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Background Faecal microbiota transplantation [FMT] shows some efficacy in treating patients with ulcerative colitis [UC], although variability has been observed among donors and treatment regimens. We investigated the effect of FMT using rationally selected donors after pretreatment with budesonide or placebo in active UC. Methods Patients ≥18 years old with mild to moderate active UC were randomly assigned to 3 weeks of budesonide [9 mg] or placebo followed by 4-weekly infusions of a donor faeces suspension. Two donors were selected based on microbiota composition, regulatory T cell induction and short-chain fatty acid production in mice. The primary endpoint was engraftment of donor microbiota after FMT. In addition, clinical efficacy was assessed. Results In total, 24 patients were enrolled. Pretreatment with budesonide did not increase donor microbiota engraftment [ p  = 0.56] nor clinical response, and engraftment was not associated with clinical response. At week 14, 10/24 [42%] patients achieved [partial] remission. Remarkably, patients treated with FMT suspensions from one donor were associated with clinical response [80% of responders, p  < 0.05] but had lower overall engraftment of donor microbiota. Furthermore, differences in the taxonomic composition of the donors and the engraftment of certain taxa were associated with clinical response. Conclusion In this small study, pretreatment with budesonide did not significantly influence engraftment or clinical response after FMT. However, clinical response appeared to be donor-dependent. Response to FMT may be related to transfer of specific strains instead of overall engraftment, demonstrating the need to characterize mechanisms of actions of strains that maximize therapeutic benefit in UC. [ABSTRACT FROM AUTHOR]

Background & aimsPersistent activation of the inflammatory response contributes to the development of inflammatory bowel diseases, which increase the risk of colorectal cancer. We aimed to identify microRNAs that regulate inflammation during the development of ulcerative colitis (UC) and progression to colitis-associated colon cancer (CAC).MethodsWe performed a quantitative polymerase chain reaction analysis to measure microRNAs in 401 colon specimens from patients with UC, Crohn's disease, irritable bowel syndrome, sporadic colorectal cancer, or CAC, as well as subjects without these disorders (controls); levels were correlated with clinical features and disease activity of patients. Colitis was induced in mice by administration of dextran sodium sulfate (DSS), and carcinogenesis was induced by addition of azoxymethane; some mice also were given an inhibitor of microRNA214 (miR214).ResultsA high-throughput functional screen of the human microRNAome found that miR214 regulated the activity of nuclear factor-κB. Higher levels of miR214 were detected in colon tissues from patients with active UC or CAC than from patients with other disorders or controls and correlated with disease progression. Bioinformatic and genome-wide profile analyses showed that miR214 activates an inflammatory response and is amplified through a feedback loop circuit mediated by phosphatase and tensin homolog (PTEN) and PDZ and LIM domain 2 (PDLIM2). Interleukin-6 induced signal transducer and activator of transcription 3 (STAT3)-mediated transcription of miR214. A miR214 chemical inhibitor blocked this circuit and reduced the severity of DSS-induced colitis in mice, as well as the number and size of tumors that formed in mice given azoxymethane and DSS. In fresh colonic biopsy specimens from patients with active UC, the miR214 inhibitor reduced inflammation by increasing levels of PDLIM2 and PTEN.ConclusionsInterleukin-6 up-regulates STAT3-mediated transcription of miR214 in colon tissues, which reduces levels of PDLIM2 and PTEN, increases phosphorylation of AKT, and activates nuclear factor-κB. The activity of this circuit correlates with disease activity in patients with UC and progression to colorectal cancer.

The ability of mesenchymal stromal cells (MSCs) to suppress immune responses combined with their potential to actively participate in tissue repair provides a strong rationale for the use of MSCs as a new treatment option in diseases characterized by inflammation and severe tissue damage, such as Crohn's disease (CD) and perianal fistulas. Multiple studies have shown that MSCs suppress a range of immune cells, such as dendritic cells (DC), naïve and effector T cells, and natural killer (NK) cells. Recently published papers attribute the immunosuppressive capacity of MSCs to soluble factors produced by MSCs, such as prostaglandin E2 (PGE(2)), inducible nitric oxide synthase (iNOS), and indoleamine 2,3-dioxygenase (IDO). Promising results are obtained from phase I and II clinical trials with autologous and allogeneic MSCs as treatment for refractory CD and perianal fistulas; however the question remains: what are the molecular mechanisms underlying the immunomodulating properties of MSCs? This paper highlights the present knowledge on the immunosuppressive effects of MSCs and its complexity in relation to CD and perianal fistulas.

Supplemental Digital Content is available in the text Objective: To assess time trends in intestinal resection and re-resection in Crohn's disease (CD) patients. Summary of Background Data: CD treatment has changed considerably over the past decades. The effect of these advances on the necessity of intestinal resections and the risk of re-resection is unclear. Methods: In this nationwide cohort study, adult CD patients with ileocolonic, small bowel, colon, or rectum resections between 1991 and 2015 were included. Data were retrieved from the Dutch nationwide network and registry of histopathology and cytopathology (PALGA). Time trends were analyzed with a broken stick model and Cox proportional hazard model with smoothing splines. Results: The identified cohort comprised 8172 CD patients (3293/4879 male/female) in whom 10,315 intestinal resections were performed. The annual intestinal resection rate decreased nonlinearly from 22.7/100,000 CD patients (1991) to 2.5/100,000 (2015). A significantly steeper decrease was observed before 1999 (slope −1.56) as compared to subsequent years (slope −0.41) (P < 0.001). Analogous trends were observed for ileocolonic, small bowel, and colon resections. Overall cumulative risk of re-resection was 10.9% at 5 years, 18.6% at 10 years, and 28.3% at 20 years after intestinal resection. The hazard for intestinal re-resection showed a nonlinear decreasing trend, with hazard ratio 0.39 (95% confidence interval 0.36–0.44) in 2000 and hazard ratio 0.25 (95% confidence interval 0.18–0.34) in 2015 as compared to 1991. Conclusion: Over the past 25 years, intestinal resection rate has decreased significantly for ileocolonic, small bowel, and colonic CD. In addition, current postoperative CD patients are at 75% lower risk of intestinal re-resection. [ABSTRACT FROM AUTHOR]

This article reports on the sixth scientific workshop of the European Crohn's and Colitis Organisation [ECCO] on the pathogenesis of extraintestinal manifestations [EIMs] in inflammatory bowel disease [IBD]. This paper has been drafted by 15 ECCO members and 6 external experts [in rheumatology, dermatology, ophthalmology, and immunology] from 10 European countries and the USA. Within the workshop, contributors formed subgroups to address specific areas. Following a comprehensive literature search, the supporting text was finalized under the leadership of the heads of the working groups before being integrated by the group consensus leaders. [ABSTRACT FROM AUTHOR]

Background and Aim: Little is known about the risk of serious infection when combining antitumour necrosis factor [TNF] therapy for refractory inflammatory bowel disease [IBD] with immunosuppression after liver transplantation [LT]. Our aim was to investigate the infection risk in this patient group by systematic review and meta-analysis of the available data. Methods: A search was conducted for full papers and conference proceedings through September 2015, regarding liver transplant recipients and anti-TNF therapy. All studies were appraised using the adapted Newcastle-Ottawa Scale [NOS]. Two reviewers independently extracted patient data [age, duration of follow-up, number of all infections, number of serious infections, time since transplant]. As an additional control population, primary sclerosing cholangitis [PSC]-IBD patients from the Leiden University Medical Center [LUMC] LT cohort were used. Poisson regression was used to compare serious infections (according to International Conference on Harmonisation [ICH] definition) per patien-year follow-up between the anti-TNF and control groups. Results: In all 465 articles and abstracts were identified, of which eight were included. These contained 53 post-LT patients on anti-TNF therapy and 23 post-LT patients not exposed to anti- TNF therapy. From the LUMC LT-cohort, 41 PSC patients with PSC-IBD not exposed to anti-TNF therapy were included as control population. The infection rate for TNF-exposed patients was 0.168 serious infections per patient year, compared with 0.149 in the control patients (rate ratio 1.12 [95% confidence interval: 0.233-5.404, P = 0.886]. When correcting for time since transplant, the infection rate was 0.194 in the TNF-exposed vs 0.115 in the non-exposed [p = 0.219]. Conclusions: No significant increase in the rate of serious infection was observed in LT recipients with PSC-IBD during exposure to anti-TNF therapy. [ABSTRACT FROM AUTHOR]

Background and Aims: Non-adherence to anti-tumour necrosis factor [TNF] agents in patients with inflammatory bowel disease [IBD] is a serious problem. In this study, we assessed risk factors for non-adherence and examined the association between adherence to anti-TNF agents and loss of response [LOR]. Methods: In this multicentre, 12-month observational study, outpatients with IBD were included. Demographic and clinical characteristics were recorded. Adherence was measured with the Modified Morisky Adherence Scale-8 [MMAS-8] and 12-month pharmacy refills [medication possession ratio, MPR]. Risk factors included demographic and clinical characteristics, medication beliefs, and illness perceptions. Cox regression analysis was performed to determine the association between MPR and LOR to anti-TNF, IBD-related surgery or hospitalisation, dose intensification, or discontinuation of anti-TNF. Results: In total, 128 patients were included [67 infliximab, 61 adalimumab], mean age 37 (± standard deviation [SD] 14) years, 71 [56%] female. Median disease duration was 8 (interquartile range [IQR] 4-14) years. Clinical disease activity was present in 41/128 [32%] patients, 36/127 [28%] patients had an MMAS-8 < 6 ['low adherence'], and 25/99 [25%] patients had an MPR < 80% [nonadherence]. Risk factors for non-adherence included adalimumab use (odds ratio [OR] 10.1, 95% confidence interval [CI] 2.62-40.00), stronger emotional response [OR 1.16, 95% CI 1.02-1.31], and shorter timeline perception, i.e. short perceived illness duration [OR 0.60, 95% CI 0.38-0.96]. Adherence is linearly and negatively [OR 0.14, 95% CI 0.03-0.63] associated with LOR. Conclusion: Non-adherence to anti-TNF agents is strongly associated with LOR to anti-TNF agents, adalimumab use, and illness perceptions. The latter may provide an important target for interventions aimed at improving adherence and health outcomes. [ABSTRACT FROM AUTHOR]

Background and Aims: Peripheral joint complaints [pJTC] and chronic back pain [CBP] are the most common extra-intestinal manifestations in patients with inflammatory bowel disease [IBD]. This prospective study evaluates variables associated with joint/back pain, including IBD disease activity. Methods: IBD patients with back pain ≥ 3 months and/or peripheral joint pain/swelling [n = 155], and IBD patients without joint complaints [n = 100; controls], were followed for a period of 1 year. Patients were classified as having SpondyloArthritis [SpA] according to several sets of criteria. Statistical analysis included logistic regression models and linear mixed model analysis. Results: Of the 155 patients with joint/back pain, 13 had chronic back pain, 80 peripheral joint complaints, and 62 axial and peripheral joint complaints. Smoking, female gender, and IBD disease activity were independently associated with IBD joint/back pain. The Assessment in Spondyloarthritis International Society criteria for axial and peripheral SpA were fulfilled in 12.3% of patients, with 9.7% [n = 15] receiving a rheumatological diagnosis of arthritis. During the 12-month follow-up, the majority of the patients reporting joint/back pain remained stable. Conclusions: In our cohort, the majority of IBD patients reported joint/back pain and SpA was relatively common. To facilitate effective care, gastroenterologists should be aware of the various features of SpA to classify joint complaints and, by making use of an efficient referral algorithm, to refer CBP patients to the rheumatologist. [ABSTRACT FROM AUTHOR]

Background and Aims: Conventional thiopurine [azathioprine and mercaptopurine] treatment during pregnancy in patients with inflammatory bowel disease [IBD] is considered to be safe; however data on the safety and teratogenicity of the non-conventional thiopurine tioguanine [TG] in pregnant IBD patients are lacking. We aim to describe the safety and teratogenicity of TG treatment during pregnancy in IBD patients. Methods: This was a retrospective, multicentre descriptive case series of female IBD patients using TG during pregnancy. Data on disease and medication history, pregnancy complications, pregnancy outcome, mode of delivery, preterm birth, birthweight, congenital abnormalities, laboratory signs of myelosuppression or hepatotoxicity, and 6-thioguaninenucleotide [6-TGN] concentrations in mother and neonate were collected. Results: In all, 13 patients [77% Crohn's disease, 23% ulcerative colitis] used TG [median dose 18 g/day] during pregnancy; 19 pregnancies, including 1 twin pregnancy, were included. Spontaneous abortion occurred in three pregnancies. In 7 of the 16 ongoing pregnancies a caesarean section was performed. One neonate had a mild congenital abnormality [distal shaft hypospadias]. In the singleton pregnancies, the median birthweight was 3410 g at a median of gestational age of 39 weeks. No preterm birth [< 37 weeks] or low birthweight [< 2500 g] was observed in the singleton newborns. In the twin pregnancy an induction of labour was performed at 35 + 1 weeks of gestation because of pre-eclampsia. Both neonates had a low birthweight. Conclusions: This relatively small case series supports safe use of TG in pregnant IBD patients. Still, consideration should be given to the indication and continuation of TG during pregnancy. [ABSTRACT FROM AUTHOR]

Background & Aims Surveillance is recommended for patients with long-term inflammatory bowel disease because they have an increased risk of colorectal cancer (CRC). To study the effectiveness of surveillance, we determined the incidence of CRC after negative findings from surveillance colonoscopies (interval CRC). Methods We collected data from 1273 patients with ulcerative colitis or Crohn's disease, enrolled in a surveillance program at 7 hospitals in The Netherlands, who underwent 4327 surveillance colonoscopies from January 1, 2000, through January 1, 2014. Patients were followed up from their first surveillance colonoscopy until the last surveillance colonoscopy, colectomy, or CRC. Factors that might have contributed to the occurrence of CRC were categorized as inadequate procedures (ie, inadequate bowel preparation), inadequate surveillance (CRC occurring outside the appropriate surveillance interval), or inadequate management of dysplasia (CRC diagnosed in the same colonic segment as a previous diagnosis of dysplasia). The remaining CRC cases were classified as true interval CRCs. Results CRC was diagnosed in 17 patients (1.3%), with an incidence of 2.5 per 1000 years of follow-up evaluation. Factors that might account for the occurrence of CRC were identified in 12 patients (70%). These were inadequate colonoscopies in 4 patients (24%), inadequate surveillance intervals in 9 patients (53%), and inadequate management of dysplasia in 2 patients (12%). The remaining 5 cases of CRC (30%) were classified as true interval CRCs. Conclusions In a retrospective analysis of patients with inflammatory bowel disease participating in a surveillance program, the incidence of CRC was only 1%, which supports the implementation of longer surveillance intervals. However, the fact that 30% of CRC cases were interval cancers indicates the need for variable surveillance intervals based on risk factors for CRC. [ABSTRACT FROM AUTHOR]

Background and aims: Back and joint pain are the most common extraintestinal symptoms reported by patients with inflammatory bowel disease (IBD). We assessed the impact of back/joint pain, illness perceptions, and coping on quality of life (QOL) and work productivity in patients with IBD. Methods: Our cohort included 155 IBD patients with and 100 without arthropathy. Arthropathy was defined as daily back pain for ≥3 months and/or peripheral joint pain and/or joint swelling over the last year. At baseline and at 12 months, patients completed questionnaires on the extent of back/ joint pain, IBD disease activity, illness perceptions, coping, QOL, and work productivity. The impact of back/joint pain, illness perceptions and coping on QOL and work productivity was determined, using linear mixed models. Results: In total, 204 IBD patients (72% Crohn's disease, 40% male, mean age 44 ± 14 years) completed questionnaires at both time points. At both time points, IBD patients with back/joint pain reported a significantly lower QOL and work productivity compared with IBD patients without back/joint pain. Predictors of low QOL were back/joint pain (β = -1.04, 95% confidence interval [CI] -1.40, -0.68), stronger beliefs about the illness consequences (β = -0.39, 95% CI -0.59, -0.18) and emotional impact of IBD (β = -0.47, 95% CI -0.66, -0.28), and the coping strategy 'decreasing activity' (β = -0.26, 95% CI -0.48, -0.03). Predictors of work productivity were back/joint pain (β = 0.22, 95% CI 0.07, 0.37) and illness consequences (β = 0.14, 95% CI 0.06, 0.22). Conclusion: Back/joint pain, illness perceptions, and coping are significant predictors of QOL and work productivity, after controlling for disease activity. [ABSTRACT FROM AUTHOR]

Background & Aims Patients with perianal fistulizing Crohn’s disease have a poor prognosis because these lesions do not heal well. We evaluated the effects of local administration of bone marrow−derived mesenchymal stromal cells (MSCs) to these patients from healthy donors in a double-blind, placebo-controlled study. Methods Twenty-one patients with refractory perianal fistulizing Crohn’s disease were randomly assigned to groups given injections of 1 × 10 7 (n = 5, group 1), 3 × 10 7 (n = 5, group 2), or 9 × 10 7 (n = 5, group 3) MSCs, or placebo (solution with no cells, n = 6), into the wall of curettaged fistula, around the trimmed and closed internal opening. The primary outcome, fistula healing, was determined by physical examination 6, 12, and 24 weeks later; healing was defined as absence of discharge and <2 cm of fluid collection—the latter determined by magnetic resonance imaging at week 12. All procedures were performed at Leiden University Medical Center, The Netherlands, from June 2012 through July 2014. Results No adverse events were associated with local injection of any dose of MSCs. Healing at week 6 was observed in 3 patients in group 1 (60.0%), 4 patients in group 2 (80.0%), and 1 patient in group 3 (20.0%), vs 1 patient in the placebo group (16.7%) ( P = .08 for group 2 vs placebo). At week 12, healing was observed in 2 patients in group 1 (40.0%), 4 patients in group 2 (80.0%), and 1 patient in group 3 (20.0%), vs 2 patients in the placebo group (33.3%); these effects were maintained until week 24 and even increased to 4 (80.0%) in group 1. At week six, 4 of 9 individual fistulas had healed in group 1 (44.4%), 6 of 7 had healed in group 2 (85.7%), and 2 of 7 had healed in group 3 (28.6%) vs 2 of 9 (22.2%) in the placebo group ( P = .04 for group 2 vs placebo). At week twelve, 3 of 9 individual fistulas had healed in group 1 (33.3%), 6 of 7 had healed in group 2 (85.7%), 2 of 7 had healed in group 3 (28.6%), and 3 of 9 had healed in the placebo group (33.3%). These effects were stable through week 24 and even increased to 6 of 9 (66.7%) in group 1 ( P = .06 group 2 vs placebo, weeks 12 and 24). Conclusions Local administration of allogeneic MSCs was not associated with severe adverse events in patients with perianal fistulizing Crohn’s disease. Injection of 3 × 10 7 MSCs appeared to promote healing of perianal fistulas. ClinicalTrials.gov ID NCT01144962 . [ABSTRACT FROM AUTHOR]