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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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Rodríguez-Moranta F, Argüelles-Arias F, Hinojosa Del Val J, Iborra Colomino M, Martín-Arranz MD, Menchén Viso L, Muñoz Núñez F, Ricart Gómez E, Sánchez-Hernández JG, Valdés-Delgado T, Guardiola Capón J, Barreiro-de Acosta M, Mañosa Ciria M, Zabana Abdo Y, Gutiérrez Casbas A. Therapeutic drug monitoring in inflammatory bowel diseases. Position statement of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis. GASTROENTEROLOGIA Y HEPATOLOGIA 2024; 47:522-552. [PMID: 38311005 DOI: 10.1016/j.gastrohep.2024.01.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 12/31/2023] [Accepted: 01/18/2024] [Indexed: 02/06/2024]
Abstract
The treatment of inflammatory bowel disease has undergone a significant transformation following the introduction of biologic drugs. Thanks to these drugs, treatment goals have evolved from clinical response and remission to more ambitious objectives, such as endoscopic or radiologic remission. However, even though biologics are highly effective, a significant percentage of patients will not achieve an initial response or may lose it over time. We know that there is a direct relationship between the trough concentrations of the biologic and its therapeutic efficacy, with more demanding therapeutic goals requiring higher drug levels, and inadequate exposure being common. Therapeutic drug monitoring of biologic medications, along with pharmacokinetic models, provides us with the possibility of offering a personalized approach to treatment for patients with IBD. Over the past few years, relevant information has accumulated regarding its utility during or after induction, as well as in the maintenance of biologic treatment, in reactive or proactive strategies, and prior to withdrawal or treatment de-escalation. The aim of this document is to establish recommendations regarding the utility of therapeutic drug monitoring of biologics in patients with inflammatory bowel disease, in different clinical practice scenarios, and to identify areas where its utility is evident, promising, or controversial.
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Affiliation(s)
- Francisco Rodríguez-Moranta
- Servicio de Aparato Digestivo, Hospital Universitario de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, Barcelona, España.
| | - Federico Argüelles-Arias
- Servicio de Aparato Digestivo, Hospital Universitario Virgen Macarena, Sevilla, España; Facultad de Medicina, Universidad de Sevilla, Sevilla, España
| | | | - Marisa Iborra Colomino
- Servicio de Aparato Digestivo, Hospital Universitario y Politécnico de La Fe, Valencia, España
| | - M Dolores Martín-Arranz
- Servicio de Aparato Digestivo, Hospital Universitario La Paz, Facultad de Medicina de la UAM, Fundación para la investigación del Hospital Universitario la Paz (IDIPAZ), Madrid, España
| | - Luis Menchén Viso
- Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón-IiSGM, Madrid, España; Departamento de Medicina, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, España
| | - Fernando Muñoz Núñez
- Servicio de Aparato Digestivo, Hospital Universitario de Salamanca, Salamanca, España
| | - Elena Ricart Gómez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), H. Clínic Barcelona, Barcelona, IDIBAPS, Barcelona, España
| | | | - Teresa Valdés-Delgado
- Servicio de Aparato Digestivo, Hospital Universitario Virgen Macarena, Sevilla, España
| | - Jordi Guardiola Capón
- Servicio de Gastroenterología, Hospital Universitario de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, Barcelona, España
| | - Manuel Barreiro-de Acosta
- Servicio de Gastroenterología, Hospital Clínico Universitario de Santiago, A Coruña, España; Fundación Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), A Coruña, España
| | - Míriam Mañosa Ciria
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, España; Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Gastroenterología, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, España
| | - Yamile Zabana Abdo
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, España; Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Gastroenterología, Hospital Mútua de Terrassa (HMT), Terrassa, Barcelona, España
| | - Ana Gutiérrez Casbas
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, España; Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, España
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3
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Anjie SI, Hanzel J, Gecse KB, D'Haens GR, Brandse JF. Anti-drug antibodies against anti-TNF in patients with inflammatory bowel disease: an evaluation of possible strategies. Scand J Gastroenterol 2024; 59:169-175. [PMID: 37961895 DOI: 10.1080/00365521.2023.2278424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 10/25/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023]
Abstract
OBJECTIVE Immunogenicity against anti-TNF antibodies usually leads to loss of response. We aimed to evaluate the efficacy of clinical strategies to improve clinical remission and pharmacokinetics upon detection of anti-drug antibodies (ADA). METHODS Inflammatory bowel disease (IBD) patients with ADA against infliximab or adalimumab were identified through a single centre database search covering 2004-2022. Criteria for successful intervention upon ADA detection (baseline) were clinical remission after 1 year without further change in strategy. RESULTS Two-hundred-and-fifty-five IBD patients (206 Crohn's disease) were identified. At baseline, median ADA level was 77 AU/ml; 50.2% of patients were in clinical remission. Implemented strategies were: (1) 81/255 (32%) conservative management, (2) 102/255 (40%) anti-TNF optimisation, (3) 72/255 (28%) switch within or out of class. Switching was the most successful strategy for clinical remission (from 19% at baseline to 69% at 1 year, p < 0.001). Patients that continued the same dose anti-TNF or discontinued biological therapy were often in clinical remission, but deteriorated significantly (-22.7%, p = 0.004). Anti-TNF dose intensification with immunomodulator optimisation was the fastest (median 3.0 months, p = 0.009) and most effective (65% ADA suppression, p < 0.001) strategy to suppress ADA compared to solely anti-TNF or immunomodulator optimisation. CONCLUSIONS Switching therapy, within or out of class, is the most successful strategy to regain and maintain clinical remission upon immunogenicity. When switching to another anti-TNF, concomitant immunomodulatory therapy should be started or continued to prevent repeated immunogenic loss of response. Anti-TNF dose escalation with concomitant immunomodulator optimisation is the fastest and most effective strategy to suppress ADA.
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Affiliation(s)
- Suzanne I Anjie
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | - Jurij Hanzel
- Department of Gastroenterology and Hepatology, Ljubljana University Medical Centre, Ljubljana, Slovenia
| | - Krisztina B Gecse
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | - Geert R D'Haens
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | - Johannan F Brandse
- Department of Gastroenterology and Hepatology, Rijnstate, Arnhem, The Netherlands
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Na SY, Choi CH, Song EM, Bang KB, Park SH, Kim ES, Park JJ, Keum B, Lee CK, Lee BI, Ryoo SB, Koh SJ, Choi M, Kim JS, on behalf of the IBD Research Group of the Korean Association for the Study of Intestinal Diseases. Korean clinical practice guidelines on biologics and small molecules for moderate-to-severe ulcerative colitis. Intest Res 2023; 21:61-87. [PMID: 35645321 PMCID: PMC9911265 DOI: 10.5217/ir.2022.00007] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 03/07/2022] [Indexed: 02/09/2023] Open
Abstract
Ulcerative colitis (UC), a relapsing-remitting chronic inflammatory bowel disease (IBD), has a variable natural course but potentially severe disease course. Since the development of anti-tumor necrosis factor (TNF) agents has changed the natural disease course of moderate-to-severe UC, therapeutic options for patients who failed conventional treatments are expanding rapidly. IBD clinical trials have demonstrated the potential efficacy and safety of novel biologics such as anti-integrin α4β7 and anti-interleukin-12/23 monoclonal antibodies and small molecules such as a Janus kinase inhibitor. Anti-TNF biosimilars also have been approved and are widely used in IBD patients. Wise drug choices should be made considering evidence-based efficacy and safety. However, the best position of these drugs remains several questions, with limited data from direct comparative trials. In addition, there are still concerns to be elucidated on the effect of therapeutic drug monitoring and combination therapy with immunomodulators. The appropriate treatment regimens in acute severe UC and the risk of perioperative use of biologics are unclear. As novel biologics and small molecules have been approved in Korea, we present the Korean guidelines for medical management of adult outpatients with moderate-to-severe UC and adult hospitalized patients with acute severe UC, focusing on biologics and small molecules.
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Affiliation(s)
- Soo-Young Na
- Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea
| | - Chang Hwan Choi
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea,Correspondence to Chang Hwan Choi, Department of Internal Medicine, Chung-Ang University College of Medicine, 102 Heukseok-ro, Dongjak-gu, Seoul 06973, Korea. Tel: +82-2-6299-1418, Fax: +82-2-6299-2064, E-mail:
| | - Eun Mi Song
- Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea
| | - Ki Bae Bang
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea
| | - Sang Hyoung Park
- Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Eun Soo Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Jae Jun Park
- Department of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Bora Keum
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Chang Kyun Lee
- Department of Gastroenterology, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Bo-In Lee
- Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung-Bum Ryoo
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Seong-Joon Koh
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Miyoung Choi
- National Evidence-based Healthcare Collaborating Agency, Seoul, Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Qu JH, Ordutowski H, Van Tricht C, Verbruggen R, Barcenas Gallardo A, Bulcaen M, Ciwinska M, Gutierrez Cisneros C, Devriese C, Guluzade S, Janssens X, Kornblum S, Lu Y, Marolt N, Nanjappan C, Rutten E, Vanhauwaert E, Geukens N, Thomas D, Dal Dosso F, Safdar S, Spasic D, Lammertyn J. Point-of-care therapeutic drug monitoring of adalimumab by integrating a FO-SPR biosensor in a self-powered microfluidic cartridge. Biosens Bioelectron 2022; 206:114125. [DOI: 10.1016/j.bios.2022.114125] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 01/31/2022] [Accepted: 02/20/2022] [Indexed: 12/11/2022]
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Xie Y, Liu Y. Would previous use of TNF inhibitors affect the therapeutic effect of IL-17 or IL-12/23 inhibitors on psoriasis and psoriatic arthritis: results from a systematic review. Clin Exp Dermatol 2022; 47:1627-1635. [PMID: 35466472 DOI: 10.1111/ced.15237] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/19/2022] [Indexed: 02/05/2023]
Abstract
OBJECTIVES To investigate the therapeutic effect of interleukin (IL)-17 and IL-12/23 inhibitors in Psoriatic arthritis (PsA) or psoriasis patients who were intolerant or responded inadequately to tumor necrosis factor (TNF) inhibitors (TNFi-experienced). METHODS A systematic review of randomized controlled trials searched from the Pubmed, Cochrane Library, and Embase was conducted on May 17, 2021. Psoriasis Area and Severity Index (PASI) responses (PASI75/90), the American College of Rheumatology (ACR) response criteria (ACR20/50/70), and full resolution of dactylitis/enthesitis were used to assess the treatment efficiency. RESULTS A total of 7 studies with 3398 PsA patients were included, 1330 of whom were intolerant or responded inadequately to TNFi. All studies were categorized as low risk of bias. For IL-17A inhibitors, significant higher achievements in all of the endpoints were observed when comparing with placebo. However, the proportions of patients achieving these endpoints were lower in TNFi-experienced patients when compared with that in TNFi-naïve patients. However, the differences between TNFi-naïve and TNFi-experienced patients were only significant for ACR responses and full resolution of enthesitis. As for IL-12/23 inhibitors, only results of ACR20 response were reported. And significantly more TNFi-experienced patients achieved ACR 20 response when compared to that receiving placebo. The differences in treatment efficacy between TNFi-experienced patients and TFNi-naïve patients was not significant. CONCLUSIONS IL-17A and IL-12/23 inhibitors were still efficient for PsA or psoriasis patients who were TNFi-failed or intolerant. However, the efficacy was lower than that in TNFi-naïve patients. And more studies are warranted to elucidate relevant problems.
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Affiliation(s)
- Yan Xie
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Liu
- Tsinghua Clinical Research Institute (TCRI), School of Medicine, Tsinghua University, Beijing, China
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7
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Trotta MC, Alfano R, Cuomo G, Romano C, Gravina AG, Romano M, Galdiero M, Montemurro MV, Giordano A, D'Amico M. Comparison of Timing to Develop Anti-Drug Antibodies to Infliximab and Adalimumab Between Adult and Pediatric Age Groups, Males and Females. J Pediatr Pharmacol Ther 2021; 27:63-71. [PMID: 35002561 PMCID: PMC8717619 DOI: 10.5863/1551-6776-27.1.63] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 06/05/2021] [Indexed: 01/15/2023]
Abstract
OBJECTIVE To compare the timing of serum anti-drug antibodies in adult and pediatric age groups, males and females, treated for inflammatory bowel disease or arthritis with adalimumab or infliximab by retrospectively combining data collected during a 2-year therapeutic drug monitoring period. METHODS Four hundred thirty sera were divided in groups collected at 0, 3, 6, 12, and 24 months (T0, T3, T6, T12, and T24) after initiation of therapy and assayed for drug and relative anti-drug antibodies levels. At each time point, the percentage of sera presenting anti-drug antibodies, as well as the drug concentrations, were calculated and correlated with patient age and sex. RESULTS Anti-drug antibodies were present in 31.5% of sera and were significantly higher in the pediatric age group than in the adult age group, through all time points. The percentages of sera showing anti-drug antibodies were significantly different as early as 3 months and were sera from pediatric female group. The percentages of sera showing anti-drug antibodies reached the highest value at 6 months in the pediatric age group and at 12 months in the adult age group. CONCLUSIONS Sera from pediatric had an earlier presence of anti-drug antibodies than adults. In particular, pediatric females sera showed the fastest anti-drug antibodies development.
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Affiliation(s)
- Maria Consiglia Trotta
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli” (MCT, MG) Naples, Italy
| | - Roberto Alfano
- Department of Advanced Medical and Surgical Sciences “DAMSS”, University of Campania “Luigi Vanvitelli” (RA, CR), Naples, Italy
| | - Giovanna Cuomo
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli” (GC, MR, AGG), Naples, Italy
| | - Ciro Romano
- Department of Advanced Medical and Surgical Sciences “DAMSS”, University of Campania “Luigi Vanvitelli” (RA, CR), Naples, Italy
| | - Antonietta Gerarda Gravina
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli” (GC, MR, AGG), Naples, Italy
| | - Marco Romano
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli” (GC, MR, AGG), Naples, Italy
| | - Marilena Galdiero
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli” (MCT, MG) Naples, Italy
| | | | - Antonio Giordano
- General Directorate, University Polyclinic “Luigi Vanvitelli” (AG), Naples, Italy
| | - Michele D'Amico
- Therapeutic Monitoring Unit for Biological Drugs, University “Luigi Vanvitelli” (MDA), Naples, Italy
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8
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Albader F, Golovics PA, Gonczi L, Bessissow T, Afif W, Lakatos PL. Therapeutic drug monitoring in inflammatory bowel disease: The dawn of reactive monitoring. World J Gastroenterol 2021; 27:6231-6247. [PMID: 34712029 PMCID: PMC8515794 DOI: 10.3748/wjg.v27.i37.6231] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/08/2021] [Accepted: 08/31/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic condition that significantly affects the quality of life of its patients. Biologic drugs have been the mainstay treatment in the management of IBD patients but despite their significant contribution, there remains a proportion of patients that do not respond or lose response to treatment. Therapeutic drug monitoring (TDM) involves measuring levels of serum drug concentrations and anti-drug antibodies. TDM of biologic drugs initially emerged to understand treatment failure in other immune mediated inflammatory diseases. This was then introduced in IBD to rationalize primary non-response or secondary loss of response, given that low serum drug concentrations or the formation of anti-drug antibodies are variably associated with treatment failure. The aim of this narrative review is to provide an overview regarding the current use of TDM in clinical practice and to present the evidence available regarding its use in both proactive and reactive clinical settings in preventing and managing treatment failure. This review also presents the existing evidence regarding the association of various clinical outcomes with specific thresholds of drug concentrations, in everyday practice. A narrative review of published articles and conference abstracts regarding the use of TDM in IBD management, through an electronic search using PubMed and ScienceDirect. TDM has proven to be superior and more cost effective in guiding management of patients with treatment failure compared to empiric dose escalation or change in treatment. Despite a trend towards an association between clinical outcomes and drug concentrations, proactive TDM based strategies have not been shown to achieve clear benefit in long-term outcomes. In the clinical setting, TDM has proven to be useful in managing IBD patients, and its use in the reactive setting, as an additional tool to help manage patients with treatment failure, is being promoted as newer guidelines and consensus groups implement TDM as part of the management plan.
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Affiliation(s)
- Farah Albader
- Department of Internal Medicine, McGill University, Montreal H3G1A4, Quebec, Canada
| | - Petra Anna Golovics
- Division of Gastroenterology, Hungarian Defence Forces, Medical Centre, Budapest H-1062, Hungary
- Division of Gastroenterology, McGill University, Montreal H3G 1A4, Quebec, Canada
| | - Lorant Gonczi
- First Department of Medicine, Semmelweis University, Budapest H-1083, Hungary
| | - Talat Bessissow
- Division of Gastroenterology, McGill University Health Centre, Montreal H3G 1A4, Quebec, Canada
| | - Waqqas Afif
- Division of Gastroenterology, McGill University, Montreal H3G 1A4, Quebec, Canada
| | - Peter Laszlo Lakatos
- Division of Gastroenterology, McGill University, Montreal H3G 1A4, Quebec, Canada
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9
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Abidin AZ, Snoswell CL, Shafiee Hanjani L, Callaghan G, Edmonds M. Infliximab switching from reference product to biosimilar: a review of evidence regarding the clinical efficacy, safety profile and immunogenicity. JOURNAL OF PHARMACY PRACTICE AND RESEARCH 2021. [DOI: 10.1002/jppr.1754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Ahmad Zainal Abidin
- Centre for Health Services Research The University of Queensland Brisbane Qld Australia
| | - Centaine L. Snoswell
- Centre for Health Services Research The University of Queensland Brisbane Qld Australia
- Pharmacy Department Princess Alexandra Hospital Brisbane Qld Australia
- School of Pharmacy The University of Queensland Brisbane Qld Australia
| | - Leila Shafiee Hanjani
- Centre for Health Services Research The University of Queensland Brisbane Qld Australia
| | - Gavin Callaghan
- Pharmacy Department Princess Alexandra Hospital Brisbane Qld Australia
| | - Michelle Edmonds
- Pharmacy Department Princess Alexandra Hospital Brisbane Qld Australia
- Pharmacy Department Royal Darwin Hospital Darwin NT Australia
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10
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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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11
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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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12
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Linares R, Francés R, Gutiérrez A, Juanola O. Bacterial Translocation as Inflammatory Driver in Crohn's Disease. Front Cell Dev Biol 2021; 9:703310. [PMID: 34557484 PMCID: PMC8452966 DOI: 10.3389/fcell.2021.703310] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/30/2021] [Indexed: 12/26/2022] Open
Abstract
Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract responsible for intestinal lesions. The multifactorial etiology attributed to CD includes a combination of environmental and host susceptibility factors, which result in an impaired host–microbe gut interaction. Bacterial overgrowth and dysbiosis, increased intestinal barrier permeability, and altered inflammatory responses in patients with CD have been described in the past. Those events explain the pathogenesis of luminal translocation of bacteria or its products into the blood, a frequent event in CD, which, in turn, favors a sustained inflammatory response in these patients. In this review, we navigate through the interaction between bacterial antigen translocation, permeability of the intestinal barrier, immunologic response of the host, and genetic predisposition as a combined effect on the inflammatory response observed in CD. Several lines of evidence support that translocation of bacterial products leads to uncontrolled inflammation in CD patients, and as a matter of fact, the presence of gut bacterial genomic fragments at a systemic level constitutes a marker for increased risk of relapse among CD patients. Also, the significant percentage of CD patients who lose response to biologic therapies may be influenced by the translocation of bacterial products, which are well-known drivers of proinflammatory cytokine production by host immune cells. Further mechanistic studies evaluating cellular and humoral immune responses, gut microbiota alterations, and genetic predisposition will help clinicians to better control and personalize the management of CD patients in the future.
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Affiliation(s)
- Raquel Linares
- Hepatic and Intestinal Immunobiology Group, Department of Clinical Medicine, Miguel Hernández University, San Juan de Alicante, Spain
| | - Rubén Francés
- Hepatic and Intestinal Immunobiology Group, Department of Clinical Medicine, Miguel Hernández University, San Juan de Alicante, Spain.,CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.,Instituto ISABIAL, Hospital General Universitario de Alicante, Alicante, Spain
| | - Ana Gutiérrez
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.,Instituto ISABIAL, Hospital General Universitario de Alicante, Alicante, Spain.,Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Alicante, Spain
| | - Oriol Juanola
- Translational Research Laboratory, Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, Lugano, Switzerland.,Faculty of Biomedical Sciences, Universitá della Svizzera Italiana, Lugano, Switzerland
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13
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Mc Gettigan N, Afridi AS, Harkin G, Lardner C, Patchett S, Cheriyan D, Harewood G, Boland K, O'Toole A. The optimal management of anti-drug antibodies to infliximab and identification of anti-drug antibody values for clinical outcomes in patients with inflammatory bowel disease. Int J Colorectal Dis 2021; 36:1231-1241. [PMID: 33515082 DOI: 10.1007/s00384-021-03855-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/21/2021] [Indexed: 02/04/2023]
Abstract
PURPOSE Secondary loss of response (LOR) to infliximab (IFX) commonly occurs. One cause is the development of anti-drug antibodies (ADAs). Evidence regarding the optimal management of ADAs is lacking. We aim to identify the best practice of management of ADAs to IFX to avoid discontinuation of therapy and to determine specific ADA cut-off values to determine pre-specified clinical outcomes. METHODS This is a 3-year study of patients receiving IFX who developed ADAs > 8μg/ml. We reviewed the management strategies and subsequent outcomes in patients who developed ADAs. RESULTS A total of 132 patients are included. Baseline characteristics include 54% male patients and mean age of 39.4 years. Fifty-two percent (n = 69) of patients discontinued IFX following the development of ADAs, 33.3% (n = 44) sited as secondary to LOR. Both an increase in IFX and adjustments to combination therapy were associated with lower rates of discontinuation of IFX vs no intervention (p value < 0.001, p value < 0.001). An increase in IFX resulted in a significant difference in ADAs/IFX trough levels pre- and post-intervention (p value < 0.001, p value = 0.032). ROC curve analysis yielded significant cut-off values for ADAs and treatment failure (ADA >16μg/ml, AUC 0.642, p value 0.003), steroid use (ADA >19 μg/ml, AUC 0.61, p value 0.048) development of infusion reactions (ADA> 37 μg/ml, AUC 0.68, p value 0.045) and switch to another biologic (ADA >45 μg/ml, AUC 0.739, p value <0.001). CONCLUSION Both escalation of IFX and combination therapy resulted in lower rates of LOR. ROC curve analysis identified significant cut-off values for ADA trough levels and important clinical outcomes.
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14
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Jessen B, Rodriguez-Sillke Y, Sonnenberg E, Schumann M, Kruglov A, Freise I, Schmidt F, Maul J, Kühl AA, Glauben R, Lissner D, Siegmund B. Level of Tumor Necrosis Factor Production by Stimulated Blood Mononuclear Cells Can Be Used to Predict Response of Patients With Inflammatory Bowel Diseases to Infliximab. Clin Gastroenterol Hepatol 2021; 19:721-731.e1. [PMID: 32272247 DOI: 10.1016/j.cgh.2020.03.066] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 03/11/2020] [Accepted: 03/30/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS A substantial proportion patients with inflammatory bowel disease (IBD) have a primary non-response to infliximab; markers are needed to identify patients most likely to respond to treatment. We investigated whether production of tumor necrosis factor (TNF) by peripheral blood mononuclear cells (PBMCs) can be used as a marker to predict response. METHODS We performed a prospective study of 41 adults with IBD (mean age, 38 years; 21 male; 21 with Crohn's disease and 20 with ulcerative colitis) not treated with a biologic agent within the past 6 months; patients were given their first infusion of infliximab at a hospital or clinic in Berlin, Germany. We collected data on clinical scores, levels of C-reactive protein, and ultrasound results (Limberg scores) at baseline (before the first infusion) and after 6 weeks (3rd infliximab infusion). PMBCs were obtained from patients at baseline and 10 healthy individuals (controls) and incubated with lipopolysaccharide. We measured production of cytokines (TNF, interleukin 1 [IL1], IL6, IL8, IL10, IL12p70, and IL22) by ELISA and performed cytometric bead array and flow cytometry analyses. The primary endpoint was clinical response (decrease in Harvey Bradshaw Index scores of 2 or more or decrease in partial Mayo scores of 3 or more at week 6) in patients with PBMCs that produced high vs low levels of TNF. RESULTS Responders had a shorter median disease duration (P = .018) and higher median Limberg score (P = .021), than nonresponders. Baseline PBMCs from responders produced significantly more TNF (P = .049) and IL6 (P = .028) than from nonresponders; a level of 500 pg/ml TNF identified responders with 82% sensitivity and 78% specificity. In patients with Crohn's disease, this cutoff value (500 pg/ml TNF) identified responders with 100% sensitivity and 82% specificity; TNF levels above this level were independently associated with response to infliximab in multivariate analysis (odds ratio, 16.2; 95% CI, 1.8-148.7; P = .014). The percentage of TNF-positive cells was higher among CD14+ monocytes than lymphocytes after stimulation. CONCLUSIONS Production of a high level of TNF by PBMCs (specifically CD14+ cells) from patients with IBD can identify those most likely to have a clinical response to infliximab therapy. In patients with Crohn's disease, a cutoff value of 500 pg/ml TNF identified responders with 100% sensitivity and 82% specificity.
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Affiliation(s)
- Bosse Jessen
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, Department for Medicine (Gastroenterology, Infectious diseases, Rheumatology), Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany.
| | - Yasmina Rodriguez-Sillke
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, Department for Medicine (Gastroenterology, Infectious diseases, Rheumatology), Berlin, Germany
| | - Elena Sonnenberg
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, Department for Medicine (Gastroenterology, Infectious diseases, Rheumatology), Berlin, Germany
| | - Michael Schumann
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, Department for Medicine (Gastroenterology, Infectious diseases, Rheumatology), Berlin, Germany
| | - Andrey Kruglov
- German Rheumatism Research Center (DRFZ), A Leibniz Institute, Berlin, Germany
| | - Inka Freise
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, Department for Medicine (Gastroenterology, Infectious diseases, Rheumatology), Berlin, Germany
| | - Franziska Schmidt
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, Department for Medicine (Gastroenterology, Infectious diseases, Rheumatology), Berlin, Germany
| | - Jochen Maul
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, Department for Medicine (Gastroenterology, Infectious diseases, Rheumatology), Berlin, Germany; Gastroenterologie am Bayerischen Platz, Berlin, Germany
| | - Anja A Kühl
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, iPATH.Berlin-Core Unit, Berlin, Germany
| | - Rainer Glauben
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, Department for Medicine (Gastroenterology, Infectious diseases, Rheumatology), Berlin, Germany
| | - Donata Lissner
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, Department for Medicine (Gastroenterology, Infectious diseases, Rheumatology), Berlin, Germany
| | - Britta Siegmund
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, Department for Medicine (Gastroenterology, Infectious diseases, Rheumatology), Berlin, Germany
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15
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Zhang J, Gao Y, Liu P, Yan J, Zhang X, Xing Y, Song W. Charge transfer accelerated by internal electric field of MoS2 QDs-BiOI p-n heterojunction for high performance cathodic PEC aptasensing. Electrochim Acta 2021. [DOI: 10.1016/j.electacta.2020.137392] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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16
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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: 11] [Impact Index Per Article: 2.2] [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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17
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Fritz D, Timmermans WMC, van Laar JAM, van Hagen PM, Siepman TAM, van de Beek D, Brouwer MC. Infliximab treatment in pathology-confirmed neurosarcoidosis. NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION 2020; 7:7/5/e847. [PMID: 32718952 PMCID: PMC7413716 DOI: 10.1212/nxi.0000000000000847] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 06/16/2020] [Indexed: 12/23/2022]
Abstract
Objective To assess the efficacy and risks of treatment with infliximab (anti–tumor necrosis factor alpha) in pathology-confirmed neurosarcoidosis. Methods In a retrospective study in 2 tertiary referral centers in the Netherlands, we analyzed clinical characteristics, complications, and outcome of patients with neurosarcoidosis treated with infliximab. Results Twenty-eight patients were identified with a mean age of 42 years. Neurosarcoidosis presented with a cerebral parenchymal localization in 16 (59%), pituitary gland/hypothalamic sarcoidosis in 15 (54%), peripheral nerve involvement in 12 (43%), and chronic meningitis in 11 patients (41%). Initial treatment response after the start of infliximab was complete remission in 6 (21%) and improvement in 14 (50%), whereas 7 patients had stable disease (25%), and 1 (4%) deteriorated and died. At the end of follow-up, with a median of 32 months, 5 patients (18%) had died, and 2 (40%) were using infliximab at the time of death. Tapering or discontinuation of corticosteroids without a relapse was achieved in 19 of 28 patients (68%). In patients with decreasing dosing or discontinuation of infliximab, a relapse occurred in 5 of 19 patients (26%). Complications of infliximab were reported in 10 of 28 patients (36%) and mainly consisted of infections in 8 (29%). Conclusion Infliximab is an effective treatment in neurosarcoidosis leading to remission or improvement in 70%. The mortality rate in infliximab-treated patients was substantial, indicating the severity of disease and treatment-associated complications. Classification of evidence This study provides Class IV evidence that in people with pathology-confirmed neurosarcoidosis, infliximab is beneficial.
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Affiliation(s)
- Daan Fritz
- From the Amsterdam UMC (D.F., D.B., M.C.B.), University of Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam; Erasmus MC (W.M.C.T., J.A.M.L., P.M.H.), Department of Internal Medicine; Erasmus MC (W.M.C.T., J.A.M.L., P.M.H.), Department of Immunology; and Erasmus MC (T.A.M.S.), Department of Neurology, Rotterdam, the Netherlands
| | - Wilhelmina M C Timmermans
- From the Amsterdam UMC (D.F., D.B., M.C.B.), University of Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam; Erasmus MC (W.M.C.T., J.A.M.L., P.M.H.), Department of Internal Medicine; Erasmus MC (W.M.C.T., J.A.M.L., P.M.H.), Department of Immunology; and Erasmus MC (T.A.M.S.), Department of Neurology, Rotterdam, the Netherlands
| | - Jan A M van Laar
- From the Amsterdam UMC (D.F., D.B., M.C.B.), University of Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam; Erasmus MC (W.M.C.T., J.A.M.L., P.M.H.), Department of Internal Medicine; Erasmus MC (W.M.C.T., J.A.M.L., P.M.H.), Department of Immunology; and Erasmus MC (T.A.M.S.), Department of Neurology, Rotterdam, the Netherlands
| | - P Martin van Hagen
- From the Amsterdam UMC (D.F., D.B., M.C.B.), University of Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam; Erasmus MC (W.M.C.T., J.A.M.L., P.M.H.), Department of Internal Medicine; Erasmus MC (W.M.C.T., J.A.M.L., P.M.H.), Department of Immunology; and Erasmus MC (T.A.M.S.), Department of Neurology, Rotterdam, the Netherlands
| | - Theodora A M Siepman
- From the Amsterdam UMC (D.F., D.B., M.C.B.), University of Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam; Erasmus MC (W.M.C.T., J.A.M.L., P.M.H.), Department of Internal Medicine; Erasmus MC (W.M.C.T., J.A.M.L., P.M.H.), Department of Immunology; and Erasmus MC (T.A.M.S.), Department of Neurology, Rotterdam, the Netherlands
| | - Diederik van de Beek
- From the Amsterdam UMC (D.F., D.B., M.C.B.), University of Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam; Erasmus MC (W.M.C.T., J.A.M.L., P.M.H.), Department of Internal Medicine; Erasmus MC (W.M.C.T., J.A.M.L., P.M.H.), Department of Immunology; and Erasmus MC (T.A.M.S.), Department of Neurology, Rotterdam, the Netherlands
| | - Matthijs C Brouwer
- From the Amsterdam UMC (D.F., D.B., M.C.B.), University of Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam; Erasmus MC (W.M.C.T., J.A.M.L., P.M.H.), Department of Internal Medicine; Erasmus MC (W.M.C.T., J.A.M.L., P.M.H.), Department of Immunology; and Erasmus MC (T.A.M.S.), Department of Neurology, Rotterdam, the Netherlands.
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18
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Prediction of treatment failure during infliximab induction therapy in inflammatory bowel disease patients based on pharmacokinetic and pharmacodynamic modeling. Eur J Pharm Sci 2020; 150:105317. [PMID: 32205229 DOI: 10.1016/j.ejps.2020.105317] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 02/27/2020] [Accepted: 03/19/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND In infliximab (IFX) treatment for Crohn's disease (CD) and ulcerative colitis (UC), it is difficult to predict treatment failure during the induction phase. In the present study for optimal IFX treatment, we attempted to estimate serum IFX concentration and clinical response in individual patients during the induction phase to predict the indication of therapeutic effect and the possibility of treatment failure in the maintenance phase. METHODS We estimated pharmacokinetic and pharmacodynamic (PK/PD) parameters and predicted the serum IFX concentration and clinical response using a PK/PD model and Markov chain Monte Carlo Bayesian analysis method during the induction phase. Then, we determined whether the indication of therapeutic effect between predicted and observed clinical response were matched during the maintenance phase. RESULTS Data obtained from 15 patients were analyzed. The correlation between predicted and observed values of serum IFX concentration (Pearson product-moment correlation coefficient, 0.700; P < 0.0001, n = 68) and clinical response of CD patients (0.790; P < 0.0001, n = 25) and UC patients (0.702; P = 0.0004, n = 21) were significantly high. The indication of therapeutic effect at the final time point of each patient (from day 115 to day 203) were successfully predicted in 14 of 15 patients (93.3%). CONCLUSIONS This study presents prediction of serum IFX concentration and clinical response in individual patients during induction therapy, with presumption of the indication of therapeutic effect and the treatment failure in the maintenance phase. Our results show the possibility of optimizing IFX therapy during the induction phase.
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19
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Choi SY, Kang B, Choe YH. Serum Infliximab Cutoff trough Level Values for Maintaining Hematological Remission in Pediatric Inflammatory Bowel Disease. Gut Liver 2020; 13:541-548. [PMID: 30970435 PMCID: PMC6743797 DOI: 10.5009/gnl18129] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 11/02/2018] [Accepted: 11/20/2018] [Indexed: 12/14/2022] Open
Abstract
Background/Aims Infliximab (IFX) often loses its therapeutic effect in initial responders with inflammatory bowel disease (IBD) over time. Low serum IFX trough levels (TLs) are linked to poor clinical response and outcomes. Maintenance of optimal therapeutic IFX concentrations is important for sustaining response and achieving good clinical outcomes. Measurement of serum IFX TLs is helpful for determining a further proper therapeutic plan. However, adequate therapeutic IFX TLs in pediatric IBD is uncertain. We aimed to identify the cutoff values for IFX TLs associated with laboratory response to IFX maintenance therapy. Methods Patients with pediatric IBD who had received IFX infusions between December 2008 and March 2015 at Samsung Medical Center were retrospectively investigated. We analyzed 239 blood samples that were collected from 103 pediatric patients. We measured IFX TLs at induction (6 and 14 weeks) and during maintenance therapy (>22 weeks, 8 weeks interval) by fluid-phase radioimmunoassays. Results A significant association was found between the erythrocyte sedimentation rate (ESR) and IFX TLs during maintenance (correlation coefficient, -0.11; p=0.0005). A cutoff value of 18 mm/hr for ESR was used to define higher levels. Receiver operating characteristic analysis identified optimal cutoff values: IFX TL >1.58 µg/mL (sensitivity 82% and specificity 73%). Conclusions Cutoff values are considered a prerequisite for further investigating the clinical usefulness of measurements of IFX in patients maintained with IFX treatment.
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Affiliation(s)
- So Yoon Choi
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Pediatrics, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Ben Kang
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Yon Ho Choe
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Christian KE, Russman KM, Rajan DP, Barr EA, Cross RK. Gender Differences and Other Factors Associated with Weight Gain Following Initiation of Infliximab: A Post Hoc Analysis of Clinical Trials. Inflamm Bowel Dis 2020; 26:125-131. [PMID: 31265730 DOI: 10.1093/ibd/izz133] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND In our clinical practice, women often report excess weight gain with infliximab (IFX) use. There are currently no studies investigating weight gain after antitumor necrosis factor therapy in patients with inflammatory bowel disease. The objective of this study was to evaluate the association of clinical factors, with a particular focus on sex and weight gain in patients with moderate to severe Crohn's disease (CD) or ulcerative colitis (UC) initiating IFX. METHODS Data was extracted from ACCENT I, ACCENT II, ACT 1, and SONIC; included patients received IFX for induction or maintenance of remission of CD or UC. Patients treated with azathioprine (IFX 0 mg/kg) were included as controls. Baseline demographics, clinical characteristics, and weight at each follow-up for the study duration were collected. In addition to descriptive statistics, adjusted mixed effects models were used to test the association between clinical variables and weight gain. RESULTS There were 1273 patients included for analysis; the majority was white (91%), with CD (81%), and half of patients (50%) were women. Upon univariate analysis, IFX dose, African American race, diagnosis of CD, elevated C-reactive protein, and low hematocrit and albumin were associated with weight gain (P < 0.001). Upon adjusted analysis, sex was significantly associated with weight gain (P = 0.009), with women experiencing a lower percentage increase from baseline weight than men (3.9% increase vs 4.3% increase). CONCLUSIONS When starting IFX, those with markers of severe disease and with a diagnosis of CD are likely to gain more weight. Adjusting for confounding variables, women actually gain less weight than men after IFX treatment, although this difference is not clinically relevant.
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Affiliation(s)
- Kaci E Christian
- University of Maryland School of Medicine, Division of Gastroenterology and Hepatology
| | - Katharine M Russman
- University of Maryland School of Medicine, Division of Gastroenterology and Hepatology
| | - Dhyan P Rajan
- University of Maryland School of Medicine, Division of Gastroenterology and Hepatology
| | - Erik A Barr
- University of Maryland School of Medicine, Department of Epidemiology and Public Health
| | - Raymond K Cross
- University of Maryland School of Medicine, Division of Gastroenterology and Hepatology
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21
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Bar-Yoseph H, Pressman S, Blatt A, Gerassy Vainberg S, Maimon N, Starosvetsky E, Ungar B, Ben-Horin S, Shen-Orr SS, Chowers Y. Infliximab-Tumor Necrosis Factor Complexes Elicit Formation of Anti-Drug Antibodies. Gastroenterology 2019; 157:1338-1351.e8. [PMID: 31401142 DOI: 10.1053/j.gastro.2019.08.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 07/25/2019] [Accepted: 08/01/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Some patients develop anti-drug antibodies (ADAs), which reduce the efficacy of infliximab, a monoclonal antibody against tumor necrosis factor (TNF), in the treatment of immune-mediated diseases, including inflammatory bowel diseases. ADAs arise inconsistently, and it is not clear what factors determine their formation. We investigated features of the immune system, the infliximab antibody, and its complex with TNF that might contribute to ADA generation. METHODS C57BL/6 mice were given injections of infliximab and recombinant human TNF or infliximab F(ab')2 fragments. Blood samples were collected every 2-3 days for 2 weeks and weekly thereafter for up to 6 weeks; infliximab-TNF complexes and ADAs were measured by enzyme-linked immunosorbent assay (ELISA). Intestinal biopsy and blood samples were obtained from patients having endoscopy who had received infliximab therapy for inflammatory bowel diseases; infliximab-TNF complexes were measured with ELISA. Infliximab-specific plasma cells were detected in patient tissue samples by using mass cytometry. We studied activation of innate immune cells in peripheral blood mononuclear cells (PBMCs) from healthy donors incubated with infliximab or infliximab-TNF complexes; toll-like receptors (TLRs) were blocked with antibodies, endocytosis was blocked with the inhibitor PitStop2, and cytokine expression was measured by real-time polymerase chain reaction and ELISAs. Uptake of infliximab and infliximab-TNF complexes by THP-1 cells was measured with confocal microscopy. RESULTS Mice given increasing doses of infliximab produced increasing levels of ADAs. Blood samples from mice given injections of human TNF and infliximab contained infliximab-TNF complexes; complex formation was associated with ADA formation with an area under the curve of 0.944 (95% confidence interval, 0.851-1.000; P = .003). Intestinal tissues from patients, but not blood samples, contained infliximab-TNF complexes and infliximab-specific plasma cells. Incubation of PBMCs with infliximab-TNF complexes resulted in a 4.74-fold increase in level of interleukin (IL) 1β (IL1B) messenger RNA (P for comparison = .005), increased IL1B protein secretion, and a 2.69-fold increase in the expression of TNF messenger RNA (P for comparison = 0.013) compared with control PBMCs. Infliximab reduced only IL1B and TNF expression. Antibodies against TLR2 or TLR4 did not block the increases in IL1B or TNF expression, but endocytosis was required. THP-1 cells endocytosed higher levels of infliximab-TNF complexes than infliximab alone. CONCLUSIONS In mice, we found ADA formation to increase with dose of infliximab given and concentration of infliximab-TNF complexes detected in blood. Based on studies of human intestinal tissues and blood samples, we propose that infliximab-TNF complexes formed in the intestine are endocytosed by and activate innate immune cells, which increase expression of IL1B and TNF and production of antibodies against the drug complex. It is therefore important to optimize the infliximab dose to a level that is effective but does not activate an innate immune response against the drug-TNF complex.
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Affiliation(s)
- Haggai Bar-Yoseph
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel; Bruce Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa, Israel
| | - Sigal Pressman
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Alexandra Blatt
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | | | - Naama Maimon
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel; Bruce Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa, Israel
| | - Elina Starosvetsky
- Bruce Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa, Israel
| | - Bella Ungar
- Department of Gastroenterology, Chaim Sheba Medical Center, Ramat-Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shomron Ben-Horin
- Department of Gastroenterology, Chaim Sheba Medical Center, Ramat-Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shai S Shen-Orr
- Bruce Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa, Israel
| | - Yehuda Chowers
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel; Bruce Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa, Israel; Clinical Research Institute, Rambam Health Care Campus, Haifa, Israel.
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22
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Papamichael K, Cheifetz AS, Melmed GY, Irving PM, Vande Casteele N, Kozuch PL, Raffals LE, Baidoo L, Bressler B, Devlin SM, Jones J, Kaplan GG, Sparrow MP, Velayos FS, Ullman T, Siegel CA. Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 2019; 17:1655-1668.e3. [PMID: 30928454 PMCID: PMC6661210 DOI: 10.1016/j.cgh.2019.03.037] [Citation(s) in RCA: 236] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 02/24/2019] [Accepted: 03/24/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Therapeutic drug monitoring (TDM) is widely available for biologic therapies in patients with inflammatory bowel disease (IBD). We reviewed current data and provided expert opinion regarding the clinical utility of TDM for biologic therapies in IBD. METHODS We used a modified Delphi method to establish consensus. A comprehensive literature review was performed regarding the use of TDM of biologic therapy in IBD and presented to international IBD specialists. Subsequently, 28 statements on the application of TDM in clinical practice were rated on a scale of 1 to 10 (1 = strongly disagree and 10 = strongly agree) by each of the panellists. Statements were accepted if 80% or more of the participants agreed with a score ≥7. The remaining statements were discussed and revised based on the available evidence followed by a second round of voting. RESULTS The panel agreed on 24 (86%) statements. For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics. Reactive TDM was appropriate for all agents both for primary non-response and secondary loss of response. The panellists also agreed on several statements regarding TDM and appropriate drug and anti-drug antibody (ADA) concentration thresholds for biologics in specific clinical scenarios. CONCLUSION Consensus was achieved towards the utility of TDM of biologics in IBD, particularly anti-TNF therapies. More data are needed especially on non-anti-TNF biologics to further define optimal drug concentration and ADA thresholds as these can vary depending on the therapeutic outcomes assessed.
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Affiliation(s)
| | - Adam S Cheifetz
- Beth Israel Deaconess Medical Center, Boston, Massachusetts.
| | - Gil Y Melmed
- Cedars-Sinai Medical Center, Los Angeles, California
| | | | | | | | | | - Leonard Baidoo
- Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | | | | | | | | | | | | | - Thomas Ullman
- Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York
| | - Corey A Siegel
- Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
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23
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Gomes LEM, da Silva FAR, Pascoal LB, Ricci RL, Nogueira G, Camargo MG, de Lourdes Setsuko Ayrizono M, Fagundes JJ, Leal RF. Serum Levels of Infliximab and Anti-Infliximab Antibodies in Brazilian Patients with Crohn's Disease. Clinics (Sao Paulo) 2019; 74:e824. [PMID: 30994711 PMCID: PMC6445154 DOI: 10.6061/clinics/2019/e824] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 11/28/2018] [Indexed: 01/15/2023] Open
Abstract
OBJECTIVES The aim of this study was to evaluate the quantitative serum level of infliximab (IFX) as well as the detection of anti-infliximab antibodies (ATIs) in patients with Crohn's disease (CD). METHOD Forty patients with CD under treatment at a tertiary center in southeastern Brazil were evaluated. Their use of infliximab was continuous and regular. We analyzed and compared the differences in the IFX and ATI levels between the patients with active CD (CDA) and those with CD in remission (CDR). RESULTS There was no difference in the IFX level between the CDA and CDR groups (p>0.05). Eighty percent of all patients had IFX levels above the therapeutic concentration (6-10 μg/mL). Two (9%) of the 22 patients with active disease and four (22.2%) of the 18 patients in remission had undetectable levels of IFX. Four (66.6%) of the six patients with undetectable levels of IFX had positive ATI levels; three of these patients were in remission, and one had active disease. In addition, the other two patients with undetectable levels of IFX presented ATI levels close to positivity (2.7 and 2.8 AU/ml). None of the patients with therapeutic or supratherapeutic IFX levels had positive ATI levels. CONCLUSIONS The undetectable levels of IFX correlated with the detection of ATIs, which was independent of disease activity. Immunogenicity was not the main factor for the loss of response to IFX in our study, and the majority of patients in both groups (CDA and CDR) had supratherapeutic levels of IFX.
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Affiliation(s)
- Luis Eduardo Miani Gomes
- Laboratorio de Investigacao em Doencas Inflamatorias Intestinais, Servico de Coloproctologia, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, BR
| | - Francesca Aparecida Ramos da Silva
- Laboratorio de Investigacao em Doencas Inflamatorias Intestinais, Servico de Coloproctologia, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, BR
| | - Lívia Bitencourt Pascoal
- Laboratorio de Investigacao em Doencas Inflamatorias Intestinais, Servico de Coloproctologia, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, BR
| | - Renato Lazarin Ricci
- Laboratorio de Investigacao em Doencas Inflamatorias Intestinais, Servico de Coloproctologia, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, BR
| | - Guilherme Nogueira
- Laboratorio de Sinalizacao Celular, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, BR
| | - Michel Gardere Camargo
- Laboratorio de Investigacao em Doencas Inflamatorias Intestinais, Servico de Coloproctologia, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, BR
| | - Maria de Lourdes Setsuko Ayrizono
- Laboratorio de Investigacao em Doencas Inflamatorias Intestinais, Servico de Coloproctologia, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, BR
| | - João José Fagundes
- Laboratorio de Investigacao em Doencas Inflamatorias Intestinais, Servico de Coloproctologia, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, BR
| | - Raquel Franco Leal
- Laboratorio de Investigacao em Doencas Inflamatorias Intestinais, Servico de Coloproctologia, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, BR
- Corresponding author. E-mail:
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24
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Zhang QW, Shen J, Zheng Q, Ran ZH. Loss of response to scheduled infliximab therapy for Crohn's disease in adults: A systematic review and meta-analysis. J Dig Dis 2019; 20:65-72. [PMID: 30582302 DOI: 10.1111/1751-2980.12698] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 09/08/2018] [Accepted: 11/14/2018] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To determine the potential predictors of loss of response (LOR) to infliximab (IFX) maintenance therapy for adult patients with Crohn's disease (CD). METHODS We searched for English-language articles published between 1990 and March 2017 in PubMed, Embase, and the Cochrane Library. After identifying eligible studies, data extraction was performed independently by two reviewers. The potential prognostic variables were identified and dichotomized for meta-analysis. Based on the heterogeneity among study variables, random-effects models was used in our meta-analysis. RESULTS Twenty-six studies met our eligibility criteria and consolidated drug response data were obtained from 3212 patients. The pooled rate of LOR to IFX maintenance therapy with a median follow-up of 1.1 years was 34%. The incidence of LOR to IFX therapy was increased in CD patients with perianal lesions (odds ratio [OR] 1.69, 95% confidence interval [CI] 1.04-2.75, P = 0.03), colon involvement (OR 2.56, 95% CI 1.20-5.50, P = 0.02) and younger age at CD onset (standardized mean difference -0.79, 95% CI -1.41 to -0.18, P = 0.01). CONCLUSIONS The meta-analysis estimates the incidence of LOR among adult CD patients undergoing IFX therapy is 34%. The presence of perianal lesions, younger age at CD onset, and involvement of the colon are relative risk factors of LOR in CD patients received scheduled IFX maintenance therapy.
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Affiliation(s)
- Qi Wei Zhang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Shen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qing Zheng
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhi Hua Ran
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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25
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Buurman DJ, Blokzijl T, Festen EAM, Pham BT, Faber KN, Brouwer E, Dijkstra G. Quantitative comparison of the neutralizing capacity, immunogenicity and cross-reactivity of anti-TNF-α biologicals and an Infliximab-biosimilar. PLoS One 2018; 13:e0208922. [PMID: 30533022 PMCID: PMC6289430 DOI: 10.1371/journal.pone.0208922] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 11/26/2018] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION TNF-α-neutralizing antibodies, such as infliximab (IFX) and adalimumab (ADA), are effective in the treatment of inflammatory bowel diseases (IBD), but they are expensive and become ineffective when patients develop anti-IFX or anti-ADA antibodies (ATI and ATA, respectively). Second-generation anti-TNF-α antibodies, such as Golimumab, Etanercept, Certolizumab-pegol and IFX biosimilars, may solve these issues. AIM To determine the neutralizing capacity of first- and second generation anti-TNF-α antibodies and to determine whether ATI show cross-reactivity with the IFX biosimilar CT-P13 (Inflectra). METHODS TNF-α neutralization was measured using a quantitative TNF-α sensor assay consisting of HeLa 8D8 cells that express the Green Fluorescence Protein (GFP) under control of a NF-кB response element. All available anti-TNF-α drugs and the IFX biosimilar CT-P13 (Inflectra) were tested for their TNF-α-neutralizing capacity. In addition, patient sera with ATI were tested for their potential to block the activity of IFX, IFX (F)ab2-fragment, biosimilar CT-P13 (Inflectra) and ADA. RESULTS TNF-α strongly induced GFP expression in Hela 8D8 cells. Higher concentrations of first-generation anti-TNF-α drugs were required to neutralize TNF-α compared to the second-generation anti-TNF-α drugs. Serum of IBD patients with proven ATI blocked TNF-α-neutralizing properties of IFX biosimilar CT-P13 (Inflectra), whereas such sera did not block the effect of ADA. CONCLUSION The second-generation anti-TNF-α drugs show increased TNF-α-neutralizing potential compared to first-generation variants. ATI show cross-reactivity toward IFX biosimilar CT-P13 (Inflectra), consequently patients with ATI are unlikely to benefit from treatment with this IFX biosimilar.
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Affiliation(s)
- D. J. Buurman
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- * E-mail:
| | - T. Blokzijl
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, Department of Laboratory Medicine, Groningen, The Netherlands
| | - E. A. M. Festen
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - B. T. Pham
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - K. N. Faber
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - E. Brouwer
- Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - G. Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Nencini F, Vultaggio A, Pratesi S, Cammelli D, Milla M, Fiori G, Bagnoli S, Prignano F, Romagnani S, Maggi E, Matucci A. The Kinetics of Antidrug Antibodies, Drug Levels, and Clinical Outcomes in Infliximab-Exposed Patients with Immune-Mediated Disorders. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2018; 6:2065-2072.e2. [DOI: 10.1016/j.jaip.2018.04.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 03/15/2018] [Accepted: 04/05/2018] [Indexed: 02/07/2023]
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Goncalves J, Santos M, Acurcio R, Iria I, Gouveia L, Matos Brito P, Catarina Cunha-Santos A, Barbas A, Galvão J, Barbosa I, Aires da Silva F, Alcobia A, Cavaco M, Cardoso M, Delgado Alves J, Carey JJ, Dörner T, Eurico Fonseca J, Palmela C, Torres J, Lima Vieira C, Trabuco D, Fiorino G, Strik A, Yavzori M, Rosa I, Correia L, Magro F, D'Haens G, Ben-Horin S, Lakatos PL, Danese S. Antigenic response to CT-P13 and infliximab originator in inflammatory bowel disease patients shows similar epitope recognition. Aliment Pharmacol Ther 2018; 48:507-522. [PMID: 29873091 DOI: 10.1111/apt.14808] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 03/18/2018] [Accepted: 04/25/2018] [Indexed: 12/14/2022]
Abstract
AIM To test the cross-immunogenicity of anti-CT-P13 IBD patients' sera to CT-P13/infliximab originator and the comparative antigenicity evoked by CT-P13/infliximab originator sera. METHODS Sera of patients with IBD with measurable anti-CT-P13 antibodies were tested for their cross-reactivity to 5 batches of infliximab originator and CT-P13. Anti-drug antibody positive sera from treated patients were used to compare antigenic epitopes. RESULTS All 42 anti-CT-P13 and 37 anti-infliximab originator IBD sera were cross-reactive with infliximab originator and CT-P13 respectively. Concentration of anti-drug antibodies against infliximab originator or CT-P13 were strongly correlated both for IgG1 and IgG4 (P < 0.001). Anti-CT-P13 sera of patients with IBD (n = 32) exerted similar functional inhibition on CT-P13 or infliximab originator TNF binding capacity and showed reduced binding to CT-P13 in the presence of five different batches of CT-P13 and infliximab originator. Anti-CT-P13 and anti-infliximab originator IBD sera selectively enriched phage-peptides from the VH (CDR1 and CDR3) and VL domains (CDR2 and CDR3) of infliximab. Sera reactivity detected major infliximab epitopes in these regions of infliximab in 60%-79% of patients, and no significant differences were identified between CT-P13 and infliximab originator immunogenic sera. Minor epitopes were localised in framework regions of infliximab with reduced antibody reactivity shown, in 30%-50% of patients. Monoclonal antibodies derived from naïve individuals and ADA-positive IBD patients treated with CT-P13 provided comparable epitope specificity to five different batches of CT-P13 and infliximab originator. CONCLUSIONS These results strongly support a similar antigenic profile for infliximab originator and CT-P13, and point toward a safe switching between the two drugs in anti-drug antibody negative patients.
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Affiliation(s)
| | | | | | | | | | | | | | - A Barbas
- Oeiras, Portugal
- Carnaxide, Portugal
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28
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Gorovits B, Baltrukonis DJ, Bhattacharya I, Birchler MA, Finco D, Sikkema D, Vincent MS, Lula S, Marshall L, Hickling TP. Immunoassay methods used in clinical studies for the detection of anti-drug antibodies to adalimumab and infliximab. Clin Exp Immunol 2018; 192:348-365. [PMID: 29431871 PMCID: PMC5980437 DOI: 10.1111/cei.13112] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/01/2018] [Indexed: 12/13/2022] Open
Abstract
We examined the assay formats used to detect anti-drug antibodies (ADA) in clinical studies of the anti-tumour necrosis factor (TNF) monoclonal antibodies adalimumab and infliximab in chronic inflammatory disease and their potential impact on pharmacokinetic and clinical outcomes. Using findings of a recent systematic literature review of the immunogenicity of 11 biological/biosimilar agents, we conducted an ancillary qualitative review of a subset of randomized controlled trials and observational studies of the monoclonal antibodies against anti-TNF factor adalimumab and infliximab. Among studies of adalimumab and infliximab, the immunoassay method used to detect antibodies was reported in 91 of 111 (82%) and 154 of 206 (75%) adalimumab and infliximab studies, respectively. In most adalimumab and infliximab studies, an enzyme-linked immunosorbent assay or radioimmunoassay was used [85 of 91 (93%) and 134 of 154 (87%), respectively]. ADA incidence varied widely among assays and inflammatory diseases (adalimumab, 0-87%; infliximab, 0-79%). Pharmacokinetic and clinical outcomes were only reported for ADA-positive patients in 38 of 91 (42%) and 61 of 154 (40%) adalimumab and infliximab studies, respectively. Regardless of assay format or biological used, ADA formation was associated with lower serum concentrations, reduced efficacy and elevated rates of infusion-related reactions. Consistent with previous recommendations to improve interpretation of immunogenicity data for biologicals, greater consistency in reporting of assay methods and clinical consequences of ADA formation may prove useful. Additional standardization in immunogenicity testing and reporting, application of modern, robust assays that satisfy current regulatory expectations and implementation of international standards for marketed products may help to improve our understanding of the impact of immunogenicity to biologics.
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Affiliation(s)
| | | | | | | | | | | | | | - S. Lula
- Envision Pharma GroupLondonUK
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29
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Hvas CL, Bendix M, Dige A, Dahlerup JF, Agnholt J. Current, experimental, and future treatments in inflammatory bowel disease: a clinical review. Immunopharmacol Immunotoxicol 2018; 40:446-460. [PMID: 29745777 DOI: 10.1080/08923973.2018.1469144] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel diseases (IBDs) may result from dysregulated mucosal immune responses directed toward the resident intestinal microbiota. This review describes the hallmark immunobiology of Crohn's disease and ulcerative colitis as well as therapeutic targets and mechanisms of action for current, experimental, and future treatments in IBD. Conventional therapies include 5-aminosalicylic acid, glucocorticosteroids, thiopurines, and methotrexate. Since 1997, monoclonal antibodies have gained widespread use. These consist of antibodies directed against pro-inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)-12, and IL-23, or anti-homing antibodies directed against α4β7 integrin. Emerging oral therapies include modulators of intracellular signal transduction such as Janus kinase inhibitors. Vitamin D may help to regulate innate and adaptive immune responses. Modulation of the intestinal microbiota, using live microorganisms (probiotics), substrates for the colonic microbiota (prebiotics), or fecal microbiota transplantation (FMT), is in development. Dietary supplements are in widespread use, but providing evidence for their benefit is challenging. Stem cell treatment and nervous stimulation are promising future treatments.
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Affiliation(s)
- Christian L Hvas
- a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark
| | - Mia Bendix
- a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark.,b Medical Department, Randers Regional Hospital , Randers , Denmark
| | - Anders Dige
- a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark
| | - Jens F Dahlerup
- a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark
| | - Jørgen Agnholt
- a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark
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Freeman K, Connock M, Auguste P, Taylor-Phillips S, Mistry H, Shyangdan D, Court R, Arasaradnam R, Sutcliffe P, Clarke A. Clinical effectiveness and cost-effectiveness of use of therapeutic monitoring of tumour necrosis factor alpha (TNF-α) inhibitors [LISA-TRACKER® enzyme-linked immunosorbent assay (ELISA) kits, TNF-α-Blocker ELISA kits and Promonitor® ELISA kits] versus standard care in patients with Crohn's disease: systematic reviews and economic modelling. Health Technol Assess 2018; 20:1-288. [PMID: 27845027 DOI: 10.3310/hta20830] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND OBJECTIVES Systematic reviews and economic modelling of clinical effectiveness and cost-effectiveness of therapeutic monitoring of tumour necrosis factor alpha (TNF-α) inhibitors [using LISA-TRACKER® enzyme-linked immunosorbent assay (ELISA) kits (Theradiag, Marne La Vallee, France, or Alpha Laboratories, Heriot, UK), TNF-α-Blocker ELISA kits (Immundiagnostik AG, Bensheim, Germany) and Promonitor® ELISA kits (Proteomika, Progenika Biopharma, Bizkaia, Spain)] versus standard care for Crohn's disease (CD). METHODS Multiple electronic databases were searched from inception to December 2014 in order to identify primary studies and meta-analyses. POPULATION Patients with moderate to severe active CD treated with infliximab (IFX) (Remicade®, Merck Sharp & Dohme Ltd, Kenilworth, NJ, USA) or adalimumab (ADA) (Humira®, AbbVie Inc., North Chicago, IL, USA). INTERVENTION Monitoring of serum anti-TNF-α (IFX or ADA) and/or of anti-drug antibody levels using test assays with a test-treatment algorithm. COMPARATOR Standard care. OUTCOMES Any patient-related outcome, test agreement and cost-effectiveness estimates. The quality assessments used recognised checklists (Quality Assessment of Diagnostic Accuracy Studies-2, Cochrane, Philips and Consolidated Health Economic Evaluation Reporting Standards). Evidence was synthesised using narrative review and meta-analysis. A Markov model was built in TreeAge Pro 2013 (TreeAge Software, Inc., Williamstown, MA, USA). The model had a 4-week cycle and a 10-year time horizon, adopted a NHS and Personal Social Services perspective and used a linked evidence approach. Costs were adjusted to 2013/14 prices and discounted at 3.5%. RESULTS We included 68 out of 2434 and 4 out of 2466 studies for the clinical effectiveness and cost-effectiveness reviews, respectively. Twenty-three studies comparing test methods were identified. Evidence on test concordance was sparse and contradictory, offering scant data for a linked evidence approach. Three studies [two randomised controlled trials (RCTs) and one retrospective observational study] investigated outcomes following implementation of a test algorithm. None used the specified commercial ELISA immunoassay test kits. Neither of the two RCTs demonstrated clinical benefit of a test-treatment regimen. A meta-analysis of 31 studies to estimate test accuracy for predicting clinical status indicated that 20-30% of test results are likely to be inaccurate. The four cost-effectiveness studies suggested that testing results in small cost reductions. In the economic analysis the base-case analysis showed that standard practice (no testing/therapeutic monitoring with the intervention tests) was more costly and more effective than testing for IFX. Sensitivity and scenario analyses gave similar results. The probabilistic sensitivity analysis indicated a 92% likelihood that the 'no-testing' strategy was cost-effective at a willingness to pay of £20,000 per quality-adjusted life-year. STRENGTHS AND LIMITATIONS Rigorous systematic reviews were undertaken; however, the underlying evidence base was poor or lacking. There was uncertainty about a linked evidence approach and a lack of gold standard for assay comparison. The only comparative evidence available for economic evaluation was for assays other than the intervention assays. CONCLUSIONS Our finding that testing is not cost-effective for IFX should be viewed cautiously in view of the limited evidence. Clinicians should be mindful of variation in performance of different assays and of the absence of standardised approaches to patient assessment and treatment algorithms. FUTURE WORK RECOMMENDATIONS There is substantial variation in the underlying treatment pathways and uncertainty in the relative effectiveness of assay- and test-based treatment algorithms, which requires further investigation. There is very little research evidence on ADA or on drug monitoring in children with CD, and conclusions on cost-effectiveness could not be reached for these. STUDY REGISTRATION This study is registered as PROSPERO CRD42014015278. FUNDING The National Institute for Health Research Health Technology Assessment programme.
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Affiliation(s)
- Karoline Freeman
- Warwick Evidence, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK
| | - Martin Connock
- Warwick Evidence, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK
| | - Peter Auguste
- Warwick Evidence, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK
| | - Sian Taylor-Phillips
- Warwick Evidence, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK
| | - Hema Mistry
- Warwick Evidence, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK
| | - Deepson Shyangdan
- Warwick Evidence, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK
| | - Rachel Court
- Warwick Evidence, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK
| | - Ramesh Arasaradnam
- Clinical Sciences Research Institute, University of Warwick, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
| | - Paul Sutcliffe
- Warwick Evidence, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK
| | - Aileen Clarke
- Warwick Evidence, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK
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Hiraoka S, Takashima S, Kondo Y, Inokuchi T, Sugihara Y, Takahara M, Kawano S, Harada K, Kato J, Okada H. Efficacy of restarting anti-tumor necrosis factor α agents after surgery in patients with Crohn's disease. Intest Res 2018; 16:75-82. [PMID: 29422801 PMCID: PMC5797275 DOI: 10.5217/ir.2018.16.1.75] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 08/06/2017] [Accepted: 08/08/2017] [Indexed: 12/23/2022] Open
Abstract
Background/Aims The efficacy of anti-tumor necrosis factor α (anti-TNFα) antibodies for postoperative Crohn's disease (CD) in patients who were treated with these agents prior to surgery is largely unknown. Methods CD patients who underwent intestinal resection and received anti-TNFα agents after surgery were divided into 2 groups according to the presence or absence of preoperative anti-TNFα treatment: anti-TNFα restart group or anti-TNFα naïve group. Endoscopic recurrence after surgery was examined according to the preoperative conditions, including administration of anti-TNFα agents before surgery. Results Thirty-six patients received anti-TNFα antibody after surgery: 22 in the anti-TNFα restart group and 14 in the anti-TNFα naïve group. Endoscopic recurrence after surgery was more frequently observed in the anti-TNFα restart group than in the anti-TNFα naïve group (68% vs. 14%, P<0.001). Multivariate analysis revealed the following significant risk factors of endoscopic recurrence after surgery: anti-TNF restart group (odds ratio [OR], 28.10; 95% CI, 3.08-722.00), age at diagnosis <23 years (OR, 24.30; 95% CI, 1.67-1,312.00), serum albumin concentration at surgery <3.3 g/dL (OR, 34.10; 95% CI, 1.72-2,804.00), and presence of inflammation outside of the surgical site (OR, 21.40; 95% CI, 1.02-2,150.00). Treatment intensification for patients with endoscopic recurrence in the anti-TNFα restart group showed limited responses, with only 1 of 12 patients achieving endoscopic remission. Conclusions The efficacy of restarting anti-TNFα antibody treatment after surgery was limited, and treatment intensification or a change to different classes of biologics should be considered for those patients.
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Affiliation(s)
- Sakiko Hiraoka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shiho Takashima
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yoshitaka Kondo
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Toshihiro Inokuchi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yuusaku Sugihara
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Masahiro Takahara
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Seiji Kawano
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Keita Harada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Jun Kato
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Hiroyuki Okada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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Vermeire S, Gils A, Accossato P, Lula S, Marren A. Immunogenicity of biologics in inflammatory bowel disease. Therap Adv Gastroenterol 2018; 11:1756283X17750355. [PMID: 29383030 PMCID: PMC5784568 DOI: 10.1177/1756283x17750355] [Citation(s) in RCA: 178] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 11/21/2017] [Indexed: 02/04/2023] Open
Abstract
Crohn's disease and ulcerative colitis are chronic inflammatory disorders of the gastrointestinal tract. Treatment options include biologic therapies; however, a proportion of patients lose response to biologics, partly due to the formation of anti-drug antibodies (ADAbs). Concomitant immunosuppressive agents reduce the development of ADAbs. This review article aims to assess the immunogenicity of biologic therapies and their clinical implications. A comprehensive literature search was conducted for articles published January 2009 to August 2015 reporting immunogenicity to adalimumab (ADM), certolizumab pegol (CZP), golimumab, infliximab (IFX), ustekinumab, and vedolizumab in inflammatory bowel disease (IBD). Eligible articles were reviewed and quality assessed by independent reviewers. Overall, 122 publications reporting 114 studies were assessed. ADAbs were reported for all agents, but the percentage of patients developing ADAbs was extremely variable, with the highest (65.3%) being for IFX administration to patients with IBD. ADAb presence was frequently associated with a reduction in primary efficacy and a loss of response, and, for IFX, an increase in adverse events (AEs). Lower serum levels of ADM, CZP and IFX were seen in ADAbs-positive rather than ADAbs-negative patients; pharmacokinetic data were unavailable for other therapies. Little information was available regarding the timing of ADAb development; studies reported their detection from as early as 10-14 days up to months after treatment initiation. Biologic therapies carry an intrinsic risk of immunogenicity, although reported rates of ADAbs vary considerably. The clinical implications of immunogenicity are a concern for effective treatment; further research, particularly into the more recently approved biologics, is required.
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Affiliation(s)
- Séverine Vermeire
- Department of Gastroenterology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Ann Gils
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | | | - Sadiq Lula
- Market Access Solutions, Envision Pharma Group Ltd, London, UK
| | - Amy Marren
- Pfizer Innovative Health, Pfizer Inc, Collegeville, PA, USA
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Affiliation(s)
- Mohammed Razvi
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Mark Lazarev
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA
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Patients with Crohn's Disease with High Body Mass Index Present More Frequent and Rapid Loss of Response to Infliximab. Inflamm Bowel Dis 2017; 23:1853-1859. [PMID: 28837519 DOI: 10.1097/mib.0000000000001179] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Infliximab (IFX) is effective in inducing and maintaining remission in patients with luminal and anoperineal Crohn's disease (CD). However, treatment failure within 12 months after initiating IFX is observed in a significant proportion of patients. The aim of the present study was to determine whether the body mass index (BMI) affects response to IFX during the first year of treatment in patients with CD. METHODS All patients with luminal CD who began IFX between January 2010 and May 2014 were prospectively included. BMI was calculated before IFX treatment was begun, and patients were divided into 3 groups: normal BMI (BMI < 25 kg/m), overweight patients (BMI of 25.0-30 kg/m), and obese patients (BMI > 30.0 kg/m). The primary outcome was to evaluate the rate and delay of IFX optimization during the first year of treatment among normal weight, overweight, and obese patients. RESULTS One hundred forty patients were included. Demographic and clinical characteristics at IFX initiation were comparable among the 3 groups. Within 12 months after the initiation of IFX, the rate of IFX optimization was significantly higher in overweight and obese patients than in the normal BMI group: 52%, 56%, and 20%, respectively (P = 0.0002). The median time until optimization of IFX was significantly shorter in overweight and obese patients than in the normal BMI group: 7, 7, and 10 months, respectively (P = 0.03). A BMI >25 kg/m was significantly associated with IFX optimization within 12 months on multivariate analysis. CONCLUSION This is the first study to show that optimization of IFX is more frequent and faster in obese and overweight patients with CD and occurs within 12 months after beginning IFX, suggesting that an induction regimen with higher doses of IFX and a tight control of IFX concentrations may be needed in these patients.
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Qiu Y, Mao R, Chen BL, Zhang SH, Guo J, He Y, Zeng ZR, Ben-Horin S, Chen MH. Effects of Combination Therapy With Immunomodulators on Trough Levels and Antibodies Against Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Disease: A Meta-analysis. Clin Gastroenterol Hepatol 2017; 15:1359-1372.e6. [PMID: 28232073 DOI: 10.1016/j.cgh.2017.02.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 02/06/2017] [Accepted: 02/08/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS It is not clear whether combination therapy with immunomodulators affects the immunogenicity of tumor necrosis factor (TNF) antagonists in patients with inflammatory bowel disease. We performed a meta-analysis to quantify the effects of combined immunomodulator therapy on the presence of antibodies against TNF antagonists (antidrug antibodies [ADAs]) and trough levels of anti-TNF agents. METHODS We systematically searched publication databases for studies that reported prevalence of ADAs in patients who received anti-TNF agents. Raw data from studies that met the inclusion criteria were pooled to determine effect estimates. We performed subgroup and metaregression analyses to determine the level of heterogeneity among study outcomes. RESULTS We analyzed findings from 35 studies that met inclusion criteria (results reported from 6790 patients with inflammatory bowel disease). The pooled risk ratio for formation of ADAs in patients receiving combined therapy with immunomodulators, versus that of patients receiving anti-TNF monotherapy, was 0.49 (95% confidence interval, 0.41-0.59; P < .001). However, the pooled analysis did not demonstrate a significant difference in trough levels of anti-TNF agents between patients with versus without concurrent use of immunomodulators (standardized mean difference, 0.11; 95% confidence interval, 0.19-0.41; P = .47). Subgroup analyses of patients treated with different TNF antagonists revealed no difference in the formation of ADAs (P = .50 for interaction); the protective effect of immunomodulators did not differ with type of drug patients were given (methotrexate vs thiopurines), or assay for ADA. We observed heterogeneity only among studies of patients with ulcerative colitis (I2 = 76%). Funnel plot and Egger test analyses indicated publication bias in the studies (P = .001). CONCLUSIONS In a meta-analysis of published studies, we associated combined treatment with immunomodulators with reduced risk of formation of antibodies against TNF antagonists in patients with inflammatory bowel disease.
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Affiliation(s)
- Yun Qiu
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Ren Mao
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Bai-Li Chen
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Sheng-Hong Zhang
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jing Guo
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yao He
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Zhi-Rong Zeng
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Shomron Ben-Horin
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; IBD Service, Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Tel Hashomer, Israel.
| | - Min-Hu Chen
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
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Abstract
In patients with Crohn's disease on biologic medications, the use of therapeutic drug monitoring leads to a personalized approach to optimize treatment. Using an algorithmic approach, measurement of drug concentrations and anti-drug antibodies can be used to improve treatment outcomes. Therapeutic drug concentrations and absence of antibodies are associated with improved clinical and endoscopic outcomes. In clinical practice, therapeutic drug monitoring has been shown to be clinically useful and cost-effective in patients experiencing a loss of response to treatment. This review highlights the available data on therapeutic drug monitoring in the treatment of patients with Crohn's disease on biologic medications.
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Affiliation(s)
- Valérie Heron
- Division of Gastroenterology, McGill University Health Center, Montreal General Hospital, McGill University, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada
| | - Waqqas Afif
- Division of Gastroenterology, McGill University Health Center, Montreal General Hospital, McGill University, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada.
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Strand V, Balsa A, Al-Saleh J, Barile-Fabris L, Horiuchi T, Takeuchi T, Lula S, Hawes C, Kola B, Marshall L. Immunogenicity of Biologics in Chronic Inflammatory Diseases: A Systematic Review. BioDrugs 2017; 31:299-316. [PMID: 28612180 PMCID: PMC5548814 DOI: 10.1007/s40259-017-0231-8] [Citation(s) in RCA: 244] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVES A systematic review was conducted to explore the immunogenicity of biologic agents across inflammatory diseases and its potential impact on efficacy/safety. METHODS Literature searches were conducted through November 2016 to identify controlled and observational studies of biologics/biosimilars administered for treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), non-radiographic axial spondyloarthritis (nr-axSpA), psoriasis (Ps), Crohn's disease, and ulcerative colitis. RESULTS Of >21,000 screened publications, 443 were included. Anti-drug antibody (ADAb) rates varied widely among biologics across diseases (and are not directly comparable because of immunoassay heterogeneity); the highest overall rates were reported with infliximab (0-83%), adalimumab (0-54%), and infliximab biosimilar CT-P13 (21-52%), and the lowest with secukinumab (0-1%), ustekinumab (1-11%), etanercept (0-13%), and golimumab (0-19%). Most ADAbs were neutralizing, except those to abatacept and etanercept. ADAb+ versus ADAb- patients had lower rates of clinical response to adalimumab (RA, PsA, JIA, AS, Ps), golimumab (RA), infliximab (RA, PsA, AS, Ps), rituximab (RA), ustekinumab (Ps), and CT-P13 (RA, AS). Higher rates of infusion-related reactions were reported in infliximab- and CT-P13-treated ADAb+ patients. Background immunosuppressives/anti-proliferatives reduced biologic immunogenicity across diseases. CONCLUSIONS Based on reviewed reports, biologic/biosimilar immunogenicity differs among agents, with the highest rates observed with infliximab and adalimumab. As ADAb formation in biologic-/biosimilar-treated patients may increase the risk of lost response, the immunogenicity of these agents is an important (albeit not the only) consideration in the treatment decision-making process.
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Affiliation(s)
- Vibeke Strand
- Division of Immunology/Rheumatology, Stanford University School of Medicine, 306 Ramona Road, Portola Valley, CA, 94028, USA.
| | - Alejandro Balsa
- Rheumatology Unit, Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ), Madrid, Spain
| | - Jamal Al-Saleh
- Rheumatology Section, Dubai Hospital, Dubai, United Arab Emirates
| | - Leonor Barile-Fabris
- Hospital de Especialidades Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México City, Mexico
| | - Takahiko Horiuchi
- Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu, Japan
| | - Tsutomu Takeuchi
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Sadiq Lula
- Market Access Solutions, Envision Pharma Group, London, UK
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Freeman K, Taylor-Phillips S, Connock M, Court R, Tsertsvadze A, Shyangdan D, Auguste P, Mistry H, Arasaradnam R, Sutcliffe P, Clarke A. Test accuracy of drug and antibody assays for predicting response to antitumour necrosis factor treatment in Crohn's disease: a systematic review and meta-analysis. BMJ Open 2017; 7:e014581. [PMID: 28674134 PMCID: PMC5734585 DOI: 10.1136/bmjopen-2016-014581] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE To present meta-analytic test accuracy estimates of levels of antitumour necrosis factor (anti-TNF) and antibodies to anti-TNF to predict loss of response or lack of regaining response in patients with anti-TNF managed Crohn's disease. METHODS MEDLINE, Embase, the Cochrane Library and Science Citation Index were searched from inception to October/November 2014 to identify studies which reported 2×2 table data of the association between levels of anti-TNF or its antibodies and clinical status. Hierarchical/bivariate meta-analysis was undertaken with the user-written 'metandi' package of Harbord and Whiting using Stata V.11 software, for infliximab, adalimumab,anti-infliximab and anti-adalimumab levels as predictors of loss of response. Prevalence of Crohn's disease in included studies was meta-analysed using a random effects model in MetaAnalyst software to calculate positive and negative predictive values. The search was updated in January 2017. RESULTS 31 studies were included in the review. Studies were heterogeneous with respect to the type of test used, criteria for establishing response and loss of response, population examined and results. Meta-analytic summary point estimates for sensitivity and specificity were 65.7% and 80.6% for infliximab trough levels and 56% and 79% for antibodies to infliximab, respectively. Pooled results for adalimumab trough levels and antibodies to adalimumab were similar. Pooled positive and negative predictive values ranged between 70% and 80% implying that between 20% and 30% of both positive and negative test results may be incorrect in predicting loss of response. CONCLUSION The available evidence suggests that these tests have modest predictive accuracy for clinical status; direct test accuracy comparisons in the same population are needed. More clinical trial evidence from test-treat studies is required before the clinical utility of the tests can be reliably evaluated.
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Affiliation(s)
- Karoline Freeman
- Warwick Medical School, University of Warwick, Coventry, Warwickshire, UK
| | | | - Martin Connock
- Warwick Medical School, University of Warwick, Coventry, Warwickshire, UK
| | - Rachel Court
- Warwick Medical School, University of Warwick, Coventry, Warwickshire, UK
| | | | - Deepson Shyangdan
- Warwick Medical School, University of Warwick, Coventry, Warwickshire, UK
| | - Peter Auguste
- Warwick Medical School, University of Warwick, Coventry, Warwickshire, UK
| | - Hema Mistry
- Warwick Medical School, University of Warwick, Coventry, Warwickshire, UK
| | - Ramesh Arasaradnam
- Warwick Medical School, University of Warwick, Coventry, Warwickshire, UK
- Department of Gastroenterology, University Hospital Coventry and Warwickshire, Coventry, UK
| | - Paul Sutcliffe
- Warwick Medical School, University of Warwick, Coventry, Warwickshire, UK
| | - Aileen Clarke
- Warwick Medical School, University of Warwick, Coventry, Warwickshire, UK
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Qiu Y, Chen BL, Mao R, Zhang SH, He Y, Zeng ZR, Ben-Horin S, Chen MH. Systematic review with meta-analysis: loss of response and requirement of anti-TNFα dose intensification in Crohn's disease. J Gastroenterol 2017; 52:535-554. [PMID: 28275925 DOI: 10.1007/s00535-017-1324-3] [Citation(s) in RCA: 138] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 02/21/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND To review the frequency with which anti-TNF-α loses its effect and dose "intensification" is required for Crohn's disease (CD) treatment. METHODS Electronic databases were searched for eligible studies. Raw data from studies meeting inclusion criteria were pooled for effect estimates. Subgroup analyses were performed for exploration of heterogeneity regarding all outcomes. RESULTS Eighty-six eligible studies were included. Estimates of loss of response (LOR) incidence ranged from 8 to 71%. The random effects pooled incidence of LOR with a median follow-up of 1-year was 33% (95% CI 29-38, 55 studies, n = 6135). The effect estimate based on data from patients with infliximab was 33% (95% CI 27-40), 30% (95% CI 22-39) for adalimumab, and 41% (95% CI 30-53) for certolizumabpegol. Overall, the mean percentage of patients' LOR to anti-TNFs was 38.5%. The annual risk for LOR was 20.9% per patient-year. The random-effects pooled rate of need for dose intensification with a median follow-up of 1 year was 34% (95% CI 28-41, 38 studies, n = 10,690). The effect estimate for infliximab was 38% (95% CI 28-50), 36% (95% CI 30-43) for adalimumab, and 2% (95% CI 2-3) for certolizumab-pegol. The mean percentage of patients who needed an anti-TNF dose escalation was 23% with an annual risk of 18.5% per patient-year. There was no evidence of publication bias for incidence of LOR but not for the dose intensification (p = 0.001). CONCLUSIONS Overall, around one-third of CD patients experience a LOR and required dose intensification in primary anti-TNF-α responders.
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Affiliation(s)
- Yun Qiu
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Bai-Li Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Sheng-Hong Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Yao He
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Zhi-Rong Zeng
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Shomron Ben-Horin
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China.,IBD Service, Department of Gastroenterology, Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University, 52621, Tel Hashomer, Israel
| | - Min-Hu Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China.
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Proposal for an anti-TNF-exit strategy based on trough serum level. Biologicals 2017; 47:81-85. [PMID: 28400083 DOI: 10.1016/j.biologicals.2017.03.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 02/04/2017] [Accepted: 03/08/2017] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND AND AIMS The aim of the study was to evaluate, if the strategy to stop anti-TNF treatment after determination of low trough serum levels and exclusion of inflammation is associated with lower relapse rates. METHODS Since 2013 we followed an exit strategy in patients treated with anti-TNF treatment for inflammatory bowel disease based on trough serum levels. The relapse rates were observed prospectively, data analysis was performed in a retrospective manner of the collected clinical data. RESULTS Forty patients were enrolled, who stopped anti-TNF therapy. 13 Patients followed the clinical algorithm, 27 patients were used as control group (13 patients with ulcerative colitis and 14 patients with Crohn's disease). 19 patients received Infliximab, 21 Adalimumab. The median follow-up time after discontinuation was 19 months (IQR 18). Relapses were observed in 22/40 patients (55%). Among the 13 patients with a targeted discontinuation of therapy based on the algorithm, three relapses were observed (23%), compared to 19/27 (70%) from the non-algorithm group (OR: 7.9; 95%-CI: 1.7-36.5). Relapse-free-survival after anti-TNF discontinuation was significantly higher in patients treated by the algorithm compared to the non-algorithm group (p = 0.032). CONCLUSION An exit strategy based on trough serum levels significantly reduces the relapse rate.
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Biancone L, Annese V, Ardizzone S, Armuzzi A, Calabrese E, Caprioli F, Castiglione F, Comberlato M, Cottone M, Danese S, Daperno M, D'Incà R, Frieri G, Fries W, Gionchetti P, Kohn A, Latella G, Milla M, Orlando A, Papi C, Petruzziello C, Riegler G, Rizzello F, Saibeni S, Scribano ML, Vecchi M, Vernia P, Meucci G. Safety of treatments for inflammatory bowel disease: Clinical practice guidelines of the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD). Dig Liver Dis 2017; 49:338-358. [PMID: 28161290 DOI: 10.1016/j.dld.2017.01.141] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Revised: 12/19/2016] [Accepted: 01/07/2017] [Indexed: 02/08/2023]
Abstract
Inflammatory bowel diseases are chronic conditions of unknown etiology, showing a growing incidence and prevalence in several countries, including Italy. Although the etiology of Crohn's disease and ulcerative colitis is unknown, due to the current knowledge regarding their pathogenesis, effective treatment strategies have been developed. Several guidelines are available regarding the efficacy and safety of available drug treatments for inflammatory bowel diseases. Nevertheless, national guidelines provide additional information adapted to local feasibility, costs and legal issues related to the use of the same drugs. These observations prompted the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) to establish Italian guidelines on the safety of currently available treatments for Crohn's disease and ulcerative colitis. These guidelines discuss the use of aminosalicylates, systemic and low bioavailability corticosteroids, antibiotics (metronidazole, ciprofloxacin, rifaximin), thiopurines, methotrexate, cyclosporine A, TNFα antagonists, vedolizumab, and combination therapies. These guidelines are based on current knowledge derived from evidence-based medicine coupled with clinical experience of a national working group.
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Affiliation(s)
- Livia Biancone
- Gastroenterology Unit, University of Rome "Tor Vergata", Department of Systems Medicine, Rome, Italy.
| | - Vito Annese
- AOU Careggi, Gastroenterology, Florence, Italy
| | - Sandro Ardizzone
- Gastrointestinal Unit, ASST Fatebenefratelli Sacco - University of Milan, Milan, Italy
| | - Alessandro Armuzzi
- IBD Unit, Presidio Columbus, Fondazione Policlinico Gemelli Universita' Cattolica, Rome, Italy
| | - Emma Calabrese
- Gastroenterology Unit, University of Rome "Tor Vergata", Department of Systems Medicine, Rome, Italy
| | - Flavio Caprioli
- Department of Pathophysiology and Transplantation, University of Milan and Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda,Ospedale Policlinico di Milano, Milan, Italy
| | | | - Michele Comberlato
- Department of Gastroenterology and Digestive Endoscopy, Central Hospital, Bolzano, Italy
| | - Mario Cottone
- Division of Internal Medicine 2, IBD Unit, Hospital "Riuniti Villa Sofia-Cervello", Palermo, Italy
| | - Silvio Danese
- Humanitas Research Hospital and Humanitas University, Rozzano (Milan), Italy
| | - Marco Daperno
- Hospital "Ordine Mauriziano di Torino", Turin, Italy
| | - Renata D'Incà
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Italy
| | - Giuseppe Frieri
- University of L'Aquila, Gastroenterology Unit, L'Aquila, Italy
| | - Walter Fries
- Department of Clinical and Experimental Medicine, Clinical Unit for Chroric Bowel Disorders, University of Messina, Messina, Italy
| | - Paolo Gionchetti
- IBD Unit, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Anna Kohn
- San Camillo-Forlanini Hospital, IBD Unit, Rome, Italy
| | | | | | - Ambrogio Orlando
- Division of Internal Medicine 2, IBD Unit, Hospital "Riuniti Villa Sofia-Cervello", Palermo, Italy
| | - Claudio Papi
- IBD Unit, San Filippo Neri Hospital, Rome, Italy
| | - Carmelina Petruzziello
- Gastroenterology Unit, University of Rome "Tor Vergata", Department of Systems Medicine, Rome, Italy
| | - Gabriele Riegler
- U.O. of Gastroenterology C.S. - University della Campania "Luigi Vanvitelli", Naples, Italy
| | - Fernando Rizzello
- IBD Unit, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Simone Saibeni
- Gastroenterology Unit, Rho Hospital, ASST Rhodense, Rho, Italy
| | | | - Maurizio Vecchi
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Policlinico San Donato and University of Milan, San Donato Milanese, Milan, Italy
| | - Piero Vernia
- Gastroenterology Unit, Sapienza, University of Rome, Rome, Italy
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Schmitz EMH, van de Kerkhof D, Hamann D, van Dongen JLJ, Kuijper PHM, Brunsveld L, Scharnhorst V, Broeren MAC. Therapeutic drug monitoring of infliximab: performance evaluation of three commercial ELISA kits. Clin Chem Lab Med 2017; 54:1211-9. [PMID: 26587745 DOI: 10.1515/cclm-2015-0987] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 10/19/2015] [Indexed: 01/24/2023]
Abstract
BACKGROUND Therapeutic drug monitoring (TDM) of infliximab (IFX, Remicade®) can aid to optimize therapy efficacy. Many assays are available for this purpose. However, a reference standard is lacking. Therefore, we evaluated the analytical performance, agreement and clinically relevant differences of three commercially available IFX ELISA kits on an automated processing system. METHODS The kits of Theradiag (Lisa Tracker Infliximab), Progenika (Promonitor IFX) and apDia (Infliximab ELISA) were implemented on an automated processing system. Imprecision was determined by triplicate measurements of patient samples on five days. Agreement was evaluated by analysis of 30 patient samples and four spiked samples by the selected ELISA kits and the in-house IFX ELISA of Sanquin Diagnostics (Amsterdam, The Netherlands). Therapeutic consequences were evaluated by dividing patients into four treatment groups using cut-off levels of 1, 3 and 7 μg/mL and determining assay concordance. RESULTS Within-run and between-run imprecision were acceptable (≤12% and ≤17%, respectively) within the quantification range of the selected ELISA kits. The apDia assay had the best precision and agreement to target values. Statistically significant differences were found between all assays except between Sanquin Diagnostics and the Lisa Tracker assay. The Promonitor assay measured the lowest IFX concentrations, the apDia assay the highest. When patients were classified in four treatment categories, 70% concordance was achieved. CONCLUSIONS Although all assays are suitable for TDM, significant differences were observed in both imprecision and agreement. Therapeutic consequences were acceptable when patients were divided in treatment categories, but this could be improved by assay standardization.
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Tighe D, McNamara D. Clinical impact of immunomonitoring in the treatment of inflammatory bowel disease. World J Gastroenterol 2017; 23:414-425. [PMID: 28210077 PMCID: PMC5291846 DOI: 10.3748/wjg.v23.i3.414] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 04/29/2016] [Accepted: 06/02/2016] [Indexed: 02/06/2023] Open
Abstract
Despite improvement in outcomes, loss of response (LOR) to tumor necrosis factor-alpha (TNFα) therapies is a big concern in the management of inflammatory bowel disease. LOR is associated with flares of disease, increased hospitalisation rates, need for surgical interventions, and decline in quality of life. LOR may be multifactorial, but immunogenicity makes a significant contribution. Traditionally doses of anti-TNFα have been adjusted based on clinical response, using a standard approach. Immunomonitoring involves the measurement of anti-TNFα trough and antibody levels. It takes into account the underlying pharmacokinetics of anti-TNFα therapies. Expanding on this a treat to target approach may be used, where doses are intensified, or tailored to the individual based on the measurement of anti-TNFα trough and antibody levels. This review looks at the history, evolution, and clinical impact that immunomonitoring is having in the treatment of inflammatory bowel disease. It will focus on the role of immunomonitoring in helping to achieve long lasting deep remission and mucosal healing. It will explore the different options in terms of best measuring trough and antibody levels, explore possible advantages of immunomonitoring, and discuss its role in best optimising response, at induction, during the maintenance phase of treatment, as well as a role in withdrawing or switching therapy.
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Papamichael K, Cheifetz AS. Use of anti-TNF drug levels to optimise patient management. Frontline Gastroenterol 2016; 7:289-300. [PMID: 28839870 PMCID: PMC5369499 DOI: 10.1136/flgastro-2016-100685] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2016] [Accepted: 01/23/2016] [Indexed: 02/04/2023] Open
Abstract
Anti-tumour necrosis factor (TNF) therapies, such as infliximab, adalimumab, certolizumab pegol and golimumab, have been proven to be effective for the treatment of patients with Crohn's disease and ulcerative colitis. However, 10%-30% of patients with inflammatory bowel disease (IBD) show no initial clinical benefit to anti-TNF therapy (primary non-response), and over 50% after an initial favourable outcome will lose response over time (secondary loss of response (SLR)). Numerous recent studies in IBD have revealed an exposure-response relationship suggesting a positive correlation between high serum anti-TNF concentrations and favourable therapeutic outcomes including clinical, biomarker and endoscopic remission, whereas antidrug antibodies have been associated with SLR and infusion reactions. Currently, therapeutic drug monitoring (TDM) is typically performed when treatment failure occurs either for SLR, drug intolerance (potential immune-mediated reaction) or infusion reaction (reactive TDM). Nevertheless, recent data demonstrate that proactive TDM and a treat-to-target (trough) therapeutic approach may more effectively optimise anti-TNF therapy efficacy, safety and cost. However, implementing TDM in real-life clinical practice is currently limited by the diversity in study design, therapeutic outcomes and assays used, which have hindered the identification of robust clinically relevant concentration thresholds. This review will focus mainly on the pharmacodynamic properties of anti-TNF therapy and the role of TDM in guiding therapeutic decisions in IBD.
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Affiliation(s)
- Konstantinos Papamichael
- Division of Gastroenterology, Center for Inflammatory Bowel Diseases, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Adam S Cheifetz
- Division of Gastroenterology, Center for Inflammatory Bowel Diseases, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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Melmed GY, Irving PM, Jones J, Kaplan GG, Kozuch PL, Velayos FS, Baidoo L, Sparrow MP, Bressler B, Cheifetz AS, Devlin SM, Raffals LE, Vande Casteele N, Mould DR, Colombel JF, Dubinsky M, Sandborn WJ, Siegel CA. Appropriateness of Testing for Anti-Tumor Necrosis Factor Agent and Antibody Concentrations, and Interpretation of Results. Clin Gastroenterol Hepatol 2016; 14:1302-1309. [PMID: 27189916 DOI: 10.1016/j.cgh.2016.05.010] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Revised: 04/15/2016] [Accepted: 05/01/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The availability of tests for blood concentrations of anti-tumor necrosis factor (TNF) agents and antibodies against these drugs could improve dose selection for patients with inflammatory bowel disease (IBD). However, there is little consensus on when to test and how to interpret test results. We used the RAND/UCLA Appropriateness Method to determine when these tests are appropriate and how to clinically interpret their results. METHODS We conducted a systematic literature search in November 2013 to identify observational or experimental studies of the measurement of anti-TNF drug and antibody concentrations in patients with IBD and interpretation of their results. We developed 35 scenarios that assessed the appropriateness of testing and 143 scenarios that addressed clinical strategies in response to test results, and presented the findings to an expert panel. The appropriateness of each scenario was rated before and after an in-person meeting with the panel. Panelists rated the appropriateness of various clinical management options including changing therapy within class, switching out of class, adjusting drug dose or interval, adding or adjusting concomitant immune modulators, and doing nothing for each of 6 permutations of high versus low drug concentrations and high, low, or undetectable antibody concentrations. Disagreement was assessed using a validated index. RESULTS Assessment of anti-TNF drug and antibody concentrations was rated appropriate at the end of induction therapy in primary nonresponders, in secondary nonresponders, at least once during the first year of maintenance therapy, and following a drug holiday. Routine assessment in responders at the end of induction was rated uncertain. In nearly all scenarios, escalation of drug dosing was rated appropriate when drug concentration was low in the absence of antibodies, and switching within class was rated appropriate when antibodies were present. Other recommendations depended on the specific clinical scenario for which the test was obtained. CONCLUSIONS Based on the RAND/UCLA Appropriateness Method of analysis, an expert panel recommends testing for drug and antibody concentrations in many clinical scenarios. The appropriate timing and best way to respond to anti-TNF drug and antibody testing for IBD depends on the specific clinical scenario. These recommendations can help guide clinicians to best optimize anti-TNF therapy.
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Affiliation(s)
- Gil Y Melmed
- Cedars-Sinai Medical Center, Los Angeles, California.
| | | | | | | | | | | | | | | | | | | | | | | | - Niels Vande Casteele
- University of California San Diego, San Diego, California; KU Leuven - University of Leuven, Leuven, Belgium
| | - Diane R Mould
- Projections Research Inc, Phoenixville, Pennsylvania
| | | | - Marla Dubinsky
- Icahn School of Medicine at Mount Sinai, New York, New York
| | | | - Corey A Siegel
- Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
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Optimizing Treatment with TNF Inhibitors in Inflammatory Bowel Disease by Monitoring Drug Levels and Antidrug Antibodies. Inflamm Bowel Dis 2016; 22:1999-2015. [PMID: 27135483 DOI: 10.1097/mib.0000000000000772] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Biological tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of inflammatory bowel disease and redefined treatment goals to include mucosal healing. Clinicians are faced with challenges such as inadequate responses, treatment failures, side effects, and high drug costs. The objective is to review optimization of anti-TNF therapy by use of personalized treatment strategies based on circulating drug levels and antidrug antibodies (Abs), i.e. therapeutic drug monitoring (TDM). Furthermore, to outline TDM-related pitfalls and their prevention. METHODS Literature review. RESULTS Circulating anti-TNF drug trough level is a marker for the pharmacokinetics (PK) of TNF inhibitors. Because of a number of factors, including antidrug antibodies, PK varies between and within patients across time leading to variable clinical outcomes. Differences in intestinal inflammatory phenotype influencing the pharmacodynamic (PD) responses to TNF inhibitors also affect treatment outcomes. As an alternative to handling anti-TNF-treated patients by empiric strategies, TDM identifies underlying PK and PD-related reasons for treatment failure and aids decision making to secure optimal clinical and economic outcomes. Although promising, evidence does not the support use of TDM to counteract treatment failure in quiescent disease. Use of TDM is challenged by methodological biases, difficulties related to differentiation between PK and PD problems, and temporal biases due to lack of chronology between changes in PK versus symptomatic and objective disease activity manifestations. Biases can be accommodated by knowledgeable interpretation of results obtained by validated assays with clinically established thresholds, and by repeated assessments over time using complimentary techniques. CONCLUSIONS TDM-guided anti-TNF therapy at treatment failure has been brought from bench to bedside.
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Kopylov U, Seidman E. Predicting durable response or resistance to antitumor necrosis factor therapy in inflammatory bowel disease. Therap Adv Gastroenterol 2016; 9:513-26. [PMID: 27366220 PMCID: PMC4913332 DOI: 10.1177/1756283x16638833] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Monoclonal antibodies to tumor necrosis factor (TNF) have become a mainstay of the therapeutic armamentarium in inflammatory bowel disease (IBD) over the last 15 years. Although highly effective, primary and secondary nonresponse are common and associated with poor clinical outcomes and significant costs. Multiple clinical, genetic and immunopharmacological factors may impact the response to anti-TNFs. Early stratification of IBD patients by the expected risk of therapeutic failure during the induction and maintenance phases of treatment may allow for treatment optimization and potentially optimal short- and long-term outcomes. The aim of this review is to summarize the current data concerning the potential predictors of therapeutic success and failure of anti-TNFs in IBD.
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Affiliation(s)
- Uri Kopylov
- Division of Gastroenterology, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv, Israel
| | - Ernest Seidman
- Professor of Medicine and Pediatrics McGill University, Director, IBD Center of Excellence at McGill, Bruce Kaufman Endowed Chair in IBD at McGill, Canada Research Chair in Immune Mediated Gastrointestinal Disorders, Digestive Lab Research Institute of the McGill University Health Centre, 1650 Cedar Avenue C10.145, Montreal, QC H3G 1A4, Canada
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Anti-infliximab Antibodies with Neutralizing Capacity in Patients with Inflammatory Bowel Disease: Distinct Clinical Implications Revealed by a Novel Assay. Inflamm Bowel Dis 2016; 22:1655-61. [PMID: 27120567 DOI: 10.1097/mib.0000000000000797] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND About 60% of infliximab (IFX)-treated patients develop antidrug antibodies (ADA), although their clinical significance remains disputed. The aim of this study was to develop an assay for assessing ADA-neutralizing potential, and clinical significance. METHODS An immune assay was devised in which the inhibition of IFX binding to plated-tumor necrosis factor in the presence of patient sera or controls, was assessed and defined as IFX-tumor necrosis factor binding reduction ratio (ITBR). The assay was compared to a bioassay in which tumor necrosis factor-α-induced interleukin-8 secretion from HT-29 cells was assessed after addition of IFX to ADA-containing sera or control sera. RESULTS Both assays detected neutralizing antibodies in 39 of 44 ADA-positive sera. The median ITBR was 3.66 (mean 4.9 ± 3.2) in 29 ADA-positive patients with loss of response (LOR), and 1.3 (mean 1.9 ± 1.3) in 15 patients without LOR (P = 0.001). ADA titers in both groups were similar (median 9.5 and 10.2 μg/mL, respectively P = 0.74). Using an ITBR of 1.65, the sensitivity for LOR detection was 86.2% and the specificity was 66.7%. (positive predictive value 83%; negative predictive value 71.4%; P = 0.001). When early ADA-IFX-sera from IFX-treated patients with or without subsequent LOR were compared, the median ITBRs were 1.1 and 0.57, respectively (P = 0.028). CONCLUSIONS Detection of neutralizing antibody activity was superior to antibody quantization by enzyme-linked immunosorbent assay with respect to correlation with clinical LOR, and for prediction of subsequent LOR. These findings may assist in optimizing infliximab therapy in patients with inflammatory bowel disease.
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Ben-Horin S, Yavzori M, Benhar I, Fudim E, Picard O, Ungar B, Lee S, Kim S, Eliakim R, Chowers Y. Cross-immunogenicity: antibodies to infliximab in Remicade-treated patients with IBD similarly recognise the biosimilar Remsima. Gut 2016; 65:1132-8. [PMID: 25897019 DOI: 10.1136/gutjnl-2015-309290] [Citation(s) in RCA: 134] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Accepted: 03/28/2015] [Indexed: 12/12/2022]
Abstract
OBJECTIVE The cross-immunogenicity of the recently approved infliximab-biosimilar Remsima (CT-P13) with the originator drug Remicade is still unknown. DESIGN Sera of patients with IBD with or without measurable anti-Remicade antibodies to infliximab (ATI) were tested for their cross-reactivity to two batches of Remsima. Experiments were repeated after deglycosylation of Remicade/Remsima, IgG purification, excipients' dialysis and monomer purification by size exclusion chromatography. Anti-Remicade antibodies were tested for their functional inhibition of TNF-α binding by Remsima/Remicade by competition assay. Cross-reactivity of anti-adalimumab antibodies with Remicade/Remsima was also investigated. RESULTS 125 patients' and controls' sera were tested (median age 31 years, IQR 24.5-39.5). All 56 anti-Remicade ATI-negative controls (14 healthy individuals, 42 patients with IBD) were also negative for anti-Remsima ATI. All 69 positive anti-Remicade IBD sera were cross-reactive with Remsima. ATI titres against Remicade or Remsima were strongly correlated (r values between 0.92 and 0.99, p<0.001 for all experiments, Spearman's correlation test). The background ELISA signal for Remsima was slightly higher compared with Remicade in negative controls (1.25±0.6 µg/mL vs 0.76±0.5 µg/mL, respectively, p<0.001), and persisted after deglycosylation, dialysis or protein size filtration, but abolished by IgG purification and significantly diminished by monomer purification. Anti-Remicade ATIs of patients with IBD (n=10) exerted similar functional inhibition on Remsima or Remicade TNF-α binding capacity (p=NS for all inhibition curve points). Antibodies-to-adalimumab in adalimumab-treated patients with IBD (n=7) did not cross-react with either Remicade or Remsima. CONCLUSIONS Anti-Remicade antibodies in patients with IBD recognise and functionally inhibit Remsima to a similar degree, suggesting similar immunogenicity and shared immunodominant epitopes on these two infliximab agents. In contrast, anti-adalimumab antibodies do not cross-react with Remsima or Remicade.
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Affiliation(s)
- Shomron Ben-Horin
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
| | - Miri Yavzori
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
| | - Itai Benhar
- Department of Molecular Microbiology and Biotechnology, Tel-Aviv University, Tel-Aviv, Israel
| | - Ella Fudim
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
| | - Orit Picard
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
| | - Bella Ungar
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
| | | | | | - Rami Eliakim
- Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel
| | - Yehuda Chowers
- Rambam Health Care Campus & Bruce Rappaport School of Medicine, Technion Institute of Technology, Haifa, Israel
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Minar P, Saeed SA, Afreen M, Kim MO, Denson LA. Practical Use of Infliximab Concentration Monitoring in Pediatric Crohn Disease. J Pediatr Gastroenterol Nutr 2016; 62:715-22. [PMID: 26551317 PMCID: PMC4842082 DOI: 10.1097/mpg.0000000000001029] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Therapeutic drug monitoring (TDM) that guides infliximab (IFX) intensification strategies has been shown to improve IFX efficacy. We conducted a review to evaluate the utility of TDM in the assessment and subsequent management of IFX loss of response in our pediatric population with Crohn disease (CD). METHODS Single-center retrospective study of patients with CD receiving IFX that had TDM from December 2009 to September 2013. We defined subtherapeutic trough as a drug level below the detection limit of the Prometheus enzyme-linked immunoabsorbant assay and Anser reference values (1.4 and 1 μg/mL, respectively) or a mid-interval level <12 μg/mL. RESULTS One hundred ninety-one IFX concentration tests were performed on 72 patients with CD with loss of response to therapy as the primary indication (72%). 34% of all TDM were subtherapeutic. After initial TDM, 25 of the 72 patients received regimen intensification with 72% in clinical remission at 6 months. Including all of the TDM that resulted in IFX dose intensification, we found a significant improvement in 6-month remission rates whether intensification followed mid-interval (88% remission) or trough (56% remission) testing (P = 0.026). Antibody to infliximab was found in 14 patients with 5 occurring in the first year of therapy. Furthermore, 71% of patients with antibody to infliximab that were switched to an alternative anti-tumor necrosis factor achieved clinical remission at six months. In multivariable regression analysis, we found IFX dose (mg/kg), IFX dosing frequency (weeks), and the erythrocyte sedimentation rate at the previous infusion were significantly associated with the IFX concentration. CONCLUSIONS TDM in our pediatric population with CD led to informed clinical decisions and improved rates of clinical remission.
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Affiliation(s)
- Phillip Minar
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
| | - Shehzad A. Saeed
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
| | - Mahrukh Afreen
- Dow Medical College, Dow University of Health Sciences, Pakistan
| | - Mi-Ok Kim
- Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center
| | - Lee A. Denson
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
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