bluuebunny/crossref_metadata_2025 huggingface dataset:
P608 Time to onset of effect of biologics and small molecules in moderate-to-severe or acute severe ulcerative colitis – a systematic review and network meta-analysis
Authors: Attauabi M , Dahl E K , Burisch J , Gubatan J , Nielsen O H , Seidelin J B
Published: January 2023

Background

Time to response of advanced therapies is an important parameter due to the symptom load and risk of disease complications in moderate-to-severe ulcerative colitis (UC), but comparative data are lacking. We aimed to assess the comparative onset of effectiveness of biological therapies and small molecules for this patient population.

Methods

In this systematic review and network meta-analysis, we searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials from inception to 24 August 2022, for randomized controlled trials or open-label studies assessing the effectiveness of biologics or small molecule drugs within the first six weeks of treatment in adults with UC. The co-primary outcomes were the induction of clinical response and clinical remission at week 2. Network meta-analyses was conducted under the Bayesian framework. This study is registered with PROSPERO: CRD42021250236.

Results

The systematic literature search identified 20,406 citations, of which 28 studies comprising 11,155 patients fulfilled the eligibility criteria (Figure 1). All agents were superior to placebo for the induction of a clinical response at week 2 (Figure 2). Upadacitinib ranked highest for induction of clinical response and clinical remission at week 2 and was significantly superior to all agents but tofacitinib, which ranked second highest (Figures 3-4). Although the rankings remained consistent, no differences between upadacitinib and biological therapies were demonstrated in the sensitivity analyses of partial Mayo clinic score response or resolution of rectal bleeding at week 2. Tumor necrosis factor-α (TNF) inhibitors were significantly superior to vedolizumab and ustekinumab for patient-reported outcome-2 (PRO-2) remission at week 2 in bio-naïve patients. Ustekinumab, and ozanimod ranked lowest across all endpoints.

Figure 1: Flow diagram of assessment of studies identified in the systematic review

Figure 2: Forest plot for achievement of clinical response at week 2 among patients with moderate to severe ulcerative colitis

Figure 3: Indirect comparison of biologics and small molecule drugs for the induction of clinical response at week 2 in patients with moderate-to-severe ulcerative colitis

Figure 4: Indirect comparison of biologics and small molecule drugs for the induction of clinical remission at week 2 in patients with moderate-to-severe ulcerative colitis

Conclusion

In this network meta-analysis, we found upadacitinib to be significantly superior to all agents but tofacitinib for induction of clinical response and clinical remission two weeks after treatment initiation. In contrast, ustekinumab and ozanimod ranked lowest. Our findings help to establish the evidence regarding the onset of effectiveness of advanced therapies.
P617 Dual biologic therapy in pediatric Inflammatory Bowel Disease
Authors: Abbas R , Ibrahim N , Elawad M , Al-Mudahka F , Abdelrhman H , Akobeng A K
Published: January 2023

Background

There is paucity of data on the effectiveness of combination biologic agents as an option for children with refractory inflammatory bowel disease (IBD) that is inadequately controlled by biologic monotherapy. The aims of this study were to determine the effectiveness and safety of combination biologic use in pediatrics IBD.

Methods

A retrospective cohort study of children with IBD seen at Sidra Medicine and who received combination biologic therapy from October 2018 to April 2022. The diagnosis of IBD was established according to the revised Porto criteria. Children with IBD on two or more biologics were identified from our IBD database and their electronic medical records were reviewed. Patients included in the study must have been on combination biologic therapy for at least two months. Relevant clinical and demographic data were collected.

Results

Out of the 211 patients in our IBD database, we identified a total of 14 patients who had received dual biologic therapy within the study period. 3 patients were excluded because they had received dual biologic therapy for less than 2 months. 11 patients with IBD met our inclusion criteria and were included in this study. All 11 patients had Crohn’s disease. Overall, 7 patients (63%) were male, the median age at the start of starting combination therapy was 15.1 years (IQR 13.9 to 17.4), and the median disease duration was 2.3 years (IQR 1.4 to 3.2). Patients had been on the first biologic for a median of 20.3 months (IQR 13.0 to 32.3) before the addition of the second biologic. The reasons for dual biologic therapy included active disease, failure of single biological therapy, and development of complications. The patients had failed therapy with a median of two (range 1-3) prior biological medications. Concomitant dermatological disease (psoriasis) was present in one patient (9.1%). After a median follow-up of 5.2 months (IQR 2.9-5.5), median PCDAI significantly reduced from 22.5(IQR 16.75-30) to 5(1.25-13.75) {P<0.001}…Figure 1. Median fecal calprotectin reduced from 1534 (1361-1612) to 489 (379-658) {P<0.001}. No adverse events were noted.

Conclusion

Dual biologic therapy was associated with clinical and biomarker improvements in patients with Crohn’s disease who previously failed at least one single biologic. Dual biologic treatment was not associated with adverse events during the study period. Dual biologic therapy may be an attractive strategy but the lack of randomized controlled trials as well as long-term safety concerns means that there is a need for further trials on this subject. Future studies should assess risk: benefit ratios, safety, and efficacy of specific combinations of biologic use in IBD.
P625 Randomized controlled trial on the effect of megaboluses of intravenous corticosteroids added to oral corticosteroids in the treatment of moderately active ulcerative colitis
Authors: Llaó J , Martín-Arranz E , Zabana Y , Navarro-Llavat M , Garcia-Planella E , Busquets D , Monfort D , Pineda J R , Gutiérrez A , Villoria A , Menchén L , Bastida G , García-Alonso F J , Rivero M , Chaparro M , Riestra S , Merino O , Rodríguez-Lago I , Barreiro-de-Acosta M , Domènech Moral PhD E
Published: January 2023

Background

Oral corticosteroids remain as the first-line treatment for moderately active ulcerative colitis (UC). In controlled studies, they achieved clinical remission in 30-60% of patients at 30 days. In severe systemic diseases, intravenous bolus administration of methyl-prednisolone accelerates the clinical response and increases the therapeutic efficacy of corticosteroids.

Aims

To assess the additive effect of IV boluses of methyl-prednisolone in an outpatient Schedule on the remission rate of moderately active UC.

Methods

Randomized, controlled, open study. Inclusion criteria: 1) moderately active (complete May 6-10) distal or extensive UC; 2) never exposed to immunosuppressants or biologicals; 3) without corticosteroid therapy within the last 6 months. Randomization to oral prednisone 60mg/day (ORAL arm) or the same regimen preceded by intravenous boluses of 500mg methyl-prednisolone for 3 days (BOLUS arm). Primary endpoint: clinical and endoscopic remission at week 8 as defined by a complete Mayo score <3 with no subscore >1. Results are expressed in frequencies, medians and interquartile range.

Results

75 patients (39 ORAL, 36 BOLUS) were included, 24% at diesease onset, 49% extensive UC, 68% were on maintenance with oral 5ASA, and 31% had ever received systemic corticosteroids. At baseline, complete Mayo score was 9 (7-9), with C-reactive protein 9.25 mg/L (3.85-20.17) and fecal calprotectin 1430 ug/g (501-2702), with no differences in the baseline clinical-epidemiological characteristics between both treatment arms. At 8 weeks, 37% of patients achieved clinical-endoscopic remission (47% BOLUS vs 28% ORAL; p=0.089), 52% mucosal healing -Mayo endoscopic subscore <2- (61% BOLUS vs 44% ORAL; p=0.129), 24% endoscopic remission -Mayo endoscopic=0- (31% BOLUS vs 18% ORAL; p=0.202) and 55% clinical remission - partial Mayo score <2- (61% BOLUS vs 49% ORAL; p=0.281). No associated factors with clinical-endoscopic remission were identified.

Conclusion

The addition of three intravenous megaboluses at the beginning of a conventional regimen of oral prednisone achieves a non-significant increase in clinical-endoscopic remission rates at the end of corticosteroid treatment in patients with moderately active UC.
P633 Choice of first biologic in moderate to severe ulcerative colitis – a decision analysis using time-on-treatment and UK costs
Authors: Dhar A , Wilson A , Reid V , Clark T , Tibbatts C , Dallongeville A , Robertson J , Eaton J , Cranmer H , Owen G
Published: January 2023

Background

Vedolizumab and anti-TNFα drugs are biologics that are used to treat moderate to severe ulcerative colitis (UC). In the UK, the decision of which drug to use at first-line is often based on a combination of clinical factors and the price of the drug (based on the one-year cost analysis from the NICE appraisal). The cost of the treatment pathway is rarely considered. Therefore, we investigated whether the choice of first-line biologic affects time-on-treatment and the overall treatment pathway costs by creating a cost model for vedolizumab followed by an anti-TNFα (VDZ–anti-TNFα) compared to anti-TNFα followed by vedolizumab (anti-TNFα–VDZ).

Methods

A targeted literature search identified 19 studies reporting time-on-treatment data for vedolizumab or anti-TNFαs in UC. We pooled data into four categories: 1) vedolizumab in people who were biologic-naïve (VDZ-1L), 2) anti-TNFα in people who were biologic-naïve (anti-TNFα-1L), 3) vedolizumab after first-line anti-TNFα (VDZ-2L) and 4) anti-TNFα after first-line vedolizumab (anti-TNFα-2L). We then fitted parametric curves to inform time-on-treatment estimates for each category. We calculated ‘direct’ treatment costs by considering drug acquisition, drug administration, dose escalation, concomitant use of immunomodulators and drug monitoring; all costs were sourced from four NHS hospital trusts (cost year 2022). As the duration of the anti-TNFα–VDZ pathway was shorter in duration than VDZ–anti-TNFα (62- vs 44-months), we modelled third line options in the shorter pathway using a weighted basket approach. Third line options included colectomy, tofacitinib, ustekinumab or dose escalation of second-line biologic.

Results

Over the 62-month time horizon (duration of the longer VDZ–anti-TNFα pathway), pathway costs per patient were similar: £41,439 for VDZ–anti-TNFα and £48,027 for anti-TNFα–VDZ (or £8,021 per year and £9,295 per year, respectively). The model predicted that using vedolizumab first-line delayed the time to costly third-line therapies compared to first-line anti-TNFα. This delay resulted from the pooled time-on-treatment data: VDZ-1L median time-on-treatment 43-months (n=585 people) and anti-TNFα-2L 19-months (n=47); anti-TNFα-1L 17-months (n=7690) and VDZ-2L 27-months (n=549).

Conclusion

When viewed over a longer period and considering all associated direct costs, a biologic treatment pathway that begins with first-line vedolizumab is not more expensive than one beginning with first-line anti-TNFα in treating moderate to severe UC in the UK. The model shows that considering the longer-term costs of a treatment pathway can give a different result compared to considering the short-term costs of single therapies alone.
P642 Network meta-analysis: efficacy and safety of treatments for fistulising Crohn’s disease
Authors: Chahal J , Sriranganathan D , Poo S , Lo S W , Kashkooli S , Garg M , Segal J P
Published: January 2023

Background

Fistulas are a debilitating complication of Crohn’s disease (CD) and treatment options remain limited, with sub-optimal efficacy. It is essential that other treatment options are considered, and there is a lack of head-to-head comparisons between them making positioning treatments challenging. To our knowledge this is the first network meta-analysis to help position all treatments for fistulising CD.

Methods

MEDLINE, EMBASE, EMBASE classic, the Cochrane central registry and Cochrane Specialised Trial Register were searched between 1978 and 2022 for randomised controlled trials (RCTs) reporting on treatments for fistulising CD. The primary outcomes were the efficacy of medical therapies at achieving fistula remission and maintenance of fistula closure. A network meta-analysis was performed using the frequentist model with pooled relative risks and P scores used to rank treatments, in accordance to PRISMA guidelines [Figure 1].

Results

964 studies were identified with the search criteria, with 28 RCTs after screening included for analysis with a total of 2,239 patients. At the 8 – 12 week end-point, none of the interventions were statistically significant, with tacrolimus ranked first at 4 times better than placebo (RR, 4.56; 95% CI, 0.76 – 27.30) at inducing remission of fistulas [Figure 2]. At the 16 – 24 week time point, infliximab produced the only statistically significant result with the 5mg/kg dose proving most effective (RR, 2.30; 95% CI, 1.40 – 3.77) [Figure 3]. At 44 weeks ustekinumab was found to be most superior with it being 2.38 times (RR, 2.38; 95% CI, 1.24 – 4.56) more superior to placebo, with adalimumab (RR, 2.06; 95% CI, 1.06 – 3.99) and infliximab 5mg/kg (RR, 1.68; 95% CI, 1.03 – 2.75) also producing a statistically significant result [Figure 4]. A limitation of this network meta-analysis is the significant heterogeneity between studies and variations in end-point definition, with certain small numbers in certain intervention groups limiting generalisability.

Conclusion

Despite infliximab being favoured in international guidelines for the treatment of perianal fistulising CD, other biologics such as ustekinumab and adalimumab may have a role. Future RCTs with standardised end-points are needed to further investigate biologics, especially ustekinumab and adalimumab, head-to-head against infliximab in the treatment of fistulising CD.
P651 Comparison of Adverse Events of SARS-CoV-2 Vaccination between Patients with Inflammatory Bowel Disease and Healthcare Workers
Authors: Kim J , Sagong M , Lee Y J , Kim K O , Kim E S , Kim E Y , Jang B I
Published: January 2023

Background

This study aimed to investigate the adverse events (AEs) after SARS-CoV-2 vaccination in patients with inflammatory bowel disease (IBD) and to compare them with healthcare workers (HCWs).

Methods

We conducted a web-based survey on the local and systemic AEs experienced within 7 days of SARS-CoV-2 vaccination (BNT162b2, mRNA-1273, or ChAdOx1 nCoV-19) in IBD patients and HCWs between October 2021 and February 2022. The frequency of all AEs was compared between IBD patients and HCWs, and propensity score matching method was used to control confounding factors.

Results

A total of 336 IBD patients (139 Crohn’s disease [CD] and 197 ulcerative colitis [UC]) and 288 HCWs who completed the questionnaire had received the same type of vaccine for their first and second doses. Common local AEs in patients with IBD were injection site pain (78.9% and 70.8% after receiving first and second vaccine doses, respectively), swelling (35.4% and 31.5%), and induration (35.1% and 26.5%), and systemic AEs were fatigue (44.6% and 42.0%), myalgia (42.6% and 37.2%), and fever or febrile sense (29.5% and 32.1%). All severe AEs were rarely observed (0-3.9%). Hospital visits or hospitalizations associated with AEs were observed in 16 (4.8%) and 18 (5.4%) patients, respectively. A small number of patients reported deterioration of bowel frequency (CD: 10.1% and 12.2%, UC: 8.1% and 11.7%), abdominal pain (CD: 5.0% and 7.9%), and rectal bleeding (UC: 5.1% and 7.6%). About 30% of IBD patients reported a worsening of their sense of well-being. After propensity score matching, there was no significant increase in the frequency of AEs in IBD patients except for diarrhea (14.5% vs 4.8%, P = 0.005) and dyspepsia (15.2% vs 5.5%, P= 0.007) after first vaccination.

Conclusion

SARS-CoV-2 vaccination in patients with IBD was generally well-tolerated and severe AEs occurred rarely. Compared with HCWs, the frequency of AEs does not seem to increase except for diarrhea and dyspepsia.
P659 Continuing or stopping 5-aminosalicylate in patients with Inflammatory Bowel Disease under anti-TNF therapy: A nationwide population-based study
Authors: Seo J , Kim S , Song S , Shin S H , Park S , Hong S W , Hwang S W , Park S H , Yang D H , Byeon J S , Myung S J , Yang S K , Kim Y J , Ye B D
Published: January 2023

Background

The clinical impact of continuing or stopping 5-aminosalicylate (5-ASA) after escalating to treatment with an anti-tumour necrosis factor (TNF) agent in patients with inflammatory bowel disease (IBD) is currently unclear. We aimed to compare the outcomes of IBD patients who stopped or continued 5-ASA after starting anti-TNF therapy.

Methods

We analysed data obtained from the Korean National Health Insurance claims database between 2007 and 2020. Our analysis included IBD patients already on 5-ASA treatment who started anti-TNF treatment. We compared the prognosis of patients who stopped 5-ASA within 90 days of anti-TNF initiation with those who continued 5-ASA. The primary outcome was any adverse clinical event defined as a composite of intestinal surgery, IBD-related hospitalization, or new corticosteroid use. Kaplan-Meier method and Cox proportional hazards models at landmark time were used to calculate adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs).

Results

Among 62,262 patients diagnosed with IBD during the study period, 7,442 patients were included for analysis. A total of 1,037 (13.9%) patients discontinued 5-ASA within 90 days of starting anti-TNF therapy (Figure 1). Among the included patients, 4,479 (60.2%) had Crohn’s disease, while 2,963 (39.8%) had ulcerative colitis (Table 1). Discontinuation of 5-ASA was not associated with an increased risk of any adverse clinical events, as well as its component outcomes of intestinal surgery, IBD-related hospitalization, and corticosteroid use, with aHRs of 1.011 (95% CI, 0.934 to 1.095), 0.954 (95% CI 0.760 to 1.198), 0.995 (95% CI 0.894 to 1.107), and 0.969 (95% CI, 0.890 to 1.056), respectively (Table 2). In addition, the cumulative incidence of each adverse clinical event, as well as the composite outcome, were not significantly different between the two groups (all, p > 0.05) (Figure 2). Subgroup analysis by sex, IBD type, the timeframe of anti-TNF use, pre-anti-TNF 5-ASA use duration, pre-anti-TNF corticosteroid use, pre-anti-TNF hospitalizations, pre-anti-TNF emergency department visits, and anti-TNF agent type also showed no significant difference in the development of adverse clinical events between the two groups.

Conclusion

In this nationwide population-based study, we observed that discontinuing 5-ASA after starting anti-TNF therapy was not associated with an increased risk of adverse clinical events.
P661 Clinical response over 24 weeks for initial and delayed responders to induction therapy with risankizumab in Crohn’s disease: data from the ADVANCE and MOTIVATE studies
Authors: Panaccione R , Dotan I , Ferrante M , Danese S , Bossuyt P , Kligys K , Neimark E , Zambrano J , Liao X , D’Haens G
Published: January 2023

Background

The efficacy and safety of risankizumab (RZB) in patients with Crohn’s disease (CD) has been demonstrated.1,2 We reported that an additional 12 weeks (ie, induction period 2) of RZB therapy could induce clinical response in patients with CD who did not achieve clinical response after an initial 12-week induction period.3 In this post hoc analysis, we report the proportion of patients who achieved clinical response over 24 weeks (initial and delayed responders to RZB induction therapy).

Methods

Data were pooled from the ADVANCE and MOTIVATE phase 3 RZB studies. Patients who had not achieved stool frequency (SF)/abdominal pain score (APS) clinical response (≥ 30% decrease in average daily SF and/or ≥ 30% decrease in average daily APS and both not worse than baseline) after an initial 12-week induction with intravenous (IV) RZB (600 mg or 1200 mg) at weeks 0, 4, and 8 were rerandomized 1:1:1 in induction period 2 to receive IV RZB 1200 mg (at weeks 12, 16, and 20) or subcutaneous (SC) RZB (180 mg or 360 mg at weeks 12 and 20) in a double-dummy–blinded fashion. In this post hoc analysis, efficacy was analysed in patients treated with either 600 mg RZB IV or placebo (PBO) for 12 weeks in the PBO-controlled induction period and patients who did not achieve clinical response with 600 mg RZB IV for 12 weeks and were rerandomized to 360 mg RZB SC every 8 weeks during induction period 2 (currently marketed RZB doses). SF/APS clinical response was assessed at week 12 for initial responders and at week 24 for delayed responders in induction period 2. Non-responder imputation with no special data handling for data missing due to COVID-19 was used. No multiplicity adjustment was performed.

Results

Of the 889 patients randomised to 600 mg IV RZB or PBO in the induction studies, 70.0% (369/527) in the RZB group compared with 45.6% (165/362) in the PBO group achieved SF/APS clinical response at week 12. Of the 47 patients who did not achieve initial clinical response to 600 mg IV RZB and received 360 mg SC in induction period 2, 32 (68.1%) achieved delayed SF/APS clinical response at week 24. The proportion of patients achieving SF/APS clinical response over 24 weeks (either initial or delayed responders) was 89.1% (401/450). The safety profile of RZB in patients with CD has been reported.1,2

Conclusion

In patients with moderate-to-severe CD, RZB treatment leads to approximately 9 of 10 patients achieving either initial (600 mg IV) or delayed (600 mg IV followed by 360 mg SC) clinical response over 24 weeks.

References:

1. D’Haens G, et al. Lancet. 2022; 399: 2015-30.

2. Ferrante M, Panaccione R, et al. Lancet. 2022; 399: 2031-46.

3. D’Haens G, et al. United European Gastroenterol J. 2021; 9(S8): 96-7.
P668 Differential efficacy of biologic agents for Inflammatory Bowel Disease Unclassified and comparison with Ulcerative Colitis: a propensity score analysis of 4054 patients from the UK IBD BioResource
Authors: Kapizioni C , Desoki R , Balendran K , Lam D , Shawky R , Pele L , Parkes M , Raine T
Published: January 2023

Background

Data on efficacy of biologic drugs in Inflammatory Bowel Diseases Unclassified (IBDU) are lacking as these patients are commonly excluded from randomised controlled trials. In addition, real world data on the use of biologic agents in IBDU are scarce. We explored the effectiveness of first line biologic therapy in patients with IBDU and compared between drugs and with outcomes for patients with Ulcerative Colitis (UC) in the UK IBD BioResource.

Methods

Demographic, disease, treatment and outcome data were retrieved from the UK IBD BioResource, capturing >36,000 subjects across >100 UK centres. Treatment failure was assessed according to persistence on therapy with clinician assessment of treatment success, without the need for treatment change or surgery. Dose-escalation was not considered indicative of treatment failure. Inverse probability of treatment weighting (IPTW) was used to balance groups using a propensity score-weighting approach accounting for baseline patient or disease related clinical characteristics. We compared Kaplan Meier curves for treatment survival using log rank test.

Results

In total, 198 and 3856 evaluable patients with IBDU and UC respectively received first line biologic therapy and were included in the analysis. Median follow up was 2.6 years (IQR 1.1-4.6). In the IBDU group, 104 were female (52.5%), median age at diagnosis was 28 years (IQR 19.7-42) and median disease duration was 10.4 years (IQR 6.7-15.7). The majority of IBDU patients used infliximab (n=143), while the rest used adalimumab (n=42) and vedolizumab (n=13) with no difference in biologic therapy persistence before and after adjustment (before IPTW adjustment, log rank p = 0.062; after IPTW, log rank p = 0.135, Figure 1). No difference was found in biologic therapy persistence between patients with IBDU and UC (before IPTW adjustment, log rank p = 0.581; after IPTW, log rank p = 0.438, Figure 2).

Conclusion

Outcomes for patients with IBDU receiving first line biologic therapy were similar for those observed in patients with UC. This should lend confidence to patients and physicians using biologic therapy for this under-investigated condition. For patients with IBDU, although persistence on vedolizumab was numerically better than for anti-TNFs, this difference did not reach significance and the vedolizumab sample was small. Adalimumab and infliximab appeared to offer similar efficacy for patients with IBDU.
P680 A real-life experience of Crohn’s Disease Exclusion Diet use at disease onset and as an add-on therapy in pediatric Crohn’s disease
Authors: Scarallo L , Fioretti L , Pochesci S , Pierattini V , Banci E , De Blasi A , Di Paola M , Lionetti P
Published: January 2023

Background

We aimed at appraising real-life efficacy of Crohn’s Disease Exclusion Diet (CDED) coupled with partial enteral nutrition (PEN) in inducing clinical and biochemical remission at disease onset and in patients with loss of response to biologics in a tertiary-level center. We also aimed at identifying early responders to this dietary regimen.

Methods

We gathered clinical, anthropometric and laboratory data of patients aged less then 18 years of age with a diagnosis of CD, who were consecutively treated with CDED coupled with PEN as main treatment for the induction of remission or in the setting of loss of response to other therapies. We collected data of patients who received CDED plus PEN from April 2019 to June 2022 at diagnosis, at the beginning of the dietary treatment, and at the phase 1. Patients who interrupted diet during follow-up were considered as treatment failures on an intent to treat basis. We compared groups using chi-square, Fisher’s exact test, Mann-Whitney U or related-samples Wilcoxon signed rank tests or McNemar’s test as appropriate.

Results

47 patients were retrospectively identified. Table 1. summarizes clinical and biochemical characteristics at diagnosis and at CDED with PEN initiation. 24 (51.1%) patients started CDED as induction therapy at disease onset, whereas 23 (48.9%) of them received CDED with PEN as add-on therapy. 32/47 (68%) patients achieved clinical remission (wPCDAI < 12.5) at the end of phase 1, 16/24 patients (66.7%) who started CDED as induction therapy and 16/23 (69.5%) of those who started CDED as add-on, with no statistically significant difference among the two groups (p=1.00). Laboratory parameters significantly improved in both groups (Figure 1.). There were no statistically significant differences in clinical remission rates between patients with mild-to-moderate and severe disease at the end of phase 1 (25/35 vs 7/12, p=0.481). At disease onset, 14 patients added a concomitant treatment (11 patients added anti-TNF alpha, 3 patients added IMM and one patient added anti-TNF alpha + IMM) after a median time of 4 weeks (IQR: 3-5 weeks). 28 patients had clinical data gathered at week 3. Patients who achieved clinical response at week 3 (a change in wPCDAI > 12.5) were more likely to be in clinical remission at the end of phase 1 (17/20 vs 1/8, p<0.01), both in patients who started CDED at disease onset and in the add-on setting.

Conclusion

CDED with PEN confirmed its efficacy in a real-life setting, both as induction regimen and as add-on therapy, also in patients with clinically severe disease. Early clinical response predicts clinical remission at the end of phase 1, possibly allowing identification of dietary responsive disease.

Table 1.

Figure 1.
P689 Predictive transcriptional signatures associated to vedolizumab therapy response in patients with ulcerative colitis
Authors: Camba Gómez M , Arosa L , Calviño-Suárez C , Bastón-Rey I , Ferreiro-Iglesias R , Porto M , Nieto L , Domínguez-Muñoz J E , Barreiro-de Acosta M , Conde-Aranda J
Published: January 2023

Background

Vedolizumab is one of the current treatments for patients with inflammatory bowel disease (IBD). The efficacy and safety, along with its gut specificity, make this drug an appealing therapeutic option for IBD patients with moderate to severe disease. However, as observed for other biologic treatments, a significant proportion of patients do not have an initial response to vedolizumab treatment. Currently, there is a lack of reliable predictive tools for vedolizumab treatment response, although this would help to alleviate the socioeconomic costs derived from this disease. For that reason, the primary aim of this study is to show putative transcriptional signatures associated with vedolizumab treatment response.

Methods

For the realization of this study, we used RNA-seq datasets from the Gene Expression Omnibus (GEO) database: GSE191328. This dataset includes samples from peripheral blood cells from responder and non-responder ulcerative colitis (UC) patients treated with vedolizumab and infliximab at baseline. Gene Set Enrichment Analysis (GSEA) was performed to compare the differential expression and the enrichment analysis was calculated using ssGSEA of the different groups under study.

Results

The analysis of the transcriptome of peripheral blood cells from responder (R) and non-responder (NR) vedolizumab-treated patients at baseline revealed interesting enrichment results. We found 20 gene sets positively enriched in NR versus R and only 9 gene sets negatively enriched in the same phenotypes. In order to find vedolizumab specific transcriptional signatures, we performed a similar analysis in samples from infliximab-treated patients. After that second round of analysis, we observed that around 50% of the enriched gene sets were similar for both biological treatments. Nevertheless, several interesting biological functions such as peroxisome function, reactive oxygen function or beta-catenin signalling are specifically enriched in NR patients to vedolizumab treatment.

Conclusion

Our data suggest that vedolizumab NR patients specifically show a transcriptional enrichment profile, which differs from vedolizumab R patients. Also, the comparative analysis with infliximab-treated patients reveals that those specific transcripts are modulated in response to this α4β7 integrin antibodies in peripheral blood cells. Therefore, we found a solid system to search for vedolizumab therapy predictive response markers using low invasive techniques.
P696 Design and rationale for the multicentre, randomised, controlled VERDICT trial to determine the optimal treatment target in patients with ulcerative colitis
Authors: Jairath V , Zou G , Radulescu G , Sigler J , Mcfarlane S C , Adsul S , Freire M , Peyrin-Biroulet L , Colombel J F , Moran G W , Sebastian S , Travis S , Vermeire S , Sandborn W J , D’Haens G R , Feagan B G
Published: January 2023

Background

Symptoms, endoscopy, histology, and biomarkers are used to evaluate disease activity and response to therapy in ulcerative colitis (UC). Histologic disease activity may persist in ~25% of patients with normal-appearing endoscopic mucosa, and observational studies demonstrate an association between the achievement of histologic remission (vs endoscopic remission alone) and a lower risk of complications. These findings suggest that histologic remission may be a distinct treatment target. The aim of the VERDICT trial is to determine the optimal treatment target in UC to inform clinical practice and future drug development.

Methods

The primary objective of the multicentre, randomised, controlled VERDICT trial (Figure 1) is to determine whether a treatment target of corticosteroid (CS)-free symptomatic + endoscopic + histologic remission is superior to CS-free symptomatic remission alone in moderately to severely active UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2). Patients are randomised to 3 treatment targets (2:3:5 ratio): CS-free symptomatic remission (Mayo RBS = 0) (Group 1); CS-free endoscopic remission (MES ≤1) + symptomatic remission (Group 2); or CS-free histologic remission (Geboes score <2B.0) + endoscopic remission + symptomatic remission (Group 3). Therapy is administered according to a treatment algorithm that is dependent on each patient’s existing UC treatment regimen at study entry (Figures 2-4). Early introduction of vedolizumab and dose escalation to a maximum of 300 mg every 4 weeks until the assigned treatment target is reached are central to each algorithm. There are 3 opportunities, 16 weeks apart (weeks 16, 32, or 48), to achieve the treatment target. Urine, stool, mucosa, and serum samples are collected at these follow-up time points and at baseline for subsequent biomarker and prediction model development.

Results

The primary efficacy outcome is the time from treatment target achievement to a UC-related complication, defined as a UC-related hospitalisation, colectomy, need for rescue therapy, or treatment-related or other complication. This composite outcome will be compared among treatment target Groups 1 and 3 using the Cox proportional hazard model analysis. The trial was initiated in September 2020, and 660 patients are planned for enrolment. Of these, ~50% are currently enrolled at 55 sites across 10 North American and European countries. Prespecified interim analyses will be conducted when the first 50 patients in each group reach weeks 16, 32, and 48.

Conclusion

The VERDICT trial in active UC is designed to determine the optimal treatment target to inform clinical practice, drug trials, and future evidence-based recommendations.
P704 The effect of antiTNFα and anti-integrin agents on liver steatosis in inlamatory bowel disease patients with non-alcoholic fatty liver disease
Authors: Mitrovic M , Marković S , Kalaba A , Zarić D , Kralj Đ , Milić A , Svorcan P
Published: January 2023

Background

Non-alcoholic fatty liver disease (NAFLD) has been recognized as a common condition in inflammatory bowel disease (IBD) patients and could contribute to their overall morbidity. Anti-TNFα and anti-integrin agents have been the cornerstones of IBD therapy with proven clinical efficacy, but it΄s effect on liver steatosis is still unclear. Therefore this study aimed to evaluate the impact of anti-TNFα and anti-integrin agents on liver steatosis in IBD patients with proven NAFLD.

Methods

A total of 32 IBD patients with NAFLD, naive to biologic agents, 21 with an established diagnosis of ulcerative colitis, and 11 with Crohn’s disease were prospectively recruited for the study. NAFLD was defined by a baseline attenuation (ATT) coefficient measured by shear-wave (SW) elastometry of 0.63 dB/cm/MHz or higher and a baseline alanine aminotransferase (ALT) of more than 40 IU/L for males and 35 IU/L for females. The exclusion criteria were alcohol use (consuming > 40 g alcohol/day for men and > 20 g/day for women in the preceding 12 months), concomitant chronic viral hepatitis, the presence of hepatic carcinoma, biliary disease, drug use, and hypothyroidism. A total of 11 patients were treated with Adalimumab, 9 patients with Infliximab, and 12 patients with Vedolizumab. The SW elastometry and laboratory exams were performed at the moment of therapy induction and after the 6-month course of therapy.

Results

The anti-TNFα treatment significantly reduced liver steatosis according to the ATT coefficient dynamic (0.70±0.07 vs 0.66±0.03 dB/cm/MHz, p=0.021) and ALT level dynamic came on the verge of statistical significance (44±7 vs 40±6 IU/L, p=0.058). We did not observe a significant difference between the Infliximab- and Adalimumab-treated patients. The anti-integrin agent, Vedolizumab, had no impact on liver steatosis (0.66±0.03 vs 0.67±0.04 dB/cm/MHz) and ALT level dynamic (47±4 vs 45±5, p=0.29). Both groups of agents had no impact on patients’ lipid profile dynamic. We found no correlation between liver steatosis level and CRP and fecal calprotectin dynamic.

Conclusion

In the short term, we observed potential beneficial effects of anti-TNFα agents on liver steatosis of IBD patients with proven NAFLD.
P722 Symptom-based disease trajectories Identify a population of early super-responders in ulcerative colitis achieving complete disease control under targeted therapy
Authors: Tran F , Brard R , Flechsenhar K , Aden K , Rosenstiel P , Agueusop I , Schreiber S
Published: January 2023

Background

Clinical trials with advanced therapies typically document the efficacy of induction and maintenance therapies as landmark endpoints. In ulcerative colitis (UC), independent assessments of clinical remission, endoscopic improvement, inflammatory biomarker, and histologic response are used, while little is known about the individual patient benefit. Disease control (DC) as a composite of symptomatic, biochemical, and morphologic remission becomes important to achieve for patients. By analysing their symptom trajectories towards the new outcome DC, distinct subpopulations of the seemingly uniform therapy response phenotype in UC can be identified. In a prospective cohort, we investigate UC patients using symptoms (i.e., partial Mayo Clinical Score (PCMS)) to detect different trajectories that may lead to DC.

Methods

231 UC patients from Kiel Campus of University Hospital Schleswig-Holstein receiving first time induction and maintenance therapy with anti-TNF, anti-IL-12/23, anti-Integrin or JAK inhibitors (JAKi) between 2010-2022 were enrolled. Patients were assigned by clinical choice to their therapy and received standard care: Symptoms were assessed by PCMS with laboratory investigations at each visit (every 4-12 weeks) and endoscopies (at week 0, 14, 52) were evaluated using Mayo endoscopic score (eMayo) and histology assessment with Nancy index (NI). We defined DC at week 52 (DC52) as the combination of eMayo =0, NI =0-1, PMCS =0-1, C-reactive protein <5 mg/l and leucocyte counts 2.5-12/nl. We performed ANOVA and unpaired Wilcoxon tests at each timepoint as well as ROC analyses to identify thresholds discriminating different trajectories.

Results

24.2% (56) of patients achieved DC52, while 25.6% (59) reached week 52 without DC and 50.2% (116) changed therapy within 52 weeks due to inefficacy. We identified an early separation of PMCS trajectories between DC52 (2.07, ±0.27SEM) vs. non-DC52 (3.49, ±0.27SEM) already 6 weeks after induction (p <0.001; Figure 1&2). At week 6, PMCS ≤2 (41.76% vs. 14.06%; sensitivity 0.47, specificity 0.76) and PMCS change from baseline >3 (40.24% vs. 16.92%; sensitivity 0.79, specificity 0.60) were associated with higher rates of DC52 vs. non-DC52. Linking DC52 with prospective outcomes, we observed higher rates of clinical remission (75.00% vs. 27.12%) and DC at week 104 (57.14% vs. 20.34%) in DC52 vs. non-DC52.

Conclusion

In this real-world cohort, DC52 was characterized by early drop of PMCS and a higher likelihood of DC until week 104. While our results await replication, the observation of discrete super-response trajectories leading to DC could give rise to algorithmic trials investigating early change of therapy for patients not joining an ideal trajectory as early as week 6.
P736 Factors associated with partial Mayo Clinic Score over time in patients with Ulcerative Colitis treated with filgotinib in the phase 2b/3 SELECTION trial
Authors: Peyrin-Biroulet L , Louis E , Hisamatsu T , Jamoul C , Santermans E , Harris K , de Haas A , Oortwijn A , Feagan B
Published: January 2023

Background

Responses to ulcerative colitis (UC) treatments vary considerably between individuals, and factors associated with a stable response are not well defined. Filgotinib (FIL) is an oral, Janus kinase 1 preferential inhibitor approved in the EU and the UK as a UC therapy. We aimed to identify factors associated with partial Mayo Clinic Score (pMCS) over time in FIL-treated patients with UC in the phase 2b/3 SELECTION trial (NCT02914522).

Methods

In SELECTION, adults with moderately to severely active UC received FIL 200 mg (FIL200), FIL 100 mg (FIL100) or placebo once daily for 11 weeks in Induction (IND) Study A (biologic-naive) or B (biologic-experienced).1 Patients in clinical remission or with a Mayo Clinic Score (MCS) response at week 10 could enter the 47-week Maintenance (MNT) Study. To evaluate factors associated with pMCS during MNT this post hoc analysis used a mixed model for repeated measures (MMRM), which included fixed effects of time, IND dose (FIL200 or FIL100), the factor of interest and pMCS at IND baseline, and correlated patient residual errors. For categorical factors, the least-squares mean difference with 95% confidence interval (CI) and the overall type III p value were calculated. For continuous factors, the difference in pMCS for a one-unit change in the factor of interest was estimated with 95% CI. Multiplicity adjustment of p values was not performed.

Results

Data from 371 patients treated with FIL200 (n=199) or FIL100 (n=172) were included. Previous use of at least one biologic therapy or a tumour necrosis factor antagonist/vedolizumab, and week 10 MCS subscores of ≤1 were associated with higher pMCS over time than their respective reference categories (p<0.0001; Table 1). Over time, pMCS was 0.45 units higher in patients assigned to IND Study A versus IND Study B (p=0.0002). Week 10 endoscopic score ≤1, Geboes histologic remission and Inflammatory Bowel Disease Questionnaire total score >170 were associated with lower pMCS over time than their respective reference categories (p≤0.0001). Change from baseline in pMCS at week 10 and faecal calprotectin levels at week 10 were positively associated with pMCS over time (p<0.0001; Table 2). Patient-reported outcome (PRO) measures at week 10 were negatively associated with pMCS over time (p≤0.0001).

Conclusion

History of previous biologic therapy, and week 10 assessments (endoscopic, clinical, biomarker and PRO) were among the factors influencing pMCS over the course of 1 year of FIL treatment, consistent with previous findings from trajectory modeling.2 Further MMRM analyses may help to identify patients who benefit most from FIL treatment.

1. Feagan BG et al. Lancet 2021;397:2372–84.

2. Schreiber S et al. MP443 [abstract]. UEGJ 2022;10:459.
P741 Do gastroenterology services need published standards for provision of antenatal care in patients with Inflammatory Bowel Disease? A local evaluation of UK practice
Authors: Tolan M , Nartey J , Dattoo M , King D , de Silva S
Published: January 2023

Background

Inflammatory bowel disease (IBD) is common with 0.5-1% of the UK living with the disease. Poor disease control can result in adverse pregnancy outcomes including low birth weight and preterm labour. It is essential that pregnant patients with IBD receive care from physicians experienced in management of antenatal IBD. Furthermore patients must be equipped with the knowledge to make decisions on their care and the care of their new-born. Audit standards by Selinger et al 20201 for the British Society of Gastroenterology (endorsed by the British Maternal and Fetal Medicine Society) have been published for UK practice but local service standards are unknown.

Methods

Pregnant patients with Crohn’s disease (CD) and Ulcerative Colitis (UC) between 2017-2020 were identified with ICD-10 and OPSC-4 codes for a hospital with 650 inpatient beds and a catchment area of 450,000 with around 4,600 births per annum. The service was assessed against a 90% compliance standard for documentation of: a decision on biological therapy during pregnancy; discussion on mode of delivery (MoD); antenatal live vaccine counselling; and breast-feeding advice.

Results

48 eligible patients were identified. Mean birth weight and delivery date were in line with the national average with no preterm births. 41 of 48 patients (85%) were in remission at the time of conception. 9 of 25 CD pregnancies were on biologics at conception and 7 of 9 (78%) discontinued this by 24-weeks gestation; one continued vedolizumab to 30-weeks and received antenatal vaccine counselling; one continued ustekinumab to 34-weeks. 4 out of 23 UC pregnancies were on biologics at conception; all ceased biologics by 24-weeks and vaccine counselling was not indicated. Only one published standard was achieved, with decision on biologics in pregnancy discussed in 100% (13/13). 3 standards were not met; MoD discussion (23%, 11/48); antenatal vaccine counselling (50%, 1/2); and breast-feeding advice (4%, 2/48).

Conclusion

Our service did not meet new standards for antenatal IBD care, demonstrating a need for improvement. We recommend that all IBD teams understand the expected service standards, perform a baseline service evaluation and develop clear patient pathways and departmental guidelines to identify pregnant patients with IBD. Clear patient information and close collaboration between obstetricians and gastroenterologists is essential to optimise the outcome for mother and baby.

1) Selinger C et al Standards for the provision of antenatal care for patients with inflammatory bowel disease: guidance endorsed by the British Society of Gastroenterology and the British Maternal and Fetal Medicine Society. Frontline Gastroenterology 2021;12:182-187 BMJ 2020