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Zhao X, Shan D, Han J. Optimizing CT-P13 SC Use in IBD: ADA Formation, Comparative Efficacy, and Dose Adjustment Strategies. Gastroenterology 2025; 168:630-631. [PMID: 39608684 DOI: 10.1053/j.gastro.2024.09.048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 09/26/2024] [Indexed: 11/30/2024]
Affiliation(s)
- Xiaolei Zhao
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China
| | - Dan Shan
- Department of Biobehavioral Sciences, Columbia University, New York, New York
| | - Jiashu Han
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
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Lowell JA, Sharma G, Chua V, Ben-Horin S, Swaminath A, Sultan K. Reactive Immunomodulator Addition to Infliximab Monotherapy Restores Clinical Response in Inflammatory Bowel Disease: A Meta-Analysis. Dig Dis Sci 2024; 69:3920-3931. [PMID: 38877332 DOI: 10.1007/s10620-024-08515-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 05/29/2024] [Indexed: 06/16/2024]
Abstract
BACKGROUND AND AIMS Patients with inflammatory bowel disease (IBD) receiving infliximab (IFX) commonly experience immunogenic loss of response (LOR) by formation of anti-drug antibodies (ADAs). An immunomodulator (IMM) used in combination with initial IFX induction is known to reduce ADA development and improve clinical outcomes. We aimed to assess the impact of reactively adding an IMM to patients on IFX monotherapy. METHODS We conducted a retrospective cohort study and systematic review with meta-analysis of patients with IBD demonstrating immunologic LOR, with or without clinical LOR, that had an IMM (azathioprine, 6-mercaptopurine, or methotrexate) reactively added (reactive combination therapy; rCT) to combat elevated ADAs and raise IFX level. Data were extracted for pooled effect size estimation using random-effects models, and ADA and IFX trough levels were compared pre- and post-IMM initiation. RESULTS We identified 6 patients who received rCT due to rising ADA titers and low IFX levels. Median ADA titer decreased from 506 ng/mL (interquartile range (IQR) [416-750]) to 76.5 ng/mL (IQR [25.8-232]), an 85% decrease (p = 0.031). Median IFX trough increased from 0.4 µg/mL (IQR [0.4-0.48]) to 8.25 µg/mL (IQR [3.7-9.6]), a 20.6-fold increase (p = 0.038). Meta-analysis pooled effect size of 7 studies with 89 patients showed an 87% ADA titer reduction [95% confidence interval (CI) = 72-94%], 6.7-fold increased IFX trough (95% CI = 2.4-18.7), and 76% clinical remission rescue rate (95% CI = 59-93%). CONCLUSIONS These results suggest rCT is a valid rescue strategy in patients with immunogenic LOR to IFX to reduce ADA titers, restore therapeutic IFX levels, and recapture clinical remission of IBD.
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Affiliation(s)
- Jeffrey A Lowell
- Department of Medicine, Zucker School of Medicine at Hofstra/Northwell, Northwell Health, Manhasset, NY, 11030, USA.
- , 300 Community Drive, Manhasset, NY, 11030, USA.
| | - Garvita Sharma
- Arkansas College of Osteopathic Medicine, Fort Smith, AR, 72916, USA
- Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Vincent Chua
- Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Shomron Ben-Horin
- Gastroenterology Department, Sheba Medical Center, Tel-Aviv University, Tel Aviv, Israel
| | - Arun Swaminath
- Division of Gastroenterology, Lenox Hill Hospital, Northwell Health, New York, NY, 10075, USA
| | - Keith Sultan
- Department of Gastroenterology, Zucker School of Medicine at Hofstra/Northwell, Northwell Health, Manhasset, NY, 11030, USA
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Hanauer SB, Sands BE, Schreiber S, Danese S, Kłopocka M, Kierkuś J, Kulynych R, Gonciarz M, Sołtysiak A, Smoliński P, Srećković S, Valuyskikh E, Lahat A, Horyński M, Gasbarrini A, Osipenko M, Borzan V, Kowalski M, Saenko D, Sardinov R, Lee SJ, Kim S, Bae Y, Lee S, Lee S, Lee JH, Yang S, Lee J, Lee J, Kim JM, Park G, Sandborn WJ, Colombel JF. Subcutaneous Infliximab (CT-P13 SC) as Maintenance Therapy for Inflammatory Bowel Disease: Two Randomized Phase 3 Trials (LIBERTY). Gastroenterology 2024; 167:919-933. [PMID: 38788861 DOI: 10.1053/j.gastro.2024.05.006] [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: 11/07/2023] [Revised: 05/03/2024] [Accepted: 05/04/2024] [Indexed: 05/26/2024]
Abstract
BACKGROUND & AIMS CT-P13 subcutaneous (SC), an SC formulation of the intravenous (IV) infliximab biosimilar CT-P13 IV, creates a unique exposure profile. The LIBERTY studies aimed to demonstrate superiority of CT-P13 SC vs placebo as maintenance therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS Two randomized, placebo-controlled, double-blind studies were conducted in patients with moderately to severely active CD or UC and inadequate response or intolerance to corticosteroids and immunomodulators. All patients received open-label CT-P13 IV 5 mg/kg at weeks 0, 2, and 6. At week 10, clinical responders were randomized (2:1) to CT-P13 SC 120 mg or placebo every 2 weeks until week 54 (maintenance phase) using prefilled syringes. (Co-) primary end points were clinical remission and endoscopic response (CD) and clinical remission (UC) at week 54 (all-randomized population). RESULTS Overall, 396 patients with CD and 548 patients with UC received induction treatment. At week 54 in the CD study, statistically significant higher proportions of CT-P13 SC-treated patients vs placebo-treated patients achieved clinical remission (62.3% vs 32.1%; P < .0001) and endoscopic response (51.1% vs 17.9%; P < .0001). In the UC study, clinical remission rates at week 54 were statistically significantly higher with CT-P13 SC vs placebo (43.2% vs 20.8%; P < .0001). Achievement of key secondary end points was significantly higher with CT-P13 SC vs placebo across both studies. CT-P13 SC was well tolerated, with no new safety signals identified. CONCLUSIONS CT-P13 SC was more effective than placebo as maintenance therapy and was well tolerated in patients with moderately to severely active CD or UC who responded to CT-P13 IV induction. CLINICALTRIALS gov, Numbers: NCT03945019 (CD) and NCT04205643 (UC).
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Affiliation(s)
- Stephen B Hanauer
- Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
| | - Bruce E Sands
- Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Stefan Schreiber
- Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Silvio Danese
- Department of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Hospital and Vita-Salute University, Milan, Italy
| | - Maria Kłopocka
- Department of Gastroenterology and Nutrition Disorders, Nicolaus Copernicus University, Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
| | - Jarosław Kierkuś
- Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, Children's Memorial Health Institute, Warsaw, Poland
| | - Roman Kulynych
- Department of Gastroenterology and Endoscopy, Zaporizhzhia Regional Clinical Hospital, Zaporizhzhia, Ukraine
| | - Maciej Gonciarz
- Department of Gastroenterology and Internal Medicine, Military Institute of Medicine-National Research Institute, Warsaw, Poland
| | - Artur Sołtysiak
- Department of Gastroenterology and General Surgery, Centrum Medyczne Lukamed Joanna Łuka, Chojnice, Poland
| | - Patryk Smoliński
- Department of Gastroenterology Clinical Trials, EuroMediCare Szpital Specjalistyczny, Wrocław, Poland
| | - Slobodan Srećković
- Department of Gastroenterology and Hepatology, Clinical University Hospital Zvezdara, Belgrade, Serbia
| | - Ekaterina Valuyskikh
- Department of Clinical Research, LLC Novosibirskiy Gastrocenter, Novosibirsk, Russia
| | - Adi Lahat
- Department of Gastroenterology, Chaim Sheba Medical Center, Tel Hashomer, Israel, affiliated with Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Marek Horyński
- Department of Gastroenterology, Endoskopia Sp. Z o.o, Sopot, Poland
| | - Antonio Gasbarrini
- Medicina Interna e Gastroenterologia, Università Cattolica del Sacro Cuore; Fondazione Policlinico Universitario Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| | | | - Vladimir Borzan
- Department of Gastroenterology, Faculty of Medicine, Clinical Hospital Center Osijek, Osijek, Croatia
| | - Maciej Kowalski
- Department of Gastroenterology, Centrum Diagnostyczno - Lecznicze Barska, Włocławek, Poland
| | - Daria Saenko
- LLC "Clinica UZI 4D," Stavropol Region, Pyatigorsk, Russia
| | - Ruslan Sardinov
- Department of Therapy, BioTechService LLC, St Petersburg Medical and Social Institute, Saint Petersburg, Russia
| | - Sang Joon Lee
- Data Science Institute, Celltrion, Inc, Incheon, Republic of Korea
| | - Sunghyun Kim
- Medical Science Division, Celltrion, Inc, Incheon, Republic of Korea
| | - Yunju Bae
- Medical Science Division, Celltrion, Inc, Incheon, Republic of Korea
| | - Sunhee Lee
- Medical Science Division, Celltrion, Inc, Incheon, Republic of Korea
| | - Seulgi Lee
- Data Science Institute, Celltrion, Inc, Incheon, Republic of Korea
| | - Joon Ho Lee
- Medical Science Division, Celltrion, Inc, Incheon, Republic of Korea
| | - Siyoung Yang
- Medical Science Division, Celltrion, Inc, Incheon, Republic of Korea
| | - Jimin Lee
- Medical Science Division, Celltrion, Inc, Incheon, Republic of Korea
| | - Juhyun Lee
- Medical Science Division, Celltrion, Inc, Incheon, Republic of Korea
| | - Jong Min Kim
- Data Science Institute, Celltrion, Inc, Incheon, Republic of Korea
| | - Gahee Park
- Data Science Institute, Celltrion, Inc, Incheon, Republic of Korea
| | - William J Sandborn
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, California.
| | - Jean-Frederic Colombel
- Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.
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Husman J, Černá K, Matthes K, Gilger M, Arsova M, Schmidt A, Winzer N, Brosch AM, Brinkmann F, Hampe J, Zeissig S, Lukáš M, Schmelz R. Subcutaneous infliximab in Crohn's disease patients with previous immunogenic failure of intravenous infliximab. Int J Colorectal Dis 2024; 39:151. [PMID: 39317813 PMCID: PMC11422436 DOI: 10.1007/s00384-024-04727-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/16/2024] [Indexed: 09/26/2024]
Abstract
PURPOSE Immunogenicity is a major reason for secondary loss of response to infliximab (IFX). Recent work suggested potentially lower immunogenicity of subcutaneous (SC) compared to intravenous (IV) IFX. However, it is unknown whether re-exposure to IFX SC after secondary loss of response and immunogenicity to its intravenous formulation is safe and effective. METHODS In a retrospective cohort study conducted at two medical centers, patients with clinically (Harvey-Bradshaw Index ≥ 5) and/or biochemically (fecal calprotectin > 250 µg/g) active Crohn's disease (CD) and previous immunogenic failure of IFX IV underwent exposure to IFX SC. Harvey-Bradshaw Index, fecal calprotectin, IFX serum concentration, and anti-drug antibodies were assessed until month 12. RESULTS Twenty CD patients were included. The majority of patients (90%) had previous treatment with three or more biologics. Fifteen (75%) and ten (50%) of 20 patients continued IFX SC treatment until months 6 and 12, respectively. No immediate hypersensitivity reactions were observed. Two patients discontinued IFX SC treatment because of delayed hypersensitivity at week 2 and week 4. IFX serum concentrations increased from baseline to month 12, while anti-drug antibody levels decreased. Combined clinical and biochemical remission at month 12 was observed in seven of 20 patients (35%). CONCLUSION Subcutaneous infliximab treatment of Crohn's disease patients with previous immunogenic failure of intravenous infliximab was well tolerated and effective in a cohort of patients with refractory Crohn's disease.
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Affiliation(s)
- Julia Husman
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
| | - Karin Černá
- Clinical and Research Center for Inflammatory Bowel Disease ISCARE and First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Katja Matthes
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
| | - Maximilian Gilger
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
| | - Maia Arsova
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
| | - Alexandra Schmidt
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
| | - Nadia Winzer
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
| | - Anna-Magdalena Brosch
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
| | - Franz Brinkmann
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
| | - Jochen Hampe
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
| | - Sebastian Zeissig
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany
- Center for Regenerative Therapies Dresden (CRTD), Technische Universität (TU), Dresden, Germany
- Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Milan Lukáš
- Clinical and Research Center for Inflammatory Bowel Disease ISCARE and First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Renate Schmelz
- Department of Medicine 1, University Hospital Carl Gustav Carus Dresden, Technische Universität (TU), Fetscherstrasse 74, 01307, Dresden, Germany.
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5
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Srinivasan A, van Langenberg D, De Cruz P, Segal J, Vasudevan A, Upton RN. Treatment Targets Should Influence Choice of Infliximab Dose Intensification Strategy in Inflammatory Bowel Disease: A Pharmacokinetic Simulation Study. BioDrugs 2024; 38:691-702. [PMID: 39168947 PMCID: PMC11358351 DOI: 10.1007/s40259-024-00673-2] [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: 07/24/2024] [Indexed: 08/23/2024]
Abstract
BACKGROUND The optimal infliximab dose intensification strategy to address loss of response associated with subtherapeutic infliximab trough levels remains uncertain, as does whether post-intensification trough and treatment targets should influence this decision. OBJECTIVES This pharmacokinetic simulation study aimed to identify infliximab dose intensification strategies capable of achieving post-intensification infliximab trough thresholds associated with clinical and objective treatment targets in Crohn's disease and ulcerative colitis. METHODS A validated pharmacokinetic infliximab model, applied to 200 simulated patients, identified those with subtherapeutic (< 3.00 mg/L) trough levels after 30 weeks of standard (5 mg/kg 8-weekly) dosing, and subsequently applied 10 dose intensification strategies over a further 32 weeks. The proportion of simulations achieving 32-week post-intensification infliximab trough levels associated with endoscopic remission (ulcerative colitis > 7.50 mg/L, Crohn's disease > 9.70 mg/L) was the primary outcome, with perianal fistula healing (Crohn's disease > 10.10 mg/L) and clinical improvement (ulcerative colitis > 3.70 mg/L, Crohn's disease > 7.00mg/L) evaluated as secondary outcomes. All outcomes were stratified by intensity of dose intensification, with standard (≤ 10 mg/kg 8-weekly or 5 mg/kg 4-weekly; n = 5) and intensive (> 10 mg/kg 8-weekly or 5 mg/kg 4-weekly; n = 5) dosing strategies defined, respectively. RESULTS The median pre-intensification infliximab trough level was 0.91 mg/L (interquartile range 1.37). Intensive dosing strategies were more likely to achieve infliximab trough concentrations associated with endoscopic remission (ulcerative colitis 36.48% vs. 10.80%, Crohn's disease 25.98 vs. 4.68%), perianal fistula healing (24.52% vs. 4.36%) and clinical improvement (ulcerative colitis 61.90% vs. 34.86%, Crohn's disease 40.32 vs. 12.08%) than standard intensification strategies (all p < 0.01). When controlling for cumulative (mg/kg) infliximab dose over 32 weeks, strategies that concurrently dose increased and interval shortened achieved the highest infliximab trough levels (all p < 0.01). CONCLUSION This simulation-based analysis highlights the potential of using post-intensification infliximab trough thresholds associated with aspirational treatment targets in Crohn's disease and ulcerative colitis to guide choice of infliximab dose intensification strategy. Intensive dose intensification strategies, particularly those that concurrently dose increase and interval shorten, appear to achieve higher infliximab levels than standard dose intensification strategies. This may be particularly important in the pursuit of stringent endpoints, such as endoscopic remission and fistula healing, which have been consistently associated with higher infliximab trough levels. These findings require validation across real-world cohorts.
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Affiliation(s)
- Ashish Srinivasan
- Department of Gastroenterology, Eastern Health, Melbourne, VIC, Australia.
- Monash University, Eastern Health Clinical School, Melbourne, VIC, Australia.
- Department of Gastroenterology, Austin Health, Melbourne, VIC, Australia.
- The University of Melbourne, Austin Academic Centre, Melbourne, VIC, Australia.
| | | | - Peter De Cruz
- Department of Gastroenterology, Austin Health, Melbourne, VIC, Australia
- The University of Melbourne, Austin Academic Centre, Melbourne, VIC, Australia
| | - Jonathan Segal
- Royal Melbourne Hospital, Melbourne, VIC, Australia
- The University of Melbourne, Royal Melbourne Hospital, Melbourne, VIC, Australia
| | - Abhinav Vasudevan
- Department of Gastroenterology, Eastern Health, Melbourne, VIC, Australia
- Monash University, Eastern Health Clinical School, Melbourne, VIC, Australia
| | - Richard N Upton
- Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
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Trivedi PJ, Hirschfield GM, Adams DH, Vierling JM. Immunopathogenesis of Primary Biliary Cholangitis, Primary Sclerosing Cholangitis and Autoimmune Hepatitis: Themes and Concepts. Gastroenterology 2024; 166:995-1019. [PMID: 38342195 DOI: 10.1053/j.gastro.2024.01.049] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 01/21/2024] [Accepted: 01/28/2024] [Indexed: 02/13/2024]
Abstract
Autoimmune liver diseases include primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis, a family of chronic immune-mediated disorders that target hepatocytes and cholangiocytes. Treatments remain nonspecific, variably effective, and noncurative, and the need for liver transplantation is disproportionate to their rarity. Development of effective therapies requires better knowledge of pathogenic mechanisms, including the roles of genetic risk, and how the environment and gut dysbiosis cause immune cell dysfunction and aberrant bile acid signaling. This review summarizes key etiologic and pathogenic concepts and themes relevant for clinical practice and how such learning can guide the development of new therapies for people living with autoimmune liver diseases.
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Affiliation(s)
- Palak J Trivedi
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Liver Unit, University Hospitals Birmingham, Birmingham, United Kingdom; Institute of Translational Medicine, University of Birmingham, Birmingham, United Kingdom.
| | - Gideon M Hirschfield
- Division of Gastroenterology and Hepatology, Toronto Centre for Liver Disease, University of Toronto, Toronto, Ontario, Canada
| | - David H Adams
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Liver Unit, University Hospitals Birmingham, Birmingham, United Kingdom
| | - John M Vierling
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Division of Abdominal Transplantation, Department of Surgery, Baylor College of Medicine, Houston, Texas.
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7
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Vermeire S, Dubinsky MC, Rabizadeh S, Panetta JC, Spencer EA, Dreesen E, D'Haens G, Dervieux T, Laharie D. Forecasted infliximab concentrations during induction predict time to remission and sustained disease control of inflammatory bowel disease. Clin Res Hepatol Gastroenterol 2024; 48:102374. [PMID: 38750934 DOI: 10.1016/j.clinre.2024.102374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 05/06/2024] [Accepted: 05/12/2024] [Indexed: 05/20/2024]
Abstract
BACKGROUND Infliximab (IFX) exposure is established as a predictive factor of pharmacokinetic (PK) origin in inflammatory bowel disease (IBD), and expert consensus is to achieve adequate exposure during induction to achieve and sustain remission. METHODS We retrospectively evaluated the performance of a Bayesian PK tool in IBD patients starting IFX. Trough IFX serum levels collected immediately before the third (at week 6) and fourth (at week 14) infusions were evaluated from 307 IBD patients (median age=17 years, 50 % females, 83 % with Crohn's disease). Forecasted IFX concentration at the fourth infusion were estimated using serum IFX, antibodies to IFX, albumin and weight determined immediately before the third infusion using population PK calculator with Bayesian prior. The outcome variable was a clinical & biochemical remission status achieved (CRP levels below 3 mg/L in presence of clinical remission). Statistics consisted of Kaplan Meier analysis with calculation of Hazard ratio (HR), and logistic regression. RESULTS IFX concentration above 15 µg/mL immediately before the third infusion associated with shorter time to clinical & biochemical remission than concentration below 15 µg/mL without reaching significance (163±14 days vs 200±16 days, respectively; p=0.052). However, using PK parameters at the third infusion, forecasted IFX concentrations above 10 µg/mL immediately before the fourth infusion were significantly associated with a higher rate (HR=1.6 95 %CI: 1.1 to 2.1 p<0.01) and shorter time to remission (148±18 days vs 200±13 days p<0.01). In the presence of IFX concentration above 15 µg/mL at the third infusion, there was a significant 2.5-fold higher likelihood of sustained clinical & biochemical remission status during maintenance as compared to IFX concentrations below 15 µg/mL (p<0.01). Forecasted IFX level above 10 µg/mL at fourth infusion associated with significantly 3.9-fold higher likelihood of clinical & biochemical remission as compared to forecasted IFX concentrations below 10 µg/mL (p<0.01). CONCLUSIONS These data further support that optimized IFX concentrations during induction are associated with enhanced disease control in IBD.
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Affiliation(s)
| | | | | | | | | | | | | | | | - David Laharie
- Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
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Gomes LEM, Genaro LM, de Castro MM, Ricci RL, Pascoal LB, Silva FBC, Bonfitto PHL, Camargo MG, Corona LP, Ayrizono MDLS, de Azevedo AT, Leal RF. Infliximab monitoring in Crohn's disease: a neural network approach for evaluating disease activity and immunogenicity. Therap Adv Gastroenterol 2024; 17:17562848241251949. [PMID: 39664232 PMCID: PMC11632880 DOI: 10.1177/17562848241251949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 04/15/2024] [Indexed: 12/13/2024] Open
Abstract
Background The treatment for Crohn's disease (CD) has increasingly required the use of biological agents. Safe and affordable tests have led to the active implementation of therapeutic drug monitoring (TDM) in clinical practice, which, although not yet widely available across all health services, has been proven effective. Objective To analyze serum infliximab (IFX) and antidrug antibody (ADA) levels in CD patients, compare two tests, as well as construct a prediction of neural network using a combination of clinical, epidemiological, and laboratory variables. Design Cross-sectional observational study. Method A cross-sectional observational study was conducted on 75 CD patients in the maintenance phase of IFX treatment. The participants were allocated into two groups: CD in activity (CDA) and in remission (CDR). Disease activity was defined by endoscopic or radiological criteria. Serum IFX levels were measured by enzyme-linked immunosorbent assay (ELISA) and rapid lateral flow assay; ADA levels were measured by ELISA. A nonparametric test was used for statistical analysis; p value of ⩽0.05 was considered significant. Differences between ELISA and rapid lateral flow results within the measurement range were assessed by the Wilcoxon test, Passing-Bablok regression, and Bland-Altman method. Prediction models were created using four neural network sets. Neural networks and performance receiver operating characteristic curves were created using the Keras package in Python software. Results Most participants exhibited supratherapeutic IFX levels (>7 mg/mL). Both tests showed no difference in IFX levels between the CDA and CDR groups (p > 0.05). The use of immunosuppressive therapy did not affect IFX levels (p > 0.05). Only 14.66% of patients had ADA levels >5 AU/mL, and all ADA-positive participants exhibited subtherapeutic IFX levels in both tests. The median results of both tests showed significant differences and moderate agreement (r = -0.6758, p < 0.001). Of the four neural networks developed, two showed excellent performance, with area under the curve (AUCs) of 82-92% and 100%. Conclusion Most participants exhibited supratherapeutic IFX levels, with no significant serum level difference between the groups. There was moderate agreement between tests. Two neural network sets showed disease activity and the presence of ADA, noninvasively determined in patients using IFX by presenting an AUC of >80%.
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Affiliation(s)
- Luis Eduardo Miani Gomes
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Livia Moreira Genaro
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Marina Moreira de Castro
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Renato Lazarin Ricci
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Livia Bitencourt Pascoal
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Filipe Botto Crispim Silva
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Pedro Henrique Leite Bonfitto
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Michel Gardere Camargo
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Ligiana Pires Corona
- Nutritional Epidemiology Laboratory, School of Applied Sciences, University of Campinas, Limeira, São Paulo, Brazil
| | - Maria de Lourdes Setsuko Ayrizono
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Anibal Tavares de Azevedo
- Simulation Laboratory, School of Applied Sciences, University of Campinas, Limeira, São Paulo, Brazil
| | - Raquel Franco Leal
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas, Carlos Chagas Street, 420, Cidade Universitária Zeferino Vaz, Campinas 13083-878, São Paulo, Brazil
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Hammoudi N, Hassid D, Bonnet J, Tran Minh ML, Baudry C, Vauthier A, Chedouba L, Houzé P, Lourenco N, Aparicio T, Gornet JM, Allez M. Infliximab desensitization in patients with inflammatory bowel diseases: a safe therapeutic alternative. Scand J Gastroenterol 2024; 59:553-560. [PMID: 38353236 DOI: 10.1080/00365521.2024.2316765] [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: 11/29/2023] [Revised: 02/05/2024] [Accepted: 02/05/2024] [Indexed: 04/26/2024]
Abstract
BACKGROUND Hypersensitivity reactions (HSR) to the administration of infliximab (IFX) in Inflammatory Bowel Diseases (IBD) patients are not rare and usually lead to drug discontinuation. We report data on safety and effectiveness of desensitization to IFX in patients with previous HSR. METHODS We conducted a retrospective monocentric observational study. Patients for whom a desensitization protocol to IFX was realized after a previous HSR were included. Anti-drug antibodies (ADA) and IFX trough levels at both inclusion and six months after desensitization were collected. Clinical outcomes, including recurrence of HSR were evaluated. RESULTS From 2005 to 2020, 27 patients (Crohn's Disease: 26 (96%) were included). Desensitization after HSR was performed after a median time of 10.4 months (2.9-33.1). Nineteen (70%) patients received immunosuppressants at time of desensitization. Eight (30%) patients presented HSR at first (n = 2), second (n = 4) or third (n = 2) IFX perfusion after desensitization. None led to intensive care unit transfer or death. Thirteen (48%) had clinical response at 6 months and 8 (29%) were still under IFX treatment two years after desensitization. IFX trough levels and ADA were available for 14 patients at time of desensitization. Most patients (12 out of 14) had ADA at a high level. At 6 months, among the 7 patients with long term response to IFX, 4 presented a decrease of ADA titers and 2 had a significant trough level of IFX. CONCLUSION IFX desensitization in patients with IBD is a safe therapeutic alternative and represents a potential option for patients refractory to multiple biologics.What is already known? Hypersensitivity reactions to the administration of infliximab is frequent. Occurrence of hypersensitivity reaction, either immediate or delayed, usually leads to permanent drug discontinuation.What is new here? Infliximab desensitization is well tolerated with no hypersensitivity reaction recurrence in 70% of patients. Clinical success at 6 months was of 48% and around a third of patients remained under infliximab therapy two years after desensitization. Antidrug antibodies decreased and infliximab trough levels increased in these patients showing the impact of desensitization on immunogenicity.How can this study help patient care? Infliximab desensitization represents a potential option for patients refractory to multiple biologics who presented hypersensitivity reaction to the drug.
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Affiliation(s)
- Nassim Hammoudi
- INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Université de Paris Cité, Paris, France
- Gastroenterology Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
| | - Déborah Hassid
- Gastroenterology Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
| | - Joëlle Bonnet
- INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Université de Paris Cité, Paris, France
- Gastroenterology Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
| | - My-Linh Tran Minh
- Gastroenterology Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
| | - Clotilde Baudry
- Gastroenterology Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
| | - Anne Vauthier
- Gastroenterology Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
| | - Leila Chedouba
- INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Université de Paris Cité, Paris, France
- Gastroenterology Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
| | - Pascal Houzé
- Laboratory of Toxicology, Federation of Toxicology, Lariboisière Hospital, Paris, France
- INSERM UMRS-1144, University of Paris, Paris, France
| | - Nelson Lourenco
- Gastroenterology Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
| | - Thomas Aparicio
- INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Université de Paris Cité, Paris, France
- Gastroenterology Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
| | - Jean-Marc Gornet
- Gastroenterology Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
| | - Matthieu Allez
- INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Université de Paris Cité, Paris, France
- Gastroenterology Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
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10
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Manrai M, Jha AA, Dawra S, Pachisia AV. Biologics, Small Molecules and More in Inflammatory Bowel Disease: The Present and the Future. FUTURE PHARMACOLOGY 2024; 4:279-316. [DOI: 10.3390/futurepharmacol4010017] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/16/2024]
Abstract
Inflammatory bowel disease (IBD) is a group of heterogeneous chronic inflammatory diseases of the gut presenting with intestinal and extraintestinal manifestations. Most cases fit in predominantly two types, namely, ulcerative colitis and Crohn’s disease. The incidence of IBD has been increasing steadily in the past three decades. Focused research has resulted in many therapeutic options. Biologics (derived from humans or animals) and small molecules have emerged as the cornerstone in the management of IBD and have become widely available. Currently, monoclonal antibodies against tumor necrosis factor-alpha (infliximab, adalimumab, certolizumab, and golimumab), integrins (vedolizumab and natalizumab), and interleukin (IL)-12 and IL-23 antagonists (ustekinumab), along with small molecules (tofacitinib), are approved for use. This article summarizes various aspects of these drugs, like clinical pharmacology, indications for use in IBD, safety in pregnancy and lactation, and the adverse effects profile based on the studies leading to their approval. This review also focuses on the recent advances and future perspectives specific to biologics in IBD.
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Affiliation(s)
- Manish Manrai
- Department of Gastroenterology, Command Hospital, Lucknow Pin 226002, Uttar Pradesh, India
| | - Atul Abhishek Jha
- Department of Gastroenterology, Command Hospital, Lucknow Pin 226002, Uttar Pradesh, India
| | - Saurabh Dawra
- Department of Gastroenterology, Command Hospital, Pune Pin 411040, Maharashtra, India
| | - Aditya Vikram Pachisia
- Department of Gastroenterology, Command Hospital, Bengaluru Pin 560007, Karnataka, India
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11
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Otten AT, van der Meulen HH, Steenhuis M, Loeff FC, Touw DJ, Kosterink JGW, Frijlink HW, Rispens T, Dijkstra G, Visschedijk MC, Bourgonje AR. Clinical Validation of a Capillary Blood Home-Based Self-Sampling Technique for Monitoring of Infliximab, Vedolizumab, and C-Reactive Protein Concentrations in Patients With Inflammatory Bowel Disease. Inflamm Bowel Dis 2024; 30:325-335. [PMID: 37265165 PMCID: PMC10906358 DOI: 10.1093/ibd/izad103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Indexed: 06/03/2023]
Abstract
BACKGROUND Therapeutic drug monitoring provides important guidance for treatment of patients with inflammatory bowel disease (IBD) and could help to early identify treatment failure. This study aimed to validate a finger prick-based capillary blood sampling technique to measure biological trough levels and C-reactive protein (CRP) and evaluate patient performance and -support. METHODS In this prospective cohort study, patients with IBD receiving infliximab (IFX) or vedolizumab (VEDO) therapy performed finger prick-based capillary blood sampling at home. Additionally, blood was collected through routinely performed in-hospital venepuncture prior to biological infusion. IFX, VEDO, and CRP concentrations were measured by enzyme-linked immunosorbent assay. The concordance between methods was statistically evaluated and a survey was conducted to assess practicality and patient support. RESULTS In total, 81 patients (46 IFX, 35 VEDO) were enrolled. Mean differences between both methods were 0.42 (95% confidence interval, -1.74 to 2.58) μg/mL for IFX and 0.72 (95% confidence interval, -5.50 to 6.94) μg/mL for VEDO. Passing-Bablok regressions demonstrated no evidence for systematic or proportional biases. Venous and capillary IFX (ρ = 0.96, P < .001) and VEDO (ρ = 0.97, P < .001) levels strongly correlated and showed high intermethod agreement (Cohen's kappa: IFX = 0.82; VEDO = 0.94). Similarly, venous and capillary CRP levels were strongly correlated (ρ = 0.99, P < .001). Most patients (>95%) were able to successfully perform the self-sampling at home without prior instructions. CONCLUSIONS This study clinically validated a finger prick-based capillary blood self-sampling technique allowing concomitant home monitoring of biological levels and CRP for patients with IBD, who reported substantial support, tolerability, and practicality.
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Affiliation(s)
- Antonius T Otten
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, Groningen, the Netherlands
| | - Hedwig H van der Meulen
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, Groningen, the Netherlands
| | - Maurice Steenhuis
- Biologics Laboratory, Sanquin Diagnostic Services, Amsterdam, the Netherlands
| | - Floris C Loeff
- Biologics Laboratory, Sanquin Diagnostic Services, Amsterdam, the Netherlands
| | - Daan J Touw
- Department of Pharmaceutical Analysis, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, the Netherlands
| | - Jos G W Kosterink
- Department of PharmacoTherapy, Epidemiology and Economy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, the Netherlands
| | - Henderik W Frijlink
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, the Netherlands
| | - Theo Rispens
- Department of Immunopathology, Sanquin Research, Amsterdam, the Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, Groningen, the Netherlands
| | - Marijn C Visschedijk
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, Groningen, the Netherlands
| | - Arno R Bourgonje
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, Groningen, the Netherlands
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12
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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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13
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De Mello MK, Freitas Queiroz NS, Papamichael K. Can Proactive Therapeutic Drug Monitoring Overcome Pharmacogenomic-Associated Immunogenicity to Anti-Tumor Necrosis Factor Agents? Clin Gastroenterol Hepatol 2024; 22:200-201. [PMID: 37211267 DOI: 10.1016/j.cgh.2023.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 05/04/2023] [Indexed: 05/23/2023]
Affiliation(s)
| | - Natália Sousa Freitas Queiroz
- Division of Gastroenterology, Pontifical Catholic University of Paraná (PUCPR), Curitiba, Brazil; Santa Cruz Hospital, Curitiba, Brazil
| | - Konstantinos Papamichael
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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14
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Luo Y, Liu C, Luo Y, Zhang X, Li J, Hu C, Yang S. Thiostrepton alleviates experimental colitis by promoting RORγt ubiquitination and modulating dysbiosis. Cell Mol Immunol 2023; 20:1352-1366. [PMID: 37752225 PMCID: PMC10616104 DOI: 10.1038/s41423-023-01085-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 09/08/2023] [Indexed: 09/28/2023] Open
Abstract
Thiostrepton (TST) is a natural antibiotic with pleiotropic properties. This study aimed to elucidate the therapeutic effect of TST on experimental colitis and identify its targets. The effect of TST on colon inflammation was evaluated in a dextran sulfate sodium (DSS)-induced colitis model and a T-cell transfer colitis model. The therapeutic targets of TST were investigated by cytokine profiling, immunophenotyping and biochemical approaches. The effect of TST on the gut microbiota and its contribution to colitis were evaluated in mice with DSS-induced colitis that were subjected to gut microbiota depletion and fecal microbiota transplantation (FMT). Alterations in the gut microbiota caused by TST were determined by 16S rDNA and metagenomic sequencing. Here, we showed that TST treatment significantly ameliorated colitis in the DSS-induced and T-cell transfer models. Specifically, TST targeted the retinoic acid-related orphan nuclear receptor RORγt to reduce the production of IL-17A by γδ T cells, type 3 innate lymphoid cells (ILC3s) and Th17 cells in mice with DSS-induced colitis. Similarly, TST selectively prevented the development of Th17 cells in the T-cell transfer colitis model and the differentiation of naïve CD4+ T cells into Th17 cells in vitro. Mechanistically, TST induced the ubiquitination and degradation of RORγt by promoting the binding of Itch to RORγt. Moreover, TST also reversed dysbiosis to control colonic inflammation. Taken together, these results from our study describe the previously unexplored role of TST in alleviating colonic inflammation by reducing IL-17A production and modulating dysbiosis, suggesting that TST is a promising candidate drug for the treatment of IBD.
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Affiliation(s)
- Ya Luo
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
- Department of Gastroenterology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi Medical University, Zunyi, 563006, China
| | - Cheng Liu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Yuan Luo
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xianglian Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Jing Li
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Changjiang Hu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
| | - Shiming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
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15
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Kim YZ, Kang B, Kim ES, Kwon Y, Choe YH, Kim MJ. Efficacy of Combined Initial Treatment of Methotrexate with Infliximab in Pediatric Crohn's Disease: A Pilot Study. Biomedicines 2023; 11:2575. [PMID: 37761016 PMCID: PMC10526834 DOI: 10.3390/biomedicines11092575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 09/18/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND The combination of antitumor necrosis factor-alpha (TNF-α) agents with immunomodulators (IMMs) is a common treatment for pediatric Crohn's disease (CD). Although methotrexate (MTX) can be a first-line medication as an IMM, most clinicians in real-life practice, especially in South Korea, are more familiar with thiopurines. This study aimed to compare the efficacy and immunogenicity of MTX and azathioprine (AZA) as concurrent therapies for pediatric CD. METHODS In this pilot study, 29 newly diagnosed pediatric patients with moderate-to-severe CD were randomized to receive either MTX (n = 15) (15 mg/body surface area (BSA) per week) or oral AZA (n = 14) (0.5 mg/kg per day) in combination with Infliximab (IFX). The primary outcomes were the proportion of patients in endoscopic, biochemical, and transmural remission after 14 and 54 weeks of IFX therapy. The trough levels (TLs) of IFX and anti-drug antibody (ADA) levels were also compared. RESULTS Among the 29 patients, there were no significant differences in the biochemical (p = 1.0 at week 14, p = 0.45 at week 54), endoscopic (p = 0.968 at week 14, p = 0.05 at week 54), or transmural (p = 0.103 at week 54) remission rates between the two medications during the concurrent therapy. Additionally, the trends in the IFX trough and ADA levels over time during the treatments were similar for both medications, with no significant differences (p = 0.686, p = 0.389, respectively). CONCLUSION The MTX showed comparable efficacy to the AZA in pediatric CD patients with moderate-to-severe disease. This effectively maintained adequate IFX levels and reduced ADA production. Therefore, although additional large-scale clinical trials are needed, this study demonstrated that either MTX or AZA can be selected as IMMs in the concurrent treatment of pediatric CD, depending on individual medical institutions' circumstances.
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Affiliation(s)
- Yoon-Zi Kim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Ben Kang
- Department of Pediatrics, School of Medicine, Kyungpook National University Chilgok Hospital, Daegu 41944, Republic of Korea
| | - Eun-Sil Kim
- Department of Pediatrics, Kangbuk Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 03181, Republic of Korea
| | - Yiyoung Kwon
- Department of Pediatrics, Inha University Hospital, Inha University School of Medicine, Incheon 22188, Republic of Korea;
| | - Yon-Ho Choe
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Mi-Jin Kim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
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16
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Gonzalez Caldito N. Role of tumor necrosis factor-alpha in the central nervous system: a focus on autoimmune disorders. Front Immunol 2023; 14:1213448. [PMID: 37483590 PMCID: PMC10360935 DOI: 10.3389/fimmu.2023.1213448] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 06/14/2023] [Indexed: 07/25/2023] Open
Abstract
Tumor necrosis factor-alpha (TNF-α) is a pleiotropic immune cytokine that belongs to the TNF superfamily of receptor ligands. The cytokine exists as either a transmembrane or a soluble molecule, and targets two distinct receptors, TNF-α receptor 1 (TNFR1) and TNF-α receptor 2 (TNFR2), which activate different signaling cascades and downstream genes. TNF-α cellular responses depend on its molecular form, targeted receptor, and concentration levels. TNF-α plays a multifaceted role in normal physiology that is highly relevant to human health and disease. In the central nervous system (CNS), this cytokine regulates homeostatic functions, such as neurogenesis, myelination, blood-brain barrier permeability and synaptic plasticity. However, it can also potentiate neuronal excitotoxicity and CNS inflammation. The pleiotropism of TNF-α and its various roles in the CNS, whether homeostatic or deleterious, only emphasizes the functional complexity of this cytokine. Anti-TNF-α therapy has demonstrated effectiveness in treating various autoimmune inflammatory diseases and has emerged as a significant treatment option for CNS autoimmune diseases. Nevertheless, it is crucial to recognize that the effects of this therapeutic target are diverse and complex. Contrary to initial expectations, anti-TNF-α therapy has been found to have detrimental effects in multiple sclerosis. This article focuses on describing the various roles, both physiological and pathological, of TNF-α in the CNS. Additionally, it discusses the specific disease processes that are dependent or regulated by TNF-α and the rationale of its use as a therapeutic target.
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Affiliation(s)
- Natalia Gonzalez Caldito
- Department of Neurology, Northwestern Memorial Hospital, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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17
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Kappelman MD, Wohl DA, Herfarth HH, Firestine AM, Adler J, Ammoury RF, Aronow JE, Bass DM, Bass JA, Benkov K, Tobi CB, Boccieri ME, Boyle BM, Brinkman WB, Cabera JM, Chun K, Colletti RB, Dodds CM, Dorsey JM, Ebach DR, Entrena E, Forrest CB, Galanko JA, Grunow JE, Gulati AS, Ivanova A, Jester TW, Kaplan JL, Kugathasan S, Kusek ME, Leibowitz IH, Linville TM, Lipstein EA, Margolis PA, Minar P, Molle-Rios Z, Moses J, Olano KK, Osaba L, Palomo PJ, Pappa H, Park KT, Pashankar DS, Pitch L, Robinson M, Samson CM, Sandberg KC, Schuchard JR, Seid M, Shelly KA, Steiner SJ, Strople JA, Sullivan JS, Tung J, Wali P, Zikry M, Weinberger M, Saeed SA, Bousvaros A. Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: A Pragmatic Randomized Trial. Gastroenterology 2023; 165:149-161.e7. [PMID: 37004887 PMCID: PMC10330864 DOI: 10.1053/j.gastro.2023.03.224] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/02/2023] [Accepted: 03/10/2023] [Indexed: 04/04/2023]
Abstract
BACKGROUND & AIMS Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. METHODS Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. RESULTS Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. CONCLUSIONS Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. CLINICALTRIALS gov, Number: NCT02772965.
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Affiliation(s)
- Michael D Kappelman
- Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
| | - David A Wohl
- Institute of Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Hans H Herfarth
- Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina
| | - Ann M Firestine
- Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Jeremy Adler
- Susan B. Meister Child Health Evaluation and Research Center and Division of Pediatric Gastroenterology, University of Michigan, Ann Arbor, Michigan
| | - Rana F Ammoury
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital of The King's Daughters, Norfolk, Virginia
| | | | - Dorsey M Bass
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Stanford University School of Medicine, Lucile Packard Children's Hospital, Palo Alto, California
| | - Julie A Bass
- Department of Pediatrics, School of Medicine, University of Missouri Kansas City, Division of Gastroenterology, Children's Mercy Kansas City, Kansas City, Missouri
| | - Keith Benkov
- Division of Pediatric Gastroenterology, Icahn School of Medicine at Mt Sinai, New York, New York
| | | | - Margie E Boccieri
- Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Brendan M Boyle
- Division of Gastroenterology, Hepatology, and Nutrition, Nationwide Children's Hospital, Columbus, Ohio
| | - William B Brinkman
- Department of Pediatrics, University of Cincinnati College of Medicine, Division of General and Community Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Jose M Cabera
- Division of Pediatric Gastroenterology, Department of Pediatrics, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Kelly Chun
- Esoterix Specialty Laboratory, Labcorp, Calabasas, California
| | - Richard B Colletti
- Division of Gastroenterology, Department of Pediatrics, University of Vermont, Burlington, Vermont
| | - Cassandra M Dodds
- James M. Anderson Center for Health Systems Excellence, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Jill M Dorsey
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nemours Children's Health, Jacksonville, Florida
| | - Dawn R Ebach
- Division of Pediatric Gastroenterology, Hepatology, Pancreatology, and Nutrition, University of Iowa, Iowa City, Iowa
| | - Edurne Entrena
- Progenika Biopharma, a Grifols Company, Derio, Bizkaia, Spain
| | - Christopher B Forrest
- Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Philadelphia
| | - Joseph A Galanko
- Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - John E Grunow
- University of Oklahoma Children's Physicians, Pediatric Gastroenterology, Oklahoma City, Oklahoma
| | - Ajay S Gulati
- Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Anastasia Ivanova
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Traci W Jester
- Department of Pediatrics, Division of Gastroenterology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Jess L Kaplan
- Division of Pediatric Gastroenterology, Mass General for Children and Harvard Medical School, Boston, Massachusetts
| | | | - Mark E Kusek
- Division of Pediatric Gastroenterology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Ian H Leibowitz
- Division of Gastroenterology, Hepatology and Nutrition, Children's National Medical Center, Department of Pediatrics, George Washington University, Washington, District of Columbia
| | - Tiffany M Linville
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Levine Children's Hospital, Charlotte, North Carolina
| | - Ellen A Lipstein
- Department of Pediatrics, University of Cincinnati College of Medicine, James M. Anderson Center for Health Systems Excellence, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Peter A Margolis
- Department of Pediatrics, University of Cincinnati College of Medicine, James M. Anderson Center for Health Systems Excellence, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Phillip Minar
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Zarela Molle-Rios
- Division of Pediatric Gastroenterology, Nemours Children's Hospital, Wilmington, Delaware
| | - Jonathan Moses
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, University Hospitals Rainbow Babies and Children's Hospital, Cleveland, Ohio
| | - Kelly K Olano
- Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Lourdes Osaba
- Progenika Biopharma, a Grifols Company, Derio, Bizkaia, Spain
| | - Pablo J Palomo
- Division of Pediatric Gastroenterology, Nemours Children's Hospital, Orlando, Florida
| | - Helen Pappa
- Division of Pediatric Gastroenterology, Cardinal Glennon Children's Hospital, Saint Louis University School of Medicine, St Louis, Missouri
| | - K T Park
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Stanford University School of Medicine, Lucile Packard Children's Hospital, Palo Alto, California
| | - Dinesh S Pashankar
- Section of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, Yale School of Medicine, Yale University, New Haven, Connecticut
| | - Lisa Pitch
- ImproveCareNow Inc, Essex Junction, Vermont
| | - Michelle Robinson
- Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Charles M Samson
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri
| | - Kelly C Sandberg
- Department of Gastroenterology, Dayton Children's Hospital, Boonshoft School of Medicine, Wright State University, Dayton, Ohio
| | - Julia R Schuchard
- Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Philadelphia
| | - Michael Seid
- Department of Pediatrics, University of Cincinnati College of Medicine, Division of Pulmonary Medicine, James M. Anderson Center for Health Systems Excellence, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Kimberly A Shelly
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana
| | - Steven J Steiner
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana
| | - Jennifer A Strople
- Division of Gastroenterology, Hepatology and Nutrition, Ann and Robert H. Lurie Children's Hospital of Chicago, Department of Pediatrics, Northwestern Feinberg School of Medicine, Chicago, Illinois
| | - Jillian S Sullivan
- The University of Vermont Children's Hospital and Department of Pediatrics, Larner College of Medicine, The University of Vermont, Burlington, Vermont
| | - Jeanne Tung
- University of Oklahoma Children's Physicians, Pediatric Gastroenterology, Oklahoma City, Oklahoma
| | - Prateek Wali
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, State University of New York Upstate Medical University, Syracuse, New York
| | - Michael Zikry
- Esoterix Specialty Laboratory, Labcorp, Calabasas, California
| | - Morris Weinberger
- Department of Health Policy and Management, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Shehzad A Saeed
- Boonshoft School of Medicine, Wright State University, Dayton Children's Hospital, Dayton, Ohio
| | - Athos Bousvaros
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts
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18
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Kim ES, Kim SK, Park DI, Kim HJ, Lee YJ, Koo JS, Kim ES, Yoon H, Lee JH, Kim JW, Shin SJ, Kim HW, Kim HS, Park YS, Kim YS, Kim TO, Lee J, Choi CH, Han DS, Chun J, Kim HS. Comparison of the Pharmacokinetics of CT-P13 Between Crohn's Disease and Ulcerative Colitis. J Clin Gastroenterol 2023; 57:601-609. [PMID: 35470308 DOI: 10.1097/mcg.0000000000001715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 03/20/2022] [Indexed: 12/10/2022]
Abstract
BACKGROUND We aimed to compare trough infliximab levels and the development of antidrug antibody (ADA) for 1 year between Crohn's disease (CD) and ulcerative colitis (UC) patients who were biologic-naive, and to evaluate their impact on clinical outcomes. METHODS This was a prospective, multicenter, observational study. Biologic-naive patients with moderate to severe CD or UC who started CT-P13, an infliximab biosimilar, therapy were enrolled. Trough drug and ADA levels were measured periodically for 1 year after CT-P13 initiation. RESULTS A total of 267 patients who received CT-P13 treatment were included (CD 168, UC 99). The rates of clinical remission (72% vs. 32.3%, P <0.001) at week 54 were significantly higher in CD than in UC. The median trough drug level (μg/mL) was significantly higher in CD than in UC up to week 14 (week 2, 18.7 vs. 14.7, P <0.001; week 6, 12.5 vs. 8.6, P <0.001; week 14, 3.4 vs. 2.5, P =0.001). The median ADA level (AU/mL) was significantly lower in CD than in UC at week 2 (6.3 vs. 6.5, P =0.046), week 30 (7.9 vs. 11.8, P =0.007), and week 54 (9.3 vs. 12.3, P =0.032). Development of ADA at week 2 [adjusted odds ratio (aOR)=0.15, P =0.026], initial C-reactive protein level (aOR=0.87, P =0.032), and CD over UC (aOR=1.92, P <0.001) were independent predictors of clinical remission at week 54. CONCLUSION Infliximab shows more favorable pharmacokinetics, including high drug trough and low ADA levels, in CD than in UC, which might result in better clinical outcomes for 1-year infliximab treatment in CD patients.
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Affiliation(s)
- Eun Soo Kim
- Department of Internal Medicine, Kyungpook National University, School of Medicine
| | - Sung Kook Kim
- Department of Internal Medicine, Kyungpook National University, School of Medicine
| | - Dong Il Park
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine
| | - Hyo Jong Kim
- Center for Crohn's and Colitis, Kyung Hee University Hospital
| | - Yoo Jin Lee
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu
| | - Ja Seol Koo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ansan Hospital, Korea University College of Medicine, Ansan
| | - Eun Sun Kim
- Department of Internal Medicine, Korea University College of Medicine
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam
| | - Ji Hyun Lee
- Digestive Endoscopic Center, Seoul Song Do Colorectal Hospital
| | - Ji Won Kim
- Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul National University College of Medicine
| | - Sung Jae Shin
- Department of Internal Medicine, Ajou University School of Medicine, Suwon
| | - Hyung Wook Kim
- Department of Internal Medicine, Pusan National University School of Medicine And Medical Research Institute
| | - Hyun-Soo Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju
| | - Young Sook Park
- Department of Internal Medicine, Eulji University School of Medicine, Eulji Hospital
| | - You Sun Kim
- Department of Internal Medicine, Seoul Paik Hospital, Inje University College of Medicine
| | - Tae Oh Kim
- Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan
| | - Jun Lee
- Department of Internal Medicine, Chosun University, School of Medicine
| | - Chang Hwan Choi
- Department of Internal Medicine, College of Medicine, Chung-Ang University
| | - Dong Soo Han
- Department of Internal Medicine, Hanyang University College of Medicine, Guri, Korea
| | - Jaeyoung Chun
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul
| | - Hyun Soo Kim
- Department of Internal Medicine, Chonnam University Medical School, Gwangju
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19
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Phillips J, Leary S, Tyrrell-Price J. Association between 6-thioguanine nucleotide levels and preventing production of antibodies to infliximab in patients with inflammatory bowel disease. BMJ Open Gastroenterol 2023; 10:e001149. [PMID: 37328288 PMCID: PMC10277032 DOI: 10.1136/bmjgast-2023-001149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Accepted: 05/30/2023] [Indexed: 06/18/2023] Open
Abstract
OBJECTIVE Combination therapy with infliximab and a thiopurine has been shown to be more effective than monotherapy in patients with inflammatory bowel disease (IBD). The therapeutic efficacy of thiopurines is correlated with 6-thioguanine (6-TGN) levels between 235 and 450 pmol/8×108 erythrocytes. The primary aim of the study was to investigate the association between 6-TGN levels and inhibition prevention of the production of antibodies to infliximab (ATI). DESIGN We performed a retrospective review of the medical records of patients being treated with infliximab for IBD at University Hospitals Bristol NHS Foundation Trust. Demographic and biochemical data were extracted, alongside thiopurine metabolite levels, trough levels of infliximab and the presence of ATI. χ2 tests were used to investigate the association between 6-TGN levels and prevention of ATI. Logistic regression was used to compare the odds of prevented ATI between those with a 6-TGN level between 235 and 450 pmol/8×108 erythrocytes, those with a 6-TGN level outside of this range, and the baseline group who were on infliximab monotherapy. RESULTS Data were extracted for 100 patients. Six of 32 patients with a 6-TGN level between 235 and 450 pmol/8×108 erythrocytes developed ATI (18.8%) compared with 14 out of 22 (63.6%) patients with a 6-TGN outside of this range and 32 out of 46 (69.6%) patients on monotherapy (p=0.001). The OR (95% CI) for prevented ATI in those with a 6-TGN between 235 and 450 pmol/8×108 erythrocytes compared with a 6-TGN outside of this range was 7.6 (2.2, 26.3) (p=0.001) and compared with monotherapy was 9.9 (3.3, 29.4) (p=0.001). CONCLUSION 6-TGN levels between 235 and 450 pmol/8×108 erythrocytes prevented production of ATI. This supports therapeutic drug monitoring to help guide treatment and maximise the beneficial effects of combination therapy for patients with IBD.
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Affiliation(s)
- Jennifer Phillips
- Department of Gastroenterology, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
- Population Health Sciences, University of Bristol, Bristol, UK
| | - Sam Leary
- Bristol Dental School, University of Bristol, Bristol, UK
| | - Jonathan Tyrrell-Price
- Department of Gastroenterology, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
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20
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Smeijsters EH, van der Elst KCM, Visch A, Göbel C, Loeff FC, Rispens T, Huitema ADR, van Luin M, El Amrani M. Optimization of a Quantitative Anti-Drug Antibodies against Infliximab Assay with the Liquid Chromatography-Tandem Mass Spectrometry: A Method Validation Study and Future Perspectives. Pharmaceutics 2023; 15:pharmaceutics15051477. [PMID: 37242719 DOI: 10.3390/pharmaceutics15051477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/02/2023] [Accepted: 05/06/2023] [Indexed: 05/28/2023] Open
Abstract
Monoclonal antibodies (mAbs), such as infliximab, are important treatment options for different diseases. Immunogenicity is a major risk, resulting in anti-drug antibodies (ADAs), being associated with adverse events and loss of response, influencing long-term outcomes. The development of ADAs against infliximab is primarily measured by immunoassays like radioimmunoassay (RIA). Although liquid chromatography-tandem mass spectrometry (LC-MS/MS) is increasingly utilized across different fields, this technique is currently not used for ADAs against infliximab measurements. Therefore, we developed the first LC-MS/MS method. Stable isotopically labeled infliximab antigen-binding fragments (SIL IFX F(ab')2) were used to bind and measure ADAs indirectly. Protein A magnetic beads were used to capture IgG, including ADAs, whereafter SIL IFX F(ab')2 was added for labeling. After washing, internal standard addition, elution, denaturation and digestion samples were measured by LC-MS/MS. Internal validation showed good linearity between 0.1 and 16 mg/L (R2 > 0.998). Sixty samples were used for cross-validation with RIA, and no significant difference between ADA concentrations was found. The methods had high correlation (R = 0.94, p < 0.001) and excellent agreement, intraclass correlation coefficient = 0.912 (95% confidence interval 0.858-0.947, p < 0.001). We present the first ADA against the infliximab LC-MS/MS method. The method is amendable for quantifying other ADAs, making it applicable as a template for future ADA methods.
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Affiliation(s)
- Erin H Smeijsters
- Department of Clinical Pharmacy, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Kim C M van der Elst
- Department of Clinical Pharmacy, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Amy Visch
- Department of Clinical Pharmacy, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Camiel Göbel
- Department of Clinical Pharmacy, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Floris C Loeff
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, 1066 CX Amsterdam, The Netherlands
| | - Theo Rispens
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, 1066 CX Amsterdam, The Netherlands
| | - Alwin D R Huitema
- Department of Clinical Pharmacy, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
- Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
| | - Matthijs van Luin
- Department of Clinical Pharmacy, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Mohsin El Amrani
- Department of Clinical Pharmacy, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
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21
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Orfanoudaki E, Foteinogiannopoulou K, Theodoraki E, Koutroubakis IE. Recent Advances in the Optimization of Anti-TNF Treatment in Patients with Inflammatory Bowel Disease. J Clin Med 2023; 12:jcm12072452. [PMID: 37048536 PMCID: PMC10095227 DOI: 10.3390/jcm12072452] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/11/2023] [Accepted: 03/16/2023] [Indexed: 04/14/2023] Open
Abstract
Despite the evolution in inflammatory bowel disease (IBD) management during the last 20 years owing to the advent of new advanced therapies, anti-TNF agents still remain the cornerstone of therapy for both Crohn's disease and ulcerative colitis. However, this does not only secure favorable outcomes for patients considering the progressive disease character and the high likelihood of primary or secondary loss of response. Therefore, trying to reach a better treatment approach and maximize the benefits anti-TNF agents offer, optimization strategies should be examined. It has been indicated that optimizing treatment with anti-TNF enhances drug efficacy and has been associated with improved disease outcomes and a complication-free disease course. From this perspective, we aim to provide an overview of currently available data and recent advances in the practices of anti-TNF treatment optimization. Special focus has been given to the role of therapeutic drug monitoring (TDM), as well as the utility of combining anti-TNF with an immunomodulator and the treat-to-target approach.
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Affiliation(s)
- Eleni Orfanoudaki
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Kalliopi Foteinogiannopoulou
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Eirini Theodoraki
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Ioannis E Koutroubakis
- Department of Gastroenterology, University Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
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22
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Jukic T, Drobne D, Pusavec S, Ihan A, Stubljar D, Starc A. Comparison of 3 Enzyme-Linked Immunoassay Methods to Evaluate Serum Concentrations of Infliximab and Antibodies to Infliximab in 32 Patients with Moderate to Severe Inflammatory Bowel Disease. Med Sci Monit 2023; 29:e939084. [PMID: 36807319 PMCID: PMC9945009 DOI: 10.12659/msm.939084] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023] Open
Abstract
BACKGROUND Monitoring of trough levels and anti-drug antibodies is important when patients with inflammatory bowel disease (IBD) are treated with anti-TNF biologics due to guided therapeutic decisions. The comparability of 3 ELISA tests for detection of the lowest serum concentration of infliximab (IFX) or antibodies to IFX (ATIs) was evaluated. MATERIAL AND METHODS Two commercial assays for measuring IFX levels were compared with the in-house (UHL) test. ATIs were measured with 1 commercial test and compared to the in-house test. According to the guidelines, IFX levels were within the range of 3 to 7 µg/mL. RESULTS The decision to continue therapy would be the same for 11 out of 16 patients when comparing the apDia Infliximab ELISA and UHL test, and for 12 out of 18 patients when comparing the Lisa-Tracker and in-house UHL test. Linear correlations between the tests were R=0.92 (UHL and apDia), R=0.91 (apDia and Lisa-Tracker), and R=0.89 (UHL and Lisa-Tracker) with P<0.001, respectively. CONCLUSIONS As the IFX levels are important for decisions on further therapy, detectable IFX levels realistically reflect the presence of the drug in the patients' blood and thus control inflammatory activity. The tests were found as comparable and performed well in this aspect and might be used in everyday clinical practice.
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Affiliation(s)
- Tomislav Jukic
- Department of Internal Medicine, History of Medicine and Medical Ethics, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - David Drobne
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Sasa Pusavec
- Institute of Microbiology and Immunology, Medical Faculty of Ljubljana, Ljubljana, Slovenia
| | - Alojz Ihan
- Institute of Microbiology and Immunology, Medical Faculty of Ljubljana, Ljubljana, Slovenia
| | - David Stubljar
- Department of Research & Development, In-Medico, Metlika, Slovenia
| | - Andrej Starc
- Department of Public Health, Faculty of Health Sciences, Ljubljana, Slovenia
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23
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Na SY, Choi CH, Song EM, Bang KB, Park SH, Kim ES, Park JJ, Keum B, Lee CK, Lee BI, Ryoo SB, Koh SJ, Choi M, Kim JS. Korean clinical practice guidelines on biologics and small molecules for moderate-to-severe ulcerative colitis. Intest Res 2023; 21:61-87. [PMID: 35645321 PMCID: PMC9911265 DOI: 10.5217/ir.2022.00007] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 03/07/2022] [Indexed: 02/09/2023] Open
Abstract
Ulcerative colitis (UC), a relapsing-remitting chronic inflammatory bowel disease (IBD), has a variable natural course but potentially severe disease course. Since the development of anti-tumor necrosis factor (TNF) agents has changed the natural disease course of moderate-to-severe UC, therapeutic options for patients who failed conventional treatments are expanding rapidly. IBD clinical trials have demonstrated the potential efficacy and safety of novel biologics such as anti-integrin α4β7 and anti-interleukin-12/23 monoclonal antibodies and small molecules such as a Janus kinase inhibitor. Anti-TNF biosimilars also have been approved and are widely used in IBD patients. Wise drug choices should be made considering evidence-based efficacy and safety. However, the best position of these drugs remains several questions, with limited data from direct comparative trials. In addition, there are still concerns to be elucidated on the effect of therapeutic drug monitoring and combination therapy with immunomodulators. The appropriate treatment regimens in acute severe UC and the risk of perioperative use of biologics are unclear. As novel biologics and small molecules have been approved in Korea, we present the Korean guidelines for medical management of adult outpatients with moderate-to-severe UC and adult hospitalized patients with acute severe UC, focusing on biologics and small molecules.
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Affiliation(s)
- Soo-Young Na
- Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea
| | - Chang Hwan Choi
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea,Correspondence to Chang Hwan Choi, Department of Internal Medicine, Chung-Ang University College of Medicine, 102 Heukseok-ro, Dongjak-gu, Seoul 06973, Korea. Tel: +82-2-6299-1418, Fax: +82-2-6299-2064, E-mail:
| | - Eun Mi Song
- Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea
| | - Ki Bae Bang
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea
| | - Sang Hyoung Park
- Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Eun Soo Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Jae Jun Park
- Department of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Bora Keum
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Chang Kyun Lee
- Department of Gastroenterology, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Bo-In Lee
- Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung-Bum Ryoo
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Seong-Joon Koh
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Miyoung Choi
- National Evidence-based Healthcare Collaborating Agency, Seoul, Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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24
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Dodero-Anillo JM, Lozano-Cuadra IC, Rios-Sanchez E, Pedrosa-Martinez MJ, Ruiz-Carrascosa JC, Galan-Gutierrez M, Armario-Hita JC. Optimising the Therapeutic Interval for Biologics in Patients with Psoriasis. Life (Basel) 2022; 12:2075. [PMID: 36556440 PMCID: PMC9787329 DOI: 10.3390/life12122075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 10/25/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022] Open
Abstract
In our clinical experience, more than half of patients do not present a complete response to biologic drugs, or drug loses its efficacy over time. Plasma determinations of drug and anti-drug antibodies levels are an objective tool for optimisation in these patients; however, established therapeutic ranges are not suitable, so the objective of this study was to study these patients and optimise their healthcare. We have made a retrospective, observational study, using data of plasma levels of drugs and anti-drugs antibodies of infliximab, adalimumab or Etanercept, we summarise all data and make a study of sensitivity, specificity, positive and negative predictive value on current therapeutic ranges. We have found a statistically significant association between subtherapeutic levels and therapeutic failure in psoriasis treated with infliximab and adalimumab. New ranges were found with higher sensitivity than the established ones, we propose 2-10 µg/mL therapeutic range for infliximab, 3-11 µg/mL for adalimumab, and 1-7 µg/mL for etanercept. In conclusion, levels of drug and anti-drug antibodies are a decisive tool for predicting therapeutic response. The current therapeutic ranges may have minimum values that are excessively high, owing to which lowering them significantly increases the sensitivity of the test in all cases, and negative predictive value in the case of etanercept. Further prospective studies are needed to prove the usefulness of these new ranges.
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25
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Khan DA, Banerji A, Blumenthal KG, Phillips EJ, Solensky R, White AA, Bernstein JA, Chu DK, Ellis AK, Golden DBK, Greenhawt MJ, Horner CC, Ledford D, Lieberman JA, Oppenheimer J, Rank MA, Shaker MS, Stukus DR, Wallace D, Wang J, Khan DA, Golden DBK, Shaker M, Stukus DR, Khan DA, Banerji A, Blumenthal KG, Phillips EJ, Solensky R, White AA, Bernstein JA, Chu DK, Ellis AK, Golden DBK, Greenhawt MJ, Horner CC, Ledford D, Lieberman JA, Oppenheimer J, Rank MA, Shaker MS, Stukus DR, Wallace D, Wang J. Drug allergy: A 2022 practice parameter update. J Allergy Clin Immunol 2022; 150:1333-1393. [PMID: 36122788 DOI: 10.1016/j.jaci.2022.08.028] [Citation(s) in RCA: 226] [Impact Index Per Article: 75.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 08/18/2022] [Accepted: 08/30/2022] [Indexed: 12/14/2022]
Affiliation(s)
- David A Khan
- Department of Internal Medicine, Division of Allergy and Immunology, University of Texas Southwestern Medical Center, Dallas, Tex
| | - Aleena Banerji
- Department of Internal Medicine, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, Mass
| | - Kimberly G Blumenthal
- Department of Internal Medicine, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, Mass
| | - Elizabeth J Phillips
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn
| | - Roland Solensky
- Corvallis Clinic, Oregon State University/Oregon Health Science University College of Pharmacy, Corvallis, Ore
| | - Andrew A White
- Department of Allergy, Asthma and Immunology, Scripps Clinic, San Diego, Calif
| | - Jonathan A Bernstein
- Department of Internal Medicine, Division of Immunology, Allergy Section, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Derek K Chu
- Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada; The Research Institute of St Joe's Hamilton, Hamilton, Ontario, Canada
| | - Anne K Ellis
- Division of Allergy and Immunology, Department of Medicine, Queen's University, Kingston, Ontario, Canada
| | - David B K Golden
- Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Matthew J Greenhawt
- Food Challenge and Research Unit Section of Allergy and Immunology, Children's Hospital Colorado University of Colorado School of Medicine, Aurora, Colo
| | - Caroline C Horner
- Department of Pediatrics, Division of Allergy Pulmonary Medicine, Washington University School of Medicine, St Louis, Mo
| | - Dennis Ledford
- Division of Allergy and Immunology, Department of Medicine, University of South Florida Morsani College of Medicine, Tampa, Fla; James A. Haley Veterans Affairs Hospital, Tampa, Fla
| | - Jay A Lieberman
- Division of Allergy and Immunology, The University of Tennessee Health Science Center, Memphis, Tenn
| | - John Oppenheimer
- Division of Allergy, Rutgers New Jersey Medical School, Rutgers, NJ
| | - Matthew A Rank
- Division of Allergy, Asthma, and Clinical Immunology, Mayo Clinic in Arizona, Scottsdale, Ariz
| | - Marcus S Shaker
- Department of Pediatrics, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - David R Stukus
- Division of Allergy and Immunology, Nationwide Children's Hospital, Columbus, Ohio; The Ohio State University College of Medicine, Columbus, Ohio
| | - Dana Wallace
- Nova Southeastern Allopathic Medical School, Fort Lauderdale, Fla
| | - Julie Wang
- Division of Allergy and Immunology, Department of Pediatrics, The Elliot and Roslyn Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, New York, NY
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26
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Aslam N, Lo SW, Sikafi R, Barnes T, Segal J, Smith PJ, Limdi JK. A review of the therapeutic management of ulcerative colitis. Therap Adv Gastroenterol 2022; 15:17562848221138160. [PMID: 36478780 PMCID: PMC9720837 DOI: 10.1177/17562848221138160] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 10/26/2022] [Indexed: 12/03/2022] Open
Abstract
Ulcerative colitis (UC) is a chronic relapsing and remitting gastrointestinal disorder of uncertain aetiology. The last two decades have seen an expansion in the therapeutic arsenal used to treat UC. This has resulted in improved clinical remission and response rates. Nonetheless, staples in our current medical management originate from trials conducted in the early 20th century. In this review article, we aim to outline the key milestones in the history of the medical management of UC in addition to highlighting promising therapeutic developments for the future.
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Affiliation(s)
| | | | - Rafid Sikafi
- St Mark’s Hospital, London North West University Healthcare NHS Trust, London, UK
| | - Tom Barnes
- Section of IBD – Division of Gastroenterology, Northern Care Alliance NHS Foundation Trust, Salford, UK
| | - Jonathan Segal
- Northern Hospital, Epping, Melbourne, VIC, Australia,Department of Medicine, University of Melbourne, Parkville, VIC, Australia
| | - Philip J Smith
- Department of Gastroenterology, Royal Liverpool Hospital, Liverpool University Hospitals Foundation NHS Trust, Liverpool, UK
| | - Jimmy K Limdi
- Section of IBD – Division of Gastroenterology, Northern Care Alliance NHS Foundation Trust, Manchester, UK,Manchester Academic Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
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27
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Barrau M, Duprat M, Veyrard P, Tournier Q, Williet N, Phelip JM, Waeckel L, Cheifetz AS, Papamichael K, Roblin X, Paul S. A Systematic Review on the interest of Drug Tolerant assay in the monitoring of Inflammatory Bowel Disease. J Crohns Colitis 2022; 17:633-643. [PMID: 36301958 DOI: 10.1093/ecco-jcc/jjac164] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Indexed: 02/08/2023]
Abstract
Many patients with inflammatory bowel disease (IBD) are treated with anti-tumor necrosis factor (TNF) therapies, of which infliximab (IFX) is most commonly used. Loss of response (LOR) to anti-TNF therapy due to immunogenic failure accounts for 20% of subsequent medical intervention and is defined, using a drug sensitive assay, as low or undetectable concentration of drug with high titers of anti-drug antibodies (ADAb). We performed a systematic review to investigate the use of a drug tolerant assay during both induction and maintenance to monitor patients treated with anti-TNFs. After the search on PubMed, 90 publications were reviewed. Most ADAb detection methods are drug sensitive, cannot detect ADAb in the presence of drug, and therefore cannot be used close to drug administration, when the drug concentration is too high. To overcome this major limitation, several drug-tolerant techniques have been developed and will be discussed in this review. Using drug-tolerant assays ADAb against infliximab (IFX) or adalimumab (ADM) can be detected during induction and predict primary non-response or LOR. Drug sensitive assays do not allow detection of ADAb during the induction phase as IFX or ADM concentration is typically high.
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Affiliation(s)
- Mathilde Barrau
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - Manon Duprat
- Department of Immunology, CIRI - Centre International de Recherche en Infectiologie, Team GIMAP, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR530, CIC 1408 Vaccinology, F42023 Saint-Etienne, France
| | - Pauline Veyrard
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - Quentin Tournier
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - Nicolas Williet
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - Jean Marc Phelip
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - Louis Waeckel
- Department of Immunology, CIRI - Centre International de Recherche en Infectiologie, Team GIMAP, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR530, CIC 1408 Vaccinology, F42023 Saint-Etienne, France
| | - Adam S Cheifetz
- Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center Instructor in Medicine, Harvard Medical School
| | - Konstantinos Papamichael
- Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center Instructor in Medicine, Harvard Medical School
| | - Xavier Roblin
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - Stephane Paul
- Department of Immunology, CIRI - Centre International de Recherche en Infectiologie, Team GIMAP, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR530, CIC 1408 Vaccinology, F42023 Saint-Etienne, France
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28
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Wilson AS. Editorial: the immunogenicity to second anti-TNF therapy (IMSAT) therapeutic drug monitoring study-defining the risk of the in-class switch. Aliment Pharmacol Ther 2022; 56:1294-1295. [PMID: 36168263 DOI: 10.1111/apt.17188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Affiliation(s)
- Aze Suzanne Wilson
- Division of Clinical Pharmacology, Department of Medicine, Western University, London, Ontario, Canada.,Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada.,Department of Physiology & Pharmacology, Western University, London, Ontario, Canada
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29
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Ulcerative Colitis and Acute Severe Ulcerative Colitis Patients Are Overlooked in Infliximab Population Pharmacokinetic Models: Results from a Comprehensive Review. Pharmaceutics 2022; 14:pharmaceutics14102095. [PMID: 36297530 PMCID: PMC9610912 DOI: 10.3390/pharmaceutics14102095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/07/2022] [Accepted: 09/15/2022] [Indexed: 11/18/2022] Open
Abstract
Ulcerative colitis (UC) is part of the inflammatory bowels diseases, and moderate to severe UC patients can be treated with anti-tumour necrosis α monoclonal antibodies, including infliximab (IFX). Even though treatment of UC patients by IFX has been in place for over a decade, many gaps in modelling of IFX PK in this population remain. This is even more true for acute severe UC (ASUC) patients for which early prediction of IFX pharmacokinetic (PK) could highly improve treatment outcome. Thus, this review aims to compile and analyse published population PK models of IFX in UC and ASUC patients, and to assess the current knowledge on disease activity impact on IFX PK. For this, a semi-systematic literature search was conducted, from which 26 publications including a population PK model analysis of UC patients receiving IFX therapy were selected. Amongst those, only four developed a model specifically for UC patients, and only three populations included severe UC patients. Investigations of disease activity impact on PK were reported in only 4 of the 14 models selected. In addition, the lack of reported model codes and assessment of predictive performance make the use of published models in a clinical setting challenging. Thus, more comprehensive investigation of PK in UC and ASUC is needed as well as more adequate reports on developed models and their evaluation in order to apply them in a clinical setting.
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30
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Long MD, Cohen RD, Smith TW, DiBonaventura M, Gruben D, Bargo D, Salese L, Quirk D. Retrospective Database Analysis: Dose Escalation and Adherence in Patients Initiating Biologics for Ulcerative Colitis. Dig Dis 2022; 40:553-564. [PMID: 34879378 PMCID: PMC9501753 DOI: 10.1159/000521299] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 12/01/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND Biologic therapies are often used in patients with ulcerative colitis (UC) who are nonresponsive to conventional treatments. However, nonresponse or loss of response to biologics often occurs, leading to dose escalation, combination therapy, and/or treatment switching. We investigated real-world treatment patterns of biologic therapies among patients with UC in the USA. METHODS This study analyzed data from the IBM® MarketScan® Commercial and Medicare Supplemental Databases (medical/pharmacy claims for >250 million patients in the USA) to identify patients with UC initiating a biologic therapy (adalimumab, infliximab, golimumab, or vedolizumab) with 12 months of follow-up post-initiation. Key measures were patient baseline characteristics, dose escalation (average maintenance dose >20% higher than label), adherence (proportion of days covered), and ulcerative colitis-related healthcare costs in the 12 months following biologic therapy initiation. RESULTS Of 2,331 patients included in the study (adalimumab [N = 1,291], infliximab [N = 810], golimumab [N = 127], and vedolizumab [N = 103]), 28.1% used concomitant immunosuppressant therapy within 12 months post-initiation. Overall, 23.6% (adalimumab), 34.8% (infliximab), 9.9% (golimumab), and 39.2% (vedolizumab) of patients dose escalated within 12 months. Patients who dose escalated incurred USD 20,106 higher total UC-related healthcare costs over 12 months than those who did not. Adherence (covariate-adjusted proportion of days covered) ranged from 0.63 to 0.73, and 39.3% of patients discontinued within 12 months (median treatment duration = 112 days). CONCLUSION Dose escalation was common, and incurred higher costs, in patients with UC initiating biologic therapies. Suboptimal adherence and/or discontinuation within 12 months of initiation occurred frequently, highlighting the challenges in managing these patients.
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Affiliation(s)
- Millie D. Long
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Russell D. Cohen
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | | | | | | | | | - Leonardo Salese
- Pfizer Inc., Collegeville, Pennsylvania, USA,*Leonardo Salese,
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31
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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 2022; 27:63-71. [PMID: 35002561 DOI: 10.5863/1551-6776-27.1.63] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [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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Bavbek S, Pagani M, Alvarez‐Cuesta E, Castells M, Dursun AB, Hamadi S, Madrigal‐Burgaleta R, Sanchez‐Sanchez S, Vultaggio A. Hypersensitivity reactions to biologicals: An EAACI position paper. Allergy 2022; 77:39-54. [PMID: 34157134 DOI: 10.1111/all.14984] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/31/2021] [Accepted: 06/15/2021] [Indexed: 12/15/2022]
Abstract
Biologicals are crucial targeted therapeutic agents in oncological, immunological, and inflammatory diseases, and their use in clinical practice is broadening. In recent years, the spread of Personalized Precision Medicine has facilitated a proliferation of new treatment options, especially biologicals. Consequently, biologicals are now among the drugs that most frequently cause hypersensitivity reactions (HSRs). Patients can develop HSRs to these agents during the first-lifetime exposure or after repeated exposure, and these HSRs can be potentially life-threatening or limit therapeutic options. Despite the relatively high prevalence, the underlying mechanisms of these HSRs remain obscure, and the optimal management pathways are still a matter of discussion. In this Position Paper, the authors will provide evidence-based recommendations for diagnosing and managing HSRs to biologicals. Additionally, the document defines unmet needs as an opportunity to shape future research.
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Affiliation(s)
- Sevim Bavbek
- Division of Immunology and Allergy Department of Chest Diseases School of Medicine Ankara University Ankara Turkey
| | - Mauro Pagani
- Medical Department Medicine Ward ASST di Mantova Mantova Italy
| | | | - Mariana Castells
- Division of Allergy and Immunology Department of Medicine Brigham and Women's Hospital Harvard Medical School Boston Massachusetts USA
| | - Adile Berna Dursun
- Department of Immunology and Allergic Diseases Recep Tayyip Erdoğan University Rize Turkey
| | - Sahar Hamadi
- Division of Allergy and Immunology Department of Medicine Brigham and Women's Hospital Harvard Medical School Boston Massachusetts USA
| | - Ricardo Madrigal‐Burgaleta
- Allergy & Severe Asthma Service St Bartholomew's Hospital Barts Health NHS Trust London UK
- Drug Desensitisation Centre Catalan Institute of Oncology Barcelona Spain
| | | | - Alessandra Vultaggio
- Department of Biomedicine Azienda Ospedaliera Universitaria Careggi Florence Italy
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Intermittent Appearance of Antibodies to Infliximab Is Not Associated With Reduced Efficacy in Patients With Inflammatory Bowel Diseases. J Clin Gastroenterol 2022; 56:e47-e51. [PMID: 33252556 DOI: 10.1097/mcg.0000000000001469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 10/13/2020] [Indexed: 12/10/2022]
Abstract
GOALS To assess the clinical significance of antibodies to infliximab (ATI) formation in patients with inflammatory bowel disease (IBD). BACKGROUND Infliximab therapy in patients with IBD is highly effective though up to 50% of patients lose response to infliximab. ATI formation occurs in 6% to 60% of patients on scheduled infliximab maintenance therapy. METHODS Infliximab trough levels and ATI at trough were prospectively determined in patients with IBD on maintenance infliximab therapy. Patients on infliximab maintenance therapy with at least 3 ATI measurements were included. Patients were divided into 2 groups: sustained negative (<1 µg/mL) ATI levels, and fluctuating ATI levels (at least 1 sample with ATI <1 and at least one >1 µg/mL). RESULTS Forty-eight patients with IBD with available clinical data and serum samples were included. 25 patients had sustained low ATI levels and 23 patients had fluctuating ATI levels. Both groups were similar in IBD subtype distribution (Crohn's disease in 73.9% and 60%), mean serum albumin levels (4.2 vs. 3.9 g/dL), and mean trough serum infliximab levels (3.3 vs. 4.6 µg/mL) in fluctuating ATI and low ATI groups, respectively. There were no significant differences in the rate of clinical response (64% vs. 76%) and mean serum C-reactive protein levels (9.4 vs. 8.5 mg/dL, ULN=5) in the fluctuating ATI and low ATI groups. Similar rates of clinical response in the fluctuating ATI and low ATI groups were observed in ulcerative colitis (33% vs. 40%) and Crohn's disease (76% vs. 100%). CONCLUSIONS The fluctuating pattern of appearance of ATI in patients with IBD was not associated with loss of clinical response or a rise in C-reactive protein. The authors suggest that in clinical decision making, only sustained appearance of ATI should be considered as an adverse therapeutic factor.
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A Practical Guide to Therapeutic Drug Monitoring of Biologic Medications for Inflammatory Bowel Disease. J Clin Med 2021; 10:jcm10214990. [PMID: 34768509 PMCID: PMC8584740 DOI: 10.3390/jcm10214990] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/19/2021] [Accepted: 10/20/2021] [Indexed: 02/07/2023] Open
Abstract
Therapeutic drug monitoring (TDM) is a useful strategy to optimize biologic medications for inflammatory bowel disease not responsive to standard dosing regimens. TDM is cost effective for anti-tumor necrosis factor agents in the setting of loss of response (reactive TDM). Optimizing drug dosing when patients are in remission (proactive TDM) may be beneficial in certain circumstances. However, frequently the serum drug concentration in isolation becomes the focus TDM. Additionally, the lines of reactive and proactive TDM can quickly blur in many common clinical settings. Physicians employing a TDM based strategy need to place the drug concentration in context with the inflammatory status of the patient, the underlying pharmacokinetics and pharmacodynamics of the drug, the risk of immunogenicity, and the therapeutic goals for the patient. Physicians should understand the limits of TDM and feel comfortable making therapeutic decisions with imperfect information. The goal of this narrative review is to provide a framework of questions that physicians can use to employ TDM effectively in practice.
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Salvador-Martín S, Melgarejo-Ortuño A, López-Fernández LA. Biomarkers for Optimization and Personalization of Anti-TNFs in Pediatric Inflammatory Bowel Disease. Pharmaceutics 2021; 13:pharmaceutics13111786. [PMID: 34834201 PMCID: PMC8617733 DOI: 10.3390/pharmaceutics13111786] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/11/2021] [Accepted: 10/15/2021] [Indexed: 12/14/2022] Open
Abstract
The use of biological drugs has improved outcomes in pediatric inflammatory bowel disease (IBD). Prediction of the response to biological drugs would be extremely useful in IBD, and even more so in children, who are still growing physically and psychologically. Specific clinical, biochemical, and genetic parameters are considered predictive of response to biological drugs, although few studies have been carried out in children with IBD. In this review, we present current evidence on biological treatments used in pediatric IBD and the available biomarkers of response. We examine demographics, clinical characteristics, biomarkers (genetic, genomic, and cellular), and microbiota.
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Affiliation(s)
- Sara Salvador-Martín
- Servicio de Farmacia, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain; (S.S.-M.); (A.M.-O.)
| | - Alejandra Melgarejo-Ortuño
- Servicio de Farmacia, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain; (S.S.-M.); (A.M.-O.)
| | - Luis A. López-Fernández
- Servicio de Farmacia, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain; (S.S.-M.); (A.M.-O.)
- Spanish Clinical Research Network (SCReN), 28040 Madrid, Spain
- Correspondence:
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Albader F, Golovics PA, Gonczi L, Bessissow T, Afif W, Lakatos PL. Therapeutic drug monitoring in inflammatory bowel disease: The dawn of reactive monitoring. World J Gastroenterol 2021; 27:6231-6247. [PMID: 34712029 PMCID: PMC8515794 DOI: 10.3748/wjg.v27.i37.6231] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/08/2021] [Accepted: 08/31/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic condition that significantly affects the quality of life of its patients. Biologic drugs have been the mainstay treatment in the management of IBD patients but despite their significant contribution, there remains a proportion of patients that do not respond or lose response to treatment. Therapeutic drug monitoring (TDM) involves measuring levels of serum drug concentrations and anti-drug antibodies. TDM of biologic drugs initially emerged to understand treatment failure in other immune mediated inflammatory diseases. This was then introduced in IBD to rationalize primary non-response or secondary loss of response, given that low serum drug concentrations or the formation of anti-drug antibodies are variably associated with treatment failure. The aim of this narrative review is to provide an overview regarding the current use of TDM in clinical practice and to present the evidence available regarding its use in both proactive and reactive clinical settings in preventing and managing treatment failure. This review also presents the existing evidence regarding the association of various clinical outcomes with specific thresholds of drug concentrations, in everyday practice. A narrative review of published articles and conference abstracts regarding the use of TDM in IBD management, through an electronic search using PubMed and ScienceDirect. TDM has proven to be superior and more cost effective in guiding management of patients with treatment failure compared to empiric dose escalation or change in treatment. Despite a trend towards an association between clinical outcomes and drug concentrations, proactive TDM based strategies have not been shown to achieve clear benefit in long-term outcomes. In the clinical setting, TDM has proven to be useful in managing IBD patients, and its use in the reactive setting, as an additional tool to help manage patients with treatment failure, is being promoted as newer guidelines and consensus groups implement TDM as part of the management plan.
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Affiliation(s)
- Farah Albader
- Department of Internal Medicine, McGill University, Montreal H3G1A4, Quebec, Canada
| | - Petra Anna Golovics
- Division of Gastroenterology, Hungarian Defence Forces, Medical Centre, Budapest H-1062, Hungary
- Division of Gastroenterology, McGill University, Montreal H3G 1A4, Quebec, Canada
| | - Lorant Gonczi
- First Department of Medicine, Semmelweis University, Budapest H-1083, Hungary
| | - Talat Bessissow
- Division of Gastroenterology, McGill University Health Centre, Montreal H3G 1A4, Quebec, Canada
| | - Waqqas Afif
- Division of Gastroenterology, McGill University, Montreal H3G 1A4, Quebec, Canada
| | - Peter Laszlo Lakatos
- Division of Gastroenterology, McGill University, Montreal H3G 1A4, Quebec, Canada
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External Evaluation of Population Pharmacokinetic Models and Bayes-Based Dosing of Infliximab. Pharmaceutics 2021; 13:pharmaceutics13081191. [PMID: 34452152 PMCID: PMC8398005 DOI: 10.3390/pharmaceutics13081191] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 12/29/2022] Open
Abstract
Despite the well-demonstrated efficacy of infliximab in inflammatory diseases, treatment failure remains frequent. Dose adjustment using Bayesian methods has shown in silico its interest in achieving target plasma concentrations. However, most of the published models have not been fully validated in accordance with the recommendations. This study aimed to submit these models to an external evaluation and verify their predictive capabilities. Eight models were selected for external evaluation, carried out on an independent database (409 concentrations from 157 patients). Each model was evaluated based on the following parameters: goodness-of-fit (comparison of predictions to observations), residual error model (population weighted residuals (PWRES), individual weighted residuals (IWRES), and normalized prediction distribution errors (NPDE)), and predictive performances (prediction-corrected visual predictive checks (pcVPC) and Bayesian simulations). The performances observed during this external evaluation varied greatly from one model to another. The eight evaluated models showed a significant bias in population predictions (from -7.19 to 7.38 mg/L). Individual predictions showed acceptable bias and precision for six of the eight models (mean error of -0.74 to -0.29 mg/L and mean percent error of -16.6 to -0.4%). Analysis of NPDE and pcVPC confirmed these results and revealed a problem with the inclusion of several covariates (weight, concomitant immunomodulatory treatment, presence of anti-drug antibodies). This external evaluation showed satisfactory results for some models, notably models A and B, and highlighted several prospects for improving the pharmacokinetic models of infliximab for clinical-biological application.
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Vande Casteele N, Feagan BG, Wolf DC, Pop A, Yassine M, Horst SN, Ritter TE, Sandborn WJ. Therapeutic Drug Monitoring of Tumor Necrosis Factor Antagonists in Crohn Disease: A Theoretical Construct to Apply Pharmacokinetics and Guidelines to Clinical Practice. Inflamm Bowel Dis 2021; 27:1346-1355. [PMID: 33051647 PMCID: PMC8314098 DOI: 10.1093/ibd/izaa265] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Indexed: 12/13/2022]
Abstract
Therapeutic drug monitoring (TDM) is the measurement of drug and antidrug antibody concentrations in individuals to guide treatment decisions. In patients with Crohn disease (CD), TDM, used either reactively or proactively, is emerging as a valuable tool for optimization of tumor necrosis factor (TNF) antagonist therapy. Reactive TDM is carried out in response to treatment failure, whereas proactive TDM involves the periodic monitoring of patients responding to TNF antagonist therapy to allow treatment optimization. In patients with CD, most of the available data for TDM relate to the first-to-market TNF antagonist infliximab and, to a lesser extent, to adalimumab and certolizumab pegol. Several gastroenterology associations, including the American Gastroenterology Association, have endorsed the use of reactive TDM in patients with active CD. However, fewer recommendations currently exist for the use of proactive TDM, although several new prospective randomized controlled trials evaluating proactive TDM strategies have been published. In this review, the current evidence for reactive and proactive TDM is discussed, and a proactive treatment algorithm for certolizumab pegol based on previously published threshold concentrations is proposed.
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Affiliation(s)
- Niels Vande Casteele
- Division of Gastroenterology, University of California San Diego, La Jolla, California, USA
| | | | - Douglas C Wolf
- Atlanta Gastroenterology Associates, Atlanta, Georgia, USA
| | - Anca Pop
- UCB Pharma, Smyrna, Georgia, USA
| | | | - Sara N Horst
- Vanderbilt University, Nashville, Tennessee, USA
| | | | - William J Sandborn
- Division of Gastroenterology, University of California San Diego, La Jolla, California, USA
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Surface plasmon resonance unveils important pitfalls of enzyme-linked immunoassay for the detection of anti-infliximab antibodies in patients' sera. Sci Rep 2021; 11:14976. [PMID: 34294782 PMCID: PMC8298394 DOI: 10.1038/s41598-021-94431-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 07/08/2021] [Indexed: 02/08/2023] Open
Abstract
Measurements of serum concentrations of therapeutic antibodies and anti-drug antibodies (ADA) can support clinical decisions for the management of non-responders, optimizing the therapy. In the present study we compared the results obtained by classical ELISA and a recently proposed surface plasmon resonance (SPR)-based immunoassay, in 76 patients receiving infliximab for inflammatory bowel diseases. The two methods indicated very similar serum concentrations of the drug, but there were striking differences as regards ADA. All the sera showing ADA by ELISA (14) also showed ADA by SPR, but the absolute amounts were different, being 7–490 times higher with SPR, with no correlation. Eight patients showed ADA only with SPR, and these ADA had significantly faster dissociation rate constants than those detectable by both SPR and ELISA. The underestimation, or the lack of detection, of ADA by ELISA is likely to reflect the long incubation steps which favor dissociation of the patient’s low-affinity ADA, while the commercial, high-affinity anti-infliximab antibodies used for the calibration curve do not dissociate. This problem is less important with SPR, which monitors binding in real time. The possibility offered by SPR to detect ADA in patients otherwise considered ADA-negative by ELISA could have important implications for clinicians.
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Kim JY, Lee Y, Choe BH, Kang B. Factors Associated with the Immunogenicity of Anti-Tumor Necrosis Factor Agents in Pediatric Patients with Inflammatory Bowel Disease. Gut Liver 2021; 15:588-598. [PMID: 33024062 PMCID: PMC8283299 DOI: 10.5009/gnl20134] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 08/23/2020] [Accepted: 08/24/2020] [Indexed: 01/15/2023] Open
Abstract
Background/Aims Anti-drug antibodies (ADAs) can develop during treatment with anti-tumor necrosis factor (TNF) agents. We aimed to investigate the factors associated with immunogenicity of anti-TNF agents in pediatric patients with inflammatory bowel disease (IBD) and observe the clinical course of ADA-positive patients. Methods Pediatric IBD patients receiving maintenance treatment with anti-TNF agents who had been tested for ADAs against infliximab (IFX) or adalimumab (ADL) were included in this cross-sectional study. Factors associated with ADA positivity were investigated by analyzing clinicodemographic, laboratory, and treatment-related factors. Results A total of 76 patients (Crohn’s disease, 65; ulcerative colitis, 11) were included. Among these, 59 and 17 patients were receiving IFX and ADL, respectively. ADAs were found in 10 patients (13.2%), all of whom were receiving IFX. According to multivariable logistic regression analysis, the IFX trough level (TL) was associated with ADA positivity (odds ratio, 0.25; 95% confidence interval [CI], 0.08 to 0.51; p=0.002). According to the receiver operating characteristic analysis, the optimal cutoff of the IFX TLs for stratifying patients based on the presence of ADAs against IFX was 1.88 μg/mL (area under curve, 0.941; 95% CI, 0.873 to 1.000; sensitivity, 80.0%; specificity, 95.9%; p<0.001). Among the 10 patients with ADAs against IFX, five patients (50%) switched to ADL within 1 year, while five patients (50%) kept receiving IFX. Transient ADAs were observed in three patients (30%). Conclusions IFX TL was the only factor associated with ADA formation in pediatric IBD patients receiving IFX. Future studies based on serial and proactive therapeutic drug monitoring are required in the future.
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Affiliation(s)
- Ju Young Kim
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea.,Department of Pediatrics, Eulji University School of Medicine, Daejeon, Korea
| | - Yoon Lee
- Department of Pediatrics, Korea University School of Medicine, Seoul, Korea
| | - Byung-Ho Choe
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea.,Crohn's and Colitis Association in Daegu-Gyeongbuk (CCAiD), Daegu, Korea
| | - Ben Kang
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea.,Crohn's and Colitis Association in Daegu-Gyeongbuk (CCAiD), Daegu, Korea
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Kato M, Sugimoto K, Ikeya K, Takano R, Matsuura A, Miyazu T, Ishida N, Tamura S, Tani S, Yamade M, Hamaya Y, Iwaizumi M, Osawa S, Furuta T, Hanai H. Therapeutic monitoring of adalimumab at non-trough levels in patients with inflammatory bowel disease. PLoS One 2021; 16:e0254548. [PMID: 34242369 PMCID: PMC8270420 DOI: 10.1371/journal.pone.0254548] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 06/29/2021] [Indexed: 12/15/2022] Open
Abstract
Adalimumab (ADA) trough level and anti-ADA antibody (AAA) positivity influence mucosal healing and loss of response in patients with inflammatory bowel disease (IBD). In this study, we clarified the correlation between ADA monitoring, including non-trough level, and real-world IBD clinical outcomes. This retrospective, observational, single-center study involved patients with ulcerative colitis (19) and Crohn's disease (33) treated with ADA from January 2007 to August 2018. Serum ADA and AAA levels were measured 4‒14 days after ADA administration. The AAA positivity rate was 23.1% (12/52). ADA continuity was higher in AAA-negative patients than in AAA-positive patients (P = 0.223). Receiver operating characteristic (ROC) analysis revealed that a serum AAA cut-off of 9.2 μg/mL was associated with ADA continuity. The ADA level was significantly higher in the endoscopic remission group than in the non-remission group (P = 0.02). Based on the ROC curve analysis results of serum ADA level and endoscopic remission, the cut-off value of the serum ADA level was set to 11.1 μg/mL. Under the combined use of ADA with immunomodulators and AAA positivity, ADA continuity was significantly higher when the serum AAA level at 4-14 days after ADA administration was ≥9.2 μg/mL. Furthermore, endoscopic remission can be expected with a serum ADA level of ≥11.1 μg/mL. Overall, to predict clinical outcomes, it would be useful to measure the blood level of ADA regardless of the timing of the trough.
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Affiliation(s)
- Masaichi Kato
- Center for Gastroenterology and Inflammatory Bowel Disease Research, Hamamatsu South Hospital, Hamamatsu, Japan
| | - Ken Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
- * E-mail:
| | - Kentaro Ikeya
- Center for Gastroenterology and Inflammatory Bowel Disease Research, Hamamatsu South Hospital, Hamamatsu, Japan
| | - Ryosuke Takano
- Center for Gastroenterology and Inflammatory Bowel Disease Research, Hamamatsu South Hospital, Hamamatsu, Japan
| | - Ai Matsuura
- Center for Gastroenterology and Inflammatory Bowel Disease Research, Hamamatsu South Hospital, Hamamatsu, Japan
| | - Takahiro Miyazu
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Natsuki Ishida
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Satoshi Tamura
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Shinya Tani
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Mihoko Yamade
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yasushi Hamaya
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Moriya Iwaizumi
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Satoshi Osawa
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hiroyuki Hanai
- Center for Gastroenterology and Inflammatory Bowel Disease Research, Hamamatsu South Hospital, Hamamatsu, Japan
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Therapeutic Drug Monitoring of Adalimumab During Long-term Follow-up in Paediatric Patients With Crohn Disease. J Pediatr Gastroenterol Nutr 2021; 72:870-876. [PMID: 33908743 DOI: 10.1097/mpg.0000000000003070] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVES We investigated the therapeutic drug monitoring of adalimumab (ADL) on clinical remission (CR) and mucosal healing (MH) rates in paediatric patients with Crohn disease (CD). Furthermore, long-term treatment efficacy of ADL in paediatric CD was evaluated through 3-year follow-up. METHODS We conducted a prospective study of 31 patients with CD who received ADL maintenance therapy and underwent endoscopic evaluation of MH and pharmacokinetic analysis. Patients in CR were identified based on Paediatric Crohn Disease Activity Index (PCDAI) scores less than 10. Patients with MH were identified based on Simple Endoscopic Scores for Crohn Disease (SES-CD) of less than 2. RESULTS At 4 months and 1 year of ADL treatment, 28 and 26 patients, respectively, were under CR; 13 and 17 patients, respectively, achieved MH. The median trough levels (TLs) of ADL were higher in patients in CR (7.6 ± 3.5 μg/mL) than in patients with active disease (5.1 ± 2.2 μg/mL). ADL TLs were significantly higher in patients who achieved MH than in those who did not (14.2 ± 7.6 vs 7.8 ± 5.2 μg/mL). The optimal cut-point for predicting MH at 1 year of ADL treatment was 8.18 μg/mL. During long-term follow-up, ADL TLs were stably maintained over 10 μg/mL; not only CR and MH but also histologic remission was obtained at a high rate. ADL administration maintained a positive effect on growth during the maintenance period. CONCLUSIONS ADL TLs were significantly higher in paediatric patients with CD who achieved CR or MH. ADL treatment showed long-term stable efficacy and positive effects on growth indicators.
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Luo YR, Chakraborty I, Lazar-Molnar E, Wu AHB, Lynch KL. Development of Label-Free Immunoassays as Novel Solutions for the Measurement of Monoclonal Antibody Drugs and Antidrug Antibodies. Clin Chem 2021; 66:1319-1328. [PMID: 32918468 DOI: 10.1093/clinchem/hvaa179] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 07/14/2020] [Indexed: 01/07/2023]
Abstract
BACKGROUND Immunoassays based on label-free technologies (label-free immunoassay [LFIA]) offer an innovative approach to clinical diagnostics and demonstrate great promise for therapeutic drug monitoring (TDM) of monoclonal antibody (mAb) drugs. An LFIA measures immunocomplex formation in real time and allows for quantification on initial binding rate, which facilitates fast measurement within a few minutes. METHODS Based on thin-film interferometry (TFI) technology, open-access LFIAs were developed for the quantification of the mAb drugs adalimumab (ADL) and infliximab (IFX) and for the detection of the antidrug antibodies (ADAs) to the mAb drugs (ADL-ADAs and IFX-ADAs). RESULTS The LFIAs for active mAb drugs (ADL and IFX) and for ADAs (ADL-ADAs and IFX-ADAs) were validated. The analytical measurement range (AMR) for both ADL and IFX was from 2 to 100 μg/mL. The AMR for ADL-ADAs was from 5 to 100 μg/mL and for IFX-ADAs was 10 to 100 μg/mL. In the comparison of LFIAs and reporter gene assays, the correlation coefficient was 0.972 for the quantification of ADL and 0.940 for the quantification of IFX. The concordance rate was 90% for the detection of ADL-ADAs and 76% for the detection of IFX-ADAs. CONCLUSIONS The LFIAs for active mAb drugs and ADAs were appropriate for the TDM of ADL and IFX. The TFI technology has unique advantages compared with other technologies used for the measurement of mAb drugs. Label-free technologies, especially those allowing for open-access LFIAs, have great potential for clinical diagnostics.
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Affiliation(s)
- Yiqi Ruben Luo
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA
| | | | - Eszter Lazar-Molnar
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT
| | - Alan H B Wu
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA
| | - Kara L Lynch
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA
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Tran-Minh ML, Gornet JM, Maillet M, Houze P, Simon M, McLellan P, Hassid D, Vivier-Chicoteau J, Baudry C, Hammoudi N, Allez M. Safety of Hydrocortisone Premedication Discontinuation in Patients with Inflammatory Bowel Disease on Maintenance Therapy with Infliximab: a Prospective Clinical and Pharmacological Study. J Crohns Colitis 2021; 15:742-748. [PMID: 33205193 DOI: 10.1093/ecco-jcc/jjaa231] [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] [Indexed: 02/08/2023]
Abstract
BACKGROUND Hydrocortisone premedication reduces the risk of antibodies to infliximab [ATIs] formation in patients receiving infliximab [IFX] therapy for inflammatory bowel disease [IBD]. AIM We aimed to determine the safety of hydrocortisone premedication withdrawal in IBD patients with sustained clinical response on maintenance therapy with IFX. METHODS We performed an observational prospective pharmacoclinical study in a tertiary referral centre, including all consecutive IBD outpatients with no previous IFX infusion reaction and in clinical remission on maintenance IFX [alone or in combination therapy] for at least 6 months. This cohort was followed for 1 year after discontinuation of hydrocortisone premedication. RESULTS Among the 268 IBD outpatients, 95 patients met the inclusion criteria [mean age 38 years; 64% male; 80% Crohn's disease; 45% combination therapy]. The median IFX duration was 5 years [0.54-14] with a mean infused dose of 533 mg [200-1000] and a mean interval duration of 7.9 weeks [4-10]. None of the patients developed permanent ATIs or infusion-related reaction at 1 year. Four patients developed transient ATIs without loss of clinical response. There was no significant variation of infliximab serum trough levels [5.5 µg/mL vs 5.9 µg/mL] measured at the time of the three IFX infusions before and after hydrocortisone withdrawal. Loss of response rate to IFX was 18% at 1 year. CONCLUSIONS Hydrocortisone discontinuation is safe in IBD patients with sustained clinical remission on maintenance therapy with IFX. Our data suggest that routine premedication with hydrocortisone is unnecessary in patients in prolonged remission under IFX maintenance therapy.
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Affiliation(s)
- My-Linh Tran-Minh
- Service de Gastroentérologie, Université de Paris, APHP, Hôpital Saint-Louis, Paris, France
| | - Jean-Marc Gornet
- Service de Gastroentérologie, Université de Paris, APHP, Hôpital Saint-Louis, Paris, France
| | - Marianne Maillet
- Service de Gastroentérologie, Université de Paris, APHP, Hôpital Saint-Louis, Paris, France
| | - Pascal Houze
- Service de Biochimie, Université de Paris, APHP, Hôpital Necker, Paris, France
| | - Marion Simon
- Service de Gastroentérologie, Institut Mutualiste Montsouris, Paris, France
| | - Paul McLellan
- Service de Gastroentérologie, Université de Paris, APHP, Hôpital Saint-Louis, Paris, France
| | - Deborah Hassid
- Service de Gastroentérologie, Université de Paris, APHP, Hôpital Saint-Louis, Paris, France
| | | | - Clotilde Baudry
- Service de Gastroentérologie, Université de Paris, APHP, Hôpital Saint-Louis, Paris, France
| | - Nassim Hammoudi
- Service de Gastroentérologie, Université de Paris, APHP, Hôpital Saint-Louis, Paris, France
| | - Matthieu Allez
- Service de Gastroentérologie, Université de Paris, APHP, Hôpital Saint-Louis, Paris, France
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Predictors of Infliximab Trough Concentrations in Inflammatory Bowel Disease Patients Using a Repeated-Measures Design. Ther Drug Monit 2021; 42:102-110. [PMID: 31283556 DOI: 10.1097/ftd.0000000000000669] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIMS Treating patients based on a treat-to-trough approach has been shown to be a cost-effective strategy for inflammatory bowel disease (IBD) patients who have become unresponsive to infliximab (IFX). However, the documented evidence for this is limited, and some controversy remains regarding the use of routine proactive therapeutic drug monitoring (TDM). To support routine TDM of IFX and regimen optimization in IBD patients, more in-depth knowledge of the covariates that affect the pharmacokinetic (PK) variability of IFX is needed. The aim of this study was to identify the characteristics of the patient, disease, and treatments that influence IFX PK and exposure in our cohort of IBD patients using a repeated-measures design. METHODS We performed a prospective observational study of adult IBD patients who received IFX between July 2013 and March 2017. We obtained repeated IFX trough concentration (Cmin) measurements and implemented a previously described population pharmacokinetic model to estimate individual clearance (CL). From the individual primary parameters, the area under the curve (AUC), half-life (t1/2), and central elimination rate constant (K10) were estimated. We performed a repeated-measures analysis to evaluate whether patient characteristics, disease status, concomitant immunosuppressive therapy, and immunogenicity are associated with IFX Cmin and PK parameters. RESULTS We collected 429 Cmin measurements from 112 patients. The median of the Cmin values was 3.62 mg/L (1.47-6.02). Antibodies to IFX (ATI) were detected in 14 patients. The predicted median AUC was 28,421 mg/h/L (22,336-36,903). The median individual predicted CL, K10, and t1/2 values were 4.77 mL/kg/day (3.88-5.90), 0.09 days (0.08-0.12), and 12.22 days (9.49-14.87), respectively. IFX Cmin, AUC, CL, and K10 were significantly influenced by ATI and serum albumin concentrations. Moreover, body weight was significantly associated with AUC, CL, and K10. Patients receiving concurrent immunosuppressive therapy had higher Cmin and AUC values and lower CL and K10 values than those treated with IFX monotherapy. We also observed high intrapatient variability in Cmin values during the study period. CONCLUSIONS In this repeated-measures study in a population of IBD patients, we observed significant associations between ATI, serum albumin concentration, concomitant immunosuppressive therapy, body weight and gender, and IFX Cmin, and CL. The high PK variability observed in this study supports the need for proactive TDM to optimize the use of IFX as early as possible in IBD patients.
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Abstract
PURPOSE To evaluate the effect of tumor necrosis factor (TNF) inhibitor therapy on ocular relapses in patients with Susac syndrome. METHODS Multicenter retrospective cohort study of patients diagnosed with Susac syndrome according to classical clinical criteria. We evaluated the disease activity before and after introduction of anti-TNF therapy and its value as a steroid-sparing agent. RESULTS Five patients were included. All were initially treated with a combination of corticosteroids and classical immunosuppressive drugs. Infliximab was started in three patients, and adalimumab was started in two patients. Patients had on average 5 ocular relapses during a mean follow-up time of 2.59 years before introducing a TNF inhibitor, corresponding with on average 1.93 relapses per year. After the introduction of an anti-TNF agent, this number was reduced by factor 5.51 to an average of 0.35 relapses per year for a mean follow-up of 2.86 years (P = 0.10). Before anti-TNF introduction ocular relapses occurred at a mean daily dose of 34 mg of prednisone, whereas with anti-TNF treatment, corticosteroid administration could be completely stopped in four patients with one patient still needing 5 mg daily (P = 0.10). Infliximab and adalimumab generally were well tolerated, and no serious adverse events were reported. CONCLUSION Although not statistically significant, our results suggest that anti-TNF therapy can be a valuable option for the treatment of ocular Susac syndrome and may especially be considered in those patients unresponsive to more conventional immunosuppressive treatment.
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Bravo F, Macpherson JA, Slack E, Patuto N, Cahenzli J, McCoy KD, Macpherson AJ, Juillerat P. Prospective Validation of CD-62L (L-Selectin) as Marker of Durable Response to Infliximab Treatment in Patients With Inflammatory Bowel Disease: A 5-Year Clinical Follow-up. Clin Transl Gastroenterol 2021; 12:e00298. [PMID: 33735154 PMCID: PMC7886452 DOI: 10.14309/ctg.0000000000000298] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 11/23/2020] [Indexed: 12/20/2022] Open
Abstract
INTRODUCTION The development of biomarkers to guide management of anti-tumor necrosis factor (TNF) agents in patients with inflammatory bowel disease (IBD) is an unmet need. We developed an in vitro blood assay to predict patient long-term outcome with the anti-TNFα agent infliximab (IFX). METHODS Patients with IBD were classified according to the shedding of an L-selectin (CD62L) from the surface of their granulocytes in whole blood. CD62L shedding was quantified by flow cytometry before and after drug administration. A clinical data collection from June 2012 to August 2017 with blinded IFX management was aimed at validating the long-term predictive value of this test. RESULTS Among 33 patients with IBD (17 Crohn's disease and 5 ulcerative colitis), 22 were predicted functional responders (PFR) and 11 were predicted as nonresponders (NR) according to the in vitro test. Five years after study initiation, 72% of PFR were still treated with IFX (vs 27% in the NR group; P < 0.05), with a median time spent under IFX of 45 vs 12 months (P = 0.019), respectively. Thirty-five medicosurgical events occurred with a median time to first event of 3 vs 30 months (P = 0.023), respectively. Our assay was the best independent predictor of staying long term on IFX (P = 0.056). DISCUSSION An assay-based in vitro test for functional blockade of TNFα (CD62L shedding) provides an excellent long-term (at 3-5 years) independent predictor of durable use of IFX in patients with IBD. Testing patients could personalize decision making to significantly reduce costs and risk of adverse events and complications.
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Affiliation(s)
- Francisco Bravo
- Maurice E Müller Laboratories, Universitätsklinik für Viszerale Chirurgie und Medizin, Inselspital, University of Bern, Bern, Switzerland
- Gastroenterology, Clinic for Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland
| | - Jamie A. Macpherson
- Maurice E Müller Laboratories, Universitätsklinik für Viszerale Chirurgie und Medizin, Inselspital, University of Bern, Bern, Switzerland
| | - Emma Slack
- Maurice E Müller Laboratories, Universitätsklinik für Viszerale Chirurgie und Medizin, Inselspital, University of Bern, Bern, Switzerland
| | - Nicolas Patuto
- Gastroenterology, Clinic for Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland
| | - Julia Cahenzli
- Maurice E Müller Laboratories, Universitätsklinik für Viszerale Chirurgie und Medizin, Inselspital, University of Bern, Bern, Switzerland
| | - Kathy D. McCoy
- Maurice E Müller Laboratories, Universitätsklinik für Viszerale Chirurgie und Medizin, Inselspital, University of Bern, Bern, Switzerland
| | - Andrew J. Macpherson
- Maurice E Müller Laboratories, Universitätsklinik für Viszerale Chirurgie und Medizin, Inselspital, University of Bern, Bern, Switzerland
- Gastroenterology, Clinic for Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland
| | - Pascal Juillerat
- Maurice E Müller Laboratories, Universitätsklinik für Viszerale Chirurgie und Medizin, Inselspital, University of Bern, Bern, Switzerland
- Gastroenterology, Clinic for Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland
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Rocha C, Lago P, Fernandes S, Correia L, Portela F, Vieira AI, Patita M, Arroja B, Ministro P, Alves C, Dias CC, Magro F. Rapid test detection of anti-infliximab antibodies: performance comparison with three different immunoassays. Therap Adv Gastroenterol 2020; 13:1756284820965790. [PMID: 33281935 PMCID: PMC7682213 DOI: 10.1177/1756284820965790] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 09/15/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND AND AIMS Therapeutic drug monitoring (TDM) of infliximab (IFX) and anti-infliximab antibodies (ATIs) is essential for treatment optimisation in inflammatory bowel disease (IBD) patients. The aim of this study was to estimate and compare the agreement and accuracy between a new rapid test and three established enzyme-linked immunosorbent assays (ELISAs) to quantify ATIs levels, and to evaluate the impact of exogenous IFX on the performance of these assays. METHODS We analysed 200 serum samples from 57 IBD outpatients in IFX induction or maintenance therapy at six IBD centres in Portugal. ATI levels were quantified using the rapid test Quantum Blue® (QB) Anti-Infliximab (Bühlmann) and three established ELISAs: In-House, Theradiag (Lisa Tracker Anti-Infliximab), and Immundiagnostik (IDKmonitor Infliximab). ATIs were quantified in patients' serum samples and spiked samples with exogenous IFX, based on analytical and clinical cutoffs. Qualitative agreement and accuracy were estimated by Cohen's kappa (k) with 95% confidence intervals. RESULTS ATIs quantification with clinical cutoffs showed a slight agreement between QB rapid test and In-House [k = 0.163 (0.051-0.276)] and Immundiagnostik [k = 0.085 (0.000-0.177)]. Regarding IFX/ATIs status, the QB rapid test showed a substantial agreement with Theradiag [k = 0.808 (0.729-0.888)] and a fair agreement with In-House [k = 0.343 (0.254-0.431)] and Immundiagnostik [k = 0.217 (0.138-0.297)]. The QB rapid test could not detect ATI-positive levels in samples with exogenous IFX at 5-300 µg/ml. Interference on ATIs detection was observed at exogenous IFX ⩾30 µg/ml for In-house and Immundiagnostik assays. CONCLUSION QB rapid test is only suitable to detect ATI-positive levels in the absence of IFX.
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Affiliation(s)
- Cátia Rocha
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal
- Faculty of Medicine, University of Lisbon, Lisbon, Portugal
- Institute of Environmental Health, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
| | - Paula Lago
- Department of Gastroenterology, Centro Hospitalar do Porto, Porto, Portugal
| | - Samuel Fernandes
- Department of Gastroenterology and Hepatology, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal
| | - Luís Correia
- Department of Gastroenterology and Hepatology, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal
| | - Francisco Portela
- Department of Gastroenterology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Ana Isabel Vieira
- Department of Gastroenterology, Hospital Garcia de Orta, Almada, Portugal
| | - Marta Patita
- Department of Gastroenterology, Hospital Garcia de Orta, Almada, Portugal
| | - Bruno Arroja
- Department of Gastroenterology, Hospital de Braga, Braga, Portugal
| | - Paula Ministro
- Department of Gastroenterology, Centro Hospitalar Tondela-Viseu, Viseu, Portugal
| | - Catarina Alves
- Faculty of Medicine, University of Porto, Porto, Portugal
| | - Cláudia Camila Dias
- Center for Health Technology and Services Research (CINTESIS), Faculty of Medicine, University of Porto, Porto, Portugal
- Health Information and Decision Sciences Department, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Fernando Magro
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, Porto, 4200-319, Portugal
- Portuguese IBD Study Group (GEDII), Porto, Portugal
- Department of Gastroenterology, São João Hospital Centre, Porto, Portugal
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Frias Gomes C, Chapman TP, Satsangi J. De-escalation of medical therapy in inflammatory bowel disease. Curr Opin Pharmacol 2020; 55:73-81. [PMID: 33160250 DOI: 10.1016/j.coph.2020.09.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 09/24/2020] [Accepted: 09/27/2020] [Indexed: 02/07/2023]
Abstract
Treatment strategies for inflammatory bowel disease (IBD) now increasingly target deep remission, yet the resultant more aggressive use of medical therapy is associated with potentially serious adverse events and significant costs. It is, therefore, of vital importance to consider when, how and in whom medical therapy may be safely de-escalated. This issue is of great potential relevance in the current SARS-Cov-2 pandemic. In this review, we first discuss the rationale for drug withdrawal in IBD, before considering the available data on withdrawal of 5-aminosalicylates (5-ASA), immunomodulators (IM) and biological therapy in both ulcerative colitis (UC) and Crohn's Disease (CD). We consider how to identify patients most appropriate for drug withdrawal and outline a potential monitoring strategy for the early detection of relapse following drug withdrawal. We conclude with important future perspectives in this challenging field, and highlight ongoing trials that are likely to shape practice in the years to come.
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Affiliation(s)
- Catarina Frias Gomes
- Surgical Department, Gastroenterology Division, Hospital Beatriz Ângelo, Loures, Portugal.
| | - Thomas P Chapman
- Translational Gastroenterology Unit, Nuffield Department of Experimental Medicine, University of Oxford, Oxford, UK
| | - Jack Satsangi
- Translational Gastroenterology Unit, Nuffield Department of Experimental Medicine, University of Oxford, Oxford, UK
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Pierre N, Baiwir D, Huynh-Thu VA, Mazzucchelli G, Smargiasso N, De Pauw E, Bouhnik Y, Laharie D, Colombel JF, Meuwis MA, Louis E. Discovery of biomarker candidates associated with the risk of short-term and mid/long-term relapse after infliximab withdrawal in Crohn's patients: a proteomics-based study. Gut 2020; 70:gutjnl-2020-322100. [PMID: 33106355 DOI: 10.1136/gutjnl-2020-322100] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 09/30/2020] [Accepted: 10/02/2020] [Indexed: 02/06/2023]
Abstract
OBJECTIVE A subset of Crohn's disease (CD) patients experiences mid/long-term remission after infliximab withdrawal. Biomarkers are needed to identify those patients. DESIGN New biomarkers of relapse were searched in the baseline serum of CD patients stopping infliximab when they were under combined therapy (antimetabolite and infliximab) and stable clinical remission (diSconTinuation in CrOhn's disease patients in stable Remission on combined therapy with Immunosuppressors cohort, n=102). From shotgun proteomics experiment (discovery step), biomarker candidates were identified and further targeted by selected reaction monitoring (verification step). The dataset was stratified to search for markers of short-term (<6 months) or mid/long-term relapse (>6 months). The risk of relapse and the predicting capacity associated with biomarker candidates were evaluated using univariate Cox model and log-rank statistic, respectively. To test their complementary predicting capacity, biomarker candidates were systematically combined in pairs. RESULTS Distinct biomarker candidates were associated with the risk (HR) of short-term (15 proteins, 2.9 CONCLUSION We identified for the first time circulating biomarker candidates associated with the risk of mid/long-term relapse in CD patients stopping infliximab. We also highlight a sequence of pathophysiological processes leading to relapse, this could help to better understand the disease progression. Our findings may pave the way for a better non-invasive evaluation of the risk of relapse when contemplating antitumour necrosis factor α withdrawal in CD patients.
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Affiliation(s)
- Nicolas Pierre
- Laboratory of Translational Gastroenterology, GIGA-Institute, Liege University, Liege, Belgium
| | | | - Vân Anh Huynh-Thu
- Department of Electrical Engineering and Computer Science, Liege University, Liege, Belgium
| | - Gabriel Mazzucchelli
- Laboratory of Mass Spectrometry, MolSys Research Unit, Liege University, Liege, Belgium
| | - Nicolas Smargiasso
- Laboratory of Mass Spectrometry, MolSys Research Unit, Liege University, Liege, Belgium
| | - Edwin De Pauw
- Laboratory of Mass Spectrometry, MolSys Research Unit, Liege University, Liege, Belgium
| | - Yoram Bouhnik
- Service de Gastroentérologie et Assistance Nutritive, Hôpital Beaujon, Clichy, France
| | - David Laharie
- Service d'Hépato-Gastroentérologie, CHU de Bordeaux, Bordeaux, France
| | - Jean-Frédéric Colombel
- Division of Gastroenterology, Icahn School of Medicine at Mount Sina, New York, New York, USA
| | - Marie-Alice Meuwis
- Laboratory of Translational Gastroenterology, GIGA-Institute, Liege University, Liege, Belgium
- Hepato-Gastroenterology and Digestive Oncology Department, Liege University, Liege, Belgium
| | - Edouard Louis
- Laboratory of Translational Gastroenterology, GIGA-Institute, Liege University, Liege, Belgium
- Hepato-Gastroenterology and Digestive Oncology Department, Liege University, Liege, Belgium
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