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Background: Despite advancements in treatment for inflammatory bowel disease (IBD), surgery remains inevitable for patients and IBD management is costly. Introduction: Frequent postoperative monito...

Background and Aims The long-term safety and efficacy of allogeneic bone marrow-derived mesenchymal stromal cell [bmMSC] therapy in perianal Crohn’s disease [CD] fistulas is unknown. We aimed to provide a 4-year clinical evaluation of allogeneic bmMSC treatment of perianal CD fistulas. Methods A double-blind dose-finding study for local bmMSC therapy in 21 patients with refractory perianal fistulising Crohn’s disease was performed at the Leiden University Medical Center in 2012–2014. All patients treated with bmMSCs [1 x 107 bmMSCs cohort 1, n = 5; 3 × 107 bmMSCs cohort 2, n = 5; 9 × 107 bmMSCs cohort 3, n = 5] were invited for a 4-year evaluation. Clinical events were registered, fistula closure was evaluated, and anti-human leukocyte antigen [HLA] antibodies were assessed. Patients were also asked to undergo a pelvic magnetic resonance imaging [MRI] and rectoscopy. Results Thirteen out of 15 patients [87%] treated with bmMSCs were available for long-term follow-up. Two non-MSC related malignancies were observed. No serious adverse events thought to be related to bmMSC therapy were found. In cohort 2 [n = 4], all fistulas were closed 4 years after bmMSC therapy. In cohort 1 [n = 4] 63%, and in cohort 3 [n = 5] 43%, of the fistulas were closed, respectively. In none of the patients anti-HLA antibodies could be detected 24 weeks and 4 years after therapy. Pelvic MRI showed significantly smaller fistula tracts after 4 years. Conclusions Allogeneic bmMSC therapy for CD-associated perianal fistulas is also in the long-term a safe therapy. In bmMSC-treated patients, fistulas with closure at Week 24 were still closed after 4 years.

Background: Rising healthcare expenditures have been partially attributed to suboptimal management of inflammatory bowel diseases (IBD). Electronic health interventions may help improve care management for IBD patients, but there is a need to better understand patient perspectives on these emerging technologies. Aims: The primary aim was to evaluate patient satisfaction and experience with the UCLA eIBD mobile application, an integrative care management platform with disease activity monitoring tools and educational modules. The secondary objective was to capture patient feedback on how to improve the mobile application. Methods: We surveyed IBD patients treated at the UCLA Center for Inflammatory Bowel Diseases. The patient experience survey assessed the patients’ overall satisfaction with the application, perception of health outcomes after participation in the program, and feedback on educational modules as well as areas for application improvement. Results: 50 patients were included. The responses indicated that the patients were greatly satisfied with the ease of patient–provider communication within the application and appointment scheduling features (68%). A majority of respondents (54%) also reported that program participation resulted in improved perception of disease control and quality of life. Lastly, a majority of participants (79%) would recommend this application to others. Conclusions: Mobile tools such as UCLA eIBD have promising implications for integration into patients’ daily lives. This patient satisfaction study suggests the feasibility of using this mobile application by patients and providers. We further showed that UCLA eIBD and its holistic approach led to improved patient experience and satisfaction, which can provide useful recommendations for future electronic health solutions.

Background Caregiver burden is the emotional, physical, practical, and/or financial burden associated with taking care of a patient with a chronic condition. Limited literature on caregiver burden in Inflammatory Bowel Diseases (IBD) has accounted for some predictors, but its effect on work productivity (absenteeism and presenteeism) is unknown. Methods In a prospective study, patients and their respective caregivers were surveyed from November 2015 until July 2017. Data on demographics, work productivity, quality of life, disease activity, caregiver burden and productivity were collected. The burden on caregivers was assessed and associations between caregiver productivity and caregiver burden were analyzed. Additionally, predictors for caregiver burden were identified. Results One hundred two IBD patients and their respective caregiver were included. In total, 39% of IBD caregivers experienced burden. Caregivers with burden experienced significantly more absenteeism and presenteeism (65 and 85% respectively). Furthermore, 51% of caregivers felt that they should be doing more for their care recipient and felt they could do a better job at caregiving. Predictors of burden included race/ethnicity, history of fistulas, diagnosis of ulcerative colitis, higher caregiver education, and hours spent caregiving. Conclusion Caregivers with burden had significantly more productivity decrease compared to those without burden. Additionally, the majority of caregivers feel they should be providing more and better care for their recipients. The development of strategies to address caregiver’s distress and perceived burden when caring for IBD patients is warranted.

Background The emergence of chatbots in health care is fast approaching. Data on the feasibility of chatbots for chronic disease management are scarce. Objective This study aimed to explore the feasibility of utilizing natural language processing (NLP) for the categorization of electronic dialog data of patients with inflammatory bowel diseases (IBD) for use in the development of a chatbot. Methods Electronic dialog data collected between 2013 and 2018 from a care management platform (UCLA eIBD) at a tertiary referral center for IBD at the University of California, Los Angeles, were used. Part of the data was manually reviewed, and an algorithm for categorization was created. The algorithm categorized all relevant dialogs into a set number of categories using NLP. In addition, 3 independent physicians evaluated the appropriateness of the categorization. Results A total of 16,453 lines of dialog were collected and analyzed. We categorized 8324 messages from 424 patients into seven categories. As there was an overlap in these categories, their frequencies were measured independently as symptoms (2033/6193, 32.83%), medications (2397/6193, 38.70%), appointments (1518/6193, 24.51%), laboratory investigations (2106/6193, 34.01%), finance or insurance (447/6193, 7.22%), communications (2161/6193, 34.89%), procedures (617/6193, 9.96%), and miscellaneous (624/6193, 10.08%). Furthermore, in 95.0% (285/300) of cases, there were minor or no differences in categorization between the algorithm and the three independent physicians. Conclusions With increased adaptation of electronic health technologies, chatbots could have great potential in interacting with patients, collecting data, and increasing efficiency. Our categorization showcases the feasibility of using NLP in large amounts of electronic dialog for the development of a chatbot algorithm. Chatbots could allow for the monitoring of patients beyond consultations and potentially empower and educate patients and improve clinical outcomes.

OBJECTIVE Biomarkers that are associated with future progression to rheumatoid arthritis (RA) and joint destruction have been discovered previously in patients with arthralgia. The present study examined these RA biomarkers in inflammatory bowel disease (IBD) patients with arthropathies. PATIENTS AND METHODS Sera from 155 IBD patients with and 99 IBD patients without arthropathies were analyzed for immunoglobulin (Ig) M rheumatoid factor (RF), IgA-RF, anti-cyclic citrullinated peptide 2, anti-cyclic citrullinated peptide 3.1, and anti-carbamylated protein antibody positivity using enzyme-linked immunosorbent assays. The prevalence of the autoantibodies in the IBD patients was compared with the prevalence in RA patients. RESULTS No differences were found in biomarker positivity between IBD patients with and without arthropathies. Significantly more biomarker positivity (P

NK cells, which contribute to immune defense against certain viral infections and neoplasia, are emerging as modifiers of chronic immunologic diseases including transplant rejection and autoimmune diseases. Immunobiology and genetic studies have implicated NK cells as a modifier of Crohn’s disease, a condition often treated with thiopurine agents such as 6-mercaptopurine (6-MP). Here, we demonstrate that thiopurines mediate NK cell apoptosis via a caspase 3 and 9 inclusive pathway, and that this process is triggered by thiopurine-mediated inhibition of Rac1. We also show that CD patients in clinical remission maintained on 6-MP have decreased NK cell Rac1 activity, and decreased NK cell numbers in their intestinal biopsies. These observations suggest that thiopurine targeting of NK cells may be a previously unappreciated therapeutic action of these agents in IBD.

Background and Aims: The ENCORE registry aimed at comparing the long-term safety of Crohn’s disease [CD] treatment with infliximab [Remicade®] and with conventional therapies in real-world clinical practice. Methods: The 5-year, prospective, observational ENCORE registry followed patients with CD in nine European countries, who received treatment with infliximab, conventional therapies, or switched to infliximab from conventional therapy. Adverse events [AEs] in pre-specified categories and serious AEs were recorded at least every 6 months of the 5-year observation period. Frequency of events was evaluated, and multivariable analyses using follow-up time [Cox proportion hazards model] and exposure time [Poisson regression] were used to identify risk factors for time to AEs in pre-specified categories. Results: Patients who received infliximab [ N = 1541], conventional therapies [ N = 1121], or switched to infliximab [ N = 298] were followed for medians of 60.4, 55.6, and 42.5 months, respectively. Infliximab median exposure was 18.7 and 19.3 months in the infliximab and switched-to-infliximab groups, respectively. In time-to-event Cox proportion hazards [PH] analyses adjusting for confounders, infliximab [vs conventional therapy] was associated with serious infections (hazard ratio [HR] = 1.64, 95% confidence interval [CI]: 1.17, 2.31] and haematological conditions [HR = 2.91, CI: 1.51, 5.59], and not associated with lymphoproliferative disorders/malignancy [HR = 1.44, CI: 0.86, 2.42] or death [HR = 1.22, CI: 0.63, 2.36]. Prednisone use was associated with higher mortality [HR = 3.58, CI: 1.49, 8.61]. In exposure-adjusted Poisson regression analyses, infliximab was associated with lower mortality (risk ratio [[RR] 0.39, CI: 0.17, 0.88]). Conclusions: Data from 5-year safety follow-up of patients with CD in the ENCORE registry demonstrate that infliximab [Remicade®] exposure is associated with increased risk of serious infections and haematological conditions, whereas mortality may be decreased.

Background Medication nonadherence is a challenge in chronic disease management. Tools that can both determine adherence levels and analyze patient-specific reasons for nonadherence are lacking. Methods Our tool was developed using 23 patient-reported items and its predictive performance was compared with the most widely used instrument in the literature. Results One hundred thirty-three IBD patients were included, 44 (33%) were nonadherent and 89 (67%) were adherent. Our screening question, with 87% sensitivity and 64% specificity, was followed by a 9-item survey for patients qualified as nonadherent. Conclusions Quantifying reasons for nonadherence can lead to more effective and personalized interventions for nonadherent patients.

Autotaxin (ATX) converts lysophosphatidylcholine and sphingosyl‐phosphorylcholine into lysophosphatidic acid and sphingosine 1‐phosphate, respectively. Despite the pivotal function of ATX in lipid metabolism, mechanisms by which ATX regulates immune and inflammatory disorders remain elusive. Here, using myeloid cell lineage‐restricted Atx knockout mice, we show that Atx deficiency disrupts membrane microdomains and lipid rafts, resulting in the inhibition of Toll‐like receptor 4 (TLR4) complex formation and the suppression of adaptor recruitment, thereby inhibiting TLR4‐mediated responses in macrophages. Accordingly, TLR4‐induced innate immune functions, including phagocytosis and iNOS expression, are attenuated in Atx‐deficient macrophages. Consequently, Atx(−/−) mice exhibit a higher bacterial prevalence in the intestinal mucosa compared to controls. When combined with global Il10(−/−) mice, which show spontaneous colitis due to the translocation of luminal commensal microbes into the mucosa, myeloid cell lineage‐restricted Atx knockout accelerates colitis development compared to control littermates. Collectively, our data reveal that Atx deficiency compromises innate immune responses, thereby promoting microbe‐associated gut inflammation.

Objectives The objective of this study was to use natural language processing (NLP) as a supplement to International Classification of Diseases, Ninth Revision (ICD-9) and laboratory values in an automated algorithm to better define and risk-stratify patients with cirrhosis. Background Identification of patients with cirrhosis by manual data collection is time-intensive and laborious, whereas using ICD-9 codes can be inaccurate. NLP, a novel computerized approach to analyzing electronic free text, has been used to automatically identify patient cohorts with gastrointestinal pathologies such as inflammatory bowel disease. This methodology has not yet been used in cirrhosis. Study design This retrospective cohort study was conducted at the University of California, Los Angeles Health, an academic medical center. A total of 5343 University of California, Los Angeles primary care patients with ICD-9 codes for chronic liver disease were identified during March 2013 to January 2015. An algorithm incorporating NLP of radiology reports, ICD-9 codes, and laboratory data determined whether these patients had cirrhosis. Of the 5343 patients, 168 patient charts were manually reviewed at random as a gold standard comparison. Positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity of the algorithm and each of its steps were calculated. Results The algorithm's PPV, NPV, sensitivity, and specificity were 91.78%, 96.84%, 95.71%, and 93.88%, respectively. The NLP portion was the most important component of the algorithm with PPV, NPV, sensitivity, and specificity of 98.44%, 93.27%, 90.00%, and 98.98%, respectively. Conclusions NLP is a powerful tool that can be combined with administrative and laboratory data to identify patients with cirrhosis within a population.

Inflammatory bowel disease (IBD) is a chronic, often relapsing, condition that deeply impacts the quality of life for many patients. Although there have been significant advances in medical treatments, a large proportion of patients become refractory to available therapeutic options. Stem-cell therapy through hematopoietic stem cells (HSCs) or mesenchymal stem (stromal) cells (MSCs) is a promising therapeutic option for severe refractory cases especially when surgery is not feasible. In HSC transplantation, the objective is to destroy the ‘autoreactive’ immune cells responsible for disease chronicity, and to re-establish gut tolerance to gut microbes. In perianal Crohn’s disease (CD), the objective is to deposit MSCs locally in fistulizing tracts to down-regulate the local immune response and induce wound healing. Results from upcoming and ongoing clinical trials will set the path of these novel therapeutic options that have the capability to successfully treat severe refractory Crohn’s patients.

Background Alongside a clinical and research setting, whole body magnetic resonance imaging (WB-MRI) is increasingly offered as a direct-to-consumer screening service. Data is needed on the clinical relevance of findings and associated psychological impact of such screening. Therefore, we conducted a prospective follow-up study to provide insight in the effectiveness and psychological impact of direct-to-consumer screening using both WB-MRI and cardiological examination. Methods and findings The study population consisted of 3603 voluntary, primarily middle-aged participants who underwent commercial WB-MRI and cardiological screening at one of 6 study clinics in Germany or the Netherlands between July 2014 and March 2016. MRI investigation consisted of directed scans of the brain, neck, abdomen and pelvis. Cardiovascular examination included pulmonary function, resting electrocardiogram, transthoracic echocardiogram and a bicycle exercise stress test. Findings were assessed by experienced radiologists and cardiologists. In addition, participants were inquired about several (psychological) domains, including the expectations and consequences of the screening procedure. Out of 3603 individuals, 402 (11.2%) demonstrated abnormal MRI (n = 381) and/or cardiological findings (n = 79) for which they were advised to undergo further consultation Conclusions Direct-to-consumer screening using whole-body MRI and cardiological testing is feasible and effective for the detection of clinically relevant and treatable abnormalities. Psychological harm was not frequently reported in study participants.

Long non-coding RNAs (LncRNAs) through interactions with other cellular macromolecules drive cell processes contributing to important cancer phenotypes. Here we show that HOTAIR, a highly up-regulated lncRNA in human colon cancers, induces transformation of human non-transformed colon epithelial cells. An exon 6 HOTAIR region directly binds the histone acetyltransferase PCAF (KAT2B). The HOTAIR/PCAF complex regulates H3K27 acetylation and transcriptional activation preferentially of genes encoding components of the PI3K/AKT/MEK pathways and induces cell metabolic reprogramming. The transcriptional signature of this HOTAIR/PCAF metabolic circuit is active in colon cancer and correlates with overall patient survival. Topological and mechanistic analyses were employed to characterize the HOTAIR/PCAF interface and design a reversible specific inhibitor (CPDI-1). Selective blocking of the HOTAIR-PCAF interaction, suppresses AKT activation and tumor growth. In conclusion, we demonstrate that disruption of a lncRNA-histone modifier complex interferes with the cancer epigenome and represents a novel approach for cancer therapeutics. Citation Format: Christos Polytarchou, Maria Hatziapostolou, Marina Koutsioumpa, Niki Christodoulou, Tung On Yau, Eleni Birli, Odette Pomenya, Cristina Montiel-Duarte, Swapna Mahurkar Joshi, Daniel W. Hommes, Hein W. Verspaget, Jun Yu, Dimitrios Iliopoulos. A lncRNA-histone acetyltransferase complex induces colorectal oncogenesis through regulation of a metabolic kinase network [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-184.

Background Local administration of mesenchymal stromal cells (MSCs) into the fistula tract seems to improve patient outcome in perianal fistulas due to Crohn's disease (CD). In this paper we propose a standardized and validated protocol for the local administration of MSCs for CD perianal fistulas to be able to reliably assess efficacy. Materials and methods A working group consisting of gastroenterologists and surgeons with expertise in the treatment of perianal CD developed a consensus perianal fistula treatment protocol for local MSC treatment of perianal fistulizing CD. The treatment protocol was validated during a trial of allogeneic bone marrow-derived MSCs for the treatment of refractory perianal Crohn's fistulas. Results Localization and classification of perianal fistulas with MRI and rectoscopy is of crucial importance prior to surgical intervention with local therapy administration. Examination under anesthesia is necessary to incise and drain abscesses when present. Optimization of medical treatment when active luminal CD is present, is the first step before embarking on surgery and local therapy administration. In addition, strictures preventing the surgeon from adequately performing the surgical procedure have to be endoscopically dilated. Curettage of the fistula tract has an important role as long-standing CD perianal fistulas close poorly without removal of their epithelial lining. To diminish bacterial contamination of the fistula, the internal opening has to be closed. The origin of the fistula is the internal opening, therefore, efficacy of MSCs is presumably the highest when they are injected into the tissue around the internal opening. Conclusion In this article, we propose a standardized method of local MSC administration for perianal fistulizing CD. The use of this standardized and validated protocol for the administration of local treatment of CD perianal fistulas will allow reliable comparison of the efficacy of local therapies in future.

According to recent clinical consensus, pharmacotherapy of inflammatory bowel disease (IBD) is, or should be, personalized medicine. IBD treatment is complex, with highly different treatment classes and relatively few data on treatment strategy. Although thorough evidence-based international IBD guidelines currently exist, appropriate drug and dose choice remains challenging as many disease (disease type, location of disease, disease activity and course, extraintestinal manifestations, complications) and patient characteristics [(pharmaco-)genetic predisposition, response to previous medications, side-effect profile, necessary onset of response, convenience, concurrent therapy, adherence to (maintenance) therapy] are involved. Detailed pharmacological knowledge of the IBD drug arsenal is essential for choosing the right drug, in the right dose, in the right administration form, at the right time, for each individual patient. In this in-depth review, clinical pharmacodynamic and pharmacokinetic considerations are provided for tailoring treatment with the most common IBD drugs. Development (with consequent prospective validation) of easy-to-use treatment algorithms based on these considerations and new pharmacological data may facilitate optimal and effective IBD treatment, preferably corroborated by effectiveness and safety registries.

Quality improvement (QI) identifies practical methods to improve patient care; however, it is not always widely known which QI methods are successful. We sought to create a primer of QI in gastroenterology for the practicing clinician. We performed a systematic review of QI literature in gastroenterology. We included search terms for inflammatory bowel disease, irritable bowel syndrome, celiac disease, gastroesophageal reflux disease, pancreatitis, liver disease, colorectal cancer screening, endoscopy, and gastrointestinal bleeding. We used general search terms for QI as well as specific terms to capture established quality metrics for each GI disease area. We found 33 studies that met our definitions for QI. There were 17 studies of endoscopy including screening colonoscopy, six on liver disease, four on IBD, two on GERD, three on GI bleeding, and one on celiac disease. Education was the most common intervention, although most successful studies combined education with another intervention. Other effective interventions included retraining sessions to reach ADR goals in colonoscopy, nursing protocols to increase HCC screening, and EMR decision support tools to prompt reassessment of PPI therapy. Many studies showed improved compliance to metrics, but few were able to show differences in length of stay, readmissions, or mortality. Our review of quality improvement literature in gastroenterology revealed common themes of successful programs: Education was frequently used but often insufficient, the EMR may be underutilized in guiding decision making, and patient-reported outcomes were infrequently assessed. Further research may be needed to compare QI strategies directly.

Background and aims Long-term outcomes of early combined immunosuppression [top-down] compared to conventional management [step-up] in recently diagnosed Crohn's disease [CD] are unknown. We aimed to investigate long-term outcomes of participants of the Step-up/Top-down-trial. Methods Trial participants' medical records were reviewed retrospectively. For 16 semesters following the 2-year trial, we recorded: clinical activity, medication use, flares, hospitalization, surgery and fistulas. Colonoscopy reports were scored as: endoscopic remission, aphthous/small ulcers or large ulcers. The primary endpoint was the proportion of semesters in remission. Results Data were available from 119/133 patients [step-up n = 60]. During a median follow-up of 8 years, clinical remission rates were similar (70% vs 73% [p = 0.85] in step-up and top-down patients, respectively). A shorter time to flare was observed in step-up patients [median five vs nine semesters, p = 0.01]. Cumulatively, 62% of step-up patients used corticosteroids compared to 41% of top-down patients [p = 0.02]. Anti-tumour necrosis factor [anti-TNF] use was higher in the step-up group [73% vs 54%, p = 0.04]. No differences were found in to time to CD hospitalization [respectively 13 vs 14 semesters, p = 0.30], new fistula [14 vs 15 semesters, p = 0.20] or CD surgery [14 vs 15 semesters, p = 0.25]. Mucosal healing 2 years after treatment was associated with a reduced anti-TNF use, but not with differences in other long-term outcomes. Endoscopic remission occurred at similar rates between groups. Conclusions Top-down treatment did not result in increased clinical remission during long-term follow-up, compared to step-up treatment. However, lower relapse rates and a reduced use of anti-TNF agents and corticosteroids were observed. No difference was found in rates of endoscopic remission, hospitalization, surgery or new fistulas.

Objectives Arthropathies are a common extraintestinal manifestation (EIM) in inflammatory bowel disease (IBD). This study evaluated the differences in illness perceptions, coping strategies, and illness outcomes between patients with IBD with and without arthropathies at baseline and examined changes at 12 months in these variables in patients with arthropathies. Methods In total, 204 patients with (n=123) and without (n=81) arthropathies completed questionnaires at baseline and after 1 year, assessing illness perceptions, coping strategies, quality of life, and work and activity impairment. A linear regression analysis assessed the effect of arthropathies on these factors compared with patients without arthropathies. A mixed model analysis evaluated changes in illness perceptions, coping strategies, and outcomes in patients with arthropathies over time. Results Patients with arthropathies had more persistent thoughts on symptomatology and the variability of symptoms, held more negative views on the effects of illness, had heightened emotions that affected daily functioning, and had a poorer understanding of IBD than patients without arthropathies. Patients with arthropathies could more efficiently divert attention, felt more useful to others, and perceived a reduced physical and mental health and an increased activity impairment compared with patients without arthropathies. At follow-up, patients with arthropathies were more sceptical about the effectiveness of medical treatment but were better able to adapt their activities to their complaints compared with baseline. Conclusion Patients with arthropathies in IBD adopt different illness perceptions and coping strategies and have different outcomes compared with patients without arthropathies, which is important to know when designing behavioral and physical interventions to improve functioning.

Background: Clinical decision and patient care management in inflammatory bowel diseases is largely based on the assessment of clinical symptoms, while the biomarkers currently in use poorly reflect the actual disease activity. Therefore, the identification of novel biomarkers will serve an unmet clinical need for IBD screening and patient management. We examined the utility of circulating microRNAs for diagnosis and disease activity monitoring in ulcerative colitis (UC) patients.\ud \ud Methods: Blood serum microRNAs were isolated from UC patients with active and inactive disease and healthy donors. High-throughput microRNA profiling was performed using the Nanostring technology platform. Clinical disease activity was captured by calculating the partial Mayo score. C-reactive protein (CRP) was measured in UC patients as part of their clinical monitoring. The profiles of circulating microRNAs and CRP were correlated with clinical disease indices. \ud \ud Results: We have identified a signature of 12 circulating microRNAs that differentiate UC patients from control subjects. Moreover, six of these microRNAs significantly correlated with UC disease activity. Importantly, a set of four microRNAs (hsa-miR-4454, hsa-miR-223-3p, hsa-miR-23a-3p, and hsa-miR-320e) which correlated with UC disease activity, were found to have higher sensitivity and specificity values than CRP. \ud \ud Conclusions: Circulating microRNAs provide a novel diagnostic and prognostic marker for UC patients. The use of an FDA approved platform could accelerate the application of microRNA screening in a GI clinical setting. When used in combination with current diagnostic and disease activity assessment modalities, microRNAs could improve both IBD screening and care management.

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 x 10(7) (n = 5, group 1), 3 x 10(7) (n = 5, group 2), or 9 x 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

Haematopoietic stem cell transplantation for refractory Crohn's disease has the potential to halt therapy-resistant inflammation. Hawkey et al. argue that HSCT does not offer sustained benefit based upon their recent study; however, their study was designed using suboptimal end points and patients were not offered post-transplantation Crohn's disease medication.

Objective Inflammatory Bowel Disease (IBD) is an inflammatory disorder of the gastrointestinal tract that can necessitate hospitalization and the use of expensive biologics. Models predicting these interventions may improve patient quality of life and reduce expenditures. Materials and methods We used insurance claims from 2011 to 2013 to predict IBD-related hospitalizations and the initiation of biologics. We derived and optimized our model from a 2011 training set of 7771 members, predicting their outcomes the following year. The best-performing model was then applied to a 2012 validation set of 7450 members to predict their outcomes in 2013. Results Our models predicted both IBD-related hospitalizations and the initiation of biologics, with average positive predictive values of 17% and 11%, respectively - each a 200% improvement over chance. Further, when we used topic modeling to identify four member subpopulations, the positive predictive value of predicting hospitalization increased to 20%. Discussion We show that our hospitalization model, in concert with a mildly-effective interventional treatment plan for members identified as high-risk, may both improve patient outcomes and reduce insurance expenditures. Conclusion The success of our approach provides a roadmap for how claims data can complement traditional medical decision making with personalized, data-driven predictive medicine.

Treatment for patients with Crohn’s disease (CD) has changed substantially with the introduction of agents targeting tumor necrosis factor alpha. Therapeutic aims have evolved to include not just clinical improvement but also mucosal healing. Today, upon diagnosing CD, clinicians are able to use predictors of a complicated disease course and act accordingly when designing an individual medical strategy.

Background and objectives Value-based healthcare (VBHC) is considered to be the solution that will improve quality and decrease costs in healthcare. Many hospitals are implementing programs on the basis of this strategy, but rigorous scientific reports are still lacking. In this pilot study, we present the first-year outcomes of a VBHC program for inflammatory bowel disease (IBD) management that focuses on highly coordinated care, task differentiation of providers, and continuous home monitoring. Methods IBD patients treated within the VBHC program were identified in an administrative claims database from a commercial insurer allowing comparisons to matched controls. Only patients for whom data were available the year before and after starting the program were included. Healthcare utilization including visits, hospitalizations, laboratory and imaging tests, and medications were compared between groups. Results In total, 60 IBD patients treated at the VBHC Center were identified and were matched to 177 controls. Significantly fewer upper endoscopies were performed (-10%, P=0.012), and numerically fewer surgeries (-25%, P=0.49), hospitalizations (-28%, 0=0.71), emergency department visits (-37%, P=0.44), and imaging studies (-25 to -86%) were observed. In addition, 65% fewer patients (P=0.16) used steroids long term. IBD-related costs were 16% ($771) lower than expected (P=0.24). Conclusion These are the first results of a successfully implemented VBHC program for IBD. Encouraging trends toward fewer emergency department visits, hospitalizations, and long-term corticosteroid use were observed. These results will need to be confirmed in a larger sample with more follow-up.

Biomarkers of intestinal inflammation, such as faecal calprotectin and C-reactive protein, have been recommended for monitoring patients with Crohn's disease, but whether their use in treatment decisions improves outcomes is unknown. We aimed to compare endoscopic and clinical outcomes in patients with moderate to severe Crohn's disease who were managed with a tight control algorithm, using clinical symptoms and biomarkers, versus patients managed with a clinical management algorithm. CALM was an open-label, randomised, controlled phase 3 study, done in 22 countries at 74 hospitals and outpatient centres, which evaluated adult patients (aged 18-75 years) with active endoscopic Crohn's disease (Crohn's Disease Endoscopic Index of Severity [CDEIS] >6; sum of CDEIS subscores of >6 in one or more segments with ulcers), a Crohn's Disease Activity Index (CDAI) of 150-450 depending on dose of prednisone at baseline, and no previous use of immunomodulators or biologics. Patients were randomly assigned at a 1:1 ratio to tight control or clinical management groups, stratified by smoking status (yes or no), weight ( 2 years) after 8 weeks of prednisone induction therapy, or earlier if they had active disease. In both groups, treatment was escalated in a stepwise manner, from no treatment, to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to both weekly adalimumab and daily azathioprine. This escalation was based on meeting treatment failure criteria, which differed between groups (tight control group before and after random assignment: faecal calprotectin ≥250 μg/g, C-reactive protein ≥5mg/L, CDAI ≥150, or prednisone use in the previous week; clinical management group before random assignment: CDAI decrease of 200; clinical management group after random assignment: CDAI decrease of

Objective Neurotensin (NT) mediates colonic inflammation through its receptor neurotensin receptor 1 (NTR1). NT stimulates miR-133α expression in colonic epithelial cells. We investigated the role of miR-133α in NT-associated colonic inflammation in vitro and in vivo. Design miR-133α and aftiphilin (AFTPH) levels were measured by quantitative PCR. Antisense (as)-miR-133α was administrated intracolonicaly prior to induction of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis and dextran sodium sulfate (DSS)-induced colitis. The effect of AFTPH was examined by gene silencing in vitro. Results NT increased miR-133α levels in NCM-460 overexpressing NTR1 (NCM460-NTR1) and HCT-116 cells. NT-induced p38, ERK1/2, c-Jun, and NF-κB activation, as well as IL-6, IL-8 and IL-1β messenger RNA (mRNA) expression in NCM-460-NTR1 cells were reduced in miR-133α-silenced cells, while overexpression of miR-133α reversed these effects. MiR-133α levels were increased in TNBS (2 day) and DSS (5 day) colitis, while NTR1 deficient DSS-exposed mice had reduced miR-133α levels, compared to wild-type colitic mice. Intracolonic as-miR-133α attenuated several parameters of colitis as well expression of proinflammatory mediators in the colonic mucosa. In silico search coupled with qPCR identified AFTPH as a downstream target of miR-133α, while NT decreased AFTPH expression in NCM-460-NTR1 colonocytes. Gene silencing of AFTPH enhanced NT-induced proinflammatory responses and AFTPH levels were downregulated in experimental colitis. Levels of miR-133α were significantly upregulated, while AFTPH levels were downregulated in colonic biopsies of patients with ulcerative colitis compared to controls. Conclusions NT-associated colitis and inflammatory signalling are regulated by miR-133α-AFTPH interactions. Targeting of miR-133α or AFTPH may represent a novel therapeutic approach in inflammatory bowel disease.

Objective To assess whether a combination of adalimumab and ciprofloxacin is superior to adalimumab alone in the treatment of perianal fistulising Crohn's disease (CD).Design Randomised, double-blind, placebo controlled trial in eight Dutch hospitals. In total, 76 CD patients with active perianal fistulising disease were enrolled. After adalimumab induction therapy (160/80mg week 0, 2), patients received 40mg every other week together with ciprofloxacin 500mg or placebo twice daily for 12weeks. After 12weeks, adalimumab was continued. Follow-up was 24weeks. Primary endpoint (clinical response) was defined as 50% reduction of fistulas from baseline to week 12. Secondary endpoints included remission (closure of all fistulas), Perianal Crohn's Disease Activity Index, Crohn's Disease Activity Index (CDAI) and Inflammatory Bowel Disease Questionnaire (IBDQ).Results Clinical response was observed in 71% of patients treated with adalimumab plus ciprofloxacin and in 47% treated with adalimumab plus placebo (p=0.047). Likewise, remission rate at week 12 was significantly higher (p=0.009) in the combination group (65%) compared with adalimumab plus placebo (33%). Combination treatment was associated with a higher mean CDAI change and mean IBDQ change at week 12 (p=0.005 and p=0.009, respectively). At week 24, no difference in clinical response between the two treatment groups was observed (p=0.22). No difference in safety issues was observed.Conclusions Combination therapy of adalimumab and ciprofloxacin is more effective than adalimumab monotherapy to achieve fistula closure in CD. However, after discontinuation of antibiotic therapy, the beneficial effect of initial coadministration is not maintained.Trial registration ClinicalTrials.gov Identifier: NCT00736983.

Stem cell therapy has emerged as a promising therapeutic strategy for inflammatory bowel diseases (IBDs). Currently, stem cell therapy is not part of the standard of care and is usually only performed as a part of clinical trials. In this review, clinical results, proposed underlying mechanisms, and future research directions will be discussed.Administration of mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) has been evaluated for IBD treatment over the past years. MSC therapy is being explored as a treatment option for fistulizing Crohn's disease and for luminal Crohn's disease. It is shown to be well tolerated, but results on efficacy are inconsistent. HSC transplantation seems to be very effective, but serious adverse events are common. Therefore, future research should focus on improving efficacy of MSC therapy, and on improvement of safety of HSC therapy.Both MSC and HSC therapy offer clinical potential, but currently are not routinely used for IBD treatment. MSC therapy seems well tolerated but results on efficacy are conflicting. HSC transplantation is shown to be effective but safety concerns remain. Nonetheless, for severe refractory IBD cases, stem cell therapy could well become the next-generation treatment option.

Stem cells generate rapidly dividing transit-amplifying cells that have lost the capacity for self-renewal but cycle for a number of times until they exit the cell cycle and undergo terminal differentiation. We know very little of the type of signals that trigger the earliest steps of stem cell differentiation and mediate a stem cell to transit-amplifying cell transition. We show that in normal intestinal epithelium, endoplasmic reticulum (ER) stress and activity of the unfolded protein response (UPR) are induced at the transition from stem cell to transit-amplifying cell. Induction of ER stress causes loss of stemness in a Perk-eIF2alpha-dependent manner. Inhibition of Perk-eIF2alpha signaling results in stem cell accumulation in organoid culture of primary intestinal epithelium. Our findings show that the UPR plays an important role in the regulation of intestinal epithelial stem cell differentiation.

The glucocorticoid receptor is present in a TCR-associated complex, which includes the Src family tyrosine kinase Lck. Glucocorticoids rapidly dissociate this complex, resulting in the inhibition of canonical Lck-phospholipase C (PLC)γ–dependent TCR signaling. The relative importance of this nongenomic role for the glucocorticoid receptor compared with its direct transcriptional effects is not known. Superantigens induce a state of steroid resistance in activated T cells. It was reported that, in addition to canonical Lck-PLCγ signaling, superantigens can activate a noncanonical G protein–PLCβ–dependent signaling pathway. In this study, we show that staphylococcal enterotoxin B activates a Gαq and PLCβ2–dependent pathway in human T cells. We find that this pathway bypasses the need for canonical Lck-PLCγ signaling in T cell activation and renders superantigen-stimulated T cells insensitive to glucocorticoids in vitro. We show that the PLCβ inhibitor U-73122 sensitizes staphylococcal enterotoxin B–treated mice to dexamethasone in vivo. In conclusion, we find that effects of glucocorticoids on TCR-induced T cell proliferation are mainly nongenomic and can be bypassed by the activation of an Lck-independent signaling pathway.

Background: The repertoire of immunomodulators that can be used for the treatment of inflammatory bowel disease is limited. The use of these drugs is further restricted by the occurrence of side effects in a proportion of patients. Miltefosine (hexadecylphosphocholine) is a lipid drug developed in the 1980s for the treatment of cancer but is nowadays best known for its application in the oral treatment of leishmaniasis. Although the exact mechanism of action of miltefosine has yet to be elucidated, the drug has previously been shown to inhibit phospholipases and protein kinase C, both key components of proproliferative signal transduction in T cells. Methods: Stimulated peripheral blood lymphocyte were treated with miltefosine, and proliferation was measured. We use the CD45RBhighT-cell transfer colitis model to investigate the effect of miltefosine treatment on intestinal inflammation. Effects on the severity of colitis were studied by histochemical and immunohistochemical staining, and cytokine levels were determined using a cytokine bead array. Results: Miltefosine inhibited T-cell proliferation in vitro. In the transfer model, miltefosine significantly ameliorated the severity of colitis as measured by clinical, (immuno)histochemical, and biochemical parameters. Conclusions: Miltefosine inhibits T-cell proliferation and effectively reduces inflammation in the T-cell transfer model. The drug may therefore be a candidate immunomodulator for inflammatory bowel disease. Copyright

Monitoring levels of biologicals against tumor necrosis factor (TNF) has been suggested to improve therapeutic outcomes in inflammatory bowel diseases (IBDs). This pilot study describes a rapid lateral flow (LF)-based assay for on-site monitoring of serum trough levels of humanized monoclonal antibody infliximab (IFX). The applied chromatographic method utilizes sequential flows of diluted serum, wash buffer, and an immunoglobulin generic label on LF strips with a Test line comprised of TNF-α. The successive flows permitted enrichment of IFX at the Test line before the label was applied. The label, luminescent upconverting phosphor (UCP) particles coated with protein-A, emits a 550-nm visible light upon excitation with 980-nm infrared light. IFX concentrations were determined through measurement of UCP fluorescence at the Test line. The assay was optimized to detect IFX levels as low as 0.17 μg/mL in serum. For patients with IBD, this limit is appropriate to detect levels associated with loss of response (0.5 μg IFX/mL). The assay was evaluated with clinical samples from patients with Crohn’s disease and correlated well within the physiologically relevant range from 0.17 to 10 μg/mL with an IFX-specific ELISA. Performance of the assay was further successfully validated with samples from blood donors, IFX negative IBD patients, and rheumatoid arthritis patients that had developed anti-IFX antibodies. Because of its generic nature, the assay is suited for detecting most therapeutic anti-TNF-α monoclonal antibodies.

Mobile health technologies are advancing rapidly as smartphone use increases. Patients with inflammatory bowel disease (IBD) might be managed remotely through smartphone applications, but no tools are yet available. We tested the ability of an IBD monitoring tool, which can be used with mobile technologies, to assess disease activity in patients with Crohn's disease (CD) or ulcerative colitis (UC). We performed a prospective observational study to develop and validate a mobile health index for CD and UC, which monitors IBD disease activity using patient-reported outcomes. We collected data from disease-specific questionnaires completed by 110 patients with CD and 109 with UC who visited the University of California, Los Angeles, Center for IBD from May 2013 through January 2014. Patient-reported outcomes were compared with clinical disease activity index scores to identify factors associated with disease activity. Index scores were validated in 301 patients with CD and 265 with UC who visited 3 tertiary IBD referral centers (in California or Europe) from April 2014 through March 2015. We assessed activity of CD based on liquid stool frequency, abdominal pain, patient well-being, and patient-assessed disease control, and activity of UC based on stool frequency, abdominal pain, rectal bleeding, and patient-assessed disease control. The indices identified clinical disease activity with area under the receiver operating characteristic curve values of 0.90 in patients with CD and 0.91 in patients with UC. They identified endoscopic activity with area under the receiver operating characteristic values of 0.63 in patients with CD and 0.82 in patients with UC. Both scoring systems responded to changes in disease activity (P < .003). The intraclass correlation coefficient for test-retest reliability was 0.94 for CD and for UC. We developed and validated a scoring system to monitor disease activity in patients with CD and UC that can be used with mobile technologies. The indices identified clinical disease activity with area under the receiver operating characteristic curve values of 0.9 or higher in patients with CD or UC, and endoscopic activity in patients with UC but not CD

Background Current clinical indices, such as Harvey-Bradshaw index, are often inadequate for the assessment of disease activity in Crohn's disease (CD). Alternative methods including imaging modalities and laboratory markers, such as C-reactive protein (CRP), are routinely applied to assess disease activity. However, laboratory markers poorly reflect the actual disease activity. Consequently, novel biomarkers represent a clinical necessity for CD patient management. We hypothesized that circulating serum-derived microRNAs may be used as diagnosis and disease activity monitoring tools of CD patients. Methods To test this hypothesis, we performed microRNA expression profiling through Nanostring nCounter technology in blood serum samples of CD patients and healthy control subjects. Harvey-Bradshaw index score was used to capture clinical disease activity; CRP was measured as part of standard clinical practice. The expression profile of circulating microRNAs and the levels of CRP correlated with Harvey-Bradshaw index. Results We identified a signature of 10 circulating microRNAs that are differentially expressed in CD patients compared with healthy control subjects. Two of these microRNAs (hsa-miR-1286 and hsa-miR-1273d) correlated with CD disease activity and exhibited higher correlation values compared with CRP. Further analysis revealed distinct microRNA signatures between CD patients with ileal and colonic involvement. Conclusions Circulating microRNAs show superior value as diagnostic and disease activity markers in comparison to traditional methods. Circulating microRNAs could improve CD patient management, if applied in combination with current state-of-the-art diagnostic and disease activity assessment modalities.

Value-based healthcare is an upcoming field. The core idea is to evaluate care based on achieved outcomes divided by the costs. Unfortunately, the optimal way to evaluate outcomes is ill-defined. In this study, we aim to develop a single, preference based, outcome metric, which can be used to quantify overall health value in inflammatory bowel disease (IBD). IBD patients filled out a choice-based conjoint (CBC) questionnaire in which patients chose preferable outcome scenarios with different levels of disease control (DC), quality of life (QoL), and productivity (Pr). A CBC analysis was performed to estimate the relative value of DC, QoL, and Pr. A patient-centered composite score was developed which was weighted based on the stated preferences. We included 210 IBD patients. Large differences in stated preferences were observed. Increases from low to intermediate outcome levels were valued more than increases from intermediate to high outcome levels. Overall, QoL was more important to patients than DC or Pr. Individual outcome scores were calculated based on the stated preferences. This score was significantly different from a score not weighted based on patient preferences in patients with active disease. We showed the feasibility of creating a single outcome metric in IBD which incorporates patients’ values using a CBC. Because this metric changes significantly when weighted according to patients’ values, we propose that success in healthcare should be measured accordingly.

In recent years, mesenchymal stromal cells [MSCs] emerged as a promising therapeutic option for various diseases, due to their immunomodulatory properties. We previously observed that intraperitoneally injected MSCs in experimental colitis form spherical shaped aggregates. Therefore, we aggregated MSCs in vitro into spheroids and injected them intraluminally in mice with established colitis, to investigate whether these MSC spheroids could alleviate the colitis.We injected 0.5 x 10(6) MSCs in spheroids, 2.0 x 10(6) MSCs in spheroids, or phosphate-buffered saline [PBS] as a treatment control, via an enema in mice with established dextran sulphate sodium [DSS]-induced colitis. Body weight was measured daily and disease activity score was determined at sacrifice. Endoscopy was performed to evaluate mucosal healing. After sacrifice, both systemic and local inflammatory responses were evaluated.Intraluminally injected MSC spheroids alleviated DSS-induced colitis, resulting in significantly less body weight loss and lower disease activity score at sacrifice when a high dose of MSC spheroids was administered. However, the percentage of mucosal lesions in the distal colon and endoscopy scores were not significantly lower after treatment with 2.0 x 10(6) MSCs in spheroids compared with PBS-treated mice. Systemic inflammation marker serum amyloid A [SAA] was significantly reduced after treatment with 2.0 x 10(6) MSCs in spheroids. In addition, local cytokine levels of IFN-ɣ, TNF-α, IL-6, and IL-17a, as well as numbers of macrophages and neutrophils, showed a clear decrease-though not always significant-after intraluminal injection of the MSC spheroids.Intraluminally injected MSC spheroids at least partially attenuate experimental colitis, with fewer phagocytes and proinflammmatory cytokines, when a high dose of MSCs in spheroids was administered.

Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohn's disease (IPNIC) group. This instrument, called the Crohn's Disease Digestive Damage Score (the Lemann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be "diagnostic modality driven": for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lemann score is expected to be able to portray a patient's disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage. RI Loftus, Edward/E-8304-2011; Schreiber, Stefan/B-6748-2008

Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology. Currently approved therapies include prednisone, TNF antagonists and anti-metabolites which often are ineffective and have frequent adverse effects. Consequently, UC patients are always at risk for developing serious complications that affect their quality of life. Therefore, new treatment options are required.This article discusses etrolizumab, its mechanism and the potential role it can have in the future of treating UC. Etrolizumab is a humanized monoclonal antibody that selectively blocks lymphocyte trafficking and retention in the gut. The safety and efficacy data was reviewed from all randomized placebo-controlled trials which evaluated etrolizumab for the treatment of UC.Etrolizumab is an effective and well-tolerated drug for the treatment of UC. It appears to be a promising molecule that can benefit UC patients.

AIM: To explore the anti-inflammatory potential of adeno-associated virus-mediated delivery of Tregitope 167 in an experimental colitis model. METHODS: The trinitrobenzene sulfonate (TNBS) model of induced colitis was used in Balb/c mice. Subsequently after intravenous adeno-associated virus-mediated regulatory T-cell epitopes (Tregitope) delivery, acute colitis was initiated by intra-rectal administration of 1.5 mg TNBS in 40% ethanol followed by a second treatment with TNBS (0.75 mg in 20% ethanol) 8 d later. Control groups included mice not treated with TNBS (healthy control group) and mice treated by TNBS only (diseased group). At the time of sacrifice colon weight, the disease activity index and histology damage score were determined. Immunohistochemical staining of the colonic tissues was performed to asses the cellular infiltrate and the presence of transcription factor forkhead Box-P3 (Foxp3). Thymus, mesenteric lymph nodes, liver and spleen tissue were collected and the corresponding lymphocyte populations were further assessed by flow cytometry analysis for the expression of CD4+ T cell and regulatory T cell associated markers. RESULTS: The Tregitope 167 treated mice gained an average of 4% over their initial body weight at the time of sacrifice. In contrast, the mice treated with TNBS alone (no Tregitope) developed colitis, and lost 4% of their initial body weight at the time of sacrifice (P

Background 5-aminosalicylic acid (5-ASA) may protect against the development of inflammation-associated colorectal cancer. In vitro data suggest that, in colorectal cancer cells, 5-ASA induces cell cycle arrest, but the molecular mechanism leading to this arrest remains to be determined. Aim To dissect the signal transduction events that lead to 5-ASA mediated inhibition of proliferation of colorectal cancer cells, focusing on mammalian target of rapamycin (mTOR), a regulator of cell cycle progression. Methods The influence of 5-ASA on mTOR signalling was examined in a panel of colorectal cancer cell lines. The effects of 5-ASA on the pathways that control mTOR activity were studied in detail in two different colorectal cancer cell lines, using western blot, siRNA, a phospholipase D (PLD) activity assay, proliferation assays and cell cycle analysis. The phosphorylation status of mTOR and its downstream target, ribosomal protein S6, was studied in colorectal cancers before and after topical 5-ASA treatment. Results Treatment of colorectal cancer with 5-ASA inhibited mTOR signalling in vitro and in vivo. 5-ASA had no effect on any of the pathways that regulate the activity of the tuberous sclerosis complex in colorectal cancer cells. Both proliferation and mTOR activity depended on PLD, an enzyme that generates phosphatidic acid (PA). 5-ASA treatment inhibited PLD activity and proliferation; these effects could be rescued with exogenous PA. Conclusion 5-ASA interferes with proliferation of colorectal cancer cells via inhibition of PLD-dependent generation of PA and loss of mTOR signalling.