Mitochondrial dysfunction has been implicated in ulcerative colitis (UC), but human data evaluating mucosal bioenergetics alongside inflammatory responses remain limited. The contribution of metabolism to irritable bowel syndrome (IBS) is also unclear. This study aimed to characterise ex vivo colonic metabolic and inflammatory profiles across healthy control (HC), IBS, UC in remission, and active UC cohorts, and to assess associations with clinical characteristics including disease duration and progression. Sigmoid biopsies from HC, IBS, UC in remission, and active UC were prospectively collected and underwent Seahorse analysis to quantify oxidative phosphorylation (OCR) and glycolysis (ECAR). Explant-conditioned media was analysed for ten cytokines and normalised to tissue protein. Group comparisons, principal component analysis, correlations, and multivariable regression were performed. Twenty-four participants were included (HC n = 6, IBS n = 6, UC remission n = 6, active UC n = 8). OCR was significantly lower in UC remission (78.3 pmol O2/min/µg protein; p = 0.024) and active UC (67.1 pmol O2/min/µg protein; p = 0.004) compared with HC (571.7 pmol O2/min/µg protein). OCR:ECAR ratios were similarly reduced in UC remission (2.1; p = 0.013) and active UC (2.7; p = 0.008) versus HC (18.7). Active UC demonstrated markedly elevated IL-4, IL-6, IFN-γ, and IL-1β compared with HC. ECAR was independently associated with UC disease duration (β = 0.03; p = 0.043). IBS showed no significant metabolic or cytokine differences relative to HC. UC is characterised by impaired oxidative phosphorylation, enhanced cytokine secretion, and greater glycolytic activity with longer disease duration. These findings support progressive mucosal metabolic alteration as a feature of chronic UC.

BACKGROUND AND AIMS:The British Society of Gastroenterology recommend use of structured transition programs to improve control of chronic gastrointestinal disease in adolescents. We sought to determine the impact of attending a structured transition program on engagement of patients with inflammatory bowel disease (IBD) services and disease outcomes. METHODS:We performed a retrospective multicenter study of patients with IBD prior to and post-transfer to adult services. Patients were grouped into those who attended a structured transition program and those who received standard care, transferred with a referral letter. RESULTS:A total of 282 patients were included: 155 patients in our structured transition program cohort and 127 patients in the standard care cohort. Patients who took part in a structured transition program had significantly better engagement with adult IBD services with significantly lower rates of nonattendance at outpatient clinics 1-year post-transfer (12.3% vs 27.2%, P = .002) and significantly lower rates of disengagement with services (4.2% vs 13.1%, P = .015). There were no significant differences seen in rates of biologic failure, need for steroid/surgery or median fecal calprotectin levels between either group. Attending a structured transition program was the only factor that positively impacted engagement with IBD services in a multivariate analysis (OR 4.08, confidence interval 1.41-11.91, P = .01). CONCLUSION:Structured transition programs in IBD can improve engagement of patients with IBD services with significantly lower rates of disengagement with IBD services seen in our study. Large prospective studies are needed in this field to further investigate this and the impact of these programs on disease outcomes.

Resistance surveillance programmes are essential for choosing the most appropriate eradication therapy for the stomach pathogen Helicobacter pylori. This study aimed to determine H. pylori antimicrobial resistance rates in Ireland. H. pylori was cultured from patients attending four gastroenterology clinics from 2018 to 2023. Antimicrobial susceptibility testing (AST) was performed using Etests for metronidazole, clarithromycin, levofloxacin, amoxicillin, tetracycline and rifampicin and resistance classified using EUCAST guidelines. Resistance rates were compared between H. pylori treatment-naïve and previously treated patients (primary and secondary resistance, respectively). Samples from 138 culture-positive patients (mean age 49.4 ± 15.7 years, 47.1% female) were analysed. A total of 28.7% of isolates from treatment-naïve patients were susceptible to all antimicrobials tested. Primary resistance rates to metronidazole, clarithromycin, levofloxacin, amoxicillin, tetracycline and rifampicin were 44.3%, 36.5%, 18.3%, 14.6%, 9.6% and 9.6%, respectively. Primary dual resistance to clarithromycin and metronidazole was 22.6% and primary multidrug resistance was 13.0%. Secondary resistance rates were significantly higher than primary resistance rates for clarithromycin, metronidazole, dual resistance to clarithromycin and either amoxicillin, metronidazole or levofloxacin, and multidrug resistance. Female sex and older age were associated with increased risk of resistance. H. pylori resistance rates were high in our cohort. Clarithromycin-based triple therapy should no longer be used in Ireland in the absence of pre-treatment AST. Resistance to amoxicillin, tetracycline and rifampicin should be monitored closely.

Abstract Background Ustekinumab (UST) is an anti-IL12/23 monoclonal antibody approved for use in psoriasis and inflammatory bowel disease (IBD). HLA-C*06 allele carriage has been associated with higher rates of response to UST in psoriasis patient populations.1 The association between HLA-C*06 carriage and UST response in IBD has not been previously evaluated. We aimed to further explore HLA-C*06 carriage as a pharmacogenetic marker as a response to UST therapy in IBD patients. Methods A multi-centre retrospective study of IBD patients treated with UST in Ireland was performed. Baseline demographics of the cohort were collected. HLA-C*06 genotypes were generated by imputation from whole genome sequence using HIBAG. UST therapy persistence, was considered a proxy for treatment response, and was expressed as time to discontinuation of UST therapy. The primary endpoint was UST therapy persistence segregated by HLA-C*06 allele genotype. Statistical analysis was performed using survival analysis and multivariate cox logistic regression with effect of covariates on outcome expressed as odds ratios (OR). Results 143 IBD patients were identified and included in the study population. In this population, 32 patients (22%) carried at least one HLA-C*06 allele. There was no significant difference in median time to UST therapy discontinuation comparing HLA-C*06 carriers to non-carriers at 700-days follow-up, p=0.32 [Figure 1]. In a multivariate regression neither HLA-C*06 allele carriage (OR 1.2, p=0.5), male gender (OR 1.2, p=0.6), CD phenotype (OR 1.6, p=0.44), nor concomitant immunomodulator use (OR 1.1, p=0.8) were independently associated with time to UST therapy discontinuation. Conclusion HLA-C*06 allele carriage is not associated with increased UST therapy persistence in IBD. Larger studies of UST therapy outcome in IBD patients with characterised HLA-C*06 genotype are required to confirm this finding. References 1.Talamonti M, Galluzzo M, Chimenti S, Costanzo A. HLA-C*06 and response to ustekinumab in Caucasian patients with psoriasis: Outcome and long-term follow-up. J Am Acad Dermatol. 2016;74(2):374-5.

Abstract Background Patient-derived inflammatory bowel disease (IBD) ex-plants have potential for biomarker and therapy discovery. Infliximab (IFX), ustekinumab (UST) and vedolizumab (VDZ) are biologic therapies licenced for the induction and maintenance of remission in ulcerative colitis (UC) and Crohn’s disease (CD). All have demonstrated efficacy in IBD despite differing mechanisms of action. IBD explants have the potential to be used as a precision medicine tool, to gain further insights into disease biology and therapeutic mechanisms of action. We aimed to evaluate the effect of IFX, UST and VDZ on inflammatory protein secretion profiles in ex-vivo human IBD ex-plants, whilst comparing these explant secretome variations with in-vivo patient data of patients who commenced these therapies in clinic. Methods Patients with IBD due to commence in-vivo biologic therapy, undergoing endoscopy, were prospectively recruited. Endoscopic biopsies were collected from the sigmoid colon and IBD ex-plants generated as per previously described methods. IBD explants were then cultured for 24 hours with an IgG control vehicle, IFX, UST and VDZ. After 24 hours, tissue conditioned media (TCM) from IBD explants was collected. TCM secreted inflammatory protein profiles were quantified using 54 V-plex ELISA (Meso Scale Diagnostics, USA). Secreted inflammatory protein profiles were compared between IgG vehicle (control) and UST, IFX, VDZ treated ex-plants. Principal component analysis (PCA) was carried out to characterise the influence of biologics on ex-vivo explant secreted inflammatory profiles. Clinical responses of patients treated with biologics in-vivo were also compared with explants inflammatory profiles. Results 37 patients with were included (51% CD, 49% UC); age (median, [IQR]) 41[33-53] years, 49% male; disease duration (median, [IQR]) 9 [5-14] years. 23 patients were subsequently commenced on either IFX, UST or VDZ in-vivo and followed over 2 years to determine therapy response. PCA identified significant variation in the CD and UC secretome. Biologic therapy ex-vivo resulted in significant alterations and clustering in the UC secretome compared to control. Conclusion The IBD explant model recapitulates expected IBD pathology. These data demonstrate that significant differences between the CD and UC secretome. Treatment with licenced biologic therapies ex-vivo significantly alters multiple pro-inflammatory cytokines, chemokines and secreted proteins in IBD explants. Further study is required to completely understand the effects of licenced biologic therapies on the IBD tissue microenvironment.

Abstract Background The National Bowel Screening Program (Bowelscreen), a nationwide initiative program, aims to provide direct access to those aged 55-74 (currently 59-69) for colonoscopy assessment deemed high risk for colorectal cancer via positive faecal immunochemical test (FIT). Inflammatory Bowel Disease (IBD) follows a bimodal distribution of onset with European studies reporting 10-15% diagnosis after age 60. Limited published research exists on IBD incidence in Ireland via FIT-based population screening and associated outcomes. We aim to dtermine incidence rates/severity of incident IBD cases found via FIT-based colorectal screening programme and hRetrospective review was conducted of all index colonoscopes conducted in FIT positive screening participants (aged 59-69) in multiple Irish centres between 2015-2024. Inclusion criteria: histological diagnosis of colitis. Parameters measured: distribution of colitis, histology, clinical sequalae/IBD history, faecal calprotectin (FCP) and treatment escalation based on screening colonoscopyow often screening colonoscopy is performed for patients with known IBD and positive FIT. Methods Retrospective review was conducted of all index colonoscopes conducted in FIT positive screening participants (aged 59-69) in multiple Irish centres between 2015-2024. Inclusion criteria: histological diagnosis of colitis. Parameters measured: distribution of colitis, histology, clinical sequalae/IBD history, faecal calprotectin (FCP) and treatment escalation based on screening colonoscopy. Results 203/8070 (2.52%) of index screening colonoscopies analysed reported endoscopic diagnosis of colitis. 105/8070 (1.3%) satisfied diagnostic criteria for classic IBD (65.7% UC; 34.2% Crohn’s), of which the majority were new diagnosis (73.3%). 32% cases of segmental colitis associated with diverticulosis (SCAD) were identified. 21% cases of NSAID induced colitis were identified. UC Colitis distribution: 18.8% pancolitis, 38.4% proctitis and 42.8% left-sided. Crohn’s distribution: 8.3% small bowel solely; 89% colonic and 2.7% mixed. 48% reported symptoms at endoscopy. Median FCP following diagnostic colonoscopy was 216.5μg/g. 10% of newly diagnosed IBD patients required biologic escalation. Conclusion Incidental diagnosis of colitis occurs in 3% of FIT-positive screening participants in a population based screening programme with new diagnoses of IBD including UC, Crohn’s and SCAD requiring treatment. This is a novel, unintended benefit to FIT-based population screening.

Abstract Background The British Society of Gastroenterology recommend the use of structured transition programmes to improve control of chronic GI disease in adolescents. Although research is limited structured transition programmes have been shown to improve disease outcomes in IBD {1}. Methods We performed a retrospective multicentre study In collaboration with our National Children’s Hospital. Data was collected on patients prior to transition to adult services and after they transitioned to five adult hospitals across Ireland. Our aim was to look at the impact of attending a structured transition programme on disease outcomes including need for escalation of medical therapy after transition to adult services, need for steroids, median FCP levels and engagement with services. Patients were broken up into two groups: patients who attended a structured transition programme and our control patients who were transitioned with a referral letter to the adult gastroenterologist. Results In total 282 patients were included in our study. 155 attended a structured transition programme and 127 patients were transitioned with a written referral letter. No significant differences were seen in basic demographics, median FCP levels or biologic use between either group at the time of transition to adult services. Patients who attended a structured transition programme had significantly lower rates of escalation of medical therapy after transition to adult services compared to our control cohort (38.8% versus 54.4%, p =0.012) (Figure 1). There was no significant difference seen in rates of biologic failure (p = 0.089), need for steroid (p = 0.35) or median FCP levels at 1 (p = 0.09) or 3 years (p = 0.30) between either group after transition to adult services. Patients who took part in a structured transition programme did have significantly better engagement with adult IBD services with significantly lower rates of non-attendance at outpatient clinics in the 1st year after transition (11.6% versus 27.2%, p = 0.04) and significantly lower rates of disengagement with services (4.2% versus 13.1%, p = 0.015) (Figure 2). Conclusion Structured transition programmes in IBD improve disease outcome for patients and overall improve engagement with IBD services. More research and funding is required in the field of transition services in IBD to improve outcomes for patients long-term. References 1.Brooks AJ, Smith PJ, Cohen R, Collins P, Douds A, Forbes V, et al. UK guideline on transition of adolescent and young persons with chronic digestive diseases from paediatric to adult care. Gut [Internet]. 2017;66(6):988–1000. Available from: http://dx.doi.org/10.1136/gutjnl-2016-313000

Abstract Background Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) represent chronic and occasionally disabling conditions, necessitating innovative treatment strategies. Covering 14% of Ireland's landscape, bogland ecosystems house unique plant biodiversity, yielding biologically active secondary metabolites. Informed by traditional medicinal knowledge and in vitro screening for immunomodulatory potential, three plant extracts (NTP0226A, NTP0127B, NTP0206EA) were selected for exploration of their potential to treat IBD and IBS within the "Unlocking Nature’s Pharmacy from Bogland Species" project. Methods Patients undergoing colonoscopy were prospectively recruited in three cohorts: healthy controls, IBS, and ulcerative colitis (UC). Recto-sigmoid biopsies were collected and cultured for 24 h with treatments (Infliximab, NTP0226A, NTP0127B, NTP0206EA). Colonic tissue explants underwent real-time energy metabolism profiling and quantification of 10 inflammatory mediators using Seahorse Xfe24 analyser and multiplex ELISA, respectively. P values <0.05 were considered significant in analyses. Results Twenty-seven patients were recruited (6 healthy controls, 6 IBS, and 15 UC). UC patient explants exhibited elevated glycolytic metabolism and increased IL-4, IL-6, and IL-12p70 secretion compared to non-UC patients. No differences were observed between healthy controls and IBS patients. Linear regression did not show correlation between age and mitochondrial bioenergetics. There was no change in metabolism profiles of any cohort following treatment with Infliximab or the 3 novel extracts. In the UC tissue, treatment with Infliximab reduced IL-12p70 secretion (p=0.0098), this reduction was not seen in the other 2 cohorts. NTP0206EA reduced IL-10 secretion in the UC cohort (p=0.0255). In the IBS cohort; NTP0127B reduced IL-10 secretion (p=0.0048) and NTP0226A reduced IL-4 (p=0.004) and IL-6 (p=0.0219) secretion. Principal component analysis demonstrated reduced separation between the immune-metabolic profiles of UC patients and healthy controls following treatment with NTP0226A (Figure 1). Conclusion Using an explant model, we have shown that UC patients have a distinct immune-metabolic profile modifiable by a standard IBD therapy and novel plant extracts. Blockade of IL-6 trans-signalling has recently shown promise as an effective treatment target in IBD. Our natural extract NTP0226A reduced IL-6 secretion in IBS patients and is a promising candidate for therapeutic exploration. These findings contribute to our understanding of the complex interplay in the colonic microenvironment and highlight potential avenues for novel therapeutic interventions.

Background There has been an increase in resistance to many of the antimicrobials used to treat Helicobacter pylori (H. pylori) nationally and internationally. Primary clarithromycin resistance and dual clarithromycin and metronidazole resistance are high in Ireland. These trends call for an evaluation of best-practice management strategies. Objective The objective of this study was to revise the recommendations for the management of H. pylori infection in adult patients in the Irish healthcare setting. Methods The Irish H. pylori working group (IHPWG) was established in 2016 and reconvened in 2023 to evaluate the most up-to-date literature on H. pylori diagnosis, eradication rates and antimicrobial resistance. The ‘GRADE’ approach was then used to rate the quality of available evidence and grade the resulting recommendations. Results The Irish H. pylori working group agreed on 14 consensus statements. Key recommendations include (1) routine antimicrobial susceptibility testing to guide therapy is no longer recommended other than for clarithromycin susceptibility testing for first-line treatment (statements 6 and 9), (2) clarithromycin triple therapy should only be prescribed as first-line therapy in cases where clarithromycin susceptibility has been confirmed (statement 9), (3) bismuth quadruple therapy (proton pump inhibitor, bismuth, metronidazole, tetracycline) is the recommended first-line therapy if clarithromycin resistance is unknown or confirmed (statement 10), (4) bismuth quadruple therapy with a proton pump inhibitor, levofloxacin and amoxicillin is the recommended second-line treatment (statement 11) and (5) rifabutin amoxicillin triple therapy is the recommend rescue therapy (statement 12). Conclusion These recommendations are intended to provide the most relevant current best-practice guidelines for the management of H. pylori infection in adults in Ireland.

Abstract Background Ulcerative Colitis (UC) is a chronic inflammatory bowel disease (IBD) often leading to impaired quality of life in affected patients. Current treatment modalities include anti-tumour necrosis factor (anti-TNF) monoclonal antibodies including infliximab, adalimumab and golimumab (GLM). RCT show higher trough drug levels (DL) following induction are associated with enhanced rates of remission in maintenance. GOAL-ARC is a pragmatic RCT to examine if dose optimisation of GLM following induction in response to suboptimal DL or persistently raised faecal calprotectin (FCP) improves rates of patient continuous clinical response (pCCR) and reduces maintenance disease activity in UC Methods A pragmatic randomised, multi-centre two-arm investigator initiated trial (NCT0268772) . Population – Patients with moderate to severe UC requiring TNF inhibitor therapy. Intervention - one arm receiving GLM treatment as per SMPC and one arm with dose optimisation of GLM based on FCP and DL from week 6 according to a dedicated algorithm. Eligible patients were randomised in a 1:1 ratio to 1 of 2 treatment groups. Study Duration - 46 weeks. Primary end-point pCCR = absence of flare defined as no increase in modified partial Mayo (MPM) score of 2 points from week 14-46 (requiring treatment intervention). Secondary endpoints included rate of clinical response to induction (week 14), defined as a drop of MPM of 2 points or decrease of ≥30% from baseline and level of FCP and rate of mucosal healing (Mayo endoscopic subscore of 0/1) at Wk 46 Results 107 patients were enrolled (target enrolment n=135, study enrolment terminated early due to recruitment problems during and following C19 pandemic). 97 patients (median age 42) were randomised, with one patient subsequently excluded due to ineligibility. Of 96 evaluable patients, 46 were randomised to SMPC treatment and 50 were randomised to the intervention. Baseline characteristic were comparable. 28/46 (61%) achieved wk 14 clinical response with SMPC and 19/46 (41%) met the primary endpoint (pCCR wk 14-46). In the intervention arm 28/50 (56%) achieved wk 14 clinical response and 24/50 (48%) met the primary endpoint (pCCR wk 14-46). The difference between groups in the rates of pCCR was 6.7% (95% CI:-0.15,0.29) in favour of the intervention and was not statistically significant. No safety signal associated with the intervention was observed. Conclusion In a pragmatic RCT no significant increase in the rate of pCCR was observed with personalised dosing of GLM for treatment of moderate to severe UC. A numerical trend towards reduced loss of response during maintenance (20% with SMPC versus 8% with intervention) is observed with personalised dosing of GLM suggesting this strategy may be beneficial in some patients

Abstract Background Vedolizumab (VDZ) is an anti α4β7-integrin inflammatory bowel disease (IBD) therapy postulated to reduce immune cell trafficking to the intestine. A significant proportion of patients fail to respond to VDZ. We aimed to assess the effect of VDZ on a panel serum inflammatory proteins (IPs) during induction therapy for IBD with the aim of identifying a serum biomarker of VDZ therapy response. We also aimed to gain further insights in VDZ mechanism of action by evaluating changes in serum IP concentrations during induction. Methods Patients commencing VDZ for IBD were prospectively recruited. All received standard VDZ induction. Baseline and week 6 serum concentrations of 54 IPs were measured by ELISA (Meso Scale Discovery, USA). Clinical outcomes were evaluated at weeks 14 and 30 of VDZ therapy. Corticosteroid-free remission (SFR) was defined as persistence of VDZ therapy, absence of corticosteroid therapy, a partial Mayo score ≤1 Ulcerative Colitis (UC) or HBI <5 Crohn’s Disease (CD). The associations between baseline serum IP concentrations and VDZ therapy outcome at weeks 14 and 30 were evaluated. Changes in IP concentrations from week 0 to week 6 of VDZ therapy were assessed. P values <0.05 following multiple test correction were considered significant in all analyses. Results Thirty-nine patients were included: 51% male, 51% UC, median [range]: age 52 [18.2-75.8] years; disease duration 13.4 [0.4–40.8] years; clinical Mayo subscore 4 [0–9]; and HBI 7 [1–20]. 28(72%) had received prior anti-TNF therapy. In univariate analysis, at higher baseline serum TNF-β concentration and lower IL-22, VEGF-C, and IL-7 concentrations were associated with week 14 SFR, p values p=0.003, 0.034, 0.042, and 0.045 respectively. Higher baseline serum IL-4, MDC and MCP-4 concentrations and lower baseline IL-10 concentration were associated with week 30 SFR, p=0.011, 0.026, 0.028 and 0.03 respectively. Significance was not maintained after correction for multiple testing. From baseline to week 6 post VDZ initiation, significant increases were observed in the concentration of six IPs: bFGF, eotaxin, eotaxin-3, MIP-1β, TARC and TNF-β, p=0.034, 0.0012, 0.0013, 0.043, 0.015 and 0.0077 respectively; and a significant decrease in one IP, IL-15, p=0.0004. The significant changes observed in IL-15, eotaxin, and eotaxin-3 concentrations from baseline to week 6 following VDZ initiation remained significant after multiple test correction. Conclusion No serum inflammatory protein was identified as a biomarker of SFR in patients receiving VDZ therapy for IBD. VDZ was observed to significantly affect serum IPs known to be involved in chemotaxis. Further study is required to identify biomarkers of VDZ therapy response.

Abstract Background Despite recent advancements in the treatment of ulcerative colitis (UC), a substantial number of patients fail to achieve long-term remission. Persistent histological activity has been linked with poorer treatment outcomes. Histological remission is now an accepted treatment target; however there remains significant variability in the interpretation of UC histology. As such, there is a need for novel biomarker identification to aid assessment and ultimately predict disease relapse. Serum amyloid A (SAA) is an acute-phase protein, of which serum levels have shown promise as a biomarker in IBD1. This study aims to explore the utility of SAA levels in UC colonic tissue as a diagnostic biomarker for disease activity and progression. Methods Two cohorts were prospectively recruited, including healthy controls and UC patients. Sigmoid biopsies were collected and tissue explants generated. Tissue-conditioned media from these explants was collected and secreted SAA quantified using 54 V-plex ELISA. Demographic information, disease characteristics, endoscopic Mayo scores and disease progression were documented. Endoscopic remission was defined as a Mayo endoscopic sub-score ≤1. Disease progression was defined as the requirement for corticosteroid therapy, UC-related hospitalisation, UC-related surgery or the introduction of a new immunomodulatory agent in follow-up period. P values <0.05 were considered significant in analyses. Results The two cohorts included 11 healthy controls and 16 UC patients (endoscopic remission n=6). Active UC patients demonstrated significantly higher SAA concentrations than healthy controls (p=0.0013) and those in endoscopic remission (p=0.02). There was no significant difference in SAA concentrations between healthy controls and UC patients in remission (p=NS). UC patients in the lowest SAA concentration quartile had a significantly longer time to disease progression (p=0.0462) (Figure 1). Conclusion Quantification of SAA secretion in IBD ex-plants has potential as a biomarker of UC activity and progression. Further investigation of SAA as a biomarker in IBD is warranted. References 1. Chen R, Chen Q, Zheng J, Zeng Z, Chen M, Li L, et al. Serum amyloid protein A in inflammatory bowel disease: from bench to bedside. Cell Death Discov. 2023;9(1):154.

Abstract Background Ustekinumab (UST) is a monoclonal antibody that binds to the p40 subunit shared by pro-inflammatory interleukins 12 and 23. UST has demonstrated efficacy for the induction and maintenance of remission in patients with Crohn’s disease (CD). A proportion of patients with CD do not respond to UST at the standard dose of 90 mg every 8 weeks. Methods A multi-centre retrospective study of CD patient who commenced UST therapy at two specialist tertiary referral centres between October 2012 and March 2021 was performed. Patient demographics, baseline characteristics, medication history and disease behaviour were characterised. Duration of UST therapy and UST dose escalation were documented. UST therapy persistence, was considered a proxy for treatment response, and was expressed as time to discontinuation of UST therapy. The study evaluated whether UST dose optimisation was associated with increased UST therapy persistence; and clinical factors associated with UST therapy persistence. Optimised dosing was defined as a dosing regimen of UST 90mg at less than an 8-weekly interval. Statistical analysis was performed using survival analysis and multivariate cox logistic regression with effect of covariates on outcome expressed as odds ratios (OR). Results 133 patients commenced UST during the study period (age [mean, range] 39 years, 16-79; 59% female; disease duration [mean, range] 12.4 years, 1-35). 99% of patients had failed at least 1 biologic and 72 patients (54%) required dose escalation during the study period. The mean duration of UST therapy was 74 weeks (range 2-427). 75 (56%) patients were still receiving UST at end of study period. Survival analysis demonstrated that there was no significant difference in UST persistence between patients receiving standard and optimised UST dosing regimens, p=0.58. Patients with early UST dose optimisation (within 6 months of therapy initiation) had increased UST therapy persistence, p=0.003. A multivariate regression analysis demonstrated that early UST dose optimisation (within 6 months of therapy initiation) was independently associated with a longer time to UST therapy discontinuation (OR 0.31 (95%CI 0.15-0.68), p=0.003). Neither disease duration (OR 1.11, p=0.66), male sex (OR 0.91, p=0.83), concomitant immunomodulator use (OR 1.03, p=0.95), perianal disease (OR 1.09, p=0.85), smoking status (OR 1.16, p=0.68) nor previous surgery (OR 1.47, p=0.33) were independently associated with time to UST therapy discontinuation. Conclusion UST is an effective treatment for CD patients with prior biologic therapy exposure. Optimised UST dosing regimens are frequently utilised in routine clinical practice. There appears to be an increased likelihood of treatment success with early UST dose optimisation.

Abstract Background Carriage of HLA-DQA1*05 allele is associated with development of antidrug antibodies (ADA) in patients with Crohn’s Disease (CD) receiving anti-TNF therapy. The presence of ADA is not uniformly associated with anti-TNF therapy failure as patients with adequate trough drug concentrations, even where ADA are present, can maintain therapy response. We aimed to determine the impact of carriage of HLA-DQA1*05 allele on outcome of anti-TNF therapy evaluated by drug persistence in routine clinical practice. Methods A multi-centre retrospective study of IBD patients treated with anti-TNF therapy was performed. HLA-DQA1*05 genotypes were generated for each included patient by imputation from whole genome sequence using HIBAG. Only outcome of first anti-TNF therapy received by patients was evaluated in this study. Study primary endpoint was anti-TNF therapy persistence, expressed as time to discontinuation of anti-TNF therapy, segregated by HLA-DQA1*05 allele genotype. Patients discontinuing anti-TNF therapy due to primary or secondary loss of response or due to side-effects were considered therapy failures. Statistical analysis was performed using survival analysis and multivariate cox logistic regression with effect of covariates on outcome expressed as odds ratios (OR). Results 921 IBD patients were identified with 877 included in the study population. Baseline demographics for the entire cohort and segregated by HLA-DQA1*05 allele status are summarised in Figure 1. In the study population, 543 (62%) had no copy, 281 (32%) one copy and 53 (6%) two copies of HLA-DQA1*05 allele. Median time to anti-TNF therapy discontinuation in patients with 2 copies of HLA-DQA1*05 allele was significantly shorter compared to patients with 1 or no copy at 700-days follow-up: 418 versus 513 versus 541 days respectively, p=0.007 (Figure 2) with similar results observed at 2000-days follow-up (p=0.04). In a multivariate regression, factors independently associated with time to anti-TNF therapy discontinuation included: carriage of HLA-DQA1*05 allele OR 1.2, p=0.02; male gender OR 1.6, p=4.2 x 10-5; CD phenotype OR 0.7, p=0.009; and anti-TNF therapy type (infliximab) OR 1.5, p=0.002. Concomitant immunomodulator use was not associated with time to anti-TNF therapy discontinuation in this model, OR 0.97, p=0.84. Conclusion Carriage of two HLA-DQA1*05 alleles is associated with a less favorable outcome of anti-TNF therapy with shorter time to therapy discontinuation. Carriage of one HLA-DQA1*05 allele is not associated with outcome of anti-TNF therapy. Assessing HLA-DQA1*05 genotype has value in routine clinical practice as HLA-DQA1*05 homozygotes are at increased risk of anti-TNF failure which should be a consideration in IBD therapy selection.

Introduction Carriage of the HLA-DQA1*05 allele is associated with development of antidrug antibodies (ADAs) to antitumor necrosis factor (anti-TNF) therapy in patients with Crohn's disease. However, ADA is not uniformly associated with treatment failure. We aimed to determine the impact of carriage of HLA-DQA1*05 allele on outcome of biologic therapy evaluated by drug persistence. Methods A multicenter, retrospective study of 877 patients with inflammatory bowel disease (IBD) treated with anti-TNF therapy with HLA-DQA1*05 genotypes were generated by imputation from whole genome sequence using the HIBAG package, in R. Primary end point was anti-TNF therapy persistence, (time to therapy failure), segregated by HLA-DQA1*05 allele genotype and development of a risk score to predict anti-TNF therapy failure, incorporating HLA-DQA1*05 allele genotype status (LORisk score). Results In all, 877 patients receiving anti-TNF therapy were included in our study; 543 (62%) had no copy, 281 (32%) one copy, and 53 (6%) 2 copies of HLA-DQA1*05 allele. Mean time to anti-TNF therapy failure in patients with 2 copies of HLA-DQA1*05 allele was significantly shorter compared with patients with 0 or 1 copy at 700 days' follow-up: 418 vs 541 vs 513 days, respectively (P = .012). Factors independently associated with time to anti-TNF therapy failure included carriage of HLA-DQA1*05 allele (hazard ratio [HR], 1.2, P = .02; female gender HR, 1.6, P < .001; UC phenotype HR, 1.4, P = .009; and anti-TNF therapy type [infliximab], HR, 1.5, P = .002). The LORisk score was significantly associated with shorter time to anti-TNF therapy failure (P < .001). Conclusions Carriage of 2 HLA-DQA1*05 alleles is associated with less favorable outcomes for patients receiving anti-TNF therapy with shorter time to therapy failure. HLA-DQA1*05 genotype status in conjunction with clinical factors may aid in therapy selection in patients with IBD.

Aims We aimed to audit our treatment of EOE against European and American guidelines and we sought to reject the null hypothesis that there has been no temporal trend in its incidence.

Abstract Background Biologic and small molecule therapies have revolutionised the treatment of inflammatory bowel disease (IBD). Despite these advances, there appears to be a therapeutic ceiling with single agent therapy with up to 50% of patients failing to achieve long term remission. Combination of two biologic therapies or a biologic therapy and small molecule agent, with differing mechanisms of action, has the potential to improve IBD therapy outcomes. Information on the effectiveness and safety of this treatment strategy in IBD remains limited. Methods A retrospective, multicentre study was carried out at five Irish Academic Centres within the Initiative Network. Combination biologic or small molecule use was defined as concomitant use of two biologics or one biologic and small molecule therapy licenced or undergoing clinical trial assessment for treatment of IBD. Patients who had received combination therapy were identified from institutional databases. Review of clinical records was performed and demographic data collected. Combination therapy persistence was considered a proxy for successful therapy outcome. Adverse events were documented. P values < 0.05 were considered significant in analyses. Results The study cohort included 85 patients; 70% Crohn’s disease (CD), 30% ulcerative colitis (UC); median (IQR) number of prior biologic therapies 3 (2 – 3); median (IQR) study follow up 40.71 weeks (13.68 – 82.86). Further baseline characteristics are described in Figure 1. 97 combination therapy trials were undertaken in 85 patients. 13 different combination therapy regimes were utilised with ustekinumab & vedolizumab being the most common regimen. 76.5% (n=65 patients) remained on combination therapy at last follow up. Higher rates of combination therapy discontinuation (p=0.04) and shorter time to combination therapy discontinuation were observed in UC compared with with CD (HR 0.48 [95% CI 0.21-1.11], p<0.05). 3.1% of the study cohort developed a serious or opportunistic infection. No deaths or intensive care unit admissions occurred during study follow up. Conclusion Combination therapy is an effective therapeutic strategy with an acceptable safety profile in refractory IBD patients. Randomised controlled trials are required to clearly define the role of combination therapy in the management of IBD.

Abstract Background Patient-derived inflammatory bowel disease (IBD) ex-plants have potential for biomarker and therapy discovery. Infliximab (IFX), ustekinumab (USTK) and vedolizumab (VDZ) are biologic therapies licenced for the induction and maintenance of remission in ulcerative colitis (UC) and Crohn’s disease (CD). All are efficacious in IBD despite differing mechanisms of action. Treatment of IBD explants ex-vivo with licensed biologic therapies may result in further insights into their mechanism of action. We aimed to evaluate the effect of IFX, USTK and VDZ on inflammatory protein secretion profiles in ex-vivo human IBD ex-plants. Methods Patients with IBD, undergoing endoscopy, were prospectively recruited. Biopsies were collected from the sigmoid and IBD ex-plants generated as per previously described methods. IBD explants were then co-cultured for 24 hours with an IgG control vehicle, IFX, USTK and VDZ. After 24 hours, tissue conditioned media (TCM) from IBD explants was collected. TCM secreted inflammatory protein profiles were quantified using 54 V-plex ELISA (Meso Scale Diagnostics, USA). Secreted inflammatory protein profiles were compared between IgG vehicle (control) and USTK, IFX, VDZ treated ex-plants. All continuous variables are presented as median [interquartile range (IQR)]. P values < 0.05 were considered significant in analyses. Results 37 patients with IBD were included (51% CD, 49% UC); age (median, [IQR]) 41[33-53] years, 49% male; disease duration (median, [IQR]) 9 [5-14] years; 51% of patients were anti-TNF naïve. TNF-a secretion was significantly lower in IBD explants treated with IFX compared with IgG control, p=0.006. IL-23 secretion was significantly lower in IBD explants treated with USTK compared with IgG control, p=0.043. Biologic therapy ex-vivo resulted in significant differences in angiogenesis and vascular injury panel biomarkers compared to control; CRP, VEGF-A and SAA. Pro-inflammatory cytokines and chemokines were also significantly decreased with ex-vivo biologic therapy compared to control; IL-2, IL-10, IL-6, MCP-1, IL-1a, TNF-a and MDC. Three Th17 panel proteins were significantly decreased with ex-vivo biologic therapy compared to control; IL-22, IL-17A, IL17A Gen B. Conclusion The statistically significant decrease in both TNF-a and IL-23 secretion with ex vivo IFX and USTK treatment respectively demonstrates that the IBD explant model recapitulates expected IBD disease biology and therapy responses. These data demonstrate that treatment with licenced biologic therapies ex-vivo reduces multiple pro-inflammatory cytokines, chemokines and secreted proteins in IBD explants. Further study is required to completely understand the effects of licenced biologic therapies on the IBD tissue microenvironment.