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1
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Moneo M, Ruiz Del Agua A, Ruiz-Argüello B, Rapun N, Nagore D, El Hamss R. Comparison between monotest and traditional batch-based ELISA assays for therapeutic drug monitoring of infliximab and adalimumab levels and anti-drug antibodies. Clin Chem Lab Med 2025:cclm-2024-1258. [PMID: 39781652 DOI: 10.1515/cclm-2024-1258] [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: 10/28/2024] [Accepted: 12/24/2024] [Indexed: 01/12/2025]
Abstract
OBJECTIVES To compare a new ready-to-use monotest immunoassay, CHORUS Promonitor, for the quantification of serum biological drug levels and anti-drug antibodies of anti-TNF agents, against the reference batch-based ELISA test, Promonitor. METHODS Blood samples were collected from patients treated with anti-TNF agents, infliximab (IFX) or adalimumab (ADL). IFX and ADL levels, as well as anti-IFX and anti-ADL antibodies were quantified and compared between the standard ELISA reference test, Promonitor, and the automated monotest ELISA assay, CHORUS Promonitor. Data analysis included both qualitative and quantitative comparison between both tests. For the qualitative comparison, overall percent agreement (OPA) was calculated. For the quantitative comparison, Passing-Bablok regression analysis and Bland-Altman analysis were used. RESULTS For IFX and ADL levels, the qualitative overall agreement between methods was 100 % (Cohen's coefficient=1). For anti-IFX and anti-ADL antibodies, OPA was 98.8 % and 97.3 %, respectively. Quantitative comparison indicated a very strong correlation between both assays: IFX (r=0.97, n=74), ADL (r=0.95, n=54), anti-IFX (r=0.93, n=72), and anti-ADL (r=0.97, n=61). The regression analysis determined an excellent comparability of drug levels between methods. Bland-Altman analysis showed a bias difference between assays of 6 % for IFX, 0 % for ADL, 24 % for anti-IFX, and 14 % for anti-ADL. CONCLUSIONS Monotest CHORUS Promonitor was a reliable assay to quantify IFX, ADL, anti-IFX and anti-ADL in samples with comparable results to those obtained with the reference batch-based ELISA technique.
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Affiliation(s)
- Mikel Moneo
- Product Development and Support, Progenika Biopharma, SA, Derio, Spain
| | | | | | - Noelia Rapun
- Operations & Strategy, Diagnostic Grifols, S.A, Progenika Biopharma, SA, Derio, Spain
| | - Daniel Nagore
- Research and Development, Progenika Biopharma, SA, Derio, Spain
| | - Rachid El Hamss
- Product Development and Support, Progenika Biopharma, SA, Derio, Spain
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2
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Nielsen OH, Hammerhøj A, Ainsworth MA, Gubatan J, D'Haens G. Immunogenicity of Therapeutic Antibodies Used for Inflammatory Bowel Disease: Treatment and Clinical Considerations. Drugs 2025; 85:67-85. [PMID: 39532820 DOI: 10.1007/s40265-024-02115-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/15/2024] [Indexed: 11/16/2024]
Abstract
The introduction of tumor necrosis factor inhibitors has led to a paradigm shift in the management of inflammatory bowel disease (IBD). The subsequent introduction of both anti-integrins and cytokine blockers has since expanded the biologic armamentarium. However, immunogenicity, defined as the production of anti-drug antibodies (ADAs) to the prescribed biopharmaceutical, means a significant fraction of patients exposed to biologic agents will experience a secondary loss of response to one or more of the drugs. In clinical settings, immunogenicity may be caused by several factors, both patient related (e.g., underlying chronic disease, systemic immune burden, including previous biologic therapy failure, and [epi]genetic background) and treatment related (e.g., dose and administration regimens, drug physical structure, photostability, temperature, and agitation). Here, we outline these elements in detail to enhance biopharmaceutical delivery and therapy for patients with IBD. Moreover, concurrent immunomodulator medication may reduce the risks of ADA generation, especially when using the chimeric drug infliximab. Summarizing the latest developments and knowledge in the field, this review aims to provide strategies to prevent ADA production and information on managing non-responsiveness or loss of response to biologics. Better understanding of the molecular mechanisms underlying the formation of ADAs and the critical factors influencing the immunogenicity of biopharmaceuticals may lead to improved health outcomes in the IBD community that may benefit both the individual patient and society through lower healthcare expenses.
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Affiliation(s)
- Ole Haagen Nielsen
- Department of Gastroenterology D112, Herlev Hospital, University of Copenhagen, Borgmester Ib Juuls Vej 1, 2730 Herlev, Copenhagen, Denmark.
| | - Alexander Hammerhøj
- Department of Gastroenterology D112, Herlev Hospital, University of Copenhagen, Borgmester Ib Juuls Vej 1, 2730 Herlev, Copenhagen, Denmark
| | - Mark Andrew Ainsworth
- Department of Gastroenterology, Odense University Hospital, University of Southern Denmark, Odense, Denmark
| | - John Gubatan
- Department of Gastroenterology & Hepatology, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Geert D'Haens
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam, The Netherlands
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3
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Keating PE, Hock BD, Chin PKL, O'Donnell JL, Barclay ML. Evaluation of the Homogenous Mobility Shift Assay for Infliximab and Adalimumab Anti-drug Antibody Detection in the Clinical Laboratory. Ther Drug Monit 2024; 46:619-626. [PMID: 38648648 DOI: 10.1097/ftd.0000000000001200] [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: 08/02/2023] [Accepted: 02/08/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND Detecting antidrug antibodies (ADAs) against infliximab or adalimumab is useful for therapeutic drug monitoring. Various ADA detection methods exist, and antibody titer is an output in some algorithms. Homogenous mobility shift assay (HMSA) measures relative ADA concentration and determines drug-ADA complex size in vitro. However, the relevance of complex size determination in drug monitoring remains unclear. Hence, the association between complex size, ADA concentration, and sample detectable neutralizing activity was evaluated. METHODS Sera from infliximab-treated and adalimumab-treated patients who tested positive for ADA in the National Screening Service were analyzed using 3 ADA assays. HMSA determined the relative ADA concentrations and complex sizes, competitive ligand-binding assay evaluated the sample neutralizing capacity, and enzyme-linked immunosorbent assay detected immunoglobulin (Ig)G4 ADA. RESULTS Most ADA-positive samples (>80%) formed drug-ADA dimer complexes, whereas 17% had dimer and multimer complexes, and 3% had multimeric complexes. Multimer presence had 100% positive predictive value for detectable neutralizing activity. ADA concentration and detectable neutralizing activity were moderately correlated (r = 0.65) in adalimumab-treated patients and strongly correlated (r = 0.81) in infliximab-treated patients. In adalimumab-treated patients, multimer presence was a stronger predictor of neutralizing activity than ADA concentration was, but not in infliximab-treated patients. However, in infliximab-treated patient samples, multimer presence revealed a distinct subset with high ADA concentrations, neutralizing activity, and IgG4 ADA. CONCLUSIONS Multimers detected using HMSA had a strong positive predictive value for competitive ligand-binding assay detectable neutralizing activity. Multimeric IgG4-containing ADA-drug complexes revealed a distinct subset of infliximab-treated patient samples, whose clinical relevance merits further investigation.
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Affiliation(s)
| | - Barry D Hock
- Department of Hematology, University of Otago, Christchurch, New Zealand
| | - Paul K L Chin
- Department of Medicine, University of Otago, Christchurch, New Zealand ; and
- Department of Clinical Pharmacology, Christchurch Hospital, Christchurch, New Zealand
| | | | - Murray Lindsay Barclay
- Department of Medicine, University of Otago, Christchurch, New Zealand ; and
- Department of Clinical Pharmacology, Christchurch Hospital, Christchurch, New Zealand
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4
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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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5
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Velikova T, Sekulovski M, Peshevska-Sekulovska M. Immunogenicity and Loss of Effectiveness of Biologic Therapy for Inflammatory Bowel Disease Patients Due to Anti-Drug Antibody Development. Antibodies (Basel) 2024; 13:16. [PMID: 38534206 DOI: 10.3390/antib13010016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 02/12/2024] [Accepted: 02/21/2024] [Indexed: 03/28/2024] Open
Abstract
Many patients with inflammatory bowel disease (IBD) experience a loss of effectiveness to biologic therapy (i.e., anti-TNF therapy, etc.). Therefore, in addition to the adverse effects of the treatment, these patients also face failure to achieve and maintain remission. Immunogenicity, the process of production of antibodies to biological agents, is fundamental to the evolution of loss of response to treatment in IBD patients. The presence of these antibodies in patients is linked to decreased serum drug levels and inhibited biological activity. However, immunogenicity rates exhibit significant variability across inflammatory disease states, immunoassay formats, and time periods. In this review, we aimed to elucidate the immunogenicity and immune mechanisms of antibody formation to biologics, the loss of therapy response, clinical results of biological treatment for IBD from systematic reviews and meta-analyses, as well as to summarize the most recent strategies for overcoming immunogenicity and approaches for managing treatment failure in IBD.
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Affiliation(s)
- Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
| | - Metodija Sekulovski
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Department of Anesthesiology and Intensive Care, University Hospital Lozenetz, 1 Kozyak Str., 1407 Sofia, Bulgaria
| | - Monika Peshevska-Sekulovska
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Department of Gastroenterology, University Hospital Lozenetz, 1407 Sofia, Bulgaria
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Keating PE, Hock BD, Smith SM, Chin PKL, O'Donnell JL, Barclay ML. Four-year review of New Zealand laboratory infliximab and adalimumab concentration results indicating potential for improved dosing. Intern Med J 2023; 53:2123-2127. [PMID: 37997271 DOI: 10.1111/imj.16264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 09/12/2023] [Indexed: 11/25/2023]
Abstract
A review of laboratory results across New Zealand for therapeutic drug monitoring (TDM) of infliximab and adalimumab concentrations and antidrug antibodies (ADAs) over 4 years was completed. Of 6591 results, the median serum concentration for infliximab was 5.7 mg/L and for adalimumab was 5.5 mg/L. Subtherapeutic drug concentrations (<7 mg/L) were measured in 54% of samples. Drug concentrations <2 mg/L were measured in 23% of samples, with ADAs detected in 51% of these. The high number of samples with subtherapeutic drug concentrations and common ADA detection is consistent with failing therapy but could also suggest that standard dosing is frequently too low for patients. These results reinforce the value of antitumour necrosis factor drug TDM in making decisions to adjust dosing or switch agents in patients taking infliximab and adalimumab.
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Affiliation(s)
- Paula E Keating
- Immunology Section, Canterbury Health Laboratories, Christchurch, New Zealand
| | - Barry D Hock
- Department of Haematology, University of Otago, Christchurch, New Zealand
| | - Stewart M Smith
- Immunology Section, Canterbury Health Laboratories, Christchurch, New Zealand
| | - Paul K L Chin
- Department of Medicine, University of Otago, Christchurch, New Zealand
- Department of Clinical Pharmacology, Christchurch Hospital, Christchurch, New Zealand
| | - John L O'Donnell
- Immunology Section, Canterbury Health Laboratories, Christchurch, New Zealand
| | - Murray L Barclay
- Department of Medicine, University of Otago, Christchurch, New Zealand
- Department of Clinical Pharmacology, Christchurch Hospital, Christchurch, New Zealand
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7
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Grasmeier MK, Weber S, Treiber M, Thaler MA, Luppa PB. Surface plasmon resonance assays for the therapeutic drug monitoring of infliximab indicate clinical relevance of anti-infliximab antibody binding properties. Clin Chem Lab Med 2023; 61:1255-1265. [PMID: 36753693 DOI: 10.1515/cclm-2022-0949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 01/27/2023] [Indexed: 02/10/2023]
Abstract
OBJECTIVES The therapeutic antibody infliximab (IFX) has improved the life quality of numerous autoinflammatory disease patients. However, IFX can trigger the generation of anti-drug antibodies (ADA), whose optimal evaluation and management are currently subject of controversial discussions. We present two novel surface plasmon resonance (SPR) biosensor assays for therapeutic drug monitoring of IFX and characterization of ADA and investigated the diagnostic value of ADA binding properties. METHODS IFX and ADA were quantified via developed SPR biosensor assays (IFXmon and ADAmon, respectively) and diagnostics-approved ELISA in sera from inflammatory bowel disease patients. Pre-analytic ADA enrichment with magnetic beads enabled analytical drug tolerance of the ADAmon assay. The dissociation ratio (DissR) as an index for ADA:IFX binding stability was calculated from the SPR sensorgrams of ADA quantification runs. RESULTS IFX levels determined by IFXmon assay and ELISA showed high agreement, whereas ADA quantification concordance between ADAmon assay and ELISA was poor. In patients, DissR was predominantly constant over time and differed significantly between therapy outcomes. A DissR cut-off of 1.524 indicated undetectable IFX levels with 71.4% sensitivity and 88.9% specificity. Additionally, the SPR reference surface was exploited as serum-individual negative control to check result plausibility within multi-sample run sequences. CONCLUSIONS Overall, both SPR biosensor assays exhibited reliable quantitative performance with accuracies superior to their ELISA counterparts and precision inferior to ELISA only for ADAmon. DissR presented itself as promising ADA binding parameter and could contribute to both earlier and more tailored therapeutic decisions.
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Affiliation(s)
- Melina K Grasmeier
- Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Susanne Weber
- Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Matthias Treiber
- Clinic and Polyclinic for Internal Medicine II (Gastroenterology), Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Markus A Thaler
- Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Peter B Luppa
- Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
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Reinert T, Gahoual R, Mignet N, Kulus A, Allez M, Houzé P, François YN. Simultaneous quantification and structural characterization of monoclonal antibodies after administration using capillary zone electrophoresis-tandem mass spectrometry. J Pharm Biomed Anal 2023; 233:115446. [PMID: 37209497 DOI: 10.1016/j.jpba.2023.115446] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/27/2023] [Accepted: 05/06/2023] [Indexed: 05/22/2023]
Abstract
Monoclonal antibodies (mAbs) are demonstrating major success in various therapeutic areas such as oncology and the treatment of immune disorders. Over the past two decades, novel analytical methodologies allowed to address the challenges of mAbs characterization in the context of their production. However, after administration only their quantification is performed and insights regarding their structural evolution remain limited. For instance, clinical practice has recently highlighted significant inter-patient differences in mAb clearance and unexpected clinical responses, without providing alternative interpretations. Here, we report the development of a novel analytical strategy based on capillary zone electrophoresis coupled to tandem mass spectrometry (CE-MS/MS) for the simultaneous absolute quantification and structural characterization of infliximab (IFX) in human serum. CE-MS/MS quantification was validated over the range 0.4-25 µg·mL-1 corresponding to the IFX therapeutic window and achieved a LOQ of 0.22 µg·mL-1 (1.5 nM) while demonstrating outstanding specificity compared to the ELISA assay. CE-MS/MS allowed structural characterization and estimation of the relative abundance of the six major N-glycosylations expressed by IFX. In addition, the results allowed characterization and determination of the level of modification of post-translational modifications (PTMs) hotspots including deamidation of 4 asparagine and isomerization of 2 aspartate. Concerning N-glycosylation and PTMs, a new normalization strategy was developed to measure the variation of modification levels that occur strictly during the residence time of IFX in the patient's system, overcoming artefactual modifications induced by sample treatment and/or storage. The CE-MS/MS methodology was applied to the analysis of samples from patients with Crohn's disease. The data identified a gradual deamidation of a particular asparagine residue located in the complementary determining region that correlated with IFX residence time, while the evolution of IFX concentration showed significant variability among patients.
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Affiliation(s)
- Tessa Reinert
- Laboratoire de Spectrométrie de Masse des Interactions et des Systèmes (LSMIS) UMR 7140 (Unistra-CNRS), Université de Strasbourg, France; Université Paris Cité, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS), CNRS, Inserm, Faculté de sciences pharmaceutiques et biologiques, Paris, France
| | - Rabah Gahoual
- Université Paris Cité, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS), CNRS, Inserm, Faculté de sciences pharmaceutiques et biologiques, Paris, France.
| | - Nathalie Mignet
- Université Paris Cité, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS), CNRS, Inserm, Faculté de sciences pharmaceutiques et biologiques, Paris, France
| | - Alexandre Kulus
- Laboratoire de Spectrométrie de Masse des Interactions et des Systèmes (LSMIS) UMR 7140 (Unistra-CNRS), Université de Strasbourg, France
| | - Matthieu Allez
- Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris (AP-HP), Inserm, U1160 Paris, France
| | - Pascal Houzé
- Université Paris Cité, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS), CNRS, Inserm, Faculté de sciences pharmaceutiques et biologiques, Paris, France; Laboratoire de Toxicologie Biologique, Hôpital Lariboisière, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France
| | - Yannis-Nicolas François
- Laboratoire de Spectrométrie de Masse des Interactions et des Systèmes (LSMIS) UMR 7140 (Unistra-CNRS), Université de Strasbourg, France
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9
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Kim ES, Kwon Y, Choe YH, Kim MJ. Free antibodies-to-infliximab are biomarker for predicting the effect of dose intensification in pediatric Crohn's disease patients with secondary loss of response. Therap Adv Gastroenterol 2023; 16:17562848231170948. [PMID: 37168401 PMCID: PMC10164862 DOI: 10.1177/17562848231170948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 04/04/2023] [Indexed: 05/13/2023] Open
Abstract
Background Immunogenicity to antitumor necrosis factor alpha agents, such as infliximab (IFX), may lead to therapeutic failure. Objectives This study evaluated the relationship between free and total antibodies-to-infliximab (ATIs), trough levels (TLs) of IFX, and the response to dose intensification. Design We performed a prospective, observational study including pediatric patients with Crohn's disease (CD) receiving IFX maintenance therapy without dose intensification. Methods We compared clinical and laboratory outcomes according to the presence of free and total ATIs. Factors associated with response to IFX dose intensification were investigated by analyzing IFX TLs and free and total ATIs. Results Of the 98 patients, 9 patients had detectable free ATIs and 38 patients had total ATIs. Patients with free ATIs had significantly lower TLs (0.7 versus 5.1 µg/mL, p < 0.001) than patients without free ATIs. However, there was no difference in the IFX TLs according to the presence of total ATIs (p = 0.2523). Analysis of the 38 samples with total ATIs showed that response to dose intensification was significantly lower in patients with free ATIs than those without free ATIs (22.2% versus 65.5%, p < 0.001). In addition, free ATIs were the only factor with poor response to dose intensification [odds ratio (OR): 14.15, 95% confidence interval (CI): 1.31-151.97, p = 0.0140]. According to the receiver operating characteristic analysis, the optimal cutoff level indicating non-response to IFX dose intensification was 30.0 AU/mL for free ATIs concentration (area under curve, 0.792; 95% CI: 0.590-0.942; sensitivity, 60.0%; specificity, 96.7%; p = 0.0241). Conclusion Free ATIs, but not total ATIs, have a negative impact on the course of CD. Free ATIs are potential reliable biomarker for predicting the effect of dose intensification in patients with loss of response to IFX. Future studies based on serial and proactive therapeutic drug monitoring are required in the future.
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Affiliation(s)
- Eun Sil Kim
- Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yiyoung Kwon
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yon Ho Choe
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-Gu, Seoul 06351, Korea
| | - Mi Jin Kim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-Gu, Seoul 06351, Korea
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10
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Vande Casteele N, Yang L, Dobler I, Agboton C, McRorie Osborn T, Suri A, Lindner D, Smithson GM. Measuring Serum Vedolizumab and Vedolizumab Antibodies: Comparison of Commercial Assays with the Vedolizumab Clinical Development Assay. Ther Drug Monit 2023; 45:236-244. [PMID: 36788448 PMCID: PMC10013162 DOI: 10.1097/ftd.0000000000001068] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 07/19/2022] [Indexed: 02/16/2023]
Abstract
BACKGROUND Vedolizumab (VDZ) is an anti-α 4 β 7 integrin monoclonal antibody approved for inflammatory bowel disease treatment. VDZ serum and antidrug antibody (ADA) concentrations may be used for treatment optimization. In this article, the results of 5 commercial assays (Grifols, Immundiagnostik, Progenika, Sanquin, and Theradiag) measuring VDZ concentration and ADA were compared with those of the reference assays used in VDZ clinical studies. Our findings will assist clinicians in interpreting commercial assay results in the context of VDZ clinical trial data. METHODS VDZ-treated patient samples were used to evaluate the agreement between commercial assays and the reference VDZ serum concentration assay, based on linear regression, Bland-Altman, and qualitative agreement analyses. VDZ ADAs were detected using qualitative assays. Specificity, selectivity, accuracy, and precision were assessed using serum samples from healthy donors or patients with IBD (VDZ serum concentration <0.5 mcg/mL) spiked with VDZ, with/without other biologics (identical sample sets per assay). RESULTS All assays were specific and selective for VDZ. Overall, the commercial assay results for VDZ-spiked samples correlated well with those of the reference serum concentration assay (R 2 ≥ 0.98). Compared with the Immundiagnostik and Theradiag assays, the Grifols, Sanquin, and Progenika assays had the best reference assay agreement (based on regression analysis, Bland-Altman plots, and qualitative agreement [Cohen's kappa ≥0.92]). All immunogenicity assays detected VDZ ADAs; only the reference assay detected VDZ ADAs in the presence of 15 mcg/mL VDZ, advising caution with commercial ADA assays if VDZ is present. CONCLUSIONS All 5 commercial assays are suitable for VDZ therapeutic monitoring and ADA testing. However, the absolute values from the reference assays and the different commercial assays were not comparable, indicating that the same assay must be used for repeated monitoring of VDZ serum concentrations.
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Affiliation(s)
- Niels Vande Casteele
- Department of Medicine, University of California San Diego, School of Medicine, San Diego, California
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11
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Krieckaert CL, van Tubergen A, Gehin JE, Hernández-Breijo B, Le Mélédo G, Balsa A, Böhm P, Cucnik S, Elkayam O, Goll GL, Hooijberg F, Jani M, Kiely PD, McCarthy N, Mulleman D, Navarro-Compán V, Payne K, Perry ME, Plasencia-Rodriguez C, Stones SR, Syversen SW, de Vries A, Ward KM, Wolbink G, Isaacs JD. EULAR points to consider for therapeutic drug monitoring of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases. Ann Rheum Dis 2023; 82:65-73. [PMID: 35551063 DOI: 10.1136/annrheumdis-2022-222155] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 04/06/2022] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To develop EULAR points-to-consider for therapeutic drug monitoring (TDM) of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases (RMDs). METHODS The points-to-consider were developed in accordance with EULAR standardised operation procedures by a multidisciplinary task force from eight European countries, based on a systematic literature review and expert consensus. Level of evidence and strength of the points-to-consider were determined, and mean levels of agreement among the task force were calculated using a 10-point rating scale. RESULTS Six overarching principles and 13 points-to-consider were formulated. The level of agreement among the task force for the overarching principles and points-to-consider ranged from 8.4 to 9.9.The overarching principles define TDM and its subtypes, and reinforce the underlying pharmacokinetic/pharmacodynamic principles, which are relevant to all biopharmaceutical classes. The points-to-consider highlight the clinical utility of the measurement and interpretation of biopharmaceutical blood concentrations and antidrug antibodies in specific clinical scenarios, including factors that influence these parameters. In general, proactive use of TDM is not recommended but reactive TDM could be considered in certain clinical situations. An important factor limiting wider adoption of TDM is the lack of both high quality trials addressing effectiveness and safety of TDM and robust economic evaluation in patients with RMDs. Future research should focus on providing this evidence, as well as on further understanding of pharmacokinetic and pharmacodynamic characteristics of biopharmaceuticals. CONCLUSION These points-to-consider are evidence-based and consensus-based statements for the use of TDM of biopharmaceuticals in inflammatory RMDs, addressing the clinical utility of TDM.
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Affiliation(s)
- Charlotte Lm Krieckaert
- Reumatology, Amsterdam Rheumatology and Immunology Center, Reade, Amsterdam, The Netherlands
| | - Astrid van Tubergen
- Medicine, Division of Rheumatology, Maastricht University Medical Centre+, Maastricht, The Netherlands.,CAPHRI, Care and Public Health Research Institute, Maastricht University, Maastricht, The Netherlands
| | - Johanna Elin Gehin
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.,Faculty of Medicine, University of Oslo, Oslo, Norway
| | | | | | - Alejandro Balsa
- Immuno-Rheumatology Research Group, La Paz University Hospital, Madrid, Spain.,Rheumatology, La Paz University Hospital, Madrid, Spain
| | - Peter Böhm
- Forschungspartner, Deutsche Rheuma-Liga Bundesverband, Bonn, Germany
| | - Sasa Cucnik
- Rheumatology, Ljubljanski Univerzitetni klinicni center, Ljubljana, Slovenia.,Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Ori Elkayam
- Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Guro L Goll
- Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway
| | - Femke Hooijberg
- Rheumatology, Reade Hoofdlocatie Dr Jan van Breemenstraat, Amsterdam, The Netherlands
| | - Meghna Jani
- Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.,Rheumatology, Salford Royal NHS Foundation Trust, Salford, UK
| | - Patrick Dw Kiely
- Department of Rheumatology, St George's University Hospitals NHS Foundation Trust, London, UK.,Institute of Medical and Biochemical Education, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Neil McCarthy
- Patient Representative, Newcastle upon Tyne Hospitals NHS Foundation Trust, Manchester, UK
| | - Denis Mulleman
- Rheumatology, Regional University Hospital Centre Tours, Tours, France
| | | | - Katherine Payne
- Division of Population Health, Health Services Research and Primary Care, Manchester Academic Health Science Centre, Manchester, UK.,NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester, UK
| | - Martin E Perry
- Centre for Rheumatic Diseases, Royal Alexandra Hospital, Paisley, UK
| | | | - Simon R Stones
- EULAR Patient Research partner, Collaboro Consulting, Manchester, UK
| | | | | | - Katherine M Ward
- Department of Rheumatology, Diakonhjemmet Hospital Department of Rheumatology, Oslo, Norway
| | - Gertjan Wolbink
- Reumatology, Amsterdam Rheumatology and Immunology Center, Reade, Amsterdam, The Netherlands.,Immunopathology, Sanquin Research, Amsterdam, The Netherlands
| | - John D Isaacs
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK .,Musculoskeletal Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
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12
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Megna BW, Vaughn BP. Therapeutic Drug Monitoring in Practice for Inflammatory Bowel Disease. Curr Gastroenterol Rep 2022; 24:191-200. [PMID: 36459387 DOI: 10.1007/s11894-022-00854-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2022] [Indexed: 06/17/2023]
Abstract
PURPOSE OF REVIEW To outline the development, rationale, and practical use of therapeutic drug monitoring in patients with inflammatory bowel disease. RECENT FINDINGS Therapeutic drug monitoring is traditionally discussed in terms of a proactive or reactive approach. However, these terms are not always consistently defined and can be confusing when translating research to clinical practice. Personalized approaches incorporating clinical context and precision medicine are emerging. Personalized therapeutic drug monitoring combines a structured and proactive strategy for monitoring biologic concentrations as well as identification of antidrug antibody development or subtherapeutic dosing in the setting of loss of response. Optimizing biologic therapy can improve outcomes and avoid loss of response. Why, when, and how we measure drug troughs and anti-drug antibodies is a moving target, though what is known is that the appropriate and evidence-based use of this practice prevents adverse events and improves outcomes in patients with inflammatory bowel disease.
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Affiliation(s)
- Bryant W Megna
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, MN, USA.
| | - Byron P Vaughn
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, MN, USA
- Inflammatory Bowel Disease Program, University of Minnesota, Minneapolis, MN, USA
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13
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Gehin JE, Goll GL, Brun MK, Jani M, Bolstad N, Syversen SW. Assessing Immunogenicity of Biologic Drugs in Inflammatory Joint Diseases: Progress Towards Personalized Medicine. BioDrugs 2022; 36:731-748. [PMID: 36315391 PMCID: PMC9649489 DOI: 10.1007/s40259-022-00559-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/26/2022] [Indexed: 11/30/2022]
Abstract
Biologic drugs have greatly improved treatment outcomes of inflammatory joint diseases, but a substantial proportion of patients either do not respond to treatment or lose response over time. Drug immunogenicity, manifested as the formation of anti-drug antibodies (ADAb), constitute a significant clinical problem. Anti-drug antibodies influence the pharmacokinetics of the drug, are associated with reduced clinical efficacy, and an increased risk of adverse events such as infusion reactions. The prevalence of ADAb differs among drugs and diseases, and the detection of ADAb also depends on the assay format. Most data exist for the tumor necrosis factor-alpha inhibitors infliximab and adalimumab, with a frequency of ADAb that ranges from 10 to 60% across studies. Measurement of ADAb and serum drug concentrations, therapeutic drug monitoring, has been suggested as a strategy to optimize therapy with biologic drugs. Although the recent randomized clinical Norwegian Drug Monitoring (NOR-DRUM) trials show promise towards a personalized medicine prescribing approach by therapeutic drug monitoring, several challenges remain. A plethora of assay formats, with widely differing properties, is currently used for measuring ADAb. Comparing results between different assays and laboratories is difficult, which complicates the development of cut-offs necessary for guidelines and the implementation of ADAb measurements in clinical practice. With the possible exception of infliximab, limited data on clinical relevance and cost effectiveness exist to support therapeutic drug monitoring as a routine clinical strategy to monitor biologic drugs in inflammatory joint diseases. The aim of this review is to provide an overview of the characteristics and prevalence of ADAb, predisposing factors to ADAb formation, commonly used assessment methods, clinical consequences of ADAb, and the potential implications of ADAb assessments for everyday treatment of inflammatory joint diseases.
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Affiliation(s)
- Johanna Elin Gehin
- Department of Medical Biochemistry, Oslo University Hospital, Radiumhospitalet, Nydalen, Box 4953, 0424, Oslo, Norway.
| | - Guro Løvik Goll
- Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway
| | - Marthe Kirkesæther Brun
- Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Meghna Jani
- Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK
- Department of Rheumatology, Salford Royal NHS Foundation Trust, Salford, UK
| | - Nils Bolstad
- Department of Medical Biochemistry, Oslo University Hospital, Radiumhospitalet, Nydalen, Box 4953, 0424, Oslo, Norway
| | - Silje Watterdal Syversen
- Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway
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14
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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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15
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Krieckaert C, Hernández-Breijo B, Gehin JE, le Mélédo G, Balsa A, Jani M, Mulleman D, Navarro-Compan V, Wolbink G, Isaac J, van Tubergen A. Therapeutic drug monitoring of biopharmaceuticals in inflammatory rheumatic and musculoskeletal disease: a systematic literature review informing EULAR points to consider. RMD Open 2022; 8:e002216. [PMID: 35980738 PMCID: PMC9171282 DOI: 10.1136/rmdopen-2022-002216] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 05/18/2022] [Indexed: 01/08/2023] Open
Abstract
The objectives of this review were to collect and summarise evidence on therapeutic drug monitoring (TDM) of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases and to inform the EULAR Task Force for the formulation of evidence-based points to consider. A systematic literature review (SLR) was performed, covering technical aspects and (clinical) utility of TDM, to answer 13 research questions. MEDLINE, Embase and Cochrane were searched until July 2020. American College of Rheumatology and EULAR abstracts were also considered for inclusion. Data were extracted in evidence tables and risk of bias assessment was performed. For the search on technical aspects, 678 records were identified, of which 22 papers were selected. For the clinical utility search, 3846 records were identified, of which 108 papers were included. Patient-related factors associated with biopharmaceutical blood concentrations included body weight, methotrexate comedication and disease activity. The identification of a target range was hampered by study variability, mainly disease activity measures and study type. Evidence was inconsistent for multiple clinical situations in which TDM is currently applied. However, for some particular scenarios, including prediction of future treatment response, non-response to treatment, tapering and hypersensitivity reactions, robust evidence was found. There is currently no evidence for routine use of proactive TDM, in part because published cost-effectiveness analyses do not incorporate the current landscape of biopharmaceutical costs and usage. This SLR yields evidence in favour of TDM of biopharmaceuticals in some clinical scenarios, but evidence is insufficient to support implementation of routine use of TDM.
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Affiliation(s)
- Charlotte Krieckaert
- Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, Reade, Amsterdam, The Netherlands
| | | | - Johanna Elin Gehin
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | | | | | - Meghna Jani
- Centre for Epidemiology versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK
- department of Rheumatology, Salford Royal Hospitals NHS Trust, Salford, UK
| | | | | | - Gertjan Wolbink
- Immunopathology, Sanquin Research, Amsterdam, The Netherlands
| | - John Isaac
- Translational and Clinical Research Institute, Newcastle University and Musculoskeletal Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Astrid van Tubergen
- department of Medicine, Division of Rheumatology, Maastricht University Medical Centre+, Maastricht, The Netherlands
- Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, The Netherlands
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16
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Suh K, Kyei I, Hage DS. Approaches for the detection and analysis of anti-drug antibodies to biopharmaceuticals: A review. J Sep Sci 2022; 45:2077-2092. [PMID: 35230731 DOI: 10.1002/jssc.202200112] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 02/10/2022] [Accepted: 02/26/2022] [Indexed: 11/10/2022]
Abstract
Antibody-based therapeutic agents and other biopharmaceuticals are now used in the treatment of many diseases. However, when these biopharmaceuticals are administrated to patients, an immune reaction may occur that can reduce the drug's efficacy and lead to adverse side effects. The immunogenicity of biopharmaceuticals can be evaluated by detecting and measuring antibodies that have been produced against these drugs, or anti-drug antibodies (ADAs). Methods for ADA detection and analysis can be important during the selection of a therapeutic approach based on such drugs and is crucial when developing and testing new biopharmaceuticals. This review examines approaches that have been used for ADA detection, measurement, and characterization. Many of these approaches are based on immunoassays and antigen binding tests, including homogeneous mobility shift assays. Other techniques that have been used for the analysis of ADAs are capillary electrophoresis, reporter gene assays, surface plasmon resonance spectroscopy, and liquid chromatography-mass spectrometry. The general principles of each approach will be discussed, along with their recent applications with regards to ADA analysis. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Kyungah Suh
- Department of Chemistry, University of Nebraska-Lincoln
| | - Isaac Kyei
- Department of Chemistry, University of Nebraska-Lincoln
| | - David S Hage
- Department of Chemistry, University of Nebraska-Lincoln
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17
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Assessing aCCess to Investigations in Inflammatory Bowel Disease (ACCID): results from an international survey. Eur J Gastroenterol Hepatol 2021; 33:e837-e842. [PMID: 35048653 DOI: 10.1097/meg.0000000000002276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND Multiple investigations are available to aid the diagnosis and monitoring of disease activity in inflammatory bowel disease (IBD). Fecal calprotectin (FC) is an established surrogate for intestinal inflammatory activity. Therapeutic drug monitoring (TDM) including thiopurine metabolites, anti-tumor necrosis factor (TNF) levels and antidrug antibody measurements are a step toward personalized medicine in IBD, but face access barriers. We aimed to assess test availability and barriers for these investigations in European practice. METHODS Five-hundred questionnaires were distributed to workshop participants at the 11th Congress of the European Crohn's and Colitis Organisation (ECCO). Access to FC, TDM for thiopurines and anti-tumor necrosis factor agents, as well as factors associated with usage and barriers to access were recorded. RESULTS Responses were obtained from 195 attendees from 38 countries across a range of practices, healthcare settings and levels of experience. FC was available to 92.3% while access to anti-TNF (78.9%, P = 0.02 vs. thiopurine TDM, P = 0.0002 vs. FC) and thiopurine TDM (67.7%, P = 0.0001) were less widespread. Cost was a frequently cited barrier to test access or usage, with access having a significant West-East and North-South divide across all three investigations. The strongest independent predictor of access to all tests was healthcare spending per capita (P = 0.005 for FC; P < 0.0001 for both TDM). CONCLUSION FC, anti-TNF and thiopurine TDM are increasingly incorporated as part of routine practice in IBD care across Europe and have the potential to impact positively on patient care. However, access barriers remain of which we found test cost the most significant with the investment required to reduce these barriers.
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18
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Bots SJ, Parker CE, Brandse JF, Löwenberg M, Feagan BG, Sandborn WJ, Jairath V, D'Haens G, Vande Casteele N. Anti-Drug Antibody Formation Against Biologic Agents in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis. BioDrugs 2021; 35:715-733. [PMID: 34797516 PMCID: PMC9826743 DOI: 10.1007/s40259-021-00507-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/23/2021] [Indexed: 01/11/2023]
Abstract
BACKGROUND AND AIMS Immunogenicity with formation of anti-drug antibodies (ADA) to biologics is an important reason for treatment failure in inflammatory bowel disease (IBD). Our aim was to assess the rate of ADA, the effect of combination therapy with immunomodulators on ADA and the influence of ADA on efficacy and safety of biologics for IBD treatment. METHODS MEDLINE, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to April 2020 for trials of biologics that assessed immunogenicity. The overall certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). The primary outcome was rate of ADA. Secondary outcomes included efficacy and safety outcomes among patients with detectable versus undetectable ADA. For dichotomous outcomes, pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated. RESULTS Data from 68 studies were analyzed and 33 studies (5850 patients) were included in the meta-analysis. Pooled ADA rates for biologic monotherapy were 28.0% for infliximab, 7.5% for adalimumab, 3.8% for golimumab, 10.9% for certolizumab, 6.2% for ustekinumab and 16.0% for natalizumab. Pooled ADA rates were 8.4% for vedolizumab and 5.0% for etrolizumab for combo- and monotherapy combined. In all biologics, ADA rates were underestimated by use of drug-sensitive ADA assays and higher dose and/or frequency. ADA rate was significantly reduced in patients treated with combination therapy for infliximab (RR 0.52; 95% CI 0.44-0.62), adalimumab (RR 0.31; 95% CI 0.14-0.69), golimumab (RR 0.29; 95% CI 0.10-0.83), certolizumab pegol (RR 0.30; 95% CI 0.14-0.67) and natalizumab (RR 0.20; 95% CI 0.11-0. 39). ADA to infliximab were associated with lower clinical response rates (RR 0.75; 95% CI 0.61-0.91) and higher rates of infusion reactions (RR 2.36; 95% CI 1.85-3.01). CONCLUSIONS Differences in analytical methods to detect ADA hamper comparison of true ADA rates across biologics in IBD. Use of combination therapy with immunomodulators appeared to reduce ADA positivity for most biologics. For infliximab, ADA were associated with reduced drug efficacy and increased adverse events.
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Affiliation(s)
- Steven J Bots
- Amsterdam University Medical Center, Amsterdam, The Netherlands
| | | | | | - Mark Löwenberg
- Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Brian G Feagan
- Alimentiv Inc, London, ON, Canada
- Department of Medicine, Western University, London, ON, Canada
- Department of Epidemiology and Biostatistics, Western University, London, ON, Canada
| | - William J Sandborn
- Division of Gastroenterology, Department of Medicine, School of Medicine, IBD Center, University of California San Diego, 9500 Gilman Drive #0956, La Jolla, CA, 92093, USA
- Alimentiv Inc, London, ON, Canada
| | - Vipul Jairath
- Alimentiv Inc, London, ON, Canada
- Department of Medicine, Western University, London, ON, Canada
- Department of Epidemiology and Biostatistics, Western University, London, ON, Canada
| | - Geert D'Haens
- Amsterdam University Medical Center, Amsterdam, The Netherlands
- Alimentiv Inc, London, ON, Canada
| | - Niels Vande Casteele
- Division of Gastroenterology, Department of Medicine, School of Medicine, IBD Center, University of California San Diego, 9500 Gilman Drive #0956, La Jolla, CA, 92093, USA.
- Alimentiv Inc, London, ON, Canada.
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19
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Narula N, Wong ECL, AlRamdan R, Bualbanat H, Marshall JK, Steinhart AH, Greener T, Silverberg MS. Comparative effectiveness of higher adalimumab maintenance therapy versus standard dose in anti-tumor necrosis factor experienced Crohn's disease patients: A propensity-score matched cohort analysis. J Gastroenterol Hepatol 2021; 36:2803-2812. [PMID: 34020510 DOI: 10.1111/jgh.15551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 05/11/2021] [Accepted: 05/19/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Crohn's disease (CD) patients who previously failed anti-tumor necrosis factor (TNF) therapy are at higher risk of treatment failure with subsequent biologics. This study aims to determine the effectiveness and safety of higher maintenance dose regimens of adalimumab compared with standard doses in CD patients who failed anti-TNF. METHODS In this retrospective observational study, CD patients who failed anti-TNF and received adalimumab were categorized according to their post-induction maintenance regimen; 40 mg subcutaneous (sc) weekly or 80 mg sc every other week were defined as a high-dose (HD) maintenance regimen, and 40 mg sc every other week was defined as a standard-dose (SD) maintenance regimen. The primary outcome was time to treatment failure. Cox proportional hazards regression was used to adjust for confounders. Sensitivity analysis was conducted using propensity scores to create a cohort of matched participants with similar distribution of baseline covariates. RESULTS Forty patients started on HD regimens following induction, and 77 patients received the SD regimen. The median time to failure in the HD group was 6.6 years (interquartile range [IQR] 4.0-9.6) and 3.0 years (IQR 0.9-9.4) in the SD group (log-rank test P = 0.006). Patients on HD adalimumab had a lower hazard rate of treatment failure (hazard ratio: 0.27; 95% confidence interval [0.12, 0.62]; P = 0.002) compared with SD patients. No difference in adverse events was identified between groups (30% vs 31.2%, P = 1.0). Results were similar in the propensity score-matched cohort. CONCLUSIONS High-dose maintenance regimens were associated with longer time-to-failure as compared with SD regimens in CD patient who failed anti-TNF.
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Affiliation(s)
- Neeraj Narula
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Emily C L Wong
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Raed AlRamdan
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Hasan Bualbanat
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - John K Marshall
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - A Hillary Steinhart
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Centre, Toronto, Ontario, Canada.,Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Tomer Greener
- Edit Wolfson Medical Center, Tel-Aviv University, Tel-Aviv, Israel
| | - Mark S Silverberg
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Centre, Toronto, Ontario, Canada.,Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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20
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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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21
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Greener T, Boland K, Milgrom R, Ben-Bassat O, Steinhart AH, Silverberg MS, Narula N. Higher adalimumab maintenance regimen is more effective than standard dose in anti-TNF experienced Crohn's disease patients. Eur J Gastroenterol Hepatol 2021; 33:1274-1279. [PMID: 34402466 DOI: 10.1097/meg.0000000000002250] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Many Crohn's disease patients treated with anti-tumor necrosis factor (TNF) therapies suffer from loss of response over time and require dose escalation. The aim of this study was to evaluate the efficacy and safety of treating anti-TNF experienced Crohn's disease patients with higher maintenance regimens of adalimumab. METHODS In a retrospective observational study, Crohn's disease patients receiving adalimumab were categorized according to their maintenance regimen; 40 mg weekly, 80 mg every other week or greater were defined as a high-dose maintenance regimen and 40 mg every other week was defined as a standard maintenance regimen. The primary outcome was time to treatment failure. RESULTS Thirty-nine patients were started on high-dose regimens following induction and 40 patients received the standard regimen. According to a Kaplan-Meier survival curve analysis, time to treatment failure was significantly longer in patients in the high-dose group (P = 0.0015). Patients on high-dose adalimumab had a lower treatment failure rate (hazard ratio 0.21; P = 0.0005) when compared to patients on the standard regimen, after adjusting for induction dose and concomitant immunomodulator use. No difference in adverse events was identified between the groups (31 vs. 30%; P = 0.94). CONCLUSION High-dose maintenance regimens were more effective than the standard adalimumab maintenance protocol with better short and long-term clinical outcomes.
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Affiliation(s)
- Tomer Greener
- Digestive Disease Institute, Sha'are Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Karen Boland
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Centre, Ontario
- Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada
| | - Raquel Milgrom
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Centre, Ontario
- Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada
| | - Ofer Ben-Bassat
- Department of Gastroenterology, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - A Hillary Steinhart
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Centre, Ontario
- Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada
| | - Mark S Silverberg
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Centre, Ontario
- Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada
| | - Neeraj Narula
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
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22
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Serkland TT, Skrede S, Berg JA. Therapeutic Drug Monitoring vs Standard Therapy During Infliximab Induction in Patients With Chronic Immune-Mediated Inflammatory Diseases. JAMA 2021; 326:1068-1069. [PMID: 34546308 DOI: 10.1001/jama.2021.11471] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Affiliation(s)
| | - Silje Skrede
- Haukeland University Hospital, University of Bergen, Bergen, Norway
| | - Jon Andsnes Berg
- Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway
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23
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Drug Levels Associated with Optimal Discrimination Between Remission and Non-Remission and Comparison of Antibody Assays During First Year of Stable Infliximab Maintenance Therapy in Inflammatory Bowel Disease. Ther Drug Monit 2021; 44:290-300. [PMID: 34387220 DOI: 10.1097/ftd.0000000000000913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 06/18/2021] [Indexed: 11/25/2022]
Abstract
BACKGROUND In order to implement therapeutic drug monitoring (TDM)-based strategies for infliximab (IFX) in inflammatory bowel disease (IBD), the authors assessed IFX levels for optimal discrimination between remission and non-remission and compared assays for anti-IFX antibodies (Abs). METHODS The retrospective cohort comprised 163 bionaïve patients with IBD who received stable IFX maintenance therapy (5 mg/kg every 8 weeks [q8w]) for one year. The clinical and biochemical remission status was assessed at all infusions (weeks 14-22-30-38-46-54), and IFX and anti-IFX Abs were estimated using a time-resolved fluorometric assay (n=690; 88% of infusions). Samples positive for anti-IFX Abs or IFX levels <limit of detection (LOD; n=102) were analyzed by two binding assays (ELISA) and functional reporter gene assay/drug-tolerant enzyme immunoassay (RGA/EIA). RESULTS At all assessed time points, IFX levels were more than double in patients presenting clinical or biochemical remission. An IFX concentration of 4.5 µg/mL was associated with clinical remission during the entire first year of therapy (sensitivity 54% [49-59], specificity 73% [67-78], AUCROC 0.65 [0.60-0.69], p<0.0001); these values were comparable with biochemical remission. Exploratory assessments for endoscopic remission (n=131) were performed at the discretion of the treating physician. Anti-IFX Abs were associated with undetectable IFX and treatment failure (OR 2.9 [1.4-6.0], p<0.01), irrespective of persistency or transiency. All performed assays detected anti-IFX Abs in [SWUNG DASH]2/3 of samples. Binding assays demonstrated a higher sensitivity to anti-IFX Abs. CONCLUSION IFX at [SWUNG DASH]5 µg/mL was associated with clinical and biochemical remission during the first year of maintenance therapy. During this phase of therapy, standard binding assays are appropriate for TDM.
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24
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Wu Y, Wen A, Selvanderan SP, Xuan W, Andrews JM, Koo JH, Williams AJ, Ng W, Connor S. Management Decisions in Crohn's Disease Are Changed by Knowledge of Proactive and Reactive Testing of Antitumor Necrosis Factor Drug Levels. CROHN'S & COLITIS 360 2021; 3:otab042. [PMID: 36776656 PMCID: PMC9802446 DOI: 10.1093/crocol/otab042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Indexed: 11/14/2022] Open
Abstract
Background There is controversy about the proactive clinical application of therapeutic drug monitoring (TDM) of biologic drugs in Crohn's disease (CD). One way to practically assess this is to examine how TDM influences management decisions. We examined how knowledge of proactive and reactive antitumor necrosis factor (anti-TNF) drug levels changes management in a variety of clinical scenarios. Methods In this retrospective cohort study, all adults with CD having trough level infliximab or adalimumab measurements at Liverpool Hospital between June 2013 and July 2016 were included. Demographics, indications for testing, anti-TNF drug levels, and treatment details were collected along with subsequent management decisions. The decision made by the treating clinician after receiving the drug level was compared to a consensus decision from a panel of 3 gastroenterologists based on the clinical, laboratory, imaging, and/or endoscopic results without the drug level. When these 2 decisions were discrepant, the anti-TNF drug level was deemed to have changed management. Results One hundred and eighty-seven trough levels of infliximab or adalimumab from 108 patients were analyzed. Overall, assessment of anti-TNF levels affected management in 46.9% of the instances. Knowledge of the drug level was also more likely to result in management change when the test was performed for reactive TDM compared to proactive TDM (63% vs 36%, P = .001). Conclusions The addition of TDM of anti-TNF agents to routine investigations alters management decisions in adult CD patients on anti-TNF therapy in both proactive and reactive settings.
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Affiliation(s)
- Yang Wu
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, New South Wales, Australia,Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia,Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia,Address correspondence to: Yang Wu, MD, Ingham Institute for Applied Medical Research, 1 Campbell St, Liverpool, NSW 2170, Australia ()
| | - Amy Wen
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, New South Wales, Australia,Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Shane P Selvanderan
- IBD Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia,Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
| | - Wei Xuan
- Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia
| | - Jane M Andrews
- IBD Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia,Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
| | - Jenn H Koo
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, New South Wales, Australia,Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Astrid-Jane Williams
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, New South Wales, Australia,Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Watson Ng
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, New South Wales, Australia,Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Susan Connor
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, New South Wales, Australia,Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia,Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
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25
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Pękala A, Filip R, Aebisher D. Anti-Drug Antibodies in Patients with Inflammatory Bowel Diseases Treated with Biosimilar Infliximab: A Prospective Cohort Study. J Clin Med 2021; 10:2653. [PMID: 34208676 PMCID: PMC8235171 DOI: 10.3390/jcm10122653] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/26/2021] [Accepted: 05/27/2021] [Indexed: 01/14/2023] Open
Abstract
Reports of the prevalence of antibodies to infliximab (anti-drug antibodies, ADA) are inconsistent due in part to the various assay formats used to monitor immunogenicity in the clinic and under clinical trial settings. This study aimed to determine the frequency of ADA in patients with inflammatory bowel disease (IBD) during induction and maintenance therapy with biosimilar infliximab (CT-P13) using the ELISA (enzyme-linked immunosorbent assay) method. In this prospective single-center study, we analyzed the incidence of ADA and the relationship between the presence of ADA and the following variables: gender, type of disease, immunosuppressive therapy used, and duration of treatment. A total of 84 patients with IBD received CT-P13 and were followed up for an average of 7 months. We found ADA in 50% of the patients with undetectable levels of the drug. The percentage of persons with antibodies detected during induction treatment was 11.3% compared to 9.6% during maintenance therapy. The analysis showed no relationship between response to treatment and antibody titers (p = 0.381). The study showed a statistically significant relationship between undetectable levels of CT-P13 and the presence of ADA at week 6 of therapy (i.e., ADA were detected in all the patients with undetectable levels of CT-P13). Patients with IBD and undetectable levels of CT-P13 before administration of the third induction dose were at high risk of the presence of anti-drug antibodies as well as primary non-response.
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Affiliation(s)
- Anna Pękala
- Department of Gastroenterology, IBD Unit of Clinical Hospital 2, Lwowska 60 Str., 35-301 Rzeszow, Poland;
| | - Rafał Filip
- Department of Gastroenterology, IBD Unit of Clinical Hospital 2, Lwowska 60 Str., 35-301 Rzeszow, Poland;
- Faculty of Medicine, University of Rzeszow, Kopisto 2A Str., 35-315 Rzeszow, Poland
| | - David Aebisher
- Department of Photomedicine and Physical Chemistry, Faculty of Medicine, University of Rzeszow, Warzywna 1A Str., 35-310 Rzeszow, Poland;
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26
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Syversen SW, Goll GL, Jørgensen KK, Sandanger Ø, Sexton J, Olsen IC, Gehin JE, Warren DJ, Brun MK, Klaasen RA, Karlsen LN, Noraberg G, Zettel C, Ljoså MKA, Haugen AJ, Njålla RJ, Bruun TJ, Seeberg KA, Michelsen B, Strand EK, Skorpe S, Blomgren IM, Bragnes YH, Dotterud CK, Thune T, Ystrøm CM, Torp R, Mielnik P, Mørk C, Kvien TK, Jahnsen J, Bolstad N, Haavardsholm EA. Effect of Therapeutic Drug Monitoring vs Standard Therapy During Infliximab Induction on Disease Remission in Patients With Chronic Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial. JAMA 2021; 325:1744-1754. [PMID: 33944876 PMCID: PMC8097498 DOI: 10.1001/jama.2021.4172] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
IMPORTANCE Proactive therapeutic drug monitoring (TDM), defined as individualized drug dosing based on scheduled monitoring of serum drug levels, has been proposed as an alternative to standard therapy to maximize efficacy and safety of infliximab and other biological drugs. However, whether proactive TDM improves clinical outcomes when implemented at the time of drug initiation, compared with standard therapy, remains unclear. OBJECTIVE To assess whether TDM during initiation of infliximab therapy improves treatment efficacy compared with standard infliximab therapy without TDM. DESIGN, SETTING, AND PARTICIPANTS Randomized, parallel-group, open-label clinical trial of 411 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis initiating infliximab therapy in 21 hospitals in Norway. Patients were recruited from March 1, 2017, to January 10, 2019. Final follow-up occurred on November 5, 2019. INTERVENTIONS Patients were randomized 1:1 to receive proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 207) or standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 204). MAIN OUTCOMES AND MEASURES The primary end point was clinical remission at week 30. RESULTS Among 411 randomized patients (mean age, 44.7 [SD, 14.9] years; 209 women [51%]), 398 (198 in the TDM group and 200 in the standard therapy group) received their randomized intervention and were included in the full analysis set. Clinical remission at week 30 was achieved in 100 (50.5%) of 198 and 106 (53.0%) of 200 patients in the TDM and standard therapy groups, respectively (adjusted difference, 1.5%; 95% CI, -8.2% to 11.1%; P = .78). Adverse events were reported in 135 patients (68%) and 139 patients (70%) in the TDM and standard therapy groups, respectively. CONCLUSIONS AND RELEVANCE Among patients with immune-mediated inflammatory diseases initiating treatment with infliximab, proactive therapeutic drug monitoring, compared with standard therapy, did not significantly improve clinical remission rates over 30 weeks. These findings do not support routine use of therapeutic drug monitoring during infliximab induction for improving disease remission rates. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03074656.
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Affiliation(s)
| | - Guro Løvik Goll
- Division of Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway
| | | | | | - Joseph Sexton
- Division of Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway
| | - Inge Christoffer Olsen
- Department of Research Support for Clinical Trials, Oslo University Hospital, Oslo, Norway
| | - Johanna Elin Gehin
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - David John Warren
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Marthe Kirkesæther Brun
- Division of Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Rolf Anton Klaasen
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Lars Normann Karlsen
- Department of Gastroenterology, Stavanger University Hospital, Stavanger, Norway
| | - Geir Noraberg
- Department of Gastroenterology, Hospital of Southern Norway Trust, Arendal, Norway
| | - Camilla Zettel
- Department of Rheumatology, Betanien Hospital, Skien, Norway
| | | | | | | | | | | | - Brigitte Michelsen
- Division of Rheumatology, Department of Medicine, Hospital of Southern Norway Trust, Kristiansand, Norway
| | | | - Svanaug Skorpe
- Haugesund Hospital for Rheumatic Diseases, Haugesund, Norway
| | | | | | | | - Turid Thune
- Department of Dermatology, Haukeland University Hospital, Bergen, Norway
| | | | - Roald Torp
- Department of Medicine, Innlandet Hospital Trust, Hamar, Norway
| | - Pawel Mielnik
- Department of Neurology, Rheumatology, and Physical Medicine, Førde Hospital Trust, Førde, Norway
| | - Cato Mørk
- Akershus Dermatology Center, Lørenskog, Norway
| | - Tore K. Kvien
- Division of Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Jørgen Jahnsen
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Nils Bolstad
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Espen A. Haavardsholm
- Division of Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
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27
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Papamichael K, Clarke WT, Vande Casteele N, Germansky KA, Feuerstein JD, Melmed GY, Siegel CA, Irving PM, Cheifetz AS. Comparison of Assays for Therapeutic Monitoring of Infliximab and Adalimumab in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 2021; 19:839-841.e2. [PMID: 32147594 PMCID: PMC7483237 DOI: 10.1016/j.cgh.2020.03.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 02/27/2020] [Accepted: 03/02/2020] [Indexed: 02/07/2023]
Abstract
Comparison data regarding anti-tumor necrosis factor drug concentrations in inflammatory bowel disease (IBD) between the enzyme-linked immunosorbent assay (ELISA) and the homogenous mobility shift assay (HMSA) are scarce.1-3 As decisions in clinical practice depend on the thresholds that define a therapeutic drug concentration, it is important to determine if this varies based on the type of assay used for therapeutic drug monitoring.4 We recently showed a discrepancy between a commercially available ELISA and the HMSA for both infliximab and adalimumab concentrations in patients with IBD.5 Based on the results of the study, Prometheus Laboratories (San Diego, CA) initiated a comprehensive review of their HMSA assays and found that there was an upward drift for both infliximab (from December 2017 to May 2019) and adalimumab (from August 2017 to May 2019), including when our study was performed. Prometheus Laboratories corrected the errant values and reported the revised drug concentrations to physicians (Supplementary Methods). We aimed to compare the corrected infliximab and adalimumab concentrations with the original ELISA values.
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Affiliation(s)
| | - William T Clarke
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Niels Vande Casteele
- Department of Medicine, University of California, San Diego, La Jolla, California
| | - Katharine A Germansky
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Joseph D Feuerstein
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Gil Y Melmed
- Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Corey A Siegel
- Department of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
| | - Peter M Irving
- Department of Gastroenterology and Hepatology, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom
| | - Adam S Cheifetz
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
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28
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Judit Szántó K, Madácsy T, Kata D, Ferenci T, Rutka M, Bálint A, Bor R, Fábián A, Milassin Á, Jójárt B, Szepes Z, Nagy F, Molnár T, Földesi I, Maléth J, Farkas K. Advances in the optimization of therapeutic drug monitoring using serum, tissue and faecal anti-tumour necrosis factor concentration in patients with inflammatory bowel disease treated with TNF-α antagonists. Expert Opin Biol Ther 2021; 21:539-548. [PMID: 33583295 DOI: 10.1080/14712598.2021.1890712] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
INTRODUCTION The relationship between clinical outcomes and serum anti-TNF levels is controversial. The aim of this study was to perform simultaneous analyses of serum, mucosal, and fecal anti-TNF-α levels. METHODS Consecutive IBD patients who received maintenance anti-TNF-α therapy were enrolled. The number of TNF-α positive cells in the mucosa was detected using immunofluorescent labeling on biopsy samples. Serum, mucosal and fecal anti-TNF-α, serum anti-drug antibody, and fecal calprotectin levels were determined using ELISA. Each patient underwent body composition analysis as well. RESULTS Data of 50 patients were analyzed. The number TNF-α positive cells was significantly higher in the inflamed part of the colon than in the un-inflamed part of the colon. Tissue and fecal drug levels did not show any association with serum drug levels; moreover, serum anti-TNF concentration did not correlate with endoscopic activity. Mucosal anti-TNF levels were higher only in IFX-treated patients in remission and IFX-treated patients with detectable fecal anti-TNF had lower tissue drug levels. Presence of the drug in the feces was significantly different according to disease activity. CONCLUSION Fecal drug concentration is suggested to be a better predictor of endoscopic activity and loss of response, and fecal drug monitoring may improve the estimation accuracy of tissue drug levels.
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Affiliation(s)
| | - Tamara Madácsy
- Department of Medicine, University of Szeged, Szeged, Hungary
| | - Diána Kata
- Department of Laboratory Medicine, University of Szeged, Szeged, Hungary
| | - Tamás Ferenci
- Physiological Controls Research Center, John von Neumann Faculty of Informatics, Institute of Biomatics, Óbuda University, Budapest, Hungary
| | - Mariann Rutka
- Department of Medicine, University of Szeged, Szeged, Hungary
| | - Anita Bálint
- Department of Medicine, University of Szeged, Szeged, Hungary
| | - Renáta Bor
- Department of Medicine, University of Szeged, Szeged, Hungary
| | - Anna Fábián
- Department of Medicine, University of Szeged, Szeged, Hungary
| | - Ágnes Milassin
- Department of Medicine, University of Szeged, Szeged, Hungary
| | | | - Zoltán Szepes
- Department of Medicine, University of Szeged, Szeged, Hungary
| | - Ferenc Nagy
- Department of Medicine, University of Szeged, Szeged, Hungary
| | - Tamás Molnár
- Department of Medicine, University of Szeged, Szeged, Hungary
| | - Imre Földesi
- Department of Laboratory Medicine, University of Szeged, Szeged, Hungary
| | - József Maléth
- Department of Medicine, University of Szeged, Szeged, Hungary.,HCEMM-SZTE Molecular Gastroenterology Research Group, University of Szeged, Szeged, Hungary.,HAS-USZ Momentum Epithelial Cell Signalling and Secretion Research Group, University of Szeged, Szeged, Hungary
| | - Klaudia Farkas
- Department of Medicine, University of Szeged, Szeged, Hungary
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29
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Laserna-Mendieta EJ, Salvador-Martín S, Marín-Jiménez I, Menchén LA, López-Cauce B, López-Fernández LA, Lucendo AJ. Comparison of a new rapid method for determination of serum anti-adalimumab and anti-infliximab antibodies with two established ELISA kits. J Pharm Biomed Anal 2021; 198:114003. [PMID: 33714800 DOI: 10.1016/j.jpba.2021.114003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/01/2021] [Accepted: 03/02/2021] [Indexed: 11/25/2022]
Abstract
BACKGROUND Adalimumab (ADL), infliximab (IFX) and their biosimilars are widely used biological drugs. Some patients, however, generate neutralizing antibodies that hamper the effectiveness of these drugs. Evidence shows therapeutic drug monitoring of serum levels ADL/IFX and anti-drug antibodies (ADA) is useful to improve treatment effectiveness. We evaluated a new rapid quantitative method, Quantum Blue (QB), for determining serum anti-ADL and anti-IFX antibodies (Research Use Only labelling) by comparing it with two established ELISA kits, Promonitor (PM) and Lisa-Tracker (LT). METHODS Eighty samples (40 for each drug type) were analysed. Percentage of agreement and kappa statistic were used to compare positive/negative ADA results. Clinical implications for drug treatment in the patients with discordant results were evaluated. The Chi-square test was used to analyze differences for ADA detection in patients with disease flare and without concomitant immunosuppressant treatment. RESULTS Agreement exceeded 80 % among anti-ADL methods. Although LT ELISA showed a lower capacity in detecting anti-ADL antibodies, discrepancies were found for levels close to the cut-off concentration, thus having minimal impact on clinical decisions. Conversely, QB anti-IFX displayed low agreement with PM and LT ELISA kits (67.5 % and 50 %, respectively), and was unable to detect high levels of antibodies, therefore having major clinical implications. Agreement between PM and LT ELISA anti-IFX kits was 82.5 % with all discordant results being undetected for PM and slightly positive for LT. CONCLUSION QB anti-ADL shows similar performance to ELISA kits while QB anti-IFX needs further improvements to achieve reliable antibody detection.
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Affiliation(s)
- Emilio J Laserna-Mendieta
- Department of Gastroenterology, Hospital General de Tomelloso, Tomelloso, Spain; Clinical Laboratory, Hospital Universitario de La Princesa, Madrid, Spain; Instituto de Investigación Sanitaria de La Princesa, Madrid, Spain.
| | - Sara Salvador-Martín
- Department of Pharmacy, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Ignacio Marín-Jiménez
- Department of Gastroenterology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Luis A Menchén
- Department of Gastroenterology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Beatriz López-Cauce
- Department of Gastroenterology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Luis A López-Fernández
- Department of Pharmacy, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Spanish Clinical Research Network (SCReN), Madrid, Spain
| | - Alfredo J Lucendo
- Department of Gastroenterology, Hospital General de Tomelloso, Tomelloso, Spain; Instituto de Investigación Sanitaria de La Princesa, Madrid, Spain; Biomedical Research Network Centre for Liver and Digestive Diseases (CIBEREHD), Madrid, Spain.
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Villemonteix J, Guérin-El Khourouj V, Hugot JP, Giardini C, Carcelain G, Martinez-Vinson C. Comparison of three immunoassays for infliximab trough level monitoring in paediatric inflammatory bowel diseases. Biologicals 2021; 70:17-21. [PMID: 33676831 DOI: 10.1016/j.biologicals.2021.02.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 02/10/2021] [Accepted: 02/12/2021] [Indexed: 02/07/2023] Open
Abstract
Many clinical studies in paediatric inflammatory bowel diseases (IBD) use infliximab trough level (IFX-TL) and detection of antibody against infliximab (ATI). Hence, comparison of commercially available assays is needed in paediatric samples to assess their reliability and their comparability. We measured IFX-TL and ATI-TL in sera samples of 53 IBD children using three ELISA kits: Lisa-Tracker® Duo Infliximab (Theradiag®), Ridascreen® IFX monitoring (R-Biopharm®) and Promonitor® IFX (Grifols®). Regarding IFX-TL, median values were comparable (p > 0.05), a good statistical correlation has been observed (0.73 ≤ R2 ≤ 0.85) between tested assays and the Bland-Altman analysis found an excellent agreement with a bias estimated between -0.56 and 0.12 and few values outside the 95% limits of agreement. However, qualitative comparison with therapeutic interval classifications showed some discrepancies (30.2%), mainly due to values near thresholds and more often than not with Theradiag® (22.6%). For ATI, because of non-standardized units, the qualitative comparison found a sensibly good agreement (98.1%). These data show a good agreement of IFX-TL and ATI measurement between three marketed ELISA assays with a small bias obtained. Variations in some results can lead to divergent therapeutic interval classifications and prompt us to be cautious in the interpretation of values near therapeutic thresholds.
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Affiliation(s)
- Juliette Villemonteix
- Laboratory of Immunology, Hôpital Universitaire Robert Debré, 48, Boulevard Sérurier 75935 PARIS Cedex 19, Assistance Publique Hôpitaux de Paris, Université de Paris, Paris, France.
| | - Valérie Guérin-El Khourouj
- Laboratory of Immunology, Hôpital Universitaire Robert Debré, 48, Boulevard Sérurier 75935 PARIS Cedex 19, Assistance Publique Hôpitaux de Paris, Université de Paris, Paris, France
| | - Jean-Pierre Hugot
- Department of Paediatric Gastroenterology, Hôpital Universitaire Robert Debré, 48, Boulevard Sérurier 75935 PARIS Cedex 19, Assistance Publique Hôpitaux de Paris, Université de Paris, Paris, France
| | - Caroline Giardini
- Laboratory of Immunology, Hôpital Universitaire Robert Debré, 48, Boulevard Sérurier 75935 PARIS Cedex 19, Assistance Publique Hôpitaux de Paris, Université de Paris, Paris, France
| | - Guislaine Carcelain
- Laboratory of Immunology, Hôpital Universitaire Robert Debré, 48, Boulevard Sérurier 75935 PARIS Cedex 19, Assistance Publique Hôpitaux de Paris, Université de Paris, Paris, France
| | - Christine Martinez-Vinson
- Department of Paediatric Gastroenterology, Hôpital Universitaire Robert Debré, 48, Boulevard Sérurier 75935 PARIS Cedex 19, Assistance Publique Hôpitaux de Paris, Université de Paris, Paris, France
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31
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Azzam N, Aljebreen A, Alharbi O, Charabaty A, Alanazi M, Alkuwaykibi N, Alfaraidi J, Bashamil A, Almansour T, Almadi M. Impact of infliximab therapeutic drug level monitoring on outcomes of patients with inflammatory bowel disease: A real-world experience from a Middle Eastern cohort. Arab J Gastroenterol 2021; 22:66-72. [PMID: 33632623 DOI: 10.1016/j.ajg.2021.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/16/2020] [Accepted: 01/25/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND STUDY AIM Therapeutic drug monitoring (TDM) through measurement of infliximab (IFX) trough levels and antibodies to infliximab (ATI) is performed to guide IFX intensification strategies and improve its efficacy. We conducted this study to explore the relationship between clinical and endoscopic/radiological remission and IFX and ATI levels in patients with inflammatory bowel disease (IBD) treated with IFX and to evaluate the appropriateness of treatment decision post TDM. PATIENTS AND METHODS This was a cross-sectional study of a cohort of adult patients with IBD. Serum IFX trough concentrations and ATI were measured. RESULTS A total of 129 patients [104] with ulcerative colitis (UC) and 25 with Crohn's disease (CD)] were included in this study, of whom 61.2% were men. The mean disease duration was 6.7 years, and 72% of patients with UC had extensive colitis. The mean serum IFX trough level was 4.1 µg/mL; the IFX trough levels were subtherapeutic in 75 patients (58%), therapeutic in 37 patients (29%), and supratherapeutic in 17 patients (13%). Positivity to ATI was found in 16 patients (12.4%). Only 43 patients (33.3%) underwent an appropriate change in therapy after TDM, patients with penetrating CD disease had low IFX levels and higher C-reactive protein levels at 12 months before TDM. CONCLUSIONS Patients with IBD with therapeutic IFX levels tend to have increased endoscopic/radiological remission rates. However, an appropriate change in management based on TDM was absent in the majority of patients, potentially reflecting the need to have a dashboard to support and guide clinicians in decision-making.
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Affiliation(s)
- Nahla Azzam
- Division of Gastroenterology, Department of Medicine, King Saud University, Riyadh, Saudi Arabia.
| | - Abdulrahman Aljebreen
- Division of Gastroenterology, Department of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Othman Alharbi
- Division of Gastroenterology, Department of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Aline Charabaty
- Division of Gastroenterology, Department of Internal Medicine, Johns Hopkins Medicine, Washington, DC, United States
| | - Mohammed Alanazi
- Division of Gastroenterology, Department of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Nashmi Alkuwaykibi
- Division of Gastroenterology, Department of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Jowaher Alfaraidi
- Division of Gastroenterology, Department of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Ahmad Bashamil
- Division of Gastroenterology, Department of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Tarik Almansour
- Division of Gastroenterology, Department of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Majid Almadi
- Division of Gastroenterology, Department of Medicine, King Saud University, Riyadh, Saudi Arabia; Division of Gastroenterology, The McGill University Health Center, Montreal General Hospital, Mc, Canada
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32
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Strand V, Goncalves J, Isaacs JD. Immunogenicity of biologic agents in rheumatology. Nat Rev Rheumatol 2020; 17:81-97. [PMID: 33318665 DOI: 10.1038/s41584-020-00540-8] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/03/2020] [Indexed: 12/12/2022]
Abstract
Biologic agents have become a core component of therapeutic strategies for many inflammatory rheumatic diseases. However, perhaps reflecting the specificity and generally high affinity of biologic agents, these therapeutics have been used by rheumatologists with less consideration of their pharmacokinetics than that of conventional synthetic DMARDs. Immunogenicity was recognized as a potential limitation to the use of biologic agents at an early stage in their development, although regulatory guidance was relatively limited and assays to measure immunogenicity were less sophisticated than today. The advent of biosimilars has sparked a renewed interest in immunogenicity that has resulted in the development of increasingly sensitive assays, an enhanced appreciation of the pharmacokinetic consequences of immunogenicity and the development of comprehensive and specific guidance from regulatory authorities. As a result, rheumatologists have a greatly improved understanding of the field in general, including the factors responsible for immunogenicity, its potential clinical consequences and the implications for everyday treatment. In some specialties, immunogenicity testing is becoming a part of routine clinical management, but definitive evidence of its cost-effectiveness in rheumatology is awaited.
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Affiliation(s)
- Vibeke Strand
- Division of Immunology and Rheumatology, Stanford University, Palo Alto, CA, USA.
| | - Joao Goncalves
- Research Institute for Medicines (iMed), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
| | - John D Isaacs
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.,Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
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Rocha C, Lago P, Fernandes S, Correia L, Portela F, Vieira AI, Patita M, Arroja B, Ministro P, Alves C, Dias CC, Magro F. Rapid test detection of anti-infliximab antibodies: performance comparison with three different immunoassays. Therap Adv Gastroenterol 2020; 13:1756284820965790. [PMID: 33281935 PMCID: PMC7682213 DOI: 10.1177/1756284820965790] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 09/15/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND AND AIMS Therapeutic drug monitoring (TDM) of infliximab (IFX) and anti-infliximab antibodies (ATIs) is essential for treatment optimisation in inflammatory bowel disease (IBD) patients. The aim of this study was to estimate and compare the agreement and accuracy between a new rapid test and three established enzyme-linked immunosorbent assays (ELISAs) to quantify ATIs levels, and to evaluate the impact of exogenous IFX on the performance of these assays. METHODS We analysed 200 serum samples from 57 IBD outpatients in IFX induction or maintenance therapy at six IBD centres in Portugal. ATI levels were quantified using the rapid test Quantum Blue® (QB) Anti-Infliximab (Bühlmann) and three established ELISAs: In-House, Theradiag (Lisa Tracker Anti-Infliximab), and Immundiagnostik (IDKmonitor Infliximab). ATIs were quantified in patients' serum samples and spiked samples with exogenous IFX, based on analytical and clinical cutoffs. Qualitative agreement and accuracy were estimated by Cohen's kappa (k) with 95% confidence intervals. RESULTS ATIs quantification with clinical cutoffs showed a slight agreement between QB rapid test and In-House [k = 0.163 (0.051-0.276)] and Immundiagnostik [k = 0.085 (0.000-0.177)]. Regarding IFX/ATIs status, the QB rapid test showed a substantial agreement with Theradiag [k = 0.808 (0.729-0.888)] and a fair agreement with In-House [k = 0.343 (0.254-0.431)] and Immundiagnostik [k = 0.217 (0.138-0.297)]. The QB rapid test could not detect ATI-positive levels in samples with exogenous IFX at 5-300 µg/ml. Interference on ATIs detection was observed at exogenous IFX ⩾30 µg/ml for In-house and Immundiagnostik assays. CONCLUSION QB rapid test is only suitable to detect ATI-positive levels in the absence of IFX.
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Affiliation(s)
- Cátia Rocha
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal
- Faculty of Medicine, University of Lisbon, Lisbon, Portugal
- Institute of Environmental Health, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
| | - Paula Lago
- Department of Gastroenterology, Centro Hospitalar do Porto, Porto, Portugal
| | - Samuel Fernandes
- Department of Gastroenterology and Hepatology, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal
| | - Luís Correia
- Department of Gastroenterology and Hepatology, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal
| | - Francisco Portela
- Department of Gastroenterology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Ana Isabel Vieira
- Department of Gastroenterology, Hospital Garcia de Orta, Almada, Portugal
| | - Marta Patita
- Department of Gastroenterology, Hospital Garcia de Orta, Almada, Portugal
| | - Bruno Arroja
- Department of Gastroenterology, Hospital de Braga, Braga, Portugal
| | - Paula Ministro
- Department of Gastroenterology, Centro Hospitalar Tondela-Viseu, Viseu, Portugal
| | - Catarina Alves
- Faculty of Medicine, University of Porto, Porto, Portugal
| | - Cláudia Camila Dias
- Center for Health Technology and Services Research (CINTESIS), Faculty of Medicine, University of Porto, Porto, Portugal
- Health Information and Decision Sciences Department, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Fernando Magro
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, Porto, 4200-319, Portugal
- Portuguese IBD Study Group (GEDII), Porto, Portugal
- Department of Gastroenterology, São João Hospital Centre, Porto, Portugal
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Optimization of azathioprine dose in combined treatment with anti-TNF-alpha in inflammatory bowel disease. GASTROENTEROLOGIA Y HEPATOLOGIA 2020; 44:337-345. [PMID: 33272733 DOI: 10.1016/j.gastrohep.2020.10.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 09/28/2020] [Accepted: 10/01/2020] [Indexed: 11/22/2022]
Abstract
INTRODUCTION The dose of thiopurine drugs in combined treatments with anti-TNF in inflammatory bowel disease (IBD) has not been clearly established. The purpose of this study is to assess whether the dose of azathioprine influences clinical and biochemical response/remission rates, and anti-TNF drug levels/antibody formation. MATERIAL AND METHODS Patients with IBD on combined maintenance treatment with azathioprine and infliximab or adalimumab were selected. Based on the dose of azathioprine, two groups were defined (standard: 2-2.5mg/kg/day; and decreased: less than 2mg/kg/day). RESULTS In the IFX group, there were no statistically significant differences (p=0.204) in the rates of remission (39% vs 41.3%), response (10% vs 21.7%) or failure (51.5% vs 37%) depending on the dose of thiopurine drugs. No differences were found between AZA-dose dependent IFX levels (2.46 vs 3.21μg/mL; p=0.211). In the adalimumab group, there were no statistically significant differences (p=0.83) in the rates of remission (66% vs 56%), response without remission (15.38% vs 25%) or failure (18% vs 18%) depending on the dose of thiopurines. With respect to ADA-levels, no differences were found in both groups (7.69 vs 8.23μg/mL; p=0.37). CONCLUSION In our experience, no statistically significant differences were found in either anti-TNF levels or clinical-biological response/remission rates based on doses of azathioprine.
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Verdon C, Vande Casteele N, Heron V, Germain P, Afif W. Comparison of Serum Concentrations of Ustekinumab Obtained by Three Commercial Assays in Patients with Crohn's Disease. J Can Assoc Gastroenterol 2020; 4:73-77. [PMID: 33855264 PMCID: PMC8023823 DOI: 10.1093/jcag/gwaa003] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 01/26/2020] [Indexed: 12/14/2022] Open
Abstract
Background Data on the association of ustekinumab (UST) drug concentrations and clinical outcomes are conflicting. We assessed serum UST drug and anti-UST antibody concentrations using three commercially available assays. Methods Sixty-one blood samples were analyzed for serum UST drug and anti-UST antibody concentrations using three assays: one homogeneous mobility shift assay (HMSA, Prometheus, Assay A), and two enzyme-linked immunosorbent assays (ELISA; Progenika, Dynacare, Assay B and Theradiag, Assay C). Results The median (IQR) serum UST concentrations for the three assays were: Assay A 7.50 (5.35 to 12.88) µg/mL, Assay B 4.02 (2.46 to 6.95) µg/mL and Assay C 4.35 (2.62 to 7.50) µg/mL. A Kruskal-Wallis test confirmed a statistically significant difference between the different assays, X2(2) = 30.606, p < 0.001. Linear regression showed near twofold increased difference in the absolute drug concentrations between the HMSA and either ELISA. Linear quantitative correlation was observed for all three assays (r = 0.836 for A versus B, r = 0.792 for A versus C, r = 0.936 for B versus C; p < 0.01). The intraclass correlation coefficient (ICC) between assay A and B was 0.649 (95% confidence interval [CI] -0.208 to 0.874); assay A and C was 0.671 (95% CI -0.165 to 0.878); and assay B and C was 0.958 (95% CI 0.928 to 0.975); p < 0.001. No anti-UST antibodies were detected. Conclusion A good correlation was observed for serum UST drug concentrations and a good agreement was observed between the ELISA tests. However, agreement was poor between the HMSA and each ELISA tests. Clinical recommendations regarding drug concentrations should be based on assay type used.
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Affiliation(s)
- Christine Verdon
- McGill University Health Centre, McGill University, Montreal, Quebec, Canada
| | - Niels Vande Casteele
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Valérie Heron
- McGill University Health Centre, McGill University, Montreal, Quebec, Canada
| | - Pascale Germain
- McGill University Health Centre, McGill University, Montreal, Quebec, Canada
| | - Waqqas Afif
- McGill University Health Centre, McGill University, Montreal, Quebec, Canada
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36
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Benucci M, Grossi V, Manfredi M, Damiani A, Infantino M, Moscato P, Cinquanta L, Gremese E, Tolusso B, Petricca L, Fedele AL, Alivernini S, Atzeni F, Minisola G, Verna R. Laboratory Monitoring of Biological Therapies in Rheumatology: The Role of Immunogenicity. Ann Lab Med 2020; 40:101-113. [PMID: 31650726 PMCID: PMC6822010 DOI: 10.3343/alm.2020.40.2.101] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 06/09/2019] [Accepted: 10/15/2019] [Indexed: 12/11/2022] Open
Abstract
Biological drugs, such as proteins and immunogens, are increasingly used to treat various diseases, including tumors and autoimmune diseases, and biological molecules have almost completely replaced synthetic drugs in rheumatology. Although biological treatments such as anti-tumor necrosis factor (TNF) drugs seem to be quite safe, they cause some undesirable effects, such as the onset of infections due to weakening of the immune system. Given the biological nature of these drugs, they might be recognized as extraneous; this would induce an immune reaction that neutralizes their effectiveness or lead to more serious consequences. Laboratories play a pivotal role in appropriate therapeutic management. The aim of this review was to underline the production of anti-drug antibodies during treatment with biological drugs and highlight the role of laboratories in ensuring appropriate use of these drugs.
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Affiliation(s)
| | - Valentina Grossi
- Immunology and Allergology Laboratory Unit, S.Giovanni di Dio Hospital, Florence, Italy
| | - Mariangela Manfredi
- Immunology and Allergology Laboratory Unit, S.Giovanni di Dio Hospital, Florence, Italy
| | - Arianna Damiani
- Rheumatology Unit, S.Giovanni di Dio Hospital, Florence, Italy
| | - Maria Infantino
- Immunology and Allergology Laboratory Unit, S.Giovanni di Dio Hospital, Florence, Italy
| | - Paolo Moscato
- Department of Medicine, University Hospital San Giovanni di Dio e Ruggi d'Aragona, Salerno, Italy
| | | | - Elisa Gremese
- Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.,Division of Rheumatology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Barbara Tolusso
- Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy
| | - Luca Petricca
- Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy
| | - Anna Laura Fedele
- Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy
| | - Stefano Alivernini
- Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.,Division of Rheumatology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Fabiola Atzeni
- Rheumatology Unit, University of Messina, Messina, Italy
| | | | - Roberto Verna
- World Association of Societies of Pathology and Laboratory Medicine, Milan, Italy.,Department of Experimental Medicine Sapienza University of Rome, Rome, Italy.
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Development of a competitive binding homogeneous mobility shift assay for the quantification of adalimumab levels in patient serum. J Immunol Methods 2019; 474:112672. [DOI: 10.1016/j.jim.2019.112672] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 08/05/2019] [Accepted: 09/12/2019] [Indexed: 01/20/2023]
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38
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Clarke WT, Papamichael K, Vande Casteele N, Germansky KA, Feuerstein JD, Melmed GY, Siegel CA, Irving PM, Cheifetz AS. Infliximab and Adalimumab Concentrations May Vary Between the Enzyme-Linked Immunosorbent Assay and the Homogeneous Mobility Shift Assay in Patients With Inflammatory Bowel Disease: A Prospective Cross-Sectional Observational Study. Inflamm Bowel Dis 2019; 25:e143-e145. [PMID: 31559417 DOI: 10.1093/ibd/izz202] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
This prospective observational study including consecutive patients with inflammatory bowel disease treated with either infliximab or adalimumab showed that although the correlation between the ELISA and the homogeneous mobility shift assay was good for both drugs, the agreement was poor.
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Affiliation(s)
- William T Clarke
- Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | | | | | | | | | - Gil Y Melmed
- Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Corey A Siegel
- Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Peter M Irving
- Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom
| | - Adam S Cheifetz
- Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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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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40
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Grossi V, Gulli F, Infantino M, Stefanile A, Napodano C, Benucci M, Pocino K, Li Gobbi F, Damiani A, Di Pino A, Manfredi M, Marino M, Basile V, Rapaccini GL, Basile U. The Laboratory Role in anti-TNF Biological Therapy Era. Immunol Invest 2019; 49:317-332. [DOI: 10.1080/08820139.2019.1637434] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Valentina Grossi
- Immunology and Allergology Laboratory Unit, Azienda USL Toscana Centro, S. Giovanni di Dio Hospital, Florence, Italy
| | - Francesca Gulli
- Department of Laboratory Medicine, Madre Giuseppina Vannini Hospital, Rome, Italy
| | - Maria Infantino
- Immunology and Allergology Laboratory Unit, Azienda USL Toscana Centro, S. Giovanni di Dio Hospital, Florence, Italy
| | - Annunziata Stefanile
- Laboratory Diagnostics Area - Fondazione Policlinico Universitario Agostino Gemelli- IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Cecilia Napodano
- Department of Internal Medicine and Gastroenterology - Fondazione Policlinico Universitario Agostino Gemelli- IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Maurizio Benucci
- Rheumatology Unit, Azienda USL Toscana Centro, S. Giovanni di Dio Hospital, Florence, Italy
| | - Krizia Pocino
- Department of Internal Medicine and Gastroenterology - Fondazione Policlinico Universitario Agostino Gemelli- IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francesca Li Gobbi
- Rheumatology Unit, Azienda USL Toscana Centro, S. Giovanni di Dio Hospital, Florence, Italy
| | - Arianna Damiani
- Rheumatology Unit, Azienda USL Toscana Centro, S. Giovanni di Dio Hospital, Florence, Italy
| | - Antonella Di Pino
- Laboratory Diagnostics Area - Fondazione Policlinico Universitario Agostino Gemelli- IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Mariangela Manfredi
- Immunology and Allergology Laboratory Unit, Azienda USL Toscana Centro, S. Giovanni di Dio Hospital, Florence, Italy
| | - Mariapaola Marino
- Istituto di Patologia Generale - Fondazione Policlinico Universitario Agostino Gemelli- IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Valerio Basile
- Department of Experimental Medicine and Surgery, “Tor Vergata” University Hospital, Rome, Italy
| | - Gian Ludovico Rapaccini
- Laboratory Diagnostics Area - Fondazione Policlinico Universitario Agostino Gemelli- IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Umberto Basile
- Istituto di Patologia Generale - Fondazione Policlinico Universitario Agostino Gemelli- IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
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Franca R, Curci D, Lucafò M, Decorti G, Stocco G. Therapeutic drug monitoring to improve outcome of anti-TNF drugs in pediatric inflammatory bowel disease. Expert Opin Drug Metab Toxicol 2019; 15:527-539. [PMID: 31177858 DOI: 10.1080/17425255.2019.1630378] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: Medical treatment of pediatric inflammatory bowel diseases (IBD) has been greatly changed by the introduction of a number of biologic agents that are able to target various players of the immune response. In particular, monoclonal antibodies against the pro-inflammatory cytokine TNF-alpha (TNF) such as infliximab, adalimumab, and golimumab are now in the clinics both in induction and maintenance therapy, and several efforts are currently ongoing to optimize the use of these drugs in children. Areas covered: This review focuses on therapeutic drug monitoring (TDM) of anti-TNF levels and antidrug antibodies (ADAs), in IBD children. A revision of the analytical assays used for assessing anti-TNF plasma levels is also provided. Expert opinion: Although there is a consensus across studies that higher anti-TNF trough levels are associated with a better clinical outcome, and that early anti-TNF serum measurements could be predictive of long-term response, it is still not clear what the best predictive time of sampling is and what the ideal target drug plasma concentration to achieve. Indeed, there are a number of published studies, particularly in pediatric cohorts, limited by the population size analyzed and more prospective large studies are needed to examine the value of these predictive markers.
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Affiliation(s)
- Raffaella Franca
- a University of Trieste, Department of Medical , Surgical and Health Sciences , Trieste , Italy
| | - Debora Curci
- b University of Trieste, PhD Course in Reproductive and Developmental Sciences , Trieste , Italy
| | - Marianna Lucafò
- c Centro di Riferimento Oncologico (CRO) , Aviano , Italy.,d Institute for Maternal and Child Health I.R.C.C.S. Burlo Garofolo , Trieste , Italy
| | - Giuliana Decorti
- a University of Trieste, Department of Medical , Surgical and Health Sciences , Trieste , Italy.,d Institute for Maternal and Child Health I.R.C.C.S. Burlo Garofolo , Trieste , Italy
| | - Gabriele Stocco
- e University of Trieste , Department of Life Sciences , Trieste , Italy
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Nemoz B, Ternant D, Bailly S, Gautier‐Veyret E, Jourdil J, Bonaz B, Stanke‐Labesque F. New steps in infliximab therapeutic drug monitoring in patients with inflammatory bowel diseases. Br J Clin Pharmacol 2019; 85:722-728. [PMID: 30575085 PMCID: PMC6422646 DOI: 10.1111/bcp.13845] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 11/29/2018] [Accepted: 12/09/2018] [Indexed: 12/15/2022] Open
Abstract
AIMS Therapeutic drug monitoring (TDM) of infliximab (IFX) appears to be beneficial for patients with inflammatory bowel disease (IBD). However, the recommended target concentrations depend partly on the method used to quantify IFX. Since we recently developed a liquid chromatography-tandem mass spectrometry method to quantify IFX, we aimed to determine IFX trough concentrations (Cmin) associated with biological remission. METHODS We retrospectively measured IFX Cmin in sera from 55 patients with IBD, on IFX maintenance therapy, and for whom demographic, biological and clinical data were collected from medical records. A threshold of IFX Cmin associated with biological remission (defined by C-reactive protein < 5 mg l-1 and faecal calprotectin <150 μg g-1 ) was determined using receiver operating characteristics analysis. RESULTS IFX Cmin ranged from <1 mg l-1 to 57.2 mg l-1 . IFX Cmin were higher (P = 0.038) in patients with biological remission and a cut-off of IFX Cmin set to 6.2 mg l-1 was associated with biological remission (sensitivity = 0.75, 95% confidence interval 0.58-0.75; specificity = 0.61, 95% confidence interval 0.39-0.83). CONCLUSION Liquid chromatography-tandem mass spectrometry measurement of IFX Cmin and the determination of a new threshold of IFX Cmin associated with biological remission are new steps towards IFX treatment personalization in patients with IBD.
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Affiliation(s)
- Benjamin Nemoz
- Laboratory of Pharmacology, Toxicology and PharmacogeneticsGrenoble‐Alpes University HospitalGrenobleFrance
| | - David Ternant
- Laboratory of Pharmacology‐ToxicologyCHRU de Tours University HospitalFrance
| | - Sébastien Bailly
- INSERM U1042, HP2GrenobleFrance
- EFCR Laboratory, Pole Thorax et VaisseauxGrenoble Alpes University HospitalGrenobleFrance
| | - Elodie Gautier‐Veyret
- Laboratory of Pharmacology, Toxicology and PharmacogeneticsGrenoble‐Alpes University HospitalGrenobleFrance
- INSERM U1042, HP2GrenobleFrance
- Univ. Grenoble AlpesGrenobleFrance
| | - Jean‐François Jourdil
- Laboratory of Pharmacology, Toxicology and PharmacogeneticsGrenoble‐Alpes University HospitalGrenobleFrance
| | - Bruno Bonaz
- Division of Hepato‐GastroenterologyUniversity Hospital Grenoble‐AlpesFrance
| | - Françoise Stanke‐Labesque
- Laboratory of Pharmacology, Toxicology and PharmacogeneticsGrenoble‐Alpes University HospitalGrenobleFrance
- INSERM U1042, HP2GrenobleFrance
- Univ. Grenoble AlpesGrenobleFrance
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43
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Advances in Therapeutic Drug Monitoring for Small-Molecule and Biologic Therapies in Inflammatory Bowel Disease. ACTA ACUST UNITED AC 2019; 17:127-145. [PMID: 30680599 DOI: 10.1007/s11938-019-00222-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW Therapeutic drug monitoring (TDM) is increasingly utilized as a strategy to optimize inflammatory bowel disease (IBD) therapeutics. As management paradigms have evolved towards treat-to-target strategies, there has been growing interest in expanding the role of TDM to guide drug optimization for achieving objective endpoints. This review summarizes the evidence for using TDM with biologic and oral small-molecule therapies, evaluates the role of reactive versus proactive TDM in treatment algorithms, and identifies potential future applications for TDM. RECENT FINDINGS Achieving therapeutic drug concentrations has been associated with important clinical, endoscopic, and histologic outcomes in IBD. However, the optimal drug concentration varies by therapeutic agent, disease phenotype, inflammatory burden, phase of treatment, and target outcome. Traditionally, TDM has been used reactively to define pharmacokinetic versus mechanistic failures after loss of response to a tumor necrosis factor-α (TNF) antagonist and while observational data suggests a benefit to proactive TDM, this has not been definitively confirmed in prospective randomized controlled trials. The role of TDM in optimizing vedolizumab, ustekinumab, and tofacitinib remains unclear, given differences in pharmacokinetics and immunogenicity compared to TNF antagonists. Measuring drug action at the site of inflamed tissue may provide additional insights into treatment optimization. The use of TDM offers the possibility of a more personalized treatment approach for patients with IBD. High-quality studies are needed to delineate the role of proactive TDM for maintaining remission, for optimizing induction regimens, and for novel agents.
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Iwamoto N, Yokoyama K, Takanashi M, Yonezawa A, Matsubara K, Shimada T. Verification between Original and Biosimilar Therapeutic Antibody Infliximab Using nSMOL Coupled LC-MS Bioanalysis in Human Serum. Curr Pharm Biotechnol 2018; 19:495-505. [PMID: 29968534 PMCID: PMC6198460 DOI: 10.2174/1389201019666180703093517] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 05/29/2018] [Accepted: 07/02/2018] [Indexed: 12/14/2022]
Abstract
Background: Infliximab (IFX) is a chimeric therapeutic monoclonal antibody targeting tumor necrosis factor alpha (TNFα)-mediated inflammatory immune diseases. However, despite of an initial good clinical response, decrease in response to long-term treatment is a common observation. Objective: Recent studies suggest that IFX level in circulation has a correlation with clinical bioavailabil-ity. Therefore, the management of IFX dosage for individual manifestation by IFX monitoring may be valuable for the improvement of therapeutic response and outcomes. Method: In order to develop a broad IFX therapeutic monitoring in human serum, we have developed the validated IFX bioanalysis for RemicadeTM and its biosimilar product using our nano-surface and molecu-lar-orientation limited proteolysis (nSMOL) technology coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The nSMOL chemistry has a unique property of Fab-selective prote-olysis, and makes it possible a global bioanalysis for many monoclonal antibodies. Results: The quantitation range of IFX in serum was from 0.293 to 300 μg/ml with good linearity. Quan-titation verification at the concentrations of 0.293, 0.879, 14.1 and 240 μg/ml was within 1.56-7.53% of precision and 98.9-111% of accuracy using H-chain signature peptide SINSATHYAESVK. Moreover, cross-verified bioanalysis of Remicade quantitation using biosimilar standard, and its opposite combina-tion, obtained an identical and inter-comparative results. Conclusion: The nSMOL strategy has the potential as a practical therapeutic monitoring technology in IFX therapeutic applications.
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Affiliation(s)
- Noriko Iwamoto
- Leading Technology of Bioanalysis and Protein Chemistry, Shimadzu Corporation, Kyoto, Japan
| | - Kotoko Yokoyama
- Leading Technology of Bioanalysis and Protein Chemistry, Shimadzu Corporation, Kyoto, Japan
| | - Megumi Takanashi
- Leading Technology of Bioanalysis and Protein Chemistry, Shimadzu Corporation, Kyoto, Japan
| | - Atsushi Yonezawa
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan.,Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Kazuo Matsubara
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan
| | - Takashi Shimada
- Leading Technology of Bioanalysis and Protein Chemistry, Shimadzu Corporation, Kyoto, Japan
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Discrimination of Anti-drug Antibodies With Neutralizing Capacity in Infliximab- and Adalimumab-Treated Patients: Comparison of the Homogeneous Mobility Shift Assay and the Affinity Capture and Elution Assay. Ther Drug Monit 2018; 40:705-715. [DOI: 10.1097/ftd.0000000000000553] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Samaan MA, Arkir Z, Ahmad T, Irving PM. Wide variation in the use and understanding of therapeutic drug monitoring for anti-TNF agents in inflammatory bowel disease: an inexact science? Expert Opin Biol Ther 2018; 18:1271-1279. [PMID: 30339466 DOI: 10.1080/14712598.2018.1537367] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND We aimed to understand the way in which therapeutic drug monitoring (TDM) is used, understood and interpreted for anti-TNF agents in IBD. RESEARCH DESIGN AND METHODS We designed an 18-question survey that included 5 TDM-based clinical scenarios, for which the 'most appropriate' responses were based on the BRIDGe groups 'Anti-TNF Optimizer'. This resource combines TDM evidence with expert consensus. RESULTS We received 110 complete responses: 50 (45%) consultants, 30 (27%) trainees, 25 (23%) IBD nurse specialists and 5 (5%) gastroenterology pharmacists. Over half (61, 55%) only carry out TDM in non-response. The remainder use TDM routinely, including during stable maintenance therapy for patients in remission. Lower therapeutic thresholds used were variable. Most (82, 75%) were unsure whether their laboratory uses a drug-tolerant or drug-sensitive antidrug antibody assay and few (15, 14%) understand the difference. Consultants, high-frequency users (> 3requests/month) and clinicians with larger anti-TNF cohorts (> 100) were significantly more likely to select the 'most appropriate' answer to at least 1 of the 5 TDM-based clinical scenarios. CONCLUSIONS There exists marked heterogeneity in the practical use, understanding and interpretation of biologic TDM. Biologic decision-making, informed by TDM, should involve consultation with experienced clinicians who are frequent TDM users, ideally, as part of a multidisciplinary, biologics-focused IBD meeting. ABBREVIATIONS TDM: therapeutic drug monitoring; CNS: clinical nurse specialist; ELISA: enzyme-linked immunosorbent assay; RIA: radioimmunoassays; HMSA: homogenous mobility shift assays; BSG: British Society of Gastroenterology.
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Affiliation(s)
- Mark A Samaan
- a Guy's & St. Thomas' NHS Foundation Trust , IBD Centre , London , UK
| | - Zehra Arkir
- b Viapath, Reference Chemistry Laboratory, St Thomas' Hospital , London , UK
| | - Tariq Ahmad
- c Royal Devon & Exeter NHS Foundation Trust , IBD and Pharmacogenetics Research Group , Exeter , UK
| | - Peter M Irving
- a Guy's & St. Thomas' NHS Foundation Trust , IBD Centre , London , UK
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Papamichael K, Rakowsky S, Rivera C, Cheifetz AS, Osterman MT. Association Between Serum Infliximab Trough Concentrations During Maintenance Therapy and Biochemical, Endoscopic, and Histologic Remission in Crohn's Disease. Inflamm Bowel Dis 2018; 24:2266-2271. [PMID: 29718327 PMCID: PMC7190934 DOI: 10.1093/ibd/izy132] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIM Objective and more rigorous therapeutic outcomes are emerging as novel targets in Crohn's disease (CD). We investigated the association between maintenance serum infliximab trough concentrations and biochemical, endoscopic, or histologic remission in CD. METHODS This retrospective multicenter study involved consecutive CD patients treated with infliximab who had a serum C-reactive protein (CRP) measured within 1 week or endoscopic evaluation within 12 weeks of therapeutic drug monitoring between January 2010 and June 2016. Biochemical remission was defined as a normal CRP (≤5 mg/L). Endoscopic remission was defined as absence of any mucosal break (ulceration or erosion) or for patients with an ileocolonic resection, a Rutgeerts score of ≤i1. Histologic remission was defined as absence of active inflammation. RESULTS Seventy-one CRP levels and 96 colonoscopies from 110 CD patients were evaluated. Based on ROC analyses, infliximab concentration thresholds of 2.2, 9.7, and 9.8 μg/mL were found to be related with biochemical, endoscopic, and histologic remission, respectively. Multiple logistic regression analyses identified infliximab concentration ≥2.2 (OR 6.4; 95% CI, 1.5-27.1; P = 0.011), ≥9.7 (OR 3.6; 95% CI, 1.4-9; P = 0.006) and ≥9.8 μg/mL (OR 3.2; 95% CI, 1.3-7.9; P = 0.011) as variables independently associated with biochemical, endoscopic, and histologic remission, respectively. CONCLUSIONS This study showed that higher maintenance infliximab trough concentrations are associated with more favorable rates of biochemical, endoscopic, or histologic remission in CD patients and that infliximab concentrations may differ based on the treatment goal.
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Affiliation(s)
- Konstantinos Papamichael
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA,Address correspondence to: Konstantinos Papamichail, MD, PhD, FEBGH, Harvard Medical School, Beth Israel Deaconess Medical Center, Center for Inflammatory Bowel Diseases, Division of Gastroenterology, 330 Brookline Ave, Boston, MA 02215. E-mail:
| | - Shana Rakowsky
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Claudio Rivera
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Adam S Cheifetz
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Mark T Osterman
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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48
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Simultaneous Quantification of Adalimumab and Infliximab in Human Plasma by Liquid Chromatography–Tandem Mass Spectrometry. Ther Drug Monit 2018; 40:417-424. [DOI: 10.1097/ftd.0000000000000514] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
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49
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Clinically important neutralizing anti-drug antibodies detected with an in-house competitive ELISA. Clin Rheumatol 2018; 38:361-370. [DOI: 10.1007/s10067-018-4213-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 07/09/2018] [Indexed: 12/14/2022]
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50
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Pérez I, Fernández L, Sánchez-Ramón S, Alba C, Zatarain A, Cañas M, López ON, Olivares D, Rey E, Taxonera C. Reliability evaluation of four different assays for therapeutic drug monitoring of infliximab levels. Therap Adv Gastroenterol 2018; 11:1756284818783613. [PMID: 30034528 PMCID: PMC6048662 DOI: 10.1177/1756284818783613] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 05/24/2018] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The aim of this study was to evaluate reliability of four different assays for measuring infliximab trough levels and antibodies to infliximab (ATI). METHODS In this non-interventional, cross-sectional study including IBD patients, infliximab levels and ATI were measured using four different assays: Lisa-Tracker, Promonitor, Q-Inflixi and Sanquin. Reliability and agreement for infliximab levels was assessed using the intraclass correlation coefficient (ICC) and Bland-Altman plots. Qualitative agreement for infliximab (based on a pre-established target window of trough levels between 3 µg/ml and 7 µg/ml) and for ATI were estimated by Cohen's kappa. RESULTS Serum samples of 84 IBD patients were evaluated for infliximab using the four assays. Reliability was 'substantial' between Lisa-Tracker versus Promonitor and 'almost perfect' between the remaining assay pairs, with ICCs [95% confidence interval (CI)] ranging from 0.93 (0.70-0.97) for Lisa-Tracker versus Promonitor to 0.97 (0.95-0.98) for Q-Inflixi versus Sanquin. Bland-Altman plots showed significant bias between assays except Promonitor versus Q-Inflixi, which had excellent agreement. The greatest differences in mean infliximab were found between Promonitor versus Lisa-Tracker (-0.91 µg/ml) and Lisa-Tracker versus Q-Inflixi (0.69 µg/ml). Qualitative agreement for infliximab was 'almost perfect' for Promonitor versus Q-Inflixi (kappa 0.84) and Q-Inflixi versus Sanquin (kappa 0.81), and 'substantial' for the remaining pairs. More than 10% of patients who had infliximab levels within the target interval by Lisa-Tracker had suboptimal concentrations (<3 µg/ml) with Promonitor and Q-Inflixi. Furthermore, 11% of patients within the target interval by Q-Inflixi had supra-optimal levels (>7 µg/ml) by Lisa-Tracker. In the remaining paired comparisons, fewer than 5% of patients were placed in different subgroups. Qualitative agreement for ATI fluctuated between 'moderate' and 'almost perfect'. CONCLUSIONS All four assays seem suitable for therapeutic drug monitoring of infliximab. Promonitor and Q-Inflixi had the best agreement, making those assays fully interchangeable. Systematic biases between Lisa-Tracker with Promonitor and Q-Inflixi suggest that these assays should not be interchanged during the follow up of an individual patient.
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Affiliation(s)
- Irene Pérez
- Inflammatory Bowel Disease Unit, Department of
Gastroenterology, Hospital Clínico San Carlos, Madrid, Spain,Department of Gastroenterology, Hospital La Paz,
Madrid, Spain
| | - Lidia Fernández
- Department of Clinical Immunology, Hospital
Clínico San Carlos, Madrid, Spain,Instituto de Investigación del Hospital Clínico
San Carlos (IdISSC), Madrid, Spain
| | - Silvia Sánchez-Ramón
- Department of Clinical Immunology, Hospital
Clínico San Carlos, Madrid, Spain,Instituto de Investigación del Hospital Clínico
San Carlos (IdISSC), Madrid, Spain
| | - Cristina Alba
- Inflammatory Bowel Disease Unit, Department of
Gastroenterology, Hospital Clínico San Carlos, Madrid, Spain
| | - Ana Zatarain
- Inflammatory Bowel Disease Unit, Department of
Gastroenterology, Hospital Clínico San Carlos, Madrid, Spain
| | - Mercedes Cañas
- Inflammatory Bowel Disease Unit, Department of
Gastroenterology, Hospital Clínico San Carlos, Madrid, Spain
| | - Olga N. López
- Inflammatory Bowel Disease Unit, Department of
Gastroenterology, Hospital Clínico San Carlos, Madrid, Spain
| | - David Olivares
- Inflammatory Bowel Disease Unit, Department of
Gastroenterology, Hospital Clínico San Carlos, Madrid, Spain,Instituto de Investigación del Hospital Clínico
San Carlos (IdISSC), Madrid, Spain
| | - Enrique Rey
- Inflammatory Bowel Disease Unit, Department of
Gastroenterology, Hospital Clínico San Carlos, Madrid, Spain,Instituto de Investigación del Hospital Clínico
San Carlos (IdISSC), Madrid, Spain
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