bluuebunny/crossref_metadata_2025_split huggingface dataset:
P963 The comparative effectiveness and safety of different biologics in young (&lt;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

Abstract

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 (&lt;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&lt;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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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&lt;5) and biochemical remission (fecal calprotectin &lt;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

Abstract

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&lt;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.
P1013 Placebo rates in Crohn's disease: An individual patient data meta-analysis from multiple randomised controlled trials
Authors: Solitano V , Hogan M , Singh S , Danese S , Peyrin-Biroulet L , Zayadi A , Zou G , Sands B E , Feagan B G , Narula N , Ma C , Jairath V 
Published: January 2024

Abstract

Background
Estimating placebo rates and their determinants is essential for designing efficient randomised clinical trials (RCTs) in inflammatory bowel disease. We conducted an individual patient data (IPD) meta-analysis of placebo data from RCTs in Crohn’s disease (CD).

Methods
MEDLINE, Embase, and CENTRAL were searched from 01/2010 to 01/2020 for contemporary phase 2 and 3 placebo-controlled RCTs of biologics in moderate-to-severe CD. De-identified IPD from eligible trials that were available through the Vivli and Yale University Open Data Access data-sharing platforms were obtained. Primary outcomes were placebo clinical response and remission. Pooled placebo rates and 95% CIs were estimated using a 2-stage meta-analytical approach. Significant patient-level factors (P&lt;0.05) associated with placebo rates were identified using regression analyses.

Results
Placebo IPD were available from 8 induction (n=1147) and 4 maintenance trials (n=524). Pooled placebo clinical response and remission rates varied based on outcome definition and prior biologic exposure (Figure). In induction trials, overall placebo response and remission rates were 27% (95% CI 23-32%) and 10% (95% CI 8-14%), respectively. Among bio-exposed patients, placebo response and remission rates were 27% (95% CI 16-40%) and 9% (95% CI 6-15%), respectively, compared with 29% (95% CI 24-34%) and 11% (95% CI 8-15%) for bio-naïve patients. Overall placebo response and remission rates in maintenance trials were 32% (95% CI 23%-42%) and 22% (95% CI 14-33%), respectively. Corresponding placebo response and remission rates for bio-exposed patients were 21% (95% CI 8-46%) and 17% (95% CI 11-25%), and 36% (95% CI 28-44%) and 24% (95% CI 15-36%) for bio-naïve patients. Placebo rates were lowest when response was defined as a ≥100-point decrease from baseline in the Crohn's Disease Activity Index (CDAI) score, and when remission was defined using stool frequency (≤1.5) and abdominal pain (≤1) subscores. Higher baseline C-reactive protein concentrations were associated with lower odds of placebo response and remission, while higher baseline albumin levels increased the odds of these outcomes (Table). Increased baseline CDAI and 2-item patient-reported outcome (PRO2) scores predicted higher odds of placebo response in induction trials, yet this reduced the odds of remission in induction trials and of both outcomes in maintenance trials. Prior failure to tumour necrosis factor (TNF) antagonist therapy was more predictive than prior TNF antagonist/biologic exposure for reducing the odds of placebo response and remission.

Conclusion
Placebo rates and the patient-level factors influencing them vary according to study design, clinical outcome measure and outcome definitions.