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 Golimumab is a monoclonal anti-TNF drug used in the treatment of Ulcerative Colitis (UC). GOAL-ARC is a multi-centered investigator initiated randomized control trial seeking to evaluate the utility of personalized Golimumab dose adjustment in UC versus standard dosing as per summary of product characteristics (SMPC) post-induction. From early analysis data, we aimed to ascertain if Golimumab induces response at 2 weeks and if this early response impacts disease activity at 6 weeks and the need for dose escalation at this interval. Methods Patients recruited to the trial were randomized to an intervention or a standard dosing arm. Golimumab was administered at 200mg at week 0 and 100mg at week 2 with assessments at weeks 0, 2, and 6. Baseline data was obtained including patient demographics and burden of disease. Outcomes measured were clinical response (defined by a decrease in partial mayo score of 2 points or a decrease of ≥30% from baseline), change in Faecal Calprotectin (FCP) as well as improvement in Short Health Scale (SHS) score and serum golimumab levels at 6 weeks. We also looked at FCP≤250μg/g (STRIDE II – intermediate treatment target) as an outcome. Results A total of 94 patients were recruited with 90 (95.7%) patients completing 2-week follow up and 79 (84%) patients completing 6-week follow-up. The median age was 37 years (IQR 28-46), 58.5% were male, and 76.6% (n=72) had a Mayo endoscopic subscore of 2 and the median DUBLIN Score was 4 (IQR 4-6). At 2 weeks, a clinical response was observed in 68.9% of patients (n=62). There was a significantly lower median modified partial mayo score (2 vs 4, p<0.001), rectal bleeding score (0 vs 2, p<0.001), stool frequency score (1 vs 2, p<0.001) and total SHS score (21.0 vs 25.8, p<0.001) after 2 weeks of treatment. The median FCP was numerically lower (354.7μg/g vs 1111.5μ/g, p=0.207) with an overall reduction by 32.5%. Patients who achieved a clinical response at 2 weeks were noted to have a lower baseline total SHS score (23.9 vs 29.0, p=0.017). 2-week response did not correlate with 6-week outcomes. Median FCP was significantly lower at 6 weeks (254.2μg/g vs 1111.5μ/g, p=0.008) with an overall reduction by 74.0%. There was a significantly higher median Golimumab level in patients with FCP≤250μg/g at 6 weeks (5.59μg/ml vs 2.41μg/ml, p<0.001). Conclusion Golimumab shows efficacy in Ulcerative Colitis as early as 2 weeks with significant clinical response and a biochemical response. Early data suggests that response at 2 weeks, however, is not a reliable indicator of a sustained clinical response.

Abstract Background Anti-TNF agents are effective therapies for Inflammatory Bowel Disease (IBD), however, a significant proportion of patients lose response over time. Real world data on prescribing practices and outcome of anti-TNF therapy are of utility to practicing clinicians Methods To evaluate Anti-TNF prescribing practice and durability of Anti-TNF response in a large multicentre IBD cohort. IBD patients commencing an anti-TNF agent, as first biologic therapy, at participating academic centres were identified from institutional databases. Baseline demographic data, concomitant medication and biologic therapy history were collected. Adalimumab(ADA) and Golimumab(GOL) were consider subcutaneous(SC) anti-TNF agents. Date of commencement and discontinuation of first and second line anti-TNF therapy was documented. Kaplan-Meier survival curves were constructed for time based analyses. P values less than 0.05 were considered significant in all analyses. Results N=991 patients with IBD were included in the study. 29%, 69% and 2% had UC, CD and IBD-U respectively; median [IQR] age 27 [19–37] years; 50% female. 31%, 63% and 4% received infliximab(IFX), ADA and GOL respectively as first-line anti-TNF therapy. 35% of patients received an immunomodulator in combination with first-line anti-TNF agent. Median [95% CI] survival free of therapy discontinuation for first and second-line anti-TNF agents was 4.6 [3.7 – 5.3] years and 3.0 [2.1 – 3.9] years respectively. Survival free of anti-TNF discontinuation was significantly shorter for IFX monotherapy group compared with IFX combination therapy, SC anti-TNF monotherapy and SC anti-TNF combination therapy groups, p=0.005. Conclusion While anti-TNF therapies are effective a significant proportion of patients discontinue therapy over time. Second line anti-TNF therapy results in a less durable response with a shorter time to drug discontinuation compared with first line anti-TNF therapy. The use of a combination immunomodulator is particularly important with infliximab therapy, however, does not influence durability of response for subcutaneous anti-TNF agents.

Abstract Background The DUBLIN (Degree of Ulcerative colitis Burden of Luminal Inflammation) is a novel simple clinical score of inflammation in patients with Ulcerative Colitis (UC) which can be used easily in outpatients and at the bedside. Methods We sought to validate the clinical utility of scoring UC inflammatory burden at diagnosis in predicting disease outcomes using the DUBLIN score (DS). We performed a multicentre retrospective study of patients recruited to the Genuity medicine IBD research project at three centres. DS at diagnosis was calculated based on disease extent and endoscopic severity. Study outcomes were need for immunomodulators and/or biologic therapy and need for surgery. We also examined the association between DS and FCP, albumin and C-reactive protein. Results 679 patients with confirmed UC were identified. 291 had data allowing calculation of DS at diagnosis (median age 38.9 years, 53% male). Median DS was 4 [1–9]. 122 patients were treated with biologic therapy during follow-up. Median DS at diagnosis was significantly higher in patients requiring biologic therapy compared to those not requiring biologic therapy [4 versus 3, p = < 0.001]. Of patients requiring biologic therapy patients with a DS > 3 had a significantly shorter time on 1st biologic therapy [2.1 versus 3.9 years, p = 0.005]. There was no difference in median DS dependent on immunomodulator use. Similarly median DS at diagnosis was significantly higher in patients requiring colectomy compared to those not requiring colectomy [6 versus 4, p = 0.001]. There was a weak positive correlation between both DS and faecal calprotectin [correlation coefficient 0.27, p = 0.001] and C-reactive protein [correlation coefficient 0.7, p = 0.01] and a weak negative correlation between DS and albumin level [correlation coefficient -0.22, p = 0.04]. Conclusion Our study validates the clinical utility DS is an accurate clinical tool at diagnosis and during a patients’ disease course for identifying disease burden. A higher DS correlates with an increased need for biologic therapy, need for colectomy and increased biomarkers of disease activity. This is a useful tool for day to day use in clinical practise providing personalised management of patients with UC.