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Wadhwa M, Cludts I, Atkinson E, Rigsby P. The first WHO reference panel for Infliximab anti-drug antibodies: a step towards harmonizing therapeutic drug monitoring. Front Immunol 2025; 16:1550655. [PMID: 40181987 PMCID: PMC11965635 DOI: 10.3389/fimmu.2025.1550655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 02/24/2025] [Indexed: 04/05/2025] Open
Abstract
Immunogenicity testing for anti-drug antibodies (ADA) is mandatory for regulatory approval of a biotherapeutic and can, in some instances, continue post-licensure. Typical examples are TNF inhibitors where biotherapeutic and ADA levels are relevant in clinical decision-making for optimal patient therapy. However, challenges with non-comparability of results due to plethora of bioanalytical techniques and the lack of standardization has hindered ADA monitoring in clinical practice. Two human anti-infliximab monoclonal antibodies (A, B) with defined characteristics were therefore lyophilized and assessed for suitability as a reference panel for ADA assays in an international study. Binding assays included the simple ELISA and common electrochemiluminescence (ECL) to the rare antigen binding test and lateral flow assays. For neutralisation, competitive ligand binding and reporter-gene assays were employed. Sample testing (e.g., antibodies, sera) showed differential reactivity depending on the assay and sample. Estimates for ADA levels using in-house standards varied substantially among assays/laboratories. In contrast, using antibody A for quantitating ADA levels reduced the interlaboratory variability and provided largely consistent estimates. The degree of harmonization was dependent on the assay, sample and the laboratory. Importantly, antibody A allowed ADA detection when missed using in-house standards. Recognition of sample B varied, possibly due to its fast dissociation. Overall, the panel comprising A (coded 19/234) and B (coded 19/232) was suitable and established by the WHO Expert Committee on Biological Standardization in October 2022 as the WHO international reference panel for infliximab ADA assays. Sample A (coded 19/234) with an arbitrarily assigned unitage of 50,000IU/ampoule for binding activity and 50,000 IU/ampoule for neutralising activity is intended as a 'common standard' for assay characterization and where possible for calibration of anti-infliximab preparations to facilitate comparison and harmonization of results across infliximab ADA assays. Sample B (19/232) with its unique characteristics and variable detection but no assigned unitage is intended for assessing the suitability of the assay for detecting ADAs with fast dissociation. It is anticipated that this panel would help towards selecting and characterizing suitable assays, benchmarking of in-house standards where feasible and in harmonizing ADA assays used in clinical practice for better patient outcome globally.
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Affiliation(s)
- Meenu Wadhwa
- Biotherapeutics and Advanced Therapies Group, R&D Division, Science and Research, Medicines and Healthcare Products Regulatory Agency (MHRA), South Mimms, United Kingdom
| | - Isabelle Cludts
- Biotherapeutics and Advanced Therapies Group, R&D Division, Science and Research, Medicines and Healthcare Products Regulatory Agency (MHRA), South Mimms, United Kingdom
| | - Eleanor Atkinson
- Analytical and Biological Sciences Group, R&D Division, Science and Research, Medicines and Healthcare products Regulatory Agency (MHRA), South Mimms, United Kingdom
| | - Peter Rigsby
- Analytical and Biological Sciences Group, R&D Division, Science and Research, Medicines and Healthcare products Regulatory Agency (MHRA), South Mimms, United Kingdom
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Chen HC, Shunyakova J, Reddy AK, Pandiri S, Hassman L. Therapeutic drug monitoring and neutralizing anti-drug antibody detection to optimize TNF-alpha inhibitor treatment for uveitis. FRONTIERS IN OPHTHALMOLOGY 2025; 5:1432935. [PMID: 39936006 PMCID: PMC11810949 DOI: 10.3389/fopht.2025.1432935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 01/10/2025] [Indexed: 02/13/2025]
Abstract
Background Adalimumab taken every other week is an effective treatment in patients with chronic refractory uveitis. Patients who have a suboptimal response to this treatment may suffer from recurrent inflammation and vision loss. Here, we investigated the use of therapeutic drug monitoring and neutralizing anti-drug antibody detection as a strategy to optimize tumor necrosis factor (TNF)-alpha inhibitor treatment in patients who have a suboptimal response to the initial dosing of adalimumab. Method Retrospective cohort study performed in two tertiary referral uveitis services in the United States between 2015 to 2023. Patients with non-infectious uveitis who had a suboptimal response to every two-week dosing of adalimumab and underwent serum adalimumab level with reflex to anti-drug antibody testing were followed. Patients were considered to have neutralizing drug antibodies when serum drug levels were low (less than or equal to 6 mcg/mL) and anti-adalimumab antibodies were present on reflex testing. Treatment adjustment was made by clinicians with the knowledge of serum adalimumab level and the presence or absence of neutralizing drug antibodies. Every two-week dosing of adalimumab was either escalated to weekly dosing or switched to infliximab, an alternate TNF-alpha inhibitor, based on these findings. The primary outcome was success or failure at 12 months, as determined by disease inactivity on steroid-sparing therapy. Results 32 patients with suboptimal response to the initial dosing of adalimumab were included. 31.2% (n=10) of patients were found to have neutralizing drug antibodies. All patients with neutralizing drug antibodies underwent a medication switch to infliximab with a remission rate of 40% at 12 months. Patients without neutralizing drug antibodies (n=22) underwent dose escalation (77.3%; n=17) or medication switch (22.7%; n=5) and achieved a remission rate of 68.2% at 12 months. Altogether, treatment adjustment based on therapeutic drug monitoring and neutralizing drug antibody detection, in our cohort, resulted in a remission rate of 62.5%. Conclusions For patients with uveitis experiencing suboptimal therapeutic response to adalimumab dosed every two weeks, therapeutic drug monitoring and neutralizing drug antibody detection may help clinicians optimize TNF-alpha inhibitor treatment.
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Affiliation(s)
- Howard C. Chen
- John F. Hardesty Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
| | - Jenny Shunyakova
- Department of Ophthalmology, University of Kansas City School of Medicine, Kansas City, MO, United States
| | - Amit K. Reddy
- Department of Ophthalmology, University of Colorado, Aurora, CO, United States
| | - Srujay Pandiri
- Department of Ophthalmology, University of Kansas City School of Medicine, Kansas City, MO, United States
| | - Lynn Hassman
- Department of Ophthalmology, University of Colorado, Aurora, CO, United States
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Bouhuys M, Wessels MMS, de Vries W, Lambeck AJA, Touw DJ, van Rheenen PF. Lateral flow test versus enzyme-linked immunosorbent assay to measure infliximab trough concentrations: A head-to-head comparison. J Pediatr Gastroenterol Nutr 2024; 79:1134-1141. [PMID: 39390697 PMCID: PMC11615136 DOI: 10.1002/jpn3.12372] [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] [Received: 07/18/2024] [Revised: 08/27/2024] [Accepted: 08/28/2024] [Indexed: 10/12/2024]
Abstract
OBJECTIVES Infliximab is an antitumour necrosis factor agent used to treat inflammatory bowel disease (IBD). Measurement of infliximab trough concentrations (C-troughs) are used to optimize drug exposure and improve outcomes. Currently, enzyme-linked immunosorbent assays (ELISAs) are used predominantly for this purpose. Novel lateral flow immunoassays provide a rapid result. METHODS We collected 100 paired serum samples of adolescents and young adults with IBD, who were treated with infliximab maintenance infusions. C-troughs were measured with the Quantum Blue® lateral flow test (QB) with ELISA. Results were categorized as low-range (mean C-trough ≤5 µg/mL) or high-range (>5 µg/mL). A Bland-Altman plot was created with limits of clinical acceptability set at ≤2 µg/mL for low-range and ≤40% for high-range C-troughs. A concordance matrix was created to evaluate the C-trough-based clinical scenario (whether or not to escalate infliximab) using a cutoff value of 5 µg/mL. RESULTS Agreement between QB and ELISA was good (intraclass correlation coefficient: 0.85). In the low-range, 90% (95% confidence interval [CI]: 79-96) of measurements were within the limits of clinical acceptability. In the high-range this was 67% (95% CI: 53-79). QB provided higher results than ELISA. The concordance matrix showed 81% agreement (95% CI: 72-88, κ: 0.62). CONCLUSIONS Lateral flow- and ELISA-based infliximab C-trough measurements were in agreement. The swift establishment of infliximab C-troughs matters for patients experiencing increased disease activity. In the event of a low C-trough, prompt dose escalation can be initiated.
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Affiliation(s)
- Marleen Bouhuys
- Department of Paediatric Gastroenterology, Hepatology and NutritionUniversity Medical Centre Groningen, University of GroningenGroningenThe Netherlands
| | | | | | - Annechien J. A. Lambeck
- Department of Laboratory MedicineUniversity Medical Centre Groningen, University of GroningenGroningenThe Netherlands
| | - Daan J. Touw
- Department of Clinical Pharmacy and PharmacologyUniversity Medical Centre Groningen, University of GroningenGroningenThe Netherlands
| | - Patrick F. van Rheenen
- Department of Paediatric Gastroenterology, Hepatology and NutritionUniversity Medical Centre Groningen, University of GroningenGroningenThe Netherlands
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Kamal MA, Kosloski MP, Lai CH, Partridge MA, Rajadhyaksha M, Kanamaluru V, Bansal A, Shabbir A, Shumel B, Ardeleanu M, Richards SM, Yan H, Xu CR, Rodríguez-Marco A, Xiao J, Khokhar FA, Gherardi G, Babilonia E, Maloney J, Mortensen E, Akinlade B, Braunstein N, Stahl N, Torri A, Davis JD, DiCioccio AT. Immunogenicity of dupilumab in adult and pediatric patients with atopic dermatitis. Front Immunol 2024; 15:1466372. [PMID: 39588375 PMCID: PMC11586717 DOI: 10.3389/fimmu.2024.1466372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 09/09/2024] [Indexed: 11/27/2024] Open
Abstract
Background Development of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) to monoclonal antibodies may adversely impact pharmacokinetics, efficacy, and/or safety. Objective To describe incidence, titer, and persistence of dupilumab ADAs and NAbs, and their effects on pharmacokinetics, efficacy, and safety in patients with atopic dermatitis (AD). Methods This analysis included seven phase 3 randomized, placebo-controlled (N=2,992) and two long-term open-label extension (N=2,287) trials of subcutaneous dupilumab in adults and pediatric patients with moderate-to-severe AD. ADA, NAb, and dupilumab concentration in serum were assessed using validated immunoassays. ADA impacts on efficacy (EASI) and safety were assessed. Results Treatment-emergent ADAs were observed in up to 8.6% (aged ≥18 years), 16.0% (12-17 years), 5.3% (6-11 years), and 2.0% (6 months to 5 years) dupilumab-treated patients. Among dupilumab-treated patients, ≤3.7% had persistent responses, <1% had high titers (≥10,000), and ≤5.1% were NAb-positive. NAbs were more common in patients with moderate- and high-titer ADA responses. High-titer ADAs, while infrequent, were the variable most associated with lower dupilumab concentrations in serum and loss of efficacy, independent of NAb status. Efficacy was generally similar in ADA-positive and -negative patients. For most patients with high- or moderate-titer ADAs, titers decreased and efficacy improved over time with continued dupilumab treatment. ADA-positive and -negative patients had similar incidences of treatment-emergent and serious treatment-emergent adverse events. One patient with high-titer ADAs developed serum sickness. Conclusion In patients with AD, ADAs and NAbs had minimal impact on dupilumab concentration, efficacy, and safety, except for high-titer ADAs in a small number of patients. Clinical trial registration ClinicalTrials.gov, identifiers (NCT02277743, NCT02277769, NCT02260986, NCT02395133, NCT01949311, NCT03054428, NCT03345914, NCT02612454, and NCT03346434).
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MESH Headings
- Adolescent
- Adult
- Child
- Child, Preschool
- Female
- Humans
- Male
- Middle Aged
- Young Adult
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/pharmacokinetics
- Antibodies, Neutralizing/blood
- Antibodies, Neutralizing/immunology
- Dermatitis, Atopic/drug therapy
- Dermatitis, Atopic/immunology
- Dermatitis, Atopic/blood
- Treatment Outcome
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Affiliation(s)
| | | | - Ching-Ha Lai
- Regeneron Pharmaceuticals Inc., Tarrytown, NY, United States
| | | | | | | | - Ashish Bansal
- Regeneron Pharmaceuticals Inc., Tarrytown, NY, United States
| | - Arsalan Shabbir
- Regeneron Pharmaceuticals Inc., Tarrytown, NY, United States
| | - Brad Shumel
- Regeneron Pharmaceuticals Inc., Tarrytown, NY, United States
| | | | | | - Hong Yan
- Regeneron Pharmaceuticals Inc., Tarrytown, NY, United States
| | | | | | - Jing Xiao
- Regeneron Pharmaceuticals Inc., Tarrytown, NY, United States
| | | | | | - Elisa Babilonia
- Regeneron Pharmaceuticals Inc., Tarrytown, NY, United States
| | | | - Eric Mortensen
- Regeneron Pharmaceuticals Inc., Tarrytown, NY, United States
| | | | - Ned Braunstein
- Regeneron Pharmaceuticals Inc., Tarrytown, NY, United States
| | - Neil Stahl
- Regeneron Pharmaceuticals Inc., Tarrytown, NY, United States
| | - Albert Torri
- Regeneron Pharmaceuticals Inc., Tarrytown, NY, United States
| | - John D. Davis
- Regeneron Pharmaceuticals Inc., Tarrytown, NY, United States
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Venetsanopoulou AI, Voulgari PV, Drosos AA. Optimizing withdrawal strategies for anti-TNF-α therapies in rheumatoid arthritis. Expert Opin Biol Ther 2024; 24:815-825. [PMID: 39051615 DOI: 10.1080/14712598.2024.2384000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 07/20/2024] [Indexed: 07/27/2024]
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is a chronic autoimmune disease that significantly impacts patients' quality of life. While treatment options have expanded over the years, including the introduction of tumor necrosis factor-alpha (TNFα) inhibitors (TNFi), optimizing withdrawal strategies for these agents remains a challenge. AREAS COVERED This review examines the current evidence on TNFi withdrawal strategies in RA, focusing on factors influencing withdrawal decisions such as disease activity monitoring, treatment response, patient characteristics, and biomarkers. A comprehensive literature search was conducted, including randomized controlled trials, observational studies, and expert guidelines. The pathophysiology of RA, current pharmacological agents, and the treat-to-target strategy are discussed to provide a holistic understanding of RA management. EXPERT OPINION Withdrawal strategies could be suitable for certain patients, keeping in mind that several factors influence withdrawal decisions, including treatment response, disease activity and monitoring, and patient characteristics. The decision to withdraw TNFi must balance the benefits against the potential risks of disease flare and long-term treatment-related adverse effects. Combining DMARDs and TNFi early improves outcomes, supporting tapering strategies for cost-effectiveness and flare prevention. Future directions, including precision medicine approaches, patient-centered care models, and health economics analyses, are proposed to further optimize RA management and improve patient outcomes.
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Affiliation(s)
- Aliki I Venetsanopoulou
- Department of Rheumatology, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Paraskevi V Voulgari
- Department of Rheumatology, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Alexandros A Drosos
- Department of Rheumatology, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina, Greece
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Bevers NC, Keizer RJ, Wong DR, Aliu A, Pierik MJ, Derijks LJJ, van Rheenen PF. Performance of Eight Infliximab Population Pharmacokinetic Models in a Cohort of Dutch Children with Inflammatory Bowel Disease. Clin Pharmacokinet 2024; 63:529-538. [PMID: 38488984 PMCID: PMC11052775 DOI: 10.1007/s40262-024-01354-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/04/2024] [Indexed: 03/17/2024]
Abstract
BACKGROUND AND OBJECTIVE Efficacy of infliximab in children with inflammatory bowel disease can be enhanced when serum concentrations are measured and further dosing is adjusted to achieve and maintain a target concentration. Use of a population pharmacokinetic model may help to predict an individual's infliximab dose requirement. The aim of this study was to evaluate the predictive performance of available infliximab population pharmacokinetic models in an independent cohort of Dutch children with inflammatory bowel disease. METHODS In this retrospective study, we used data of 70 children with inflammatory bowel disease (443 infliximab concentrations) to evaluate eight models that focused on infliximab pharmacokinetic models in individuals with inflammatory bowel disease, preferably aged ≤ 18 years. Predictive performance was evaluated with prior predictions (based solely on patient-specific covariates) and posterior predictions (based on covariates and infliximab trough concentrations). Model accuracy and precision were calculated with relative bias and relative root mean square error and we determined the classification accuracy at the trough concentration target of ≥ 5 mg/L. RESULTS The population pharmacokinetic model by Fasanmade was identified to be most appropriate for the total dataset (relative bias before/after therapeutic drug monitoring: -20.7%/11.2% and relative root mean square error before/after therapeutic drug monitoring: 84.1%/51.6%), although differences between models were small and several were deemed suitable for clinical use. For the Fasanmade model, sensitivity and specificity for maximum posterior predictions for the next infliximab trough concentration to be ≥ 5 mg/L were respectively 83.5% and 80% with an area under the receiver operating characteristic curve of 0.870. CONCLUSIONS In our paediatric cohort, various models provided acceptable predictive performance, with the Fasanmade model deemed most suitable for clinical use. Model-informed precision dosing can therefore be expected to help to maintain infliximab trough concentrations in the target range.
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Affiliation(s)
- Nanja C Bevers
- Department of Paediatrics, Zuyderland Medical Center, Dr. H. van der Hoffplein 1, 6162 BG, Sittard-Geleen, The Netherlands.
- NUTRIM, School of Nutrition and Translational Research in Metabolism, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.
| | | | - Dennis R Wong
- Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands
| | - Arta Aliu
- Department of Gastroenterology-Hepatology and NUTRIM, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Marieke J Pierik
- Department of Gastroenterology-Hepatology and NUTRIM, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Luc J J Derijks
- Department of Clinical Pharmacy and Clinical Pharmacology, Máxima Medical Center, Veldhoven, The Netherlands
- Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Patrick F van Rheenen
- Department of Paediatric Gastroenterology Hepatology and Nutrition, University of Groningen, University Medical Centre Groningen - Beatrix Children's Hospital, Groningen, The Netherlands
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Jagt JZ, Holleman KW, Benninga MA, Van Limbergen JE, de Boer NKH, de Meij TGJ. Effectiveness of strategies to suppress antibodies to infliximab in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2024; 78:57-67. [PMID: 38291692 DOI: 10.1002/jpn3.12041] [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] [Received: 07/05/2023] [Revised: 09/27/2023] [Accepted: 10/24/2023] [Indexed: 02/01/2024]
Abstract
OBJECTIVES Antibodies to infliximab (ATIs) are associated with loss of response in children with inflammatory bowel disease (IBD). We aimed to describe the effectiveness of strategies for treatment modification following ATI development in pediatric IBD: (1) treatment escalation; and (2) switching to another anti-TNF agent. METHODS This multicenter retrospective study included children with IBD (4-18 years) on infliximab. Therapeutic drug monitoring (TDM) < 6 months and corticosteroid-free remission following each strategy were evaluated for low ATI titers (≤30 AU/mL) and high ATI titers (>30 AU/mL). RESULTS Anti-infliximab antibodies were detected in 52/288 patients (18%) after a median of 15.3 months. Three of 52 ATI-positive patients were excluded due to alternative treatments. Of the remaining 49 patients, 19 had low titers and 30 had high titers. Of 19 low-ATIs, 16 (84%) underwent treatment escalation with infliximab (IFX). Of 13 patients with TDM available, seven (54%) achieved ATI suppression at subsequent TDM and 12 (92%) at any time point. Among 30 patients with high-ATIs, 17 (57%) continued with IFX; immunomodulators were started in seven patients. Of 14 patients with TDM, seven (50%) achieved ATI suppression at subsequent TDM and 10 (71%) at any time point. At 24 months of follow-up, 73% of low-ATI patients and 50% of high-ATI patients could continue with IFX without steroids. Thirteen of 30 high-ATI patients (43%) switched to another anti-TNF agent, of whom 54% and 46% had clinical response at 6 and 24 months, respectively. CONCLUSIONS Dose optimization and/or adding an immunomodulator seem effective in suppressing low ATI titers. This strategy could also be considered in high ATI titers before switching.
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Affiliation(s)
- Jasmijn Z Jagt
- Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Pediatric Gastroenterology, Amsterdam Gastroenterology Endocrinology Metabolism, De Boelelaan, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Koen W Holleman
- Faculty of Medicine, Amsterdam UMC, Academic Medical Centre, Amsterdam, The Netherlands
| | - Marc A Benninga
- Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, Academic Medical Centre, Amsterdam, The Netherlands
| | - Johan E Van Limbergen
- Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, Academic Medical Centre, Amsterdam, The Netherlands
| | - Nanne K H de Boer
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, Amsterdam University Medical Centre, VU University Amsterdam, Amsterdam, The Netherlands
| | - Tim G J de Meij
- Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, Academic Medical Centre, Amsterdam, The Netherlands
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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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Bevers N, Aliu A, Wong DR, Winkens B, Vreugdenhil A, Pierik MJ, Derijks LJJ, van Rheenen PF. Early infliximab trough levels in paediatric IBD patients predict sustained remission. Therap Adv Gastroenterol 2023; 17:17562848231222337. [PMID: 38164362 PMCID: PMC10757796 DOI: 10.1177/17562848231222337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 12/06/2023] [Indexed: 01/03/2024] Open
Abstract
Background Exposure-response studies have shown that higher infliximab concentrations are associated with better outcomes in inflammatory bowel disease. There is little agreement about the optimal time to measure infliximab levels in children. Objectives We aimed to evaluate whether trough levels at week 6 or week 14 predict sustained remission. The secondary aim was to define target trough levels at weeks 6 and 14. Design We used routinely collected electronic healthcare data of 70 anti-tumour necrosis factor naïve children with inflammatory bowel disease treated with a standard infliximab induction- and variable maintenance scheme. Methods Trough levels and blood and faecal markers for disease activity were measured before every infliximab administration. Sustained remission was defined as the absence of symptoms and low inflammatory markers between weeks 26 and 52 after the start of infliximab therapy. Optimal infliximab levels at weeks 6 and 14 were determined using the receiver operating characteristic curve. Results The median infliximab level at week 6 was not significantly higher in children who achieved sustained remission compared to those who did not (16.9 mg/L versus 12.0 mg/L; p = 0.058) but the median infliximab level at week 14 was significantly higher in those with sustained remission (7.7 mg/L versus 3.8 mg/L; p = 0.006). The area under the receiver operating characteristics curves at weeks 6 and 14 to predict sustained remission was 0.67 (95% CI 0.51-0.83) and 0.75 (95% CI 0.60-0.90), respectively. Target trough levels at weeks 6 and 14 were ⩾13.2 and ⩾6.9 mg/L, respectively. Conclusion An infliximab measurement at week 14 with a target through level ⩾6.9 mg/L best predicted sustained remission.
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Affiliation(s)
- Nanja Bevers
- Department of Paediatrics, Zuyderland Medical Center, Dr. H. van der Hoffplein 1, 6162 BG Sittard, The Netherlands
| | - Arta Aliu
- Department of Gastroenterology and Hepatology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Dennis R. Wong
- Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands
| | - Bjorn Winkens
- Department of Methodology and Statistics, Care and Public Health Research Institute, Maastricht University, Maastricht, The Netherlands
| | - Anita Vreugdenhil
- Department of Paediatrics, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Marieke J. Pierik
- Division of Gastroenterology and Hepatology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Luc J. J. Derijks
- Department of Clinical Pharmacy and Pharmacology, Máxima Medical Center, Veldhoven, The Netherlands Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Patrick F. van Rheenen
- Department of Paediatric Gastroenterology Hepatology and Nutrition, University Medical Center Groningen – Beatrix Children’s Hospital, University of Groningen, Groningen, The Netherlands
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10
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Xiang D, Li N, Liu L, Yu H, Li X, Zhao T, Liu D, Gong X. Development and validation of enzyme-linked immunosorbent assays for the measurement of infliximab and anti-drug antibody levels. Heliyon 2023; 9:e21858. [PMID: 38034789 PMCID: PMC10682623 DOI: 10.1016/j.heliyon.2023.e21858] [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: 05/25/2023] [Revised: 09/11/2023] [Accepted: 10/30/2023] [Indexed: 12/02/2023] Open
Abstract
Infliximab and its anti-drug antibody (ADA) serum concentrations exhibit a strong correlation with clinical response and loss of response. The use of therapeutic drug monitoring to measure the concentration of infliximab and ADA can facilitate clinical decision-making, helping patients attain optimal therapeutic effects. However, there are still limitations to the existing infliximab and its ADA detection methods. Therefore, this study aimed to develop and validate enzyme-linked immunosorbent assay (ELISA)-based methods for measuring infliximab and its ADA levels in human plasma according to the general recommendations for immunoassays. Free infliximab is bound by recombinant TNF-α and detected using HRP-labeled anti-human antibody. The ADA is captured by on-plate-coated infliximab and recognized by biotin-labeled infliximab. Two bridging ELISA assays were developed and after assay optimization and validation, these assays have been applied in ten patients with inflammatory bowel disease (IBD). In infliximab detection assay, a standard curve ranging from 0.10 μg/mL to 8.0 μg/mL with great precision and accuracy has been established. Drug tolerance of the ADA assay was that 100 ng/mL ADA could tolerate at least 5.0 μg/mL infliximab in the plasma using a commercially available monoclonal anti-infliximab antibody as the positive control. The ADA screening and confirmatory assays achieved a sensitivity of 36.74 ng/mL and 37.15 ng/mL, respectively. All other assay characteristics met the requirements. The mean concentration of infliximab in eight patients with IBD was 7.88 (1.87-21.1) μg/mL, and the ADA levels were all negative. Moreover, the concentrations of infliximab in the remaining two patients were below the LLOQ and the ADAs were positive. Thus, accurate and sensitive ELISA methods have been developed and validated for the detection of infliximab and its ADA concentrations and have been successfully applied to clinical therapeutic drug monitoring.
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Affiliation(s)
- Dong Xiang
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ninghong Li
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Department of Pharmacy, Nanchang First Hospital, Nanchang, 330008, China
| | - Lu Liu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Hengyi Yu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiping Li
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Tinghui Zhao
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Dong Liu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xuepeng Gong
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
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11
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Guo H, Li L, Liu B, Lu P, Cao Z, Ji X, Li L, Ouyang G, Nie Z, Lyu A, Lu C. Inappropriate treatment response to DMARDs: A pathway to difficult-to-treat rheumatoid arthritis. Int Immunopharmacol 2023; 122:110655. [PMID: 37481847 DOI: 10.1016/j.intimp.2023.110655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 07/03/2023] [Accepted: 07/12/2023] [Indexed: 07/25/2023]
Abstract
In recent years, difficult-to-treat rheumatoid arthritis (D2T RA) has attracted significant attention from rheumatologists due to its poor treatment response and the persistent symptoms or signs experienced by patients. The therapeutic demands of patients with D2T RA are not properly met due to unclear pathogenic causes and a lack of high-quality data for current treatment options, creating considerable management difficulties with this patient population. This review describes the clinical challenges associated with disease-modifying antirheumatic drugs (DMARDs) and explores contributing factors associated with inappropriate response to DMARDs that may lead to D2T RA and related immunological dysregulation. It is now understood that D2T RA is a highly heterogeneous pathological status that involves multiple factors. These factors include but are not limited to genetics, environment, immunogenicity, comorbidities, adverse drug reactions, inappropriate drug application, poor adherence, and socioeconomic status. Besides, these factors may manifest in the selection and utilization of specific DMARDs, either individually or in combination, thereby contributing to inadequate treatment response. Finding these variables may offer hints for enhancing DMARD therapy plans and bettering the condition of D2T RA patients.
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Affiliation(s)
- Hongtao Guo
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, 16# Dongzhimen Nei Nan Xiao Jie, Dongcheng District, Beijing 100700, China; Department of Rheumatology, the First Affiliated Hospital of Henan University of TCM, Zhengzhou 450000, China
| | - Li Li
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, 16# Dongzhimen Nei Nan Xiao Jie, Dongcheng District, Beijing 100700, China
| | - Bin Liu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, 16# Dongzhimen Nei Nan Xiao Jie, Dongcheng District, Beijing 100700, China
| | - Peipei Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, 16# Dongzhimen Nei Nan Xiao Jie, Dongcheng District, Beijing 100700, China
| | - Zhiwen Cao
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, 16# Dongzhimen Nei Nan Xiao Jie, Dongcheng District, Beijing 100700, China
| | - Xinyu Ji
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, 16# Dongzhimen Nei Nan Xiao Jie, Dongcheng District, Beijing 100700, China
| | - Li Li
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, 16# Dongzhimen Nei Nan Xiao Jie, Dongcheng District, Beijing 100700, China
| | - Guilin Ouyang
- Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Zhixin Nie
- Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Aiping Lyu
- Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Cheng Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, 16# Dongzhimen Nei Nan Xiao Jie, Dongcheng District, Beijing 100700, China.
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12
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Chen SF, Yeh FC, Chen CY, Chang HY. Tailored therapeutic decision of rheumatoid arthritis using proteomic strategies: how to start and when to stop? Clin Proteomics 2023; 20:22. [PMID: 37301840 DOI: 10.1186/s12014-023-09411-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 05/23/2023] [Indexed: 06/12/2023] Open
Abstract
Unpredictable treatment responses have been an obstacle for the successful management of rheumatoid arthritis. Although numerous serum proteins have been proposed, there is a lack of integrative survey to compare their relevance in predicting treatment outcomes in rheumatoid arthritis. Also, little is known about their applications in various treatment stages, such as dose modification, drug switching or withdrawal. Here we present an in-depth exploration of the potential usefulness of serum proteins in clinical decision-making and unveil the spectrum of immunopathology underlying responders to different drugs. Patients with robust autoimmunity and inflammation are more responsive to biological treatments and prone to relapse during treatment de-escalation. Moreover, the concentration changes of serum proteins at the beginning of the treatments possibly assist early recognition of treatment responders. With a better understanding of the relationship between the serum proteome and treatment responses, personalized medicine in rheumatoid arthritis will be more achievable in the near future.
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Affiliation(s)
- Shuo-Fu Chen
- Department of Heavy Particles & Radiation Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Fu-Chiang Yeh
- Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Ching-Yun Chen
- Department of Biomedical Sciences and Engineering, Institute of Biomedical Engineering and Nanomedicine, National Central University, Taoyuan, Taiwan
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli, Taiwan
| | - Hui-Yin Chang
- Department of Biomedical Sciences and Engineering, Institute of Systems Biology and Bioinformatics, National Central University, No. 300, Zhongda Rd., Zhongli District, Taoyuan, 320317, Taiwan.
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13
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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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14
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Sakane H, Okamura K, Inoue M, Inoue H, Yonemoto Y, Mitomi H, Tsuchida K, Suto T, Kaneko T, Chikuda H. Anti-drug antibodies and rheumatoid factor level in patients with rheumatoid arthritis using the infliximab biosimilar CT-P13. BMC Rheumatol 2022; 6:74. [PMID: 36474258 PMCID: PMC9727853 DOI: 10.1186/s41927-022-00304-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 08/26/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND This study evaluated the existence of anti-drug antibodies (ADAs) before and 52 weeks after switching from intravenous infliximab (IFX) to intravenous CT-P13 in patients with rheumatoid arthritis (RA). METHODS We performed a prospective observational study. Twenty-eight patients (7 males and 21 females) received intravenous CT-P13 after intravenous IFX, and the clinical data were collected from medical records. Rheumatoid factor (RF) and anti-CCP antibody were examined at baseline. At baseline and 52 weeks after the start of CT-P13 treatment, the Disease Activity Score based on the 28-joint count and the levels of C-reactive protein, matrix metalloproteinase-3, and ADA, as well as the erythrocyte sedimentation rate were evaluated. ADAs were measured using an enzyme-linked immunosorbent assay kit. RESULTS Seven (25%) and 6 (21.4%) cases were positive for ADAs at baseline and 52 weeks after, respectively. One case became newly positive for ADAs at week 52. Two of the ADA-positive cases became ADA-negative 52 weeks after. The ADA-positive group showed significantly higher RF values at baseline than the ADA-negative group (p = 0.03). No difference was observed between the ADA-positive group and the ADA-negative group regarding other clinical parameters. CONCLUSIONS The positive rate of ADAs did not increase after switching from intravenous IFX to intravenous CT-P13. Among the patients with ADAs, a high level of RF was observed at baseline.
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Affiliation(s)
- Hideo Sakane
- grid.256642.10000 0000 9269 4097Department of Orthopaedic Surgery, Gunma University Graduate School of Medicine, 3-39-22, Showamachi, Maebashi, Gunma 371-8511 Japan
| | - Koichi Okamura
- grid.256642.10000 0000 9269 4097Department of Orthopaedic Surgery, Gunma University Graduate School of Medicine, 3-39-22, Showamachi, Maebashi, Gunma 371-8511 Japan
| | - Makoto Inoue
- grid.414621.40000 0004 0404 6655Department of Rheumatology, Inoue Hospital, 55, Torimachi, Takasaki, Gunma 370-0053 Japan
| | - Hiroshi Inoue
- grid.414621.40000 0004 0404 6655Department of Rheumatology, Inoue Hospital, 55, Torimachi, Takasaki, Gunma 370-0053 Japan
| | - Yukio Yonemoto
- grid.414621.40000 0004 0404 6655Department of Rheumatology, Inoue Hospital, 55, Torimachi, Takasaki, Gunma 370-0053 Japan
| | - Hirofumi Mitomi
- grid.414621.40000 0004 0404 6655Department of Rheumatology, Inoue Hospital, 55, Torimachi, Takasaki, Gunma 370-0053 Japan
| | - Kosei Tsuchida
- grid.414621.40000 0004 0404 6655Department of Rheumatology, Inoue Hospital, 55, Torimachi, Takasaki, Gunma 370-0053 Japan
| | - Takahito Suto
- grid.256642.10000 0000 9269 4097Department of Orthopaedic Surgery, Gunma University Graduate School of Medicine, 3-39-22, Showamachi, Maebashi, Gunma 371-8511 Japan
| | - Tetsuya Kaneko
- grid.256642.10000 0000 9269 4097Department of Orthopaedic Surgery, Gunma University Graduate School of Medicine, 3-39-22, Showamachi, Maebashi, Gunma 371-8511 Japan ,Department of Orthopaedic Surgery, Fukaya Red Cross Hospital, 5-8-1, Kamishibacho-Nishi, Fukaya, Saitama 366-0052 Japan
| | - Hirotaka Chikuda
- grid.256642.10000 0000 9269 4097Department of Orthopaedic Surgery, Gunma University Graduate School of Medicine, 3-39-22, Showamachi, Maebashi, Gunma 371-8511 Japan
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15
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Gehin JE, Goll GL, Brun MK, Jani M, Bolstad N, Syversen SW. Assessing Immunogenicity of Biologic Drugs in Inflammatory Joint Diseases: Progress Towards Personalized Medicine. BioDrugs 2022; 36:731-748. [PMID: 36315391 PMCID: PMC9649489 DOI: 10.1007/s40259-022-00559-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/26/2022] [Indexed: 11/30/2022]
Abstract
Biologic drugs have greatly improved treatment outcomes of inflammatory joint diseases, but a substantial proportion of patients either do not respond to treatment or lose response over time. Drug immunogenicity, manifested as the formation of anti-drug antibodies (ADAb), constitute a significant clinical problem. Anti-drug antibodies influence the pharmacokinetics of the drug, are associated with reduced clinical efficacy, and an increased risk of adverse events such as infusion reactions. The prevalence of ADAb differs among drugs and diseases, and the detection of ADAb also depends on the assay format. Most data exist for the tumor necrosis factor-alpha inhibitors infliximab and adalimumab, with a frequency of ADAb that ranges from 10 to 60% across studies. Measurement of ADAb and serum drug concentrations, therapeutic drug monitoring, has been suggested as a strategy to optimize therapy with biologic drugs. Although the recent randomized clinical Norwegian Drug Monitoring (NOR-DRUM) trials show promise towards a personalized medicine prescribing approach by therapeutic drug monitoring, several challenges remain. A plethora of assay formats, with widely differing properties, is currently used for measuring ADAb. Comparing results between different assays and laboratories is difficult, which complicates the development of cut-offs necessary for guidelines and the implementation of ADAb measurements in clinical practice. With the possible exception of infliximab, limited data on clinical relevance and cost effectiveness exist to support therapeutic drug monitoring as a routine clinical strategy to monitor biologic drugs in inflammatory joint diseases. The aim of this review is to provide an overview of the characteristics and prevalence of ADAb, predisposing factors to ADAb formation, commonly used assessment methods, clinical consequences of ADAb, and the potential implications of ADAb assessments for everyday treatment of inflammatory joint diseases.
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Affiliation(s)
- Johanna Elin Gehin
- Department of Medical Biochemistry, Oslo University Hospital, Radiumhospitalet, Nydalen, Box 4953, 0424, Oslo, Norway.
| | - Guro Løvik Goll
- Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway
| | - Marthe Kirkesæther Brun
- Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Meghna Jani
- Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK
- Department of Rheumatology, Salford Royal NHS Foundation Trust, Salford, UK
| | - Nils Bolstad
- Department of Medical Biochemistry, Oslo University Hospital, Radiumhospitalet, Nydalen, Box 4953, 0424, Oslo, Norway
| | - Silje Watterdal Syversen
- Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway
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16
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Wang X, Tang Z, Huang T, Hu H, Zhao Y, Liu Y. Withdrawal of MTX in rheumatoid arthritis patients on bDMARD/tsDMARD plus methotrexate at target: a systematic review and meta-analysis. Rheumatology (Oxford) 2022; 62:1410-1416. [PMID: 36125185 DOI: 10.1093/rheumatology/keac515] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 08/05/2022] [Accepted: 08/30/2022] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES To evaluate the effect of methotrexate (MTX) withdrawal on disease activity and remission rate in patients at target after treatment with bDMARDs/tsDMARDs plus MTX. METHODS We searched the PubMed, EMBASE, and CENTRAL databases for all RCTs on MTX withdrawal in patients with rheumatoid arthritis at target after combination therapy from inception to 2022-3-7 in order to extract data, including the change from withdrawal in DAS28 at the end point; proportion of low disease activity (LDA) assessed by DAS28, SDAI or CDAI; proportion of remission assessed by DAS28, SDAI, CDAI or ACR/EULAR Boolean remission. The Cochrane Q test and I2 test were used to assess heterogeneity, and random-effects models were used for data synthesis. This study is registered with PROSPERO (CRD42022303891). RESULTS Six articles were included for qualitative and quantitative analysis, all of which were noninferior RCTs involving 1430 patients (734 in the withdrawal group and 696 in the continuation group). Compared with continuing combination therapy, tapering off or discontinuing MTX increased DAS28 by 0.20 (95% CI 0.09-0.32, I2 = 0%) and decreased the percentage of patients with LDA assessed by DAS28 to < 3.2 (RR 0.88 [0.80, 0.97] I2 = 0%). However, MTX withdrawal did not decrease remission rates assessed by DAS28, SDAI, CDAI or ACR/EULAR Boolean remission (RR 0.90 [0.81, 1.01], 0.93 [0.77, 1.11], 0.90 [0.74, 1.11], 0.95 [0.70, 1.29], respectively). CONCLUSION Withdrawing MTX slightly increases the RA disease activity in patients treated at target with bDMARDs/tsDMARDs plus MTX and has limited effects for patients with deep remission.
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Affiliation(s)
- Xiangpeng Wang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Ziyi Tang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Tianwen Huang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Huifang Hu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Yaxi Zhao
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
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17
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Casasola-LaMacchia A, Seward RJ, Tourdot S, Willetts M, Kruppa G, Agostino MJ, Bergeron G, Ahyi-Amendah N, Ciarla A, Lu Z, Kim HY, Hickling TP, Neubert H. HLAII peptide presentation of infliximab increases when complexed with TNF. Front Immunol 2022; 13:932252. [PMID: 36177046 PMCID: PMC9513746 DOI: 10.3389/fimmu.2022.932252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
CD4+ T-cell activation through recognition of Human Leukocyte Antigen II (HLAII)-presented peptides is a key step in the development of unwanted immune response against biotherapeutics, such as the generation of anti-drug antibodies (ADA). Therefore, the identification of HLAII-presented peptides derived from biotherapeutics is a crucial part of immunogenicity risk assessment and mitigation strategies during drug development. To date, numerous CD4+ T-cell epitopes have been identified by HLAII immunopeptidomics in antibody-based biotherapeutics using either their native or aggregated form. Antibody-target immune complexes have been detected in patients with ADA and are thought to play a role in ADA development by enhancing the presentation of CD4+ T-cell epitopes at the surface of antigen presenting cells (APCs). The aim of this study was to investigate the effect of biotherapeutic antibody-target immune complexes on the HLAII peptide presentation of biotherapeutics in human primary monocyte-derived dendritic cells (DCs). The trimeric tumor necrosis factor (TNF) and its biotherapeutic antagonists infliximab (INFL), adalimumab (ADAL), and a single armed Fab' were used as a model system. The HLAII immunopeptidome of DCs loaded with antagonists or their immune complexes with TNF was analyzed by trapped ion mobility time-of-flight mass spectrometry (timsTOF MS) leading to the identification of ~ 12,000 unique HLAII-associated peptides per preparation. Anti-TNF sequences were detected at a median of 0.3% of the total immunopeptidome, against a majority background of peptides from endogenous and media-derived proteins. TNF antagonist presentation spanned the variable and constant regions in a widespread manner in both light and heavy chains, consistent with previously discovered HLAII peptides. This investigation extends the collection of observed HLAII peptides from anti-TNF biotherapeutics to include sequences that at least partially span the complementary determining regions (CDRs), such as the LCDR1 for both INFL and ADAL. Although antagonist presentation varied significantly across donors, peptides from both bivalent antagonists INFL and ADAL were more highly presented relative to the Fab'. While TNF immune complexes did not alter overall HLAII presentation, a moderate increase in presentation of a subset of peptide clusters was observed in the case of INFL-TNF, which included HCDR2, HCDR3 and LCDR2 sequences.
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Affiliation(s)
- Andrea Casasola-LaMacchia
- BioMedicine Design, Worldwide Research, Development and Medical, Pfizer Inc., Andover, MA, United States
| | - Robert Joseph Seward
- BioMedicine Design, Worldwide Research, Development and Medical, Pfizer Inc., Andover, MA, United States
| | - Sophie Tourdot
- BioMedicine Design, Worldwide Research, Development and Medical, Pfizer Inc., Andover, MA, United States
| | | | - Gary Kruppa
- Bruker Daltonics, Billerica, MA, United States
| | | | - Gabrielle Bergeron
- BioMedicine Design, Worldwide Research, Development and Medical, Pfizer Inc., Andover, MA, United States
| | - Nathalie Ahyi-Amendah
- BioMedicine Design, Worldwide Research, Development and Medical, Pfizer Inc., Andover, MA, United States
| | - Andrew Ciarla
- BioMedicine Design, Worldwide Research, Development and Medical, Pfizer Inc., Andover, MA, United States
| | - Zhaojiang Lu
- Analytical Research and Development, Biotherapeutics Pharmaceutical Sciences, Pfizer Inc., Andover, MA, United States
| | - Hai-Young Kim
- Analytical Research and Development, Biotherapeutics Pharmaceutical Sciences, Pfizer Inc., Andover, MA, United States
| | - Timothy P. Hickling
- BioMedicine Design, Worldwide Research, Development and Medical, Pfizer Inc., Andover, MA, United States
| | - Hendrik Neubert
- BioMedicine Design, Worldwide Research, Development and Medical, Pfizer Inc., Andover, MA, United States
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18
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Valdes L, Cox JT, Yang J, Susarla G, Han S, Papaliodis GN, Sobrin L. Anti-infliximab antibodies and clinical response in noninfectious uveitis and scleritis patients treated with infliximab: A retrospective review. Am J Ophthalmol Case Rep 2022; 27:101634. [PMID: 35800400 PMCID: PMC9253593 DOI: 10.1016/j.ajoc.2022.101634] [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: 02/05/2022] [Revised: 06/14/2022] [Accepted: 06/21/2022] [Indexed: 12/01/2022] Open
Abstract
Purpose To investigate the clinical response to infliximab in ocular inflammation patients who develop anti-infliximab antibodies (AIA) vs. those patients who do not develop AIA. Observations A retrospective review was performed of patients treated with infliximab for noninfectious uveitis (NIU) or scleritis. Clinical response was determined as a composite clinical endpoint and classified as complete, partial, or absent. Nine of 32 infliximab-treated patients (28%) were found to develop AIA. Among the AIA-positive patients, clinical response was complete in 7 patients (78%) and partial in 2 patients (22%). Among the AIA-negative patients, clinical response was complete in 15 patients (65%), partial in 6 patients (26%) and absent in 2 patients (9%). Serum infliximab levels tended to decrease with appearance of AIA but rarely became undetectable. Conclusions and Importance In this pilot study, AIA-positive patients did not have diminished clinical response to infliximab when compared with AIA-negative patients. There was a high rate of complete clinical response to infliximab in this group of NIU and scleritis patients. Approximately a quarter of patients developed AIA. AIA-positive patients did not have diminished rates of clinical response when compared with AIA-negative patients. This suggests that routine AIA monitoring may not be clinically useful, although validation of this finding in larger cohorts is necessary.
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Affiliation(s)
| | | | | | - Gayatri Susarla
- Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
| | - Samuel Han
- Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
| | - George N. Papaliodis
- Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
| | - Lucia Sobrin
- Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
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19
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Brun MK, Goll GL, Jørgensen KK, Sexton J, Gehin JE, Sandanger Ø, Olsen IC, Klaasen RA, Warren DJ, Mørk C, Kvien TK, Jahnsen J, Bolstad N, Haavardsholm EA, Syversen SW. Risk factors for anti-drug antibody formation to infliximab: Secondary analyses of a randomised controlled trial. J Intern Med 2022; 292:477-491. [PMID: 35411981 PMCID: PMC9545769 DOI: 10.1111/joim.13495] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Anti-drug antibodies (ADAb) frequently form early in the treatment course of infliximab and other tumour necrosis factor (TNF) inhibitors, leading to treatment failure and adverse events. OBJECTIVE To identify risk factors for ADAb in the early phase of infliximab treatment. METHODS Patients (n = 410) with immune-mediated inflammatory diseases who initiated infliximab treatment were included in the 38-week Norwegian Drug Monitoring Trial (NOR-DRUM) A and randomised 1:1 to therapeutic drug monitoring (TDM) or standard therapy. Serum levels of infliximab and ADAb were measured at each infusion. Possible risk factors for ADAb formation were assessed using logistic regression, adjusting for potential confounders. RESULTS ADAb were detected in 78 (19%) patients. A diagnosis of rheumatoid arthritis (RA) (odds ratio [OR], 1.9 [95% confidence interval [CI] 1.0-3.6]) and lifetime smoking (OR, 2.0 [CI 1.1-3.6]) were baseline risk factors, while baseline use of concomitant immunosuppressors (OR, 0.4 [CI 0.2-0.8]) and a diagnosis of spondyloarthritis (SpA) (OR, 0.4 [CI 0.2-0.8]) reduced the risk of ADAb. Higher disease activity during follow-up (OR, 1.1 [CI 1.0-1.1]) and "drug holidays" of more than 11 weeks (OR, 4.1 [CI 1.2-13.8]) increased the risk of ADAb, whereas higher infliximab doses (OR, 0.1 [CI 0.0-0.3) and higher serum infliximab concentrations (OR, 0.7 [CI 0.6-0.8]) reduced the risk of immunogenicity. CONCLUSION Several risk factors for ADAb formation during early-phase infliximab treatment were identified. This knowledge provides a basis for treatment strategies to mitigate the formation of ADAb and identify patients in whom these measures are of particular importance.
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Affiliation(s)
- Marthe Kirkesaether Brun
- Division of Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Guro Løvik Goll
- Division of Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway
| | | | - Joseph Sexton
- Division of Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway
| | - Johanna Elin Gehin
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | | | - Inge Christoffer Olsen
- Department of Research Support for Clinical Trials, Oslo University Hospital, Oslo, Norway
| | - Rolf Anton Klaasen
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - David John Warren
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Cato Mørk
- Akershus Dermatology Center, Lørenskog, Norway
| | - Tore K Kvien
- Division of Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Jørgen Jahnsen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
| | - Nils Bolstad
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Espen A Haavardsholm
- Division of Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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20
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Gelis S, Verdesoto JT, Pascal M, Muñoz-Cano RM. Hypersensitivity Reactions to Monoclonal Antibodies: New Approaches. CURRENT TREATMENT OPTIONS IN ALLERGY 2022. [DOI: 10.1007/s40521-022-00318-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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21
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Mosch R, Guchelaar HJ. Immunogenicity of Monoclonal Antibodies and the Potential Use of HLA Haplotypes to Predict Vulnerable Patients. Front Immunol 2022; 13:885672. [PMID: 35784343 PMCID: PMC9249215 DOI: 10.3389/fimmu.2022.885672] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/24/2022] [Indexed: 01/14/2023] Open
Abstract
The use of monoclonal antibodies (mAbs) in the clinic has successfully expanded to treatment of cancer, viral infections, inflammations, and other indications. However, some of the classes of mAbs that are used in the clinic show the formation of anti-drug antibodies (ADAs) leading to loss of efficacy. This review describes ADA formation for the various mAbs, and its clinical effect. Lastly, this review considers the use of HLA-haplotypes as biomarkers to predict vulnerability of patients sensitive to formation of ADAs.
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22
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Krieckaert C, Hernández-Breijo B, Gehin JE, le Mélédo G, Balsa A, Jani M, Mulleman D, Navarro-Compan V, Wolbink G, Isaac J, van Tubergen A. Therapeutic drug monitoring of biopharmaceuticals in inflammatory rheumatic and musculoskeletal disease: a systematic literature review informing EULAR points to consider. RMD Open 2022; 8:e002216. [PMID: 35980738 PMCID: PMC9171282 DOI: 10.1136/rmdopen-2022-002216] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 05/18/2022] [Indexed: 01/08/2023] Open
Abstract
The objectives of this review were to collect and summarise evidence on therapeutic drug monitoring (TDM) of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases and to inform the EULAR Task Force for the formulation of evidence-based points to consider. A systematic literature review (SLR) was performed, covering technical aspects and (clinical) utility of TDM, to answer 13 research questions. MEDLINE, Embase and Cochrane were searched until July 2020. American College of Rheumatology and EULAR abstracts were also considered for inclusion. Data were extracted in evidence tables and risk of bias assessment was performed. For the search on technical aspects, 678 records were identified, of which 22 papers were selected. For the clinical utility search, 3846 records were identified, of which 108 papers were included. Patient-related factors associated with biopharmaceutical blood concentrations included body weight, methotrexate comedication and disease activity. The identification of a target range was hampered by study variability, mainly disease activity measures and study type. Evidence was inconsistent for multiple clinical situations in which TDM is currently applied. However, for some particular scenarios, including prediction of future treatment response, non-response to treatment, tapering and hypersensitivity reactions, robust evidence was found. There is currently no evidence for routine use of proactive TDM, in part because published cost-effectiveness analyses do not incorporate the current landscape of biopharmaceutical costs and usage. This SLR yields evidence in favour of TDM of biopharmaceuticals in some clinical scenarios, but evidence is insufficient to support implementation of routine use of TDM.
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Affiliation(s)
- Charlotte Krieckaert
- Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, Reade, Amsterdam, The Netherlands
| | | | - Johanna Elin Gehin
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | | | | | - Meghna Jani
- Centre for Epidemiology versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK
- department of Rheumatology, Salford Royal Hospitals NHS Trust, Salford, UK
| | | | | | - Gertjan Wolbink
- Immunopathology, Sanquin Research, Amsterdam, The Netherlands
| | - John Isaac
- Translational and Clinical Research Institute, Newcastle University and Musculoskeletal Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Astrid van Tubergen
- department of Medicine, Division of Rheumatology, Maastricht University Medical Centre+, Maastricht, The Netherlands
- Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, The Netherlands
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23
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Hanzel J, Dreesen E, Vermeire S, Löwenberg M, Hoentjen F, Bossuyt P, Clasquin E, Baert FJ, D’Haens GR, Mathôt R. Pharmacokinetic-Pharmacodynamic Model of Vedolizumab for Targeting Endoscopic Remission in Patients With Crohn Disease: Posthoc Analysis of the LOVE-CD Study. Inflamm Bowel Dis 2022; 28:689-699. [PMID: 34137430 PMCID: PMC9071095 DOI: 10.1093/ibd/izab143] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Higher serum concentrations of vedolizumab have been associated with improved outcomes in inflammatory bowel disease. It is unclear how vedolizumab exposure is linked to endoscopic remission in Crohn disease (CD). We aimed to develop a pharmacokinetic-pharmacodynamic model linking vedolizumab exposure to endoscopic remission in CD. METHODS Data were obtained from the first 110 patients participating in a phase 4 prospective multicenter trial (LOVE-CD; ClinicalTrials.gov identifier: NCT02646683), where vedolizumab was dosed at 300 mg every 8 weeks and serum concentrations and antibodies to vedolizumab were measured before each infusion. Concentration-time profiles were described by a 2-compartment model with parallel linear and nonlinear elimination. A first-order discrete-time Markov model was used to describe the relationship between pharmacokinetic exposure metrics and the probability of endoscopic remission (Simple Endoscopic Score for CD < 4). RESULTS Linear clearance was 0.215 L/d, and the volume of distribution of the central compartment was 4.92 L. Linear clearance was higher and vedolizumab exposure was lower in patients with lower serum albumin concentrations, in the presence of antibodies to vedolizumab, and in patients with previous exposure to other biologic therapy. A week 22 vedolizumab concentration of 20.0 mg/L was predicted to yield a 35% probability of achieving endoscopic remission at week 26. Model-based simulations suggested that endoscopic remission rates of 46.5% or 40.0% could be reached with every-4-weeks dosing in patients who were naïve or previously exposed to biologic therapy, respectively. CONCLUSIONS Model-informed dosing of vedolizumab in CD provides a foundation for future research aiming to maximize endoscopic remission rates.
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Affiliation(s)
- Jurij Hanzel
- Faculty of Medicine, University of Ljubljana, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, the Netherlands
| | - Erwin Dreesen
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
- Department of Pharmacy, Uppsala University, Uppsala, Sweden
| | - Séverine Vermeire
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Mark Löwenberg
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, the Netherlands
| | - Frank Hoentjen
- Department of Gastroenterology and Hepatology, Radboud UMC, Nijmegen, the Netherlands
| | - Peter Bossuyt
- Imelda GI Clinical Research Centre, Imelda General Hospital, Bonheiden, Belgium
| | - Esmé Clasquin
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, the Netherlands
| | - Filip J Baert
- Division of Gastroenterology, AZ Delta, Roeselare, Belgium
| | - Geert R D’Haens
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, the Netherlands
| | - Ron Mathôt
- Department of Hospital Pharmacy—Clinical Pharmacology, Amsterdam UMC, Amsterdam, the Netherlands
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24
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Hanzel J, Jansen JM, ter Steege RWF, Gecse KB, D’Haens GR. Multiple Switches From the Originator Infliximab to Biosimilars Is Effective and Safe in Inflammatory Bowel Disease: A Prospective Multicenter Cohort Study. Inflamm Bowel Dis 2022; 28:495-501. [PMID: 34013959 PMCID: PMC8972297 DOI: 10.1093/ibd/izab099] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Though a single nonmedical switch from the originator infliximab (IFX) to a biosimilar is considered effective and safe for most patients with inflammatory bowel disease (IBD), very limited data are available on multiple successive switches. METHODS We performed a prospective multicenter cohort study of adult IBD patients who underwent 2 switches from the originator IFX to CT-P13 to SB2 (group 1), 1 switch from CT-P13 to SB2 (group 2), and 1 switch from the originator IFX to CT-P13 (group 3). Patients were assessed at 4 and 12 months since the most recent switch for remission using clinical (physician's assessment) and biochemical (C-reactive protein [CRP], and fecal calprotectin [FC]) measures. Patients discontinuing treatment for ineffectiveness or adverse events before month 12 were imputed as nonremitters. RESULTS One hundred seventy-six patients (Crohn's disease 71%, ulcerative colitis 27.8%, IBD unclassified 1.2%; group 1, 69; group 2, 80; group 3, 27) were included. At 12 months after the most recent switch 76.9% (40 of 52, group 1), 65.7% (46 of 70, group 2) and 76.9% (20 of 26, group 3) of patients were in clinical remission. Treatment persistence at 12 months was 85.0%, 87.0%, and 70.1%, respectively. There were no significant differences in the rate of clinical, CRP, FC remission, or treatment persistence at 12 months between the 3 groups. Infusion reactions occurred in 1.7% of patients (3/176), all in patients with antidrug antibodies from group 2. CONCLUSIONS Multiple successive switching and switching between biosimilars of IFX seemed to be effective and safe.
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Affiliation(s)
- Jurij Hanzel
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Academic Medical Centre, Amsterdam, the Netherlands
- Medical Faculty, University of Ljubljana, Department of Gastroenterology, UMC Ljubljana, Ljubljana, Slovenia
| | - Jeroen M Jansen
- Department of Gastroenterology and Hepatology, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands
| | - Rinze W F ter Steege
- Department of Gastroenterology and Hepatology, Martini Ziekenhuis, Groningen, the Netherlands
| | - Krisztina B Gecse
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Academic Medical Centre, Amsterdam, the Netherlands
| | - Geert R D’Haens
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Academic Medical Centre, Amsterdam, the Netherlands
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25
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Tesser J, Lin I, Shiff NJ, Chakravarty SD, Schmajuk G, Hammam N, Desai S. Improvement in disease activity among patients with rheumatoid arthritis who switched from intravenous infliximab to intravenous golimumab in the ACR RISE registry. Clin Rheumatol 2022; 41:2319-2327. [PMID: 35312895 PMCID: PMC9287251 DOI: 10.1007/s10067-022-06116-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 02/15/2022] [Accepted: 02/22/2022] [Indexed: 11/25/2022]
Abstract
Infliximab and golimumab are intravenously (IV) administered tumor necrosis factor inhibitors approved to treat moderate-to-severe rheumatoid arthritis (RA) with concomitant methotrexate. Owing to differences in biologic construct, patients with IV-infliximab treatment failure may benefit from switching to IV-golimumab. Utilizing the ACR’s Rheumatology Informatics System for Effectiveness (RISE), a large electronic health records registry based in the USA, we assessed RA disease activity in patients switching from IV-infliximab to IV-golimumab. This retrospective, longitudinal, single-arm study included adults (≥ 18 years) with ≥ 1 RA diagnosis code between 2014 and 2018 and ≥ 1 IV-infliximab prescription within 6 months of a new IV-golimumab order (index date). Longitudinal assessments of disease activity using the Clinical Disease Activity Index (CDAI) were calculated in patients continuing IV-golimumab for 6–9- and 9–12-months post-switch. Paired t-tests evaluated significance of mean improvements during the follow-up periods. Most RA patients with disease activity assessments during the 6-month follow-up (N = 100; mean age: 65.3 years; 81% female; 74% white) demonstrated moderate-to-high disease activity (CDAI: 73% [38/52]) at enrollment. On average, patients showed significant improvement in disease activity within 6–9 months of switching; mean CDAI scores improved from 21.3 to 14.1 (p < 0.0001) and were durable through 9–12 months of treatment. Real-world patients with moderate-to-high disease activity who switched from IV-infliximab to IV-golimumab demonstrated significant and sustained improvements post-switch as measured by the CDAI.
Key Points • This study used real-world data from the Rheumatology Informatics System for Effectiveness (RISE) registry to evaluate the efficacy of directly switching from intravenous (IV)-infliximab to IV-golimumab to control rheumatoid arthritis (RA) disease activity. • Most IV-infliximab patients had moderate-to-high disease activity at the time of the switch. • On average, IV-golimumab was effective in improving RA disease activity after switching from IV-infliximab as measured by the Clinical Disease Activity Index. • These data suggest that real-world RA patients with persistent symptoms despite treatment with IV-infliximab may realize improved disease control with a switch to IV-golimumab. |
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Affiliation(s)
- John Tesser
- Arizona Arthritis & Rheumatology Associates, 4550 E. Bell Road, Suite 172, Phoenix, AZ, 85032, USA.
| | - Iris Lin
- Janssen Scientific Affairs, LLC, Horsham, PA, USA
| | - Natalie J Shiff
- Janssen Scientific Affairs, LLC, Horsham, PA, USA
- Adjunct, Department of Community Health and Epidemiology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Soumya D Chakravarty
- Janssen Scientific Affairs, LLC, Horsham, PA, USA
- Drexel University College of Medicine, Philadelphia, PA, USA
| | | | - Nevin Hammam
- University of California San Francisco, San Francisco, CA, USA
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26
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Sun P, Su J, Wang X, Zhou M, Zhao Y, Gu H. Nucleic Acids for Potential Treatment of Rheumatoid Arthritis. ACS APPLIED BIO MATERIALS 2022; 5:1990-2008. [PMID: 35118863 DOI: 10.1021/acsabm.1c01205] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Rheumatoid arthritis (RA) is a common systemic inflammatory autoimmune disease that severely affects the life quality of patients. Current therapeutics in clinic mainly focus on alleviating the development of RA or relieving the pain of patients. The emerging biological disease-modifying antirheumatic drugs (DMARDs) require long-term treatment to achieve the expected efficacy. With the development of bionanotechnology, nucleic acids fulfill characters as therapeutics or nanocarriers and can therefore be alternatives to combat RA. This review summarizes the therapeutic RNAs developed through RNA interference (RNAi), nucleic acid aptamers, DNA nanostructures-based drug delivery systems, and nucleic acid vaccines for the applications in RA therapy and diagnosis. Furthermore, prospects of nucleic acids for RA therapy are intensively discussed as well.
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Affiliation(s)
- Pengchao Sun
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, and Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Jingjing Su
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, and Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Xiaonan Wang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, and Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Mo Zhou
- Fudan University Shanghai Cancer Center, and the Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Shanghai Stomatological Hospital, Fudan University, Shanghai 200433, China
| | - Yongxing Zhao
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, and Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Hongzhou Gu
- Fudan University Shanghai Cancer Center, and the Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Shanghai Stomatological Hospital, Fudan University, Shanghai 200433, China
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27
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Kim M, Kim JT. Differences in the incidence of aflibercept-related sterile endophthalmitis according to types of disposable syringes used. Graefes Arch Clin Exp Ophthalmol 2022; 260:1139-1145. [PMID: 34977967 DOI: 10.1007/s00417-021-05454-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 09/15/2021] [Accepted: 10/12/2021] [Indexed: 11/29/2022] Open
Abstract
PURPOSE To evaluate the difference between the incidences of sterile endophthalmitis after administration of intravitreal aflibercept injection using two different types of syringes. METHODS We administered a total of 498 intravitreal aflibercept injections between September 2017 and August 2021. The disposable syringe used was changed from a 1-mL disposable syringe (Profi syringe, Shinchang Medical., Ltd. Korea) to a 1-mL Becton Dickenson Luer-Lok syringe (BD, Franklin, NJ, USA) in September 2019. Thus, the patients who received injections before and after September 1, 2019, were classified into group 1 and group 2, respectively. The incidence of aflibercept-related sterile endophthalmitis between the two groups was compared. RESULTS In group 1, six (2.791%) out of 215 cases were diagnosed with sterile endophthalmitis and prescribed topical or oral steroids. In group 2, one (0.353%) out of 283 cases was diagnosed with sterile endophthalmitis and prescribed a steroid eye drop. The incidence of sterile endophthalmitis was significantly different between the two groups (P = 0.046). CONCLUSION The BD Luer-Lok syringe is associated with a lower incidence of aflibercept-related sterile endophthalmitis than the conventional polypropylene syringe. Differences in immunogenicity associated with silicone oil lubricants within the syringes might be one of the potential reasons behind the difference in the incidence of the sterile endophthalmitis.
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Affiliation(s)
- Minjeong Kim
- Department of Ophthalmology, Chung-Ang University College of Medicine, Chung-Ang University Hospital, 102 Heukseok-ro, Dongjak-gu, Seoul, Republic of Korea, #06974
| | - Jee Taek Kim
- Department of Ophthalmology, Chung-Ang University College of Medicine, Chung-Ang University Hospital, 102 Heukseok-ro, Dongjak-gu, Seoul, Republic of Korea, #06974.
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28
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Wang Z, Huang J, Xie D, He D, Lu A, Liang C. Toward Overcoming Treatment Failure in Rheumatoid Arthritis. Front Immunol 2021; 12:755844. [PMID: 35003068 PMCID: PMC8732378 DOI: 10.3389/fimmu.2021.755844] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 12/06/2021] [Indexed: 12/29/2022] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disorder characterized by inflammation and bone erosion. The exact mechanism of RA is still unknown, but various immune cytokines, signaling pathways and effector cells are involved. Disease-modifying antirheumatic drugs (DMARDs) are commonly used in RA treatment and classified into different categories. Nevertheless, RA treatment is based on a "trial-and-error" approach, and a substantial proportion of patients show failed therapy for each DMARD. Over the past decades, great efforts have been made to overcome treatment failure, including identification of biomarkers, exploration of the reasons for loss of efficacy, development of sequential or combinational DMARDs strategies and approval of new DMARDs. Here, we summarize these efforts, which would provide valuable insights for accurate RA clinical medication. While gratifying, researchers realize that these efforts are still far from enough to recommend specific DMARDs for individual patients. Precision medicine is an emerging medical model that proposes a highly individualized and tailored approach for disease management. In this review, we also discuss the potential of precision medicine for overcoming RA treatment failure, with the introduction of various cutting-edge technologies and big data.
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Affiliation(s)
- Zhuqian Wang
- Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
- Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
| | - Jie Huang
- Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
| | - Duoli Xie
- Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
| | - Dongyi He
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai, China
| | - Aiping Lu
- Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, China
| | - Chao Liang
- Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
- Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
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Czyz CN, Burns JA, Bergstrom RE. Antibody Development in Patients Treated Long-Term With OnabotulinumtoxinA for Benign Essential Blepharospasm and Hemifacial Spasm. J Neuroophthalmol 2021; 41:e684-e687. [PMID: 33470741 DOI: 10.1097/wno.0000000000001171] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Report the development of onabotulinumtoxinA neutralizing antibodies in patients treated consecutively for 20 years or longer for benign essential blepharospasm (BEB), hemifacial spasm (HFS), and Meige Syndrome. METHODS Prospective, randomized, cross-sectional study of 12 randomly selected patients from a single clinical practice that have been treated consecutively for 20 or more years with onabotulinumtoxinA for BEB, HFS, or Meige Syndrome. Serum samples were collected from each subject and analyzed for neutralizing antibody formation using the Mouse Protection Assay. RESULTS None of the tested patients (0%) displayed neutralizing antibodies to onabotulinumtoxinA. The mean duration of treatment was 27.5 years (range 22.1-34.1, SD 3.1, 95% confidence interval 25.45-29.50). Nine of the patients had a diagnosis of BEB, 2 HFS, and one Meige. Eleven of the 12 patients were women. There was no statistically significant difference in treatment dosage or interval over the course of treatment. CONCLUSIONS The data support previous studies showing low incidence of antibody formation for botulinum A toxins with this subset of long-term treated patients. The results also provide further evidence for studies that have suggested increased onabotulinumtoxinA treatment volumes and/or decreased intervals between treatments are not due to neutralizing antibody formation and secondary non-response, but rather study designs that do not consider the titration phase of initial treatments. This study is specific to long-term treated patients, and the results cannot be generalized to patients naive to treatment.
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Affiliation(s)
- Craig N Czyz
- Division of Ophthalmology (CNC, RB), Section Oculofacial Plastic and Reconstructive Surgery, Ohio University/Ohio Health Doctor's Hospital, Columbus, Ohio; and Department of Ophthalmology (CNC, JAB), Oral and Maxillofacial Surgery, Grant Medical Center, Columbus, Ohio
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Mora JR, Wong R, Shaikh M, Askelson M. Analysis of the Immunogenicity from Abatacept-Treated Pediatric Patients With Polyarticular-Course Juvenile Idiopathic Arthritis: Findings From Two Phase III Clinical Trials. ACR Open Rheumatol 2021; 4:177-186. [PMID: 34792858 PMCID: PMC8843768 DOI: 10.1002/acr2.11375] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/29/2021] [Accepted: 10/04/2021] [Indexed: 11/20/2022] Open
Abstract
Objective The goal of this article is to present the analysis of anti‐abatacept antibody data from children with polyarticular‐course juvenile idiopathic arthritis (pJIA), treated with abatacept. The data are from 395 participants with pJIA from two abatacept registrational trials. Methods We analyzed immunogenicity data according to age groups, administration route (intravenous [IV] or subcutaneous [SC]), drug treatment interruption, and co‐medications (with or without methotrexate [MTX]) to assess impact on the incidence of anti‐abatacept antibodies. Results The overall immunogenicity incidences observed in both JIA trials ranged between 4.7% and 23.3%. There was a slightly higher immunogenicity incidence in the 2–5‐year‐old participants (15.2%) compared with 6–17‐year‐old participants (4.7%). In the study with SC dosing, the overall incidence on treatment was 2.3% (3% if co‐dosed with MTX), similar to the incidence for Period A of the IV study (similar duration of treatment as the SC study), which was 2.1% (1.4% if co‐dosed with MTX). In the IV study, the period following a 6‐month interruption in treatment had comparable immunogenicity incidences (22.9% with interruption vs. 18.2% without interruption, both co‐dosed with MTX and 0% for both not co‐dosed with MTX). In most cases, participants co‐dosed with MTX had higher immunogenicity incidences than those on abatacept alone. Conclusion Although some trends were noted in terms of incidence according to age and MTX co‐dosing, none where conclusive owing to differences in population size. Drug holiday had no impact on immunogenicity incidence once treatment was resumed, and incidences across SC and IV dosing were comparable. There was no impact of immunogenicity on pharmacokinetics, safety, and efficacy.
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Affiliation(s)
- Johanna R Mora
- Non-clinical Disposition and Bioanalysis, Bristol Myers Squibb, Princeton, New Jersey
| | - Robert Wong
- Immunology and Fibrosis, Bristol Myers Squibb, Princeton, New Jersey
| | - Mehmooda Shaikh
- Non-clinical Disposition and Bioanalysis, Bristol Myers Squibb, Princeton, New Jersey
| | - Margarita Askelson
- Global Biometrics and Data Science, Bristol Myers Squibb, Princeton, New Jersey
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Immunosuppression in Rheumatologic and Auto-immune Disease. Handb Exp Pharmacol 2021; 272:181-208. [PMID: 34734308 DOI: 10.1007/164_2021_551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Many rheumatologic diseases are thought to originate in dysregulation of the immune system; lupus nephritis, for example, involves humoral immunity, while autoinflammatory diseases such as familial Mediterranean fever are caused by defects in innate immunity. Of note, this dysregulation may involve both upregulation of immune system components and aspects of immunodeficiency. Treatment of rheumatologic diseases thus requires a familiarity with a variety of immunosuppressive medications and their effects on immune system function.In many rheumatologic conditions, due to an incompletely elucidated mechanism of disease, immunosuppression is relatively broad in contrast to agents used, for example, in treatment of transplant rejection. Multiple immunosuppressive drugs may also be used in succession or in combination. As such, an understanding of the mechanisms and targets of immunosuppressive drugs is essential to appreciating their utility and potential adverse effects. Because of the overlap between therapies used in rheumatologic as well as other inflammatory disorders, some of these medications are discussed in other disease processes (e.g., Immunosuppression for inflammatory bowel disease) or in greater detail in other chapters of this textbook (corticosteroids, mTOR inhibitors, antiproliferative agents).
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Berkhout LC, l'Ami MJ, Wolbink GJ, Rispens T. Comment on 'Sustained discontinuation of infliximab with a raising-dose strategy after obtaining remission in patients with rheumatoid arthritis: the RRRR study, a randomised controlled trial' by Tanaka et al. Ann Rheum Dis 2021; 80:e172. [PMID: 31744825 DOI: 10.1136/annrheumdis-2019-216557] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 11/01/2019] [Indexed: 11/04/2022]
Affiliation(s)
- Lea C Berkhout
- Immunopathology, Sanquin Research, Amsterdam, The Netherlands
| | - Merel J l'Ami
- Reade, Amsterdam Rheumatology and immunology Center, Amsterdam, The Netherlands
| | - Gerrit Jan Wolbink
- Immunopathology, Sanquin Research, Amsterdam, The Netherlands
- Reade, Amsterdam Rheumatology and immunology Center, Amsterdam, The Netherlands
| | - Theo Rispens
- Immunopathology, Sanquin Research, Amsterdam, The Netherlands
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Pintea I, Petricau C, Dumitrascu D, Muntean A, Branisteanu DC, Branisteanu DE, Deleanu D. Hypersensitivity reactions to monoclonal antibodies: Classification and treatment approach (Review). Exp Ther Med 2021; 22:949. [PMID: 34335891 PMCID: PMC8290432 DOI: 10.3892/etm.2021.10381] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 03/18/2021] [Indexed: 12/27/2022] Open
Abstract
The present paper aims to review the topic of adverse reactions to biological agents, in terms of the incriminating mechanisms and therapeutic approach. As a result of immunomodulatory therapy, the last decade has achieved spectacular results in the targeted treatment of inflammatory, autoimmune, and neoplastic diseases, to name a few. The widespread use of biological agents is, however, associated with an increase in the number of observed adverse drug reactions ranging from local erythema to systemic reactions, including life-threatening immunologically mediated events, which justifies the need for a deeper understanding of this subject. Rapid desensitization to biological agents emerges as a treatment strategy for anaphylactic (immediate or delayed) hypersensitivity reactions as well as for severe infusion reactions. Drug desensitization is the administration of progressively increasing doses of the specific preparation until reaching the therapeutic dose in order to induce immunological tolerance and is indicated when the drugs are indispensable to the therapeutic regimen of individuals with hypersensitivity reactions to the preparation, with no reasonable alternatives.
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Affiliation(s)
- Irena Pintea
- Allergy Department, 'Professor Doctor Octavian Fodor' Regional Institute of Gastroenterology and Hepatology, 400000 Cluj-Napoca, Romania.,Allergology and Immunology Discipline, 'Iuliu Hatieganu' University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania
| | - Carina Petricau
- Allergy Department, 'Professor Doctor Octavian Fodor' Regional Institute of Gastroenterology and Hepatology, 400000 Cluj-Napoca, Romania.,Allergology and Immunology Discipline, 'Iuliu Hatieganu' University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania
| | - Dinu Dumitrascu
- Anatomy Discipline, 'Iuliu Hatieganu' University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania
| | - Adriana Muntean
- Allergy Department, 'Professor Doctor Octavian Fodor' Regional Institute of Gastroenterology and Hepatology, 400000 Cluj-Napoca, Romania.,Allergology and Immunology Discipline, 'Iuliu Hatieganu' University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania
| | | | - Daciana Elena Branisteanu
- Department of Dermatology, 'Grigore T. Popa' University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Diana Deleanu
- Allergy Department, 'Professor Doctor Octavian Fodor' Regional Institute of Gastroenterology and Hepatology, 400000 Cluj-Napoca, Romania.,Allergology and Immunology Discipline, 'Iuliu Hatieganu' University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania.,Department of Internal Medicine Department, 'Professor Doctor Octavian Fodor' Regional Institute of Gastroenterology and Hepatology, 400000 Cluj-Napoca, Romania
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Nassar-Sheikh Rashid A, Schonenberg-Meinema D, Bergkamp SC, Bakhlakh S, de Vries A, Rispens T, Kuijpers TW, Wolbink G, van den Berg JM. Therapeutic drug monitoring of anti-TNF drugs: an overview of applicability in daily clinical practice in the era of treatment with biologics in juvenile idiopathic arthritis (JIA). Pediatr Rheumatol Online J 2021; 19:59. [PMID: 33926495 PMCID: PMC8082819 DOI: 10.1186/s12969-021-00545-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 04/14/2021] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Anti-tumor necrosis factor (TNF) drugs have improved the prognosis for juvenile idiopathic arthritis (JIA) significantly. However, evidence for individual treatment decisions based on serum anti-TNF drug levels and the presence of anti-drug antibodies (ADAbs) in children is scarce. We aimed to assess if anti-TNF drug levels and/or ADAbs influenced physician's treatment decisions in children with JIA. METHODS Patients' records in our center were retrospectively screened for measurements of anti-TNF drug levels and ADAbs in children with JIA using etanercept, adalimumab or infliximab. Clinical characteristics and disease activity were retrieved from patient charts. RESULTS We analyzed 142 measurements of anti-TNF drug levels in 65 children with JIA. Of these, ninety-seven (68.3%) were trough concentrations. N = 14/97 (14.4%) of these showed trough concentrations within the therapeutic drug range known for adults with RA and IBD. ADAbs against adalimumab were detected in seven patients and against infliximab in one patient. Seven (87,5%) of these ADAb-positive patients had non-detectable drug levels. A flowchart was made on decisions including rational dose escalation, stopping treatment in the presence of ADAbs and undetectable drug levels, showing that 45% of measurements influenced treatment decisions, which concerned 65% of patients (n = 42/65). CONCLUSIONS In the majority of patients, measurement of anti-TNF drug levels led to changes in treatment. A wide variation of anti-TNF drug levels was found possibly due to differences in drug clearance in different age groups. There is need for determination of therapeutic drug ranges and pharmacokinetic curves for anti-TNF and other biologics in children with JIA.
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Affiliation(s)
- A. Nassar-Sheikh Rashid
- grid.7177.60000000084992262Zaans Medical Center, Zaandam and Emma Children’s Hospital, Amsterdam UMC, Pediatric Immunology, Rheumatology and Infectious Diseases, University of Amsterdam, Amsterdam, The Netherlands
| | - D. Schonenberg-Meinema
- grid.7177.60000000084992262Emma Children’s Hospital, Amsterdam UMC, Pediatric Immunology, Rheumatology and Infectious Diseases, University of Amsterdam, Amsterdam, The Netherlands
| | - S. C. Bergkamp
- grid.7177.60000000084992262Emma Children’s Hospital, Amsterdam UMC, Pediatric Immunology, Rheumatology and Infectious Diseases, University of Amsterdam, Amsterdam, The Netherlands
| | - S. Bakhlakh
- grid.7177.60000000084992262Emma Children’s Hospital, Amsterdam UMC, Pediatric Immunology, Rheumatology and Infectious Diseases, University of Amsterdam, Amsterdam, The Netherlands
| | - A. de Vries
- grid.417732.40000 0001 2234 6887Department of Immunopathology, Sanquin Diagnostic Services Amsterdam, Amsterdam, The Netherlands
| | - T. Rispens
- grid.417732.40000 0001 2234 6887Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands
| | - T. W. Kuijpers
- grid.7177.60000000084992262Emma Children’s Hospital, Amsterdam UMC, Pediatric Immunology, Rheumatology and Infectious Diseases, University of Amsterdam, Amsterdam, The Netherlands
| | - G. Wolbink
- grid.418029.60000 0004 0624 3484Department of Immunopathology, CLB Sanquin Amsterdam and Department of Rheumatology, Jan van Breemen Institute Amsterdam, Amsterdam, The Netherlands
| | - J. M. van den Berg
- grid.7177.60000000084992262Emma Children’s Hospital, Amsterdam UMC, Pediatric Immunology, Rheumatology and Infectious Diseases, University of Amsterdam, Amsterdam, The Netherlands
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Pardeshi NN, Ahmadi M, Sierzputowska I, Fogg M, Baker M, Carpenter JF. Subvisible Particles in Solutions of Remicade in Intravenous Saline Activate Immune System Pathways in In Vitro Human Cell Systems. J Pharm Sci 2021; 110:2894-2903. [PMID: 33864780 DOI: 10.1016/j.xphs.2021.04.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 04/03/2021] [Accepted: 04/05/2021] [Indexed: 11/24/2022]
Abstract
Among patients that receive Remicade® therapy, more than 20% have adverse infusion related reactions and approximately 50% have immunogenic responses.1-3 Upon characterization of initial Remicade®-IV solution we observed a high concentration of subvisible particles that could inadvertently be delivered to patients. This solution was processed through the IV infusion system, mimicking the typical clinical administration setup - either with or without an in-line filter connected to the IV line. The samples generated thereafter were tested using various in vitro assays for activation of the innate immune system via cytokine release in whole blood and in peripheral blood mononuclear cell (PBMC) cultures, and activation of the Toll like receptors (TLRs). Activation of the adaptive immune system was evaluated by monitoring upregulation of surface receptors on dendritic cells (DCs) and CD4+ T cell proliferation in response to IV solution of Remicade®. Our results indicate that subvisible particles in Remicade®-saline solution have a significant role in activation of the immune system but there are extrinsic factors potentially contributed by the in-line filters or other process parameters that also contribute to immune system activation.
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Affiliation(s)
- Neha N Pardeshi
- Department of Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, United States
| | - Maryam Ahmadi
- Abzena Ltd, Babraham Research Campus, Babraham, Cambridge CB22 3AT, UK
| | | | - Mark Fogg
- Abzena Ltd, Babraham Research Campus, Babraham, Cambridge CB22 3AT, UK
| | - Matthew Baker
- Abzena Ltd, Babraham Research Campus, Babraham, Cambridge CB22 3AT, UK
| | - John F Carpenter
- Department of Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, United States.
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Strik AS, Löwenberg M, Mould DR, Berends SE, Ponsioen CI, van den Brande JMH, Jansen JM, Hoekman DR, Brandse JF, Duijvestein M, Gecse KB, de Vries A, Mathôt RA, D'Haens GR. Efficacy of dashboard driven dosing of infliximab in inflammatory bowel disease patients; a randomized controlled trial. Scand J Gastroenterol 2021; 56:145-154. [PMID: 33290108 DOI: 10.1080/00365521.2020.1856405] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Loss of response (LOR) to infliximab (IFX) remains a challenge in the management of inflammatory bowel diseases (IBD). Proactive dosing strategies to achieve and maintain predefined IFX trough levels (TL) may prevent LOR. We aimed to investigate the efficacy of dashboard driven IFX dosing compared to standard dosing in a prospective trial in IBD patients. METHODS In this multicentre 1:1 'PRECISION' trial, we randomized IBD patients in clinical remission (Harvey Bradshaw Index ≤4 for Crohn's disease (CD) or a partial Mayo score ≤2 for ulcerative colitis (UC)) receiving IFX maintenance treatment. The precision group (PG) received IFX dosing guided by a Bayesian pharmacokinetic model, aiming to achieve and maintain a TL of 3 µg/ml by treatment (de)escalation as indicated by the dashboard. Patients in the control group (CG) continued treatment without dose adaptations. The primary endpoint was the proportion of patients in sustained clinical remission after 1 year. RESULTS Eighty patients were enrolled (66 CD, 14 UC), and the median [interquartile range] age was 37 years [27-51]). After one year, 28/32 (88%) of patients in the PG were in sustained clinical remission versus 25/39 (64%) in the CG (p = .017). PG patients had lower median faecal calprotectin levels after 1 year (p = .031), whereas no significant differences in median CRP levels were found. CONCLUSION We demonstrated that the use of a Bayesian dashboard for IFX dosing in maintenance treatment for IBD reduced the incidence of LOR compared to standard dosing. Precision dosing also resulted in lower FCP levels. CLINICALTRIALS.GOV NUMBER NCT02453776.
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Affiliation(s)
- Anne S Strik
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Location AMC , Amsterdam, The Netherlands
| | - Mark Löwenberg
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Location AMC , Amsterdam, The Netherlands
| | | | - Sophie E Berends
- Department of Hospital Pharmacy, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands
| | - Cyriel I Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Location AMC , Amsterdam, The Netherlands
| | - Jan M H van den Brande
- Department of Gastroenterology and Hepatology, Tergooi Hospital, Hilversum, The Netherlands
| | - Jeroen M Jansen
- Department of Gastroenterology and Hepatology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
| | - Daniël R Hoekman
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Location AMC , Amsterdam, The Netherlands
| | - Johannan F Brandse
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Location AMC , Amsterdam, The Netherlands
| | - Marjolijn Duijvestein
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Location AMC , Amsterdam, The Netherlands
| | - Krisztina B Gecse
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Location AMC , Amsterdam, The Netherlands
| | | | - Ron A Mathôt
- Department of Hospital Pharmacy, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands
| | - Geert R D'Haens
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Location AMC , Amsterdam, The Netherlands
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Guinn D, Madabushi R, Wang YM, Brodsky E, Zineh I, Maxfield K. Communicating Immunogenicity-Associated Risk in Current U.S. FDA Prescription Drug Labeling: A Systematic Evaluation. Ther Innov Regul Sci 2020; 54:1363-1371. [PMID: 33258100 DOI: 10.1007/s43441-020-00161-z] [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: 02/19/2020] [Accepted: 05/02/2020] [Indexed: 11/28/2022]
Abstract
BACKGROUND Communicating the clinical impact of immunogenicity in labeling is important for safe and effective use of certain prescription products. Current U.S. Food and Drug Administration (FDA) guidance does not provide comprehensive recommendations on the communication of clinical impact of immunogenicity in labeling. To understand current labeling practice, we evaluated the immunogenicity data and clinical impact information in labeling of selected prescription products. METHODS We created a database of 71 therapeutic biologics and drug products that had an immunogenicity assessment initially approved by FDA's Center for Drug Evaluation and Research between 2014 and 2018. We analyzed the content and format of immunogenicity information (e.g., anti-drug antibody incidence and/or immunogenicity impact on pharmacokinetics (PK), safety, and/or effectiveness) in the most recent approved labeling. RESULTS Immunogenicity information was in the ADVERSE REACTIONS section in 98% of the reviewed labeling. Immunogenicity impact on PK was reported in 52% of the labeling, typically within the ADVERSE REACTIONS section, but supportive PK data were often not included in the CLINICAL PHARMACOLOGY section. Additionally, the immunogenicity impact on safety and/or effectiveness was communicated in 70% of the labeling, with 23% clearly communicating the effect as clinically meaningful, and 10% providing actionable recommendations. CONCLUSIONS Most of the reviewed labeling includes immunogenicity information within the ADVERSE REACTIONS section. However, there is inconsistency in providing supportive PK data and high variability in reporting immunogenicity impact on safety and effectiveness in labeling. Development of a communication framework that allows for consistent inclusion of immunogenicity impact statements in labeling could improve how immunogenicity risk is conveyed in prescription drug labeling.
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Affiliation(s)
- Daphne Guinn
- Office of Clinical Pharmacology, Office of Translational Sciences, US Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD, 20993, USA.
| | - Rajanikanth Madabushi
- Office of Clinical Pharmacology, Office of Translational Sciences, US Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD, 20993, USA
| | - Yow-Ming Wang
- Office of Clinical Pharmacology, Office of Translational Sciences, US Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD, 20993, USA
| | - Eric Brodsky
- Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD, 20993, USA
| | - Issam Zineh
- Office of Clinical Pharmacology, Office of Translational Sciences, US Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD, 20993, USA
| | - Kimberly Maxfield
- Office of Clinical Pharmacology, Office of Translational Sciences, US Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD, 20993, USA
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Shimizu H, Kobayashi H, Kanbori M, Ishii Y. Clinical response among golimumab-treated Japanese patients with rheumatoid arthritis by number of previous biologic therapies: Real-world evidence from post-hoc analysis of post-marketing surveillance data. Mod Rheumatol 2020; 31:566-574. [PMID: 32678990 DOI: 10.1080/14397595.2020.1797283] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
OBJECTIVES To assess the real-world effectiveness of golimumab in Japanese patients with rheumatoid arthritis who had previously received one or more biologic therapies. METHODS A post-hoc analysis of post-marketing surveillance was performed. The clinical response to golimumab was analyzed in 1216 patients who had previously received one or more biologic agents including non-TNF inhibitors with stratification by the number of previous biologic agents. Logistic regression analyses were conducted to identify factors associated with DAS28-CRP response to golimumab. RESULTS While treatment persistence is comparable, the response to golimumab declined with an increasing number of previous biologic therapies. When stratified by golimumab dose, patients receiving golimumab at 100 mg had higher disease activity at baseline with an increasing number of previous bDMARDs, but they still achieved comparable disease activity at 24 weeks regardless of how many bDMARDs had been previously used. Univariate and multivariate analyses both identified concomitant oral corticosteroid therapy as a factor negatively associated with the likelihood of achieving a DAS28-CRP response. CONCLUSION Switching to golimumab was effective regardless of how many biologic agents had been previously used, but the response declined with an increasing number of prior biologic agents. A golimumab dose of 100 mg was also effective for those who previously received three or more bDMARDs.
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Affiliation(s)
- Hirohito Shimizu
- Immunology Department, Medical Affairs Division, Janssen Pharmaceutical K.K., Tokyo, Japan
| | - Hisanori Kobayashi
- External Collaboration and Portfolio Management Department, Clinical Science Division, R&D Janssen Pharmaceutical K.K., Tokyo, Japan
| | - Masayoshi Kanbori
- Japan Safety & Surveillance Division, Research & Development Division (R&D), Janssen Pharmaceutical K.K., Tokyo, Japan
| | - Yutaka Ishii
- Immunology Department, Medical Affairs Division, Janssen Pharmaceutical K.K., Tokyo, Japan
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Meunier S, de Bourayne M, Hamze M, Azam A, Correia E, Menier C, Maillère B. Specificity of the T Cell Response to Protein Biopharmaceuticals. Front Immunol 2020; 11:1550. [PMID: 32793213 PMCID: PMC7387651 DOI: 10.3389/fimmu.2020.01550] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 06/12/2020] [Indexed: 12/17/2022] Open
Abstract
The anti-drug antibody (ADA) response is an undesired humoral response raised against protein biopharmaceuticals (BPs) which can dramatically disturb their therapeutic properties. One particularity of the ADA response resides in the nature of the immunogens, which are usually human(ized) proteins and are therefore expected to be tolerated. CD4 T cells initiate, maintain and regulate the ADA response and are therefore key players of this immune response. Over the last decade, advances have been made in characterizing the T cell responses developed by patients treated with BPs. Epitope specificity and phenotypes of BP-specific T cells have been reported and highlight the effector and regulatory roles of T cells in the ADA response. BP-specific T cell responses are assessed in healthy subjects to anticipate the immunogenicity of BP prior to their testing in clinical trials. Immunogenicity prediction, also called preclinical immunogenicity assessment, aims at identifying immunogenic BPs and immunogenic BP sequences before any BP injection in humans. All of the approaches that have been developed to date rely on the detection of BP-specific T cells in donors who have never been exposed to BPs. The number of BP-specific T cells circulating in the blood of these donors is therefore limited. T cell assays using cells collected from healthy donors might reveal the weak tolerance induced by BPs, whose endogenous form is expressed at a low level. These BPs have a complete human sequence, but the level of their endogenous form appears insufficient to promote the negative selection of autoreactive T cell clones. Multiple T cell epitopes have also been identified in therapeutic antibodies and some other BPs. The pattern of identified T cell epitopes differs across the antibodies, notwithstanding their humanized, human or chimeric nature. However, in all antibodies, the non-germline amino acid sequences mainly found in the CDRs appear to be the main driver of immunogenicity, provided they can be presented by HLA class II molecules. Considering the fact that the BP field is expanding to include new formats and gene and cell therapies, we face new challenges in understanding and mastering the immunogenicity of new biological products.
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Affiliation(s)
- Sylvain Meunier
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, France
| | - Marie de Bourayne
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, France
| | - Moustafa Hamze
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, France
| | - Aurélien Azam
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, France
| | - Evelyne Correia
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, France
| | - Catherine Menier
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, France
| | - Bernard Maillère
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, France
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Kharlamova N, Hermanrud C, Dunn N, Ryner M, Hambardzumyan K, Vivar Pomiano N, Marits P, Gjertsson I, Saevarsdottir S, Pullerits R, Fogdell-Hahn A. Drug Tolerant Anti-drug Antibody Assay for Infliximab Treatment in Clinical Practice Identifies Positive Cases Earlier. Front Immunol 2020; 11:1365. [PMID: 32793189 PMCID: PMC7385065 DOI: 10.3389/fimmu.2020.01365] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 05/28/2020] [Indexed: 01/14/2023] Open
Abstract
A subgroup of patients treated with infliximab lose response to the treatment and one reason for this is the development of anti-drug antibodies (ADA). If used optimally, measuring drug and ADA level could lead to a more personalized and efficient treatment regime, and enable identification of ADA-positive patients before the underlying disease flares or allergic reactions occur. With the use of a drug-tolerant ADA assay which can detect ADA irrespective of drug levels in the sample, we determined the impact of ADA on treatment failure to infliximab. The aims of this study were to estimate the real-life optimal serum infliximab (sIFX) level and set a clinical threshold value for a drug-tolerant ADA assay. Trough levels of sIFX were measured with ELISA. Free ADA was measured with two drug-sensitive methods (ELISA and a bioassay) and one drug-tolerant method (PandA). Two real-life cohorts treated with infliximab were included; a cross-sectional cohort including patients with inflammatory rheumatic diseases (n = 270) and a prospective cohort of rheumatoid arthritis (RA) patients (n = 73) followed for 1 year. Normal range of sIFX was estimated from the prospective cohort and an arbitrary optimal drug level was set to be between 1 and 6 μg/mL. Using this range, optimal sIFX was found in only 60% (163/270) of the patients in the cross-sectional cohort. These patients had significantly better treatment response than those with a drug level under 1 μg/mL, who had an ADA frequency of 34% (19/56) using the drug-tolerant method. In the prospective cohort, the drug-tolerant assay could identify 34% (53/155 samples) as ADA positive in samples with sIFX level >0.2 μg/mL. ADA were seldom detected in patients with >1 μg/mL sIFX, with three interesting exceptions. A clinically relevant ADA threshold was determined to be >3 RECL as measured with the drug-tolerant assay. In a real-life setting, there was a substantial number of patients with suboptimal drug levels and a proportion of these had ADA. Both too low and too high drug levels correlated with worse disease, but for different reasons. Adding a drug-tolerant assay enabled detection of ADA earlier and regardless of drug level at time of sampling.
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Affiliation(s)
- Nastya Kharlamova
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Stockholm, Sweden
| | - Christina Hermanrud
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Stockholm, Sweden
| | - Nicky Dunn
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Stockholm, Sweden
| | - Malin Ryner
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Stockholm, Sweden
| | - Karen Hambardzumyan
- Rheumatology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Nancy Vivar Pomiano
- Rheumatology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Per Marits
- Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Inger Gjertsson
- Department of Rheumatology and Inflammation Research, Institution of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Saedis Saevarsdottir
- Rheumatology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
- Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | - Rille Pullerits
- Department of Rheumatology and Inflammation Research, Institution of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Immunology and Transfusion Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Anna Fogdell-Hahn
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Stockholm, Sweden
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Lorenzin M, Ometto F, Ortolan A, Felicetti M, Favero M, Doria A, Ramonda R. An update on serum biomarkers to assess axial spondyloarthritis and to guide treatment decision. Ther Adv Musculoskelet Dis 2020; 12:1759720X20934277. [PMID: 32636944 PMCID: PMC7315656 DOI: 10.1177/1759720x20934277] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 05/22/2020] [Indexed: 12/17/2022] Open
Abstract
Axial spondyloarthritis (axSpA) is a group of debilitating, chronic, rheumatic conditions characterized by inflammation and new bone formation, mainly involving the spine and the sacroiliac joints. The lack of biomarkers in axSpA is well known. Despite significant treatment advances in recent years thanks to the introduction of drugs with a new mode of action, such as new biologic and targeted synthetic disease-modifying antirheumatic drugs, no relevant improvement in the identification of disease biomarkers has been achieved. Common parameters, such as erythrocyte sedimentation rate and C-reactive protein, which are routinely used to measure systemic inflammation, are the sole markers available to date and are not adequate to assess disease activity in all patients. The aim of this study is to review the most promising serum biomarkers that may help treatment decision in axSpA via a proper assessment of disease activity and identification of negative prognostic factors.
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Affiliation(s)
- Mariagrazia Lorenzin
- Rheumatology Unit, Department of Medicine -DIMED, University of Padova, Padova, Italy
| | - Francesca Ometto
- Rheumatology Unit, Department of Medicine -DIMED, University of Padova, Padova, Italy
| | - Augusta Ortolan
- Rheumatology Unit, Department of Medicine -DIMED, University of Padova, Padova, Italy
| | - Mara Felicetti
- Rheumatology Unit, Department of Medicine -DIMED, University of Padova, Padova, Italy
| | - Marta Favero
- Rheumatology Unit, Department of Medicine -DIMED, University of Padova, Padova, Italy
| | - Andrea Doria
- Rheumatology Unit, Department of Medicine -DIMED, University of Padova, Padova, Italy
| | - Roberta Ramonda
- Rheumatology Unit, Department of Medicine -DIMED, University of Padova, Via Giustiniani 2, Padova, 35128, Italy
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Matucci A, Nencini F, Vivarelli E, Bormioli S, Maggi E, Vultaggio A. Immunogenicity-unwanted immune responses to biological drugs - can we predict them? Expert Rev Clin Pharmacol 2020; 14:47-53. [PMID: 32432941 DOI: 10.1080/17512433.2020.1772053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
INTRODUCTION Biological agents (BAs) target molecules involved in disease mechanisms and have modified the natural history of several immune-mediated disorders. All BAs are immunogenic, resulting in the formation of antidrug antibodies (ADAs), which can neutralize drug activity leading to loss of response and potential relapse, or serious adverse events such as infusion hypersensitivity reactions. The production of ADAs is the result of a specific adaptive immune response in which T and B cells are involved. AREAS COVERED Factors conditioning the immunogenicity of BAs, including drug-, treatment- and patient-related factors are currently the subject of many studies. Among them, a lot of attention is dedicated to define the impact of BAs structure, the effect of targeting (soluble or membrane) molecules, the impact of interruption of therapy as well as the role of genetic (HLA and non-HLA) predisposing factors and disease activity. EXPERT OPINION Knowledge of factors capable of influencing the immunogenicity of BAs may help to understand, in a predictive manner and at the single patient level, the presence of risk factors influencing the production of ADAs and their impact on clinical outcomes.
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Affiliation(s)
- Andrea Matucci
- Immunoallergology Unit, University Hospital Careggi , Florence, Italy
| | - Francesca Nencini
- Immunoallergology Unit, University Hospital Careggi , Florence, Italy
| | | | - Susanna Bormioli
- Immunoallergology Unit, University Hospital Careggi , Florence, Italy
| | - Enrico Maggi
- Translational Unit, Immunology Area, Pediatric Hospital Bambino Gesù, IRCCS , Rome, Italy
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Bangma A, Voskuil MD, Uniken Venema WTC, Brugge H, Hu S, Lanting P, Franke L, Dijkstra G, Festen EAM, Weersma RK. Predicted efficacy of a pharmacogenetic passport for inflammatory bowel disease. Aliment Pharmacol Ther 2020; 51:1105-1115. [PMID: 32363635 PMCID: PMC7318341 DOI: 10.1111/apt.15762] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/03/2019] [Accepted: 04/09/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND High inter-individual variability in therapeutic response to drugs used in the management of Inflammatory Bowel Disease (IBD) leads to high morbidity and high costs. Genetic variants predictive of thiopurine-induced myelosuppression, thiopurine-induced pancreatitis and immunogenicity of Tumour Necrosis Factor alpha (TNFα) antagonists have been identified, but uptake of pre-treatment pharmacogenetic testing into clinical guidelines has been slow. AIM To explore the efficacy of a pharmacogenetic passport for IBD that includes multiple pharmacogenetic predictors of response. METHODS Patients with IBD exposed to thiopurines and/or TNFα antagonists were retrospectively evaluated for the presence of thiopurine toxicity and/or immunogenicity of TNFα antagonists. All patients were genotyped using both whole-exome sequencing and the Illumina Global Screening Array. An in-house-developed computational pipeline translated genetic data into an IBD pharmacogenetic passport that predicted risks for thiopurine toxicity and immunogenicity of TNFα antagonists per patient. Using pharmacogenetic-guided treatment guidelines, we calculated clinical efficacy estimates for pharmacogenetic testing for IBD. RESULTS Among 710 patients with IBD exposed to thiopurines and/or TNFα antagonists, 150 adverse drug responses occurred and our pharmacogenetic passport would have predicted 54 (36%) of these. Using a pharmacogenetic passport for IBD that includes genetic variants predictive of thiopurine-induced myelosuppression, thiopurine-induced pancreatitis, and immunogenicity of TNFα antagonists, 24 patients need to be genotyped to prevent one of these adverse drug responses. CONCLUSIONS This study highlights the clinical efficacy of a pharmacogenetic passport for IBD. Implementation of such a pharmacogenetic passport into clinical management of IBD may contribute to a reduction in adverse drug responses.
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Affiliation(s)
- Amber Bangma
- Department of Gastroenterology and HepatologyUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands,Department of GeneticsUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Michiel D. Voskuil
- Department of Gastroenterology and HepatologyUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands,Department of GeneticsUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Werna T. C. Uniken Venema
- Department of Gastroenterology and HepatologyUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands,Department of GeneticsUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Harm Brugge
- Department of GeneticsUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Shixian Hu
- Department of Gastroenterology and HepatologyUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands,Department of GeneticsUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Pauline Lanting
- Department of GeneticsUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Lude Franke
- Department of GeneticsUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and HepatologyUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Eleonora A. M. Festen
- Department of Gastroenterology and HepatologyUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands,Department of GeneticsUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Rinse K. Weersma
- Department of Gastroenterology and HepatologyUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
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Santin G, da Silva MMM, Villarreal VA, Laste LDD, de Freitas Montin E, Betiol LER, Azevedo VF. Home storage of biological medications administered to patients with rheumatic diseases. Adv Rheumatol 2020; 60:30. [DOI: 10.1186/s42358-020-00131-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 04/30/2020] [Indexed: 12/12/2022] Open
Abstract
Abstract
Background
The inadequate storage of biopharmaceuticals may result in an ineffective therapeutic response since poor conservation can lead to the emergence of protein aggregates and cause immunogenicity in patients, which can increase the risk of adverse events by inducing the production of anti-drug antibodies. This can also lead to significant economic losses for public health, given the high cost of these medicines. The aim of this study was to verify whether the home storage of biopharmaceuticals dispensed by the Unified Public System was in accordance with the manufacturers’ specified standards and whether external variables interfered with the correct home storage.
Methods
This was a prospective observational study. Patients with a confirmed diagnosis of rheumatoid arthritis, ankylosing spondylitis or psoriatic arthritis who were using a biologic exclusively dispensed by Unified Public System were included. Storage temperature was measured by digital thermometer inserted into the refrigerator of the participant’s home. Fisher’s exact test was performed to cross-reference the temperature data and the qualitative variables obtained using an epidemiologic questionnaire. Mean, minimum, maximum values and standard deviation were described in the quantitative data. Mann-Whitney non-parametric test was performed to the association between temperature excursion and the number of people in the house.
Results
A total of 81 participants were included and 67 (82.71%) did not maintain home storage correctly. The maximum temperature observed among all patients was 15.5 °C, the minimum was − 4.4 °C and the average was 5.6 °C (standard deviation 2.8); 10 (12.3%) had at least one negative temperature measured. The average time for participants who had an inadequate temperature record was 8 h and 31 min. Nine participants (90%) who stored the medication into the shelf/drawer below the freezer had a temperature excursion (p = 0.011). Most of the participants (88.5%) who stored their biopharmaceutical near the back side, close to the wall of the refrigerator had a negative temperature record (p < 0.001).
Conclusion
Most of the study participants (82.71%) did not maintain adequate home storage conditions for their biopharmaceutical. Intrinsic factors of household refrigerators may be involved in temperature deviations.
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Ito S, Ikuno T, Mishima M, Yano M, Hara T, Kuramochi T, Sampei Z, Wakabayashi T, Tabo M, Chiba S, Kubo C. In vitro human helper T-cell assay to screen antibody drug candidates for immunogenicity. J Immunotoxicol 2020; 16:125-132. [PMID: 31179789 DOI: 10.1080/1547691x.2019.1604586] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Monoclonal antibody (mAb) drugs offer a number of valuable treatments. Many newly developed mAb drugs include artificial modification of amino acid sequences from human origin, which may cause higher immunogenicity to induce anti-drug antibodies (ADA). If the immunogenicity of a new candidate can be understood in the nonclinical phase, clinical studies will be safer and the success rate of development improved. Empirically, in vitro immunogenicity assays with human cells have proved to be sufficiently sensitive to nonhuman proteins, but not to human/humanized mAb. To detect the weaker immunogenicity of human-based mAb, a more sensitive biomarker for in vitro assays is needed. The in vitro study here developed a proliferation assay (TH cell assay) using flow cytometry analysis that can detect a slight increase in proliferating TH cells. Samples from 218 donors treated with a low-immunogenic drug (etanercept) were measured to determine a positive threshold level. With this threshold, positive donor percentages among PBMC after treatment with higher-immunogenicity mAb drugs were noted, that is, 39.5% with humanized anti-human A33 antibody (hA33), 27.3% with abciximab, 25.9% with adalimumab, and 14.8% with infliximab. Biotherapeutics with low immunogenicity yielded values of 0% for basiliximab and 3.7% for etanercept. These data showed a good comparability with previously reported incidences of clinical ADA with the evaluated drugs. Calculations based on the data here showed that a TH cell assay with 40 donors could provide statistically significant differences when comparing low- (etanercept) versus highly immunogenic mAb (except for infliximab). Based on the outcomes here, for screening purposes, a practical cutoff point of 3/20 positives with 20 donors was proposed to alert immunogenicity of mAb drug candidates.
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Affiliation(s)
- Shunsuke Ito
- a Research Division , Chugai Pharmaceutical Co., Ltd. Shizuoka , Japan
| | - Tatsuya Ikuno
- a Research Division , Chugai Pharmaceutical Co., Ltd. Shizuoka , Japan
| | - Masayuki Mishima
- a Research Division , Chugai Pharmaceutical Co., Ltd. Shizuoka , Japan
| | - Mariko Yano
- a Research Division , Chugai Pharmaceutical Co., Ltd. Shizuoka , Japan
| | - Toshiko Hara
- a Research Division , Chugai Pharmaceutical Co., Ltd. Shizuoka , Japan
| | | | - Zenjiro Sampei
- a Research Division , Chugai Pharmaceutical Co., Ltd. Shizuoka , Japan
| | | | - Mitsuyasu Tabo
- a Research Division , Chugai Pharmaceutical Co., Ltd. Shizuoka , Japan
| | - Shuichi Chiba
- a Research Division , Chugai Pharmaceutical Co., Ltd. Shizuoka , Japan
| | - Chiyomi Kubo
- a Research Division , Chugai Pharmaceutical Co., Ltd. Shizuoka , Japan
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Clinical Consequences of Antibody Formation, Serum Concentrations, and HLA-Cw6 Status in Psoriasis Patients on Ustekinumab. Ther Drug Monit 2020; 41:634-639. [PMID: 31107404 PMCID: PMC6752798 DOI: 10.1097/ftd.0000000000000646] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Ustekinumab for the treatment of psoriasis is currently administered in a standard dosing regimen. However, some patients tend to benefit from alternative dosing regimens, a step toward personalized medicine. METHODS To investigate the role of ustekinumab serum concentrations, anti-ustekinumab antibodies [AUA] and HLA-Cw6 status as tools for optimizing ustekinumab treatment, a multicenter prospective cohort study was conducted at an academic hospital with affiliated nonacademic hospitals in Belgium (cohort 1) and 2 academic hospitals in the Netherlands (cohort 2 and 3). Patients with plaque-type psoriasis were eligible if treated with ustekinumab for ≥16 weeks. Serum samples and Psoriasis Area and Severity Index scores were obtained at baseline, week 16, 28, 40, 52, and/or ≥64 of ustekinumab treatment. RESULTS A total of 137 patients with 229 observations for serum concentrations and AUA and 61 observations for HLA-Cw6 status were included. Presence of AUA (prevalence of 8.7%) was significantly associated with a diminished clinical response (P = 0.032). The median ustekinumab trough concentration was 0.3 mcg/mL (<0.02-3.80). No differences in serum concentrations were observed between moderate to good responders and nonresponders (P = 0.948). Serum trough concentrations were not affected by methotrexate comedication. Prevalence of HLA-Cw6 positivity was 41% with no statistically significant difference in clinical response between HLA-Cw6-positive and HLA-Cw6-negative patients (P = 0.164). CONCLUSIONS The presence of AUA was associated with treatment failure in this patient population; measurement of AUA may therefore be a candidate marker for personalized pharmacotherapy. The clinical utility of ustekinumab serum trough concentrations or HLA-Cw6 status determination remains less clear. Further exploration on the potential of measuring ustekinumab serum concentrations and other biomarkers in predicting therapy outcomes should be encouraged.
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Simultaneous Quantification of Free Adalimumab and Infliximab in Human Plasma Using a Target-Based Sample Purification and Liquid Chromatography-Tandem Mass Spectrometry. Ther Drug Monit 2020; 41:640-647. [PMID: 31584927 DOI: 10.1097/ftd.0000000000000633] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Therapeutic drug monitoring of tumor necrosis factor alpha (TNF-α) inhibitors such as adalimumab (ADM) and infliximab (IFX) is considered of added value for patients with systemic inflammatory diseases. In contrast to enzyme-linked immunosorbent assay methods, liquid chromatography-tandem mass spectrometry methods allow for simultaneous quantification of multiple target antibodies in 1 run and thus providing a higher sample throughput. We describe a fast sample work-up strategy for the absolute and simultaneous quantification of ADM and IFX therapeutic monoclonal antibodies in human plasma samples using a target-specific sample purification in combination with liquid chromatography-tandem mass spectrometry. METHODS The sample purification was based on the selective capture of ADM and IFX in human plasma or serum using biotinylated TNF-α (b-TNF-α), which was coated on a streptavidin 96-well plate. After elution, analytes were heat denatured and trypsin digested to obtain signature peptides for quantification. Stable isotopically labeled ADM and IFX were introduced as internal standard before sample purification. RESULTS The method was successfully validated following current European medicines agency guidelines. The linear dynamic rage for both analytes were 1-32 mcg/mL with an excellent mean coefficient of determination, R = 0.9994 for ADM and 0.9996 for IFX. Within-run and between-run imprecision and accuracy were within acceptance criteria. Cross-validation against enzyme-linked immunosorbent assay method showed a high between-method correlation R = 0.962 for ADM and R = 0.982 for IFX. CONCLUSIONS This method provides an easy, efficient, and cost-effective workflow for therapeutic drug monitoring patients treated with ADM or IFX.
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Effect of Golimumab Dose Escalation in Japanese Patients With Rheumatoid Arthritis: Post-Hoc Analysis of Post-Marketing Surveillance Data. Rheumatol Ther 2020; 7:311-325. [PMID: 32114644 PMCID: PMC7211224 DOI: 10.1007/s40744-020-00198-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Indexed: 01/13/2023] Open
Abstract
Introduction While dose escalation of golimumab has been used for patients with rheumatoid arthritis who demonstrate an inadequate response to the standard dose, its effectiveness has not been fully evaluated. The aim of this study was to assess the clinical outcome observed by dose escalation of golimumab for patients with rheumatoid arthritis in the daily clinical setting. Methods A post hoc analysis was performed of data from the 24-week post-marketing surveillance conducted in Japan (n = 5154). A total of 301 patients with moderate or high disease activity at baseline who underwent dose escalation of golimumab were assessed for effectiveness at 24 weeks based on several variables, such as DAS28-CRP, SDAI, and CDAI, as well as for medication persistence through 24 weeks. In addition, the study population was stratified by the time to dose escalation, and effectiveness was likewise evaluated. Logistic regression analysis was performed to identify factors associated with a moderate/good EULAR response to golimumab at 24 weeks. Results Patients with golimumab dose escalation showed significant improvement of the clinical signs and symptoms of rheumatoid arthritis at 24 weeks, as indicated by reduction of the DAS28-CRP (∆0.89), SDAI (∆8.64), and CDAI (∆8.28) scores. This result was relatively consistent across the subgroups stratified by the timing of dose escalation. According to Kaplan-Meier analysis, 78.1% of the patients continued to receive golimumab at 24 weeks, and this was also similar among the subgroups stratified by the time to dose escalation. Multivariate analysis identified male sex and previous biologic therapy as factors that were significantly associated with the clinical response at 24 weeks. Conclusion In real-world clinical practice, improvement of disease activity was observed after uptitration of golimumab from 50 to 100 mg regardless of the timing. Male patients and biologic-naive patients were more likely to respond to dose escalation of golimumab. Trial Registration UMIN-CTR, Identifier: UMIN000015895. Electronic Supplementary Material The online version of this article (10.1007/s40744-020-00198-4) contains supplementary material, which is available to authorized users.
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Berends SE, Strik AS, Löwenberg M, D'Haens GR, Mathôt RAA. Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Ulcerative Colitis. Clin Pharmacokinet 2020; 58:15-37. [PMID: 29752633 PMCID: PMC6326086 DOI: 10.1007/s40262-018-0676-z] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) of unknown etiology, probably caused by a combination of genetic and environmental factors. The treatment of patients with active UC depends on the severity, localization and history of IBD medication. According to the classic step-up approach, treatment with 5-aminosalicylic acid compounds is the first step in the treatment of mild to moderately active UC. Corticosteroids, such as prednisolone are used in UC patients with moderate to severe disease activity, but only for remission induction therapy because of side effects associated with long-term use. Thiopurines are the next step in the treatment of active UC but monotherapy during induction therapy in UC patients is not preferred because of their slow onset. Therapeutic drug monitoring (TDM) of the pharmacologically active metabolites of thiopurines, 6-thioguanine nucleotide (6-TGN), has proven to be beneficial. Thiopurine S-methyltransferase (TMPT) plays a role in the metabolic conversion pathway of thiopurines and exhibits genetic polymorphism; however, the clinical benefit and relevance of TPMT genotyping is not well established. In patients with severely active UC refractory to corticosteroids, calcineurin inhibitors such as ciclosporin A (CsA) and tacrolimus are potential therapeutic options. These agents usually have a rather rapid onset of action. Monoclonal antibodies (anti-tumor necrosis factor [TNF] agents, vedolizumab) are the last pharmacotherapeutic option for UC patients before surgery becomes inevitable. Body weight, albumin status and antidrug antibodies contribute to the variability in the pharmacokinetics of anti-TNF agents. Additionally, the use of concomitant immunomodulators (thiopurines/methotrexate) lowers the rate of immunogenicity, and therefore the concomitant use of anti-TNF therapy with an immunomodulator may confer some advantage compared with monotherapy in certain patients. TDM of anti-TNF agents could be beneficial in patients with primary nonresponse and secondary loss of response. The potential benefit of applying TDM during vedolizumab treatment has yet to be determined.
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Affiliation(s)
- Sophie E Berends
- Department Hospital Pharmacy, Academic Medical Center, Amsterdam, The Netherlands.
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
| | - Anne S Strik
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Mark Löwenberg
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Geert R D'Haens
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Ron A A Mathôt
- Department Hospital Pharmacy, Academic Medical Center, Amsterdam, The Netherlands
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Perry M, Abdullah A, Frleta M, MacDonald J, McGucken A. The potential value of blood monitoring of biologic drugs used in the treatment of rheumatoid arthritis. Ther Adv Musculoskelet Dis 2020; 12:1759720X20904850. [PMID: 32095163 PMCID: PMC7011331 DOI: 10.1177/1759720x20904850] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 12/30/2019] [Indexed: 12/21/2022] Open
Abstract
The advent of biological therapies has been a major therapeutic advance in rheumatology. Many patients now enjoy improved quality of life through better disease control. The number of therapies continues to grow both within drug class (including biosimilar drugs) and via new mechanisms. For the first time, nonbiological drugs such as small-molecule inhibitors (Janus kinase inhibitors) have shown clinical equivalence. However, clinical unmet need remains with up to a third of patients commenced on a biologic therapy having minimal or no response: (a) Generally, the first biologic used secures the best response, with likelihood of remission falling thereafter with successive therapies; (b) the success of strategy trials using biological therapies can be difficult to replicate in clinical practice due to a combination of patient factors and service limitations. Accordingly, ensuring optimization of initial treatment is an important consideration before switching to alternatives. Therapeutic drug monitoring (TDM) is the measurement of serum levels of a biologic drug with the aim of improving patient care. It is usually combined with detection of any antidrug antibodies that could neutralize the effect of the therapy. This technology has the potential to be a form of 'personalized medicine' by individualizing therapy, in particular, dosing and likelihood of sustained treatment response. It requires a clear relationship between drug dose, blood concentration and therapeutic effect. This paper will outline the technology behind TDM and unpack what we can learn from our colleagues in gastroenterology, where the adoption of TDM is at a more advanced stage than in rheumatology. It will explore and set out a number of clinical scenarios where rheumatologists might find TDM helpful in day-to-day practice. Finally, an outline is given of international developments, including regulatory body appraisals and guideline development.
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Affiliation(s)
- Martin Perry
- Department Rheumatology, Royal Alexandra
Hospital, 9 Corsebar Road, Paisley Renfrewshire PA2 9PN, UK
| | - Azhar Abdullah
- Department Rheumatology, Royal Alexandra
Hospital, Paisley, UK
| | - Marina Frleta
- Department Rheumatology, Royal Alexandra
Hospital, Paisley, UK
| | - Jonathan MacDonald
- Department Gastroenterology, Queen Elizabeth
University Hospital, Glasgow, UK
| | - Andrew McGucken
- Department Rheumatology, Royal Alexandra
Hospital, Paisley, UK
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