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GENETIC SUSCEPTIBILITY AND SEVERITY – A FALSE DICHOTOMY? POLYGENIC SCORES OF INFLAMMATORY BOWEL DISEASE SUSCEPTIBILITY ARE PREDICTIVE OF DISEASE SEVERITY COURSE

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Introduction

Polygenic scores (PGS) use the results of genome-association studies (GWAS) to calculate the aggregate effect of trait-associated variants carried by the individual. To date, PGS have primarily been used to model the individual risk of disease onset using summary statistics from susceptibility GWAS, typically with modest clinical relevance. For example, we can identify 1.5% of the population with a threefold increased risk of IBD onset (Khera et al.).
Much less is known about the impact of this onset PGS burden on the presentation and progression of patients with diagnosed IBD. Previous studies have failed to identify an effect of onset PGS on early onset vs late onset presentation (Serra et al.) and CD severity (Lee et al.).

Aims & Methods

We hypothesised that an increased genetic susceptibility burden for IBD has a direct impact on the severity of an individual's IBD disease course.
We genotyped 8179 patients with IBD (3688 CD; 4491 UC), linking them with registry data that captures medical interactions throughout patients' lifetimes. Patients who required 2+ IBD-related hospitalizations, 2+ IBD-related major surgeries, 1 IBD-related hospitalization and 1 IBD-related major surgery or use of systemic corticosteroids (≥5000 mg) in the first 3 years of diagnosis were defined as severe. We conducted a GWAS comparing severe patients (N=1203 UC; N=1165 CD) to those who had a less severe disease course (N=3288 UC; N=2523 CD).
We calculated individual PGS for UC and CD among individuals using the PSG scores from Middha et al. (based on De Lange et al. summary statistics) and association tests controlling for age of onset, year of onset, sex and diagnostic cohorts.

Results

We identified a significant difference in PGS between individuals with less severe and severe disease course for both CD (beta=0.23, p=2.17×10^-9) and UC (beta=0.3, p<1×10^-16).
Next, we split the cohort into quintiles by PGS and generated a stratified Kaplan-Meier curve for time to hospitalisation and surgery. Remarkably, for both outcomes and in both CD and UC the curves were ranked according to their PGS quintiles with lower ones consistently having a lower risk of adverse outcomes compared to the higher quintiles, suggesting an additive effect of genetic susceptibility on IBD severity.
In a time to event proportional hazards analysis, compared to the 20% of patients with lowest PGS, the top 20% had a much quicker time to hospitalization (CD: HR=1.79 (1.55-2.07), p=1.82×10^-15; UC: 1.68 (1.46-1.94), p=7.92×10^-13) and surgery (CD: 2.76 (2.19-3.47), p=4.69×10^-18; UC: 2.03 (1.54-2.68), p=5.57×10^-7).

Conclusion

To our knowledge, this work is the first systematic evidence of a link between IBD disease susceptibility genetics and the severity of the phenotype – patients with a higher genetic burden suffer from a more severe IBD presentation and quicker progression, suggesting that the etiology of the disease susceptibility and severity is not orthogonal.
PGS will not become the singular tool for predicting patient severity, however these are useful to add to the prognostic toolkit. Genotyping required to calculate the PGS can be done for less than €100 and can be combined with known clinically actionable pharmacogenomic variant tests and, in the future, additional targeted PGS of severity, drug response and comorbidity risk.

References

Khera, Amit V., et al. "Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations." Nature Genetics 50.9 (2018): 1219-1224.
Serra, Eva Gonçalves, et al. "Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease." Nature Communications 11.1 (2020): 995.
Lee, James C., et al. "Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease." Nature Genetics 49.2 (2017): 262-268.
Middha, Pooja, et al. "Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis." Nature Communications 15.1 (2024): 2568.
De Lange, Katrina M., et al. "Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease." Nature Genetics 49.2 (2017): 256-261.

GENETIC SUSCEPTIBILITY AND SEVERITY – A FALSE DICHOTOMY? POLYGENIC SCORES OF INFLAMMATORY BOWEL DISEASE SUSCEPTIBILITY ARE PREDICTIVE OF DISEASE SEVERITY COURSE

Marie Vestergaard 1, Kristine Allin 2, Anne Krogh Nøhr* 1, Jesus Vicente Torresano Lominchar 1, Heidi Søgaard Christensen 1, Rasmus Froberg Brøndum 1, Martin Bøgsted 1, Henrik Bygum Krarup 3, Kaspar René Nielsen 4, Henrik Albæk Jacobsen 1, Lone Larsen 5, Aleksejs Sazonovs 1, Tine Jess 6

1 Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT), Aalborg University Copenhagen, Copenhagen, Denmark

2 Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT), Aalborg University Copenhagen, Copenhagen, Denmark|||Aalborg University Hospital, Aalborg, Denmark

3 Aalborg University Hospital, Aalborg, Denmark

4 Zealand University Hospital, Roskilde, Denmark

5 Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT), Aalborg University Copenhagen, Copenhagen, Denmark|||Aalborg Universitetshospital, Aalborg, Denmark

6 Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT), Aalborg University Copenhagen, Copenhagen, Denmark|||Aalborg University Copenhagen, Hellerup, Denmark

Event

UEG Week Vienna 2024

Topics

IBD Immunology

Submission format

Abstract

Session

Understanding disease primers of IBD: Part 1

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

UEG Podcast Episode

UEG Podcast

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Best of UEG Week - IBD with Bel Kok

Bel Klaartje Kok, Pradeep Mundre

Topics

IBD

Published

2025

UEG Podcast Episode

Journal Podcast

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Comparison of two strategies for the management of postoperative recurrence in Crohn’s disease patients with one clinical risk factor

Haluk Tarik Kani 1, Gabriele Dragoni 2

1 Department of Gastroenterology, Marmara University, School Of Medicine, Istanbul, Turkey

2 University of Florence, Italy

Topics

IBD

Published

2023

UEG Podcast Episode

UEG Podcast

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The future of immunotherapy → are surgeons obsolete soon? with Jeroen Dekervel

Jeroen Dekervel, Pradeep Mundre

Topics

Digestive Oncology

Published

2026

UEG Standards and Guidelines

Clinical Practice Guideline

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Abstract

This manuscript describes the use of ultrasound elastography, with the exception of liver applications, and represents an update of the 2013 EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) Guidelines and Recommendations on the clinical use of elastography.

Keywords: ultrasound elastography - guideline - EFSUMB

The EFSUMB Guidelines and Recommendations for the Clinical Practice of Elastography in Non-Hepatic Applications: Update 2018

Adrian Săftoiu

Guideline

Clinical Practice Guideline

Topics

Radiology & Imaging

Citation

Ultraschall Med 2019; 40(04): 425-453

Published

2019

UEG Poster

Audio / Video Poster

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Introduction

Risankizumab (RZB) is a high-affinity humanised immunoglobulin (Ig) G1 monoclonal antibody that selectively binds to the p19 subunit of the interleukin-23 (IL-23) cytokine and inhibits its interaction with the IL-23 receptor.^1,2Long-term RZB therapy for 3 years of maintenance showed durable efficacy and a well-tolerated safety profile in patients with ulcerative colitis (UC) in the COMMAND open-label extension (OLE) study.^1,3This post hoc analysis evaluated the long-term efficacy of RZB in improving patient-reported outcomes through week (wk) 96 of the ongoing COMMAND OLE study.

Aims & Methods

COMMAND OLE is a 220-wk study enrolling patients who completed 52-wks maintenance dosing or enrolled directly as responders to induction.^1,3 This analysis included patients who completed 52 wks maintenance and an additional 96 wks of RZB treatment in the OLE. All patients received subcutaneous (SC) RZB180 Q8w starting at OLE wk 0, except patients who had prior rescue therapy (single RZB 1200 mg intravenous dose, then SC RZB360 Q8w) who continued RZB360 in the OLE. The OLE study was not designed to compare RZB180 and RZB360 groups. The data cut-off date for this interim analysis was 30 June 2024. Efficacy outcomes included the percentage of patients who achieved the absence of abdominal pain, bowel urgency, faecal incontinence, nocturnal bowel movements, tenesmus, sleep disruption due to UC symptoms; Inflammatory Bowel Disease Questionnaire (IBDQ) response; a meaningful within-person change (MWPC) in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, Short-Form Health Survey-36 version 2 Mental Component Score (SF-36v2 MCS), and SF-36v2 Physical Component Score (PCS). Results were reported using as-observed (AO; Table) and nonresponder imputation (NRI) methods (Table). Safety was reported previously.³

Results

Of the 1003 patients (RZB180 = 701; RZB360 = 302) who entered the OLE, 398 (39.7%) patients (RZB180 = 262; RZB360 = 136) completed wk 96 at data cut-off date. In the AO analysis, RZB180- or RZB360-treated patients showed sustained improvements from OLE wks 0 to 96 in the absence of abdominal pain, bowel urgency, nocturnal bowel movements, tenesmus, faecal incontinence, sleep disruption due to UC symptoms, IBDQ response, MWPC in FACIT-Fatigue, SF-36 PCSv2, and SF-36v2 MCS (Table). Using the more conservative NRI analysis, similar results were observed for most endpoints through OLE wk 96 (Table). Despite RZB360-treated patients were more likely to have numerically higher clinical and endoscopic activity at OLE wk 0 compared with RZB180-treated patients (Adapted Mayo Score [AMS], mean [standard deviation], RZB180, 2.0 [1.4]; RZB360, 3.5 [2.0]; endoscopic subscore: RZB180, 1.1 [1.0]; RZB360, 1.9 [1.0]; clinical remission per AMS, RZB180, 54.8%; RZB360, 24.8%), at OLE wk 96, both RZB dosing regimens exhibited consistent and similar sustained improvements throughout all investigated patient-reported outcomes.

Endpoint, (n/N) % [95% CI]^a	AO analysis^b		NRI analysis^c
Endpoint, (n/N) % [95% CI]^a	RZB 180 mg SC	RZB 360 mg SC	RZB 180 mg SC	RZB 360 mg SC
No abdominal pain^d Week 0 Week 96 No bowel urgency^d Week 0 Week 96 No nocturnal bowel movement^d Week 0 Week 96 No tenesmus^d Week 0 Week 96 No faecal incontinence^d Week 0 Week 96 No sleep disruptiondue to UC symptoms^d Week 0 Week 96	(441/701) 62.9 [59.3, 66.5] (129/180) 71.7 [65.1, 78.2] (504/701) 71.9 [68.6, 75.2] (129/180) 71.7 [65.1, 78.2] (499/552) 90.4 [87.9, 92.9] (166/179) 92.7 [88.9, 96.5] (423/552) 76.6 [73.1, 80.2] (154/179) 86.0 [81.0, 91.1] (495/549) 90.2 [87.7, 92.7] (160/171) 93.6 [89.9, 97.2] (486/549) 88.5 [85.9, 91.2] (155/171) 90.6 [86.3, 95.0]	(145/302) 48.0 [42.4, 53.6] (49/79) 62.0 [51.3, 72.7] (156/302) 51.7 [46.0, 57.3] (53/79) 67.1 [56.7, 77.5] (195/233) 83.7 [78.9, 88.4] (73/79) 92.4 [86.6, 98.2] (145/233) 62.2 [56.0, 68.5] (63/79) 79.7 [70.9, 88.6] (198/230) 86.1 [81.6, 90.6] (66/74) 89.2 [82.1, 96.3] (181/230) 78.7 [73.4, 84.0] (70/74) 94.6 [89.4, 99.7]	(162/262) 61.8 [55.9, 67.7] (129/262) 49.2 [43.2, 55.3] (175/262) 66.8 [61.1, 72.5] (129/262) 49.2 [43.2, 55.3] (108/262) 41.2 [35.3, 47.2] (166/262) 63.4 [57.5, 69.2] (92/262) 35.1 [29.3, 40.9] (154/262) 58.8 [52.8, 64.7] (100/262) 38.2 [32.3, 44.1] (160/262) 61.1 [55.2, 67.0] (104/262) 39.7 [33.8, 45.6] (155/262) 59.2 [53.2, 65.1]	(63/136) 46.3 [37.9, 54.7] (48/136) 35.3 [27.3, 43.3] (65/136) 47.8 [39.4, 56.2] (51/136) 37.5 [29.4, 45.6] (57/136) 41.9 [33.6, 50.2] (71/136) 52.2 [43.8, 60.6] (42/136) 30.9 [23.1, 38.6] (61/136) 44.9 [36.5, 53.2] (49/136) 36.0 [28.0, 44.1] (64/136) 47.1 [38.7, 55.4] (51/136) 37.5 [29.4, 45.6] (68/136) 50.0 [41.6, 58.4]
IBDQ response^e Week 0 Week 96	(629/689) 91.3 [89.2, 93.4] (182/191) 95.3 [92.3, 98.3]	(266/299) 89.0 [85.4, 92.5] (76/78) 97.4 [93.9, 100.9]	(238/262) 90.8 [87.3, 94.3] (182/262) 69.5 [63.9, 75.0]	(118/136) 86.8 [81.1, 92.5] (76/136) 55.9 [47.5, 64.2]
MWPC in FACIT-Fatigue^f Week 0 Week 96	(494/683) 72.3 [69.0, 75.7] (147/189) 77.8 [71.9, 83.7]	(227/298) 76.2 [71.3, 81.0] (63/77) 81.8 [73.2, 90.4]	(190/262) 72.5 [67.1, 77.9] (147/262) 56.1 [50.1, 62.1]	(105/136) 77.2 [70.2, 84.3] (63/136) 46.3 [37.9, 54.7]
MWPC in SF-36v2 PCS^g Week 0 Week 96 MWPC in SF-36v2 MCS^g Week 0 Week 96	(526/683) 77.0 [73.9, 80.2] (153/188) 81.4 [75.8, 86.9] (472/683) 69.1 [65.6, 72.6] (130/188) 69.2 [62.5, 75.8]	(228/298) 76.5 [71.7, 81.3] (65/77) 84.4 [76.3, 92.5] (197/298) 66.1 [60.7, 71.5] (52/77) 67.5 [57.1, 78.0]	(196/262) 74.8 [69.6, 80.1] (153/262) 58.4 [52.4, 64.4] (177/262) 67.6 [61.9, 73.2] (130/262) 49.6 [43.6, 55.7]	(107/136) 78.7 [71.8, 85.6] (65/136) 47.8 [39.4, 56.2] (87/136) 64.0 [55.9, 72.0] (52/136) 38.2 [30.1, 46.4]
Table. Patient-Reported Outcomes and Health-Related Quality of Life Efficacy Analysis From the COMMAND Open-Label Extension Study. AO, As-observed; CI, confidence interval; FACIT-Fatigue, Functional Assessment of Chronic Illness Therapy-Fatigue, IBDQ, inflammatory bowel disease questionnaire; IV, intravenous; MCS, Mental Component Score; MWPC, meaningful within-person change; NRI, nonresponder imputation; OLE, open-label extension; PCS, Physical Component Score; RZB, risankizumab; SC, subcutaneous; SF-36v2, Short-Form Health Survey-36 version 2; SS, substudy. Efficacy analysis included patients who entered the OLE from SS1 and SS2 and received at least 1 dose of study drug. Analysis included patients who received RZB 180 mg starting at OLE week 0, and patients who had prior rescue therapy (single RZB 1200 mg IV dose, then 360 mg SC Q8w) during SS1 and SS2 and continued with RZB 360 mg in OLE. The data cut-off date was 30 June 2024. Week 0 was defined as the entry of the OLE period, based on the last nonmissing value prior to the first dose of study drug in the OLE. ^a95% CI for response rate was based on the normal approximation to the binomial distribution. ^bData after rescue therapy during the OLE was excluded. ^cMissing data or patients who received rescue therapy during the OLE were imputed as nonresponders. ^dQuantified as the percent of patients who achieved the absence of each symptom. ^eIncrease in IBDQ score ≥ 16 points from baseline of induction. ^fIncrease in FACIT-Fatigue ≥ 5 points from baseline of induction. ^gIncrease in SF-36v2 PCS/MCS ≥ 4.1 point from baseline of induction.

Conclusion

RZB-treated patients who completed OLE wk 96 (3 years of total maintenance therapy) experienced sustained improvement in quality of life and patient-reported outcomes.

References

Louis E, et al. JAMA. 2024; 332:881-97.
Singh S, et al. mAbs. 2015;7:778-91.
Atreya R, et al. J Crohn’s Colitis. 2025;19(S1):i108-i110 [Abstract].

Disclosure

Funding: AbbVie funded this study (COMMAND; NCT03398135) and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.
Acknowledgments: AbbVie and the authors thank the participants, study sites, and investigators who participated in this clinical trial. Paulette A. Krishack, PhD, of AbbVie, provided medical writing support; S. Michael Austin, of AbbVie, provided editorial support.
Disclosures: Luc Biedermann has received lecture and consulting fees from Takeda, Sanofi, AbbVie, Falk, Bristol Myer Squibb, and Pfizer and is on advisory boards for AbbVie, Amgen, Bristol Myers Squibb, Falk, Janssen, Pfizer, Takeda, and Sanofi.
Julian Panés received consultancy fees/honorarium from AbbVie, Alimentiv, Athos, Atomwise, Boehringer Ingelheim, Celsius, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Nimbus, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Sanofi, Sorriso, Surrozen, Takeda, and Wasserman, and has served on a data safety monitoring board for Alimentiv, Mirum, Sorriso, Sanofi, and Surrozen.
Silvio Danese has received consultancy fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Enthera, Ferring, Gilead, Hospira, Janssen, Johnson & Johnson, Lilly, Merck Sharp and Dohme, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB and Vifor.
Satoshi Tanida received speaker fees from JIMRO, Mitsubishi Tanabe Pharma, AbbVie, Janssen, Kissei, writing fees from Pfizer, and research funding from AbbVie.
Parambir S. Dulai received research support and/or consulting for AbbVie, Abivax, Adiso, Alimentiv, Bristol Meyer Squibb, Celltrion, Genentech/Roche, Geneoscopy, Janssen, Pfizer, Takeda.
Nidhi Shukla, Jasmina Kalabic, Pierre Morisset, Cecile Holweg, and Dolly Sharma, are employees of AbbVie and may own stock options.
Joana Torres has received grant funding/speaker fees from and/or has participated in advisory boards for AbbVie, Galapagos, Janssen, and Pfizer.