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Wang KY, Heikal OS, van Rheenen PF, Touw DJ, Bourgonje AR, Mian P. Clinical and Biochemical Factors Associated with Infliximab Pharmacokinetics in Paediatric Patients with Inflammatory Bowel Disease. J Clin Med 2025; 14:845. [PMID: 39941516 PMCID: PMC11818818 DOI: 10.3390/jcm14030845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 01/23/2025] [Accepted: 01/24/2025] [Indexed: 02/16/2025] Open
Abstract
Monitoring infliximab (IFX) concentrations is crucial for optimizing IFX therapy in children with inflammatory bowel diseases (IBDs) who show low response rates due to inadequate drug exposure. Substantial variation occurs in IFX trough concentrations in paediatric patients. Objectives: This study aimed to investigate IFX pharmacokinetics (PK) in children with IBD during both the induction phase and maintenance phases and to identify covariates associated with IFX PK. Methods: This single-centre retrospective cohort study was conducted at an academic children's hospital. Data was extracted from paediatric IBD patients receiving IFX between January 2018 and October 2023 and included demographic-, clinical- and laboratory parameters collected from electronic health records. Linear mixed model analysis was performed to investigate associations between these parameters and IFX trough concentrations. Target attainment [≥15 μg/mL in induction or 5-10 μg/mL in maintenance phase] of the IFX dosing regimens was evaluated. Results and Conclusions: A total of 115 children (417 unique IFX concentrations) were included. Multivariate analysis revealed significant positive associations between IFX and albumin concentrations (β = 0.388, p = 0.010) and IFX concentrations with dose (β = 6.534, p < 0.001), and an inversion association between IFX concentrations and treatment phase (β = -4.922, p < 0.001). During the induction and maintenance phases, 57.2% and 30.6% of IFX concentrations were subtherapeutic, respectively. A systematic search of studies investigating factors influencing IFX concentrations was concurrently performed. Our findings were critically compared against existing literature to assess relevant clinical and biochemical determinants of IFX PK in children with IBD. Our findings highlight the need for personalized dosing strategies in pediatric IBD patients, particularly during the induction phase. By implementing therapeutic drug monitoring (TDM) and considering clinical and biochemical factors, clinicians can implement more personalized strategies, potentially improving treatment efficacy and reducing the risk of treatment failure or adverse effects. This approach could lead to better target attainment, potentially enhancing clinical outcomes and minimizing premature switching to other therapies.
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Affiliation(s)
- Ka Yu Wang
- Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen, 9713 GZ Groningen, The Netherlands; (K.Y.W.); (O.S.H.); (D.J.T.)
| | - Omnia Salah Heikal
- Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen, 9713 GZ Groningen, The Netherlands; (K.Y.W.); (O.S.H.); (D.J.T.)
| | - Patrick F. van Rheenen
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Beatrix Children’s Hospital, University of Groningen, University Medical Centre Groningen, 9713 GZ Groningen, The Netherlands;
| | - Daan J. Touw
- Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen, 9713 GZ Groningen, The Netherlands; (K.Y.W.); (O.S.H.); (D.J.T.)
- Department of Pharmaceutical Analysis, Groningen Research Institute of Pharmacy, University of Groningen, 9713 GZ Groningen, The Netherlands
| | - Arno R. Bourgonje
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
- The Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Paola Mian
- Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen, 9713 GZ Groningen, The Netherlands; (K.Y.W.); (O.S.H.); (D.J.T.)
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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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Genaro LM, Carron J, de Castro MM, Franceschini APMDF, Lourenço GJ, da Cruz CKNV, Reis GFSR, Pascoal LB, Mello JDC, Pereira IM, Nascimento ML, Oliveira PDSP, Corona LP, Ayrizono MDLS, Lima CSP, Leal RF. Therapeutic drug monitoring and immunogenetic factors associated with the use of adalimumab in Crohn's disease patients. Int J Immunopathol Pharmacol 2025; 39:3946320251319379. [PMID: 39959979 PMCID: PMC11831650 DOI: 10.1177/03946320251319379] [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] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 01/24/2025] [Indexed: 02/20/2025] Open
Abstract
Crohn's disease (CD) involves immune system interactions with intestinal tissue, driven by pro-inflammatory cytokines like Tumor Necrosis Factor (TNF-α). Adalimumab, targeting TNF-α, regulates associated inflammatory responses. Despite being humanized, it may induce immunogenic processes, affecting treatment effectiveness. Thus, monitoring serum adalimumab and anti-drug antibody (ADA) levels can optimize therapy. Understanding genetic factors influencing adalimumab response can enhance personalized treatment and improve patient quality of life. We aimed to quantify adalimumab serum levels, assess test interchangeability, detect ADA, examine immune complex formation, and investigate genetic phenotypes related to immunogenicity in CD patients. Seventy CD patients in the maintenance phase with adalimumab were classified into active (CDA) and remission (CDR) groups. Adalimumab concentration was determined via enzyme-linked immunosorbent assay (ELISA-Promonitor) and lateral flow assay (Quantum Blue), with assay interchangeability assessed statistically. ADA and immune complex formation were quantified using ELISA assays. DNA was genotyped for the genes ATG16L1, CD96, and CD155. No significant differences in adalimumab serum concentrations were observed between groups, regardless of the assay. However, a statistical difference between the tests indicated measurement disparity (P = 0.003), with moderate agreement (Lin's correlation of 0.247). ADA was detected in 4 of 27 of the patients with infratherapeutic levels, 3 in the CDA group and 1 in the CDR group. Analysis of immune complexes revealed significantly higher concentrations in the CDA group (P = 0.0125). The genotypic evaluation revealed significant associations for the CD96 CC (wild-type) genotype with higher CRP levels, colonic involvement, and infratherapeutic levels of adalimumab. ATG16L1 CC genotype was associated with higher CDEIS and fecal calprotectin values, while the variant (TT) genotype had lower platelet counts. The effectiveness of treatment with adalimumab was not directly related to higher medication levels in this cohort. The disparity between tests indicates the need to use only one test in patient follow-up to ensure accuracy in therapeutic monitoring. Genotypic differences highlight the correlation between the wild genotype for CD96 and ATG16L1 with unfavorable laboratory and endoscopic response to adalimumab. Finally, the more significant levels of immune complexes in the CDA group indicate an association with a worse response to adalimumab.
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Affiliation(s)
- Livia Moreira Genaro
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Juliana Carron
- Laboratory of Cancer Genetics (Lageca), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Marina Moreira de Castro
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Ana Paula Menezes de Freitas Franceschini
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Gustavo Jacob Lourenço
- Laboratory of Cancer Genetics (Lageca), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | | | | | - Livia Bitencourt Pascoal
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Juliana Delgado Campos Mello
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Isabela Machado Pereira
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Millene Leal Nascimento
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Priscilla De Sene Portel Oliveira
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Ligiana Pires Corona
- Nutritional Epidemiology Laboratory, School of Applied Sciences, University of Campinas (Unicamp), Limeira, São Paulo, Brazil
| | - Maria de Lourdes Setsuko Ayrizono
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Carmen Silvia Passos Lima
- Laboratory of Cancer Genetics (Lageca), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Raquel Franco Leal
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
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Toskas A, Manti M, Kamperidis N, Arebi N. Infliximab Precision Dosing in Inflammatory Bowel Disease (IBD) Patients: A Review of Current Literature. Cureus 2024; 16:e76424. [PMID: 39867090 PMCID: PMC11763272 DOI: 10.7759/cureus.76424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/24/2024] [Indexed: 01/28/2025] Open
Abstract
The therapeutic failure of infliximab therapy remains a challenge in patients with inflammatory bowel disease (IBD), and dose optimization is often required. Accelerated or intensified regimes showed value in treating patients in the acute setting with high CRP or low albumin levels, which are suggested by recent guidelines; however, evidence is weak. Therapeutic drug monitoring (TDM), with anti-tumor necrosis factor-alpha (TNF-α) trough levels and antibodies, showed value during maintenance therapy, but not in induction and can guide clinical decisions in patients that might be undertreated with the standard dosing regimen. Combining the impact of therapeutic drug monitoring with a Bayesian forecasting methodology to calculate drug clearance can help on calculating the optimal infliximab dose for patients with ulcerative colitis (UC) and Crohn's disease (CD) on both the induction and maintenance phase. This will help to identify those who need intensification of their current regime to boost the therapeutic effect and those who are non-responders. This review aims to summarize the recent literature regarding infliximab precision dosing in IBD patients using forecasting methodology.
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Affiliation(s)
- Alexandros Toskas
- Gastroenterology, St Mark's Hospital and Academic Institute, London, GBR
| | - Magdalini Manti
- Gastroenterology, St Mark's Hospital and Academic Institute, London, GBR
| | | | - Naila Arebi
- Gastroenterology, St Mark's Hospital and Academic Institute, London, GBR
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Fischer S, Donhauser M, Cohnen S, Fietkau K, Vetter M, Grübel-Liehr M, Dietrich P, Rath T, Wilfer A, Sologub L, Krebs S, Dörje F, Nagore D, Meyer S, Neurath MF, Atreya R. Reverse switching from the biosimilar SB2 to the originator infliximab in previously switched patients with inflammatory bowel diseases: results of a prospective long-term cohort study. Therap Adv Gastroenterol 2024; 17:17562848241301887. [PMID: 39619829 PMCID: PMC11608450 DOI: 10.1177/17562848241301887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 10/07/2024] [Indexed: 02/04/2025] Open
Abstract
BACKGROUND Data regarding multiple switches including reverse switching between infliximab and its biosimilars are scarce in the field of inflammatory bowel diseases (IBD). OBJECTIVES We investigated the clinical effectiveness as primary outcome measure after repeated switches. Secondary endpoints included C-reactive protein (CRP) levels, immunogenicity (trough levels (TL); anti-drug antibodies (ADA), safety and drug persistence. DESIGN This study is a prospective, single-centre, observational cohort study. IBD patients receiving originator infliximab were switched to biosimilar SB2 and then reverse switched after 96 weeks and followed up for another 48 weeks. METHODS Clinical disease activity (Harvey-Bradshaw-index (HBI) in Crohn's disease (CD), partial Mayo score (pMS) in ulcerative colitis (UC)), CRP, TL, ADA, therapy-discontinuations and (serious) adverse events ((S)AE)) were monitored throughout the study. RESULTS Ninety-five patients (60 CD, 38 female) were enrolled. The median HBI was 2 (interquartile range (IQR) 1-4) at baseline and 2 (1-4) at week 48, resulting in a mean intra-individual change of 0.0 (standard deviation (SD) 1.5). The median pMS was 1 (IQR 0-1) at baseline and 0.5 (0-1) at week 48 resulting in a mean intra-individual change of 0.0 (SD 0.8). Clinical remission was achieved in 80% at baseline and 82% at week 48. Median CRP 2.0 mg/l (IQR 1.0-4.1) at baseline and 2.4 mg/l (1.1-5.2) at week 48 resulted in a mean change of 1.7 (SD 5.8) and no significant differences in CD (p = 0.3) and UC (p = 0.9). Median TL were 7.2 µg/ml (IQR 3.8-19.3) at baseline and 5.5 µg/ml (3.5-13.1) at week 48, resulting in a mean change of -1.0 (SD 7.4) with no statistical significance (CD p = 0.26, UC p = 0.41). De-novo-ADA were developed by 3.4%. The discontinuation rate was 14.7%. Safety signals were consistent with previous studies. CONCLUSION Reverse switching had no impact on efficacy of infliximab therapy in our cohort of IBD patients. The switch didn't influence immunogenicity or safety of therapy.
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Affiliation(s)
- Sarah Fischer
- First Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany Deutsches Zentrum Immuntherapie, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Moritz Donhauser
- Department of Orthopaedic and Trauma Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Sarah Cohnen
- First Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany Deutsches Zentrum Immuntherapie, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Konstantin Fietkau
- First Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany Deutsches Zentrum Immuntherapie, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Marcel Vetter
- First Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany Deutsches Zentrum Immuntherapie, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Maria Grübel-Liehr
- First Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany Deutsches Zentrum Immuntherapie, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Peter Dietrich
- First Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany Deutsches Zentrum Immuntherapie, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Timo Rath
- First Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany Deutsches Zentrum Immuntherapie, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Angelika Wilfer
- First Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany Deutsches Zentrum Immuntherapie, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Ludmilla Sologub
- First Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany Deutsches Zentrum Immuntherapie, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Sabine Krebs
- Pharmacy Department, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Frank Dörje
- Pharmacy Department, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | | | - Sebastian Meyer
- Department of Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Markus F. Neurath
- First Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Raja Atreya
- First Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, Erlangen 91054, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
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Little RD, McKenzie J, Srinivasan A, Hilley P, Gilmore RB, Chee D, Sandhu M, Saitta D, Chow E, Thin L, Walker GJ, Moore GT, Lynch K, Andrews J, An YK, Bryant RV, Connor SJ, Garg M, Wright EK, Hold G, Segal JP, Boussioutas A, De Cruz P, Ward MG, Sparrow MP. Switching from Dose-Intensified intravenous to SubCutaneoUS infliximab in Inflammatory Bowel Disease (DISCUS-IBD): protocol for a multicentre randomised controlled trial. BMJ Open 2024; 14:e081787. [PMID: 39032928 PMCID: PMC11261670 DOI: 10.1136/bmjopen-2023-081787] [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: 11/06/2023] [Accepted: 05/24/2024] [Indexed: 07/23/2024] Open
Abstract
INTRODUCTION A substantial proportion of patients with inflammatory bowel disease (IBD) on intravenous infliximab require dose intensification. Accessing additional intravenous infliximab is labour-intensive and expensive, depending on insurance and pharmaceutical reimbursement. Observational data suggest that subcutaneous infliximab may offer a convenient and safe alternative to maintain disease remission in patients requiring dose-intensified infliximab. A prospective, controlled trial is required to confirm that subcutaneous infliximab is as effective as dose-intensified intravenous infliximab, to identify predictors of disease flare and to establish the role of subcutaneous infliximab therapeutic drug monitoring. METHODS AND ANALYSIS The DISCUS-IBD trial is an investigator-initiated, prospective, multicentre, randomised, open-label non-inferiority study comparing the rate of disease flares in participants randomised to continue dose-intensified intravenous infliximab to those switched to subcutaneous infliximab after 48 weeks. Participants are adult patients with IBD in sustained corticosteroid-free remission on any regimen of dose-intensified infliximab up to a maximum of 10 mg/kg 4-weekly intravenously. Participants allocated to intravenous infliximab will continue infliximab at the same dose-intensified regimen they were receiving at study enrolment. Subcutaneous infliximab dosing will be stratified by prior intravenous infliximab dosing. Clinical (Harvey-Bradshaw Index, partial Mayo score), biochemical (C reactive protein, faecal calprotectin), pharmacokinetic (drug-level±antidrug antibodies) and qualitative data are collected 12-weekly until study conclusion at week 48. 13 sites across Australia will participate in recruitment to reach a calculated sample size of 120 participants. ETHICS AND DISSEMINATION Multisite ethics approval was obtained from the Health District Human Research Ethics Committee (HREC) at The Alfred Hospital under a National Mutual Acceptance (NMA) agreement (HREC/90559/Alfred-2022; Local Reference: Project 618/22, version 1.6, 2 March 2023). Findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals. DISCUS-IBD was prospectively registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR) prior to commencing recruitment. TRIAL REGISTRATION NUMBER ACTRN12622001458729.
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Affiliation(s)
- Robert D Little
- Department of Gastroenterology, Alfred Hospital, Melbourne, Victoria, Australia
- Monash University, Faculty of Medicine Nursing and Health Sciences, Clayton, Victoria, Australia
| | - Jo McKenzie
- Department of Gastroenterology, Alfred Hospital, Melbourne, Victoria, Australia
| | - Ashish Srinivasan
- Department of Gastroenterology, Austin Health, Melbourne, Victoria, Australia
- Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne Melbourne Medical School, Melbourne, Victoria, Australia
| | - Patrick Hilley
- Department of Gastroenterology, Austin Health, Melbourne, Victoria, Australia
| | - Robert B Gilmore
- Department of Gastroenterology, Mater Hospital Brisbane, Brisbane, Queensland, Australia
- Mater Research Institute-UQ, South Brisbane, Queensland, Australia
| | - Desmond Chee
- Gastroenterology Department, Monash Health, Melbourne, Victoria, Australia
| | - Manjeet Sandhu
- Gastroenterology Department, Monash Health, Melbourne, Victoria, Australia
| | - Daniel Saitta
- Department of Gastroenterology, Western Health, Melbourne, Victoria, Australia
| | - Elizabeth Chow
- Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne Melbourne Medical School, Melbourne, Victoria, Australia
- Department of Gastroenterology, Western Health, Melbourne, Victoria, Australia
| | - Lena Thin
- Department of Gastroenterology, Fiona Stanley Hospital, Perth, Western Australia, Australia
- Department of Internal Medicine, The University of Western Australia Faculty of Medicine Dentistry and Health Sciences, Perth, Western Australia, Australia
| | - Gareth J Walker
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Gregory T Moore
- Monash University, Faculty of Medicine Nursing and Health Sciences, Clayton, Victoria, Australia
- Gastroenterology Department, Monash Health, Melbourne, Victoria, Australia
| | - Kate Lynch
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
- School of Medicine, The University of Adelaide Faculty of Health and Medical Sciences, Adelaide, South Australia, Australia
| | - Jane Andrews
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
- School of Medicine, The University of Adelaide Faculty of Health and Medical Sciences, Adelaide, South Australia, Australia
| | - Yoon K An
- Department of Gastroenterology, Mater Hospital Brisbane, Brisbane, Queensland, Australia
- Mater Research Institute-UQ, South Brisbane, Queensland, Australia
| | - Robert V Bryant
- School of Medicine, The University of Adelaide Faculty of Health and Medical Sciences, Adelaide, South Australia, Australia
- Department of Gastroenterology and Hepatology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
| | - Susan J Connor
- Department of Gastroenterology, Liverpool Hospital, Sydney, New South Wales, Australia
- South West Sydney Clinical Campuses, University of New South Wales Medicine & Health, Sydney, New South Wales, Australia
| | - Mayur Garg
- Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne Melbourne Medical School, Melbourne, Victoria, Australia
- Department of Gastroenterology, Northern Health, Melbourne, Victoria, Australia
| | - Emily K Wright
- Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne Melbourne Medical School, Melbourne, Victoria, Australia
- Department of Gastroenterology, St Vincent's Hospital, Melbourne, Victoria, Australia
| | - Georgina Hold
- Microbiome Research Centre, University of New South Wales, Sydney, New South Wales, Australia
| | - Jonathan P Segal
- Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne Melbourne Medical School, Melbourne, Victoria, Australia
- Department of Gastroenterology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - Alex Boussioutas
- Department of Gastroenterology, Alfred Hospital, Melbourne, Victoria, Australia
- Monash University, Faculty of Medicine Nursing and Health Sciences, Clayton, Victoria, Australia
| | - Peter De Cruz
- Department of Gastroenterology, Austin Health, Melbourne, Victoria, Australia
- Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne Melbourne Medical School, Melbourne, Victoria, Australia
| | - Mark G Ward
- Department of Gastroenterology, Alfred Hospital, Melbourne, Victoria, Australia
- Monash University, Faculty of Medicine Nursing and Health Sciences, Clayton, Victoria, Australia
| | - Miles P Sparrow
- Department of Gastroenterology, Alfred Hospital, Melbourne, Victoria, Australia
- Monash University, Faculty of Medicine Nursing and Health Sciences, Clayton, Victoria, Australia
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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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8
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Kim K, Park JJ, Yoon H, Lee J, Kim KO, Kim ES, Kim SY, Boo SJ, Jung Y, Yoo JH, Hwang SW, Park SH, Yang SK, Ye BD. Application of clinical decision support tools for predicting outcomes with vedolizumab therapy in patients with inflammatory bowel disease: A KASID multicentre study. Aliment Pharmacol Ther 2024; 59:1539-1550. [PMID: 38616380 DOI: 10.1111/apt.17989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 09/25/2023] [Accepted: 03/25/2024] [Indexed: 04/16/2024]
Abstract
BACKGROUND/AIM We aimed to validate clinical decision support tools (CDSTs) to predict real-life effectiveness of vedolizumab (VDZ) in patients with inflammatory bowel disease. METHODS We retrospectively enrolled patients with Crohn's disease (CD) or ulcerative colitis (UC) treated with VDZ at 10 tertiary referral centres in Korea between January 2017 and November 2021. We assessed clinical remission (CREM) and response (CRES), corticosteroid-free clinical remission (CSF-CREM) and response (CSF-CRES), biochemical response based on C-reactive protein (BioRES[CRP]) and faecal calprotectin (BioRES[FC]), endoscopic healing (EH), and the need to optimise or switch drugs based on CDST-defined response groups. Additionally, the area under the receiver operating characteristics curve (AUC) for the CDSTs was calculated. RESULTS We included 143 patients with CD and 219 with UC. We observed incremental trends on CSF-CRES at week 14 (W14) (ptrend = 0.004) and decreasing trends for the need to optimise or switch drugs (ptrend = 0.016) in CD from the low to high probability groups. Except for CSF-CREM at W54, we noticed incremental trends for all clinical responses at W14, W26 and W54 (ptrend <0.001) in UC. W26 and W54 BioRES[CRP] and W14 EH also showed increasing trends (ptrend <0.05) in UC. With increasing probabilities of response, drug optimisation or switching was less frequently required in UC (ptrend = 0.013). With 26 points cut-off, CDSTs effectively identified W14 CSF-CRES, W26 BioRES[CRP], BioRES[FC] and W54 BioRES[CRP] in UC, all with AUCs >0.600, whereas CDSTs showed poor accuracy in CD. CONCLUSIONS CDSTs for VDZ had acceptable accuracy in predicting effectiveness outcomes including clinical and biochemical outcomes in UC. However, their utility in CD was limited.
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Affiliation(s)
- Kyuwon Kim
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Jae Jun Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Jun Lee
- Department of Internal Medicine, Chosun University College of Medicine, Gwangju, Republic of Korea
| | - Kyeong Ok Kim
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Eun Sun Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Su Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Sun-Jin Boo
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Republic of Korea
| | - Yunho Jung
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea
| | - Jun Hwan Yoo
- Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, South Korea
| | - Sung Wook Hwang
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
- Inflammatory Bowel Disease Center, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Sang Hyoung Park
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
- Inflammatory Bowel Disease Center, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Suk-Kyun Yang
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
- Inflammatory Bowel Disease Center, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Byong Duk Ye
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
- Inflammatory Bowel Disease Center, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
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9
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Lecoutour A, Dupont C, Caldari D, Dumant C, Vanrenterghem A, Ruiz M, Duclaux-Loras R, Berthet S, Dimitrov G, Lacroix D, Duvant P, Roman C, Wagner AC, Bourmaud A, Viala J, Ruemmele FM, Pigneur B. Efficacy of infliximab after loss of response of/intolerance to adalimumab in pediatric Crohn's disease: A retrospective multicenter cohort study of the "GETAID pédiatrique". J Pediatr Gastroenterol Nutr 2024; 78:1116-1125. [PMID: 38314896 DOI: 10.1002/jpn3.12044] [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: 05/22/2023] [Revised: 09/17/2023] [Accepted: 10/19/2023] [Indexed: 02/07/2024]
Abstract
BACKGROUND Infliximab (IFX) and adalimumab (ADA) are recommended for induction and maintenance of remission in pediatric Crohn's disease (CD). ADA is now often used in first line due to its efficacy and tolerability, but a loss of response (LOR) can occur over time. The aim was to assess the efficacy of IFX as second line therapy after LOR or intolerance to ADA in pediatric CD patients at 1 year. METHODS We conducted a retrospective and multicenter study in France among the "GETAID pédiatrique" centers between April 2019 and April 2022. CD patients under 18 years old and treated with IFX after ADA failure or intolerance were included. We collected anthropometric, clinical, and biological data at baseline (start of IFX), at 6 and 12 months. Clinical remission was defined by a Weighted Pediatric CD Activity Index (wPCDAI) score less than 12.5 points. RESULTS Of the 32 patients included in our study, 27 (84.4%) were still on IFX at 12 months of the switch. Among them, 13 had discontinued ADA because of a LOR, 12 for insufficient response and 2 due to primary nonresponse. At M12, 22 patients were in corticosteroid free clinical remission (68.7%). Under IFX, the wPCDAI decreased over time (47.5 ± 24.1, 16.6 ± 21.2 and 9.7 ± 19.0 at M0, M6 and M12 respectively). The only factor associated with clinical remission at 12 months was absence of perianal disease at the end of the IFX induction. CONCLUSIONS IFX is effective in maintaining remission at 1 year in pediatric CD patients experiencing a LOR or intolerance with ADA, and IFX could be an interesting therapeutic choice instead of other biologics in this situation.
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Affiliation(s)
- Anne Lecoutour
- Service de Gastro-entérologie et Nutrition pédiatrique, Centre de Référence des Maladies rares digestives (MARDI), Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants malades, Université Paris Cité, Paris, France
| | - Claire Dupont
- Service de pédiatrie médicale, CHU de Caen, Caen, France
| | - Dominique Caldari
- Clinique Médicale Pédiatrique, CHU de Nantes-Hôpital Mère-Enfant, Nantes, France
| | - Clémentine Dumant
- Département de Pédiatrie Médicale, Hôpital Charles Nicolle, Rouen, France
| | - Audrey Vanrenterghem
- Centre d'activité Pédiatrie médicale et Médecine de l'Adolescent, CHU Amiens Picardie, Amiens, France
| | - Mathias Ruiz
- Hépatologie Gastroentérologie Nutrition, Hôpital Femme Mère Enfant, Bron, France
| | - Rémi Duclaux-Loras
- Hépatologie Gastroentérologie Nutrition, Hôpital Femme Mère Enfant, Bron, France
| | - Stéphanie Berthet
- Service de pédiatrie, Hôpitaux pédiatriques CHU Lenval, Nice, France
| | - Georges Dimitrov
- Service de chirurgie pédiatrique et pédiatrie, CHR d'Orléans, Orléans, France
| | | | - Pauline Duvant
- Service de Pédiatrie Multidisciplinaire, Hôpital La Timone-Enfants, APHM, Marseille, France
| | - Céline Roman
- Service de Pédiatrie Multidisciplinaire, Hôpital La Timone-Enfants, APHM, Marseille, France
| | | | - Aurélie Bourmaud
- Unité d'Épidémiologie Clinique, INSERM CIC 1426, Hôpital Robert Debré, APHP, Université Paris Cité, INSERM UMR, Paris, France
| | - Jérôme Viala
- Service de Maladies digestives et respiratoires de l'enfant, CHU Robert Debré, Centre de Référence des Maladies rares digestives (MARDI), Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France
| | - Frank M Ruemmele
- Service de Gastro-entérologie et Nutrition pédiatrique, Centre de Référence des Maladies rares digestives (MARDI), Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants malades, Université Paris Cité, Paris, France
- INSERM UMR 1163, Immunité intestinale, Institut Imagine, Paris, France
| | - Bénédicte Pigneur
- Service de Gastro-entérologie et Nutrition pédiatrique, Centre de Référence des Maladies rares digestives (MARDI), Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants malades, Université Paris Cité, Paris, France
- INSERM UMR S 1139, Faculté de Pharmacie de Paris, Université Paris Cité, Paris, France
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10
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Chiorean M, Jiang J, Candela N, Chen G, Romdhani H, Latremouille-Viau D, Shi S, Bungay R, Guerin A, Fan T. Real-world clinical outcomes and healthcare costs in patients with Crohn's disease treated with vedolizumab versus ustekinumab in the United States. Curr Med Res Opin 2024; 40:877-885. [PMID: 38586979 DOI: 10.1080/03007995.2024.2326585] [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: 07/13/2023] [Accepted: 02/29/2024] [Indexed: 04/09/2024]
Abstract
OBJECTIVE To compare real-world treatment persistence, dose escalation, rates of opportunistic or serious infections, and healthcare costs in patients with Crohn's disease (CD) receiving vedolizumab (VDZ) vs ustekinumab (UST) in the United States. METHODS A retrospective observational study in adults with CD initiated on VDZ or UST on/after 26 September 2016, was performed using the IBM Truven Health MarketScan databases (1 January 2009-30 September 2018). Rates of treatment persistence, dose escalation, opportunistic or serious infection-related encounters, and healthcare costs per patient per month (PPPM) were evaluated. Entropy balancing was used to balance patient characteristics between cohorts. Event rates were assessed using weighted Kaplan-Meier analyses and compared between cohorts using log-rank tests. Healthcare costs were compared between cohorts using weighted 2-part models. RESULTS 589 VDZ and 599 UST patients were included (172 [29.2%] and 117 [19.5%] were bio-naïve, respectively). After weighting, baseline characteristics were comparable between cohorts. No significant difference in rates of treatment persistence (12-month: VDZ, 76.5%; UST, 82.1%; p = .17), dose escalation (12-month: VDZ, 29.3%; UST, 32.7%; p = .97), or opportunistic or serious infection-related encounters were observed between VDZ and UST. Total mean healthcare costs were significantly lower for patients treated with VDZ vs UST (mean cost difference = -$5051 PPPM; p < .01). Findings were consistent in bio-naïve patients. CONCLUSIONS In this real-world study, similar treatment persistence, dose escalation, and rates of opportunistic or serious infections were observed with VDZ- and UST-treated patients with CD. However, VDZ was associated with a significantly lower cost outlay for healthcare systems.
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Affiliation(s)
- Michael Chiorean
- IBD Center, Gastroenterology, Swedish Medical Center, Seattle, WA, USA
| | - Jeanne Jiang
- HEOR/Value & Evidence Generation, Medical Affairs, Quantitative Clinical Pharmacology, IGI & Neuro and Vaccine, Takeda Development Center Americas, Inc, Lexington, MA, USA
| | - Ninfa Candela
- HEOR/Value & Evidence Generation, Medical Affairs, Quantitative Clinical Pharmacology, IGI & Neuro and Vaccine, Takeda Development Center Americas, Inc, Lexington, MA, USA
| | - Grace Chen
- HEOR/Value & Evidence Generation, Medical Affairs, Quantitative Clinical Pharmacology, IGI & Neuro and Vaccine, Takeda Development Center Americas, Inc, Lexington, MA, USA
| | - Hela Romdhani
- HEOR, Epidemiology & Market Access, Analysis Group, Inc, Montreal, Canada
| | | | - Sherry Shi
- HEOR, Epidemiology & Market Access, Analysis Group, Inc, Montreal, Canada
| | - Rebecca Bungay
- HEOR, Epidemiology & Market Access, Analysis Group, Inc, Montreal, Canada
| | - Annie Guerin
- HEOR, Epidemiology & Market Access, Analysis Group, Inc, Montreal, Canada
| | - Tao Fan
- HEOR/Value & Evidence Generation, Medical Affairs, Quantitative Clinical Pharmacology, IGI & Neuro and Vaccine, Takeda Development Center Americas, Inc, Lexington, MA, USA
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11
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Li P, Wang L, Tang Z, Wang Y, Liu Z, Ge W, Huang Y. Ustekinumab in pediatric patients with Crohn's disease: safety, and efficacy results from a multicenter retrospective study in China. Front Pediatr 2024; 12:1371322. [PMID: 38665375 PMCID: PMC11043477 DOI: 10.3389/fped.2024.1371322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 04/01/2024] [Indexed: 04/28/2024] Open
Abstract
Background Ustekinumab (UST) is approved as an effective therapy for Crohn's disease (CD) in adults. Off-label use is increasing in the pediatric population, more data on safety and efficacy in pediatric patients with CD is urgently needed. Aims This study aimed to evaluate the clinical efficacy and safety of UST in children and adolescents with Crohn's disease. Methods This multicenter retrospective study carried out at three tertiary care centers, and identified children who received their first dose of UST at 18 years old or younger and followed up for a minimum of 24 weeks. Data on demographics, disease behavior, location and activity, treatment history were collected. The primary outcomes were clinical remission at weeks 24-32 and weeks 48-56 of UST therapy. Secondary outcomes were clinical response at the same time points, endoscopic remission, changes in C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), albumin and fecal calprotectin, improvement in growth parameters, and rate of adverse events. Results Sixteen patients were included, and 11/13 (84.6%) continued to receive UST after 1 year. Our data demonstrate that the clinical remission rates were 41.7% at weeks 24∼32 with the Weighted pediatric CD activity index (wPCDAI) was lower than baseline (43.8, IQR: 31.3-51.9 vs.15, IQR: 5.6-25, p < 0.001) and 75% at weeks 48-56 with wPCDAI was lower than baseline (42.5, IQR: 23.8-50 vs. 7.5, IQR: 0-13.8, p = 0.004). Five of eleven children achieved endoscopic remission. No serious adverse events were recorded during the study period. Conclusions UST is efficacious and safe in pediatric patients with CD. Pediatric patients could benefit from UST as either a primary or secondary biologic therapy for the induction, or maintenance of remission of CD.
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Affiliation(s)
- Ping Li
- Department of Gastroenterology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Lin Wang
- Department of Gastroenterology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Zifei Tang
- Department of Gastroenterology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Yuhuan Wang
- Department of Gastroenterology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Zhanju Liu
- Department of Gastroenterology, The Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
| | - Wensong Ge
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Huang
- Department of Gastroenterology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
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12
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Tursi A, Mocci G, Del Gaudio A, Papa A. Clinical use of biologics for Crohn's disease in adults: lessons learned from real-world studies. Expert Opin Biol Ther 2024:1-19. [PMID: 38321868 DOI: 10.1080/14712598.2024.2316180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 02/05/2024] [Indexed: 02/08/2024]
Abstract
INTRODUCTION The therapeutic armamentarium for managing Crohn's disease (CD) has expanded significantly in recent decades. Several biologics with three different mechanisms of action [anti-tumor necrosis factor (TNF)-α, anti-integrin α4β7, and anti-IL 12/23] are currently available to manage CD. AREA COVERED This narrative review aims to summarize the most significant efficacy and safety data on the use of infliximab (IFX), adalimumab (ADA), vedolizumab (VDZ) and ustekinumab (UST) for the treatment of CD obtained from studies conducted in the real world (RW), compared to the results of randomized clinical trials (RCTs). EXPERT OPINION RW studies reported that biologic agents included in this analysis have higher remission rates and lower adverse event rates than findings from RCTs for treating patients with CD. All biological agents have proven effective and safe in RW studies, even when using biosimilars or switching to subcutaneous administration of the molecules for which they are available. Finally, anti-TNF-α agents, particularly IFX, have a higher rate of adverse events (AEs) than VDZ and UST. Therefore, patients at higher risk of AEs may benefit from other biologics than anti-TNF-α. However, further long-term RW studies are needed to confirm these findings.
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Affiliation(s)
- Antonio Tursi
- Territorial Gastroenterology Service, ASL BAT, Andria, Italy
- Department of Medical and Surgical Sciences, Catholic University, School of Medicine, Rome, Italy
| | - Giammarco Mocci
- Division of Gastroenterology, "Brotzu" Hospital, Cagliari, Italy
| | - Angelo Del Gaudio
- Division of Internal Medicine and Gastroenterology, Policlinico Universitario "A. Gemelli" IRCCS Foundation, Rome, Italy
| | - Alfredo Papa
- Department of Medical and Surgical Sciences, Catholic University, School of Medicine, Rome, Italy
- Division of Internal Medicine and Gastroenterology, Policlinico Universitario "A. Gemelli" IRCCS Foundation, Rome, Italy
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Song F, Ma M, Zeng S, Shao F, Huang W, Feng Z, Rong P. CT enterography-based radiomics combined with body composition to predict infliximab treatment failure in Crohn's disease. LA RADIOLOGIA MEDICA 2024; 129:175-187. [PMID: 37982937 DOI: 10.1007/s11547-023-01748-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 10/27/2023] [Indexed: 11/21/2023]
Abstract
PURPOSE Accurately predicting the treatment response in patients with Crohn's disease (CD) receiving infliximab therapy is crucial for clinical decision-making. We aimed to construct a prediction model incorporating radiomics and body composition features derived from computed tomography (CT) enterography for identifying individuals at high risk for infliximab treatment failure. METHODS This retrospective study included 137 patients with CD between 2015 and 2021, who were divided into a training cohort and a validation cohort with a ratio of 7:3. Patients underwent CT enterography examinations within 1 month before infliximab initiation. Radiomic features of the intestinal segments involved were extracted, and body composition features were measured at the level of the L3 lumbar vertebra. A model that combined radiomics with body composition was constructed. The primary outcome was the occurrence of infliximab treatment failure within 1 year. The model performance was evaluated using discrimination, calibration, and decision curves. RESULTS Fifty-two patients (38.0%) showed infliximab treatment failure. Eight significant radiomic features were used to develop the radiomics model. The model incorporating radiomics model score, skeletal muscle index (SMI), and creeping fat showed good discrimination for predicting infliximab treatment failure, with an area under the curve (AUC) of 0.88 (95% CI 0.81, 0.95) in the training cohort and 0.83 (95% CI 0.66, 1.00) in the validation cohort. The favorable clinical application was observed using decision curve analysis. CONCLUSIONS We constructed a comprehensive model incorporating radiomics and muscle volume, which could potentially be used to facilitate the individualized prediction of infliximab treatment response in patients with CD.
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Affiliation(s)
- Fulong Song
- Department of Radiology, Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Mengtian Ma
- Department of Radiology, Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Shumin Zeng
- Department of Radiology, Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Fang Shao
- Department of Radiology, Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Weiyan Huang
- Department of Radiology, Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Zhichao Feng
- Department of Radiology, Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha, 410013, Hunan, China.
| | - Pengfei Rong
- Department of Radiology, Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha, 410013, Hunan, China.
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Zitomersky N, Chi L, Liu E, Bray KR, Papamichael K, Cheifetz AS, Snapper SB, Bousvaros A, Silvester JA. Anti-infliximab antibodies and low infliximab levels correlate with drug discontinuation in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2024; 78:261-271. [PMID: 38374555 PMCID: PMC10883602 DOI: 10.1002/jpn3.12074] [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: 10/07/2023] [Revised: 10/11/2023] [Accepted: 10/13/2023] [Indexed: 02/21/2024]
Abstract
BACKGROUND Infliximab (IFX) use is limited by loss of response often due to the development of anti-IFX antibodies and low drug levels. METHODS We performed a single center prospective observational cohort study of pediatric and young adult subjects with inflammatory bowel disease (IBD) on IFX with over 3 years of follow-up. Infliximab levels (IFXL) and antibodies to infliximab (ATI) were measured throughout the study. Subjects were followed until IFX was discontinued. RESULTS We enrolled 219 subjects with IBD (184: Crohn's disease; 33: Ulcerative colitis; and 2 Indeterminant colitis; 84 female, median age 14.4 years, 37% on concomitant immunomodulator). Nine hundred and nineteen serum samples (mean 4.2 ± 2.1 per patient) were tested for IFXL and ATI. During the study, 31 (14%) subjects discontinued IFX. Sixty patients had ATI. Twenty-two of those 60 patients with ATI discontinued IFX; 14 of 31 patients who discontinued IFX had detectable ATI at study onset. The combination of ATI and IFXL < 5 µg/mL at study entry was associated with the highest risk of drug discontinuation (hazard ratios [HR] ATI 4.27 [p < 0.001] and IFXL < 5 µg/mL [HR]: 3.2 p = 0.001). Patients with IFXL 5-10 µg/mL had the lowest rate of discontinuation (6%). IFX dose escalation eliminated ATI in 21 of 60 subjects. CONCLUSIONS ATI is a strong predictor of needing to stop IFX use and inversely correlates with IFXL. Detection of ATI during therapeutic drug monitoring postinduction but also periodically during maintenance therapy identifies individuals who may benefit from IFX dose escalation and/or the addition of an immunomodulator, as these interventions may reduce or eliminate ATI.
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Affiliation(s)
- Naamah Zitomersky
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Boston Children’s Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Lisa Chi
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Boston Children’s Hospital, Boston, MA
| | - Enju Liu
- Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital, Boston, MA
| | - Kurtis R. Bray
- Prometheus Laboratories Inc. San Diego, CA
- ProciseDx LLC, San Diego, CA
| | | | - Adam S. Cheifetz
- Harvard Medical School, Boston, MA
- Beth Israel Deaconess Medical Center, Boston, MA
| | - Scott B. Snapper
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Boston Children’s Hospital, Boston, MA
- Harvard Medical School, Boston, MA
- Division of Gastroenterology, Brigham and Women’s Hospital, Boston, MA
| | - Athos Bousvaros
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Boston Children’s Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Jocelyn A. Silvester
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Boston Children’s Hospital, Boston, MA
- Harvard Medical School, Boston, MA
- Beth Israel Deaconess Medical Center, Boston, MA
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Alrashed F, Abdullah I, Alfadhli A, Shehab M. Effectiveness of vedolizumab and ustekinumab as second biologic agent in achieving target outcomes in tumor necrosis factor antagonists experienced patients with inflammatory bowel disease (enroll-ex study). Front Pharmacol 2023; 14:1243080. [PMID: 37876726 PMCID: PMC10590879 DOI: 10.3389/fphar.2023.1243080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 09/25/2023] [Indexed: 10/26/2023] Open
Abstract
Background: About a third of patients with inflammatory bowel disease (IBD) do not respond to anti-tumor necrosis factor (anti-TNF) therapy. In our study, we evaluated the effectiveness of vedolizumab and ustekinumab in achieving clinical and endoscopic outcomes in anti-TNF-experienced patients with IBD. Methods: We conducted a retrospective cohort study. Electronic medical records of patients with moderate to severe IBD, who were previously received anti-TNF therapies, were reviewed and evaluated retrospectively in a gastroenterology center. Outcomes of patients treated with ustekinumab or vedolizumab after failing one anti-TNF agent were evaluated. The primary outcomes were the percentage of hospitalization, surgery, mucosal healing and steroid-free remission. Mucosal healing was defined as a Mayo endoscopic score of 0 or 1 in ulcerative colitis (UC) and an SES-CD score of less than 3 in Crohn's disease (CD). Outcomes were quantified using descriptive analysis. Results: A total of 207 (130 CD: 77 UC) patients with IBD who had previously received one anti-TNF agent were included in the study. Of the total cohort, 62 (30.0%) patients were receiving vedolizumab, and 145 (70.0%) patients were on ustekinumab. 101 (77.6%) patients with CD who failed one anti-TNF therapy were on ustekinumab. Of these patients, 26 (19.7%) patients were hospitalized, and 12 (11.9%) patients had IBD-related surgery. 16 (16.1%) patients had at least one corticosteroid course. 60 (59.0%) patients with CD on ustekinumab achieved mucosal healing. 29 (22.3%) patients with CD who failed one anti-TNF therapy were receiving vedolizumab. Of those, 7 (25%) patients were hospitalized, and 11 (37.9%) patients had IBD-related surgery. 15 (51.0%) patients achieved mucosal healing. 44 (57.1%) patients with UC who failed one anti-TNF therapy were on ustekinumab. Of these 6 (14.1%) patients were hospitalized, 3 (7.0%) patients had IBD-related surgery and 13 (30%) patients had at least 1 corticosteroid course. 25 (57.0%) patients achieved mucosal healing. 33 (42.8%) patients with UC who failed one anti-TNF therapy were receiving vedolizumab. Of those, 6 (18.6%) patients were hospitalized, and 16 (49.6%) patients had at least 1 corticosteroid course. 17 (53.2%) patients achieved mucosal healing. Conclusion: Ustekinumab and vedolizumab were both effective in achieving clinical outcomes in patients with IBD after failing an anti-TNF agent. However, patients receiving ustekinumab had numerically higher percentages of reaching target outcomes than patients receiving vedolizumab. A prospective head-to-head trial is warranted to confirm these findings.
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Affiliation(s)
- Fatema Alrashed
- Department of Pharmacy Practice, College of Pharmacy, Kuwait University, Kuwait City, Kuwait
| | - Israa Abdullah
- Department of Internal Medicine, Mubarak Al-Kabeer University Hospital, Jabriya, Kuwait
| | - Ahmad Alfadhli
- Department of Internal Medicine, Mubarak Al-Kabeer University Hospital, Jabriya, Kuwait
| | - Mohammad Shehab
- Department of Pharmacy Practice, College of Pharmacy, Kuwait University, Kuwait City, Kuwait
- Department of Internal Medicine, Mubarak Al-Kabeer University Hospital, Jabriya, Kuwait
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait
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Kumar P, Vuyyuru SK, Das P, Kante B, Ranjan MK, Thomas DM, Mundhra S, Sahu P, Venigalla PM, Jain S, Goyal S, Golla R, Virmani S, Singh MK, Sachdeva K, Sharma R, Dash NR, Makharia G, Kedia S, Ahuja V. Serum albumin is the strongest predictor of anti-tumor necrosis factor nonresponse in inflammatory bowel disease in resource-constrained regions lacking therapeutic drug monitoring. Intest Res 2023; 21:460-470. [PMID: 36926698 PMCID: PMC10626021 DOI: 10.5217/ir.2022.00128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/03/2023] [Accepted: 01/09/2023] [Indexed: 03/18/2023] Open
Abstract
BACKGROUND/AIMS Evidence on predictors of primary nonresponse (PNR), and secondary loss of response (SLR) to anti-tumor necrosis factor (anti-TNF) agents in inflammatory bowel disease is scarce from Asia. We evaluated clinical/biochemical/molecular markers of PNR/SLR in ulcerative colitis (UC) and Crohn's disease (CD). METHODS Inflammatory bowel disease patients treated with anti-TNF agents (January 2005-October 2020) were ambispectively included. Data concerning clinical and biochemical predictors was retrieved from a prospectively maintained database. Immunohistochemistry for expression of oncostatin M (OSM), OSM receptor (OSM-R), and interleukin-7 receptor (IL-7R) were done on pre anti-TNF initiation mucosal biopsies. RESULTS One-hundred eighty-six patients (118 CD, 68 UC: mean age, 34.1±13.7 years; median disease duration at anti-TNF initiation, 60 months; interquartile range, 28-100.5 months) were included. PNR was seen in 17% and 26.5% and SLR in 47% and 28% CD and UC patients, respectively. In CD, predictors of PNR were low albumin (P<0.001), postoperative recurrence (P=0.001) and high IL-7R expression (P<0.027) on univariate; and low albumin alone (hazard ratio [HR], 0.09; 95% confidence interval [CI], 0.03-0.28; P<0.001) on multivariate analysis respectively. Low albumin (HR, 0.31; 95% CI, 0.15-0.62; P=0.001) also predicted SLR. In UC, predictors of PNR were low albumin (P<0.001), and high C-reactive protein (P<0.001), OSM (P<0.04) and OSM-R (P=0.07) stromal expression on univariate; and low albumin alone (HR, 0.11; 95% CI, 0.03-0.39; P=0.001) on multivariate analysis respectively. CONCLUSIONS Low serum albumin at baseline significantly predicted PNR in UC and PNR/SLR in CD patients. Mucosal markers of PNR were high stromal OSM/OSM-R in UC and high IL-7R in CD patients.
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Affiliation(s)
- Peeyush Kumar
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Sudheer K. Vuyyuru
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Bhaskar Kante
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Mukesh Kumar Ranjan
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - David Mathew Thomas
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Sandeep Mundhra
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Pabitra Sahu
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Pratap Mouli Venigalla
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Saransh Jain
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Sandeep Goyal
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Rithvik Golla
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Shubi Virmani
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Mukesh K. Singh
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Karan Sachdeva
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Raju Sharma
- Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Nihar Ranjan Dash
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Govind Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Saurabh Kedia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
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Bokemeyer B, Hlavaty T, Allez M, Selema P, Moosavi S, Cadatal MJ, Fowler H, Mueller M, Liau KF, Gisbert JP. Real-world observational cohort study of treatment patterns and safety outcomes of infliximab biosimilar CT-P13 for the treatment of inflammatory bowel disease (CONNECT-IBD). Expert Opin Biol Ther 2023; 23:791-800. [PMID: 37038897 DOI: 10.1080/14712598.2023.2200883] [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: 09/29/2022] [Accepted: 04/05/2023] [Indexed: 04/12/2023]
Abstract
BACKGROUND The objective of this non-interventional, observational prospective cohort study (CONNECT-IBD) was to assess the use of CT-P13 (Inflectra®) in the treatment of patients with Crohn's disease (CD) and ulcerative colitis (UC) in the context of treatment with reference infliximab (IFX; Remicade®). METHODS Patients (recruited April 2015 to October 2018) at 150 sites across 13 European countries were followed for up to 2 years. Primary outcomes were safety, population characteristics, and drug utilization patterns. Secondary outcomes included clinical assessment of disease activity. Data were analyzed descriptively. RESULTS Overall, 2543 patients (CD, n = 1676; UC, n = 867) were included. In the CT-P13 cohort (n = 1522), median disease duration was 63 (0-579) months and 30% of patients were IFX naïve; median duration of prior IFX treatment was 5 months. During the observation period, median duration of drug exposure was 14 (0-28) months. 41% of patients reported 912 all-causality treatment-emergent adverse events (TEAEs); 24% experienced treatment-related TEAEs. Most TEAEs were of mild-to-moderate severity. Treatment-emergent serious adverse events were reported by 17% of patients. CONCLUSION Safety information for CT-P13 in this large study was consistent with the known safety profile for IFX and did not alter the established benefit-risk profile of CT-P13.
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Affiliation(s)
- Bernd Bokemeyer
- Interdisciplinary Crohn Colitis Centre Minden, Minden, Germany
| | - Tibor Hlavaty
- 5th Department of Internal Medicine, Sub-department of Gastroenterology and Hepatology, University Hospital Bratislava and Comenius University, Bratislava, Slovakia
| | - Matthieu Allez
- Gastroenterology Department, Hôpital Saint-Louis - APHP, INSERM U1160, Université De Paris, Paris, France
| | - Pamela Selema
- Worldwide Safety and Risk Management, Pfizer, Inc, New York City, NY, USA
| | - Shahrzad Moosavi
- Worldwide Safety and Risk Management, Pfizer, Inc, New York City, NY, USA
| | - Mary Jane Cadatal
- Global Biometrics and Data Management, Pfizer, Inc, Manila, Philippines
| | - Heather Fowler
- Clinical Development and Operations, Pfizer, Inc, London, UK
| | | | | | - Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
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18
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Phillips J, Leary S, Tyrrell-Price J. Association between 6-thioguanine nucleotide levels and preventing production of antibodies to infliximab in patients with inflammatory bowel disease. BMJ Open Gastroenterol 2023; 10:e001149. [PMID: 37328288 PMCID: PMC10277032 DOI: 10.1136/bmjgast-2023-001149] [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: 03/19/2023] [Accepted: 05/30/2023] [Indexed: 06/18/2023] Open
Abstract
OBJECTIVE Combination therapy with infliximab and a thiopurine has been shown to be more effective than monotherapy in patients with inflammatory bowel disease (IBD). The therapeutic efficacy of thiopurines is correlated with 6-thioguanine (6-TGN) levels between 235 and 450 pmol/8×108 erythrocytes. The primary aim of the study was to investigate the association between 6-TGN levels and inhibition prevention of the production of antibodies to infliximab (ATI). DESIGN We performed a retrospective review of the medical records of patients being treated with infliximab for IBD at University Hospitals Bristol NHS Foundation Trust. Demographic and biochemical data were extracted, alongside thiopurine metabolite levels, trough levels of infliximab and the presence of ATI. χ2 tests were used to investigate the association between 6-TGN levels and prevention of ATI. Logistic regression was used to compare the odds of prevented ATI between those with a 6-TGN level between 235 and 450 pmol/8×108 erythrocytes, those with a 6-TGN level outside of this range, and the baseline group who were on infliximab monotherapy. RESULTS Data were extracted for 100 patients. Six of 32 patients with a 6-TGN level between 235 and 450 pmol/8×108 erythrocytes developed ATI (18.8%) compared with 14 out of 22 (63.6%) patients with a 6-TGN outside of this range and 32 out of 46 (69.6%) patients on monotherapy (p=0.001). The OR (95% CI) for prevented ATI in those with a 6-TGN between 235 and 450 pmol/8×108 erythrocytes compared with a 6-TGN outside of this range was 7.6 (2.2, 26.3) (p=0.001) and compared with monotherapy was 9.9 (3.3, 29.4) (p=0.001). CONCLUSION 6-TGN levels between 235 and 450 pmol/8×108 erythrocytes prevented production of ATI. This supports therapeutic drug monitoring to help guide treatment and maximise the beneficial effects of combination therapy for patients with IBD.
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Affiliation(s)
- Jennifer Phillips
- Department of Gastroenterology, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
- Population Health Sciences, University of Bristol, Bristol, UK
| | - Sam Leary
- Bristol Dental School, University of Bristol, Bristol, UK
| | - Jonathan Tyrrell-Price
- Department of Gastroenterology, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
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Núñez P, Quera R, Yarur AJ. Safety of Janus Kinase Inhibitors in Inflammatory Bowel Diseases. Drugs 2023; 83:299-314. [PMID: 36913180 PMCID: PMC10010235 DOI: 10.1007/s40265-023-01840-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/29/2023] [Indexed: 03/14/2023]
Abstract
In recent years, better knowledge of the pathophysiology of inflammatory bowel diseases (IBD) has led to a relevant expansion of the therapeutic arsenal for these conditions. Janus kinase (JAK) inhibitors are a family of small molecules that block one or more of the intracellular tyrosine kinases, including JAK-1, JAK-2, JAK-3 and TYK-2. Tofacitinib, a non-selective small molecule JAK inhibitor, and upadacitinib and filgotinib, which are selective JAK-1 inhibitors, have been approved by the US Food and Drug Administration (FDA) for moderate-to-severe active ulcerative colitis. Compared to biological drugs, JAK inhibitors have a short half-life, rapid onset of action, and no immunogenicity. Both clinical trials and real-world evidence support the use of JAK inhibitors in the treatment of IBD. However, these therapies have been linked with multiple adverse events (AEs) including infection, hypercholesterolemia, venous thromboembolism, major adverse cardiovascular events, and malignancy. While early studies recognized several potential AEs, post-marketing trials have shown that tofacitinib may increase the risk of thromboembolic diseases and major cardiovascular events. The latter are seen in patients aged 50 years or older with cardiovascular risk factors. Hence, the benefits of treatment and risk stratification need to be considered when positioning tofacitinib. Novel JAK inhibitors with a more selective effect on JAK-1 have proven to be effective in both Crohn's disease and ulcerative colitis, offering a potentially safer and efficacious therapeutic option to patients, including those with previous non-response to other therapies such as biologics. Nevertheless, long-term effectiveness and safety data are required.
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Affiliation(s)
- Paulina Núñez
- Department of Gastroenterology, Hospital San Juan De Dios-Universidad de los Andes, Digestive Disease Center, Clínica Universidad de los Andes, Universidad de Chile Santiago, 7620157, Santiago, Chile
| | - Rodrigo Quera
- Universidad de los Andes, Digestive Disease Center, Clínica Universidad de los Andes, 7620157, Santiago, Chile
| | - Andres J Yarur
- Cedars-Sinai Medical Center, 8730 Alden Dr.Thalians 2E, Los Angeles, CA, 90048, USA.
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20
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Srinivasan A, De Cruz P, Sam M, Toong C, van Langenberg DR. Dose intensification strategy influences infliximab pharmacokinetics but not clinical response after the same number of doses. J Gastroenterol Hepatol 2023; 38:724-732. [PMID: 36692034 DOI: 10.1111/jgh.16133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/16/2023] [Accepted: 01/20/2023] [Indexed: 01/25/2023]
Abstract
BACKGROUND The optimal infliximab dose intensification strategy to address secondary loss of response (LOR) remains unclear. This study aimed to compare clinical and pharmacokinetic outcomes following (i) upfront infliximab re-induction with (ii) ongoing 6-weekly dose interval shortening (DIS), after the same number of doses. METHODS A prospective parallel cohort study of inflammatory bowel disease patients who required infliximab dose intensification for secondary LOR using (i) re-induction (i.e., repeat 5 mg/kg 0, 2, 6-week dosing) followed by 8-weekly maintenance or (ii) 6-weekly 5 mg/kg DIS was undertaken. Week 32 clinical response was the primary outcome, with secondary evaluation of infliximab pharmacokinetics and predictors of response. RESULTS Of 104 patients, 54 underwent re-induction, and 50 underwent 6-weekly DIS; 43 per cohort had clinically active disease, with comparable baseline infliximab levels (2.03 vs 2.02 ug/mL, P = 0.83). Clinical response was similar across re-induction and DIS cohorts at weeks 12 (69.8 vs 65.1%) and 32 (53.5 vs 62.8%, each P > 0.50); however, both strategies demonstrated distinct pharmacokinetic profiles at weeks 6 (18.45 vs 5.36 ug/mL, P < 0.01), 12 (8.94 vs 5.96 ug/mL, P = 0.02) and 30 (3.89 vs 6.35 ug/mL, P = .0.02). In multivariable analyses, objectively verified active disease at baseline (OR 12.92, 95% CI [1.84-90.84], P = 0.01), subtherapeutic week 6 infliximab levels (OR 0.12, 95% CI [0.01, 0.99], P = 0.049) and week 12 clinical response (OR 5.44, 95% CI [1.20-19.97], P = 0.04) were associated with week 32 response, as were week 2 infliximab levels (OR 1.34, 95% CI [1.02-1.47], P = 0.04) following re-induction. Following re-induction, week 2 infliximab levels <15.6 ug/mL (AUROC 0.76, 95% CI [0.54-0.99], P < 0.05) predicted nonresponse at week 32. CONCLUSION Dose intensification strategy impacted immediate and sustained infliximab levels but not clinical response. Upfront intensification was associated with short-term pharmacokinetic advantages, including predictors of response, that diminished with time. Hence, when applying upfront dose intensification, clinicians should consider continuing intensified dosing to sustain early pharmacokinetic advantages based on predictors of (non)response.
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Affiliation(s)
- Ashish Srinivasan
- Department of Gastroenterology, Eastern Health, Melbourne, Australia.,Eastern Health Clinical School, Monash University, Melbourne, Australia.,Department of Gastroenterology, Austin Health, Melbourne, Australia.,Austin Academic Centre, University of Melbourne, Melbourne, Australia
| | - Peter De Cruz
- Department of Gastroenterology, Austin Health, Melbourne, Australia.,Austin Academic Centre, University of Melbourne, Melbourne, Australia
| | - Melissa Sam
- Department of Immunopathology, NSW Health Pathology Liverpool Hospital, Sydney, Australia.,Ingham Institute of Applied Sciences, Immunology Research Group, Sydney, Australia.,South Western Sydney Clinical School, University of NSW, Sydney, Australia
| | - Catherine Toong
- Department of Immunopathology, NSW Health Pathology Liverpool Hospital, Sydney, Australia.,Ingham Institute of Applied Sciences, Immunology Research Group, Sydney, Australia.,South Western Sydney Clinical School, University of NSW, Sydney, Australia.,Department of Immunology, Liverpool Hospital, Sydney, Australia
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Vieujean S, Louis E. Precision medicine and drug optimization in adult inflammatory bowel disease patients. Therap Adv Gastroenterol 2023; 16:17562848231173331. [PMID: 37197397 PMCID: PMC10184262 DOI: 10.1177/17562848231173331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 04/16/2023] [Indexed: 05/19/2023] Open
Abstract
Inflammatory bowel diseases (IBD) encompass two main entities including ulcerative colitis and Crohn's disease. Although having a common global pathophysiological mechanism, IBD patients are characterized by a significant interindividual heterogeneity and may differ by their disease type, disease locations, disease behaviours, disease manifestations, disease course as well as treatment needs. Indeed, although the therapeutic armamentarium for these diseases has expanded rapidly in recent years, a proportion of patients remains with a suboptimal response to medical treatment due to primary non-response, secondary loss of response or intolerance to currently available drugs. Identifying, prior to treatment initiation, which patients are likely to respond to a specific drug would improve the disease management, avoid unnecessary side effects and reduce the healthcare expenses. Precision medicine classifies individuals into subpopulations according to clinical and molecular characteristics with the objective to tailor preventative and therapeutic interventions to the characteristics of each patient. Interventions would thus be performed only on those who will benefit, sparing side effects and expense for those who will not. This review aims to summarize clinical factors, biomarkers (genetic, transcriptomic, proteomic, metabolic, radiomic or from the microbiota) and tools that could predict disease progression to guide towards a step-up or top-down strategy. Predictive factors of response or non-response to treatment will then be reviewed, followed by a discussion about the optimal dose of drug required for patients. The time at which these treatments should be administered (or rather can be stopped in case of a deep remission or in the aftermath of a surgery) will also be addressed. IBD remain biologically complex, with multifactorial etiopathology, clinical heterogeneity as well as temporal and therapeutic variabilities, which makes precision medicine especially challenging in this area. Although applied for many years in oncology, it remains an unmet medical need in IBD.
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Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
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22
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Na SY, Choi CH, Song EM, Bang KB, Park SH, Kim ES, Park JJ, Keum B, Lee CK, Lee BI, Ryoo SB, Koh SJ, Choi M, Kim JS. Korean clinical practice guidelines on biologics and small molecules for moderate-to-severe ulcerative colitis. Intest Res 2023; 21:61-87. [PMID: 35645321 PMCID: PMC9911265 DOI: 10.5217/ir.2022.00007] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 03/07/2022] [Indexed: 02/09/2023] Open
Abstract
Ulcerative colitis (UC), a relapsing-remitting chronic inflammatory bowel disease (IBD), has a variable natural course but potentially severe disease course. Since the development of anti-tumor necrosis factor (TNF) agents has changed the natural disease course of moderate-to-severe UC, therapeutic options for patients who failed conventional treatments are expanding rapidly. IBD clinical trials have demonstrated the potential efficacy and safety of novel biologics such as anti-integrin α4β7 and anti-interleukin-12/23 monoclonal antibodies and small molecules such as a Janus kinase inhibitor. Anti-TNF biosimilars also have been approved and are widely used in IBD patients. Wise drug choices should be made considering evidence-based efficacy and safety. However, the best position of these drugs remains several questions, with limited data from direct comparative trials. In addition, there are still concerns to be elucidated on the effect of therapeutic drug monitoring and combination therapy with immunomodulators. The appropriate treatment regimens in acute severe UC and the risk of perioperative use of biologics are unclear. As novel biologics and small molecules have been approved in Korea, we present the Korean guidelines for medical management of adult outpatients with moderate-to-severe UC and adult hospitalized patients with acute severe UC, focusing on biologics and small molecules.
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Affiliation(s)
- Soo-Young Na
- Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea
| | - Chang Hwan Choi
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea,Correspondence to Chang Hwan Choi, Department of Internal Medicine, Chung-Ang University College of Medicine, 102 Heukseok-ro, Dongjak-gu, Seoul 06973, Korea. Tel: +82-2-6299-1418, Fax: +82-2-6299-2064, E-mail:
| | - Eun Mi Song
- Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea
| | - Ki Bae Bang
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea
| | - Sang Hyoung Park
- Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Eun Soo Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Jae Jun Park
- Department of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Bora Keum
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Chang Kyun Lee
- Department of Gastroenterology, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Bo-In Lee
- Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung-Bum Ryoo
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Seong-Joon Koh
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Miyoung Choi
- National Evidence-based Healthcare Collaborating Agency, Seoul, Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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23
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Abstract
INTRODUCTION Anti-tumor necrosis factor (TNF)-α have been the mainstay therapy for Crohn's (CD) and ulcerative colitis (UC) for decades. With growing need for highly effective therapy, various therapeutic targets have been introduced including anti-integrins, anti-interleukin (IL) 12/23, selective anti-IL23, Janus Kinase (JAK) inhibitors, sphingosine-1-phosphate (S1P) receptor modulators, and mRNA-124 splicing agent. AREAS COVERED The current state of available IBD therapies and those in development are reviewed, with recommendations made on positioning in clinical practice. EXPERT OPINION Selecting and sequencing IBD therapies remains a clinical challenge. Disease phenotype, severity of symptoms, patient comorbidities, and prior drug exposure should be considered when considering therapy options. Anti-TNF remains a time-tested option that is effective in both UC and CD. The perception that newer biologics have slower onset of action is probably overestimated and providers should reconsider need for concurrent corticosteroid. JAK-inhibitors provide rapid symptom improvement in patients with moderate-severe UC. Due to safety concerns, it is recommended as a second-line therapy for UC. The goal for IBD treatment should be personalized, have rapid onset of action, induce durable clinical and endoscopic remission, and have excellent safety.
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Affiliation(s)
- Uni Wong
- University of Maryland School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Baltimore, Maryland, USA
| | - Raymond K Cross
- University of Maryland School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Baltimore, Maryland, USA
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Astorga J, Gasaly N, Dubois-Camacho K, De la Fuente M, Landskron G, Faber KN, Urra FA, Hermoso MA. The role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD. Front Immunol 2022; 13:1028953. [PMID: 36466902 PMCID: PMC9716353 DOI: 10.3389/fimmu.2022.1028953] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 10/26/2022] [Indexed: 10/15/2023] Open
Abstract
Inflammatory Bowel Disease (IBD) is characterized by a loss of intestinal barrier function caused by an aberrant interaction between the immune response and the gut microbiota. In IBD, imbalance in cholesterol homeostasis and mitochondrial bioenergetics have been identified as essential events for activating the inflammasome-mediated response. Mitochondrial alterations, such as reduced respiratory complex activities and reduced production of tricarboxylic acid (TCA) cycle intermediates (e.g., citric acid, fumarate, isocitric acid, malate, pyruvate, and succinate) have been described in in vitro and clinical studies. Under inflammatory conditions, mitochondrial architecture in intestinal epithelial cells is dysmorphic, with cristae destruction and high dynamin-related protein 1 (DRP1)-dependent fission. Likewise, these alterations in mitochondrial morphology and bioenergetics promote metabolic shifts towards glycolysis and down-regulation of antioxidant Nuclear erythroid 2-related factor 2 (Nrf2)/Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling. Although the mechanisms underlying the mitochondrial dysfunction during mucosal inflammation are not fully understood at present, metabolic intermediates and cholesterol may act as signals activating the NLRP3 inflammasome in IBD. Notably, dietary phytochemicals exhibit protective effects against cholesterol imbalance and mitochondrial function alterations to maintain gastrointestinal mucosal renewal in vitro and in vivo conditions. Here, we discuss the role of cholesterol and mitochondrial metabolism in IBD, highlighting the therapeutic potential of dietary phytochemicals, restoring intestinal metabolism and function.
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Affiliation(s)
- Jessica Astorga
- Laboratory of Innate Immunity, Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Naschla Gasaly
- Laboratory of Innate Immunity, Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
- Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, Netherlands
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, Netherlands
| | - Karen Dubois-Camacho
- Laboratory of Innate Immunity, Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
- Laboratory of Metabolic Plasticity and Bioenergetics, Program of Molecular and Clinical Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Marjorie De la Fuente
- Laboratory of Biomedicine Research, School of Medicine, Universidad Finis Terrae, Santiago, Chile
| | - Glauben Landskron
- Laboratory of Biomedicine Research, School of Medicine, Universidad Finis Terrae, Santiago, Chile
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, Netherlands
| | - Félix A. Urra
- Laboratory of Metabolic Plasticity and Bioenergetics, Program of Molecular and Clinical Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Marcela A. Hermoso
- Laboratory of Innate Immunity, Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, Netherlands
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Kita T, Ashizuka S, Takeda T, Matsumoto T, Ohmiya N, Nakase H, Motoya S, Ohi H, Mitsuyama K, Hisamatsu T, Kanmura S, Kato N, Ishihara S, Nakamura M, Moriyama T, Saruta M, Nozaki R, Yamamoto S, Inatsu H, Watanabe K, Kitamura K. Adrenomedullin for biologic-resistant Crohn's disease: A randomized, double-blind, placebo-controlled phase 2a clinical trial. J Gastroenterol Hepatol 2022; 37:2051-2059. [PMID: 35840351 PMCID: PMC9796011 DOI: 10.1111/jgh.15945] [Citation(s) in RCA: 4] [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: 10/28/2021] [Revised: 06/26/2022] [Accepted: 07/05/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIM Adrenomedullin is a bioactive peptide with many pleiotropic effects, including mucosal healing and immunomodulation. Adrenomedullin has shown beneficial effects in rodent models of inflammatory bowel disease and, more importantly, in clinical trials including patients with ulcerative colitis. We performed a successive clinical trial to investigate the efficacy and safety of adrenomedullin in patients with Crohn's disease (CD). METHODS This was a multicenter, double-blind, placebo-controlled phase 2a trial that evaluated 24 patients with biologic-resistant CD in Japan. Patients were randomly assigned to three groups and were given an infusion of 10 or 15 ng/kg/min of adrenomedullin or placebo for 8 h per day for 7 days. The primary endpoint was the change in the CD activity index (CDAI) at 8 weeks. The main secondary endpoints included changes in CDAI from week 4 to week 24. RESULTS No differences in the primary or secondary endpoints were observed between the three groups by the 8th week. Changes in CDAI in the placebo group gradually decreased and disappeared at 24 weeks, but those in the adrenomedullin-treated groups (10 or 15 ng/kg/min group) remained at steady levels for 24 weeks. Therefore, a significant difference was observed between the placebo and adrenomedullin-treated groups at 24 weeks (P = 0.043) in the mixed-effects model. We noted mild adverse events caused by the vasodilatory effect of adrenomedullin. CONCLUSION In this trial, we observed a long-lasting (24 weeks) decrease in CDAI in the adrenomedullin-treated groups. Adrenomedullin might be beneficial for biologic-resistant CD, but further research is needed.
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Affiliation(s)
- Toshihiro Kita
- Department of Projects Research, Frontier Science Research CenterUniversity of MiyazakiMiyazakiJapan
| | - Shinya Ashizuka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of MedicineUniversity of MiyazakiMiyazakiJapan
| | - Teruyuki Takeda
- Department of GastroenterologyFukuoka University Chikushi HospitalFukuokaJapan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of MedicineIwate Medical UniversityMoriokaJapan
| | - Naoki Ohmiya
- Department of GastroenterologyFujita Health University School of MedicineToyoakeJapan
| | - Hiroshi Nakase
- Department of Gastroenterology and HepatologySapporo Medical University School of MedicineSapporoJapan
| | | | - Hidehisa Ohi
- Department of GastroenterologyIdzuro Imamura HospitalKagoshimaJapan
| | - Keiichi Mitsuyama
- Division of Gastroenterology, Department of MedicineKurume University School of MedicineKurumeJapan
| | - Tadakazu Hisamatsu
- Department of Gastroenterology and HepatologyKyorin University School of MedicineMitakaJapan
| | - Shuji Kanmura
- Digestive and Lifestyle DiseasesKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of MedicineChiba UniversityChibaJapan
| | - Shunji Ishihara
- Department of GastroenterologyShimane University HospitalIzumoJapan
| | - Masanao Nakamura
- Department of Gastroenterology and HepatologyNagoya University Graduate School of MedicineNagoyaJapan
| | - Tomohiko Moriyama
- Department of Medicine and Clinical Science, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal MedicineThe Jikei University School of MedicineTokyoJapan
| | | | - Shojiro Yamamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of MedicineUniversity of MiyazakiMiyazakiJapan
| | - Haruhiko Inatsu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of MedicineUniversity of MiyazakiMiyazakiJapan
| | - Koji Watanabe
- Department of Projects Research, Frontier Science Research CenterUniversity of MiyazakiMiyazakiJapan
| | - Kazuo Kitamura
- Department of Projects Research, Frontier Science Research CenterUniversity of MiyazakiMiyazakiJapan
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Kwon Y, Kim ES, Kim YZ, Choe YH, Kim MJ. Cytokine Profile at Diagnosis Affecting Trough Concentration of Infliximab in Pediatric Crohn’s Disease. Biomedicines 2022; 10:biomedicines10102372. [PMID: 36289634 PMCID: PMC9598182 DOI: 10.3390/biomedicines10102372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 09/17/2022] [Accepted: 09/19/2022] [Indexed: 11/30/2022] Open
Abstract
Background: This study aims to measure the concentration of cytokines produced during the inflammation process to investigate if there are any differences in response to treatment of pediatric Crohn’s disease and to determine if the initial tumor necrosis factor-alpha (TNF-α) level affected the trough concentration of infliximab (IFX). Methods: This study included 30 pediatric patients with moderate-to-severe Crohn’s disease. At the time of diagnosis, blood samples were collected for the measurement of cytokines (IL-6, TNF-α, IL-17A, and IL-10). Blood samples were extracted from patients who had begun IFX treatment to measure the IFX trough concentration immediately before the fourth dose administration. Results: All cytokines (TNF-α, IL-6, IL-10, and IL-17A) were significantly higher in patients who did not achieve clinical or biochemical remission than in those who did (p = 0.027, 0.006, 0.017, 0.032, respectively). TNF-α had a negative correlation with the IFX trough concentration (Pearson coefficient = −0.425, p = 0.034). The diagnostic capability of the initial TNF-α concentration to predict under the therapeutic IFX trough concentration, defined as less than 3 µg/mL, had an area under the receiver operating characteristic of 0.730 (p = 0.049). The TNF-α concentration was set at 27.6 pg/mL as the cutoff value. Conclusions: Measuring cytokines at the time of diagnosis can be used to predict the treatment response. Measuring the initial TNF-α concentration may help to predict the treatment response to IFX. When the initial TNF-α concentration is greater than 27.6 pg/mL, a higher dose of IFX may be more appropriate than routinely administering 5 mg/kg of IFX to maintain the therapeutic concentration.
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Affiliation(s)
- Yiyoung Kwon
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Eun-Sil Kim
- Department of Pediatrics, Kangbuk Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Yoon-Zi Kim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Yon-Ho Choe
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
- Correspondence: (Y.-H.C.); (M.-J.K.); Tel.: +82-2-3410-0951 (M.-J.K.)
| | - Mi-Jin Kim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
- Correspondence: (Y.-H.C.); (M.-J.K.); Tel.: +82-2-3410-0951 (M.-J.K.)
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Yasmin F, Sahito AM, Mir SL, Khatri G, Shaikh S, Gul A, Hassan SA, Koritala T, Surani S. Electrical neuromodulation therapy for inflammatory bowel disease. World J Gastrointest Pathophysiol 2022; 13:128-142. [PMID: 36187600 PMCID: PMC9516456 DOI: 10.4291/wjgp.v13.i5.128] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 02/19/2022] [Accepted: 07/18/2022] [Indexed: 02/08/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an inflammatory disease of the gastrointestinal (GI) tract. It has financial and quality of life impact on patients. Although there has been a significant advancement in treatments, a considerable number of patients do not respond to it or have severe side effects. Therapeutic approaches such as electrical neuromodulation are being investigated to provide alternate options. Although bioelectric neuromodulation technology has evolved significantly in the last decade, sacral nerve stimulation (SNS) for fecal incontinence remains the only neuromodulation protocol commonly utilized use for GI disease. For IBD treatment, several electrical neuromodulation techniques have been studied, such as vagus NS, SNS, and tibial NS. Several animal and clinical experiments were conducted to study the effectiveness, with encouraging results. The precise underlying mechanisms of action for electrical neuromodulation are unclear, but this modality appears to be promising. Randomized control trials are required to investigate the efficacy of intrinsic processes. In this review, we will discuss the electrical modulation therapy for the IBD and the data pertaining to it.
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Affiliation(s)
- Farah Yasmin
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Abdul Moiz Sahito
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Syeda Lamiya Mir
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Govinda Khatri
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Somina Shaikh
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Ambresha Gul
- Department of Medicine, People’s University of Medical and Health Sciences, Nawabshah 67480, Pakistan
| | - Syed Adeel Hassan
- Department of Medicine, University of Louisville, Louiseville, KY 40292, United States
| | - Thoyaja Koritala
- Department of Medicine, Mayo Clinic, Rochester, NY 55902, United States
| | - Salim Surani
- Department of Medicine, Texas A&M University, College Station, TX 77843, United States
- Department of Anesthesiology, Mayo Clinic, Rochester, MN 55902, United States
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28
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Casasola-LaMacchia A, Seward RJ, Tourdot S, Willetts M, Kruppa G, Agostino MJ, Bergeron G, Ahyi-Amendah N, Ciarla A, Lu Z, Kim HY, Hickling TP, Neubert H. HLAII peptide presentation of infliximab increases when complexed with TNF. Front Immunol 2022; 13:932252. [PMID: 36177046 PMCID: PMC9513746 DOI: 10.3389/fimmu.2022.932252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
CD4+ T-cell activation through recognition of Human Leukocyte Antigen II (HLAII)-presented peptides is a key step in the development of unwanted immune response against biotherapeutics, such as the generation of anti-drug antibodies (ADA). Therefore, the identification of HLAII-presented peptides derived from biotherapeutics is a crucial part of immunogenicity risk assessment and mitigation strategies during drug development. To date, numerous CD4+ T-cell epitopes have been identified by HLAII immunopeptidomics in antibody-based biotherapeutics using either their native or aggregated form. Antibody-target immune complexes have been detected in patients with ADA and are thought to play a role in ADA development by enhancing the presentation of CD4+ T-cell epitopes at the surface of antigen presenting cells (APCs). The aim of this study was to investigate the effect of biotherapeutic antibody-target immune complexes on the HLAII peptide presentation of biotherapeutics in human primary monocyte-derived dendritic cells (DCs). The trimeric tumor necrosis factor (TNF) and its biotherapeutic antagonists infliximab (INFL), adalimumab (ADAL), and a single armed Fab' were used as a model system. The HLAII immunopeptidome of DCs loaded with antagonists or their immune complexes with TNF was analyzed by trapped ion mobility time-of-flight mass spectrometry (timsTOF MS) leading to the identification of ~ 12,000 unique HLAII-associated peptides per preparation. Anti-TNF sequences were detected at a median of 0.3% of the total immunopeptidome, against a majority background of peptides from endogenous and media-derived proteins. TNF antagonist presentation spanned the variable and constant regions in a widespread manner in both light and heavy chains, consistent with previously discovered HLAII peptides. This investigation extends the collection of observed HLAII peptides from anti-TNF biotherapeutics to include sequences that at least partially span the complementary determining regions (CDRs), such as the LCDR1 for both INFL and ADAL. Although antagonist presentation varied significantly across donors, peptides from both bivalent antagonists INFL and ADAL were more highly presented relative to the Fab'. While TNF immune complexes did not alter overall HLAII presentation, a moderate increase in presentation of a subset of peptide clusters was observed in the case of INFL-TNF, which included HCDR2, HCDR3 and LCDR2 sequences.
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Affiliation(s)
- Andrea Casasola-LaMacchia
- BioMedicine Design, Worldwide Research, Development and Medical, Pfizer Inc., Andover, MA, United States
| | - Robert Joseph Seward
- BioMedicine Design, Worldwide Research, Development and Medical, Pfizer Inc., Andover, MA, United States
| | - Sophie Tourdot
- BioMedicine Design, Worldwide Research, Development and Medical, Pfizer Inc., Andover, MA, United States
| | | | - Gary Kruppa
- Bruker Daltonics, Billerica, MA, United States
| | | | - Gabrielle Bergeron
- BioMedicine Design, Worldwide Research, Development and Medical, Pfizer Inc., Andover, MA, United States
| | - Nathalie Ahyi-Amendah
- BioMedicine Design, Worldwide Research, Development and Medical, Pfizer Inc., Andover, MA, United States
| | - Andrew Ciarla
- BioMedicine Design, Worldwide Research, Development and Medical, Pfizer Inc., Andover, MA, United States
| | - Zhaojiang Lu
- Analytical Research and Development, Biotherapeutics Pharmaceutical Sciences, Pfizer Inc., Andover, MA, United States
| | - Hai-Young Kim
- Analytical Research and Development, Biotherapeutics Pharmaceutical Sciences, Pfizer Inc., Andover, MA, United States
| | - Timothy P. Hickling
- BioMedicine Design, Worldwide Research, Development and Medical, Pfizer Inc., Andover, MA, United States
| | - Hendrik Neubert
- BioMedicine Design, Worldwide Research, Development and Medical, Pfizer Inc., Andover, MA, United States
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29
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Sato M, Fujii K, Takagi H, Shibuya I, Oka D, Yamaya N, Hagita H, Matsumoto M, Inagaki K. Antibacterial and Immunosuppressive Effects of OPS-2071, a Candidate Therapy for Inflammatory Bowel Disease. Dig Dis Sci 2022; 67:3993-4007. [PMID: 34463880 DOI: 10.1007/s10620-021-07237-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 08/19/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract. Although many types of drug are used, clinical outcomes are still unsatisfactory. Previous studies have suggested that intestinal bacteria are involved in the pathogenesis of IBD. Accordingly, in an IBD model we evaluated the therapeutic effects of OPS-2071, a low-absorption quinolone antibacterial agent indicated for intestinal infection, and investigated its mechanism of action. METHODS The therapeutic effects of OPS-2071 and comparison therapies were evaluated using naive CD4 + T cell-transfer IBD model mice. In vitro inhibition of LPS-induced TNF-α production and inhibitory effects on T cell responses stimulated using anti-CD3/CD28 antibody-loaded beads were evaluated using mouse splenocytes and human peripheral blood mononuclear cells. In addition, in vitro activities against bacteria implicated in IBD pathogenesis were tested. RESULTS OPS-2071 dose-dependently decreased both colonic weight/length ratio and the colitis histological score as compared with the vehicle group. The therapeutic effect of OPS-2071 was equivalent to that of anti-IL-12/23 (p40) antibody. In vitro, OPS-2071 suppressed TNF-α production induced by LPS stimulation and T cell responses in a dose-dependent manner. At high concentrations, these effects were comparable to those of existing immunosuppressive agents, such as prednisolone, in both mouse and human cells. OPS-2071 also showed antibacterial activity against IBD-related bacteria. CONCLUSIONS Our results suggest that OPS-2071 had both immunosuppressive and antibacterial effects. This dual effect makes OPS-2071 a unique and promising candidate for IBD.
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Affiliation(s)
- Masayoshi Sato
- Infectious Diseases Unit, Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd, 463-10, Kagasuno, Kawauchi-cho, Tokushima-shi, Tokushima, 771-0192, Japan
| | - Kazuyuki Fujii
- Infectious Diseases Unit, Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd, 463-10, Kagasuno, Kawauchi-cho, Tokushima-shi, Tokushima, 771-0192, Japan
| | - Hiroko Takagi
- Infectious Diseases Unit, Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd, 463-10, Kagasuno, Kawauchi-cho, Tokushima-shi, Tokushima, 771-0192, Japan.
| | - Isao Shibuya
- Infectious Diseases Unit, Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd, 463-10, Kagasuno, Kawauchi-cho, Tokushima-shi, Tokushima, 771-0192, Japan
| | - Daisuke Oka
- Infectious Diseases Unit, Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd, 463-10, Kagasuno, Kawauchi-cho, Tokushima-shi, Tokushima, 771-0192, Japan
| | - Naomitsu Yamaya
- Department of Drug Metabolism and Pharmacokinetics, Otsuka Pharmaceutical Co., Ltd, 463-10, Kagasuno, Kawauchi-cho, Tokushima-shi, Tokushima, 771-0192, Japan
| | - Hiraku Hagita
- Department of Drug Metabolism and Pharmacokinetics, Otsuka Pharmaceutical Co., Ltd, 463-10, Kagasuno, Kawauchi-cho, Tokushima-shi, Tokushima, 771-0192, Japan
| | - Makoto Matsumoto
- Pharmaceutical Business Division, Otsuka Pharmaceutical Co., Ltd, Shinagawa Grand Central Tower, 2-16-4 Konan, Minato-ku, Tokyo, 108-8242, Japan
| | - Katsuya Inagaki
- Infectious Diseases Unit, Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd, 463-10, Kagasuno, Kawauchi-cho, Tokushima-shi, Tokushima, 771-0192, Japan
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30
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Buhl S, Steenholdt C, Brynskov J, Christensen KR, Dorn-Rasmussen M, Thomsen OØ, Bendtzen K, Klausen TW, Dahlerup JF, Thorsgaard N, Jahnsen J, Molazahi A, Pedersen N, Kjeldsen J, Almer S, Dahl EE, Vind I, Cannon AG, Marsal J, Sipponen T, Agnholt JS, Kievit HAL, Aure SL, Martinsen L, Meisner S, Hansen JM, Ainsworth MA. Discontinuation of Infliximab Therapy in Patients with Crohn's Disease. NEJM EVIDENCE 2022; 1:EVIDoa2200061. [PMID: 38319804 DOI: 10.1056/evidoa2200061] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2024]
Abstract
BACKGROUND: Whether infliximab therapy can be successfully discontinued after patients with Crohn’s disease have attained sustained, clinical, biochemical, and endoscopic remission is unknown. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled withdrawal study of infliximab in patients with Crohn’s disease who were in clinical, biochemical, and endoscopic remission after standard infliximab maintenance therapy for at least 1 year. Patients were randomly assigned 1:1 to continue infliximab therapy or to receive matching placebo for 48 weeks. The primary end point was time to relapse. RESULTS: This study randomly assigned 115 patients to either the infliximab-continuation group or to the infliximab-discontinuation group. No relapses were observed among the 59 patients continuing infliximab, whereas 23 of 56 patients discontinuing infliximab experienced relapse. Time to relapse was significantly shorter among patients who discontinued infliximab than among those who continued infliximab (hazard ratio, 0.080; 95% confidence interval [CI], 0.035 to 0.186; P<0.001). At the end of the trial at week 48, relapse-free survival was 100% in the infliximab-continuation group and 51% in the infliximab-discontinuation group. The key secondary end point, time to loss of remission, was significantly shorter among patients discontinuing infliximab therapy than those continuing infliximab (hazard ratio, 0.025; 95% CI, 0.003 to 0.187; P<0.001). No unexpected adverse events were reported. CONCLUSIONS: Discontinuation of infliximab for patients with Crohn’s disease receiving long-term infliximab therapy and in clinical, biochemical, and endoscopic remission leads to a considerable risk of relapse. (Funded by the Nordic Trial Alliance [NordForsk], the Medical Fund of the Danish Regions [Regionernes Medicin og Behandlingspulje], the Danish Colitis-Crohn Association, and the A.P. Moller Foundation; ClinicalTrials.gov number, NCT01817426; EudraCT number, 2012-002702-51.)
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Affiliation(s)
- Sine Buhl
- Department of Gastroenterology, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark
| | - Casper Steenholdt
- Department of Gastroenterology, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark
| | - Jørn Brynskov
- Department of Gastroenterology, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark
| | | | - Maria Dorn-Rasmussen
- Department of Gastroenterology, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark
| | - Ole Østergaard Thomsen
- Department of Gastroenterology, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark
| | - Klaus Bendtzen
- Institute for Inflammation Research IRR, Rigshospitalet University Hospital, Copenhagen
| | | | - Jens Frederik Dahlerup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Niels Thorsgaard
- Department of Medical Diseases, Herning Regional Hospital, Herning, Denmark
| | - Jørgen Jahnsen
- Department of Gastroenterology, Akershus University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo
| | - Akbar Molazahi
- Department of Medical Diseases, Nykøbing F. Regional Hospital, Nykøbing, Denmark
| | - Natalia Pedersen
- Department of Gastroenterology, Slagelse Regional Hospital, Slagelse, Denmark
| | - Jens Kjeldsen
- Department of Medical Gastroenterology S, Odense University Hospital, Odense, Denmark
| | - Sven Almer
- Inflammatory Bowel Disease Unit, Division of Gastroenterology, Karolinska University Hospital, Stockholm, Sweden
- Departement of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Eva Efsen Dahl
- Department of Gastroenterology K, Copenhagen University Hospital-Bispebjerg, Frederiksberg, Denmark
| | - Ida Vind
- Department of Gastroenterology, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark
| | | | - Jan Marsal
- Department of Gastroenterology, Skåne University Hospital, Malmö, Sweden
| | - Taina Sipponen
- Gastroenterology, Abdominal Center, Helsinki University Hospital, University of Helsinki, Helsinki
| | - Jørgen Steen Agnholt
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Synnøve Louise Aure
- Department of Gastroenterology, Akershus University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo
| | - Lars Martinsen
- Department of Medical Diseases, Nykøbing F. Regional Hospital, Nykøbing, Denmark
| | - Svetlana Meisner
- Department of Gastroenterology, Slagelse Regional Hospital, Slagelse, Denmark
| | - Jane Møller Hansen
- Department of Medical Gastroenterology S, Odense University Hospital, Odense, Denmark
| | - Mark Andrew Ainsworth
- Department of Gastroenterology, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark
- Department of Medical Gastroenterology S, Odense University Hospital, Odense, Denmark
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Marsal J, Barreiro-de Acosta M, Blumenstein I, Cappello M, Bazin T, Sebastian S. Management of Non-response and Loss of Response to Anti-tumor Necrosis Factor Therapy in Inflammatory Bowel Disease. Front Med (Lausanne) 2022; 9:897936. [PMID: 35783628 PMCID: PMC9241563 DOI: 10.3389/fmed.2022.897936] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 05/25/2022] [Indexed: 11/30/2022] Open
Abstract
Anti-tumor necrosis factor (anti-TNF) therapy has been successfully used as first-line biologic treatment for moderate-to-severe inflammatory bowel disease (IBD), in both "step-up" and "top-down" approaches, and has become a cornerstone of IBD management. However, in a proportion of patients the effectiveness of anti-TNF therapy is sub-optimal. Either patients do not achieve adequate initial response (primary non-response) or they lose response after initial success (loss of response). Therapeutic drug monitoring determines drug serum concentrations and the presence of anti-drug antibodies (ADAbs) and can help guide treatment optimization to improve patient outcomes. For patients with low drug concentrations who are ADAb-negative or display low levels of ADAbs, dose escalation is recommended. Should response remain unchanged following dose optimization the question whether to switch within class (anti-TNF) or out of class (different mechanism of action) arises. If ADAb levels are high and the patient has previously benefited from anti-TNF therapy, then switching within class is a viable option as ADAbs are molecule specific. Addition of an immunomodulator may lead to a decrease in ADAbs and a regaining of response in a proportion of patients. If a patient does not achieve a robust therapeutic response with an initial anti-TNF despite adequate drug levels, then switching out of class is appropriate. In conjunction with the guidance above, other factors including patient preference, age, comorbidities, disease phenotype, extra-intestinal manifestations, and treatment costs need to be factored into the treatment decision. In this review we discuss current evidence in this field and provide guidance on therapeutic decision-making in clinical situations.
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Affiliation(s)
- Jan Marsal
- Department of Gastroenterology, Skåne University Hospital, Lund/Malmö, Sweden
- Department of Immunology, Lund University, Lund, Sweden
| | - Manuel Barreiro-de Acosta
- Gastroenterology Department, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain
| | - Irina Blumenstein
- Department of Internal Medicine 1, Gastroenterology, Hepatology and Clinical Nutrition, University Clinic Frankfurt, Frankfurt, Germany
| | - Maria Cappello
- Gastroenterology and Hepatology Section, Promise, University of Palermo, Palermo, Italy
| | - Thomas Bazin
- Department of Gastroenterology, Université Paris Saclay/UVSQ, INSERM, Infection and Inflammation, UMR 1173, AP-HP, Hôpital Ambroise Paré, Boulogne Billancourt, France
| | - Shaji Sebastian
- Inflammatory Bowel Disease (IBD) Unit, Hull University Teaching Hospitals National Health Service (NHS) Trust, Hull, United Kingdom
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Development of a Machine Learning Model to Predict Non-Durable Response to Anti-TNF Therapy in Crohn’s Disease Using Transcriptome Imputed from Genotypes. J Pers Med 2022; 12:jpm12060947. [PMID: 35743732 PMCID: PMC9224874 DOI: 10.3390/jpm12060947] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/05/2022] [Accepted: 06/08/2022] [Indexed: 11/25/2022] Open
Abstract
Almost half of patients show no primary or secondary response to monoclonal anti-tumor necrosis factor α (anti-TNF) antibody treatment for inflammatory bowel disease (IBD). Thus, the exact mechanisms of a non-durable response (NDR) remain inadequately defined. We used our genome-wide genotype data to impute expression values as features in training machine learning models to predict a NDR. Blood samples from various IBD cohorts were used for genotyping with the Korea Biobank Array. A total of 234 patients with Crohn’s disease (CD) who received their first anti-TNF therapy were enrolled. The expression profiles of 6294 genes in whole-blood tissue imputed from the genotype data were combined with clinical parameters to train a logistic model to predict the NDR. The top two and three most significant features were genetic features (DPY19L3, GSTT1, and NUCB1), not clinical features. The logistic regression of the NDR vs. DR status in our cohort by the imputed expression levels showed that the β coefficients were positive for DPY19L3 and GSTT1, and negative for NUCB1, concordant with the known eQTL information. Machine learning models using imputed gene expression features effectively predicted NDR to anti-TNF agents in patients with CD.
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Yang H, Li B, Guo Q, Tang J, Peng B, Ding N, Li M, Yang Q, Huang Z, Diao N, Zhu X, Deng J, Guo H, Hu P, Chao K, Gao X. Systematic review with meta-analysis: loss of response and requirement of ustekinumab dose escalation in inflammatory bowel diseases. Aliment Pharmacol Ther 2022; 55:764-777. [PMID: 35141914 DOI: 10.1111/apt.16802] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 01/24/2022] [Accepted: 01/24/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Ustekinumab is effective in treating Crohn's disease (CD) and ulcerative colitis (UC). However, the loss of response (LOR) to ustekinumab and the efficacy of dose escalation have not been systematically explored. METHODS Databases were searched for eligible studies from inception through July 2021. Summary estimates were pooled, and subgroup analyses were performed to explore heterogeneity. RESULTS We included 14 studies (CD: 13; UC: 1). In CD patients, the annual risk of LOR to ustekinumab and dose escalation among primary responders was 21% (95% confidence interval [CI] 12-31%, 1530 person-years, n = 9) per person-year and 25% (95% CI 12-32%, 657 person-years, n = 5) per person-year respectively. Clinical response was regained in 58% (95% CI 49-67%, 279 patients, n = 8) of secondary non-responders after dose escalation (interval reduction or intravenous reinduction). In UC patients, no studies provided data on LOR, but only one study showed that 35% (100/284) of patients underwent dose escalation (or sham dose adjustment), leading to an annual risk of dose escalation of 18% per person-year. After dose escalation, 58% (14/24) of the patients regained symptomatic remission. CONCLUSIONS Primary responders with CD experienced LOR to ustekinumab at a risk of 21% per person-year and required dose escalation at a risk of 25% per person-year. Fifty-eight per cent of secondary non-responders with CD may benefit from dose escalation. LOR has not been well characterized in patients with UC.
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Affiliation(s)
- Hongsheng Yang
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Bingyang Li
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Qin Guo
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Jian Tang
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Bo Peng
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Ni Ding
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Miao Li
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Qingfang Yang
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Zicheng Huang
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Na Diao
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Xia Zhu
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Jun Deng
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Huili Guo
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Pinjin Hu
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Kang Chao
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Xiang Gao
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
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Gorelik Y, Freilich S, Gerassy-Vainberg S, Pressman S, Friss C, Blatt A, Focht G, Weisband YL, Greenfeld S, Kariv R, Lederman N, Dotan I, Geva-Zatorsky N, Shen-Orr SS, Kashi Y, Chowers Y. Antibiotic use differentially affects the risk of anti-drug antibody formation during anti-TNFα therapy in inflammatory bowel disease patients: a report from the epi-IIRN. Gut 2022; 71:287-295. [PMID: 34344783 PMCID: PMC8762017 DOI: 10.1136/gutjnl-2021-325185] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 07/21/2021] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Anti-drug antibodies (ADA) to anti-tumour necrosis factor (anti-TNF) therapy drive treatment loss of response. An association between intestinal microbial composition and response to anti-TNF therapy was noted. We therefore aimed to assess the implications of antibiotic treatments on ADA formation in patients with inflammatory bowel disease (IBD). DESIGN We analysed data from the epi-IIRN (epidemiology group of the Israeli IBD research nucleus), a nationwide registry of all patients with IBD in Israel. We included all patients treated with anti-TNF who had available ADA levels. Survival analysis with drug use as time varying covariates were used to assess the association between antibiotic use and ADA development. Next, specific pathogen and germ-free C57BL mice were treated with respective antibiotics and challenged with infliximab. ADA were assessed after 14 days. RESULTS Among 1946 eligible patients, with a median follow-up of 651 days from initiation of therapy, 363 had positive ADA. Cox proportional hazard model demonstrated an increased risk of ADA development in patients who used cephalosporins (HR=1.97, 95% CI 1.58 to 2.44), or penicillins with β-lactamase inhibitors (penicillin-BLI, HR=1.4, 95% CI 1.13 to 1.74), whereas a reduced risk was noted in patients treated with macrolides (HR=0.38, 95% CI 0.16 to 0.86) or fluoroquinolones (HR=0.20, 95% CI 0.12 to 0.35). In mice exposed to infliximab, significantly increased ADA production was observed in cephalosporin as compared with macrolide pretreated mice. Germ-free mice produced no ADA. CONCLUSION ADA production is associated with the microbial composition. The risk of ADA development during anti-TNF therapy can possibly be reduced by avoidance of cephalosporins and penicillin-BLIs, or by treatment with fluoroquinolones or macrolides.
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Affiliation(s)
- Yuri Gorelik
- Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Shay Freilich
- Faculty of Biotechnology and Food Engineering, Technion Israel Institute of Technology, Haifa, Israel,Clinical Research Institute, Rambam Health Care Campus, Haifa, Israel
| | - Shiran Gerassy-Vainberg
- Clinical Research Institute, Rambam Health Care Campus, Haifa, Israel,Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel
| | - Sigal Pressman
- Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Chagit Friss
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, The Hebrew University of Jerusalem, Jerusalem, Israel
| | | | - Gili Focht
- The Juliet Keiden Institute of Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, Jerusalem, Israel
| | | | - Shira Greenfeld
- Medical Informatics, Maccabi Health Services, Tel Aviv, Israel,Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Revital Kariv
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel,Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Nathan Lederman
- Gastroenterology, Meuhedet Health Services, Jerusalem, Israel
| | - Iris Dotan
- Gastroenterology, Rabin Medical Center, Petah Tikva, Israel,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Naama Geva-Zatorsky
- Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel,Rappaport Technion Integrated Cancer Center (RTICC), Technion Israel Institute of Technology, Haifa, Israel
| | | | - Yechezkel Kashi
- Faculty of Biotechnology and Food Engineering, Technion Israel Institute of Technology, Haifa, Israel
| | - Yehuda Chowers
- Gastroenterology, Rambam Health Care Campus, Haifa, Israel
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Shmais M, Regueiro M, Hashash JG. Proactive versus Reactive Therapeutic Drug Monitoring: Why, When, and How? Inflamm Intest Dis 2022; 7:50-58. [PMID: 35224018 PMCID: PMC8820143 DOI: 10.1159/000518755] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 07/12/2021] [Indexed: 08/08/2023] Open
Abstract
BACKGROUND Up to a third of inflammatory bowel disease) patients show primary nonresponse to antitumor necrosis factor (anti-TNF) biological therapy, and of those who respond, up to 40% develop secondary loss of response (LOR). Therapeutic drug monitoring (TDM) plays a crucial role in assessing patients with LOR to guide therapy by giving more of the drug or switching to a different biological agent. Although reactive TDM is suggested or recommended by the majority of gastroenterology associations, proactive TDM seems to be more controversial. SUMMARY In this article, we discuss the updated guidelines on TDM and will also discuss the available data supporting proactive and reactive TDM in patients with Crohn's disease and those with ulcerative colitis using the different available biological agents. KEY MESSAGES Therapeutic drug monitoring (TDM) is a valuable tool to aid in inflammatory bowel disease (IBD) therapy optimization. Reactive TDM is widely accepted in IBD patients with suspected loss of response, especially in those receiving antitumor necrosis factor (anti-TNF) agents. Proactive TDM is emerging as a reasonable approach to patients initiated on anti-TNF therapy, specifically infliximab and, to some extent, adalimumab, particularly for patients with severe ulcerative colitis and fistulizing Crohn's disease. Similarly, TDM may play a role in patients considering de-escalation from combination therapy. To date, proactive TDM is not widely applied to ustekinumab and vedolizumab and more data are required before this becomes part of clinical practice.
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Affiliation(s)
- Manar Shmais
- Division of Gastroenterology and Hepatology, American University of Beirut, Beirut, Lebanon
| | - Miguel Regueiro
- Division of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Jana G. Hashash
- Division of Gastroenterology and Hepatology, American University of Beirut, Beirut, Lebanon
- Division of Gastroenterology and Hepatology, Inflammatory Bowel Disease Center, Mayo Clinic, Jacksonville, Florida, USA
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36
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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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37
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Annese V, Nathwani R, Alkhatry M, Al-Rifai A, Al Awadhi S, Georgopoulos F, Jazzar AN, Khassouan AM, Koutoubi Z, Taha MS, Limdi JK. Optimizing biologic therapy in inflammatory bowel disease: a Delphi consensus in the United Arab Emirates. Therap Adv Gastroenterol 2021; 14:17562848211065329. [PMID: 34987611 PMCID: PMC8721421 DOI: 10.1177/17562848211065329] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 11/19/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Inflammatory bowel diseases (IBD) are chronic, relapsing-remitting inflammatory conditions with a substantial negative impact on health-related quality of life and work productivity. Treatment of IBD has been revolutionized by the advent of biologic therapies, initially with anti-TNF agents and more recently with multiple alternatives targets, and yet more under development. OBJECTIVES Approximatively one third of patients do not respond to biologic therapy and more importantly a significant proportion experiences partial response or loss of response during treatment. The latter are common clinical situations and paradoxically are not addressed in the commercial drug labels and available guidelines. There is therefore a clinical need for physicians to understand when and how eventually to optimize the biologic therapy. DESIGN This consensus using a Delphi methodology was promoted and supported by the Emirates Society of Gastroenterology and Hepatology to close this gap. DATA SOURCES AND METHODS Following an extensive systematic review of over 60,000 studies, 81 studies with dose escalation and five addressing drug monitoring were selected and in addition five systematic reviews and three guidelines. RESULTS AND CONCLUSION after three rounds of voting 18 statements were selected with agreement ranging from of 80% to 100.
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Affiliation(s)
| | - Rahul Nathwani
- Department of Gastroenterology, Mediclinic City Hospital, Mohammed Bin Rashid University, Dubai, United Arab Emirates
| | - Maryam Alkhatry
- Gastroenterology and Endoscopy Department, Ibrahim Bin Hamad Obaid Allah Hospital, Ministry of Health and Prevention, Ras Al Khaimah, United Arab Emirates
| | - Ahmad Al-Rifai
- Department of Gastroenterology, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
| | - Sameer Al Awadhi
- Digestive Disease Unit, Rashid Hospital, Dubai, United Arab Emirates
| | - Filippos Georgopoulos
- Gastroenterology and Endoscopy Unit, Al Zahra Hospital Dubai, Dubai, United Arab Emirates
| | - Ahmad N. Jazzar
- Gastroenterology Division, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates
| | | | - Zaher Koutoubi
- Digestive Disease Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Mazen S. Taha
- Gastroenterology and Hepatology, Tawam Hospital, Al Ain, United Arab Emirates
| | - Jimmy K. Limdi
- Department of Gastroenterology, The Pennine Acute Hospitals NHS Trust, Manchester Academic Health Sciences, University of Manchester, Manchester, UK
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38
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Dudek P, Fabisiak A, Zatorski H, Malecka-Wojciesko E, Talar-Wojnarowska R. Efficacy, Safety and Future Perspectives of JAK Inhibitors in the IBD Treatment. J Clin Med 2021; 10:jcm10235660. [PMID: 34884361 PMCID: PMC8658230 DOI: 10.3390/jcm10235660] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/22/2021] [Accepted: 11/28/2021] [Indexed: 12/16/2022] Open
Abstract
Although development of biologics has importantly improved the effectiveness in inducing and maintaining remission in inflammatory bowel disease (IBD), biologic therapies still have several limitations. Effective, low-cost drug therapy with good safety profile and compliance is therefore a substantial unmet medical need. A promising target for IBD treatment strategies are Janus kinase (JAK) inhibitors, which are small molecules that interact with cytokines implicated in pathogenesis of IBD. In contrast to monoclonal antibodies, which are able to block a single cytokine, JAK inhibitors have the potential to affect multiple cytokine-dependent immune pathways, which may improve the therapeutic response in some IBD patients. Tofacitinib, inhibiting signaling via different types of JAKs, has been already approved for ulcerative colitis, and several other small-molecule are still under investigation. However, one of the main concerns about using JAK inhibitors is the risk of thromboembolic events. Moreover, patients with COVID-19 appear to have an increased susceptibility for immunothrombosis. Therefore, thrombotic complications may become a serious limitation in the use of JAK inhibitors in the SARS-CoV-2 pandemic. As many questions about safety and efficacy of small molecules still remain unclear, in our review we present the current data regarding approved JAK inhibitors, as well as those in clinical development for the treatment of IBD.
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Affiliation(s)
- Patrycja Dudek
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, 90-153 Lodz, Poland; (A.F.); (H.Z.); (E.M.-W.); (R.T.-W.)
- Correspondence: ; Tel.: +48-42677-66-67
| | - Adam Fabisiak
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, 90-153 Lodz, Poland; (A.F.); (H.Z.); (E.M.-W.); (R.T.-W.)
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland
| | - Hubert Zatorski
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, 90-153 Lodz, Poland; (A.F.); (H.Z.); (E.M.-W.); (R.T.-W.)
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland
| | - Ewa Malecka-Wojciesko
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, 90-153 Lodz, Poland; (A.F.); (H.Z.); (E.M.-W.); (R.T.-W.)
| | - Renata Talar-Wojnarowska
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, 90-153 Lodz, Poland; (A.F.); (H.Z.); (E.M.-W.); (R.T.-W.)
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39
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Louis E. Stopping Anti-TNF in Crohn’s Disease Remitters: Pros and Cons: The Pros. Inflamm Intest Dis 2021; 7:64-68. [DOI: 10.1159/000520942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 11/15/2021] [Indexed: 11/19/2022] Open
Abstract
<b><i>Background:</i></b> There is no cure for Crohn’s disease (CD). Available treatments and treatment strategies, particularly anti-TNF, allow healing intestinal lesions and maintaining steroid-free remission in a subset of patients. Having in mind the remitting/relapsing nature of the disease, patients and health care providers often ask themselves whether the treatment could be withdrawn. Several studies have demonstrated a risk of relapse of CD after anti-TNF withdrawal, which varies from 20 to 50% at 1 year and from 50 to 80% beyond 5 years. These numbers clearly highlight that stopping therapy should not be a systematically proposed strategy in those remitting patients. <b><i>Summary:</i></b> Nobody would argue for anti-TNF withdrawal in patients with a high risk of short-term relapse. Nevertheless, they also indicate that a minority of patients may not relapse over midterm and that those who have relapsed may have benefited from a drug-free period before being again treated for a new cycle of treatment. The most relevant question is thus whether in those patients with a low to medium risk of disease relapse, treatment withdrawal could be contemplated. In this specific setting, there may be pros and cons for anti-TNF withdrawal. Among the pros are the potential side effects and toxicity of anti-TNF, the risk of loss of response over time, the patient preference allowing the patient to regain control of one’s health and investing in it, also improving adherence, the absence of a negative impact on disease evolution of a transient anti-TNF withdrawal, and finally the cost. <b><i>Key Messages:</i></b> Although anti-TNF withdrawal in patients with sustained clinical remission is associated with a high risk of relapse, this risk seems to be much lower in a subgroup of patients, particularly in endoscopic and biologic remission. Stopping anti-TNF in this subgroup of patients may be associated with a favorable benefit/risk ratio.
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40
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Gisbert JP, Chaparro M. Primary Failure to an Anti-TNF Agent in Inflammatory Bowel Disease: Switch (to a Second Anti-TNF Agent) or Swap (for Another Mechanism of Action)? J Clin Med 2021; 10:5318. [PMID: 34830595 PMCID: PMC8625924 DOI: 10.3390/jcm10225318] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/10/2021] [Accepted: 11/13/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND About a third of patients with inflammatory bowel disease do not respond to anti-tumour necrosis factor (anti-TNF) therapy, which is challenging. AIM To review the current data on the two main strategies when facing primary non-response to an anti-TNF agent in inflammatory bowel disease: changing to a second anti-TNF (switching) or to a drug with another mechanisms of action (swapping). METHODS We performed a bibliographic search to identify studies reporting on efficacy of any biologic treatment after primary anti-TNF non-response. RESULTS The efficacy of a second anti-TNF is lower when the reason to withdraw the first one is primary failure. Nevertheless, switching to another anti-TNF even after primary failure may still be effective in some patients. Both vedolizumab and ustekinumab have generally been shown to be less effective in anti-TNF exposed patients. However, despite primary anti-TNF failure, patients may respond to vedolizumab or ustekinumab in a limited but considerable number of cases. The cause for swapping (primary vs. secondary anti-TNF failure) seems to have limited effect on vedolizumab efficacy. Primary anti-TNF non-response seems to be a clearer predictor of treatment failure for ustekinumab. Unfortunately, the two main strategies to treat specifically a patient with primary non-response to an anti-TNF agent-switching to a second anti-TNF or swapping for vedolizumab/ustekinumab-have not been properly compared. CONCLUSION The data reviewed in the present study clearly emphasise the imperative need to carry out head-to-head randomised trials in patients exposed to anti-TNF agents in general, and specifically in those with primary non-response to these agents.
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Affiliation(s)
- Javier P. Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28006 Madrid, Spain;
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Schultheiss JPD, Mahmoud R, Louwers JM, van der Kaaij MT, van Hellemondt BP, van Boeckel PG, Mahmmod N, Jharap B, Fidder HH, Oldenburg B. Loss of response to anti-TNFα agents depends on treatment duration in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2021; 54:1298-1308. [PMID: 34559428 PMCID: PMC9292495 DOI: 10.1111/apt.16605] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 08/23/2021] [Accepted: 09/01/2021] [Indexed: 01/11/2023]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is often managed with anti-tumour necrosis factor-α therapy (anti-TNFα), but treatment efficacy is compromised by high annual rates of loss of response (13%-21% per patient-year). AIMS To assess whether the incidence of loss of response decreases with longer treatment duration METHODS: This was a multicentre, retrospective cohort study of patients with ulcerative colitis (UC) or Crohn's disease (CD) who received anti-TNFα for at least 4 months between 2011 and 2019. We studied the incidence of loss of response as a function of treatment duration, employing parametric survival modelling. Predictors of loss of response were identified by Cox regression analysis. Secondary outcomes included overall anti-TNFα discontinuation and dose escalation. RESULTS We included 844 anti-TNFα treatment episodes in 708 individuals. Loss of response occurred in 211 (25.0%) episodes, with anti-drug antibodies detected in 66 (31.3%). During the first year, the incidence of loss of response was three-fold higher than after four years of treatment (17.2% vs 4.8% per patient-year, P < 0.001). The incidence of anti-TNFα discontinuation (28.6% vs 14.0% per patient-year, P < 0.001) and dose escalations (38.0% vs 6.8% per patient-year, P < 0.001) also decreased significantly from the first year to after four years, respectively. Predictors of loss of response included UC (vs CD, adjusted hazard ratio [aHR] 1.53, 95% CI 1.10-2.15) and, among patients with CD, stricturing or penetrating disease (aHR 1.68, 95% CI 1.15-2.46) and male sex (aHR 0.55, 95% CI 0.38-0.78). Immunomodulators were protective against loss of response with anti-drug antibodies (aHR 0.42, 95% CI 0.24-0.74). CONCLUSIONS Patients with sustained benefit to anti-TNFα after 2 years are at low risk of subsequent loss of response.
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Affiliation(s)
- Johannes P. D. Schultheiss
- Division of Internal Medicine and DermatologyDepartment of Gastroenterology and HepatologyUniversity Medical Centre UtrechtUtrechtThe Netherlands
| | - Remi Mahmoud
- Division of Internal Medicine and DermatologyDepartment of Gastroenterology and HepatologyUniversity Medical Centre UtrechtUtrechtThe Netherlands
| | - Jonas M. Louwers
- Division of Internal Medicine and DermatologyDepartment of Gastroenterology and HepatologyUniversity Medical Centre UtrechtUtrechtThe Netherlands
| | - Michiel T. van der Kaaij
- Division of Internal Medicine and DermatologyDepartment of Gastroenterology and HepatologyUniversity Medical Centre UtrechtUtrechtThe Netherlands
| | - Boris P. van Hellemondt
- Division of Internal Medicine and DermatologyDepartment of Gastroenterology and HepatologyUniversity Medical Centre UtrechtUtrechtThe Netherlands
| | - Petra G. van Boeckel
- Division of Internal MedicineDepartment of Gastroenterology and HepatologySt. Antonius HospitalNieuwegeinThe Netherlands
| | - Nofel Mahmmod
- Division of Internal MedicineDepartment of Gastroenterology and HepatologySt. Antonius HospitalNieuwegeinThe Netherlands
| | - Bindia Jharap
- Division of Internal MedicineDepartment of Gastroenterology and HepatologyMeander Medical CentreAmersfoortThe Netherlands
| | - Herma H. Fidder
- Division of Internal Medicine and DermatologyDepartment of Gastroenterology and HepatologyUniversity Medical Centre UtrechtUtrechtThe Netherlands
| | - Bas Oldenburg
- Division of Internal Medicine and DermatologyDepartment of Gastroenterology and HepatologyUniversity Medical Centre UtrechtUtrechtThe Netherlands
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Sorrentino D, Nguyen VQ, Love K. Fecal Lactoferrin Predicts Primary Nonresponse to Biologic Agents in Inflammatory Bowel Disease. Dig Dis 2021; 39:626-633. [PMID: 33631768 PMCID: PMC8686729 DOI: 10.1159/000515432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 02/22/2021] [Indexed: 02/02/2023]
Abstract
INTRODUCTION Fecal lactoferrin (FL) is a timely and accurate marker of inflammation in ulcerative colitis (UC) and Crohn's disease (CD). The aim of this study was to verify whether FL can predict primary nonresponse (PNR) to biologic agents during induction. METHODS Retrospective outcome review in 27 patients (13 with CD and 14 with UC) tested for baseline FL and retested within a week after the first and second induction doses. Clinical/biochemical outcomes were evaluated at end of induction and at follow-up (3-24 months). RESULTS Compared to baseline, changes of the Harvey-Bradshaw (CD) and Partial Mayo Scoring (UC) indices at end of induction separated responders (18/27 or 67%) from nonresponders (9/17 or 33%). In all patients, the initial FL value at induction decreased compared to baseline, continuing to decrease after the following dose in clinical responders while bouncing back in the others. Models targeting the 2 consecutively decreased FL values or the second FL value compared to baseline or the second FL value compared to the first were able to accurately predict response at end of induction. Follow-up assessment confirmed clinical remission in initial responders (with FL values reduced on the average by 94 ± 10% compared to baseline). CONCLUSIONS In CD and UC patients during induction with biologic agents, early FL measurements accurately separate clinical responders from those experiencing PNR. The method described here offers several potential advantages over other strategies to assess and manage these patients.
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Affiliation(s)
- Dario Sorrentino
- IBD Center, Division of Gastroenterology, Virginia Tech Carilion School of Medicine, Roanoke, Virginia, USA,Department of Clinical and Experimental Medical Sciences, University of Udine School of Medicine, Udine, Italy,*Dario Sorrentino,
| | - Vu Q. Nguyen
- IBD Center, Division of Gastroenterology, Virginia Tech Carilion School of Medicine, Roanoke, Virginia, USA
| | - Kim Love
- K.R. Love Quantitative Consulting and Collaboration, Athens, Georgia, USA
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Wallace JW, Constant DA, Nice TJ. Interferon Lambda in the Pathogenesis of Inflammatory Bowel Diseases. Front Immunol 2021; 12:767505. [PMID: 34712246 PMCID: PMC8547615 DOI: 10.3389/fimmu.2021.767505] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 09/23/2021] [Indexed: 12/12/2022] Open
Abstract
Interferon λ (IFN-λ) is critical for host viral defense at mucosal surfaces and stimulates immunomodulatory signals, acting on epithelial cells and few other cell types due to restricted IFN-λ receptor expression. Epithelial cells of the intestine play a critical role in the pathogenesis of Inflammatory Bowel Disease (IBD), and the related type II interferons (IFN-γ) have been extensively studied in the context of IBD. However, a role for IFN-λ in IBD onset and progression remains unclear. Recent investigations of IFN-λ in IBD are beginning to uncover complex and sometimes opposing actions, including pro-healing roles in colonic epithelial tissues and potentiation of epithelial cell death in the small intestine. Additionally, IFN-λ has been shown to act through non-epithelial cell types, such as neutrophils, to protect against excessive inflammation. In most cases IFN-λ demonstrates an ability to coordinate the host antiviral response without inducing collateral hyperinflammation, suggesting that IFN-λ signaling pathways could be a therapeutic target in IBD. This mini review discusses existing data on the role of IFN-λ in the pathogenesis of inflammatory bowel disease, current gaps in the research, and therapeutic potential of modulating the IFN-λ-stimulated response.
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Affiliation(s)
- Jonathan W Wallace
- Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, United States
| | - David A Constant
- Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, United States
| | - Timothy J Nice
- Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, United States
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Albader F, Golovics PA, Gonczi L, Bessissow T, Afif W, Lakatos PL. Therapeutic drug monitoring in inflammatory bowel disease: The dawn of reactive monitoring. World J Gastroenterol 2021; 27:6231-6247. [PMID: 34712029 PMCID: PMC8515794 DOI: 10.3748/wjg.v27.i37.6231] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/08/2021] [Accepted: 08/31/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic condition that significantly affects the quality of life of its patients. Biologic drugs have been the mainstay treatment in the management of IBD patients but despite their significant contribution, there remains a proportion of patients that do not respond or lose response to treatment. Therapeutic drug monitoring (TDM) involves measuring levels of serum drug concentrations and anti-drug antibodies. TDM of biologic drugs initially emerged to understand treatment failure in other immune mediated inflammatory diseases. This was then introduced in IBD to rationalize primary non-response or secondary loss of response, given that low serum drug concentrations or the formation of anti-drug antibodies are variably associated with treatment failure. The aim of this narrative review is to provide an overview regarding the current use of TDM in clinical practice and to present the evidence available regarding its use in both proactive and reactive clinical settings in preventing and managing treatment failure. This review also presents the existing evidence regarding the association of various clinical outcomes with specific thresholds of drug concentrations, in everyday practice. A narrative review of published articles and conference abstracts regarding the use of TDM in IBD management, through an electronic search using PubMed and ScienceDirect. TDM has proven to be superior and more cost effective in guiding management of patients with treatment failure compared to empiric dose escalation or change in treatment. Despite a trend towards an association between clinical outcomes and drug concentrations, proactive TDM based strategies have not been shown to achieve clear benefit in long-term outcomes. In the clinical setting, TDM has proven to be useful in managing IBD patients, and its use in the reactive setting, as an additional tool to help manage patients with treatment failure, is being promoted as newer guidelines and consensus groups implement TDM as part of the management plan.
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Affiliation(s)
- Farah Albader
- Department of Internal Medicine, McGill University, Montreal H3G1A4, Quebec, Canada
| | - Petra Anna Golovics
- Division of Gastroenterology, Hungarian Defence Forces, Medical Centre, Budapest H-1062, Hungary
- Division of Gastroenterology, McGill University, Montreal H3G 1A4, Quebec, Canada
| | - Lorant Gonczi
- First Department of Medicine, Semmelweis University, Budapest H-1083, Hungary
| | - Talat Bessissow
- Division of Gastroenterology, McGill University Health Centre, Montreal H3G 1A4, Quebec, Canada
| | - Waqqas Afif
- Division of Gastroenterology, McGill University, Montreal H3G 1A4, Quebec, Canada
| | - Peter Laszlo Lakatos
- Division of Gastroenterology, McGill University, Montreal H3G 1A4, Quebec, Canada
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Abidin AZ, Snoswell CL, Shafiee Hanjani L, Callaghan G, Edmonds M. Infliximab switching from reference product to biosimilar: a review of evidence regarding the clinical efficacy, safety profile and immunogenicity. JOURNAL OF PHARMACY PRACTICE AND RESEARCH 2021. [DOI: 10.1002/jppr.1754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Ahmad Zainal Abidin
- Centre for Health Services Research The University of Queensland Brisbane Qld Australia
| | - Centaine L. Snoswell
- Centre for Health Services Research The University of Queensland Brisbane Qld Australia
- Pharmacy Department Princess Alexandra Hospital Brisbane Qld Australia
- School of Pharmacy The University of Queensland Brisbane Qld Australia
| | - Leila Shafiee Hanjani
- Centre for Health Services Research The University of Queensland Brisbane Qld Australia
| | - Gavin Callaghan
- Pharmacy Department Princess Alexandra Hospital Brisbane Qld Australia
| | - Michelle Edmonds
- Pharmacy Department Princess Alexandra Hospital Brisbane Qld Australia
- Pharmacy Department Royal Darwin Hospital Darwin NT Australia
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Hashash JG, Fadel CGA, Rimmani HH, Sharara AI. Biologic monotherapy versus combination therapy with immunomodulators in the induction and maintenance of remission of Crohn's disease and ulcerative colitis. Ann Gastroenterol 2021; 34:612-624. [PMID: 34475731 PMCID: PMC8375659 DOI: 10.20524/aog.2021.0645] [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: 01/16/2021] [Accepted: 03/12/2021] [Indexed: 12/19/2022] Open
Abstract
Despite current guidelines, the optimal treatment of patients with inflammatory bowel disease (IBD) remains challenging. The available medications are not without risk and there is not a single correct treatment regimen for every patient. Personalizing treatment and selecting the most appropriate therapy is crucial for optimal response, remission, quality of life, and healthcare utilization. Biologics, especially anti-tumor necrosis factor-α medications, are widely used in the induction and maintenance of disease remission in patients with IBD. Similarly, immunomodulators, including thiopurines and methotrexate, are traditionally popular for the maintenance of remission. In this manuscript, we review the use of biologic monotherapy vs. combination therapy with immunomodulators for the treatment of ulcerative colitis and Crohn’s disease. We examine overall remission, immunogenicity and adverse effects, mainly serious infections and malignancy, in an effort to help guide treatment decisions and weigh the risks and benefits of biologic monotherapy vs. combination therapy.
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Affiliation(s)
- Jana G Hashash
- Division of Gastroenterology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut (Jana G. Hashash, Hussein H. Rimmani, Ala I. Sharara)
| | - Carla G Abou Fadel
- Division of Gastroenterology, Bellevue Medical Center, Mansourieh (Carla G. Abou Fadel), Lebanon
| | - Hussein H Rimmani
- Division of Gastroenterology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut (Jana G. Hashash, Hussein H. Rimmani, Ala I. Sharara)
| | - Ala I Sharara
- Division of Gastroenterology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut (Jana G. Hashash, Hussein H. Rimmani, Ala I. Sharara)
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Luber RP, O'Neill R, Singh S, Sharma E, Cunningham G, Honap S, Meade S, Ray S, Anderson SH, Mawdsley J, Sanderson JD, Samaan MA, Arkir Z, Irving PM. An observational study of switching infliximab biosimilar: no adverse impact on inflammatory bowel disease control or drug levels with first or second switch. Aliment Pharmacol Ther 2021; 54:678-688. [PMID: 34223654 DOI: 10.1111/apt.16497] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 04/16/2021] [Accepted: 06/08/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Biologics account for a significant cost in inflammatory bowel disease (IBD) management; however, switching from infliximab originator to its biosimilars has enabled cost saving without compromising disease control. The effects on IBD activity and infliximab trough levels of a second switch to another biosimilar are, however, uncertain. AIMS To assess the effects on disease activity and infliximab trough levels associated with switching from infliximab biosimilar CT-P13 to another biosimilar SB2 and compare outcomes in those switching for the first and second time. METHODS IBD patients on CT-P13, including some previously switched from originator, were prospectively followed during a switch to SB2. C-reactive protein (CRP), trough infliximab level and clinical disease activity indices were collected at baseline, Infusion 3 or 4 ('early' after switch), and 1 year. RESULTS One hundred eighty-six patients (n = 99 second switch) on stable infliximab dosing underwent switching. Compared with baseline, there was no significant change in CRP, clinical disease activity scores or median trough infliximab level at the early time point among first-switch (baseline vs early: 5.7 vs 6.6 µg/mL, P = 0.05) and second-switch (4.3 vs 4.9 µg/mL, P = 0.07) patients nor at 1 year (median infliximab trough levels, baseline vs 1 year, in first-switch [5.7 vs 5.7 µg/mL, P = 0.37] and second-switch [4.3 vs 4.7 µg/mL, P = 0.06] patients). The proportion of patients in clinical remission did not significantly change at the early (92% vs 91% at baseline, P = 0.75) or 1 year (95% vs 91% at baseline, P = 0.16) time points. There was no significant difference in time to loss of response between patients switching for the first or second time (P = 0.69). CONCLUSIONS Switching from one infliximab biosimilar to another had no adverse impact on infliximab trough levels, and clinical and biochemical disease activity, regardless of whether switching for the first or second time.
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Affiliation(s)
- Raphael P Luber
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Rhona O'Neill
- Department of Pharmacy, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Sukhpreet Singh
- Department of Pharmacy, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Esha Sharma
- Department of Pharmacy, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Georgina Cunningham
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Sailish Honap
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Susanna Meade
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Shuvra Ray
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Simon H Anderson
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Joel Mawdsley
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Jeremy D Sanderson
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Mark A Samaan
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Zehra Arkir
- Viapath Analytics, Guy's & St Thomas' NHS Foundation Trust, London, UK
| | - Peter M Irving
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK.,School of Immunology and Microbial Sciences, King's College London, London, UK
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Cho CW, You MW, Oh CH, Lee CK, Moon SK. Long-term Disease Course of Crohn's Disease: Changes in Disease Location, Phenotype, Activities, and Predictive Factors. Gut Liver 2021; 16:157-170. [PMID: 34456186 PMCID: PMC8924800 DOI: 10.5009/gnl210118] [Citation(s) in RCA: 8] [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: 03/13/2021] [Revised: 07/01/2021] [Accepted: 07/13/2021] [Indexed: 11/04/2022] Open
Abstract
Crohn's disease (CD) is a chronic destructive inflammatory bowel disease that affects young people and is associated with significant morbidity. The clinical spectrum and disease course of CD are heterogeneous and often difficult to predict based on the initial presentation. In this article, changes in the disease location, behavior, clinical course during long-term follow-up, and predictive factors are reviewed. Generally, four different patterns of clinical course are discussed: remission, stable disease, chronic relapsing disease, and chronic refractory disease. Understanding the long-term disease course of CD is mandatory to reveal the underlying pathophysiology of the disease and to move toward a more optimistic disease course, such as remission or stability, and less adverse outcomes or devastating sequelae.
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Affiliation(s)
- Choong Wui Cho
- Department of Radiology, Kyung Hee University Hospital, Seoul, Korea
| | - Myung-Won You
- Department of Radiology, Kyung Hee University Hospital, Seoul, Korea
| | - Chi Hyuk Oh
- Department of Internal Medicine, Kyung Hee University Hospital, Seoul, Korea
| | - Chang Kyun Lee
- Department of Internal Medicine, Kyung Hee University Hospital, Seoul, Korea
| | - Sung Kyoung Moon
- Department of Radiology, Kyung Hee University Hospital, Seoul, Korea
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Schräpel C, Kovar L, Selzer D, Hofmann U, Tran F, Reinisch W, Schwab M, Lehr T. External Model Performance Evaluation of Twelve Infliximab Population Pharmacokinetic Models in Patients with Inflammatory Bowel Disease. Pharmaceutics 2021; 13:pharmaceutics13091368. [PMID: 34575443 PMCID: PMC8468301 DOI: 10.3390/pharmaceutics13091368] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/26/2021] [Accepted: 08/27/2021] [Indexed: 01/12/2023] Open
Abstract
Infliximab is approved for treatment of various chronic inflammatory diseases including inflammatory bowel disease (IBD). However, high variability in infliximab trough levels has been associated with diverse response rates. Model-informed precision dosing (MIPD) with population pharmacokinetic models could help to individualize infliximab dosing regimens and improve therapy. The aim of this study was to evaluate the predictive performance of published infliximab population pharmacokinetic models for IBD patients with an external data set. The data set consisted of 105 IBD patients with 336 infliximab concentrations. Literature review identified 12 published models eligible for external evaluation. Model performance was evaluated with goodness-of-fit plots, prediction- and variability-corrected visual predictive checks (pvcVPCs) and quantitative measures. For anti-drug antibody (ADA)-negative patients, model accuracy decreased for predictions > 6 months, while bias did not increase. In general, predictions for patients developing ADA were less accurate for all models investigated. Two models with the highest classification accuracy identified necessary dose escalations (for trough concentrations < 5 µg/mL) in 88% of cases. In summary, population pharmacokinetic modeling can be used to individualize infliximab dosing and thereby help to prevent infliximab trough concentrations dropping below the target trough concentration. However, predictions of infliximab concentrations for patients developing ADA remain challenging.
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Affiliation(s)
- Christina Schräpel
- Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany; (C.S.); (L.K.); (D.S.)
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, 70376 Stuttgart, Germany; (U.H.); (M.S.)
| | - Lukas Kovar
- Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany; (C.S.); (L.K.); (D.S.)
| | - Dominik Selzer
- Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany; (C.S.); (L.K.); (D.S.)
| | - Ute Hofmann
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, 70376 Stuttgart, Germany; (U.H.); (M.S.)
| | - Florian Tran
- Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, 24105 Kiel, Germany;
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany
| | - Walter Reinisch
- Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria;
| | - Matthias Schwab
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, 70376 Stuttgart, Germany; (U.H.); (M.S.)
- Departments of Clinical Pharmacology, Pharmacy and Biochemistry, University of Tübingen, 72076 Tübingen, Germany
| | - Thorsten Lehr
- Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany; (C.S.); (L.K.); (D.S.)
- Correspondence: ; Tel.: +49-681-302-70255
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Hedin CRH, Sonkoly E, Eberhardson M, Ståhle M. Inflammatory bowel disease and psoriasis: modernizing the multidisciplinary approach. J Intern Med 2021; 290:257-278. [PMID: 33942408 DOI: 10.1111/joim.13282] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 01/11/2021] [Accepted: 01/18/2021] [Indexed: 12/11/2022]
Abstract
Psoriasis and inflammatory bowel disease (IBD) are immune-mediated diseases occurring in barrier organs whose main task is to protect the organism from attack. These disorders are highly prevalent especially in northern Europe where psoriasis has a prevalence of around 3-4% and IBD around 0.3%. The prevalence of IBD in North America has been estimated at around 0.4%. The total incidence rates in northern Europe have been estimated at around 6 for Crohn's disease and 11 for ulcerative colitis per 100 000 person-years, compared with an incidence rate of around 280 per 100 000 person-years for psoriasis. Both diseases are less common in countries with a lower index of development. The rise in IBD appears to occur as populations adopt a westernized lifestyle, whereas psoriasis seems more stable and prevalence differences may derive more from variation in genetic susceptibility. The gut microbiota is clearly an important driver of IBD pathogenesis; in psoriasis, changes in gut and skin microbiota have been reported, but it is less clear whether and how these changes contribute to the pathogenesis. Large studies show that most identified genes are involved in the immune system. However, psoriasis and IBD are highly heterogeneous diseases and there is a need for more precise and deeper phenotyping to identify specific subgroups and their genetic, epigenetic and molecular signatures. Epigenetic modifications of DNA such as histone modifications, noncoding RNA effects on transcription and translation and DNA methylation are increasingly recognized as the mechanism underpinning much of the gene-environment interaction in the pathogenesis of both IBD and psoriasis. Our understanding of underlying pathogenetic mechanisms has deepened fundamentally over the past decades developing hand in hand with novel therapies targeting pathways and proinflammatory cytokines incriminated in disease. There is not only substantial overlap between psoriasis and IBD, but also there are differences with implication for therapy. In psoriasis, drugs targeting interleukin-23 and interleukin-17 have shown superior efficacy compared with anti-TNFs, whilst in IBD, drugs targeting interleukin-17 may be less beneficial. The therapeutic toolbox for psoriasis is impressive and is enlarging also for IBD. Still, there are unmet needs reflecting the heterogeneity of both diseases and there is a need for closer molecular diagnostics to allow for the development of precise therapeutics.
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Affiliation(s)
- C R H Hedin
- From the, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Division of Gastroenterology, Medical Unit Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - E Sonkoly
- From the, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Division of Dermatology, Medical Unit Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - M Eberhardson
- From the, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Department of Gastroenterology, University Hospital in Linkoping, Linkoping, Sweden
| | - M Ståhle
- From the, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Division of Dermatology, Medical Unit Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
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