Introduction

To examine the effect of Body Mass Index (BMI) on treatment response in patients with inflammatory bowel disease (IBD).

Aims & Methods

Patients ≥ 16 years old with IBD, a documented baseline BMI and starting thiopurines, intravenous (iv) vedolizumab, subcutaneous (sc) vedolizumab, ustekinumab, ozanimod, filgotinib, or tofacitinib were selected from the Initiative on Crohn and Colitis (ICC) registry in the Netherlands. Patients with a current follow-up shorter than 24 weeks were excluded. Some of the patients in the registry started vedolizumab sc electively whilst in remission after being treated with vedolizumab iv. Therefore, patients with vedolizumab sc were excluded if they were in steroid-free clinical remission (SFCR) (i.e. Simple Clinical Colitis Activity Index (SCCAI) ≤ 2 for ulcerative colitis and Harvey Bradshaw Index (HBI) < 5 for Crohn’s disease) at baseline. Patients who discontinued treatment were classified as non-responders at all timepoints after treatment discontinuation. SFCR at baseline, week 12 and week 24 was compared between patients with normal weight (BMI < 25 kg/m²), overweight (BMI 25-30 kg/m²) and obesity (BMI ≥ 30 kg/m²) using Chi-Square tests. SFCR rates over time in the three groups were analysed using generalized linear mixed modelling.

Results

1101 patients with IBD (631 Crohn’s disease, 470 ulcerative colitis) were included, 636 had normal weight, 313 were overweight and 152 were obese. Generalized linear mixed model demonstrated that the course of SFCR over time after initiating treatment was significantly different between the three groups (p = 0.038). Chi-Square tests showed significant differences in SFCR between the normal weight, overweight and obese patients at week 12 (40.1%, 49.8%, 42.9%, respectively, p = 0.027) and week 24 (48.2%, 49.4%, 34.7%, respectively, p = 0.015). No significant difference in SFCR was found between groups at baseline.

Conclusion

Obesity was associated with a lower SFCR rate at week 24. Surprisingly, at week 12, overweight was associated with a higher rate of SFCR. Although overweight patients have shown a faster treatment response, this advantage had vanished at 24 weeks. The week 12 results could possibly be explained by the protective effect of excess bodyweight during illness, which is an hypothesis of the ‘obesity paradox’, concerning the finding of lower mortality rates in overweight and obese patients with cardiovascular diseases and malignancies^1,2.

References

1. Tutor AW, Lavie CJ, Kachur S, Milani RV, Ventura HO. Updates on obesity and the obesity paradox in cardiovascular diseases. Prog Cardiovasc Dis. 2023 May-Jun;78:2-10. doi: 10.1016/j.pcad.2022.11.013. Epub 2022 Dec 5. PMID: 36481212.
2. Hahn AW, Venkatesh N, Msaouel P, McQuade JL. The Influence of Obesity on Outcomes with Immune Checkpoint Blockade: Clinical Evidence and Potential Biological Mechanisms. Cells. 2023 Oct 31;12(21):2551. doi: 10.3390/cells12212551. PMID: 37947629; PMCID: PMC10649394.

Disclosure

Dorien Oomkens: none. Zlatan Mujagic: reports grants from MLDS, Niels Stensen Fellowship, and Galapagos, and has served as speaker for Galapagos, adviser for Johnson and Johnson, all outside the submitted work. Annemarie C de Vries: has served on advisory boards for Takeda, Janssen, Bristol Myers Squibb, Abbvie, Pfizer, and Galapagos and has received unrestricted research grants from Takeda, Janssen, and Pfizer outside the submitted work. Andrea E. van der Meulen-de Jong has served as speaker for: Galapagos, Janssen‐Cilag, Takeda, Tramedico. She has received research grants from Cablon, Galapagos, Nestle, Norgine and ZonMW. Tessa Straatmijer: none. Mark Lowenberg: Abbvie, Alimentiv, Bristol Myers Squibb, Celgene, Covidien, Dr. Falk, Ferring Pharmaceuticals, Galapagos, Gilead, GlaxoSmithKline, Janssen-Cilag, Medtronic, Merck Sharp & Dohme, Pfizer, Protagonist therapeutics, Receptos, Takeda, Tillotts, Tramedico. He has received research grants from AbbVie, Merck Sharp & Dohme, Dr Falk, Achmea healthcare, Galapagos and ZonMW. Sander van der Marel: none. Rachel West: has participated in advisory board or as speaker for Jansen, Abbvie and Pfizer. Alexander Bodelier: has served on the advisory board of Takeda, Abbvie, and Janssen outside the submitted work. Fiona van Schaik: served as adviser for Takeda, Galapagos, and Dr Falk. LPLG has served as a speaker for AbbVie and Boston, and received a grant from Ferring to develop e-learning about therapeutic drug monitoring. Marijn C Visschedijk: received speaker fees from Janssen-Cilag, Galapagos, and Ferring B.V. Marjolijn Duijvestein: reports advisory fees from Echo Pharma and Robarts Clinical Trials, Inc., speaker fees from Janssen, Merck & Co., Inc., Pfizer, Takeda and Tillotts Pharma, and nonfinancial support from Dr. Falk Pharm.

Introduction

Risankizumab is an interleukin-23 inhibitor approved for the treatment of Crohn’s disease (CD). Its efficacy and safety have recently been demonstrated in trial-setting but there is yet limited evidence of its real-world effectiveness, especially on the middle- and long-term.

Aims & Methods

Using prospective data from the Dutch Initiative on Crohn and Colitis (ICC) Registry, we aimed to evaluate the effectiveness and adverse events of risankizumab in patients with difficult-to-treat CD, defined as the failure of advanced therapies with at least two different mechanisms of action¹. The primary endpoint was corticosteroid-free (CSF) clinical remission at week (W) 24. CSF clinical remission was defined as Harvey Bradshaw Index (HBI) ≤ 4 and no use of systemic corticosteroids at the time of the visit. As secondary outcomes, we examined clinical remission, biochemical remission (faecal calprotectin (FC) level ≤ 250μg/g) and combined clinical and biochemical remission at W24. Furthermore, remission rates between patients without history of bowel resection (i.e. surgery-naïve) and with bowel resection (i.e. surgery-experienced) at W24, drug survival and adverse events were assessed. Patients were included in the analysis if they received at least one intravenous dose of risankizumab before the 28^th of February 2025. Patients without available remission data at W24 and who remained on treatment were excluded from the W24 analysis population. Patients who discontinued treatment before W24 due to non-response, adverse events or loss to follow-up were considered non-responders.

Results

Eighty-five patients were included in the current analysis; 56 (65.9%) were female. Patients had a median disease duration of 16.0 years (IQR 14.0). Surgery history was available for 83 patients; 33 (39.8%) patients did not undergo surgery, while 50 (60.2%) were considered as surgery-experienced. At baseline, HBI was available for 72 patients; the median HBI was 6 (IQR 5); 24 (33.3%) patients had an HBI ≤ 4. Biochemical data were available for 19 (79.2%) patients in clinical remission: only one (5.3%) was in biochemical remission. At W24, HBI was available for 62 patients; 34 (54.8%) patients were in CSF clinical remission. Independent of CSF status, 62.9% (39/62) of the patients were in clinical remission. FC levels at W24 were available for 55 patients; 17 (30.9%) patients were in biochemical remission. Remission rates were not influenced by surgery history (Table 1). Over time, 16.5% (14/85) patients stopped risankizumab, after a median treatment duration of 182 days (IQR 188). Three (21.4%) patients discontinued risankizumab before W12, three (21.4%) between W12 and W24, and eight (57.2%) between W24 and W52. Reasons for discontinuation were non-response (42.9%), loss of response (42.9%) and adverse events (14.2%). A total of 83 adverse events were reported in 51 patients. Most common adverse events included respiratory infections (13.2%), skin problems (10.8%) and herpes zoster infections (8.4%). No hospitalisation or death were reported.

Table 1. Overview of the remission rates at W24 between surgery-naïve and surgery-experienced patients
	CSF clinical remission	Clinical remission	Biochemical remission	Combined remission
Total	34/62 54.8%	39/62 62.9%	17/55 30.9%	17/43 39.5%
Surgery-naïve	15/23 65.2%	17/23 73.9%	6/21 28.6%	6/16 37.5%
Surgery-experienced	19/37 51.3%	22/37 59.5%	11/32 34.8%	11/24 45.8%

Conclusion

This prospective real-world study demonstrates the clinical effectiveness and the favourable safety profile of risankizumab at W24 in a difficult-to-treat Crohn’s disease population, including a high proportion of patients with bowel resection.

References

1. Parigi TL, D'Amico F, Abreu MT, Dignass A, Dotan I, Magro F, Griffiths AM, Jairath V, Iacucci M, Mantzaris GJ, O'Morain C, Reinisch W, Sachar DB, Turner D, Yamamoto T, Rubin DT, Peyrin-Biroulet L, Ghosh S, Danese S. Difficult-to-treat inflammatory bowel disease: results from an international consensus meeting. Lancet Gastroenterol Hepatol. 2023 Sep;8(9):853-859. doi: 10.1016/S2468-1253(23)00154-1. Epub 2023 Jul 6. PMID: 37423233.

Disclosure

LMMV - none FDMvS - adviser and/or speaker for Takeda, Galapagos, Dr. Falk, Lilly, and Janssen-Cilag; received an unrestricted grant from Takeda MRN - none ACdV - advisory boards for Takeda, Janssen, Bristol Myers Squibb, Abbvie, Pfizer, and Galapagos; research grants from Takeda, Janssen, and Pfizer AEvdMDJ - speaker fee from AbbVie, Alfasigma, Ferring, Janssen Pharmaceuticals, Takeda, Tramedico, and Vedanta; grants from Norgine, Cablon, Alfasigma, and ZonMW MCV - speaker fees from Janssen-Cilag, Galapagos, and Ferring B.V. WAvD - none WSN - none TER - none RLW - speaker fee from Abbvie, Ferring, and Pfizer BJ - none AGLB - none PV - speaker fee from Takeda, Abbvie, Janssen, Alfa Sigma, Lilly, and BMS BO - advisory boards of Takeda, BMS, Galapagos, Janssen, AbbVie, BMS, and Ferring; grants from Takeda, Pfizer, Galapagos, Ferring, Celltrion, BMS, and AbbVie ML - consultancy/lecture fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, Janssen-Cilag, Johnson & Johnson, Medtronic, Pfizer, Takeda, and Tillotts Pharma; grants from Alfasigma, the Netherlands Federation of University Medical Centres, TKI, and ZonMW JELS - none LAAPD - served on advisory boards as a speaker for Abbvie, Alfasigma, Janssen, and Pfizer; independent research funding from Pfizer HHF - none MJP - speaker fee from BMS, Janssen Cilag, and Takeda; non-restricted research grants from Horizon 2020, ZONMW (Dutch national research fund), MLDS, Takeda, Johnson and Johnson, Abbvie, and Galapagos MD - speaking fee from Bristol Meyers Squibb, Takeda, Galapagos, Janssen, and Dr. Falk; advisory board fees from Abbvie, Bristol Meyers Squibb, Celltrion, Galapagos/Alfasigma, Janssen, Takeda; grant/research support from Pfizer, Bristol Meyers Squibb, Galapagos Alfasigma, and Janssen ZM - speaker fee from Friso – Friesland Campina, Galapagos, Eli Lilly, and Takeda (paid to host institution); ; advisory board fees from Johnson & Johnson, Eli Lilly, Pfizer (paid to host institution); grants from ZonMw, Niels Stensen Fellowship, MLDS, Top consortium for Knowledge and Innovation (TKI), and Galapagos

Introduction

Mirikizumab is an interleukin (IL)-23 inhibitor approved for the treatment of ulcerative colitis (UC); however, real-world data are limited.

Aims & Methods

The Dutch Initiative on Crohn and Colitis (ICC) Registry is a prospective multicentre study collecting real-world data on advanced therapeutic agents in inflammatory bowel disease (IBD). Patients included in the current study had a confirmed diagnosis of UC and received at least one intravenous induction dose of mirkizumab before the 28^th of February 2025. Patients who did not use at least two therapies with different mechanisms of action (i.e. difficult-to-treat UC) or with colectomy were excluded. The primary endpoint was clinical remission at week (W) 12, defined as Simple Clinical Colitis Activity Index (SCCAI) ≤ 2. Secondary outcomes at W12 included corticosteroid-free (CSF) clinical remission (i.e. clinical remission without the use of systemic corticosteroids on the day of the visit), biochemical remission (faecal calprotectin (FC) level ≤ 250μg/g) and endoscopic remission (Mayo endoscopic subscore = 0). In addition, drug survival and adverse events were assessed.

Results

In total, 22 patients were included; 13 (59.1%) were male. Most patients (n = 12; 54.5%) were diagnosed with pancolitis. Patients had a median disease duration of 9.5 years (IQR 18.0). Twelve patients (54.5%) had used at least four different advanced therapies; 19 (86.4%) patients have previously used ustekinumab (IL-12/23 inhibitor). At treatment initiation, all patients showed active disease, either clinically, biochemically or endoscopically. Median SCCAI was 7.0 (IQR 6); median FC was 1696.5μg/g (IQR 2079). As the study is still ongoing, data at W12 were available for 19 (86.4%) patients. Clinical data were available for 14 patients; 35.7% (5/14) of them were in clinical remission. These five patients were also in CSF clinical remission. Similar rates were observed between ustekinumab-experienced and ustekinumab-naïve patients, although the naïve subgroup was rather small (3/14). Biochemical data were available for 12 patients; median FC was 1434.5μg/g (IQR 824). Only one (8.3%) patient was in biochemical remission at W12; this patient was ustekinumab-naïve. Another patient, with only endoscopic data, was in endoscopic remission. Two patients discontinued mirikizumab before W12: one patient stopped mirikizumab after the intravenous injection because of fever; the other patient showed no response. Four other patients discontinued mirikizumab after W12; none of them were in clinical or biochemical remission at W12. Reasons for treatment discontinuation were primary non-response (5/6) and adverse event (1/6). Four adverse events were reported in four patients: nausea and skin problems, both classified as possibly related to the treatment, a gastrointestinal infection requiring antibiotics and fever during the infusion.

Conclusion

We found that 7/16 patients with difficult-to-treat UC were in either clinical, biochemical or endoscopic remission at W12. Moreover, all patients in clinical remission at W12 were not using other medications. Mirikizumab was well tolerated, although the follow-up period was relatively short. The ICC Registry is ongoing, and results with higher patient numbers with longer exposure to mirikizumab will be analysed to further characterise the real-world effectiveness and safety for patients with difficult-to-treat UC.

Disclosure

LMMV - none MRN - none ACdV - advisory boards for Takeda, Janssen, Bristol Myers Squibb, Abbvie, Pfizer, and Galapagos; research grants from Takeda, Janssen, and Pfizer WAvD - none MCV - speaker fees from Janssen-Cilag, Galapagos, and Ferring B.V. IM - advisory board/lecture fee from Abbvie, dr. Falk, and Janssen-Cilag FDMvS - adviser and/or speaker for Takeda, Galapagos, Dr. Falk, Lilly, and Janssen-Cilag; received an unrestricted grant from Takeda JMJ -consultant/speaker for AbbVie, Lilly, Takeda, and Janssen; consultant for MSD AGLB - none ML - consultancy/lecture fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, Janssen-Cilag, Johnson & Johnson, Medtronic, Pfizer, Takeda, and Tillotts Pharma; grants from Alfasigma, the Netherlands Federation of University Medical Centres, TKI, and ZonMW AEvdMDJ - speaker fee from AbbVie, Alfasigma, Ferring, Janssen Pharmaceuticals, Takeda, Tramedico, and Vedanta; grants from Norgine, Cablon, Alfasigma, and ZonMW MJP - speaker fee from BMS, Janssen Cilag, and Takeda; non-restricted research grants from Horizon 2020, ZONMW (Dutch national research fund), MLDS, Takeda, Johnson and Johnson, Abbvie, and Galapagos ZM - speaker fee from Friso – Friesland Campina, Galapagos, Eli Lilly, and Takeda (paid to host institution); advisory board fees from Johnson & Johnson, Eli Lilly, Pfizer (paid to host institution); grants from ZonMw, Niels Stensen Fellowship, MLDS, Top consortium for Knowledge and Innovation (TKI), and Galapagos MD - speaking fee from Bristol Meyers Squibb, Takeda, Galapagos, Janssen, and Dr. Falk; advisory board fees from Abbvie, Bristol Meyers Squibb, Celltrion, Galapagos/Alfasigma, Janssen, Takeda; grant/research support from Pfizer, Bristol Meyers Squibb, Galapagos Alfasigma, and Janssen

Introduction

The therapeutic goal in inflammatory bowel disease (IBD), which includes Crohn´s disease (CD) and ulcerative colitis (UC), is the control of the inflammatory process frequently through biologic and JAK-inhibitor therapies, which are generally expensive and can cause adverse effects. Unfortunately, only about one-third of patients respond to these treatments, and there are no markers that accurately predict this response.

Aims & Methods

The aim of this study was to identify potential serum and urinary metabolic biomarkers predictive of IBD response to different drugs at baseline (before treatment), which could facilitate the selection of the most appropriate therapy for each patient. For this purpose, a prospective multicenter study was conducted including CD and UC patients who initiated biologic (anti-TNF, ustekinumab or vedolizumab) or JAK-inhibitor (tofacitinib) therapies. Patients were assessed at 14 weeks to determine if they had achieved an endoscopic response, based on the SES-CD and on the endoscopic subscore of the Partial Mayo Score. The analyses of the serum and urine metabolome, along with the deconvolution of the serum lipoprotein profile, were performed using nuclear magnetic resonance for a quantitative differential analysis comparing the baseline serum samples of responders and non-responders.

Results

A total of 150 patients were included (30 CD anti-TNF, 30 UC anti-TNF, 30 CD ustekinumab, 30 UC vedolizumab and 30 UC tofacitinib). Metabolomic analysis identified 55 potential predictive biomarkers of IBD treatment response with significantly altered levels (p<0.05) in the baseline urine and serum samples of subsequent responders compared to non-responders. Among them, 44 were drug-specific and none were shared between serum and urine. Moreover, based on ROC curve analysis, some of these biomarkers showed good sensitivity and specificity for distinguishing between responders and non-responders before treatment (Table 1). Finally, the integrated metabolite set enrichment analysis of urine and serum samples identified distinct biological pathways associated with the response to each treatment for IBD, with common pathways highlighted, including the metabolism of short-chain fatty acids, the citrate cycle and the metabolism of amino acids such as alanine, aspartate, glutamate, and arginine.

Conclusion

The present study represents a step towards personalized medicine in the selection of targeted therapies for IBD patients, addressing an important unmet need. Although further validation is needed, we have identified serum and urinary metabolic biomarkers with the potential to predict response to biologic and JAK-inhibitor therapies.

Table 1. Summary of potential metabolic biomarkers identified as predictive of endoscopic response before each IBD treatment.

*Biomarkers with significantly altered levels (p<0.05) in baseline serum or urine samples of responders vs non-responders. **AUC corresponding to the biomarkers with the best sensitivity and specificity for distinguishing between responder and non-responder patients before treatment. AUC: Area Under the Curve calculated using the Metabolanalyst software in univariate analysis; CD: Crohn's disease; IBD: Inflammatory bowel disease; UC: Ulcerative colitis.

Introduction

The true effect of having inflammatory bowel disease (IBD) in the development of infections has not been studied in depth since cohort studies are scarce and the results of studies are sometimes contradictory. Especially, this complication has not been addressed prospectively in an incident cohort of patients with IBD.

Aims & Methods

Aims: To assess, regarding infections in IBD: 1) incidence and type, 2) risk factors, 3) effect of type and the duration of IBD treatment, 4) impact in mortality 5) effect of IBD activity.
Methods: The INFEII registry (ClinicalTrials.gov: NCT02904590) is a prospective study promoted by GETECCU to determine the incidence and risk factors of infection in an inception cohort of patients with IBD and follow-up of at least 5 years. This longitudinal prospective study within the ENEIDA registry included incident cases with IBD. Patients were recruited between 2016 and 2020 with a planned follow-up of 5 years. All infections were detailed analysed. An infection was considered relevant when: 1) required hospital admission, 2) led to death or endangered the patient’s life, 3) was treated with specific antibiotics,4) occurred recurrently, and/or 5) required change/withdrawal of immunosuppressive treatment.

Results

The INFEII registry recruited 1456 patients from 28 centres throughout Spain. The median follow-up was 71 months (IQR 60-79 months). The description of the cohort is presented in Table 1. Of the 1456 patients, 580 (40%) presented at least one relevant infection. In total, 1321 infections were collected. One-hundred and seven infections (8%) required hospitalisation and four patients died (0.3%) over infection. Ninety-nine patients were lost to follow-up (22 died and 34 changed hospitals). The most prevalent infections were: ear-nose-throat in 238 cases, urinary tract infections in 237, respiratory in 234, COVID-19 in 133, skin infections in 127, dental in 64 and colitis/enteritis in 64. From the whole cohort and at some point, in time, 756 (52%) patients received 5ASA, 481 (33%) steroids (369 (25%) oral, 112 (7.7%) intravenous), 568 (39%) azathioprine, 72 (4.9%) methotrexate, 21 (1.4%) tofacitinib, 533 (37%) antiTNF, 141 (9.9%) ustekinumab and 77 (5.3%) vedolizumab. The effect of treatment and IBD activity in each infection is being analysed.

Table 1. Clinical characteristics of patients included in the INFEII study

Variable (N%)	Total 1456	No infections 876	Any Infection 580	Univariate P
Gender (female)	668 (46)	378 (43)	290 (50)	0.01
Active smokers	314 (22)	177 (20)	137 (24)	0.09
Age at IBD diagnosis Mean (IQR) >50 years	42 (29-55) 529 (36)	42 (29-54) 319 (36)	41 (28-56) 210 (36)	0.74 0.93
Unclassified colitis Ulcerative colitis Crohn’s disease L1 L2 L3 L4	27 (1.85) 781 (54) 648 (45) 280 (43) 122 (19) 235 (36) 121 (19)	20 (2.28) 484 (55) 372 (42) 153 (41) 77 (21) 133 (36) 58 (16)	7 (1.2) 297 (51) 276 (48) 127 (46) 45 (16) 102 (37) 63 (23)	0.14 0.14 0.29
Crohn’s behaviour B1 B2 B3 perianal	486 (75) 109 (17) 61 (9) 123 (20)	284 (76) 61 (16) 33 (8.9) 65 (17)	202 (73) 48 (17) 28 (10) 58 (21)	0.34 0.32 0.32 0.28
History of severe infections (before IBD diagnosis)	36 (2.5)	13 (1.5)	23 (3.96)	0.004
Occupational risk	450 (31)	252 (29)	198 (34)	0.03
Comorbidity	256 (18)	143 (16)	113 (19)	0.12
Death (all causes)	22 (1.5)	11 (1.3)	11 (1.9)	0.33

Conclusion

Infections are frequent complications in patients with IBD, presented in 40% of them. Being a woman, having a history of past serious infections or occupational risk may be associated with infection occurrence. It has to be determined if IBD activity and treatment pose a greater risk for infections. This paradigmatic study implies the first use of the ENEIDA registry in prospective research.