflammatory bowel disease (IBD) is characterized by a low level of quality of life (QoL) and a high prevalence of anxiety and depression, especially in patients with poor QoL. We examined the effect of IBD-specific cognitive-behavioral therapy (CBT) on QoL, anxiety, and depression in IBD patients with poor mental QoL. METHOD: This study is a parallel-group multicenter randomized controlled trial. One hundred eighteen IBD patients with a low level of QoL (score ≤23 on the mental health subscale of the Medical Outcomes Study Short Form 36 Health Survey [SF-36]) were included from 2 academic medical centers (Academic Medical Center Amsterdam, VU University Medical Centre Amsterdam) and 2 peripheral medical centers (Flevo Hospital, Slotervaart Hospital) in the Netherlands. Patients were randomized to an experimental group receiving CBT (n = 59) versus a wait-list control group (n = 59) receiving standard medical care for 3.5 months, followed by CBT. Both groups completed baseline and 3.5 months follow-up assessments. The primary outcome was a self-report questionnaire and disease-specific QoL (Inflammatory Bowel Disease Questionnaire [IBDQ]). Secondary outcomes were depression (Hospital Anxiety and Depression Scale-Depression Subscale [HADS-D], Center for Epidemiologic Studies Depression Scale [CES-D]), anxiety (HADS-Anxiety Subscale [HADS-A]) and generic QoL (SF-36). RESULTS: Data were analyzed both on intention to treat as well as on per protocol analysis (completed ≥5 sessions). CBT had a positive effect on disease-specific-QoL (Cohen's d = .64 for IBDQ total score), depression (Cohen's d = .48 for HADS-D and .78 for CES-D), anxiety (Cohen's d = .58 for HADS-A), and generic QoL (Cohen's d = 1.08 for Mental Component Summary of the SF-36; all ps < .01). CONCLUSIONS: IBD-specific CBT is effective in improving QoL and in decreasing anxiety and depression in IBD patients with poor QoL. Clinicians should incorporate screening on poor mental QoL and consider offering CBT. (PsycINFO Database Record

Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn's disease: a randomised controlled, open-label, multicentre trial.

BACKGROUND: Treatment of patients with ileocaecal Crohn's disease who have not responded to conventional therapy is commonly scaled up to biological agents, but surgery can also offer excellent short-term and long-term results. We compared laparoscopic ileocaecal resection with infliximab to assess how they affect health-related quality of life. METHODS: In this randomised controlled, open-label trial, in 29 teaching hospitals and tertiary care centres in the Netherlands and the UK, adults with non-stricturing, ileocaecal Crohn's disease, in whom conventional therapy has failed were randomly allocated (1:1) by an internet randomisation module with biased-coin minimisation for participating centres and perianal fistula to receive laparoscopic ileocaecal resection or infliximab. Eligible patients were aged 18-80 years, had active Crohn's disease of the terminal ileum, and had not responded to at least 3 months of conventional therapy with glucocorticosteroids, thiopurines, or methotrexate. Patients with diseased terminal ileum longer than 40 cm or abdominal abscesses were excluded. The primary outcome was quality of life on the Inflammatory Bowel Disease Questionnaire (IBDQ) at 12 months. Secondary outcomes were general quality of life, measured by the Short Form-36 (SF-36) health survey and its physical and mental component subscales, days unable to participate in social life, days on sick leave, morbidity (additional procedures and hospital admissions), and body image and cosmesis. Analyses of the primary outcome were done in the intention-to-treat population, and safety analyses were done in the per-protocol population. This trial is registered at the Dutch Trial Registry (NTR1150). FINDINGS: Between May 2, 2008, and October 14, 2015, 73 patients were allocated to have resection and 70 to receive infliximab. Corrected for baseline differences, the mean IBDQ score at 12 months was 178·1 (95% CI 171·1-185·0) in the resection group versus 172·0 (164·3-179·6) in the infliximab group (mean difference 6·1 points, 95% CI -4·2 to 16·4; p=0·25). At 12 months, the mean SF-36 total score was 112·1 (95% CI 108·0-116·2) in the resection group versus 106·5 (102·1-110·9) in the infliximab group (mean difference 5·6, 95% CI -0·4 to 11·6), the mean physical component score was 47·7 (45·7-49·7) versus 44·6 (42·5-46·8; mean difference 3·1, 4·2 to 6·0), and the mean mental component score was 49·5 (47·0-52·1) versus 46·1 (43·3-48·9; mean difference 3·5, -0·3 to 7·3). Mean numbers of days of sick leave were 3·4 days (SD 7·1) in the resection group versus 1·4 days (4·7) in the infliximab group (p<0·0001), days not able to take part in social life were 1·8 days (6·3) versus 1·1 days (4·5; p=0·20), days of scheduled hospital admission were 6·5 days (3·8) versus 6·8 days (3·2; p=0·84), and the number of patients who had unscheduled hospital admissions were 13 (18%) of 73 versus 15 (21%) of 70 (p=0·68). Body-image scale mean scores in the patients who had resection were 16·0 (95% CI 15·2-16·8) at baseline versus 17·8 (17·1-18·4) at 12 months, and cosmetic scale mean scores were 17·6 (16·6-18·6) versus 18·6 (17·6-19·6). Surgical intervention-related complications classified as IIIa or worse on the Clavien-Dindo scale occurred in four patients in the resection group. Treatment-related serious adverse events occurred in two patients in the infliximab group. During a median follow-up of 4 years (IQR 2-6), 26 (37%) of 70 patients in the infliximab group had resection, and 19 (26%) of 73 patients in the resection group received anti-TNF. INTERPRETATION: Laparoscopic resection in patients with limited (diseased terminal ileum <40 cm), non-stricturing, ileocaecal Crohn's disease in whom conventional therapy has failed could be considered a reasonable alternative to infliximab therapy. FUNDING: Netherlands Organisation for Health Research and Development.

Employment status, difficulties at work and quality of life in inflammatory bowel disease patients.

OBJECTIVES: To assess employment status, difficulties at work and sick leave in inflammatory bowel disease (IBD) patients and their relation with sociodemographic and clinical factors, quality of life (QoL), and anxiety and depression. MATERIALS AND METHODS: IBD patients attending an IBD outpatients' clinic received self-report questionnaires on employment status, IBD-related difficulties at work and sick leave (Trimbos/iMTA questionnaire for Costs associated with Psychiatric Illness), sociodemographic factors, QoL (Inflammatory Bowel Disease Questionnaire and 12-item Short-form Health Survey) and anxiety and depression (Hospital Anxiety and Depression Scale). Disease activity was assessed by their gastroenterologist. Associations between paid employment and sick leave with sociodemographic and clinical factors, QoL and anxiety and depression were assessed by regression analyses. RESULTS: In total, 202 IBD patients of working age, with a mean age of 41 years, participated; 63% had Crohn's disease and 37% had ulcerative colitis, and 57% were women and 19% had active disease. In all, 123 (61%) patients were in paid employment, of whom 31 (25%) were on sick leave, whereas 46 (23%) received a disability pension. Concentration problems (72%), low working pace (78%) and delayed work production (50%) were the most prevalent IBD-related work difficulties. IBD patients without paid employment were older and more often women, with active disease, lower QoL and higher anxiety and depression rates. Sick leave was associated with lower QoL and higher anxiety and depression rates. CONCLUSION: More than half of IBD patients were in paid employment, whereas almost a quarter was receiving a disability pension. A large majority experienced work difficulties. Having no paid employment was associated with poorer QoL and more anxiety and depression symptomatology.

Characterization and treatment of persistent hepatocellular secretory failure.

BACKGROUND & AIMS: Hepatocellular secretory failure induced by drugs, toxins or transient biliary obstruction may sometimes persist for months after removal of the initiating factor and may then be fatal without liver transplantation. We characterized patients with severe persistent hepatocellular secretory failure (PHSF) and treated them with the pregnane X receptor (PXR) agonist, rifampicin. We also studied the effect of rifampicin on PXR-dependent expression of genes involved in biotransformation and secretion in vitro. METHODS: Thirteen patients (age 18-81 years, 6 male) with hepatocellular secretory failure that persisted after removal of the inducing factor (drugs/toxin: 9) or biliary obstruction (4) were identified over 6 years. Six of these patients were screened for ATP8B1 or ABCB11 mutations. All were treated with rifampicin (300 mg daily) for 1-10 weeks. Expression of genes involved in biotransformation and secretion was determined by rtPCR in human hepatocytes and intestinal cells incubated with rifampicin (10 µmol/L). RESULTS: Serum bilirubin of patients with PHSF ranged from 264 to 755 µmol/L. Normal γGT was found in 10/13 patients of whom 3/6 tested positive for ATP8B1/ABCB11 mutations. Serum bilirubin declined to <33 µmol/L after 1-10 weeks of rifampicin treatment. In vitro, rifampicin PXR-dependently upregulated biotransformation phase 1 (CYP3A4), phase 2 (UGT1A1) and phase 3 (MRP2) enzymes/carriers as well as the basolateral bile salt exporter OSTß. CONCLUSION: Persistent hepatocellular secretory failure may develop in carriers of transporter gene mutations. In severe cases, rifampicin may represent an effective therapeutic option of PHSF. PXR-dependent induction of CYP3A4, UGT1A1, MRP2 and OSTß could contribute to the anticholestatic effect of rifampicin in PHSF.

ATG16L1 and NOD2 polymorphisms enhance phagocytosis in monocytes of Crohn's disease patients.

AIM: To investigate if the presence of relevant genetic polymorphisms has effect on the effectual clearance of bacteria by monocytes and granulocytes in patients with Crohn's disease (CD). METHODS: In this study, we assessed the differential responses in phagocytosis by measuring the phagocytic activity and the percentage of active phagocytic monocytes and granulocytes in inflammatory bowel disease patients as well as healthy controls. As both autophagy related like 1 (ATG16L1) and immunity-related guanosine triphosphatase gene are autophagy genes associated with CD and more recently nucleotide-binding ligomerization domain-containing protein 2 (NOD2) has been identified as a potent inducer of autophagy we genotyped the patients for these variants and correlated this to the phagocytic reaction. The genotyping was done with restriction fragment length polymorphisms analysis and the phagocytosis was determined with the pHrodo™ Escherichia coli Bioparticles Phagocytosis kit for flowcytometry. RESULTS: In this study, we demonstrate that analysis of the monocyte and granulocyte populations of patients with CD and ulcerative colitis showed a comparable phagocytic activity (ratio of mean fluorescence intensity) between the patient groups and the healthy controls. CD patients show a significantly higher phagocytic capacity (ratio mean percentage of phagocytic cells) compared to healthy controls (51.91% ± 2.85% vs 37.67% ± 7.06%, P = 0.05). The extend of disease was not of influence. However, variants of ATG16L1 (WT: 2.03 ± 0.19 vs homozygoot variant: 4.38 ± 0.37, P < 0.009) as well as NOD2 (C-ins) (heterozygous variant: 42.08 ± 2.94 vs homozygous variant: 75.58 ± 4.34 (P = 0.05) are associated with the phagocytic activity in patients with CD. CONCLUSION: Monocytes of CD patients show enhanced phagocytosis associated with the presence of ATG16L1 and NOD2 variants. This could be part of the pathophysiological mechanism resulting in the disease.

Adalimumab for Crohn's disease: long-term sustained benefit in a population-based cohort of 438 patients.

BACKGROUND AND AIMS: Adalimumab is an effective therapy for induction and maintenance of Crohn's disease. However, results in clinical trials don't necessarily reflect daily clinical practice. Therefore, we assessed real-life long-term clinical response to adalimumab in a large population-based cohort and identified clinical parameters affecting response METHODS: All consecutive patients in North-Holland that started adalimumab between 2003 and 2011 were included, of which medical charts were reviewed. Response to induction therapy was assessed after 3months. Sustained benefit of maintenance therapy was calculated from Kaplan-Meier survival tables depicting ongoing adalimumab treatment. Regression analyses were performed to identify factors predicting response to adalimumab therapy. RESULTS: In total 438 Crohn's patients started adalimumab with 92.5% response to the induction phase. After 1year 83.3% showed sustained benefit of maintenance treatment, followed by 74.0% after 2years. Nevertheless, one third of patients were in steroid-free remission at the end of their follow-up. Response to induction was negatively affected by longer disease duration (OR 1.05; p<0.01) and strictures (OR 3.73; p=0.04). Increased CRP levels predicted higher rates of initial response (OR 0.31; p<0.01). Concomitant thiopurines in the first 6months of adalimumab treatment decreased the risk to fail maintenance therapy (HR 0.69, p=0.05). Previous infliximab therapy did not affect response to adalimumab, however dose escalation was more often deemed necessary (p<0.01). CONCLUSION: Adalimumab was successful in the majority of patients, with 10% loss of response per subsequent year. Concomitant thiopurines might improve adalimumab maintenance treatment.

Exogenous pigment in Peyer patches of children suspected of having IBD.

OBJECTIVES: The base of human Peyer patches of the terminal ileum has been noted to contain black granular pigment deposits, composed of titanium dioxide and aluminosilicate, which are food additives typically present in a Western diet, and pharmaceuticals. In the present study, we investigated the distribution of exogenous pigment throughout the gastrointestinal tract of children suspected of having inflammatory bowel disease (IBD), the correlation between their age and the presence and amount of pigment in Peyer patches, and its relation to pediatric IBD. METHODS: Biopsies (upper and lower gastrointestinal tract) from children suspected of having IBD who underwent endoscopy, were reassessed by a blinded, expert pathologist. The amount of pigment in biopsies was scored using a semiquantitative scale (range 0 to +++). RESULTS: A total of 151 children were included: 62 with Crohn disease (CD), 26 with ulcerative colitis, and 63 with non-IBD. In 63 children (42%), deposits of black pigment were found only in biopsies from the terminal ileum, located in Peyer patches. A significant correlation was found between increasing age and the amount of pigment (P = 0.004). Pigment deposits were found significantly less in the patients with CD compared with those in patients with ulcerative colitis and those with non-IBD (26% vs 62% and 49%, P = 0.002). CONCLUSIONS: These results provide support for the hypothesis that the amount of pigment, only present in Peyer patches in the terminal ileum, becomes denser with increasing age. Absence of pigment in Peyer patches in a higher number of patients with CD suggests that microparticles may have become involved in the inflammatory process, possibly because of disrupted autophagy.

Random biopsies taken during colonoscopic surveillance of patients with longstanding ulcerative colitis: low yield and absence of clinical consequences.

OBJECTIVES: To evaluate the yield and clinical impact of random biopsies taken during colonoscopic surveillance of patients with longstanding ulcerative colitis (UC). METHODS: Retrospective analysis of 1,010 colonoscopies performed from 1998 to 2008. Colonoscopy and pathology reports were reviewed to assess the yield and clinical impact of random biopsies. In total, 475 patients with UC who underwent colonoscopy at the Academic Medical Centre Amsterdam were included in this study. The main outcome measures are neoplasia yield per-colonoscopy and clinical impact per-patient of random biopsies. RESULTS: Of all colonoscopies, 466 were performed for surveillance (in 167 patients) during which 11,772 random biopsies were taken (median 29). Overall, neoplasia was detected in 88 colonoscopies (53 patients): in 75 colonoscopies (85%) by targeted biopsies only and in 8 (9.1%) by both targeted and random biopsies. Neoplasia was detected in random biopsies only in five (5.7%) colonoscopies in four (7.5%) patients. Two of these four patients with neoplasia detected only by random biopsies had visible neoplasia in previous colonoscopies. One patient had unifocal low-grade intraepithelial neoplasia (LGIN) that could not be confirmed in three subsequent colonoscopies. The last patient had multifocal LGIN and suspicious appearing ulcerations. Proctocolectomy confirmed the presence of neoplasia. CONCLUSIONS: The yield of random biopsies is low whereas UC-associated neoplasia is macroscopically visible in 94% of colonoscopies. During 10-year surveillance, neoplasia was detected in only random biopsies in four patients of whom only one had clinical consequences. The low yield and lack of clinical consequences from random biopsies in this high-risk population raise questions about the necessity and cost-effectiveness of their routine use during UC surveillance.

Treatment of bone loss in osteopenic patients with Crohn's disease: a double-blind, randomised trial of oral risedronate 35†mg once weekly or placebo, concomitant with calcium and vitamin D supplementation.

OBJECTIVE: Osteoporosis and fractures are frequently encountered in patients with Crohn's disease. In order to prevent fractures, treatment with bone protecting drugs appears warranted early in the course of bone disease when bone loss is not yet prominent. We therefore aimed to demonstrate a beneficial effect on bone density of the bisphosphonate risedronate in osteopenic Crohn's disease patients. METHODS: This double-blind, placebo-controlled randomised trial of risedronate with calcium and vitamin D supplementation was performed in osteopenic Crohn's disease patients. Patients were treated for 2 years with follow-up after 3 and after every 6 months. Disease characteristics and activity and bone turnover markers were assessed at all visits; dual x-ray absorptiometry was performed at baseline, 12 and 24 months; radiographs of the spine at baseline and 24 months. RESULTS: Of 132 consenting patients, 131 were randomised (67 placebo and 64 risedronate). Patient characteristics were similar in both groups, although the risedronate group was slightly heavier (body mass index 24.3 vs 23.0 kg/m(2)). Bone mineral density at lumbar spine increased 0.04 g/cm(2) on average in the risedronate group versus 0.01 g/cm(2) in the placebo group (p=0.007). The mean increase in total hip bone mineral density was 0.03 versus 0.01 g/cm(2), respectively (p=0.071). Fracture prevalence and incidence were similar. Change of T-scores and concentrations of bone turnover markers were consistent with a beneficial effect of risedronate when compared with placebo. The effect of risedronate was primarily demonstrated in the first 12 months of treatment. No serious unexpected suspected adverse events were observed. CONCLUSIONS: A 24-month treatment course with risedronate 35 mg once weekly, concomitant with calcium and vitamin D supplementation, in osteopenic Crohn's disease patients improved bone density at lumbar spine. NTR 163 Dutch Trial Register.

Development of the patient Harvey Bradshaw index and a comparison with a clinician-based Harvey Bradshaw index assessment of Crohn's disease activity.

GOALS AND BACKGROUND: The objective is to develop a patient-based Harvey Bradshaw Index (P-HBI) of Crohn's Disease (CD) activity and to compare it with the clinician-based HBI of CD activity in CD outpatients. STUDY: Consecutive patients with CD randomly completed the P-HBI either before or after the consultation. The gastroenterologist assessed patient's CD activity on the same day. Overall agreement between HBI and P-HBI was calculated with Spearman's ρ and Mann-Whitney U test. Agreement regarding active disease versus remission and agreement at item level was calculated by percent agreement and Cohen's κ. RESULTS: One hundred eighty-one (response rate 88.3%) CD patients participated. P-HBI and HBI showed a large correlation (rs=0.82). The medians (interquartile range) of the total HBI (2; 0 to 4) and P-HBI (4; 1 to 7) were statistically significantly different (z=-8.411; P<0.001). Fortunately, in 82.6% of the cases this difference between clinicians and patients was not clinically significant (<3.2). The percentage agreement between clinician and patient, judging CD as active or as in remission, was 77%, rs=0.56, κ=0.52, indicating a moderate agreement. P-HBI and HBI on frequent extraintestinal manifestations in CD varied from less than chance (κ=-0.02) to a perfect agreement (κ=1). Patients tended to report more symptoms while completing the patient-based questionnaire compared to what they reported to the clinician during consultation. CONCLUSIONS: The P-HBI is the first step in developing a potential promising tool given its adequate agreement with the original HBI and its feasibility, especially in patients with low scores. Future research is necessary to develop a validated patient-based version studied in several patient populations.

Ten years of infliximab for Crohn's disease: outcome in 469 patients from 2 tertiary referral centers.

BACKGROUND: Aim was to assess the long-term clinical efficacy of infliximab therapy in patients with Crohn's disease treated in a cohort of 2 tertiary referral centers in the Netherlands. METHODS: All consecutive patients with Crohn's disease treated with infliximab were assessed. Endpoints were primary clinical efficacy, sustained benefit, efficacy of retreatment, surgical intervention rates, and safety. Sustained benefit was determined by Kaplan-Meier analysis. The estimated 5-year benefit was calculated. RESULTS: A total of 469 patients were included. Median follow-up length was 4.5 years (interquartile range, 2.7-6.8). Seventy patients (15%) had unsuccessful remission induction, and 316 patients received maintenance therapy. Scheduled maintenance regimen was successful in 169 of 276 (61%). Episodic maintenance therapy was successful in 19 of 40 patients (48%). Estimated 5-year sustained benefit was 55.7% (95% confidence interval, 48.8-62.6). Concomitant thiopurines were associated with improved sustained benefit. A second course of infliximab after previous discontinuation was prescribed in 131 patients with similar efficacy rates. Abdominal surgical intervention rate per 100 patient-years was significantly reduced after infliximab initiation in patients with a scheduled maintenance regime (reduction, 2.70; 95% confidence interval, -4.82 to -0.35; P = 0.018). Mortality and malignancy rates were 1.9% (0.39/100 patient-years) and 3.4% (0.70/100 patient-years), respectively. CONCLUSIONS: The present study shows an estimated 5-year sustained benefit of 55.7% in patients with Crohn's disease treated with infliximab maintenance therapy. Remission induction and maintenance were equally successful in patients starting infliximab and patients who temporarily stopped and were retreated. Long-term use of infliximab was safe and reduced the need for surgery in patients on scheduled maintenance therapy.