bluuebunny/crossref_metadata_2025 huggingface dataset:
P864 The Effect of Ustekinumab on Mucosal Inflammation in Paediatric Crohn’s Disease: The REALITI Real-World Evidence Effectiveness Study
Authors: Adler J , Steiner S , Saeed S , Colletti R , Strauss R , Godwin B , Sheahan A , Zhang R , Kim L , Xiao Y , Volger S
Published: January 2024

Background

Crohn's disease (CD) research using real world evidence (RWE) has been hampered by lack of validated endoscopic outcome measures. The recently validated Simplified Endoscopic Mucosal Assessment of CD (SEMA-CD) provides a reliable way to evaluate mucosal inflammation in paediatric CD patients (pts), making it suitable for use in clinical practice and relevant to real world data. REALITI is a RWE study of the effectiveness and safety of ustekinumab (UST) in paediatric pts.

Methods

REALITI used data from pts with CD in the ImproveCareNow (ICN) registry. Colonoscopy reports (reports) from 2010-2020 identified by chart review were redacted and uploaded to the registry. Central endoscopy readers underwent SEMA-CD training and were randomly assigned to score reports. No reader reviewed reports from their own institution. Three readers independently scored reports blinded to each other’s scores and to clinical information. Demographic and clinical data, prospectively recorded in ICN, were summarized and compared between pts with and without endoscopy. Clinical remission was defined as Short Paediatric CD Activity Index (sPCDAI) ≤10 and endoscopic remission as SEMA-CD ≤1.

Results

Analyses of mucosal inflammation by SEMA-CD in 114 pts age 2 to <18 yr with moderate-severe CD (sPCDAI ≥30) and body weight ≥40 kg at UST initiation (baseline) and after 52 weeks (wk) of treatment are reported. Overall, 77/114 pt had ≥1 report during the study and 20 had a report at Wk 52. Baseline median age of all pts was 16 yr (interquartile range [IQR] 15-16). Pts with endoscopic assessments (N=77) vs pts without (N=37) were more often female (56% vs 41%) and had more ileocolonic disease activity (73% vs 54%), perianal disease (39% vs 35%), and stricturing phenotype (B2; 10% vs 5%), respectively. No pts had B2/B3 phenotype. At baseline, median sPCDAI for all pts was 40 (IQR 35-50; N=114) and median SEMA-CD was 8.5 (IQR 5-13; N=38). At Wk 52, 4/20 pts (20% [95% CI, 8.1%, 41.6%]) were in endoscopic remission. Despite small sample sizes, there appears to be lower clinical remission rates at Wk 52 in pts with baseline endoscopic assessments (17/77; 22.1% [95% CI, 14.3%, 32.5%]) vs without (10/37; 27.0% [95% CI, 15.4%, 43,0%).

Conclusion

Use of SEMA-CD to assess mucosal inflammation in paediatric pts with moderate-severe CD treated with UST demonstrated rates of endoscopic remission similar to clinical remission at Wk 52. Endoscopy was performed more often in sicker pts, with a greater proportion of pts who did not undergo endoscopy achieving clinical remission. Future routine SEMA-CD assessment of mucosal inflammation in clinical practice may improve analyses in observational and retrospective studies.
P890 Usefulness of subcutaneous Infliximab in patients with Inflammatory Bowel Disease in clinical practice: are increased levels associated with clinical benefit?
Authors: De La Filia Molina I Garcia , Gismero F Mesonero , Cardona J López , Aldehuelo R Sánchez , De la Serna Gamboa Á , Gramage Caro T , Fernández Fernández C , Garbiñe R A , Agustín A M , San Román A López
Published: January 2024

Background

Switch from intravenous Infliximab (IFXiv) to subcutaneous Infliximab (IFXsc) in Inflammatory Bowel Disease (IBD) has been associated with an increase in trough levels. However, whether this increase is correlated with additional clinical benefit has not thus far been evaluated in clinical practice.

Methods

Single-center retrospective study of IBD patients who switched from IFXiv to IFXsc (for at least 3 months), between July 2021 and August 2023, due to unfavorable pharmacokinetics (IFX serum levels <3 +/- anti-IFX antibodies). Disease activity was defined as clinically: Simple Clinical Colitis Activity Index (SCCAI) ≥2 for Ulcerative Colitis (UC), Harvey Bradshaw Index (HBI) ≥5 for Crohn´s Disease (CD) or perianal fistulae with active drainage; and biochemical: C-reactive protein (CRP) >5 mg/L and/or fecal calprotectin (FC) >250 µg/g in UC and >150 µg/g in CD. Primary endpoint was to evaluate the effectiveness of IFXsc switch: achieving clinical response (decrease of SCCAI ≥2, IHB ≥3 or ≥50% in fistula drainage) or remission (SCCAI ≤1, IHB ≤4 or absence of active fistula drainage) with biomarkers normalization, or maintenance of remission, in patients with and without previous activity, respectively. Secondary endpoints were to assess IFX levels change and safety of IFXsc switch.

Results

Twenty-five patients (23 CD, 2 UC) were included (Table 1). Previous IFXiv therapy lasted for a median of 55 (20.6-74.1) months (100% with intensified dose and 48% with combined therapy). Median baseline IFX level was 1.7 (0.4-3) μg/mL, with anti-IFX antibodies in two cases. At baseline, 7 patients were in remission and 18 had active disease: 15/18 clinical or both clinical and biochemical (3/15 luminal, 11/15 perianal or 1/15 both), and 3/18 biochemical only. Median follow-up was 15.2 (10.2-19.2) months. After IFXsc switch, an increase of IFX level was achieved in 96% of cases, with a median final level of 12.4 μg/mL (9.2-18) (Figure 1). None of the patients in remission at the beginning relapsed during follow-up. Of patients with previous clinical activity, 66.6% achieved clinical remission (53.3%) or response (13.3%), which was seen in 50% of patients with luminal and 66.7% with perianal activity, after a median of 79 (75-210) days. CRP and FC normalization was reported in 53.3% of patients with previous biochemical activity. Treatment was discontinued only in one patient due to inefficacy. IFXsc was intensified in 8% and concomitant treatment could be withdrawn in four patients. No adverse events we reported.

Conclusion

Switching to IFXsc in patients with previous therapy with intensified IFXiv is not only associated with a more favorable pharmacokinetic profile but also with a greater effectiveness.
P893 Transition from intravenous to subcutaneous infliximab: effectiveness in a cohort of patients with inflammatory bowel disease
Authors: Todeschini A , Geccherle A , Signoretto P , Colaci N , Barugola G , Variola A
Published: January 2024

Background

Inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn’s disease (CD), is a group of chronic inflammatory disorders. Biologics are indicated for patients failing conventional maintenance therapy with moderate to severe activity. Different routes of administration, intravenous (IV), subcutaneous (SC) or oral have been approved. For chronic diseases such as IBD, some patients may prefer self-administered SC dosing to IV dosing as a less time-intensive and more convenient treatment option. This study aims to evaluate evaluate the success of infliximab subcutaneous administration after switching from intravenous administration in IBD patients.

Methods

The transition from IV to SC administration was proposed to 60 IBD patients in clinical remission. Data on medical history and laboratory tests were collected from electronic health records. Moreover, patients filled a paper questionnaire 8 weeks after the switch focused on the level of satisfaction and onset of adverse event (AE).

Results

Overall 60 patients were enrolled for switching from IV to SC therapy. Most of patients (>80%) did not experience any difficulties in handling the device and respected the correct time-table of administration. The switch was a complete success in 50 out of 60 patients (83.3%). Ten patients stopped subcutaneous formulation: five of these switched back to intravenous formulation for adverse event or patient’s preference, four swap or swop to other therapy and one withdraw from biologic. No predictor of loss of response was found at multivariate analysis. Faecal calprotectin and C-reactive protein values significantly improve after the switch at 3, 6 and 12 months (p= 0.03, p= 0.004, p = 0.01 and p= 0.06, p= 0.001, p= 0.007 respectively). About 16.7 % of patients had at least one side effect after switching. Local pain and swelling at site of injection were the most common AEs. The vast majority of AE were mild and lasted only a few days. No serious AEs were reported and no patient was hospitalized.

Conclusion

Effectiveness of switching from intravenous to subcutaneous infliximab administration in IBD patients is confirmed in our real world cohort of patients.
P896 You Can Lead a Horse to Water But You Can’t Make it Drink: A Study on Medication Adherence of Inflammatory Bowel Disease Patients in Ireland
Authors: Kumar L , Hanly M , Drudy A , Girod P , Fennessy A , Mulcahy H , Horgan G , McDermott E , Buckley M , Sheridan J , Cullen G , Doherty G
Published: January 2024

Background

Medication adherence is important in ensuring adequate treatment of Inflammatory Bowel Disease (IBD). The High Tech Hub (HTH) is an online system used in Ireland to prescribe and monitor the ordering of High-Tech Medication, specifically oral small molecules and subcutaneously-delivered biologics. We aimed to observe compliance rates of treatment in our centre, observe trends between different medication and identify factors associated with adherence.

Methods

We extracted prescribing and medication dispensing information from the HTH database for our centre between May and November 2023. We collected information on patient demographics such as age and gender, patient disease subtype, medication class and duration of prescription given against the duration of prescription collected by the patient with an 85% threshold as a marker of compliance to treatment. Statistical analysis was used to compare differences in adherence between subsets of the population and a multivariate regression model was used to identify factors associated with adherence.

Results

We extracted information from 824 prescriptions from 644 unique patients. The median age was 42 years (IQR 32-52) with 52.2% males. 60.7% (n=391) had Crohn’s Disease, 33.4% (n=215) had Ulcerative Colitis and 3.1% (n=20) had IBD-U. Majority of patients, 77.3% (n=498), were on Anti-TNF medication, followed by 13.2% (n=75) on anti-Interleukins, 6.2% (n=40) on JAK Inhibitors and 3.3% (n=21) Anti-Integrins.

6.5% (n=42) of patients required dose optimization during the 6-month observation and 1.7% (n=11) required a change of medication. 9.5% (n=61) of patients collected prescriptions for steroids. Further analysis demonstrated no significant difference in adherence within gender (Male: 61.0% vs. Female 53.6%, p=0.056), age (<25 years: 66.2%, 25-39 years: 55.0%, 40-54 years: 58.6%, ≥55 years: 54.6%, p=0.346), disease type (Crohn’s: 58.6%, Ulcerative Colitis: 56.7%, IBD-U: 50%, p=0.776), medication class (Anti-TNF: 56.4%, Anti-Interleukin: 65.9%, Anti-Integrin: 57.1%, JAK Inhibitor: 52.5%, p=0.378).

However, we found significant lower adherence rates in patients who required dose optimization (21.4% vs. 60.0%, p<0.001) and those who required a change in medication (18.2% vs. 58.1%, p=0.008) in the observation window. There was also a lower rate of adherence noted in those who received prescriptions for steroids (45.9% vs 58.9%, p=0.051).

Conclusion

There was a high rate of non-adherence noted in our IBD population, worse in those who ended up requiring dose optimization or change in therapy. Addressing compliance by monitoring the online dispensing of medication may be a useful way to ensure adequate treatment and avoid unnecessary treatment escalation.
P899 Inflammatory Bowel Disease Patients Show More Recognizable Digestive Symptoms of COVID-19: A Questionnaire Study
Authors: Xu Z , zhimin M , lujia J
Published: January 2024

Background

It's important to manage IBD patients in the era of coronavirus pandemic (COVID-19). However, there is few studies on the clinical symptoms and prognosis of COVID-19 in IBD patients.

Methods

A web-based survey concerning symptoms of COVID-19 in people with or without IBD was designed. A pilot-test was carried out to ensure the feasibility of the questionnaire. Propensity score matching (PSM) was used to compensate for differences in baseline characteristics. Wilcoxon rank-sum test and Chi-square test were used to compare the clinical and prognosis differences between two groups.

Results

A total of 1274 individuals (including 631 with IBD) completed the questionnaire. After the use of PSM, 786 cases including 393 of IBD and non-IBD individuals respectively were included in the analysis. Fever and nasal congestion were the most common clinical manifestations of COVID-19 in our study. As for gastrointestinal (GI) symptoms, more IBD patients presented with new-onset abdominal pain (26.7% vs. 12.7%, p<0.001), diarrhea (22.4% vs. 14.5%, p<0.005) and altered bowel habits (38.7% vs. 24.9%, p<0.001).

Conclusion

COVID-19-related GI symptoms are more common in IBD patients. It is important to rule out COVID-19 infection in patients experiencing recurrence or exacerbation of GI symptoms.
P906 The drug-survival of low-dose thioguanine in patients with inflammatory bowel disease. A retrospective observational study
Authors: Karling P , Werner M , Gensmyr-Singer H
Published: January 2024

Background

Thiopurines are commonly used to treat inflammatory bowel disease but withdrawal due to side-effects are common. Thioguanine has been suggested to be better tolerated than conventional thiopuries. We aimed to study drug-survival of low-dose of thioguanine in real-life clinical practice in comparison to conventional thiopurines.

Methods

All patients born in the year 1956 and later, and who at least once started thiopurine treatment between the years 2006-2022 were included. A medical chart review was performed that noted drug-survival for every thiopurine treatment attempt. Mantel-Cox rank test was used to test differences in drug-survival for different thiopurines. Blood chemistry analysis and faecal calprotectin levels was registered the first five years of treatment.

Results

In the study population there was 379 initiated thiopurine treatments (210 for Crohns disease and 169 for ulcerative colitis) in 307 patients with IBD. Low-dose thioguanine (median dose 11 mg; 25-75th percentile 7-19 mg) had been initiated in 31 patients. Overall, when including all thiopurine attempts, the median time on treatment for the different thiopurine treatments were for azathioprine 24 months (25th-75th percentile 3-59 months), for 6-mercaptopurine 15 months (3-59 months), for azathioprine/allopurinol 22 months (1-25 months) and for thioguanine 33 months (11-64 months). Thioguanine had longest drug-survival (Mantel-cox rank test: thioguanine versus azathioprine p=0.014; thioguanine versus 6-mercaptopurine (6-MP) p<0.001). For second line thiopurine treatment, the median time on treatment for 6-mercaptopurine were 13 months (2-69) and for thioguanine 33 months (11-64). Thioguanine had longer drug-survival than 6-MP (Mantel-Cox rank test: p=0.006) (Figure). At 60 months, 86% of the patients who started low dose thioguanine was still on treatment compared to 42% of the patients who started 6-MP (p=0.022). The median 6-TGN levels in patients treated with thioguanine was 364 pmol/8x108. Patients on thioguanine treatment showed significantly lower values of median mean corpuscular volume at follow-up than patients treated with azathioprine and 6-MP. Patients treated with 6-MP had signficantly lower levels of F-calprotectin at year three and year four compared to patients treated with azathioprine. Overall there was a similar response on inflammatory markers the first five years from starting treatment with thioguanines compared to conventional thiopurines.

Conclusion

Treatment with a low-dose of thioguanine is well tolerated in patients with IBD and have a significantly higher drug survival than conventional thiopurines.
P928 "Metabolism and Response to Stress" (MARS) gene signatures reveal heterogeneity in patients with Ulcerative Colitis and identify characteristics of patients with increased response to therapy
Authors: Linggi B , Sangiorgi B , Smith M I , Teft W , Jairath V , Ma C , Vande Casteele N
Published: January 2024

Background

Ulcerative colitis (UC) therapies lead to variable remission in participants in clinical trials likely due to interindividual variability, differences in active biological pathways, feedback, and/or resistance mechanisms. We sought to characterise these differences using mucosal biopsy transcriptomics datasets from two recent UC clinical trials.

Methods

Two clinical trial datasets including patients with moderate to severe UC with mucosal biopsy RNA-Sequencing analysis were used: a phase 2/3 study of andecaliximab (anti-matrix metalloproteinase-9, NCT02520284) and a phase 3 study of ustekinumab (anti-interleukin-12/23, UNIFI, NCT02407236). Samples were scored for enrichment of ~5200 MSigDB signatures using Geneset Variation Analysis and were evaluated for correlation to the sample Robarts Histopathology Index (RHI) (Figure).

Results

From the andecaliximab baseline and follow-up samples, 11 Reactome pathways were specifically selected that were moderately correlated with RHI (r=~0.4) and had low correlation to each other (r<0.7). The 11 genesets, called Metabolism and Response to Stress (MARS) signatures, can generally be sorted into 2 categories: 5 metabolism-related and 6 related to stress response. Clustering of baseline andecaliximab samples scored with MARS signatures revealed 3 major sample groups (baseline and follow-up samples). Group 1 had low metabolism/high stress scores, group 2 had high metabolism/low stress scores, and group 3 had a mixture of samples that had high metabolism/low stress and low metabolism/high stress. Group 2 was associated with a lower proportion of current smokers (p=.04), and group 3 had a higher proportion of immunomodulator failure (p=.03), but not associated with disease duration or prior biologic use. Group 2 had lower Geboes score for epithelial neutrophils (p=.02), lamina propria neutrophils (p=.002), and inflammatory infiltrate (p=.03), while eosinophils increased (p=.01). To evaluate prediction of response to therapy, we evaluated the UNIFI dataset baseline samples using the MARS signatures and identified 4 groups. Group 2 had low metabolism/high stress response, group 3 had high metabolism/low stress response, and groups 1 and 4 had a mixture. The mucosal healing response rate was 3- to 4-fold lower for group 2 than other groups (5.3% [group 2] and 19%, 23%, and 21% for other groups, p=.0009).

Conclusion

We describe the MARS signatures which characterise the heterogeneity of participants with UC clinical trials and identify participants most likely to respond to ustekinumab at baseline. These signatures may be generally useful to predict patient response, match therapeutics to patient profiles, or identify pathways to target in difficult-to-treat patients.
P935 Remission rates of biologics and small molecules in extension studies of moderate to severe Ulcerative Colitis; A systematic review and Network Meta-analysis
Authors: Godfrey D , Parkash N , Segal J
Published: January 2024

Background

Ulcerative colitis is a relapsing and remitting inflammatory bowel disease characterised by symptoms of bloody diarrhoea and abdominal pain. In recent years, newer therapies have emerged such as biologics and small molecule therapies. However, these therapies have not been compared head-to-head in the longer term, and the choice in clinical practice is often at the discretion of the clinician. In this study we aim to compare these biologics and small molecule therapies across outcomes such as remission (as defined by the Mayo score) as well as histological, endoscopic and corticosteroid free remission in data beyond 52 weeks of medication administration.

Methods

Medical databases including MEDLINE, EMBASE and Cochrane were searched for phase III and IV randomised control trials examining efficacy of biologic and small molecule therapies in adults with moderate to severe ulcerative colitis beyond 52 weeks. A network meta-analysis was performed using the frequentist model to compare the aforementioned outcomes with pooled relative risk, heterogeneity and P values used to rank treatments.

Results

13 randomised control trials (RCT) were included for analysis from a screen of 2516 abstracts. Of these 13 RCTs, there were 8 treatments directly compared to placebo beyond week 52. In terms of remission as defined by the Mayo score, Upadacitinib 30mg was found to be the best treatment for moderate-severe ulcerative colitis when compared to Upadacitnib 15mg, Vedolizumab and Etrolizumab in consecutive order. In achieving histological remission, Upadacitinib 30mg was superior to Upadacitinib 15mg, Filgotinib (200mg and 100mg) and Etrolizumab. For endoscopic remission, Upadacitinib 30mg was superior to Upadacitinib 15mg, Filgotinib (200mg and 100mg), Vedolizumab, Etrolizumab and Golimumab. For corticosteroid free remission, Filgotinib 200mg was superior to Golimumab, Upadacitinib (30mg and 15mg), Vedolizumab and Etrolizumab.

Conclusion

Large head-to-head trials of biologic and small molecule therapies in the treatment of moderate to severe ulcerative colitis beyond 52 weeks have not been performed. However, our results show Upadacitinib 30mg to be efficacious in terms of remission defined by the Mayo score as well as histologic, endoscopic and corticosteroid free remission when compared to other biologics and small molecule therapies. Whilst these newer therapies show promise, their overall performance over an extended period remains unclear and their use often precludes the efficacy of subsequent biologic or small molecule therapies. As such, the first choice of therapy must be made carefully to increase the probability of remission whilst also balancing the burden of adverse events.
P945 Crohn´s disease response to ustekinumab measured by bowel ultrasound
Authors: Navarro-Gerrard C , Bastón Rey I , González López J , Ferreiro Iglesias R , Sequeiros Portela M D , Dominguez Munoz J E , Barreiro de Acosta M
Published: January 2024

Background

After the STRIDE-II update for patients with Crohn’s disease (CD) one of the new possible adjunct treatment goals was transmural healing, yet its assessment is still not fully cost/risk-benefit proven. A valuable tool to assess this adjunct goal is bowel ultrasound. For this reason, our aim was to evaluate the bowel ultrasonographic response to ustekinumab at one year.

Methods

Retrospective, observational, single center study was designed. All adult patients with CD who were treated with ustekinumab and had a bowel ultrasound just before the induction dose with ustekinumab and who repeated the bowel ultrasound one year after it were included. Examination was done by ultrasound machine (Hitachi Avius) with low frequency curved-array (1-5 MHz) and high-frequency linear-array (5-13 MHz) transducers. The measured bowel ultrasonographic variables were: wall thickness, Doppler activity (Limberg index) and fatty striation. Ultrasonographic response was defined as a reduction in wall thickness of at least 25%, 2mm or 1mm plus 1 Doppler sign. Remission was defined as wall thickness less than 3mm plus absent Doppler sign. Patient demographics and disease characteristics were also collected: age, sex, extension of CD, previous biologic treatments and ustekinumab trough levels. Demographic and clinical characteristics were compared using χ2 analysis (or Fisher’s exact test), Student’s t test or Spearman correlation. All statistical analyses were performed using the STATA Statistical Software.

Results

A total of 41 patients (56.1% female) with a mean age of 57.9 years (SD ±2.7) were included. 63.4% had ileal disease and 36.6% ileocolonic involvement. Ustekinumab was first line of biologic treatment in 7.3%, second line in 61.0%, third line in 29.3% and fourth line in 2.4% of patients. 63.4% of patients were on ustekinumab 90mg subcutaneous every 4 weeks at one year with a median trough level of 8.6 (range 7.9-10.6). The median wall thickness measured by bowel ultrasound before induction was 5.5 mm (range 5.0-6.4) and after one year it was 5.0 mm (4.1-5.7) (p=0.47) Figure 1. Before treatment Limberg index was 3 in 26.8% and after treatment it was 3 in 4.9% (p=0.052). Fatty striation was present in 90.2% of patients at the beginning of treatment and in 63.4% at one year (p=0.013). Ultrasound response was achieved in 36.6% of patients while transmural remission was achieved in 12.2% of patients in the first year. No association between ustekinumab trough levels and response/remission were found (p=0.70/p=0.83)

Conclusion

Treatment with USK was related with an ultrasonographic response in one third of patients with refractory CD at one year. No association between ustekinumab trough levels and ultrasonographic response/remission were found
P963 The comparative effectiveness and safety of different biologics in young (<60 years) versus elderly (≥60 years) patients with IBD: results from a real-world experience at a Belgian tertiary centre
Authors: Deroo L , Truyens M , Geldof J , Akhayad S , Dewitte G , Glorieus E , Lobaton T
Published: January 2024

Background

The therapeutic armamentarium for inflammatory bowel disease (IBD) is rapidly expanding as well as the number of elderly patients with IBD. Given the frailty of this subpopulation, it is of increasing importance to have data on the efficacy and safety of different therapies in this cohort. Aim: To assess the efficacy and severe adverse event (SAE) rate of different biologics in young (<60 years (yr)) versus elderly patients with IBD (≥60 yr) in a real-world tertiary cohort.

Methods

A retrospective monocentric study was performed at the Ghent University Hospital. Patients starting anti-TNF, ustekinumab (UST) or vedolizumab (VDZ) from 01/2018 to 06/2021 with follow-up until 12/2022 were included. Co-primary endpoints after induction and after 1 yr of therapy were: clinical response (CRp) and remission (CRm), biochemical response (BRp) and remission (BRm) and endoscopic response (ERp) and remission (ERm). The secondary endpoint was treatment survival. Severe adverse events (SAE) were defined as intestinal resection (IR), IBD-inflammation related hospitalization (IBD-hosp), IBD-treatment related hospitalization (e.g. infections) (treat-hosp), malignancy and death. Multivariate logistic regression (MLR) and Cox regression model (CRM) were applied to assess potential risk factors (RF).

Results

A total of 267 patients were included (33 patients ≥60 yr). Significantly different baseline characteristics are shown in Table 1A. After induction, no differences in CRp, CRm, BRp, ERp or ERm were found between both groups (Table 1B). Only BRm was numerically higher in younger patients, but not statistically significant after MLR (Table 1C). After one year of therapy, no difference was seen for CRp, CRm, BRp, BRm, ERp or ERm (Table 1B). There was no difference regarding treatment survival for both groups (aHR 0.701, [0.346-1.420], P=0.324) (figure 1), as well as for reason to stop biologic (P=0.336). Regarding SAEs, a higher rate was seen for elderly patients (26.9% vs. 45.5%, P=0.028), also after CRM (aHR 1.86, [1.01-3.44], P=0.047), adjusting for type of biologic, use of systemic corticosteroids or immunomodulators, previous IR, disease duration and number of previous biologics used. Regarding different subtypes of SAE, no difference for IR (P=0.503), IBD-hosp (P=0.714), specific IBD related SAE (P=0.480), malignancy (P=0.162) and death (P=1.000) were found. Treat-hosp was higher in elderly patients (5.1% vs. 24.2%, P=0.001), which was confirmed in the CRM (aHR 5.01, [1.92-13.04], P<0.001).

Conclusion

No difference was seen regarding efficacy of different biologics in younger versus elderly patients with IBD. SAE rate was higher in elderly patients.
P969 Unveiling the molecular mechanisms of the combination of vedolizumab with JAK inhibitors in Crohn’s Disease through a systems biology and artificial intelligence-based approach
Authors: Marín-Jiménez I , Sierra-Ausín M , Letosa-Abián T , Aparicio J , Montoto-Otero C , Sánchez-Ramón S
Published: January 2024

Background

Clinical evidence supports the combination therapy of vedolizumab (a gut-selective, anti-lymphocyte trafficking drug inhibiting α4β7-integrin) with JAK 1, 2, 3 inhibitors (JAKi) for Inflammatory Bowel Disease. However, the mechanistic explanation for the improved outcomes in Ulcerative Colitis patients treated with vedolizumab plus JAKi remains unknown and even more in Crohn's Disease (CD). In this study we used an unbiased in silico systems biology and artificial intelligence approach to gain a holistic view of the mechanisms that may underpin the potential benefits of the mentioned combination therapy in the treatment of CD.

Methods

The drugs under study -vedolizumab and JAKi- and CD were characterized at protein level by compiling data from extensive literature search. Through it, human protein interaction networks focused on CD protein effectors were generated and used to construct mathematical models using Therapeutic Performance Mapping System (TPMS) technology (Anaxomics Biotech, Barcelona, Spain). Sampling-based methods were employed to assess the impact on CD of the combined therapy vedolizumab plus JAKi and to describe underlying molecular mechanisms.

Results

Characterization of CD allowed identifying 4 pathological processes (referred to as motives-M) underlying the manifestation of the disease: intestinal barrier disruption (M1), increased innate immune response (M2), chronic inflammation and Th1/Th17 adaptive immune response (M3) and tissue remodeling (M4) and the molecular effectors or proteins involved in each motive. The combination of vedolizumab and JAKi induced a high degree of reversion of the effectors altered in CD (54.76%), higher than the percentage reverted by the individual drugs. Combined vedolizumab plus JAKi therapy mainly modulated M3, where both drugs mostly converge although by distinct mechanisms, thus providing additional individual benefits. The combination therapy reverted a great percentage of M3 effectors, for example, CCR9 and FASLG which were increased in CD, were reverted (or downregulated). In addition to M3 modulation, the combination therapy also modulated M1 and M4. In M1, vedolizumab is the one that would provide more complementary mechanisms apart from those that already converge in both drugs. Regarding M4, it seems that main contribution comes from complementarity pathways of the different mechanisms of action of each individual drug.

Conclusion

The constructed in silico models reveal that the combined vedolizumab plus JAKi therapy could modulate a high array of effectors altered in CD, more than any of the therapies alone, by enhancing the effects of the individual drugs, and provide a mechanistic rationale for employing the combination of these drugs as potential therapy for CD.
P982 Patients in trials of moderate-to-severe CD who are exposed to placebo are more likely to suffer harm than those receiving active treatment: The lack of clinical equipoise in traditional study designs
Authors: Fear E , Fine Z D , St-Pierre J , Klein J A , Choi N K , Rubin D T
Published: January 2024

Background

Crohn’s disease (CD) is a relapsing-remitting inflammatory disease of the gastrointestinal tract characterized by a progressive nature and a variety of complications. There are many challenges to the recruitment of eligible individuals into clinical trials for IBD, including the availability of multiple standard-of-care treatment options and patient refusal to participate in randomized placebo (PBO)-controlled trials due to fear of receiving PBO. Patient harm across clinical trials for moderate-to-severe CD has not been adequately examined. We sought to quantify the potential harms to patients recruited to PBO.

Methods

We reviewed phase 3 clinical trials of therapies including anti-TNF-alpha (infliximab, adalimumab, certolizumab pegol), anti-integrin (vedolizumab, natalizumab, etrolizumab), anti-interleukin (IL) 12/23 (ustekinumab), anti-IL23 (ustekinumab, risankizumab), and Janus kinase inhibitor (upadacitinib). We analyzed the proportions (# of pts. with events/cohort size) of adverse events (AEs), serious adverse events (SAEs), disease exacerbation AEs (DEAEs), and disease exacerbation SAEs (DESAEs). We calculated Number Needed to Harm (NNH), 1 / (Incidence rate in cohort) for PBO (NNHPBO) and experimental therapy (NNHRx) in each trial. Maintenance phase NNHs were categorized as treat-through (TT) or re-randomized (RR).

Results

We identified increased probability of AEs in the PBO arm of 5/12 induction (NNHPBO= 1.2-3.6; NNHRx=1.2-5.2), 3/6 TT maintenance, and 6/9 RR maintenance (NNHTTPBO= 1.2-3.4; NNHTTRx= 1.1-4.5; NNHRRPBO= 1.0-2.0; NNHRRRx= 1.1-1.4). There was an increased probability of SAEs for patients exposed to PBO in 4/11 induction (NNHPBO= 6.6-24.7; NNHRx= 4.8-26.6), 5/6 TT, and 8/9 RR (NNHTTPBO= 3.4-15.1; NNHTTRx=3.6-19.0; NNHRRPBO= 6.0-13.1; NNHRRRx= 8.1-11.9). Patients were at increased probability of DEAEs in the PBO arm of 5/8 induction (NNHPBO= 6.3-12.3; NNHRx= 10.0-62.0), 5/5 TT, and 6/9 RR (NNHTTPBO= 3.1-8.5; NNHTTRx= 4.4-24.0; NNHRRPBO= 2.5-7.0; NNHRRRx= 7.1-9.4). There was an increased probability of DESAEs for patients exposed to PBO in 5/6 induction (NNHPBO = 10.4-42.4; NNHRx= 43.2-206.0), 3/4 TT, and 3/4 RR (NNHTTPBO= 11.4-42.4; NNHTTRx= 8.2-216.0; NNHRRPBO= 15.5-26.8; NNHRRRx= NA).

Conclusion

In PBO-controlled clinical trials of therapies for moderate-to-severe CD there are increased AEs and SAEs for patients exposed to PBO, notably in DEAEs and DESAEs. Induction treatment responders re-randomized in maintenance to PBO experienced greater harms (i.e. lower NNH) than TT PBO patients. These findings raise concerns about clinical equipoise and support ongoing efforts to design trials with active comparator arms and adaptive or platform methodologies.
P988 Preliminary report on short-term post-operative outcomes of robotic versus laparoscopic approach for restorative procto-colectomy with ileal-pouch-anal anastomosis in ulcerative colitis: a comparative study
Authors: Emma E P , Palleschi C V , Mariatti M , Minuzzo A , Perna F , Gia E , Ferrara A , Ficari F , Scaringi S
Published: January 2024

Background

Restorative proctocolectomy with ileal pouch–anal anastomosis (IPAA) performed in two or three stages has become the standard surgical treatment in patients with ulcerative colitis (UC) in which the medical management fails. It is a technically complex operation associated with significant morbidity that can be performed with a laparoscopic or robotic approach. Robotic colorectal surgery is gaining popularity because it overcomes many of the mechanical and optical disadvantages of laparoscopy, although limited data are available regarding its safety, efficacy, and costs. This study compares the postoperative short-terms surgical outcomes of the two surgical approaches.

Methods

Robotic and laparoscopic restorative proctocolectomy procedures with IPAA consecutively performed between June 2015 and May 2023 were retrospectively collected. Inclusion criteria was UC not responders to medical therapy. Exclusion criteria was conversion to open surgery. Primary analyzed outcome were complications rate in the first month (30 days) according to Clavien Dindo Score and length of hospital stay (days). Statistical analysis was performed with a dedicated software (SPSS).

Results

A total of 54 patients with UC refractory to medical therapy were included, with 31 laparoscopic procedure and 23 robotic procedures.

Demographic data were comparable between two groups in terms of age (48.7 vs 45.7 years; p= 0.62), BMI (22,0 vs 23,7 Kg/m2; p= 1.311) and ASA score (p=0,72).Short-term complications defined as Clavien Dindo scores 2-3, (compared with score 1) were 13% in the robotic group and 31% in the laparoscopic group (RR= 0.27, 95% conf. interv. 0.11-1.06). In particular, no high-grade Clavien-Dindo complications occurred in the robotic group while 3 events (grade 3) occurred in the laparoscopic group. No surgical reintervention was needed in both groups.

Length of hospital stay was a mean of 7.3 days in lap-group and 6.3 days in rob-group with no statistical significativity (p=0,09).

Conclusion

This preliminary study concludes that robot-assisted surgery allows a reduction of short-term complications compared to laparoscopic approach. Moreover, robotic surgery allows a reduction of length of hospital stay although not statistically significant. Limits of the study were the retrospective design and the low numerosity of the sample, although comparable with the experiences already published.
P991 Serum anti-TNF levels correlate with tissue levels in perianal fistulising Crohn’s Disease
Authors: Anandabaskaran S , Liu Z , Hanna L , Hart A , Tozer P
Published: January 2024

Background

Perianal fistulising Crohn’s Disease (PFCD) affects up to 25% of patients and remains difficult to treat despite medical and surgical advancements.1 Perianal fistulas have unique immunopathogenic features associated with an aggressive phenotype of CD with studies showing the need for higher drug levels for fistula healing in pCD.2-4 Unfortunately, no medical therapy has been shown to be more than 40% effective in maintaining sustained remission suggesting a therapeutic ceiling in PFCD management.5 This calls for a better understanding of the role tissue drug penetrance plays in PFCD patients on biologic therapy. Previously, Adegbola et al.4 failed to identify tissue levels in PFCD patients using a Liquid chromatography-mass spectrometry (LC-MS) assay. Enzyme-linked immunosorbent assay (ELISA) is well validated and used in standard clinical practice for anti-TNF drug level measurement in blood samples. We aimed to determine tissue biologic drug penetrance in PFCD by quantifying rectal and fistula biologic levels in patients on established anti-TNF therapy using ELISA.

Methods

Paired blood, rectal and fistula tract biopsies were collected from 15 patients undergoing examination under anaesthesia for active pCD on established anti-TNF therapy (greater than 14 weeks since induction). Sample handling involved centrifugation within 12 hours of collection into serum and storage at −80°C for blood, snap-freezing with liquid nitrogen and storage at −80°C for tissue. Extraction was with an ELISA buffer based on tissue weight and the supernatants were extracted for anti-TNF measurement. Patient demographics including symptom burden were collected on the day of surgery.

Results

Patient demographics are shown on Table 1. Analysis (Figure 1) showing a trend towards correlation of high symptom burden (PDAI score) with low serum, rectum, and fistula anti-TNF levels (highlighted in yellow) across both Infliximab and Adalimumab patients. Furthermore, serum anti-TNF levels correlated positively with tissue levels in rectum and fistula samples (highlighted in green).

Conclusion

This is a first-of-a-kind experiment to detect anti-TNF levels in PFCD patients on established biologic therapy. We were able firstly to show that patients with highly symptomatic disease tend to have lower drug penetrance in rectum and fistula tract tissue, and secondly that serum anti-TNF levels correlate positively with tissue levels. This study further reaffirms the importance of aiming for high anti-TNF levels in serum to ensure adequate tissue penetrance. Limitations include the small number of patients recruited, and it is unclear how well a single biopsy represents the anti-TNF drug distribution across the entire rectum and fistula tract.
P994 Single center assessment of intravenous ustekinumab maintenance in Crohn’s disease
Authors: Fernández Prada S J , Fuentes-Valenzuela E A , Barrio Andrés J , De Prado Santos Á , Marinero Muñoz M Á , Calleja Carbajosa R , García Alonso F J
Published: January 2024

Background

Ustekinumab (UST) is usually employed in Crohn’s disease (CD) after anti-tumor necrosis factor (TNF) therapy failure or if anti-TNF therapy is contraindicated. Higher UST trough levels have been associated with better clinical/endoscopic outcomes, so dose escalation (reducing dosing intervals or reinduction) is widely used. Intravenous (iv) maintenance has been proposed, but it has been barely assessed.

Methods

Single center, retrospective case series. All patients with CD starting treatment with UST and receiving at least one dose were eligible. Subjects started on UST in other centers or those prescribed for any indication different than IBD were excluded.

Dose escalation to iv maintenance was performed in case of lack or loss of response or persisting significant inflammation in laboratory tests, imaging or endoscopy. Following dose escalation, Harvey Bradshaw Index (HBI), fecal calprotectin and C reactive protein (CRP) were checked at each visit. UST trough levels were also assessed.

Primary outcomes were clinical remission (HBI<5) and biochemical remission (fecal calprotectin <250 mg/kg). Adverse events, and treatment persistence were also assessed.

Results

A total of 131 patients treated between May 2017 and August 2023 were included. Sixty (45.8%) patients were escalated to iv UST maintenance after a median of 14.1 (IQR: 8-50.4) weeks of UST treatment. Baseline characteristics are shown in table 1.

Patients were started on iv UST maintenance due to persistent inflammatory activity in imaging/endoscopic procedures in 21 (35%), clinical response without remission in 17 (28.3%), low trough concentrations in 16 (26.7%) and primary non-response in 6 (10%). Thirty-three (55%) were receiving sc UST every 4 weeks and 23 (38.3%) started iv maintenance directly after UST induction. At initiation of iv maintenance, patients presented a median HBI index of 4 (IQR: 2-7), a fecal calprotectin of 514 (IQR: 213-1078) mg/kg and UST trough levels of 4.8 (IQR: 3-7.3) μg/mL.

Following iv maintenance, UST trough levels increased to 10.9 (IQR: 8-17.4). Clinical remission rates increased from baseline (48.3%) at weeks 8 (79.6%, p=0.001), 24 (72%, p=0.01) and 48 (74.4%, p=0.01). However, the 10-13% increase observed in the biochemical remission rates was not statistically significant (figure 1). Treatment persistence 2 years after starting UST iv maintenance was 72.2% (95% CI: 54.7-83.8%). Only 2 infectious adverse events were observed in the whole cohort (2/131, 1.6%), both in patients receiving sc maintenance.

Conclusion

UST iv maintenance in bio-experienced patients is safe and increases clinical remission rates, although it did not achieve a relevant improvement in biochemical remission rates.
P996 Clinical Efficacy and Predictive Factors for the Effectiveness of Granulocyte and Monocyte Adsorption Apheresis Therapy for Ulcerative Colitis：A Retrospective Observational Single Center Study
Authors: Kenta F , Kensuke S , Shun T , Ryosuke W , Yusuke N , Ren Y , Kentaro S , Itsuki S , Hisashi O , Takuto M
Published: January 2024

Background

Granulocyte and Monocyte Adsorption Apheresis (GMA) is one of the valuable non-immunosuppressive therapies in the treatment of ulcerative colitis (UC). However, due to the limited number of facilities where GMA can be performed, there are few reports on the combined effects of GMA and prednisolone (PSL), the frequency of GMA implementation or predictive factors for the effectiveness. In this study, we examined the combined effect of GMA and PSL as a remission induction therapy, the frequency of GMA and predictive factors.

Methods

A retrospective observational study was conducted at Kushiro Rosai Hospital. We analyzed clinical data from UC patients who underwent GMA from February 2015 to May 2023.

Results

The study included 54 patients (30 males and 24 females), with a median age of 48 years and a median disease duration of 2 years. The median Lichtiger-CAI (L-CAI) was 8. There were 43 patients of pancolitis. There were 51 biologics-naïve patients and 3 biologics-experienced patients. Concomitant medications included 5-ASA agents in 21 patients, immunomodulators in 7 patients, and PSL in 31 patients. The median CRP was 1.19 mg/dl and the median albumin was 3.5 g/dl. Adverse events were observed in 3 patients (fatigue, dizziness, palpitations). The median number of GMA sessions was 10, with 33 patients undergoing twice weekly and 9 patients three times weekly. The clinical remission rate was 80% (43/54), and the clinical response rate was 89% (48/54), with a significant improvement in the median L-CAI from 8 to 3 before and after GMA (P<0.001). In the comparison between the PSL concomitant group and the non-PSL group, the clinical remission rate was 83.9% (26/31) in PSL group and 73.9% (17/23) in non-PSLgroup (P=0.369). The clinical response rate was significantly higher in the PSL group (87% (27/31)) than in non-PSL group (52.2% (12/23)) (P=0.004). There was no significant difference in the clinical remission/response rate between the group that underwent GMA twice a week (76.9% (30/39)/84.6% (33/39)) and three times a week (77.8% (7/9)/77.8% (7/9)). In univariate analysis, biologics-naïve was extracted as a contributing factor to clinical remission. The cumulative remission rate at 52 weeks was 72% overall. There was no significant difference in the cumulative remission rate between the PSL group (76.8%) and the non-PSL group (67.6%) (P=0.524). There was also no significant difference between the twice-weekly group (75%) and the three-times-weekly group (57.1%) (P=0.236).

Conclusion

GMA for UC was found to be useful and safely performed as a remission induction therapy. Concomitant use of PSL increased the clinical response rate. The frequency of GMA showed that three times per week was as effective as two times per week.