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Aljabri A, Soliman GM, Ramadan YN, Medhat MA, Hetta HF. Biosimilars versus biological therapy in inflammatory bowel disease: challenges and targeting strategies using drug delivery systems. Clin Exp Med 2025; 25:107. [PMID: 40186719 DOI: 10.1007/s10238-025-01558-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 01/03/2025] [Indexed: 04/07/2025]
Abstract
Inflammatory bowel disease (IBD) is a multifactorial illness with a climbing prevalence worldwide. While biologics are commonly prescribed especially for severe cases, they may worsen patients' outcomes due to financial burden. Consequently, there has been an increased focus on biosimilars to improve overall disease outcomes by maintaining similar efficacy and safety while minimizing the cost of therapy. Infliximab-dyyb was the first biosimilar approved by US-FDA for IBD. Since that, the US-FDA approved 14 biosimilars with different mechanisms of action and different routes of administration for IBD patients (four infliximab biosimilars, nine adalimumab biosimilars, and most recently one ustekinumab biosimilar). It should be noted that more biologics are in the pipeline as golimumab and natalizumab patents are set to expire in the near future, and biosimilars are now in pre-clinical to phase 3 trials. Different studies have evaluated biologics' effectiveness and safety and concluded that the majority of available biosimilars are efficacious and have similar adverse effect profiles compared to their reference biologics. It is worth mentioningthat post-marketing surveillance reports revealed some risks associated with biosimilars which should be taken into consideration in future research and clinical trials to avoid health hazards. Most biologics and biosimilars are administered parenterally which results in several drawbacks such as raised risk of infections, hypersensitivity, autoimmunity, development of malignancies, liver toxicity as well as worsening of heart failure. Several drug delivery systems based on passive and active targeting mechanisms are under active investigation to overcome these limitations. This review sheds light on the emergence of biologics and biosimilars as alternatives in IBD management, the differences between them, challenges and risks, and future perspectives in IBD therapy and new trends in drug delivery systems.
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Affiliation(s)
- Ahmed Aljabri
- Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk, 71491, Saudi Arabia
| | - Ghareb M Soliman
- Department of Pharmaceutics, Faculty of Pharmacy, University of Tabuk, Tabuk, 71491, Saudi Arabia
| | - Yasmin N Ramadan
- Department of Microbiology and Immunology, Faculty of Pharmacy, Assiut University, Assiut, 71515, Egypt.
| | - Mohammed A Medhat
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt
| | - Helal F Hetta
- Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, University of Tabuk, Tabuk, 71491, Saudi Arabia
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Peruhova M, Stoyanova D, Miteva DG, Kitanova M, Mirchev MB, Velikova T. Genetic factors that predict response and failure of biologic therapy in inflammatory bowel disease. World J Exp Med 2025; 15:97404. [PMID: 40115750 PMCID: PMC11718585 DOI: 10.5493/wjem.v15.i1.97404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 10/09/2024] [Accepted: 11/14/2024] [Indexed: 12/26/2024] Open
Abstract
Inflammatory bowel disease (IBD) represents a significant disease burden marked by chronic inflammation and complications that adversely affect patients' quality of life. Effective diagnostic strategies involve clinical assessments, endoscopic evaluations, imaging studies, and biomarker testing, where early diagnosis is essential for effective management and prevention of long-term complications, highlighting the need for continual advancements in diagnostic methods. The intricate interplay between genetic factors and the outcomes of biological therapy is of critical importance. Unraveling the genetic determinants that influence responses and failures to biological therapy holds significant promise for optimizing treatment strategies for patients with IBD on biologics. Through an in-depth examination of current literature, this review article synthesizes critical genetic markers associated with therapeutic efficacy and resistance in IBD. Understanding these genetic actors paves the way for personalized approaches, informing clinicians on predicting, tailoring, and enhancing the effectiveness of biological therapies for improved outcomes in patients with IBD.
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Affiliation(s)
- Milena Peruhova
- Department of Gastroenterology, University Hospital Heart and Brain, Burgas 1000, Bulgaria
| | - Daniela Stoyanova
- Department of Gastroenterology, Military Medical Academy, Sofia 1606, Bulgaria
| | | | - Meglena Kitanova
- Department of Genetics, Faculty of Biology, Sofia University St. Kliment Ohridski, Sofia 1164, Bulgaria
| | | | - Tsvetelina Velikova
- Department of Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
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Samanta A, Srivastava A. Biologics in the management of pediatric inflammatory bowel disease: When and what to choose. World J Clin Pediatr 2025; 14:100938. [DOI: 10.5409/wjcp.v14.i1.100938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/14/2024] [Accepted: 12/02/2024] [Indexed: 12/20/2024] Open
Abstract
Pediatric inflammatory bowel disease (PIBD) is a chronic inflammatory disorder of the gastrointestinal tract, with rising global incidence and prevalence. Over the past two decades, biologics have added to the therapeutic armamentarium and revolutionized the approach to treatment of inflammatory bowel disease. The available biologics include monoclonal antibodies which target inflammatory cytokines (anti-tumor necrosis factor alpha, anti-interleukin 12/23) or recruitment of leucocytes to the gastrointestinal tract (anti-alpha4beta7 integrin) and small molecules (Janus kinase inhibitors, sphingosine 1-phosphate-inhibitors) which modify the proinflammatory signaling. Considering their potential disease-modifying ability, recent pediatric guidelines from the West have advocated upfront use of biologics in appropriate clinical scenarios as a top-down approach rather than the conventional step-up approach. Although real-world studies are available regarding the clinical efficacy of biologics in PIBD, there is paucity of long-term outcome and safety data in children. Also, little information is available about the best approach in the newly industrialized - developing countries where PIBD is rising but at the same time, infections are prevalent and resources are limited. In this review, we summarize the efficacy and safety profile of biologics and small molecule drugs and discuss the challenges in the management of PIBD, especially in the developing world, and future directions.
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Affiliation(s)
- Arghya Samanta
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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Xue JC, Hou XT, Zhao YW, Yuan S. Biological agents as attractive targets for inflammatory bowel disease therapeutics. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167648. [PMID: 39743022 DOI: 10.1016/j.bbadis.2024.167648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 12/08/2024] [Accepted: 12/26/2024] [Indexed: 01/04/2025]
Abstract
Inflammatory bowel disease (IBD) refers to a group of chronic, recurrent intestinal inflammatory conditions with a complex cause and unclear underlying mechanisms. It includes two main types: Ulcerative colitis (UC) and Crohn's disease (CD). The conventional treatment of IBD mainly includes 5-aminosalicylates, glucocorticoids, and immunosuppressive drugs, which have their limitations. Recent advancements in IBD research have expanded treatment options, with biological agents playing a key role. Anti-tumor necrosis factor alpha has emerged as the first-line therapy for moderate to severe IBD. Anti-integrin antibodies have also become important for the treatment, and vedolizumab is often used in cases of anti-tumor necrosis factor-alpha failure and intolerance to other treatments. Other biological agents are being tested in clinical trials at different stages. This article reviews the efficacy and safety of the primary biological therapies for IBD and provides a comprehensive analysis of the current clinical challenges associated with the disease.
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Affiliation(s)
- Jia-Chen Xue
- Department of Nuclear Medicine, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, China; Key Laboratory of Microenvironment Regulation and Immunotherapy of Urinary Tumors in Liaoning Province, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, China.
| | - Xiao-Ting Hou
- Blood Laboratory, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, 116001, China
| | - Yu-Wei Zhao
- Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, China
| | - Shuo Yuan
- Department of Neuroscience, Center for Brain Immunology and Glia (BIG), School of Medicine, University of Virginia, Charlottesville, Virginia, 22908, United States.
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Däbritz J, Classen M, Krohn K, Krahl A, Buderus S, Lainka E, de Laffolie J, Posovszky C. [Position paper of the Society for Paediatric Gastroenterology and Nutrition (GPGE) on the off-label use of biologics and signal inhibitors in children and adolescents with IBD that have already been approved for adults]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2025; 63:255-268. [PMID: 39961333 DOI: 10.1055/a-2474-3104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2025]
Abstract
Therapy for children and adolescents with chronic inflammatory bowel disease (IBD) is basically no different from that for adult patients. However, of the steadily increasing number of biologics and signalling inhibitors for adults, only two TNFα antibodies are currently approved in Germany for the treatment of IBD from the age of 6. This means that a large proportion of the drugs authorised for adults with IBD are not available for children and adolescents with moderate to severe disease. The small number of approved drugs also makes it difficult to achieve the prognostically important goal of achieving a sustained remission of IBD soon after diagnosis, which is characterised by the patient being free of symptoms and also the objectifiable goal of mucosa healing. This position paper is intended to present the current study situation on the drug treatment of children and adolescents with IBD outside the age limit and to serve as a basis for information and decision-making for the Medical Service in the assessment of individual case applications as well as for the treating physicians, the cost bearers, health policy and social court decision-makers.
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Affiliation(s)
- Jan Däbritz
- Universitätsmedizin Greifswald Klinik und Poliklinik für Kinder und Jugendmedizin, Greifswald, Deutschland
- Kinder- und Jugendklinik, Klinikum Westbrandenburg, Potsdam, Deutschland
| | - Martin Classen
- Kindergastroenterologische Praxis M. Schacht, Bremen, Deutschland
| | - Kathrin Krohn
- Integriertes Sozialpädiatrisches Zentrum im Dr. von Haunerschen Kinderspital, Ludwig-Maximilians-Universität München, München, Deutschland
| | - Andreas Krahl
- Klinik für Kinder- und Jugendmedizin, Kinder-Gastroenterologie, Sana Klinikum Offenbach GmbH, Offenbach, Deutschland
| | - Stephan Buderus
- GFO Kliniken Bonn Betriebsstätte St. Marien, Bonn, Deutschland
| | - Elke Lainka
- Zentrum für Kinder- und Jugendmedizin, Kinderklinik II, Pädiatrische Gastroenterologie, Hepatologie und Lebertransplantation, Universitätsmedizin Essen, Essen, Deutschland
| | - Jan de Laffolie
- Abteilung Allgemeine Pädiatrie und Neonatologie, Universitätsklinikum Giessen Zentrum für Kinderheilkunde und Jugendmedizin, Giessen, Deutschland
| | - Carsten Posovszky
- Gastroenterologie, Hepatologie und Ernährung, Universitäts-Kinderspital Zürich, Zürich, Schweiz
- Klinik für Kinder- und Jugendmedizin, University Ulm Medical Centre, Ulm, Deutschland
- Universität Zürich, Zürich, Schweiz
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Rébus S, Coopman S, Djeddi D, Vanrenterghem A, Dupont C, Lacotte E, Ley D. Efficacy of vedolizumab and ustekinumab in pediatric-onset inflammatory bowel disease: A real-world multicenter study. J Pediatr Gastroenterol Nutr 2025; 80:113-123. [PMID: 39415517 DOI: 10.1002/jpn3.12384] [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: 06/30/2024] [Revised: 09/14/2024] [Accepted: 09/19/2024] [Indexed: 10/18/2024]
Abstract
OBJECTIVES Vedolizumab and ustekinumab are effective in inducing and maintaining corticosteroid-free clinical remission (CFR) in adult patients with inflammatory bowel disease (IBD). This study describes the efficacy and safety of vedolizumab and ustekinumab in pediatric IBD. METHODS All patients ≤18 years of age with Crohn's disease (CD) or ulcerative colitis (UC) treated with vedolizumab or ustekinumab in three centers in Northern France were followed retrospectively. The primary outcome was CFR at Week 14 (W14). RESULTS Twenty-five patients (9 CD, 16 UC) and 33 patients (28 CD, 5 UC) were started on vedolizumab and ustekinumab respectively between 2016 and 2021. All were previously treated with antitumor necrosis factor (TNF). The median time from diagnosis to treatment initiation was 21.0 (12.0-44.0) and 42.0 (22.0-73.5) months for vedolizumab and ustekinumab, respectively. Among vedolizumab-treated patients, 36% were in CFR at W14, including 22% in CD and 44% in UC. At W52, 56% were in CFR, including 33% in CD and 69% in UC. Among ustekinumab-treated patients, 49% were in CFR at W14, including 54% in CD and 20% in UC. At W52, 55% were in CFR, including 57% in CD and 40% in UC. There was a significant increase in median growth velocity between W0 and W52 of +2 SD in vedolizumab-treated patients (p = 0.0002). Four adverse events were reported during vedolizumab treatment, none for ustekinumab-treated patients. CONCLUSIONS Vedolizumab and ustekinumab appear to be effective in inducing and maintaining CFR in pediatric-onset IBD. Randomized controlled trials are needed to confirm these results.
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Affiliation(s)
- Soleynne Rébus
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, CHU Lille, Lille, France
| | - Stéphanie Coopman
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, CHU Lille, Lille, France
| | - Djamal Djeddi
- Department of Pediatrics, Amiens-Picardie University Medical Center, Amiens, France
| | - Audrey Vanrenterghem
- Department of Pediatrics, Amiens-Picardie University Medical Center, Amiens, France
| | - Claire Dupont
- Medical Pediatrics Department, Caen Normandie UHC, Caen, France
- Caen Univ., Inserm UMR 1073 ADEN, Rouen, France
| | - Edouard Lacotte
- Medical Pediatrics Department, Caen Normandie UHC, Caen, France
- Caen Univ., Inserm UMR 1073 ADEN, Rouen, France
| | - Delphine Ley
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, CHU Lille, Lille, France
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France
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Fanizzi F, Allocca M, Fiorino G, Zilli A, Furfaro F, Parigi TL, Peyrin-Biroulet L, Danese S, D’Amico F. Raising the bar in ulcerative colitis management. Therap Adv Gastroenterol 2024; 17:17562848241273066. [PMID: 39600566 PMCID: PMC11589388 DOI: 10.1177/17562848241273066] [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: 03/28/2024] [Accepted: 07/17/2024] [Indexed: 11/29/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by growing incidence and prevalence around the world in the last few decades. The range of available existing treatment and strategies for its management is being implemented. Given the introduction of newly developed molecules and the lack of specific guidelines, drug positioning may represent a tough clinical challenge. UC management is mostly medical, and it has been shifting toward a more personalized approach with the aim to create a tailored strategy depending on the patient's profile. A treat-to target strategy seems to be the best approach to reach disease control as it allows to carry out therapeutic choices based on objective and specific parameters: histological, ultrasonographic, and molecular targets may add to the already used clinical, endoscopic, and biochemical targets. In addition, dual-targeted therapy has emerged as an attractive therapeutic strategy for patients not achieving remission. This review aims to provide an overview of the available strategies to raise the bar in UC.
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Affiliation(s)
- Fabrizio Fanizzi
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Mariangela Allocca
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Gionata Fiorino
- Gastroenterology and Digestive Endoscopy, San Camillo-Forlanini Hospital, Rome, Italy
| | - Alessandra Zilli
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Federica Furfaro
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Tommaso Lorenzo Parigi
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- INSERM, NGERE, University of Lorraine, Nancy, France
- INFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- FHU-CURE, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- Groupe Hospitalier Privé Ambroise Paré—Hartmann, Paris IBD Center, Neuilly sur Seine, France
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, QC, Canada
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Ferdinando D’Amico
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Via Olgettina 60, Milan 20132, Italy
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Curci D, Lucafò M, Decorti G, Stocco G. Monoclonal antibodies against pediatric ulcerative colitis: a review of clinical progress. Expert Opin Biol Ther 2024; 24:1133-1144. [PMID: 39285823 DOI: 10.1080/14712598.2024.2404076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 09/10/2024] [Indexed: 09/21/2024]
Abstract
INTRODUCTION In children, ulcerative colitis (UC) is often more severe and extensive than in adults and hospitalization for acute exacerbations occurs in around a quarter of subjects. There is a need for effective drugs, which could avoid or reduce the use of corticosteroids which, especially in children, are burdened by a number of severe side effects. The introduction in therapy of monoclonal antibodies has completely changed the therapeutic scenario and the prognosis of the disease. AREAS COVERED In this review, the use of the monoclonal antibodies directed against tumor necrosis factor (TNF)α or other inflammatory targets for the treatment of pediatric UC will be discussed. A search of the literature was done using the keywords 'pediatric,' 'ulcerative colitis,' 'inflammatory bowel disease,' 'monoclonal antibodies;' 'infliximab,' 'adalimumab,' 'golimumab,' vedolizumab," 'ustekinumab' and 'risankizumab.' EXPERT OPINION The use of monoclonal antibodies has greatly increased in recent years in pediatric UC, both in patients who did not respond to conventional therapies, and, more often, as initial therapy. Thanks to therapeutic drug monitoring and to the availability of biologics with different targets, therapy has become more targeted and personalized, with a significant improvement in response, in quality of life, and with a good safety profile.
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Affiliation(s)
- Debora Curci
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - Marianna Lucafò
- Department of Life Sciences, University of Trieste, Trieste, Italy
| | - Giuliana Decorti
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Gabriele Stocco
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
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Forss A, Flis P, Sotoodeh A, Kapraali M, Rosenborg S. Acute interstitial nephritis in patients with inflammatory bowel disease treated with vedolizumab: a systematic review. Scand J Gastroenterol 2024; 59:821-829. [PMID: 38682791 DOI: 10.1080/00365521.2024.2345383] [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: 02/19/2024] [Revised: 04/05/2024] [Accepted: 04/13/2024] [Indexed: 05/01/2024]
Abstract
BACKGROUND Acute interstitial nephritis (AIN) is a complication of drugs that may cause permanent kidney injury. AIN has been reported in patients with inflammatory bowel disease (IBD) treated with the integrin inhibitor vedolizumab. Through systematic review of existing literature, we aimed to identify and describe cases of AIN in patients with IBD treated with vedolizumab. METHODS We searched Medline, Embase, Cochrane, and Web of Science Core Collection between 1 January 2009 and 25 April 2023. The search yielded 1473 publications. Titles and abstracts were screened by two independent reviewers. Seventy publications were reviewed in full-text. Eight met the inclusion criteria. Clinical characteristics of AIN cases were extracted. Case causality assessment was performed according to two international adverse drug reaction probability assessment scales. Results were reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS Nine biopsy-confirmed cases of AIN were reported in six patients with ulcerative colitis and three with Crohn's disease. Mean age at AIN onset was 36 years (range = 19-58) and the majority of patients were females (n = 6/9). Time from vedolizumab treatment initiation to AIN onset spanned from hours to 12 months. Common symptoms were fever and malaise. Creatinine levels were elevated in all patients. Five patients sustained permanent kidney injury. CONCLUSION Our findings suggest that vedolizumab, although rarely, could cause AIN in patients with IBD. Awareness of laboratory findings and symptoms consistent with AIN, along with monitoring of the kidney function, could be warranted in patients with IBD treated with vedolizumab.
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Affiliation(s)
- Anders Forss
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Gastroenterology Unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - Paulina Flis
- Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden
| | - Adonis Sotoodeh
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Marjo Kapraali
- Gastroenterology Unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Staffan Rosenborg
- Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden
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10
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Miller M, Patel AS, Pasternak B. Rescue therapy with upadacitinib in medically refractory pediatric ulcerative colitis. JPGN REPORTS 2024; 5:197-199. [PMID: 38756133 PMCID: PMC11093917 DOI: 10.1002/jpr3.12067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 02/13/2024] [Accepted: 03/06/2024] [Indexed: 05/18/2024]
Abstract
Approved options for advanced therapy in pediatric inflammatory bowel disease (IBD) are limited. Although Janus kinase (JAK) inhibitors are approved in adult IBD, their benefit in pediatric populations is not yet delineated. We present a 13-year-old female patient with ulcerative colitis (UC) refractory to numerous therapies and courses of prednisone that ultimately responded to a JAK inhibitor. Initial treatment consisted of 5-aminosalicylate and azathioprine. This was changed to adalimumab due to persistent symptoms. Repeat colonoscopy revealed pancolitis, thus she was transitioned to vedolizumab. She was hospitalized twice for uncontrolled symptoms on vedolizumab and subsequent scope showed continued pancolitis. As a result, she transitioned to ustekinumab without symptomatic relief after adjusting to monthly dosing. The family declined colectomy, opting to exhaust all medical therapies. Upadacitinib was started and her symptoms resolved within 1 week, and she remains in steroid-free remission. This case illustrates the possible role of JAK inhibitors in extensively refractory pediatric UC patients before colectomy.
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Affiliation(s)
- Maria Miller
- Division of Pediatric GastroenterologyPhoenix Children's HospitalPhoenixArizonaUSA
- Creighton University School of MedicinePhoenixArizonaUSA
| | - Ashish S. Patel
- Division of Pediatric GastroenterologyPhoenix Children's HospitalPhoenixArizonaUSA
- Creighton University School of MedicinePhoenixArizonaUSA
| | - Brad Pasternak
- Division of Pediatric GastroenterologyPhoenix Children's HospitalPhoenixArizonaUSA
- Creighton University School of MedicinePhoenixArizonaUSA
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11
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Kumar M, Murugesan S, Ibrahim N, Elawad M, Al Khodor S. Predictive biomarkers for anti-TNF alpha therapy in IBD patients. J Transl Med 2024; 22:284. [PMID: 38493113 PMCID: PMC10943853 DOI: 10.1186/s12967-024-05058-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 03/04/2024] [Indexed: 03/18/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic gastrointestinal condition characterized by severe gut inflammation, commonly presenting as Crohn's disease, ulcerative colitis or categorized as IBD- unclassified. While various treatments have demonstrated efficacy in adult IBD patients, the advent of anti-TNF therapies has significantly revolutionized treatment outcomes and clinical management. These therapies have played a pivotal role in achieving clinical and endoscopic remission, promoting mucosal healing, averting disease progression, and diminishing the necessity for surgery. Nevertheless, not all patients exhibit positive responses to these therapies, and some may experience a loss of responsiveness over time. This review aims to present a comprehensive examination of predictive biomarkers for monitoring the therapeutic response to anti-TNF therapy in IBD patients. It will explore their limitations and clinical utilities, paving the way for a more personalized and effective therapeutic approach.
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Affiliation(s)
- Manoj Kumar
- Research Department, Sidra Medicine, Doha, Qatar
| | | | - Nazira Ibrahim
- Division of Gastroenterology, Hepatology and Nutrition, Sidra Medicine, Doha, Qatar
| | - Mamoun Elawad
- Division of Gastroenterology, Hepatology and Nutrition, Sidra Medicine, Doha, Qatar
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12
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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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Sokic-Milutinovic A, Milosavljevic T. Inflammatory Bowel Disease: From Conventional Immunosuppression to Biologic Therapy. Dig Dis 2023; 42:325-335. [PMID: 38096793 DOI: 10.1159/000535647] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 12/04/2023] [Indexed: 07/17/2024]
Abstract
BACKGROUND Inflammatory bowel diseases (IBDs) are chronic, recurrent inflammatory diseases with partly understood etiology and pathogenesis. The course of IBD, both ulcerative colitis and Crohn's disease, is characterized by periods of relapse and remission with the possible occurrence of extraintestinal manifestations. SUMMARY During the last decades, therapeutic goals in IBD evolved toward endoscopic remission and mucosal healing creating the need for early administration of disease-modifying agents (DMAs). DMAs include conventional immunosuppressants (thiopurines, methotrexate), biologic drugs (anti-TNF, anti-integrin, and anti-IL-12/23 monoclonal antibodies), and small molecules (JAK inhibitors, S1P receptor modulators). Patients with aggressive course of disease and risk factors for poor prognosis should be treated with biologic therapy early, while conventional immunomodulators should be used in those with milder course of disease in the absence of risk factors. KEY MESSAGES Challenges in the treatment of IBD patients include the choice of effective yet safe drug and prevention or overcoming loss of response.
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Affiliation(s)
- Aleksandra Sokic-Milutinovic
- Clinic for Gastroenterology and Hepatology, University Clinical Center of Serbia, Belgrade, Serbia
- School of Medicine, University of Belgrade, Belgrade, Serbia
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14
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Gallagher J, Rosh JR, Sahn B. The Future of Advanced Therapies for Pediatric Crohn's Disease. Paediatr Drugs 2023; 25:621-633. [PMID: 37612580 DOI: 10.1007/s40272-023-00590-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/07/2023] [Indexed: 08/25/2023]
Abstract
Pediatric Crohn's disease commonly presents with moderate-to-severe intestinal inflammation with a greater risk of complications if remission is not achieved. Anti-tumor necrosis factor therapies have offered the possibility of deep and durable remission; however, many children do not respond or no longer respond over time. Further, some children do not require broader systemic immunosuppression to achieve remission and are better served by an alternative treatment strategy. Proper utilization of advanced biologic and small-molecule therapies, which have become available for adult patients since anti-tumor necrosis factor medications, is paramount for tighter disease control for a large proportion of children. Newer advanced therapies such as anti-integrin and anti-interleukin biologics, and several small-molecule agents capitalize on various mechanisms through narrower immunologic targets and reduced immunogenicity. Given limited regulatory approvals of these agents for use in children with Crohn's disease, clinicians continue to rely on data extrapolated from clinical trials in adult patients, sparse pediatric studies, and a growing real-world experience for treatment selection and optimization. In this article, we discuss currently available treatment options, pipeline drugs, and relevant data as they pertain to some of the most pressing clinical challenges faced in treating pediatric Crohn's disease.
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Affiliation(s)
- Julie Gallagher
- Division of Pediatric Gastroenterology, Liver Diseases, and Nutrition, Steven and Alexandra Cohen Children's Medical Center, Northwell Health, 1991 Marcus Ave, Suite M100, New Hyde Park, NY, 11042, USA
| | - Joel R Rosh
- Division of Pediatric Gastroenterology, Liver Diseases, and Nutrition, Steven and Alexandra Cohen Children's Medical Center, Northwell Health, 1991 Marcus Ave, Suite M100, New Hyde Park, NY, 11042, USA
| | - Benjamin Sahn
- Division of Pediatric Gastroenterology, Liver Diseases, and Nutrition, Steven and Alexandra Cohen Children's Medical Center, Northwell Health, 1991 Marcus Ave, Suite M100, New Hyde Park, NY, 11042, USA.
- Feinstein Institutes for Medical Research, Manhasset, NY, USA.
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15
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Codina-Jiménez C, Bosch Peligero M, Rodríguez-Bernuz C, Montraveta M, Marin S, Quiñones C. Successful long-term treatment of paediatric ulcerative colitis with vedolizumab: a case report. Eur J Hosp Pharm 2023; 30:e30. [PMID: 36600475 PMCID: PMC10647864 DOI: 10.1136/ejhpharm-2022-003434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 11/22/2022] [Indexed: 12/14/2022] Open
Abstract
Biologics are recommended to treat paediatric ulcerative colitis (UC) that is chronically active or steroid-dependent despite aminosalicylic acids (5-ASA) and thiopurine treatments. Anti-tumour necrosis factor inhibitors (Anti-TNF inhibitors) are the agents of choice and vedolizumab could be considered as second-line biologic therapy.In the current case, we aim to describe a successful long-term treatment with vedolizumab in a 9-year-old boy with severe UC and primary non-response to infliximab. Concomitant azathioprine was used, and steroid refractoriness was also detected. Drug and anti-drug antibody levels were negative after infliximab induction so a switch to a 6-week-induction vedolizumab regimen followed by a maintenance regimen as a monotherapy was decided. The clinical response and tolerability to vedolizumab allowed long-term disease remission. Vedolizumab is currently non-authorised to treat paediatric patients and there is limited data on long-term treatments to date. This case contributes to the literature by adding evidence on the long-term efficacy and safety of vedolizumab in paediatric UC.
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Affiliation(s)
- Carla Codina-Jiménez
- Pharmacy Department, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain
| | - Maite Bosch Peligero
- Pharmacy Department, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Universitat de Barcelona, Barcelona, Barcelona, Spain
| | | | - Montserrat Montraveta
- Paediatric Gastroenterology, Hepatology and Nutrition Department, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain
| | - Sergio Marin
- Pharmacy Department, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain
| | - Carles Quiñones
- Pharmacy Department, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain
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16
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Vera Chamorro JF, Sánchez Franco C, Vargas Sandoval M, Mora Quintero DV, Riveros López JP, Sarmiento Quintero F, Ortiz-Piedrahita C, Calderón-Guerrero OG, Laignelet H, Losada Gómez CL, Sánchez DP, López Panqueva RDP, Aponte Barrios W, Triana Rodríguez GA, Osorno A, Becerra Granados LM, Ortega López MC, Correa Jiménez Ó, Maradei Anaya SJ, García Acero M, Acevedo Forero AM, Prada A, Ramírez Urrego LC, Salcedo Castilla LK, Enríquez A, Suárez Fuentes MA, González Leal N, Peña Hernández S, Sotaquirá Guáqueta L, Sosa F, Fierro F, Correa S, Martín de Carpi FJ. Consenso colombiano de la enfermedad inflamatoria intestinal pediátrica. REVISTA COLOMBIANA DE GASTROENTEROLOGÍA 2023; 38:1-75. [DOI: 10.22516/25007440.943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Introducción: la colitis ulcerativa pediátrica (CUP), la enfermedad de Crohn pediátrica (ECP) y la enfermedad inflamatoria intestinal pediátrica no clasificable (EIIPNC) tienen particularidades clínicas y psicosociales que las diferencian de las del adulto y pueden condicionar enfoques terapéuticos distintos por las posibles repercusiones nutricionales, crecimiento y desarrollo, lo que representa un desafío para el pediatra y el gastroenterólogo. Objetivo: desarrollar recomendaciones basadas en la evidencia por consenso de expertos para el diagnóstico y el tratamiento oportunos y seguros de la enfermedad inflamatoria intestinal pediátrica (EIIP) en menores de 18 años, para los profesionales que atienden estos pacientes y los pagadores en salud. Metodología: a través de un panel de expertos del Colegio Colombiano de Gastroenterología, Hepatología y Nutrición Pediátrica (COLGAHNP) y un grupo multidisciplinario se formularon 35 preguntas en relación con el cuadro clínico, el diagnóstico y el tratamiento de la EIIP. A través de una revisión y un análisis crítico de la literatura, con especial énfasis en las principales guías de práctica clínica (GPC), estudios clínicos aleatorizados (ECA) y metaanálisis de los últimos 10 años, los expertos plantearon 77 recomendaciones que respondían a cada una de las preguntas de investigación con sus respectivos puntos prácticos. Posteriormente, cada una de las afirmaciones se sometieron a votación dentro del grupo desarrollador, incluyendo las afirmaciones que alcanzaron > 80 %. Resultados: todas las afirmaciones alcanzaron una votación > 80 %. La EIIP tiene mayor extensión, severidad y evolución hacia la estenosis, enfermedad perianal, manifestaciones extraintestinales y retraso en el crecimiento en comparación con los pacientes adultos, por lo que su manejo debe ser realizado por grupos multidisciplinarios liderados por gastroenterólogos pediatras y prepararlos para una transición a la edad adulta. Los criterios de Porto permiten una clasificación práctica de la EIIP. En la ECP, debemos usar la clasificación de París y debemos realizar ileocolonoscopia y esofagogastroduodenoscopia, ya que el 50 % tienen un compromiso superior, usando el SES-CD (UCEIS/Mayo en CUP) y tomando múltiples biopsias. Los laboratorios iniciales deben incluir marcadores de inflamación, calprotectina fecal y descartar infecciones intestinales. El tratamiento, la inducción y el mantenimiento de la EIIP deben ser individualizados y decididos según la estratificación de riesgo. En el seguimiento se debe usar el Pediatric Crohn Disease Activity Index (PCDAI) y Pediatric Ulcerative Colitis Activity Index (PUCAI) de las últimas 48 horas. Los pacientes con EIIP temprana e infantil, deben ser valorados por inmunólogos y genetistas. Conclusión: se proporciona una guía de consenso con recomendaciones basadas en la evidencia sobre el diagnóstico y los tratamientos oportunos y seguros en los pacientes con EIIP.
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17
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Baldwin K, Grossi V, Hyams JS. Managing pediatric Crohn's disease: recent insights. Expert Rev Gastroenterol Hepatol 2023; 17:949-958. [PMID: 37794692 DOI: 10.1080/17474124.2023.2267431] [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: 05/03/2023] [Accepted: 10/03/2023] [Indexed: 10/06/2023]
Abstract
INTRODUCTION Children and adolescents with Crohn's disease present unique challenges due to extensive disease at diagnosis and the effect of bowel inflammation on growth. Historical approaches with corticosteroids and immunomodulators are far less effective than early treatment with anti-TNF biologics. AREAS COVERED This review covers recent literature delineating the crucial role of early anti-TNF therapy in the treatment of moderate- to- severe Crohn's disease in children and adolescents. The potential risks and benefits of concomitant immunomodulators are discussed, along with therapeutic anti-TNF drug monitoring, and reassessment by endoscopy and cross-sectional imaging to evaluate success beyond symptom control. EXPERT OPINION Standard of care therapy for moderate-to-severe pediatric Crohn's disease now entails precision dosing of anti-TNF therapy with periodic reassessment of bowel inflammation. The role of dietary modification continues to evolve. Current and future efforts need to be directed to elucidating ways to predict response to anti-TNF therapy and quickly changing to agents with other mechanisms of action when needed. Inordinate regulatory delays in approval of new therapies approved for adults continue to handicap pediatric clinicians and frequently limits their treatment choices, or forces them to give medications "off label." Only a concerted effort by clinicians, pharma, and regulators will improve this situation.
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Affiliation(s)
- Katherine Baldwin
- Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT, USA
- Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Victoria Grossi
- Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT, USA
- Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Jeffrey S Hyams
- Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT, USA
- Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT, USA
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18
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Konovalova AM, Pechkurov DV, Tyazheva AA. Chronic Diarrhea as a Debut Manifestation of Crohn’s Disease in Infant: Clinical Case. CURRENT PEDIATRICS 2023. [DOI: 10.15690/vsp.v22i1.2518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/27/2023]
Abstract
Background. Chronic diarrhea can be a symptom of a wide variety of diseases, either of which requires special therapy approaches. The diagnosis of rare causes of chronic diarrhea is especially difficulty as it may be associated with inflammatory bowel disease (IBD) with very early (under 1 year of age) debut.Clinical case description. Boy E. had chronic diarrhea manifested on the first year of life. Ulcerative colitis was diagnosed at the age of 1.5 years, then the diagnosis was changed to Crohn’s disease at the age of 2.5 years. The results of 6-years-follow-up of the patient were presented, as well as analysis of diagnosis and treatment difficulties was carried out.Conclusion. The clinical case of Crohn’s disease with diarrhea as the leading clinical manifestation at the disease onset is described. Sequential diagnostic search allowed us to establish the diagnosis of IBD and to exclude other causes of chronic diarrhea that determined the correct therapeutic strategy.
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19
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Patel H, Karam L, Kellermayer R. A Single-Center Study of Long-Term Effectiveness of Vedolizumab in Anti-TNF Refractory Pediatric Inflammatory Bowel Disease. JPGN REPORTS 2023; 4:e276. [PMID: 36915867 PMCID: PMC10004749 DOI: 10.1097/pg9.0000000000000276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 10/01/2022] [Indexed: 05/14/2023]
Abstract
Vedolizumab is an anti-α4β7 integrin antibody that has been used successfully in the treatment of adult-onset inflammatory bowel diseases (IBDs: Crohn disease [CD] and ulcerative colitis [UC]). Its off-label use in the pediatric IBD (PIBD) population is increasing, but knowledge on durability beyond 6 months of treatment is limited. Methods A real-life, single-center, retrospective study of PIBD patients treated with vedolizumab was performed. Data on demographics, prior and concomitant treatments, and disease activity were obtained at 14 weeks, 26 weeks, 1 year, and 2 years of therapy. Primary outcome was corticosteroid- and other biologic-free remission (based on pediatric ulcerative colitis activity index [PUCAI]). Results Thirty-nine patients were studied. By 1 year, 65% of CD and 68% of UC patients continued on vedolizumab therapy. Corticosteroid- and other biologic-free remission was 29% in CD and 16% in UC. By 2 years, 36% of CD and 47% of UC patients continued therapy. Corticosteroid- and other biologic-free remission was 21% in CD and 40% in UC. By 2 years, 80% of CD and 100% of UC patients were on intensified treatment regimen compared to the manufacturer guidance. Nine patients (23%) required surgical intervention within 26 months of starting vedolizumab indicating the severity of IBD in this cohort. Conclusions Vedolizumab is a useful therapeutic modality in PIBD patients refractory to anti-TNF therapy, although with declining effectiveness by 2 years. Intensified treatment regimens are associated with long-term durability. Larger prospective trials in children are warranted.
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Affiliation(s)
- Halee Patel
- From the Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine/Texas Children’s Hospital, Houston, TX
| | - Lina Karam
- From the Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine/Texas Children’s Hospital, Houston, TX
| | - Richard Kellermayer
- From the Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine/Texas Children’s Hospital, Houston, TX
- Children’s Nutrition and Research Center, Houston, TX
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20
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Atia O, Shavit-Brunschwig Z, Mould DR, Stein R, Matar M, Aloi M, Ledder O, Focht G, Urlep D, Hyams J, Broide E, Weiss B, Levine J, Russell RK, Turner D. Outcomes, dosing, and predictors of vedolizumab treatment in children with inflammatory bowel disease (VEDOKIDS): a prospective, multicentre cohort study. Lancet Gastroenterol Hepatol 2023; 8:31-42. [PMID: 36306803 DOI: 10.1016/s2468-1253(22)00307-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 09/09/2022] [Accepted: 09/09/2022] [Indexed: 11/07/2022]
Abstract
BACKGROUND Scarce data are available on the use of vedolizumab in children with inflammatory bowel disease (IBD). We aimed to evaluate the safety, effectiveness, and dosing of vedolizumab to induce remission of IBD. METHODS VEDOKIDS was a paediatric, multicentre, prospective cohort study done in 17 centres in six countries. We report the 14-week outcomes as the first analyses of the planned 3-year follow-up of the VEDOKIDS cohort. Children (aged 0-18 years) with IBD who had commenced vedolizumab were followed up at baseline and at 2, 6, and 14 weeks. Children were managed according to local prescribing practices without standardisation of dosing or criteria for escalation, but the study protocol suggested dosing of 177 mg/m2 body surface area (up to 300 mg maximum). The primary outcome was steroid-free and exclusive enteral nutrition-free remission at 14 weeks, analysed according to the intention-to-treat principle. Serum samples were taken for analysis of drug concentration and faecal calprotectin at baseline, and at 2, 6, and 14 weeks. Adverse events were recorded in real time and classified as severe or non-severe and related or unrelated to vedolizumab. This study is registered with ClinicalTrials.gov, NCT02862132. FINDINGS Between May 19, 2016, and April 1, 2022, 142 children (76 [54%] girls and 66 [46%] boys; mean age 13·6 years [SD 3·6]) were enrolled. 65 (46%) children had Crohn's disease, 68 (48%) had ulcerative colitis, and nine (6%) had unclassified IBD (those with unclassified IBD were analysed with the ulcerative colitis group). 32 (42% [95% CI 30-54]) of 77 children with ulcerative colitis and 21 (32% [23-45]) of 65 children with Crohn's disease were in steroid-free and exclusive enteral nutrition-free remission at 14 weeks. Median drug concentrations at week 14 were higher in children with ulcerative colitis than in those with Crohn's disease (11·5 μg/mL [IQR 5·5-18·1] vs 5·9 μg/mL [3·0-12·7]; p=0·006). In children who weighed less than 30 kg, the optimal drug concentration associated with steroid-free and exclusive enteral nutrition-free clinical remission was 7 μg/mL at week 14 (area under the curve 0·69 [95% CI 0·41-0·98]), corresponding to a dose of 200 mg/m2 body surface area or 10 mg/kg. 32 (23%) of 142 children reported at least one adverse event, the most common were headache (five [4%]), myalgia (four [3%]), and fever (three [2%]). None of the adverse events were classified as severe, and only two (1%) patients discontinued treatment due to adverse events. INTERPRETATION Vedolizumab showed good safety and effectiveness at inducing remission in children with IBD at 14 weeks, especially those with ulcerative colitis. Vedolizumab should be considered in children when other approved drug interventions for IBD are unsuccessful. In children who weigh less than 30 kg, vedolizumab should be dosed by the child's body surface area (200 mg/m2) or weight (10 mg/kg). FUNDING The European Crohn's and Colitis Organization, the European Society for Paediatric Gastroenterology Hepatology and Nutrition, and Takeda.
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Affiliation(s)
- Ohad Atia
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University School of Medicine, Jerusalem, Israel
| | - Zivia Shavit-Brunschwig
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University School of Medicine, Jerusalem, Israel
| | | | - Ronen Stein
- Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Manar Matar
- Division of Gastroenterology, Hepatology, and Nutrition, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
| | - Marina Aloi
- Pediatric Gastroenterology, Hepatology and Nutrition Institute, Sapienza University of Rome, Rome, Italy
| | - Oren Ledder
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University School of Medicine, Jerusalem, Israel
| | - Gili Focht
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University School of Medicine, Jerusalem, Israel
| | - Darja Urlep
- Pediatric Gastroenterology and Liver Unit, University Children's Hospital of the University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Jeffrey Hyams
- Clinic of Pediatrics, Connecticut Children's Medical Center, Hartford, CT, USA
| | - Efrat Broide
- Division of Digestive Diseases, Shamir Medical Center, Be'er Ya'akov, Israel
| | - Batia Weiss
- Pediatric Gastroenterology and Nutrition, The Edmond & Lily Safra Children's Hospital, Sheba Medical Center, Tel HaShomer, Israel
| | - Jeremiah Levine
- Pediatric Gastroenterology, New York University Langone Health, New York, NY, USA
| | - Richard K Russell
- Division of Pediatric Gastroenterology, The Royal Hospital for Children & Young People, Edinburgh, UK
| | - Dan Turner
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University School of Medicine, Jerusalem, Israel.
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21
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Hu Q, Tang XZ, Liu F, Liu DW, Cao B. Vedolizumab subcutaneous formulation maintenance therapy for patients with IBD: a systematic review and meta-analysis. Therap Adv Gastroenterol 2023; 16:17562848231166227. [PMID: 37124368 PMCID: PMC10141260 DOI: 10.1177/17562848231166227] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 03/07/2023] [Indexed: 05/02/2023] Open
Abstract
Background The application of vedolizumab (VDZ) subcutaneous (SC) formulation has brought more convenience and hope to patients with moderate-to-severe inflammatory bowel diseases (IBDs) in the coronavirus disease 2019 context. Objective This study aimed to systematically evaluate all previous studies that used VDZ SC formulation for maintenance therapy in patients with IBD. Design Systematic review and meta-analysis. Data Sources and Methods The search was conducted using the subject and free terms related to 'Vedolizumab', 'Subcutaneous', and 'IBD', in Embase, PubMed, Web of Science, Cochrane, and at ClinicalTrials.gov databases between 2008 and 2022. The methodological quality of randomized controlled trials (RCTs) and cohort studies was assessed using the Cochrane Handbook of Systematic Reviews and the Newcastle-Ottawa Scale, respectively. The endpoints included efficacy, safety, and immunogenicity. Results A total of 60 studies and 2 completed clinical registry trials were retrieved, of which 3 RCTs with high methodological quality, and 3 cohort studies with large heterogeneity were included in the meta-analysis. In the RCT study design, patients with ulcerative colitis (UC) under different conditions after treated with VDZ SC were significantly distinct than those for placebo (PBO) in clinical remission, endoscopic remission, and biochemical remission. In Crohn's disease (CD), the aforementioned parameters were slightly higher than those for PBO, but there was not statistically significant in endoscopic remission and the efficacy of anti-tumor necrosis factor-naive patients. The clinical remission, endoscopic remission, and biochemical remission in patients with UC after VDZ SC treatment were similar to those after intravenous (IV) treatment. The risk ratios in patients experiencing adverse events (AEs) and serious AEs after VDZ SC and PBO treatments were 86% and 89% in UC, and 96% and 80% in CD, respectively. Compared with IV, safety was not statistically different. The risk of developing anti-VDZ antibody after VDZ SC treatment was only 20% of that after PBO in patients with UC, but it was 9.38 times in CD. Conclusion VDZ SC treatment maintained the clinical efficacy of IV induction in patients with IBD without increasing the safety risk, and the efficacy was more pronounced in patients with UC. Immunogenicity might be a potential factor for the decrease in efficacy rate in patients with IBD. Registration INPLASY 2022120115.
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Affiliation(s)
| | | | - Fang Liu
- AnoRectal Surgery, Sixth affiliated hospital of
Sun Yat-sen University, Guangdong, Guangzhou, China
| | - De-wu Liu
- AnoRectal Surgery, Second Affiliated Hospital
of Guizhou University of Traditional Chinese Medicine, Guizhou, Guiyang,
China
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22
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Aldouby Bier G, Zaidman I, Dinur Schejter Y, NaserEddin A, Stepensky P, Even-Or E. Vedolizumab for pediatric patients with gastrointestinal acute graft-versus-host-disease. Pediatr Blood Cancer 2023; 70:e30061. [PMID: 36326084 DOI: 10.1002/pbc.30061] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 09/06/2022] [Accepted: 09/26/2022] [Indexed: 11/06/2022]
Abstract
Vedolizumab, an anti-α4β7 integrin monoclonal antibody, impairs homing of T-cells to the gastrointestinal (GI) endothelium and acts as a gut-selective anti-inflammatory agent. Recent reports of the efficacy of vedolizumab in treating lower GI acute graft-versus-host disease (aGVHD) are promising, but experience in children is scarce. We present a cohort of 13 pediatric patients who were treated with vedolizumab for GI aGVHD. Ten of the patients were treated for steroid-refractory disease, out of which, six suffered from severe (stage 3 or 4) GI disease before the first dose of vedolizumab. In the other three patients, vedolizumab was introduced early in the disease course. Median time between GI GVHD onset to vedolizumab treatment was 23 days (range 7-59 days), with a median of 3 doses (range 1-5) per patient. GI GVHD staging was evaluated at various time points after the first vedolizumab dose, showing improvement in nine of the 13 patients. After a median follow-up time of 13 months (range 6-34 months), eight patients completely recovered, two had ongoing chronic colitis, and three patients died. During the vedolizumab treatment period, 38 infectious episodes were noted, most of them GI related. The unique activity profile of vedolizumab makes it an appealing treatment option for lower GI aGVHD, but caution for concurrent infections is warranted.
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Affiliation(s)
- Gefen Aldouby Bier
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hebrew University of Jerusalem, Hadassah Medical Center, Jerusalem, Israel.,Faculty of Medicine, Pharmacy Division, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Irina Zaidman
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hebrew University of Jerusalem, Hadassah Medical Center, Jerusalem, Israel
| | - Yael Dinur Schejter
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hebrew University of Jerusalem, Hadassah Medical Center, Jerusalem, Israel
| | - Adeeb NaserEddin
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hebrew University of Jerusalem, Hadassah Medical Center, Jerusalem, Israel
| | - Polina Stepensky
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hebrew University of Jerusalem, Hadassah Medical Center, Jerusalem, Israel
| | - Ehud Even-Or
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Faculty of Medicine, Hebrew University of Jerusalem, Hadassah Medical Center, Jerusalem, Israel
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23
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Denials, Dilly-dallying, and Despair: Navigating the Insurance Labyrinth to Obtain Medically Necessary Medications for Pediatric Inflammatory Bowel Disease Patients. J Pediatr Gastroenterol Nutr 2022; 75:418-422. [PMID: 35836325 DOI: 10.1097/mpg.0000000000003564] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
Increasingly, in the United States, the prescribing of high-cost drugs has become a challenge for physicians and other practitioners. Such drugs are highly regulated by third-party payers (aka insurance), as well as pharmacy benefit managers. Not infrequently, a clinician prescribing a medication will have the payment for the prescription denied by the third-party payer, with the end result being a delay in getting a medically necessary medication to a patient. This article highlights the challenges involved in the prior authorization and denial process, with a focus on pediatric inflammatory bowel disease. The article reviews the role of pharmacy benefits managers in restricting access to drugs, and the reasons why denials of medically necessary medications may occur. The article also provides information on how to appeal denials, how to write a letters of medical necessity, and how to conduct a proper peer-to-peer review. Advocacy from patients and clinicians will be important, as we want to reform the process in the future.
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Choi S, Kim ES, Kwon Y, Kim MJ, Choe YH, Choe BH, Kang B. Vedolizumab Is Safe and Efficacious for the Treatment of Pediatric-Onset Inflammatory Bowel Disease Patients Who Fail a Primary Biologic Agent. J Korean Med Sci 2022; 37:e282. [PMID: 36163478 PMCID: PMC9512676 DOI: 10.3346/jkms.2022.37.e282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 07/25/2022] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Vedolizumab (VDZ) is currently licensed for use in adults for the treatment of inflammatory bowel disease (IBD). We aimed to investigate the clinical course of pediatric-onset IBD following treatment with VDZ as more than a secondary biologic agent. We also evaluated factors associated with secondary loss of response (LOR) and durability of VDZ treatment. METHODS Pediatric-onset IBD patients diagnosed at an age younger than 18 years who had received VDZ as more than a secondary biologic agent were included in this retrospective observational study conducted at the Department of Pediatrics of two centers in Korea. Comparative analysis was conducted between groups divided according to the development of secondary LOR during VDZ treatment. RESULTS A total of 24 patients comprising 10 patients with Crohn's disease and 14 with ulcerative colitis were included. Of these, 19 were male and 5 were female. The mean age at diagnosis was 14.6 ± 2.5 years. The mean age at initiation of VDZ was 20.5 ± 2.8 years. Nine patients (37.5%) had received two or more biologic agents before starting VDZ. During a median of 0.9 years follow-up from VDZ initiation, 9 patients (37.5%) experienced LOR requiring interval shortening and 4 patients (16.7%) were changed to a different biologic agent. According to multivariate Cox proportional hazard regression analysis, administration of two or more biologic agents before VDZ treatment was the only factor positively associated with LOR (hazard ratio [HR], 5.6; 95% confidence interval [CI], 1.026-30.56; P = 0.047), while LOR was the only factor negatively associated with VDZ durability (HR, 0.003; 95% CI, 0.00-0.08; P = 0.010). No adverse events were observed during treatment with VDZ. CONCLUSION VDZ is safe and efficacious for the treatment of pediatric-onset IBD patients failing a primary biologic agent. The durability of VDZ may be enhanced by introducing VDZ earlier in the disease course. Further prospective studies in children are required in the future to validate these findings.
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Affiliation(s)
- Sujin Choi
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Eun Sil Kim
- Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yiyoung Kwon
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Mi Jin Kim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yon Ho Choe
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Byung-Ho Choe
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Ben Kang
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea.
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Attauabi M, Madsen GR, Bendtsen F, Seidelin JB, Burisch J. Vedolizumab as the first line of biologic therapy for ulcerative colitis and Crohn's disease - a systematic review with meta-analysis. Dig Liver Dis 2022; 54:1168-1178. [PMID: 34903497 DOI: 10.1016/j.dld.2021.11.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 11/06/2021] [Accepted: 11/15/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND The efficacy and safety of vedolizumab in bio-naïve patients with ulcerative colitis (UC) and Crohn's disease (CD) remain unknown. AIMS To perform a meta-analysis regarding vedolizumab as first line of biological therapy for UC or CD. METHODS A systematic review of Medline, EMBASE, and Cochrane databases per December 2020 was undertaken. Meta-analysis was conducted using random-effects models. RESULTS This systematic review identified 79 eligible studies with 4,520 and 3,494 bio-naïve patients with UC and CD, respectively, and 8,105 and 11,140 bio-exposed patients. Among bio-naïve patients with UC, a total of 40.0% (95%CI 27.0-54.0, I2=86%) and 63.9% (95%CI 47.0-79.2, I2=36%) achieved clinical remission at weeks 14 and 52, respectively. The corresponding rates in CD were 54.0% (95%CI 42.0-66.0, I2=23%), and 61.7% (95%CI 55.2-68.1, I2=0%). Bio-naïvety was associated with a higher probability of clinical remission at week 52 in UC (relative risk (RR)=1.32 (95%CI 1.14-1.53)), while this was only apparent until week 26 in CD (RR=1.60 (95%CI 1.30-1.95)). Finally, bio-naïve UC patients had a lower risk of serious adverse events (RR=0.29 (95%CI 0.09-0.95)). CONCLUSION Vedolizumab was found to have a favorable efficacy and safety profile in bio-naïve patients with UC and CD. The findings have implications in the management of IBD.
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Affiliation(s)
- Mohamed Attauabi
- Department of Gastroenterology and Hepatology, Herlev Hospital, University of Copenhagen, Borgmester Ib Juuls Vej 1, 2730 Denmark; Gastrounit, Medical Section, Hvidovre University Hospital, Hvidovre, Kettegaard Alle 30, 2650 Denmark; Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, University of Copenhagen, Hvidovre Hospital, Hvidovre, Kettegaard Alle 30, 2650 Denmark.
| | - Gorm Roager Madsen
- Gastrounit, Medical Section, Hvidovre University Hospital, Hvidovre, Kettegaard Alle 30, 2650 Denmark; Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, University of Copenhagen, Hvidovre Hospital, Hvidovre, Kettegaard Alle 30, 2650 Denmark
| | - Flemming Bendtsen
- Gastrounit, Medical Section, Hvidovre University Hospital, Hvidovre, Kettegaard Alle 30, 2650 Denmark; Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, University of Copenhagen, Hvidovre Hospital, Hvidovre, Kettegaard Alle 30, 2650 Denmark
| | - Jakob Benedict Seidelin
- Department of Gastroenterology and Hepatology, Herlev Hospital, University of Copenhagen, Borgmester Ib Juuls Vej 1, 2730 Denmark
| | - Johan Burisch
- Gastrounit, Medical Section, Hvidovre University Hospital, Hvidovre, Kettegaard Alle 30, 2650 Denmark; Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, University of Copenhagen, Hvidovre Hospital, Hvidovre, Kettegaard Alle 30, 2650 Denmark
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Anderson K, Moss K, Campbell B, Moote D, Kakazu K, Hyams JS. Follicular Dendritic Cell Sarcoma in a Patient With Adolescent-Onset Crohn's Disease Exposed to Multiple Immunomodulator and Biologic Therapies. JPGN REPORTS 2022; 3:e231. [PMID: 37168632 PMCID: PMC10158454 DOI: 10.1097/pg9.0000000000000231] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 05/06/2022] [Indexed: 05/13/2023]
Abstract
Children and adolescents with inflammatory bowel disease are often treated with immunomodulators (thiopurines, methotrexate) and biologics (anti-TNF, anti-integrin) for extended periods despite concerns about long-term safety. Here, we report a case of follicular dendritic cell sarcoma, a very rare malignancy, and the first reported presentation in a patient with inflammatory bowel disease exposed to infliximab, methotrexate, and vedolizumab. We review the key clinical features and diagnostic factors of this malignancy. The pathogenesis of follicular dendritic cell sarcoma is largely unknown, however, knock out of B-cell TNF in mice has been related to follicular dendritic cell dysregulation through its impact on NF-κB pathways and CXCL13 chemokines. It is unknown whether any relationship exists between this patient's diagnosis of Crohn's disease and therapeutic exposures to this rare malignancy. We document this case in the literature to raise awareness among other clinicians who may observe a similar case.
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Affiliation(s)
- Kaitlyn Anderson
- From the Department of Graduate Medical Education, Connecticut Children’s Medical Center, The University of Connecticut School of Medicine, Hartford, CT
| | - Kerry Moss
- Department of Hematology/Oncology, Connecticut Children’s Medical Center, The University of Connecticut School of Medicine, Hartford, CT
| | - Brendan Campbell
- Department of Surgery, Connecticut Children’s Medical Center, The University of Connecticut School of Medicine, Hartford, CT
| | - Douglas Moote
- Department of Radiology, Connecticut Children’s Medical Center, The University of Connecticut School of Medicine, Hartford, CT
| | - Kari Kakazu
- Department of Pathology, Connecticut Children’s Medical Center, The University of Connecticut School of Medicine, Hartford, CT
| | - Jeffrey S. Hyams
- Department of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children’s Medical Center, The University of Connecticut School of Medicine, Hartford, CT
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Elhag DA, Kumar M, Saadaoui M, Akobeng AK, Al-Mudahka F, Elawad M, Al Khodor S. Inflammatory Bowel Disease Treatments and Predictive Biomarkers of Therapeutic Response. Int J Mol Sci 2022; 23:ijms23136966. [PMID: 35805965 PMCID: PMC9266456 DOI: 10.3390/ijms23136966] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/05/2022] [Accepted: 06/06/2022] [Indexed: 02/08/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammation of the gastrointestinal tract with a highly heterogeneous presentation. It has a relapsing and remitting clinical course that necessitates lifelong monitoring and treatment. Although the availability of a variety of effective therapeutic options including immunomodulators and biologics (such as TNF, CAM inhibitors) has led to a paradigm shift in the treatment outcomes and clinical management of IBD patients, some patients still either fail to respond or lose their responsiveness to therapy over time. Therefore, according to the recent Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) recommendations, continuous disease monitoring from symptomatic relief to endoscopic healing along with short- and long-term therapeutic responses are critical for providing IBD patients with a tailored therapy algorithm. Moreover, considering the high unmet need for novel therapeutic approaches for IBD patients, various new modulators of cytokine signaling events (for example, JAK/TYK inhibitors), inhibitors of cytokines (for example IL-12/IL-23, IL-22, IL-36, and IL-6 inhibitors), anti-adhesion and migration strategies (for example, β7 integrin, sphingosine 1-phosphate receptors, and stem cells), as well as microbial-based therapeutics to decolonize the bed buds (for example, fecal microbiota transplantation and bacterial inhibitors) are currently being evaluated in different phases of controlled clinical trials. This review aims to offer a comprehensive overview of available treatment options and emerging therapeutic approaches for IBD patients. Furthermore, predictive biomarkers for monitoring the therapeutic response to different IBD therapies are also discussed.
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Affiliation(s)
- Duaa Ahmed Elhag
- Research Department, Sidra Medicine, Doha 26999, Qatar; (D.A.E.); (M.K.); (M.S.)
| | - Manoj Kumar
- Research Department, Sidra Medicine, Doha 26999, Qatar; (D.A.E.); (M.K.); (M.S.)
| | - Marwa Saadaoui
- Research Department, Sidra Medicine, Doha 26999, Qatar; (D.A.E.); (M.K.); (M.S.)
| | - Anthony K. Akobeng
- Division of Gastroenterology, Hepatology and Nutrition, Sidra Medicine, Doha 26999, Qatar; (A.K.A.); (F.A.-M.); (M.E.)
| | - Fatma Al-Mudahka
- Division of Gastroenterology, Hepatology and Nutrition, Sidra Medicine, Doha 26999, Qatar; (A.K.A.); (F.A.-M.); (M.E.)
| | - Mamoun Elawad
- Division of Gastroenterology, Hepatology and Nutrition, Sidra Medicine, Doha 26999, Qatar; (A.K.A.); (F.A.-M.); (M.E.)
| | - Souhaila Al Khodor
- Research Department, Sidra Medicine, Doha 26999, Qatar; (D.A.E.); (M.K.); (M.S.)
- Correspondence:
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28
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Pediatric Management of Crohn's Disease. Gastroenterol Clin North Am 2022; 51:401-424. [PMID: 35595422 DOI: 10.1016/j.gtc.2021.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Pediatric Crohn's disease is often more severe, requires higher levels of immunosuppression, and is associated with greater morbidity compared with adult Crohn's disease. Unique considerations in pediatric Crohn's disease include growth impairment, pubertal delay, bone disease, longevity of disease burden, and psychosocial impact. Treatment options are limited, requiring off-label use of therapy in this challenging patient population. Understanding the medications available, the existing evidence supporting their use, and side effects is important. There is tremendous potential for growth and improvement in this field and it is essential that all gastroenterologists have an understanding of this complex and unique patient population.
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29
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Fang S, Song Y, Zhang C, Wang L. Efficacy and safety of vedolizumab for pediatrics with inflammatory bowel disease: a systematic review. BMC Pediatr 2022; 22:175. [PMID: 35379216 PMCID: PMC8978350 DOI: 10.1186/s12887-022-03229-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 01/05/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Vedolizumab use in pediatrics is still off-label and the data are limited. We conducted a systematic review evaluating the efficacy and safety of vedolizumab in children and adolescents with inflammatory bowel disease (IBD). METHODS PubMed, EMBASE and Cochrane databases were systematically searched for studies of vedolizumab in children and adolescents with IBD reporting clinical remission, response, corticosteroid-free (CS-free) remission, mucosal healing, or safety up to December 3rd 2021. RESULTS Ten studies, comprising 455 patients were included. For CD, the pooled clinical remission rates were 25% (19/75) at 6 weeks, 28% (25/85) at 14 weeks, 32% (17/53) at 22 weeks, and 46% (43/92) at 1 year. For UC/IBD-U, the pooled clinical remission rates were 36% (25/70) at 6 weeks, 48% (52/101) at 14 weeks, 53% (24/45) at 22 weeks, and 45% (50/112) at 1 year. Mucosal healing was found in 17%-39% of CD and 15%-34% of UC/IBD-U respectively. Six percent of patients reported serious adverse events. CONCLUSIONS According to low-quality evidence based on case series, approximately one-third and one-half of patients for CD and UC/IBD-U respectively achieved remission within 22 weeks, and about half of patients achieved remission at 1 year with reasonable safety profile. Long-term benefit profile data and high quality evidence are still needed.
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Affiliation(s)
- Shengbo Fang
- Department of Pharmacy, First Hospital of Jilin University, Changchun, China
| | - Yanqing Song
- Department of Pharmacy, First Hospital of Jilin University, Changchun, China
| | - Chunyan Zhang
- Department of Pediatric Gastroenterology Unit, First Hospital of Jilin University, Changchun, China
| | - Libo Wang
- Department of Pediatric Gastroenterology Unit, First Hospital of Jilin University, Changchun, China.
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30
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Hyams JS, Turner D, Cohen SA, Szakos E, Kowalska-Duplaga K, Ruemmele F, Croft NM, Korczowski B, Lawrence P, Bhatia S, Kadali H, Chen C, Sun W, Rosario M, Kabilan S, Treem W, Rossiter G, Lirio RA. Pharmacokinetics, Safety and Efficacy of Intravenous Vedolizumab in Paediatric Patients with Ulcerative Colitis or Crohn's Disease: Results from the Phase 2 HUBBLE Study. J Crohns Colitis 2022; 16:1243-1254. [PMID: 35301512 PMCID: PMC9426668 DOI: 10.1093/ecco-jcc/jjac036] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 02/10/2022] [Accepted: 03/16/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS To date, there are no systematic pharmacokinetic [PK] data on vedolizumab in paediatric inflammatory bowel disease [IBD]. We report results from HUBBLE, a dose-ranging, phase 2 trial evaluating the PK, safety and efficacy of intravenous vedolizumab for paediatric IBD. METHODS Enrolled patients [aged 2-17 years] with moderate to severe ulcerative colitis [UC] or Crohn's disease [CD] and body weight ≥10 kg were randomized by weight to receive low- or high-dose vedolizumab [≥30 kg, 150 or 300 mg; <30 kg, 100 or 200 mg] on Day 1 and Weeks 2, 6 and 14. Week 14 assessments included PK, clinical response and exposure-response relationship. Safety and immunogenicity were assessed. RESULTS Randomized patients weighing ≥30 kg [UC, n = 25; CD, n = 24] and <30 kg [UC, n = 19; CD, n = 21] had a baseline mean [standard deviation] age of 13.5 [2.5] and 7.6 [3.2] years, respectively. In almost all indication and weight groups, area under the concentration curve and average concentration increased ~2-fold from low to high dose; the trough concentration was higher in each high-dose arm compared with the low-dose arms. At Week 14, clinical response occurred in 40.0-69.2% of patients with UC and 33.3-63.6% with CD in both weight groups. Clinical responders with UC generally had higher trough concentration vs non-responders, while this trend was not observed in CD. Fourteen per cent [12/88] of patients had treatment-related adverse events and 6.8% [6/88] had anti-drug antibodies. CONCLUSIONS Vedolizumab exposure increased in an approximate dose-proportional manner. No clear dose-response relationship was observed in this limited cohort. No new safety signals were identified.
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Affiliation(s)
- Jeffrey S Hyams
- Corresponding author: Jeffrey S. Hyams, Connecticut Children’s Medical Center, Hartford, CT, USA. Tel: +1 860 545 9532;
| | - Dan Turner
- Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Stanley A Cohen
- Children’s Center for Digestive Health Care, Atlanta, GA, USA
| | - Erzsébet Szakos
- Borsod-A-Z County Central University Teaching Hospital, Velkey Laszlo Paediatric Health Centre, University of Miskolc, Miskolc, Hungary
| | - Kinga Kowalska-Duplaga
- Department of Paediatrics, Gastroenterology and Nutrition, Jagiellonian University Medical College, Kraków, Poland
| | - Frank Ruemmele
- Université de Paris, APHP, Hôpital Necker Enfants Malades, Paediatric Gastroenterology, Paris, France
| | - Nicholas M Croft
- Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine, Queen Mary University of London and The Royal London Children’s Hospital, Barts Health NHS Trust, London, UK
| | - Bartosz Korczowski
- Department of Paediatrics and Paediatric Gastroenterology, University of Rzeszów, Rzeszów, Poland
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Abstract
Inflammatory bowel diseases (IBD) consist of Crohn's disease and ulcerative colitis. These are conditions that, although managed by pediatric gastroenterologists, are encountered frequently by the general pediatrician. The purpose of this article is to review the use of targeted antibody treatments, also known as biologics, in the treatment of pediatric IBD as well as complications and adverse effects for the pediatrician to consider when caring for a patient with IBD who is taking biologics. [Pediatr Ann. 2022;51(2):e77-e81.].
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32
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Bousvaros A. Management of Pediatric Patients Hospitalized with Ulcerative. MANAGEMENT OF INPATIENT INFLAMMATORY BOWEL DISEASE 2022:225-246. [DOI: 10.1007/978-1-0716-1987-2_11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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33
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Rao A, Gokhale R. Ulcerative Colitis. TEXTBOOK OF PEDIATRIC GASTROENTEROLOGY, HEPATOLOGY AND NUTRITION 2022:401-421. [DOI: 10.1007/978-3-030-80068-0_30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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34
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Li QQ, Zhang HH, Dai SX. New Insights and Advances in Pathogenesis and Treatment of Very Early Onset Inflammatory Bowel Disease. Front Pediatr 2022; 10:714054. [PMID: 35299671 PMCID: PMC8921506 DOI: 10.3389/fped.2022.714054] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 01/25/2022] [Indexed: 12/26/2022] Open
Abstract
Very early onset inflammatory bowel disease (VEO-IBD) is characterized by multifactorial chronic recurrent intestinal inflammation. Compared with elderly patients, those with VEO-IBD have a more serious condition, not responsive to conventional treatments, with a poor prognosis. Recent studies found that genetic and immunologic abnormalities are closely related to VEO-IBD. Intestinal immune homeostasis monogenic defects (IIHMDs) are changed through various mechanisms. Recent studies have also revealed that abnormalities in genes and immune molecular mechanisms are closely related to VEO-IBD. IIHMDs change through various mechanisms. Epigenetic factors can mediate the interaction between the environment and genome, and genetic factors and immune molecules may be involved in the pathogenesis of the environment and gut microbiota. These discoveries will provide new directions and ideas for the treatment of VEO-IBD.
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Affiliation(s)
- Qi-Qi Li
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Hui-Hong Zhang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Shi-Xue Dai
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Department of Gastroenterology, Guangdong Provincial Geriatrics Institute, National Key Clinical Specialty, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, South China University of Technology, Guangzhou, China
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35
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Shah P, McDonald D. Vedolizumab: An Emerging Treatment Option for Pediatric Inflammatory Bowel Disease. J Pediatr Pharmacol Ther 2021; 26:795-801. [PMID: 34790068 DOI: 10.5863/1551-6776-26.8.795] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 06/09/2021] [Indexed: 12/11/2022]
Abstract
Vedolizumab is a humanized α4β7-integrin antagonist that is currently FDA-approved for adult inflammatory bowel disease. Limited evidence is available to guide use in pediatric patients, though off-label use is described in the form of retrospective reviews and case series. Collectively these publications begin to establish safety and efficacy data in pediatric patients < 18 years of age. Additionally, dosing regimens described in the literature serve to guide weight-based dosing, which is not established at this time. This narrative review aims to summarize the available literature and provide recommendations for vedolizumab use in the pediatric population. A literature search was performed in PubMed (January 2014-December 2020) using the keyword vedolizumab. Based on the available evidence, vedolizumab appears to be a safe and moderately effective agent for treatment of refractory pediatric inflammatory bowel disease. Prospective, randomized trials are warranted to optimize dosing regimens and to establish long-term safety.
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Garcia-Romero R, Martinez de Zabarte Fernandez JM, Pujol-Muncunill G, Donat-Aliaga E, Segarra-Cantón O, Irastorza-Terradillos I, Medina-Benitez E, Ruiz-Hernández CJ, Carrillo-Palau M, Ros-Arnal I, Rodriguez-Martínez A, Escartin-Madurga L, Gutiérrez-Junquera C, Vicente-Santamaría S, Velasco Rodriguez-Belvis M, Fernández-Fernández S, Alberto-Alonso JR, Montraveta M, Torres-Peral R, Navalon-Rubio M, Navas-López VM, Martin de Carpi J. Safety and effectiveness of vedolizumab in paediatric patients with inflammatory bowel disease: an observational multicentre Spanish study. Eur J Pediatr 2021; 180:3029-3038. [PMID: 33880650 DOI: 10.1007/s00431-021-04063-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 02/27/2021] [Accepted: 04/04/2021] [Indexed: 12/23/2022]
Abstract
Vedolizumab is a humanised monoclonal antibody that binds to integrin α4β7 expressed in T-cells, inhibiting its binding to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is specifically expressed in the small intestine and colon, playing a fundamental role in T-cell migration to the gastrointestinal tract. Vedolizumab has been shown to be effective in treating adults with inflammatory bowel disease; however, efficacy data for paediatric use are scarce. The objective of the present study was to assess the effectiveness and safety of vedolizumab for inducing and maintaining clinical remission in children with inflammatory bowel disease. We conducted a retrospective multicentre study of patients younger than 18 years with inflammatory bowel disease refractory to anti-tumour necrosis factor alpha (anti-TNF-α) drugs, who underwent treatment with vedolizumab. Clinical remission was defined as a score < 10 points in the activity indices. We included 42 patients, 22 of whom were male (52.3%), with a median age of 13.1 years (IQR 10.2-14.2) at the start of treatment. Of the 42 patients, 14 (33.3%) had Crohn's disease (CD) and 28 (66.7%) had ulcerative colitis (UC). At the start of treatment with vedolizumab, the Paediatric Crohn's Disease Activity Index was 36 (IQR 24-40) and the Paediatric Ulcerative Colitis Activity Index was 47 (IQR 25-65). All of them had received prior treatment with anti-TNF and 3 patients ustekinumab. At week 14, 69% of the patients responded to the treatment (57.1% of those with CD and 75% of those with UC; p=0.238), and 52.4% achieved remission (35.7% with CD and 60.7% with UC; p=0.126). At 30 weeks, the response rate was 66.7% (46.2% and 78.3% for CD and UC, respectively; p=0.049), and 52.8% achieved remission (30.8% and 65.2% for CD and UC, respectively; p=0.047). Among the patients with remission at week 14, 80% of the patients with CD and 84.5% of those with UC maintained the remission at 52 weeks. Adverse effects were uncommon and mild. Three patients (7.1%) presented headaches, 1 presented alopecia, 1 presented anaemia and 1 presented dermatitis.Conclusion: The results show that treatment with vedolizumab is a safe and effective option for achieving clinical remission in paediatric patients with inflammatory bowel disease with primary failure or loss of response to other treatments, especially in UC. What is Known: • Vedolizumab is effective in inducing and maintaining remission in adult patients with inflammatory bowel disease. • Most studies and clinical trials have been performed on adult populations, and there is currently no indication for paediatric populations. What is New: • Children with inflammatory bowel disease refractory to anti-TNF presented higher clinical remission rates than those published for adults. • There are few publications of this magnitude on paediatric populations treated with vedolizumab and with long-term follow-up (52 weeks).
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Affiliation(s)
- Ruth Garcia-Romero
- Paediatric Gastroenterology, Hepatology and Nutrition, Paediatric University Hospital Miguel Servet, Zaragoza, Spain.
| | | | - Gemma Pujol-Muncunill
- Paediatric Gastroenterology, Hepatology and Nutrition, Hospital Sant Joan de Déu, Barcelona, Spain
| | - Ester Donat-Aliaga
- Paediatric Gastroenterology, Hepatology and Nutrition, Polytechnic University Hospital La Fe, Valencia, Spain
| | - Oscar Segarra-Cantón
- Paediatric Gastroenterology, Hepatology and Nutrition, Mother-Child University Hospital, Vall Hebrón, Barcelona, Spain
| | | | - Enrique Medina-Benitez
- Paediatric Gastroenterology, Hepatology and Nutrition Unit, University Hospital 12 de Octubre, Madrid, Spain
| | - Carlos José Ruiz-Hernández
- Paediatric Gastroenterology and Nutrition, Department of Paediatrics, Hospital Parc Taulí, Sabadell, Spain
| | - Marta Carrillo-Palau
- Department of Gastroenterology, University Hospital of the Canary Islands, La Laguna, Tenerife, Spain
| | - Ignacio Ros-Arnal
- Paediatric Gastroenterology, Hepatology and Nutrition, Paediatric University Hospital Miguel Servet, Zaragoza, Spain
| | | | - Laura Escartin-Madurga
- Paediatric Gastroenterology, Hepatology and Nutrition, University Clinic Hospital Lozano Blesa, Zaragoza, Spain
| | - Carolina Gutiérrez-Junquera
- Paediatric Gastroenterology, Hepatology and Nutrition, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
| | - Saioa Vicente-Santamaría
- Paediatric Gastroenterology, Hepatology and Nutrition, University Hospital Ramon y Cajal, Madrid, Spain
| | | | - Sonia Fernández-Fernández
- Paediatric Gastroenterology, Hepatology and Nutrition, University Hospital Severo Ochoa, Leganés, Madrid, Spain
| | - José Ramón Alberto-Alonso
- Paediatric Gastroenterology, Hepatology and Nutrition, University Hospital Ntra. Sra. de Candelaria, Tenerife, Spain
| | - Montserrat Montraveta
- Paediatric Gastroenterology, Hepatology and Nutrition, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Ricardo Torres-Peral
- Paediatric Gastroenterology and Nutrition Unit, Department of Paediatrics, University Hospital Complex, Salamanca, Spain
| | - María Navalon-Rubio
- Paediatric Gastroenterology, Hepatology and Nutrition, Hospital Virgen de la Arrixaca, Murcia, Spain
| | - Víctor Manuel Navas-López
- Paediatric Gastroenterology and Nutrition Section, Regional University Hospital of Malaga, Málaga, Spain
| | - Javier Martin de Carpi
- Paediatric Gastroenterology, Hepatology and Nutrition, Hospital Sant Joan de Déu, Barcelona, Spain
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Dolinger MT, Spencer EA, Lai J, Dunkin D, Dubinsky MC. Dual Biologic and Small Molecule Therapy for the Treatment of Refractory Pediatric Inflammatory Bowel Disease. Inflamm Bowel Dis 2021; 27:1210-1214. [PMID: 33125058 DOI: 10.1093/ibd/izaa277] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Nontraditional combination of existing therapies is often the only option to avoid surgery in refractory inflammatory bowel disease (IBD) patients. We aim to assess the efficacy and safety of concomitant use of 2 biologic therapies or combination of biologic and tofacitinib in a refractory pediatric IBD cohort. METHODS As part of an ongoing single-center observational cohort study of therapeutic outcomes in pediatric IBD patients (younger than 18 years), data were collected for patients receiving dual therapy. Primary outcome was 6 months of steroid-free remission. Secondary outcomes included time to steroid-free remission, change in serum biomarkers (C-reactive protein and erythrocyte sedimentation rate) and albumin between baseline and 6 months, and adverse events. RESULTS Sixteen children (9 ulcerative colitis/IBD-unspecified, 7 Crohn's disease), with a disease duration of 3 (2.1-5.0) years, initiated dual therapy at an age of 15.9 (13.5-16.8) years after failing ≥2 biologic therapies. Nine (56%) were treated with vedolizumab/tofacitinib, 4 (25%) with ustekinumab/vedolizumab, and 3 (19%) with ustekinumab/tofacitinib. Twelve (75%; 7 ulcerative colitis/IBD-unspecified, 5 Crohn's disease ) achieved steroid-free remission at 6 months. Erythrocyte sedimentation rate and C-reactive protein decreased (P = 0.021 and P = 0.015, respectively) and albumin increased (P = 0.003) between baseline and 6 months. One patient on 30 mg of vedolizumab/tofacitinib and prednisone daily developed septic arthritis and a deep vein thrombosis. CONCLUSIONS Our data suggest that dual therapy may be an option for patients with limited therapeutic options remaining. Safety concerns should always be at the forefront of decision-making, and larger studies are needed to help confirm the preliminary safety data observed.
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Affiliation(s)
- Michael T Dolinger
- Department of Pediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Elizabeth A Spencer
- Department of Pediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Joanne Lai
- Department of Pediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY
| | - David Dunkin
- Department of Pediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Marla C Dubinsky
- Department of Pediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY
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38
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Fabiszewska S, Derda E, Szymanska E, Osiecki M, Kierkus J. Safety and Effectiveness of Vedolizumab for the Treatment of Pediatric Patients with Very Early Onset Inflammatory Bowel Diseases. J Clin Med 2021; 10:2997. [PMID: 34279480 PMCID: PMC8268556 DOI: 10.3390/jcm10132997] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/30/2021] [Accepted: 07/01/2021] [Indexed: 12/30/2022] Open
Abstract
Background: Vedolizumab (vedo) is effective for induction and maintenance of remission in adults with inflammatory bowel disease (IBD). Pediatric data are still limited, especially for the youngest children with very early onset disease (VEO-IBD). The aim of this study was to assess the safety and efficacy of vedo in VEO-IBD. Methods: We performed a retrospective review of pediatric IBD patients with VEO-IBD (defined as aged <6 years) receiving vedo. Data on demographics, disease behavior, activity, and previous treatments/surgeries were collected. Disease activity was assessed using the pediatric Crohn's disease (CD) activity index (PCDAI) for CD or pediatric ulcerative colitis (UC) activity index (PUCAI) for UC. Primary outcome was clinical response after induction therapy with vedolizumab (4th dose week). It was defined as a decrease in PCDAI of at least 12.5 points between baseline and 4th dose week for CD, and a decrease in PUCAI of at least 20 points between baseline and this time for UC. Descriptive statistics were performed to analyze the data. Results: The study included 16 patients with VEO-IBD who have received vedo: 4/16 (25%) with CD, and 12/16 (75%) with UC at the median age of diagnosis 33.7 months (6.6 months-4.5 years). Median age at vedo initiation was 6.5 years (2.2-16.5 years). Among the analyzed individuals, 56.25% had failed more than one anti-tumor necrosis factor (TNF) alfa agent. Clinical response at 4th dose week was observed in 9/16 (56.3%) patients: mean baseline PCDAI score was 34.4 ± 1.9 and 10.6 ± 1.8 after induction therapy with vedo, while PUCAI score was 26 ± 6 vs. 18 ± 8, respectively. There was improvement in patients' nutritional state: at baseline 2/16 (12.5%) children had body mass index (BMI) below 1 percentile and no child had such BMI after induction therapy with vedo. No infusion reactions or serious adverse events/infections were reported. Conclusion: Vedolizumab is safe and effective in the medical management of pediatric patients with VEO-IBD.
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Affiliation(s)
| | | | - Edyta Szymanska
- Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland; (S.F.); (E.D.); (M.O.); (J.K.)
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Hajjat TM, Mosha M, Whaley KG, Rosen MJ, Suppa C, Markowitz J, Dufour L, Sauer C, Shukla-Udawatta M, Boyle B, Gibson M, Shapiro J, Sams D, Sylvester F, Hunter G, Perez ME, Hyams JS. Vedolizumab Experience in Children and Adolescents With Inflammatory Bowel Disease: A Multicenter Observational Study. CROHN'S & COLITIS 360 2021; 3:otab039. [PMID: 36776669 PMCID: PMC9802305 DOI: 10.1093/crocol/otab039] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Indexed: 11/13/2022] Open
Abstract
Background Vedolizumab is increasingly used off-label to treat children and adolescents with inflammatory bowel disease (IBD). In the absence of rigorous clinical trial experience, multicenter observational data are important to establish expectations for efficacy and safety. We examined 1-year outcomes following vedolizumab therapy in a large multicenter pediatric IBD cohort. Methods We performed a retrospective study of 159 pediatric patients (4-17 years old) with IBD [78, Crohn disease (CD); 81, ulcerative colitis/IBD-unspecified (UC/IBD-U)] treated with vedolizumab for 1 year at 8 pediatric medical centers in the United States. Demographics, clinical outcomes, laboratory data, and vedolizumab dosing were recorded. The primary outcome was corticosteroid (CS)-free clinical remission at 1 year. Other measured outcomes were clinical remission at 12 and/or 24 weeks, laboratory outcomes at 1 year, and endoscopy/histology results at 1 year. Results Among the 159 patients (mean age, 14.5 ± 2.4 years; 86% anti-TNF experienced), 68/159 (43%) achieved CS-free clinical remission at 1 year (CD, 35/78, 45%; UC/IBD-U, 33/81, 40%). Vedolizumab therapy failed and was discontinued in 33/159 (21%) patients prior to 1 year (CD, 18/78, 23%; UC/IBD-U, 15/81, 19%). While week 12 clinical remission was not predictive of 1-year clinical remission in either CD or UC/IBD-U, week 24 clinical remission was predictive of 1-year clinical remission only in CD patients. No infusion reactions or serious side effects were noted. Conclusions Vedolizumab was safe and effective in this pediatric population with approximately 43% achieving CS-free clinical remission at 1 year. Similar efficacy was noted in both CD and UC.
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Affiliation(s)
- Temara M Hajjat
- Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children’s Medical Center, Hartford, Connecticut, USA,Address correspondence to: Temara M. Hajjat, MD, Pediatric Gastroenterology, Cincinnati Children’s Hospital and Medical Center, 3333 Burnet Avenue, MLC T8 (Office: 535), Cincinnati, OH 45229-3039, USA ()
| | - Maua Mosha
- Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children’s Medical Center, Hartford, Connecticut, USA
| | - Kaitlin G Whaley
- Division of Pediatric Gastroenterology, Cincinnati Children’s Hospital Medical Center, and the Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Michael J Rosen
- Division of Pediatric Gastroenterology, Cincinnati Children’s Hospital Medical Center, and the Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Carmine Suppa
- Division of Pediatric Gastroenterology, Cohen Children’s Medical Center of NY, New Hyde Park, New York, USA
| | - James Markowitz
- Division of Pediatric Gastroenterology, Cohen Children’s Medical Center of NY, New Hyde Park, New York, USA
| | - Lauren Dufour
- Division of Pediatric Gastroenterology, Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Cary Sauer
- Division of Pediatric Gastroenterology, Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Monica Shukla-Udawatta
- Division of Pediatric Gastroenterology, Nationwide Children’s Hospital, Columbus, Ohio, USA
| | - Brendan Boyle
- Division of Pediatric Gastroenterology, Nationwide Children’s Hospital, Columbus, Ohio, USA
| | - Meghan Gibson
- Division of Pediatric Gastroenterology, Hasbro Children’s Hospital, Providence, Rhode Island, USA
| | - Jason Shapiro
- Division of Pediatric Gastroenterology, Hasbro Children’s Hospital, Providence, Rhode Island, USA
| | - Derica Sams
- Division of Pediatric Gastroenterology, University of North Carolina Health Care, Chapel Hill, North Carolina, USA
| | - Francisco Sylvester
- Division of Pediatric Gastroenterology, University of North Carolina Health Care, Chapel Hill, North Carolina, USA
| | - Gabriele Hunter
- Division of Pediatric Gastroenterology Goryeb Children’s Hospital AHS, Morristown, New Jersey, USA
| | - Maria E Perez
- Division of Pediatric Gastroenterology Goryeb Children’s Hospital AHS, Morristown, New Jersey, USA
| | - Jeffrey S Hyams
- Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children’s Medical Center, Hartford, Connecticut, USA
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Choi S, Choi BS, Choe BH, Kang B. Successful treatment with vedolizumab in an adolescent with Crohn disease who had developed active pulmonary tuberculosis while receiving infliximab. Yeungnam Univ J Med 2021; 38:251-257. [PMID: 33601494 PMCID: PMC8225501 DOI: 10.12701/yujm.2020.00878] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 01/20/2021] [Indexed: 01/03/2023] Open
Abstract
Vedolizumab (VDZ) has been approved for the treatment of inflammatory bowel diseases (IBDs) in patients aged ≥18 years. We report a case of a pediatric patient with Crohn disease (CD) who was successfully treated with VDZ. A 16-year-old female developed severe active pulmonary tuberculosis (TB) during treatment with infliximab (IFX). IFX was stopped, and TB treatment was started. After a 6-month regimen of standard TB medication, her pulmonary TB was cured; however, gastrointestinal symptoms developed. Due to the concern of the patient and parents regarding TB reactivation on restarting treatment with IFX, VDZ was started off-label. After the second dose of VDZ, the patient was in clinical remission and her remission was continuously sustained. Ileocolonoscopy at 1-year after VDZ initiation revealed endoscopic healing. Therapeutic drug monitoring conducted during VDZ treatment showed negative antibodies to VDZ. No serious adverse events occurred during the VDZ treatment. This is the first case report in Korea demonstrating the safe and effective use of VDZ treatment in a pediatric CD patient. In cases that require recommencement of treatment with biologics after recovery of active pulmonary TB caused by anti-tumor necrosis factor agents, VDZ may be a good option even in pediatric IBD.
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Affiliation(s)
- Sujin Choi
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea.,Crohn's and Colitis Association in Daegu-Gyeongbuk (CCAiD), Daegu, Korea
| | - Bong Seok Choi
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Byung-Ho Choe
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea.,Crohn's and Colitis Association in Daegu-Gyeongbuk (CCAiD), Daegu, Korea
| | - Ben Kang
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea.,Crohn's and Colitis Association in Daegu-Gyeongbuk (CCAiD), Daegu, Korea
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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: 19] [Impact Index Per Article: 4.8] [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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Colman RJ, Dhaliwal J, Rosen MJ. Predicting Therapeutic Response in Pediatric Ulcerative Colitis-A Journey Towards Precision Medicine. Front Pediatr 2021; 9:634739. [PMID: 33681110 PMCID: PMC7925616 DOI: 10.3389/fped.2021.634739] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 01/08/2021] [Indexed: 12/12/2022] Open
Abstract
Ulcerative colitis (UC) is a disabling disease, characterized by chronic inflammation of the colon, with a rising prevalence worldwide in the pediatric age group. Although UC presents in children with varying severity, disease extent, and comorbidities, initial treatment is essentially uniform, consisting of 5-aminosalicylate drugs with corticosteroid induction for those with moderately to severely active disease. With the advent of anti-tumor necrosis factor (TNF) biologic therapy and several new biologics and small-molecule drugs for UC, precision medicine approaches to treatment are needed to more rapidly achieve sustained remission, restore quality of life, normalize development, and limit exposure to toxic corticosteroids in children with UC. Here, we review available data on clinical, biochemical, histopathologic, and molecular predictors of treatment response in UC. We also address known predictors and special treatment considerations in specific relevant scenarios such as very-early-onset UC, acute severe UC, ileal pouch anal anastomosis, and UC with concomitant primary sclerosing cholangitis. The review concludes with a prediction of how machine learning will integrate multimodal patient data to bring precision medicine to the bedside of children with UC in the future.
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Affiliation(s)
- Ruben J Colman
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Jasbir Dhaliwal
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Michael J Rosen
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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Giannoudaki E, Gargan S, Hussey S, Long A, Walsh PT. Opportunities to Target T Cell Trafficking in Pediatric Inflammatory Bowel Disease. Front Pediatr 2021; 9:640497. [PMID: 33816403 PMCID: PMC8012547 DOI: 10.3389/fped.2021.640497] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 02/08/2021] [Indexed: 12/12/2022] Open
Abstract
T cell subsets are considered central orchestrators of inflammation and homeostasis in the intestine and are established targets for the treatment of inflammatory bowel disease. While approaches aimed at the neutralization of T cell effector cytokines have provided significant benefits for pediatric and adult patients, more recent strategies aimed at inhibiting the infiltration of pathogenic T cell subsets have also emerged. In this review, we describe current knowledge surrounding the function of T cell subsets in pediatric inflammatory bowel disease and outline approaches aimed at targeting T cell trafficking to the intestine which may represent a new treatment option for pediatric inflammatory bowel disease.
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Affiliation(s)
- Eirini Giannoudaki
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Siobhan Gargan
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Seamus Hussey
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Department of Paediatrics, Royal College of Surgeons of Ireland, Dublin, Ireland
| | - Aideen Long
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Patrick T Walsh
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
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van Rheenen PF, Aloi M, Assa A, Bronsky J, Escher JC, Fagerberg UL, Gasparetto M, Gerasimidis K, Griffiths A, Henderson P, Koletzko S, Kolho KL, Levine A, van Limbergen J, Martin de Carpi FJ, Navas-López VM, Oliva S, de Ridder L, Russell RK, Shouval D, Spinelli A, Turner D, Wilson D, Wine E, Ruemmele FM. The Medical Management of Paediatric Crohn's Disease: an ECCO-ESPGHAN Guideline Update. J Crohns Colitis 2020; 15:jjaa161. [PMID: 33026087 DOI: 10.1093/ecco-jcc/jjaa161] [Citation(s) in RCA: 308] [Impact Index Per Article: 61.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVE We aimed to provide an evidence-supported update of the ECCO-ESPGHAN guideline on the medical management of paediatric Crohn's disease [CD]. METHODS We formed 10 working groups and formulated 17 PICO-structured clinical questions [Patients, Intervention, Comparator, and Outcome]. A systematic literature search from January 1, 1991 to March 19, 2019 was conducted by a medical librarian using MEDLINE, EMBASE, and Cochrane Central databases. A shortlist of 30 provisional statements were further refined during a consensus meeting in Barcelona in October 2019 and subjected to a vote. In total 22 statements reached ≥ 80% agreement and were retained. RESULTS We established that it was key to identify patients at high risk of a complicated disease course at the earliest opportunity, to reduce bowel damage. Patients with perianal disease, stricturing or penetrating behaviour, or severe growth retardation should be considered for up-front anti-tumour necrosis factor [TNF] agents in combination with an immunomodulator. Therapeutic drug monitoring to guide treatment changes is recommended over empirically escalating anti-TNF dose or switching therapies. Patients with low-risk luminal CD should be induced with exclusive enteral nutrition [EEN], or with corticosteroids when EEN is not an option, and require immunomodulator-based maintenance therapy. Favourable outcomes rely on close monitoring of treatment response, with timely adjustments in therapy when treatment targets are not met. Serial faecal calprotectin measurements or small bowel imaging [ultrasound or magnetic resonance enterography] are more reliable markers of treatment response than clinical scores alone. CONCLUSIONS We present state-of-the-art guidance on the medical treatment and long-term management of children and adolescents with CD.
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Affiliation(s)
- Patrick F van Rheenen
- Department of Paediatric Gastroenterology, University of Groningen, University Medical Centre Groningen, Beatrix Children's Hospital, Groningen, The Netherlands
| | - Marina Aloi
- Pediatric Gastroenterology and Liver Unit, Maternal and Child Health Department, Sapienza - University of Rome, Rome, Italy
| | - Amit Assa
- Department of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center, Petach Tikvah, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Israel
| | - Jiri Bronsky
- Paediatric Gastroenterology Unit, Department of Paediatrics, University Hospital Motol, Prague, Czech Republic
| | - Johanna C Escher
- Department of Paediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Ulrika L Fagerberg
- Department of Pediatrics/Centre for Clinical Research, Västmanland Hospital, Västeras and Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Marco Gasparetto
- Department of Paediatric Gastroenterology, Barts Health Trust, The Royal London Children's Hospital, London, UK
| | | | - Anne Griffiths
- Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Paul Henderson
- Child Life and Health, University Of Edinburgh, Edinburgh, UK
| | - Sibylle Koletzko
- Department of Pediatrics, Division of Gastroenterology and Hepatology, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
- Department of Pediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland
| | - Kaija-Leena Kolho
- Department of Paediatrics, Children´s Hospital, University of Helsinki and Tampere University, Tampere, Finland
| | - Arie Levine
- Pediatric Gastroenterology and Nutrition Unit, Wolfson Medical Center, Tel Aviv University, Israel
| | - Johan van Limbergen
- Division of Pediatric Gastroenterology and Nutrition, Amsterdam UMC - location AMC, Amsterdam, The Netherlands
| | | | - Víctor Manuel Navas-López
- Pediatric Gastroenterology and Nutrition Unit, IBIMA, Hospital Regional Universitario de Málaga, Málaga, Spain
| | - Salvatore Oliva
- Pediatric Gastroenterology and Liver Unit, Maternal and Child Health Department, Sapienza - University of Rome, Rome, Italy
| | - Lissy de Ridder
- Department of Paediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Richard K Russell
- Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK
| | - Dror Shouval
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Antonino Spinelli
- Department of Colon and Rectal Surgery, Humanitas Clinical and Research Center - IRCCS, Rozzano Milano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Dan Turner
- Paediatric Gastroenterology, Shaare Zedek Medical Centre, the Hebrew University of Jerusalem, Israel
| | - David Wilson
- Child Life and Health, University Of Edinburgh, Edinburgh, UK
| | - Eytan Wine
- Division of Pediatric Gastroenterology, Edmonton Pediatric IBD Clinic (EPIC), Departments of Pediatrics & Physiology, University of Alberta, Edmonton, Canada
| | - Frank M Ruemmele
- Assistance Publique- Hôpitaux de Paris, Hôpital Necker Enfants Malades, Pediatric Gastroenterology, Paris, France
- Faculté de Médecine, Université Sorbonne Paris Cité, Paris Descartes, Paris, France
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Vedolizumab Trough Levels in Children With Anti-Tumor Necrosis Factor Refractory Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2020; 71:501-507. [PMID: 32639455 DOI: 10.1097/mpg.0000000000002833] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Inflammatory bowel disease (IBD) can be successfully treated with vedolizumab. Studies in adult IBD patients have shown that differences in response to vedolizumab may be related to variability in vedolizumab trough levels, but in children with pediatric-onset IBD data regarding vedolizumab trough levels are not available. Thus far, the role of trough levels in pediatric-onset IBD treatment remains unclear. We aimed to investigate predictors of vedolizumab trough levels in pediatric-onset IBD patients. METHODS Data from anti-tumor necrosis factor refractory pediatric-onset IBD patients who received vedolizumab were collected retrospectively. Vedolizumab trough levels were measured in serum samples collected before each infusion. A linear mixed model was conducted to analyze factors that influence trough levels. RESULTS Twenty-six pediatric-onset IBD patients (14 ulcerative colitis [UC]), 9 Crohn Disease [CD], 3 IBD-unclassified [IBD-U]) received 258 vedolizumab infusions. Mean vedolizumab trough level at week 6 was 29.9 μg/mL (SD 17.8), and 11.5 μg/mL (SD 4.9) during maintenance therapy. CD patients had significantly lower trough levels than IBD-U patients (β 15.2; 95% confidence interval [CI] -1.1 to 29.2; P = 0.036). Higher fecal calprotectin (β -0.009; 95% CI -0.02 to -0.003; P = 0.007) and C-reactive protein levels (β -0.4; 95% CI -0.72 to -0.04; P = 0.027) were associated with lower trough levels, whereas shortening of time between infusions led to higher trough levels (β -0.77; 95% CI -0.9 to 0.64; P < 0.001). CONCLUSIONS In this group of pediatric-onset IBD patients, trough levels were significantly lower in CD patients compared with UC/IBD-U patients. Higher levels of inflammatory markers were associated with lower vedolizumab trough levels.
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Abstract
Biological therapies, especially blocking tumor necrosis factor-α (TNFα) agents have radically changed the therapeutic approach and disease course of pediatric inflammatory bowel disease (IBD). In particular, drugs such as infliximab (IFX) and adalimumab (ADA) have been demonstrated to be effective in inducing and maintaining corticosteroid-free remission in both adult and pediatric patients with Crohns Disease (CD) and Ulcerative colitis (UC). Biosimilar biological (BioS) therapy is increasingly being used in pediatric age even though most knowledge on the safety and efficacy of these agents is based on IFX in adult IBD data. Studies show high rates of clinical response and remission in both IFX naïve patients and in patients switched from originator to BioS with similar risks of adverse events (AEs) as those reported with IFX originator. In the present review indications, efficacy and AEs of biological therapy in pediatric IBD will be discussed, as well as the role of other biological agents such as Golimumab, Vedolizumab and Ustekinumab, the role of BioS biological therapy and utility of therapeutic drug monitoring in clinical practice.
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Pai V, Abu-Arja R, Auletta JJ, Rangarajan HG. Successful treatment of steroid-refractory gastrointestinal acute graft-versus-host disease with adjuvant vedolizumab therapy in a pediatric allogeneic stem cell transplant recipient. Pediatr Blood Cancer 2020; 67:e28298. [PMID: 32472970 DOI: 10.1002/pbc.28298] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 02/29/2020] [Accepted: 03/16/2020] [Indexed: 12/14/2022]
Affiliation(s)
- Vinita Pai
- College of Pharmacy, The Ohio State University, Columbus, Ohio.,Pharmacy Department, Nationwide Children's Hospital, Columbus, Ohio
| | - Rolla Abu-Arja
- Division of Hematology, Oncology, Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio.,Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio
| | - Jeffery J Auletta
- Division of Hematology, Oncology, Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio.,Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio
| | - Hemalatha G Rangarajan
- Division of Hematology, Oncology, Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio.,Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio
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Olbjørn C, Rove JB, Jahnsen J. Combination of Biological Agents in Moderate to Severe Pediatric Inflammatory Bowel Disease: A Case Series and Review of the Literature. Paediatr Drugs 2020; 22:409-416. [PMID: 32378002 PMCID: PMC7383034 DOI: 10.1007/s40272-020-00396-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Treatment with biological agents such as anti-tumor necrosis factors (TNFs) has become standard of care in moderate to severe pediatric inflammatory bowel disease (IBD). However, a significant proportion of patients experience loss of response to anti-TNFs, need treatment escalation, or develop side effects. There is no data in the literature regarding combination of biological agents in pediatric IBD. METHODS At our hospital, which is a tertiary referral center, we have combined the anti-TNF infliximab with either vedolizumab or ustekinumab in patients with severe pediatric IBD. The indications for dual biological therapy were insufficient efficacy of infliximab or vedolizumab monotherapy, or side effects such as psoriasis due to anti-TNFs. RESULTS Eight patients (four boys) aged 14-17.5 years received a combination of infliximab and vedolizumab due to only a partial response to infliximab, four with Crohn's disease (CD) and four with ulcerative colitis (UC). Clinical remission was achieved in four patients (3 UC) and four had a colectomy (3 CD, 1 UC). Five CD patients (3 girls) aged 11-17 years, on maintenance therapy with infliximab, developed psoriasis resistant to topical treatment. A combination of infliximab and ustekinumab resulted in clinical remission of CD without skin symptoms. No serious adverse events occurred in any of the patients on combination therapy. Thirteen publications report on combining biologicals, all in adult IBD. CONCLUSION In pediatric IBD, combining biological agents seems to be safe and beneficial in selected patients. The safety should be addressed in long-term follow-up studies.
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Affiliation(s)
- Christine Olbjørn
- Department of Pediatric and Adolescent Medicine, Akershus University Hospital, 1478, Lørenskog, Norway.
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Jon Bergreen Rove
- Department of Pediatric and Adolescent Medicine, Akershus University Hospital, 1478, Lørenskog, Norway
| | - Jørgen Jahnsen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
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Optimizing Antitumor Necrosis Factor Treatment in Pediatric Inflammatory Bowel Disease With Therapeutic Drug Monitoring. J Pediatr Gastroenterol Nutr 2020; 71:12-18. [PMID: 32142005 DOI: 10.1097/mpg.0000000000002704] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Biological agents have revolutionized inflammatory bowel disease treatment but primary nonresponse and secondary loss of response are common with resulting adverse outcomes. Clinical trials demonstrated an association between serum drug concentrations, as well as the presence of antidrug antibodies, and loss-of-response. Therapeutic drug monitoring (TDM), defined as the evaluation of drug concentrations and antidrug antibodies, is appearing as a strategy to optimize treatment and take full advantage from these drugs. TDM appears to be a promising tool in clinical practice, especially in pediatric patients, who have pronounced fluctuations in the pharmacokinetics of the drugs.The authors present a literature review about antitumor necrosis factor therapy optimization based on personalized treatment strategies according to TDM and possible strategies to recapture loss of response, including an algorithm for practical management.
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