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Background: Stress has been suggested to play a potential role in inflammatory bowel disease (IBD) pathogenesis, but studies focussing on the occurrence of specific life stress events among IBD patients are scarce. Therefore, the aim of the present study was to explore the association between various life stress events and IBD., Methods: Patients with IBD (N = 98, mean age: 38.45, 54.1% men) were compared to a group of healthy controls (N = 405, mean age: 36.45, 58.0% men) originating from a health survey conducted on a representative population sample of Czech adults. The Life Stressor Checklist-Revised (LSC-R) was used to assess the stressors., Results: IBD patients had higher odds of reporting life stressors overall ( p < 0.001), life stressors before the age of 16 ( p < 0.004) and a higher score in traumatic stress ( p < 0.005) and interpersonal violence ( p < 0.001) when compared to the control group. Gender- and diagnosis-related differences are discussed., Conclusion: Reporting life stressors experienced during childhood or adulthood is strongly associated with IBD. This should be considered in illness management, especially in a severe course of IBD.

Background: Ustekinumab is effective in Crohn's disease. However, a substantial proportion of patients will not respond or lose response to ustekinumab. The current evidence to support the effectiveness of dose-optimisation for ustekinumab nonresponse is limited., Aim: To assess the effectiveness of dose escalation of ustekinumab., Methods: This was a multicentre retrospective cohort study. We included active Crohn's disease patients who received a standard-dose intravenous induction and at least one subcutaneous ustekinumab 90 mg dose. All enrolled patients received dose escalation by either shortening the interval between the doses to every 4 or 6 weeks, intravenous reinduction or a combination of strategies. The primary outcome of the study was clinical response at week 16 after dose escalation., Results: A total of 142 patients (22 centres/14 countries) were included. The patients were dose-escalated after a median treatment duration of 30 weeks. At week 16 from escalation, 73/142 (51.4%) responded to treatment, including 55/142 (38.7%) in clinical remission. Corticosteroid-free remission was achieved in 6/34 (17.6%) patients on corticosteroids at the time of escalation; 118/142 (83%) continued treatment beyond week 16. Follow-up data beyond week 16 were available for 74/118 (62.7%) patients. On the last follow-up, 51/98 (52%) patients with available data responded to treatment, including 41/98 (42%) in clinical remission., Conclusions: Intensification of ustekinumab maintenance dosage was effective in over 50% of the patients. This strategy should be considered in patients who are nonresponsive to every 8 weeks ustekinumab maintenance dosing., (© 2020 John Wiley & Sons Ltd.)

Background: Adalimumab is an effective therapy for Crohn's disease patients. However, there is limited knowledge on the pharmacokinetic properties of adalilumab in patients with Crohn's disease., Aim: To assess the pharmacokinetic properties of adalilumab in a retrospective clinical cohort of patients with Crohn's disease, naïve to anti-tumour necrosis factor alpha therapy (anti-TNF)., Methods: In a single tertiary centre, a clinical retrospective cohort was formed out of 76 patients with Crohn's disease who started adalilumab treatment (160/80/40EOW) between July 2007 and September 2010. We serially evaluated adalilumab serum levels at week 0, 12 and 28., Results: Patients were followed for a median time of 201 days (range 120-244) and received a median of 14 adalilumab injections (range 6-25). Adalilumab levels, although divergent between patients, were stable between week 12 and week 28. There was no correlation between adalilumab level and time since last administration (r = -0.061). In a multivariable regression analysis of patient factors influencing week 28 adalilumab levels, the regression model containing CRP at week 28 and BMI at baseline weakly but significantly predicted week 28 adalilumab levels (R(2) = 0.193, P = 0.004). Concomitant use of immunosuppressives was not a significant predictor (P = 0.304)., Conclusions: Intra-individual adalilumab levels seem very stable during the first 28 weeks of treatment, whereas inter-individual levels vary. Adalilumab levels appear stable over a 2-week period, as the time since last adalilumab administration did not affect the adalilumab level. CRP and BMI weakly predict week 28 adalilumab levels, whereas the use of immunosuppressives does not., (© 2014 John Wiley & Sons Ltd.)

Background and Aim: Although the genetic risk factors for familial and sporadic inflammatory bowel disease (IBD) seem identical, the relative risk for contracting IBD in the familial setting is larger as that seen in the population at large, suggesting an important role of epi- and/or paragenetic factors in familial IBD. Epidemiological data indicate a female predominance in IBD, but how this relates to familial IBD has not been assessed., Methods: Familial IBD patients (N=608) were compared with a cohort of 415 sporadic IBD patients with regards to the patterns of sex and disease type distribution. The imprinting pattern in 87 families in which both a parent and a child had IBD was tested using Galton binominal statistics., Results: The percentage of females in familial IBD population was significantly higher (61%; female/male ratio 1.5) compared with sporadic IBD (54%; female/male ratio 1.2; p=0.011). The analysis of offspring sex distribution pattern revealed significantly higher female to female transmission compared with female to male transmission rate (36 vs. 18, respectively; p=0.02). A significantly higher number of mother to child transmissions (55 vs. 32 of father to child transmissions) was observed (p=0.018). The female imprinting was specifically related to Crohn's disease (31 vs. 14 mother vs. father to child transmissions, respectively; p=0.016)., Conclusion: We propose that a female sex-specific epigenetic inheritance pattern for Crohn's disease is a major contributing factor in the family-specific risk in Crohn's disease. Sex-specific manifestation of familial Crohn's disease can partly explain the epidemiologically observed increased relative risk for females for contracting IBD., (Copyright © 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Background: Adalimumab is effective for the induction and maintenance of remission in Crohn's disease (CD)-patients., Aim: To find predictors for adalimumab dose escalation at initiation of adalimumab., Methods: Crohn's disease patients in a single tertiary referral centre who started adalimumab between July 2007 and March 2010 at an induction dose (week 0 160 mg subcutaneously (sc), week 2 80 mg sc) and maintenance dose of 40 mg sc thereafter every other week were followed prospectively. Patients on adalimumab for at least 3 months were included. The number of patients needing dose escalation was assessed. Patients that needed dose escalation were compared with patients that did not need dose escalation., Results: Of 199 CD patients treated with adalimumab and followed prospectively, 122 patients (M/F 54/68, median age 35 years, range 18-66 years, median CDAI 164, range 6-468) were treated for 3 months. In total 38% of these patients (46/122) needed a dose escalation within a median time of 21 weeks after adalimumab introduction (range 4-105). Body mass index (BMI) (P < 0.03) and secondary non-response to infliximab (IFX) (P < 0.06) were identified as predictors for dose escalation. Concomitant use of immunomodulators at initiation of adalimumab and the presence of autoantibodies to IFX did not predict dose escalation., Conclusions: Over one-third adalimumab-treated patients are dose escalated within a median of 5 months. Higher BMI and secondary non-response to IFX treatment are predictive for a dose escalation during adalimumab treatment., (© 2011 Blackwell Publishing Ltd.)

Background and Aims: Data on the optimal use of conventional therapies in Crohn's disease are lacking in guidelines. An educational programme was established to explore questions raised in clinical practice and to provide practical answers., Methods: Telephone interviews with 96 gastroenterologists and a web survey of 1370 gastroenterologists identified 26 key questions. Ten questions were taken forward to the next stage based on the opinion of an International Steering Committee. Draft answers to the questions were prepared from available evidence following a literature search. The draft answers were debated in national meetings of participating countries (n=36) and voted on using a standard scoring system. Revised answers went forward to an international meeting and were debated and voted on using the same methodology. Final answers were developed, based on evidence and clinical experience of the participants., Results: Evidence on corticosteroid and immunomodulator use such as dosage, timing and duration, choice of drug or regimen, and safety is scarce. Key points of the answers included the importance of: identifying patients with poor prognosis; early intervention with optimal doses of immunomodulators; avoiding prolonged or repetitive corticosteroid therapy; achieving corticosteroid-free remission; achieving a balance between clinical benefit and safety when intensifying or prolonging therapy or combining different agents; re-evaluating therapy at appropriate time points; and considering the role of biomarkers and mucosal healing., Conclusions: The answers to 10 key questions were based on available evidence and clinical experience of programme participants. It is hoped they will be of practical use in everyday gastroenterology practice., (Copyright © 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Background: Although new therapeutic strategies have been developed to control Crohn's disease, medical treatment for refractory cases is not able to prevent extensive and/or repeat surgery. Recently, several cases have been reported of successful remission induction in Crohn's disease patients by means of hematopoietic stem cell transplantation (HSCT). Here we report our long-term (4 to 6 years) outcome in three patients., Patients: Three patients (two male, one female) with active severe Crohn's disease were planned to undergo autologous HSCT. All patients were intolerant or refractory to conventional therapies, including anti-TNFα antibodies. Patients either refused surgery or surgery was considered not to be a feasible alternative due to the extensive disease involvement of the small intestine., Methods: Peripheral blood stem cells were mobilized using a single infusion of cyclophosphamide 4 g/m(2), followed on day 4 by subcutaneous injections with G-CSF 5 μg/kg twice daily until leukapheresis. CD34+ cells were isolated after leukapheresis by magnetic cell sorting. In two of the three patients a second round of stem cell mobilization using G-CSF only was required, either because of low yield or because of insufficient recovery after CD34 selection. Prior to transplantation, immune ablation was achieved using cyclophosphamide 50mg/kg/day (4 days), antithymocyte globulin 30 mg/kg/day (3 days) and prednisolone 500 mg (3 days). Endoscopy, barium small bowel enteroclysis and MRI enterography were performed., Results: All three patients successfully completed stem cell mobilization, and two of them subsequently underwent conditioning and autologous HSCT with CD34+ cell selection. Treatment was well tolerated, with acceptable toxicity. Now, 5 and 6 years post-transplantation, these patients are in remission under treatment. The third patient went into remission after mobilization and therefore she decided not to undergo conditioning and HSCT transplantation. After a successful pregnancy she relapsed two years later. Since then, she suffers from refractory Crohn's disease for which we are now reconsidering conditioning and transplantation., Conclusion: Autologous HSCT appears to be safe and can be an alternative strategy for Crohn's disease patients with severe and therapy resistant disease., (Copyright © 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Objective: It is estimated that 10%-30% of Crohn's disease (CD) patients have small-bowel lesions, but the exact frequency and clinical relevance of these findings are unknown. Double-balloon enteroscopy (DBE) enables endoscopic visualization of the small bowel. The aim of this study was to evaluate the use of DBE for detecting small-bowel lesions in CD patients suspected of having small-bowel involvement. Furthermore, the clinical impact of adjusting treatment in these patients was assessed., Material and Methods: A prospective study was performed in a tertiary referral center. CD patients suspected of small-bowel involvement and in whom distal activity had previously been excluded were included. All patients underwent DBE, followed by step-up therapy in patients with small-bowel lesions. The presence of small-bowel lesions during DBE was noted and clinical outcome was assessed after adjusting therapy., Results: Thirty-five patients (70%) showed small-bowel lesions; these lesions could not be assessed by conventional endoscopy in 23 (46%). At 1-year follow-up, step-up therapy in 26 patients (74%) led to clinical remission in 23 (88%). This was confirmed by a significant decrease in Crohn's disease activity index and mucosal repair on second DBE., Conclusions: DBE showed a high frequency of small-bowel lesions in known CD patients with clinically suspected small-bowel activity. Most of these lesions were not accessible for conventional endoscopy. Adjusting treatment in patients with small-bowel CD involvement led to clinical remission and mucosal repair in the majority of cases.

Background: Adherence is important for successful treatment in inflammatory bowel disease (IBD) patients. Previous studies demonstrated high prevalence of non-adherence., Aim: To assess IBD-patients' perceptions of therapy adherence and disease-related functional status in members of the Dutch patients' association of Crohn's disease and ulcerative colitis (CCUVN)., Methods: Inflammatory bowel disease-patients completed anonymously a survey at the website of the CCUVN. Statistical analysis was performed using principal component analysis, univariate and multivariate logistic regression., Results: The questionnaire was completed by 1067 patients [617 (58%) Crohn's disease (CD) and 450 (42%) ulcerative colitis (UC)]. Mean age was 43 years (s.d. 13.7); women (66%). Of 920 patients currently using medication, 797 (87%) were adherent. Of the patients using 5-ASA, 91% were adherent (527/582), vs. 96% using corticosteroids (316/330) and 97% (414/425) using immunosuppressives. CD patients (OR 1.54; 95% CI 1.05-2.27), patients with duration of disease

Background: Adalimumab is an effective treatment in patients with Crohn's disease; as it is a humanized anti-tumour necrosis factor monoclonal antibody, immunogenicity is thought not to be of any significance., Aim: To assess whether antibodies to adalimumab (ATAs) affect adalimumab treatment outcome in patients with Crohn's disease previously treated with infliximab., Methods: A retrospective study was performed. Patients with active Crohn's disease and who had lost response or were intolerant to infliximab were treated with adalimumab. Clinical response and side effects were assessed as were serum ATAs and antibodies to infliximab (ATIs)., Results: In total 30 patients [M/F (7/23)], median age 36 years (range 21-73) were treated with adalimumab for 318 days (median range 83-632). Clinical response was 77% (23/30), a dose escalation was necessary in eight (27%) patients and side effects were observed in 47% (14/30). In five patients (17%) ATAs were detected; of these patients, four were nonresponders. The presence of ATAs was related to nonresponse to adalimumab (P = 0.006). ATIs were positive in 57% of patients (17/30) and serum levels were significantly increased in adalimumab nonresponders (P = 0.01)., Conclusion: Immunogenicity plays a role in adalimumab treatment because of the development of ATAs.

Background: Mutations in the gene encoding the nucleotide-binding oligomerization domain 2 (NOD2) protein are associated with Crohn's disease (CD), but the mechanism underlying this is not completely understood. To study the mechanism of CD resulting from NOD2 mutations, we analyzed NOD2-dependent whole-genome expression profiles of patient-derived antigen-presenting cells., Patients and Methods: Monocyte-derived dendritic cells (DCs) from CD carriers of double-dose NOD2 mutations, wild-type CD patients, and wild-type healthy volunteers were stimulated with the NOD2 ligand muramyl dipeptide. Whole-genome microarrays were used to assess the differential gene expression. The clustering of significantly changed genes was analyzed by online gene ontology mapping software., Results: In the DCs from the wild-type CD patient group, 683 genes were significantly changed, with most of the genes clustering in the pathways of inflammatory response. In addition, a significant number of genes clustered in the apoptosis regulation-related pathway. In the DCs from the healthy volunteer group, only 50 genes were significantly changed, predominantly those belonging to the response to pathogen pathway. Analysis of differentially expressed gene ontology pathways in the DCs from the NOD2 mutant CD patient group showed that the transcription of pathogen response genes was absent. In this group, 298 genes were significantly changed, predominantly clustering in the negative apoptosis regulation and cell organization and biogenesis pathways., Conclusions: Our results suggest that NOD2 mutations may result in perpetuation of mucosal inflammation through insufficient pathogen elimination. Further, these observations implicate a possible role of defective regulation of dendritic cell apoptosis in CD pathogenesis.

Background: The human anti-tumour necrosis factor (TNF) antibody infliximab binds to the membrane TNF and subsequently induces apoptosis of activated lamina propria T lymphocytes in patients with Crohn's disease in vitro., Aim: To test whether the ability of rapid anti-TNF-induced apoptosis in the gut predicts the efficacy of anti-TNF treatment in inflammatory bowel disease., Methods: (99m)Technetium-annexin V single-photon emission computer tomography (SPECT) was performed in 2 models of murine experimental colitis and in 14 patients with active Crohn's disease as assessed by the Crohńs Disease Activity Index (CDAI) to study the effect of anti-TNF treatment on apoptosis in the intestine during active colitis. Disease activity was evaluated 2 weeks after infliximab infusion using the CDAI (definition response: drop of >100 points)., Results: Colonic uptake of (99m)Tc-annexin V significantly increased in 2,4,6-trinitrobenzene sulphonate-induced colitis as well as in transfer colitis on administration of anti-TNF antibodies compared with a control antibody as determined with dedicated animal pinhole SPECT. In addition, uptake of (99m)Tc-annexin V significantly increased in patients with active Crohn's disease responding to infliximab treatment. Colonic (99m)Tc-annexin V uptake ratio (mean (SEM)) increased from 0.24 (0.03) to 0.41(0.07) (p<0.01), 24 h after infliximab infusion (5 mg/kg). A mean increase of 98.7% in colonic uptake of (99m)Tc-annexin V could be detected in 10 of the 14 responding patients (CDAI >100 points at week 2) compared with 15.2% in non-responding patients (p = 0.03). Analysis of the mucosal biopsy specimens identified lamina propria T cells as target cells undergoing apoptosis., Conclusions: These in vivo observations support the notion that colonic uptake of (99m)Tc-annexin V correlates with clinical benefit of anti-TNF treatment and might be predictive of therapeutic success.