IBD Therapy Research Articles

PROMOTING AT-HOME DISEASE MANAGEMENT OF IBD WITH A MULTIDISCIPLINARY DIGITAL THERAPY APP: SHORT-TERM RESULTS

Abstract BACKGROUND Although current concepts of disease management of Crohn’s Disease and ulcerative colitis (IBD) provide evidence of active engagement of patients, such a strategy is difficult to comply with unless multidisciplinary therapy is practiced. In the past years mobile and/or digital health solutions have proven to be competent tools to promote and retain self management for patients across many disease areas. The Nori Health mobile application was developed as multi-faceted digital therapy for IBD based on existing evidence in at-home management and treatment with the aim to accommodate multidisciplinary therapy remotely. OBJECTIVE The objective of this paper was to report on the retrospective short-term results of a multidisciplinary digital therapy app for the treatment and self-management of IBD; Nori Health. METHODS Nori Health is a mobile application that digitalizes multidisciplinary therapy, such as education, behavioral intervention and cognitive behavioral therapy (CBT), and is in the market as a CE class I medical device. For the current study, the internal data of anonymized Nori Health users was retrospectively analyzed. User data was evaluated for 8 weeks regarding duration of use (Figures 1, 2) and effect on in-app user reported disease management levels, using the short IBD Control questionnaire (IBD-CONTROL). RESULTS Data of 273 users were available, of which 29 users completed the IBD-CONTROL questionnaire both prior and after the duration of the analysis period. The gender of the users was 61% female and 39% male. Disease management levels increased 34% from baseline 50 to 67 for all users at the end of the observation period. CONCLUSION This retrospective study showed that in a randomized population of app users, an app digitalizing multidisciplinary interventions for the self-management of IBD improved user-reported disease management levels significantly. Additional RCTs will be needed to adjust for selection effects, potential bias, and to further improve clinical relevance of these short-term results.

P686 Outcomes of COVID-19 among patients with inflammatory bowel diseases and the influence of IBD-related medications– A Danish prospective population-based cohort study

BackgroundPopulation-based data regarding outcomes of coronavirus disease 2019 (COVID-19) among patients with ulcerative colitis (UC) and Crohn’s disease (CD) remain limited.MethodsWe conducted a population-based study investigating the outcomes of COVID-19 among patients with UC and CD in Denmark. The Danish COVID-19 IBD Database is an extensive population-based database which prospectively monitors the disease course of laboratory-confirmed COVID-19 among patients with UC and CD. Severe COVID-19 was defined as COVID-19 necessitating intensive care unit admission, ventilator use, or death, while adverse COVID-19 was defined as requirement of COVID-19 related hospitalization. Regression analysis was adjusted for age, sex, disease type, disease activity, cardiovascular disease, and corticosteroids. Outcomes of COVID-19 among patients with UC and CD were compared with those among the background population covering all incidents of COVID-19 in Denmark.ResultsThe study included 319 patients with UC and 197 patients with CD from January 28th, 2020, to April 1st, 2021. Baseline characteristics are presented in Table 1. A significantly higher risk of COVID-19-related hospitalization was observed among patients with UC (N=46(14.4%), RR=2.49 (95%CI 1.91–3.26)) and CD (N=24(12.2%), RR=2.11 (95%CI 1.45–3.07)) as compared with the background population (N=13,306 (5.8%)). A similar pattern was observed for admission to intensive care (UC: N=8(2.51%), RR=27.88 (95%CI 13.88–56.00); CD: N=3 (1.52%), RR=16.92 (95%CI 5.46–52.46)) (Figure 1). The association between these outcomes and IBD-related clinical characteristics and treatments is presented in Tables 2–3. As shown, none of the IBD-related medications were associated with severe COVID-19 in univariate and multivariable analysis. However, systemic steroids were found to be associated with an increased risk of adverse COVID-19 among patients with CD (adjusted odds ratio (aOR)=13.62 (95% CI 1.98–17.77)). ConclusionThis Danish population-based study on COVID-19 outcomes among patients with UC and CD demonstrated severe COVID-19 among only a minority of patients, which was not associated with IBD-related medications. Apart from systemic steroids, this study encourages continued use of IBD therapy to prevent IBD relapse and complications.

Reactive oxygen species-scavenging hollow MnO2 nanozymes as carriers to deliver budesonide for synergistic inflammatory bowel disease therapy.

Inflammatory bowel disease (IBD) is related to excessive reactive oxygen species (ROS) and high expression of proinflammatory cytokines. An enzymatically active drug carrier that can simultaneously scavenge excessive ROS and deliver anti-inflammatory drugs to inhibit the production of inflammatory cytokines may lead to improved therapeutic effects. Herein, nanoparticles (NPs) that can target activated macrophages, remove ROS and release anti-inflammatory drugs are fabricated by loading budesonide (Bud) into dextran sulfate sodium (DSS)-coated hollow mesoporous manganese dioxide (hMnO2) NPs. This strategy can treat IBD better through the synergistic effect of the ROS-scavenging hMnO2 carriers and anti-inflammatory drug by blocking the amplification effect of inflammation. In addition, compared with free Bud, the drug delivery system can reduce side effects of Bud and improve its treatment outcome at the same dosage. Therefore, this study provides a new method for the design of highly effective synergistic anti-inflammatory nanomedicines.

P076 The Role of Dual Biologic Therapy in Inflammatory Bowel Disease.

As the prevalence of complex inflammatory bowel disease and extraintestinal manifestations continue to rise, more patients are requiring complex treatment regimens. In some cases, patients may require more than one biologic agent to target different areas in the inflammatory cascade. Although a body of data is emerging, there is currently no consensus on patient and agent selection for dual therapy or adverse outcomes of therapy. A retrospective chart review of all patients receiving dual biologic therapy for IBD at a single tertiary care center was conducted. This was exempted by the IRB. Data regarding the patient and disease course, indication for dual biologic use, other concurrent therapies, infections and any adverse events was collected from the EMR. Ten patients (9 Crohn's Disease, 1 Ulcerative Colitis) were identified as receiving dual biologic therapy. The most common combination therapy was ustekinumab with vedolizumab (5) or an anti-TNF (4); one patient was receiving adalimumab with vedolizumab. Nine patients were also on an immunomodulator (6 methotrexate, 2 6-mercaptopurine, 1 azathioprine) and three required steroids in addition to dual biologic therapy. The majority (8) of the patients were started on dual biologic therapy due to refractory GI symptoms, the others were due to extraintestinal manifestations (EIMs) with psoriatic arthritis and ankylosing spondylitis. Nine patients had significant symptomatic improvement on dual biologic regimen and all six patients with follow-up endoscopy demonstrated improvement. Two patients developed infectious diarrhea (C.difficile and e. coli), no other significant infections were noted. No patients were found to have malignancy or any other adverse effects of treatment during the reviewed period. Dual biologic therapy can be used with improvement in symptomatic and endoscopic findings of IBD. The combination use of two biologic agents does not appear to have additional infectious risk compared to single agent and no other adverse events were described. Longer follow-up and larger patient populations are needed to verify the combination of biologic mechanisms for therapy of refractory IBD and EIMs.

P053 Interstitial Nephritis from IBD: Complicated Conclusions.

BACKGROUND: Kidney injury in IBD is challenging. Tubulointerstitial nephritis (TIN) is linked to aminosalicylates, but also described in drug-naïve patients, suggesting that TIN may be a direct manifestation of IBD. We describe three cases of TIN in IBD to illustrate the challenges in determining the etiology of the injury. Case #1: 58-year-old male with a horseshoe kidney deformity, uncontrolled hypertension, GERD and small bowel stricturing Crohn's disease (CD), previously on mercaptopurine and allopurinol, subsequently transitioned to adalimumab, maintaining clinical and radiologic remission. Two years later, he developed acute kidney injury in setting of high fevers and sweats, with negative infectious evaluation. Medications included adalimumab, PPI, valacyclovir and torsemide. Renal biopsy revealed TIN with dense, zonal and focal granulomatous features suggestive of drug-induced hypersensitivity, chronic infection, sarcoidosis or an extra-intestinal manifestation of CD. Case #2: 45-year-old female with SLE, nephrolithiasis, GERD, hypertension and ulcerative colitis (UC), initially on mesalamine, then vedolizumab, with clinical and endoscopic remission. Her SCr increased at the time of her UC diagnosis, and worsened over 6 months while on mesalamine, vedolizumab, PPI and losartan. Renal biopsy demonstrated acute and chronic TIN with eosinophils raising concern for an allergic/drug-induced injury. Nephrology concluded that her TIN was secondary to either UC or one of her medications. Case #3: 33-year-old male with UC transitioned to vedolizumab, having failed budesonide and mesalamine. He had latent TB and received 9 months of isoniazid. While on mesalamine, vedolizumab and PPI, he developed fever, chills and night sweats, with an acute rise in SCr, prompting discontinuation of meds. Three months later, still in remission and with improved SCr, he restarted vedolizumab. A year later he developed low-grade fever with elevated SCr, prompting discontinuation. Renal biopsy revealed acute and chronic TIN with severe interstitial fibrosis, tubular atrophy and focal global glomerulosclerosis. He started prednisone and remained off other IBD therapy for 6 months, but repeat colonoscopy revealed mild colitis. He restarted mesalamine, but again developed elevated SCr 2 months later. Repeat renal biopsy revealed TIN with less interstitial fibrosis and focal global glomerulosclerosis, and nephrology suggested his interstitial nephritis was likely secondary to UC over his medications. He started azathioprine with significant improvement in SCr and clinical remission of UC. In all three cases, neither nephrology consultation nor renal biopsy helped distinguish the etiology of renal injury, defaulting to either the IBD meds or an extra-intestinal manifestation of IBD, and not accounting for the acute inflammatory symptoms in two of the cases. While literature review reveals several cases that allege kidney injury as an extra-intestinal target of IBD serious doubts remain. TIN secondary to aminosalicylates is well-documented, but there are few reports of adalimumab-induced granulomatous TIN and only one report of vedolizumab-induced TIN. Each of our patients had well-controlled IBD and multiple confounding variables that could impact kidney function or cause TIN, including hypertension and multiple potential culprit medications, illustrating the dilemma of determining the etiology of renal injury in IBD patients.

Pattern-based Histologic Approach in Very Early Onset IBD: Main Features and Differential Diagnosis.

Very early onset inflammatory bowel disease (VEO-IBD) is a clinical umbrella classification composed of IBD-like diseases encompassing both classic IBD (Crohn's disease and ulcerative colitis) and monogenic disorder, both arising before 6 years of age. VEO-IBD patients present significant clinical differences from IBD occurring in older children and in adults, including more severe disease, often unresponsive to conventional IBD therapy and a greater proportion of cases featuring an underlying genetic alteration. Histologic findings of gastrointestinal biopsies can show an IBD-like pattern (both Crohn's disease-like and ulcerative colitis-like pattern), an apoptotic-like and enterocolitis-like pattern. Findings of specific morphologic alterations, such as villous blunting, apoptosis, dense eosinophilic infiltrates, lack of plasma cells and severe glandular atrophy, can suggest a monogenic disorder. Moreover, individuals with monogenic disorders may develop significant problems such as primary immunodeficiency, impacting treatment options. Finally, IBD histology in childhood can differ from that in older patients and adults. This complexity makes a differential diagnosis between IBD and other pediatric diseases involving the gastrointestinal tract difficult, especially considering that histologic features can be similar between different diseases. Without an appropriate diagnosis, the clinical course of VEO-IBD has greater potential for escalated treatment regimens involving extensive surgery and more intensive medical therapies rather than specific therapy directed toward the underlying defect. For these reasons, a pattern-based histologic approach correlated with clinical and laboratory findings with a multidisciplinary approach is fundamental to reach a correct diagnosis in an adequate clinical context.

S819 Incidence, Outcomes, and Impact of COVID-19 on Inflammatory Bowel Disease: Propensity Matched Analysis of a Large Research Network

Introduction: Several studies have examined outcomes of COVID-19 in patients with IBD however these reports have inherent limitations including a lack of matched controls precluding accurate assessment of risk, and lack of follow up data to assess for IBD flares and risk of de novo IBD in COVID-19 affected populations. Methods: We performed a retrospective cohort study using a multi-institutional research network TriNETX. Patients with IBD >16 yrs of age with COVID-19 (up to Feb 7, 2021) were matched 1:1 with non-IBD COVID-19 patients based on demographic variables and known risk factors for severe COVID-19 infection. Outcomes of COVID-19 disease in IBD were compared to the matched control cohort, and outcomes in IBD subpopulations were explored. The incidence of COVID-19 disease in patients with IBD was compared to the general population, and the relationship of incident cases of IBD with prior COVID-19 disease was investigated. Results: A total of 628,947 patients with COVID-19 met inclusion criteria (3486 in IBD and 625,461 in the non- IBD cohort). Prevalence of COVID-19 in patients with IBD cohort was 5.95%. Patients with IBD had a lower incidence of COVID-19 compared to the general population; IRR: 0.79 (95% CI: 0.72-0.86). The IBD cohort had a higher rate of inpatient treatment with no difference in mortality, mechanical ventilation or AKI noted in the propensity-matched analysis. Patients with IBD corticosteroids at baseline were found to be at increased risk for mortality (RR: 2.08, 95% CI:1.06-4.10, hospitalization and 30-day composite outcome (hospitalization or mortality). No difference in composite outcome was noted in the 5-ASA, biologic agent, and anti-TNF group compared to non-IBD cohort. 210 patients (6.0%) and 243 patients (7.0%) developed an IBD flare in 1 month and 3 months after COVID-19 diagnosis respectively. A total of 774 patients (0.10%) with no prior history of IBD were diagnosed with de novo IBD after COVID-19 infection. The IBD diagnosis rate after COVID-19 was lower compared to a control group of patients who were never diagnosed with COVID-19, on propensity score-matched analysis (RR 0.59; 95% CI:0.54-0.65). Conclusion: In a large cohort of patients with IBD infected with COVID-19, we found a higher rate of in-patient treatment without differences in other clinical outcomes compared to a matched cohort of patients without IBD. The rate of de novo IBD after COVID-19 and disease exacerbations in cases of prior IBD was low, and no IBD therapy was linked to worse outcomes.

S955 Differential Risk of Colorectal Cancer in Inflammatory Bowel Disease Patients Treated With Advanced Therapies, Immunomodulators, and 5-Aminosalicylates: A Multi-Research Network Study Utilizing the TrinetX Database

Introduction: Colonic inflammation is an established risk factor for Colorectal Cancer (CRC) in IBD. The decrease in CRC risk by modulating underlying inflammation with different mechanistic forms of medical therapy is unclear. We hypothesized that advanced therapy for IBD is chemoprotective. We compared the rates of CRC in patients on different classes of medications. Methods: Clinical data was compiled from the TriNetX database, accessed on April, 14, 2021. TriNetX is a globally federated research network, that provides clinical information from 51 HCOs in the US. Patients with reported ICD-10 codes of K50 (Crohn’s Disease, CD) and K51 (Ulcerative Colitis, UC) from 2005-21, were included. Patients were subdivided into 6 cohorts within each form of IBD (CD, UC), categorized by therapy type: 5-aminosalicylic acid (5-ASA), anti-TNFs (IFX, ADA, GOL, CZP), Immunomodulators (AZA, 6-MP, MTX), tofacitinib (TOF), ustekinumab (USK) and Vedolizumab (VEDO). We evaluated demographics, CRC risk factors, inflammatory markers, IBD-related surgery, behavior and extent. The primary outcome of interest was diagnosis of CRC at least 3 month from therapy initiation. For continuous data, analyses were conducted using independent t-tests. For categorical data, analyses were conducted using chi-square tests. All tests were two-tailed with α=.05. Results: At the time of data collection, 35,243 patients were on therapy for CD and 39,223 patients were on therapy for UC. In the CD cohort, majority of the patients were on 5-ASAs (47.3%) followed by anti-TNFs (28.2%), immunomodulators (18%), USK (3.8%) and VEDO (2.7%). Incidence of CRC at least 3 months after initiation of therapy was lowest for anti-TNFs and USK at 0.45% and 0.44%; followed by VEDO at 0.73% and immunomodulators at 1.03%; and highest for 5-ASA at 1.24%. In the UC cohort, the majority of the patients were on 5-ASAs (86%) followed by immunomodulators (6.3%), anti-TNFs (5.4%), VEDO (1.5%), TOF (0.4%) and USK (0.3%). Incidence of CRC at least 3 months after initiation of therapy was lowest for USK at 0%, followed by VEDO (0.82%), anti-TNFs (0.85%), 5-ASA (1.21%), immunomodulators (1.66%) and TOF at 2.11%. The limitation of the study are small sample size for certain treatments and limited information on IBD phenotypes and disease behavior. Conclusion: In this multi-network database study, the incidence of CRC among CD was lowest for patients on anti-TNFs and highest for patients on 5-ASAs. For UC, incidence of CRC was lowest for patients on biologic therapies.Table 1.: Incidence of Colorectal Cancer (CRC) after at least 3 months of initiation of medication therapy

Preclinical development of a bispecific TNF\u03b1/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease

Anti-TNFα and anti-IL-23 antibodies are highly effective therapies for Crohn’s disease or ulcerative colitis in a proportion of patients. V56B2 is a novel bispecific domain antibody in which a llama-derived IL-23p19-specific domain antibody, humanised and engineered for intestinal protease resistance, V900, was combined with a previously-described TNFα-specific domain antibody, V565. V56B2 contains a central protease-labile linker to create a single molecule for oral administration. Incubation of V56B2 with trypsin or human faecal supernatant resulted in a complete separation of the V565 and V900 monomers without loss of neutralising potency. Following oral administration of V900 and V565 in mice, high levels of each domain antibody were detected in the faeces, demonstrating stability in the intestinal milieu. In ex vivo cultures of colonic biopsies from IBD patients, treatment with V565 or V900 inhibited tissue phosphoprotein levels and with a combination of the two, inhibition was even greater. These results support further development of V56B2 as an oral therapy for IBD with improved safety and efficacy in a greater proportion of patients as well as greater convenience for patients compared with traditional monoclonal antibody therapies.

An Escherichia coli strain with extra catalase activity protects against murine colitis by scavenging hydrogen peroxide and regulating regulatory t cell/interleukin-17 pathways

BackgroundInflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract whose occurrence is attributed to various factors, including genetic factors, immune response, microbial changes, and oxidative stress. Microbial-targeted therapy has emerged as an alternative to immunosuppressive therapy for IBD. MethodsThe effects of an atypical commensal Escherichia coli strain harboring an additional catalase gene (compared to typical E. coli strain) on dextran sulfate sodium (DSS)-induced colitis were explored in mice. ResultsThe atypical E. coli (atEc) significantly restored body weight, reduced disease activity score, and improved histological scores in mice with colitis. Hydrogen peroxide levels in colitis mice were noticeably decreased when the mice were administered atEc. The proinflammatory cytokine levels were decreased and regulatory T cell numbers were increased after the administration of atEc. The abundance of Firmicutes was significantly recovered, while that of Proteobacteria decreased in atEc -treated mice compared with that in vehicle-treated wild-type mice. To investigate the role of interleukin (IL)-17A in mediating the anti-inflammatory effects of the atEc, IL-17A‒knockout mice were orally administered atEc. Clinical and immune responses and microbial composition were significantly reduced in IL-17A‒knockout mice compared with those in wild-type mice. ConclusionsatEc ameliorates colonic inflammation by controlling hydrogen peroxide levels, immune responses (including regulatory T cells and IL-17A), and microbial composition. atEc could be a novel candidate of probiotic for IBD treatment.

Novel probiotic yeast from Miso promotes regulatory dendritic cell IL-10 production and attenuates DSS-induced colitis in mice.

Yeasts are a type of fungi thought to have probiotic functions. In this study, we isolated a novel probiotic yeast (Zygosaccharomyces sapae strain I-6) from Miso (a traditional Japanese fermented food). We examined its effects on phenotypic changes in intestinal dendritic cells (DCs), and evaluated its anti-inflammatory effects in dextran sulfate sodium (DSS)-induced colitis. A single colony was selected from homogenized Miso, based on its ability to produce interleukin (IL)-10 in CD11c+ bone marrow DCs (BMDCs) in vitro. The anti-inflammatory effects of strain I-6 on CD11c+ BMDCs and CD11c+ CD103+ DCs were analyzed in mouse mesenteric lymph nodes in vitro and in a DSS mouse model. The IL-10 concentrations in the co-culture BMDC supernatants treated with I-6 were dramatically higher than in those treated with Saccharomyces cerevisiae (Sc). IL-10 production is mediated by both TLR2 and Dectin-1. β-Glucan extracted from I-6 also induced higher levels of IL-10 production in BMDCs than β-glucan from Sc. The number of mesenteric lymph node CD11c+ CD103+ DCs was significantly increased by I-6 administration, compared with Sc administration. Strain I-6 showed strong anti-inflammatory effects on DSS-induced colitis compared to Sc. Moreover, the adoptive transfer of I-6-treated BMDCs showed anti-inflammatory effects on DSS-induced colitis in mice without oral administration of I-6 cells. Strain I-6 induced phenotypic changes in intestinal CD11c+ DCs characterized by high IL-10 production and exerted strong anti-inflammatory effects on DSS-induced colitis. Traditional Japanese fermented foods may be a valuable source of probiotic yeasts for effective IBD therapy and treatment.

P657 Acceptability of a COVID-19 vaccine among cohort of Croatian IBD patients treated in tertiary IBD centre

BackgroundSeveral different types of COVID-19 vaccines are currently available in the EU. Although the massive prophylactic vaccination campaign is the best global solution that may bring an end to the pandemic, a certain proportion of the population seems to remain reluctant to it. No specific data for IBD patients is yet available. We aimed to assess prevalence and characteristics of IBD patients with COVID-19 vaccine hesitancy.MethodsAdult IBD patients treated in our centre were invited to fulfil anonymous online survey from January 17th to February 25th, 2021. Participants’ characteristics were assessed using descriptive statistics. Normal distribution was assessed using Kolmogorov-Smirnov and Shapiro-Wilk tests. Continuous variables were compared with independent t-test and Mann–Whitney test when appropriate. Categorical variables were analyzed using the Chi-square test.ResultsA total of 120 subjects (43.3% female, mean age 34.5±12.3 years, 56.7% Crohn’s disease) completed the survey with a response rate of 96%. Median of disease duration was 8 years (IQR 3–12 years) and 65.8% of participants were on biologics. Overall, only 51.7% were willing to get a COVID-19 vaccine. Mean age of subjects who were inclined to vaccination was higher compared to those who are not (38.1 vs 30.4 years), t(118)=3.43, p=.001. There wasn’t statistically significant difference in median of disease duration between these two groups U=1551, N1=58, N2=62, p=.194, two-tailed. Mean BMI was higher in group of patients who were willing to get vaccinated (25.4 vs 23.2 kg/m2) t(111.67)=2.94, p=.004. There was no difference in vaccine acceptance between IBD patients who identified themselves as a high-risk group and the other which didn’t. Also, acceptability of a COVID-19 vaccine in IBD patients with or without comorbidities didn’t differ significantly (χ 2 (1, N = 120) = .52, p < .47). Connection between biologic use and willingness to vaccination wasn’t observed (χ 2 (1, N = 120) = 2.06, p < .15). Reported reasons for COVID-19 vaccine unacceptability were belief that vaccine can’t be safe because of its rapid development (55%), fear from possible interaction between IBD therapy and vaccine (44%), and fear that vaccine may lead to disease flare (36%).ConclusionA high proportion of Croatian IBD patients are unwilling to get vaccinated against COVID-19. Further patient education, motivation strategies and positive vaccination campaign by gastroenterologists are warranted. Those could be the most significant factors in driving the compliance to COVID-19 vaccination and in reducing IBD patient’s hesitancy to get vaccinated.

P029 Activation of FXR restores expression of genes dysregulated in human IBD and suppresses TNFa and IL-6 signaling pathways in adoptive transfer colitis model

Abstract Background Farnesoid X receptor (FXR) is a ligand-activated nuclear hormone receptor highly expressed in the gastrointestinal tract. We have shown that FXR agonists improve disease in multiple chronic IBD models (Adoptive transfer (AT) colitis, Mdr1a-/- colitis, and SAMP1/YitFc ileitis) with efficacy similar to anti-IL-12/23. To explore the mechanisms by which FXR agonists reduce colitis in these models and the relevance to human IBD, we identified the genes and pathways regulated by FXR in the AT colitis mice, and compared them with the gene expression profile in human IBD patients. Methods Colitis was induced by transplanting CD4+CD45RBhi T-cells to C.B-17 SCID mice. Mice were treated with vehicle (n=10), an FXR agonist (p.o. daily, n=10) or anti-IL-12p40 (i.p., weekly, n=5) in therapeutic mode (started 21 days post AT) for 4 weeks. Efficacy was assessed by colon histopathology of inflammation, erosion, gland loss and hyperplasia (0–5 each). RNAseq was performed on colon RNAs (n=5–7 samples/group). Genes differentially regulated by the FXR agonist were compared with published FXR ChIPSeq data (Thomas et al 2010 Hepatology) and a IBD patients’ gene expression dataset (GSE73661) to identify FXR target genes associated with human IBD. Gene set enrichment analysis (GSEA) was performed to identify enriched pathways. Results Direct FXR target genes were identified by comparing genes upregulated by the FXR agonist in the AT mice with FXR ChIPSeq data. Further comparison with GSE73661 identified FXR target genes relevant to human IBD. The majority of these genes are down-regulated in diseased mice and IBD patients compared to healthy controls. Importantly, in GSE73661 dataset, those genes were upregulated in patients that responded to therapy, while remained down-regulated in refractory patients. The function of those genes includes reducing inflammation, improving gut healing and transporter activities. Further pathway analysis by GSEA identified a number of inflammatory pathways significantly upregulated in AT mice and IBD patients, many of which show reduction with the FXR agonist treatment. Of note, TNFα/NF-κB and IL-6/STAT3 pathways, targeted by approved IBD therapies, were significantly elevated in AT mice but reduced by the FXR agonist or anti-IL-12/23. Conclusion Activation of FXR directly induces IBD-dysregulated genes that can suppress inflammation, promote gut healing and transporter functions. In addition, FXR activation reduced TNFα/NF-κB and IL-6/STAT3 pathways in AT colitis model. These findings support further development of novel FXR agonists as a potential oral therapy for IBD.

P379 Variations in disease monitoring between Inflammatory Bowel Disease patients on intravenous and subcutaneous biologic agents

BackgroundThe availability of subcutaneous (SC) administration devices of biologics in addition to intravenous (IV) administration has influenced patients’ and clinicians’ preferences towards initiating or transitioning to SC administration particularly during the COVID-19 pandemic. Whilst SC administration improves patient convenience and reduces demands on infusion centres we hypothesised that the reduction in healthcare contact associated with SC therapies may reduce the opportunities available for objective disease assessment. We aimed to compare the uptake of objective assessment of disease activity between patients receiving IV and SC biologic therapy.MethodsPatients on maintenance infusion-based or subcutaneous biologic therapy for IBD between 09/2020 and 02/2021 were identified from a prospectively maintained database at an Australian tertiary IBD centre. Patients scheduled for review in IBD clinic for a prescription of maintenance biologic therapy during the follow-up period were included. Clinic records were reviewed to determine whether patients had undergone objective disease assessment including: biochemical investigation (C-Reactive protein) and Faecal Calprotectin (FCP) within the preceding 8 weeks and/or endoscopic/imaging assessment within the preceding 6 months of clinic review. Frequency of objective disease assessment was compared between patients who received IV versus SC maintenance biologic therapy.ResultsA total of 307 patients were included: IV maintenance n=195 (Infliximab n=135; Vedolizumab n= 60) and SC maintenance n=112 (Adalimumab n=54; Ustekinumab n=54; Golimumab n=4). Patients who received IV biologics were more likely than the SC cohort to have had biochemical assessment in the form of CRP (90% vs 72%, p<0.001) and FCP (54% vs 46%, p=0.16). Patients in the SC biologic cohort were more likely not to have had investigations completed prior to their clinical review (20% versus 4%, p<0.001). There was no difference in the overall rates of complete objective disease assessment (CRP/FCP and endoscopy/imaging) between the IV and SC cohort (28% vs 30% (p=0.74).ConclusionPatients on subcutaneous biologic therapies in our cohort were less likely to have had objective disease monitoring than those receiving intravenous biologics prior to scheduled IBD clinic review. Route of of biologic administration may influence rates of uptake of objective disease activity assessment. Tools that safeguard against the disparity of monitoring uptake, including messaging prompts and patient-centric mobile applications may help standardise the approach to objective disease assessment independent of the route of biologic administration.

P452 Oral ciclosporin is a convenient, effective and safe rescue therapy in steroid refractory Acute Severe Ulcerative Colitis: A single tertiary centre experience

Abstract Background Parenteral ciclosporin (CsA) is an effective rescue therapy for acute severe ulcerative colitis (ASUC) and has similar efficacy to infliximab (IFX). Although CsA is cheaper and can facilitate bridging to any IBD therapy, including newer biologics, its use is limited by variable pharmacokinetics and possibility of significant systemic toxicity particularly associated with the intravenous preparation. Despite favourable pharmacokinetics and bioavailability, the use of lipid-emulsified oral CsA in steroid-refractory ASUC is undefined. Methods All patients who received oral CsA (Neoral®) rescue therapy for ASUC at Addenbrooke’s Hospital, Cambridge, UK from Nov 2014 to May 2020 were identified from electronic healthcare records. Baseline data and outcomes were extracted and compared to patients who received IFX rescue therapy. Statistical significance was assessed using non-parametric tests. Survival estimates were computed using the Kaplan-Meier method. Results A total of 37 patients received oral CsA for refractory ASUC. Median time from admission to CsA initiation was 5 days (IQR 4–6 d) and median initial dose was 8 mg/kg/d (IQR 7–8 mg/kg/d). At admission, the median CRP was 26 (IQR 14–95) and Truelove and Witt’s severity criteria met in 21/37 (57%). 70% of patients (26/37) avoided colectomy during the index admission. No parameters were demonstrated to predict need for acute colectomy. Median follow-up after hospital discharge was 3 years (IQR 2-5years). For those who avoided acute colectomy, median duration of therapy was 4 months (IQR 2.5-5months) with bridging to azathioprine (24/26, 92%), vedolizumab (1/26, 4%), or 5-ASA (1/26, 4%). Estimated colectomy-free survival in responders were 84%, 84% and 78% at 12, 24, and 60 months. No parameters were shown to predict colectomy-free survival. Comparable colectomy-free outcomes were obtained for contemporaneous IFX-treated ASUC patients in our hospital. 9 of 26 patients remained biologic-naïve and colectomy-free after a median of 3 years. Estimated colectomy and biologic-free survival were 51%, 47% and 18% at 12, 24, and 60 months. 15 patients experienced adverse events, which were all mild and self-limiting. There were 3 infective complications. No patients required drug cessation and no serious adverse events associated with parenteral CsA occurred. Conclusion In this cohort, oral CsA was a safe, well tolerated and effective rescue therapy for steroid-refractory ASUC. A proportion of patients remain biologic and colectomy-free for up to 5 years. Given the feasibility to bridge to effective maintenance therapies, including newer biologics, oral CsA should be considered as a rescue therapy in ASUC and avoids many of the side effects associated with intravenous CsA.

DOP77 Effect of Inflammatory Bowel Disease and Related Medications on COVID-19 Incidence, Disease Severity, and Outcome -The Israeli Experience

BackgroundThe COVID-19 pandemic raised concerns among IBD patients fearing an increased risk of infection and poor outcomes. We aimed to evaluate the incidence of COVID-19 among IBD patients; its influence on disease severity and outcome; its relationship to medication use; and how the pandemic affected IBD management.MethodsAn anonymous questionnaire was posted online to members of the Israel Crohn’s Disease and Ulcerative Colitis Foundation (November 2020- January 2021). The questionnaire addressed the course of IBD disease and COVID-19 infection over the past year.Results2152 IBD patients completed the questionnaire. 104 (4.8%) had been infected with COVID-19, significantly lower than the “expected” infected cases among the Israeli population (p=0.033). The median age of participants was 39; 60.5% were female. Most patients (75.6%) had no comorbidities other than IBD.No correlation was found between IBD type or disease severity and COVID-19 infection. Most IBD patients reported mild COVID-19 disease, regardless of the type of IBD medications. Multivariable logistic regression analysis revealed that younger age, elevated BMI, and diabetes were independent risk factors for COVID-19 infection. IBD treatment including 5-aminosalicylic acid, smoking, and hypertension were protective factors. 25.2% of COVID-19 patients discontinued their IBD treatment, compared to 8.5% of non-COVID-19 infected patients. IBD flares were significantly higher in those who discontinued treatment (p<0.001).ConclusionIBD patients do not have an increased risk for COVID-19, regardless of IBD activity or treatment. Patients should be encouraged to continue effective IBD therapy, including biologics and steroids, to minimize active IBD.

Novel polyurethane based particulate formulations of infliximab reduce inflammation in DSS induced murine model of colitis – A preliminary study

Our recent study showed that novel infliximab (INF) loaded polyesterurethane (INF-PU) and INF-PU-PEG particulate formulations reduced inflammation in an in-vitro epithelial inflammation model. In this study we investigated therapeutic potential of novel INF-PU and INF-PU-PEG particulate formulations to reduce inflammation in a dextran sodium sulfate (DSS) induced murine model of colitis. Severity of colitis was assessed by measurement of disease activity index (DAI) score, inflammatory markers (neutrophil infiltration, TNFα) and histological score. Treatment groups orally administered with INF-PU and INF-PU-PEG particulate formulations showed improvement in the clinical signs of colitis, similar to that observed with intraperitoneally administered INF, in both, moderate and severe DSS induced colitis model. This was related to a significant reduction in inflammatory cytokines, resulting in a significant reduction in histological score (ANOVA; p < 0.05), indicative of mucosal healing, a key goal of IBD therapy. This could be attributed to its targeted delivery to the inflamed colon and higher permeation of these particulate formulations across the inflamed colonic mucosa, as observed by the confocal images, resulting in local inhibition of TNFα at its site of production. These promising preliminary results warrant further investigation of orally administered INF and its novel particulate formulations in a wider preclinical study.

A164 PATTERNS IN MEDICAL THERAPY AND CLINICAL OUTCOMES IN PATIENTS WITH CONCOMITANT INFLAMMATORY BOWEL DISEASE AND PRIMARY SCLEROSING CHOLANGITIS: A SINGLE CENTRE RETROSPECTIVE ANALYSIS

Abstract Background Inflammatory bowel disease (IBD) in patients with primary sclerosing cholangitis (PSC) is characterized by pancolitis with rectal sparing and is associated with an increased risk of colorectal and biliary malignancies. Currently, pharmacologic management of IBD in the setting of PSC is the same as in IBD alone. Aims To assess patterns in medical therapy, and incidence of adverse outcomes in patients with concomitant IBD and PSC. Methods A retrospective review was conducted on all PSC-IBD patients followed between January 2010 and June 2018. The Endoscopic Mayo Score was used to grade IBD severity in PSC-ulcerative colitis (UC). Results 69 patients were identified, 44 (63.8%) were male. The mean ages of IBD and PSC diagnosis were 28.6 (SD 14.9) and 37.0 (SD 18.9) years, respectively. The median length of follow up was 12 (range 2–49) years. 52 (75.4%) patients had UC, and 17 (24.6%) had Crohn’s disease (CD). 28 (87.5%) PSC-UC patients had pancolitis, and 4 (12.5 %) had proctitis. Among those with pancolitis, 8 (28.6%) had relative rectal sparing. 4 (14.3%) patients had more severe inflammation proximally, whereas only 1 (3.6%) had more severe distal inflammation. 23 (82.1%) patients had the same degree of inflammation throughout. 14 (93.3%) PSC-CD patients had colitis/ileocolitis and 1 (6.7%) had ileitis. Among those with PSC-UC, 16 (50.0%), 12 (37.5%), and 4 (12.5%) patients had grade 1, 2, and 3 disease, respectively. 62 (89.9%) PSC-IBD patients were treated with aminosalicylates, and 26 (37.7%) with biologics at some point in their IBD course. 26 (37.7%) were treated with aminosalicylates alone. 4 (5.8%) did not require any IBD therapy. Cholangiocarcinoma, colorectal cancer, and gallbladder cancer developed in 8 (11.6%), 1 (1.4%), and 1 (1.4%) PSC-IBD patients, respectively. 16 (23.2%) patients required partial or total colectomy. Indication for surgery was inflammation or stenosis, dysplasia, and neoplasia in 13 (81.3%), 2 (12.5%), and 1 (6.3%) patients, respectively. Conclusions The majority of this cohort had UC with mild disease activity. Pancolitis was common, with frequent rectal sparing and more severe right-sided inflammation. Despite the predominance of low-grade colitis, a large portion of patients required treatment with biologics. The incidence of adverse outcomes underscores the need for strict adherence to recommended surveillance practices. Low grade endoscopic activity, typical of the quiescent IBD course in PSC-IBD, may mask low grade histologic inflammation, which in turn may contribute to the increased risk of colonic neoplasia. Further studies are needed to determine the best management strategy for IBD in patients with PSC. Funding Agencies None

Secukinumab as a potential trigger of inflammatory bowel disease in ankylosing spondylitis or psoriatic arthritis patients

Abstract Objective Real-world secukinumab gastrointestinal-related adverse events (GIRAE) data during treatment for AS and PsA are lacking. We aimed to obtain this through baseline evaluation of pre-existing IBD rates and predictors of GIRAE. Methods Patient electronic and paper records commencing secukinumab from 10 UK hospitals between 2016 and 2019 were reviewed. GIRAE after initiation were defined as: definite [objective evidence of IBD (biopsy proven), clear temporal association, resolution of symptoms on drug withdrawal, no alternative explanation felt more likely], probable (as per definite, but without biopsy confirmation) or possible (gastrointestinal symptoms not fulfilling definite or probable criteria). Results Data for all 306 patients started on secukinumab were analysed: 124 (40.5%) AS and 182 (59.5%) PsA. Twenty-four of 306 (7.8%) experienced GIRAE after starting secukinumab. Amongst patients who developed GIRAE, four (1.3%) had definite, seven (2.3%) probable and 13 (4.2%) possible IBD. All definite cases were patients with AS and stopped secukinumab; two had pre-existing IBD and two (0.7%) were de novo cases of which one required surgical intervention. Seven patients (2.3%) had pre-existing diagnoses of IBD prior to initiation, of which five patients experienced GIRAE. Conclusion Absolute rates of new IBD in patients starting secukinumab are low. The majority of patients developing new GIRAE did not develop objective evidence of IBD or stop therapy. For patients with pre-existing IBD and AS the risk of GIRAE is much higher, and prescribing alternatives should be considered.

TREM-1+ Macrophages Define a Pathogenic Cell Subset in the Intestine of Crohn's Disease Patients.

Background and AimsUncontrolled activation of intestinal mononuclear phagocytes [MNPs] drives chronic inflammation in inflammatory bowel disease [IBD]. Triggering receptor expressed on myeloid cells 1 [TREM-1] has been implicated in the pathogenesis of IBD. However, the role of TREM-1+ cell subsets in driving IBD pathology and the link with clinical parameters are not understood. We investigated TREM-1 expression in human intestinal MNP subsets and examined blocking TREM-1 as a potential IBD therapy.Methods TREM-1 gene expression was analysed in intestinal mucosa, enriched epithelial and lamina propria [LP] layers, and purified cells from controls and IBD patients. TREM-1 protein on immune cells was assessed by flow cytometry and immunofluorescence microscopy. Blood monocyte activation was examined by large-scale gene expression using a TREM-1 agonist or LP conditioned media [LP-CM] from patients in the presence or absence of TREM-1 and tumour necrosis factor [TNF] antagonist antibodies.Results TREM-1 gene expression increases in intestinal mucosa from IBD patients and correlates with disease score. TREM-1+ cells, which are mainly immature macrophages and CD11b+ granulocytes, increase among LP cells from Crohn’s disease patients and their frequency correlates with inflammatory molecules in LP-CM. LP-CM from Crohn’s disease patients induces an inflammatory transcriptome in blood monocytes, including increased IL-6 expression, which is reduced by simultaneous blocking of TREM-1 and TNF.ConclusionsHigh intestinal TREM-1 expression, reflecting a high frequency of TREM-1+ immature macrophages and TREM-1+CD11b+ granulocytes, is linked to the deleterious inflammatory microenvironment in IBD patients. Therefore, blocking the TREM-1 pathway, especially simultaneously with anti-TNF therapy, has potential as a new IBD therapy.