Therapy In IBD Research Articles

P889 Facilitating equitable IBD care trust-wide: a need for treatment targets in IBD?

Abstract Background Timely biological therapy in IBD is associated with reduced disease progression, especially in CD (Berg et al 2019). However, there are no clear UK standards detailing the timescale in which IBD care should be delivered. We evaluated the time between initial consideration of therapy and first dose in a district general hospital and tertiary referral centre in Barts Health NHS Trust. Methods Details of patients receiving biologics for IBD at Newham (NUH) and Royal London Hospital (RLH) (between 2018 – 2022) were obtained from infusion clinics; electronic records were reviewed for 50 recent referrals. The following information was collected: demographics, phenotype, drug, first documentation of consideration of biologic, completion of funding application, onset of therapy. Results Demographics: NUH: Age (median(IQR)) = 43.5(30.3 – 50.56) Gender (F:M) = 26:24, CD:UC = 34:16, Biologic: infliximab:vedolizumab:ustekinumab:adalimumab: 29:5:11:5, First biologic: n=34 RLH: Age (median(IQR)) = 31.6 (24.6 – 41.1) Gender (F:M) = 27:23 CD:UC = 23:27, Biologic: infliximab:vedolizumab:ustekinumab:adalimumab: 34:12:3:1, First biologic: n=25 There was substantially longer time between initial consideration of therapy and first dose delivered at NUH 94.5 days (44 – 174) compared with RLH 35.5 days (23.75 –69) (p<0.01). However, time from completion of funding application to first dose did not differ significantly between sites (43.5 days (30.3 – 50.6) vs 31.6 (24.6 – 41.1), p=0.42). In patients receiving first biologic, there was a trend towards a longer time since diagnosis at NUH (3.2 years (1.0 – 9.1) vs 1.7 years (0.5 – 4.3), p=0.08). Conclusion Patients treated in a tertiary referral centre started biologics sooner after consideration, and earlier in disease course. This does not appear due to availability of infusion services, but due to time to complete initial investigations and finalise escalation. This may reflect differences in service set-up; in particular, NUH manages IBD care with a single IBD nurse, and fewer options for fast-track clinic follow up. A clear UK IBD standards framework identifying recommended time frames for establishing biologics is indicated, to ensure equity in care across tertiary and DGH settings.

P769 Impact of discontinuation of anti-TNF therapy: A long term follow-up data of risks and predictors relapse in a large Indian cohort

Abstract Background Discontinuation of anti-TNF therapy in IBD is an important consideration in TB endemic low resource settings of the developing world. There are no established guidelines on withdrawal of biologics. A proper exit strategy on when and how biologics can be stopped is therefore warranted. We aimed to identify risk factors and rates of relapse post withdrawal in a large real-life cohort of patients from India. Methods Prospectively collected data of consecutive patients treated with anti-TNFs from the IBD registry of a large tertiary care centre was analyzed. Demographics,baseline disease characteristics,reasons for discontinuation, response to anti-TNF,and relapse rate after withdrawal were analysed. Time to event analysis was done to evaluate relapse rates over time. Cox proportional hazard analysis and non-parametric tests were performed to identify risk factors of relapse. Results Of 8300 patients, only 725(8.7%),(Median age-36y,IQR:26-47,61.2% male,61.2%CD, 32%UC, IBD-U 1.8%) received anti-TNFs. 445 (61.3%) discontinued with median follow up of 54 m(IQR:31-81). Reasons for discontinuation were primary non-response(64,14.3%);secondary loss of response (44,9.8%);financial constraints(27,6.1%);TB reactivation (18,4%), side effects(17,3.2%); infusion reactions(20,4.4%);non-compliance(4,0.9%), and COVID lockdown (6,1.3%). Overall, 232/445 (52%) were in clinical and endoscopic remission while stopping anti-TNFs with median follow up of 41 months(IQR:24.5-67). Relapse rates at 1,2,3,4, and 5 years after discontinuation were 16%,5.6%,5.2%,2.6% and 1.3% respectively. Overall,161/232(69%) patients remained in remission(Fig1A). Patients who stopped after clinical and endoscopic remission had higher likelihood of maintaining remission after discontinuation of biologics (Log-rank test,p=0.001). On multivariate analysis, fistulizing disease(p=0.03), prior history of bowel surgery (p=0.019), immunomodulator usage (p=0.001) and shorter duration of therapy (p=0.017) were associated with significantly higher rate of relapse(Table1). Cumulative time to relapse was significantly longer in those with or without endoscopic remission (median 17.3 vs 7 months;p=0.04)(Fig1B). On the other hand, shorter disease duration (p=0.001) and absence of extra-intestinal manifestations (p=0.009) were associated with lower risks of relapse. Conclusion 60% of patients discontinued anti-TNF therapy in this real world cohort. However, long-term cumulative relapse rates were low(30%), particularly in non-fistulizing disease, with no history of bowel surgery or extra intestinal manifestations and in endoscopic remission. A definite exit strategy appears feasible and would be a practical and affordable management approach.

P385 Epithelial neutrophil localization and Claudin-2 immunohistochemical "leaky gut" expression are innovative predictors of outcomes in Ulcerative Colitis patients in endoscopic remission

Abstract Background Patients with Ulcerative Colitis (UC) in clinical and endoscopic remission (ER) may still experience disease relapse, emphasizing the need to identify reliable predictors of outcome in clinical practice. Recently, neutrophil-based histological scores have highlighted the pivotal role of neutrophils in predicting disease outcome. Furthermore, the impairment of the intestinal barrier has been proposed as a crucial element in forecasting disease outcomes. Hence, this study aims to assess the predictive role of epithelial versus lamina propria neutrophil localization and barrier proteins expression in UC patients in ER. Methods UC patients in clinical remission who underwent colonoscopy between January 2020 and June 2022 at two tertiary referral centres were retrospectively enrolled. Patients in ER, defined by Mayo Endoscopic Score (MES) ≤1 and UC Endoscopic Index of Severity (UCEIS) ≤1 were included. Histological activity was assessed with Robarts Histopathology Index (RHI), Nancy Histological Index (NHI) and PICaSSO Histological Remission Index (PHRI). Neutrophil localization in the epithelium and lamina propria was accurately evaluated. Additionally, immunohistochemical expression of epithelial barrier proteins, namely Claudin-2 and JAM-A, was assessed to evaluate the integrity of intestinal barrier. Two pathologists experienced in IBD independently analysed all histological slides to ensure reliability. Kaplan-Meier were plotted to analyse survival free from adverse events such as flare-up, change/optimization of medication or hospitalization over a 12-month follow-up period. Results Out of 60 UC patients in ER (58.3% males, mean age 44.2±13.6 years), 36.7%, 38.3% and 36.7% were in histological remission according to RHI, NHI and PHRI, respectively. 25% of patients developed an adverse outcome within 12 months. Neutrophils in the epithelium significantly correlated with adverse outcomes compared with lamina propria localization (p=0.03) or their absence altogether (p<0.01). Claudin-2 showed significantly higher expression according to endoscopic and histological activity (Table 1), while no significant difference was found for JAM-A. Notably, strong and diffuse claudin-2 expression was associated with a higher rate of adverse outcomes (p<0.01), as well as the simultaneous presence of epithelial neutrophils and Claudin-2 (p=0.04). Substantial agreement between pathologists was found (K=0.67). Conclusion This multicentre retrospective study highlights the potential role of epithelial neutrophils localization and claudin-2 ‘leaky gut’ protein expression as practical clinical tools to predict outcomes in UC patients. These findings hold promise in guiding patient-tailored therapy in IBD.

De-escalation of Biologic Treatment in Inflammatory Bowel Disease: A Comprehensive Review.

Biologic therapy is an effective treatment for inflammatory bowel disease [IBD]. However due to cost and safety concerns, dose de-escalation strategies after achieving remission have been suggested. To critically review available data on dose de-escalation of biologics [or other advanced therapies] in IBD. We will focus on studies evaluating de-escalation to standard dosing in patients initially optimised, and also on studies assessing de-escalation from standard dosing. A systematic bibliographic search was performed. The mean frequency of de-escalation after previous dose intensification [12 studies, 1,474 patients] was 34%. The corresponding frequency of de-escalation from standard dosing [five studies, 3,842 patients] was 4.2%. The relapse rate of IBD following anti-tumour necrosis factor [TNF] de-escalation to standard dosing in patients initially dose-escalated [10 studies, 301 patients] was 30%. The corresponding relapse rate following anti-TNF de-escalation from standard dosing [nine studies, 494 patients] was 38%. The risk of relapse was lower for patients in clinical, biologic, and endoscopic/radiological remission at the time of de-escalation. A role of anti-TNF therapeutic drug monitoring in the decision to dose de-escalate has been demonstrated. In patients relapsing after de-escalation, re-escalation is generally effective. De-escalation is not consistently associated with a better safety profile. The cost-effectiveness of the de-escalation strategy remains uncertain. Finally, there is not enough evidence to recommend dose de-escalation of biologics different from anti-TNFs or small molecules. Any consideration for de-escalation of biologic therapy in IBD must be tailored, taking into account the risks and consequences of a flare and patients' preferences.

Gut microbiome–based therapeutics in inflammatory bowel disease

AbstractInflammatory bowel disease (IBD), including both ulcerative colitis and Crohn's disease, is a chronic inflammatory disease of the gastrointestinal tract that is thought to arise from a combination of environmental, genetic and immunological factors. The gut microbiome, a diverse ecosystem of microorganisms residing in the digestive tract, has been proposed to play a role in the pathogenesis of IBD. There is an unmet clinical need for microbiome‐based therapies. This review will discuss the landscape of microbiome‐based therapeutics in IBD. Microbiome‐targeted therapeutics, such as antibiotics, pre‐/probiotics and faecal microbiota transplant (FMT), are based on the premise that restoring a healthy gut microbiome can attenuate mucosal inflammation. Antibiotics work directly to impede growth or eradicate specific gut microorganisms. Antibiotics may play a role in inducing clinical remission and treating refractory pouchitis and may be associated with immunogenicity to anti‐TNF biologics in IBD. Prebiotics are the molecular metabolic building blocks for commensal gut bacteria. Probiotics artificially introduce gut microorganisms thought to be beneficial to the local microenvironment and maybe be associated with symptom relief in IBD. FMT similarly introduces bacteria found in higher proportions of healthy persons, though in a more direct manner than probiotics. FMT has been associated with increased rates of clinical remission in IBD, but heterogeneity in FMT response may be influenced by IBD subtype, FMT donor selection and delivery protocols. Current evidence suggests that microbiome‐targeted therapeutics may have some benefit for IBD. Several studies are underway exploring the targeting of specific gut microbes or microbial pathways as therapy in IBD.

Current Role of Monoclonal Antibody Therapy in Pediatric IBD: A Special Focus on Therapeutic Drug Monitoring and Treat-to-Target Strategies

In the last two decades, biologicals have become essential in treating children and adolescents with inflammatory bowel disease. TNF-α inhibitors (infliximab, adalimumab and golimumab) are preferentially used. Recent studies suggest that early application of TNF-α inhibitors is beneficial to inducing disease remission and preventing complications such as development of penetrating ulcers and fistulas. However, treatment failure occurs in about one third of pediatric patients. Particularly, children and adolescents differ in drug clearance, emphasizing the importance of pharmacokinetic drug monitoring in the pediatric setting. Here, current data on the choice and effectiveness of biologicals and therapeutic drug monitoring strategies are reviewed.

A163 INFECTION WITH HYMENOLEPIS DIMINUTA ELICITS A TH2 IMMUNITY AND ALLEVIATES DNBS-COLITIS IN A MOUSE MODEL WITH MINIMAL INTESTINAL MICROBIOTA

Abstract Background Immunocompetent mice infected with the rat tapeworm Hymenolepis diminuta are protected from dinitrobenzene sulphonic-acid (DNBS)-induced colitis that was accompanied by the increased relative abundance of short-chain fatty acid (SCFA)-producing bacteria and fecal SCFA levels at 8 days post-infection (dpi). These changes were not observed in antibiotic-treated BALB/c mice or germ-free mice. To further characterize the host-parasite-microbiota interaction in the control of colitis, experiments have been conducted in a reductionist system in which the H. diminuta anti-colitic response was tested in mice colonized with 12 commensal bacteria representing the major five phyla of the mouse gut. Purpose To identify key bacterial species and microbe-derived mediators involved in the H. diminuta-induced protection from DNBS-induced colitis. Method OligoMM12 (Oligo-Mouse-Microbiota) mice (n=4-8/group) were infected with 10 viable antibiotic-treated H. diminuta cysticercoids eight days prior to challenge with DNBS (3mg, i.r.). Mice were monitored daily and necropsied 72h post-DNBS. Disease was assessed by a macroscopic disease activity score, colon length and histopathology on H&E sections of mid-colon. Production of IL-4, -5, -10 and -13 by concanavalin-A treated spleen cells by ELISA was used as an index of successful helminth infection. Result(s) OligoMM12 mice treated with DNBS developed acute colitis, with 3/8 mice requiring humane euthanization, while all mice infected with H. diminuta survived the DNBS challenge. Successful infection was confirmed by statistically significant increases in splenic output of the Th2-cytokines in response to mitogenic stimulation and efficient expulsion of the worms burden by 11 dpi. The severity of DNBS-induced colitis was reduced in H. diminuta-infected mice (n=4), although additional experiments are required to confirm the statistical significance of these data. Conclusion(s) Reproducible DNBS-induced colitis in mice with the simplified OligoMM12 consortium of bacteria and reduced disease in H. diminuta-infected mice has created a model by which the participation of exact bacterial groups or species in H. diminuta-induced suppression of colitis can be tested. This is of translational value, since the failure of helminth therapy in IBD could be predicated by dysbiosis in the patient, and therefore potentially overcome by combination therapy of ‘probiotic’ and helminth. Please acknowledge all funding agencies by checking the applicable boxes below CIHR, Other Please indicate your source of funding; NSERC-CGS D, Eyes High doctoral Recruitment Scholarship Disclosure of Interest None Declared

DOP71 TREM1, OSM and a co-expressed transcriptional module are core components of the molecular resistome to anti-cytokine therapy in Ulcerative Colitis

Abstract Background Molecular biomarkers are emerging as promising tools to predict response to advanced therapy in IBD. For instance, mucosal expression of Triggering Receptor Expressed on Myeloid cells-1 (TREM1) and oncostatin M (OSM) are associated with anti-TNF non-response in Ulcerative Colitis (UC). The specificity of such transcriptional features is poorly understood. We investigated whether mucosal expression of TREM1 and OSM influences ustekinumab response in UC. Methods UNIFI is a landmark, phase III, registration trial that evaluated the efficacy of ustekinumab as induction and maintenance therapy in patients with moderate to severe UC. In a subset of patients (n=358), colonic biopsies were sampled at baseline and gene expression profiled by RNA microarray (Affymetrix HT HG-U133+ PM). Normalised expression levels of TREM1 and OSM for responders and non-responders to induction (week 8 mucosal healing) were compared using Mann-Whitney U test on GraphPad Prism 9.2.0. Co-expressed transcripts were determined with Morpheus matrix visualisation software (Broad Institute, USA). Gene set variation analysis was used to calculate gene set enrichment scores (ES) within the expression data. Multivariable models were developed to construct receiver operating characteristic curve (ROC) analyses. Deeper biological insights of TREM1- and OSM-expressing cells were explored using single cell RNA sequencing and Gene Ontology over-representation analysis (R 4.2.2). Results Mucosal expression of TREM1 and OSM in inflamed colonic biopsies correlated highly (r = 0.81, p<0.0001) and TREM1 was the third-highest correlate with OSM across the entire genome. Pathway analysis showed that a 20-gene module (GS1) of transcripts co-expressed with TREM1 and OSM was enriched for immune cell adhesion, migration and differentiation (Fig 1). Expression of TREM1 (median: 6.27 vs 5.55, p<0.001), OSM (5.00 vs 4.72, p=0.002) and GS1 (ES: 0.00221 vs -0.496, p<0.0001) were all significantly increased in ustekinumab non-responders compared to responders (Fig 2). Although key clinical parameters correlated weakly with TREM1 and OSM expression, they improved the performance of multivariate models to predict non-response (Fig 3). TREM1 and OSM were predominantly expressed by the same population of inflammatory monocytes accumulating in inflamed colon tissue (Fig 4). Conclusion Colonic expression of TREM1 and OSM is associated with resistance to both anti-TNF therapy and ustekinumab, supporting the notion that they constitute a core molecular resistome in UC patients treated with anti-cytokine agents. Their predominant co-expression in infiltrating, inflammatory monocytes indicates that treatment resistance is likely underpinned by biological pathways regulated by this cell population.

P760 Adalimumab biosimilars versus Azathioprine: indirect comparison of efficacy, safety and persistence in treatment

Abstract Background The advent of low-cost adalimumab (ADA) biosimilars is expected to increase access to biologics. Whether ADA biosimilars influence the use of conventional immunomodulators, especially azathioprine (AZA), which should be the alternative in steroid-dependant IBD, has not been investigated and comparative data on efficacy and safety are scanty. The aim of this study is to compare ADA biosimilars and Azathioprine (AZA) in patients with IBD naive to biologics and/or immunosuppressive agents. Methods A retrospective-prospective observational study was conducted on 55 consecutive IBD-patients (30 CD, 25 UC), in follow up in our tertiary referral center, who started ADA biosimilars or AZA between 11/2018 and 11/2021. Drug choice was upon clinical judgement. Primary outcomes, clinical response and steroid-free clinical remission, were evaluated at 12 and 84 weeks, using HBI for CD and p-Mayo score for UC. Active disease was defined HBI>5 for CD e p-Mayo>2 for UC. Secondary outcomes were persistence and retention rate. Results The two treatment groups showed similar baseline characteristics regarding age, sex, familial predisposition, smoking, type of IBD and previous surgery, except the use of systemic steroids (42,85% of patients treated with ADA and 18,5% of patients with AZA; p= 0,029) and presence of active disease (60,71 % of ADA and 37,03% of AZA; p=0,082). At week 12 clinical response was obtained in 22/28 (78,6%) treated with ADA and in 22/27 (81,5%) with AZA (p=0.789), at week 84 response rate was obtained in 10/10 (100%) of ADA e 10/13 (76,9%) of AZA (p= 0,155). Clinical remission at week 12 was achieved by 19/28 (67,9%) of ADA patients and by 24/27 (88,9%) AZA (p=0,061), at week 84 by 10/10 (100%) of ADA and by 12/13 (92,3%) of AZA (p=0,380). No adverse events were registered in the ADA group, 5 AE leading to discontinuation occurred in the AZA group (0% VS 18,52% , p=0,018). The retention rate was 85,7% for ADA and 74,1% and AZA (p= 0,285). According to IBD type, treatment persistence of ADA was higher in patients with CD (Log-rank test p=0,004); in CD the persistence rate is significantly better for ADA as compared to AZA. (Log-rank test p=0,008), in UC the difference was not significant (p=0,41). Conclusion Our results suggest that ADA biosimilars are an effective therapy in steroid-dependent IBD, with a better safety profile compared to AZA, thus resulting in a higher probability of treament persistence especially in CD. The use of AZA is expected to decline in the next years.

VEDOLIZUMAB, USTEKINUMAB AND TOFACITINIB AS TRIPLE THERAPY FOR ULCERATIVE COLITIS

Abstract BACKGROUND Therapies for ulcerative colitis include mesalamine, immunomodulators, biologics, and small molecules. Unfortunately, patient response is not universal, and efficacy can diminish with time, postulated to be from increased drug clearance, anti-drug antibodies with biologics, and immune mediated pathogenesis changes. Biologic combinations have been investigated for producing synergistic drug effects and extending targeted therapy in patients lacking monotherapy response, with promise shown in two drug combinations (1), but not investigated using three. CASE A 20-year-old Caucasian male with UC presented in August 2015 following 1 month hospitalization for Clostridium difficile infection. He had 2 infusions of infliximab 10 mg/kg continued post-discharge, and started mesalamine 4.8gm qd, 6-mercaptopurpine (6MP) 100mg qd, and prednisone taper. By November 2015, colonoscopy showed severe Mayo 3 pancolitis. Due to insufficient response 6MP and infliximab were discontinued and he started vedolizumab. August 2016 colonoscopy had chronic colitis with Mayo 2 inflammation of the ascending, transverse, descending and rectosigmoid colon so prednisone 40mg was initiated and vedolizumab increased to vedolizumab q4 weeks. He responded well clinically and was tapered off prednisone by October 2016. November 2016 colonoscopy had right sided colitis resolution with residual proctosigmoiditis (Mayo 2); May 2017 colonoscopy still had rectosigmoid inflammation (Mayo 2) with chronic active colitis, so ustekinumab q8 weeks was added. December 2017 colonoscopy was unimproved so ustekinumab increased to q4 weeks, prednisone was increased, and he requested addition of budesonide and mesalamine. With clinical improvement, prednisone was tapered by February 2020. However, December 2020 colonoscopy showed severe (Mayo 3) recto-sigmoiditis with mild colitis in the descending to transverse colon, so tofacitinib XR 22 mg qd was added. He improved clinically, so budesonide was discontinued in February 2021. November 2021 colonoscopy showed complete endoscopic remission (Mayo 0) so he initiated de-escalation with initially discontinuing mesalamine and increasing ustekinumab initially to q8 week intervals and later vedolizumab to q8 weeks with maintenance of clinical remission. Given marginal effect, ustekinumab was discontinued initially and later, tofacitinib was discontinued. He remains in remission on vedolizumab q8 weeks monotherapy. CONCLUSION Combination therapies may be considered for suitable patients experiencing severe, refractory disease. Although patients with multiple comorbidities, frailty, immunosuppression or certain contraindications may not be well suited, this patient presents as an ideal candidate with no comorbidities and few other therapeutic options. REFERENCES (1) Privitera G et al. Combination therapy in IBD. Autoimmunity Reviews. 2021 Jun 1;20(6):102832.

Prognostic Factors of Biologic Therapy in Pediatric IBD.

This was a retrospective cohort study aimed at identifying parameters measured at diagnosis of pediatric IBD to predict subsequent biologic therapy, as an equivalent to an unfavorable clinical course. Identification of predictors of poor outcomes is an important issue in current ECCO guidelines on pIBD. The study population consisted of 119 children with Crohn’s disease and 112 with ulcerative colitis, diagnosed and monitored for at least 1 year from 2009–2019. The population was divided into the study groups separately: 39 children with CD and 14 with UC who received biologics before the age of 18 y compared to 80 with CD and 98 with UC who did not. The combined analysis of 53 biologic therapy recipients vs. 178 non-recipients with IBD was also conducted. Logistic regression tests (OR, RR) and sensitivity, specificity, PPV, and NPV were used. Factors significantly correlated with subsequent biologic therapy were perianal disease, complicated disease behavior, high PCDAI (CD), fatigue, hypoalbuminemia, high PUCAI (UC) and fever, fatigue, hypoalbuminemia, hypoproteinemia, and elevated CRP (IBD). Marginally significant factors were ileocecal disease, elevated serum IgA, anemia, and L4a–L4b coexistence. Apart from parameters already accepted as POPO (B2/3, perianal disease), interesting observations are the significance of IgA, L4a–L4b in CD, and hypoalbuminemia in UC.

Phage therapy in IBD.

Phage therapy in IBD.

AUPHOS, A “FIRST-IN CLASS“ ORAL AGENT FOR CORRECTING METABOLIC DYSFUNCTION IN IBD

Abstract BACKGROUND Mucosal repair is the goal of medical therapy in IBD. Prospective inception cohort pediatric studies suggest that suppression of mitochondrial genes lead to unfavorable clinical outcomes in ulcerative colitis (UC) and Crohn’s disease (CD). We posit that the inability to restore epithelial mitochondrial respiration impairs ulcer healing in IBD. In the current study, we tested whether a novel compound (AuPhos) that improves mitochondrial function promotes ulcer healing in IBD. METHODS Biodistribution and pharmacokinectic (PK) studies were performed (6h, 12h, 24h) after single oral dose (25mg/kg) of AuPhos using C57/BL/6 (WT) mice. Mitochondrial uptake of AuPhos was determined by measuring gold content in normal colonocytes (NCM460) using graphite furnace atomic absorption spectroscopy. Oxygen consumption rate (OCR) in isolated crypt-IECs from AuPhos-fed WT mice were examined using high-resolution respirometry. The effect of AuPhos in colitis was tested in DSS (2%; 7d) WT (B6) mice. Disease activity index (DAI) (weight loss, diarrhea, and hematochezia), intestinal permeability (FITC-dextran), histological scoring and the frequency of fissioning crypts were determined throughout the 21d time course. Tissue mRNA levels for mitochondrial enzyme, cytokine, chemokine and intestinal stem cell (ISC) marker genes were assessed by RT-qPCR. RESULTS Biodistribution and PK studies revealed that higher levels of orally administered AuPhos in small intestine and colon tissue, with limited systemic absorption. AuPhos displayed a dose-dependent mitochondrial uptake in IEC where respirometry showed >30% increase in OCR after oral dosing in vivo. AuPhos treatment decreased DAI (**; p<0.01), histologic colitis scores D11-15 (*; p<0.05) and FITC-dextran permeability in DSS colitis mice. Notably, AuPhos increased fissioning crypt numbers near healing ulcers in DSS-colitis mice (**; p<0.01) while it reduced mRNA for pro-inflammatory cytokines/chemokines (IL-1β, IL-6, IFN-γ, IP10). AuPhos induced mRNA for ISC markers [Lgr4 (*; p<0.05), Lgr5, Lrig1 (***; p<0.001)] and mitochondrial complexes [mtCO1 (**; p<0.01) and COX2 (***; p<0.001)]. These findings suggest that AuPhos-induced mitochondrial respiration drives transcriptomic regulation of IEC genes involved in colitis ulcer healing. CONCLUSION Our data suggests that AuPhos compound improves ulcer healing under acute colitis conditions by increasing mucosal OxPHOS metabolism. Specifically, we find that AuPhos increases mitochondrial respiration-induced crypt fissioning and ulcer healing associated with reduced mucosal inflammation and increased barrier integrity. Overall, AuPhos may be an important “first-in class” oral therapeutic for correcting the metabolic dysfunction central to IBD pathogenesis.

AUPHOS, A “FIRST-IN CLASS” ORAL AGENT FOR CORRECTING METABOLIC DYSFUNCTION IN IBD

Mucosal repair is the goal of medical therapy in IBD. Prospective inception cohort pediatric studies suggest that suppression of mitochondrial genes lead to unfavorable clinical outcomes in ulcerative colitis (UC) and Crohn’s disease (CD). We posit that the inability to restore epithelial mitochondrial respiration impairs ulcer healing in IBD. In the current study, we tested whether a novel compound (AuPhos) that improves mitochondrial function promotes ulcer healing in IBD.

S834 Non-Adherence to Self-injectable Biologic Therapy in IBD Increases ED Visits and Hospitalizations

S834 Non-Adherence to Self-injectable Biologic Therapy in IBD Increases ED Visits and Hospitalizations

Integrin-based therapy in IBD.

Integrin-based therapy in IBD.

Pharmacotherapy of inflammatory bowel diseases: efficacy performance and safety management

Treatment of inflammatory bowel diseases IBD (Crohns disease, ulcerative colitis) is aimed at achieving clinical, endoscopic and histological remission, minimizing surgical complications, and ensuring a normal quality of life. However, the use of medical treatment is potentially associated with various adverse events, among which infectious complications, malignant neoplasms, as well as myelotoxicity, hepatotoxicity, skin lesions and others. The risk of side effects depends on the type of drug therapy (5-aminosalicylates, thiopurines, biologicals, etc.), the duration of treatment, the presence of extra-intestinal manifestations, etc. The article provides an overview of data on both the effectiveness and frequency of various side effects of the main classes of drugs in IBD, presents methods of investigation which can predict the effectiveness and development of side effects, the implementation of which can be considered as a variant of personalized therapy in IBD.

Continued 5ASA use after initiation of anti-TNF or immunomodulator confers no benefit in IBD: a population-based study.

With the advent of biological therapy in IBD, it is uncertain to what extent 5aminosalicylates (5ASA) are used. To explore whether or not 5ASA is continued once biological or immunomodulator therapy is initiated, and the outcomes in those who continued the 5ASAs. We conducted a retrospective cohort study using the population-based University of Manitoba IBD Epidemiologic Database which includes prescription drug dispensation from 1996 through 2018. We assessed outcomes among 5ASA users who continued versus discontinued 5ASA after initiation of anti-TNF therapy or immunomodulators. In all, 8379 (77%) of persons with IBD received at least one 5ASA dispensation (85% of ulcerative colitis, UC and 68% of Crohn's disease, CD). There was a reduction in later years, particularly for CD. The most common pattern of 5ASA use was intermittent at 65.1% (stopping and restarting use) versus one-time (4.1%), previous continuous (13.8%) and persistent (17%). Among the total IBD population use was 59% oral, 3% rectal and 14% combination. Of all 5ASA starts, only 25% were continued longer than 20 months. After immunomodulator or anti-TNF initiation, there was no difference in either UC or CD for negative outcomes (hospitalisation, surgery, corticosteroid starts, colorectal cancers or drug-related adverse events) between those who continued 5ASA versus those who discontinued. 5ASA remains commonly prescribed in UC and CD. Rates of persistent use in UC are low. Once an anti-TNF or immunomodulator is initiated, continuation of 5ASA seems to add no benefit.

DOP70 Exosomes derived from human umbilical cord mesenchymal stem cells to attenuate colitis through repairing intestinal mucosal barrier

Abstract Background Inflammatory bowel diseases (IBD) is a chronic intestinal disease characterized by persistent intestinal inflammation and mucosal damage. Mesenchymal stem cells (MSCs) transplantation is a promising therapy in IBD and other autoimmune diseases. Recent studies indicated that exosomes are the main therapeutic vectors of MSCs in treatment of IBD, but the therapeutic mechanism of exosomes derived from MSCs (MSCs-EXO) remains to be explored. The aims of our research is to explore whether MSCs-EXO have a protective effect on the intestinal barrier. Methods The serum-free cell culture supernatant of Human umbilical cord MSCs (hUC-MSCs) cultured for 48 hours was collected to extract exosomes. Two separate mouse models of IBD induced by dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzenesulfonic acid (TNBS) were administered MSCs-EXO intraperitoneally. The effects of MSCs-EXO on intestinal inflammation, colon barrier function and proportion of T cells were investigated. Results Intraperitoneal injection of MSCs-EXO significantly ameliorated colitis, especially reduced disease activity index and mortality, and inhibited inflammatory cells infiltration. The protective effect of MSCs-EXO on intestinal barrier was demonstrated by reducing the loss of goblet cells and the intestinal mucosa permeability, improving the destruction of tight junctions (TJs) structures and microvilli, and increasing the expression of TJs proteins ZO-1, Claudin-1, and Occludin. MSCs-EXO administration downregulated the level of proinflammatory cytokines, including CXCL14, IL-1β, IL-11, and IL-12 and upregulated the anti-inflammatory cytokine IL-4 and TGF-β in colon tissue. MSCs-EXO also modulated the response of Th2 cells and Th17 cells in mesenteric lymph nodes (MLN). Conclusion Our findings suggested that MSCs-EXO promoted mucosal barrier repair and maintained intestinal immune homeostasis in murine colitis model.

P276 Influence of vedolizumab on extraintestinal manifestations in Inflammatory Bowel Disease: a nationwide multicenter study of the GETECCU Eneida registry

Abstract Background Evidence regarding vedolizumab (VDZ) influence on extraintestinal manifestations (EIMs) in inflammatory bowel disease patients (IBD) is scarce. Our aim was to analyze the effectiveness of VDZ in pre-existing EIMs and the occurrence of de novo EIMs during VDZ therapy in IBD. Methods We performed an observational, multicenter, retrospective cohort study including patients from the Spanish ENEIDA registry promoted by GETECCU. We retrospectively identified 551 patients from 20 centers. The co-primary outcomes were to evaluate the response of EIMs to VDZ and to assess the frequency of de novo EIMs during therapy. Secondary outcomes were to analyze associated factors with EIMs response to VDZ, time from VDZ initiation to occurrence of de novo EIMs and the discontinuation rate of VDZ because of worsening/de novo EIMs. Response and worsening of IBD and EIMs were defined by clinical and laboratory criteria according to the physician’s assessment. Results The median age of the cohort was 49.7 years (IQR 38-60), 50.8% were female, 50.8% had Crohn’s disease and 90.4% had prior biologic exposure (more than 1 biologic drug in 57.9%). At baseline 133 patients (24.1%) had pre-existing EIMs of whom 21 showed more than 1 EIM; 76.7% of EIMs were articular and 31% cutaneous. Regarding 77 patients with active EIMs at baseline, response of EIMs to VDZ at 3 months was observed in 23 (29.9%), worsening in 13 (16.9%) and no change in 41 (53.2%). Response rates for active EIMs were 35.4% for peripheral arthritis (PA), 11.8% for axial arthropathy (AA), 35.7% for cutaneous EIMs and 33.3% for ocular EIMs. Response of IBD at 3 months was the only associated factor with response of EIMs to VDZ (OR=3.72; CI 95% [1.08-12.83]). Among 56 patients with inactive EIMs at baseline, worsening of EIMs was observed in 5 patients after 12 months of VDZ therapy (13.5%) (3 cases of PA and 2 of AA). During follow-up 25 patients (4.5%) developed 27 de novo EIMs (17 cases of PA, 4 of AA, 4 of erythema nodosum, 1 of pyoderma gangrenosum and 1 of episcleritis). Median time from VDZ initiation to onset of de novo EIMs was 244 days (IQR 115-693). Presence of more than 1 pre-existing EIM was the only associated factor with de novo EIM onset during first year of VDZ therapy (OR=14.5; 95% CI [3.3-62]). Worsening of pre-existing EIMs or de novo EIMs was the cause of VDZ discontinuation in 15 patients (5.8% of all patients who discontinued VDZ). Conclusion VDZ achieved clinical response of active EIMs in nearly a third of patients after 3 months of therapy, being the response of IBD to VDZ the only associated factor. Worsening of inactive EIMs or de novo EIMs during VDZ therapy was infrequent.