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Background: The incidence and prevalence of inflammatory bowel disease (IBD) in the Faroe Islands have increased drastically during the past 60 years, presumably due to changing environmental risk factors in a genetically susceptible population., Aim: This study investigated differing environmental factors present in Faroese and Danish patients., Methods: From 2010 to 2022, all incident Faroese patients with IBD were invited to complete the International Organization of IBD (IOIBD) questionnaire about environmental factors at the time of their diagnosis. The findings were compared to a cohort of incident Danish patients diagnosed between 2010 and 2011., Results: Questionnaires were completed by 293 of 388 Faroese patients (75%), of whom 15% (n = 45) had Crohn's disease (CD), 63% (n = 185) had ulcerative colitis (UC), and 22% (n = 63) had IBD unclassified (IBDU). Faroese patients with IBD and UC were found to have higher pertussis vaccination coverage (p < 0.05), and more childhood infections of measles and pertussis (p < 0.05). Faroese patients with IBD consumed more fast food and less fiber but consumed less sugar (p < 0.001) and more caffeine (p < 0.001). No differences were found regarding gender, having been breastfed, use of oral contraceptives, or the number of first-degree relatives with IBD; however, differences in smoking at diagnosis were found in a subset analysis of Faroese patients diagnosed in 2010-11 compared with Danish patients., Conclusions: Faroese patients with IBD were more exposed to some environmental risk factors prior to diagnosis than Danish patients. However, certain beneficial dietary habits were more common in Faroese patients than in Danish patients., Competing Interests: Declarations. Conflict of interest: JB reports grants and personal fees from AbbVie, Janssen-Cilag, MSD, Takeda, Tillots Pharma, and Bristol Myers Squibb. JB also reports personal fees from Celgene, Pfizer, Samsung Bioepis, Pharmacosmos, Ferring, and Galapagos and grants from Novo Nordisk, unrelated to the submitted work. EL reports speaker’s fees from Ferring Pharmaceuticals, Takeda, Janssen-Cilag, Tillotts, and MSD. EL also reports having served as an advisory board member for Ferring Pharmaceuticals and Takeda. VA reports personal fees from MSD (Merck) unrelated to the submitted work., (© 2024. The Author(s).)

Background: Elderly patients with inflammatory bowel disease [IBD] are fragile in many respects. Therefore, in these patients, we studied postoperative complications [new abdominal surgery and serious infections after the first IBD surgery]., Methods: This is a nationwide cohort study based on Danish health registries and included patients with IBD undergoing surgery. The study population was split into ulcerative colitis [UC] and Crohn's disease [CD]. The exposed cohort [elderly] constituted those at an age of ≥60 years at first IBD surgery, and the unexposed [adults] those with surgery at the age of 18-59 years. We estimated adjusted hazard ratios [aHRs] of: a] new abdominal surgery within 2 years; and b] serious [hospital-diagnosed] infections within 6 and 12 months. We adjusted for several confounders including type of index surgery [laparoscopic or open]., Results: The aHR for a new surgery among elderly with UC and CD were 0.69 [95% CI 0.58-0.83] and 0.98 [95% CI 0.83-1.15], respectively. In elderly with UC, the aHRs of infections within 6 and 12 months after surgery were 1.07 [95% CI 0.81-1.40] and 0.85 [95% CI 0.67-1.08], respectively. In the elderly with CD, the aHRs of infections within 6 and 12 months were 1.45 [95% CI 1.12-1.88] and 1.26 [95% CI 1.00-1.59], respectively., Conclusion: The elderly with IBD did not have an increased risk of new abdominal surgery within 2 years of the first surgery. Elderly with CD, but not UC, had an increased risk of serious infections within 6 months of surgery., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Up to 15% of women with Crohn's disease (CD) or ulcerative colitis (UC) undergo bowel surgery before pregnancy, and there is little data on pregnancy outcomes in this population. We aimed to assess maternal/fetal outcomes in women with CD or UC who underwent surgeries before pregnancy., Methods: In this nationwide study, we included all pregnancies in women with CD or UC from 1997 to 2022 and examined 6 categories of CD and UC surgeries before pregnancy. We used multilevel logistic regression to compute crude and adjusted odds ratios (aOR) with 95% confidence intervals (95% CI) for the risk of pregnancy and offspring complications in women who did, vs did not, undergo surgery before pregnancy., Results: There were 833 UC and 3,150 CD pregnancies with prior surgery and 12,883 UC and CD 6,972 pregnancies without surgery. For UC, prior surgery was associated with Cesarian section (C-section) (ileoanal pouch: aOR: 20.03 [95% CI 10.33-38.83]; functional ileostomy: aOR:8.55 [6.10-11.98]; diverting ileostomy: aOR: 38.96 [17.05-89.01]) and preterm birth (aOR: 2.25 [1.48-3.75]; 3.25 [2.31-4.59]; and 2.17 [1.17-4.00]) respectively. For CD and prior intestinal surgery, the risks of C-section (aOR: 1.94 [1.66-2.27]), preterm birth (aOR: 1.30 [1.04-1.61]), and low 5-minute Apgar (aOR: 1.95 [95% CI 1.07-3.54]) increased and premature rupture of membranes (aOR: 0.68 [0.52-0.89]) decreased. For CD with only prior perianal surgery, the risk of C-section (aOR: 3.02 [2.31-3.95]) increased and risk of gestational hypertension/preeclampsia/eclampsia (aOR: 0.52 [0.30-0.89]) decreased., Discussion: Providers should be aware there is an increased likelihood of C-section and certain perinatal complications in patients with CD or UC surgery before pregnancy., (Copyright © 2024 by The American College of Gastroenterology.)

Background: The risk of chronic opioid use after surgery for Crohn's disease (CD) is not known., Aim: The aim of this study is to examine the chronic opioid use after surgery according to age at time of surgery and to opioid use prior to surgery., Methods: This nationwide cohort study included patients with a first surgery for CD (January 1, 1996 through 2021). We examined prescribed opioids 9 months after surgery and estimated adjusted odds ratios (OR) for chronic opioid use in elderly (≥60 years), adults (≥40 and <60 years), and young adults (≥18 and <40 years) according to opioid use prior to surgery. Chronic opioid use was defined as prescriptions in at least two of three consecutive quarters., Results: A total of 797 patients had surgery as elderly, 1603 as adults, and 2786 as young adults. Across all age groups, 18%-38% received opioid prescriptions throughout 9 months after surgery, if opioids were prescribed prior to surgery. If opioids were not prescribed prior to surgery, the corresponding proportions were 2%-5%. If patients were prescribed opioids (≥1) prior to surgery, the adjusted ORs (95% CIs) for their chronic use after surgery in elderly, adults, and young adults were 10.37 (6.77-15.88), 10.48 (7.74-14.19), and 6.55 (4.93-8.72), respectively., Conclusion: Clinicians should be aware that in patients with a need for opioids before surgery, the surgery may not change the need for opioids. Future research should examine effective analgesic strategies that help minimise opioid use in this population., (© 2024 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background and Aim: Pan-enteric capsule endoscopy [PCE] is a highly sensitive but time-consuming tool for detecting pathology. Artificial intelligence [AI] algorithms might offer a possibility to assist in the review and reduce the analysis time of PCE. This study examines the agreement between PCE assessments aided by AI technology and standard evaluations, in patients suspected of Crohn's disease [CD]., Method: PCEs from a prospective, blinded, multicentre study, including patients suspected of CD, were processed by the deep learning solution AXARO® [Augmented Endoscopy, Paris, France]. Based on the image output, two observers classified the patient's PCE as normal or suggestive of CD, ulcerative colitis, or cancer. The primary outcome was per-patient sensitivities and specificities for detecting CD and inflammatory bowel disease [IBD]. Complete reading of PCE served as the reference standard., Results: A total of 131 patients' PCEs were analysed, with a median recording time of 303 min. The AXARO® framework reduced output to a median of 470 images [2.1%] per patient, and the pooled median review time was 3.2 min per patient. For detecting CD, the observers had a sensitivity of 96% and 92% and a specificity of 93% and 90%, respectively. For the detection of IBD, both observers had a sensitivity of 97% and had a specificity of 91% and 90%, respectively. The negative predictive value was 95% for CD and 97% for IBD., Conclusions: Using the AXARO® framework reduced the initial review time substantially while maintaining high diagnostic accuracy-suggesting its use as a rapid tool to rule out IBD in PCEs of patients suspected of Crohn's disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis are chronic autoimmune lifelong diseases with fluctuating activity over time. The treatment includes medical therapy and surgery, however, there is no definite cure. Therefore, the quest for new and supplementary treatment options is imperative to improve patients' general health and quality of life. Physical activity and exercise have been suggested to be elements in both the prevention and supplementary treatment of IBD; however, this is based on limited underpowered trials. Thus, the role of exercise as a treatment option still has to be settled. We aim to investigate the effect of a 12-week exercise intervention in adult patients with moderately active IBD on three categories of outcomes (1) disease-specific health-related quality of life (IBDQ); (2) general health status of the patients, i.e., waist circumference, disease activity by clinical scorings systems (Harvey Bradshaw Index, Simple Clinical Colitis Activity Index), blood pressure, blood lipids, and non-disease specific quality of life (EQ5D) scores; and (3) explorative outcomes on biomarkers (C-reactive protein and fecal calprotectin) plus different biomarkers of immunology (cytokine panel)., Methods: We will apply a superiority design in this open-label randomized clinical trial including 150 patients equally allocated to intervention and usual care. The intervention will be based on a 12-week aerobic exercise program and will include two supervised exercise sessions of 60 min per week, combined with one weekly home training session. We have defined a moderate exercise level as 60-80% of patients' maximum heart rate. The patients in the intervention group will also be offered an online video lesson of 15-25 min on lifestyle guidance, and the same online video lesson will be offered in the comparator group. Questionnaires on quality of life will be forwarded electronically both at inclusion and at the end of the study, and the patients will have blood samples, and fecal samples for calprotectin at baseline, weeks 4 and 8, as well as after 12 weeks (study end)., Discussion: This will be a clinical trial investigating the effect of exercise on patients with Crohn's disease and ulcerative colitis. This trial will add to the evidence on the possible effect of exercise and might clarify whether exercise can benefit as a supplementary treatment addendum. Thus, the trial may provide a new patient-active disease management approach., Trial Registration: ClinicalTrials.gov NCT04816812. Date of first registration: March 23, 2021., (© 2023. The Author(s).)

Background: It is not known whether coronavirus 2019 (COVID-19) is a trigger for disease activity in patients with inflammatory bowel diseases (IBD). In patients with IBD, we aimed to examine the association between COVID-19 infection and prescriptions of systemic and local corticosteroids (used as proxy for disease activity)., Methods: This nationwide cohort study was based on Danish health registries and included all patients in Denmark with ulcerative colitis (UC) or Crohn's disease (CD) by the start of the pandemic (March 1, 2020) and who had a positive COVID-19 polymerase chain reaction (PCR) test from March 1, 2020, to July 31, 2022. We calculated rates of corticosteroid prescriptions 6 months before and 6 months after a positive COVID-19 PCR test, and we calculated adjusted incidence rate ratios (aIRR)., Results: We included 30,102 patients with IBD and a positive COVID-19 test (11,159 with CD, 18,493 with UC). The aIRR for having corticosteroid prescriptions after a COVID-19 positive test was 0.85 (95% confidence interval [CI], 0.79-0.91). When we stratified for underlying disease, the aIRR for having corticosteroid after a COVID-19 positive test in UC was 0.82 (95% CI, 0.75-0.90), and in CD 0.91 (95% CI, 0.81-1.02). Stratifications according to calendar periods and age groups showed consistent results., Conclusions: An infection with COVID-19 did not result in a higher rate of filled corticosteroid prescriptions. Using corticosteroids as a proxy for disease activity, COVID-19 did not seem to trigger disease activity, which is a reassuring result for patients with IBD., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: In patients with elderly (≥60 years) onset inflammatory bowel disease (IBD), we studied initiation of medications, drug persistency and surgeries., Design: A nationwide cohort study based on Danish registries, comprising incident IBD patients ≥18 years from 1995 to 2020 (N = 69,039). Patients were divided into elderly (N = 19,187) and adult onset (N = 49,852). Outcomes were initiation of thiopurines, 5-ASA, biologics and corticosteroids within 1 and 5 years after diagnosis, and for those who initiated medications, we estimated drug persistency. Surgeries were examined within 1 and 5 years. We used regression models controlling for covariates., Results: In elderly patients, the adjusted hazard ratios (aHR) for initiating thiopurines, 5-ASA and biologics within 1 year were 0.44 (95% CI 0.42-0.47), 0.77 (95% CI 0.75-0.79) and 0.29 (95% CI 0.26-0.31) respectively. The results were similar within 5 years. In elderly patients, drug persistency for thiopurines, 5-ASA and biologics was not impaired within 5 years. The aHR of stopping steroids within 1 and 5 years were 0.80 (95% CI 0.76-0.84) and 0.77 (95% CI 0.74-0.80) respectively. The risk of surgeries was increased in the elderly patients (in ulcerative colitis, within 5 years, aHR 1.39 [95% CI 1.27-1.52], and in Crohn's disease 1.13 [95% CI 1.04-1.23])., Conclusion: We found significantly low chance of initiation of IBD medications in elderly patients, the reason may not be due to mild disease course. In elderly patients, drug persistency was comparable to adults. Clinicians should carefully consider whether they underuse IBD-specific medications in elderly patients, and special attention should be applied to timely discontinuation of corticosteroids., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background and Aims: Intestinal ultrasound (IUS) performed by experts is a valuable tool for the diagnostic work-up and monitoring of Crohn's disease (CD). However, concern about insufficient training and perceived high inter-observer variability limit the adoption of IUS in CD. We examined the diagnostic accuracy of trainee-performed IUS in patients with suspected CD., Method: Patients recruited to a prospective trial investigating the diagnostic accuracy of magnetic resonance enterocolonography (MREC) in patients with clinically suspected CD underwent IUS performed by trainees. The primary end-point was IUS per-patient sensitivity and specificity for ileocolonic CD determined by ileocolonoscopy., Results: 129 patients with clinically suspected CD and a complete IC and IUS were included in the analysis. IUS detected signs of CD in 49 cases (small bowel 31, colon 15, small bowel, and colon 3). The sensitivity and specificity for detection of ileocolonic CD by trainee performed IUS improved during the first to the second half of the study period from 57.1% (CI 34.0-78.2) to 73.1% (CI 52.2-88.4) and 76.5% (CI 58.8-89.3) to 89.7% (CI 72.6-97.8). The overall sensitivity and specificity of diagnosing CD with IUS were 65.4% (CI 50.9-78.0) and 80.5% (CI 69.9-88.7). There was no difference in diagnostic performance between IUS and MREC for the detection of CD., Conclusion: Trainees improved during the study, and IUS performance in disease detection corresponded to expert-evaluated MREC. Registered at ClinicalTrials.gov (NCT03134586).

Background: Secondary loss of response to biological therapy is a challenge when treating Crohn's disease (CD) and ulcerative colitis (UC). Currently, no single marker has been found to be valid as a prognostic indicator of response to biologic therapy in patients with CD and UC. In this study, we aimed to assess whether disease activity after 14 weeks of biologic therapy has a prognostic impact on surgery and steroid-free remission during 6 months following completion of induction therapy., Methods: In an unselected cohort study based on data from 4 national Danish health registries, we identified 493 patients with UC and 620 patients with CD who completed induction therapy with biologics from 2016 to 2019. Following induction therapy with biologics, we defined disease activity based on C-reactive protein and clinical scores of disease activity. The composite endpoint, "not being well treated," included surgery or use of corticosteroid within 6 months following induction therapy., Results: In patients with UC with disease activity following induction therapy, the adjusted odds ratio for surgery or steroid treatment during 6 months of follow-up was 3.9 (95% CI, 1.6-9.3) compared with patients without disease activity, and in patients with CD, the adjusted odds ratio was 3.6 (95% CI, 1.7-7.6)., Conclusions: A positive treatment response to biologic treatment after induction therapy (measured by C-reactive protein and clinical scores) predicts a better short-term outcome in patients with CD and UC., (© The Author(s) 2022. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: Magnetic resonance enterocolonography (MREC) and pan-enteric capsule endoscopy (CE) offers visualization of the entire gastrointestinal tract in a single examination. We examined the diagnostic accuracy of MREC and CE in patients with suspected Crohn's disease (CD)., Method: In a prospective, blinded, multicenter study, we included patients with clinically suspected CD. Patients were examined with MREC, CE, and ileocolonoscopy (IC) within 2 weeks. The primary outcome was per patient sensitivity, specificity, and diagnostic accuracy for ileocolonic CD. IC served as reference standard., Results: 153 patients were included in the study and IC, MREC, and CE was performed in 152, 151, 133 patients, respectively. CD was diagnosed with IC in 59 (39%) patients (terminal ileum (TI) 22, colon 20, TI and colon 17). The sensitivity and specificity for diagnosing ileocolonic CD with MREC was 67.9% (CI 53.7-80.1) and 76.3% (CI 65.2-85.3) (TI 76.9% and 85.6%; colon 27% and 93%) compared to 87.5% (CI 73.2-95.8) and 87.8% (CI 78.2-94.3) with CE (TI 96.6% and 87.5%; colon 75.0% and 93.0%). The sensitivity of CE was superior to that of MREC (p = 0.02). The patient experienced discomfort was equal with CE and MREC and significantly less than with IC., Conclusion: In patients with suspected CD, CE has a high sensitivity for diagnosing CD in the TI and colon, which is superior to that of MREC. The sensitivity of MREC for diagnosing CD in the colon is poor. CE could be a patient-friendly alternative to IC in selected patients with suspected CD. Registered at ClinicalTrials.gov: NCT03134586., (© 2022 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)

Background: Data on the safety of paternal use of 5-aminosalicylic acid (5-ASA) prior to conception are lacking, and the safety of maternal use of 5-ASA during pregnancy has not been examined in nationwide data., Aims: To examine offspring outcomes after paternal pre-conception use of 5-ASA, and after maternal use during pregnancy METHODS: This nationwide cohort study was based on Danish health registries. The study population included live born singletons of patients with ulcerative colitis (UC) or Crohn's disease (CD). Paternal exposure included 2168 children fathered by men treated with 5-ASA, and 7732 unexposed. Maternal exposure included 3618 children exposed in utero to 5-ASA, and 7128 unexposed. The outcomes were pre-term birth, small for gestational age (SGA), low Apgar score and major congenital abnormalities (CAs) according to EUROCAT guidelines., Results: The vast majority of fathers and mothers used mesalazine. In children fathered by men with UC using 5-ASA, we found no increased risk of pre-term birth, SGA or low Apgar score. The hazard ratio (HR) of CAs was 1.30 (95% CI 0.92-1.85). In children of fathers with CD, the odds ratio (OR) of SGA was 1.52 (95% CI 0.65-3.55). After maternal 5-ASA exposure, the OR of SGA in children of women with UC was 1.46 (95% CI: 0.93-2.30); for CAs in children of women with CD, HR was 1.44 (95% CI 0.84-2.47)., Conclusions: Paternal and maternal use of 5-ASA was safe across offspring outcomes; none of the findings reached statistical significance. The safety of 5-ASA formulations that are used infrequently cannot be settled here., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: We assessed whether 5-aminosalicylic acid (5-ASA), as treatment for inflammatory bowel disease (IBD), was associated with an increase in hospitalization for coronavirus disease 2019 and adverse in-hospital outcomes., Methods: This was a Danish nationwide register study. The study population consisted of all patients with an IBD diagnosis between March 1, 2010, and March 1, 2020, and living in Denmark on March 1, 2020. Patients with IBD treated with 5-ASA (exposed) were compared with patients not receiving 5-ASA (unexposed)., Results: We identified 60 242 patients with IBD; 15 635 (40.5%) with ulcerative colitis (UC) and 964 (4.5%) with Crohn's disease (CD) were exposed to 5-ASA. For patients with UC who were 5-ASA exposed, the hazard ratio of hospitalization was 1.18 (95% confidence interval, 0.79-1.78). In-hospital outcomes were not statistical significant from those not exposed to 5-ASA (median length of hospital stay 5.6 days vs 7.2 days), mechanical ventilation (0% vs 14%), continuous positive airway pressure (7.9% vs 9.4%), and in-hospital mortality (21.1% vs 17.2%). For patients with CD, the hazard ratio of hospitalization was 2.25 (95% confidence interval, 1.02-4.97). We found no statistically significant difference in length of hospital stay (7.1 days vs 3.9 days), mechanical ventilation (0% vs 1.8%), use of continuous positive airway pressure (0% vs 1.8%), or in-hospital mortality (0% vs 9%) between exposed and unexposed patients., Conclusions: Patients with UC, treated with 5-ASA, had no increased risk of hospitalization for coronavirus disease 2019 or more adverse in-hospital outcomes. In patients with CD, 5-ASA may be associated with an increased risk of hospitalization but not with more adverse in-hospital outcomes., (© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

BACKGROUND: Whether infliximab therapy can be successfully discontinued after patients with Crohn’s disease have attained sustained, clinical, biochemical, and endoscopic remission is unknown. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled withdrawal study of infliximab in patients with Crohn’s disease who were in clinical, biochemical, and endoscopic remission after standard infliximab maintenance therapy for at least 1 year. Patients were randomly assigned 1:1 to continue infliximab therapy or to receive matching placebo for 48 weeks. The primary end point was time to relapse. RESULTS: This study randomly assigned 115 patients to either the infliximab-continuation group or to the infliximab-discontinuation group. No relapses were observed among the 59 patients continuing infliximab, whereas 23 of 56 patients discontinuing infliximab experienced relapse. Time to relapse was significantly shorter among patients who discontinued infliximab than among those who continued infliximab (hazard ratio, 0.080; 95% confidence interval [CI], 0.035 to 0.186; P<0.001). At the end of the trial at week 48, relapse-free survival was 100% in the infliximab-continuation group and 51% in the infliximab-discontinuation group. The key secondary end point, time to loss of remission, was significantly shorter among patients discontinuing infliximab therapy than those continuing infliximab (hazard ratio, 0.025; 95% CI, 0.003 to 0.187; P<0.001). No unexpected adverse events were reported. CONCLUSIONS: Discontinuation of infliximab for patients with Crohn’s disease receiving long-term infliximab therapy and in clinical, biochemical, and endoscopic remission leads to a considerable risk of relapse. (Funded by the Nordic Trial Alliance [NordForsk], the Medical Fund of the Danish Regions [Regionernes Medicin og Behandlingspulje], the Danish Colitis-Crohn Association, and the A.P. Moller Foundation; ClinicalTrials.gov number, NCT01817426; EudraCT number, 2012-002702-51.)

Background: The laminin gamma 1 chain (LMγ1) is abundant along the crypt-villus axis in the intestinal basement membrane., Aims: We investigated whether a serological biomarker of laminin degradation was associated with disease activity in patients with Crohn's disease (CD) and in rats with dextran sulfate sodium (DSS)-induced colitis., Methods: Serum samples from CD patients (n = 43), healthy subjects (n = 19), and Sprague Dawley rats receiving 5-6% DSS water for five days and regular drinking water for 11 days were included in this study. The LG1M biomarker, a neo-epitope degradation fragment of the LMγ1 chain generated by matrix metalloproteinases-9 (MMP-9), was measured in serum to estimate the level of laminin degradation., Results: Serum LG1M was elevated in CD patients with active and inactive disease compared to healthy subjects (p < 0.0001). LG1M distinguished CD patients from healthy subjects, with an area under the curve (AUC) of 0.81 (p < 0.0001). Serum LG1M was decreased in DSS rats compared to controls 2 days after DSS withdrawal, and increased upon reversal of the disease., Conclusions: Increased serum LG1M in active and inactive CD patients supports the evidence of altered LM expression in both inflamed and non-inflamed tissue. Moreover, lower LG1M levels in the early healing phase of DSS-induced colitis may reflect ongoing mucosal repair., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Physical activity in paediatric and young adult patients suffering from inflammatory bowel disease (IBD) may play an important role in the overall health status. However, physical activity in these patients has not been reported using objective methods. We aimed to describe accelerometry-measured physical activity levels in paediatric and young adult IBD patients with either ulcerative colitis (UC) or Crohn's disease (CD)., Methods: We recruited Danish patients with IBD aged 10-20 years in clinical remission and with a faecal calprotectin below 200 µg/mg. Physical activity was assessed using tri-axial wrist accelerometry over seven days and quantified using the activity-related acceleration derived as the conventional Euclidian Norm Minus One (ENMO) metric expressed in milli-gravity units (mg). Time spent in Moderate-to-Vigorous Physical Activity (MVPA) was classified as ENMO > 210 mg in 5 s epoch resolution (unbouted)., Results: We included 61 patients with a median age of 17 years [Inter Quartile Range, IQR 14-19]. The total volume of activity expressed as average acceleration (ENMO) per day was 31.5 mg (95% CI 29.1-33.9). Time spent in unbouted MVPA was 32 min per day (95% CI 26-37). There was no significant difference in activity volume between patients with UC to patients with CD, the adjusted linear regression coefficient was - 1.7 mg (95% CI -6.2-2.7). Activity volume was higher for males (36.2 mg, 95% CI 31.9-40.5) than for females (27.8 mg, 95% CI 25.6-30.0), and younger patients were more active than older patients; Activity volume in 10-13 year olds was 37.2 mg (95% CI 28.6-45.7), whereas it was 28.5 mg (95% CI 25.2-31.7) for those aged 18-20 years., Conclusions: We collected tri-axial accelerometry in young patients with IBD in clinical remission, and described their level of physical activity by the conventional ENMO measure. We found no statistically significant difference in patients with UC compared to patients with CD. The volume of physical activity was higher in males compared to females, and inversely associated with age., (© 2022. The Author(s).)

Introduction: Patients with Crohn's disease (CD) and ulcerative colitis (UC) may lose weight during periods of active disease and may gain weight when inflammation heals. Studies have hypothesized an association between antitumor necrosis factor-alpha (anti-TNF-α) and unintended weight gain during maintenance therapy, and this association has not been previously clarified., Methods: In a nationwide observational study based on Danish national health registries, we included patients who initiated therapy with infliximab and followed changes in weight during induction therapy (0-90 days) and maintenance therapy (91-270 days). The association between the use of infliximab and weight gain was analyzed by a multilevel mixed-effects linear regression model., Results: Among 851 patients with CD and UC who initiated infliximab therapy, long-term weight gain was not observed during maintenance therapy in most of the patients. Women with CD who were underweight at the initiation of therapy had an average weight gain of 7.5 kg. Men and women with CD and UC with normal or increased body mass index had an average weight gain of <2 kg during maintenance therapy. Underweight men with CD and UC gained 2.9 kg (95% confidence interval 2.1-3.6) and 2.9 kg (95% confidence interval 1.9-3.9), respectively, in the first 90 days, although neither group had statistically significant weight gain in the maintenance period. Less than 3% of the patients had weight gain greater than 10% of their baseline body weight during the study period., Discussion: Weight gain among patients treated with anti-TNF-α therapies is unlikely to be due to an effect from anti-TNF-α therapy., (Copyright © 2022 by The American College of Gastroenterology.)

Background and Aim: Health-related quality of life (HRQoL) is impaired in patients with Crohn's disease (CD). This study aimed to identify the impact of clinical disease activity on HRQoL in CD patients treated with biological agents., Methods: Patients with moderate to severe active CD treated with biological agents in Denmark were included from 2016-2018. Disease related symptoms were assessed via the Harvey Bradshaw Index. HRQoL was measured on the Short Health Scale (SHS). Multivariable linear regression models were conducted separately for each SHS item and average SHS score stratified for sex, adjusting for clinical manifestation and age., Results: In total, 1,181 CD patients were included. The mean age was 33 years and 56% were women. Abdominal pain (range of regression coefficients 1.18-1.42), number of liquid stools (0.33-0.58), and the appearance of a new rectal fistula (0.91-1.32) affected all domains in the SHS negatively for men and women. Arthralgia (0.47-0.67) and abdominal mass (0.54-0.62) affected 4 out of 5 items on SHS negatively for women and men, respectively. Female sex was found a predictor of lower HRQoL across all SHS items, whereas age and fistulizing disease, as phenotype, were not associated with lower HRQoL., Conclusions: Abdominal pain, number of liquid stools, a new rectal fistula, arthralgia for women, clinically assessed abdominal mass for men as well as female sex, were all found to be predictors of decreased HRQoL.

Background and Aims: In paediatric patients with Crohn's disease, the role of combination therapy, infliximab plus immunomodulators [thiopurine or methotrexate], is debated and data are sparse. We examined whether infliximab plus immunomodulators, compared to infliximab therapy alone, reduces the risk of treatment failure measured by intestinal surgery or switching type of anti-tumour necrosis factor [TNF] α agent within 24 months., Design: Using Danish registries, we identified patients with Crohn's disease, aged ≤ 20 years at the time of the first infliximab treatment, and retrieved data on their co-medications. We used Cox regression models to examine surgery or switching type of anti-TNFα agent from January 1, 2003 to December 31, 2015., Results: We included 581 patients. The 2-year cumulative percentage of surgery was 8.5% among patients receiving combination therapy and 14.5% in those receiving infliximab alone. The adjusted 2-year hazard ratio [HR] of surgeries was 0.53 (95% confidence interval [CI] 0.32-0.88) in patients receiving combination therapy, compared to patients receiving infliximab alone. When examining a switch of anti-TNFα we included 536 patients. Within 2 years, 18.3% experienced a switch among patients receiving combination therapy and 24.8% in patients treated with infliximab alone, corresponding to an adjusted HR of 0.66 [95% CI 0.45-0.97] in patients receiving combination therapy., Conclusions: The HR of intestinal surgeries and the risk of a switch to another anti-TNFα was reduced in paediatric and adolescent patients receiving combination therapy, compared to patients receiving only infliximab. These results suggest a benefit for infliximab therapy combined with immunomodulators, but these need to be confirmed in data with additional clinical information., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The lack of scientific evidence regarding the effectiveness of 5-aminosalicylate in patients with Crohn's disease is in sharp contrast to its widespread use in clinical practice., Aims: The aim of the study was to investigate the use of 5-aminosalicylate in patients with Crohn's disease as well as the disease course of a subgroup of patients who were treated with 5-aminosalicylate as maintenance monotherapy during the first year of disease., Methods: In a European community-based inception cohort, 488 patients with Crohn's disease were followed from the time of their diagnosis. Information on clinical data, demographics, disease activity, medical therapy and rates of surgery, cancers and deaths was collected prospectively. Patient management was left to the discretion of the treating gastroenterologists., Results: Overall, 292 (60%) patients with Crohn's disease received 5-aminosalicylate period during follow-up for a median duration of 28 months (interquartile range 6-60). Of these, 78 (16%) patients received 5-aminosalicylate monotherapy during the first year following diagnosis. Patients who received monotherapy with 5-aminosalicylate experienced a mild disease course with only nine (12%) who required hospitalization, surgery, or developed stricturing or penetrating disease, and most never needed more intensive therapy. The remaining 214 patients were treated with 5-aminosalicylate as the first maintenance drug although most eventually needed to step up to other treatments including immunomodulators (75 (35%)), biological therapy (49 (23%)) or surgery (38 (18%))., Conclusion: In this European community-based inception cohort of unselected Crohn's disease patients, 5-aminosalicylate was commonly used. A substantial group of these patients experienced a quiescent disease course without need of additional treatment during follow-up. Therefore, despite the controversy regarding the efficacy of 5-aminosalicylate in Crohn's disease, its use seems to result in a satisfying disease course for both patients and physicians.

Background: Inflammatory bowel disease (IBD) places a significant burden on health-care systems because of its chronicity and need for expensive therapies and surgery. With increasing use of biological therapies, contemporary data on IBD health-care costs are important for those responsible for allocating resources in Europe. To our knowledge, no prospective long-term analysis of the health-care costs of patients with IBD in the era of biologicals has been done in Europe. We aimed to investigate cost profiles of a pan-European, community-based inception cohort during 5 years of follow-up., Methods: The Epi-IBD cohort is a community-based, prospective inception cohort of unselected patients with IBD diagnosed in 2010 at centres in 20 European countries plus Israel. Incident patients who were diagnosed with IBD according to the Copenhagen Diagnostic Criteria between Jan 1, and Dec 31, 2010, and were aged 15 years or older the time of diagnosis were prospectively included. Data on clinical characteristics and direct costs (investigations and outpatient visits, blood tests, treatments, hospitalisations, and surgeries) were collected prospectively using electronic case-report forms. Patient-level costs incorporated procedures leading to the initial diagnosis of IBD and costs of IBD management during the 5-year follow-up period. Costs incurred by comorbidities and unrelated to IBD were excluded. We grouped direct costs into the following five categories: investigations (including outpatient visits and blood tests), conventional medical treatment, biological therapy, hospitalisation, and surgery., Findings: The study population consisted of 1289 patients with IBD, with 1073 (83%) patients from western Europe and 216 (17%) from eastern Europe. 488 (38%) patients had Crohn's disease, 717 (56%) had ulcerative colitis, and 84 (6%) had IBD unclassified. The mean cost per patient-year during follow-up for patients with IBD was €2609 (SD 7389; median €446 [IQR 164-1849]). The mean cost per patient-year during follow-up was €3542 (8058; median €717 [214-3512]) for patients with Crohn's disease, €2088 (7058; median €408 [133-1161]) for patients with ulcerative colitis, and €1609 (5010; median €415 [92-1228]) for patients with IBD unclassified (p<0·0001). Costs were highest in the first year and then decreased significantly during follow-up. Hospitalisations and diagnostic procedures accounted for more than 50% of costs during the first year. However, in subsequent years there was a steady increase in expenditure on biologicals, which accounted for 73% of costs in Crohn's disease and 48% in ulcerative colitis, in year 5. The mean annual cost per patient-year for biologicals was €866 (SD 3056). The mean yearly costs of biological therapy were higher in patients with Crohn's disease (€1782 [SD 4370]) than in patients with ulcerative colitis (€286 [1427]) or IBD unclassified (€521 [2807]; p<0·0001)., Interpretation: Overall direct expenditure on health care decreased over a 5-year follow-up period. This period was characterised by increasing expenditure on biologicals and decreasing expenditure on conventional medical treatments, hospitalisations, and surgeries. In light of the expenditures associated with biological therapy, cost-effective treatment strategies are needed to reduce the economic burden of inflammatory bowel disease., Funding: Kirsten og Freddy Johansens Fond and Nordsjællands Hospital Forskningsråd., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Extracellular matrix (ECM) remodeling is a hallmark of the pathology of gastrointestinal disorders. Collagen type VI (COL6) is produced by fibroblasts, and the COL6 α3-chain has shown to be elevated in patients with ulcerative colitis (UC), Crohn's disease (CD) and colorectal cancer (CRC). Measuring COL6α3 in serum may therefore have potential as a biomarker for gastrointestinal disorders. The aims of this study were to develop and validate a competitive ELISA targeting a specific neo-epitope of COL6α3 and evaluate its associations with the gastrointestinal disorders UC, CD and CRC, in comparison to healthy controls. A monoclonal antibody was raised against a matrix metalloproteinase-2 and -9 specific cleavage site of COL6α3 (C6Mα3) and employed in a competitive enzyme-linked immunosorbent assay (ELISA). The assay was developed and technically validated. Levels of C6Mα3 were measured in serum from patients with UC (n = 58), CD (n = 44) and CRC (n = 39) and compared to healthy controls (n = 32). The levels of C6Mα3 were elevated in patients with UC, CD and CRC patients compared to healthy controls (all p < 0.0001). The area under the receiver operating characteristics (AUROC) curve for separation of patients with UC from healthy controls was 0.972 (95% CI: 0.925-1.020, p < 0.0001), with CD from healthy controls was 0.947 (95% CI: 0.885-1.009, p < 0.0001) and with CRC from healthy controls was 0.890 (95% CI: 0.809-0.972, p < 0.0001). We developed a technically robust assay targeting a fragment of COL6, which was elevated in serum from patients with UC, CD and CRC.

Background: Anti-TNFα agents have revolutionised management of chronic inflammatory diseases. Paradoxically, these agents might provoke development of de novo autoimmune diseases., Aim: To examine whether there is an increased risk of developing Crohn's disease (CD) and ulcerative colitis (UC) while under treatment with anti-TNFα agents for diseases other than inflammatory bowel disease (IBD) METHODS: A nationwide cohort study, based on Danish health registries, of all patients who utilised anti-TNFα agents for non-IBD indications. Included were patients, who had diseases for which anti-TNFα agent is indicated (rheumatoid arthritis, psoriasis/psoriatic arthritis, ankylosing spondylitis, others). The observation period for development of de novo IBD started from 2004. Exposed patients had received at least one dose of anti-TNFα., Results: In total 17 018 individuals with autoimmune diseases were exposed to anti-TNFα (the vast majority had infliximab, etanercept and adalimumab), and 63 308 individuals were not. Patients treated with etanercept had an increased risk of being diagnosed with CD and UC while under treatment, adjusted hazard ratio 2.0 [95% CI: 1.4-2.8] and 2.0 [95% CI: 1.5-2.8], respectively. The corresponding hazards ratios for infliximab were 1.3 [95% CI: 0.8-2.2] and 1.0 [95% CI:0.6-1.6], and for adalimumab 1.2 [95% CI: 0.8-1.8] and 0.6 [95% CI: 0.3-1.0]., Conclusions: Patients treated for autoimmune diseases with anti-TNFα had an increased risk of being diagnosed with CD or UC while under treatment with etanercept. The nature of this association is uncertain. This finding has relevance to clinical care and insights into common mechanisms of the pathophysiology of these diseases., (© 2019 John Wiley & Sons Ltd.)

Background and Aims: Crohn's disease (CD) is a chronic inflammatory condition characterized by continuous mucosal damage and ongoing wound healing of the intestines. The fibrinolytic system is involved in early parts of the wound healing process. Fibrin is a key mediator of primary blood clot formation and is formed by cross-linking of fibrinogen. To gain insights into the dynamics of wound healing in CD patients we investigated the conversion of fibrinogen into fibrin by the pro-peptide FPA, the amount of factor XIII cross-linked fibrin and total fibrin clot., Methods: Serum samples of 35 CD patients, 15 non-inflammatory bowel disease (non-IBD) patients and 39 age-matched healthy controls were analyzed for three novel neo-epitope markers: D-fragment and D-dimer, reflecting the degradation of total fibrin clot and factor XIII cross-linked fibrin, as well as FPA, reflecting synthesis of fibrin., Results: Crohn's disease patients had a significantly lower D-dimer level (p=0.0001) compared to healthy controls. Crohn's disease and non-IBD patients had a significantly higher level of FPA (p<0.0001) and D-fragment/D-dimer ratio (p<0.0001 and p=0.02). FPA, D-dimer and D-fragment/D-dimer ratio could distinguish CD patients from healthy controls with area under the curve of 0.92 (95% CI 0.83-0.97), 0.78 (95% CI 0.67-0.87) and 0.85 (95% CI 0.75-0.93), respectively., Conclusion: Wound healing parameters were clearly changed in CD patients. FPA levels were higher in CD patients as compared to healthy controls, indicating more ongoing wound healing. D-dimer levels were lower in CD patients than in healthy controls, indicating impaired wound healing due to poor quality of factor XIII cross-linked fibrin and clot resolution.

Objective: The Epi-IBD cohort is a prospective population-based inception cohort of unselected patients with inflammatory bowel disease from 29 European centres covering a background population of almost 10 million people. The aim of this study was to assess the 5-year outcome and disease course of patients with Crohn's disease (CD)., Design: Patients were followed up prospectively from the time of diagnosis, including collection of their clinical data, demographics, disease activity, medical therapy, surgery, cancers and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis., Results: In total, 488 patients were included in the study. During follow-up, 107 (22%) patients received surgery, while 176 (36%) patients were hospitalised because of CD. A total of 49 (14%) patients diagnosed with non-stricturing, non-penetrating disease progressed to either stricturing and/or penetrating disease. These rates did not differ between patients from Western and Eastern Europe. However, significant geographic differences were noted regarding treatment: more patients in Western Europe received biological therapy (33%) and immunomodulators (66%) than did those in Eastern Europe (14% and 54%, respectively, P<0.01), while more Eastern European patients received 5-aminosalicylates (90% vs 56%, P<0.05). Treatment with immunomodulators reduced the risk of surgery (HR: 0.4, 95% CI 0.2 to 0.6) and hospitalisation (HR: 0.3, 95% CI 0.2 to 0.5)., Conclusion: Despite patients being treated early and frequently with immunomodulators and biological therapy in Western Europe, 5-year outcomes including surgery and phenotype progression in this cohort were comparable across Western and Eastern Europe. Differences in treatment strategies between Western and Eastern European centres did not affect the disease course. Treatment with immunomodulators reduced the risk of surgery and hospitalisation., Competing Interests: Competing interests: JB: consulting fees from Celgene, Janssen-Cilag, AbbVie A/S and Ferring and lecture fees from Abbvie A/S, Pfizer, MSD and Takeda Pharma A/S. VA: consultancy for Janssen and MSD. RS: consulting fees and/or lecture fees from AbbVie, MSD, Takeda, Janssen-Cilag. RD’I: consulting fees from Abbvie, Biocure and lecture fees from Takeda and Mundipharma. MF: speaker/lecture fees for Abbvie, Ferring, MSD, Takeda, Boehringer and Hospira. CG-R: lecture fees from Takeda, MSD, Ferring and Tillots. CE: lecture fees from Takeda. JH: research grants from Janssen, MSD and Takeda and lecture and/or consultancy fees from Abbvie, Cellgene, Ferring, Hospira, Janssen, Medivir, MSD, Pfizer, Vifor Pharma, Takeda and Tillotts Pharma. EL: lecture or consultancy fees from MSD, Abbvie and Ferring Pharmaceuticals. DD: lecture or consultancy fees from AbbVie, Takeda and Janssen. NA: lecture fees from MSD and Jansen. VH: personal fees, non-financial support and other from MSD, AbbVie, Ferring, Faes Farma, Shire, Falk Pharma, Tillots, Otsuka, Hospira Biologicals, Takeda, Jansen and Kernpharma Biologics. AF: personal fees and non-financial support from MSD, AbbVie, Shire and Tillots. SČ-Č: lecture fees from Takeda, MSD, Abbvie., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Increased protease activity is a key pathological feature of inflammatory bowel disease (IBD). However, the differences in extracellular matrix remodelling (ECM) in Crohn's disease (CD) and ulcerative colitis (UC) are not well described. An increased understanding of the inflammatory processes may provide optimized disease monitoring and diagnostics. We investigated the tissue remodelling in IBD and IBS patients by using novel blood-based biomarkers reflecting ECM remodelling., Methods: Five ECM biomarkers (VICM, BGM, EL-NE, C5M, Pro-C5) were measured by competitive ELISAs in serum from 72 CD patients, 60 UC patients, 22 patients with irritable bowel syndrome (IBS), and 24 healthy donors. One-way analysis of variance, Mann-Whitney U-test, logistic regression models, and receiver operator characteristics (ROC) curve analysis was carried out to evaluate the diagnostic accuracy of the biomarkers., Results: The ECM remodelling was significantly different in UC compared to CD. The best biomarker combination to differentiate UC from CD and colonic CD was BGM and VICM (AUC = 0.98, P<0.001; AUC = 0.97, P<0.001), and the best biomarker combination to differentiate IBD from IBS patients were BGM, EL-NE, and Pro-C5 (AUC = 0.8, P<0.001). When correcting for the use of immunosuppressant and elevated CRP levels (CRP>5mg/mL), correlation of Pro-C5 (r = 0.36) with CDAI was slightly improved compared to CRP (r = 0.27) corrected for the use of immunosuppressant. Furthermore, BGM and EL-NE biomarkers were highly associated with colon inflammation in CD patients., Conclusion: ECM fragments of tissue remodelling in IBD affect UC and CD differently, and may aid in differentiating IBD from IBS (EL-NE, BGM, Pro-C5), and UC from CD patients (BGM, VICM). Formation of type V collagen is related to the level of inflammation in CD and may reflect disease activity in CD.

Aim: To investigate whether immune mediated diseases (IMD) are more frequent in patients with inflammatory bowel disease (IBD)., Methods: In this population based registry study, a total of 47325 patients with IBD were alive and registered in the Danish National Patient Registry on December 16, 2013. Controls were randomly selected from the Danish Civil Registration System (CRS) and matched for sex, age, and municipality. We used ICD 10 codes to identify the diagnoses of the included patients. The IBD population was divided into three subgroups: Ulcerative colitis (UC), Crohn's disease (CD) and Both the latter referring to those registered with both diagnoses. Subsequently, odds-ratios (OR) and 95%CI were obtained separately for each group and their respective controls. The use of Bonferoni post-test correction adjusted the significance level to P < 0.00125. P -values were estimated using Fisher's exact test., Results: There were significantly more women than men in the registry, and a greater percentage of comorbidity in the IBD groups ( P < 0.05). Twenty different IMDs were all significantly more frequent in the IBD group. Sixteen were associated with UC versus twelve with CD. In both UC and CD ORs were significantly increased ( P < 0.00125) for primary sclerosing cholangitis (PSC), celiac disease, type 1 diabetes (T1D), sarcoidosis, asthma, iridocyclitis, psoriasis, pyoderma gangrenosum, rheumatoid arthritis, and ankylosing spondylitis. Restricted to UC ( P < 0.00125) were autoimmune hepatitis, primary biliary cholangitis, Grave's disease, polymyalgia rheumatica, temporal arteritis , and atrophic gastritis. Restricted to CD ( P < 0.00125) were psoriatic arthritis and episcleritis. Restricted to women with UC ( P < 0.00125) were atrophic gastritis, rheumatoid arthritis, temporal arteritis, and polymyalgia rheumatica. Restricted to women with CD were episcleritis, rheumatoid arthritis, and psoriatic arthritis. The only disease restricted to men ( P < 0.00125) was sarcoidosis., Conclusion: Immune mediated diseases were significantly more frequent in patients with IBD. Our results strengthen the hypothesis that some IMDs and IBD may have overlapping pathogenic pathways., Competing Interests: Conflict-of-interest statement: The authors report no conflict of interest.

Background and Aims: It is debated whether the need for surgery has changed following introduction of anti-TNFα agents in the treatment of paediatric ulcerative colitis [UC] and Crohn's disease [CD]. We aimed to describe the implementation of anti-TNFα agents in paediatric patients, and the need of first-time surgery before and after introduction of anti-TNFα agents., Methods: In the Danish National Patient Registry, we identified incident paediatric patients diagnosed from 1998. We calculated the proportion of patients receiving anti-TNFα agents within 5 years from diagnosis, and the cumulative 5 year proportion of surgery, according to calendar periods of diagnosis., Results: At the end of our study period [2007 and 2008], 29-41% of CD children were treated with anti-TNFα agents within 5 years, and for UC children 17-19%. In 1278 CD patients, the 5 year cumulative proportions of surgery were 14.6-15.6% for children diagnosed in 1998-2008 and 9.7% (95% confidence interval [CI]: 6.7-13.7) for those diagnosed in 2009-2013. In 1468 UC patients, the cumulative proportion of surgery suggested a decline in patients diagnosed after mid 2005, and the hazard ratio of surgery was 0.64 [95% CI: 0.47-0.86] after the introduction of anti-TNFα agents compared with before. For UC patients diagnosed in 2009-2013, the 5 year cumulative proportion of surgery was 7.6% [95% CI: 5.2-11.2]., Conclusions: This nationwide study showed an extensive use of anti-TNFα agents at the end of our study period. For UC children, our data suggest a decline in the proportion of surgery in the period of increasing use of anti-TNFα agents., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Approximately 80% of patients with Crohn's disease will require surgery. Surgery for Crohn's disease is not curative, and recurrence is typical. In this cohort study, based on nationwide Danish registries, we examined the association between postoperative treatment with anti-tumor necrosis factor α (anti-TNF-α) agents and reoperation., Methods: The association was examined in cohort 1 = patients not treated with anti-TNF-α agents within 6 months before operation, cohort 2 = patients treated with anti-TNF-α agents within 6 months before operation. Within both cohorts, we defined postoperative exposure to anti-TNF-α agents as at least 1 treatment within 6 months after the first operation and the reference cohorts were those not treated. Patients were followed from 6 months after operation and until 5 years. We used Cox proportional-hazards regression to compute adjusted hazard ratios with 95% confidence intervals., Results: In cohort 1, 31 (1.3%) were treated with anti-TNF-α agents within 6 months after operation and compared with those not treated, the adjusted hazard ratio of reoperation among those treated with anti-TNF-α agents was 3.53 (95% confidence interval: 1.61-7.72). In cohort 2, 63 (16.3%) were treated with anti-TNF-α agents within 6 months after operation, and the corresponding adjusted hazard ratio of reoperation was 2.16 (95% confidence interval: 1.11-4.18)., Conclusions: Our data suggest that anti-TNF-α treatment within 6 months after the first operation is not associated with a reduction in the need for subsequent operation. Uncontrolled confounding might have influenced our results, and, furthermore, future studies are warranted to clarify whether our study population is different from populations most often associated with postoperative anti-TNF-α treatment.

Background: Therapeutic antibodies are a developing field for treatment of an expanding number of inflammatory diseases, including Crohn's disease. Treatment with monoclonal antibodies is frequently hampered by development of anti-drug antibodies (ADAs) that may compromise the treatment., Materials and Methods: We addressed this issue in a rabbit model of treatment with the anti-tumor-necrosis factor alpha (TNFα) antibody, infliximab (IFX). We developed an inhibition ELISA to selectively measure absolute concentrations of neutralizing antibodies and another ELISA for measuring the concentration of functional IFX in the circulation., Results: We found that the concentration of functional IFX was inversely proportional to the concentration of neutralizing antibodies., Conclusion: Administration of IFX to rabbits showed diversity in immune responses/tolerance toward IFX, corresponding to responses observed in patients. The applied assay technology is easily adapted to human plasma samples and/or other therapeutic antibodies, including fully humanized antibodies, for which immunogenicity also is observed., (Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: This study assessed the effects of infliximab (IFX) treatment failure on patient-reported outcomes and explored the influence of using personalized treatment in this situation., Methods: Sixty-nine Crohn's disease patients with IFX treatment failure were randomized to an intensified IFX regimen (n = 36) or personalized treatment defined by IFX and anti-IFX antibodies (n = 33). Health-related quality of life evaluated with the Short Inflammatory Bowel Disease Questionnaire (IBDQ) and productivity evaluated with the Work Productivity and Activity Impairment Questionnaire (WPAI:CD) were assessed at treatment failure and after 4, 8, 12 and 20 weeks., Results: Median IBDQ score at manifestation of IFX treatment failure was 40 and improved markedly in responders by 11 at weeks 4 and 8 (p < 0.001) and by 13 at weeks 12 and 20 (p < 0.001). Non-responders improved modestly at weeks 12 and 20 (increase of median 4, p < 0.05). Overall activity impairment was high at IFX failure (median 70%) and decreased substantially in responders (40-50%, p < 0.001) and to a lesser extent in non-responders (15-40%, p < 0.05). In employed patients (55%), absenteeism was negligible during the entire study period. However, median presenteeism was 40% at manifestation of IFX failure and decreased only among responders across time (decrease 10-30%, p < 0.05). Although anti-tumour necrosis factor (TNF) therapy was discontinued in most patients handled by personalized treatment, IBDQ and WPAI:CD scores were similar in these patients compared with patients routinely dose-intensified on IFX., Conclusion: Regaining low disease activity after IFX failure is necessary for minimizing patient impairment and indirect disease-related costs. A personalized treatment strategy does not have a negative influence on patient-reported outcomes., (Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: A hallmark of inflammatory bowel disease [IBD] is chronic inflammation, which leads to excessive extracellular matrix [ECM] remodelling and release of specific protein fragments, called neoepitopes. We speculated that the biomarker profile panel for ulcerative colitis [UC] and Crohn's disease [CD] represent a heterogeneous expression pattern, and may be applied as a tool to aid in the differentiation between UC and CD., Methods: Serum biomarkers of degraded collagens I, III-IV [C1M, C3M, and C4M], collagen type 1 and IV formation [P1NP, P4NP], and citrullinated and MMP-degraded vimentin [VICM] were studied with a competitive ELISA assay system in a cohort including 164 subjects [CD n = 72, UC n = 60, and non-IBD controls n = 32] and a validation cohort of 61 subjects [CD n = 46, and UC n = 15]. Receiver operating characteristic curve analysis and logistic regression modelling were carried out to evaluate the discriminative power of the biomarkers., Results: All biomarkers were corrected for confounding factors. VICM and C3M demonstrated the highest diagnostic power, alone, to differentiate CD from UC with an area under the curve [AUC] of 0.77 and 0.69, respectively. Furthermore, the biomarkers C1M [AUC = 0.81], C3M [AUC = 0.83], VICM [AUC = 0.83], and P1NP [AUC = 0.77] were best to differentiate UC from non-IBD. The best combinations of biomarkers to differentiate CD from UC and UC from non-IBD were VICM, C3M, C4M [AUC = 0.90] and VICM, C3M [AUC = 0.98] respectively., Conclusions: Specific extracellular matrix degradation markers are elevated in IBD and can discriminate CD from UC and UC from non-IBD controls with a high diagnostic accuracy., (Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Previous studies have found a differential expression of microRNAs (miRNAs) in the blood of patients with Crohn's disease (CD) compared with healthy controls. The aim of this study was to identify circulating miRNAs expressed in CD and assess their performance as biomarkers in patients with clinically suspected or known CD., Methods: The study consisted of two parts: (a) miRNA profiling: The miRNA expression pattern was examined in six patients with CD and six controls using OpenArray miRNA profiling, and the best miRNAs were selected according to their P-value. (b) Validation cohort: In a well-characterized cohort of 102 patients with suspected or known CD, miRNAs identified by miRNA profiling or selected from previously published studies (hsa-miR-16, hsa-miR-21, hsa-miR-106a, and hsa-miR-140-3p) were measured in plasma using reverse transcription PCR., Results: miRNA profiling: hsa-miR-369-3p, hsa-miR-376a, hsa-miR-376, hsa-miR-411#, hsa-miR-411, and mmu-miR-379 were downregulated in CD patients compared with the controls; hsa-miR-200c, hsa-miR-181-2#, and hsa-miR-125a-5p were upregulated (P<0.05). Validation cohort: Only hsa-miR-16 was significantly downregulated in patients with CD compared with patients without CD (fold change 0.83, P=0.02). Receiver operating characteristic analyses showed an area under the curve of 0.65. miRNAs could not discriminate inflammatory from stricturing CD or small bowel CD from CD involving the colon., Conclusion: In a clinically relevant cohort of patients, miRNAs in plasma identified in the present and previous studies were inadequate biomarkers for the diagnosis of CD.

Background: In Crohn's disease patients failing infliximab therapy, interventions defined by an algorithm based on infliximab and anti-infliximab antibody measurements have proven more cost-effective than intensifying the infliximab regimen., Aim: This study investigated long-term economic outcomes at the week 20 follow-up study visit and after 1 year. Clinical outcomes were assessed at week 20., Methods: Follow-up from a 12-week, single-blind, clinical trial where patients with infliximab treatment failure were randomized to infliximab intensification (5 mg/kg every 4 weeks) (n = 36), or algorithm-defined interventions (n = 33). Accumulated costs, expressed as mean costs per patient, were based on the Danish National Patient Registry., Results: At the scheduled week 20 follow-up study visit, response and remission rates were similar in all study subpopulations between patients treated by the algorithm or by infliximab intensification. However, the sum of healthcare costs related to Crohn's disease was substantially lower (31 %) for patients randomized to algorithm-based interventions than infliximab intensification in the intention-to-treat population: $11,940 versus $17,236; p = 0.005. For per-protocol patients (n = 55), costs at the week 20 follow-up visit were even lower (49 %) in the algorithm group: $8,742 versus $17,236; p = 0.002. Figures were similar for patients having completed the 12-week trial as per protocol (50 % reduction in costs) (n = 45). Among patients continuing the allocated study intervention throughout the entire 20-week follow-up period (n = 29), costs were reduced by 60 % in algorithm-treated patients: $7,056 versus $17,776; p < 0.001. Cost-reduction percentages remained stable throughout one year., Conclusion: Economic benefit of algorithm-based interventions at infliximab failure is maintained throughout 1 year.

Background and Aims: Intensification of the infliximab (IFX) regimen is recommended if the treatment effect is inadequate. However, the rationale for this is not well defined as the underlying mechanisms vary. The aim of this study was to explore the association between changes in serum IFX and anti-IFX antibodies (Abs) after IFX intensification and clinical outcomes., Methods: We performed a post hoc analysis of a randomized clinical trial including 42 Crohn's disease patients with IFX treatment failure, all treated with an intensified IFX regimen (5mg/kg every 4 week) for 12 weeks. Trough serum IFX and anti-IFX Ab concentrations were measured by a homogeneous mobility shift binding assay (HMSA) and a functional cell-based reporter gene assay (RGA) at treatment failure and the end of the trial., Results: Twenty-one patients (50%) regained clinical response on the intensified IFX regimen. The increase in serum trough levels of IFX during treatment intensification was higher among responders than non-responders (RGA, 8.8 versus 3.0 μg/mL, p = 0.035; HMSA, 9.9 versus 4.7 μg/mL, p = 0.040), and differentiated patients by clinical outcome (RGA, area under receiver operating characteristic curve [AUC] 0.75 [0.53-0.97], p = 0.035; HMSA, AUC 0.74 [0.53-0.95], p = 0.042). All responders exhibited an IFX increase ≥2.6 μg/mL (sensitivity 100%, specificity 50%). Anti-IFX Abs detected by HMSA in 13 patients (32%) were often non-functional and became undetectable during IFX intensification. However, even functional anti-IFX Abs detected by RGA in six patients (15%) became undetectable., Conclusion: Increase in IFX levels following treatment intensification was associated with improved clinical outcomes, indicating insufficient drug levels in a subgroup of patients. Anti-IFX Abs may become undetectable during treatment intensification, suggesting lowered production or the formation of immune complexes., (Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: The incidence of ulcerative colitis (UC) and Crohn's disease (CD) has increased during the 20th century in North America and Western Europe. However, there are conflicting reports whether the incidence has declined, stabilized or even continued to increase. No nationwide Danish data on the incidence of UC and CD exist after 1992, and therefore we studied the incidence of UC (1995 through 2011) and CD (1995 through 2012)., Methods: Based on data from the Danish National Patient Registry we identified patients recorded with a first time diagnosis of UC or CD in the study periods. Among these - patients were only included in the study as incident cases if they had at least one more discharge diagnosis of UC/CD or at least three subsequent outpatient visits., Results: We identified 17,500 patients with UC and 7863 patients with CD. The mean incidence rate for UC in 1995-1998 was 14.4 per 100,000 per year for women and 13.8 for men, increasing to 23.2 per 100,000 per year for women and 23.4 for men in the period of 2009-2011. The mean incidence rate for CD in 1995-1998 was 7.8 per 100,000 per year for women and 5.6 for men, increasing to 10.3 per 100,000 per year for women and 8.9 for men in the period of 2009-2012., Conclusions: Based on nationwide Danish data from the last two decades, the incidence rates of UC and CD have continued to increase., (Copyright © 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Objective: Although the reasons for secondary loss of response to infliximab (IFX) maintenance therapy in Crohn's disease vary, dose intensification is usually recommended. This study investigated the cost-effectiveness of interventions defined by an algorithm designed to identify specific reasons for therapeutic failure., Design: Randomised, controlled, single-blind, multicentre study. 69 patients with secondary IFX failure were randomised to IFX dose intensification (5 mg/kg every 4 weeks) (n=36) or interventions based on serum IFX and IFX antibody levels using the proposed algorithm (n=33). Predefined co-primary end points at week 12 were proportion of patients responding (Crohn's Disease Activity Index (CDAI) decrease ≥ 70, or ≥ 50% reduction in active fistulas) and accumulated costs related to treatment of Crohn's disease, expressed as mean cost per patient, based on the Danish National Patient Registry for all hospitalisation and outpatient costs in the Danish healthcare sector., Results: Costs for intention-to-treat patients were substantially lower (34%) for those treated in accordance with the algorithm than by IFX dose intensification: € 6038 vs € 9178, p<0.001. However, disease control, as judged by response rates, was similar: 58% and 53%, respectively, p=0.81; difference 5% (-19% to 28%). For per-protocol patients, treatment costs were even lower (56%) in the algorithm-treated group (€ 4062 vs € 9178, p<0.001) and with similar response rates (47% vs 53%, p=0.78; difference -5% (-33% to 22%))., Conclusions: Treatment of secondary IFX failure using an algorithm based on combined IFX and IFX antibody measurements significantly reduces average treatment costs per patient compared with routine IFX dose escalation and without any apparent negative effect on clinical efficacy., Trial Registration No: NCT00851565.

Background and Aim: Capsule endoscopy (CE) has a high sensitivity for diagnosing small bowel Crohn's disease, but video analysis is time-consuming. The quick view (qv) function is an effective tool to reduce time consumption. The aim of this study was to determine the rate of missed small bowel ulcerations with qv-CE compared with standard view and the diagnostic accuracy of qv-CE in suspected Crohn's disease., Methods: This study consisted of two parts: (i) 12 small bowel segments with Crohn's disease of varying severity were selected for a detailed analysis of the number and type of lesions visualized with CE and qv-CE, and (ii) a blinded study of the diagnostic accuracy of qv-CE including 40 patients with suspected Crohn's disease. Ileocolonoscopy and CE served as gold standard., Results: Part 1: CE visualized 171 ulcerations compared with 102 detected with qv-CE (miss rate 40%, P = 0.02). Part 2: qv-CE identified 15 of 16 patients with small bowel Crohn's disease corresponding to a 94% sensitivity, and overall, 39 out of 40 patients were classified correct (diagnostic accuracy 98%). Qv-CE was false negative in one patient because of a leap of 3 min and 20 s in the terminal ileum. Reading times varied from 5 to 18 min (median 10)., Conclusion: Despite a significant number of missed lesions, qv-CE is a safe and time-reducing method for diagnosing small bowel Crohn's disease. To avoid false negative cases, we recommend viewing the terminal ileum in standard view., (© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Introduction: In suspected Crohn's disease (CD), current diagnostic guidelines recommend additional small bowel imaging irrespective of the findings at ileocolonoscopy. Magnetic resonance imaging enterography (MRE) and computed tomography enterography (CTE) are regarded first line imaging techniques and should generally precede capsule endoscopy., Material and Methods: This article brings together results from a prospective blinded diagnostic study of MRE, CTE, capsule endoscopy and faecal calprotectin (fCal) in 93 patients undergoing their first diagnostic work-up for CD., Results: In patients with suspected CD, fCal is useful for the identification patients without need for colonoscopy or small bowel imaging. Patients with an elevated fCal should undergo colonoscopy including a persistent attempt to intubate the terminal ileum. CD isolated in the upper small bowel is rare, and in patients with a normal ileocolonoscopy or non-complicated CD in the colon and/or terminal ileum, small bowel imaging provides little extra information compared to ileoscopy alone. Small bowel imaging is primarily indicated if ileoscopy is not achieved and capsule endoscopy is recommended as first line imaging technique. If small bowel stenosis is not ruled out, a preceding test with a patency capsule can be performed to avoid capsule retention. MRE and CTE are complimentary modalities preferably used in patients with stenosis detected at ileocolonoscopy or suspicion of extra-intestinal disease complications., Conclusion: Our results suggest that a diagnostic approach different to that described in the guidelines may be expedient., Funding: not relevant., Trial Registration: The study was approved by the Ethics Committee of Southern Denmark (S-20070072) and the Danish Data Protection Agency (journal number: 2007-41-0675). ClinicalTrials.gov identifier: NCT01019460.

Objective: In patients, with symptomatic Crohn's disease (CD), valid information about the presence or absence of small bowel disease activity and stenosis is clinically important. Such information supports decisions about medical or surgical therapy and can be obtained with MR enterography (MRE) or CT enterography (CTE)., Materials and Methods: A total of 50 patients with symptomatic pre-existing CD and a demand for small bowel imaging to support changes in treatment strategy were included in this prospective and blinded study. MRE and CTE were performed on the same day in alternating order and subsequently compared with the gold standard: pre-defined lesions at ileoscopy (n = 30) or surgery with (n = 12) or without (n = 3) intra-operative enteroscopy., Results: A total of 35 patients had active small bowel CD (jejunum 0, ileum 1, (neo)-terminal ileum 34) and 20 had small bowel stenosis. The sensitivity and specificity of MRE for detection of small bowel CD was 74% and 80% compared to 83% and 70% with CTE (p ≥ 0.5). MRE and CTE detected small bowel stenosis with 55% and 70% sensitivities, respectively (p = 0.3) and 92% specificities., Conclusions: MRE and CTE have comparable diagnostic accuracies for detection of small bowel CD and stenosis. In symptomatic patients with CD and high disease prevalence, positive predictive values are favorable but negative predictive values are low. Consequently, MRE and CTE can be relied upon, if a positive result is obtained whereas a negative enterography should be interpreted with caution.

Objective: The utility of fecal calprotectin (fCal) in small bowel Crohn's disease (CD) remains to be clarified. The primary aim of this study was to determine levels of fCal in CD restricted to the small bowel compared with CD affecting the colon, in patients undergoing their first diagnostic work-up. In addition, the study assessed the sensitivity and specificity of fCal in suspected CD., Material and Methods: A total of 83 patients referred to gastroenterology out-patient clinic with suspected CD were included in this prospective, blinded study, and fCal was measured during diagnostic work-up. Ileo-colonoscopy + capsule endoscopy/surgery (n = 81), ileo-colonoscopy + upper endoscopy (n = 1), and ileo-colonoscopy (n = 1) served as gold standard for the presence and location of CD., Results: A total of 40 patients were diagnosed with CD: small bowel 13, colonic 16, and ileo-colonic 11. Levels of fCal were equal in patients with small bowel or colonic CD: median 890 mg/kg and 830 mg/kg, respectively (p = 1.0). With a 50 mg/kg cut-off, CD in the small intestine and colon was diagnosed with 92% and 94% sensitivities, respectively, and the overall sensitivity and specificity of fCal was 95% and 56%. In this cohort, CD was ruled out with a negative predictive value of 92%., Conclusions: This is the first study to show that fCal is equally sensitive in colonic and small bowel CD. In patients suspected of CD, fCal is an effective marker to rule out this diagnosis and select patients for endoscopy.

Background & Aims: Capsule endoscopy (CE) detects small bowel Crohn's disease with greater diagnostic yield than radiologic procedures, although there are concerns that CE has low specificity. We compared the sensitivity and specificity of CE, magnetic resonance imaging enterography (MRE) and computed tomography enterography (CTE) in patients with suspected or newly diagnosed Crohn's disease., Methods: We performed a prospective, blinded study of 93 patients scheduled to undergo ileocolonoscopy, MRE, and CTE and subsequently CE if stenosis was excluded. Physicians reporting CE, MRE, and CTE results were blinded to patient histories and findings from ileocolonoscopy and other small bowel examinations. Results were compared with those from ileoscopy (n = 70), ileoscopy and surgery (n = 4), or surgery (n = 1)., Results: Twenty-one patients had Crohn's disease in the terminal ileum. The sensitivity and specificity for diagnosis of Crohn's disease of the terminal ileum were 100% and 91% by CE, 81% and 86% by MRE, and 76% and 85% by CTE, respectively. Proximal Crohn's disease was detected in 18 patients by using CE, compared with 2 and 6 patients by using MRE or CTE, respectively (P < .05). Small bowel stenosis was observed in 5 patients by using CTE and 1 patient by using MRE. Cross-sectional imaging results indicated additional stenoses in only 2 of the patients who received complete ileocolonoscopies., Conclusions: In suspected or newly diagnosed Crohn's disease, MRE and CTE have comparable sensitivities and specificities. In patients without endoscopic or clinical suspicion of stenosis, CE should be the first line modality for detection of small bowel Crohn's disease beyond the reach of the colonoscope., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: Compared to other modalities, capsule endoscopy (CE) has a high diagnostic yield for diagnosing small bowel Crohn's disease (CD). The aim of this study was to determine the inter-observer agreement for detection of small bowel CD with predefined diagnostic criteria., Material and Methods: Thirty patients with suspected or known CD were included in the study. Observers were blind to patient histories, the results of ileo-colonoscopies, and small bowel examinations. More than three ulcerations (aphthous lesions or ulcers) or the presence of stenosis caused by inflammation or fibrosis was diagnostic of small bowel CD. Three observers with experience in gastrointestinal endoscopy and CE participated in the study., Results: The presence or absence of small bowel CD was determined with complete agreement in 23 patients, nine patients with and 14 without small bowel CD. The inter-observer agreement was substantial for the diagnosis (kappa = 0.68) and moderate for the localization of CD (kappa = 0.44). Aphthous lesions were detected with only fair agreement (kappa = 0.38). The time intervals to passage of the pylorus and ileo-caecal valve were detected with excellent intra-class correlation., Conclusions: CE is performed with substantial inter-observer agreement for detection of small bowel CD. In the majority of patients, the presence or absence of small bowel CD is unequivocal. However, in patients with few or minor lesions, the diagnosis is observer dependent.

Aim: To determine the frequency and clinical impact of incidental findings detected with magnetic resonance imaging (MRI)-enterography in patients with suspected or known Crohn's disease (CD)., Methods: Incidental findings were defined as unexpected lesions outside the small intestine, not previously known or suspected at the time of referral, and not related to inflammatory bowel disease. Through a systematic review of medical charts we analyzed the clinical impact of incidental findings, and compared the MRI findings with subsequent diagnostic procedures., Results: A total of 283 patients were included in the analysis, and MRI detected active CD in 31%, fistula in 1.4% and abscess in 0.7%. Extra-intestinal findings not related to CD were recorded in 72 patients (25%), of which 58 patients (20%) had 74 previously unknown lesions. Important or incompletely characterized findings were detected in 17 patients (6.0%). Incidental findings led to 12 further interventions in 9 patients (3.2%) revealing previously unknown pathological conditions in 5 (1.8%). One patient (0.4%) underwent surgery and one patient was diagnosed with a malignant disease. MRI detected incidental colonic lesions in 16 patients of which additional work-up in 4 revealed normal anatomy. Two patients (0.7%) benefitted from the additional examinations, whereas incidental findings led to unnecessary examinations in 9 (3.2%)., Conclusion: In a minority of patients with suspected or known CD, important incidental findings are diagnosed at MRI-enterography. However, a substantial number of patients experience unnecessary morbidity because of additional examinations of benign or normal conditions.

Diagnosing Crohn's disease in the small intestine can be troublesome. Traditionally, the small bowel is evaluated by ileocolonoscopy and small bowel follow-through or enteroclysis. In recent years MRI, CT, ultrasound and capsule endoscopy have emerged. All are validated and implemented in clinical practice. Double-balloon enteroscopy, PET-CT and SPECT are newer methods, which are still being evaluated in clinical trials. The purpose of this article is to review clinical studies focusing on the validity of modalities for diagnosing Crohn's disease of the small intestine.