Publications by authors named "Séverine Vermeire"

534 Publications

Short chain fatty acids and its producing organisms: An overlooked therapy for IBD?

EBioMedicine 2021 Apr 1;66:103293. Epub 2021 Apr 1.

Department of Chronic Diseases, Metabolism & Ageing [CHROMETA], Translational Research Center for Gastrointestinal Disorders [TARGID], KU Leuven, Leuven, Belgium; Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium. Electronic address:

The gut microbiome and the intestinal immune system are driving contributors to inflammatory bowel diseases (IBD). Both have an important signalling factor in common: short-chain fatty acids (SCFAs). SCFAs (acetate, propionate and butyrate) are produced by bacterial fermentation in the gut and exert several effects on host metabolism and immune system. This review provides an overview of the current knowledge of these effects, with specific focus on energy metabolism, intestinal barrier, immune system, and disease activity in IBD. To conclude, more research is needed on the cross-feeding mechanisms in the gut microbiome, as well as on the therapeutic potential of SCFAs on different disease models. Also randomized controlled trials and prospective cohort studies should investigate the clinical impact of SCFA administration.
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http://dx.doi.org/10.1016/j.ebiom.2021.103293DOI Listing
April 2021

Let Food Be Thy Medicine-Its Role in Crohn's Disease.

Nutrients 2021 Mar 3;13(3). Epub 2021 Mar 3.

Department of Gastroenterology and Hepatology, University Hospitals Leuven, 3000 Leuven, Belgium.

The food we eat is thought to play a role in both the increasing incidence as well as the course of Crohn's disease. What to eat and what to avoid is an increasingly important question for both patients and physicians. Restrictive diets are widely adopted by patients and carry the risk of inducing or worsening malnutrition, without any guarantees on anti-inflammatory potential. Nevertheless, exploration of novel therapies to improve long-term management of the disease is desperately needed and the widespread use of exclusive enteral nutrition in the induction of paediatric Crohn's disease makes us wonder if a similar approach would be beneficial in adult patients. This narrative review discusses the current clinical evidence on whole food diets in achieving symptomatic and inflammatory control in Crohn's disease and identifies knowledge gaps with areas for future research.
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http://dx.doi.org/10.3390/nu13030832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001864PMC
March 2021

Monocyte TREM-1 Levels Associate With Anti-TNF Responsiveness in IBD Through Autophagy and Fcγ-Receptor Signaling Pathways.

Front Immunol 2021 15;12:627535. Epub 2021 Mar 15.

Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Location AMC, Amsterdam, Netherlands.

The expression of ( has been described as a predictive marker for anti-Tumor Necrosis Factor (TNF)-α monoclonal antibody (mAb) therapy responsiveness in patients with inflammatory bowel disease (IBD). Here we investigated expression of specifically in CD14+ monocytes in relation to anti-TNF response. The pretreatment expression levels of CD14+ monocytes of Crohn's disease (CD) patients were predictive of outcome to anti-TNF mAb therapy, with low expression associated with response to anti-TNF. FACSorting of CD14+ monocytes with different TREM-1 levels showed that differentiation towards regulatory CD206+ M2 type macrophages by anti-TNF was suppressed in CD14+ monocytes with high TREM-1 expression. Activity of the Fcγ-Receptor and autophagy pathway, both necessary for M2 type differentiation and the response to anti-TNF, were decreased in CD14+ monocytes with high expression of TREM-1. We confirmed that the activity of the Fcγ-Receptor pathway was decreased in the CD patients that did not respond to anti-TNF therapy and that it was negatively correlated with expression levels in the CD patient cohort. In conclusion, our results indicate that expression levels in CD14+ monocytes associate with decreased autophagy and FcγR activity resulting in decreased differentiation to M2 type regulatory macrophages upon anti-TNF mAb treatment, which may explain anti-TNF non-response in IBD patients with high expression levels of .
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http://dx.doi.org/10.3389/fimmu.2021.627535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005579PMC
March 2021

Collecting New Peak and Intermediate Infliximab Levels to Predict Remission in Inflammatory Bowel Diseases.

Inflamm Bowel Dis 2021 Mar 30. Epub 2021 Mar 30.

Department of Gastroenterology, Hôpital Erasme, ULB, Brussels, Belgium.

Background: The loss of response to infliximab is a challenge for clinicians in the management of inflammatory bowel disease (IBD). Mounting evidence suggests that therapeutic drug monitoring at induction may predict remission during maintenance. The aim of the study was to improve predictive models of remission by exploring new peak and intermediate infliximab measurements during induction.

Methods: This was a prospective multicenter study evaluating the pharmacokinetics of infliximab during induction in a pioneer cohort of 63 patients with IBD. Pharmacokinetics data including peak, intermediate, and trough levels were combined with clinical and biological parameters and were subsequently fed into tailored logistic regression and tree-based techniques to predict remission at week 30.

Results: Infliximab peak levels at week 2, intermediate levels at week 3, and trough levels at week 6 were correlated with remission at week 30. Predictive models exhibited an increased accuracy over the successive timepoints of the induction with key inputs such as albumin, C-reactive protein, eosinophils, neutrophils, lymphocytes, intermediate level at week 3, trough level at week 6, and age at diagnosis. Our predictive model of remission at week 30 was obtained with an area under the receiver operating characteristic curve of 0.9 ± 0.12, a sensitivity of 89%, and a specificity of 75%.

Conclusions: This study showed the clinical relevance of measuring new infliximab levels to predict remission in patients with IBD. These findings lay the foundation for a personalized medicine in which biotherapies could be monitored at an early stage, thereby improving patients' clinical management.
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http://dx.doi.org/10.1093/ibd/izab042DOI Listing
March 2021

Induction and Long-term Follow-up With ABX464 for Moderate-to-severe Ulcerative Colitis: Results of Phase IIa Trial.

Gastroenterology 2021 Mar 2. Epub 2021 Mar 2.

Department of Pathology, University Hospitals Leuven, Leuven, Belgium(5)Abivax, Paris, France.

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http://dx.doi.org/10.1053/j.gastro.2021.02.054DOI Listing
March 2021

Oncostatin M Is a Biomarker of Diagnosis, Worse Disease Prognosis, and Therapeutic Nonresponse in Inflammatory Bowel Disease.

Inflamm Bowel Dis 2021 Feb 24. Epub 2021 Feb 24.

Translational Research Center for GastroIntestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Leuven, Belgium.

Background: Oncostatin M (OSM) has been implicated in the pathogenesis of inflammatory bowel disease (IBD) and as a marker for nonresponsiveness to anti-tumor necrosis factor (TNF) therapy. We further unraveled the potential of OSM and related receptors as markers of diagnosis, prognosis, and therapy response in IBD.

Methods: We collected inflamed mucosal biopsies and serum from patients with Crohn disease (CD) and with ulcerative colitis: (1) newly diagnosed patients who were treatment-naïve, (2) patients initiating anti-TNF or (3) vedolizumab therapy, (4) postoperative patients with CD, and (5) multiple-affected families with IBD including unaffected first-degree relatives (FDRs). We measured the gene expression of mucosal OSM and its receptors OSMR/LIFR and co-receptor IL6ST, and the protein expression of serum OSM. Statistical significance was defined as P < 0.05.

Results: Newly diagnosed patients showed significantly increased mucosal OSM/OSMR compared with control patients, with the highest enrichment for OSM (fold change [FC] >17.9). Likewise, ileal OSM/OSMR were significantly upregulated in postoperative recurrent CD. Serum OSM was increased in newly diagnosed patients and postoperative patients with recurrent CD (FC ≥ 2.6). In families with IBD, higher serum levels were observed in FDRs than in control families (FC = 2.2). Furthermore, elevated colonic OSM/OSMR (but not serum OSM) were associated with the early need for biologic therapy (FC ≥ 1.9), and higher OSM was also predictive of primary nonresponse to both anti-TNF and vedolizumab therapy (FC ≥ 2.4). Immunohistochemistry highlighted mucosal OSM expression in macrophages.

Conclusions: We found that OSM is a diagnostic biomarker in the tissue and serum not only of newly diagnosed patients with IBD and postoperative patients with recurrent CD but also of their FDRs. Higher colonic OSM levels are furthermore associated with poor prognosis and with primary nonresponse to biologic therapies. Therefore, OSM could guide clinical decision-making.
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http://dx.doi.org/10.1093/ibd/izab032DOI Listing
February 2021

Health Literacy and Quality of Life in Young Adults From The Belgian Crohn's Disease Registry Compared to Type 1 Diabetes Mellitus.

Front Pediatr 2021 5;9:624416. Epub 2021 Feb 5.

Pediatric Gastroenterology, UZ Brussels, Jette, Belgium.

The management of chronic inflammatory bowel diseases in youth is challenging. We aimed to determine health literacy (HL), quality of life (QoL) and clinical outcomes in young adults from the BELgian CROhn's disease registry (BELCRO) in comparison to type 1 diabetes mellitus (DM) as a control. In this prospective and observational study, young adults with Crohn's disease (CD) diagnosed < 18 years and with > 5 years disease duration and a comparable group of patients with DM completed validated HL, QoL and work productivity and activity impairment questionnaires (HLS-EU-Q16, EQ-5D-5L and WPAI). HL was scored as sufficient (13-16), problematic (9-12) or inadequate (0-8). QoL was dichotomized into "no problems" (EQ-5D level 1) or "problems" (EQ-5D levels 2 to 5). Non-parametric (Mann-Whitney ) analyses and Spearman correlations were performed. A total of 52 CD (median [IQR] age of 25.0 [23.8-27.0], 64% male) and 50 DM (age 20.0 [19.0-22.0], 50% male) patients were included. HL was 14.0 [11.0-16.0] for CD and 14.0 [11.3-14.8] for DM ( = 0.6) with similar proportions of sufficient (60 vs. 68%, = 0.4), problematic (34 vs. 26%, = 0.3) and inadequate HL (both 6%, = 1). Although QoL was comparable for CD and DM (77.0 [68.8-82.0] vs. 75.0 [65.0-80.0] %, =0.4), CD had a trend for higher pain/discomfort (50 vs. 32%, = 0.06). HL and QoL correlated in CD ( = 0.6, < 0.001) and DM patients ( = 0.6, < 0.001). Fewer CD patients with recent hospitalization/surgery had sufficient HL (31 vs. 69%, = 0.01) and had lower QoL (70.0 [60.0-77.0] vs. 80.0 [70.0-85.0], = 0.04) compared to those without. Selected young Belgian adults suffering from CD for >5 years have similar and sufficient HL compared to DM patients. However, CD patients requiring hospitalization/surgery have lower HL, which indicates the need for targeted educational programs.
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http://dx.doi.org/10.3389/fped.2021.624416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892785PMC
February 2021

The effect of aging on infliximab exposure and response in patients with inflammatory bowel diseases.

Br J Clin Pharmacol 2021 Feb 19. Epub 2021 Feb 19.

Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.

Aims: Controversies regarding infliximab treatment in elderly patients with inflammatory bowel diseases remain. We evaluated the effect of patient's age on infliximab exposure, efficacy and safety.

Methods: Retrospective case-control data of patients receiving infliximab induction treatment were analysed. A population pharmacokinetic model was developed to estimate individual pharmacokinetic parameters. A logistic regression model was used to investigate the effect of exposure on endoscopic remission. Repeated time-to-event models were developed to describe the hazard of safety events over time.

Results: A total of 104 patients (46 elderly, ≥65 years) were included. A two-compartment population pharmacokinetic model with linear elimination adequately described the data. Infliximab clearance decreased with older age, higher serum albumin, lower fat-free mass, lower C-reactive protein and absence of immunogenicity. Yet, infliximab exposure was not significantly different between elderly and nonelderly. Regardless of age, an infliximab trough concentration at week (w)14 of 15.6 mg/L was associated with a 50% probability of attaining endoscopic remission between w6 and w22. Infliximab exposure during induction treatment was not a risk factor of (severe) adverse events. The hazard of severe adverse events and malignancy increased by 2% and 7%, respectively, with increasing year of age. Concomitant immunomodulator use increased the hazard of infection by 958%, regardless of age.

Conclusions: Elderly patients attained infliximab exposure and endoscopic remission similarly to nonelderly patients. Therefore, the same infliximab trough concentration target can be used in therapeutic drug monitoring. The hazards of severe adverse events and malignancy increased with age, but not with infliximab exposure.
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http://dx.doi.org/10.1111/bcp.14785DOI Listing
February 2021

Long-term safety and efficacy of the anti-MAdCAM-1 monoclonal antibody ontamalimab (SHP647) for the treatment of ulcerative colitis: the open-label study TURANDOT II.

J Crohns Colitis 2021 Feb 18. Epub 2021 Feb 18.

University Hospitals Leuven, Leuven, Belgium.

Background And Aims: Ontamalimab, a fully-human monoclonal antibody targeting MAdCAM1, induced remission in patients with moderate-to-severe ulcerative colitis (UC) in TURANDOT. We assessed long-term safety, tolerability and efficacy of ontamalimab in TURANDOT II.

Methods: TURANDOT II was a phase 2, multicentre, open-label (OL) study in patients with moderate-to-severe UC who completed TURANDOT on placebo or ontamalimab. Patients were randomized to 75mg or 225mg ontamalimab every 4 weeks for 72 weeks (OL1). Dosage could be increased to 225mg from week 8 at the investigator's discretion. All patients then received 75mg every 4 weeks for 72 weeks (OL2), followed by 6-month safety follow-up. The primary objective was safety, measured by adverse events (AEs), serious AEs (SAEs) and AEs leading to withdrawal. Mucosal healing (MH; centrally read endoscopy) was assessed.

Results: Of 330 patients, 180 completed OL1; 94 escalated to 225mg; 127 completed OL2. Overall, 36.1% experienced drug-related AEs. The most common SAE (10.0%) was worsening/ongoing UC; 5.5% of patients had serious infections, the most common being gastroenteritis (0.9%). One death and four cancers (all unrelated to ontamalimab) occurred. No PML/lymphoproliferative disorders occurred. Geometric mean hsCRP and faecal calprotectin decreased across OL1 in both dose groups. The proportion of patients assigned placebo in TURANDOT achieving MH increased from 8.8% (6/68) at baseline to 35.3% at week 16 (24/68; non-responder imputation). The corresponding increase in the ontamalimab group was from 23.3% (61/262) to 26.7% (70/262).

Conclusions: Ontamalimab was well tolerated up to 144 weeks in patients with moderate-to-severe UC, with good safety and efficacy.
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http://dx.doi.org/10.1093/ecco-jcc/jjab023DOI Listing
February 2021

PPIs and anti-TNF in patients with IBD: a forbidden combination?

Gut 2021 Jan 29. Epub 2021 Jan 29.

Gastroenterology and Hepatology, KU Leuven University Hospitals Leuven, Leuven, Flanders, Belgium.

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http://dx.doi.org/10.1136/gutjnl-2021-324040DOI Listing
January 2021

Positioning strictureplasty in the treatment of extensive Crohn's disease ileitis: a comparative study with ileocecal resection.

Int J Colorectal Dis 2021 Apr 22;36(4):791-799. Epub 2021 Jan 22.

Department of Abdominal Surgery, University Hospitals Leuven, KU Leuven, Leuven, Belgium.

Purpose: The optimal surgical approach to extensive Crohn's disease (CD) terminal ileitis is debated. To date, no studies have directly compared the short- and long-term outcomes of modified side-to-side isoperistaltic strictureplasty over the valve (mSSIS) to traditional ileocecal resection.

Methods: A retrospective, observational, comparative study was conducted in consecutive CD patients operated for extensive involvement of the terminal ileum (≥ 20 cm). Ninety-day postoperative morbidity was assessed using the comprehensive complication index (CCI). Surgical recurrence was defined as the need for any surgical intervention related to CD during the follow-up period. Endoscopic remission was defined as ≤ i2a, according to the modified Rutgeerts score. Deep remission was defined as the combination of endoscopic remission and absence of clinical symptoms. Perioperative factors related to clinical recurrence were evaluated.

Results: Eighty-seven patients were included (47 (54%) ileocecal resection and 40 (46%) mSSIS). Median follow-up was 56 (IQR 34.7-94.4) and 72 (IQR 48.3-87.2) months for resection and mSSIS, respectively (p < 0.001). No mortality occurred. Mean CCI was 9.1 vs 8.5 for ileocecal resection and mSSIS, respectively (p = 0.48). Throughout the follow-up, 8 patients in the resection group (17%) and 5 patients in the mSSIS group (12.5%) experienced surgical recurrence (p = 0.393). Thirty-seven (92.5%) of patients kept the mSSIS. No difference in deep remission was observed (41% vs 22.5%, p = 0.34).

Conclusions: Modified SSIS seems to be non-inferior in terms of safety, recurrence, and durability to traditional resections with the advantage of mitigating the risk of a short bowel syndrome. Larger prospective studies are required to confirm these findings.
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http://dx.doi.org/10.1007/s00384-021-03837-6DOI Listing
April 2021

Long-term Safety and Efficacy of Etrasimod for Ulcerative Colitis: Results from the Open-label Extension of the OASIS Study.

J Crohns Colitis 2021 Jan 21. Epub 2021 Jan 21.

University of California San Diego, La Jolla, CA, USA.

Background And Aims: Etrasimod is an oral, selective, sphingosine 1-phosphate receptor modulator. In a phase 2, randomised, double-blind, placebo-controlled trial in adults with moderately-to-severely active ulcerative colitis (OASIS), etrasimod 2 mg provided significant benefit versus placebo and was generally well tolerated. This open-label extension (OLE) evaluated safety and efficacy of etrasimod for up to 52 weeks.

Methods: In OASIS, 156 patients received etrasimod 1 mg, etrasimod 2 mg, or placebo once-daily for 12 weeks. After completing OASIS, patients could enrol in the OLE and receive etrasimod 2 mg for an additional 34-40 weeks.

Results: 118 patients enrolled in the OLE; 112 patients received etrasimod 2 mg at any point and were evaluated for safety and efficacy. A total of 92 (82%) patients who received etrasimod 2 mg in the OLE completed the study. Treatment-emergent adverse events occurred in 60% (67/112) of patients receiving etrasimod 2 mg at any time, most commonly worsening ulcerative colitis and anaemia; 94% of adverse events were mild/moderate. At end of treatment, 64% of patients met the criteria for clinical response, 33% for clinical remission, and 43% for endoscopic improvement. Week 12 clinical response, clinical remission, or endoscopic improvement was maintained to end of treatment in 85%, 60%, or 69% of patients, respectively. Steroid-free clinical remission occurred in 22% of overall patients.

Conclusions: In this long-term extension study, etrasimod 2 mg demonstrated a favourable safety profile. Most patients with clinical response, clinical remission, or endoscopic improvement at Week 12 maintained that status to end of treatment. ClinicalTrials.gov numbers NCT02447302, NCT02536404.
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http://dx.doi.org/10.1093/ecco-jcc/jjab016DOI Listing
January 2021

NOD2 drives early IL-33-dependent expansion of group 2 innate lymphoid cells during Crohn's disease-like ileitis.

J Clin Invest 2021 Mar;131(5)

Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.

Innate lymphoid cells (ILCs) are enriched at barrier surfaces, including the gastrointestinal tract. While most studies have focused on the balance between pathogenic group 1 ILCs (ILC1s) and protective ILC3s in maintaining gut homeostasis and during chronic intestinal inflammation, such as Crohn's disease (CD), less is known regarding ILC2s. Using an established murine model of CD-like ileitis, i.e., the SAMP1/YitFc (SAMP) mouse strain, we showed that ILC2s, compared with ILC1s and ILC3s, were increased within draining mesenteric lymph nodes and ilea of SAMP versus AKR (parental control) mice early, during the onset of disease. Gut-derived ILC2s from CD patients versus healthy controls were also increased and expanded, similarly to ILC1s, in greater proportion compared with ILC3s. Importantly, we report that the intracellular bacteria-sensing protein, nucleotide-binding oligomerization domaining-containing protein 2, encoded by Nod2, the first and strongest susceptibility gene identified for CD, promoted ILC2 expansion, which was dramatically reduced in SAMP mice lacking NOD2 and in SAMP mice raised under germ-free conditions. Furthermore, these effects occurred through a mechanism involving the IL-33/ST2 ligand-receptor pair. Collectively, our results indicate a functional link between NOD2 and ILC2s, regulated by the IL-33/ST2 axis, that mechanistically may contribute to early events leading to CD pathogenesis.
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http://dx.doi.org/10.1172/JCI140624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919719PMC
March 2021

Long-Term Efficacy And Safety Of Ozanimod In Moderate-To-Severe Ulcerative Colitis: Results From The Open-Label Extension Of The Randomized, Phase 2 Touchstone Study.

J Crohns Colitis 2021 Jan 13. Epub 2021 Jan 13.

Inflammatory Bowel Disease Center, Amsterdam University Medical Center, Amsterdam, the Netherlands.

Background And Aims: This analysis examined long-term safety and efficacy of ozanimod in patients with moderate-to-severe UC with ≥4 years of follow-up in the phase 2 TOUCHSTONE open-label extension (OLE).

Methods: Patients receiving placebo or ozanimod HCl 0.5 mg or 1 mg during the double-blind period could enter the OLE (ozanimod HCl 1 mg daily). Partial Mayo score (pMS) clinical response and remission were assessed through OLE week 200 and summarized descriptively using observed cases (OC) and non-responder imputation (NRI). Endoscopy was required at OLE week 56 and end of treatment. Parameters associated with endoscopy were summarized at weeks 56 and 104 (OC), and week 56 (NRI). C-reactive protein and fecal calprotectin were assessed. Adverse events were monitored throughout the study.

Results: Of 197 patients receiving double-blind treatment, 170 entered the OLE. Discontinuation rates were 28% at year 1 and 15% to 18% annually through year 4. Partial Mayo measures indicated clinical response and remission rates at OLE week 200 of 93.3% and 82.7%, respectively, using OC and 41% and 37% with the more conservative NRI analysis. At weeks 56 and 104, respectively, histologic remission rates were 46.3% and 38.5%, and endoscopic improvement rates were 46.4% and 46.5% (OC). No new safety signals were identified during ≥4 years of follow-up.

Conclusions: There was a high rate of continued study participation and long-term benefit with ozanimod HCl 1 mg daily by clinical, histologic, and biomarker measures in patients with moderate-to-severe UC in the TOUCHSTONE OLE. (NCT02531126).
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http://dx.doi.org/10.1093/ecco-jcc/jjab012DOI Listing
January 2021

Understanding the Molecular Drivers of Disease Heterogeneity in Crohn's Disease Using Multi-omic Data Integration and Network Analysis.

Inflamm Bowel Dis 2020 Dec 14. Epub 2020 Dec 14.

Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID).

Crohn's disease (CD), a form of inflammatory bowel disease (IBD), is characterized by heterogeneity along multiple clinical axes, which in turn impacts disease progression and treatment modalities. Using advanced data integration approaches and systems biology tools, we studied the contribution of CD susceptibility variants and gene expression in distinct peripheral immune cell subsets (CD14+ monocytes and CD4+ T cells) to relevant clinical traits. Our analyses revealed that most clinical traits capturing CD heterogeneity could be associated with CD14+ and CD4+ gene expression rather than disease susceptibility variants. By disentangling the sources of variation, we identified molecular features that could potentially be driving the heterogeneity of various clinical traits of CD patients. Further downstream analyses identified contextual hub proteins such as genes encoding barrier functions, antimicrobial peptides, chemokines, and their receptors, which are either targeted by drugs used in CD or other inflammatory diseases or are relevant to the biological functions implicated in disease pathology. These hubs could be used as cell type-specific targets to treat specific subtypes of CD patients in a more individualized approach based on the underlying biology driving their disease subtypes. Our study highlights the importance of data integration and systems approaches to investigate complex and heterogeneous diseases such as IBD.
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http://dx.doi.org/10.1093/ibd/izaa281DOI Listing
December 2020

Outcomes of Tofacitinib Dose Reduction in Patients with Ulcerative Colitis in Stable Remission from the Randomized RIVETING Trial.

J Crohns Colitis 2020 Dec 8. Epub 2020 Dec 8.

Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain.

Background And Aims: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. We present primary completion analysis from RIVETING, an ongoing, double-blind, randomized, parallel-group trial evaluating efficacy and safety of tofacitinib dose reduction to 5 mg twice daily [BID] versus remaining on 10 mg BID in patients in stable remission on tofacitinib 10 mg BID maintenance therapy.

Methods: Patients had received tofacitinib 10 mg BID for ≥2 consecutive years and been in stable remission for ≥6 months before enrollment. The primary endpoint was modified Mayo score remission at month 6. Safety was assessed up to February 20, 2020 [data cut-off].

Results: 140 patients were randomized [1:1] to tofacitinib 5 or 10 mg BID; 77.1% and 90.0% of patients in the 5 and 10 mg BID groups, respectively, were in modified Mayo score remission at month 6 [adjusted difference 12.9%; 95% CI 0.5-25.0]. Smaller differences between treatment groups were seen in patients with baseline endoscopic subscore of 0 versus 1 [9.8%; -3.0-22.6 and 21.1%; -6.1-48.2, respectively], and in patients without versus with prior tumor necrosis factor inhibitor [TNFi] failure [9.5%; -6.6-25.6 and 17.4%; -1.6-36.3, respectively]. AE and serious AE rates were similar across treatment groups; no deaths were reported.

Conclusions: Most patients in stable remission on 10 mg BID maintenance therapy maintained remission following dose de-escalation. For patients who dose de-escalated, those in deep endoscopic remission and those without prior TNFi failure were more likely to maintain remission. Efficacy data were limited to the first 6-months; a longer duration of follow-up during RIVETING will further characterize the impact of dose reduction on maintenance of remission. Safety findings were consistent with the established safety profile of tofacitinib.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa249DOI Listing
December 2020

Tissue exposure does not explain non-response in ulcerative colitis patients with adequate serum vedolizumab concentrations.

J Crohns Colitis 2020 Nov 27. Epub 2020 Nov 27.

Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.

Background And Aims: Some patients with ulcerative colitis (UC) do not respond to vedolizumab treatment despite adequate drug exposure in serum. This study aimed to investigate vedolizumab in tissue and questioned whether insufficient tissue exposure could explain non-response in UC patients with adequate serum vedolizumab concentrations.

Methods: A paired serum sample and colonic mucosal biopsy was collected from 40 UC patients (20 endoscopic responders, 20 non-responders) at week 14 of vedolizumab treatment. Vedolizumab, soluble (s)-mucosal addressin cell adhesion molecule-1 (MAdCAM-1), s-vascular cell adhesion molecule-1 (VCAM-1) and s-intercellular adhesion molecule-1 (ICAM-1) were measured in serum and/or tissue. Endoscopic response was defined as Mayo endoscopic sub-score ≤1.

Results: A significant positive correlation was observed between vedolizumab serum and colonic tissue concentrations (ρ = 0.84, p<0.0001), regardless of the macroscopic inflammatory state of the tissue. Vedolizumab tissue concentrations were lower in non-responders than in responders (0.07 vs 0.11 µg/mg, p = 0.04). In the subgroup of patients with adequate vedolizumab serum concentrations (>14.6 µg/mL), tissue vedolizumab was not significantly different between responders and non-responders (0.15 vs 0.13 µg/mg; p = 0.92). Serum sMAdCAM-1, but not serum sICAM-1 or sVCAM-1 concentrations, were significantly higher in responders than non-responders with adequate vedolizumab serum concentrations (1.04 vs 0.83 ng/mL, p =0.03).

Conclusions: Vedolizumab concentrations in colonic mucosal tissue of UC patients reflect the concentration in serum regardless of the macroscopic inflammatory state of the tissue. Our data shows that insufficient tissue exposure does not explain non-response in UC patients with adequate serum vedolizumab concentrations.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa239DOI Listing
November 2020

Vedolizumab treatment persistence and safety in a 2-year data analysis of an extended access programme.

Aliment Pharmacol Ther 2021 01 18;53(2):265-272. Epub 2020 Nov 18.

Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.

Background: Vedolizumab was shown to be effective and safe for patients with ulcerative colitis (UC) or Crohn's disease (CD) in the GEMINI phase 3 and long-term safety (LTS) studies.

Aim: To report treatment persistence and safety results up to 2 years after enrolment in the vedolizumab extended access programme (XAP) METHODS: Vedolizumab XAP is a phase 3b/4, prospective, open-label, multinational, interventional study. At rollover from GEMINI LTS, patients who were experiencing continued clinical benefit with vedolizumab received reduced dosing frequency from every 4 weeks (Q4W) to every 8 weeks (Q8W). Patient persistence on Q8W dosing, incidence of relapse, and safety 2 years after enrolment were investigated.

Results: We enrolled 311 patients (142 UC and 169 CD). At baseline, 93.7% (UC) and 89.3% (CD) of patients were in clinical remission; 93.0% (UC) and 84.6% (CD) reduced dosing frequency to Q8W at enrolment. Of those who reduced dosing frequency to Q8W at enrolment, 93.9% (UC) and 91.6% (CD) remained on Q8W dosing; 6.1% (UC) and 8.4% (CD) re-escalated to Q4W dosing. Relapse was reported in 9.1% (UC) and 14.0% (CD) of patients who reduced dosing to Q8W. Adverse events related to vedolizumab were infrequent; no new events were reported.

Conclusion: We observed high patient persistence on vedolizumab Q8W in the first 2 years after the reduction of dosing frequency in the XAP along with low rates of Q4W dose re-escalation and relapse. The safety profile was consistent with previous reports. ClinicalTrials.gov: NCT02743806.
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http://dx.doi.org/10.1111/apt.16160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839669PMC
January 2021

Location but Not Severity of Endoscopic Lesions Influences Endoscopic Remission Rates in Crohn's Disease: A Post Hoc Analysis of TAILORIX.

Am J Gastroenterol 2021 01;116(1):134-141

CHU de Bordeaux, Hôpital Haut-Lévêque, Service d'Hépato-gastroentérologie et oncologie digestive - Université de Bordeaux, Bordeaux, France.

Introduction: The impact of severity and location of Crohn's disease (CD) endoscopic ulcers on endoscopic remission in patients treated with antitumor necrosis factor is poorly known. We aimed to describe the endoscopic evolution of CD lesions in a prospective cohort of patients treated with infliximab (IFX) in combo therapy.

Methods: We conducted a post hoc analysis of the TAILORIX randomized controlled trial, which studied biologic-naïve patients with active CD and endoscopic ulcers receiving IFX combo therapy. Ileocolonoscopies were performed at week 0, 12, and 54. Endoscopic healing was defined as the absence of ulcers and complete endoscopic remission as CD Endoscopic Index of Severity (CDEIS) <3. Ileocolonic segments were scored separately for remission by blinded readers.

Results: A total of 122 (median disease duration: 7 months) patients were included, corresponding with 379 diseased segments. The median (IQR) CDEIS scores at week 0, 12, and 54 were 9.9 (6.1-14.4), 2.4 (0.2-4.6), and 0.2 (0.0-3.7), respectively. At weeks 12 and 54, the rates of endoscopic healing and complete endoscopic remission were 41% and 61% and 61% and 73%, respectively. Median CDEIS scores were similar among patients with deep ulcers at baseline and those with only superficial ulcers at week 12 and 54. Segmental remission rates were lower both at week 12 and 54 in the ileum compared with colonic segments (P < 0.01 all comparisons) and in the rectum (P = 0.02 and P = 0.03).

Discussion: In biologic-naive patients with CD treated with IFX combo therapy, the severity of endoscopic lesions at the baseline did not influence healing rates. Endoscopic remission occurs less frequently in the ileum compared with the colon.
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http://dx.doi.org/10.14309/ajg.0000000000000834DOI Listing
January 2021

Worries and concerns of inflammatory bowel disease (IBD) patients in Belgium - a validation of the Dutch rating form.

Scand J Gastroenterol 2020 Dec 1;55(12):1427-1432. Epub 2020 Nov 1.

Health Psychology Research Group, KU Leuven, Leuven, Belgium.

Objectives: Worry is the most common psychological complaint among patients with Inflammatory Bowel Disease (IBD). This study aimed to translate and test the psychometric properties the Rating Form of IBD Patient Concerns (RFIPC) among Dutch-speaking patients with IBD in Belgium. It also aimed to describe worries and concerns, and to examine possible differences in worry patterns between patients with different disease types and disease activities.

Methods: The RFIPC was translated into Dutch following the guidelines of the Rome Foundation and was completed by patients with Crohn's disease (CD,  = 336) and ulcerative colitis (UC,  = 160). To test concurrent validity, the Depression Anxiety Stress Scales (DASS-21) were used. Factor structure was examined with confirmatory factor analysis.

Results: The four-factor structure including subscales 'impact of the disease', 'sexual intimacy', 'complications of the disease' and 'body stigma' was confirmed in the Dutch sample. All factors had high internal consistency (>.70). Correlations with DASS-21 suggest good concurrent validity, all s>.30, s<.001. No differences in the RFIPC scores were observed between patients with CD and UC. Patients with active disease (53%) had higher scores than patients in remission (47%). Across all groups, the order of top concerns was consistent and included worries about energy level, side effects of medication, having an ostomy bag/surgery, and uncertain nature of the disease.

Conclusions: The Dutch version of the RFIPC is a valid and reliable measure of IBD-specific worries and concerns which can be used in both research and clinical settings.
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http://dx.doi.org/10.1080/00365521.2020.1839962DOI Listing
December 2020

Inflammatory bowel disease and Parkinson's disease: common pathophysiological links.

Gut 2021 Feb 16;70(2):408-417. Epub 2020 Oct 16.

Department of Human Genetics, KU Leuven, Leuven, Belgium

Inflammatory bowel disease and Parkinson's disease are chronic progressive disorders that mainly affect different organs: the gut and brain, respectively. Accumulating evidence has suggested a bidirectional link between gastrointestinal inflammation and neurodegeneration, in accordance with the concept of the 'gut-brain axis'. Moreover, recent population-based studies have shown that inflammatory bowel disease might increase the risk of Parkinson's disease. Although the precise mechanisms underlying gut-brain interactions remain elusive, some of the latest findings have begun to explain the link. Several genetic loci are shared between both disorders with a similar direction of effect on the risk of both diseases. The most interesting example is (leucine-rich repeat kinase 2), initially identified as a causal gene in Parkinson's disease, and recently also implicated in Crohn's disease. In this review, we highlight recent findings on the link between these seemingly unrelated diseases with shared genetic susceptibility. We discuss supporting and conflicting data obtained from epidemiological and genetic studies along with remaining questions and concerns. In addition, we discuss possible biological links including the gut-brain axis, microbiota, autoimmunity, mitochondrial function and autophagy.
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http://dx.doi.org/10.1136/gutjnl-2020-322429DOI Listing
February 2021

Computer-Aided Diagnosis With Monochromatic Light Endoscopy for Scoring Histologic Remission in Ulcerative Colitis.

Gastroenterology 2021 Jan 12;160(1):23-25. Epub 2020 Oct 12.

University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1053/j.gastro.2020.09.053DOI Listing
January 2021

Variability in the Distribution of Histological Disease Activity in the Colon of Patients with Ulcerative Colitis.

J Crohns Colitis 2021 Apr;15(4):603-608

Department of Pathology, University Hospitals Leuven, Leuven, Belgium.

Background And Aims: Histological activity scores have been developed and validated. However, data on the distribution of histological inflammation within one segment in patients with ulcerative colitis [UC] are lacking. This impacts on the reliability of histological activity scores. The aim of this study was to assess the variability in histological activity within one endoscopic segment in patients with UC.

Methods: Biopsies were taken in sequential patients with UC in three adjacent contiguous regions within a macroscopically homogeneous colonic segment. Biopsies were scored for Geboes score [GS], Robarts histological index [RHI] and Nancy histological index [NHI]. Variability was assessed by Kappa statistics for categorical outcomes and intraclass correlation coefficient [ICC] for continuous outcomes.

Results: A total of 161 biopsy sets from 55 endoscopic segments of 21 patients were analysed. Endoscopically active disease was present in 45% of segments. The continuous histological scores showed excellent agreement between the different regions. The ICC for RHI in all segments was 0.974 (95% confidence interval [CI] 0.958-0.984; p < 0.0001) and 0.98 [95% CI: 0.968-0.988; p < 0.0001] for the numerically converted GS. The categorical NHI showed higher variability: κ = 0.574 [95% CI: 0.571-0.577; p < 0.0001]. In all segments the highest variability was seen in samples with NHI = 2. When dichotomizing based on histological remission, substantial agreement was seen for all scores, with κ > 0.734 for all cut-offs. The homogeneity in the distribution of histological disease activity was comparable between colonic segments.

Conclusion: The distribution of histological disease activity in UC follows a homogeneous pattern in different locations of one segment.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa206DOI Listing
April 2021

Monitoring vedolizumab and ustekinumab drug levels in patients with inflammatory bowel disease: hype or hope?

Curr Opin Pharmacol 2020 12 9;55:17-30. Epub 2020 Oct 9.

KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research in Gastrointestinal Disorders (TARGID) - IBD Unit, Leuven, Belgium; University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium. Electronic address:

Therapeutic drug monitoring (TDM) plays a vital role in implementing precision medicine in inflammatory bowel disease (IBD), and may contribute to increased effectiveness, lower rates of drug toxicity and cost savings. While expert panels advocate the use of reactive TDM for anti-tumor necrosis factor (anti-TNF) agents, TDM is not yet widely recommended for non-anti TNF biologicals. We provide an overview of the observational evidence of the value of TDM in case of vedolizumab and ustekinumab. We also shed light on obstacles that need to be addressed before establishing wide acceptance of TDM in the field of IBD. In this respect, new analytical techniques and modelling approaches are being developed to further optimize efficacy of TDM and to facilitate general acceptance of this tool in personalizing IBD management.
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http://dx.doi.org/10.1016/j.coph.2020.09.002DOI Listing
December 2020

Biological Therapy in Inflammatory Bowel Disease Patients Partly Restores Intestinal Innate Lymphoid Cell Subtype Equilibrium.

Front Immunol 2020 27;11:1847. Epub 2020 Aug 27.

KU Leuven Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, Leuven, Belgium.

Patients with Crohn disease (CD) and ulcerative colitis (UC) suffer from chronic relapsing intestinal inflammation. While many studies focused on adaptive immunity, less is known about the role of innate immune cells in these diseases. Innate lymphoid cells (ILCs) are recently identified cells with a high cytokine-producing capacity at mucosal barriers. The aim was to study the impact of biological treatment on ILC in CD and UC. Patients initiating anti-tumor necrosis factor (TNF), ustekinumab, or vedolizumab treatment were prospectively followed up and peripheral and intestinal ILCs were determined. In the inflamed gut tissue of patients with inflammatory bowel disease, we found an increase of ILC1 and in immature NKp44 ILC3, whereas there was a decrease of mature NKp44 ILC3 when compared to healthy controls (HCs). Similar but less pronounced changes in ILC1 were observed in blood, whereas circulating NKp44 ILC3 were decreased. Fifteen percent of CD patients had NKp44 ILC3 in blood and these cells were not detected in blood of HCs or UC patients. Therapy with three different biologicals (ustekinumab targeting the IL-12/23 cytokines, anti-TNF and vedolizumab) partly restored intestinal ILC subset equilibrium with a decrease of ILC1 (except for ustekinumab) and an increase of NKp44 ILC3. Anti-TNF also mobilized more NKp44 ILC3 in circulation. As ILC1 are proinflammatory cells and as NKp44 ILC3 contribute to homeostasis of intestinal mucosa, the observed effects of biologicals on ILCs might contribute to their clinical efficacy.
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http://dx.doi.org/10.3389/fimmu.2020.01847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481382PMC
April 2021

Review article: how the intestinal microbiota may reflect disease activity and influence therapeutic outcome in inflammatory bowel disease.

Aliment Pharmacol Ther 2020 11 24;52(9):1453-1468. Epub 2020 Sep 24.

Department of Chronic Diseases & Metabolism, Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium.

Background: Intestinal bacteria produce metabolites and by-products necessary for homeostasis. Imbalance in this equilibrium is linked to multiple pathologies including inflammatory bowel disease (IBD). The role of the gut microbiota in determining treatment response is becoming apparent, and may act as biomarker for efficacy.

Aim: To describe knowledge about the intestinal microbiota on disease severity and treatment outcomes in IBD METHODS: Descriptive review using PubMed to identify literature on the intestinal microbiota in IBD RESULTS: Severe IBD has a less diverse microbiota with fewer commensal microbiota communities and more opportunistic pathogenic bacteria originating from the oral cavity or respiratory tract. IBD treatments can alter gut microbiota composition, but in vitro/in vivo studies are needed to prove causation. A diversification of the microbiota is observed during remission. Patients with a more diverse baseline microbiome and higher microbial diversity show better response to anti-tumour necrosis factor-α, vedolizumab and ustekinumab therapy. Higher abundance of short chain fatty acid-producing bacteria, fewer mucus-colonising bacteria and lower abundance of pro-inflammatory bacteria have also been associated with a favourable outcome. Predictive models, based on a combination of microbiota, clinical data and serological markers, have good accuracy for treatment outcome and disease severity.

Conclusion: The intestinal microbiota in IBD carries a set of promising biomarkers of disease activity and prediction of therapeutic outcome. Current insights may also help in designing microbiota modulation strategies to improve outcomes in IBD.
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http://dx.doi.org/10.1111/apt.16096DOI Listing
November 2020

Thiopurine monotherapy has a limited place in treatment of patients with mild-to-moderate Crohn's disease.

Gut 2020 Sep 14. Epub 2020 Sep 14.

Dpt Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium

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http://dx.doi.org/10.1136/gutjnl-2020-322646DOI Listing
September 2020

Intestinal Receptor of SARS-CoV-2 in Inflamed IBD Tissue Seems Downregulated by HNF4A in Ileum and Upregulated by Interferon Regulating Factors in Colon.

J Crohns Colitis 2021 Mar;15(3):485-498

Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.

Background: Patients with inflammatory bowel disease [IBD] are considered immunosuppressed, but do not seem more vulnerable for COVID-19. Nevertheless, intestinal inflammation has shown to be an important risk factor for SARS-CoV-2 infection and prognosis. Therefore, we investigated the role of intestinal inflammation on the viral intestinal entry mechanisms, including ACE2, in IBD.

Methods: We collected inflamed and uninflamed mucosal biopsies from Crohn's disease [CD] [n = 193] and ulcerative colitis [UC] [n = 158] patients, and from 51 matched non-IBD controls for RNA sequencing, differential gene expression, and co-expression analysis. Organoids from UC patients were subjected to an inflammatory mix and processed for RNA sequencing. Transmural ileal biopsies were processed for single-cell [sc] sequencing. Publicly available colonic sc-RNA sequencing data, and microarrays from tissue pre/post anti-tumour necrosis factor [TNF] therapy, were analysed.

Results: In inflamed CD ileum, ACE2 was significantly decreased compared with control ileum [p = 4.6E-07], whereas colonic ACE2 was higher in inflamed colon of CD/UC compared with control [p = 8.3E-03; p = 1.9E-03]. Sc-RNA sequencing confirmed this ACE2 dysregulation and exclusive epithelial ACE2 expression. Network analyses highlighted HNF4A as key regulator of ileal ACE2, and pro-inflammatory cytokines and interferon regulating factors regulated colonic ACE2. Inflammatory stimuli upregulated ACE2 in UC organoids [p = 1.7E-02], but not in non-IBD controls [p = 9.1E-01]. Anti-TNF therapy restored colonic ACE2 regulation in responders.

Conclusions: Intestinal inflammation alters SARS-CoV-2 coreceptors in the intestine, with opposing dysregulations in ileum and colon. HNF4A, an IBD susceptibility gene, seems an important upstream regulator of ACE2 in ileum, whereas interferon signalling might dominate in colon.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543339PMC
March 2021

Long-term safety of vedolizumab for inflammatory bowel disease.

Aliment Pharmacol Ther 2020 10 2;52(8):1353-1365. Epub 2020 Sep 2.

Leuven, Belgium.

Background: Vedolizumab, a gut-selective α β integrin antibody, is approved for moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD).

Aim: To report the final results from the vedolizumab GEMINI long-term safety (LTS) study.

Methods: The phase 3, open-label GEMINI LTS study (initiated May 2009) enrolled patients with UC or CD from four prior clinical trials and vedolizumab-naïve patients. Vedolizumab LTS was evaluated; efficacy and patient-reported outcomes were exploratory endpoints.

Results: Enrolled patients (UC, n = 894; CD, n = 1349) received vedolizumab 300 mg IV every 4 weeks; median cumulative exposure was 42.4 months (range: 0.03-112.2) for UC and 31.5 months (range: 0.03-100.3) for CD. Over 8 years, adverse events (AEs) occurred in 93% (UC) and 96% (CD) of patients, with UC (36%) and CD (35%) exacerbations most frequent. Serious AEs were reported for 31% (UC) and 41% (CD) of patients. Vedolizumab discontinuation due to AEs occurred in 15% (UC) and 17% (CD) of patients. There were no new trends for infections, malignancies, infusion-related reactions, or hepatic events, and no cases of progressive multifocal leukoencephalopathy. Of the ten deaths (UC, n = 4; CD, n = 6), two were considered drug-related by local investigators (West Nile virus infection-related encephalitis and hepatocellular carcinoma). Continuous vedolizumab maintained clinical response long-term, with 33% (UC) and 28% (CD) of patients in clinical remission at 400 treatment weeks.

Conclusions: The safety profile of vedolizumab remains favourable with no unexpected or new safety concerns. These results further establish the safety of vedolizumab and support its long-term use (NCT00790933/EudraCT 2008-002784-14).
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http://dx.doi.org/10.1111/apt.16060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540482PMC
October 2020