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Clemente Bautista S, Segarra Cantón Ó, Padullés-Zamora N, García García S, Álvarez Beltrán M, Larrosa García M, Cabañas Poy MJ, Sanz-Martínez MT, Vázquez A, Gorgas Torner MQ, Miarons M. Long-Term Effectiveness and Safety of Proactive Therapeutic Drug Monitoring of Infliximab in Paediatric Inflammatory Bowel Disease: A Real-World Study. Pharmaceutics 2024; 16:1577. [PMID: 39771556 PMCID: PMC11678755 DOI: 10.3390/pharmaceutics16121577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/03/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND This study evaluated the long-term effectiveness and safety of a multidisciplinary early proactive therapeutic drug monitoring (TDM) program combined with Bayesian forecasting for infliximab (IFX) dose adjustment in a real-world dataset of paediatric patients with inflammatory bowel disease (IBD). METHODS A descriptive, ambispective, single-centre study of paediatric patients with IBD who underwent IFX serum concentration measurements between September 2015 and September 2023. The patients received reactive TDM before September 2019 (n = 17) and proactive TDM thereafter (n = 21). We analysed for clinical, biological, and endoscopic remission; treatment failure; hospitalisations; emergency visits; and adverse drug reactions. The IFX doses were adjusted to maintain trough concentrations ≥ 5 µg/mL, with specific targets for proactive TDM. RESULTS Of the 38 patients, 21 had Crohn's disease (CD), 16 ulcerative colitis (UC), and 1 undetermined IBD. The mean (standard deviation) IFX trough concentrations were 6.83 (5.66) µg/mL (reactive) and 12.38 (9.24) µg/mL (proactive) (p = 0.08). No statistically significant differences between groups were found in remission rates or treatment failure. The proactive group had fewer hospitalisations (14.29% vs. 23.53%; p = 0.47) and shorter median hospitalisation days (6 vs. 19; p = 0.50), although the difference was not statistically significant. The number of patients with adverse reactions (infusion related reactions and infections) was higher in the proactive group (38.10% vs. 23.53%; p = 0.34) but the difference was not significantly different. CONCLUSIONS Proactive TDM showed no significant differences in treatment outcomes compared to reactive TDM. However, the results in both the reactive and proactive TDM groups were not worse than those reported in other studies. Further studies with larger samples are needed to optimize the treatment strategies for pediatric IBD patients.
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Affiliation(s)
- Susana Clemente Bautista
- Pharmacy Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (S.G.G.); (M.L.G.); (M.J.C.P.); (M.Q.G.T.); (M.M.)
| | - Óscar Segarra Cantón
- Paediatric Gastroenterology and Clinical Nutrition Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (Ó.S.C.); (M.Á.B.)
- Department of Paediatrics, Obstetrics and Gynaecology, Preventive Medicine and Public Health of the Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Núria Padullés-Zamora
- Pharmacy Department, Hospital Universitari de Bellvitge-IDIBELL, Feixa Llarga s/n, L’Hospitalet de Llobregat, 08907 Barcelona, Spain;
| | - Sonia García García
- Pharmacy Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (S.G.G.); (M.L.G.); (M.J.C.P.); (M.Q.G.T.); (M.M.)
| | - Marina Álvarez Beltrán
- Paediatric Gastroenterology and Clinical Nutrition Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (Ó.S.C.); (M.Á.B.)
| | - María Larrosa García
- Pharmacy Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (S.G.G.); (M.L.G.); (M.J.C.P.); (M.Q.G.T.); (M.M.)
| | - Maria Josep Cabañas Poy
- Pharmacy Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (S.G.G.); (M.L.G.); (M.J.C.P.); (M.Q.G.T.); (M.M.)
| | - Maria Teresa Sanz-Martínez
- Immunology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain;
| | - Ana Vázquez
- Department of Applied Statistics, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain;
| | - Maria Queralt Gorgas Torner
- Pharmacy Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (S.G.G.); (M.L.G.); (M.J.C.P.); (M.Q.G.T.); (M.M.)
| | - Marta Miarons
- Pharmacy Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (S.G.G.); (M.L.G.); (M.J.C.P.); (M.Q.G.T.); (M.M.)
- Pharmacy Department, Consorci Hospitalari de Vic, 08500 Barcelona, Spain
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Bonazzi E, Maniero D, Lorenzon G, Bertin L, Bray K, Bahur B, Barberio B, Zingone F, Savarino EV. Comparing Point-of-Care Technology to ELISA Testing for Infliximab and Adalimumab Levels in Adult Inflammatory Bowel Disease Patients: A Prospective Pilot Study. Diagnostics (Basel) 2024; 14:2140. [PMID: 39410544 PMCID: PMC11482612 DOI: 10.3390/diagnostics14192140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 09/19/2024] [Accepted: 09/24/2024] [Indexed: 10/19/2024] Open
Abstract
Introduction: Therapeutic drug monitoring (TDM) has proven to be a valuable strategy for optimizing biologic therapies, among which are anti-tumor necrosis factor (anti-TNF) treatments in inflammatory bowel disease (IBD). In particular, reactive TDM has been shown to manage treatment failures more cost-effectively than empirical dose adjustments for anti-TNF drugs. However, several challenges currently impede the widespread adoption of TDM in clinical practice, particularly addressing the delay between sample collection and result availability. To overcome this limitation, the use of point-of-care technology tests (POCTs) is a potential solution. Point-of-care technology tests are medical diagnostic tests performed at the site of patient care to provide immediate results, allowing for quicker decision-making and treatment. The current standard of care (SOC) for drug level measurement relies on the enzyme-linked immunosorbent assay (ELISA), a method that is time-consuming and requires specialized personnel. This study aims to evaluate a novel, user-friendly, and efficient POCT method (ProciseDx Inc.) and compare its performance with the SOC ELISA in assessing infliximab and adalimumab levels in blood samples from IBD patients. Methods: In this prospective, single-center study, we collected blood samples from IBD patients, both CD and UC, receiving infliximab (87 IBD patients; 50% UC and 50% CD) or adalimumab (60 patients; 14% UC and 48% CD) and we analyzed the blood's drugs levels using both the ProciseDx Analyzer POC and the SOC ELISA. We examined the correlation between the two methods using statistical analyses, including the Deming regression test. Additionally, we assessed the ease of use, turnaround time, and overall practicality of the POCT in a clinical setting. Results: The ProciseDx test demonstrated a strong correlation with the SOC ELISA for measuring both infliximab and adalimumab levels. In particular, the overall correlation between the ProciseDx POCT and the ELISA assessments showed an r coefficient of 0.83 with an R squared value of 0.691 (95% CI 0.717-0.902) for IFX measurements, and an r coefficient of 0.85 with an R squared value of 0.739 (95% CI 0.720-0.930). Conclusions: the ProciseDx POC test offers significantly faster turnaround times and is more straightforward to use, making it a viable alternative for routine clinical monitoring. Despite its promising potential, further refinement and validation of the ProciseDx test are necessary to ensure its effectiveness across diverse patient populations and clinical settings. Future research should focus on optimizing the POC tests' performance and evaluating its long-term impact on IBD management.
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Affiliation(s)
- Erica Bonazzi
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy; (E.B.); (D.M.); (G.L.); (L.B.); (F.Z.)
| | - Daria Maniero
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy; (E.B.); (D.M.); (G.L.); (L.B.); (F.Z.)
| | - Greta Lorenzon
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy; (E.B.); (D.M.); (G.L.); (L.B.); (F.Z.)
| | - Luisa Bertin
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy; (E.B.); (D.M.); (G.L.); (L.B.); (F.Z.)
- Gastroenterology Unit, Azienda Ospedale—Università Padova, 35128 Padua, Italy;
| | - Kurtis Bray
- ProciseDx Inc., 9449 Carroll Park Drive, San Diego, CA 92121, USA; (K.B.); (B.B.)
| | - Bayda Bahur
- ProciseDx Inc., 9449 Carroll Park Drive, San Diego, CA 92121, USA; (K.B.); (B.B.)
| | - Brigida Barberio
- Gastroenterology Unit, Azienda Ospedale—Università Padova, 35128 Padua, Italy;
| | - Fabiana Zingone
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy; (E.B.); (D.M.); (G.L.); (L.B.); (F.Z.)
- Gastroenterology Unit, Azienda Ospedale—Università Padova, 35128 Padua, Italy;
| | - Edoardo Vincenzo Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy; (E.B.); (D.M.); (G.L.); (L.B.); (F.Z.)
- Gastroenterology Unit, Azienda Ospedale—Università Padova, 35128 Padua, Italy;
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Alsoud D, Moes DJAR, Wang Z, Soenen R, Layegh Z, Barclay M, Mizuno T, Minichmayr IK, Keizer RJ, Wicha SG, Wolbink G, Lambert J, Vermeire S, de Vries A, Papamichael K, Padullés-Zamora N, Dreesen E. Best Practice for Therapeutic Drug Monitoring of Infliximab: Position Statement from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. Ther Drug Monit 2024; 46:291-308. [PMID: 38648666 DOI: 10.1097/ftd.0000000000001204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 02/21/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND Infliximab, an anti-tumor necrosis factor monoclonal antibody, has revolutionized the pharmacological management of immune-mediated inflammatory diseases (IMIDs). This position statement critically reviews and examines existing data on therapeutic drug monitoring (TDM) of infliximab in patients with IMIDs. It provides a practical guide on implementing TDM in current clinical practices and outlines priority areas for future research. METHODS The endorsing TDM of Biologics and Pharmacometrics Committees of the International Association of TDM and Clinical Toxicology collaborated to create this position statement. RESULTS Accumulating data support the evidence for TDM of infliximab in the treatment of inflammatory bowel diseases, with limited investigation in other IMIDs. A universal approach to TDM may not fully realize the benefits of improving therapeutic outcomes. Patients at risk for increased infliximab clearance, particularly with a proactive strategy, stand to gain the most from TDM. Personalized exposure targets based on therapeutic goals, patient phenotype, and infliximab administration route are recommended. Rapid assays and home sampling strategies offer flexibility for point-of-care TDM. Ongoing studies on model-informed precision dosing in inflammatory bowel disease will help assess the additional value of precision dosing software tools. Patient education and empowerment, and electronic health record-integrated TDM solutions will facilitate routine TDM implementation. Although optimization of therapeutic effectiveness is a primary focus, the cost-reducing potential of TDM also merits consideration. CONCLUSIONS Successful implementation of TDM for infliximab necessitates interdisciplinary collaboration among clinicians, hospital pharmacists, and (quantitative) clinical pharmacologists to ensure an efficient research trajectory.
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Affiliation(s)
- Dahham Alsoud
- Translational Research in Gastrointestinal Disorders, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Dirk Jan A R Moes
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, the Netherlands
| | - Zhigang Wang
- Clinical Pharmacology and Pharmacotherapy Unit, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Rani Soenen
- Dermatology Research Unit, Ghent University, Ghent, Belgium
- Department of Dermatology, Ghent University Hospital, Ghent, Belgium
| | - Zohra Layegh
- Department of Pathology, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Murray Barclay
- Departments of Gastroenterology and Clinical Pharmacology, Christchurch Hospital, Te Whatu Ora Waitaha and University of Otago, Christchurch, New Zealand
| | - Tomoyuki Mizuno
- Division of Translational and Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Iris K Minichmayr
- Department of Clinical Pharmacology, Medical University Vienna, Vienna, Austria
| | | | - Sebastian G Wicha
- Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Hamburg, Germany
| | - Gertjan Wolbink
- Department of Rheumatology, Amsterdam Rheumatology and Immunology Center Location Reade, Amsterdam, Netherlands
- Sanquin Research and Landsteiner Laboratory, Department of Immunopathology, Amsterdam UMC, Amsterdam, Netherlands
| | - Jo Lambert
- Dermatology Research Unit, Ghent University, Ghent, Belgium
- Department of Dermatology, Ghent University Hospital, Ghent, Belgium
| | - Séverine Vermeire
- Translational Research in Gastrointestinal Disorders, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Annick de Vries
- Sanquin Diagnostic Services, Pharma & Biotech Services, Amsterdam, the Netherlands
| | - Konstantinos Papamichael
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Núria Padullés-Zamora
- Department of Pharmacy, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain; and
- School of Pharmacy, University of Barcelona, Barcelona, Spain
| | - Erwin Dreesen
- Clinical Pharmacology and Pharmacotherapy Unit, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
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Rodríguez-Moranta F, Argüelles-Arias F, Hinojosa Del Val J, Iborra Colomino M, Martín-Arranz MD, Menchén Viso L, Muñoz Núñez F, Ricart Gómez E, Sánchez-Hernández JG, Valdés-Delgado T, Guardiola Capón J, Barreiro-de Acosta M, Mañosa Ciria M, Zabana Abdo Y, Gutiérrez Casbas A. Therapeutic drug monitoring in inflammatory bowel diseases. Position statement of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis. GASTROENTEROLOGIA Y HEPATOLOGIA 2024; 47:522-552. [PMID: 38311005 DOI: 10.1016/j.gastrohep.2024.01.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 12/31/2023] [Accepted: 01/18/2024] [Indexed: 02/06/2024]
Abstract
The treatment of inflammatory bowel disease has undergone a significant transformation following the introduction of biologic drugs. Thanks to these drugs, treatment goals have evolved from clinical response and remission to more ambitious objectives, such as endoscopic or radiologic remission. However, even though biologics are highly effective, a significant percentage of patients will not achieve an initial response or may lose it over time. We know that there is a direct relationship between the trough concentrations of the biologic and its therapeutic efficacy, with more demanding therapeutic goals requiring higher drug levels, and inadequate exposure being common. Therapeutic drug monitoring of biologic medications, along with pharmacokinetic models, provides us with the possibility of offering a personalized approach to treatment for patients with IBD. Over the past few years, relevant information has accumulated regarding its utility during or after induction, as well as in the maintenance of biologic treatment, in reactive or proactive strategies, and prior to withdrawal or treatment de-escalation. The aim of this document is to establish recommendations regarding the utility of therapeutic drug monitoring of biologics in patients with inflammatory bowel disease, in different clinical practice scenarios, and to identify areas where its utility is evident, promising, or controversial.
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Affiliation(s)
- Francisco Rodríguez-Moranta
- Servicio de Aparato Digestivo, Hospital Universitario de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, Barcelona, España.
| | - Federico Argüelles-Arias
- Servicio de Aparato Digestivo, Hospital Universitario Virgen Macarena, Sevilla, España; Facultad de Medicina, Universidad de Sevilla, Sevilla, España
| | | | - Marisa Iborra Colomino
- Servicio de Aparato Digestivo, Hospital Universitario y Politécnico de La Fe, Valencia, España
| | - M Dolores Martín-Arranz
- Servicio de Aparato Digestivo, Hospital Universitario La Paz, Facultad de Medicina de la UAM, Fundación para la investigación del Hospital Universitario la Paz (IDIPAZ), Madrid, España
| | - Luis Menchén Viso
- Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón-IiSGM, Madrid, España; Departamento de Medicina, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, España
| | - Fernando Muñoz Núñez
- Servicio de Aparato Digestivo, Hospital Universitario de Salamanca, Salamanca, España
| | - Elena Ricart Gómez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), H. Clínic Barcelona, Barcelona, IDIBAPS, Barcelona, España
| | | | - Teresa Valdés-Delgado
- Servicio de Aparato Digestivo, Hospital Universitario Virgen Macarena, Sevilla, España
| | - Jordi Guardiola Capón
- Servicio de Gastroenterología, Hospital Universitario de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, Barcelona, España
| | - Manuel Barreiro-de Acosta
- Servicio de Gastroenterología, Hospital Clínico Universitario de Santiago, A Coruña, España; Fundación Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), A Coruña, España
| | - Míriam Mañosa Ciria
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, España; Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Gastroenterología, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, España
| | - Yamile Zabana Abdo
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, España; Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Gastroenterología, Hospital Mútua de Terrassa (HMT), Terrassa, Barcelona, España
| | - Ana Gutiérrez Casbas
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, España; Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, España
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Gisbert JP, Chaparro M. De-escalation of Biologic Treatment in Inflammatory Bowel Disease: A Comprehensive Review. J Crohns Colitis 2024; 18:642-658. [PMID: 37943286 DOI: 10.1093/ecco-jcc/jjad181] [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: 09/04/2023] [Indexed: 11/10/2023]
Abstract
INTRODUCTION Biologic therapy is an effective treatment for inflammatory bowel disease [IBD]. However due to cost and safety concerns, dose de-escalation strategies after achieving remission have been suggested. AIM To critically review available data on dose de-escalation of biologics [or other advanced therapies] in IBD. We will focus on studies evaluating de-escalation to standard dosing in patients initially optimised, and also on studies assessing de-escalation from standard dosing. METHODS A systematic bibliographic search was performed. RESULTS The mean frequency of de-escalation after previous dose intensification [12 studies, 1,474 patients] was 34%. The corresponding frequency of de-escalation from standard dosing [five studies, 3,842 patients] was 4.2%. The relapse rate of IBD following anti-tumour necrosis factor [TNF] de-escalation to standard dosing in patients initially dose-escalated [10 studies, 301 patients] was 30%. The corresponding relapse rate following anti-TNF de-escalation from standard dosing [nine studies, 494 patients] was 38%. The risk of relapse was lower for patients in clinical, biologic, and endoscopic/radiological remission at the time of de-escalation. A role of anti-TNF therapeutic drug monitoring in the decision to dose de-escalate has been demonstrated. In patients relapsing after de-escalation, re-escalation is generally effective. De-escalation is not consistently associated with a better safety profile. The cost-effectiveness of the de-escalation strategy remains uncertain. Finally, there is not enough evidence to recommend dose de-escalation of biologics different from anti-TNFs or small molecules. CONCLUSIONS Any consideration for de-escalation of biologic therapy in IBD must be tailored, taking into account the risks and consequences of a flare and patients' preferences.
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Affiliation(s)
- 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
| | - María Chaparro
- 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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Liu D, Hu L, Shao H. Therapeutic drug monitoring of immune checkpoint inhibitors: based on their pharmacokinetic properties and biomarkers. Cancer Chemother Pharmacol 2023:10.1007/s00280-023-04541-8. [PMID: 37410155 DOI: 10.1007/s00280-023-04541-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 05/03/2023] [Indexed: 07/07/2023]
Abstract
As a new means of oncology treatment, immune checkpoint inhibitors (ICIs) can improve survival rates in patients with resistant or refractory tumors. However, there are obvious inter-individual differences in the unsatisfactory response rate, drug resistance rate and the occurrence of immune-related adverse events (irAE). These questions have sparked interest in researchers looking for a way to screen sensitive populations and predict efficacy and safety. Therapeutic drug monitoring (TDM) is a way to ensure the safety and effectiveness of medication by measuring the concentration of drugs in body fluids and adjusting the medication regimen. It has the potential to be an adjunctive means of predicting the safety and efficacy of ICIs treatment. In this review, the author outlined the pharmacokinetic (PK) characteristics of ICIs in patients. The feasibility and limitations of TDM of ICIs were discussed by summarizing the relationships between the pharmacokinetic parameters and the efficacy, toxicity and biomarkers.
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Affiliation(s)
- Dongxue Liu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Linlin Hu
- Department of Pharmacy, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
- Office of Medication Clinical Institution, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Hua Shao
- Office of Medication Clinical Institution, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
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Crispino F, Michielan A, Grova M, Tieppo C, Mazza M, Rogger TM, Armelao F. Exit strategies in inflammatory bowel disease: Looking beyond anti-tumor necrosis factors. World J Clin Cases 2023; 11:2657-2669. [PMID: 37214561 PMCID: PMC10198103 DOI: 10.12998/wjcc.v11.i12.2657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/10/2023] [Accepted: 03/29/2023] [Indexed: 04/25/2023] Open
Abstract
The long-term management of patients with inflammatory bowel disease (IBD) is still a matter of debate, and no clear guidelines have been issued. In clinical practice, gastroenterologists often have to deal with patients in prolonged remission after immunomodulatory or immunosuppressive therapies. When planning an exit strategy for drug withdrawal, the risk of disease relapse must be balanced against the risk of drug-related adverse events and healthcare costs. Furthermore, there is still a dearth of data on the withdrawal of novel biologics, such as the anti-α4β7 integrin antibody (vedolizumab) and anti-IL12/23 antibody (ustekinumab), as well as the small molecule tofacitinib. Models for estimating the risk of disease relapse and the efficacy of retreatment should be evaluated according to the patient's age and IBD phenotype. These models should guide clinicians in programming a temporary drug withdrawal after discussing realistic outcomes with the patient. This would shift the paradigm from an exit strategy to a holiday strategy.
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Affiliation(s)
- Federica Crispino
- Azienda Provinciale per i Servizi Sanitari, Gastroenterology and Digestive Endoscopy Unit, Santa Chiara Hospital, Trento 38122, Italy
| | - Andrea Michielan
- Azienda Provinciale per i Servizi Sanitari, Gastroenterology and Digestive Endoscopy Unit, Santa Chiara Hospital, Trento 38122, Italy
| | - Mauro Grova
- Inflammatory Bowel Disease Unit, Department of Medicine, Azienda Ospedaliera Ospedali Riuniti, Villa Sofia-Cervello, Palermo 90146, Italy
| | - Chiara Tieppo
- Azienda Provinciale per i Servizi Sanitari, Gastroenterology and Digestive Endoscopy Unit, Santa Chiara Hospital, Trento 38122, Italy
| | - Marta Mazza
- Azienda Provinciale per i Servizi Sanitari, Gastroenterology and Digestive Endoscopy Unit, Santa Chiara Hospital, Trento 38122, Italy
| | - Teresa Marzia Rogger
- Azienda Provinciale per i Servizi Sanitari, Gastroenterology and Digestive Endoscopy Unit, Santa Chiara Hospital, Trento 38122, Italy
| | - Franco Armelao
- Azienda Provinciale per i Servizi Sanitari, Gastroenterology and Digestive Endoscopy Unit, Santa Chiara Hospital, Trento 38122, Italy
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Orfanoudaki E, Foteinogiannopoulou K, Theodoraki E, Koutroubakis IE. Recent Advances in the Optimization of Anti-TNF Treatment in Patients with Inflammatory Bowel Disease. J Clin Med 2023; 12:jcm12072452. [PMID: 37048536 PMCID: PMC10095227 DOI: 10.3390/jcm12072452] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/11/2023] [Accepted: 03/16/2023] [Indexed: 04/14/2023] Open
Abstract
Despite the evolution in inflammatory bowel disease (IBD) management during the last 20 years owing to the advent of new advanced therapies, anti-TNF agents still remain the cornerstone of therapy for both Crohn's disease and ulcerative colitis. However, this does not only secure favorable outcomes for patients considering the progressive disease character and the high likelihood of primary or secondary loss of response. Therefore, trying to reach a better treatment approach and maximize the benefits anti-TNF agents offer, optimization strategies should be examined. It has been indicated that optimizing treatment with anti-TNF enhances drug efficacy and has been associated with improved disease outcomes and a complication-free disease course. From this perspective, we aim to provide an overview of currently available data and recent advances in the practices of anti-TNF treatment optimization. Special focus has been given to the role of therapeutic drug monitoring (TDM), as well as the utility of combining anti-TNF with an immunomodulator and the treat-to-target approach.
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Affiliation(s)
- Eleni Orfanoudaki
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Kalliopi Foteinogiannopoulou
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Eirini Theodoraki
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Ioannis E Koutroubakis
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
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9
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Miyatani Y, Kobayashi T. De-escalation of Therapy in Patients with Quiescent Inflammatory Bowel Disease. Gut Liver 2023; 17:181-189. [PMID: 36375794 PMCID: PMC10018304 DOI: 10.5009/gnl220070] [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: 02/20/2022] [Revised: 05/25/2022] [Accepted: 06/03/2022] [Indexed: 11/16/2022] Open
Abstract
Inflammatory bowel disease is a chronic disease of unknown origin that requires long-term treatment. The optical duration of maintenance treatment once remission has been achieved remains unclear. When discussing a de-escalation strategy, not only the likelihood of relapse but also, the outcome of retreatment for relapse after de-escalation should be considered. Previous evidence has demonstrated controversial results for risk factors for relapse after de-escalation due to the various definitions of remission and relapse. In fact, endoscopic or histologic remission has been suggested as a treatment target; however, it might not always be indicative of a successful drug withdrawal. For better risk stratification of relapse after de-escalation, it may be necessary to evaluate both the current and previous treatments. Following de-escalation, biomarkers should be closely monitored. In addition to the risk of relapse, a comprehensive understanding of the overall outcome, such as the long-term safety, patient quality of life, and impact on healthcare costs, is necessary. Therefore, a shared decision-making with patients on a case-by-case basis is imperative.
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Affiliation(s)
- Yusuke Miyatani
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - Taku Kobayashi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
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10
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The Appropriately Designed TDM Clinical Trial: Endpoints, Pitfalls, and Perspectives. Ther Drug Monit 2023; 45:6-10. [PMID: 36624573 DOI: 10.1097/ftd.0000000000001010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 06/24/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND Appropriately designed clinical trials can provide the evidence needed to broadly implement therapeutic drug monitoring (TDM). In the past 30 years, some stunning successes but also some fascinating failures in demonstrating the benefits of TDM have been observed. Future TDM studies can be designed based on this experience. METHODS The manuscript is based on a combination of personal experience and published articles and discusses several aspects of the design and conduct of TDM studies. RESULTS Recommendations are provided to reduce the risk of protocol violations and to maximize the potential impact of a TDM study on clinical practice. CONCLUSIONS There are lessons that can be learned from previous experience, and this article gives an overview of potential TDM study designs, endpoints, pitfalls, and perspectives.
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11
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Kantasiripitak W, Outtier A, Wicha SG, Kensert A, Wang Z, Sabino J, Vermeire S, Thomas D, Ferrante M, Dreesen E. Multi‐model averaging improves the performance of model‐guided infliximab dosing in patients with inflammatory bowel diseases. CPT Pharmacometrics Syst Pharmacol 2022; 11:1045-1059. [PMID: 35706358 PMCID: PMC9381887 DOI: 10.1002/psp4.12813] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 04/08/2022] [Accepted: 05/05/2022] [Indexed: 11/11/2022] Open
Abstract
Infliximab dosage de‐escalation without prior knowledge of drug concentrations may put patients at risk for underexposure and trigger the loss of response. A single‐model approach for model‐informed precision dosing during infliximab maintenance therapy has proven its clinical benefit in patients with inflammatory bowel diseases. We evaluated the predictive performances of two multi‐model approaches, a model selection algorithm and a model averaging algorithm, using 18 published population pharmacokinetic models of infliximab for guiding dosage de‐escalation. Data of 54 patients with Crohn’s disease and ulcerative colitis who underwent infliximab dosage de‐escalation after an earlier escalation were used. A priori prediction (based solely on covariate data) and maximum a posteriori prediction (based on covariate data and trough concentrations) were compared using accuracy and precision metrics and the classification accuracy at the trough concentration target of 5.0 mg/L. A priori prediction was inaccurate and imprecise, with the lowest classification accuracies irrespective of the approach (median 59%, interquartile range 59%–63%). Using the maximum a posteriori prediction, the model averaging algorithm had systematically better predictive performance than the model selection algorithm or the single‐model approach with any model, regardless of the number of concentration data. Only a single trough concentration (preferably at the point of care) sufficed for accurate and precise prediction. Predictive performance of both single‐ and multi‐model approaches was robust to the lack of covariate data. Model averaging using four models demonstrated similar predictive performance with a five‐fold shorter computation time. This model averaging algorithm was implemented in the TDMx software tool to guide infliximab dosage de‐escalation in the forthcoming prospective MODIFI study (NCT04982172).
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Affiliation(s)
- Wannee Kantasiripitak
- Department of Pharmaceutical and Pharmacological Sciences University of Leuven Leuven Belgium
| | - An Outtier
- Department of Gastroenterology and Hepatology University Hospitals Leuven Leuven Belgium
- Department of Chronic Diseases and Metabolism University of Leuven Leuven Belgium
| | - Sebastian G. Wicha
- Department of Clinical Pharmacy, Institute of Pharmacy University of Hamburg Hamburg Germany
| | - Alexander Kensert
- Department of Pharmaceutical and Pharmacological Sciences University of Leuven Leuven Belgium
- Department of Chemical Engineering Vrije Universiteit Brussels Brussels Belgium
| | - Zhigang Wang
- Department of Pharmaceutical and Pharmacological Sciences University of Leuven Leuven Belgium
| | - João Sabino
- Department of Gastroenterology and Hepatology University Hospitals Leuven Leuven Belgium
- Department of Chronic Diseases and Metabolism University of Leuven Leuven Belgium
| | - Séverine Vermeire
- Department of Gastroenterology and Hepatology University Hospitals Leuven Leuven Belgium
- Department of Chronic Diseases and Metabolism University of Leuven Leuven Belgium
| | - Debby Thomas
- Department of Pharmaceutical and Pharmacological Sciences University of Leuven Leuven Belgium
| | - Marc Ferrante
- Department of Gastroenterology and Hepatology University Hospitals Leuven Leuven Belgium
- Department of Chronic Diseases and Metabolism University of Leuven Leuven Belgium
| | - Erwin Dreesen
- Department of Pharmaceutical and Pharmacological Sciences University of Leuven Leuven Belgium
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12
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Martins CDA, Garcia KS, Queiroz NSF. Multi-utility of therapeutic drug monitoring in inflammatory bowel diseases. Front Med (Lausanne) 2022; 9:864888. [PMID: 35966848 PMCID: PMC9366431 DOI: 10.3389/fmed.2022.864888] [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: 01/29/2022] [Accepted: 07/04/2022] [Indexed: 11/14/2022] Open
Abstract
Inflammatory bowel disease (IBD) treatment targets have progressed over time from clinical response to clinical and endoscopic remission. Several data have shown a positive correlation between serum biologic drug concentrations and favorable therapeutic outcomes. Therapeutic drug monitoring (TDM) has evolved as an important approach for optimizing the use of immunobiologics, especially antitumor necrosis factor therapy, in patients with IBD. The use of TDM is supported by medical societies and IBD experts in different contexts; however, challenges remain due to knowledge gaps that limit the widespread use of it. The aim of this review is to assess the role of TDM in IBD, focusing on the implementation of this strategy in different scenarios and demonstrating the multi-utility aspects of this approach in clinical practice.
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Affiliation(s)
| | - Karoline Soares Garcia
- Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
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13
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Grossberg LB, Cheifetz AS, Papamichael K. Therapeutic Drug Monitoring of Biologics in Crohn's Disease. Gastroenterol Clin North Am 2022; 51:299-317. [PMID: 35595416 DOI: 10.1016/j.gtc.2021.12.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
Abstract
Reactive therapeutic drug monitoring (TDM) is considered the standard of care for optimizing biologics in inflammatory bowel disease (IBD) including Crohn's disease (CD). Preliminary data show that proactive TDM is associated with positive outcomes in IBD and can be also used to efficiently guide therapeutic decisions in specific clinical scenarios. Higher biological drug concentrations are associated with favorable therapeutic outcomes in specific IBD populations or phenotypes including pediatric CD, perianal fistulizing CD, small bowel CD, and following an ileocolonic resection for CD. Future perspectives of TDM include the use of rapid testing, pharmacogenomics, and pharmacokinetic dashboards toward individualized therapy.
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Affiliation(s)
- Laurie B Grossberg
- Division of Gastroenterology, Center for Inflammatory Bowel Diseases, Beth-Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, USA.
| | - Adam S Cheifetz
- Division of Gastroenterology, Center for Inflammatory Bowel Diseases, Beth-Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, USA
| | - Konstantinos Papamichael
- Division of Gastroenterology, Center for Inflammatory Bowel Diseases, Beth-Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, USA
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14
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De-escalation of biological therapy in inflammatory bowel disease patients following prior dose escalation. Eur J Gastroenterol Hepatol 2022; 34:488-495. [PMID: 34974465 PMCID: PMC8983943 DOI: 10.1097/meg.0000000000002336] [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] [Indexed: 12/10/2022]
Abstract
BACKGROUND Limited data are available on biological therapy de-escalation after prior escalation in inflammatory bowel disease (IBD) patients. This study aimed to assess the frequency and success rate of de-escalation of biological therapy in IBD patients after prior dose escalation and to evaluate which measures are used to guide de-escalation. METHODS This multicentre retrospective cohort study enrolled IBD patients treated with infliximab (IFX), adalimumab (ADA) or vedolizumab (VEDO) in whom therapy was de-escalated after prior biological escalation. De-escalations were considered pharmacokinetic-driven if based on clinical symptoms combined with therapeutic or supratherapeutic trough levels, and disease activity-driven if based on faecal calprotectin less than or equal to 200 µg/g or resolution of perianal fistula drainage or closure or endoscopic remission. Successful de-escalation was defined as remaining on the same or lower biological dose for greater than or equal to 6 months after de-escalation without the need for corticosteroids. RESULTS In total, 206 IFX users, 85 ADA users and 55 VEDO users underwent therapy escalation. Of these patients, 34 (17%) on IFX, 18 (21%) on ADA and 8 (15%) on VEDO underwent therapy de-escalation. De-escalation was successful in 88% of IFX patients, 89% of ADA and 100% of VEDO. The probability of remaining on the de-escalated regimen or further de-escalation after 1 year was 85% for IFX, 62% for ADA and 100% for VEDO. Disease activity-driven de-escalations were more often successful (97%) than pharmacokinetic- and no marker-driven de-escalations (76%); P = 0.017. CONCLUSION De-escalation after biological dose escalation was successful in the majority of carefully selected IBD patients. Objective assessment of remission increased the likelihood of successful de-escalation.
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15
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Papamichael K, Afif W, Drobne D, Dubinsky MC, Ferrante M, Irving PM, Kamperidis N, Kobayashi T, Kotze PG, Lambert J, Noor NM, Roblin X, Roda G, Vande Casteele N, Yarur AJ, Arebi N, Danese S, Paul S, Sandborn WJ, Vermeire S, Cheifetz AS, Peyrin-Biroulet L. Therapeutic drug monitoring of biologics in inflammatory bowel disease: unmet needs and future perspectives. Lancet Gastroenterol Hepatol 2022; 7:171-185. [PMID: 35026171 PMCID: PMC10187071 DOI: 10.1016/s2468-1253(21)00223-5] [Citation(s) in RCA: 91] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/14/2021] [Accepted: 06/15/2021] [Indexed: 01/05/2023]
Abstract
Therapeutic drug monitoring (TDM) has emerged as a useful tool for optimising the use of biologics, and in particular anti-tumour necrosis factor (anti-TNF) therapy, in inflammatory bowel disease (IBD). However, challenges remain and are hindering the widespread implementation of TDM in clinical practice. These barriers include identification of the optimal drug concentration to target, the lag time between sampling and results, and the proper interpretation of anti-drug antibody titres among different assays. Solutions to overcome these barriers include the harmonisation of TDM assays and the use of point-of-care testing. Other unmet needs include well designed prospective studies and randomised controlled trials focusing on proactive TDM, particularly during induction therapy. Future studies should also investigate the utility of TDM for biologics other than anti-TNF therapies in both IBD and other immune-mediated inflammatory diseases such as rheumatoid arthritis and psoriasis, and the use of pharmacokinetic modelling dashboards and pharmacogenetics towards individual personalised medicine.
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Affiliation(s)
- Konstantinos Papamichael
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
| | - Waqqas Afif
- Department of Medicine, Division of Gastroenterology, McGill University Health Center, Montreal, QC, Canada
| | - David Drobne
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia; Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Marla C Dubinsky
- Department of Pediatrics, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Marc Ferrante
- KU Leuven, Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Peter M Irving
- Gastroenterology, Guy's and St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | | | - Taku Kobayashi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - Paulo G Kotze
- Catholic University of Paraná (PUCPR), Curitiba, Brazil
| | - Jo Lambert
- Department of Head and Skin, Ghent University Hospital, Ghent, Belgium
| | - Nurulamin M Noor
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Xavier Roblin
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - Giulia Roda
- IBD Center, Humanitas Clinical and Research Center-IRCCS, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | | | | | - Naila Arebi
- Department of IBD, St Mark's Hospital, Imperial College London, London, UK
| | - Silvio Danese
- IBD Center, Humanitas Clinical and Research Center-IRCCS, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Stephane Paul
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - William J Sandborn
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Séverine Vermeire
- KU Leuven, Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Adam S Cheifetz
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, Nancy, France; INSERM U1256 NGERE, Lorraine University, Nancy, France
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16
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Chitosan Oligosaccharides Alleviate Colitis by Regulating Intestinal Microbiota and PPARγ/SIRT1-Mediated NF-κB Pathway. Mar Drugs 2022; 20:md20020096. [PMID: 35200626 PMCID: PMC8880253 DOI: 10.3390/md20020096] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/20/2022] [Accepted: 01/21/2022] [Indexed: 02/05/2023] Open
Abstract
Chitosan oligosaccharides (COS) have been shown to have potential protective effects against colitis, but the mechanism underlying this effect has not been fully elucidated. In this study, COS were found to significantly attenuate dextran sodium sulfate-induced colitis in mice by decreasing disease activity index scores, downregulating pro-inflammatory cytokines, and upregulating Mucin-2 levels. COS also significantly inhibited the levels of nitric oxide (NO) and IL-6 in lipopolysaccharide-stimulated RAW 264.7 cells. Importantly, COS inhibited the activation of the NF-κB signaling pathway via activating PPARγ and SIRT1, thus reducing the production of NO and IL-6. The antagonist of PPARγ could abolish the anti-inflammatory effects of COS in LPS-treated cells. COS also activated SIRT1 to reduce the acetylation of p65 protein at lysine 310, which was reversed by silencing SIRT1 by siRNA. Moreover, COS treatment increased the diversity of intestinal microbiota and partly restored the Firmicutes/Bacteroidetes ratio. COS administration could optimize intestinal microbiota composition by increasing the abundance of norank_f_Muribaculaceae, Lactobacillus and Alistipes, while decreasing the abundance of Turicibacte. Furthermore, COS could also increase the levels of propionate and butyrate. Overall, COS can improve colitis by regulating intestinal microbiota and the PPARγ/SIRT1-mediated NF-κB pathway.
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17
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Papamichael K, Cheifetz AS. Optimizing therapeutic drug monitoring in inflammatory bowel disease: a focus on therapeutic monoclonal antibodies. Expert Opin Drug Metab Toxicol 2021; 17:1423-1431. [PMID: 34996330 DOI: 10.1080/17425255.2021.2027367] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 12/01/2021] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Therapeutic drug monitoring (TDM) is useful for optimizing monoclonal antibodies (mAbs) for the treatment of immune-mediated inflammatory disorders including inflammatory bowel disease (IBD). However, TDM in clinical practice is still restricted by long turnaround times between sampling and results and the fact that dosing of mAbs to a target drug concentration is challenging due to high pharmacokinetic (PK) variability at both a population and patient level. Overcoming these barriers may be addressed by point-of-care (POC) assays, model-informed precision dosing (MIPD), and pharmacogenetics/pharmacogenomics. AREAS COVERED This review provides an overview of the optimization of TDM of mAbs in IBD including POC testing, MIPD, and pharmacogenetics. EXPERT OPINION Recent advances in sampling, quantification, and support of clinical decisions include POC assays and PK dashboards, which may allow for prompt and precise application of TDM in clinical practice. Future perspectives toward a more personalized implementation of TDM could include the incorporation of pharmacogenetics/pharmacogenomics to identify subgroups of patients who would benefit more from proactive TDM or combination therapy such as those prone to immunogenicity and/or accelerated drug clearance. However, there are still challenges regarding the implementation of these innovative approaches, and more data from prospective studies and randomized controlled trials are needed.
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Affiliation(s)
- Konstantinos Papamichael
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Adam S Cheifetz
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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18
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Allegretti JR, Canakis A, McClure E, Marcus J, Norton BA, Hamilton MJ, Winter RW, De Silva PS, Friedman S, Korzenik JR. Infliximab De-escalation in Patients With Crohn's Disease in Clinical Remission Is Safe and Well-tolerated. Inflamm Bowel Dis 2021; 27:2031-2033. [PMID: 34142700 DOI: 10.1093/ibd/izab131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Indexed: 01/07/2023]
Affiliation(s)
- Jessica R Allegretti
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
| | - Andrew Canakis
- Department of Medicine, Boston University Medical Center, Boston, Massachusetts, USA
| | - Emma McClure
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Jenna Marcus
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Beth-Ann Norton
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Matthew J Hamilton
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
| | - Rachel W Winter
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
| | - Punyanganie S De Silva
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
| | - Sonia Friedman
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
| | - Joshua R Korzenik
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
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Cheifetz AS, Abreu MT, Afif W, Cross RK, Dubinsky MC, Loftus EV, Osterman MT, Saroufim A, Siegel CA, Yarur AJ, Melmed GY, Papamichael K. A Comprehensive Literature Review and Expert Consensus Statement on Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease. Am J Gastroenterol 2021; 116:2014-2025. [PMID: 34388143 PMCID: PMC9674375 DOI: 10.14309/ajg.0000000000001396] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 07/14/2021] [Indexed: 12/11/2022]
Abstract
Therapeutic drug monitoring (TDM) of biologics is a rapidly evolving field. We aimed to provide a consensus statement regarding the clinical utility of TDM for biologics in inflammatory bowel disease (IBD). A modified Delphi method was applied to develop consensus statements. A comprehensive literature review was performed regarding TDM of biologic therapies in IBD, and 45 statements were subsequently formulated on the potential application of TDM in IBD. The statements, along with literature, were then presented to a panel of 10 gastroenterologists with expertise in IBD and TDM who anonymously rated them on a scale of 1-10 (1 = strongly disagree and 10 = strongly agree). An expert consensus development meeting was held virtually to review, discuss, refine, and reformulate statements that did not meet criteria for agreement or that were ambiguous. During the meeting, additional statements were proposed. Panelists then confidentially revoted, and statements rated ≥7 by 80% or more of the participants were accepted. During the virtual meeting, 8 statements were reworded, 7 new statements were proposed, and 19 statements were rerated. Consensus was finally reached in 48/49 statements. The panel agreed that reactive TDM should be used for all biologics for both primary nonresponse and secondary loss of response. It was recommended that treatment discontinuation should not be considered for infliximab or adalimumab until a drug concentration of at least 10-15 μg/mL was achieved. Consensus was also achieved regarding the utility of proactive TDM for anti-tumor necrosis factor therapy. It was recommended to perform proactive TDM after induction and at least once during maintenance. Consensus was achieved in most cases regarding the utility of TDM of biologics in IBD, specifically for reactive and proactive TDM of anti-tumor necrosis factors.
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Affiliation(s)
| | - Maria T. Abreu
- University of Miami - Miller School of Medicine, Miami, Florida
| | - Waqqas Afif
- McGill University Health Center, Montreal, Quebec, Canada
| | | | | | | | - Mark T. Osterman
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | | | | | | | - Gil Y. Melmed
- Cedars-Sinai Medical Center, Los Angeles, California
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20
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Xiang XW, Wang R, Yao LW, Zhou YF, Sun PL, Zheng B, Chen YF. Anti-Inflammatory Effects of Mytilus coruscus Polysaccharide on RAW264.7 Cells and DSS-Induced Colitis in Mice. Mar Drugs 2021; 19:md19080468. [PMID: 34436307 PMCID: PMC8400803 DOI: 10.3390/md19080468] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 08/12/2021] [Accepted: 08/16/2021] [Indexed: 12/15/2022] Open
Abstract
Considerable literature has been published on polysaccharides, which play a critical role in regulating the pathogenesis of inflammation and immunity. In this essay, the anti-inflammatory effect of Mytilus coruscus polysaccharide (MP) on lipopolysaccharide-stimulated RAW264.7 cells and a dextran sulfate sodium (DSS)-induced ulcerative colitis model in mice was investigated. The results showed that MP effectively promoted the proliferation of RAW264.7 cells, ameliorated the excessive production of inflammatory cytokines (TNF-α, IL-6, and IL-10), and inhibited the activation of the NF-κB signaling pathway. For DSS-induced colitis in mice, MP can improve the clinical symptoms of colitis, inhibit the weight loss of mice, reduce the disease activity index, and have a positive effect on the shortening of the colon caused by DSS, meliorating intestinal barrier integrity and lowering inflammatory cytokines in serum. Moreover, MP makes a notable contribution to the richness and diversity of the intestinal microbial community, and also regulates the structural composition of the intestinal flora. Specifically, mice treated with MP showed a repaired Firmicutes/Bacteroidetes ratio and an increased abundance of some probiotics like Anaerotruncus, Lactobacillus, Desulfovibrio, Alistipe, Odoribacter, and Enterorhabdus in colon. These data suggest that the MP could be a promising dietary candidate for enhancing immunity and protecting against ulcerative colitis.
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Affiliation(s)
- Xing-Wei Xiang
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China; (X.-W.X.); (R.W.); (P.-L.S.)
- Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Hangzhou 310014, China
| | - Rui Wang
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China; (X.-W.X.); (R.W.); (P.-L.S.)
- Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Hangzhou 310014, China
| | - Li-Wen Yao
- Food and Pharmacy College, Zhejiang Ocean University, Zhoushan 316000, China; (L.-W.Y.); (B.Z.)
| | - Yu-Fang Zhou
- Zhejiang Marine Development Research Institute, Zhoushan 316000, China
- Correspondence: (Y.-F.Z.); (Y.-F.C.); Tel.: +86-151-0580-6692 (Y.-F.Z.); +86-133-7257-2058 (Y.-F.C.)
| | - Pei-Long Sun
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China; (X.-W.X.); (R.W.); (P.-L.S.)
- Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Hangzhou 310014, China
| | - Bin Zheng
- Food and Pharmacy College, Zhejiang Ocean University, Zhoushan 316000, China; (L.-W.Y.); (B.Z.)
| | - Yu-Feng Chen
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China; (X.-W.X.); (R.W.); (P.-L.S.)
- Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Hangzhou 310014, China
- Correspondence: (Y.-F.Z.); (Y.-F.C.); Tel.: +86-151-0580-6692 (Y.-F.Z.); +86-133-7257-2058 (Y.-F.C.)
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21
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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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22
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Wu Y, Wen A, Selvanderan SP, Xuan W, Andrews JM, Koo JH, Williams AJ, Ng W, Connor S. Management Decisions in Crohn's Disease Are Changed by Knowledge of Proactive and Reactive Testing of Antitumor Necrosis Factor Drug Levels. CROHN'S & COLITIS 360 2021; 3:otab042. [PMID: 36776656 PMCID: PMC9802446 DOI: 10.1093/crocol/otab042] [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: 01/04/2021] [Indexed: 11/14/2022] Open
Abstract
Background There is controversy about the proactive clinical application of therapeutic drug monitoring (TDM) of biologic drugs in Crohn's disease (CD). One way to practically assess this is to examine how TDM influences management decisions. We examined how knowledge of proactive and reactive antitumor necrosis factor (anti-TNF) drug levels changes management in a variety of clinical scenarios. Methods In this retrospective cohort study, all adults with CD having trough level infliximab or adalimumab measurements at Liverpool Hospital between June 2013 and July 2016 were included. Demographics, indications for testing, anti-TNF drug levels, and treatment details were collected along with subsequent management decisions. The decision made by the treating clinician after receiving the drug level was compared to a consensus decision from a panel of 3 gastroenterologists based on the clinical, laboratory, imaging, and/or endoscopic results without the drug level. When these 2 decisions were discrepant, the anti-TNF drug level was deemed to have changed management. Results One hundred and eighty-seven trough levels of infliximab or adalimumab from 108 patients were analyzed. Overall, assessment of anti-TNF levels affected management in 46.9% of the instances. Knowledge of the drug level was also more likely to result in management change when the test was performed for reactive TDM compared to proactive TDM (63% vs 36%, P = .001). Conclusions The addition of TDM of anti-TNF agents to routine investigations alters management decisions in adult CD patients on anti-TNF therapy in both proactive and reactive settings.
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Affiliation(s)
- Yang Wu
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, New South Wales, Australia,Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia,Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia,Address correspondence to: Yang Wu, MD, Ingham Institute for Applied Medical Research, 1 Campbell St, Liverpool, NSW 2170, Australia ()
| | - Amy Wen
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, New South Wales, Australia,Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Shane P Selvanderan
- IBD Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia,Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
| | - Wei Xuan
- Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia
| | - Jane M Andrews
- IBD Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia,Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
| | - Jenn H Koo
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, New South Wales, Australia,Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Astrid-Jane Williams
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, New South Wales, Australia,Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Watson Ng
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, New South Wales, Australia,Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Susan Connor
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, New South Wales, Australia,Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia,Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
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23
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Bouguen G, Brunet T. Reply. Clin Gastroenterol Hepatol 2021; 19:855-856. [PMID: 33249012 DOI: 10.1016/j.cgh.2020.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/09/2020] [Accepted: 06/10/2020] [Indexed: 02/07/2023]
Affiliation(s)
- Guillaume Bouguen
- CHU Rennes, University of Rennes 1, INSERM, CIC1414, Institut NUMECAN, Rennes, France
| | - Tanguy Brunet
- CHU Rennes, University of Rennes 1, INSERM, CIC1414, Institut NUMECAN, Rennes, France
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24
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Facchin S, Buda A, Cardin R, Agbariah N, Zingone F, De Bona M, Zaetta D, Bertani L, Ghisa M, Barberio B, Savarino EV. Rapid point-of-care anti-infliximab antibodies detection in clinical practice: comparison with ELISA and potential for improving therapeutic drug monitoring in IBD patients. Therap Adv Gastroenterol 2021; 14:1756284821999902. [PMID: 33815569 PMCID: PMC7989110 DOI: 10.1177/1756284821999902] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 02/14/2021] [Indexed: 02/04/2023] Open
Abstract
Anti-drug antibodies can interfere with the activity of anti-tumor necrosis factor (TNF) agents by increasing drug clearance via direct neutralization. The presence of anti-drug antibodies is clinically relevant when trough drug concentrations are undetectable or sub-therapeutic. However, traditional immunoassay is not easily and rapidly accessible, making the translation of the results into treatment adjustment difficult. The availability of a point-of-care (POC) test for therapeutic drug monitoring (TDM) might represent an important step forward for improving the management of inflammatory bowel disease (IBD) patients in clinical practice. In this pilot study, we compared the results obtained with POC tests with those obtained by enzyme-linked immunosorbent assay (ELISA) in a group of IBD patients treated with Infliximab (IFX). We showed that POC test can reliably detect presence of antibody-to-IFX with 100% of specificity and 76% sensitivity, in strong agreement with the ELISA test (k-coefficient = 0.84).
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Affiliation(s)
- Sonia Facchin
- Department of Surgery, Oncology and Gastroenterology (DISCOG), University Hospital of Padua, Padua, Italy
| | - Andrea Buda
- Department of Oncological Gastrointestinal Surgery, Gastroenterology Unit, S. Maria del Prato Hospital, Feltre, Italy
| | - Romilda Cardin
- Department of Surgery, Oncology and Gastroenterology (DISCOG), University Hospital of Padua, Padua, Italy
| | - Nada Agbariah
- Department of Surgery, Oncology and Gastroenterology (DISCOG), University Hospital of Padua, Padua, Italy,Marienhospital Aachen, Gastroenterology Unit, Germany
| | - Fabiana Zingone
- Department of Surgery, Oncology and Gastroenterology (DISCOG), University Hospital of Padua, Padua, Italy
| | - Manuela De Bona
- Department of Oncological Gastrointestinal Surgery, Gastroenterology Unit, S. Maria del Prato Hospital, Feltre, Italy
| | - Debora Zaetta
- Department of Oncological Gastrointestinal Surgery, Gastroenterology Unit, S. Maria del Prato Hospital, Feltre, Italy
| | - Lorenzo Bertani
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Matteo Ghisa
- Department of Surgery, Oncology and Gastroenterology (DISCOG), University Hospital of Padua, Padua, Italy
| | - Brigida Barberio
- Department of Surgery, Oncology and Gastroenterology (DISCOG), University Hospital of Padua, Padua, Italy
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25
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Landemaine A, Petitcollin A, Brochard C, Miard C, Dewitte M, Le Balc'h E, Grainville T, Bellissant E, Siproudhis L, Bouguen G. Cumulative Exposure to Infliximab, But Not Trough Concentrations, Correlates With Rate of Infection. Clin Gastroenterol Hepatol 2021; 19:288-295.e4. [PMID: 32200087 DOI: 10.1016/j.cgh.2020.03.018] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 02/13/2020] [Accepted: 03/08/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Infliximab increases the risk of infection in patients with inflammatory bowel diseases (IBD), but there is controversy over the relationship between drug concentration and infections. We aimed to assess factors associated with infection in infliximab-treated patients, including pharmacokinetic features. METHODS We collected data from 209 patients with IBD (102 men; mean age, 39 y; 159 with Crohn's disease; 54 received combination therapy) who received an infliximab maintenance regimen from November 2016 through April 2017 in France. Data were collected from each infusion visit (total of 640 infusions). Infliximab exposure was estimated based on the area under the curve (AUC) of drug concentration in pharmacokinetic models; individual exposures over the 6-month period were estimated based on the sum of the AUC (ΣAUC). RESULTS The mean infliximab trough level was 5.46 mg/L, and the mean ΣAUC was 3938 ± 1427 mg.d/L. A total of 215 infections were collected from the 640 infusion visits; 123 patients (59%) had at least 1 infection. Factors independently associated with infection after multivariate analysis were smoking (odds ratio [OR], 2.05; P = .046), IBD flare (OR, 2.71; P = .006), and a high ΣAUC of infliximab (above 3234 mg x d/L) (OR, 2.02; P = .02). The ΣAUC was higher in patients with an occurrence of infection (P = .04) and correlated with the number of infections (P = .04). Trough concentration of infliximab alone was not associated with infection. CONCLUSIONS Almost two-thirds of patients treated with infliximab developed an infection; risk was individually correlated with cumulative increase in drug exposure, but not infliximab trough level.
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Affiliation(s)
| | | | - Charlène Brochard
- CHU Rennes, University of Rennes, INSERM, CIC1414, Institut NUMECAN (Nutrition Metabolism and Cancer), Rennes, France
| | - Céline Miard
- CHU Rennes, University of Rennes, Rennes, France
| | | | | | | | | | - Laurent Siproudhis
- CHU Rennes, University of Rennes, INSERM, CIC1414, Institut NUMECAN (Nutrition Metabolism and Cancer), Rennes, France
| | - Guillaume Bouguen
- CHU Rennes, University of Rennes, INSERM, CIC1414, Institut NUMECAN (Nutrition Metabolism and Cancer), Rennes, France.
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26
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Little DHW, Tabatabavakili S, Shaffer SR, Nguyen GC, Weizman AV, Targownik LE. Effectiveness of Dose De-escalation of Biologic Therapy in Inflammatory Bowel Disease: A Systematic Review. Am J Gastroenterol 2020; 115:1768-1774. [PMID: 33156094 DOI: 10.14309/ajg.0000000000000783] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION De-escalation of biologic therapy is a commonly encountered clinical scenario. Although biologic discontinuation has been associated with high rates of relapse, the effectiveness of dose de-escalation is unclear. This review was performed to determine the effectiveness of dose de-escalation of biologic therapy in inflammatory bowel disease. METHODS We searched EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials from inception to October 2019. Randomized controlled trials and observational studies involving dose de-escalation of biologic therapy in adults with inflammatory bowel disease in remission were included. Studies involving biologic discontinuation only and those lacking outcomes after dose de-escalation were excluded. Risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS We identified 1,537 unique citations with 20 eligible studies after full-text review. A total of 995 patients were included from 18 observational studies (4 prospective and 14 retrospective), 1 nonrandomized controlled trial, and 1 subgroup analysis of a randomized controlled trial. Seven studies included patients with Crohn's disease, 1 included patients with ulcerative colitis, and 12 included both. Overall, clinical relapse occurred in 0%-54% of patients who dose de-escalated biologic therapy (17 studies). The 1-year rate of clinical relapse ranged from 7% to 50% (6 studies). Eighteen studies were considered at high risk of bias, mostly because of the lack of a control group. DISCUSSION Dose de-escalation seems to be associated with high rates of clinical relapse; however, the quality of the evidence was very low. Additional controlled prospective studies are needed to clarify the effectiveness of biologic de-escalation and identify predictors of success.
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Affiliation(s)
- Derek H W Little
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | | | - Seth R Shaffer
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Geoffrey C Nguyen
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Ontario, Canada
| | - Adam V Weizman
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Ontario, Canada
| | - Laura E Targownik
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Ontario, Canada
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27
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Optimizing biologic therapy in IBD: how essential is therapeutic drug monitoring? Nat Rev Gastroenterol Hepatol 2020; 17:702-710. [PMID: 32879465 DOI: 10.1038/s41575-020-0352-2] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/20/2020] [Indexed: 02/07/2023]
Abstract
Proposed treatment targets for the management of inflammatory bowel disease (IBD) have moved beyond symptomatic improvement towards more objective end points, such as healing of the intestinal mucosa. This treat-to-target approach has been associated with improved disease outcomes such as diminished bowel damage, surgery and hospitalizations. Many patients with IBD require biologic therapy to achieve and maintain clinical and endoscopic remission, and antitumour necrosis factor antibodies remain the first-line biologic therapy in most areas of the world. Unfortunately, up to one-third of patients receiving this treatment are primary non-responders, and some patients that show an initial response can also lose response over time. Therapeutic drug monitoring (TDM) has been suggested as a useful tool to manage patients on antitumour necrosis factor treatment, including monitoring for dose escalation, de-escalation or to switch treatment. In this Perspective, we aim to summarize evidence and guidelines related to TDM in IBD management and also discuss potential strategies to optimize biologic treatment where TDM is not available.
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28
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Schots L, Grine L, Soenen R, Lambert J. Dermatologists on the medical need for therapeutic drug monitoring of biologics in psoriasis: results of a structured survey. J DERMATOL TREAT 2020; 33:1473-1481. [PMID: 33019835 DOI: 10.1080/09546634.2020.1832649] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Therapeutic drug monitoring (TDM) may lead to more rational use of biologics. Still, TDM is largely underexplored in psoriasis. Little is known about the dosing behavior of biologics by dermatologists, and their attitude toward TDM. OBJECTIVE Exploration of the awareness and need for the concept of TDM in psoriasis amongst (inter)national dermatologists. METHOD A survey was distributed at the Belgian Dermatology Days 2019 and Skin Inflammation & Psoriasis International Network (SPIN) Congress 2019. Next, an online survey version was launched amongst the SPIN Scientific Committee members. We collected physician's characteristics, prescription behavior of biologics, data regarding clinical response to biologics and attitude toward TDM. RESULTS A total of 107 surveys were included for analysis. Most dermatologists were Belgium-based (54.2%), others from European (23.4%) or non-European countries (19.6%). Seventy percent performed either dose increase (64.8%), time interval shortening (74.6%), dose lowering (16.9%) or time interval extension (33.8%). The majority who performed dose adaptations acknowledged the need for TDM. CONCLUSION This study showed most dermatologists perform dose adaptations empirically. The need for TDM was indicated by the majority, implying the need for effective communication regarding availability, utility and implementation of TDM assays in daily dermatology practice.
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Affiliation(s)
- Lisa Schots
- Department of Dermatology, Ghent University Hospital, Ghent, Belgium.,Department of Head and Skin, Ghent University, Ghent, Belgium
| | - Lynda Grine
- Department of Dermatology, Ghent University Hospital, Ghent, Belgium.,Department of Head and Skin, Ghent University, Ghent, Belgium
| | - Rani Soenen
- Department of Dermatology, Ghent University Hospital, Ghent, Belgium.,Department of Head and Skin, Ghent University, Ghent, Belgium
| | - Jo Lambert
- Department of Dermatology, Ghent University Hospital, Ghent, Belgium.,Department of Head and Skin, Ghent University, Ghent, Belgium
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29
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Sahu P, Vuyyuru SK, Kante B, Agarwal A, Sharma R, Das P, Panwar R, Jain S, Bopanna S, Makharia G, Kedia S, Ahuja V. Relapse rate following withdrawal of anti-TNF therapy in patients with inflammatory bowel disease: A real-life cohort from northern India. Indian J Gastroenterol 2020; 39:388-397. [PMID: 32880844 DOI: 10.1007/s12664-020-01043-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 04/17/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND The decision to withdraw anti-tumor necrosis factor (anti-TNF) therapy in patients with inflammatory bowel disease (IBD) remains controversial, especially in the developing world, where its long-term use is restrained by side effects and prohibitive cost. Present study evaluated the relapse rate and its predictors following anti-TNF withdrawal in a cohort of IBD patients from northern India. METHODS Patients with IBD who received anti-TNF therapy (induction and beyond), and were under follow-up at All India Institute of Medical Sciences, New Delhi, from January 2005 to July 2018 were included. Demographic features, disease characteristics, duration, response to anti-TNF therapy, and relapse rate after its withdrawal were analyzed. RESULTS Among 4600 patients with IBD under follow-up, 90 (1.9%) received anti-TNF therapy, of whom 11 were excluded (8-complete records unavailable; 3-received only single dose). Of 79 patients (mean age-40.1 ± 14.2 years; 53.2% males; 31 [39.2%] ulcerative colitis, 47 [59.5%] Crohn's disease; median follow-up-24 [12-39] months), 9 (11.4%) were primary non-responders, 19 (24.1%) had secondary loss of response, and 51 (64.5%) maintained clinical response on anti-TNF. Anti-TNF was withdrawn in 45 (57%) patients (major causes: financial burden-16.5%; tubercular reactivation-12.7%), of whom 33 were in clinical remission. Over a median follow-up of 26 (7.5-45) months, 15 patients (45.5%) relapsed. Most of them responded to antibiotics, steroids, or anti-TNF agents; only 3 required surgery. On Kaplan-Meier analysis, long disease duration prior to therapy was a significant predictor of relapse (hazard ratio [HR] = 1.33, p = 0.034). CONCLUSION Almost 50% patients with IBD in clinical remission relapse within a year of anti-TNF withdrawal. However, most of these patients have a favorable disease course and respond to medical therapy.
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Affiliation(s)
- Pabitra Sahu
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110 019, India
| | - Sudheer K Vuyyuru
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110 019, India
| | - Bhaskar Kante
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110 019, India
| | - Ashish Agarwal
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110 019, India
| | - Raju Sharma
- Department of Radiology, All India Institute of Medical Sciences, New Delhi, 110 029, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110 029, India
| | - Rajesh Panwar
- Department of GI Surgery, All India Institute of Medical Sciences, New Delhi, 110 029, India
| | - Saransh Jain
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110 019, India
| | - Sawan Bopanna
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110 019, India
| | - Govind Makharia
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110 019, India
| | - Saurabh Kedia
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110 019, India
| | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110 019, India.
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30
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Papamichael K, Cheifetz AS. Therapeutic drug monitoring in patients on biologics: lessons from gastroenterology. Curr Opin Rheumatol 2020; 32:371-379. [PMID: 32412995 PMCID: PMC8294174 DOI: 10.1097/bor.0000000000000713] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW To give an overview on the role of therapeutic drug monitoring (TDM) of biologics in patients with inflammatory bowel disease (IBD). RECENT FINDINGS Numerous prospective exposure-response relationship studies and post-hoc analyses of randomized controlled trials (RCTs) show a positive correlation between biologic drug concentrations and favorable clinical outcomes in IBD. These studies also demonstrate that higher drug concentrations appear to be needed to achieve more stringent objective therapeutic outcomes. Reactive TDM rationalizes the management of primary nonresponse and secondary loss of response to antitumor necrosis factor (anti-TNF) therapy and is more cost-effective when compared with empiric dose optimization. Furthermore, recent data suggest that proactive TDM, with the goal of targeting a threshold drug concentration, is associated with better therapeutic outcomes when compared with empiric dose escalation and/or reactive TDM of infliximab or adalimumab. Finally, proactive TDM can also efficiently guide infliximab de-escalation or discontinuation in patients with IBD in remission. SUMMARY Reactive TDM is currently considered as standard of care, whereas proactive TDM is emerging as a new therapeutic strategy for better optimizing anti-TNF therapy in IBD. However, more data from prospective studies are needed before a wide implementation of TDM-based algorithms in real life clinical practice for newer biologics.
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Affiliation(s)
- Konstantinos Papamichael
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Adam S. Cheifetz
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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31
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Santacana Juncosa E, Rodríguez-Alonso L, Padullés Zamora A, Guardiola J, Rodríguez-Moranta F, Serra Nilsson K, Bas Minguet J, Morandeira Rego F, Colom Codina H, Padullés Zamora N. Bayes-based dosing of infliximab in inflammatory bowel diseases: Short-term efficacy. Br J Clin Pharmacol 2020; 87:494-505. [PMID: 32495380 DOI: 10.1111/bcp.14410] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 05/18/2020] [Accepted: 05/24/2020] [Indexed: 12/18/2022] Open
Abstract
AIMS Therapeutic drug monitoring of infliximab can guide clinical decisions in patients with loss of response and in those who can benefit from a de-intensification. The aim of this study was to determine the impact of therapeutic drug monitoring combined with Bayesian forecasting methodology on clinical response in a real-world dataset of patients suffering from inflammatory bowel disease. METHODS We performed a single-centre prospective study with one-group pre-test/post-test design in 108 adult inflammatory bowel disease patients treated with model-based dosing of infliximab maintenance treatment. We recorded clinical activity scores (Harvey-Bradshaw index and partial Mayo) and inflammatory biomarkers per patient. RESULTS The initial infliximab regimen was maintained in 49 (45.4%) patients and was adjusted in 59 (54.6%) patients (34 treatment intensifications, 9 de-intensifications and 16 treatment discontinuations or therapy replacements). The median time from intervention to index measurement was 126 (103-160) days. The overall proportion of patients in clinical remission increased from 65.7% to 80.4% (P < .0001) and the median infliximab trough concentrations increased from 3.21 (0.99-5.45) to 5.13 mg/L (3.57-6.53) (P < .0001). In the intensified group, the remission rate increased from 35.3% to 61.8% (P = .001) and the percentage of patients in clinical remission or with mild symptoms increased from 76.5% to 94.1%. In the de-intensification cohort, no patients experienced an increase in the Harvey-Bradshaw index or partial Mayo scores, and all patients maintained an infliximab trough concentration of >5 mg/L. CONCLUSION In our cohort of inflammatory bowel disease patients, Bayes-based optimized dosing improved the short-term efficacy of infliximab treatment.
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Affiliation(s)
- Eugènia Santacana Juncosa
- Department of Pharmacy, Hospital Universitari de Bellvitge-HUB. Pharmacotherapy, Pharmacogenetics and Pharmaceutical Technology Program, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL. L'Hospitalet de Llobregat, Barcelona, Spain
| | - Lorena Rodríguez-Alonso
- Department of Gastroenterology, Hospital Universitari de Bellvitge-HUB. L'Hospitalet de Llobregat, Barcelona, Spain
| | - Ariadna Padullés Zamora
- Department of Pharmacy, Hospital Universitari de Bellvitge-HUB. Pharmacotherapy, Pharmacogenetics and Pharmaceutical Technology Program, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL. L'Hospitalet de Llobregat, Barcelona, Spain
| | - Jordi Guardiola
- Department of Gastroenterology, Hospital Universitari de Bellvitge-HUB. L'Hospitalet de Llobregat, Barcelona, Spain
| | - Francisco Rodríguez-Moranta
- Department of Gastroenterology, Hospital Universitari de Bellvitge-HUB. L'Hospitalet de Llobregat, Barcelona, Spain
| | - Katja Serra Nilsson
- Department of Gastroenterology, Hospital Universitari de Bellvitge-HUB. L'Hospitalet de Llobregat, Barcelona, Spain
| | - Jordi Bas Minguet
- Immunology, Hospital Universitari de Bellvitge-HUB. L'Hospitalet de Llobregat, Barcelona, Spain
| | | | - Helena Colom Codina
- Pharmacy and Pharmaceutical Technology Department, Universitat de Barcelona-UB, Pharmacotherapy, Pharmacogenetics and Pharmaceutical Technology Program, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL. L'Hospitalet de Llobregat, Barcelona, Spain
| | - Núria Padullés Zamora
- Department of Pharmacy, Hospital Universitari de Bellvitge-HUB. Pharmacotherapy, Pharmacogenetics and Pharmaceutical Technology Program, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL. L'Hospitalet de Llobregat, Barcelona, Spain
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Vermeire S, Dreesen E, Papamichael K, Dubinsky MC. How, When, and for Whom Should We Perform Therapeutic Drug Monitoring? Clin Gastroenterol Hepatol 2020; 18:1291-1299. [PMID: 31589978 DOI: 10.1016/j.cgh.2019.09.041] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 09/26/2019] [Accepted: 09/28/2019] [Indexed: 02/07/2023]
Abstract
The implementation of therapeutic drug monitoring (TDM) in the inflammatory bowel disease practice has evolved over the years. In the early days, the focus was merely on measuring and reporting drug concentrations. Later, these concentrations were considered in light of target concentrations that are related to clinical response. This not only allowed passively predicting a patient's future response, but it also triggered physicians and pharmacists to actively use the information to optimize the drug dosage to induce and maintain a clinical response in the future. Although reactive TDM, testing at time of loss of response, is widely accepted in practice, especially for anti-tumor necrosis factor antibodies, there are less data for the other monoclonal antibodies belonging to other classes. Besides reactive testing, there is a movement toward proactively adjusting biologic dosing to prevent loss of response, in keeping with the tight control philosophy of inflammatory bowel disease care. This review highlights the various assays available to measure drug concentrations and antidrug antibodies, as well as algorithmic approaches to TDM, the unmet needs and required studies to enable pharmacokinetics principles to be applied in the future.
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Affiliation(s)
- Severine Vermeire
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research in Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Erwin Dreesen
- Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium
| | - Konstantinos Papamichael
- Department of Medicine, Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Marla C Dubinsky
- Department of Pediatrics, Susan and Leonard Feinstein Inflammatory Bowel Disease Clinical Center, Icahn School of Medicine Mount Sinai, New York, New York.
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33
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Amiot A. Letter: new insights on tofacitinib dose de-escalation. Aliment Pharmacol Ther 2020; 51:578. [PMID: 32048759 DOI: 10.1111/apt.15638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- Aurelien Amiot
- Department of Gastroenterology, Henri Mondor Hospital, APHP, EA7375, Paris Est-Créteil Univeristy (UPEC), Creteil, France
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Chapman TP, Gomes CF, Louis E, Colombel JF, Satsangi J. De-escalation of immunomodulator and biological therapy in inflammatory bowel disease. Lancet Gastroenterol Hepatol 2020; 5:63-79. [DOI: 10.1016/s2468-1253(19)30186-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 05/01/2019] [Accepted: 05/02/2019] [Indexed: 12/11/2022]
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Lertnimitphun P, Jiang Y, Kim N, Fu W, Zheng C, Tan H, Zhou H, Zhang X, Pei W, Lu Y, Xu H. Safranal Alleviates Dextran Sulfate Sodium-Induced Colitis and Suppresses Macrophage-Mediated Inflammation. Front Pharmacol 2019; 10:1281. [PMID: 31736758 PMCID: PMC6838343 DOI: 10.3389/fphar.2019.01281] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 10/07/2019] [Indexed: 12/15/2022] Open
Abstract
Introduction: Crocus sativus (saffron) is widely used in China, Iran, and India for dyeing and as a food additive and medicinal plant. Safranal, as one of the main constituents of saffron, is responsible for its aroma and has been reported to have anticancer, antioxidant, and anti-inflammation properties. Objective: In this study, we investigated the anti-inflammatory effects of Safranal in RAW264.7 cells, bone marrow-derived macrophages (BMDMs), and dextran sulfate sodium (DSS)-induced colitis mice. Methods: Safranal toxicity was determined using an MTT assay. We evaluated the inhibitory effect of nitric oxide (NO) and levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in RAW264.7 cells and BMDMs. We assessed the inhibitory effect of pro-inflammatory cytokines, and the mRNA expressions of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), classical inflammatory pathways (MAPK and NF-κB), and the nuclear translocation factors AP-1 and NF-κB p65 were investigated. The in vivo anti-inflammatory effects of Safranal were assessed in a DSS-induced colitis model. DSS3.5% was used to induce colitis in mice with or without Safranal for 7 days; weight and disease activity index (DAI) were recorded daily. At the end of the experiment, the colon, mesenteric lymph nodes (MLNs), and spleen were collected for flow cytometry, ELISA, and Western blot analysis. Results: Safranal suppressed NO production, iNOS, and COX-2 in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and BMDMs. Safranal decreased the production and mRNA expression of IL-6 and TNF-α in the RAW264.7 cell line and inhibited the phosphorylation and nuclear translocation of components of the MAPK and NF-κB pathways. Safranal alleviated clinical symptoms in the DSS-induced colitis model, and colon histology showed decreased severity of inflammation, depth of inflammatory involvement, and crypt damage. Immunohistochemical staining and flow cytometry showed reduced macrophage infiltration in colonic tissues and macrophage numbers in MLNs and the spleen. The levels of colonic IL-6 and TNF-α also decreased in Safranal-treated colitis mice. This study elucidates the anti-inflammation activity of Safranal, which may be a candidate for inflammatory bowel syndrome (IBD) therapy.
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Affiliation(s)
| | - Yiwen Jiang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Nami Kim
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenwei Fu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Changwu Zheng
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hongsheng Tan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hua Zhou
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xue Zhang
- Shanghai Traditional Chinese medicine Co., Ltd., Shanghai, China
| | - Weizhong Pei
- Shanghai Traditional Chinese medicine Co., Ltd., Shanghai, China
| | - Yue Lu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hongxi Xu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Assa A, Matar M, Turner D, Broide E, Weiss B, Ledder O, Guz-Mark A, Rinawi F, Cohen S, Topf-Olivestone C, Shaoul R, Yerushalmi B, Shamir R. Proactive Monitoring of Adalimumab Trough Concentration Associated With Increased Clinical Remission in Children With Crohn's Disease Compared With Reactive Monitoring. Gastroenterology 2019; 157:985-996.e2. [PMID: 31194979 DOI: 10.1053/j.gastro.2019.06.003] [Citation(s) in RCA: 195] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 06/02/2019] [Accepted: 06/05/2019] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS Proactive monitoring of drug trough concentrations and antibodies against drugs might help determine whether patients are likely to respond to treatment and increase efficacy. We investigated whether proactive drug monitoring is associated with higher rates of clinical remission in pediatric patients with Crohn's disease (CD). METHODS We performed a nonblinded, randomized controlled trial of 78 children with CD (6-18 years old; 29% female; mean age, 14.3 ± 2.6 years) who had not received prior treatment with a biologic agent but had responded to adalimumab induction therapy, under scheduled monitoring of clinical and biologic measures (based on clinical factors and levels of C-reactive protein and fecal calprotectin), at pediatric gastroenterology units in Israel from July 2015 through December 2018. The patients were randomly assigned to groups that received proactive monitoring (trough concentrations measured at weeks 4 and 8 and then every 8 weeks until week 72, n = 38) or reactive monitoring (physicians were informed of trough concentrations after loss of response, n = 40). In both groups, doses and intervals of adalimumab were adjusted to achieve trough concentrations of 5 μg/mL. The primary endpoint was sustained corticosteroid-free clinical remission at all visits (week 8 through week 72). RESULTS The primary endpoint was achieved by 31 children (82%) in the proactive group and 19 children (48%) in the reactive group (P = .002). Sixteen patients in the proactive monitoring group (42%) achieved a composite outcome of sustained corticosteroid-free remission, C-reactive protein ≤0.5 mg/dL, and level of fecal calprotectin ≤150 μg/g compared with 5 patients in the reactive monitoring group (12%) (P = .003). By week 72 of treatment, 33 patients in the proactive monitoring group had received adalimumab intensification (87%) compared with 24 patients in the reactive monitoring group (60%) (P = .001). CONCLUSIONS In a randomized controlled trial of pediatric patients with CD, we found that proactive monitoring of adalimumab trough concentrations and adjustment of doses and intervals resulted in significantly higher rates corticosteroid-free clinical remission than reactive monitoring (measuring trough concentration after loss of response). Clinicaltrials.gov no.: NCT02256462.
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Affiliation(s)
- Amit Assa
- The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Hospital, Petach-Tikva, Israel; The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Manar Matar
- The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Hospital, Petach-Tikva, Israel
| | - Dan Turner
- The Juliet Keidan Institute of Pediatric Gastroenterology, Nutrition, Shaare Zedek Medical Center, The Hebrew University, Jerusalem, Israel
| | - Efrat Broide
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pediatric Gastroenterology Unit, Assaf Harofeh Medical Center, Zerifin, Israel
| | - Batia Weiss
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pediatric Gastroenterology Unit, Sheba Medical Center, Edmond and Lily Safra Childen's Hospital, Ramat-Gan, Tel-Hashomer, Israel
| | - Oren Ledder
- The Juliet Keidan Institute of Pediatric Gastroenterology, Nutrition, Shaare Zedek Medical Center, The Hebrew University, Jerusalem, Israel
| | - Anat Guz-Mark
- The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Hospital, Petach-Tikva, Israel; The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Firas Rinawi
- The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Hospital, Petach-Tikva, Israel; The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shlomi Cohen
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pediatric Gastroenterology Unit, "Dana-Dwek" Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | | | - Ron Shaoul
- Pediatric Gastroenterology Unit, Rambam Medical Center, Haifa, Israel
| | - Baruch Yerushalmi
- Pediatric Gastroenterology Unit, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Raanan Shamir
- The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Hospital, Petach-Tikva, Israel; The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Papamichael K, Cheifetz AS. Is It Prime Time for Proactive Therapeutic Drug Monitoring of Anti-Tumor Necrosis Factor Therapy in Inflammatory Bowel Disease? Gastroenterology 2019; 157:922-924. [PMID: 31400368 DOI: 10.1053/j.gastro.2019.08.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 08/01/2019] [Indexed: 02/08/2023]
Affiliation(s)
- Konstantinos Papamichael
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Adam S Cheifetz
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
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Papamichael K, Vogelzang EH, Lambert J, Wolbink G, Cheifetz AS. Therapeutic drug monitoring with biologic agents in immune mediated inflammatory diseases. Expert Rev Clin Immunol 2019; 15:837-848. [PMID: 31180729 DOI: 10.1080/1744666x.2019.1630273] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 06/07/2019] [Indexed: 12/22/2022]
Abstract
Introduction: Biologic therapy has revolutionized the treatment of immune mediated inflammatory diseases (IMID), such as inflammatory bowel disease (IBD), rheumatoid and psoriatic arthritis, ankylosing spondylitis and psoriasis. Nevertheless, some patients exhibit primary nonresponse (PNR) or secondary loss of response (SLR) to biologics. Areas covered: This collaborative review provides data on the role of therapeutic drug monitoring (TDM) in IMID for optimizing biologic therapy including infliximab, adalimumab, certolizumab pegol etanercept and golimumab vedolizumab, secukinumab and ustekinumab. Expert opinion: Most exposure-response relationship studies show a positive correlation between biologic drug concentrations and favorable therapeutic outcomes in IMID with higher drug concentrations typically associated with more objective outcomes. Clinically, reactive TDM rationalizes the management of PNR and SLR to anti-tumor necrosis factor therapy and is emerging as the new standard of care in IBD as it is also more cost-effective than empiric dose escalation. Preliminary data suggest that proactive TDM with the goal to achieve a threshold drug concentration is associated with better therapeutic outcomes when compared to empiric drug optimization and/or reactive TDM of infliximab and adalimumab in IBD. However, more data from well-designed prospective studies are needed to prove the benefit of TDM-based algorithms in real life clinical practice in IMID.
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Affiliation(s)
- Konstantinos Papamichael
- a Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School , Boston , MA , USA
| | - Erik H Vogelzang
- b Rheumatology and Immunology Center, Research by AMC, READE and VUMC , Amsterdam , the Netherlands
| | - Jo Lambert
- c Department of Dermatology, Ghent University , Ghent , Belgium
| | - Gertjan Wolbink
- b Rheumatology and Immunology Center, Research by AMC, READE and VUMC , Amsterdam , the Netherlands
- d Department of Immunopathology, Sanquin Research and Landsteiner Laboratory Academic Medical Center , Amsterdam , the Netherlands
| | - Adam S Cheifetz
- a Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School , Boston , MA , USA
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Papamichael K, Cheifetz AS, Melmed GY, Irving PM, Vande Casteele N, Kozuch PL, Raffals LE, Baidoo L, Bressler B, Devlin SM, Jones J, Kaplan GG, Sparrow MP, Velayos FS, Ullman T, Siegel CA. Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 2019; 17:1655-1668.e3. [PMID: 30928454 PMCID: PMC6661210 DOI: 10.1016/j.cgh.2019.03.037] [Citation(s) in RCA: 225] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 02/24/2019] [Accepted: 03/24/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Therapeutic drug monitoring (TDM) is widely available for biologic therapies in patients with inflammatory bowel disease (IBD). We reviewed current data and provided expert opinion regarding the clinical utility of TDM for biologic therapies in IBD. METHODS We used a modified Delphi method to establish consensus. A comprehensive literature review was performed regarding the use of TDM of biologic therapy in IBD and presented to international IBD specialists. Subsequently, 28 statements on the application of TDM in clinical practice were rated on a scale of 1 to 10 (1 = strongly disagree and 10 = strongly agree) by each of the panellists. Statements were accepted if 80% or more of the participants agreed with a score ≥7. The remaining statements were discussed and revised based on the available evidence followed by a second round of voting. RESULTS The panel agreed on 24 (86%) statements. For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics. Reactive TDM was appropriate for all agents both for primary non-response and secondary loss of response. The panellists also agreed on several statements regarding TDM and appropriate drug and anti-drug antibody (ADA) concentration thresholds for biologics in specific clinical scenarios. CONCLUSION Consensus was achieved towards the utility of TDM of biologics in IBD, particularly anti-TNF therapies. More data are needed especially on non-anti-TNF biologics to further define optimal drug concentration and ADA thresholds as these can vary depending on the therapeutic outcomes assessed.
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Affiliation(s)
| | - Adam S Cheifetz
- Beth Israel Deaconess Medical Center, Boston, Massachusetts.
| | - Gil Y Melmed
- Cedars-Sinai Medical Center, Los Angeles, California
| | | | | | | | | | - Leonard Baidoo
- Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | | | | | | | | | | | | | - Thomas Ullman
- Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York
| | - Corey A Siegel
- Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
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Papamichael K, Cheifetz AS. Therapeutic drug monitoring in inflammatory bowel disease: for every patient and every drug? Curr Opin Gastroenterol 2019; 35:302-310. [PMID: 30973355 PMCID: PMC6785387 DOI: 10.1097/mog.0000000000000536] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW The current review provides an updated overview on the role of therapeutic drug monitoring (TDM) of biological therapies in inflammatory bowel disease (IBD). We examine the data behind TDM for the antitumor necrosis factor agents, vedolizumab and ustekinumab, in patients with IBD. In addition, we discuss reactive vs. proactive TDM. RECENT FINDINGS There is a positive correlation between biologic drug concentrations and favorable therapeutic outcomes in IBD, although the majority of data refer to antitumor necrosis factor therapy. Reactive TDM has rationalized the management of patients with IBD with loss of response to biological therapy. Moreover, reactive TDM of infliximab has been proven to be more cost-effective when compared with empiric dose optimization. Preliminary data suggest that proactive TDM of infliximab and adalimumab applied in patients with clinical response/remission is associated with better therapeutic outcomes compared with standard of care (empiric treatment and/or reactive TDM). SUMMARY For all biologics in IBD, there is a positive correlation between drug concentrations and favorable therapeutic outcomes. Reactive TDM is the new standard of care for optimizing biologic therapies in IBD, whereas recent data suggest an important role of proactive TDM for optimizing antitumor necrosis factor therapy in IBD.
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Affiliation(s)
- Konstantinos Papamichael
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Adam S. Cheifetz
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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Petitcollin A, Brochard C, Siproudhis L, Tron C, Verdier M, Lemaitre F, Lucidarme C, Bouguen G, Bellissant É. Pharmacokinetic Parameters of Infliximab Influence the Rate of Relapse After De‐Escalation in Adults With Inflammatory Bowel Diseases. Clin Pharmacol Ther 2019; 106:605-615. [DOI: 10.1002/cpt.1429] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 02/22/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Antoine Petitcollin
- Department of Clinical and Biological Pharmacology Pharmacovigilance, Pharmacoepidemiology, and Drug Information Center Rennes University Hospital Rennes France
- Laboratory of Experimental and Clinical Pharmacology Faculty of Medicine Rennes 1 University Rennes France
- CIC‐P 1414 Clinical Investigation Center Inserm Rennes France
| | - Charlène Brochard
- CIC‐P 1414 Clinical Investigation Center NUMECAN (Nutrition, Metabolism, and Cancer) Institute Inserm Rennes France
- Department of Gastroenterology Rennes University Hospital Rennes France
| | - Laurent Siproudhis
- CIC‐P 1414 Clinical Investigation Center NUMECAN (Nutrition, Metabolism, and Cancer) Institute Inserm Rennes France
- Department of Gastroenterology Rennes University Hospital Rennes France
| | - Camille Tron
- Department of Clinical and Biological Pharmacology Pharmacovigilance, Pharmacoepidemiology, and Drug Information Center Rennes University Hospital Rennes France
- Laboratory of Experimental and Clinical Pharmacology Faculty of Medicine Rennes 1 University Rennes France
- CIC‐P 1414 Clinical Investigation Center Inserm Rennes France
| | - Marie‐Clémence Verdier
- Department of Clinical and Biological Pharmacology Pharmacovigilance, Pharmacoepidemiology, and Drug Information Center Rennes University Hospital Rennes France
- Laboratory of Experimental and Clinical Pharmacology Faculty of Medicine Rennes 1 University Rennes France
- CIC‐P 1414 Clinical Investigation Center Inserm Rennes France
| | - Florian Lemaitre
- Department of Clinical and Biological Pharmacology Pharmacovigilance, Pharmacoepidemiology, and Drug Information Center Rennes University Hospital Rennes France
- Laboratory of Experimental and Clinical Pharmacology Faculty of Medicine Rennes 1 University Rennes France
- CIC‐P 1414 Clinical Investigation Center Inserm Rennes France
| | - Camille Lucidarme
- Department of Gastroenterology Rennes University Hospital Rennes France
| | - Guillaume Bouguen
- CIC‐P 1414 Clinical Investigation Center NUMECAN (Nutrition, Metabolism, and Cancer) Institute Inserm Rennes France
- Department of Gastroenterology Rennes University Hospital Rennes France
| | - Éric Bellissant
- Department of Clinical and Biological Pharmacology Pharmacovigilance, Pharmacoepidemiology, and Drug Information Center Rennes University Hospital Rennes France
- Laboratory of Experimental and Clinical Pharmacology Faculty of Medicine Rennes 1 University Rennes France
- CIC‐P 1414 Clinical Investigation Center Inserm Rennes France
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Bouguen G, Siproudhis L. Editorial: infliximab de-escalation in inflammatory bowel disease using a therapeutic drug monitoring strategy - early promise but more data needed. Authors' reply. Aliment Pharmacol Ther 2019; 49:817-818. [PMID: 30811643 DOI: 10.1111/apt.15151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- Guillaume Bouguen
- Hopital Pontchaillou, Service des Maladies de l'Appareil Digestif, Rennes Cedex, France
| | - Laurent Siproudhis
- Hopital Pontchaillou, Service des Maladies de l'Appareil Digestif, Rennes Cedex, France
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Gibson DJ, Ward MG. Editorial: infliximab de-escalation in inflammatory bowel disease using a therapeutic drug monitoring strategy-early promise but more data needed. Aliment Pharmacol Ther 2019; 49:816-817. [PMID: 30811645 DOI: 10.1111/apt.15081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- David J Gibson
- Gastroenterology, Alfred Hospital, Melbourne, Vic., Australia
| | - Mark G Ward
- Gastroenterology, Alfred Hospital, Melbourne, Vic., Australia
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