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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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Mitrev N, Kariyawasam V. Treatment endpoints in ulcerative colitis: Does one size fit all? World J Gastrointest Pharmacol Ther 2024; 15:91591. [PMID: 38764502 PMCID: PMC11099350 DOI: 10.4292/wjgpt.v15.i2.91591] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 02/28/2024] [Accepted: 04/10/2024] [Indexed: 04/24/2024] Open
Abstract
A treat-to-target strategy in inflammatory bowel disease (IBD) involves treatment intensification in order to achieve a pre-determined endpoint. Such uniform and tight disease control has been demonstrated to improve clinical outcomes compared to treatment driven by a clinician's subjective assessment of symptoms. However, choice of treatment endpoints remains a challenge in management of IBD via a treat-to-target strategy. The treatment endpoints for ulcerative colitis (UC), recommended by the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) consensus have changed somewhat over time. The latest STRIDE-II consensus advises immediate (clinical response), intermediate (clinical remission and biochemical normalisation) and long-term treatment (endoscopic healing, absence of disability and normalisation of health-related quality of life, as well as normal growth in children) endpoints in UC. However, achieving deeper levels of remission, such as histologic normalisation or healing of the gut barrier function, may further improve outcomes among UC patients. Generally, all medical therapy should seek to improve short- and long-term mortality and morbidity. Hence treatment endpoints should be chosen based on their ability to predict for improvement in short- and long-term mortality and morbidity. Potential benefits of treatment intensification need to be weighed against the potential harms within an individual patient. In addition, changing therapy that has achieved partial response may lead to worse outcomes, with failure to recapture response on treatment reversion. Patients may also place different emphasis on certain potential benefits and harms of various treatments than clinicians, or may have strong opinions re certain therapies. Potential benefits and harms of therapies, incremental benefits of achieving deeper levels of remission, as well as uncertainties of the same, need to be discussed with individual patients, and a treatment endpoint agreed upon with the clinician. Future research should focus on quantifying the incremental benefits and risks of achieving deeper levels of remission, such that clinicians and patients can make an informed decision about appropriate treatment end-point on an individual basis.
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Affiliation(s)
- Nikola Mitrev
- Department of Gastroenterology, Blacktown Hospital, Blacktown 2148, NSW, Australia
- Blacktown/Mt Druitt Clinical School, University of Western Sydney, Blacktown 2148, NSW, Australia
- Department of Gastroenterology, Wollongong Hospital, Loftus St, Wollongong 2500, NSW, Australia
| | - Viraj Kariyawasam
- Department of Gastroenterology, Blacktown Hospital, Blacktown 2148, NSW, Australia
- Blacktown/Mt Druitt Clinical School, University of Western Sydney, Blacktown 2148, NSW, Australia
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O'Connell DM, Moses J. Invited commentary to immunotherapy withdrawal by step-down to mesalamine in pediatrics patients with ulcerative colitis. JPGN REPORTS 2024; 5:95-96. [PMID: 38756131 PMCID: PMC11093890 DOI: 10.1002/jpr3.12047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 12/17/2023] [Accepted: 12/29/2023] [Indexed: 05/18/2024]
Affiliation(s)
- Daniel M. O'Connell
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and NutritionUniversity of Wisconsin School of Medicine and Public HealthMadisonWisconsinUSA
| | - Jonathan Moses
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and NutritionStanford University School of MedicinePalo AltoCaliforniaUSA
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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: 0] [Impact Index Per Article: 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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Brun MK, Gehin JE, Bjørlykke KH, Warren DJ, Klaasen RA, Sexton J, Sandanger Ø, Kvien TK, Mørk C, Jahnsen J, Bolstad N, Jørgensen KK, Haavardsholm EA, Goll GL, Syversen SW. Clinical consequences of infliximab immunogenicity and the effect of proactive therapeutic drug monitoring: exploratory analyses of the randomised, controlled NOR-DRUM trials. THE LANCET. RHEUMATOLOGY 2024; 6:e226-e236. [PMID: 38402891 DOI: 10.1016/s2665-9913(23)00341-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 12/15/2023] [Accepted: 12/21/2023] [Indexed: 02/27/2024]
Abstract
BACKGROUND Antidrug antibodies to TNF inhibitors might affect clinical outcomes. Proactive therapeutic drug monitoring allows for early detection of antidrug antibodies and might reduce negative clinical consequences. We aimed to explore how antidrug antibodies to the TNF inhibitor infliximab influence treatment outcomes, and to assess the effect of proactive therapeutic drug monitoring. METHODS This was a predefined exploratory analysis of data from the randomised, controlled NOR-DRUM trials. The trials were conducted in rheumatology, gastroenterology, and dermatology departments at 21 Norwegian hospitals. Adult patients (aged 18-75 years) with immune-mediated inflammatory diseases were randomly assigned to proactive therapeutic drug monitoring or standard infliximab dosing in the NOR-DRUM A trial (30-week follow-up) and the NOR-DRUM B trial (52-week follow-up). Antidrug antibodies were assessed with a drug-sensitive assay before each infusion. The outcomes of remission (at week 30), disease worsening (during 52 weeks), infusion reactions, and infliximab discontinuation were assessed according to the presence of antidrug antibodies and use of therapeutic drug monitoring. FINDINGS Between March 1, 2017, and Dec 12, 2019, 616 patients were included in the NOR-DRUM trials, of whom 615 had at least one serum infliximab and antidrug antibody assessment and were included in the present analyses. Mean age was 45 years (IQR 32-56), 305 (50%) patients were women, and 310 (50%) patients were men. Antidrug antibodies were detected in 147 (24%) patients. Remission at week 30 occurred in 25 (35%) of 72 patients with antidrug antibodies and 180 (54%) of 335 without antidrug antibodies (risk ratio 0·62 [95% CI 0·45-0·86]; p=0·0037). In patients with antidrug antibodies compared with patients without antidrug antibodies, higher rates were found for: disease worsening over 52 weeks (0·76 per person-year vs 0· 35 per person-year, hazard ratio [HR] 2·02 [95% CI 1·33-3·07]; p=0·0009), infusion reactions (0·16 per person-year vs 0·03 per person-year, HR 17·02 [6·98-41·47]; p<0·0001), and infliximab discontinuation (1·00 per person-year vs 0·20 per person-year, HR 6·64 [4·84-9·11]; p<0·0001). These associations were more pronounced in patients with high concentrations of antidrug antibodies than in those with low concentrations of antidrug antibodies. Independent of antibody status, therapeutic drug monitoring was associated with a lower risk of disease worsening (HR 0·41 [0·29-0·59]; p=0·0001) or an infusion reaction (HR 0·30 [0·12-0·73]; p=0·0076), and was associated with an increase in the rate of infliximab discontinuation (HR 1·37 [1·02-1·83]; p=0·037). INTERPRETATION In patients where antidrug antibodies were detected, remission was less likely to be reached and sustained, and infusion reaction or discontinuation of infliximab was more likely. Timely detection of antidrug antibodies by proactive therapeutic drug monitoring facilitated treatment decisions that reduced the negative consequences, both regarding infliximab effectiveness and safety. This highlights the role of proactive therapeutic drug monitoring in optimising infliximab therapy. FUNDING Inter-regional KLINBEFORSK grants and South-Eastern Norway Regional Health Authority grants.
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Affiliation(s)
- Marthe Kirkesæther Brun
- Center for Treatment of Rheumatic and Musculoskeletal Diseases, Diakonhjemmet Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Johanna E Gehin
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Kristin Hammersbøen Bjørlykke
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
| | - David John Warren
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Rolf A Klaasen
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Joseph Sexton
- Center for Treatment of Rheumatic and Musculoskeletal Diseases, Diakonhjemmet Hospital, Oslo, Norway
| | | | - Tore K Kvien
- Center for Treatment of Rheumatic and Musculoskeletal Diseases, Diakonhjemmet Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Cato Mørk
- Akershus Dermatology Center, Lørenskog, Norway
| | - Jørgen Jahnsen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
| | - Nils Bolstad
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | | | - Espen A Haavardsholm
- Center for Treatment of Rheumatic and Musculoskeletal Diseases, Diakonhjemmet Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Guro Løvik Goll
- Center for Treatment of Rheumatic and Musculoskeletal Diseases, Diakonhjemmet Hospital, Oslo, Norway; Institute of Health and Society, University of Oslo, Oslo, Norway
| | - Silje Watterdal Syversen
- Center for Treatment of Rheumatic and Musculoskeletal Diseases, Diakonhjemmet Hospital, Oslo, Norway; Institute of Health and Society, University of Oslo, Oslo, Norway
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Selinger CP, Rosiou K, Lenti MV. Biological therapy for inflammatory bowel disease: cyclical rather than lifelong treatment? BMJ Open Gastroenterol 2024; 11:e001225. [PMID: 38341192 PMCID: PMC10870786 DOI: 10.1136/bmjgast-2023-001225] [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: 10/29/2023] [Accepted: 01/04/2024] [Indexed: 02/12/2024] Open
Abstract
Inflammatory bowel disease (IBD) treatment was revolutionised with the arrival of biological therapy two decades ago. There are now multiple biologics and increasingly novel small molecules licensed for the treatment of IBD. Treatment guidelines highlight the need for effective control of inflammation and early escalation to advanced therapies to avoid long-term complications. Consequently, a large proportion of patients with IBD receive advanced therapies for a long time. Despite their beneficial risk-benefit profile, these treatments are not without risk of side effects, are costly to healthcare providers and pose a burden to the patient. It is, therefore, paramount to examine in which circumstances a temporary cessation of therapy can be attempted without undue clinical risk. Some patients may benefit from cyclical rather than continuous treatment. This review examines the risk of relapse after discontinuation of advanced therapies, how to identify patients at the lowest risk of relapse and the chance of recapturing response when flaring after discontinuation.
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Affiliation(s)
| | - Konstantina Rosiou
- Department of Gastroenterology, St James's University Hospital, Leeds, UK
| | - Marco V Lenti
- Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
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Patel S, Yarur AJ. A Review of Therapeutic Drug Monitoring in Patients with Inflammatory Bowel Disease Receiving Combination Therapy. J Clin Med 2023; 12:6577. [PMID: 37892715 PMCID: PMC10607463 DOI: 10.3390/jcm12206577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 09/27/2023] [Accepted: 10/14/2023] [Indexed: 10/29/2023] Open
Abstract
Background: Inflammatory Bowel Disease (IBD) impacts millions worldwide, presenting a major challenge to healthcare providers and patients. The advent of biologic therapies has enhanced the prognosis, but many patients exhibit primary or secondary non-response, underscoring the need for rigorous monitoring and therapy optimization to improve outcomes. Objective: This narrative review seeks to understand the role of therapeutic drug monitoring (TDM) in optimizing treatment for IBD patients, especially for those on combination therapies of biologics and immunomodulators. Methods: A comprehensive synthesis of the current literature was undertaken, focusing on the application, benefits, limitations, and future directions of TDM in patients receiving a combination of biologic therapies and immunomodulators. Results: While biological therapies have improved outcomes, rigorous monitoring and therapy optimization are needed. TDM has emerged as a pivotal strategy, enhancing outcomes cost-effectively while reducing adverse events. While most data pertain to monotherapies, TDM's applicability also extends to combination therapy. Conclusion: TDM plays a crucial role in the treatment optimization of IBD patients on combination therapies. Further research is needed to fully understand its potential and limitations in the broader context of IBD management.
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Affiliation(s)
| | - Andres J. Yarur
- Cedars-Sinai Medical Center, 8730 Alden Dr., Los Angeles, CA 90048, USA
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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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10
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Syal G, Melmed GY, Almario CV, Spiegel BMR. Azathioprine Withdrawal Is Cost-Effective in Patients with Crohn's Disease in Remission on Infliximab and Azathioprine. Dig Dis Sci 2023; 68:404-413. [PMID: 36512266 DOI: 10.1007/s10620-022-07789-x] [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: 04/04/2022] [Accepted: 12/05/2022] [Indexed: 02/09/2023]
Abstract
BACKGROUND In Crohn's disease, combination therapy with infliximab and azathioprine is more effective than either drug alone but is associated with a higher risk of therapy-related complications. Though therapy de-escalation can reduce risks and save costs, it is associated with a risk of Crohn's disease relapse. AIMS We aimed to study the cost-effectiveness of de-escalation strategies in Crohn's disease patients in remission on infliximab and azathioprine. METHODS We constructed a decision tree with Markov models for continuation of infliximab and azathioprine, discontinuation of azathioprine followed by its re-introduction in case of relapse, discontinuation of azathioprine followed by infliximab dose intensification without azathioprine reintroduction in case of relapse and discontinuation of infliximab. Third-party payers' perspective with a willingness-to-pay threshold of $100,000/quality-adjusted life years was used. Markov cycle length was 3 months, and the study period was 5 years. A 35-year-old patient with Crohn's disease in clinical remission on azathioprine 150 mg daily and infliximab 5 mg/kg every 8 weeks was used for base-case analysis. RESULTS Azathioprine withdrawal followed by its reintroduction upon relapse was the dominant strategy as it was the most effective and least expensive approach on base-case analysis. It was also cost-effective in 99.3% of Monte Carlo trial simulations. AZA withdrawal without IFX dose intensification upon relapse was the least effective and the most expensive strategy. CONCLUSION Azathioprine withdrawal is the most effective and least costly de-escalation strategy in CD patients in remission on combination therapy if AZA re-introduction is performed upon CD relapse.
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Affiliation(s)
- Gaurav Syal
- Division of Gastroenterology, University of California at San Diego, 9452 S Medical Ctr Dr, La Jolla, San Diego, CA, 92037, USA.
| | - Gil Y Melmed
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, 8730 Alden Drive, Second Floor East, Los Angeles, CA, 90048, USA
| | - Christopher V Almario
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Pacific Theaters Building, Suite 800, 116 N. Robertson Blvd., Los Angeles, CA, 90048, USA
| | - Brennan M R Spiegel
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Pacific Theaters Building, Suite 800, 116 N. Robertson Blvd., Los Angeles, CA, 90048, USA
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11
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Colman RJ, Dykes DMH, Arce-Clachar AC, Saeed SA, Minar P. Infliximab Therapy for Pediatric Crohn Disease and Ulcerative Colitis. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:407-422. [DOI: 10.1007/978-3-031-14744-9_31] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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12
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Barrau M, Duprat M, Veyrard P, Tournier Q, Williet N, Phelip JM, Waeckel L, Cheifetz AS, Papamichael K, Roblin X, Paul S. A Systematic Review on the interest of Drug Tolerant assay in the monitoring of Inflammatory Bowel Disease. J Crohns Colitis 2022; 17:633-643. [PMID: 36301958 DOI: 10.1093/ecco-jcc/jjac164] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Indexed: 02/08/2023]
Abstract
Many patients with inflammatory bowel disease (IBD) are treated with anti-tumor necrosis factor (TNF) therapies, of which infliximab (IFX) is most commonly used. Loss of response (LOR) to anti-TNF therapy due to immunogenic failure accounts for 20% of subsequent medical intervention and is defined, using a drug sensitive assay, as low or undetectable concentration of drug with high titers of anti-drug antibodies (ADAb). We performed a systematic review to investigate the use of a drug tolerant assay during both induction and maintenance to monitor patients treated with anti-TNFs. After the search on PubMed, 90 publications were reviewed. Most ADAb detection methods are drug sensitive, cannot detect ADAb in the presence of drug, and therefore cannot be used close to drug administration, when the drug concentration is too high. To overcome this major limitation, several drug-tolerant techniques have been developed and will be discussed in this review. Using drug-tolerant assays ADAb against infliximab (IFX) or adalimumab (ADM) can be detected during induction and predict primary non-response or LOR. Drug sensitive assays do not allow detection of ADAb during the induction phase as IFX or ADM concentration is typically high.
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Affiliation(s)
- Mathilde Barrau
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - Manon Duprat
- Department of Immunology, CIRI - Centre International de Recherche en Infectiologie, Team GIMAP, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR530, CIC 1408 Vaccinology, F42023 Saint-Etienne, France
| | - Pauline Veyrard
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - Quentin Tournier
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - Nicolas Williet
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - Jean Marc Phelip
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - Louis Waeckel
- Department of Immunology, CIRI - Centre International de Recherche en Infectiologie, Team GIMAP, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR530, CIC 1408 Vaccinology, F42023 Saint-Etienne, France
| | - Adam S Cheifetz
- Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center Instructor in Medicine, Harvard Medical School
| | - Konstantinos Papamichael
- Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center Instructor in Medicine, Harvard Medical School
| | - Xavier Roblin
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - Stephane Paul
- Department of Immunology, CIRI - Centre International de Recherche en Infectiologie, Team GIMAP, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR530, CIC 1408 Vaccinology, F42023 Saint-Etienne, France
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13
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Efficacy and Safety of Infliximab Retreatment in Crohn's Disease: A Multicentre, Prospective, Observational Cohort (REGAIN) Study from the GETAID. Am J Gastroenterol 2022; 117:1482-1490. [PMID: 35973142 DOI: 10.14309/ajg.0000000000001842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 05/06/2022] [Indexed: 12/11/2022]
Abstract
INTRODUCTION The objective of this study was to describe the efficacy and safety of infliximab (IFX) reintroduction in Crohn's disease (CD) after stopping for loss of response or intolerance. METHODS We conducted a prospective multicenter observational cohort study including adult patients with clinically (CD Activity Index >150) and objectively active luminal CD in whom IFX was reintroduced after at least 6 months of discontinuation. The reasons for the initial discontinuation could be a secondary loss of response or IFX intolerance. The reintroduction schedule included 3 IFX infusions at weeks 0, 4, and 8, after a systematic premedication. The primary end point was the efficacy of IFX retreatment at week 26 defined by a CD Activity Index of <150 in the absence of IFX discontinuation or use of corticosteroids, surgery, or other biologic. RESULTS At week 26, 24 patients (35%) among the 69 analyzed reached the primary end point. No significant difference was observed between rates of clinical remission at week 26 in patients with prior LOR (n = 48) and those with IFX intolerance (n = 21) (35% and 33%, P = 0.87, respectively). Thirty-two acute infusion reactions were recorded in 27 patients, leading to withdrawal of IFX in 20 patients. No pharmacokinetic characteristic at baseline but detection of positive anti-drug antibodies at week 4 was predictive of IFX failure or infusion reaction at week 26. DISCUSSION In this first prospective cohort study, IFX retreatment was safe and effective in one-third of the patients with CD, regardless the reason of prior discontinuation. Early detection of anti-drug antibodies can predict subsequent IFX reintroduction failure and infusion reactions.
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14
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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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15
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Liefferinckx C, Bottieau J, Toubeau JF, Thomas D, Rahier JF, Louis E, Baert F, Dewint P, Pouillon L, Lambrecht G, Vallée F, Vermeire S, Bossuyt P, Franchimont D. Collecting New Peak and Intermediate Infliximab Levels to Predict Remission in Inflammatory Bowel Diseases. Inflamm Bowel Dis 2022; 28:208-217. [PMID: 33783494 DOI: 10.1093/ibd/izab042] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND The loss of response to infliximab is a challenge for clinicians in the management of inflammatory bowel disease (IBD). Mounting evidence suggests that therapeutic drug monitoring at induction may predict remission during maintenance. The aim of the study was to improve predictive models of remission by exploring new peak and intermediate infliximab measurements during induction. METHODS This was a prospective multicenter study evaluating the pharmacokinetics of infliximab during induction in a pioneer cohort of 63 patients with IBD. Pharmacokinetics data including peak, intermediate, and trough levels were combined with clinical and biological parameters and were subsequently fed into tailored logistic regression and tree-based techniques to predict remission at week 30. RESULTS Infliximab peak levels at week 2, intermediate levels at week 3, and trough levels at week 6 were correlated with remission at week 30. Predictive models exhibited an increased accuracy over the successive timepoints of the induction with key inputs such as albumin, C-reactive protein, eosinophils, neutrophils, lymphocytes, intermediate level at week 3, trough level at week 6, and age at diagnosis. Our predictive model of remission at week 30 was obtained with an area under the receiver operating characteristic curve of 0.9 ± 0.12, a sensitivity of 89%, and a specificity of 75%. CONCLUSIONS This study showed the clinical relevance of measuring new infliximab levels to predict remission in patients with IBD. These findings lay the foundation for a personalized medicine in which biotherapies could be monitored at an early stage, thereby improving patients' clinical management.
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Affiliation(s)
| | - Jérémie Bottieau
- Department of Electrical Engineering, University of Mons, Mons, Belgium
| | | | - Debby Thomas
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | | | - Edouard Louis
- Department of Gastroenterology, Centre Hospitalier Universitaire Sart-Tilman, ULG, Liège, Belgium
| | - Filip Baert
- Department of Gastroenterology, AZ Delta, Roeselare-Menen-Torhout, Belgium
| | - Pieter Dewint
- Department of Gastroenterology, AZ Maria Middelares, Ghent, Belgium.,Department of Gastroenterology, UZ Antwerp, Antwerp, Belgium
| | - Lieven Pouillon
- Department of Gastroenterology, Imelda General Hospital, Bonheiden, Belgium
| | - Guy Lambrecht
- Department of Gastroenterology, AZ Damiaan, Oostende, Belgium
| | - François Vallée
- Department of Electrical Engineering, University of Mons, Mons, Belgium
| | - Severine Vermeire
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Peter Bossuyt
- Department of Gastroenterology, Imelda General Hospital, Bonheiden, Belgium
| | - Denis Franchimont
- Department of Gastroenterology, Hôpital Erasme, ULB, Brussels, Belgium
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16
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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 2022; 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] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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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17
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Fousekis FS, Papamichael K, Kourtis G, Albani EN, Orfanidou A, Saridi M, Katsanos KH, Christodoulou DK. The efficacy of immunomodulators in the prevention and suppression of anti-drug antibodies to anti-tumor necrosis factor therapy in inflammatory bowel disease. Ann Gastroenterol 2022; 35:1-7. [PMID: 34987282 PMCID: PMC8713338 DOI: 10.20524/aog.2021.0682] [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: 07/29/2021] [Accepted: 10/28/2021] [Indexed: 11/11/2022] Open
Abstract
The development of biological agents against tumor necrosis factor (TNF) has revolutionized the management of inflammatory bowel disease (IBD), frequently achieving induction and maintenance of remission in both ulcerative colitis and Crohn's disease. However, a loss of response due to the development of anti-drug antibodies (ADA) is seen annually in approximately 20% of IBD patients receiving anti-TNF therapy. Current evidence suggests that the use of immunomodulators (IMM), such as thiopurines (azathioprine and 6-mercaptopurine) or methotrexate, may prevent or suppress ADA formation. In this article, we present a comprehensive review of the available literature regarding the efficacy of IMM in the prevention and suppression of ADA development to anti-TNF therapy in patients with IBD.
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Affiliation(s)
- Fotios S. Fousekis
- Department of Gastroenterology, School of Health Sciences, University Hospital of Ioannina, Faculty of Medicine, University of Ioannina, Ioannina, Greece (Fotios S. Fousekis, Konstantinos H. Katsanos, Dimitrios K. Christodoulou)
| | - Konstantinos Papamichael
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA (Konstantinos Papamichael)
| | - Georgios Kourtis
- Department of Department of Nursing, “Sotiria” General Hospital, Athens, Greece (Georgios Kourtis)
| | - Eleni N. Albani
- Department of Nursing, University of Patra, Patra, Greece (Eleni N. Albani)
| | - Afroditi Orfanidou
- Academic Department of Gastroenterology, Laiko General Hospital, Medical School of National Kapodistrian University of Athens, Greece (Afroditi Orfanidou)
| | - Maria Saridi
- Department of Nursing, University of Thessaly, Lamia, Greece (Maria Saridi)
| | - Konstantinos H. Katsanos
- Department of Gastroenterology, School of Health Sciences, University Hospital of Ioannina, Faculty of Medicine, University of Ioannina, Ioannina, Greece (Fotios S. Fousekis, Konstantinos H. Katsanos, Dimitrios K. Christodoulou)
| | - Dimitrios K. Christodoulou
- Department of Gastroenterology, School of Health Sciences, University Hospital of Ioannina, Faculty of Medicine, University of Ioannina, Ioannina, Greece (Fotios S. Fousekis, Konstantinos H. Katsanos, Dimitrios K. Christodoulou)
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18
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Jongsma MME, Aardoom MA, Cozijnsen MA, van Pieterson M, de Meij T, Groeneweg M, Norbruis OF, Wolters VM, van Wering HM, Hojsak I, Kolho KL, Hummel T, Stapelbroek J, van der Feen C, van Rheenen PF, van Wijk MP, Teklenburg-Roord STA, Schreurs MWJ, Rizopoulos D, Doukas M, Escher JC, Samsom JN, de Ridder L. First-line treatment with infliximab versus conventional treatment in children with newly diagnosed moderate-to-severe Crohn's disease: an open-label multicentre randomised controlled trial. Gut 2022; 71:34-42. [PMID: 33384335 PMCID: PMC8666701 DOI: 10.1136/gutjnl-2020-322339] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 10/15/2020] [Accepted: 10/18/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE In newly diagnosed paediatric patients with moderate-to-severe Crohn's disease (CD), infliximab (IFX) is initiated once exclusive enteral nutrition (EEN), corticosteroid and immunomodulator therapies have failed. We aimed to investigate whether starting first-line IFX (FL-IFX) is more effective to achieve and maintain remission than conventional treatment. DESIGN In this multicentre open-label randomised controlled trial, untreated patients with a new diagnosis of CD (3-17 years old, weighted Paediatric CD Activity Index score (wPCDAI) >40) were assigned to groups that received five infusions of 5 mg/kg IFX at weeks 0, 2, 6, 14 and 22 (FL-IFX), or EEN or oral prednisolone (1 mg/kg, maximum 40 mg) (conventional). The primary outcome was clinical remission on azathioprine, defined as a wPCDAI <12.5 at week 52, without need for treatment escalation, using intention-to-treat analysis. RESULTS 100 patients were included, 50 in the FL-IFX group and 50 in the conventional group. Four patients did not receive treatment as per protocol. At week 10, a higher proportion of patients in the FL-IFX group than in the conventional group achieved clinical (59% vs 34%, respectively, p=0.021) and endoscopic remission (59% vs 17%, respectively, p=0.001). At week 52, the proportion of patients in clinical remission was not significantly different (p=0.421). However, 19/46 (41%) patients in the FL-IFX group were in clinical remission on azathioprine monotherapy without need for treatment escalation vs 7/48 (15%) in the conventional group (p=0.004). CONCLUSIONS FL-IFX was superior to conventional treatment in achieving short-term clinical and endoscopic remission, and had greater likelihood of maintaining clinical remission at week 52 on azathioprine monotherapy. TRIAL REGISTRATION NUMBER ClinicalTrials.gov Registry (NCT02517684).
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Affiliation(s)
- Maria M E Jongsma
- Paediatric Gastroenterology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Martine A Aardoom
- Paediatric Gastroenterology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Martinus A Cozijnsen
- Paediatric Gastroenterology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Merel van Pieterson
- Paediatric Gastroenterology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Tim de Meij
- Paediatric Gastroenterology, University Medical Center Amsterdam—Location VUmc, Amsterdam, The Netherlands
| | | | | | - Victorien M Wolters
- Paediatric Gastroenterology, Utrecht Medical Center/Wilhelmina Children's Hospital, Utrecht, The The Netherlands
| | | | - Iva Hojsak
- Referral centre for Paediatric Gastroenterology and Nutrition, Children's Hospital Zagreb, Zagreb, Croatia,University JJ Strossmayer, School of Medicine Osijek, Osijek, Croatia
| | - Kaija-Leena Kolho
- Paediatric Gastroenterology, Children's Hospital, University of Tampere, Helsinki, Finland,Tampere University, Tampere, Finland
| | - Thalia Hummel
- Paediatrics, Medical Spectrum Twente, Enschede, The Netherlands
| | | | | | - Patrick F van Rheenen
- Paediatric Gastroenterology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Michiel P van Wijk
- Paediatric Gastroenterology, University Medical Center Amsterdam—Location VUmc, Amsterdam, The Netherlands
| | | | | | | | | | - Johanna C Escher
- Paediatric Gastroenterology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Janneke N Samsom
- Laboratory of Pediatrics, Division of Gastroenterology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Lissy de Ridder
- Paediatric Gastroenterology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands
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19
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Yang S, Yang S, Kwon Jo Y, Kim S, Jung Chang M, Choi J, Hee Cheon J, Yu YM. Efficacy and tolerability of infliximab retreatment in patients with inflammatory bowel disease: a systematic review and meta-analysis. Ther Adv Chronic Dis 2021; 12:20406223211041927. [PMID: 34729142 PMCID: PMC8438941 DOI: 10.1177/20406223211041927] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 08/03/2021] [Indexed: 11/30/2022] Open
Abstract
Background: A large proportion of patients with inflammatory bowel disease (IBD) relapse after drug discontinuation despite achieving a stable state of infliximab-induced clinical remission. Resuming the use of the same tumor necrosis factor-alpha (TNF-α) inhibitors in patients who relapse following TNF-α inhibitor discontinuation was suggested as a treatment strategy. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of infliximab retreatment in patients with IBD. Methods: A systematic literature search to shortlist relevant studies was conducted using the MEDLINE, Embase, CINAHL, and SCOPUS databases for studies published from inception to August 2020. Results: Nine studies were included in the meta-analysis. The pooled clinical remission rate of infliximab retreatment in patients with IBD was 85% (95% confidence interval (CI), 81–89%) for induction treatment and 73% (95% CI, 66–80%) for maintenance treatment. A clinical remission rate following infliximab reintroduction was achieved in a greater proportion of patients with Crohn’s disease (87%; 95% CI, 83–91%) than in those with ulcerative colitis (78%; 95% CI, 61–91%) for induction treatment, but the difference was not statistically significant. Infusion-related reactions after infliximab retreatment occurred in 9% of patients with IBD (95% CI, 3–16%). Conclusion: Infliximab retreatment showed high clinical remission rates with tolerable infusion-related reactions in patients with IBD who achieved remission with initial infliximab treatment but relapsed after its discontinuation. We suggest infliximab as a viable alternative in patients with IBD who previously responded well to infliximab treatment.
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Affiliation(s)
- Seungwon Yang
- Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, Republic of Korea
| | - Siyoung Yang
- Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, Republic of Korea
| | - Young Kwon Jo
- Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, Republic of Korea
| | - Seungyeon Kim
- College of Pharmacy & Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Min Jung Chang
- Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, Republic of Korea
| | - Junjeong Choi
- Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, Republic of Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Yun Mi Yu
- Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
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20
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Zeng-Wang YM, Cares K, Thomas R, El-Baba M. The Effectiveness of Methylprednisolone as a Premedication Among the Pediatric Population for Preventing Infusion-Related Reactions to Infliximab. Gastroenterol Nurs 2021; 44:449-454. [PMID: 34690297 DOI: 10.1097/sga.0000000000000592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 01/13/2021] [Indexed: 11/25/2022] Open
Abstract
Administering medications prior to infliximab infusions to prevent infusion-related infliximab reactions is a common practice in the United States. However, the premedication protocol varies among different institutions. The purpose of this study was to demonstrate whether the use of methylprednisolone was effective as a premedication to prevent infusion reactions while infliximab was administered to children with inflammatory bowel disease. The effect of concurrent use of other immunomodulators on the rate of reaction incidents was also studied. This was a retrospective chart review, assessing children younger than 21 years diagnosed with inflammatory bowel disease from January 2008 to April 2018. The incident rate of infusion reactions was also compared between two cohorts: those who received the premedication of methylprednisolone and those who did not. Subgroup analysis of concomitant immunomodulators, infliximab dose and frequency, and anti-infliximab assay were also performed. A total of 34 subjects received methylprednisolone as a premedication and 151 subjects did not. No statistically significant difference of allergic reactions was found between the two groups (p = .727). Concomitant immunomodulator therapy lowered the likelihood of developing reactions (p = .048). This study was conducted to help pediatric gastroenterology and infusion nurses better understand and implement evidence-based approaches in the premedication protocol for infusions of anti-tumor necrosis factor-α (anti-TNF-α) antibody products.
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Affiliation(s)
- Yiping Maggie Zeng-Wang
- Yiping Maggie Zeng-Wang, MSN, FNP-BC, is Nurse Practitioner, Children's Hospital of Michigan, Detroit Medical Center, Detroit
- Kristen Cares, MD, is Pediatrician/Assistant Professor, Children's Hospital of Michigan, Detroit Medical Center, Detroit
- Ronald Thomas, PhD, is Statistician, Children's Hospital of Michigan, Detroit Medical Center, Detroit
- Mohammad El-Baba, MD, is Pediatrician/Professor, Children's Hospital of Michigan, Detroit Medical Center, Detroit
| | - Kristen Cares
- Yiping Maggie Zeng-Wang, MSN, FNP-BC, is Nurse Practitioner, Children's Hospital of Michigan, Detroit Medical Center, Detroit
- Kristen Cares, MD, is Pediatrician/Assistant Professor, Children's Hospital of Michigan, Detroit Medical Center, Detroit
- Ronald Thomas, PhD, is Statistician, Children's Hospital of Michigan, Detroit Medical Center, Detroit
- Mohammad El-Baba, MD, is Pediatrician/Professor, Children's Hospital of Michigan, Detroit Medical Center, Detroit
| | - Ronald Thomas
- Yiping Maggie Zeng-Wang, MSN, FNP-BC, is Nurse Practitioner, Children's Hospital of Michigan, Detroit Medical Center, Detroit
- Kristen Cares, MD, is Pediatrician/Assistant Professor, Children's Hospital of Michigan, Detroit Medical Center, Detroit
- Ronald Thomas, PhD, is Statistician, Children's Hospital of Michigan, Detroit Medical Center, Detroit
- Mohammad El-Baba, MD, is Pediatrician/Professor, Children's Hospital of Michigan, Detroit Medical Center, Detroit
| | - Mohammad El-Baba
- Yiping Maggie Zeng-Wang, MSN, FNP-BC, is Nurse Practitioner, Children's Hospital of Michigan, Detroit Medical Center, Detroit
- Kristen Cares, MD, is Pediatrician/Assistant Professor, Children's Hospital of Michigan, Detroit Medical Center, Detroit
- Ronald Thomas, PhD, is Statistician, Children's Hospital of Michigan, Detroit Medical Center, Detroit
- Mohammad El-Baba, MD, is Pediatrician/Professor, Children's Hospital of Michigan, Detroit Medical Center, Detroit
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21
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A Practical Guide to Therapeutic Drug Monitoring of Biologic Medications for Inflammatory Bowel Disease. J Clin Med 2021; 10:jcm10214990. [PMID: 34768509 PMCID: PMC8584740 DOI: 10.3390/jcm10214990] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/19/2021] [Accepted: 10/20/2021] [Indexed: 02/07/2023] Open
Abstract
Therapeutic drug monitoring (TDM) is a useful strategy to optimize biologic medications for inflammatory bowel disease not responsive to standard dosing regimens. TDM is cost effective for anti-tumor necrosis factor agents in the setting of loss of response (reactive TDM). Optimizing drug dosing when patients are in remission (proactive TDM) may be beneficial in certain circumstances. However, frequently the serum drug concentration in isolation becomes the focus TDM. Additionally, the lines of reactive and proactive TDM can quickly blur in many common clinical settings. Physicians employing a TDM based strategy need to place the drug concentration in context with the inflammatory status of the patient, the underlying pharmacokinetics and pharmacodynamics of the drug, the risk of immunogenicity, and the therapeutic goals for the patient. Physicians should understand the limits of TDM and feel comfortable making therapeutic decisions with imperfect information. The goal of this narrative review is to provide a framework of questions that physicians can use to employ TDM effectively in practice.
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22
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Raine T, Verstockt B, Kopylov U, Karmiris K, Goldberg R, Atreya R, Burisch J, Burke J, Ellul P, Hedin C, Holubar SD, Katsanos K, Lobaton T, Schmidt C, Cullen G. ECCO Topical Review: Refractory Inflammatory Bowel Disease. J Crohns Colitis 2021; 15:1605-1620. [PMID: 34160593 DOI: 10.1093/ecco-jcc/jjab112] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease is a chronic disease with variable degrees of extent, severity, and activity. A proportion of patients will have disease that is refractory to licensed therapies, resulting in significant impairment in quality of life. The treatment of these patients involves a systematic approach by the entire multidisciplinary team, with particular consideration given to medical options including unlicensed therapies, surgical interventions, and dietetic and psychological support. The purpose of this review is to guide clinicians through this process and provide an accurate summary of the available evidence for different strategies.
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Affiliation(s)
- Tim Raine
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
- Department of Chronic Diseases and Metabolism, TARGID - IBD, KU Leuven, Leuven, Belgium
| | - Uri Kopylov
- Department of Gastroenterology, Sheba Medical Center, Ramat Gan, Israel
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | | | - Rimma Goldberg
- Department of Gastroenterology, Monash Health and School of Clinical Sciences, Monash University, Melbourne, VIC, Australia
| | - Raja Atreya
- Department of Medicine 1, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Johan Burisch
- Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - John Burke
- Colorectal and General Surgery, Beaumont Hospital, Dublin, Ireland
| | - Pierre Ellul
- Department of Medicine, Division of Gastroenterology, Mater Dei Hospital, Msida, Malta
| | - Charlotte Hedin
- Karolinska Institutet, Department of Medicine Solna, Stockholm, Sweden
- Karolinska University Hospital, Gastroenterology Unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden
| | - Stefan D Holubar
- Department of Colon & Rectal Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Konstantinos Katsanos
- Department of Gastroenterology and Hepatology, University and Medical School of Ioannina, Ioannina, Greece
| | - Triana Lobaton
- Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | - Carsten Schmidt
- Medical Faculty of the Friedrich Schiller University, Jena, Germany
| | - Garret Cullen
- Centre for Colorectal Disease, St Vincent's University Hospital and School of Medicine, University College Dublin, Gastroenterology, Dublin, Ireland
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23
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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] [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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24
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Normatov I, Fluxa D, Wang JD, Ollech JE, Gulotta GE, Patel S, Quintero MA, De la Torre B, Solis N, Damas OM, Deshpande AR, Kerman DH, Abreu MT, Rubin DT. Real-World Experience With Proactive Therapeutic Drug Monitoring During Infliximab Reintroduction. CROHN'S & COLITIS 360 2021; 3:otab048. [PMID: 36776674 PMCID: PMC9802083 DOI: 10.1093/crocol/otab048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Indexed: 01/01/2023] Open
Abstract
Background Interruptions in infliximab therapy are associated with the development of antibodies to infliximab (ATI), infusion reactions (IRs), and loss of response. Despite these challenges, recent observational studies suggest that reinitiating infliximab after a drug holiday can be safe and effective. We assessed the utility of our protocol for restarting infliximab using early serum infliximab and ATI measurements. Methods A retrospective cohort study of patients restarted on infliximab after at least a 6-month drug holiday. The cohort was divided into 2 groups: a "therapeutic drug monitoring (TDM) group," those who had serum infliximab and ATI measured 1-3 weeks after first reinduction dose, and a "non-TDM group." Outcomes included results of TDM, occurrence of immediate IR (IIR) and delayed hypersensitivity reactions, and medication persistence at 14 weeks and 1 year. Results About 76 patients were included: 49 in the TDM group and 27 in the non-TDM group. Of 76, 67 (88%) patients tolerated the first reinduction dose without IR. Formation of ATI was seen in 17 of 49 (35%) patients and was associated with longer drug holidays. Most did not experience IR during the entire therapy course-in 26 of 32 (81%) without ATI and 20 of 27 (74%) in the non-TDM group. Infliximab persistence at 14 weeks and 1 year was 76% and 57% for the cohort, respectively. Conclusion Infliximab can be safely and effectively restarted after a drug holiday. We suggest performing TDM with a drug-tolerant assay 1-3 weeks after the first reinduction infusion as a means to identify patients at risk for severe IIR at the second dose.
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Affiliation(s)
- Inessa Normatov
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, Illinois, USA
| | - Daniela Fluxa
- Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Jingzhou D Wang
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, Illinois, USA
| | - Jacob E Ollech
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, Illinois, USA
| | - George E Gulotta
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, Illinois, USA
| | - Shivani Patel
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, Illinois, USA
| | - Maria A Quintero
- Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Bety De la Torre
- Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Norma Solis
- Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Oriana M Damas
- Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Amar R Deshpande
- Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - David H Kerman
- Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Maria T Abreu
- Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - David T Rubin
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, Illinois, USA,Address correspondence to: David T. Rubin, MD, University of Chicago Medicine Inflammatory Bowel Disease Center, 5841 S. Maryland Avenue, MC 4076, Chicago, IL 60637, USA ()
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25
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Janssen L, Romberg-Camps M, van Bodegraven A, Haans J, Aquarius M, Boekema P, Munnecom T, Brandts L, Joore M, Masclee A, Jonkers D, Pierik M. Control Crohn Safe with episodic adalimumab monotherapy as first-line treatment study (CoCroS): study protocol for a randomised controlled trial. BMJ Open 2021; 11:e042885. [PMID: 33947729 PMCID: PMC8098960 DOI: 10.1136/bmjopen-2020-042885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
INTRODUCTION Crohn's disease (CD) is a chronic inflammatory bowel disease with a heterogeneous clinical presentation, relapse rate and treatment response. At present, no markers are available to adequately predict disease course at diagnosis. To prevent overtreatment of patients with a relative mild disease course, a step-up approach starting with corticosteroids is usually applied. Timely introduction of potentially disease modifying drugs and tight control of mucosal inflammation are crucial to prevent disease-related complications in patients with a complex disease course. We hypothesise that episodic treatment with adalimumab monotherapy in combination with close monitoring after drug discontinuation improves long-term outcome and reduces drug-related side effects, while preventing overtreatment. METHODS AND ANALYSIS In this pragmatic multicentre randomised controlled trial, newly diagnosed CD patients or CD patients with a flare, naïve to thiopurines and biologicals, will be included and randomised 1:1 to open-label episodic (ie, 24 weeks) adalimumab monotherapy or step-up care starting with corticosteroids. The primary outcome is the number of yearly quarters of corticosteroid free clinical (Monitor Inflammatory Bowel Disease At Home score ≤3) and biochemical (C reactive protein within normal range and faecal calprotectin ≤200 µg/g) remission at week 96. Secondary outcomes are total healthcare costs, cumulative corticosteroid dose, proportion of patients with endoscopic remission at week 24, corticosteroid-free clinical remission, time to remission and patient-reported outcome measures on quality of life, (work) disability and treatment adherence. Safety outcomes are drug-related and disease-related adverse events and disease progression on MRI-enterography at week 96. ETHICS AND DISSEMINATION This study is approved by the Medical Research Ethics Committee of azM/UM in Maastricht dated 21 August 2019 (METC18-076) and is monitored by the Clinical Trial Centre Maastricht according to Good Clinical Practice guidelines. Written informed consent will be obtained from all patients. Study results will be published in international peer-reviewed medical journals. TRIAL REGISTRATION NUMBER NCT03917303.
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Affiliation(s)
- Laura Janssen
- NUTRIM - School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
- Gastroenterology and Hepatology, Maastricht UMC+, Maastricht, The Netherlands
| | - Mariëlle Romberg-Camps
- Gastroenterology, Zuyderland Medical Centre Sittard-Geleen, Sittard-Geleen, Limburg, The Netherlands
| | - Ad van Bodegraven
- Gastroenterology, Zuyderland Medical Centre Sittard-Geleen, Sittard-Geleen, Limburg, The Netherlands
| | - Jeoffrey Haans
- Gastroenterology and Hepatology, Maastricht UMC+, Maastricht, The Netherlands
| | - Michèl Aquarius
- Gastroenterology, VieCuri Medical Centre, Venlo, The Netherlands
| | - Paul Boekema
- Gastroenterology, Maxima Medical Centre, Eindhoven, The Netherlands
| | - Tamara Munnecom
- Gastroenterology, Laurentius Hospital, Roermond, The Netherlands
| | - Lloyd Brandts
- Clinical Epidemiology and Medical Technology Assessment (KEMTA), Maastricht UMC+, Maastricht, The Netherlands
| | - Manuela Joore
- Clinical Epidemiology and Medical Technology Assessment (KEMTA), Maastricht UMC+, Maastricht, The Netherlands
- CAPHRI - School for Care and Public Health Research Institute, Maastricht University, Maastricht, The Netherlands
| | - Adrian Masclee
- Gastroenterology and Hepatology, Maastricht UMC+, Maastricht, The Netherlands
| | - D Jonkers
- NUTRIM - School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - M Pierik
- Gastroenterology and Hepatology, Maastricht UMC+, Maastricht, The Netherlands
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26
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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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27
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Nakase H, Uchino M, Shinzaki S, Matsuura M, Matsuoka K, Kobayashi T, Saruta M, Hirai F, Hata K, Hiraoka S, Esaki M, Sugimoto K, Fuji T, Watanabe K, Nakamura S, Inoue N, Itoh T, Naganuma M, Hisamatsu T, Watanabe M, Miwa H, Enomoto N, Shimosegawa T, Koike K. Evidence-based clinical practice guidelines for inflammatory bowel disease 2020. J Gastroenterol 2021; 56:489-526. [PMID: 33885977 PMCID: PMC8137635 DOI: 10.1007/s00535-021-01784-1] [Citation(s) in RCA: 251] [Impact Index Per Article: 62.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 03/25/2021] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) is a general term for chronic or remitting/relapsing inflammatory diseases of the intestinal tract and generally refers to ulcerative colitis (UC) and Crohn's disease (CD). Since 1950, the number of patients with IBD in Japan has been increasing. The etiology of IBD remains unclear; however, recent research data indicate that the pathophysiology of IBD involves abnormalities in disease susceptibility genes, environmental factors and intestinal bacteria. The elucidation of the mechanism of IBD has facilitated therapeutic development. UC and CD display heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management depends on the understanding and tailoring of evidence-based interventions by physicians. In 2020, seventeen IBD experts of the Japanese Society of Gastroenterology revised the previous guidelines for IBD management published in 2016. This English version was produced and modified based on the existing updated guidelines in Japanese. The Clinical Questions (CQs) of the previous guidelines were completely revised and categorized as follows: Background Questions (BQs), CQs, and Future Research Questions (FRQs). The guideline was composed of a total of 69 questions: 39 BQs, 15 CQs, and 15 FRQs. The overall quality of the evidence for each CQ was determined by assessing it with reference to the Grading of Recommendations Assessment, Development and Evaluation approach, and the strength of the recommendation was determined by the Delphi consensus process. Comprehensive up-to-date guidance for on-site physicians is provided regarding indications for proceeding with the diagnosis and treatment.
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Affiliation(s)
- Hiroshi Nakase
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan ,grid.263171.00000 0001 0691 0855Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuoku, Sapporo, Hokkaido 060-8543 Japan
| | - Motoi Uchino
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Shinichiro Shinzaki
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Minoru Matsuura
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Katsuyoshi Matsuoka
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Taku Kobayashi
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Masayuki Saruta
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Fumihito Hirai
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Keisuke Hata
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Sakiko Hiraoka
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Motohiro Esaki
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Ken Sugimoto
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Toshimitsu Fuji
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Kenji Watanabe
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Shiro Nakamura
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Nagamu Inoue
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Toshiyuki Itoh
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Makoto Naganuma
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Tadakazu Hisamatsu
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Mamoru Watanabe
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Nobuyuki Enomoto
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
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28
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Meredith J, Henderson P, Wilson DC, Russell RK. Combination Immunotherapy Use and Withdrawal in Pediatric Inflammatory Bowel Disease-A Review of the Evidence. Front Pediatr 2021; 9:708310. [PMID: 34621712 PMCID: PMC8490777 DOI: 10.3389/fped.2021.708310] [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: 05/11/2021] [Accepted: 07/26/2021] [Indexed: 02/05/2023] Open
Abstract
Evidence-based guidelines have been developed outlining the concomitant use of anti-tumor necrosis factor alpha (anti-TNF) agents and immunomodulators including azathioprine (AZA) and methotrexate (MTX) in both adult and pediatric populations. However, there exists a paucity of data guiding evidence-based strategies for their withdrawal in pediatric patients in sustained remission. This narrative review focuses on the available pediatric evidence on this question in the context of what is known from the larger body of evidence available from adult studies. The objective is to provide clarity and practical guidance around who, what, when, and how to step down pediatric patients with inflammatory bowel disease (IBD) from combination immunotherapy. Outcomes following withdrawal of either of the two most commonly used anti-TNF therapies [infliximab (IFX) or adalimumab (ADA)], or immunomodulator therapies, from a combination regimen are examined. Essentially, a judicious approach must be taken to identify a significant minority of patients who would benefit from treatment rationalization. We conclude that step-down to anti-TNF (rather than immunomodulator) monotherapy after at least 6 months of sustained clinical remission is a viable option for a select group of pediatric patients. This group includes those with good indicators of mucosal healing, low or undetectable anti-TNF trough levels, lack of predictors for severe disease, and no prior escalation of anti-TNF therapy. Transmural healing and specific human leukocyte antigen (HLA) typing are some of the emerging targets and tools that may help facilitate improved outcomes in this process. We also propose a simplified evidence-based schema that may assist in this decision-making process. Further pediatric clinical studies are required to develop the evidence base for decision-making in this area.
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Affiliation(s)
- Joseph Meredith
- Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Children and Young People, Edinburgh, United Kingdom.,Child Life and Health, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Paul Henderson
- Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Children and Young People, Edinburgh, United Kingdom.,Child Life and Health, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - David C Wilson
- Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Children and Young People, Edinburgh, United Kingdom.,Child Life and Health, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Richard K Russell
- Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Children and Young People, Edinburgh, United Kingdom.,Child Life and Health, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom
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Reinhold I, Blümel S, Schreiner J, Boyman O, Bögeholz J, Cheetham M, Rogler G, Biedermann L, Scharl M. Clinical Relevance of Anti-TNF Antibody Trough Levels and Anti-Drug Antibodies in Treating Inflammatory Bowel Disease Patients. Inflamm Intest Dis 2020; 6:38-47. [PMID: 33850838 DOI: 10.1159/000511296] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 08/31/2020] [Indexed: 12/16/2022] Open
Abstract
Background and Aims The majority of patients treated with anti-tumor necrosis factor (TNF) therapy develop anti-drug antibodies (ADAs), which might result in loss of treatment efficacy. Strict guidelines on measuring trough levels (TLs) and ADA in clinical routine do not exist. To provide real-world data, we took advantage of our tertiary inflammatory bowel disease (IBD) center patient cohort and determined indicators for therapeutic drug monitoring (TDM) and actual consequences in patient care. Methods We retrospectively collected clinical data of 104 IBD patients treated with infliximab or adalimumab in our IBD clinic. Patients with TL and ADA measurements between June 2015 and February 2018 were included. Results The main reason for determining TL was increased clinical disease. Subtherapeutic TLs were found in 33 patients, therapeutic TLs in 33 patients, and supratherapeutic TLs in 38 patients. Adjustments in anti-TNF therapy occurred more frequently (p = 0.01) in patients with subtherapeutic TL (24 of 33 patients; 73%) as compared to patients with therapeutic and supratherapeutic TLs (26 of 71 patients; 37%). No correlation could be found between TL and disease activity (p = 0.16). Presence of ADA was found in 16 patients, correlated with the development of infusion reactions (OR: 10.6, RR: 5.4, CI: 2.9-38.6), and was associated with subtherapeutic TL in 15 patients (93.8%). Treatment adaptations were based on TL and/or ADA presence in 36 of 63 patients. Conclusions TDM showed significant treatment adaptations in patients with subtherapeutic TL. Conversely, in patients with therapeutic and supratherapeutic TLs, reasons for adaptations were based on considerations other than TL, such as clinical disease activity. Further studies should focus on decision-making in patients presenting with supratherapeutic TL in remission.
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Affiliation(s)
- Ilana Reinhold
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Department of Internal Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Sena Blümel
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Jens Schreiner
- Department of Immunology, University Hospital Zurich, Zurich, Switzerland
| | - Onur Boyman
- Department of Immunology, University Hospital Zurich, Zurich, Switzerland.,Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Jan Bögeholz
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Department of Internal Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Marcus Cheetham
- Department of Internal Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Luc Biedermann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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Wyant T, Yang L, Rosario M. Comparison of the ELISA and ECL Assay for Vedolizumab Anti-drug Antibodies: Assessing the Impact on Pharmacokinetics and Safety Outcomes of the Phase 3 GEMINI Trials. AAPS JOURNAL 2020; 23:3. [PMID: 33200296 PMCID: PMC7669784 DOI: 10.1208/s12248-020-00518-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 10/06/2020] [Indexed: 01/12/2023]
Abstract
Vedolizumab immunogenicity has been assessed using an enzyme-linked immunosorbent assay (ELISA) with a ~ 0.5 μg/mL drug interference, which may underestimate on-drug immunogenicity. We aimed to compare immunogenicity results between ELISA and the new drug-tolerant electrochemiluminescence (ECL) assay (and the two versions of neutralizing assays, drug-sensitive versus drug-tolerant). The ECL assay drug tolerance is ~ 100 times higher than that of the ELISA (≥ 50 μg/mL vs. 0.5 μg/mL with a 500 ng/mL positive control), and assay sensitivity is < 5 ng/mL for both assays. Vedolizumab immunogenicity was assessed in 2000 GEMINI 1 and 2 patients originally tested by ELISA and retested by ECL assay. Anti-drug antibody (ADA) impact on infusion-related reactions and pharmacokinetics (PK) was examined using descriptive statistics and population PK analyses. By ECL assay, 6% (86/1427) of patients treated with vedolizumab as induction and maintenance therapy tested ADA-positive. Of these, 20 patients were persistently positive and 56 had neutralizing antibodies. By ELISA, 4% (56/1434) of these patients were ADA-positive, 9 were persistently positive, and 33 had neutralizing antibodies. Among 61 patients with infusion-related reactions, 6 (10%) were ADA-positive (2 persistently positive) by ECL assay. By ELISA, 3 (5%) patients were both ADA-positive and persistently positive. Most results (96%) were similar with both assays. In the updated population PK model, ADA-positive status was estimated to increase vedolizumab linear clearance by a factor of 1.10 (95% credible interval 1.03-1.17), which is consistent with previous reports. The impact of ADA on safety and PK modeling remained generally consistent using either ELISA or ECL assay. ClinicalTrials.gov: NCT00783718 and NCT00783692.
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Affiliation(s)
- Timothy Wyant
- Biolojic Inc., 100 Cambridge St., Cambridge, Massachusetts, USA. .,Takeda Pharmaceuticals International Inc., Cambridge, Massachusetts, USA.
| | - Lili Yang
- Development Center Americas Inc, Cambridge, Massachusetts, USA
| | - Maria Rosario
- Takeda Pharmaceuticals International Inc., Cambridge, Massachusetts, USA
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31
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Nuñez F P, Quera R, Simian D, Flores L, Figueroa C, Ibañez P, Kronberg U, Lubascher J, Pizarro G. Infliximab in inflammatory bowel disease. Is premedication necessary? GASTROENTEROLOGIA Y HEPATOLOGIA 2020; 44:321-329. [PMID: 33386199 DOI: 10.1016/j.gastrohep.2020.07.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 07/08/2020] [Accepted: 07/13/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND The use of infliximab (IFX) in inflammatory bowel disease (IBD) has been associated with a 1-6% risk of infusion reactions. The usefulness of premedication with corticosteroids, paracetamol and /or antihistamines is controversial. AIM The aim of this study is to assess, in IBD patients on IFX, whether there are differences in secondary reactions to the infusion between those who use premedication or not. METHODS A retrospective cohort study was performed identifying patients with a diagnosis of IBD who received IFX at our institution between January 2009 and July 2019. Acute reactions were defined as those that occurred in the first 24 hours postinfusion and late reactions for more than 24 hours. Infusion reactions were classified as mild, moderate and severe. Descriptive and association statistics were used (χ2; p < 0.05). RESULTS Sixty-four patients were included with 1,263 infusions in total, 52% men. Median infusions per patient was 22 (2-66). All induction infusions were administered with premedication, and in maintenance in 57% of them. Premedication was given with hydrocortisone, chlorphenamine and paracetamol. Most of reactions were acute, mild or moderate in severity and no patient needed to discontinue IFX. In the maintenance group, there were 9/718 (1.2%) infusion reactions with premedication and 4/358 (1.1%) without it (p = 0.606). In the induction group, there were 8/187 (4.3%) infusion reactions, significantly higher when compared with both maintenance groups. CONCLUSIONS In this group, premedication use during maintenance was not effective at reducing the rate of infusion reactions. These results suggest that premedication would not be necessary.
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Affiliation(s)
- Paulina Nuñez F
- Programa Enfermedad Inflamatoria Intestinal, Departamento Gastroenterología, Hospital San Juan de Dios Hospital, Universidad de Chile, Santiago, Chile
| | | | | | - Lilian Flores
- Programa Enfermedad Inflamatoria Intestinal, Departamento Gastroenterología, Hospital San Juan de Dios Hospital, Universidad de Chile, Santiago, Chile
| | - Carolina Figueroa
- Programa Enfermedad Inflamatoria Intestinal, Departamento Gastroenterología, Hospital San Juan de Dios Hospital, Universidad de Chile, Santiago, Chile
| | - Patricio Ibañez
- Programa Enfermedad Inflamatoria Intestinal, Departamento Gastroenterología, Hospital San Juan de Dios Hospital, Universidad de Chile, Santiago, Chile
| | - Udo Kronberg
- Unidad de Coloproctología, Departamento de Cirugía, Clínica Las Condes, Santiago, Chile
| | - Jaime Lubascher
- Programa Enfermedad Inflamatoria Intestinal, Departamento Gastroenterología, Hospital San Juan de Dios Hospital, Universidad de Chile, Santiago, Chile
| | - Gonzalo Pizarro
- Programa Enfermedad Inflamatoria Intestinal, Departamento Gastroenterología, Hospital San Juan de Dios Hospital, Universidad de Chile, Santiago, Chile
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Point-of-Care Assays Could Be Useful for Therapeutic Drug Monitoring of IBD Patients in a Proactive Strategy with Adalimumab. J Clin Med 2020; 9:jcm9092739. [PMID: 32854232 PMCID: PMC7565289 DOI: 10.3390/jcm9092739] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/10/2020] [Accepted: 08/19/2020] [Indexed: 01/14/2023] Open
Abstract
The objective of the study was to evaluate whether Point-of-Care (POC) assays are equivalent to ELISAs for measuring residual trough levels of adalimumab (ADA) in a cohort of Inflammatory Bowel Disease (IBD) patients. ADA trough levels obtained by POC assays were used to optimize patients in daily clinical practice. Different assays (three ELISAs (Enzyme-Linked ImmunoSorbent Assay) from two different suppliers and two POC assays) were compared to measure ADA trough levels in a first cohort of 31 IBD patients. All assays revealed a high correlation within the assays, ranging from 0.86 to 0.99. Cut-off values were always higher with ELISAs than with POC assays. Then, a small prospective clinical study with a second cohort of 37 IBD patients was performed to compare POC assays and ELISAs for their ability to optimize patients on the basis of the measured ADA trough levels. The use of a POC assay to monitor ADA trough levels did not improve the follow-up of patients with loss of response, as they were always optimized whatever their ADA residual rate. For patients in clinical remission, a POC assay can be useful in some clinical situations to maintain or de-escalate ADA doses according to the measured trough levels. In conclusion, different assays for ADA monitoring are quite equivalent. A POC assay could be only useful for a proactive strategy for asymptomatic patients with a sub-therapeutic dose of ADA, but new therapeutic thresholds need to be identified.
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A User's Guide to De-escalating Immunomodulator and Biologic Therapy in Inflammatory Bowel Disease. Clin Gastroenterol Hepatol 2020; 18:1336-1345. [PMID: 31887444 DOI: 10.1016/j.cgh.2019.12.019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 12/05/2019] [Accepted: 12/08/2019] [Indexed: 02/07/2023]
Abstract
De-escalation of immunomodulators and biologic agents in inflammatory bowel disease is frequently discussed with patients and must weigh the risk of continued medical therapy with the risk of disease recurrence. Risk factors for disease flare after withdrawal of inflammatory bowel disease medications such as disease activity at de-escalation, disease prognostic features, and prior course of disease have been identified predominately in retrospective studies, allowing for risk stratification of patients. This review evaluates the published literature regarding therapeutic de-escalation and provides a framework for physicians to apply this to clinical practice. Prospective trials are underway and planned, which should provide further insight into this treatment paradigm and better inform patient selection for this strategy.
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Trough Levels of Infliximab at Week 6 Are Predictive of Remission at Week 14 in Pediatric Crohn's Disease. J Pediatr Gastroenterol Nutr 2020; 70:310-317. [PMID: 31651668 DOI: 10.1097/mpg.0000000000002536] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Infliximab (IFX) is a frequent therapeutic option for Crohn disease (CD) patients. Early detection of responders to IFX is critical for the management of CD in order to avoid long-term exposure to the drug without benefit. This retrospective study aimed at analysing which early parameters recorded during the induction period are able to predict response to IFX during the maintenance period in pediatric CD. PATIENTS AND METHODS Medical records of all CD patients ages from 2 to 18 years who received IFX at a tertiary IBD center were retrospectively analyzed. Children were classified in 3 groups according to their response at week 14 (W14) remission, clinical response or , no response. The factors recorded at W0, W2, and W6, which were associated with remission at W14 were analyzed using a logistic regression. RESULTS Among the 111 patients included, 74.8% patients were responders to IFX at W14, including 38.7% in clinical remission and 36% with partial clinical response. Clinical remission at W14 was associated with normal growth (P < 0.01), and normal albuminemia (P = 0.01) at baseline, It was also associated with trough levels to IFX >8.3 μg/ml at week 6 (P < 0.01). CONCLUSION Trough levels to IFX >8.3 μg/ml at week 6 are predictive of remission at W14 for luminal disease.
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35
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Gibson DJ, Ward MG, Rentsch C, Friedman AB, Taylor KM, Sparrow MP, Gibson PR. Review article: determination of the therapeutic range for therapeutic drug monitoring of adalimumab and infliximab in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2020; 51:612-628. [PMID: 31961001 DOI: 10.1111/apt.15643] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Revised: 10/14/2019] [Accepted: 01/07/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Clinical application of therapeutic drug monitoring (TDM) to optimise anti-TNF therapies in patients with IBD depends upon target ranges. AIMS To review methodology used to determine therapeutic ranges and critically compare and contrast its application to infliximab and adalimumab. METHODS A systematic review was performed, and relevant literature was summarised and critically examined. RESULTS Upper limits of the therapeutic range are determined by toxicity, a plateau response and cost. Lower limits are determined by optimal concentration on the target of action in vitro and/or in vivo, or by correlation of drug levels with clinical efficacy using area-under-receiver-operator-curve (AUROC) analysis. In 43 studies, there were huge variations in time at which infliximab and adalimumab levels were measured, the end-points used (clinical remission to mucosal healing), the clinical setting (active disease vs maintenance phase) and the reason for TDM (proactive vs reactive). In the maintenance phase for infliximab, lower trough limits 2.8-5.7 µg/mL are reported depending upon end-points used, with consistent AUROC 0.68-0.77. Adalimumab TDM targets are even less consistent with a lower limit 5.9-11.8 µg/mL (AUROC 0.66-0.83) in some studies, but no cut-off can be identified that is significantly associated with outcome in others, related to inherent pharmacokinetic and pharmacodynamic differences, and heterogeneity of study design. CONCLUSIONS Evidence for exposure-response relationship is stronger for infliximab than adalimumab. Due to heterogeneity in settings for drug level measurements, therapeutic ranges vary. These factors need to be taken into account when interpreting the evidence and extending this to therapeutic strategies for IBD patients.
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Affiliation(s)
- David J Gibson
- Departments of Gastroenterology, The Alfred Hospital, Melbourne, VIC, Australia
| | - Mark G Ward
- Departments of Gastroenterology, The Alfred Hospital, Melbourne, VIC, Australia.,Monash University, Melbourne, VIC, Australia
| | | | - Antony B Friedman
- Departments of Gastroenterology, The Alfred Hospital, Melbourne, VIC, Australia.,Monash University, Melbourne, VIC, Australia
| | - Kirstin M Taylor
- Departments of Gastroenterology, The Alfred Hospital, Melbourne, VIC, Australia.,Monash University, Melbourne, VIC, Australia
| | - Miles P Sparrow
- Departments of Gastroenterology, The Alfred Hospital, Melbourne, VIC, Australia.,Monash University, Melbourne, VIC, Australia
| | - Peter R Gibson
- Departments of Gastroenterology, The Alfred Hospital, Melbourne, VIC, Australia.,Monash University, Melbourne, VIC, Australia
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Chiba M, Tsuji T, Nakane K, Obara Y, Komatsu M. Swift Efficacy with Infliximab 4 Years after Initial Standard Induction Therapy Followed by Severe Delayed Infusion Reaction in Crohn's Disease. Inflamm Bowel Dis 2020; 26:e4. [PMID: 31697829 DOI: 10.1093/ibd/izz273] [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: 12/30/2022]
Affiliation(s)
- Mitsuro Chiba
- Division of Gastroenterology, Akita City Hospital, Akita City, Japan
| | - Tsuyotoshi Tsuji
- Division of Gastroenterology, Akita City Hospital, Akita City, Japan
| | - Kunio Nakane
- Division of Gastroenterology, Akita City Hospital, Akita City, Japan
| | - Yu Obara
- Division of Gastroenterology, Akita City Hospital, Akita City, Japan
| | - Masafumi Komatsu
- Division of Gastroenterology, Akita City Hospital, Akita City, Japan
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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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Papamichael K, Cheifetz AS, Melmed GY, Irving PM, Casteele NV, 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] [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)
| | | | - Gil Y. Melmed
- Cedars-Sinai Medical Center, Los Angeles, California
| | | | | | | | | | | | | | | | | | | | | | | | - Thomas Ullman
- Montefiore Medical Center/Albert Einstein College Medicine, Bronx, NY
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Dwadasi S, Israel A, Rubin DT. The Era of Anti-Tumor Necrosis Factor Is Over. What Do We Know, What Don't We Know, and What Do We Yearn to Know? Gastrointest Endosc Clin N Am 2019; 29:405-419. [PMID: 31078244 DOI: 10.1016/j.giec.2019.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- Sujaata Dwadasi
- Inflammatory Bowel Disease Center, University of Chicago Medicine, 5841 S. Maryland Avenue, MC 4076, Chicago, IL 60637, USA
| | - Amanda Israel
- Inflammatory Bowel Disease Center, University of Chicago Medicine, 5841 S. Maryland Avenue, MC 4076, Chicago, IL 60637, USA
| | - David T Rubin
- Inflammatory Bowel Disease Center, University of Chicago Medicine, 5841 S. Maryland Avenue, MC 4076, Chicago, IL 60637, USA.
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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: 37] [Impact Index Per Article: 6.2] [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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Colombel JF, Adedokun OJ, Gasink C, Gao LL, Cornillie FJ, D'Haens GR, Rutgeerts PJ, Reinisch W, Sandborn WJ, Hanauer SB. Combination Therapy With Infliximab and Azathioprine Improves Infliximab Pharmacokinetic Features and Efficacy: A Post Hoc Analysis. Clin Gastroenterol Hepatol 2019; 17:1525-1532.e1. [PMID: 30267864 DOI: 10.1016/j.cgh.2018.09.033] [Citation(s) in RCA: 119] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 09/05/2018] [Accepted: 09/15/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Among immunosuppressive- and biologic-naïve patients with moderately-to-severely active Crohn's disease (CD), a higher proportion of those treated with the combination of infliximab and azathioprine achieved corticosteroid-free remission at week 26 (CSFR26) than those given infliximab monotherapy; patients given the combination therapy also had higher serum concentrations of infliximab. Enhanced benefit of combination therapy may occur through synergistic modes of action or the influence of azathioprine on infliximab pharmacokinetics. METHODS We analyzed data from 206 patients from whom week 30 serum samples were available: 97 received infliximab monotherapy (5 mg/kg, n = 97) and 109 received combination therapy (2.5 mg/kg/day; n = 109). Proportions of patients achieving CSFR26 and mucosal healing (absence of ulcers) at week 26 were calculated for each quartile of serum concentrations of infliximab, and exposure-response relationships were compared. RESULTS Within quartiles of serum concentrations of infliximab, CSFR26 did not differ significantly between patients who received combination therapy vs monotherapy. However, among patients in the lowest quartile of serum concentration of infliximab, twice as many patients who received infliximab monotherapy achieved CSFR26 vs combination therapy. Anti-drug antibodies were detected only in the lowest quartile of serum concentrations of infliximab-in 35.9% of patients given monotherapy and 8.3% of patients given combination therapy. CONCLUSION Among patients with CD and similar serum concentrations of infliximab, combination therapy with azathioprine was not significantly more effective than infliximab monotherapy. Combination therapy with azathioprine appears to improve efficacy by increasing pharmacokinetic features of infliximab. ClinicalTrials.gov, NCT00094458.
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Affiliation(s)
- Jean-Frédéric Colombel
- Department of Gastroenterology, Icahn School of Medicine, Mount Sinai Medical Center, New York, New York.
| | | | | | | | | | - Geert R D'Haens
- Department of Gastroenterology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - Paul J Rutgeerts
- Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
| | | | - William J Sandborn
- Division of Gastroenterology and Department of Medicine, University of California, San Diego, San Diego, California
| | - Stephen B Hanauer
- Department of Medicine, Digestive Health Center, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
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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] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
: 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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Early vedolizumab trough levels at induction in inflammatory bowel disease patients with treatment failure during maintenance. Eur J Gastroenterol Hepatol 2019; 31:478-485. [PMID: 30672828 DOI: 10.1097/meg.0000000000001356] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Vedolizumab (VDZ) is effective as an induction and maintenance treatment for Crohn's disease and ulcerative colitis, but, as observed with antitumour necrosis factor-α (anti-TNFα) agents, some patients are nonetheless experiencing loss of response. OBJECTIVE The aim of this study was to investigate the impact of the pharmacokinetics of VDZ during induction on long-term treatment response. PATIENTS AND METHODS This study focused on a single cohort of 103 inflammatory bowel disease patients treated with VDZ. VDZ trough levels (TLs) were measured by enzyme-linked immunosorbent assay (n=536 samples), and thereafter correlated to clinical, biological, endoscopic and serological data. For patients exposed previously to infliximab, antibodies to infliximab were measured at baseline. On the basis of the outcome at the end of follow-up, patients were then categorized into long-term response, optimized and treatment failure groups. RESULTS During VDZ induction, at week 6, inflammatory bowel disease patients with long-term response had higher TLs compared with patients in the treatment failure group (33 vs. 24 µg/ml, P=0.02). A cut-off TL of 28 µg/ml predicted a sustained response in the follow-up with an area under curve of 0.723 (95% confidence interval=0.567-0.878, P=0.02). Patients with mucosal healing in maintenance had higher TLs at week 6 (41.65 µg/ml) compared with patients with mild (26 µg/ml) or severe endoscopic activity (20.8 µg/ml), P=0.009. Positive perinuclear antineutrophil cytoplasmic antibody serology was associated with lower TLs. Patients previously exposed to anti-TNFα had lower TLs than naive patients (22.5 vs. 36 µg/ml, P=0.03) without any impact of detectable antibodies to infliximab. Finally, the presence of an immunomodulator at induction did not impact on VDZ TLs at induction. CONCLUSION We confirmed that a drug exposure-efficacy association was found early on at induction. This study emphasizes that previous exposure to anti-TNFα and positive perinuclear antineutrophil cytoplasmic antibody serology are important factors influencing VDZ TLs at induction.
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Drobne D, Kurent T, Golob S, Švegl P, Rajar P, Hanžel J, Koželj M, Novak G, Smrekar N, Ferkolj I, Štabuc B. Optimised infliximab monotherapy is as effective as optimised combination therapy, but is associated with higher drug consumption in inflammatory bowel disease. Aliment Pharmacol Ther 2019; 49:880-889. [PMID: 30784100 DOI: 10.1111/apt.15179] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2018] [Revised: 10/01/2018] [Accepted: 01/16/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Combination treatment with azathioprine for 6-12 months is the preferred strategy for starting infliximab due to improved pharmacokinetics. However, optimised infliximab monotherapy with proactive dose escalations in case of low trough levels is a safer but under-studied alternative. AIM To compare the clinical success and infliximab consumption of combination vs optimised monotherapy strategies. METHODS We studied the clinical success and infliximab consumption of both strategies in 149 patients (94 Crohn's disease; 55 ulcerative colitis) starting infliximab and undergoing intensive drug monitoring assisted treatment optimisation. RESULTS The drug retention rates were similar for optimised monotherapy and combination treatment after induction (96% vs 97%, P = 0.73), after the first year (90% vs 83%, P = 0.23) and at the end of follow-up (74% vs 75%, P = 0.968). Similarly, no differences were observed for steroid use at year 1 (5% vs 14%, P = 0.08) or mucosal healing at the end of follow-up (64% vs 67%, P = 0.8). Higher infliximab consumption (7.6 mg/kg q8 weeks [interquartile range (IQR): 5.9-10.3] vs 6.4 mg/kg q8 weeks [IQR: 5.2-8.0], P = 0.019) combined with lower trough levels (1.7 µg/mL [IQR: 0.3-6.6] vs 5.0 µg/mL [2.5-8.7], P = 0.012) resulted in almost 3-fold higher drug-to-trough ratio (3.9 vs 1.5) in monotherapy compared to combination strategy at year 1. At the end of follow-up, when azathioprine had been discontinued for a median of 14 [IQR: 3-33] months, these differences disappeared. CONCLUSIONS In this study, optimised infliximab monotherapy was as clinically effective as combination therapy but was associated with significantly higher infliximab consumption. The infliximab-sparing effect disappeared after azathioprine withdrawal.
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Affiliation(s)
- David Drobne
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Tina Kurent
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Saša Golob
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Polona Švegl
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Polona Rajar
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Jurij Hanžel
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Matic Koželj
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Gregor Novak
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Nataša Smrekar
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Ivan Ferkolj
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Borut Štabuc
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
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Fumery M, Tilmant M, Yzet C, Brazier F, Loreau J, Turpin J, Le Mouel JP, Goeb V, Nguyen-Khac E, Singh S, Dupas JL, Diouf M. Premedication as primary prophylaxis does not influence the risk of acute infliximab infusion reactions in immune-mediated inflammatory diseases: A systematic review and meta-analysis. Dig Liver Dis 2019; 51:484-488. [PMID: 30686715 DOI: 10.1016/j.dld.2018.12.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 11/19/2018] [Accepted: 12/05/2018] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Up to 25% of patients treated with infliximab experience hypersensitivity reactions. Prophylactic premedication prior to infliximab infusion, comprising corticosteroids and/or antihistamines, is widely used in clinical practice but its efficacy has recently been called into question due to the lack of pathophysiological rationale and validation by controlled trials. MATERIALS AND METHODS We conducted a comprehensive literature search of multiple electronic databases from inception to June 2017 to identify studies reporting the impact of corticosteroid and/or antihistamine premedication on the risk of acute (<24 h) hypersensitivity reaction to infliximab in immune-mediated inflammatory diseases (IMIDs). Random-effects meta-analysis was performed. RESULTS Ten studies, eight observational studies and two randomized control trials, were identified including a total of 3892 patients with IMIDs, and 1,385 patients with IBD. Corticosteroid premedication was not associated with a decreased risk of hypersensitivity reaction in either IMIDs (7 studies; OR, 1.07, 95%CI, 0.64-1.78; I2 = 57.5%) or IBD (3 studies; OR, 1.04, 95% CI, 0.52-2.07; I2 = 57%). Antihistamine premedication was not associated with a decreased risk of hypersensitivity reaction in IMIDs (3 studies: OR, 1.39, 95% CI, 0.70-2.73; I2 = 85%). The combination of corticosteroids and antihistamines did not decrease the risk of acute infliximab infusion reaction in IMIDs (6 studies; OR, 2.12, 95% CI, 0.61-7.35; I2 = 94%), but was associated with an increased risk in IBD (4 studies, OR, 4.17, 95% CI, 1.61-10.78; I2 = 77%). CONCLUSION Corticosteroid and/or antihistamine premedication is not associated with a decreased risk of acute hypersensitivity reactions to infliximab in patients with IMIDs. We believe that these premedications should no longer be part of standard protocols.
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Affiliation(s)
- Mathurin Fumery
- Gastroenterology, Amiens University Hospital, Université de Picardie Jules Verne, Amiens, France, France.
| | - Marion Tilmant
- Gastroenterology, Amiens University Hospital, Université de Picardie Jules Verne, Amiens, France, France
| | - Clara Yzet
- Gastroenterology, Amiens University Hospital, Université de Picardie Jules Verne, Amiens, France, France
| | - Franck Brazier
- Gastroenterology, Amiens University Hospital, Université de Picardie Jules Verne, Amiens, France, France
| | - Julien Loreau
- Gastroenterology, Amiens University Hospital, Université de Picardie Jules Verne, Amiens, France, France
| | - Justine Turpin
- Gastroenterology, Amiens University Hospital, Université de Picardie Jules Verne, Amiens, France, France
| | - Jean Philippe Le Mouel
- Gastroenterology, Amiens University Hospital, Université de Picardie Jules Verne, Amiens, France, France
| | - Vincent Goeb
- Rheumatology, Amiens University Hospital, Université de Picardie Jules Verne, Amiens, France
| | - Eric Nguyen-Khac
- Gastroenterology, Amiens University Hospital, Université de Picardie Jules Verne, Amiens, France, France
| | - Siddarth Singh
- Division of Gastroenterology, Department of Medicine, UC San Diego Health System, La Jolla, USA
| | - Jean-Louis Dupas
- Gastroenterology, Amiens University Hospital, Université de Picardie Jules Verne, Amiens, France, France
| | - Momar Diouf
- Department of Biostatistics, Amiens University Hospital, Amiens, France
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Bots SJ, Kuin S, Ponsioen CY, Gecse KB, Duijvestein M, D'Haens GR, Löwenberg M. Relapse rates and predictors for relapse in a real-life cohort of IBD patients after discontinuation of anti-TNF therapy. Scand J Gastroenterol 2019; 54:281-288. [PMID: 30907185 DOI: 10.1080/00365521.2019.1582693] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Objective: We investigated relapse rates after anti-tumor necrosis factor (anti-TNF) withdrawal in inflammatory bowel disease (IBD) patients, response to restart of anti-TNF treatment and predictors for relapse. Methods: IBD patients in remission receiving infliximab or adalimumab treatment for ≥1 year who discontinued treatment were included. Relapse rates and predictors for relapse were studied using survival and Cox regression analysis. Results: In total, 101 patients were included (77 CD, 24 UC). A total of 56 patients (55%) experienced a relapse (CD 38, UC 18) with a median time to relapse of 32 and 18 months in CD and UC, respectively. Of patients that were retreated with the same anti-TNF agent, 84% responded. A trough serum concentration ≥2 µg/ml within 1 year prior to anti-TNF discontinuation was associated with a higher relapse rate in CD patients (HR 2.89; p = .018), which was more evident in patients requiring retreatment with biologicals, bowel-related surgery or experimental medication (HR: 4.18; p = .009). A young age (<17 years) at diagnosis was associated with a higher relapse rate (HR: 2.29; p = .040) and fecal calprotectin levels <25 µg/g with a lower relapse rate in CD patients (HR: 0.34; p = .041). Relapse rates, requiring treatment with biologicals or experimental medication, was lower in UC patients who continued immunosuppressive treatment (HR: 0.26; p = .042). Conclusions: Approximately 55% of patients relapsed after anti-TNF withdrawal with a median time to relapse of 32 and 18 months in CD and UC, respectively. Retreatment with the same anti-TNF was successful in 84% of patients.
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Affiliation(s)
- Steven J Bots
- a Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam , Amsterdam , The Netherlands
| | - Sabine Kuin
- a Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam , Amsterdam , The Netherlands
| | - Cyriel Y Ponsioen
- a Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam , Amsterdam , The Netherlands
| | - Krisztina B Gecse
- a Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam , Amsterdam , The Netherlands
| | - Marjolijn Duijvestein
- a Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam , Amsterdam , The Netherlands
| | - Geert R D'Haens
- a Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam , Amsterdam , The Netherlands
| | - Mark Löwenberg
- a Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam , Amsterdam , The Netherlands
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47
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Abitbol V. [Treatment de-escalation in inflammatory bowel diseases]. Presse Med 2018; 47:931-933. [PMID: 30502826 DOI: 10.1016/j.lpm.2018.11.015] [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: 11/26/2022] Open
Affiliation(s)
- Vered Abitbol
- Hôpital Cochin, service de gastroentérologie, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France.
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Recapture and improved outcome of pegloticase response with methotrexate-A report of two cases and review of the literature. Semin Arthritis Rheum 2018; 49:56-61. [PMID: 30583886 DOI: 10.1016/j.semarthrit.2018.11.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 10/31/2018] [Accepted: 11/20/2018] [Indexed: 01/07/2023]
Abstract
INTRODUCTION Pegloticase is a PEGylated uric acid specific enzyme indicated for the treatment of refractory gout. Anti-pegloticase antibodies contribute to high discontinuation rates, increased risk of infusion reactions, and early loss of drug efficacy. OBJECTIVE To describe the use of methotrexate to recapture function of pegloticase after development of anti-drug antibodies while treating gout. METHODS We report two cases of using methotrexate as an adjunct to treatment with pegloticase for refractory tophaceous gout. We also present the results of a literature review on the use of concomitant immunosuppressive therapy with pegloticase to prevent anti-pegloticase antibody development. RESULTS Patient A, a 55-year-old man with a history of tophaceous gout, was treated with pegloticase but developed high serum urate(sUA) levels prior to his third infusion. Adjunctive treatment with methotrexate restored pegloticase response and the patient's sUA levels decreased, and remained low for the remainder of his treatment. Patient B, a 36-year-old man with a history of tophaceous gout, was treated with pegloticase. Oral methotrexate was initiated at the first infusion. Low sUA levels were achieved but increased after a lapse in methotrexate compliance. Re-initiation of methotrexate restored pegloticase response and the patient tolerated subsequent infusions. Literature review identified three reports of successful use of concomitant pegloticase and immunosuppressive therapy for refractory tophaceous gout, including an open label trial with a subset of 7 transplant recipients, an additional case study of pegloticase treatment with one transplant recipient, and a case study of pegloticase administered with low-dose azathioprine. CONCLUSION Prophylactic use of immunosuppressive therapy with pegloticase may enable sustained treatment and improve outcomes. Additionally, immunosuppressive therapy seems to show the ability to recapture pegloticase response after development of anti-drug antibodies. The use of immunosuppressants to prevent anti-drug antibody formation, recapture pegloticase efficacy, and reduce discontinuation rates warrants further study.
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Nasser Y, Labetoulle R, Harzallah I, Berger AE, Roblin X, Paul S. Comparison of Point-of-Care and Classical Immunoassays for the Monitoring Infliximab and Antibodies Against Infliximab in IBD. Dig Dis Sci 2018; 63:2714-2721. [PMID: 29948562 DOI: 10.1007/s10620-018-5144-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 05/28/2018] [Indexed: 01/04/2023]
Abstract
OBJECTIVE The primary objective is to assess whether the POC assays to measure infliximab residual trough level in the serum of IBD patients were non-inferior to the ELISA techniques available on the market, and to determine which of them was the most robust. The second is to compare three different ELISA kits for monitoring anti-infliximab antibodies (ATI). METHODS The assays were carried out on patients' sera using four ELISA kits from four different suppliers (three with a monoclonal antibody and one polyclonal) and two rapid techniques provided by BÜHLMANN (Quantum Blue®) and R-Biopharm (Ridaquick) for monitoring infliximab levels. ATI were measured by three ELISA sets (Grifols, Theradiag, and R-Biopharm) which have different positivity limits and different units. RESULTS We measured infliximab residual level and ATI in the serum of 90 IBD patients (85 treated with infliximab and five with adalimumab). All of the infliximab assays were very well correlated when analyzed with Spearman nonparametric correlation (0.93 ≤ r ≤ 0.99), and the two POC assays were also excellently correlated (r = 0.98). The ATI monitoring kits revealed a correlation ranging from 0.73 to 0.96 when comparing positive and negative patients. When normalizing the quantitative values between the different ELISA tests (expressed arbitrarily by using multiples of the positivity limits defined by each supplier), the Spearman r coefficient ranged from 0.81 to 0.93. CONCLUSION The available evidence allows us to conclude that all of the infliximab monitoring assays correlate well and may be used for IFX monitoring; albeit variations in measured IFX concentration among different assays remain present, these assays could be interchangeable. The ATI monitoring techniques are all capable of detecting ATI-positive patients, but because of the difference in the positivity limits and the measurement units, it is better to follow a patient rate with one definite kit.
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Affiliation(s)
- Yara Nasser
- Laboratoire d'Immunologie et d'Immunomonitoring, CIC Inserm 1408, GIMAP EA3064, CHU Saint-Etienne, Saint-Etienne, France
| | - Rémi Labetoulle
- Laboratoire d'Immunologie et d'Immunomonitoring, CIC Inserm 1408, GIMAP EA3064, CHU Saint-Etienne, Saint-Etienne, France
| | - Ines Harzallah
- Laboratoire d'Immunologie et d'Immunomonitoring, CIC Inserm 1408, GIMAP EA3064, CHU Saint-Etienne, Saint-Etienne, France
| | - Anne-Emmanuelle Berger
- Laboratoire d'Immunologie et d'Immunomonitoring, CIC Inserm 1408, GIMAP EA3064, CHU Saint-Etienne, Saint-Etienne, France
| | - Xavier Roblin
- Service de Gastro-Entérologie-Hépatologie, CHU de Saint-Etienne, Saint-Etienne, France
| | - Stephane Paul
- Laboratoire d'Immunologie et d'Immunomonitoring, CIC Inserm 1408, GIMAP EA3064, CHU Saint-Etienne, Saint-Etienne, France.
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Roblin X, Riviere P, Flamant M, Veyrard P, Poullenot F, Paul S, Laharie D. Proactive Therapeutic Drug Monitoring of TNF Antagonists in Inflammatory Bowel Disease. Inflamm Bowel Dis 2018; 24:1904-1909. [PMID: 29726958 DOI: 10.1093/ibd/izy069] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND Proactive therapeutic drug monitoring (TDM) to titrate tumor necrosis factor (TNF) antagonists has emerged recently as a tool to routinely monitor drug concentration to achieve target levels in patients with quiescent inflammatory bowel disease (IBD). METHODS The purpose of the present review article was to present available data exploring the concept of proactive TDM. RESULTS While several observational studies have identified an association between proactive TDM and better IBD outcomes, 2 randomized controlled studies did not confirm this advantage. CONCLUSIONS Based on the evidence to date, proactive TDM cannot be recommended in daily practice. However, analysis is hampered by the low level of evidence for the cutoffs used and the need for point-of-care assays. Regarding economic issues and de-escalating strategies, proactive TDM may have several future indications in IBD. Exploratory studies on proactive TDM with newly available biologic agents in IBD are also awaited.
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Affiliation(s)
- Xavier Roblin
- CHU de Saint-Etienne, Hôpital Nord, Service de Gastro-entérologie et Hépatologie, Saint-Etienne, France
| | - Pauline Riviere
- CHU de Bordeaux, Hôpital Haut-Lévêque, Service d'Hépato-gastroentérologie-Univ. Bordeaux, Laboratoire de Bactériologie, Bordeaux, France
| | - Mathurin Flamant
- Clinique Jules Verne and CHU de Nantes, Institut des Maladies de l'Appareil Digestif, Hotel Dieu, Nantes, France
| | - Pauline Veyrard
- CHU de Saint-Etienne, Hôpital Nord, Service de Gastro-entérologie et Hépatologie, Saint-Etienne, France
| | - Fabien Poullenot
- CHU de Bordeaux, Hôpital Haut-Lévêque, Service d'Hépato-gastroentérologie-Univ. Bordeaux, Laboratoire de Bactériologie, Bordeaux, France
| | - S Paul
- Laboratoire d'Immunologie et Immunomonitoring, CIC 1408INSERM, GIMAP EA3064, Hôpital Universitaire de Saint Etienne, France
| | - David Laharie
- CHU de Bordeaux, Hôpital Haut-Lévêque, Service d'Hépato-gastroentérologie-Univ. Bordeaux, Laboratoire de Bactériologie, Bordeaux, France
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