bluuebunny/crossref_metadata_2025_split huggingface dataset:
P633 First-in-Human Pharmacokinetic and Safety Study of an Anti-TL1A Antibody, TEV-48574, in Healthy Volunteers and Asthma Patients
Authors: Balyan R , Ghibellini G , Sunzel E M , Dreymann J , Radivojevic A , Dotan O , Angeles T , Li S , Papp A , Rasamoelisolo M , Rabinovich-Guilatt L 
Published: January 2024

Abstract

Background
TEV-48574 is a human antibody that targets tumor necrosis factor (TNF)-like ligand 1A, also known as TNF superfamily member 15 (TNFSF15). TEV-48574 is in clinical development as a potential treatment for ulcerative colitis (UC) and Crohn’s disease (CD); and has been shown to reduce fibrosis, inflammation, and mortality in animal models of IBD and asthma.1 The main objectives of this phase 1 study were to characterize the pharmacokinetics (PK) and safety of TEV-48574 in healthy subjects and mild asthmatic patients.

Methods
In the single ascending dose part of the study (SAD), healthy subjects were randomized 6:2 to active and placebo treatment; specifically participants were either administered TEV-48574 single dose (1, 4, 12, 36, 90, 200, 400, or 1000 mg) or placebo by subcutaneous route (SC). In the multiple ascending dose part of the study (MAD) patients with asthma were randomized 9:3 to active and placebo treatment in three cohorts. Cohort 1 received TEV-48574 200 mg Q2W or placebo (days 1, 15, and 29). Cohort 2 received a loading TEV-48574 dose of 800 mg on day 1 followed by 2 maintenance doses of 600 mg on days 15 and 29 (800/600 mg Q2W) or placebo. Cohort 3 received a loading TEV-48574 dose of 2300 mg on day 1 followed by 2 maintenance doses of 1600 mg on days 15 and 29 or placebo. Safety, tolerability, PK, and anti-drug antibody (ADA) levels were assessed at predetermined times. Measurement of total and free TL1A using ligand binding assays will be reported elsewhere.

Results
TEV-48574 was absorbed slowly with peak concentrations appearing at 72- 96 hours following SAD and MAD administration. It was eliminated gradually in a monophasic manner and the rate of elimination appeared similar across dose levels (Figure 1). Exposures as defined by maximum concentration (Cmax) and area under the curve (AUC) of TEV-48574 increased in a dose-proportional manner with no accumulation. Mean t½ estimates ranged from 6.5 to 9.6 days (Table 1).
Administration of TEV-48574 was generally well tolerated at doses up to 2300 mg. ADA-positive responses were observed at doses of 200 mg or lower in 23 of 48 TEV-48574-treated subjects in the SAD portion of the study and in 3 of 27 TEV-48574-treated patients in the MAD portion of the study and were not associated with safety signals.

Conclusion
TEV-48574 was well tolerated at all tested doses in healthy subjects and participants with asthma, with dose proportional increases in exposure and minimal accumulation after multiple dosing every two weeks. The data support further development of TEV-48574 in patients with IBD.
1. Clarke A. et al. mAbs.2018;10:664-677.
P635 Intravenous albumin infusion does not augment the response rate to a combination of exclusive enteral nutrition and intravenous steroids in Acute Severe Ulcerative Colitis: a randomized controlled trial
Authors: Mundhra S , Madan D , Golla R , Sahu P , K Vuyyuru S , Kante B , Kumar P , Matthew D , Prasad S , Vaishnav M , Verma M , Virmani S , Bajaj A , Markandey M , Kumar Ranjan M , Arora U , Kumar Singh M , K Makharia G , Kedia S , Ahuja V 
Published: January 2024

Abstract

Background
30-40% patients with acute severe ulcerative colitis (ASUC) fail intravenous (IV) steroids requiring medical rescue therapy/colectomy. Low baseline albumin predicts steroid non-response, and exclusive enteral nutrition (EEN) has been shown to improve steroid response and albumin levels. Albumin infusion due to its anti-inflammatory and anti-oxidant properties can further improve steroid response in ASUC, which was evaluated in present study.

Methods
In this open-label randomized controlled trial, patients with ASUC were randomized in 1:1 ratio to albumin + SOC + EEN vs. SOC + EEN (Jan2021 – Feb2023). Both arms received 5 days of EEN with 400 mg IV hydrocortisone/day. Patients in albumin arm were administered 5 days of 20% w/v intravenous albumin (100 ml). Primary outcome was steroid failure (need for rescue medical therapy or colectomy) and proportion of patients with adverse events.

Results
Sixty-one patients (albumin-30, SOC-31) (mean age-31.6 ± 10.4 years, male- 57.4%), were included. Baseline characteristics were comparable. There was no difference in steroid failure between albumin and SOC arm (10/30 (33.33 %) vs 13/31 (41.94 %), p=0.49). No adverse events were reported with albumin infusions. Colectomy rate (10 % vs 9.68 %, P=1), response to salvage medical therapy (88.89 % vs 76.92 %, P=0.62) and median duration of hospitalization (10.5 (7-16) vs 10 (7-20), P=0.43) were also comparable. Long-term composite outcome of colectomy and re-admission rates was numerically higher in the albumin than SOC arm (37.04 % vs 17.86 %), although it did not reach statistical significance.

Conclusion
There was no benefit of intravenous albumin infusion as an adjunct to IV steroids and EEN in patients with ASUC.
P636 Comparison of the real-world efficacy of filgotinib with tofacitinib in patients with refractory ulcerative colitis: A single-center retrospective study
Authors: Yagi S , Fukui H , Yokoyama K , Kaku K , Takagi Y , Ikenouchi M , Sato T , Kawai M , Kamikozuru K , Yokoyama Y , Tomita T , Shinzaki S 
Published: January 2024

Abstract

Background
Several Janus kinase inhibitors have recently been launched for the treatment of ulcerative colitis (UC). However, there are few reports comparing the efficacy and safety of each drug in patients with refractory UC, especially with filgotinib (FIL), which was recently launched and can be concomitantly used with thiopurines. We herein aimed to compare the real-world efficacy and safety of tofacitinib (TOF) and FIL in induction therapy for patients with refractory UC.

Methods
Patients with refractory UC, who received either TOF 20mg/day or FIL 200mg/day from May 2018 to October 2023 in Hyogo Medical University Hospital were included in this study. Primary outcomes were clinical response rates at 2, 4, and 8 weeks after administration of TOF or FIL. Clinical response was defined as a decrease of partial Mayo Score (pMS) of ≥2 from baseline and rectal bleeding subscore is ≤1 or a decrease of ≥1 from baseline. Secondary outcomes were cumulative incidences of adverse events during the observation period.

Results
Of the 230 refractory patients with UC, 197 received TOF and 33 received FIL treatment. The median age was 37 [IQR 27–49] and 49 [33–54] years, and the median disease duration was 3 [1–10] and 5 [2–10] years, respectively. Median durations of observation were 118 [52–188] weeks in the TOF group and 41 [29–60] weeks in the FIL group, median baseline pMS were 6 [5–7] and 5 [5–6], and serum CRP levels were 3.8 [1.3–12.3] and 1.8 [0.3–3.3] mg/L, respectively. Thirty-eight (19.3%) patients in the TOF group and 3 (9.0%) patients in the FIL group received systemic steroids, and 8 (24.2%) in the FIL group received thiopurine at baseline. The clinical response rates at 2, 4 and 8 weeks were 58.4%, 59.4% and 62.9% in the TOF group, and 42.4%, 57.6% and 48.9% in the FIL group, respectively, and the rate tended to be higher in the TOF group than in the FIL group at 2 weeks (p = 0.092). Of the patients who did not respond at 4 weeks, the TOF group had a significantly higher clinical response rate (31.3%) than the FIL group (0%) at 8 weeks (p = 0.032). Among 124 patients with prior anti-TNF-α antibody failure, 59.6% (65/109) of patients in the TOF group and 46.7% (7/15) in the FIL group achieved comparable clinical responses at 8 weeks (p = 0.407). Fifteen of 197 (7.6%) patients in the TOF group and 2 of 33 (6.1%) in the FIL group did not continue treatment until 8 weeks due to adverse events, but there were no significant differences between the groups.

Conclusion
Even in patients without a response for up to 4 weeks, TOF treatment may provide a higher clinical response than FIL treatment at 8 weeks.
P641 Faecal calprotectin determines non-response to corticosteroids in patients with immune checkpoint inhibitor colitis
Authors: Crothers-Stomps L , Kuo H , Teh W X , White L , Mohsen W , Kakkadasam Ramaswany P , Mason R , Dzienis M , Patrick D 
Published: January 2024

Abstract

Background
Immune checkpoint inhibitor (ICI) therapy has improved survival outcomes in patients with advanced malignancy. ICI colitis (ICI-C) is one of the most common adverse events which often leads to cessation of an otherwise effective therapy.1,2 Corticosteroid therapy remains first-line treatment in patients with ICI-C. The aim of this study was to assess predictors of non-response to corticosteroid therapy to help guide early escalation to biologic therapy.

Methods
Multicentre retrospective analysis of adults hospitalized with ICI-C between July 2018 to March 2023. ICI-C was defined by patients who had current or prior immunotherapy who presented with diarrhoea with negative infective faeces PCR testing and admission diagnosis of ICI-C by their treating Physician. Baseline demographic, clinical, biochemical, and endoscopic data were collected. Grading of clinical severity on presentation and response to immunosuppression was defined by CTCAE diarrhoea grading with response defined as improvement to grade 1 or less.

Results
82 patients were analysed. 31 (38%) female, median age was 65.5 years (IQR 59-72)], 27 (33%) failed corticosteroid therapy and required biologic therapy. 34 (42%) had a faecal calprotectin on admission. On univariable analysis faecal calprotectin emerged as the sole predictor of corticosteroid non-response. ROC analysis identified an optimal faecal calprotectin cut-off of 620 mcg/g to identify corticosteroid non-responders [Sensitivity 75% (57.6-92.7), Specificity 77.8% (52.4-93.6), Accuracy 76.5%, PLR 3.37 (1.36-8.38), NLR 0.32 (0.13-0.78), AUROC 0.76 (0.616-0.911), OR 10.5 (2.24-49.3), PPV 75 (47.6-92.7), NPV 77.8 ( 52.4-93.6)].12/16 (75%) of patients with a faecal calprotectin ≥ 620 required biologic therapy.

Conclusion
Faecal calprotectin is a predictor of non-response to corticosteroid therapy in patients with immune checkpoint inhibitor colitis. This study identified a faecal calprotectin threshold of 620mcg/g as the optimal cut-off to identify corticosteroid non-response and need for second-line immunosuppression. These findings may help to reduce the need for endoscopic assessment and guide early escalation to biologic therapy.
REFERENCES:
1. Fujii T, Colen RR, Bilen MA, et al. Incidence of immune-related adverse events and its association with treatment outcomes: The MD Anderson Cancer Center experience. Invest New Drugs. 2018;36(4):638-646. doi:10.1007/s10637-017-0534-0
2. Wang Y, Abu-Sbeih H, Mao E, et al. Endoscopic and Histologic Features of Immune Checkpoint Inhibitor-Related Colitis. Inflamm Bowel Dis. 2018;24(8):1695-1705. doi:10.1093/ibd/izy104.
P644 Body composition does not predict clinical course in patients with acute severe ulcerative colitis
Authors: Tassone D , Xu E , Winata S H L , Hale P , Basnayake C , Schulberg J , Flanagan E , Wright E , Kamm M A , Lust M , Niewiadomski O , Tambakis G , Clark N , Hartley I , De Gregorio M , Sutherland T , Thompson A J , Connell W R , Ding N S 
Published: January 2024

Abstract

Background
Acute Severe Ulcerative Colitis (ASUC) is a life-threatening complication of UC. Previous research has shown that body composition parameters, including sarcopaenia, are associated with outcomes in IBD. However, the relationship between body composition and the clinical outcomes of patients hospitalised with ASUC has not yet been clearly defined. We sought to further evaluate the prognostic role of body composition and further explore predictors of clinical outcome in ASUC.

Methods
We performed a cohort study of hospitalised ASUC patients. Body composition was assessed using fat and muscle segmentation, at the level of the L3 vertebral body, in patients who underwent abdominal computed tomography (CT) during hospitalisation. We defined sarcopenia according to skeletal muscle index (SMI) &lt; 38 cm2/m2 in females and &lt; 42 cm2/m2 in males. Clinical endpoints included length of hospitalisation, need for rescue medical therapy or colectomy. Between group comparisons were performed and logistic regression was used for risk factor analysis.

Results
We studied 116 patients with ASUC, 51 of whom underwent abdominal CT imaging during their hospitalisation. Median age was 32 years and 64% of patients were female. Sixty-two patients (53.5%) required rescue medical therapy. Rescue medical therapy was successful in 48 patients (77.4%) and 14 patients (22.6%) required an inpatient colectomy. Patients who underwent CT imaging during admission required increased rescue medical therapy (66.7% vs 43.1%, p=0.02) and were hospitalised for longer (11 vs 6 days, p&lt;0.001). Compared to non-sarcopaenic patients, sarcopaenic patients did not require increased rescue medical therapy (60.7 % vs 79 %, p= 0.22) nor longer median hospitalisation (10.5 vs 11.4 days, p=0.69). We observed a trend towards increased rescue therapy failure in patients with sarcopaenia (52.9% vs 33.3%, p=0.31). Higher Mayo score at presentation was associated with increased need for rescue medical therapy (OR 2.18, 95%CI: 1.43-3.33, p&lt;0.001) and an increasing C-reactive protein (CRP) to albumin ratio predicted prolonged length of stay (OR 1.44, 95%CI: 1.18-1.77, p=&lt;0.001).

Conclusion
Sarcopaenia did not predict ASUC outcomes in this cohort. Higher Mayo score and increased CRP to albumin ratio at admission predicted prolonged hospitalisation and need for rescue medical therapy.
P664 Anti-TNF exposure is associated with an increased risk of urgent and one-year colectomy in Acute Severe Ulcerative Colitis
Authors: Bourgonje A R , Posner H , Mehandru S , Colombel J F , Kayal M 
Published: January 2024

Abstract

Background
Acute severe ulcerative colitis (ASUC) affects up to 25% of patients with UC and is significantly associated with an increased risk of colectomy. Despite improvements in medical management, individual patient prognostication and risk stratification in ASUC remains clinically challenging. We explored clinical, biochemical, and endoscopic factors as potential predictors for colectomy in patients hospitalized with ASUC.

Methods
A retrospective analysis of patients with ASUC as defined by Truelove and Witts criteria admitted to the Mount Sinai Hospital between 2011 and 2020 was conducted. Patients with well-documented data on disease history, medication use, clinical symptoms, and laboratory results during admission for ASUC were included. Colectomy risk during hospitalization and within one year was assessed. Multivariable logistic regression analyses were performed to identify clinical, biochemical, and endoscopic parameters associated with colectomy risk in patients with ASUC.

Results
Out of the 158 patients included, 34 (21.5%) underwent colectomy during hospital admission, and 41 (25.9%) within one year after admission. On multivariable analysis, adjusting for age, sex, body mass index (BMI), and disease duration, prior anti-TNF exposure (odds ratio [OR] 4.59, 95% confidence interval [CI] 1.57-13.4, P=0.005) and the use of biologics (any type) at admission (OR 3.31, 95%CI: 1.14-9.63, P=0.028) were associated with an increased risk of 1-year colectomy. Conversely, the use of mesalamines at admission was associated with a decreased risk of 1-year colectomy (OR 0.31, 95%CI: [0.13-0.72], P=0.006). Furthermore, recent UC-related hospitalization (within one year of admission) (OR 2.72, 95%CI: 1.15-6.43, P=0.022) and increased number of bowel movements after 3 days of treatment (OR 1.18, 95%CI: 1.04-1.34, P=0.011) were associated with higher risk of 1-year colectomy. Biomarkers measured at admission including hemoglobin and albumin were associated with a decreased risk, while CRP was associated with an increased risk of urgent and 1-year colectomy. Patients with deep ulcerations observed at endoscopy tended to have an increased risk of urgent colectomy, although this was not statistically significant (univariable OR 3.36, P=0.081). Finally, treatment of ASUC with anti-TNF was strongly associated with a decreased risk of urgent (OR 0.30, 95%CI: 0.13-0.73, P=0.007) and 1-year colectomy (OR 0.31, 95%CI: 0.14-0.73, P=0.007).

Conclusion
In patients with ASUC, anti-TNF treatment is associated with a reduced risk of both urgent and 1-year colectomy. Conversely a history of anti-TNF exposure is linked to a higher risk of both urgent and 1-year colectomy. This data emphasizes the need for alternative therapies.
P672 Occurrence of malignancy among infliximab biosimilar and bio-originator initiators in Canada: a comparative population-based analysis
Authors: Birck M G , Lukusa L , Singh H , Narula N , Targownik L E , Leung Y , Afif W , Bernatsky S 
Published: January 2024

Abstract

Background
Infliximab (INF) downregulates the immune system. Given the immune system's role in deleting pre-cancerous cells, malignancy is a potential concern. Still, relatively few real-world data analyses have compared biosimilar versus bio-originator INF in terms of malignancy incidence. We aimed to compare malignancy occurrence among initiators of infliximab biosimilar (INF-B) and originator (INF-O).

Methods
We used data from the National Prescription Drug Utilization Information System (NPDUIS), containing pan-Canadian (except Quebec) claims-level data on prescription dispensations paid from public drug programs linked to comprehensive day surgery and inpatient care (Discharge Abstract Database, DAD) and hospital-based and community-based ambulatory care (National Ambulatory Care Reporting System, NACRS). We studied adults (≥18 years) initiating INF between January 2015 and December 2019 with no history of malignancy, HIV or organ transplant (1-year pre-baseline). Follow-up began 365 days after treatment initiation (lag period) and continued until the first cancer diagnostic code (ICD-10 C00-C97), treatment discontinuation + 365 days, or end of study period. We compared INF-B and INF-O using Cox regression models, adjusting for potential confounders/ effect modifiers: sex, age at treatment initiation, prior use of other biologics or prednisone, province (Ontario versus others), and calendar year.

Results
New users of INF-B (2,019) and INF-O (5,183) were about half female (52%), with a median age (interquartile range) of 45 years (28-62). Overall, the malignancy incidence rate was 10.2 (95% confidence interval, CI, 8.7-11.8) events per 1,000 person-years. Comparing INF-B to INF-O, the adjusted hazard ratio for malignancy was 0.97 (95% CI 0.63-1.48).

Conclusion
In this real-world dataset, we were unable to identify clear differences in malignancy comparing INF-B and INF-O. Limitations include the inability to control for residual confounders (e.g., disease severity), potential outcome misclassification, and selection bias.
P682 A Retrospective Comparison of Different Treatment Modalities in Patients with Chronic Pouchitis
Authors: Uchitel Y , Cohen N A , Hirsch A , Tulchinsky H , Zemel M , Maharshak N 
Published: January 2024

Abstract

Background
Chronic pouchitis affects ~30% of patients post total colectomy with ileal pouch anal anastomosis (IPAA) surgery. Treatment with anti-TNF, anti-integrin α4β7, anti-IL-12/23, or Crohn's disease exclusion diet (CDED), have shown promise in different studies. We aimed to compare the efficacy of these treatments in a real-world context and to detect factors that can aid in treatment choices.

Methods
A retrospective cohort study encompassing demographic, clinic, endoscopic, histologic and lab values of adult ulcerative colitis (UC) patients post-IPAA surgery with chronic pouchitis, treated with biologics or CDED at the Tel Aviv Medical Center. Data were collected at baseline, 12, 26, and 52 weeks of treatment. Primary outcomes were assessed using the modified Pouchitis Disease Activity Index (mPDAI). mPDAI response was defined as a reduction from baseline of ≥2 points, while mPDAI remission was defined as mPDAI response in addition to mPDAI score ≤4.

Results
Therapeutic interventions among 51 patients included CDED (n=10), vedolizumab (n=21), ustekinumab (n=7) and adalimumab (n=13) [Table 1].
At 12 and 26 weeks, overall mPDAI response rates were 52% and 48%, respectively, with no significant difference between groups. At 52 weeks, mPDAI response rates were significantly higher for ustekinumab and vedolizumab (60% and 55%, respectively) compared with adalimumab and CDED (27.3% and 0%, respectively), p=0.043. Fecal calprotectin reduction at week-26 was greatest for ustekinumab (93%), followed by vedolizumab (73%), adalimumab (55%), and CDED (-13%), p=0.003.
Treatment persistence over 150 weeks was significantly higher for ustekinumab (100%) compared with adalimumab (46%), vedolizumab (33%), and CDED (20%), p&lt;0.001 [Figure 1]. The predominant cause for treatment discontinuation was secondary loss of response (50%), followed by primary non-response and surgical complications (14.7% each), poor compliance (11.8%), side-effects (5.9%), and development of antibodies (2.9%).
Patients without prior biologic or immunomodulator treatment for pouchitis had significantly higher mPDAI response rates at 12 weeks (90%, p=0.016 and 73.3%, p=0.03, respectively). Patients with surgical pouch complications showed a trend towards lower mPDAI-defined response rates at 12 weeks (25% vs. 64.7%; p = 0.064).

Conclusion
Ustekinumab and vedolizumab demonstrate higher likelihood of maintaining long-term clinical and endoscopic response, along with greater reduction in fecal calprotectin compared with adalimumab and CDED. Biologic and immunomodulator therapy-naïve patients achieved higher induction response rates.