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Introduction

We conducted a retrospective analysis of a large U.S. based administrative claims database comparing the risk of major adverse cardiovascular events (MACE) and venous thromboembolism (VTE) among patients with inflammatory bowel disease (IBD) initiating advanced biological therapies.

Aims & Methods

Patients with CD and UC who were incident users of advanced biological agents from 2013 to 2023 were identified within the Optum Labs® database. The therapeutic agents included either tumor necrosis factor-α (TNF) antagonists (infliximab, adalimumab, and certolizumab pegol), IL-12/23 antagonists (ustekinumab), IL-23 antagonists (risankizumab), anti-integrin agents (vedolizumab), Janus kinase (JAK) inhibitors (tofacitinib and upadacitinib), or S1PR modulators (ozanimod). Eligible patients were required to have continuous insurance coverage for at least one year before and after treatment initiation. We estimated incidence rates (IRs) and compared risks for VTE and MACE (myocardial infarction and stroke). Fatal cardiovascular outcomes were excluded due to limited specificity and data constraints.
To account for baseline confounding, we applied stabilized inverse probability of treatment weighting (IPTW) using multinomial propensity scores. Hazard ratios were estimated using Cox proportional hazard models.

Results

We included 12,245 patients with CD (mean age: 44.5 ± 17.5 years; 54.2% female; 30.9% using concomitant steroids), and 9,430 patients with UC (mean age: 47.5 ± 17.7 years; 49.2% female; 50% on concomitant corticosteroids). Patients receiving JAK inhibitors and vedolizumab were more likely to have higher comorbidity burden than others for CD while those receiving IL-23 antagonists had the most comorbid burden for UC patients, when assessed through proportion of patients with Charlson comorbidity index of ≥ 5. In UC patients, VTE incidence rates ranged from 1.69 to 2.01 for VTE and MACE rates from 0.52 to 0.99 per 100 person-years. For CD, VTE incidence rates ranged from 0.89 to 2.33 and for MACE, 0.68 to 1.73. Hazard ratios comparing the risk of events across therapies is presented in table 1.

Table 1: Hazard ratios for risk of VTE and MACE in patients with Crohn’s disease and Ulcerative colitis receiving advanced biological therapies and small molecules

	Hazard Ratio using stabilized IPW weights (95% CI)
Therapies	Ulcerative Colitis (UC)		Crohn’s disease (CD)
	VTE	MACE	VTE	MACE
TNF antagonists (reference)	1.0 (reference)	1.0 (reference)	1.0 (reference)	1.0 (reference)
Vedolizumab	1.08 [0.81; 1.44]	0.90 [0.57; 1.39]	1.04 [0.73; 1.49]	1.11 [0.75; 1.62]
JAK inhibitors	0.72 [0.40;1.30]	0.73 [0.29; 1.85]	0.42 [0.07; 2.42]	--
IL-12/23 antagonists*	0.97 [0.65; 1.45]	1.23 [0.70; 2.16]	1.05 [0.76; 1.45]	0.94 [0.63; 1.38]
S1PR modulators	0.54 [0.13; 2.23]	--	--	--
IL23 antagonists			1.26 [0.64; 2.48]	1.37 [0.56; 3.31]

* For UC analysis, this group included 67 patients receiving IL-23 antagonists

Conclusion

In this large real-world IBD cohort, there was no difference in risk of adverse cardiovascular and thrombotic events between any biological agent or small molecule, in compairosn to TNF antagnoists.

Disclosure

CM: Consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Forte Biosciences, Fresenius Kabi, Gilead, Janssen, McKesson, Mirador Therapeutics, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Takeda, Tillotts Pharma; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Eli Lilly, Ferring, Fresenius Kabi, Janssen, Merck, Organon, Pendopharm, Pfizer, Sanofi, Takeda, Tillotts Pharma; royalties from Springer Publishing; research support from AbbVie, Eli Lilly, Ferring, Pfizer.
VJ: Consulting/advisory board fees from AbbVie, Alimentiv Inc, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Sandoz, Second Genome,Takeda, Teva, Topivert, Ventyx, Vividion; speaker’s fees from, Abbvie, Ferring, Galapagos, Janssen Pfizer Shire, Takeda, Fresenius Kabi
SS: Research grants from Pfizer

COMPARATIVE RISK OF ADVANCED BIOLOGICAL AGENTS FOR CARDIOVASCULAR AND THROMBOTIC EVENTS IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE: DATA FROM A REAL WORLD COHORT

Dhruv Ahuja 1, Kuan-Hung Yeh 2, Claudia Dziegielewski 2, Soo-Kyung Park 3, Sagar B. Patel 2, Shane W. Goodwin 4, Christopher Ma 5, Ashwin N. Ananthakrishnan 6, Namrata Singh 7, Ronghui Xu 2, Siddharth Singh 2

1 University of California, San Diego, United States|||Indira Gandhi Hospital, New Delhi, India

2 University of California, San Diego, United States

3 University of California, La Jolla, San Diego, United States|||Samsung Kangbuk Hospital, Sungkyunkwan University School of Medicine, Seoul, None

4 Western University, Ontario, Canada

5 University of Caglary, Calgary, Canada

6 Harvard Medical Schools, Boston, United States

7 University of Washington, Seattle, United States

Conference

UEG Week Berlin 2025

Topics

IBD

Submission format

Abstract

Session

Tackling IBD with epidemiology (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

UEG Presentation

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LARGE-SCALE GENOME-WIDE ASSOCIATION ANALYSIS OF IRRITABLE BOWEL SYNDROME IN 1,099,880 ADULTS REVEALS NEW GENETIC AETIOLOGY

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Introduction

Irritable bowel syndrome (IBS), the most prevalent gastrointestinal disorder globally, has a significant impact on the quality of life of 10 - 15% of the population, with a higher prevalence among women than men. Despite the identification of certain contributing factors, the pathophysiology of IBS remains largely unknown.

Aims & Methods

We firstly performed Genome-wide association study (GWAS) on the IBS cohort from the All of Us Research Program and adjusted for sex, age, and top 10 principal components. We conducted GWAS meta-analyses of IBS and its subtypes in 80,737 IBS cases and 1,019,143 asymptomatic control subjects from five independent cohorts (All of Us Research Program, UK Biobank, Bellygenes, Genetic Epidemiology Research on Aging, FinnGen). IBS risk loci were functionally annotated to identify candidate genes. Systematic variant-level analysis, including variants annotation, functional genomics and expression quantitative trait loci, prioritized potential causal variants. Gene-level analyses, including transcriptome-wide association study, colocalization analysis and Mendelian randomization, nominated the potential causal genes.

Results

We identified two independent IBS susceptibility loci at genome-wide significance (P < 5 × 10⁻⁸) in All of Us Research Program cohort totaling 14,897 cases and 245,388 controls. GWAS-meta analysis identified 12 novel independent (P < 5×10^-8) signals and 5 unreported loci (rs143348218, rs3748618, rs6432674, rs9536395, rs976714). Subtype-specific (P < 5×10^-8) findings based on subtype-specific GWAS meta-datasets included 3 loci for subtype IBS-C (3 novel independent loci) , 44 loci for IBS-M (2 novel independent loci). By integrating evidence from layers of different analyses, we prioritized the most plausible causal genes for IBS including CADM2, PCLO, PHF2 and SHISA6. Notably, PCLO (associated with bipolar disorder and major depressive disorder) and SHISA6 (overexpression in Platelet and T-lymphocyte) have been previously unreported in association with IBS.

Conclusion

Our study not only showed the power of the last large-scale GWAS in deciphering the genetic aetiology of IBS, but also uncovered 5 new genetic risk variants, potential unreported causal variants, genes and therapeutic targets for IBS.

References

1 Chey WD, Kurlander J, Eswaran S. Irritable bowel syndrome: a clinical review. JAMA. 2015;313:949–58. doi: 10.1001/jama.2015.0954
2 Soubieres A, Wilson P, Poullis A, et al. Burden of irritable bowel syndrome in an increasingly cost-aware National Health Service. Frontline Gastroenterology. 2015;6:246–51. doi: 10.1136/flgastro-2014-100542
3 Eijsbouts C, Zheng T, Kennedy NA, et al. Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders. Nat Genet. 2021;53:1543–52. doi: 10.1038/s41588-021-00950-8
4 Bonfiglio F, Zheng T, Garcia-Etxebarria K, et al. Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome. Gastroenterology. 2018;155:168–79. doi: 10.1053/j.gastro.2018.03.064
5 DeBoever C, Tanigawa Y, Aguirre M, et al. Assessing Digital Phenotyping to Enhance Genetic Studies of Human Diseases. Am J Hum Genet. 2020;106:611–22. doi: 10.1016/j.ajhg.2020.03.007
6 Venner E, Muzny D, Smith JD, et al. Whole-genome sequencing as an investigational device for return of hereditary disease risk and pharmacogenomic results as part of the All of Us Research Program. Genome Med. 2022;14:34. doi: 10.1186/s13073-022-01031-z
7 Weeks EM, Ulirsch JC, Cheng NY, et al. Leveraging polygenic enrichments of gene features to predict genes underlying complex traits and diseases. Nat Genet. 2023;55:1267–76. doi: 10.1038/s41588-023-01443-6

LARGE-SCALE GENOME-WIDE ASSOCIATION ANALYSIS OF IRRITABLE BOWEL SYNDROME IN 1,099,880 ADULTS REVEALS NEW GENETIC AETIOLOGY

Yajie Zhang 1, Zuodi Liang 2, Weihong Sha 1, Hao Chen 1

1 Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guang Zhou, China

2 School of Medicine of South China University of Technology, Guang Zhou, China|||Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guang Zhou, China

Event

UEG Week Berlin 2025

Topics

Colorectal

Submission format

Abstract

Session

Lower GI motility I

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

UEG Presentation

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Approaching the design of low prevalence diseases

Federico Biagi 1

1 University of Pavia, Pavia, Italy

Event

UEG Week Berlin 2025

Topics

Mechanisms & Personalised Medicine Standards & Guidelines

Session

The art of making clinical research precise: Options for study design

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

UEG Presentation

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UP-FRONT VEDOLIZUMAB VERSUS CONVENTIONAL TREATMENT FOR CHECKPOINT INHIBITOR INDUCED COLITIS – VEICO: AN OPEN LABEL RANDOMIZED CLINICAL TRIAL

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Introduction

Immune checkpoint inhibitor (ICI) mediated enterocolitis (IMC) may lead to treatment discontinuation. Corticosteroids for IMC is associated with serious side effects and might affect cancer progression in addition to preclude continued ICI treatment. We hypothesized that vedolizumab, a gut selective α4β7 integrin inhibitor, is effective as a first-line treatment and investigated whether vedolizumab reduces corticosteroid exposure and facilitate ICI resumption.

Aims & Methods

We conducted a single center, open-label, explorative phase 2 trial including patients treated with ICI who developed IMC. Patients were randomized 1:1 ratio to receive vedolizumab (300 mg) or standard treatment with corticosteroids, with infliximab used as recue therapy for corticosteroid failure. The primary outcome was cumulative corticosteroid dose at week 30. Key secondary outcomes included cumulative corticosteroid dose at week 10, corticosteroid free remission at week 10 and ICI resumption rates.

Results

Twenty-two patients received vedolizumab, and 19 patients received standard treatment. At week 10, the mean cumulative corticosteroid use was significantly lower in the vedolizumab arm (1157 mg vs. 2207 mg). By week 30, the mean corticosteroid use remained lower but not statistically significant (1378 mg vs. 2390 mg, estimated difference 1012 mg, 95% CI -229 to 2253, p=0.107), Among patients with less severe IMC, who did not need corticosteroids during screening, vedolizumab-treated patients used in average 1729 mg less corticosteroid (95% CI 631 to 2827). Corticosteroid-free remission at weeks 2 and 10 was more common with vedolizumab. Seven patients (33.3%) in the vedolizumab group resumed with ICI compared to three (16.7%) in the standard arm. In patients with severe colitis, who required upfront corticosteroid treatment, a trend towards longer hospitalization in the vedolizumab arm was observed.

Conclusion

For patients with less severe colitis, not needing corticosteroids during screening, vedolizumab may be a viable corticosteroid-sparing option, enabling faster remission and ICI resumption.