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Minea H, Singeap AM, Minea M, Juncu S, Chiriac SA, Sfarti CV, Stanciu C, Trifan A. Integrating Proteomics into Personalized Medicine for Inflammatory Bowel Disease—Reality or Challenge? Int J Mol Sci 2025; 26:4993. [DOI: 10.3390/ijms26114993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025] Open
Abstract
Inflammatory bowel diseases (IBD) represent chronic conditions with etiopathogenic mechanisms incompletely elucidated despite extensive research efforts. Therefore, it is essential for clinical monitoring of the implementation of personalized medicine, enabling risk stratification and the selection of therapies with the highest likelihood of a favorable response. Multi-omics approaches have emerged as an excellent opportunity for the prevention, clinical phenotype differentiation, and prediction of IBD development. Proteomics has gained significant enthusiasm in medical practice, primarily due to its focus on studying the composition and dynamic expression of various cellular and tissue structures. This approach provides critical insights into their impact on signaling pathways, post-translational modifications, and the development of sequence variations. Hence, it could provide the foundation for developing biomarkers with the potential to assess mucosal healing and predict prognostic variability among patients, facilitating the implementation of a personalized therapeutic approach. This review focuses on the recent research regarding the possibility of implementing proteomics technologies into clinical practice, given the challenges and limitations, and the advantages of increasing the quality of life in patients with IBD.
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Affiliation(s)
- Horia Minea
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Ana-Maria Singeap
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Manuela Minea
- Department of Microbiology, The National Institute of Public Health, 700464 Iasi, Romania
| | - Simona Juncu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Stefan Andrei Chiriac
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Catalin Victor Sfarti
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Carol Stanciu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Anca Trifan
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
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Horn V, Cancino CA, Steinheuer LM, Obermayer B, Fritz K, Nguyen AL, Juhran KS, Plattner C, Bösel D, Oldenburg L, Burns M, Schulz AR, Saliutina M, Mantzivi E, Lissner D, Conrad T, Mashreghi MF, Zundler S, Sonnenberg E, Schumann M, Haag LM, Beule D, Flatz L, Trajanoski Z, D'Haens G, Weidinger C, Mei HE, Siegmund B, Thurley K, Hegazy AN. Multimodal Profiling of Peripheral Blood Identifies Proliferating Circulating Effector CD4 + T Cells as Predictors for Response to Integrin α4β7-Blocking Therapy in Inflammatory Bowel Disease. Gastroenterology 2025; 168:327-343. [PMID: 39343250 DOI: 10.1053/j.gastro.2024.09.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 09/06/2024] [Accepted: 09/18/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND & AIMS Despite the success of biological therapies in treating inflammatory bowel disease, managing patients remains challenging due to the absence of reliable predictors of therapy response. METHODS In this study, we prospectively sampled 2 cohorts of patients with inflammatory bowel disease receiving the anti-integrin α4β7 antibody vedolizumab. Samples were subjected to mass cytometry; single-cell RNA sequencing; single-cell B and T cell receptor sequencing (BCR/TCR-seq); serum proteomics; and multiparametric flow cytometry to comprehensively assess vedolizumab-induced immunologic changes in the peripheral blood and their potential associations with treatment response. RESULTS Vedolizumab treatment led to substantial alterations in the abundance of circulating immune cell lineages and modified the T-cell receptor diversity of gut-homing CD4+ memory T cells. Through integration of multimodal parameters and machine learning, we identified a significant increase in proliferating CD4+ memory T cells among nonresponders before treatment compared with responders. This predictive T-cell signature demonstrated an activated T-helper 1/T-helper 17 cell phenotype and exhibited elevated levels of integrin α4β1, potentially making these cells less susceptible to direct targeting by vedolizumab. CONCLUSIONS These findings provide a reliable predictive classifier with significant implications for personalized inflammatory bowel disease management.
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Affiliation(s)
- Veronika Horn
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Camila A Cancino
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Lisa M Steinheuer
- Institute of Experimental Oncology, Biomathematics Division, University Hospital Bonn, Bonn, Germany
| | - Benedikt Obermayer
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Core Unit Bioinformatics, Berlin, Germany
| | - Konstantin Fritz
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Anke L Nguyen
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Department of Gastroenterology, Central Clinical School, Monash University and Alfred Health, Melbourne, Victoria, Australia
| | - Kim Susan Juhran
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Christina Plattner
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Diana Bösel
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Lotte Oldenburg
- Department of Gastroenterology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Marie Burns
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Axel Ronald Schulz
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Mariia Saliutina
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Eleni Mantzivi
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Donata Lissner
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Thomas Conrad
- Genomics Technology Platform, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Core Unit Genomics, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Mir-Farzin Mashreghi
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany; German Center for Child and Adolescent Health (DZKJ), Partner Site Berlin, Berlin, Germany
| | - Sebastian Zundler
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Elena Sonnenberg
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Michael Schumann
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Lea-Maxie Haag
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Dieter Beule
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Core Unit Bioinformatics, Berlin, Germany
| | - Lukas Flatz
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland; Department of Dermatology, University Hospital Tübingen, University of Tübingen, Tübingen, Germany
| | - Zlatko Trajanoski
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Geert D'Haens
- Department of Gastroenterology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Carl Weidinger
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Henrik E Mei
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Britta Siegmund
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Kevin Thurley
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany; Institute of Experimental Oncology, Biomathematics Division, University Hospital Bonn, Bonn, Germany.
| | - Ahmed N Hegazy
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin Institute of Health Academy, Clinician Scientist Program, Berlin, Germany.
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Rioux JD, Boucher G, Forest A, Bouchard B, Coderre L, Daneault C, Frayne IR, Legault JT, iGenoMed Consortium, Bitton A, Ananthakrishnan A, Lesage S, Xavier RJ, Des Rosiers C. A pilot study to identify blood-based markers associated with response to treatment with Vedolizumab in patients with Inflammatory Bowel Disease. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.09.19.24314034. [PMID: 39371119 PMCID: PMC11451768 DOI: 10.1101/2024.09.19.24314034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/08/2024]
Abstract
The inflammatory bowel diseases (IBD) known as Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal tract believed to arise because of an imbalance between the epithelial, immune and microbial systems. It has been shown that biological differences (genetic, epigenetic, microbial, environmental, etc.) exist between patients with IBD, with multiple risk factors been associated with disease susceptibility and IBD-related phenotypes (e.g. disease location). It is also known that there is heterogeneity in terms of response to therapy in patients with IBD, including to biological therapies that target very specific biological pathways (e.g. TNF-alpha signaling, IL-23R signaling, immune cell trafficking, etc.). It is hypothesized that the better the match between the biology targeted by these advanced therapies and the predominant disease-associated pathways at play in each patient will favor a beneficial response. The aim of this pilot study was to identify potential biological differences associated with differential treatment response to the anti α4β7 integrin therapy known as Vedolizumab. Our approach was to measure a broad range of analytes in the serum of patients prior to initiation of therapy and at the first clinical assessment visit, to identify potential markers of biological differences between patients at baseline and to see which biomarkers are most affected by treatment in responders. Our focus on early clinical response was to study the most proximal effects of therapy and to minimize confounders such as loss of response that occurs further distal to treatment initiation. Specifically, we performed targeted analyses of >150 proteins and metabolites, and untargeted analyses of >1100 lipid entities, in serum samples from 92 IBD patients (42 CD, 50 UC) immediately prior to initiation of therapy with vedolizumab (baseline samples) and at their first clinical assessment (14-week samples). We found lower levels of SDF-1a, but higher levels of PDGF-ββ, lactate, lysine, phenylalanine, branched chain amino acids, alanine, short/medium chain acylcarnitines, and triglycerides containing myristic acid in baseline serum samples of responders as compared to non-responders. We also observed an increase in serum levels of CXCL9 and citrate, as well as a decrease in IL-10, between baseline and week 14 samples. In addition, we observed that a group of metabolites and protein analytes was strongly associated with both treatment response and BMI status, although BMI status was not associated with treatment response.
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Affiliation(s)
- John D. Rioux
- Montreal Heart Institute Research Center, Montreal, Quebec, Canada
- Université de Montréal, Faculty of Medicine, Montreal, Quebec, Canada
| | | | - Anik Forest
- Montreal Heart Institute Research Center, Montreal, Quebec, Canada
| | | | - Lise Coderre
- Maisonneuve-Rosemont Hospital Research Center, Montréal, Québec, Canada
| | | | | | | | | | - Alain Bitton
- McGill University Health Centre, Division of Gastroenterology, Montreal, Quebec, Canada
| | - Ashwin Ananthakrishnan
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Sylvie Lesage
- Maisonneuve-Rosemont Hospital Research Center, Montréal, Québec, Canada
- Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, Canada
| | - Ramnik J. Xavier
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Christine Des Rosiers
- Montreal Heart Institute Research Center, Montreal, Quebec, Canada
- Département de Nutrition, Université de Montréal, Montréal, Québec, Canada
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D’Ambrosio A, Altomare A, Boscarino T, Gori M, Balestrieri P, Putignani L, Del Chierico F, Carotti S, Cicala M, Guarino MPL, Piemonte V. Mathematical Modeling of Vedolizumab Treatment's Effect on Microbiota and Intestinal Permeability in Inflammatory Bowel Disease Patients. Bioengineering (Basel) 2024; 11:710. [PMID: 39061792 PMCID: PMC11274165 DOI: 10.3390/bioengineering11070710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 07/04/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024] Open
Abstract
Growing evidence suggests that impaired gut permeability and gut microbiota alterations are involved in the pathogenesis of Inflammatory Bowel Diseases (IBDs), which include Ulcerative Colitis (UC) and Crohn's Disease (CD). Vedolizumab is an anti-α4β7 antibody approved for IBD treatment, used as the first treatment or second-line therapy when the first line results in inadequate effectiveness. The aim of this study is to develop a mathematical model capable of describing the pathophysiological mechanisms of Vedolizumab treatment in IBD patients. In particular, the relationship between drug concentration in the blood, colonic mucosal permeability and fecal microbiota composition was investigated and modeled to detect and predict trends in order to support and tailor Vedolizumab therapies. To pursue this aim, clinical data from a pilot study on a cluster of 11 IBD patients were analyzed. Enrolled patients underwent colonoscopy in three phases (before (t0), after 24 weeks of (t1) and after 52 weeks of (t2 ) Vedolizumab treatment) to collect mucosal biopsies for transepithelial electrical resistance (TEER) evaluation (permeability to ions), intestinal permeability measurement and histological analysis. Moreover, fecal samples were collected for the intestinal microbiota analysis at the three time points. The collected data were compared to those of 11 healthy subjects at t0, who underwent colonoscopy for screening surveillance, and used to implement a three-compartmental mathematical model (comprising central blood, peripheral blood and the intestine). The latter extends previous evidence from the literature, based on the regression of experimental data, to link drug concentration in the peripheral blood compartment with Roseburia abundance and intestinal permeability. The clinical data showed that Vedolizumab treatment leads to an increase in TEER and a reduction in intestinal permeability to a paracellular probe, improving tissue inflammation status. Microbiota analysis showed increasing values of Roseburia, albeit not statistically significant. This trend was adequately reproduced by the mathematical model, which offers a useful tool to describe the pathophysiological effects of Vedolizumab therapy on colonic mucosal permeability and fecal microbiota composition. The model's satisfactory predictive capabilities and simplicity shed light on the relationship between the drug, the microbiota and permeability and allow for its straightforward extension to diverse therapeutic conditions.
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Affiliation(s)
- Antonio D’Ambrosio
- Unit of Chemical-Physics Fundamentals in Chemical Engineering, Department of Science and Technology for Sustainable Development and One Health, University Campus Bio-Medico of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy; (T.B.); (V.P.)
| | - Annamaria Altomare
- Department of Sciences and Technology of Sustainable Development and Human Health, Università Campus Biomedico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy;
- Gastroenterology Research Unit, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy; (M.G.); (M.C.); (M.P.L.G.)
| | - Tamara Boscarino
- Unit of Chemical-Physics Fundamentals in Chemical Engineering, Department of Science and Technology for Sustainable Development and One Health, University Campus Bio-Medico of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy; (T.B.); (V.P.)
| | - Manuele Gori
- Gastroenterology Research Unit, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy; (M.G.); (M.C.); (M.P.L.G.)
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), International Campus “A. Buzzati-Traverso”, Via E. Ramarini 32, Monterotondo Scalo, 00015 Rome, Italy
| | - Paola Balestrieri
- Gastroenterology Unit, Fondazione Policlinico Campus Bio-Medico di Roma, Via Alvaro del Portillo 200, 00128 Rome, Italy;
| | - Lorenza Putignani
- Units of Microbiomics and Human Microbiome, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, 00165 Rome, Italy;
| | - Federica Del Chierico
- Unit of Human Microbiome, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, 00165 Rome, Italy;
| | - Simone Carotti
- Microscopic and Ultrastructural Anatomy Research Unit, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy;
| | - Michele Cicala
- Gastroenterology Research Unit, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy; (M.G.); (M.C.); (M.P.L.G.)
- Microscopic and Ultrastructural Anatomy Research Unit, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy;
| | - Michele Pier Luca Guarino
- Gastroenterology Research Unit, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy; (M.G.); (M.C.); (M.P.L.G.)
- Gastroenterology Unit, Fondazione Policlinico Campus Bio-Medico di Roma, Via Alvaro del Portillo 200, 00128 Rome, Italy;
| | - Vincenzo Piemonte
- Unit of Chemical-Physics Fundamentals in Chemical Engineering, Department of Science and Technology for Sustainable Development and One Health, University Campus Bio-Medico of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy; (T.B.); (V.P.)
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Roosenboom B, Wahab PJ, Smids C, Meijer J, Kemperman LGJM, Groenen MJM, van Lochem EG, Horjus Talabur Horje CS. Mucosal α4β7+ Lymphocytes and MAdCAM+ Venules Predict Response to Vedolizumab in Ulcerative Colitis. Inflamm Bowel Dis 2024; 30:930-938. [PMID: 37436917 DOI: 10.1093/ibd/izad123] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Indexed: 07/14/2023]
Abstract
BACKGROUND Therapeutic strategies for patients with ulcerative colitis (UC) are based on patient- and disease-related factors in combination with drug characteristics but fail to predict success in individual patients. A considerable proportion of UC patients do not respond to the biological vedolizumab. Therefore, pretreatment biomarkers for therapeutic efficacy are urgently needed. Mucosal markers related to the integrin-dependent T lymphocyte homing could be potent predictors. METHODS We prospectively included 21 biological- and steroid-naive UC patients with moderate-to-severe disease activity planned to escalate therapy to vedolizumab. At week 0, before initiating treatment, colonic biopsy specimens were obtained for immunophenotyping and immunohistochemistry. Clinical and endoscopic disease activity were determined at week 16 after 4 infusions of vedolizumab. In addition, we retrospectively included 5 UC patients who were first treated with anti-tumor necrosis factor α before receiving vedolizumab to compare with biological-naive patients. RESULTS Abundance of α4β7 on more than 8% of all CD3+ T lymphocytes in colonic biopsies at baseline was predictive for responsiveness to vedolizumab (sensitivity 100%, specificity 100%). The threshold for the proportion of MAdCAM-1+ and PNAd+ of all venules in the biopsies predictive for responsiveness to vedolizumab was ≥2.59% (sensitivity 89%, specificity 100%) and ≥2.41% (sensitivity 61%, specificity 50%), respectively. At week 16, a significant decrease of α4β7+CD3+T lymphocytes was demonstrated in responders (18% [12%-24%] to 8% [3%-9%]; P = .002), while no difference was seen in nonresponders (4% [3%-6%] to 3%; P = .59). CONCLUSIONS UC responders to vedolizumab have a higher percentage of α4β7+CD3+ T lymphocytes and a higher proportion of MAdCAM-1+ venules in colonic biopsies than nonresponders before initiating therapy. Both analyses could be promising predictive biomarkers for therapeutic response and may lead to more patient tailored treatment in the future.
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Affiliation(s)
- Britt Roosenboom
- Crohn & Colitis Centre Rijnstate, Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, the Netherlands
| | - Peter J Wahab
- Crohn & Colitis Centre Rijnstate, Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, the Netherlands
| | - Carolijn Smids
- Crohn & Colitis Centre Rijnstate, Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, the Netherlands
| | - Jos Meijer
- Department of Pathology, Rijnstate Hospital, Arnhem, the Netherlands
| | | | - Marcel J M Groenen
- Crohn & Colitis Centre Rijnstate, Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, the Netherlands
| | - Ellen G van Lochem
- Department of Microbiology and Immunology, Rijnstate Hospital, Arnhem, the Netherlands
| | - Carmen S Horjus Talabur Horje
- Crohn & Colitis Centre Rijnstate, Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, the Netherlands
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Boden EK, Kongala R, Hindmarch DC, Shows DM, Juarez JG, Lord JD. Vedolizumab Efficacy Is Associated With Decreased Intracolonic Dendritic Cells, Not Memory T Cells. Inflamm Bowel Dis 2024; 30:704-717. [PMID: 37837660 PMCID: PMC11063563 DOI: 10.1093/ibd/izad224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Indexed: 10/16/2023]
Abstract
BACKGROUND Vedolizumab, an antibody blocking integrin α4β7, is a safe and effective therapy for Crohn's disease and ulcerative colitis. Blocking α4β7 from binding its cognate addressin MAdCAM-1 on intestinal blood vessel endothelial cells prevents T cells from migrating to the gut mucosa in animal models. However, data supporting this mechanism of action in humans is limited. METHODS We conducted a cross-sectional case-control study to evaluate the effect of vedolizumab on intestinal immune cell populations while avoiding the confounding effect of resolving inflammation on the cellularity of the colonic mucosa in treatment-responsive patients. Colon biopsies from 65 case subjects receiving vedolizumab were matched with biopsies from 65 control individuals, similar in disease type, medications, anatomic location, and inflammation. Biopsies were analyzed by flow cytometry and full messenger RNA transcriptome sequencing of sorted T cells. RESULTS No difference was seen between vedolizumab recipients and control individuals in the quantity of any antigen-experienced T lymphocyte subset or in the quality of the transcriptome in any experienced T cell subset. Fewer naïve colonic B and T cells were seen in vedolizumab recipients than control individuals, regardless of response. However, the most striking finding was a marked reduction in CD1c+ (BDCA1+) dendritic cells exclusively in vedolizumab-responsive patients. In blood, these dendritic cells ubiquitously express high levels of α4β7, which is rapidly downregulated upon vedolizumab exposure. CONCLUSIONS The clinical effects of vedolizumab reveal integrin α4β7-dependent dendritic cell migration to the intestinal mucosa to be central to inflammatory bowel disease pathogenesis.
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Affiliation(s)
- Elisa K Boden
- Center for Translational Research, Benaroya Research Institute, Seattle, WA, USA
- Division of Gastroenterology, Oregon Health and Science University, Portland, OR, USA
| | - Ramya Kongala
- Center for Translational Research, Benaroya Research Institute, Seattle, WA, USA
| | - Duncan C Hindmarch
- Center for Translational Research, Benaroya Research Institute, Seattle, WA, USA
| | - Donna M Shows
- Center for Translational Research, Benaroya Research Institute, Seattle, WA, USA
| | - Julius G Juarez
- GI Drug Discovery, Takeda Pharmaceuticals, Cambridge, MA, USA
| | - James D Lord
- Center for Translational Research, Benaroya Research Institute, Seattle, WA, USA
- Division of Gastroenterology, Virginia Mason Medical Center, Seattle, WA, USA
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Kurumi H, Yokoyama Y, Hirano T, Akita K, Hayashi Y, Kazama T, Isomoto H, Nakase H. Cytokine Profile in Predicting the Effectiveness of Advanced Therapy for Ulcerative Colitis: A Narrative Review. Biomedicines 2024; 12:952. [PMID: 38790914 PMCID: PMC11117845 DOI: 10.3390/biomedicines12050952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 04/19/2024] [Accepted: 04/23/2024] [Indexed: 05/26/2024] Open
Abstract
Cytokine-targeted therapies have shown efficacy in treating patients with ulcerative colitis (UC), but responses to these advanced therapies can vary. This variability may be due to differences in cytokine profiles among patients with UC. While the etiology of UC is not fully understood, abnormalities of the cytokine profiles are deeply involved in its pathophysiology. Therefore, an approach focused on the cytokine profile of individual patients with UC is ideal. Recent studies have demonstrated that molecular analysis of cytokine profiles in UC can predict response to each advanced therapy. This narrative review summarizes the molecules involved in the efficacy of various advanced therapies for UC. Understanding these associations may be helpful in selecting optimal therapeutic agents.
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Affiliation(s)
- Hiroki Kurumi
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Hokkaido, Japan; (H.K.)
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Tottori University Faculty of Medicine, 36-1, Nishi-cho, Yonago 683-8504, Tottori, Japan
| | - Yoshihiro Yokoyama
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Hokkaido, Japan; (H.K.)
| | - Takehiro Hirano
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Hokkaido, Japan; (H.K.)
| | - Kotaro Akita
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Hokkaido, Japan; (H.K.)
| | - Yuki Hayashi
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Hokkaido, Japan; (H.K.)
| | - Tomoe Kazama
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Hokkaido, Japan; (H.K.)
| | - Hajime Isomoto
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Tottori University Faculty of Medicine, 36-1, Nishi-cho, Yonago 683-8504, Tottori, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Hokkaido, Japan; (H.K.)
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8
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Quénéhervé L, Trang-Poisson C, Fantou A, Flamant M, Durand T, Bouguen G, Bregeon J, Oullier T, Amil M, Dewitte M, Bardot S, Blandin S, Braudeau C, Vibet MA, Josien R, Neunlist M, Bourreille A. Confocal laser endomicroscopy as predictive biomarker of clinical and endoscopic efficacy of vedolizumab in ulcerative colitis: The DETECT study. PLoS One 2024; 19:e0298313. [PMID: 38564601 PMCID: PMC10986992 DOI: 10.1371/journal.pone.0298313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 01/21/2024] [Indexed: 04/04/2024] Open
Abstract
AIMS In patients with ulcerative colitis (UC), no biomarker is available to help the physician to choose the most suitable biotherapy. The primary objective of this pilot study was to assess the feasibility of identification of α4β7- and TNF-expressing cells, to predict the response to vedolizumab using confocal laser endoscopy (CLE). METHODS Patients with moderate-to-severe UC, naïve of biotherapy, received vedolizumab. Clinical evaluation was performed at each infusion. Endoscopic evaluation was performed before inclusion and at week 22. Fresh colonic biopsies were stained using FITC-labelled vedolizumab and Alexa fluor-labelled adalimumab and ex vivo dual-band CLE images were acquired. Blood samples were collected to measure trough concentrations of vedolizumab and to determine absolute counts of T and B cells subpopulations, NK cells and monocytes. RESULTS Nineteen patients were enrolled in the study and received at least one dose of vedolizumab. Clinical remission and endoscopic improvement were observed in 58% of whom 5 patients (45%) had an endoscopic subscore of 0. In terms of clinical response and remission, endoscopic improvement and histologic response, FITC-conjugated vedolizumab staining tended to be higher in responder patients compared to non-responders at week 22. A threshold value of 6 positive FITC-vedolizumab staining areas detected by CLE seemed informative to discriminate the responders and non-responders. The results were similar in terms of clinical remission and endoscopic improvement with a sensitivity of 78% and a specificity of 85% (p = 0.05). Trough concentrations and blood immune cells were not associated with responses to vedolizumab. CONCLUSION This pilot study demonstrate that dual-band CLE is feasible to detect α4β7- and TNF-expressing cells. Positive α4β7 staining seems to be associated with clinical and endoscopic remission in UC patients treated by anti-α4β7-integrin, subject to validation by larger-scale studies. Clinical-trial.gov: NCT02878083.
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Affiliation(s)
- Lucille Quénéhervé
- Department of Gastroenterology, University Hospital of Brest, Brest, France
| | - Caroline Trang-Poisson
- Nantes Université, CHU Nantes, Institut des Maladies de l’Appareil Digestif (IMAD), Hépato-Gastroentérologie, Inserm CIC 1413, Nantes, France
| | - Aurélie Fantou
- Nantes Université, CHU Nantes, CRT2I, UMR Inserm 1064, Nantes, France
| | - Mathurin Flamant
- Nantes Université, CHU Nantes, Institut des Maladies de l’Appareil Digestif (IMAD), Hépato-Gastroentérologie, Inserm CIC 1413, Nantes, France
| | - Tony Durand
- Nantes Université, CHU Nantes, Institut des Maladies de l’Appareil Digestif (IMAD), UMR Inserm 1235 TENS, Nantes, France
| | - Guillaume Bouguen
- Université de Rennes, CHU Rennes, Institut NUMECAN (Nutrition Metabolism and Cancer), Hepato-Gastroenterologie, Inserm CIC1414, Rennes, France
| | - Jérémy Bregeon
- Nantes Université, CHU Nantes, Institut des Maladies de l’Appareil Digestif (IMAD), UMR Inserm 1235 TENS, Nantes, France
| | - Thibauld Oullier
- Nantes Université, CHU Nantes, Institut des Maladies de l’Appareil Digestif (IMAD), UMR Inserm 1235 TENS, Nantes, France
| | - Morgane Amil
- CHD La Roche-Sur-Yon, Hepato-gastroentérologie, La Roche-Sur-Yon, France
| | - Marie Dewitte
- Université de Rennes, CHU Rennes, Institut NUMECAN (Nutrition Metabolism and Cancer), Hepato-Gastroenterologie, Inserm CIC1414, Rennes, France
| | - Stéphanie Bardot
- Nantes Université, CHU Nantes, Institut des Maladies de l’Appareil Digestif (IMAD), Hépato-Gastroentérologie, Inserm CIC 1413, Nantes, France
| | - Stéphanie Blandin
- Nantes Université, UMS BioCore, Inserm US16—UAR CNRS 3556, Nantes, France
| | - Cécile Braudeau
- Nantes Université, CHU Nantes, CRT2I, UMR Inserm 1064, Nantes, France
| | - Marie-Anne Vibet
- CHU Nantes, Methodology and Biostatistics Department, Direction de la Recherche Clinique et de l’Innovation, Nantes, France
| | - Régis Josien
- Nantes Université, CHU Nantes, CRT2I, UMR Inserm 1064, Nantes, France
| | - Michel Neunlist
- Nantes Université, CHU Nantes, Institut des Maladies de l’Appareil Digestif (IMAD), UMR Inserm 1235 TENS, Nantes, France
| | - Arnaud Bourreille
- Nantes Université, CHU Nantes, Institut des Maladies de l’Appareil Digestif (IMAD), Hépato-Gastroentérologie, Inserm CIC 1413, Nantes, France
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9
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Hemming-Harlo M, Merras-Salmio L, Nikkonen A, Kolho KL. Drug levels of VEDOLIZUMAB in patients with pediatric-onset inflammatory bowel disease in a real-life setting. Eur J Pediatr 2024; 183:313-322. [PMID: 37878072 PMCID: PMC10858127 DOI: 10.1007/s00431-023-05255-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 09/25/2023] [Accepted: 10/03/2023] [Indexed: 10/26/2023]
Abstract
Vedolizumab (VDZ) is used off-label in pediatric inflammatory bowel disease (PIBD). There are less data on drug levels to achieve and maintain remission in children. We aimed to study vedolizumab (VDZ) trough levels in a pediatric population in a real-life setting. We traced 50 patients with PIBD receiving VDZ treatment at our hospital, reviewed their treatment protocol, trough levels, and antidrug antibodies, and compared those to fecal calprotectin (FC) levels and achievement of corticosteroid-free maintenance therapy (CF). VDZ trough level was available from 198 samples during a median follow- up of 12.6 months. Proceeding to maintenance therapy was associated with a decline in FC but not with VDZ trough levels that were comparable between patients with FC < 100 μg/g (remission), 100-1000 μg/g, or > 1000 μg/g at 3 months (mean levels of 36.8, 28.6, and 27 μg/mL, respectively p = 0.188). At 3 months, patients achieving CF (41%) and those on corticosteroids had comparable VDZ trough levels (33 vs. 27.5 μg/mL, respectively). At 6 months, the trough level was similar in groups with FC < 100 μg/g or FC > 1000 μg/g (31.5 and 27.6 μg/mL, p = 0.859). Treatment intensification did not improve the achieved CF at 12 months. None developed drug antibodies nor discontinued the therapy for an adverse event. Conclusion: VDZ was a well-tolerated and safe biologic treatment. A positive response on gut inflammation after induction predicted proceeding to maintenance therapy whereas trough levels did not. A VDZ trough level associated with clinical remission or continuing with VDZ treatment could not be determined. What is Known: • In pediatric inflammatory bowel disease, vedolizumab is still in off-label use. • The results on the relationship between drug levels of vedolizumab and clinical remission in pediatric patients are contradictory. What is New: • This real-life setting in pediatric-onset inflammatory bowel disease showed no benefit of therapy enhancement during a median follow-up of one year. • Trough levels of vedolizumab were not associated with therapy outcomes.
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Affiliation(s)
- Maria Hemming-Harlo
- Children's Hospital, Helsinki University Hospital HUS and University of Helsinki, Stenbäckinkatu 11 FI-00290 , Helsinki, Finland
| | - Laura Merras-Salmio
- Children's Hospital, Helsinki University Hospital HUS and University of Helsinki, Stenbäckinkatu 11 FI-00290 , Helsinki, Finland
| | - Anne Nikkonen
- Children's Hospital, Helsinki University Hospital HUS and University of Helsinki, Stenbäckinkatu 11 FI-00290 , Helsinki, Finland
| | - Kaija-Leena Kolho
- Children's Hospital, Helsinki University Hospital HUS and University of Helsinki, Stenbäckinkatu 11 FI-00290 , Helsinki, Finland.
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10
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Kim MK, Jo SI, Kim SY, Lim H, Kang HS, Moon SH, Ye BD, Soh JS, Hwang SW. PD-1-positive cells contribute to the diagnosis of inflammatory bowel disease and can aid in predicting response to vedolizumab. Sci Rep 2023; 13:21329. [PMID: 38044341 PMCID: PMC10694145 DOI: 10.1038/s41598-023-48651-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 11/29/2023] [Indexed: 12/05/2023] Open
Abstract
Differentiating inflammatory bowel disease (IBD) from other inflammatory diseases is often challenging. Programmed cell death protein-1 (PD-1) is expressed in T cells and is an indicator of their exhaustion. The role of PD-1 expression in diagnosing IBD and predicting the response of biologic agents remains inconclusive. In this study, endoscopic biopsy samples of 19 patients diagnosed with IBD, intestinal tuberculosis, and intestinal Behcet's disease were analyzed using multiplexed immunohistochemistry. Additionally, a separate "vedolizumab (VDZ) cohort" established in ulcerative colitis patients who underwent endoscopic biopsy before VDZ administration was analyzed to predict response to VDZ. In the immunohistochemistry analysis, the cell density of T cell subsets, including PD-1 + cells, was investigated and compared between IBD and other inflammatory diseases (OID). Cell densities of PD-1 + cells (p = 0.028), PD-1 + helper T cells (p = 0.008), and PD-1 + regulatory T cells (p = 0.024) were higher in IBD compared with OID. In the VDZ cohort, patients with a 14-week steroid-free clinical response had higher levels of PD-1 + cells (p = 0.026), PD-1 + helper T cells (p = 0.026), and PD-1 + regulatory T cells (p = 0.041) than the no response group. PD-1 + immune cells may contribute to the diagnosis of IBD and could be used to predict response to VDZ in ulcerative colitis patients.
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Affiliation(s)
- Min Kyu Kim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Su In Jo
- PrismCDX Co., Ltd., Hwaseong-Si, Republic of Korea
| | - Sang-Yeob Kim
- Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea
| | - Hyun Lim
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, University of Hallym College of Medicine, Anyang, Republic of Korea
| | - Ho Suk Kang
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, University of Hallym College of Medicine, Anyang, Republic of Korea
| | - Sung-Hoon Moon
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, University of Hallym College of Medicine, Anyang, Republic of Korea
| | - Byong Duk Ye
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
- Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jae Seung Soh
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, University of Hallym College of Medicine, Anyang, Republic of Korea.
| | - Sung Wook Hwang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea.
- Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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11
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Zeng Z, Jiang M, Li X, Yuan J, Zhang H. Precision medicine in inflammatory bowel disease. PRECISION CLINICAL MEDICINE 2023; 6:pbad033. [PMID: 38638127 PMCID: PMC11025389 DOI: 10.1093/pcmedi/pbad033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 12/13/2023] [Indexed: 04/20/2024] Open
Abstract
Inflammatory bowel disease (IBD) is an incurable disease characterized by remission-relapse cycles throughout its course. Both Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of IBD, exhibit tendency to develop complications and substantial heterogeneity in terms of frequency and severity of relapse, thus posing great challenges to the clinical management for IBD. Current treatment strategies are effective in different ways in induction and maintenance therapies for IBD. Recent advances in studies of genetics, pharmacogenetics, proteomics and microbiome provide a strong driving force for identifying molecular markers of prognosis and treatment response, which should help clinicians manage IBD patients more effectively, and then, improve clinical outcomes and reduce treatment costs of patients. In this review, we summarize and discuss precision medicine in IBD, focusing on predictive markers of disease course and treatment response, and monitoring indices during therapeutic drug monitoring.
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Affiliation(s)
- Zhen Zeng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Mingshan Jiang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xi Li
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jing Yuan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
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12
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Ganesh N, Hanauer SB, Dulai PS. The importance of predicting patient responses to monoclonal antibodies for Crohn's disease. Expert Opin Biol Ther 2023; 23:941-949. [PMID: 37623370 DOI: 10.1080/14712598.2023.2252339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/15/2023] [Accepted: 08/23/2023] [Indexed: 08/26/2023]
Abstract
INTRODUCTION Crohn's disease (CD) is a chronic immune-mediated inflammatory bowel disease that results in relapsing and remitting symptoms but progressive transmural bowel damage leading to significant morbidity. CD results from dysregulation of the immune system related to genetic and environmental factors. While the use of monoclonal antibodies targeting cytokines and adhesion molecules has been shown to improve outcomes in CD patients, their widespread use has been limited due to high costs as well as variable access. Here, we summarize the factors that have been shown to correlate with responsiveness to biologic agents for use in practice. AREAS COVERED We summarize the current literature regarding factors that have been shown to influence patient response to various biologic agents including: patient-related factors (e.g. age, gender, weight smoking history); disease-specific factors (e.g. disease duration, location/extension, behavior/phenotype, severity); genetic markers; transcription factors, and the gut microbiome. Finally, we review the utility of prediction models and present data supporting the use of recently developed decision support tools. EXPERT OPINION Clinical decision support tools developed by machine learning are currently available for the selection of biologic agents in CD patients. We expect these models to become an integral tool for clinicians in the treatment of CD in the coming years.
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Affiliation(s)
- Nisha Ganesh
- Department of Medicine, Division of Gastroenterology and Hepatology, Northwestern University, Chicago, IL, United States of America
| | - Stephen B Hanauer
- Department of Medicine, Division of Gastroenterology and Hepatology, Northwestern University, Chicago, IL, United States of America
| | - Parambir S Dulai
- Department of Medicine, Division of Gastroenterology and Hepatology, Northwestern University, Chicago, IL, United States of America
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13
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Haglund S, Söderman J, Almer S. Differences in Whole-Blood Transcriptional Profiles in Inflammatory Bowel Disease Patients Responding to Vedolizumab Compared with Non-Responders. Int J Mol Sci 2023; 24:ijms24065820. [PMID: 36982892 PMCID: PMC10052064 DOI: 10.3390/ijms24065820] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 03/10/2023] [Accepted: 03/15/2023] [Indexed: 03/30/2023] Open
Abstract
Vedolizumab is efficacious in the treatment of Crohn's disease (CD) and ulcerative colitis (UC). However, a significant proportion of patients present with a non-response. To investigate whether differences in the clinical response to vedolizumab is reflected in changes in gene expression levels in whole blood, samples were collected at baseline before treatment, and at follow-up after 10-12 weeks. Whole genome transcriptional profiles were established by RNA sequencing. Before treatment, no differentially expressed genes were noted between responders (n = 9, UC 4, CD 5) and non-responders (n = 11, UC 3, CD 8). At follow-up, compared with baseline, responders displayed 201 differentially expressed genes, and 51 upregulated (e.g., translation initiation, mitochondrial translation, and peroxisomal membrane protein import) and 221 downregulated (e.g., Toll-like receptor activating cascades, and phagocytosis related) pathways. Twenty-two of the upregulated pathways in responders were instead downregulated in non-responders. The results correspond with a dampening of inflammatory activity in responders. Although considered a gut-specific drug, our study shows a considerable gene regulation in the blood of patients responding to vedolizumab. It also suggests that whole blood is not optimal for identifying predictive pre-treatment biomarkers based on individual genes. However, treatment outcomes may depend on several interacting genes, and our results indicate a possible potential of pathway analysis in predicting response to treatment, which merits further investigation.
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Affiliation(s)
- Sofie Haglund
- Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden
- Laboratory Medicine, Region Jönköping County, 551 85 Jönköping, Sweden
| | - Jan Söderman
- Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden
- Laboratory Medicine, Region Jönköping County, 551 85 Jönköping, Sweden
| | - Sven Almer
- IBD-Unit, Division of Gastroenterology, Karolinska University Hospital, 171 76 Stockholm, Sweden
- Department of Medicine, Karolinska Institutet-Solna, 171 76 Stockholm, Sweden
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14
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Liu XY, Tang H, Zhou QY, Zeng YL, Chen D, Xu H, Li Y, Tan B, Qian JM. Advancing the precision management of inflammatory bowel disease in the era of omics approaches and new technology. World J Gastroenterol 2023; 29:272-285. [PMID: 36687128 PMCID: PMC9846940 DOI: 10.3748/wjg.v29.i2.272] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 12/01/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023] Open
Abstract
There is great heterogeneity among inflammatory bowel disease (IBD) patients in terms of pathogenesis, clinical manifestation, response to treatment, and prognosis, which requires the individualized and precision management of patients. Many studies have focused on prediction biomarkers and models for assessing IBD disease type, activity, severity, and prognosis. During the era of biologics, how to predict the response and side effects of patients to different treatments and how to quickly recognize the loss of response have also become important topics. Multiomics is a promising area for investigating the complex network of IBD pathogenesis. Integrating numerous amounts of data requires the use of artificial intelligence.
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Affiliation(s)
- Xin-Yu Liu
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing 100730, China
- Eight-year Medical Doctor Program, Peking Union Medical College & Chinese Academy of Medical Science, Beijing 100730, China
| | - Hao Tang
- Department of Internal Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing 100730, China
| | - Qing-Yang Zhou
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing 100730, China
| | - Yan-Lin Zeng
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing 100730, China
- School of Medicine, Tsinghua University, Beijing 100084, China
| | - Dan Chen
- Department of Gastroenterology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing 100730, China
| | - Hui Xu
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing 100730, China
| | - Yue Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing 100730, China
| | - Bei Tan
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing 100730, China
| | - Jia-Ming Qian
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing 100730, China
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15
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Vieujean S, Louis E. Precision medicine and drug optimization in adult inflammatory bowel disease patients. Therap Adv Gastroenterol 2023; 16:17562848231173331. [PMID: 37197397 PMCID: PMC10184262 DOI: 10.1177/17562848231173331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 04/16/2023] [Indexed: 05/19/2023] Open
Abstract
Inflammatory bowel diseases (IBD) encompass two main entities including ulcerative colitis and Crohn's disease. Although having a common global pathophysiological mechanism, IBD patients are characterized by a significant interindividual heterogeneity and may differ by their disease type, disease locations, disease behaviours, disease manifestations, disease course as well as treatment needs. Indeed, although the therapeutic armamentarium for these diseases has expanded rapidly in recent years, a proportion of patients remains with a suboptimal response to medical treatment due to primary non-response, secondary loss of response or intolerance to currently available drugs. Identifying, prior to treatment initiation, which patients are likely to respond to a specific drug would improve the disease management, avoid unnecessary side effects and reduce the healthcare expenses. Precision medicine classifies individuals into subpopulations according to clinical and molecular characteristics with the objective to tailor preventative and therapeutic interventions to the characteristics of each patient. Interventions would thus be performed only on those who will benefit, sparing side effects and expense for those who will not. This review aims to summarize clinical factors, biomarkers (genetic, transcriptomic, proteomic, metabolic, radiomic or from the microbiota) and tools that could predict disease progression to guide towards a step-up or top-down strategy. Predictive factors of response or non-response to treatment will then be reviewed, followed by a discussion about the optimal dose of drug required for patients. The time at which these treatments should be administered (or rather can be stopped in case of a deep remission or in the aftermath of a surgery) will also be addressed. IBD remain biologically complex, with multifactorial etiopathology, clinical heterogeneity as well as temporal and therapeutic variabilities, which makes precision medicine especially challenging in this area. Although applied for many years in oncology, it remains an unmet medical need in IBD.
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Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
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16
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Gonzalez-Vivo M, Lund Tiirikainen MK, Andreu M, Fernandez-Clotet A, López-García A, Murciano Gonzalo F, Abril Rodriguez L, de Jesús-Gil C, Ruiz-Romeu E, Sans-de San Nicolàs L, Santamaria-Babí LF, Márquez-Mosquera L. Memory T Cell Subpopulations as Early Predictors of Remission to Vedolizumab in Ulcerative Colitis. Front Med (Lausanne) 2022; 9:837294. [PMID: 35783609 PMCID: PMC9240758 DOI: 10.3389/fmed.2022.837294] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 05/16/2022] [Indexed: 11/13/2022] Open
Abstract
Background Vedolizumab is a humanized monoclonal antibody targeting the α4β7 integrin used for the treatment of ulcerative colitis. Few biomarkers related to vedolizumab response have been identified. The aim of this work was to assess whether baseline circulating CD4+ and CD8+ memory T-lymphocyte subpopulations could help to identify patients with response to vedolizumab treatment in ulcerative colitis. Methods Prospective pilot study in 15 patients with active ulcerative colitis and previous failure to anti-TNFα starting vedolizumab treatment. Peripheral blood samples were obtained before the first dose of vedolizumab and at week 6 and 14 of treatment. Clinical remission was defined as a Mayo Clinic partial score of ≤2 points without any concomitant dose of steroids. Biochemical remission or endoscopic improvement was defined as fecal calprotectin <250 mcg/g or Mayo endoscopic subscore ≤1. Results At week 14, nine patients achieved clinical remission and eight patients achieved biochemical remission or endoscopic improvement. Patients in clinical remission presented higher baseline CD8 α4β7+ memory T cells concentration when compared with patients with no remission. In addition, patients with biochemical remission or endoscopic improvement at week 14 presented higher baseline concentration of CD8 α4β7+ memory T cells. No differences were identified according to flare severity, extent of disease or type of anti-TNFα failure. There were no significant differences regarding changes in T cell subsets during vedolizumab induction. Conclusion CD8+ α4β7+ memory T cells before starting vedolizumab therapy could be an early predictor of remission in ulcerative colitis patients and therefore help to select a subset of responders.
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Affiliation(s)
- Maria Gonzalez-Vivo
- Department of Gastroenterology, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
- *Correspondence: Maria Gonzalez-Vivo,
| | - Minna K. Lund Tiirikainen
- Grup d’Immunologia Translacional, Departament de Biologia Cel⋅lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona (UB), Parc Científic de Barcelona (PCB), Barcelona, Spain
| | - Montserrat Andreu
- Department of Gastroenterology, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | | | - Alicia López-García
- Department of Gastroenterology, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | | | | | - Carmen de Jesús-Gil
- Grup d’Immunologia Translacional, Departament de Biologia Cel⋅lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona (UB), Parc Científic de Barcelona (PCB), Barcelona, Spain
| | - Ester Ruiz-Romeu
- Grup d’Immunologia Translacional, Departament de Biologia Cel⋅lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona (UB), Parc Científic de Barcelona (PCB), Barcelona, Spain
| | - Lídia Sans-de San Nicolàs
- Grup d’Immunologia Translacional, Departament de Biologia Cel⋅lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona (UB), Parc Científic de Barcelona (PCB), Barcelona, Spain
| | - Lluis F. Santamaria-Babí
- Grup d’Immunologia Translacional, Departament de Biologia Cel⋅lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona (UB), Parc Científic de Barcelona (PCB), Barcelona, Spain
| | - Lucía Márquez-Mosquera
- Department of Gastroenterology, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
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17
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Pu D, Zhang Z, Feng B. Alterations and Potential Applications of Gut Microbiota in Biological Therapy for Inflammatory Bowel Diseases. Front Pharmacol 2022; 13:906419. [PMID: 35734396 PMCID: PMC9207480 DOI: 10.3389/fphar.2022.906419] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 04/26/2022] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a chronic immune-mediated inflammatory disorder of the gastrointestinal tract that is closely associated with dysbiosis of the intestinal microbiota. Currently, biologic agents are the mainstream therapies for IBD. With the increasing incidence of IBD, limitations of biologic agents have gradually emerged during treatment. Recent studies have indicated that gut microbiota is highly correlated with the efficacy of biologic agents. This review focuses on alterations in both the components and metabolites of gut microbiota during biological therapy for IBD, systematically summarises the specific gut microbiota closely related to the clinical efficacy, and compares current predictive models for the efficacy of biologics, further highlighting the predictive value of intestinal microbiota. Based on the mechanistic analysis of faecal microbiota transplantation (FMT) and biologic agents, a new therapeutic strategy, comprising a combination of FMT and biologics, has been proposed as a promising treatment for IBD with improved efficacy.
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Affiliation(s)
| | - Zhe Zhang
- *Correspondence: Zhe Zhang, ; Baisui Feng,
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18
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De Galan C, Gonzales GB, Van Welden S, Tavernier SJ, Lobaton T, Van Moerkercke W, Strubbe B, Peeters H, Macken E, De Vos M, Laukens D, Hindryckx P. Role of integrin expression in the prediction of response to vedolizumab: A prospective real-life multicentre cohort study. Clin Transl Med 2022; 12:e769. [PMID: 35384344 PMCID: PMC8982506 DOI: 10.1002/ctm2.769] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 02/25/2022] [Accepted: 03/02/2022] [Indexed: 12/19/2022] Open
Affiliation(s)
- Cara De Galan
- Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium.,Ghent Gut Inflammation Group (GGIG), Ghent University, Ghent, Belgium.,VIB Center for Inflammation Research, Ghent, Belgium
| | - Gerard Bryan Gonzales
- Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium.,Ghent Gut Inflammation Group (GGIG), Ghent University, Ghent, Belgium
| | - Sophie Van Welden
- Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium.,Ghent Gut Inflammation Group (GGIG), Ghent University, Ghent, Belgium.,VIB Center for Inflammation Research, Ghent, Belgium
| | - Simon Jan Tavernier
- Primary Immune Deficiency Research Lab, Centre for Primary Immunodeficiency Ghent, Jeffrey Model Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium
| | - Triana Lobaton
- Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium.,Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | | | - Beatrijs Strubbe
- Department of Gastroenterology, AZ Sint-Lucas Ghent, Ghent, Belgium
| | - Harald Peeters
- Department of Gastroenterology, AZ Sint-Lucas Ghent, Ghent, Belgium
| | - Elisabeth Macken
- Department of Gastroenterology, University Hospital Antwerp, Antwerp, Belgium
| | - Martine De Vos
- Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium.,Ghent Gut Inflammation Group (GGIG), Ghent University, Ghent, Belgium
| | - Debby Laukens
- Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium.,Ghent Gut Inflammation Group (GGIG), Ghent University, Ghent, Belgium.,VIB Center for Inflammation Research, Ghent, Belgium
| | - Pieter Hindryckx
- Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium.,Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
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19
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Verstockt B, Parkes M, Lee JC. How Do We Predict a Patient's Disease Course and Whether They Will Respond to Specific Treatments? Gastroenterology 2022; 162:1383-1395. [PMID: 34995535 DOI: 10.1053/j.gastro.2021.12.245] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 12/09/2021] [Accepted: 12/09/2021] [Indexed: 02/07/2023]
Abstract
Gastroenterologists will be all too familiar with the difficult decisions that managing inflammatory bowel disease often presents. How aggressively should I treat this patient? Do I expect them to have a mild or aggressive form of disease? Do they need a biologic? If so, which one? And when should I start it? The reality is that the answers that would be right for one patient might be disastrous for another. The growing therapeutic armamentarium will only make these decisions more difficult, and yet, we have seen how other specialties have begun to use the molecular heterogeneity in their diseases to provide some answers. Here, we review the progress that has been made in predicting the future for any given patient with inflammatory bowel disease-whether that is the course of disease that they will experience or whether or not they will respond to, or indeed tolerate, a particular therapy.
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Affiliation(s)
- Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders-Inflammatory Bowel Disease (TARGID-IBD), Katholieke Universiteit Leuven, Leuven, Belgium
| | - Miles Parkes
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - James C Lee
- Genetic Mechanisms of Disease Laboratory, Francis Crick Institute, London, United Kingdom; Institute for Liver & Digestive Health, Royal Free London Hospital, University College London, London, United Kingdom.
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20
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Ungar B, Malickova K, Hanžel J, Abu Arisha M, Paul S, Rocha C, Ben Shatach Z, Abitbol CM, Haj Natour O, Selinger L, Yavzori M, Fudim E, Picard O, Shoval I, Eliakim R, Kopylov U, Magro F, Roblin X, Chowers Y, Drobne D, Lukas M, Ben Horin S. Dose optimisation for Loss of Response to Vedolizumab- Pharmacokinetics and Immune Mechanisms. J Crohns Colitis 2021; 15:1707-1719. [PMID: 33837762 DOI: 10.1093/ecco-jcc/jjab067] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Real life data regarding pharmacokinetics of vedolizumab in patients needing dose optimisation are scarce. We set to examine whether pre-optimisation vedolizumab levels associate with therapy outcomes and which mechanisms explain the associations. METHODS A multicentre observational study assessed the outcome of dose increase in association with pre-escalation levels in vedolizumab-treated patients. SubsequentIy, α4β7 occupancy on peripheral blood [PB] and intestinal lamina propria [LP] tissues was investigated on various cellular subsets in patients undergoing lower endoscopy on infusion day. Cellular localisation of vedolizumab-bound α4β7 and effects on M1 and M2 macrophages were also explored. RESULTS A total of 161 inflammatory bowel disease [IBD] patients were included. Among 129/161 patients intensified during maintenance [Week 14 onward], pre-intensification trough levels were comparable or higher among those subsequently attaining post-optimisation clinical, biomarker, and endoscopic remission, compared with non-remitting patients [p = 0.09, 0.25, 0.04, respectively]. Similar results were demonstrated for those dose-optimised during induction [Week 6, n = 32]. In the immune sub-study [n = 43], free α4β7 receptors at trough were similarly low among patients with/without mucosal healing, on PB T cells [p = 0.15], LP T cells [p = 0.88], and on PB eosinophils [p = 0.08]. Integrin receptors on M1 and M2 macrophages were also saturated by low levels of vedolizumab and anti-inflammatory cytokine secretion was not increased. Co-localisation and dissociation experiments demonstrated membranal α4β7 receptors of two origins: non-internalised and newly generated α4β7, but re-binding was still complete at very low concentrations. CONCLUSIONS These results do not support pharmacokinetics as the mechanism responsible for loss of response to vedolizumab, nor do they support a need for higher drug concentration to enhance vedolizumab's immune effects. Higher pre-escalation levels may indicate less clearance [less severe disease] and higher likelihood of subsequent re-gained response, regardless of therapy escalation.
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Affiliation(s)
- Bella Ungar
- Gastroenterology Institute, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Karin Malickova
- IBD Clinical and Research Centre, ISCARE, Prague, Czech Republic
| | - Jurij Hanžel
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljuljana, Slovenia
| | - Muhammad Abu Arisha
- Rambam Health Care Campus, Bruce and Ruth Rappaport Faculty of Medicine, Haifa, Israel
| | - Stephane Paul
- Immunology Department, GIMAP CIC INSERM 1408, University of Lyon, Saint Etienne, France
| | - Catia Rocha
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal.,Instituto de Saúde Ambiental, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
| | - Zohar Ben Shatach
- Gastroenterology Institute, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Chaya Mushka Abitbol
- Gastroenterology Institute, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ola Haj Natour
- Gastroenterology Institute, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Limor Selinger
- Gastroenterology Institute, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Miri Yavzori
- Gastroenterology Institute, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ella Fudim
- Gastroenterology Institute, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Orit Picard
- Gastroenterology Institute, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Irit Shoval
- Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan, Ramat Gan, Israel
| | - Rami Eliakim
- Gastroenterology Institute, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Uri Kopylov
- Gastroenterology Institute, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Fernando Magro
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Xavier Roblin
- Department of Hepatogastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - Yehuda Chowers
- Rambam Health Care Campus, Bruce and Ruth Rappaport Faculty of Medicine, Haifa, Israel
| | - David Drobne
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljuljana, Slovenia.,Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Milan Lukas
- IBD Clinical and Research Centre, ISCARE, Prague, Czech Republic
| | - Shomron Ben Horin
- Gastroenterology Institute, Sheba Medical Center Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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21
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Abstract
PURPOSE OF REVIEW Since there is a lack of head-to-head randomized controlled trials, little direction is provided from guidelines on the positioning of biologics for the treatment of Crohn's disease (CD). This review utilizes comparative effectiveness and safety results from real-world data and network meta-analyses to inform clinical practice for positioning of biological therapies in the treatment of moderate-to-severe CD. RECENT FINDINGS We summarize the results of studies pertaining to the identification of predictors for response to biologics in CD. Recently published studies about the management of moderate-to-severe CD are discussed and a positioning algorithm is proposed for the therapeutic approach of these patients. SUMMARY Different classes of biologics are comparable with regards to safety and almost similar in effectiveness in the management of CD. There are certain clinical scenarios in which one biologic is more effective than another. For instance, patients with a more aggressive disease phenotype such as fistulizing disease would benefit from infliximab over other biologics, whereas in older patients at a higher risk for infectious complications, it may be more appropriate to use ustekinumab or vedolizumab over the anti-tumor necrosis factor (TNF) agents. More data pertaining to identifying predictors of response to the different available therapies and head-to-head comparison trials are needed to personalize our therapeutic approach of CD patients.
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22
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Shi Y, He W, Zhong M, Yu M. MIN score predicts primary response to infliximab/adalimumab and vedolizumab therapy in patients with inflammatory bowel diseases. Genomics 2021; 113:1988-1998. [PMID: 33872704 DOI: 10.1016/j.ygeno.2021.04.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 02/08/2021] [Accepted: 04/05/2021] [Indexed: 01/07/2023]
Abstract
Infliximab/adalimumab (IFX/ADA) and vedolizumab (VDZ) are the most widely used biologics in inflammatory bowel diseases. Current models used to predict their efficacies are restricted to either Crohn's disease or ulcerative colitis or to only one type of biologic, which makes them limited in external validation. We therefore designed a comprehensive comparison among these models to identify the most meaningful predictors for patient responses. Several biomarkers and models were compared for their abilities to predict both IFX/ADA and VDZ responses by receiver operating characteristic curves. Least absolute shrinkage and selection operator regression was adopted to determine a simplified gene signature. Verification was performed in biopsy samples by immunohistochemical staining. The GIMATS module (based on counts of IgG plasma cells, inflammatory monocytes, activated T cells, and stromal cells) had the best overall performance for response prediction in both biologics (IFX/ADA, AUC = 0.720-0.853; VDZ, AUC = 0.661-0.728). Based on this module, patients were equally divided into 3 groups: M type (GIMATS-low, metabolism), with a preference for IFX/ADA; I type (GIMATS-high, immune), with a preference for VDZ; and N type (GIMATS-medium, normal), with no preference for either treatment. Furthermore, to improve clinical utility, a simplified 6-gene model, MIN score, was established to determine the baseline expression of G0S2, S100A9, SELE, CHI3L1, MMP1 and CXCL13 and function as a substitute for GIMATS module. Our study suggested that the classification of metabolic or immune type by MIN score was valuable for IBD diagnosis to assist with selection of IFX/ADA and VDZ.
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Affiliation(s)
- Yuan Shi
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Wei He
- Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Ming Zhong
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
| | - Minhao Yu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
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23
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Predictors and Early Markers of Response to Biological Therapies in Inflammatory Bowel Diseases. J Clin Med 2021; 10:jcm10040853. [PMID: 33669579 PMCID: PMC7922976 DOI: 10.3390/jcm10040853] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 12/22/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic conditions that primarily affect the gastrointestinal tract, with a complex pathogenesis; they are characterized by a significant heterogeneity of clinical presentations and of inflammatory pathways that sustain intestinal damage. After the introduction of the first biological therapies, the pipeline of therapies for IBD has been constantly expanding, and a significant number of new molecules is expected in the next few years. Evidence from clinical trials and real-life experiences has taught us that up to 40% of patients do not respond to a specific drug. Unfortunately, to date, clinicians lack a valid tool that can predict each patient’s response to therapies and that could help them in choosing what drug to administer. Several candidate biomarkers have been investigated so far, with conflicting results: clinical, genetic, immunological, pharmacokinetic and microbial markers have been tested, but no ideal marker has been identified so far. Based on recent evidence, multiparametric models seemingly hold the greatest potential for predicting response to therapy. In this narrative review, we aim to summarize the current knowledge on predictors and early markers of response to biological therapies in IBD.
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24
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Zhang RF, Liu S, Wang YW, Li J. Potential molecular biomarkers used to predict the response to biological therapies in ulcerative colitis. Chin Med J (Engl) 2021; 134:1058-1060. [PMID: 33538506 PMCID: PMC8116026 DOI: 10.1097/cm9.0000000000001390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Affiliation(s)
- Run-Feng Zhang
- Department of Gastroenterology, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing 100730, China
| | - Shuang Liu
- Department of Gastroenterology, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing 100730, China
| | - Yun-Wei Wang
- Section of Gastroenterology, Hepatology and Nutrition, University of Chicago Medicine, Chicago, USA
| | - Ji Li
- Department of Gastroenterology, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing 100730, China
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25
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Debnath P, Rathi PM. Vedolizumab in Inflammatory Bowel Disease: West versus East. Inflamm Intest Dis 2021; 6:1-17. [PMID: 33850834 DOI: 10.1159/000512805] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 11/04/2020] [Indexed: 11/19/2022] Open
Abstract
Background Vedolizumab is a humanized immunoglobulin G1 monoclonal antibody, which binds to α4β7 integrin on T lymphocytes, thus disturbing the interaction with mucosal vascular addressin cell adhesion molecule 1 on the intestinal endothelial cells to interfere with lymphocyte trafficking to the gut. Summary Vedolizumab is a safe and effective drug to induce and maintain clinical remission in patients with Crohn's disease (CD) and ulcerative colitis (UC) in both clinical trials and real-world data. Various guidelines recommend vedolizumab as a first- or second-line treatment regimen for steroid-dependent, steroid, or immunomodulator refractory cases of UC and CD; however, it is more effective in anti-TNF-naive patients. The first head-to-head trial (VARSITY trial) comparing the efficacy of vedolizumab to adalimumab has shown better clinical remission and mucosal healing with vedolizumab. Key Messages In this review, we have discussed guidelines recommendation of vedolizumab use, as well as its safety data, use in special population, in presence of extraintestinal complications, therapeutic drug monitoring, data from Asian patients, along with other evolving concepts. Because of its excellent safety data and low immunogenicity, vedolizumab is an impressive option for patients with prior malignancy and less chance of reactivation of tuberculosis; however, cost remains an issue.
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Affiliation(s)
| | - Pravin M Rathi
- T.N.M.C. & B.Y.L. Nair Charitable Hospital, Mumbai, India
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26
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Mahajna H, Ben-Horin S. Novel bio-genetic predictors of response to biologic treatment in inflammatory bowel diseases. Curr Opin Pharmacol 2020; 55:132-140. [PMID: 33249396 DOI: 10.1016/j.coph.2020.10.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 09/29/2020] [Accepted: 10/11/2020] [Indexed: 02/07/2023]
Abstract
Despite the evolving therapeutic armamentarium, the treatment of IBD patients remains challenging and many patients fail to respond to biologic agents. With the limited yield of clinical factors to predict the outcome of biologic treatments, studies have focused on identifying genetic alterations and circulating or tissue biomarkers to identify patients who are likely to respond to therapy. In this review, we examine the current knowledge and status of genetic, expression biomarkers, and microbiome predictors. The search for genetic predictors has yielded many genetic loci variants, but few were reproducible. Expression studies of putative biomarkers show promising results, especially with TREM1, oncostatin M and TNF biomarkers, but confirmatory studies are warranted. Finally, the microbiome is emerging as an important player with specific taxa and functional pathways differentially abundant and enriched in responders versus non-responders to certain biologics. Integrating different factors into a robust predictive model, which is both reproducible, accurate and affordable, remains the main challenge before these individualized strategies can reach clinical use.
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Affiliation(s)
- Hussein Mahajna
- Gastroenterology Department, Sheba Medical Center, Affiliated to Tel-Aviv University, Tel-Aviv, Israel.
| | - Shomron Ben-Horin
- Gastroenterology Department, Sheba Medical Center, Affiliated to Tel-Aviv University, Tel-Aviv, Israel
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27
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Holmer AK, Battat R, Dulai PS, Vande Casteele N, Nguyen N, Jain A, Miralles A, Neill J, Le H, Singh S, Rivera-Nieves J, Sandborn WJ, Boland BS. Biomarkers are associated with clinical and endoscopic outcomes with vedolizumab treatment in Crohn's disease. Therap Adv Gastroenterol 2020; 13:1756284820971214. [PMID: 33240396 PMCID: PMC7675888 DOI: 10.1177/1756284820971214] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 10/12/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Vedolizumab, an α4β7 integrin antagonist, is an effective therapy for Crohn's disease (CD). Biomarkers are needed to guide therapy and predict outcomes. This study evaluated biomarker concentrations and outcomes in patients with CD undergoing vedolizumab treatment. METHODS Sera at weeks 0, 2, 6, 14, and ⩾26 were collected from vedolizumab-treated, refractory CD patients. Concentrations of soluble (s)-Vascular Cell Adhesion Molecule (VCAM)-1, s-Intercellular Cell Adhesion Molecule (ICAM)-1, s-Mucosal Addressin Cell Adhesion Molecule (MAdCAM)-1, and s-α4β7 integrin were evaluated for associations with achieving endoscopic remission. RESULTS A total of 22 patients with CD were included. In all patients, s-MAdCAM-1 decreased significantly and s-α4β7 increased compared with baseline. s-VCAM-1 and s-ICAM-1 changed differentially in patients who achieved remission. At week 6, median s-VCAM-1 (859.6 ng/ml versus 460.3 ng/ml, p = 0.03) and s-ICAM-1 (545.7 ng/ml versus 286.2 ng/ml, p = 0.03) concentrations were higher in patients who achieved endoscopic remission compared with those who did not, and similar differences were observed for s-ICAM-1 concentrations in patients who achieved clinical remission, compared with those who did not (669.1 ng/ml versus 291.0 ng/ml, p = 0.04). Week 14 s-α4β7 concentrations were lower in patients who achieved endoscopic remission, compared with those who did not (7.5 ng/ml versus 17.6 ng/ml, p = 0.020). CONCLUSION In all vedolizumab-treated CD patients, s-MAdCAM-1 decreased significantly and s-α4β7 increased. However, higher concentrations of s-ICAM-1 and s-VCAM-1 at week 6 and lower concentrations of s-α4β7 at week 14 differentiated patients who achieved endoscopic remission. These findings may help identify early predictors of response to vedolizumab treatment in patients with CD. Further validation in less refractory CD patients is needed.
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Affiliation(s)
| | | | - Parambir S. Dulai
- Inflammatory Bowel Disease Center, Division of
Gastroenterology, Department of Medicine, University of California, San
Diego, La Jolla, CA, USA
| | - Niels Vande Casteele
- Inflammatory Bowel Disease Center, Division of
Gastroenterology, Department of Medicine, University of California, San
Diego, La Jolla, CA, USA
| | - Nghia Nguyen
- Inflammatory Bowel Disease Center, Division of
Gastroenterology, Department of Medicine, University of California, San
Diego, La Jolla, CA, USA
| | | | - Ara Miralles
- Inflammatory Bowel Disease Center, Division of
Gastroenterology, Department of Medicine, University of California, San
Diego, La Jolla, CA, USA
| | - Jennifer Neill
- Inflammatory Bowel Disease Center, Division of
Gastroenterology, Department of Medicine, University of California, San
Diego, La Jolla, CA, USA
| | - Helen Le
- Inflammatory Bowel Disease Center, Division of
Gastroenterology, Department of Medicine, University of California, San
Diego, La Jolla, CA, USA
| | - Siddharth Singh
- Inflammatory Bowel Disease Center, Division of
Gastroenterology, Department of Medicine, University of California, San
Diego, La Jolla, CA, USA
| | - Jesus Rivera-Nieves
- Inflammatory Bowel Disease Center, Division of
Gastroenterology, Department of Medicine, University of California, San
Diego, La Jolla, CA, USA
| | - William J. Sandborn
- Inflammatory Bowel Disease Center, Division of
Gastroenterology, Department of Medicine, University of California, San
Diego, La Jolla, CA, USA
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28
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Verstockt B, Matteoli G. Invited Editorial: Targeting Alpha 4 Beta 7, More Trafficking Inhibition Than We Thought? J Crohns Colitis 2020; 14:1183-1184. [PMID: 32935846 DOI: 10.1093/ecco-jcc/jjaa069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Bram Verstockt
- University Hospitals Leuven Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium.,KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders [TARGID], Leuven, Belgium
| | - Gianluca Matteoli
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders [TARGID], Leuven, Belgium
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Coletta M, Paroni M, Alvisi MF, De Luca M, Rulli E, Mazza S, Facciotti F, Lattanzi G, Strati F, Abrignani S, Fantini MC, Vecchi M, Geginat J, Caprioli F. Immunological Variables Associated With Clinical and Endoscopic Response to Vedolizumab in Patients With Inflammatory Bowel Diseases. J Crohns Colitis 2020; 14:1190-1201. [PMID: 32100016 DOI: 10.1093/ecco-jcc/jjaa035] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND AND AIMS Vedolizumab [VDZ] is a monoclonal antibody directed against the α4β7 integrin heterodimer, approved for patients with inflammatory bowel diseases [IBD]. This study aimed at identifying immunological variables associated with response to vedolizumab in patients with ulcerative colitis [UC] and Crohn's disease [CD]. METHODS This is a phase IV explorative prospective interventional trial. IBD patients received open-label VDZ at Weeks 0, 2, 6, and 14. Patients with a clinical response at Week 14 were maintained with VDZ up to Week 54. At Weeks 0 and 14, their peripheral blood was obtained and endoscopy with biopsies was performed. The Week 14 clinical response and remission, Week 54 clinical remission, and Week 14 endoscopic response were evaluated as endpoints of the study. The expression of surface markers, chemokine receptors, and α4β7 heterodimer in peripheral blood and lamina propria lymphocytes was assessed by flow cytometry. A panel of soluble mediators was assessed in sera at baseline and at Week 14 by 45-plex. RESULTS A total of 38 IBD patients [20 UC, 18 CD] were included in the study. At Week 14, the clinical response and remission rates were 87% and 66%, respectively. Higher baseline levels of circulating memory Th1 cells were strongly associated with clinical response at Week 14 [p = 0.0001], whereas reduced baseline levels of lamina propria memory Th17 and Th1/17 cells were associated with endoscopic response. Immunological clusters were found to be independently associated with vedolizumab outcomes at multivariable analysis. A panel of soluble markers, including IL17A, TNF, CXCL1, CCL19 for CD and G-CSF and IL7 for UC, associated with vedolizumab-induced Week 54 clinical remission. CONCLUSIONS The results of this exploratory study uncovered a panel of circulating and mucosal immunological variables associated with response to treatment with vedolizumab.
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Affiliation(s)
- Marina Coletta
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Moira Paroni
- Istituto Nazionale di Genetica Molecolare 'Enrica ed Romeo Invernizzi' [INGM], Milan, Italy.,Department of Biosciences, Università degli Studi di Milano, Milan, Italy
| | - Maria Francesca Alvisi
- Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Matilde De Luca
- Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Eliana Rulli
- Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Stefano Mazza
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Federica Facciotti
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Georgia Lattanzi
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Francesco Strati
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Sergio Abrignani
- Istituto Nazionale di Genetica Molecolare 'Enrica ed Romeo Invernizzi' [INGM], Milan, Italy.,Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | | | - Maurizio Vecchi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Jens Geginat
- Istituto Nazionale di Genetica Molecolare 'Enrica ed Romeo Invernizzi' [INGM], Milan, Italy
| | - Flavio Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
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30
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Veny M, Garrido-Trigo A, Corraliza AM, Masamunt MC, Bassolas-Molina H, Esteller M, Arroyes M, Tristán E, Fernández-Clotet A, Ordás I, Ricart E, Esteve M, Panés J, Salas A. Dissecting Common and Unique Effects of Anti-α4β7 and Anti-Tumor Necrosis Factor Treatment in Ulcerative Colitis. J Crohns Colitis 2020; 15:441-452. [PMID: 32926095 PMCID: PMC7944518 DOI: 10.1093/ecco-jcc/jjaa178] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Vedolizumab is an anti-α4β7 antibody approved for the treatment of ulcerative colitis [UC]. Although it is assumed that vedolizumab blocks intestinal homing of lymphocytes, its effects on different intestinal cell populations are not fully stablished. In order to establish the unique mechanisms of action of vedolizumab in UC patients, we compared its effects to those induced by anti-tumour necrosis factor [TNF]. METHODS Patients with active UC [endoscopic Mayo score >1] starting vedolizumab [n = 33] or anti-TNF [n = 45] and controls [n = 22] were included. Colon biopsies [at weeks 0, 14 and 46] and blood samples [at weeks 0, 2, 6, 14, 30 and 46] were used for cell phenotyping, transcriptional analysis [qPCR], and to measure receptor occupancy. RESULTS Vedolizumab, in contrast to anti-TNF, significantly reduced the proportion of α4β7+ cells within intestinal T subsets while preserving the percentage of α4β7+ plasma cells. The marked decrease in α4β7 did not change the percentage of colonic αEβ7+ cells [at 46 weeks]. Both vedolizumab and anti-TNF significantly downregulated inflammation-related genes in the colon of responders [Mayo score < 2]. Moreover, both treatments significantly decreased the percentage of intestinal, but not blood, total lymphocytes [T and plasma cells], as well as the proportion of α4β1+ cells within intestinal T lymphocytes. CONCLUSIONS Our data show that while vedolizumab and anti-TNF block two unrelated targets, they induce remarkably similar effects. On the other hand, vedolizumab's unique mechanism of action relies on blocking intestinal trafficking of α4β7 T cells, despite effectively binding to B and plasma cells that express α4β7.
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Affiliation(s)
- Marisol Veny
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Clinic of Barcelona, Barcelona, Spain; Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
| | - Alba Garrido-Trigo
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Clinic of Barcelona, Barcelona, Spain; Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
| | - Ana M Corraliza
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Clinic of Barcelona, Barcelona, Spain; Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
| | - Maria C Masamunt
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Clinic of Barcelona, Barcelona, Spain; Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
| | - Helena Bassolas-Molina
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Clinic of Barcelona, Barcelona, Spain; Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
| | - Miriam Esteller
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Clinic of Barcelona, Barcelona, Spain; Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
| | - Montserrat Arroyes
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Clinic of Barcelona, Barcelona, Spain; Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
| | - Eva Tristán
- Hospital Universitari Mutua Terrassa, CIBERehd, Department of Gastroenterology, Terrassa, Spain
| | - Agnès Fernández-Clotet
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Clinic of Barcelona, Barcelona, Spain; Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
| | - Ingrid Ordás
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Clinic of Barcelona, Barcelona, Spain; Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
| | - Elena Ricart
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Clinic of Barcelona, Barcelona, Spain; Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
| | - Maria Esteve
- Hospital Universitari Mutua Terrassa, CIBERehd, Department of Gastroenterology, Terrassa, Spain
| | - Julian Panés
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Clinic of Barcelona, Barcelona, Spain; Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
| | - Azucena Salas
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Clinic of Barcelona, Barcelona, Spain; Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain,Corresponding author: Azucena Salas, PhD, Center Esther Koplowitz, Rossello 149–153, Barcelona 08036, Spain. Tel: 34 93 2275400 ext 2436;
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Bertani L, Antonioli L, Blandizzi C. Letter: ustekinumab's effectiveness outcomes compared with vedolizumab in Crohn's disease-what about mucosal healing and biomarkers? Aliment Pharmacol Ther 2020; 52:751-752. [PMID: 32886387 DOI: 10.1111/apt.15920] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Lorenzo Bertani
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Corrado Blandizzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Gisbert JP, Chaparro M. Predictors of Primary Response to Biologic Treatment [Anti-TNF, Vedolizumab, and Ustekinumab] in Patients With Inflammatory Bowel Disease: From Basic Science to Clinical Practice. J Crohns Colitis 2020; 14:694-709. [PMID: 31777929 DOI: 10.1093/ecco-jcc/jjz195] [Citation(s) in RCA: 178] [Impact Index Per Article: 35.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Inflammatory bowel diseases [IBD]-ulcerative colitis and Crohn's disease-are commonly treated with biologic drugs. However, only approximately two-thirds of patients have an initial response to these therapies. Personalised medicine has the potential to optimise efficacy, decrease the risk of adverse drug events, and reduce costs by establishing the most suitable therapy for a selected patient. AIM The present study reviews the potential predictors of short-term primary response to biologic treatment, including not only anti-tumour necrosis factor [TNF] agents [such as infliximab, adalimumab, certolizumab, and golimumab] but also vedolizumab and ustekinumab. METHODS We performed a systematic bibliographical search to identify studies investigating predictive factors of response to biologic therapy. RESULTS For anti-TNF agents, most of the evaluated factors have not demonstrated usefulness, and many others are still controversial. Thus, only a few factors may have a potential role in the prediction of the response, including disease behaviour/phenotype, disease severity, C-reactive protein, albumin, cytokine expression in serum, previous anti-TNF therapy, some proteomic markers, and some colorectal mucosa markers. For vedolizumab, the availability of useful predictive markers seems to be even lower, with only some factors showing a limited value, such as the expression of α4β7 integrin in blood, the faecal microbiota, some proteomic markers, and some colorectal mucosa markers. Finally, in the case of ustekinumab, no predictive factor has been reported yet to be helpful in clinical practice. CONCLUSION In summary, currently no single marker fulfils all criteria for being an appropriate prognostic indicator of response to any biologic treatment in IBD.
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Affiliation(s)
- Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa [IIS-IP], Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Madrid, Spain
| | - María Chaparro
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa [IIS-IP], Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Madrid, Spain
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33
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Bertani L, Caviglia GP, Antonioli L, Pellicano R, Fagoonee S, Astegiano M, Saracco GM, Bugianesi E, Blandizzi C, Costa F, Ribaldone DG. Serum Interleukin-6 and -8 as Predictors of Response to Vedolizumab in Inflammatory Bowel Diseases. J Clin Med 2020; 9:1323. [PMID: 32370274 PMCID: PMC7290461 DOI: 10.3390/jcm9051323] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 04/24/2020] [Accepted: 04/26/2020] [Indexed: 12/15/2022] Open
Abstract
Vedolizumab, a monoclonal antibody directed against integrin α4β7, is an effective treatment for inflammatory bowel diseases. However, a significant number of patients do not achieve steroid-free clinical remission in the first year of treatment. An early identification of these patients is one of the most important challenges for clinicians and offers the possibility of therapeutic optimization in order to personalize biological therapy. The aim of our study was to test the prediction ability of interleukin (IL)-6 and -8 of clinical response after 12 months of therapy with vedolizumab (T2). We performed a prospective, multicentre study in patients affected by inflammatory bowel disease by analysing cytokines level before starting vedolizumab (T0) and after 10 weeks of therapy (T1). In the overall cohort (n = 54), IL-8 decrease > 2.6 pg/mL in the first 10 weeks of therapy was able to predict clinical response (area under the curve (AUC) = 0.70, sensitivity = 66%, specificity = 75%, p = 0.010), negative C-reactive protein (CRP) (AUC = 0.71, sensitivity = 64%, specificity = 80%, p = 0.009) and calprotectin < 250 mg/kg (AUC = 0.69, sensitivity = 64%, specificity = 78%, p = 0.030) after 44 weeks of therapy. In patients with ulcerative colitis (n = 40), baseline IL-8 values > 8.6 pg/mL and a decrease of IL-6 values > 0.4 pg/mL from T0 to T1 were significant and independent predictors of clinical response after 12 months of vedolizumab therapy (odds ratio (OR) = 6.96, 95% CI 1.27-38.22, p = 0.026 and OR = 7.29, 95% CI 1.42-37.50, p = 0.017, respectively). In patients with Crohn's disease (n = 14), baseline IL-8 values > 8.6 pg/mL and baseline IL-6 values > 1.6 pg/mL allowed the identification of patients achieving negative CRP at T2 (AUC = 0.75, sensitivity = 74%, specificity = 76%, p < 0.001) and patients with faecal calprotectin values < 250 mg/kg at T2 (AUC = 0.71, sensitivity = 78%, specificity = 63%, p = 0.004). In conclusion, our study highlights a potential clinical role of serum cytokine levels for the prediction of clinical and biochemical steroid-free response in patients treated with vedolizumab.
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Affiliation(s)
- Lorenzo Bertani
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56100 Pisa, Italy;
| | - Gian Paolo Caviglia
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (G.M.S.); (E.B.)
| | - Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (L.A.); (C.B.)
| | - Rinaldo Pellicano
- Unit of Gastroenterology, Molinette Hospital, 10126 Turin, Italy; (R.P.); (M.A.)
| | - Sharmila Fagoonee
- Institute of Biostructure and Bioimaging, CNR c/o Molecular Biotechnology Centre, 10126 Turin, Italy;
| | - Marco Astegiano
- Unit of Gastroenterology, Molinette Hospital, 10126 Turin, Italy; (R.P.); (M.A.)
| | - Giorgio Maria Saracco
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (G.M.S.); (E.B.)
| | - Elisabetta Bugianesi
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (G.M.S.); (E.B.)
| | - Corrado Blandizzi
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (L.A.); (C.B.)
| | - Francesco Costa
- Department of General Surgery and Gastroenterology, IBD Unit, Pisa University Hospital, 56100 Pisa, Italy;
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Verstockt B, Verstockt S, Veny M, Dehairs J, Arnauts K, Van Assche G, De Hertogh G, Vermeire S, Salas A, Ferrante M. Expression Levels of 4 Genes in Colon Tissue Might Be Used to Predict Which Patients Will Enter Endoscopic Remission After Vedolizumab Therapy for Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 2020; 18:1142-1151.e10. [PMID: 31446181 PMCID: PMC7196933 DOI: 10.1016/j.cgh.2019.08.030] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Accepted: 08/09/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS We aimed to identify biomarkers that might be used to predict responses of patients with inflammatory bowel diseases (IBD) to vedolizumab therapy. METHODS We obtained biopsies from inflamed colon of patients with IBD who began treatment with vedolizumab (n = 31) or tumor necrosis factor (TNF) antagonists (n = 20) and performed RNA-sequencing analyses. We compared gene expression patterns between patients who did and did not enter endoscopic remission (absence of ulcerations at month 6 for patients with Crohn's disease or Mayo endoscopic subscore ≤1 at week 14 for patients with ulcerative colitis) and performed pathway analysis and cell deconvolution for training (n = 20) and validation (n = 11) datasets. Colon biopsies were also analyzed by immunohistochemistry. We validated a baseline gene expression pattern associated with endoscopic remission after vedolizumab therapy using 3 independent datasets (n = 66). RESULTS We identified significant differences in expression levels of 44 genes between patients who entered remission after vedolizumab and those who did not; we found significant increases in leukocyte migration in colon tissues from patients who did not enter remission (P < .006). Deconvolution methods identified a significant enrichment of monocytes (P = .005), M1-macrophages (P = .05), and CD4+ T cells (P = .008) in colon tissues from patients who did not enter remission, whereas colon tissues from patients in remission had higher numbers of naïve B cells before treatment (P = .05). Baseline expression levels of PIWIL1, MAATS1, RGS13, and DCHS2 identified patients who did vs did not enter remission with 80% accuracy in the training set and 100% accuracy in validation dataset 1. We validated these findings in the 3 independent datasets by microarray, RNA sequencing and quantitative PCR analysis (P = .003). Expression levels of these 4 genes did not associate with response to anti-TNF agents. We confirmed the presence of proteins encoded by mRNAs using immunohistochemistry. CONCLUSIONS We identified 4 genes whose baseline expression levels in colon tissues of patients with IBD associate with endoscopic remission after vedolizumab, but not anti-TNF, treatment. We validated this signature in 4 independent datasets and also at the protein level. Studies of these genes might provide insights into the mechanisms of action of vedolizumab.
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Affiliation(s)
- Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium,Translational Research Center for Gastrointestinal Disorders, Department of Chronic Disease, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Sare Verstockt
- Laboratory for Complex Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
| | - Marisol Veny
- Department of Gastroenterology, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
| | - Jonas Dehairs
- Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Kaline Arnauts
- Translational Research Center for Gastrointestinal Disorders, Department of Chronic Disease, Metabolism and Ageing, KU Leuven, Leuven, Belgium,Stem Cell Institute Leuven, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Gert Van Assche
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium,Translational Research Center for Gastrointestinal Disorders, Department of Chronic Disease, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Gert De Hertogh
- Translational Cell & Tissue Research Unit, Department of Imaging & Pathology, KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium,Translational Research Center for Gastrointestinal Disorders, Department of Chronic Disease, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Azucena Salas
- Department of Gastroenterology, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
| | - Marc Ferrante
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium; Translational Research Center for Gastrointestinal Disorders, Department of Chronic Disease, Metabolism and Ageing, KU Leuven, Leuven, Belgium.
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Roosenboom B, van Lochem EG, Meijer J, Smids C, Nierkens S, Brand EC, van Erp LW, Kemperman LG, Groenen MJ, Horjus Talabur Horje CS, Wahab PJ. Development of Mucosal PNAd + and MAdCAM-1 + Venules during Disease Course in Ulcerative Colitis. Cells 2020; 9:cells9040891. [PMID: 32268498 PMCID: PMC7226824 DOI: 10.3390/cells9040891] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 03/31/2020] [Accepted: 04/03/2020] [Indexed: 12/31/2022] Open
Abstract
PNAd and MAdCAM-1 addressins on venules are of importance in T-cell homing and potential therapeutic targets in ulcerative colitis (UC). Normally, PNAd+ high endothelial venules (HEVs) are only present in lymphoid organs, whereas small numbers of MAdCAM-1+ venules can be seen in non-lymphoid tissue. We aimed to study their presence in the intestinal mucosa of UC patients at diagnosis and during follow-up, and their correlation with disease activity. Colonic biopsy specimens of 378 UC patients were analyzed by immunohistochemistry for CD3, CD20, ERG, MECA-79 (PNAd) and MECA-376 (MAdCAM-1) and compared to healthy controls (HC). The proportion of PNAd+HEVs in UC at diagnosis was 4.9% (IQR 2.0%-8.3%), while none were detected in HC. During follow-up, PNAd+HEVs completely disappeared in remission (n = 93), whereas the proportion in active disease was similar to baseline (n = 285, p = 0.39). The proportion of MAdCAM-1+venules in UC at baseline was 5.8% (IQR 2.6-10.0). During follow-up, the proportion in remission was comparable to diagnosis, but upregulated (7.5% (IQR 4.4-10.9), p = 0.001) in active disease. In conclusion, PNAd+HEVs appear in UC during active inflammation which could thus serve as a marker for disease activity, whereas MAdCAM-1+venules remain present after inflammation is resolved and increase after subsequent flares, reflecting chronicity and potentially serving as a therapeutic target.
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Affiliation(s)
- Britt Roosenboom
- Crohn & Colitis Centre Rijnstate, Department of Gastroenterology and Hepatology, Rijnstate Hospital, 6815 AD Arnhem, The Netherlands
- Correspondence: ; Tel.: +3188-0058952; Fax: +3188-0057506
| | - Ellen G. van Lochem
- Department of Microbiology and Immunology, Rijnstate Hospital, 6815 AD Arnhem, The Netherlands
| | - Jos Meijer
- Department of Pathology, Rijnstate Hospital, 6815 AD Arnhem, The Netherlands
| | - Carolijn Smids
- Crohn & Colitis Centre Rijnstate, Department of Gastroenterology and Hepatology, Rijnstate Hospital, 6815 AD Arnhem, The Netherlands
| | - Stefan Nierkens
- U-DAIR and Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Eelco C. Brand
- Department of Gastroenterology and Hepatology and Center for Translational Immunology, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands
| | - Liselot W. van Erp
- Crohn & Colitis Centre Rijnstate, Department of Gastroenterology and Hepatology, Rijnstate Hospital, 6815 AD Arnhem, The Netherlands
| | | | - Marcel J.M. Groenen
- Crohn & Colitis Centre Rijnstate, Department of Gastroenterology and Hepatology, Rijnstate Hospital, 6815 AD Arnhem, The Netherlands
| | - Carmen S. Horjus Talabur Horje
- Crohn & Colitis Centre Rijnstate, Department of Gastroenterology and Hepatology, Rijnstate Hospital, 6815 AD Arnhem, The Netherlands
| | - Peter J. Wahab
- Crohn & Colitis Centre Rijnstate, Department of Gastroenterology and Hepatology, Rijnstate Hospital, 6815 AD Arnhem, The Netherlands
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Crooks B, Barnes T, Limdi JK. Vedolizumab in the treatment of inflammatory bowel disease: evolving paradigms. Drugs Context 2020; 9:2019-10-2. [PMID: 32180822 PMCID: PMC7055512 DOI: 10.7573/dic.2019-10-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 01/21/2020] [Accepted: 01/27/2020] [Indexed: 02/08/2023] Open
Abstract
Inflammatory bowel diseases, comprising Crohn's disease (CD) and ulcerative colitis (UC), are chronic, relapsing and remitting immune-mediated inflammatory diseases affecting the gastrointestinal tract. Vedolizumab is the first licensed drug in a group of 'gut-selective' biological agents used to treat inflammatory bowel diseases. The GEMINI registrational trials established the efficacy of vedolizumab for the induction and maintenance of remission in both CD and UC, with the most favourable results in tumour necrosis factor (TNF)-antagonist-naive patients. In recent years, a wealth of 'real-world' data has emerged supporting positive clinical, endoscopic and histological outcomes in patients treated with vedolizumab (VDZ) as well as reassuring safety data. More recently, the results of the first head-to-head trials of VDZ and TNF antagonists have been reported, as well as the results of a number of studies exploring the role of therapeutic drug monitoring with VDZ. This review brings together data reported on VDZ to date, including from the GEMINI trials, real-world data and emerging studies regarding therapeutic drug monitoring and immunogenicity. The safety profile of VDZ is also reviewed. Evolving treatment paradigms are explored, including data regarding the role of VDZ in perianal CD, post-operative complications and recurrence, extraintestinal manifestations and pregnancy.
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Affiliation(s)
- Benjamin Crooks
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester M13 9PL, UK
- Section of IBD – Division of Gastroenterology, The Pennine Acute Hospitals NHS Trust, Manchester, UK
| | - Tom Barnes
- Section of IBD – Division of Gastroenterology, The Pennine Acute Hospitals NHS Trust, Manchester, UK
| | - Jimmy K Limdi
- Section of IBD – Division of Gastroenterology, The Pennine Acute Hospitals NHS Trust, Manchester, UK
- Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
- Manchester Metropolitan University, Manchester, UK
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37
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Bertani L, Baglietto L, Antonioli L, Fornai M, Tapete G, Albano E, Ceccarelli L, Mumolo MG, Pellegrini C, Lucenteforte E, de Bortoli N, Bellini M, Marchi S, Blandizzi C, Costa F. Assessment of serum cytokines predicts clinical and endoscopic outcomes to vedolizumab in ulcerative colitis patients. Br J Clin Pharmacol 2020; 86:1296-1305. [PMID: 32027388 DOI: 10.1111/bcp.14235] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 11/26/2019] [Accepted: 12/01/2019] [Indexed: 12/13/2022] Open
Abstract
AIMS Vedolizumab (VDZ) prevents migration of activated leucocytes into inflamed mucosa. This study aimed to assess the patterns of serum cytokines in ulcerative colitis (UC) patients at baseline and during VDZ treatment, and to investigate their association with mucosal healing and clinical remission. METHODS We enrolled consecutive UC patients eligible for treatment with VDZ. A panel of serum cytokines were measured by fluorescence assay at weeks 0, 6 and 22. Colonoscopy was performed at baseline and week 54, to evaluate mucosal healing. The time trends of serum cytokines were analysed by log-linear mixed effect models, and their prognostic accuracy was evaluated by logistic regression. RESULTS Out of 27 patients included in the analysis, at week 54 mucosal healing was achieved in 12 (44%) and clinical remission in 17 (63%). Mucosal healing was associated with higher interleukin (IL)-8 values at baseline and with significant decrease in IL-6 and IL-8 levels over the first 6 weeks. A significant reduction of IL-6 and IL-8 levels over the first 6 weeks of treatment was associated also with clinical remission. Logistic models including, among the predictors, IL-6 and IL-8 at baseline and their changes over the first 6 weeks of treatment had 83% sensitivity and 87% specificity to predict mucosal healing, and 82% sensitivity and 90% specificity to predict clinical remission. CONCLUSION In UC patients, the serum patterns of IL-6 and IL-8 at baseline and over the first 6 weeks of treatment with VDZ could be useful to predict therapeutic outcome.
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Affiliation(s)
- Lorenzo Bertani
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.,Department of General Surgery and Gastroenterology, IBD Unit, Pisa University Hospital, Pisa, Italy
| | - Laura Baglietto
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Matteo Fornai
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Gherardo Tapete
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Eleonora Albano
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Linda Ceccarelli
- Department of General Surgery and Gastroenterology, IBD Unit, Pisa University Hospital, Pisa, Italy
| | - Maria Gloria Mumolo
- Department of General Surgery and Gastroenterology, IBD Unit, Pisa University Hospital, Pisa, Italy
| | | | - Ersilia Lucenteforte
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Nicola de Bortoli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Massimo Bellini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Santino Marchi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Corrado Blandizzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Francesco Costa
- Department of General Surgery and Gastroenterology, IBD Unit, Pisa University Hospital, Pisa, Italy
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38
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Yuan CW, Sun XL, Qiao LC, Xu HX, Zhu P, Chen HJ, Yang BL. Non-SMC condensin I complex subunit D2 and non-SMC condensin II complex subunit D3 induces inflammation via the IKK/NF-κB pathway in ulcerative colitis. World J Gastroenterol 2019; 25:6813-6822. [PMID: 31885422 PMCID: PMC6931004 DOI: 10.3748/wjg.v25.i47.6813] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 11/20/2019] [Accepted: 12/07/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Ulcerative colitis (UC) is a chronic, nonspecific intestinal inflammatory disease with undefined pathogenesis. Non-SMC condensin I complex subunit D2 (NCAPD2) and non-SMC condensin II complex subunit D3 (NCAPD3) play pivotal roles in chromosome assembly and segregation during both mitosis and meiosis. To date, there has been no relevant report about the functional role of NCAPD2 and NCAPD3 in UC. AIM To determine the level of NCAPD2/3 in intestinal mucosa and explore the mechanisms of NCAPD2/3 in UC. METHODS Levels of NCAPD2/3 in intestinal tissue were detected in 30 UC patients and 30 healthy individuals with in situ hybridization (ISH). In vitro, NCM60 cells were divided into the NC group, model group, si-NCAPD2 group, si-NCAPD3 group and si-NCAPD2+si-NCAPD3 group. Inflammatory cytokines were measured by ELISA, IKK and NF-κB were evaluated by western blot, and IKK nucleation and NF-κB volume were analyzed by immunofluorescence assay. RESULTS Compared with expression in healthy individuals, NCAPD2 and NCAPD3 expression in intestinal tissue was significantly upregulated (P < 0.001) in UC patients. Compared with levels in the model group, IL-1β, IL-6 and TNF-α in the si-NCAPD2, si-NCAPD3 and si-NCAPD2+si-NCAPD3 groups were significantly downregulated (P < 0.01). IKK and NF-κB protein expression in the si-NCAPD2, si-NCAPD3 and si-NCAPD2+si-NCAPD3 groups was significantly decreased (P < 0.01). Moreover, IKK nucleation and NF-κB volume were suppressed upon si-NCAPD2, si-NCAPD3 and si-NCAPD2+ si-NCAPD3 transfection. CONCLUSION NCAPD2/3 is highly expressed in the intestinal mucosa of patients with active UC. Overexpression of NCAPD2/3 promotes the release of pro-inflammatory cytokines by modulating the IKK/NF-κB signaling pathway.
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Affiliation(s)
- Chang-Wen Yuan
- Department of Neurology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Xue-Liang Sun
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Li-Chao Qiao
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Hai-Xia Xu
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Ping Zhu
- Department of Colorectal Surgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Hong-Jin Chen
- Department of Colorectal Surgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Bo-Lin Yang
- Department of Colorectal Surgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
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39
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Einwächter H. Current Concepts of Pharmacotherapy in Crohn's Disease. Visc Med 2019; 35:344-347. [PMID: 31934581 PMCID: PMC6944890 DOI: 10.1159/000504101] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 10/13/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The incidence of Crohn's disease (CD) is rising, and still many patients have to undergo repeated surgery due to failure of pharmacologic therapy. RESULTS While the introduction of anti-TNF agents started biologic therapy for CD and revolutionized the management of patients, the number of patients who do not respond to this treatment or lose their initial response to this treatment is still substantial. Therefore, the recent introduction of new therapeutic options with anti-integrins and new anti-cytokines was an important step to provide more effective treatment for our patients. Yet, next to new drugs also new treatment strategies have been proposed. CONCLUSION In this article, we will review these new aspects of pharmacologic therapy for CD -patients.
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Affiliation(s)
- Henrik Einwächter
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technische Universität München, München, Germany
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40
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Wang C, Baer HM, Gaya DR, Nibbs RJB, Milling S. Can molecular stratification improve the treatment of inflammatory bowel disease? Pharmacol Res 2019; 148:104442. [PMID: 31491469 PMCID: PMC6902263 DOI: 10.1016/j.phrs.2019.104442] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 09/02/2019] [Accepted: 09/02/2019] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) is a debilitating chronic inflammatory disease of the gastrointestinal (GI) tract. It affects more than 3.5 million people in the western world and places a huge financial burden on healthcare systems. IBD is highly heterogeneous; disease severity and outcomes in IBD are highly variable, and patients may experience episodes of relapse and remission. However, treatment often follows a step-up model whereby the patients start with anti-inflammatory agents (corticosteroids or immunosuppressants) and step-up to monoclonal anti-tumour necrosis factor-α (TNFα) antibodies and then other biologics if the initial drugs cannot control disease. Unfortunately, many patients do not respond to the costly biologics, and thus often still require gut-resective surgery, which decreases quality of life. In order to decrease rates of surgery and ineffective treatments, it is important to identify markers that accurately predict disease progression and treatment responses, to inform decisions about the best choice of therapeutics. Here we examine molecular approaches to patient stratification that aim to increase the effectiveness of treatments and potentially reduce healthcare costs. In the future, it may become possible to stratify patients based on their suitability for specific molecular-targeted therapeutic agents, and eventually use molecular stratification for personalised medicine in IBD.
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Affiliation(s)
- Claire Wang
- Institute of Infection, Inflammation & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Hannah M Baer
- Institute of Infection, Inflammation & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Daniel R Gaya
- Gastroenterology Unit, Glasgow Royal Infirmary, Glasgow, UK
| | - Robert J B Nibbs
- Institute of Infection, Inflammation & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Simon Milling
- Institute of Infection, Inflammation & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
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41
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Zundler S, Becker E, Schulze LL, Neurath MF. Immune cell trafficking and retention in inflammatory bowel disease: mechanistic insights and therapeutic advances. Gut 2019; 68:1688-1700. [PMID: 31127023 DOI: 10.1136/gutjnl-2018-317977] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 05/01/2019] [Accepted: 05/03/2019] [Indexed: 12/12/2022]
Abstract
Intestinal immune cell trafficking has been identified as a central event in the pathogenesis of inflammatory bowel diseases (IBD). Intensive research on different aspects of the immune mechanisms controlling and controlled by T cell trafficking and retention has led to the approval of the anti-α4β7 antibody vedolizumab, the ongoing development of a number of further anti-trafficking agents (ATAs) such as the anti-β7 antibody etrolizumab or the anti-MAdCAM-1 antibody ontamalimab and the identification of potential future targets like G-protein coupled receptor 15. However, several aspects of the biology of immune cell trafficking and regarding the mechanism of action of ATAs are still unclear, for example, which impact these compounds have on the trafficking of non-lymphocyte populations like monocytes and how precisely these therapies differ with regard to their effect on immune cell subpopulations. This review will summarise recent advances of basic science in the field of intestinal immune cell trafficking and discuss these findings with regard to different pharmacological approaches from a translational perspective.
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Affiliation(s)
- Sebastian Zundler
- Department of Medicine 1, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Emily Becker
- Department of Medicine 1, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Lisa Lou Schulze
- Department of Medicine 1, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
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42
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Syed S, Al-Boni M, Khan MN, Sadiq K, Iqbal NT, Moskaluk CA, Kelly P, Amadi B, Ali SA, Moore SR, Brown DE. Assessment of Machine Learning Detection of Environmental Enteropathy and Celiac Disease in Children. JAMA Netw Open 2019; 2:e195822. [PMID: 31199451 PMCID: PMC6575155 DOI: 10.1001/jamanetworkopen.2019.5822] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 04/30/2019] [Indexed: 12/16/2022] Open
Abstract
Importance Duodenal biopsies from children with enteropathies associated with undernutrition, such as environmental enteropathy (EE) and celiac disease (CD), display significant histopathological overlap. Objective To develop a convolutional neural network (CNN) to enhance the detection of pathologic morphological features in diseased vs healthy duodenal tissue. Design, Setting, and Participants In this prospective diagnostic study, a CNN consisting of 4 convolutions, 1 fully connected layer, and 1 softmax layer was trained on duodenal biopsy images. Data were provided by 3 sites: Aga Khan University Hospital, Karachi, Pakistan; University Teaching Hospital, Lusaka, Zambia; and University of Virginia, Charlottesville. Duodenal biopsy slides from 102 children (10 with EE from Aga Khan University Hospital, 16 with EE from University Teaching Hospital, 34 with CD from University of Virginia, and 42 with no disease from University of Virginia) were converted into 3118 images. The CNN was designed and analyzed at the University of Virginia. The data were collected, prepared, and analyzed between November 2017 and February 2018. Main Outcomes and Measures Classification accuracy of the CNN per image and per case and incorrect classification rate identified by aggregated 10-fold cross-validation confusion/error matrices of CNN models. Results Overall, 102 children participated in this study, with a median (interquartile range) age of 31.0 (20.3-75.5) months and a roughly equal sex distribution, with 53 boys (51.9%). The model demonstrated 93.4% case-detection accuracy and had a false-negative rate of 2.4%. Confusion metrics indicated most incorrect classifications were between patients with CD and healthy patients. Feature map activations were visualized and learned distinctive patterns, including microlevel features in duodenal tissues, such as alterations in secretory cell populations. Conclusions and Relevance A machine learning-based histopathological analysis model demonstrating 93.4% classification accuracy was developed for identifying and differentiating between duodenal biopsies from children with EE and CD. The combination of the CNN with a deconvolutional network enabled feature recognition and highlighted secretory cells' role in the model's ability to differentiate between these histologically similar diseases.
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Affiliation(s)
- Sana Syed
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, University of Virginia, Charlottesville
- Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan
| | - Mohammad Al-Boni
- Systems and Information Engineering, University of Virginia, Charlottesville
| | - Marium N. Khan
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, University of Virginia, Charlottesville
| | - Kamran Sadiq
- Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan
| | - Najeeha T. Iqbal
- Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan
| | | | - Paul Kelly
- Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom
- Tropical Gastroenterology and Nutrition Group, University of Zambia School of Medicine, Lusaka, Zambia
| | - Beatrice Amadi
- Tropical Gastroenterology and Nutrition Group, University of Zambia School of Medicine, Lusaka, Zambia
| | - S. Asad Ali
- Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan
| | - Sean R. Moore
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, University of Virginia, Charlottesville
| | - Donald E. Brown
- Data Science Institute, University of Virginia, Charlottesville
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43
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Battat R, Dulai PS, Jairath V, Vande Casteele N. A product review of vedolizumab in inflammatory bowel disease. Hum Vaccin Immunother 2019; 15:2482-2490. [PMID: 30897022 DOI: 10.1080/21645515.2019.1591139] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Vedolizumab is a monoclonal antibody to the α4β7 integrin that selectively reduces intestinal lymphocyte trafficking, thereby providing a safe and effective treatment option for patients with inflammatory bowel disease (IBD). This product review outlines the unique mechanism of vedolizumab in addition to efficacy, safety, pharmacokinetic and pharmacodynamic data from clinical trials, observational studies and meta-analyses. Vedolizumab has been shown to be effective as a first- or second-line induction and maintenance therapy in both ulcerative colitis (UC) and Crohn's disease (CD). Prolonged induction therapy may increase efficacy, particularly in tumor necrosis factor-alpha-exposed CD patients. To date, no drug-specific safety signals have been identified. In addition to the presence of an apparent exposure-response relationship, vedolizumab has demonstrated consistent pharmacodynamic effects on α4β7, mucosal vascular addressin cell adhesion molecule 1 and other cell adhesion molecules. Future efforts should focus on identifying predictive biomarkers capable of guiding personalized IBD treatment with vedolizumab.
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Affiliation(s)
- Robert Battat
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, University of California San Diego , La Jolla , CA , USA.,Robarts Clinical Trials Inc ., London , ON , Canada
| | - Parambir S Dulai
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, University of California San Diego , La Jolla , CA , USA.,Robarts Clinical Trials Inc ., London , ON , Canada
| | - Vipul Jairath
- Robarts Clinical Trials Inc ., London , ON , Canada.,Department of Medicine, University of Western Ontario , London , ON , Canada.,Department of Epidemiology and Biostatistics, University of Western Ontario , London , ON , Canada
| | - Niels Vande Casteele
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, University of California San Diego , La Jolla , CA , USA.,Robarts Clinical Trials Inc ., London , ON , Canada
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44
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Hanžel J, Sever N, Ferkolj I, Štabuc B, Smrekar N, Kurent T, Koželj M, Novak G, Compernolle G, Tops S, Gils A, Drobne D. Early vedolizumab trough levels predict combined endoscopic and clinical remission in inflammatory bowel disease. United European Gastroenterol J 2019; 7:741-749. [PMID: 31316778 DOI: 10.1177/2050640619840211] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 02/19/2019] [Indexed: 12/18/2022] Open
Abstract
Background The relationship between vedolizumab trough levels and combined endoscopic and clinical remission is unknown. Objective To compare vedolizumab trough levels in patients with and without combined remission within the first year of treatment. Methods We prospectively collected vedolizumab trough levels in 51 consecutive patients (28 Crohn's disease (CD) and 23 ulcerative colitis (UC)) before all infusions up to week 22, and at weeks 38 and 54, with concentrations measured after study completion. Centrally read endoscopy was performed at a median of 46 weeks. The primary outcome was combined endoscopic (CD: Simple endoscopic score for CD (SES-CD) < 4 without ulceration; UC: Mayo endoscopic subscore ≤ 1) and clinical remission (CD: resolution of abdominal pain; UC: resolution of rectal bleeding; both: resolution of altered bowel habit). Results Median vedolizumab trough levels at weeks 6 (25.7 vs 15.6 µg/mL; P = 0.015) and 22 (15.1 vs 4.9 µg/mL; P = 0.001) were higher in patients with combined remission. A threshold of 22 µg/mL at week 6 (area under the curve (AUC) 0.733; 95% confidence interval 0.567-0.899) and 8 µg/mL at week 22 (AUC 0.819; 95% confidence interval 0.692-0.946) predicted combined remission. Conclusion Early vedolizumab trough levels predicted combined endoscopic and clinical remission highlighting their possible use in clinical practice.
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Affiliation(s)
- Jurij Hanžel
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Nejc Sever
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Ivan Ferkolj
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Borut Štabuc
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Nataša Smrekar
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Tina Kurent
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Matic Koželj
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Gregor Novak
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Griet Compernolle
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Sophie Tops
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Ann Gils
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - David Drobne
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
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45
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Battat R, Dulai PS, Vande Casteele N, Evans E, Hester KD, Webster E, Jain A, Proudfoot JA, Mairalles A, Neill J, Singh S, Chang JT, Rivera-Nieves J, Sandborn WJ, Boland BS. Biomarkers Are Associated With Clinical and Endoscopic Outcomes With Vedolizumab Treatment in Ulcerative Colitis. Inflamm Bowel Dis 2019; 25:410-420. [PMID: 30295781 PMCID: PMC6327228 DOI: 10.1093/ibd/izy307] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Indexed: 02/07/2023]
Abstract
Background Vedolizumab inhibits α4β7-mediated lymphocyte trafficking and is effective in ulcerative colitis (UC). This study evaluated drug and biomarker concentrations and patient outcomes during vedolizumab treatment in UC. Methods Prospectively scored maintenance clinical (26.5 weeks; interquartile range [IQR], 16.3-37.0 weeks) and endoscopic (23.5 weeks; IQR, 16.8-35.6 weeks) outcomes were compared with serum vedolizumab concentrations, antivedolizumab antibodies, and serum biomarkers at baseline and weeks 2, 6, 14, and 26. A linear mixed-effects model compared biomarker trajectories over time between clinical and endoscopic remitters and nonremitters. Results Thirty-two patients were included. Soluble (s)-tumor necrosis factor (TNF)-α, s-α4β7, s-mucosal addressin cell adhesion molecule (s-MAdCAM-1), and s-amyloid A (s-AA) significantly changed with treatment. A linear mixed-effects model demonstrated that s-α4β7 (P = 0.044) increased and s-MAdCAM-1 (P = 0.006) and s-vascular cell adhesion molecule-1 (s-VCAM-1, P = 0.001) decreased more rapidly in patients achieving clinical remission in maintenance. S-MAdCAM-1 (P = 0.005), s-intracellular adhesion molecule-1 (ICAM-1; P = 0.014), s-VCAM-1 (P < 0.001), and s-TNF (P = 0.052) decreased more rapidly in endoscopic remitters. In clinical remitters, higher week 14 (20.3 ng/mL vs 6.0 ng/mL; P = 0.013) and week 26 (14.1 ng/mL vs 8.6 ng/mL; P = 0.05) s-α4β7 were observed. In endoscopic remitters, week 2 (6.7 pg/mL vs 17.8 pg/mL; P = 0.038) and week 6 (3.9 pg/mL vs 15.6 pg/mL; P = 0.005) s-TNF and week 14 s-VCAM (589.1 ng/mL vs 746.0 ng/mL; P = 0.05) were lower. Conclusion Serum biomarkers were associated with outcomes in vedolizumab-treated UC patients. s-α4β7 increased, whereas s-MAdCAM-1, s-VCAM-1, s-ICAM-1, and s-TNF decreased more rapidly in remitters. At individual time points, induction s-TNF and maintenance s-VCAM-1 concentrations were lower, whereas maintenance s-α4β7 concentrations were higher in remitters.
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Affiliation(s)
- Robert Battat
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Parambir S Dulai
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Niels Vande Casteele
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Elisabeth Evans
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | | | | | - Anjali Jain
- Prometheus Laboratories Inc., San Diego, California
| | - James A Proudfoot
- Clinical and Translational Research Institute, University of California, San Diego, La Jolla, California
| | - Ara Mairalles
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Jennifer Neill
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Siddharth Singh
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - John T Chang
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Jesus Rivera-Nieves
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - William J Sandborn
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Brigid S Boland
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
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46
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Stevens TW, Matheeuwsen M, Lönnkvist MH, Parker CE, Wildenberg ME, Gecse KB, D'Haens GR. Systematic review: predictive biomarkers of therapeutic response in inflammatory bowel disease-personalised medicine in its infancy. Aliment Pharmacol Ther 2018; 48:1213-1231. [PMID: 30378142 DOI: 10.1111/apt.15033] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 07/19/2018] [Accepted: 09/29/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is characterised by substantial heterogeneity in treatment response. With an expanding number of therapeutic agents, identifying optimal treatment at the patient level remains a major challenge. AIM To systematically review the available literature on predictive biomarkers of therapeutic response in IBD. METHODS An electronic literature search was performed on 30 January 2018 using MEDLINE, EMBASE and the Cochrane Library. Retrospective, prospective, uncontrolled and controlled studies reporting on biomarkers predicting therapeutic response in paediatric and adult IBD populations were eligible for inclusion. The methodological quality of the included studies was assessed using the QUIPS tool. Due to anticipated heterogeneity and limited data, a qualitative, rather than quantitative, assessment was planned. RESULTS Of the 10 638 citations identified, 92 articles met the inclusion criteria. Several potential DNA, mRNA and protein markers were evaluated as predictive biomarkers. Most studies focused on predicting response to anti-TNF agents. Substantial between-study heterogeneity was identified with respect to both the biomarkers studied and the definition of response. None of the included studies received a low risk of bias rating for all six domains. Currently, none of the biomarkers is sufficiently predictive for clinical use. CONCLUSIONS The search for predictive biomarkers is still in its infancy and current evidence is limited. Future research efforts should take into account the high patient heterogeneity within prospective trials with objective response assessment. Predictive models will most likely comprise a combination of several molecular markers from integrated omics-levels and clinical characteristics.
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Affiliation(s)
- Toer W Stevens
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Mijntje Matheeuwsen
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Maria H Lönnkvist
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | | | - Manon E Wildenberg
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.,Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Amsterdam, The Netherlands
| | - Krisztina B Gecse
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Geert R D'Haens
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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47
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Immunephenotype Predicts Response to Vedolizumab: Integrating Clinical and Biochemical Biomarkers in the Treatment of Inflammatory Bowel Diseases. Dig Dis Sci 2018; 63:2168-2171. [PMID: 29611077 DOI: 10.1007/s10620-018-5039-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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48
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Soendergaard C, Seidelin JB, Steenholdt C, Nielsen OH. Putative biomarkers of vedolizumab resistance and underlying inflammatory pathways involved in IBD. BMJ Open Gastroenterol 2018; 5:e000208. [PMID: 29915667 PMCID: PMC6001911 DOI: 10.1136/bmjgast-2018-000208] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 04/30/2018] [Accepted: 05/01/2018] [Indexed: 02/06/2023] Open
Abstract
Objectives Characterise the circulating inflammatory cytokine pattern among patients failing consecutive anti-tumour necrosis factor (anti-TNF) and anti-integrin treatments to identify predictors of response. Methods A retrospective single-centre cohort study of 28 patients with inflammatory bowel disease (IBD) receiving anti-integrin therapy (vedolizumab) subsequent to the failure of anti-TNF treatment was conducted. Blood samples were obtained immediately prior to initiation of vedolizumab therapy, and the response to treatment was evaluated after completion of the 14-week induction regimen. Multiplex ELISA was applied to quantify 47 preselected plasma proteins based on their putative involvement in the inflammatory process in IBD. Results Anti-TNF and vedolizumab non-responders (n=20) had significantly higher levels of circulating interleukin (IL)-6 than anti-TNF non-responders with subsequent response to vedolizumab (n=8): median 9.5 pg/mL versus 5.9 pg/mL, p<0.05. Following stratification by diagnosis, patients with Crohn's disease who failed vedolizumab therapy (n=7) had higher soluble CD40 ligand (sCD40L) than responders (n=4): 153.0 pg/mL versus 45.5 pg/mL, p<0.01; sensitivity 100% (95% CI 59% to 100%), specificity 100% (95% CI 40% to 100%). Osteocalcin was higher among patients with ulcerative colitis responding to vedolizumab (n=4) compared with those not responding (n=13): 4219 pg/mL versus 2823 pg/mL, p=0.01; sensitivity 85% (95% CI 55% to 98%), specificity 100% (95% CI 40% to 100%). Conclusions Patients with IBD failing vedolizumab induction and anti-TNF therapy have persistent IL-6 pathway activity, which could be a potential alternative treatment target. sCD40L, osteocalcin and the IL-6 pathway activity might be predictors for response to vedolizumab.
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Affiliation(s)
- Christoffer Soendergaard
- Department of Gasteroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Jakob Benedict Seidelin
- Department of Gasteroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Casper Steenholdt
- Department of Gasteroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Ole Haagen Nielsen
- Department of Gasteroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark
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49
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Lord JD, Long SA, Shows DM, Thorpe J, Schwedhelm K, Chen J, Kita M, Buckner JH. Circulating integrin alpha4/beta7+ lymphocytes targeted by vedolizumab have a pro-inflammatory phenotype. Clin Immunol 2018; 193:24-32. [PMID: 29842945 DOI: 10.1016/j.clim.2018.05.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 04/24/2018] [Accepted: 05/25/2018] [Indexed: 01/10/2023]
Abstract
Integrin alpha4/beta7 on circulating lymphocytes identifies them as gut-tropic, and can be targeted by the humanized antibody vedolizumab to treat inflammatory bowel disease (IBD). We found lymphocytes expressing alpha4/beta7 were significantly more responsive to the pro-inflammatory cytokines IL-6, IL-7, and IL-21, and less responsive to the regulatory T cell (Treg)-supporting cytokine IL-2. Alpha4/beta7 was expressed by a smaller percent of FOXP3 + Helios+ thymically-derived Tregs (tTregs) than FOXP3 + Helios- peripherally-derived Tregs (pTregs) or FOXP3- effector T cells. Integrin alpha4/beta7+ CD4 T cells were also rare among cells expressing the Th2 marker CRTh2, but enriched in cells bearing the circulating T follicular helper cell marker CXCR5. Thus the effect of this anti-integrin therapy on the mucosal immune system may be more qualitative than quantitative, and selectively replace pro-inflammatory effector cells with Tregs and Th2 cells to facilitate immune tolerance in the mucosa without globally depleting lymphocytes from the intestinal mucosa.
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Affiliation(s)
- James D Lord
- Benaroya Research Institute, Translational Research Program, United States..
| | - S Alice Long
- Benaroya Research Institute, Translational Research Program, United States
| | - Donna M Shows
- Benaroya Research Institute, Translational Research Program, United States
| | - Jerill Thorpe
- Benaroya Research Institute, Translational Research Program, United States
| | | | - Janice Chen
- Benaroya Research Institute, Translational Research Program, United States
| | - Mariko Kita
- Benaroya Research Institute, Translational Research Program, United States
| | - Jane H Buckner
- Benaroya Research Institute, Translational Research Program, United States
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50
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Fragaki M, Karmiris K. Editorial: monitoring vedolizumab trough serum concentration in inflammatory bowel disease-following the fate of anti-TNF-alpha agents? Aliment Pharmacol Ther 2018; 47:1323-1324. [PMID: 29644739 DOI: 10.1111/apt.14588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Affiliation(s)
- M Fragaki
- Department of Gastroenterology, Geniko Nosokomeio Benizeleio, Heraklion, Crete, Greece
| | - K Karmiris
- Department of Gastroenterology, Venizeleion General Hospital, Heraklion, Crete, Greece
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