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Background and Aims Following induction/maintenance treatment in the UNITI/IM-UNITI studies of ustekinumab for Crohn's disease, patients entered a long-term extension for up to 5 years from induction. Efficacy through 152 and safety through 156 weeks are reported. Methods At IM-UNITI Week 44, 567 ustekinumab-treated patients entered the long-term extension and continued to receive blinded subcutaneous ustekinumab on their assigned dose interval, without any subsequent dose adjustment. Placebo-treated patients discontinued after study unblinding [after IM-UNITI Week 44 analyses]. Efficacy data in the long-term extension [LTE] were collected every 12 weeks [q12w] before unblinding and then at q12w/q8w dosing visits. Results Through Week 156, 29.6% of ustekinumab-treated patients discontinued. In an intent-to-treat analysis of randomised patients from IM-UNITI Weeks 0–152, 38.0% of ustekinumab induction responders receiving the drug q12w and 43.0% q8w were in remission at Week 152. Among patients entering the long-term extension in their original randomised groups, 61.9% of q12w and 69.5% of q8w patients were in remission at Week 152. Across all ustekinumab-treated patients [randomised and non-randomised] entering the long-term extension, remission rates at Week 152 were 56.3% and 55.1% for q12w and q8w, respectively. Safety events [per 100 patient-years] were similar among all ustekinumab-treated patients entering the long-term extension and placebo [overall adverse events 389.70 vs 444.17; serious adverse events, 18.97 vs 19.54; serious infections, 4.21 vs 3.97]. Rates of antibodies to ustekinumab through Week 156 remained low, 4.6% in all randomised ustekinumab-treated patients; lowest among patients in the original randomised q8w group [2/82, 2.4%]. Conclusions Continued treatment with subcutaneous ustekinumab maintained clinical response and remission through 3 years in a majority of patients who responded to induction therapy and was well-tolerated. ClinicalTrials.gov number NCT01369355. [ABSTRACT FROM AUTHOR]

Background and Aims In nonresponders to golimumab induction for ulcerative colitis, we assessed clinical response rates and golimumab serum concentrations when the 100-mg dose was used early in the course of maintenance. Methods This post-hoc analysis of golimumab maintenance dosing [in the PURSUIT-M study] examined clinical outcomes and golimumab concentrations in early [Week 6] responders and nonresponders to induction, including subgroups based on body weight. Results In nonresponders to golimumab induction [assessed at Week 6], the 100-mg maintenance dose [starting at Week 6] resulted in a meaningful proportion [28.1%] of patients achieving a partial Mayo response at Week 14. After 1 year of maintenance, clinical outcome [response, remission, mucosal healing, corticosteroid-free state] rates in these "late" [Week 14] responders were similar to those in early [Week 6] responders. Golimumab concentrations in early nonresponders were approximately half those of early responders, suggesting that early nonresponders had more rapid golimumab clearance. Examined by body weight, the early nonresponders weighing <80 kg and receiving 100 mg had golimumab concentrations similar to the early responders [weighing <80 kg or ≥80 kg and receiving 50 mg or 100 mg, respectively]. Conclusions Early use of the 100-mg maintenance dose leads to positive clinical outcomes in a meaningful proportion of patients who did not respond to golimumab at Week 6. Early nonresponders <80 kg who received the 100-mg maintenance dose achieved adequate golimumab concentrations and a clinically meaningful proportion of these patients had a late clinical response. PURSUIT-M protocol number C0524T18; ClinicalTrials.gov, NCT00488631; EudraCT, 2006-003399-37. [ABSTRACT FROM AUTHOR]

Background and Aims Early treatment of Crohn's disease [CD] is required in order to optimize patient outcomes. To this end, we need to gain a better understanding of the molecular changes at the onset of CD. Methods As a model for the earliest mucosal CD lesions, we study post-operative recurrent CD [Rutgeerts score ≥ i2b]. We are the first to analyse gene and microRNA [miRNA] expression profiles in ileal biopsies from these patients, and compare them with those of newly diagnosed [≤18 months] and late-stage [>10 years after diagnosis] CD patients. Results Except for one gene [ WNT5A ], there are no differential genes in CD patients without post-operative recurrence [i0], showing that previous disease did not influence gene expression in the neoterminal ileum, and that this model can be used to study early mucosal CD lesions. Gene expression and co-expression network dysregulation is more pronounced in newly diagnosed and late-stage CD than in post-operative recurrent CD, with most important modules associated with [a]granulocyte adhesion/diapedesis, and cholesterol biosynthesis. In contrast, we found a role for snoRNAs/miRNAs in recurrent CD, highlighting the potential importance of regulatory RNAs in early disease stages. Immunohistochemistry confirmed the expression of key dysregulated genes in damaged/regenerating epithelium and immune cells in recurrent CD. Conclusions Aside from regulatory RNAs, there are no clear gene signatures separating post-operative recurrent, newly diagnosed, and late-stage CD. The relative contribution of dysregulated genes and networks differs, and suggests that surgery may reset the disease at the mucosal site, and therefore post-operative recurrent CD might be a good model a good model to study to study early mucosal CD lesions. [ABSTRACT FROM AUTHOR]

Background and Aims Analyses of Crohn's Disease [CD] studies of anti-TNF agents, including adalimumab, have reported higher remission rates among patients with shorter disease duration. To further explore the relationship between disease duration and clinical efficacy, we analysed a larger patient cohort. Methods Data were pooled from 10 clinical trials in patients with moderately to severely active CD who received treatment with either adalimumab or placebo. Analyses of efficacy using Crohn's Disease Activity Index [CDAI] endpoints [remission, clinical response [CR]-70, CR-100, patient-reported outcome [PRO] remission] or Harvey–Bradshaw Index [HBI] endpoints [remission/response] were conducted for induction and maintenance treatment periods. Logistic regression was used for comparisons between adalimumab and placebo treatment. Cochran–Armitage trend tests were used for comparisons between disease-duration subgroups [<1 year, ≥1–<2 years, 2–≤5 years, and >5 years]. Results During induction, the proportion of patients achieving CDAI remission was higher in adalimumab- versus placebo-treated patients [ p  <0.001] and was highest [adalimumab: 45.8%] in the <1 year subgroup compared with longer disease-duration subgroups [≥1–<2 years: 31.0%; 2–≤5 years: 23.1%; >5 years: 23.6%, Cochran–Armitage p  = 0.026]. In the majority of maintenance treatment analyses, patients with <1 year disease duration had the highest efficacy responses, with statistically significant differences in remission rates across disease-duration subgroups. Conclusions This analysis demonstrates that earlier initiation of adalimumab treatment shortly after diagnosis in patients with moderately to severely active CD leads to improved long-term clinical outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Vedolizumab has proven efficacy in inflammatory bowel disease [IBD], but long-term mucosal healing in Crohn's disease [CD], as well as the incidence of colorectal neoplasia in IBD, among patients treated with vedolizumab have not been studied. We aimed to document mucosal healing and to explore the risk of colorectal neoplasia with vedolizumab maintenance therapy. Methods: Surveillance colonoscopy was prospectively scheduled for patients with longstanding ulcerative coltis [UC] or CD at a tertiary referral centre, in the open-label extension phase (vedolizumab 300 mg intravenously [IV] every 4 weeks) of the Gemini studies [GEMINI LTS, study number NCT00790933]. Mayo score ⩽ 1 or ulcer disappearance [in CD] was defined as mucosal healing. Targeted biopsies were graded for inflammation and dysplasia. Results: Of 68 patients [29 CD/39 UC] treated for ⩾ 1 year [median 3.2 years, range 1.1-6.1], 58 [24 CD/34 UC] were endoscopically monitored. Durable endoscopic healing corrected by nonresponder imputation was found in 7/24, 29% [CD] and 17/34, 50% [UC]. Combined histological and mucosal healing was observed in 5/24 [CD] and 11/34 [UC] of those with endoscopic healing. Low-grade dysplasia was detected in 10% of patients and high-grade dysplasia in the resection specimen of one patient with biopsy-proven low-grade dysplasia. Conclusions: Long-term endoscopic and histological healing was observed in a proportion of patients treated with vedolizumab long-term. The dysplasia risk with vedolizumab deserves further study. [ABSTRACT FROM AUTHOR]

Background and Aims: This 11-week Phase IIa induction study evaluated the efficacy and safety of eldelumab in patients with active Crohn's disease. Methods: Adults with Crohn's Disease Activity Index 220-450 were randomised 1:1:1 to placebo or eldelumab 10 or 20 mg/kg intravenously on Days 1 and 8, and alternate weeks thereafter. All patients underwent ileocolonoscopy at baseline. Patients with active inflammation according to the Simplified Endoscopic Score for Crohn's Disease criteria [the originally planned endoscopy cohort] underwent another ileocolonoscopy at Week 11 at the investigator's discretion. All ileocolonoscopies were centrally read. The primary objective was identification of the eldelumab target exposure for induction of remission [absolute Crohn's Disease Activity Index score < 150]. Rates of clinical response [reduction of = 100 from baseline or absolute score < 150 Crohn's Disease Activity Index], remission, and endoscopic improvements were also assessed. Results: A total of 121 patients were randomised. The eldelumab exposure-remission relationship was not significant at Week 11. Numerically higher remission and response rates were reported with eldelumab 20 mg/kg [29.3% and 41.5%, respectively] and 10 mg/kg [22.5% and 47.5%] versus placebo [20.0% and 35.0%]. A higher proportion of patients with a baseline Simplified Endoscopic Score for Crohn's Disease > 2 who received eldelumab achieved a 50% improvement in score and greater reductions from baseline endoscopy scores overall versus placebo. Adverse events were comparable across treatment groups. Conclusions: No exposure-remission relationship was seen with eldelumab. Eldelumab induction treatment demonstrated trends towards clinical and endoscopic efficacy. Safety was consistent with that reported previously. [ABSTRACT FROM AUTHOR]

Background and Aims: Mucosal healing [MH] is an important goal for patients with Crohn's disease [CD], yet is incompletely characterised. We investigated whether MH differed by segments across the colon and ileum in patients who received adalimumab maintenance treatment in the EXTEND study. Methods: In this double-blind study in adults with moderate to severe ileocolonic CD and mucosal ulceration, all patients received adalimumab induction [Week 0, 160 mg; Week 2, 80 mg]. At Week 4, patients were randomised to 40 mg adalimumab or placebo every other week until Week 52. In this post-hoc analysis, MH was assessed by CD Endoscopic Index of Severity [CDEIS], Simple Endoscopic Score for CD [SES-CD], and Colonic and Ileal Global Histologic Disease Activity Scores [CGHAS/ IGHAS]. Results: Baseline endoscopic severity was similar across segments. At Week 52, mean changes in CDEIS surface involved and ulcerated surface were -68.5% to -90.6% in the rectum, sigmoid/ left colon, and transverse colon compared with -22.3% to -50.0% in the right colon and ileum. Favourable shifts by Week 52 in ulcer size and ulcerated surfaces per SES-CD were more pronounced in the rectum, sigmoid/left colon, and transverse colon vs the right colon and ileum. At Week 52, CGHAS and IGHAS healing was more common in the colon [28.3%] vs the ileum [21.2%]. Conclusions: This analysis suggests differing propensities of the ileocolonic segments to heal endoscopically during adalimumab treatment. In the sigmoid/left and transverse colon, higher MH rates may be achieved, compared with the ileum, in patients with moderate to severe CD. [ABSTRACT FROM AUTHOR]

Background and Aims: Mucosal healing is associated with favourable therapeutic outcomes in patients with ulcerative colitis [UC]. We investigated whether adalimumab concentrations during induction therapy are associated with short-term mucosal healing [STMH] in UC patients. Methods: This was a retrospective, single-centre study including consecutive UC patients treated with adalimumab from June 2005 to May 2014, who underwent an endoscopy both at baseline and after induction therapy [weeks 8-14] and at least one serum sample available at week 2 and/ or week 4. STMH was defined as Mayo endoscopic sub-score of ≤1 with a baseline sub-score of ≥2. Adalimumab concentrations were evaluated using an in-house developed enzyme-linked immunosorbent assay. Results: The study population consisted of 43 patients, the majority of whom [n = 38] were prior infliximab failures; the rest showed primary non-response [PNR, n = 5]. Twelve patients [27 .9%] achieved STMH. Patients with STMH had higher adalimumab concentrations at week 4 compared to those without [10.6 vs 7 .4 µg/ml, p = 0.014]. A receiver operating characteristic [ROC] analysis identified an adalimumab concentration threshold at week 4 of 9.4 µg/ml (area under the ROC curve [AUROC]: 0.778) and 7 .5 µg/ml [AUROC: 0.798], after excluding patients with PNR to infliximab, to be associated with STMH. Multiple logistic regression analysis, after excluding patients with PNR to infliximab, identified adalimumab concentration ≥7 .5 µg/ml at week 4 (odds ratio [OR]: 15.7; 95% confidence interval [CI]: 1.3-185; p = 0.029) and baseline endoscopic Mayo score 3 [OR: 0.13; 95% CI: 0.02-0.98; p = 0.047] as factors independently associated with STMH. Conclusions: This study, reflecting real-life clinical practice, demonstrated that post-induction adalimumab concentrations are associated with STMH, while higher baseline mucosal inflammation is related to lack of STMH in UC. [ABSTRACT FROM AUTHOR]

Background and Aims: To assess golimumab pharmacokinetics [PK] and exposure-response [ER] in adults with moderate-to-severe ulcerative colitis [UC] from the Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment [PURSUIT] studies. Methods: We analysed golimumab PK and ER data of patients with moderate-to-severe UC from the PURSUIT -subcutaneous induction [N = 1064] and maintenance [N = 464] studies. Induction analyses evaluated serum golimumab concentration [SGC] and eficacy data through Week [wk] 6 following subcutaneous doses at wk0 and wk2; maintenance analyses assessed data through wk54 following 4-weekly dosing. ER relationships were assessed using trend, logistic regression, and receiver-operating-characteristic curve analyses. Results: Median SGCs peaked at induction wk2 for golimumab 100/50 mg, 200/100 mg, and 400/200 mg. Wk6 median SGCs were 0.78, 1.78, and 4.01 µg/ml, respectively. SGCs were sustained, reaching steady state approximately 8wks after golimumab maintenance commenced [wk14 of golimumab] regardless of induction dose. Median trough SGCs from maintenance wks8-4 ranged from 0.69 to 0.83 µg/ml [50 mg] and 1.33-1.58 µg/ml [100 mg]. SGCs were approximately dose proportional, and higher SGCs were associated with higher eficacy response rates during induction and maintenance. Factors associated with golimumab exposure were body weight, antibody-to-golimumab status, serum albumin, alkaline phosphatase, faecal markers, C-reactive protein, and pancolitis. SGCs of 2.5 µg/ml [induction wk6] and 1.4 µg/ml [maintenance steady-state trough] are potential target concentrations. Immunomodulators had no apparent impact on SGC with golimumab 100 mg, whereas drug levels were slightly higher with golimumab 50 mg with vs without immunomodulators. Conclusions: SGCs are approximately dose proportional, and a positive SGC-eficacy relationship exists during induction/maintenance golimumab treatment of adult UC patients. Optimal SGC targets require validation in prospective studies [ABSTRACT FROM AUTHOR]

Background and Aims: We studied the long-term outcome of patients with ulcerative colitis [UC] and primary non response [PNR] to infliximab and searched for predictors of colectomy in these patients. Methods: This retrospective, multi-centre study included UC patients from three European referral centres, with PNR to infliximab defined as a lack of clinical improvement after the induction therapy, leading to drug discontinuation. Relapse, for patients who continued on biologicals after PNR to infliximab, was defined as drug discontinuation for PNR, loss of response, or serious adverse event. Serum infliximab concentrations at Weeks 2 and 6 were evaluated using an enzyme-linked immunosorbent assay [ELISA] developed in house. Results: The study population consisted of 99 anti-tumour necrosis factor [TNF]-naïve patients with UC and PNR to infliximab. At the end of follow-up (median: 3.2 [interquartile range 1-6.3] years), 55 [55.6%] of these patients underwent colectomy. Multiple Cox regression analysis identified acute severe UC (hazard ratio [HR]: 24; 95% confidence interval [CI]: 2.5-231; p = 0.006], baseline C-reactive protein [CRP] > 5 mg/l [HR: 11; 95% CI: 2.1-58.8; p = 0.005], baseline albumin < 40 g/l [HR: 9.5; 95% CI: 1.3-71.4; p = 0.026], and infliximab concentration at Week 2 < 16.5 μg/ml [HR: 5.6; 95% CI: 1.1-27.8; p = 0.034] as independent predictors of colectomy. Regarding patients who continued on biologicals after PNR to infliximab, there was a marginally higher cumulative probability for relapse in patients switching to another anti-TNF agent compared with those swapping to vedolizumab [p logrank = 0.08]. Conclusions: About half of UC patients with PNR to infliximab will undergo colectomy. Patients with severe inflammation and low serum infliximab concetrations during the induction phase are at greatest risk. [ABSTRACT FROM AUTHOR]

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

Background and Aims: Faecal microbiota transplantation is a successful therapy for patients with refractory Clostridium difficile infections. It has also been suggested as a treatment option for inflammatory bowel disease, given the role of the intestinal microbiota in this disease. We assessed the impact of faecal microbiota transplantation in patients with inflammatory bowel disease and studied predictors of clinical (non-)response in microbial profiles of donors and patients. Methods: Fourteen refractory patients (8 with ulcerative colitis and 6 with Crohn's disease) underwent ileocolonoscopy with faecal microbiota transplantation through a nasojejunal (n = 9) or rectal (n = 5) tube. Efficacy was assessed by endoscopic healing at week 8, clinical activity scores and C-reactive protein measurement. Faecal microbiota was analysed by 16S rDNA pyrosequencing. Results: There was no significant improvement among the 6 patients with Crohn's disease at week 8 following faecal microbiota transplantation. One patient experienced temporary clinical remission for 6 weeks. In contrast, 2/8 patients with ulcerative colitis had endoscopic remission at week 8, and of the 6 remaining patients with ulcerative colitis, 1 reported temporary remission for 6 weeks.The donor microbiota richness and the number of transferred phylotypes were associated with treatment success. Persistent increased C-reactive protein 2 weeks after transplantation was predictive of failure of response. Conclusion: Faecal microbiota transplantation led to endoscopic and long-term (>2 years) remission in 2 out of 8 ulcerative colitis patients. Higher donor richness was associated with successful transplant. Therefore, faecal microbiota transplantation with donor prescreening could be a treatment option for selected refractory ulcerative colitis patients. [ABSTRACT FROM AUTHOR]

Background and Aims: Although costly and uncomfortable for the patient, the current standard to assess mucosal healing in Crohn's disease [CD] patients is endoscopy. The aim of this study was to evaluate NGAL-MMP-9 as surrogate marker for mucosal healing in CD patients. Methods: Serum NGAL-MMP-9 levels were determined with sandwich enzyme-linked immunosorbent assay before and up to 5 years after first infliximab infusion in 108 active CD patients [median age at first infliximab 36 years, 57% female] and 43 healthy controls [HC, median age 27 years, 60% female]. Serum samples were matched to the time of endoscopy and complete endoscopic healing was defined as absence of ulcerations. Histological healing was defined as absence of epithelial damage [D'Haens score]. Results: At baseline, median [interquartile range] NGAL-MMP-9 levels were significantly higher in active CD patients vs HC (77.6 [36.9-141.0] vs 25.5 [17.8-42.8] ng/ml; p < 0.001). After treatment, NGALMMP- 9 levels significantly decreased in completely healed CD patients [n = 38] (84.5 [36.7-138.4] to 23.4 [7.4-42.5] ng/ml; p < 0.001) and-to a lesser extent-in non-healed CD patients [n = 36] (100.9 [43.4-152.6] to 43.8 [27.0-96.8] ng/ml; p = 0.001). Receiver operating characteristic analysis defined a NGAL-MMP-9 cut-off level of 45 ng/ml corresponding to complete endoscopic healing (area under the curve [AUC] = 0.79, 82% sensitivity, 65% specificity) and histological healing [AUC = 0.72, 79% sensitivity, 53% specificity]. At baseline, C-reactive protein [CRP] was not elevated in 33% of active CD patients, whereas 53% of these patients did have elevated NGAL-MMP-9 levels. Conclusions: In the search for surrogate markers to assess mucosal healing in inflammatory bowel disease, NGAL-MMP-9 supplements and outperforms CRP in both ulcerative colitis and CD patients. [ABSTRACT FROM AUTHOR]

Background and aims: Current endoscopic activity scores for ulcerative colitis (UC) do not take into account the extent of mucosal inflammation. We have developed a simple endoscopic index for UC that takes into account the severity and distribution of mucosal inflammation. Methods: In this multicentre trial, UC patients undergoing colonoscopy were prospectively enrolled. For the Modified Score (MS), the sum of Mayo Endoscopic Subscores (MESs) for five colon segments (ascending, transverse, descending, sigmoid and rectum) was calculated. The Extended Modified Score (EMS) was obtained by multiplying the MS by the maximal extent of inflammation. The Modified Mayo Endoscopic Score (MMES) was obtained by dividing the EMS by the number of segments with active inflammation. Colon biopsies were obtained from the rectum and sigmoid, as well as from all inflamed segments, by standard methods. Clinical activity was scored according to the Partial Mayo Score (PMS). Biological activity was scored according to C-reactive protein (CRP) and faecal calprotectin (FC) levels. Histological activity was scored according to the Geboes Score (GS). Results: One hundred and seventy-one UC patients (38% female, median age 47 years, median disease duration 13 years) were included. The MMES correlated significantly with the PMS (r = 0.535), CRP (r = 0.238), FC (r = 0.730) and GS (r = 0.615) (all p < 0.001). Median MMES scores were significantly higher in patients with clinical, biological or histological activity (all p ≤ 0.001) Conclusions: The MMES is an easy to use endoscopic index for UC that combines the severity analysis of the MES with disease extent, and correlates very well with clinical, biological and histological disease activity. [ABSTRACT FROM AUTHOR]

Background and Aims: Prophylactic azathioprine (AZA) is efficacious in preventing postoperative Crohn's disease (CD) recurrence. However, it is unknown whether AZA should be started immediately after surgery. We compared the efficacy of systematic vs endoscopy-driven AZA in preventing CD recurrence at week 102. Methods: This prospective, multicentre trial included CD patients undergoing curative resection with ileocolonic anastomosis and at higher risk of recurrence. Patients were randomized to systematic AZA initiated ≤2 weeks from surgery, or endoscopy-driven AZA in which therapy was only initiated in case of endoscopic recurrence (Rutgeerts' score ≥i2) at weeks 26 or 52 following surgery. The primary endpoint was endoscopic remission (i0-i1) at week 102. Secondary endpoints included complete endoscopic remission (i0) and clinical remission. Results: The study was prematurely stopped due to slow recruitment. Between 2005 and 2011, 63 patients (28 male, median age 36 years) were randomized to systematic (n = 32) or endoscopy-driven AZA (n = 31). Twenty-one patients withdrew prematurely (8 clinical recurrence, 6 adverse reactions to AZA, 7 patient's preference). In the endoscopy-driven AZA group, 14 patients had to initiate AZA (11 at week 26, 3 at week 52). Endoscopic remission was achieved by 50% in the systematic and 42% in the endoscopy-driven AZA group (p = 0.521). No difference in secondary endpoints was found. Conclusions: Systematic AZA therapy in patients at higher risk of postoperative CD recurrence is not superior to endoscopy-driven treatment. Early postoperative endoscopic evaluation between weeks 26 and 52 seems most appropriate to guide further therapy, but larger studies are warranted. (ClinicalTrials.gov NCT02247258.) [ABSTRACT FROM AUTHOR]

Background A long-lasting good functional outcome of the pelvic pouch and a subsequent satisfying quality of life (QoL) are mandatory. Long-term functional outcome and QoL in a single-center cohort were assessed. Patients and methods A questionnaire was sent to all patients with an IPAA for UC, operated between 1990 and 2010 in our department. Pouch function was assessed using the Öresland Score (OS) and the ‘Pouch Functional Score’ (PFS). QoL was assessed using a Visual Analogue Score (VAS). Results 250 patients (42% females) with a median age at surgery of 38 years (interquartile range (IQR): 29–48 years) underwent restorative proctocolectomy. Median follow‐up was 11 years (IQR: 6–17 years). Response rate was 81% (n = 191). Overall pouch function was satisfactory with a median OS of 6/15 (IQR: 4–8) and a median PFS of 6/30 (IQR: 3–11). 24-hour bowel movement is limited to 8 times in 68% of patients (n = 129), while 55 patients (29%) had less than 6 bowel movements. 12 patients (6.5%) were regularly incontinent for stools, while 154 patients (82%) reported a good fecal continence. Fecal incontinence during nighttime was more common (n = 72, 39%). Pouch function had little impact on social activity (4/10; IQR: 2–6) and on professional activity (3/10; IQR: 1–6). 172 patients (90%) reported to experience an overall better health condition since their operation. The OS and the PFS correlated well (Pearson's correlation coefficient = 0.83). Overall pouch function was stable over time. Conclusion Majority of patients report a good pouch function on the long-term with limited impact on QoL. [ABSTRACT FROM AUTHOR]

Background and aims Clinical management of inflammatory bowel diseases (IBD), new treatment modalities and the potential impact of personalised medicine remain topics of intense interest as our understanding of the pathophysiology of IBD expands. Methods Potential future strategies for IBD management are discussed, based on recent preclinical and clinical research. Results A top-down approach to medical therapy is increasingly being adopted for patients with risk factors for severe inflammation or an unfavourable disease course in an attempt to halt the inflammatory process as early as possible, prevent complications and induce mucosal healing. In the future, biological therapies for IBD are likely to be used more selectively based on personalised benefit/risk assessment, determined through reliable biomarkers and tissue signatures, and will probably be optimised throughout the course of treatment. Biologics with different mechanisms of action will be available; when one drug fails, patients will be able to switch to another and even combination biologics may become a reality. The role of biotherapeutic products that are similar to currently licensed biologics in terms of quality, safety and efficacy -- i.e. biosimilars -- is at an early stage and requires further experience. Other therapeutic strategies may involve manipulation of the microbiome using antibiotics, probiotics, prebiotics, diet and combinations of all these approaches. Faecal microbiota transplantation is also a potential option in IBD although controlled data are lacking. Conclusions The future of classifying, prognosticating and managing IBD involves an outcomes-based approach to identify biomarkers reflecting various biological processes that can be matched with clinically important endpoints. [ABSTRACT FROM AUTHOR]

Abstract: We present two patients with inflammatory bowel disease who, despite negative tuberculosis screening, developed a de novo tuberculosis infection after the start of anti tumor necrosis factor alpha treatment. We discuss current screening methods and their limitations, the approach after positive screening and the timing to resume anti-TNFα treatment after TB infection. We shortly mention the immune reconstitution inflammatory syndrome (IRIS), described in a few cases after the stop of anti-TNFalpha while treating the tuberculosis infection. We conclude with some remaining questions concerning tuberculosis in IBD patients. [Copyright &y& Elsevier]

Abstract: Background and aims: Anti TNF therapy induces mucosal healing in patients with Crohn's disease, but the effects on transmural inflammation in the ileum are not well understood. Magnetic resonance-enteroclysis (MRE) offers excellent imaging of transmural and peri-enteric lesions in Crohn's ileitis and we aimed to study its responsiveness to anti TNF therapy. Methods: In this multi-center prospective trial, anti TNF naïve patients with ileal Crohn's disease and with increased CRP and contrast enhanced wall thickening received infliximab 5mg/kg at weeks 0, 2 and 6, and q8 weeks maintenance MRE was performed at baseline, 2 weeks and 6 months and assessed based on a predefined MRE score of severity in ileal Crohn's Disease. Results: Twenty patients were included; of those, 18 patients underwent MRE at week 2 and 15 patients at weeks 2 and 26 as scheduled. Inflammatory components of the MRE index decreased by ≥2 points and by ≥50% at week 26 (primary endpoint) in 40% and 32% of patients (per protocol and intention to treat analysis, respectively). The MRE index improved in 44% at week 2 and in 80% at week 26. Complete absence of inflammatory lesions was observed in 0/18 at week 2 and 13% (2/15) at week 26. The obstructive elements did not change. Clinical and CRP improvement occurred as early as wk 2, but only CDAI correlated with the MRE index. Conclusion: Improvement of MRE occurs from 2 weeks after infliximab therapy onwards and correlates with clinical response but normalization of MRE is rare. [Copyright &y& Elsevier]

Abstract: Background and aims: Granulomas are a characteristic microscopic finding in Crohn''s disease. Their clinical significance is controversial and their pathogenesis is unknown, but impaired processing of bacterial components has been suggested. Autophagy is a fundamental process involved in the elimination of intracellular bacteria. Genetic variants in autophagy genes IRGM and ATG16L1 have been associated with susceptibility to Crohn''s disease. We therefore investigated whether variants in autophagy genes contribute to granuloma formation. Methods: Surgical specimens from 464 clinically well-documented Crohn''s patients were reviewed and scored for the presence and distribution of granulomas. All patients were genotyped for the CD-associated SNPs in ATG16L1 and IRGM as well as for 77 haplotype tagging SNPs in 13 additional autophagy genes. Results: Granulomas were found in 75% of the patients. Their frequency increased with more distal involvement of the GI tract. Granuloma positive patients were significantly younger at the time of diagnosis and surgery, and were more likely to smoke. We identified associations between granulomas and autophagy gene variants ATG4A (rs5973822), FNBP1L (rs17109951) and ATG4D (rs7248026; rs2304165; rs10439163). Conclusion: These findings suggest that granuloma formation is a marker of a more aggressive disease course, and that variants in autophagy genes ATG4A, ATG2A, FNBP1L and ATG4D, may contribute to granuloma formation. [Copyright &y& Elsevier]

Abstract: A 20-year old man with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC) was diagnosed with a rectal non-Hodgkin''s lymphoma (NHL) at surveillance endoscopy while being in remission on infliximab therapy. Further staging identified a diffuse large B-cell NHL, EBV negative restricted to the rectal submucosa (stage IA). Until now, there has not been any evidence of an increased risk of NHL in patients with UC nor of an increased risk of lymphoproliferative disorders in IBD patients. Hence, the role of concomitant PSC in the pathogenesis of intestinal NHL is unclear. However, IBD patients treated with purine analogues and with anti-TNF are at risk of NHL, especially hepatosplenic T-cell lymphoma. The management of this particular young patient is further complicated by the possibility of a future colectomy due to intractable disease which compromises the use of radiotherapy for this localized disease. [Copyright &y& Elsevier]

While some probiotic strains might have adjuvant effects in the therapy for inflammatory bowel diseases (IBD), these effects remain controversial and cannot be generalized. In this study, a dltD mutant of the model probiotic Lactobacillus rhamnosus GG (LGG), having a drastic modification in its lipoteichoic acid (LTA) molecules, was analysed for its effects in an experimental colitis model. Dextran sulphate sodium (DSS) was used to induce either moderate to severe or mild chronic colitis in mice. Mice received either phosphate-buffered saline (PBS), LGG wild-type or the dltD mutant via the drinking water. Macroscopic parameters, histological abnormalities, cytokine and Toll-like receptor (TLR) expression were analysed to assess disease activity. LGG wild-type did not show efficacy in the different experimental colitis set-ups. This wild-type strain even seemed to exacerbate the severity of colitic parameters in the moderate to severe colitis model compared to untreated mice. In contrast, mice treated with the dltD mutant showed an improvement of some colitic parameters compared to LGG wild-type-treated mice in both experimental models. In addition, treatment with the dltD mutant correlated with a significant down-regulation of Toll-like receptor-2 expression and of downstream proinflammatory cytokine expression in the colitic mice. These results show that molecular cell surface characteristics of probiotics are crucial when probiotics are considered for use as supporting therapy in IBD. [ABSTRACT FROM AUTHOR]

Abstract: Background and aims: Biological therapy with anti TNF agents requires parenteral administration and in the case of infliximab this involves in hospital treatment. We aimed to prospectively assess the safety and tolerance of infliximab infusion in patients with IBD in a specialized unit adhering to strict standard operation procedures including switch to accelerated 1h infusions. Methods: A prospective audit of a referral center IBD infusion unit was performed. We recorded infusion times and all adverse events including hypersensitivity reactions. Patients were also polled about the impact of the treatment on quality of life (QOL). Results: On 20 consecutive days 177 patients were treated with infliximab and all participated. Of those infliximab 117 received 1h infusions and 4 (2.2%) had an immediate infusion reaction. Median time on unit was optimal for those with 1h infusions [1:35h (IQR: 1:25–1:50)] without an increased risk of infusion reactions. Prophylactic therapy significantly increased the time on unit [3:20h (IQR: 2:50–3:45), p <0.001]. Patients reported a high global satisfaction and a good tolerability of the infusions with a considerable or strong impact on studies, work or QOL in one third. Conclusions: A dedicated IBD infusion unit can achieve high quality of care and shortened 1h infliximab infusions are well tolerated in patients with scheduled maintenance therapy. [ABSTRACT FROM AUTHOR]

The article discusses a study which examines the outcome of surgery for symptomatic Crohn's rectovaginal fistula (RVF) and the effect of therapy with antibody against tumour necrosis factor (TNF) on healing. The study shows that most patients achieve fistula closure but require more than one operation. It notes that 81 per cent of 52 patients achieve fistula closure and 56 per cent attain primary surgical success rate while 57 per cent achieve secondary surgical success rate.

Abstract: Introduction and aim: Over the last decade a rise in Clostridium difficile-associated diarrhea (CDAD) has been observed. A higher incidence of CDAD has also been suggested in patients with inflammatory bowel disease (IBD), and may be a challenging factor in the differential diagnosis of flares. It is unclear if the increase is caused by the enhanced use of immunosuppressive therapy in IBD. We investigated if CDAD infection is increasing in IBD patients and evaluated outcome and possible predisposing factors. Methods: Through an electronic database of the Laboratory of Microbiology of our hospital (tertiary referral center), all stool samples from patients admitted for diarrhea and hospitalized on gastroenterology wards between January 2000 and January 2008 were reviewed for diagnosis of CDAD. For analysis, we compared two periods of equal duration. Results: A total of 57 patients were diagnosed with CDAD, of whom 26.3% had concomitant IBD. A 3.75-fold increase in CDAD was observed between period 1 and period 2, irrespective of underlying IBD and with a comparable total number of analyzed stool samples between both periods. Non-IBD patients were significantly older. Antibiotic use three months prior to the infection was higher in non-IBD (29/42 or 69%) than in IBD patients (6/15 or 42%) (p = 0.047). Nine IBD patients were on concomitant immunomodulators, and this was not different between period 1 and period 2. Most patients had a successful outcome and only one patient with ulcerative colitis needed semi-urgent colectomy. Two patients died in the non-IBD group. The duration of hospital stay was significantly lower in IBD patients. Conclusion: We observed a significant rise in CDAD in both IBD and non-IBD. The clinical outcome was favorable with only one IBD patient needing semi-urgent colectomy. Because C. difficile can mimic an IBD flare, it is essential that clinicians are vigilant to this complication. The use of immunosuppressive drugs in IBD does not influence the risk. [Copyright &y& Elsevier]

Abstract: Background and aims: Infliximab (IFX) has been shown efficacious for moderate-to-severe ulcerative colitis (UC), but data on long-term efficacy are lacking. We investigated long-term outcome including colectomy rates in outpatients treated with IFX for refractory UC in a single referral centre, and evaluated if predictors could be identified. Methods: The first 121 outpatients (median age 38.0 years) with refractory UC treated with IFX were included. The primary outcome was colectomy-free survival. Secondary measures were sustained clinical response and serious adverse events. Results: From the 81 patients (67%) with an initial clinical response to IFX, 68% had a sustained clinical response. No independent predictors of sustained clinical response could be identified. Over a median (IQR) follow-up period of 33.0 (17.0–49.8) months, 21 patients (17%) came to colectomy. Independent predictors of colectomy were absence of short-term clinical response [Hazard ratio 10.8 (95% CI 3.5–32.8), p <0.001], a baseline CRP level ≥5 mg/L [Hazard ratio 14.5 (95% CI 2.0–108.6), p =0.006] and previous IV treatment with corticosteroids and/or cyclosporine [Hazard ratio 2.4 (95% CI 1.1–5.9), p =0.033]. Six patients developed a serious infection, three a malignancy, two a post-operative complication and one patient died (suicide). Conclusions: With a median follow-up of 33.0 months after start of IFX, 17% of patients with refractory UC needed colectomy, while sustained clinical response was present in 68% of initial responders. [Copyright &y& Elsevier]

Abstract: Background and Aims : Pouchitis, the most common complication after proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis, has been attributed to altered composition of faecal flora. We investigated the role of antimicrobial and antiglycan antibodies and polymorphisms in microbial pattern recognition receptor genes. Methods : Clinical charts of all 184 patients with ulcerative colitis who underwent IPAA between 1990–2004 were reviewed for pre- and post-operative disease course. Results : Follow-up data were available in 172 patients [67 female, median age at proctocolectomy 39.1 years]. During a median follow-up of 6.7 (interquartile range 3.7–10.5) years, 80 patients (47%) developed at least one episode of pouchitis. Cox proportional-hazard regression identified extra-intestinal manifestations [HR 1.78 (95%CI 1.10–2.88), p =0.020], a GT/TT genotype at Toll-like-receptor-1 S87I [HR 1.64 (1.01–2.66), p =0.047], anti-chitobioside carbohydrate antibodies [HR 2.03 (1.11–3.70), p =0.021] and young age at diagnosis [p =0.003] to be independently associated with pouchitis. Factors associated with chronic pouchitis, diagnosed in 33 patients (19%), were extra-intestinal manifestations [HR 2.45 (1.07–5.62), p =0.034], backwash ileitis [HR 3.15 (1.10–9.00), p =0.032], outer-membrane porin antibodies [HR 2.67 (1.20–5.94), p =0.016] and young age at proctocolectomy [p =0.008]. Conclusions: : The reported association with antibodies and Toll-like-receptor-1 supports the pathophysiological role of the faecal flora in the development of pouchitis. [Copyright &y& Elsevier]

Abstract: Background and aims: Infliximab (IFX) and iron sucrose (FeS) are of high value in inflammatory bowel disease (IBD). We aimed to assess the relative role of both therapies in IBD related anaemia and their safety when used in combination. Methods: IBD patients with anaemia receiving a first series of FeS infusions in addition to IFX were prospectively followed. We investigated serum kinetics of erythropoietin (EPO), soluble transferrin receptors (sTFRs) and vascular endothelial growth factor (VEGF). Results: Data analysis included 87 patients of whom 49.4% achieved the target Hb level of 12.0 g/dL. IFX resulted in a significant increase of EPO and sTFR compared to baseline pre-IFX levels (p =0.029 and p =0.005 respectively) and after a 12-week combined FeS and IFX treatment, EPO and sTFR levels dropped significantly compared to pre-FeS levels (p <0.001 for both). Infusion related adverse events were recorded in 2 IFX treated patients (2.3%, 0.7% of the infusions) and were mild. Disease activity and quality of life were not affected. Conclusions: In anaemic IBD patients treated with IFX, combined administration of FeS is safe. Infliximab significantly increases serum EPO and sTFR levels resulting in an increased functional iron deficiency, which is restored after combined treatment with I.V. iron sucrose. [Copyright &y& Elsevier]

4-1BB ligand (4-1BBL) expressed on antigen-presenting cells interacts with 4-1BB on activated T cells (especially CD8+ cells) and co-stimulates the latter to secrete cytokines and to proliferate. The role of 4-1BB−4-1BBL interaction was studied here in a model of colitis based on naive CD4+ T cell transfer to SCID mice, a disease model in which CD8 cells do not take part. We found that CD4+ T cells from 4-1BB-deficient mice, after transfer in SCID mice, proliferated more rapidly compared to wild-type CD4+ T cells. Mice reconstituted with naive CD4+ T cells from 4-1BB-deficient mice developed colitis, however, with a mixed Th1/Th2 response, in contrast to the Th1-type response in mice reconstituted with wild-type naive CD4+ T cells. Importantly, this altered cytokine response did not temper colitis severity. Although it has been reported previously that 4-1BB co-stimulation may contribute to regulatory T cell functioning, we found that CD4+CD25+ regulatory T cells from 4-1BB-deficient mice were perfectly able to prevent naive CD4+ T cell-induced colitis. In conclusion, our data provide evidence that 4-1BB−4-1BBL interaction modulates the effector CD4+ T cell-driven immune response and cytokine production in experimental colitis without affecting regulatory T cell function. [ABSTRACT FROM AUTHOR]

An imbalance of immunoregulatory factors and/or cells contributes to uncontrolled mucosal T cell activation and inflammation in Crohn's disease (CD). Bioactive interleukin (IL)-18 has been shown to be produced by macrophages in CD lesions. We report here that T cells freshly isolated from inflamed tissue of CD patients (and not T cells from control intestinal tissue) were responsive to IL-18. In the presence of IL-18, these T cells produced more interferon (IFN)- γ and less IL-10. To analyse further the role of IL-18 in this disease, an acute and a chronic model of murine colitis were used. IL-18 mRNA was significantly enhanced in trinitrobenzene sulphonic acid (TNBS) induced colitis, and treatment with IL-18 binding protein (IL-18BPa), which neutralizes IL-18 bioactivity, significantly reduced the severity of colitis. However, IL-18BPa did not affect the course of chronic colitis in CD45RBhighCD4+ T cell reconstituted SCID mice. Production of IFN- γ in lamina propria mononuclear cell cultures from IL-18BPa-treated SCID mice was decreased, but at the same time fewer lamina propria CD4+ T cells harvested from IL-18BPa-treated mice compared to non-treated mice were in apoptosis. We conclude that IL-18 clearly has a modulatory role in the inflammatory cascade of CD and experimental colitis by affecting IFN- γ and IL-10 production, and apoptosis. In view of the divergent effects of IL-18 neutralization in the two different murine colitis models, it is unlikely that IL-18 is at the top of this cascade. [ABSTRACT FROM AUTHOR]

Examines the tumor necrosis factor (TNF) gene-308 SBP polymorphism in several Crohn's disease (CD) patients. Production of TNF-α by colonic mucosa of CD patients; Extraction of the genomic DNA; Culture of colonic biopsies.

The CO-glycylcholate breath test (also called the bile acid breath test) was performed in a group of 42 normal young volunteers (group A), a group of 25 elderly subjects in apparently good health (group B) and a group of 22 hospitalized geriatric patients presenting with weight loss (group C). The 95 percentile value of the cumulative CO excretion at the third and the sixth hour in group A was taken as the limit for normal values for CO excretion. Using these criteria 56% of group B subjects and 50% of group C patients were considered abnormal at the third hour, whereas at the sixth hour these percentages were 56% and 54%, respectively. Repetition of the bile acid breath test after antibiotic treatment in the hospitalized group suggested that bacterial overgrowth in the small intestine was responsible for the abnormal CO breath test in the elderly persons. However, the large number of abnormal tests in healthy elderly people, not complaining of any gastro-intestinal discomfort, indicates that bacterial overgrowth may remain asymptomatic and that an abnormal test does not necessarily mean that the symptoms of a patient are to be ascribed to this finding. [ABSTRACT FROM PUBLISHER]

The article focuses on the treatment for Crohn's disease in Great Britain. Therapies of proven efficacy include systemic corticosteroids, budesonide and antibodies against tumor necrosis factor α infliximab. The mucosal inflammation of established Crohn's disease is dominated by CD4-positive T lymphocytes with a type 1 helper phenotype, characterize by the production of interferon-y and TNF-α. The process involves extravasation of leucocytes from the blood-stream into the tissues of the bowel.